International Journal of Clinical Images and Medical Reviews

Keywords: lithobezoar, colon, Togo

We report the case of a rectosigmoid lithobezoar. He was a 10 years old boy, without any particular history, who was seen in consultation for pelvic pain and difficulty to defecate. The examination revealed a firm mass in the left iliac fossa and hypogastrium. On rectal examination, a firm, friable formation with telluric debris on the glove was found. An unprepared abdominal radiograph was taken and a radiopaque formation was noted in the recto-sigmoid hinge (Figure 1). A posteriori, the parents reported sand consumption by the child. The patient received an evacuating enema with a favourable outcome and was managed by the paediatrician for the diet.

The term bezoar refers to a clumping of substances in the intestinal tract [1,2]. This may be undigested food or foreign bodies [2]. According to the nature of the agglutinated substance, we speak of trichobezorad for hair, lithobezorad for rocks and the like, lactobezorad for milk substances and phytobezorad for fibres or seeds from fruits and vegetables [2]. While the stomach is the frequent site of these bezoars, the colon is an exceptional location [2].

Competing interest Disclosures: The authors have no competing in- terests to declare.

Funding Statement: This article has no funding source.

A 19-year-old boy presented with status epilepticus. Computed tomography of the brain showed a big, multilobular mass, with peripheral oedema in the frontal lobe which was enhanced peripherally after intravenous administration of a contrast agent. The mass penetrated the frontal bone and extended subcutaneously. He immediately underwent right decompression craniectomy. An empyema was found and was drained. Microscopic examination of brain, dura mater and bone tissue specimens revealed a necrotizing granulomatous inflammation. Tissue cultures were positive for Mycobacterium tuberculosis. The patient received a 4-regimen antitubercular treatment combined with dexamethasone due to central nervous system penetration of the disease with complete response in the follow-up.

Abstract

Cases of bladder rupture have been rarely reported following vaginal childbirth. To the best of our knowledge, however, no cases of combined cervical laceration and bladder rupture have been reported to date. We present the first case of a 31-year-old woman with gestational diabetes who suffered a combined cervical laceration and bladder rupture after childbirth. Precipitated labor caused by oxytocin induction resulted in vaginal and cervical lacerations. The bladder rupture was confirmed by cystography. A team of obstetricians and urologists performed the laparotomy. The patient was kept under observation for two weeks before being discharged with no serious complications.

Keywords: Bladder rupture; Cervical lacerations; Precipitated labor; Childbirth trauma; Case report.

Introduction

Spontaneous bladder rupture following normal vaginal delivery is a surgical postpartum emergency. Previous cesarean section, vacuum/forceps-assisted vaginal deliveries, and distended bladder compressed by engaged head in birth canal are all risk factors for bladder injuries in healthy parturient women 1. Cases of bladder rupture, accompanied by uterine rupture, have been rarely reported following vaginal birth after cesarean section 2. To the best of our knowledge, however, no cases of combined cervical laceration and bladder rupture have been reported to date. We present the first case of spontaneous bladder rupture with cervical laceration after a precipitated vaginal delivery.

Case Presentation

A 31-year-old, G2P1L0D1, woman with gestational diabetes, was admitted to our maternity ward at 38 weeks of pregnancy for elective induction of labor to terminate her pregnancy.  She had a history of preterm birth and was a known case of minor thalassemia. The induction of labor began at 5:00 a.m. with oxytocin, and contractions began approximately two hours later. Table 1 depicts the progress of labor. During her labor, the patient urinated once. Finally, at 10:40 a.m., she gave birth to a baby boy weighing 3700 grams with an Apgar score of 7/9.  Excessive vaginal bleeding was observed following placental expulsion. The examination revealed an extensive laceration in the vagina and cervix that was repaired by the obstetrician and midwife. The patient was catheterized and was being closely monitored. A urologist was consulted due to the oliguria and hematuria (100 cc output with gross hematuria within 5 hours of childbirth). Cystography, as recommended by the urologist, revealed the bladder rupture. The patient was prepared for a laparotomy immediately. The laparotomy was performed by a team of obstetricians and urologists. Several hematomas were discovered in the uterine body and the broad ligament that the team decided not to manipulate because it did not grow during the surgery. A bladder rupture was found at the dome of bladder that was repaired in two layers. One pack cell unit and two FFP units were transfused. A peritoneal drain was placed posterior to the bladder and the skin incision was closed in layers. The patient was observed for two weeks. The result of the ultrasound revealed the shrinking of the hematoma. The blood and renal tests were normal. The catheter was removed after 2 weeks and the patient was discharged.

Table 1: The progress of labor

Discussion

Precipitate labor is defined as the expulsion of the fetus within three hours of the start of contractions. Few studies have found that precipitated labor is harmful to both the mother and the newborn. Precipitated labor, which is most commonly associated with placental abruption and induction of labor, is a significant risk factor for maternal complications 3. Maternal morbidities reported included extensive birth canal lacerations, uterine rupture, placenta retention, the need for revision of uterine cavity, post-partum hemorrhage, and blood transfusions 3,4. The lower urinary tract's anatomic proximity to the reproductive tract predisposes it to iatrogenic injury during obstetric procedures. The bladder and lower ureter are two of the most commonly involved organs. Because the dome of the bladder is the weakest area, most bladder ruptures occur through the peritoneal cavity 5. In our case, in addition to deep vaginal tears and extensive cervical laceration, bladder rupture occurred, but the diagnosis was delayed by a few hours. Given the nonspecific clinical features of bladder rupture, the diagnosis should be approached with caution. Oliguria and gross hematuria after a traumatic childbirth increase the likelihood of bladder rupture. In such cases, a cystogram is thought to be the best method for early detection.

In our case the patient had induced labour with oxytocin. The use of oxytocin to induce labour can result in tachy-systole and thus shorter deliveries. So in our case we believe that the power of uterine contractions and quick descent of passenger (3700 grams fetus) were the main risk factors of precipitated labour and the complications accompanied with it. A distended bladder during labor, particularly in our case, where the fetus descended quickly, could also be a factor in bladder rupture. Although the patient urinated normally during labor, it was critical to ensure that the bladder was empty, especially during the active phase of labor, to avoid bladder damage.

CONCLUSIONS

Bladder and cervical rupture should be considered, after precipitated vaginal delivery. When there is gross hematuria, a urinary catheter should be inserted to monitor the hematuria and urine output. If the hematuria persists and other associated symptoms appear, cystography is a useful tool for determining the severity of the bladder injury and determining the cause.

Funding

This study received no specific funding from public, commercial, or not-for-profit funding agencies.

Conflict of Interest

Authors had no conflicts of interest to declare.

Patient consent

Obtained.

Abstract

In the present study, we applied landmark-based geometric morphometrics to explore components of head profile variation (front and face) between sexes among celoid (concave) horses. For this purpose, the heads of 92 celoid adult horses -Pure Arabians and their F1 crosses- were photographed in lateral view. Our results showed that there are significative differences between stallions, mares, and geldings. This is the first attempt to make this evaluation in a geometric way.

Key words: celoid, cirtoidism, equine skull, ethnology, nasofacial profile, sexual dimorphism

Introduction

The use of shape analysis is one approach to understanding the causes of variation and the morphological transformation of animals due to selective breeding. Head shape plays a prominent part in the definition of equine breeds (Aparicio, 1944). There is a lack of objective methods to quantify skull profiles. In 1978, Dusek made an attempt to quantify the curve of the nasofacial profile of the Kladrub horse (in (Evans & McGreevy, 2006)). The Dusek method assumes the skull has a regular curve, something that seems unlikely even in this rather stylised breed. Evans and McGreevy (Evans & McGreevy, 2006) calculated the area created under the curve of the profile. Anyway, due to scale problems with linear measures, these studies do not take into account the morphological complexity of head. Among zoometric methods, one of the most advanced -but scarcely used for animal ethnology- is geometric morphometrics (GM), which is the study of the shape variation and how it covariates with other variables.

GM is a method based upon the Cartesian coordinates of landmarks which preserves the geometry configuration by allowing a statistical representation of real forms. GM relies on the detection of homologous landmarks (x, y coordinate points which are quantified as Cartesian (i.e., x, y, z) coordinates) to explore the morphospace of objects. After standardizing landmark configurations for overall position, scale, and orientation, the resulting shape coordinates represent the shape of the configurations only, whereas the overall size of the configurations is explicitly represented by a single variable: centroid size (CS), a standard measure of the overall size of a landmark configuration. So, GM deconvolutes form, separating the effects on shape that are due to, or independent of size. It is also amenable to visual representation of shape variation.

Equine studies have used traditional morphometric studies for phylogeography (Bignon et al., 2005), sexual dimorphism (Parés-Casanova & Allés, 2015), ontogenetic skull changes (Liuti & Dixon, 2020), postures (Sénèque et al., 2018), functionality (Lesniak, 2013)... However, GM appears to have been never used for the study of skull profile

Considering the analytical advantages of GM, the purposes of this study were:

to evaluate quantitatively the nasofacial profile of celoid horses (concave head profile) using geometric morphometric techniques.

to assess the strength of the association between craniofacial shape and the head size and to determine the extent to which it might be possible to predict the latter from the former.

This is the first attempt to make this evaluation in a geometric way.

MATERIALS AND METHODS

Sample

We used 92 original digital head pictures (15 stallions, 47 mares and 30 geldings) taken in left lateral norm, aged more than 2 years, on celoid horses (Arabian, Anglo-Arabian. Hispano-Arabian, Arabian-appaloosa, Thoroughbred and mixed). The photographs included a metal piece on their cheek to facilitate calibration by the software. Only horses without signs of head alterations were included. The lateral pictures originated from different private owners and breeders. Second author (CC) was responsible of this part.

Geometric morphometrics

The sample collected was studied by geometric morphometrics. A total of landmarks (5) and semi-landmarks (14) were collected on each head (left side) with the software TpsDig version 1.40 (Rohlf, 2015) (Figure 1). The present study goes further by modelling more precisely and more extensively the head outline of the horse. This structure can be considered as a homologous curve between subjects and can thus be accurately described and studied with points that don’t need to be homologous, i.e., semilandmarks. Semilandmarks are points on smooth curves, for which the exact location on the curve cannot be identified and hence is statistically estimated. The principle is to draw a curve with arbitrarily placed semilandmarks and then to optimize the position of each of them by allowing them to slide along the curve. After sliding the semilandmarks, landmark configurations were superimposed by Generalized Procrustes Analysis, a least-squares oriented registration technique, standardizing position, scale, and orientation of all configurations.

Size requires certain evaluation because traits are allometrically related to the organism’s size. For this purpose, a multivariate regression assessed the effect of size (CS as independent variable) in shape changes (Procrustes coordinates). To test the null hypothesis of independence of the variables, a non-parametric permutation test of 10,000 rounds was applied. Then, a Canonical Variate Analysis (CVA) was performed to study differences between genders. And finally, to explore general shape variation, a Principal Component Analysis (PCA) was used.

For all statistical analyses, we used MorphoJ software version 1.07a (Klingenberg 2011) with α = 0.05.

RESULTS

Allometry

Multivariate regression showed that a 6.30% of the shape variation was explained by size variation (p=0.0057), so for ulterior analysis, regression residuals were used.

Canonical Variate Analysis

CVA reflected statistical differences between genders (p<0.04 for Mahalanobis distances among groups). On the plot, first axis explained a 70.96% of the variance and second one, a 29.03% (Figure 2).

Principal Component Analysis

First two components for PCA explained 84.88% of the total observed variance (PC1+PC2=72.95%+11.93%) (Table 1).

Table 1: Results for the Principal Component Analysis. First two principal components (PC) explained 84.88% of the total observed variance (PC1+PC2=72.95%+11.93%). Most discriminative values (>[0.3]) appear in bold.

Discussion

There is no muscle tissue covering the frontal and nasal bones, only skin, superficial fascia and deep fascia. Therefore, the proposed digital method can be close and consistent approximations of the underlying bony structures, the head profile in the studied case so we propose geometric morphometric techniques as a good tool to assess head profile.

Head profile appears different between genders, being differences mainly on front profile while face profile shows less differences.

CONFLICTS OF INTERESTS

The authors declare no conflicts of interest.

ACKNOWLEDGEMENTS

We thank owners for their kind support in allowing us the access to their animals. We are also grateful to anonymous reviewers for their insightful recommendations.

AUTHORS’ CONTRIBUTION

PMPC designed the study and directed implementation and tissue collection. CC spanned pictures and obtained landmarks from them. Both authors analysed the data.

