Neurologic complications of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICPIs) have recently emerged as a novel treatment for cancer. These agents, transforming the field of oncology, are not devoid of toxicity and cause immune-related side effects which can involve any organ including the nervous system. In this study, we present 9 patients (7 men and 2 women) with neurologic complications secondary to ICPI treatment. These included meningoencephalitis, limbic encephalitis, polyradiculitis, cranial polyneuropathy, myasthenic syndrome and myositis. Four patients received dual ICPI therapy comprised of programmed cell death-1 and cytotoxic lymphocyte associated protein-4 blocking antibodies. Median time to onset of neurologic adverse event during immune checkpoint inhibitor treatment was 8 weeks (range 5 days-19 weeks). In all patients ICPIs were stopped and corticosteroids were initiated, resulting in a marked improvement in seven out of nine patients. Two patients, one with myositis and one with myasthenic syndrome, died. In two patients ICPI therapy was resumed after resolution of the neurological adverse event with no additional neurologic complications. This series highlights the very broad spectrum of neurological complications of ICPIs, emphasizes the need for expedited diagnosis and suggests that withholding treatment early, accompanied with steroid therapy, carries the potential of complete resolution of the neurological immune-mediated condition. Thus, a high level of suspicion and rapid initiation of corticosteroids are mandatory to prevent uncontrolled clinical deterioration, which might be fatal.

Is serum-derived exosomal hTERT transcript a marker of oncogenic activity in primary brain tumors? An exploratory study.

BACKGROUND: In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism. The expression of human telomerase reverse transcriptase (hTERT) enables telomere maintenance and provides cancer cells with limitless replicative potential. As such, it may serve as an attractive biomarker for oncogenic activity. This study explored whether a liquid biopsy that analyses blood derived exosomal hTERT transcript (e-hTERT-trans) may serve as such a biomarker in gliomas and meningiomas when compared to healthy controls. METHODS: Exosomes were isolated from the pre-operative sera of patients' samples stored in the biobank of both Rabin and Sheba Medical Centers. The levels of e-hTERT-trans were measured in 81 healthy controls, 117 meningiomas, 17 low-grade gliomas, and 61 glioblastomas. Clinical parameters of the patients were collected retrospectively and compared to the levels of the e-hTERT-trans. RESULTS: The upper normal limit of controls e-hTERT-trans was 1.85 relative quantitation (RQ). The rate of detection increased with rising tumor grade and correlated with tumor recurrence in meningiomas: mean RQ without recurrence (2.17 ± 11.7) versus with recurrence (3.59 ± 4.42; p = 0.002). In glioblastomas, preoperative measurements correlated with tumor volume and with the disease course on serial sampling. CONCLUSIONS: We demonstrated for the first time that the expression of e-hTERT-trans transcript can be measured in the serum of primary brain tumors. This exosomal marker carries the potential to serve as a biomarker once used in conjunction with other clinical and radiological parameters. Future studies are required to investigate whether the sensitivity could be augmented and whether it can be implemented into routine patients care.

Significant Systemic Insulin Resistance is Associated With Unique Glioblastoma Multiforme Phenotype.