SUPPORTING INFORMATION

The contents of all supporting data are the sole responsibility of the authors.

A 19-year-old boy presented with status epilepticus. Computed tomography of the brain showed a big, multilobular mass, with peripheral oedema in the frontal lobe which was enhanced peripherally after intravenous administration of a contrast agent. The mass penetrated the frontal bone and extended subcutaneously. He immediately underwent right decompression craniectomy. An empyema was found and was drained. Microscopic examination of brain, dura mater and bone tissue specimens revealed a necrotizing granulomatous inflammation. Tissue cultures were positive for Mycobacterium tuberculosis. The patient received a 4-regimen antitubercular treatment combined with dexamethasone due to central nervous system penetration of the disease with complete response in the follow-up.

Abstract

Episodes of bleeding are a common presenting symptom of acute myeloid leukemia (AML), frequently manifesting as petechiae, epistaxis, or hematuria. On the other hand, gastrointestinal (GI) bleeding is a rare sequela of disease, mainly being reported after disease recurrence or initiation of chemotherapy. This report highlights the clinical course of an 87-year-old Hispanic male who presented to his primary care physician for a routine visit reporting fatigue and dark stools. The patient was later found to have AML with probable GI involvement, which was his only primary manifestation of disease. We hope this case will encourages providers to include AML in their differential diagnosis list when evaluating a patient with persistent melena. Earlier identification of GI involvement in undiagnosed disease may improve the patient’s clinical course and treatment outcomes.

Keywords: Leukemia, melena, AML, pancytopenia

Introduction

While acute myeloid leukemia (AML) remains a common type of leukemia in adults, it is a relatively rare cancer diagnosis overall, responsible for only one percent of adult cancer deaths in the United States.1-3 AML stems from the malignant clonal expansion of undifferentiated myeloid precursor cells, resulting in ineffective hematopoiesis and bone marrow failure.1,2 The production of malfunctioning white blood cells can cause cytopenia’s, creating downstream symptoms related to anemia and thrombocytopenia.1-4 However, a handful of individuals may be asymptomatic upon diagnosis with isolated lab abnormalities.1

Episodes of bleeding have historically been attributed to a patient’s thrombocytopenic state, presenting as cutaneous bleeding, epistaxis, or hematuria.1,5 On the other hand, gastrointestinal (GI) sources of bleeding are an atypical finding in those diagnosed with AML and are seldomly a primary manifestation of disease.3,4 Those with AML and possible GI involvement should be investigated and treated promptly to avoid potentially life-threatening complications such as hemorrhage, infection, and necrotizing enterocolitis.3

A limited number of publications have documented the clinical course of AML with isolated GI bleeding as the primary manifestation of disease, with even less frequent cases describing chronic melena over a period of months.3-8 We present the clinical course of an 87-year-old Hispanic male who presented to his primary care physician for a routine visit reporting fatigue and dark stools. Bone marrow biopsy later confirmed AML with probable GI involvement manifesting as chronic melena. This case illustrates an unlikely clinical presentation that should encourage providers to include AML in their differential diagnosis list when evaluating a patient with persistent melena. In addition, we hope this case will allow for the earlier identification of disease, leading to better treatment outcomes and a greater likelihood of survival.

Case Report

Our patient is an 87-year-old Hispanic male with no significant past medical history that presented to his primary care doctor for a routine visit in September of 2021. During the interview, he reported having mild fatigue and dark stools for a few weeks. Laboratory values from this visit revealed pancytopenia, with a hemoglobin (Hb) < 6.5 g/dl, hematocrit 19%, white blood cell (WBC) count 1.6 x 109/L, and platelet count 73 x 109/L. This was incongruent with laboratory values from six months prior that were within normal limits.

The patient returned to the office three days later for repeat phlebotomy, which showed similar values. It was then recommended that this patient be seen at the local hospital for a blood transfusion, in which he received two units of packed red blood cells (pRBC) before returning home. Fecal occult blood test (FOBT) performed at this visit was negative. Appointments with a hematology and oncology specialist for pancytopenia and gastrointestinal specialist for melena were scheduled.

Two weeks following the transfusion, the patient came back into the primary care office complaining of GI upset and persistent dark stools. Laboratory values were Hb of 8.0 g/dl and hematocrit 24%. He was then started on Pantoprazole Sodium 40mg by mouth daily until he was able to see a gastroenterologist. However, phlebotomy results drawn ten days later again revealed a Hb < 6.9g/dl, hematocrit 21%, WBC 2.0 x 109/L, and platelets 75 x 109/L. He was sent for a second transfusion at the local hospital with two units of pRBCs.

Bone marrow biopsy was performed in the first week of November. The patient was found to be pale after the procedure and was admitted after his labs revealed a Hb below the transfusion threshold. He was transfused for a third time with two units of pRBCs, making this his third transfusion within a month’s time. Results of the bone marrow biopsy were available a couple days later which showed AML with 40% blast cells.

After receiving a definitive biopsy report, the patient was stable and awaiting hematology and oncology treatment recommendations until November 26th when the patient awoke with subjective severe weakness and dark stools. His son took him to the hospital where he received another two units pRBCs. He was scheduled for a colonoscopy during his stay in the intensive care unit, however left against medical advice before the procedure could be performed.

During a follow-up appointment on December 9th at the primary care office, phlebotomy revealed a Hb of <6.7 g/dL, warranting yet another transfusion. He also complained of increased weakness and shortness of breath compared to baseline. Due to a delay in care with previously scheduled hematology and oncology appointments, the patient established care with a different hematologist at this time.

Patient was admitted to the hospital on December 14th to begin induction chemotherapy regimen of azacitadine 131mg subcutaneously daily for seven days. On admission, he complained of weakness, dyspnea of exertion, lightheadedness and over thirty pounds of unintentional weight loss. Before therapy was initiated, bone marrow biopsy was repeated, confirming AML with 40% blasts. Hospital course was significant for symptomatic anemia below transfusion threshold, necessitating two units pRBCs on December 24th.

Two weeks following this discharge, he was readmitted due to laboratory results yielding a Hb 4 g/dl and platelet count 12 x 109/L. He had minimal symptoms, denying any recent subjective fever or chills. In the emergency department, he was found to have neutropenic fever and was positive for Coronavirus Disease 2019 (COVID-19). He was started on intravenous antibiotics, remdesivir, and transfused with three units pRBCs and one unit of transfused platelets. After a couple of weeks, the patient was refusing further treatment, stating that he would like to leave against medical advice. His disease was deemed advanced and with rapid progression and therapy was discontinued based on patients and families wishes. Patient now resides in hospice care.

Discussion

Our patient is an 87-year-old Hispanic male who presented to his primary care physician for a routine physical examination when he reported having mild fatigue and dark stools upon evaluation. Over the next few weeks, the patient had persistent pancytopenia, with rapidly declining hemoglobin necessitating multiple transfusions at local hospitals before a bone marrow biopsy was performed revealing AML.  This case presentation highlights an unusual presentation of disease and may assist outpatient physicians in identifying AML with isolated signs of GI bleeding. Early identification of AML as the predominant cause of GI manifestations may lead to better responses to treatment and increased likelihood of survival.

Autopsy studies predict the presence of any GI manifestation of disease in 25 percent of patients diagnosed with leukemia.3-4 Leukemic infiltrates, secondary inflammatory processes and infection are the most common culprits, with the ability to occur anywhere along the GI tract from the esophagus to the anus including the gallbladder and appendix.3,4 Symptoms can present as non-specific fever, abdominal pain, diarrhea, nausea, vomiting, abdominal distension or tenderness, making it difficult to isolate the cause of the patient’s symptomatic complaints.3 Our patient did not possess any of these presenting symptoms and unfortunately, no relevant endoscopic studies were performed to find the root cause of GI involvement.

Furthermore, clinically significant bleeding may be found in up to 32 percent of thrombocytopenic patients with AML.9 The most frequent presentations of bleeding are cutaneous petechiae or bruising, epistaxis, vaginal bleeding, or hematuria.3,4 These manifestations have mostly been documented in cases of malignancy relapse, after chemotherapy, or following a bone marrow transplant.3,4,9 Rarely has GI bleeding been documented as the first manifestation of primary disease, such as in our patient.5 In addition, the amount of blood loss was sufficient to drop his hemoglobin count in a matter of weeks, which may have led to potentially life-threatening anemia, especially in an elderly individual.

Pathophysiology behind bleeding in patients with leukemia has historically been attributed to a patient’s low platelet count, though more recent publications suggest there is no association between the two.5,9 Vinholt et al. found that clinically significant bleeding in AML is likely caused by reduced platelet function, due to a deficiency in platelet aggregation response and a reduced capacity for platelet activation.9 This may be an underlying reason for the occurrence of significant bleeding in the setting of AML with relatively high platelet counts, as seen in our patient with values consistently around 70 x 109/L. This platelet count is above the threshold that traditionally leads to clinically significant bleeding and points to another mechanism behind increased incidence of bleeding in AML.10

Most of the existing reports detailing GI bleeding in the setting of AML describe cases presenting with acute hemorrhage or cases that occurred after malignancy relapse and initiation of treatment.3,4,6,7 One case reported fatal GI bleeding after secondary formation of a granulocytic sarcoma.6 This report demonstrates a rare presentation of AML with chronic melena in an otherwise asymptomatic elderly patient.

CONCLUSIONS

Although AML commonly presents as episodes of bleeding secondary to a thrombocytopenic state or as alterations in lab values, gastrointestinal bleeding can be a presenting sign as well. We hope this detailed clinical course will prompt providers to keep AML on their list of differential diagnoses when encountering an elderly patient reporting dark stools. The early identification of GI involvement in the setting of AML could prevent otherwise severe consequences of bleeding and may improve outcomes of disease.

Abstract

Background: Epithelial cell abnormality is the outcome of a viral infection. Human papilloma virus (HPV) is the main causative agent of cervical dysplasia. Cervical dysplasia caused as a consequence of infection by this sexually transmitted virus is characterized by abnormal cells on the cervix.

Various laboratory tests with varying specificity and sensitivity, have been set for diagnosis. The present study has been carried out in order to determine the prevalence rate of cervical epithelial cell dysfunction in Papanicolaou (Pap) smear reports in low risk population referred to Imam Reza hospital- Tehran- Iran from January 2019 till August 2020.

Methods: 676 women of low risk group referring to obstetrics and gynecology clinic - Imam Reza hospital- Tehran –Iran since January 2019 till August 2020 were the study cases. Information regarding presence of atrophy while examination, erosion, cervicitis, infection, Polyp, abnormal vascularity, candidiasis was collected from patients and were recorded in a check list. Patient's sample (pap smear) was collected for pathological examination. Data were analyzed by SPSS software.

Results: Pap smear examination revealed 662 out of 676 (97.5%) cases had no abnormality in cervical epithelial cells. In 12 cases abnormality was of ASCUS type (%1.77).

Conclusion: Results of Pap smear test revealed low frequency of cervical epithelial cell abnormality among low risk group. Out of the influencing factors, cervicitis, followed by erosion, abnormal vascularity and infection seem to be more common.

Key Words- Pap smear, Low risk group, Bethesda system, ASCUS, LSIL, HSIL, Cervical Dysplasia, Cervical Smear Test.

Introduction

Cervical cancer is one of the most preventable malignancies among human cancers. Infection of the uterine cervix with human papillomavirus (HPV) is the main causative agent of cervical cancer [1]. About 15 high-risk types of human papilloma virus have been identified, which are responsible for cervical neoplasia and other related cancers [2]. Cervical cancer with worldwide distribution, though a preventable disease, is one of the leading causes of cancer death in women [1]. High risk HPV types lead to higher risk of developing cervical cancer compared to low risk types or are not being infected with HPV, at all [1]. The main characteristics of cervical dysplasia following infection with human papilloma virus (HPV) is abnormal cells on the cervix. The main screening strategy to reduce cervical cancer incidence is to detect precancerous lesions that can be treated before evolving to cancer [3]. Detection of cervical pre-cancer lesions can be achieved on the basis of cytology, implemented decades ago, or by HPV screening for women aged 30 years or older [1]. In most industrial countries cytology-based prevention programs, led to a significant reduction in the incidence and mortality from cervical cancer [1]. In other words, screening reduced the incidence of cervical cancer by at least 60%, and cancer specific mortality by 20–60% [4]. Papanicolaou (Pap) test, both conventional and liquid type, is routinely used to detect cervical epithelial cell abnormality [5]. In spite of its merits as a diagnostic and screening test, Pap test is not 100% accurate [3]. The present study has been carried out in order to determine the prevalence rate of cervical epithelial cell dysfunction in Papanicolaou (Pap) smear reports in low risk population referred to Imam Reza hospital- Tehran- Iran from January 2019 till August 2020.