Background: Some glioblastoma multiforme (GBM) are characterized by the presence of gemistocytes (GCs), a unique phenotype of reactive astrocytes. Certain GCs can be identified as neoplastic cells but these cells were also found to be associated with diabetes in non-neoplastic lesions of the central nervous system. Our aim was to find a correlation between insulin - resistance metabolic features and the presence of GCs in patients with newly diagnosed GBM. Methods: Medical records from histologically confirmed GBM patients were retrospectively extracted for different systemic metabolic variables. A statistic-based comparison was made between GBM, diabetic patients with and without GC. Patients with poorly controlled diabetes (ie, hemoglobin A1C ⩾ 8.0) were also compared between the 2 groups. Results: A total of 220 newly diagnosed GBM patients were included in our study. 58 (26.3%) patients had a history of diabetes mellitus type 2 (DM2) at the time of admission. The rate of poorly-controlled DM2 was nearly as twice in the GC-GBM group than in the non-GC GBM group (18.75% vs 9.5%; P = .130). In the DM2 cohort, the subgroup of GC-GBM was significantly associated with demographic and metabolic features related to insulin resistance such as male gender predominance (89% vs 50%, P = .073) and morbid obesity (weight ⩾85 kg: OR 6.16; P = .0019 and mean BMI: 34.1 ± 11.42 vs 28.7 ± 5.44; P = .034 for group with and without GCs, respectively). In the poorly-controlled DM2 group, none of the GC-GBM patients were using insulin prior to diagnosis, compared to 61.1% in the non-GC GBM patients (OR = 0.04, P = .045). Conclusion: Systemic metabolic factors related to marked insulin resistance (DM2, morbid obesity, male gender) are associated with a unique histologic phenotype of GBM, characterized by the presence of GCs. This feature is prominent in poorly-controlled DM2 GBM patients who are not using synthetic insulin. This novel finding may add to the growing data on the relevance of glucose metabolism in astrocytes and in astrocytes associated with high-grade gliomas. In GBM patients, a correlation between patients' metabolic status, tumor's histologic phenotype, tumor's molecular changes, use of anti-diabetic drugs and the respective impact of these factor on survival warrants further investigation.

Sarcoma incidence and subtype distribution in Israel - A population-based study.

INTRODUCTION: This report aimed to describe sarcoma incidence and subtype distribution in Israel, as well as evaluate accuracy of registration for sarcoma cases diagnosed at a single institution. METHODS: Incidence reports were issued for all sarcomas diagnosed between 1996-2017. Concordance between the WHO classification used in pathology reports and the diagnoses in the national registry were evaluated. Sarcoma subtype distribution was analysed. RESULTS: Between 1996-2017 sarcomas had an annual percent change of -2.1 in men and -1.5 in women. Concordance between the pathology report coding and registry in the INCR were 90 %. The most common subtypes were Kaposi sarcoma (KS), liposarcoma and leiomyosarcoma accounting for 21 %, 14.4 % and 10.8 % of all sarcomas, respectively. KS had the highest incidence with 1.6/100,000 persons. CONCLUSION: This is the first description of sarcoma incidence and subtype distribution in Israel. Sarcoma incidence in Israel has declined in the past two decades.

Gemistocytes in newly diagnosed glioblastoma multiforme: Clinical significance and practical implications in the modern era.

BACKGROUND: Gemistocytes (GCs) in low grade gliomas are associated with rapid growth and worse prognosis. However, their clinical significance in glioblastomas (GBM) is a matter of debate. AIM OF STUDY: To investigate the clinical significance of the presence of GCs in newly-diagnosed GBM patients in the modern era. METHODS: Computerized medical records from newly diagnosed GBM patients were retrospectively reviewed and extracted for demographic, clinical, radiological and pathological variables. Patients with at least 5% GCs of neoplastic cells were considered GC-GBM (group 1). All other cases were considered non-GC GBM (group 2). Group 1 was further divided into two subgroups: Low percentage GCs (group 1a, ≤ 20% GCs) and high percentage GC (group 1b, >20% GCs). RESULTS: A total of 220 patients with newly diagnosed GBM were included. 14.5% were defined as GC-GBM (group I, n = 32) and 85.5% were defined as non-GC GBM (group 2, n = 188). 8.5% had ≤ 20% GCs (group 1a, n = 19) and 5.9% had > 20% GCs (group 1b, n = 13). Groups were similar for most epidemiological and clinical variables. There was a trend toward worse prognosis in group 1b. Several distinguished radiological and molecular features were observed in group 1. CONCLUSION: GCs are found in minority of naïve, newly diagnosed, GBM cases in adults. They seem to carry minimal implications on daily clinical practice. Higher percentage of GCs is associated with distinct radiological features such as multifocality that might be correlated with decreased OS. High-percentage GC-GBMs are also associated with increased prevalence of isocitrate dehydrogenase (IDH) mutations.

Differences in RNA and microRNA Expression Between PTCH1- and SUFU-mutated Medulloblastoma.