Materials and Methods

Patient selection: 676 patients referring to obstetrics and gynecology clinic of Imam Reza hospital, Tehran – Iran from January 2019 till August 2020 were the study cases. The patients were included in the study on the basis of the inclusion criteria.

Inclusion criteria: Absence of risk factors for cervical cancer including having single partnership, pap smear test performed by a particular pathology laboratory, low risk cases.

Exclusion criteria : Multiple sex partners of herself or husband, pap smear test performed by other pathology laboratories, immune-suppressed patients, patients diagnosed suffering genital wart, presence of previous epithelial cell abnormality in PAP tests performed earlier, use of vaginal lubricant, gel or any cream or having intercourse 48 hours prior to sample collection, previous positive HPV test.

Study cases: Patients' age ranged from 20 up to 79 years. All the cases were married with different number of children born by Normal Vaginal Delivery (NVD) or cesarean section or both.

Methodology: Patients were examined for the presence of infection and any macroscopic abnormality. A pap smear was collected from every patient. An expert performed the PAP test sampling and fixation throughout the study to minimize the errors. Patients were asked to get the pathological examination of the smear done from a specific laboratory.

A questionnaire containing questions regarding the age, marriage age, number of sex partners, number of deliveries and abortions, kind of contraceptives used, … was filled by every patient. Result of pap smear and cervix outlook are the parameters considered in this study. A consent form was signed by each patient. Patients̛ grouping and complications are presented in Table 1. SPSS software was used for statistical analysis of the data.

Table 1: Common complications of different age groups.

Results

Study cases: Patients' age ranged from 20 up to 79 years with mean and median of 40±13.62 and 40.69±13.62 years respectively. Kolmogorov-Smirnov [6] and Shapiro-Wilk [7] tests indicate a normal distribution of the data (p>0.05). All the patients were married. Mean and median of their marriage age were 20±3.987 and 19.97±3.987 years respectively. Their minimum and maximum marriage age were 12 and 43 years respectively. Kolmogorov-Smirnov and Shapiro-Wilk tests indicate a normal distribution of the data of this variable (p>0.05). 97.5% of patients had one sex partner while 2.4% cases had married for the second time (considered as 2 partners). One case did not answer this question. 46.4% of patients had normal cervix. According to the information obtained from the questionnaire, 163 cases had given birth to child by both vaginal (41.5%) as well as cesarean section (58.5%) and 37 cases (18.5%) had no history of delivery. Maximum and minimum normal vaginal delivery were 8 and 0 respectively. 77 cases had delivery one year after first intercourse, while 2, 56,17, 7, 3 and 1 cases delivered their first child one and half, 2, 3, 4, 5 and 6 years after the first intercourse, respectively. Total number of abortions reported was 170 out of 676 cases. Microscopic examination of pap smears revealed 662 out of 676 (97.5%) cases had no abnormality in cervical epithelial cells (Table 2). Microscopic findings of patients‘ sample are also illustrated in Table 2 revealing that 14 (%2.07) patients showed epithelial cell abnormality in their pap smears:  In 12 cases abnormality was of ASCUS type (%1.77). No patients had HSIL, 2 patients had LSIL, one in each age groups of 30-39 and 40-49 years. 16.1% of cases suffered cervical atrophy, 2 cases had vaginosis and 2 patients were infected with Candida. The commonest complication in this group was cervicitis which was observed in 6 cases, erosion was observed in 4 cases and infection due to Candidiasis in 2 cases, atrophy was observed by direct observation in 1 case. Out of these 14 cases, 3 had normal vaginal examination. The mean of ASCUS cases was 4.44 that was found in age group of 60-69 years. The marriage age was the only influencing variable on mild form (p<0.05) with about 9% increase in it.

Table 2: Cases with Normal epithelium

Different types of contraceptives used by patients are presented in Figure I. test was used to find out if the type of contraceptive used and inflammation caused while collecting sample for Pap smear are co-related. The statistical analysis using Phi test with Phi correlation coefficient of 0.175 and Cramer correlation coefficient of 0.087 indicates a non- significant relationship.

χ2 test was used to find out if the type of delivery and inflammation caused while collecting sample for Pap smear are co-related. The value of 5.36 indicates that there is non- significant relationship.

To find out if the number of deliveries and inflammation caused while collecting sample for Pap smear are co-related, χ2 test was used. Pearson Chi-Square test with 44 degrees of freedom is equal to 67.53 which is significant at 5% level. Their co-relation on the basis of Phi test with Phi correlation coefficient of 0.350 and Cramer correlation coefficient of 0.175 indicates a significant correlation.

To find out if the number of abortions and inflammation caused while collecting sample for Pap smear are co-related we used χ2 test. Pearson Chi-Square test shows a non- significant relationship. Their co-relation on the basis of Phi test with Phi correlation coefficient of 0.162 and Cramer correlation coefficient of 0.081 is non-significant.

To find out the relationship between patients' age and inflammation due to sample collection for PAP test using  relation coefficient, shows a weak significant relationship.

To find out the strongest relationship for a particular variable, scatter diagram – 1 is drawn. According to the scatter diagram - 1, age is the only determinant factor for ASCUS (p<0.05) and no other factor is so effective.  Also, by a single year increase in the age, the rate of ASCUS increases up to 8%; which is equal to 1.083 times its probability. Thereby, chance of infection increases by 8 percent for single unit increase in the age. 19.1% of all patients had mild inflammation, 23.8% had moderate and 7.2% suffered severe form of inflammation. Scatter diagram – 2 is drawn to study the correlations between the studied variables and to determine which variables are related. Logistic regression outcome reveals none of the studied variables has any effect on LSIL as the significance value of all the studied variables is more than 0.05. 50.1 percent had normal pap smear.

Figure 1: Type of contraceptive used by patients IUD= Intra Uterine Device OCP= Oral contraceptive pills, WD=withdrawal COND= condom TL= Tubal ligation VAS=Vasectomy

Scattered Diagram 1- Relationship between age and type of epithelial abnormality

Scattered Diagram 2

Discussion

Cervical cancer with an estimated 604,000 new cases and 342,000 deaths is the fourth cause of cancer death worldwide in 2020 [8]. Globally,528 000 new cases of this cancer were diagnosed in 2012; of these, about 85%, occurred in less developed parts of the world and 266000 women died of it throughout the world. In another word, 231000 women who lived in low- to middle income countries died of this type of cancer. While, only 35 000, or just 1 in 10 women suffering from cervical cancer lived and died in high-income countries [3]. Cervical cancer is one of the preventable cancers involving primary (HPV vaccine) and secondary (screening) preventive measures. More than 30% of women of low middle income countries (LMICs) had received HPV vaccination programs compared with less than 80% of high-income countries [8]. In Iran, this viral infection and its resultant disease has also been reported and nation-wide screening program has been performed since 1980s. In the present study, out of 676 study cases, 97.8% had normal epithelial cell and 46.45 percent cases had normal cervix examination. Only 2.2% of our patients suffered from signs related to epithelial cell abnormality.

According to Majidi et al. (2016) incidence of cervical cancer is low in Iran [9]. Crosbie et al. (2013) estimated average prevalence rate of cervical infection with HPV at a given point, and at any time is about 10·4%, with higher prevalence rate (16·9%) in women younger than 25 years. [2]. In contrast to Crosbie et al s findings, our findings indicate a lower incidence rate as our patients are chosen from low-risk population i.e. almost all are of ASCUS type. In Iran, like many other countries, routine screening for cervical cancer is based on the microscopic examination of smears collected from the cervical mucosa, performed by conventional Pap smear test. Screening by cervical cytology in United States in the mid20th century reduced mortality from squamous cell cervical cancer [10]. More so, it led to increased number of women being identified with HPV-negative, ASCUS-cytology results [11], as is the case in the present study. Whilst cervical cancer, once the most frequent cause of cancer death in women, now ranks 14th for cancer deaths [11]. High-quality screening with cytology (Pap testing) has markedly reduced mortality from squamous cell cervical cancer, which comprises 80–90% of cervical cancers [9-11].

Screening interval that varies between countries, is an important issue. Cervical screening is performed every 3 years in the United States, New Zealand, and Norway, while its interval is 5 years in Denmark, Finland, and the Netherlands [12]. In Iran, annual cervical cancer screening program was performed for age range of 20 to 65 years. Since 2017, it changed to 3 year intervals for women at the age of 30 to 59, following three consecutive normal results. Sawaya and Smith-McCune (2007) suggested that molecular DNA test performed for HPV diagnosis every 10 years for women at the age of 35 years and more is preferred as DNA HPV test is a novel and effective screening method [13]. There is no doubt that such screening programs reduce the incidence and mortality rate of cervical cancer, globally [13].

Starting age of screening also varies in different countries. Screening starts at the age of 25 in United Kingdom, France, Italy and Portugal and at the age of 21 in the United States and Canada [12]. Cervical cancer screening in countries like Finland, Korea, the Netherlands and China begins at the age of 30 to 35 years [12]; while according to National Health service, cervical screening program is to be done every three years for women between the age of 25 - 49 years and every five years for women past 50 [14]. In spite of previous recommendation of annual or biannual cervical screening, as it seems that annual screening is of little benefit and leads to increased cost (15), some guidelines in Great Britain, recommended every three years for women under 50, and every five years for those who have passed fifty [14]. In the present study, patients' age ranged from 20 to 79 years. Based on the fact that the incidence of cervical cancer in Iran is low compared to other geographical areas, we recommend three-year interval for healthy women with no history of cytological screening.

CONCLUSIONS

Worldwide, cervical cancer is a common and deadly cancer among women. Screening programs and effective treatment of precancerous lesions are available to treat the patients. In most cases, slow progression of precancerous lesions, are accompanied by abnormal cells which are detected in Pap test. The cervical screening program using the Pap smear procedure has an influencing role in reducing the incidence and mortality rate of invasive cervical cancer in many countries, including Iran. The incidence of cervical cancer is low in Iran although its mortality is remarkable. In Iran, cervical cancer screening program was performed annually in the age range of 20 to 65 previously. Since 2017 screening is performed for women at the age of 30 to 59 at 3 year intervals after three consecutive normal results.

Conflict of interest

Authors declare no conflict of interest.

 Acknowledgments

Authors thank all patients who cooperated with us in publishing the data.

Abstract

Prurigo nodularis (PN) is a rare, chronic dermatologic disease that causes an intense pruritus that can lead to significant physiological and psychological discomfort that may impact quality of life. It is typically characterized by multiple symmetrically-distributed, firm pruritic nodules that spread as the patient scratches them. As a result, individuals with PN can experience pruritus with nodules and excoriations covering their whole body. The exact pathogenesis of PN is unclear, though it is hypothesized that it may possibly be due to increased number of nerve fibers in the papillary dermis or cutaneous small fiber neuropathy. There is no proven cure for PN, and success of management varies by case. There are no US FDA approved treatment options for PN, but photochemotherapy (PUVA) has been used with promising results.

KEYWORDS: Prurigo Nodularis, Itch, Pruritus, Medical Dermatology, Case Reports

Introduction

Prurigo nodularis (PN) is a rare, chronic dermatologic disease that causes intense pruritus, leading to significant physiological and psychological discomfort and a diminished quality of life. The estimated prevalence of PN is 72 per 100,000 Americans, and most often presents later in adulthood, between the ages of 51-65, with African-American patients 3.4 times more likely to have PN than white patients [1, 2]. The typical clinical presentations of this dermatological disorder are intensely pruritic papules, plaques, and nodules that are multiple in number, firm, and flesh to pink colored. As the individual scratches, the pruritis intensifies and the nodules progressively spread all throughout the body [3]. Currently, diagnosis of PN is entirely clinically based, making it difficult to properly identify and treat, especially due to its rarity.

METHODS

Search engines PubMed and Google Scholar were used to obtain information on PN. Keywords included “Prurigo Nodularis”, “Prurigo Nodularis Diagnosis” and “Prurigo Nodularis Treatment”.

CASE PRESENTATION

A 48-year-old African American male with a past medical history significant for end stage renal disease (ESRD) diagnosed in 2014, hypertension, diabetes mellitus, neuropathy, prostate cancer, and asthma presented to the emergency department for involuntary blinking and all over sensation of itching. He reported his symptoms began approximately 8 months ago, but became unbearable over the last 2 weeks. He describes the involuntary blinking due to a sensation of something touching his eye, making it impossible for him to keep it open for more than a minute at a time. He also admits to experiencing bilateral facial and ear tingling sensations, whole-body pruritus, and intermittent pain and discomfort worsening over the last year. He describes the pain as a sharp, shooting sensation that occurs at various parts of his body. This patient stated that he had sought treatment in the past, receiving Benadryl and hydroxyzine cream, which had not improved his symptoms. Furthermore, he added that dialysis treatment for his ESRD would exacerbate symptoms. He reported that he had a skin biopsy, which was inconclusive. It was also noted that the patient had a history of non-compliance with treatments or medications. His past surgical history included renal transplant thirteen years prior in 2008 and cardiac bypass. Pertinent positive review of systems included chest pain and pruritus.

On the physical exam, the patient appeared in significant distress due to itching and pain. His skin showed numerous excoriations throughout his entire body. Darkened, hyperpigmented nodules were noted throughout his body, which he noted were pruritic in nature. His vitals included blood pressure of 182/119, heart rate of 88, respiration rate of 22, and temperature of 97.9°F.

The initial plan for this patient was to do blood work, provide the patient with antihistamine for pruritus relief, benzodiazepine for pain relief, Wood’s lamp examination, air puff tonometry, and nephrology consult.

Table 1: Complete blood count and differential indicating of anemia

Table 2: Comprehensive metabolic panel showing signs of ESRD and poor glycemic control

Table 3: Blood differential test showing normal results

Table 4: Glomerular filtration rate (GFR) showing signs of ESRD

The patient had nonspecific lab results and his intraocular pressure was 25 according to air puff tonometry.  He also had a negative Wood’s lamp examination. Furthermore, symptoms improved minimally on Benadryl and lorazepam. Subsequently, nephrology evaluated the patient and provided the diagnosis of prurigo nodularis. This patient was recommended for PUVA therapy and outpatient management by ophthalmology, rheumatology, and dermatology.

Discussion

PN is a rare, poorly understood condition, making it difficult to identify and diagnose in the emergency department setting. It has been found that repeated scratching due to chronic pruritus leads to an increased pruritic reaction, with further formation of nodules and lichenification of skin [3]. Moreover, there is some evidence for association with various comorbidities, such as hepatitis C, Heliobacter pylori, Strongyloides sterocoralis, mycobacteria, and human immunodeficiency virus (HIV). An increase in the number of sensory structures such as merkel cells and papillary dermal nerves within the epidermis and dermis, respectively, were identified histologically, as well as increased levels of nerve growth factor and its receptor, tyrosine kinase A [3]. Laboratory tests will show an increased level of mast cells and neutrophils, as well as interleukin 4 and interleukin 31, suggesting T helper 2 (Th-2) involvement [4]. These all present potential areas for further research in discovering a consistently effective treatment option.

Currently, first line therapy includes a combination of antihistamines, oral steroids, and topical antipruritics or topical corticosteroids [5]. Despite this first line therapy, there is not much research published on the topic during literature review on this topic. There was more research noted on PUVA therapy and Dupixent as a therapy for PN. Arrieta et. al found that phototherapy with UV-B or combination UV-B and UV-A was a suitable treatment as both monotherapy or used in combination with other forms of treatment, especially when PUVA therapy was frequent [6]. Romano researched use of Dupilumab, a medication used in allergic asthma, atopic dermatitis, and chronic rhinosinusitis with nasal polyps, as a treatment of PN. Dupilumab has the ability to block IL-4, IL-13, and possibly Th2 [7]. In previous studies, Dupilumab has been found to lead to complete remission in 50% of PN patients [8]. Co-therapy of Dupilumab and

PUVA therapy have also shown promise as a treatment option.

LIMITATIONS

There are limited cases and literature on PN, as research is restricted due to the rarity of the condition and limited population size. For example, Arrieta et. al’s sample size only included 44 participants, 30 of which were women and 14 were men [6]. PN is a rare disease, so the limitation of small sample size is understandable; however, it is something future researchers should be aware of. In addition, these therapies typically are temporary and not curative of the disease symptoms. Furthermore, our case represents only one encounter in an emergency department setting.

CONCLUSIONS

Although PN is a rare diagnosis and typically one that will not present to the emergency department, this case demonstrates the importance of being cognisant of this condition, as it can cause significant discomfort for the patient and confusion for the healthcare provider. Awareness of PN and knowledge of clinical manifestations, as well as associated conditions allows for a faster diagnosis, maximized care, and knowledge of where to refer patients to help minimize their distress. With no definitive treatment option, further research into the condition is needed to better understand and potentially prevent the exacerbation of symptoms, as well as to discover more effective treatment options.

Conflicts of Interest No conflict of interest from the main authors, who are osteopathic medical students at NYITCOM.

Abstract

Ovarian cancer is one the most common gynecological cancers, and epithelial ovarian cancer is the commonest sub-type. Between 10 and 15% of all epithelial ovarian cancers occur secondary to a mutation in BRCA1 or BRCA2 gene, and may be associated with breast cancer, known as hereditary breast ovarian cancer syndrome (HBOCS). We report a case of HBOCS, highlight the importance of family history and treatment history and discuss the recent developments in surgery and systemic treatment for patients in relation to the presentation of this case.

Introduction

Ovarian cancer is one the most common gynecological cancers (Bray 2018). Epithelial ovarian cancer is the commonest sub-type (Kurman 2014). Between 10 and 15% of all ovarian cancers occur secondary to a mutation in a cancer susceptibility gene (Zhang 2011). Mutations in BRCA1 and BRCA2 gene are the commonest cause of hereditary ovarian cancer (Mikki 1994; Claus 1996). These mutations also predispose the individuals to other cancers. Patients with epithelial ovarian cancer may also develop breast cancer (Easton 1993; Easton 1997). We report one such case here, and discuss the recent advances in the medical and surgical management of hereditary breast ovarian cancer syndrome (HBOCS).

Case

A 57 year-old lady presented with abnormal vaginal bleeding and abdominal distention. She was diagnosed to have high grade ovarian cancer, underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy, and was found to have stage IIIC serous papillary type of high grade ovarian cancer. The patient was treated with 6 cycles of Carboplatin and Paclitaxel to complete serological and radiological remission, however, she tolerated the chemotherapy with frequent episodes of febrile neutropenia. Three years later, the disease relapsed and the patient was treated with 6 cycles of Liposomal Doxorubicin to state of complete serological remission. One year later, the disease relapsed yet again, and this time, she received Carboplatin as a single agent. The disease entered serological remission after 3 cycles, however, the patient could not continue treatment because of repeated febrile neutropenia and thrombocytopenia

One year later, the disease relapsed a 3rd time. CT scan showed disease only at one site (figure 1a) and the patient was treated with Carboplatin at a reduced dose, once again to a state of complete serological and radiological remission (figure 1b). A surveillance mammogram was reported as BIRADS II and the bone mineral density revealed osteopenia. One year later, the disease relapsed a 4th time, again in a solitary site, and the patient was counseled about treatment with chemotherapy followed by a secondary cyto-reductive surgery, to which the patient agreed. The patient received 6 cycles of chemotherapy at reduced doses, followed by surgery. There was no residual disease and the patient remained in complete remission for more than one year and 3 months.

At this stage the CA-125 was seen to rise again serially, and mammogram showed a 2.2 cm speculated lesion in the left breast. A fine needle aspiration was highly suggestive of breast cancer, and a core biopsy revealed an infiltrating ductal carcinoma, grade II, estrogen and progesterone receptor positive, but negative for HER-2/neu protein  (ER positive; PR positive; HER-2/neu negative). The proliferation fraction measured by Ki-67 was 40%. The morphologic and immunohistochemical patterns were consistent with a diagnosis of a primary in the breast (Table 1). Staging CT scan revealed a metastatic lesion in liver and bilateral pulmonary metastases. An attempt at guided biopsy from the pulmonary lesion was unsuccessful and led to pneumothorax. The patient refused further attempt at biopsy and agreed to be treated with Letrozole, considering that the pattern of metastases was more likely secondary to breast cancer rather than the ovarian cancer. Ten months later, the CT scan showed a marked regression in the size of pulmonary lesions, but a stable liver lesion (Figure 2).

Table 1: Immunohistochemical staining patterns of breast and ovarian cancer. WT-1 (wilm’s Tumor 1); PAX 8 (Paired box gene 8); CA 125 (Cancer antigen 125); ER/PgR (Estrogen receptor / Progesterone receptor); CK 7 (Cytokeratin 7); GCDFP-15 (Gross cystic disease fluid protein-15); TP 53 (Tumor protein 53)

Figure 1: CT scan at the time of the 3rd relapse (Figure 1A) shows a 35 mm x 28 mm mass in the region of omentum, which disappeared completely after 6 cycles of carboplatin AUC 4 (Figure 1B).

Considering that the patient had HBOCS, the patient was referred to the cancer geneticist. A detailed history revealed that her mother had dies of a malignancy of unknown primary site, her sister died at the age of 40 years, of a malignancy with ascites, but the primary site was not known to the patient or the family. The patient underwent counseling followed by assessment with a germline mutational analysis for breast and ovarian cancer panel, which revealed a pathogenic mutation in BRCA2 gene (c.4243G>T), and a variant of unknown significance in the NBN gene (c.425A>G). The BRCA2 mutation was consistent with a diagnosis of HBOCS. One year later, the CA 125 was seen to rise again serially, while the metastatic lesions in the lung and liver were under good remission. The patient was commenced on treatment with Olaparib, and the CA 125 dropped from 324 to 26 in one year (figure 3). The patient continued to receive Letrozole. Twelve years after the diagnosis of ovarian cancer, and while still on treatment for breast and ovarian cancer, the patient passed away of an unrelated cause. During the course of the treatment, patient’s three daughters agreed for mutational analysis; two tested positive for mutation on the BRCA2 gene, and one of those two was screen-detected to have a breast cancer.

Figure 3: Serum CA 125 levels (IU/L) plotted over time. The patient was commenced on treatment with olaparib in Nov 2015. The levels dropped to within the normal limits (<36IU/L) in March 2016 (within 4 months of the treatment).

Discussion

We report the case of a woman diagnosed to have HBOCS, who lived 12 years after the diagnosis of high grade ovarian cancer, received multiple lines of intra-venous chemotherapy, albeit with difficulty, underwent a secondary cyto-reductive surgery, and in the last 4 years of her illness was treated for the two cancers with an oral aromatase inhibitor and a PARP inhibitor. Both breast and ovarian cancers responded to the treatment with the two oral agents. We would like to highlight several aspects of management for the general readership of this journal.

The median survival of patients diagnosed to have high grade ovarian cancer, stage IIIC is dismal at around 3-4 years (Peres 2019). This patient lived for 12 years. Complete response to chemotherapy on five occasions, and a poor tolerance to chemotherapy, even at an age of 57-65 years indicate the tumor is exquisitely sensitive, especially to platinum containing chemotherapy. Platinum derivatives (Cisplatin, Carboplatin and Oxaliplatin) are alkylating agents, which act by disrupting the DNA repair pathways. Usually, PARP (Poly (ADP-ribose) polymerase) enzyme is required for base excision repair (BER). If the enzyme were inhibited, DNA repair would be affected. Also, if one allele is inactivated on the BRCA 1 or 2 gene, such as, because of mutations or methylation, DNA repair will be grossly affected, leading to a process called ‘synthetic lethality’ (Konstantinopoulos 2010; Helleday 2011). In the last few years, three such compounds (Olaparib, Niraparib and Rucaparib) have been developed, tested, and have become the standard of care for patients with either germline BRCA mutations, or even in patients who may have homologous reconstitution deficiency (Ledermann 2014, Mirza 2016; Pujade-Lauraine 2017; Coleman 2017). The first-in-class compound was Olaparib, approved by the FDA in 2014 for use as a single agent in patients who had germline BRCA mutations and had failed three lines of chemotherapy (Ledermann 2012). Our patient was treated and responded to the treatment.

BRCA 1 mutation is more common than mutation in BRCA 2 gene, and it is important to distinguish between the two. Although, response to platinum chemotherapy or PARP inhibitors is the same (Konstantinopoulos 2010), there are phenotypic differences, especially for breast cancer, and the susceptibility to develop other cancers, required for counseling the family members. Patients with BRCA 1 mutation are associated with triple-negative breast cancer (ER negative; PR negative; HER-2/neu negative) in more than 75% of the cases, whereas, patients with BRCA 2 mutations are associated with hormone-receptor positive breast cancer in more than two thirds of the cases (Hartmann 2016). Our patient had BRCA 2 mutation and hormone-receptor positive breast cancer, which was treated with aromatase inhibitor for more than 4 years. Although the life-time risk of developing breast cancer is same (65-70%) in the patients and the first-degree relatives, the life-time risk of ovarian cancer is 40-45% in case of BRCA 1 mutation carrier and 10-15% in case of BRCA 2 mutation career (Antoniou 2003; Hartmann 2016). Our patient had three daughters and they were counseled. Two tested positive for the same mutation. Because of their relatively young age, and the minimal increased risk of ovarian cancer in BRCA 2 mutation carriers, till the age of 45 years, they were advised to consider delaying BSO.