BACKGROUND/AIM: Germline mutations in PTCH1 or SUFU in the sonic hedgehog (SHH) pathway cause Gorlin's syndrome with increased risk of developing SHH-subgroup medulloblastoma. Gorlin's syndrome precludes the use of radiotherapy (a standard component of treatment) due to the development of multiple basal cell carcinomas. Also, current SHH inhibitors are ineffective against SUFU-mutated medulloblastoma, as they inhibit upstream genes. In this study, we aimed to detect differences in the expression of genes and microRNAs between SUFU- and PTCH1-mutated SHH medulloblastomas which may hint at new treatment directions. PATIENTS AND METHODS: We sequenced RNA and microRNA from tumors of two patients with germline Gorlin's syndrome - one having PTCH1 mutation and one with SUFU mutation - followed by bioinformatics analysis to detect changes in genes and miRNAs expression in these two tumors. Expression changes were validated using qRT-PCR. Ingenuity pathway analysis was performed in search for targetable pathways. RESULTS: Compared to the PTCH1 tumor, the SUFU tumor demonstrated lower expression of miR-301a-3p and miR-181c-5p, matrix metallopeptidase 11 (MMP11) and OTX2, higher expression of miR-7-5p and corresponding lower expression of its targeted gene, connexin 30 (GJB6). We propose mechanisms to explain the phenotypic differences between the two types of tumors, and understand why PTCH1 and SUFU tumors tend to relapse locally (rather than metastatically as in other medulloblastoma subgroups). CONCLUSION: Our results help towards finding new treatable molecular targets for these types of medulloblastomas.

Fulminant presentation of a SMARCB1-deficient, anterior cranial fossa tumor in adult.

BACKGROUND: Malignant atypical teratoid rhabdoid tumor (ATRT) usually develops in children. ATRTs are rare in adults, with only one case in the literature describing involvement of the anterior skull base. These primary intracranial tumors are characterized molecularly as SMARCB1 (INI1) deficient. Different types of such SMARCB1-deficient tumors exist in adulthood, usually in the form of extracranial tumors. Very few cases of such a new entity, named SMARCB1-deficient sinonasal carcinoma have been described with intracranial penetration and involvement of the anterior cranial fossa. CASE DESCRIPTION: A 36-year-old male presented with acute cognitive deterioration. Over few hours, he developed a fulminant herniation syndrome. Imaging showed a tumor in the anterior cranial fossa surrounded by massive brain edema. The tumor has destroyed the frontal bone with involvement of the nasal cavities and paranasal sinuses. The patient underwent emergent decompressive craniectomy and tumor debulking but could not be saved. Pathological analysis revealed a highly cellular tumor without rhabdoid cells but with areas of necrosis. Further immunohistochemical stains revealed that neoplastic cells were diffusely and strongly positive for epithelial membrane antigen and P63 and negative for SMARCB1 (i.e., loss of expression), confirming the diagnosis of sinonasal carcinoma. CONCLUSION: To the best of our knowledge, this is the first report of a fulminant presentation of a SMARCB1- deficient tumor in young adult, involving the anterior cranial fossa and the paranasal sinuses. The main differential diagnosis of aggressive, primary, intracranial SMARCB1-deficient tumors in adults includes ATRT, SMARCB1- deficient sinonasal carcinoma, rhabdoid meningioma, and rhabdoid glioblastoma. Atypical tumors involving the anterior skull base without a clear histopathological pattern should therefore be checked for SMARCB1 expression.

Elastofibroma at the scapular region.

BACKGROUND: Elastofibroma is a rare type of lesion consisting of elastic fibers within a stroma of collagen and fatty tissue. It is usually located on the lower scapular region attached firmly to the thoracic cage, often causing debilitating pain. Its clinical presentation mimics a soft tissue tumor. OBJECTIVES: To evaluate the diagnosis and treatment results of elastofibroma. METHODS: Clinical and radiographic evaluations were performed in 11 patients with thoracic wall mass. In five of them a biopsy was taken before surgery. All patients were operated and the diagnosis of elastofibroma was confirmed by histology. RESULTS: Two patients had a postoperative seroma that resolved spontaneously within a few days. All patients reesumed their preoperative activities, including sports. CONCLUSIONS: Considering the slow-growing nature of this tumor and its typical presentation, we believe that when this diagnosis is suspected, investigation does not necessitate staging (as in sarcomas). Also, marginal surgical excision is sufficient. Observation is an acceptable alternative to surgery.