The role of secondary cyto-reductive surgery in ovarian cancer has been contemplated and debated over the last several years. Three major phase III trials have been reported in the past 2 years (Please see table 2). The GOG-0213 trial was the first trial to have been reported (Coleman 2019). The primary end point was overall survival (OS); 485 patients were randomized to receive standard of care chemotherapy with or without secondary cyto-reductive surgery. The patients were selected if the treatment free interval from the last dose of platinum containing chemotherapy was more than 6 months. Although, there was a non-significant prolongation in the progression-free survival (PFS) (18.9 vs 16.2 month; HR 0.82), there was no difference in OS. Actually, the OS was inferior in the group which received secondary cyto-reductive surgery (50.6 vs 64.7 months; HR 1.29). However, a sub-set of patients who achieved R0 resection had a better PFS and OS, compared to those who could not have a R0 resection. The DESKTOP III trial randomized 407 patients to receive standard of care chemotherapy with or without secondary cyto-reductive surgery (du Bois 2017). There was a clinically and statistically significant prolongation in the PFS (19.6 vs 14 months; HR 0.66). Also, the primary end-point was met (du Bois et al 2020). The was a significant 7.6 months prolongation in OS (53.6 vs 46 months; 0.75 (0.58-0.96; P = 0.02). In addition to the criteria of treatment free interval of more than 6 months, the investigators also used the AGO criteria. The AGO criteria was developed after the DESKTOP I trial, and women with no gross residual disease after primary surgery, ECOG performance status of <1, and no ascites on CT scan at recurrence were classified as AGO score positive (Harter 2006). Subsequently, the DESKTOP II trial suggested that patients with a good performance status, absence of ascites at the time for secondary cyto-reductive surgery, more than 12 months of platinum-free interval, isolated site of recurrence, and the possibility of complete resection of disease were likely to benefit from the secondary cyto-reductive surgery (Harter 2011). The 3rd trial (SOC-1 trial) randomly assigned 356 patients with recurrent ovarian cancer in first relapse to either chemotherapy, or cyto-reductive surgery and chemotherapy (Zhang R 2020). There was a clinically meaningful (5.5 months), and statistically significant prolongation in the PFS (17.4 vs 11.9 months; HR 0.58) for the combination of cyto-reductive surgery and chemotherapy arm. The eligibility criterion was different from the first two studies. The SOC1 investigators selected patients if the platinum-free interval was at least 6 months, and an integrative model score was <4.7. However, at the time of management of our patient, results of the randomized trials were not available. We based our decision on the available data from DESKTOP I and II trials. The patient fit both the AGO score positive and the subsequent criterion developed after DESKTOP II trial. Our patient lived more than 5 years after the cyto-reductive surgery without a subsequent recurrence in the abdominal cavity.

Taken together, the three randomized trials comparing chemotherapy with or without cyto-reductive surgery suggest that there may be a benefit for surgery in carefully selected patients who can undergo potentially complete (RO) resection in women who have recurrent platinum-sensitive ovarian cancer. Although, results of randomized trials should not be compared, however, it would be useful to note that the magnitude of benefit seen in the DESKTOP III trial (HR 0.75), is similar to the recently reported SOLO2 study. The later study compared the OS in patients with platinum-sensitive ovarian cancer, but who also had a BRCA mutation, and who were treated with the PARP inhibitor, olaparib and had a median OS of 51.7 months compared to 38.8 months in the placebo arm with a HR of 0.74 (Poveda 2020). Although, olparaib is the standard of care for maintenance treatment in patients with BRCA mutated platinum-sensitive ovarian cancer, the cost of drug and the overall cost of management remains very high. Cyto-reductive surgery in carefully selected patients, with a potential to achieve R0 resection may be an alternative, especially for patients with BRCA negative platinum sensitive ovarian cancer in first relapse.

In conclusion, we report the case of a patient with HBOCS, and highlight the recent developments in the systemic and surgical management of patients with ovarian cancer.

Table 2

SCS: Secondary cyto-reductive surgery; CT: Chemotherapy; OS: Overall survival; HR: Hazard ratio; PFS: Progression-free survival

Conflict of Address

Ikram Burney:

Principal Investigator for the hospital site for Astra-Zeneca sponsored PREDICT study Served on the advisory board for Astra Zeneca Other authors declare no conflict of interest

Author’s contribution:

Dr Juhaina Al Hinai – Data curation; Writing – original draft.

Dr Moza Al Kalbani – Surgical Oncology management, Methodology; Writing – review & editing.

Dr Marwa Al Riyami – Pathology reporting, methodology; Writing – review & editing.

Dr Abeer Al Sayegh – Clinical Genetics management, methodology; Writing – review & editing.

Dr Ikram A Bunrey - Conceptualization; Formal analysis; Supervision; Writing – original draft; Writing – review & editing.

Informed Consent:

All data are anonymised, and patient identification is not possible.

A 25-year-old man was admitted in our department for management of a transient ischemic attack. It’s a patient without prior medical history.

He underwent echocardiography, which demonstrating in parasternal long axis view an important dilatation of left ventricle with reduced ejection fraction and severe hypokinesis (figure A).2-dimensional parasternal short axis show multiple prominent ventricular trabeculation with deep intertrabecular recesses particularly in the anterior lateral wall (figure B and C) associated with a voluminous thrombus of 21x11mm (figure D and E). 

The patient also underwent cardiac magnetic resonance imaging (MRI).

The final diagnosis was left ventricular non-compaction with a voluminous thrombus complicated with a transient ischemic attack. The patient is put under classic treatment of heart failure associated with an anticoagulant treatment.

Disclosures

None.

Abstract

Cyclosporine is an important component of GVHD Prophylaxis in Hematopoietic Stem Cell Transplant (HCT). It has narrow therapeutic index and is known to cause hypertension, electrolyte imbalances, Acute Kidney Injury, etc. High suspicion of these adverse effects helps us in managing them effectively. We report here two cases of pediatric age group who presented with acute pancreatitis post matched sibling HCT for Thalassemia transplant. To our knowledge we could find only 2 case reports of Cyclosporine induced pancreatitis post HCT in literature and none reported post HCT in Thalassemia. Diagnosis of acute pancreatitis especially in pediatric age group can be challenging without high suspicion.The purpose of our report is to highlight the importance of keeping acute pancreatitis in differential of unwell child post HCT in Thalassemia and careful rechallenge of Cyclosporine may be possible with careful monitoring, thereby not compromising on GVHD prophylaxis.

Key-words: Pancreatitis, Cyclosporine, Thalassemia, GVHD prophylaxis

Key Messages: This report highlights the importance of suspecting pancreatitis in a paediatric thalassemia patient post allogeneic stem cell transplant with cyclosporine –A  as possible causative factor. CSA reintroduction can be attempted with careful monitoring after recovery.

Introduction

Cyclosporine (CsA) is a cyclic polypeptide immunosuppressant agent. It is produced as a metabolite by the fungus species Beauveria nivea1. CsA has been used extensively for immune suppression in allogeneic hematopoietic cell transplantation (alloHCT) as well as solid organ transplants for prevention and treatment of graft versus host disease (GVHD) and graft rejection1. CsA has a narrow therapeutic index and requires therapeutic dose monitoring. Common adverse effects of CsA include nephrotoxicity, HCT, hypertension, and hypomagnesemia1. Acute Pancreatitis has been reported with the use of CsA in organ transplants2.

With an extensive literature search, we could not find any report of CsA induced acute pancreatitis after  alloHCT for thalassemia or other hemoglobinopathies. Here we report two pediatric patients with thalassemia major, of CsA induced acute pancreatitis after HLA matched family donor HCT.

Case History

Case 1, a 2-year-old female child with Thalassemia major, presented on day +66 of HLA matched mother donor alloHCT with a history of constipation, irritable behavior, episodes of crying, decreased oral intake and vomiting of 2 days duration. Abdominal examination was remarkable for mild diffuse tenderness and sluggish bowel sounds. X-ray abdomen was suggestive of dilated colon while an USG of abdomen was suggestive of gaseous bowel distension. Pediatric Surgery review suggested a possibility of subacute intestinal obstruction. The patient was treated conservatively by withholding oral foods and fluids (NPO) and application of bisacodyl suppositories. Constipation resolved but she continued to remain irritable with the persistence of abdominal signs. A possibility of acute pancreatitis was considered and serum amylase and lipase were sent which turned out to be 183 IU/L (normal range 22-80) and 2350 IU/L (normal range 23-300). CT Abdomen was notable for modified CT severity index for acute pancreatitis (CTSI) of 43.  A careful review of her drugs and history of illness was carried out. She was not found to be suffering from viral prodrome anytime in the previous month. Her serum calcium and triglyceride levels were normal while PCRs for CMV and EBV were negative. She was receiving CsA along with prophylactic acyclovir, penicillin V and co-trimoxazole. Her plasma CsA trough level was 61 ng/mL on the day of her presentation. A possibility of CsA induced acute pancreatitis was considered4. Naranjo algorithm for causation score was 7 for CsA suggesting probable causation5. Her blood pressure and renal functions were normal. She had no other CsA toxicity. With conservative management her symptoms improved over 1 week, USG done after 1 week was suggestive of resolving pancreatitis with falling levels of serum lipase and amylase. She was shifted to Mycophenolate Mofetil (MMF) for GVHD prophylaxis. On day+100 follow up, her chimerism was maintained at 100% donor, but liver enzymes were raised. After excluding infective and drug-induced hepatitis, a possibility of liver GVHD was considered. A decision to re-challenge with CsA under close monitoring was taken. CsA was re-introduced starting at low doses with monitoring of amylase and lipase levels and close monitoring for clinical signs. She did not have a repeat episode of acute pancreatitis and is currently on tapering immunosuppression on day+260 of follow up.

C ase 2, a 4-year-old female child with thalassemia major presented on day+154 of HLA matched sibling donor alloHCT with a history of abdominal pain, vomiting and poor oral intake of 2 days duration. The patient had no history of fever. On examination, the patient had tachyuration. The patient had no history of fever. On examination, the patient had cardia, normal blood pressure for age, abdominal distention with mild diffuse tenderness. Her USG was suggestive of the bulky pancreas, amylase, and lipase levels were 643 IU/L and 4253 IU/L. The plasma CsA trough level was 252ng/mL. Her chimerism test showed 68% of donor cells. A careful review of her clinical history, lab results, and medications couldn’t find other causes of acute pancreatitis than CsA. Naranjo algorithm causation score was 7 for CsA suggesting probable causation5. There were no other CsA toxicities. CsA was stopped and she improved with conservative management. The patient was started on MMF for GVHD prophylaxis thereafter. She was considered for a re-challenge of CsA especially after our experience of successful re-challenge of CSA in our previous patient. She was restarted on CsA starting from low doses with amylase and lipase monitoring from day +185 onwards. Currently, she is on escalating doses of CsA on day +225 of follow up with donor chimerism improved to 76%.

Discussion

Ito, T. et al showed that intravenous injection of CsA 10 and 20mg/kg body weight (BW) in rats increased the content of pancreatic amylase and protein and decreased the content of pancreatic DNA6. Histologically, intraacinar vacuolization and individual cell necrosis were observed6. CsA induced a significant increase in serum amylase and pancreatic wet weight in a dose-dependent manner6. Qi C et al reported acute pancreatitis in a 16-year-old female patient with acute leukemia on day 24 of alloHCT with CsA or Tigecycline as potential causative agents4. In a case report by Guo R et al from China, CsA induced acute pancreatitis was reported on day+20 of HLA matched alloHCT in a 49-year-old male with AML-M27.

Whether Acute pancreatitis developing in post alloHCT patients with relatively lesser duration of exposure to CsA is idiosyncratic or dose-dependent is yet to be elucidated. Although animal experiment data points towards dose-dependent toxicity, in both our cases acute pancreatitis, developed at acceptable plasma levels, questioning this notion.

Other than that, Post-transplant diabetes mellitus (PTDM) is a complication that takes place after solid organ transplant as well as alloHCTs, with reported incidences ranging from 2 to 53%. Cyclosporine is one of the risk factors for developing PTDM probably due to direct toxic effects on beta cells of the pancreas8.