Laparoscopic sleeve gastrectomy with minimal morbidity. Early results in 120 morbidly obese patients.

BACKGROUND: In recent years, laparoscopic sleeve gastrectomy (LSG) as a single-stage procedure for the treatment of morbid obesity is becoming increasingly popular. Of continuing concern are the rate of postoperative complications and the lack of consensus as to surgical technique. METHODS: A prospective study assessment was made of 120 consecutive morbidly obese patients with body mass index (BMI) of 43+/-5 (30 to 63), who underwent LSG using the following technique: (1) division of the vascular supply of the greater gastric curvature and application of the linear stapler-cutter device beginning at 6-7 cm from the pylorus so that part of the antrum remains; (2) inversion of the staple line by placement of a seroserosal continuous suture close to the staple line; (3) use of a 48 Fr bougie so as to avoid possible stricture; (4) firing of the stapler parallel to the bougie to make the sleeve as narrow as possible and prevent segmental dilatation. RESULTS: Intraoperative difficulties were encountered in four patients. There were no postoperative complications-no hemorrhage from the staple line, no anastomotic leakage or stricture, and no mortality. In 20 patients prior to the sleeve procedure, a gastric band was removed. During a median follow-up of 11.7 months (range 2-31 months), percent of excess BMI lost reached 53+/-24% and the BMI decreased from 43+/-5 to 34+/-5 kg/m(2). Patient satisfaction scoring (1-4) at least 1 year after surgery was 3.6+/-0.8. CONCLUSIONS: The good early results obtained with the above-outlined surgical technique in 120 consecutive patients undergoing LSG indicate that it is a safe and effective procedure for morbid obesity. However, long-term results are still pending.

Laparoscopic sleeve gastrectomy--volume and pressure assessment.

BACKGROUND: Aiming to clarify the mechanism of weight loss after the restrictive bariatric procedure of sleeve gastrectomy (LSG), the volumes and pressures of the stomach, of the removed part, and of the remaining sleeve were measured in 20 morbidly obese patients. METHODS: The technique used consisted of occlusion of the pylorus with a laparoscopic clamp and of the gastroesophageal junction with a special orogastric tube connected to a manometer. Instillation of methylene-blue-colored saline via the tube was continued until the intraluminal pressure increased sharply, or the inflated stomach reached 2,000 cc. After recording of measurements, LSG was performed. RESULTS: Mean volume of the entire stomach was 1,553 cc (600-2,000 cc) and that of the sleeve 129 cc (90-220 cc), i.e., 10% (4-17%) and that of the removed stomach was 795 cc (400-1,500 cc). The mean basal intragastric pressure of the whole stomach after insufflations of the abdominal cavity with CO(2) to 15 mmHg was 19 mmHg (11-26 mmHg); after occlusion and filling with saline it was 34 mmHg (21-45 mmHg). In the sleeved stomach, mean basal pressure was similar 18 mmHg (6-28 mmHg); when filled with saline, pressure rose to 43 mmHg (32-58 mmHg). The removed stomach had a mean pressure of 26 mmHg (12-47 mmHg). There were no postoperative complications and no mortality. CONCLUSIONS: The notably higher pressure in the sleeve, reflecting its markedly lesser distensibility compared to that of the whole stomach and of the removed fundus, indicates that this may be an important element in the mechanism of weight loss.

Sporadic desmoid tumors in the pediatric population: A single center experience and review of the literature.