From this experience, we conclude that studies are needed in the pathogenesis of CsA induced acute pancreatitis in post alloHCT patients. High suspicion of acute pancreatitis should be kept in post alloHCT patients with abdominal signs and symptoms especially in pediatric patients who may not be able to communicate the typical pain history. CsA re-challenge didn’t precipitate pancreatitis in our patients.

Declarations

Funding: Funding information is not applicable to this study.

Conflict of Interest: All authors declare no conflict of interest to declare.

Compliance with Ethical Standards

Ethical Approval Statement: All authors stated that the study has been approved by the appropriate institutional review board and have been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Acknowledgements We would like to acknowledge Dr Rayaz Ahmed, Dr Vishvdeep Khushoo and Dr Pallavi Mehta in treatment of the patients. We thank all the members, and staff of Rajiv Gandhi Cancer Institute and Research Centre, India for their contribution in the conduct of the study

Abstract

Amyloidosis represents a notable cause of morbidity within the developed world. Urological presentations of systemic or localised amyloidosis are rare, with penile amyloidosis being poorly reported. We performed a literature review investigating cases of penile cutaneous amyloidosis via the PubMed database during March 2020, in conjunction with clinical review of a local patient presenting with a penile lesion. Our patient is a 60-year-old uncircumcised, caucasian male presenting with a longstanding history of 2 irregular lesions affecting his glans penis and a further 2 lesions affecting the inner surface of his prepuce. He underwent excision biopsy of the largest lesion which represented cutaneous amyloid deposits. He underwent immunological testing for systemic disease which was negative.

In current literature, there are 13 cases of cutaneous amyloidosis affecting the glans penis, with 1 of those having evidence of extra genitourinary amyloid deposits. All the documented cases were treated with local excision and investigation for systemic disease. It is important to recognise alternative diagnoses in patients presenting with penile lesions. Despite cutaneous amyloidosis mimicking malignancy macroscopically, the morbidity and mortality is lower in comparison to penile cancer. Treatment remains surgical excision of the lesion and further investigations to exclude systemic disease.

Introduction

Amyloidosis is a notable cause of morbidity, and in some cases mortality within the developed world. Urological presentations of systemic or localised amyloidosis are rare, with primary penile amyloidosis being poorly reported in the literature. It can commonly mimic malignancy on imaging and macroscopically, thus representing an important differential diagnosis to be aware of when examining and investigating a penile lesion.

Case Presentation

A 60-year-old uncircumcised, Caucasian male was referred with multiple longstanding granular lesions of his penis.  His past medical history included hypertension and insulin dependent type 2 diabetes. On initial assessment there were two irregular granular lesions on his glans penis and two further similar lesions on the inner prepuce. These were initially thought to be malignant and an excision biopsy of the largest one was performed.

The histopathological examination showed an abundance of relatively amorphous pink material in the superficial to mid dermis with positive Congo red staining and mild apple-green birefringence in keeping with cutaneous amyloidosis. Further analysis with immunohistochemical staining of the sample by the National Amyloidosis Centre confirmed this result and determined this to be of the AL Kappa subtype.

Following investigation under the care of the haematology department with serum free serum light chains, electrophoresis and Bence Jones’ protein, there was no evidence of systemic amyloidosis or multiple myeloma. A diagnosis of cutaneous AL amyloidosis of Kappa subtype affecting the glans penis and prepuce was made.

The patient underwent a circumcision for localised treatment of the remaining preputial lesions. The remaining glandular one was deemed high risk for meatal stenosis due to its proximity to the urethral meatus and therefore not excised.

The patient remains well under yearly review from the National Amyloidosis Centre.

Discussion

The term ‘Amyloid’ was first coined by Virchow in the 19th century to describe a macroscopic tissue abnormality characterised by a positive iodine staining reaction. Subsequent technological advancements in light microscopy furthered Virchow’s description to include distinct birefringence of the amyloid deposits when stained with Congo red dye [1].

The pathophysiology of amyloidosis stems from a failure of proteolysis of misfolded proteins resulting in oligomeric conglomerates referred to as amyloid fibrils. As amyloidosis is caused by misfolded proteins, there are multiple classifications of the disease specifically related to the original protein involved. All of the involved proteins may form extracellular deposits and lead to subsequent organ dysfunction [2]. The most common subtypes of amyloidosis include amyloid light chain (AL), the origin of which is an immunoglobulin arising from plasma cells, and amyloid associated (AA), arising from a non-immunoglobulin synthesised by the liver. Further classification can be made by the clinical presentation of the proteinaceous deposit; whether it be systemic or localised, and the clinical syndrome it produces.

The amyloid Light Chain (AL) subtype is characterized by clonal plasma cell dyscrasia, similarly to multiple myeloma [3]. This results in a failure to produce the classical alpha-helix configuration of either kappa or lambda light chains, instead producing a beta-pleated sheet which is inherently insoluble. Classically there is involvement of the kidneys, heart or nervous system however involvement of many organ systems has been documented.

Cutaneous amyloid deposits can be seen in both systemic and localized disease. Commonly up to 40% of systemic AL amyloidosis sufferers complain of epidermal disease, which reflects amyloid deposition within the capillaries of the skin involved. Cutaneous disease typically presents as petechiae or purpuric lesions, yellow macular or nodular lesions. There are also macular and lichen subtypes which can be associated with systemic connective tissue diseases.

Statistically, within the UK the age-adjusted prevalence of amyloidosis is between 5.1 and 12.8 per 1 million per year*. Approximately 10-20% of cases remain localised, with the remainder of cases being classified as systemic disease. Although the localised form is rarer, it carries a better prognosis [5]. Rarer still is localised penile amyloidosis, with only 14 documented cases, including ours, on literature review.

Merika et al. comments on the low prevalence of systemic disease in those presenting with cutaneous penile amyloid lesions as the primary presenting complaint. Their study also highlights the increased rate of primary nodular amyloidosis amongst those with penile cutaneous lesions [4]. Of the confirmed cases of cutaneous amyloidosis of the glans penis, only one reported a second site affected, namely the trachea. This was subsequently found to be a lone deposit, with no further evidence of widespread disease identified; however, this does not exclude the possibility of this representing systemic amyloidosis [16].

Of the cases identified, most were diagnosed on a serological and histological basis, more in depth modalities such as serum amyloid protein component (SAP) scintigraphy and genetic testing were not performed routinely. SAP scintigraphy is highly sensitive for AL and AA amyloidosis (90% for both subtypes), with a specificity of 93%. The use of SAP scintigraphy may give a more definitive answer regarding the presence of systemic disease however the modiality itself is often not available in local centres [17,18].

Treatment of the lesions remains case dependent and requires a multi-disciplinary approach [19]. The underlying amyloid subtype also greatly influences management. In systemic AL amyloidosis, treatment aims to suppress plasma cell production of amyloid which predominantly involves using dexamethasone and mephalan, an oral chemotherapeutic agent, alongside supportive care for the underlying organs involved. Similarly, AA amyloidosis requires management of the underlying disease process often involving immunomodulation [19]. Localised cutaneous amyloidosis is typically managed by surgical excision, or laser ablation, systemic chemotherapeutic agents are usually not employed due to their side effect profile [16]. The majority of cases reported were treated with local excision as in our case.

Conclusion

These cases highlight the importance of consideration of alternative diagnoses in patients presenting with cutaneous penile lesions. Fortunately, despite penile cutaneous amyloidosis mimicking malignancy, the morbidity and mortality are low due to the low incidence of systemic amyloidosis in patients who present with a penile lesion. Treatment remains local excision of the lesion, histological and immunochemical confirmation of the amyloid subtype and further investigations to exclude systemic disease. Consideration could be made for the introduction of SAP scintigraphy in these cases, however the benefit of this remains unclear with such a small demographic to review.

Abstract

Background: Looking into the eyepiece of a conventional operative microscope during minimally invasive spine surgery may result in uncomfortable or highly nonergonomic postures. Robotic systems are rapidly changing the landscape of modern surgery, offering potential benefits for both patients and surgeons. This study aims to describe potential advantages of a new high-definition hands-free robotic visualization device (Robotic Scope) displaying 3D images in a head-mounted display (HMD) accessory for minimally invasive decompression and navigated transforaminal lumbar interbody fusion (TLIF).

Methods: We performed a single TLIF with prior laboratory training to assess the advantages and disadvantages of RoboticScope assistance, its integration into the operative workflow, and its qualitative appraisal in spine surgery.

Results: A senior surgeon evaluated magnification, perception of depth and robot manipulation with HMD as good. All four placed pedicle screws were assessed as grade A according to the Gertzbein-Robbins scale (GRS) No intra- or perioperative complications were experienced.

Conclusion: Maintaining ergonomic posture and hands-free control microscopy are of particular interest in minimally invasive spine surgery. Further clinical research is required to demonstrate the safety, usability and surgical outcome using the Robotic Scope.

Keywords: Smart Glasses, Minimally Invasive Surgical Procedures, Robotics, Microscopy, Spinal Fusion, Ergonomic

Introduction

Since the 1970s, the operating microscope (OM) has been a standard tool for visualization and illumination of the surgical field during spinal microsurgery. However, some limitations have been documented, e.g., the limited movability of the binocular lenses and discomfort experienced by surgeons due to the abnormal postures required, and efforts have been made to replace the OM with exoscopic and digital systems [1]. Minimally invasive spine procedures rely mostly on good visualization, which has been proven using microscopes; however, this approach comes with a price, notably the need for repetitive movement of the microscope, a limited field of view (focus) and focal length, which lead to difficulty maintaining proper visualization when working with long instruments, such as screwdrivers [2]. Furthermore, the mandatory alignment of the microscope optics with tubular retractors and the constraint of the surgeon to look at the operative field through the binoculars results in nonergonomic postures (Figure 1A), leading to discomfort, pain and eventually work-related musculoskeletal disorders with potential disability [3-5].

Figure 1(A-D): Transoperative images.

A: Figure showing a possible position of the surgeon using a traditional microscope with integrated eyepieces, the  position may not be ergonomically correct.B: Using the RoboticScope system, the surgeon shows a better ergonomic position, without forced movements, even trying to see “around the corner”.C: The eyepieces can be raised automatically on the surgeon’s command (by activating the virtual menu or via a foot pedal).

D: the system allows seeing out of the eyepiece screens, for instance to use the navigation.

Various portable head-mounted display (HMD) devices have been described in spinal surgery to superimpose valuable intraoperative information to the surgeon’s field of view in the headset, such as real-time fluoroscopic images, 3D neuronavigation or augmented reality data during minimally invasive pedicle screw placement [6-8]. By keeping “eyes on the field” during the whole procedure, without needing to frequently look at the display monitors, surgeons minimize the risk of unintentional hand deviation and complications resulting from microsurgical manipulation.

A new microscope displaying high-definition binocular 3D images of the operative field onto an HMD, with hands-free control of the robotic arm carrying the camera, has been assessed in hand, plastic and otologic microsurgery [9-12]. An HMD enables the maintenance of a safe working distance, wearing adequate personal protective equipment and additional surgical draping to reduce perioperative staff contamination risk during the coronavirus disease 2019 (COVID-19) pandemic [13].

The aim of this technical note is to appraise the feasibility of using an innovative high-definition microscope (RoboticScope®, BHS Technologies GmbH, Innsbruck, Austria) with a camera head-mounted onto a controllable robotic arm linked to an HDM displaying the images of the surgical field for minimally invasive 3D-navigated TLIF (Figure 1B-D).

Figure 2(A-B): A: Laboratory training: a training procedure was performed to demonstrate how to control the camera via the integrated virtual menu. B: The integrated virtual menu allows controlling the eyepiece aperture, camera movement, focus, magnification, light intensity etc. Everything is done through subtle movements of the head. This makes the system very intuitive (Courtesy of BHS Technologies GmbH, Innsbruck, Austria).

Materials and Methods

Operative Indication

A 76-year-old female patient with chronic radicular neurogenic claudication shown by L5-S1 discopathy and bilateral severe foraminal stenosis on preoperative MRI who was resistant to conservative treatment, underwent microsurgical decompression and instrumentation using minimally invasive surgery (MIS-TLIF) under general anesthesia.

Training

Two weeks prior to the procedure, the senior surgeon received a practical introduction to the RoboticScope on artificial models, including teaching on the use of its main functions such as orientation of the robotic arm to change the angle of vision and navigation through the interface to select and adjust the different parameters (Figure 2A).We recorded the surgeon’s head movements for camera motion control and time taken to reach different positions of the robotic arm during training.

Technique

The patient was positioned prone on a Jackson table (Mizuho, OSI®). After placing the spinous process clamp and reference on S1, 3D imaging was acquired by computer tomography (CT) intraoperative scan (O-arm™, Medtronic, Inc.) and was transferred to the spinal navigation system (StealthStation™, Medtronic, Inc.). A two-centimeter-long skin incision was made approximately 5 cm paramedian on the right side. Tubular retractors (MAST QUADRANT™ system, Medtronic, Inc.) were placed regarding the segment of interest under navigation, exposing all structures between pedicles L5 and S1 (facets and lamina). The RoboticScope® camera head was brought in after adjusting and calibrating the HMD on the surgeon’s head (Figure 1B and C). After drilling through the inferior articular process of L5 and removing the superior articular process of S1 with the drill and Kerrison rongeurs, the dura and traversing S1 nerve were exposed and medially retracted. Annulotomy was performed, the disc material removed, and endplates prepared with different curettes.

After localization confirmation with the navigation probe, an interbody titanium cage was brought under fluoroscopic control.Four titanium percutaneous pedicular screws were inserted into L5 and S1 under computer-assisted navigation. 3D intraoperative images were then acquired to confirm the correct placement of the screws and cage (Figure 3).

Smart Glasses

Figure 2(A-B): A: Laboratory training: a training procedure was performed to demonstrate how to control the camera via the integrated virtual menu. B: The integrated virtual menu allows controlling the eyepiece aperture, camera movement, focus, magnification, light intensity etc. Everything is done through subtle movements of the head. This makes the system very intuitive (Courtesy of BHS Technologies GmbH, Innsbruck, Austria).

Microscopic System: Robotic Scope

Surgical field images were captured by a high-definition (HD) dynamic camera mounted on a six degrees-of-freedom (DOF) robotic arm. Binocular digital screens fixed onto the helmet on the surgeon’s head displayed the HD 3D live operative images, irrespective of the surgeon’s head position (Figure 1 D).Taking off the HMD eye screens, orientation of the robotic arm and control of microscope settings were possible using light head gestures (Figure 1C) as follows. After pressing on a foot pedal to engage control mode, nodding and head turning detected by the HMD enable navigation through a visual user interface, allowing changing the perspective of sight or adjusting parameters such as the working distance (300-600 mm), magnification (absolute magnification 4.3-34.4x), and illumination (white LED technology) (Figure 2B). The RoboticScope received the European conformity (CE) certification in 2020.

This study was conducted in accordance with the local Swiss Ethics committee guidelines and the Declaration of Helsinki. Written consent for medical data collection and de-identified use for research was obtained from the patient.

Results

Training in the laboratory before the procedure was of great benefit. The first transition from one point to another in the mock surgical field took 10 seconds, but after 1 hour of training went down to 3 seconds. Focusing took 8 seconds vs 2 seconds after 1 hour of training. Control of the camera was highly intuitive, and no difficulties controlling the position and movements of the camera were encountered.During the real surgery, focusing and moving from one point to another required the same amount of time as after the 1-hour training period (Figure 2A).

After operation, all four placed screws were assessed as grade A according to the Gertzbein-Robbins scale (GRS), with no pedicle breach detected on the intraoperative CT scan (Figure 3,4) [14]. There were no intra- or perioperative complications.

Magnification, depth perception and robotic manipulation with the HMD were evaluated as comparable to the traditional microscope. The focal length was evaluated superior to our standard microscope and the available workspace under magnification when using long instruments. More workspace is due to freeing the space occupied by the traditional microscope. We can therefore conclude that the use of a new microscope with a robotic mounted camera fit in well with the established workflow of MIS-TLIF of our institution. The surgeon reported a significant reduction in muscle tension and fatigue after a procedure lasting several hours, being able to maintain an aligned and physiological spinal posture during all microsurgical steps.

Figure 4: A - Coronal B - Axial L5  and C - Axial S1 intraoperative CT scan acquisitions.

Discussion

In this technical note, we used a newly conceptualized 3D stereoscopic microscope previously tested in other conditions, with a robotic mounted camera from which surgical field images are displayed in an HMD to now test the feasibility of use for MIS-TLIF.  After a relatively short training, the surgeon was ready to use the new device for a designated spine procedure. The surgery was uncomplicated, the new device integrated seamlessly and safely in the usual operative process and a significant reduction in tension and muscle fatigue following ergonomic positioning was reported by the surgeon.

Extreme angulation of tubular retractors to optimize the exposure of relevant structures in a narrow operative corridor of less than 3 cm diameter represents a current maneuver in MISS. Working independently of oculars mounted on traditional microscopes in MISS was our goal to elude the classical alignment constraint of the surgeon’s eyes and eyepiece proximally to the microscope’s objective and the tubular retractor distally so that the surgeon can adopt a more neutral and ergonomic posture. Use of exoscopes with tubular retractors has also been advocated for this purpose [15] but with an exoscope, surgical site observation still depends on looking at a screen with altered field depth perception. Furthermore, preoperative placement of the 3D monitors for the first operator and the assistant can sometimes be cumbersome, while for Robotic Scope, the working images permanently follow the head movements of the surgeon in the HMD [16]. In addition, notwithstanding significant technical developments in the field of digital monitoring with 3D ultrahigh-4K definition, the tridimensional image quality, depth perception and illumination of exoscopes have not yet achieved the results of classical microscopy operating or the performances that are expected to be maintained with the binocular digital microdisplay system of RoboticScope [17].

Bringing in a navigation probe or long instruments during minimally invasive spinal procedures often results in taking operative instruments out of the surgical field to remove the microscope head leading to incapacity to look at operative 3D images through the microscope eyepiece and unergonomic body movements when observing the 2D external screen. Field obstruction by a microscope prevents camera visualization of the tracking markers and causes loss of neuronavigation. In this respect, uncoupling the surgeon’s eyes from a microscope eyepiece via an HMD enables maintaining 3D images of the neurological structures during critical instrumentation steps. In addition, hands-free control of the field view with head motion and the wide working distance of RoboticScope (300-600 mm) allows instruments to be kept in the operative field throughout.

Kwan et al. showed a significant increase in the incidence of scope adjustment during the same spinal procedure using a high-definition 3D exoscope compared to a classical operating microscope. therefore, by means of hands-free orientation of the microscope, an additional reduction in the incidence of scope adjustment could be foreseen using Robotic Scope. For narrow surgical corridors, especially when using tubular retractors, slight angulations of the microscope tube are sometimes useful to clear microsurgical instruments out of the line-of-sight of anatomical structures of interest. The head-controlled orbital mode of RoboticScope would permit gentle rotation around a chosen point to reveal the tip of instruments in a confined space without the need to manually orient the microscope.

Limitations

We report the first use of robotic microscopy with HMD for spinal surgery; however, a larger number of cases is needed to assess the safety and usability of the system on a regular basis in MISS. Further assessments are required to appraise the learning curve and the optimum length of preoperative training sessions. Ex-vivo tests on human cadavers could contribute first to assess feasibility and then to measure accuracy and reproducibility of the procedures with this new device. As Molina et al. mentioned in their study, a major obstacle interfering with a seamless and safe workflow of conventional computer-assisted spine navigation is attention shift. Repeatedly shifting looking at the surgical field and neuronavigation screen entails a risk of hand deviation and misplacement of screws. Moving the gaze away from the micro-display of the HMD (e.g., taking off the HMD eye screens as in (Figure 1C) to assess navigation information on other display screens in the operating room could easily be prevented by embedding the navigation screens into the HMD’s digital micro-display. In addition, the digital character of the HD procedural images displayed on the HMD may allow for more convenient superimposition of computer-generated data onto the patient in augmented reality than those with demanding projection techniques for overlapping supplementary images onto an optical system, such as microscope oculars [18].

We noted two possible disadvantages of Robotic Scope that could be readily addressed in the future. First, the initial delicate process of balancing the relatively heavy helmet (485 gr.) on the surgeon’s head and maintaining a constant distance from the binocular screens of the HMD to the eyes are mandatory to maintain the focus during the length of the procedure. Optimizing the fit of the HMD to the surgeon's head and especially limiting its weight would help to maintain a constant distance between eyes and the HMD screens. With conventional microscopy, this distance from eyes to binoculars is not fixed, but surgeons can adapt it with slight back and forth movement of the head. Second, a double HMD is not currently available for another surgeon, hindering the same 3D visualization of the surgical field for quality operative assistance.

Conclusion

To our knowledge, this is a first report of the use of an innovative microscope, the RoboticScope® (BHS Technologies GmbH, Innsbruck, Austria), for minimally invasive spinal stabilization procedure. In contrast to conventional operating microscopy, working independently of the eyepieces allows surgeons to adopt an ergonomic posture, even in cases of extreme tubular retractor angulations. Changing the perspective of sight and working distance while keeping operative instruments and the surgeon’s sight in the surgical field is made possible by hands-free control of the microscope’s camera head. Further pre-clinical and clinical research is required to demonstrate safety, usability, and surgical outcomes using this new technology.

Ethics approval

NA

Acknowledgements

We thank Melanie Price Hirt for English language correction and editing of the manuscript.

Declaration of Conflicting Interests:

Timo M. Ecker is a consultant for Medtronic and receives research funding from them; there is no conflict of interest with this study. Other authors declare that there is no conflict of interest.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Author contributions

Frederic Rossi-Mossuti: Conceptualization, Investigation, Writing-Original draft preparation, Visualization Timo Ecker: Resources, Writing-Review & Editing Marco Germann: Writing-Review & Editing Juan Barges-Coll: Resources, Conceptualization, Investigation, Writing-Review & Editing

Case Report

Lineage switch is an infrequent phenomenon with an incidence of ~ 0.6% of all de novo leukemias and seen in almost 6% of relapsed cases. This phenomenon is observed following therapy or at the time of relapse. Switch in lineage tends to occur in younger patients and is associated with particularly poor outcomes.[1]

https://ijcimr.org/wp-content/uploads/2022/01/Fig-1__1_.jpg

Discussion

Our clinical report illustrates an adult refractory B -ALL with t (4;11) (q21;23), AF4:MLL fusion who transformed to Mixed-phenotypic acute leukemia;KMT2A-rearranged during his second month of therapy. Lineage switch in MLL rearranged paediatric ALL is common, but in adults it is not well reported. During the literature review, we found 2 cases of adult ALL harbouring t (4;11) transformed to AML [1,4]. First case illustrated chemotherapy responsive MLL rearranged B-ALL who underwent allogeneic stem cell transplantation (Allo SCT) in remission after induction therapy, who transformed to AML post 100 days of Allo SCT[4]. Second case illustrated refractory MLL rearranged B-ALL adult that rapidly transformed to AML following initiation of blinatumomab therapy [1].  However there was no case found to have switched from B acute lymphoblastic leukemia to Mixed-phenotypic acute leukemia;KMT2A-rearranged .Mechanism for lineage switch in MLL rearranged acute leukemia is not clear yet. Reports showing a strong trend of lineage switch involving B and myeloid lineages suggest that B myeloid progenitor might be involved in the mechanism of lineage switch. Studies reporting lineage switch post anti CD19 therapy; blinatumomab and CD19 chimeric antigen receptor (CAR-T), further advocates this theory [3].In our case it is not possible to state that transformation occurred post Venetoclax therapy, as flow cytometric evaluation was not done prior to start of venetoclax therapy. Development of secondary AML as a result of therapy related process can be ruled out in view of early lineage switch (< 6 months of therapy) and consistent finding of the t (4;11) (q21;23) at diagnosis of B-ALL and transformation. The (4;11) rearrangement detected at diagnosis, and phenotypic switch suggests that the original clone harboured a bi-lineage potential. If further genetic studies including NGS or gene expression studies done at baseline could have predicted the bi lineage potential is also unclear as the case reported by Haddox C et al did not show any change in the baseline NGS and the NGS performed during relapse.In conclusion, haematologists should be cognizant while treating MLL rearranged B -ALL adults for a lineage switch. It also underlies the importance of repeat evaluation of the disease if there is no response to standard therapy.

Declarations

Letter to Editor

Postoperative sore throat (POST) is a common complaint with an incidence of 24-100% 1 that occurs following placement of airway devices in patients administered general anaesthesia. POST results in discomfort, patient dissatisfaction after surgery and leads to delay in patient’s return to normal routine activities. Severe, persistent and unresolving POST may be attributed to uvula injury. We report uvular injury in a patient inspite of uneventful placement and removal of double lumen tube (DLT). A 58-year-old male (Weight-75 kilograms, Height-172 cm, BMI-25), case of left lower lobe carcinoid tumour was posted for left lower lobe sleeve lobectomy. On preanaesthetic checkup, according to American Society of Anesthesiologists physical status (ASAPS) classification system, patient belonged to ASAPS I.