BACKGROUND/PURPOSE: We present our long experience with desmoid tumors in children. METHODS: Data were retrospectively collected from 17 children/adolescents treated for sporadic desmoid tumors at a tertiary pediatric hospital in 1988-2016. There were 10 girls and 7 boys aged 1-17years. Tumor sites included head and neck, trunk, extremity, and groin. Eight patients underwent radical resection, with complete remission in 7 and local relapse in one which was treated with chemotherapy. Four patients underwent incomplete surgical resection, three with adjuvant chemotherapy. Five patients underwent biopsy only and chemotherapy. Two of the 9 chemotherapy-treated patients also had intraarterial chemoembolization. Chemotherapy usually consisted of vincristine and actinomycin-D with or without cyclophosphamide or low-dose vinblastine and methotrexate. Two patients also received tamoxifen. RESULTS: After a median follow-up of 3.3years, 10 patients were alive in complete remission, 5 had stable disease, and 2 had reduced tumor size. Five-year overall survival was 100%, and event-free survival, 87.5%. Ten were screened for CTNNB1 mutations. CTNNB1 gene sequencing yielded mutations in 5/10 samples tested: 3 T41A, 2 S45F. There was no association of CTNNB1 mutation with clinical outcome or prognosis. CONCLUSION: Pediatric desmoid tumors are rare, with variable biologic behavior and morbidity. Treatment requires a multidisciplinary approach. LEVEL OF EVIDENCE: LEVEL IV, treatment study.

Histological changes in the gastric mucosa after Helicobacter pylori eradication.

BACKGROUND AND AIM: Correa described a stepwise model of changes in the gastric mucosa after Helicobacter pylori infection, from the normal gastric epithelium to chronic gastritis, atrophy, intestinal metaplasia, dysplasia and adenocarcinoma. The aim of this study is to assess the reversibility of these mucosal changes after H. pylori eradication. METHODS: The study sample consisted of 89 patients who underwent at least two gastric biopsies from 1990 to 2000, with a positive finding for H. pylori in the first and a negative finding in the second. Specimens were evaluated for acute and chronic inflammation, lymphoid aggregates, proliferation, mucosal atrophy, intestinal metaplasia, dysplasia, and MUC5AC and MUC6 expression using histochemical and immunohistochemical methods. RESULTS: The average time between biopsies was 23.15 +/- 26.30 months. There was a significant decrease in acute and chronic inflammation scores, from 1.48 +/- 1.10 to 0.23 +/- 0.63 and from 2.67 +/- 0.68 to 1.44 +/- 1.04, respectively (P < 0.001), and in a number of lymphoid follicles, from 42.68% to 21.95% of cases (P < 0.008). The number of glands increased from 39.08 +/- 16.67/mm to 48.86 +/- 17.93/mm after eradication (P = 0.062). Intestinal metaplasia was found in 17.07% of the cases, with no change over time. Dysplasia appeared in one case 2 years after eradication. In 27 patients, the Ki67 labeling index decreased significantly after eradication, while MUC5AC and MUC6 expression increased. CONCLUSION: Our findings, although not conclusive for arrest of the malignant potential, support the importance of H. pylori eradication in the prevention of gastric cancer.

Differential expression of proliferation- and apoptosis-related markers in lentigo maligna and solar keratosis keratinocytes.

Keratinocytes influence the number, morphology, and proliferation of melanocytes. An interference in the melanocyte-keratinocyte relationship may contribute to melanoma development. This study examined the expression of apoptotic and proliferative markers in keratinocytes in lentigo maligna to characterize the epidermis permissive to these lesions. Formalin-fixed and paraffin-embedded tissues from 25 samples of lentigo maligna, 20 samples of solar keratoses, and 5 samples each of normal sun-exposed and non-sun-exposed skin (controls) were immunostained with antibodies directed against the proapoptotic markers bax and p53, the antiapoptotic marker bcl-2, and the proliferation marker ki-67. Eight percent of the lentigo maligna samples were positive for keratinocyte expression of bcl-2, 24% were positive for p53, and 76% were positive for bax; respective findings for solar keratoses were 35%, 85%, and 90%. Comparison with normal sun-exposed skin yielded lower rates of keratinocyte proliferation in 56% of the lentigo maligna samples, similar rates in 36%, and higher rates in 8%; for solar keratoses, proliferation was higher than controls in 60% of samples, similar in 35%, and lower in 5%. All these differences were statistically significant. These findings indicate that there are variable patterns of epidermal reaction to chronic sun exposure. The epidermis in lentigo maligna shows overall low proliferation and an apparently low apoptotic tendency. The dysfunctional epidermis may be permissive to aberrant melanocyte proliferation in the early stages of melanoma development.