The patient was fasted according to standard ASA fasting guidelines. We planned combined general anaesthesia and thoracic epidural as the anaesthetic and analgesic technique. After shifting the patient to operating room, peripheral intravenous access was obtained and all standard monitoring devices including electrocardiography, noninvasive blood pressure, and pulse oximetry were attached. After positioning patient in left lateral decubitus, painting and draping, using 18-gauge Touhy needle, T6– T7   epidural space was identified at 7.5 cm mark using loss of resistance (LOR) technique and catheter threaded upto 13 cm mark. After securing catheter and confirming negative aspiration of blood or CSF, 3 ml of 2% lignocaine with 1 in 200000-unit adrenaline was given as test dose. The patient was turned supine, preoxygenation with 100% oxygen was done. The patient was premedicated with Inj Fentanyl 160 micrograms. General anaesthesia was induced using titrated doses of Inj Propofol. Adequate bag and mask ventilation were ensured and Inj atracurium 0.5 mg/kg was administered. After completion of 3 minutes, tracheal intubation was done with direct laryngoscope (Macintosh #4) and 39 Fr Robertshaw’s left sided DLT was placed. The correct position of tube was checked by auscultation and further confirmed by fiberoptic bronchoscopy. Left radial artery was cannulated. Total duration of one lung ventilation (OLV) was 4 hours 20 minutes. The overall period of OLV was uneventful as there were no episodes of desaturation and hemodynamic instability. After completion of surgical procedure, patient was turned supine, thorough suction from both lumens of DLT was done. DLT was removed and I-gel no 4 was placed.

After return of spontaneous respiratory efforts, patient was reversed and extubated. He was shited to intensive care unit (ICU) for further observation. Few hours later, he complained of foreign body sensation in throat and as if something was stuck in throat. The foreign body moved backwards during inspiration and aggravated airway obstruction. We considered it most probably as airway mucous secretions that would have accumulated due to failure to cough them out effectively.  Steam inhalation, saline nebulization and chest physiotherapy was done and patient was encouraged to cough out secretions in throat. However, few hours later he again reported same complaints as there was no improvement with measures taken by us. Hence, we decided to go for inspection of his pharynx and found an elongated, swollen, inflamed uvula was noted (Figure 1). We diagnosed as uvula injury caused by impingement of DLT. We reassured him and advised not to strain further as it would further aggravate uvular injury. He made complete recovery over a period of 5 days. Uvula injury after placement of endotracheal intubation 2 and laryngeal mask airway 3 has been reported earlier. The compression of uvula between hard palate and airway device has been reported as causative factor. Excessive compression can cause mechanical interruption of blood supply and result in uvular necrosis. Proper positioning of DLT to one side of midline can avoid this complication.

To conclude, uvular injury should always be kept as differential diagnosis in patient with severe persistent sore throat particularly if associated with foreign body like sensation. Careful and thorough examination of oropharynx should be done to confirm diagnosis. Though condition responds well to conservative management but reassurance addressing the cause and expected duration is must to reduce distress experienced by patient.

Abstract

Background: When dealing with severe and worsening headache with oculomotor dysfunction, it’s necessary to take into account the possibility of idiopathic intracranial hypertension (IHH), though it’s a rare condition. We present an atypical case of IHH in a 4-year-old patient with no apparent risk factors.

Methods: IHH was diagnosed by exclusion, by ocular fundus examination, liquor cerebrospinalis examination, anatomical cerebral magnetic resonance imaging (MRI) and MR angiography (MRA). At the onset of symptoms, the patient was treated with a diuretic and steroid therapy.

Results: After one year of medical therapy, we observed headache recurrence with positive ophalmological assessment and positive cerebral MRI. Medical treatment was deemed ineffective and it was necessary for the patient to undergo surgical intervention.

Conclusion: We report a case of severe and chronic headache with oculomotor dysfunction in a young, pre-adolescent patient. This case is atypical because of the young age of the patient, and it being refractory to medical therapy. This case confirms that when dealing with severe headache in young patients, it is necessary to take into account any rare cause of symptomatic headache.

Keywords: idiopathic intracranial hypertension, headache, papilledema, acetazolamide, steroids, ventriculoperitoneal shunt

Abbreviations: IIH: Idiopathic Intracranial Hypertension; ELISA: Enzyme-Linked Immunosorbent Assay; HSV: Herpes Simplex Virus; CMV: Citomegalovirus; EBV: Epstein-Barr Virus; EEG: Electroencephalogram; CT: Computed Tomography

Introduction

Headache is a frequent reason consulting physicians in pediatric patients. Headaches appear in about 37-51% of patients younger than 7 years and about 57-82% of patients under 15. Chronic headaches are more infrequent, with 2.5% of kids under 7 and 15% of teenagers under 15 suffering from this ailment. Most of these cases are either idiopathic headaches, mainly migraines, with respect to tension-type headaches. However, when dealing with chronic headaches it is necessary to exclude any secondary causes of headache by detailed diagnostic exams, since the treatment may significantly differ.

Case Study

D.(a 4-year-old child) was admitted to our Hospital Emergency Room with a chronic daily headache. His clinical and family history was negative for any neurological diseases. His cognitive and motor development was normal and regular. His mother reported that D. suddenly showed a monolateral exotropia affecting the right eye; this problem disappeared after a couple of hours. In the same week D. presented with a severe headache, whose intensity decreased after the administration of analgesic drugs. In the following days the headache occurred several times, accompanied by Chronic headaches are more infrequent, with vomiting, tiredness, sleepiness, and both apathy and nervousness. D. was admitted again to the Emergency Room for another visit. His vital signs were normal but the child appeared suffering and soporose. Physical neurological examination was within normal limits and the patient was afebrile. A clinical examination of the motor and  sensory system was normal. Tone, power and reflexes in all four limbs were also normal; there was no neck stiffness and Kerning’s sign was negative. Coordination was normal, the sensory system and the cranial nerves were normal too. No significant findings were revealed in further systemic examinations. Fundoscopy revealed bilateral papilledema. Routine full blood count and biochemistry did not show any abnormality.

Enzyme-linked immunosorbent assay (ELISA) of the patient’s serum was negative for Herpes Simplex virus (HSV), Citomegalovirus (CMV), Epstein-Barr virus (EBV) and toxoplasma. A  brain computed tomography (CT) scan was performed and was normal.  Cerebrospinal fluid chemistries and cytology were normal as well. However, an increase in liquor pressure was found.  Brain magnetic resonance imaging (MRI) revealed an arachnoidal space of optical nerve dilation (Figure 1). The electroencephalogram (EEG) revealed slow posterior bilateral waves without paroxysmal signs (Figure 2).

Figure 1: Brain MRI: bilateral distention of the perioptic subarachnoid spaces.

Figure 2: Electroencephalogram: bilateral posterior slow wave complexes.

Table 2: IIH Diagnostic flow chart.

https://ijcimr.org/wp-content/uploads/2022/01/table-2.jpg

With these tests we excluded venous sinus thrombosis, and made presumptive diagnosis of idiopathic intracranial hypertension on the basis of opthalmologycal and MRI findings. Treatment with acetazolamide 20mg/Kg/daily was initiated without any side effects. However, on the 6th day after treatment initiation, headache and papilledema had not resolved. Therefore, we complemented the treatment with intravenous hydrocortisone 1 mg/kg/daily followed by oral prednisolone.  In the following days D. did not present headache; ophthalmoscopic examination showed a slight swelling of the right disc but visual acuity and visual evoked potentials (VEP) were normal. After D. was discharged from the hospital, this therapeutic regimen was continued for 3 months. After stopping the administration of acetazolamide and prednisolone, D. accused headache and photophobia, while a new neurophtalmological assessment and EEG were both negative. The headache decreased again after the administration of analgesic therapy. 12 months later the patient was re-admitted to the hospital with headache, nausea, and vomiting. A neurophalmological assessment revealed bilateral optic disc edema. MRI revealed minimal arachnoidal space of optical nerve dilation. Diuretic therapy and high doses of steroids were ineffective. After 2 months of medical treatment the patient developed glucose intolerance. Some improvement was observed after repeated lumbar puncture. Since the patient was refractory to medical therapy, it was finally decided to perform surgical treatment in the form of a ventricular-peritoneal shunt. This treatment effectively resolved the symptoms.

Discussion

Idiopathic Intracranial Hypertension (IIH) is a term commonly used to describe the association of intracranial pressure without clinical laboratory or radiological evidence of an intracranial, space occupying lesion. The incidence of IIH is variable and it ranges from 0.57 to 2/100.000 in the general population. IHH is a rare entity in pediatric patients.

Known as benign intracranial hypertension or pseudotumor cerebri, IIH is a diagnosis of exclusion made in the presence of papilledema, normal neuroimaging and cerebrospinal fluid analysis, but with an elevated cerebrospinal fluid pressure. The diagnosis of IIH is suspected on the basis of the patient’s and family history, and the clinical examination. To correctly diagnose IIH it is necessary to perform: neurologic examination, ophthalmoscopy, visual field assessment, ocular motility examination and brain MRI with venography. Previously, the modified Dandy criteria were used for this diagnosis in both adults and children (Table 1,2). However, Raangwala and Liu proposed new criteria to aid diagnosing for pseudotumor cerebri in prepuberal children, as presentation in this population can be quite different compared to adolescents and adults.

The pathophysiology of IIH is not clear: there are many hypotheses on the development of this condition, including alterations in liquor absorption and production, cerebral edema, abnormalities in cerebral vasomotor control and cerebral blood flow, and venus obstruction. Risk factors for the development of IHH are: obesity, adolescent age, female sex, intake of high dose Vitamin A derivatives (e.g. isotretinoin for acne), long-term tetracicline use, steroid and hormonal contraceptives. The most common presenting symptom is a severe headache, worsening in the morning and being exacerbated by the Valsalva maneuver. The other manifestations are: exotropia, horizontal diplopia, caused by cranial nerve VI palsy, decreased visual acuity or blurring central vision caused by papilledema, nausea and vomiting.   The most significant physical finding of IIH is bilateral disc edema secondary to the increased ICP.

The pseudotumor cerebri is usually a self limited condition but a delay in treatment can lead to optic atrophy and blindness. Medical treatment with acetazolamide in association with corticosteroids has been applied with success. It is rarely necessary to perform serial lumbar punctures, lumboperitoneal or ventriculoperitoneal shunt, subtemporal decompression or optic nerve sheath fenestration.

In conclusion, our case can be considered atypical as it involved a young child without any risk factors for IHH. This demonstrates that when presented with a case of severe and recurring headache, even in children, it is necessary to follow an accurate diagnostic protocol, in order to exclude any cerebral tumors, encephalithis, hydrocephalus and venous sinus trombosis. The diagnosis involves several professionals: the neuropediatrician, ophtalomologist and neuroradiologist. Regarding the therapy, our patient required a combined regimen with acetazolamide and steroids. Once we suspended the treatment with steroids, the headache recurred, without any other associated symptoms. A relapse was confirmed, and steroids were not prescribed again.

After 12 months the patient presented again with episodes of severe headache with ophtalmoscopy and neuroimaging positive for IIH. Since in this case medical therapy was ineffective in the first place, surgical treatment was deemed necessary. The long term follow-up confirmed that the correct therapeutic approach included surgical treatment, leading to a complete recovery as well as a prevention from severe and permanent complications such as progressive blindness from postpapilledema and optic atrophy.

International Journal of Clinical Images and Medical Reviews (ISSN 2771-6309) is a peer reviewed journal dedicated to publishing clinical images, Case Reports, Researches, Reviews, Mini Reviews, Short communications etc, from all sectors of science and medicine. The goal of this magazine is to disseminate information about new discoveries and treatments in science and medicine and accepts topics such as surgery, histology and cytology, oncology, dentistry, immunology, diagnostic method, clinical case, transplantation, ophthalmology, forensic science and all medicine-related fields.

International Journal of Clinical Images and Medical Reviews is open access journal, a peer reviewed journal with a large intellectual impact. Before publishing a manuscript, it goes through a rigorous editorial review procedure. The authors are encouraged to provide the manuscripts in accordance with the guidelines. The work can be submitted online using an online submission system. The manuscripts are peer-reviewed before being verified by the editors' panels. Finally, in order to preserve the highest quality of the information in this journal, only the quality contents are published.