Prognostic value of ALK overexpression and molecular abnormalities in high-grade serous ovarian carcinoma.

BACKGROUND: ALK receptor tyrosine kinase (ALK) aberrations have an established role in pathogenesis of many neoplasms, but their clinical significance in high grade serous ovarian carcinoma (HGSOC) is unclear. OBJECTIVE: To analyse the frequency of ALK overexpression, molecular abnormalities of ALK, and their impact on the progression-free survival (PFS) and overall survival (OS) in HGSOC. METHODS: Protein expression was examined by immunohistochemistry (IHC) using three different clones of anti-ALK antibody. The presence of translocations was analysed using fluorescent in situ hybridization. Next-generation sequencing was used for studying the copy number variation, as well as point mutation and translocations involving other commonly rearranged genes. RESULTS: ALK overexpression was demonstrated in up to 52% of tumours, whereas ALK copy gains in 8.2%, with no clear impact on survival. ALK point mutations were identified in 13 tumours (8.9%), with 3 belonging to the class IV showing significantly better OS. A trend suggesting better PFS was also noticed in these cases. Additionally, three gene fusions were found: ERBB2-GRB7, PRKCA-BRCA1 and SND1-BRAF, none of which has been previously described in HGSOC. CONCLUSIONS: HGSOC harbouring activating ALK mutations might be associated with a better survival, while ALK overexpression and ALK amplification does not impact the prognosis.

Clinical, Dermoscopic, and Histological Characteristics of Melanoma Patients According to the Age Groups: A Retrospective Observational Study.

BACKGROUND: Although the role of melanoma risk factors is well documented, their correlation with patients' age is less frequently analyzed. METHOD: The analysis was performed among 189 melanoma patients in different age groups, including <30 years, 31-60 years, and >60 years, to investigate the risk factors, topography, and coexistence of morphological features of 209 melanomas (dermoscopic and histopathological). RESULTS: Among the youngest age group, no correlation with the presence of estimated risk factors was found. The most common dermoscopic pattern was spitzoid and multicomponent asymmetric. The group of middle-aged patients was the most diverse in terms of the occurrence of risk factors, solar lentiginosis, dermoscopic patterns, topography, histological subtypes, and invasiveness of melanomas. The oldest group characterized a strong correlation between solar lentiginosis, NMSC comorbidity, the prevalence of facial melanomas, the dermoscopic pattern of melanoma arising on chronic sun-damaged skin, and regression. CONCLUSION: The findings regarding the presence of age-specific features in melanoma patients, especially in the youngest and middle-aged groups, might be helpful for clinicians and to target secondary prevention efforts.

Delay in Diagnosis of Autoimmune Polyendocrine Syndrome Type 2 as a Consequence of Misinterpretation of Gastrointestinal Symptoms.

Background: Type 2 autoimmune polyendocrine syndrome (APS-2) is characterized by the presence of at least two of three endocrinopathies: Addison's disease, autoimmune thyroiditis, and diabetes type 1. The prevalence of APS-2 is estimated to be 1 : 1000 to 1 : 20.000 in the general population. Diagnosis of APS-2 often is delayed due to its rarity and wide spectrum of clinical symptoms. Case Presentation. A 27-year-old presented with a 6-month history of abdominal pain, vomiting, diarrhea, weakness, fatigue, and 15 kg of weight loss. The patient was diagnosed with Crohn's disease in a local hospital and referred to our institution because of treatment failure. Colonoscopy performed in this hospital identified irregular mucosal erosions in terminal ileum, and the microscopy of biopsy specimens demonstrated nonspecific inflammation. On physical examination, the patient appeared cachectic. Blood pressure was 90/60 mmHg. Laboratory results were significant for severe hyponatremia and mild hyperkalemia. Morning cortisol was low, and adrenocorticotropic hormone (ACTH) concentration was high. An ACTH stimulation test did not present any increase in serum cortisol, which confirmed primary adrenal insufficiency. Antithyroid peroxidase antibody (anti-TPO) as well as both anti-21-hydroxylase antibodies and antiglutamic acid decarboxylase antibodies (GAD65) were positive. So, the diagnosis of APS-2 was made, and the replacement doses of hydrocortisone and fludrocortisone has brought a rapid improvement in all clinical symptoms; colonoscopy showed normal. Conclusion: The case presented herein highlights rapidly progressive nature of untreated APS-2 and that the diagnosis of APS-2 may be challenging.

Tonsillectomy in own material.

<b>Introduction:</b> Tonsillectomy belongs to the most frequently performed surgical treatments; however, the necessity of its performance is questioned. Therefore, there are many attempts to unify and define the indications for the procedure. <br><b>Aim:</b> The main objective of the current dissertation was an analysis of the clinical symptoms occurring in patients qualified for tonsillectomy, as well as a comparison of those with a histopathological image of the removed tonsils in a repeatedly carried out, unified pathomorphological examination. The secondary objective was the designation of the demographic profile, existing comorbidities, and complications in the form of postoperative bleeding in patients after tonsillectomy in own material. <br><b>Material and method:</b> A retrospective analysis of 301 procedures of palatine tonsil removal was performed, which were completed in the years 2017-2019 at the Department of Otolaryngology with Division of Cranio-Maxillo-Facial Surgery of the Military Institute of Medicine, Warsaw, Poland. The indications were defined on the grounds of data from the anamnesis. Based on unified criteria, the removed material was divided into 2 groups: with the signs of Chronic Tonsillitis (CT) as well as Tonsillar Hyperthrophy (TH). <br><b>Results:</b> The average size of tonsils was the greatest in a group of patients under 35 years of age, and smallest in the group over 51 years of age. As patients aged, the reduction in size of the palatal tonsils was observed. In the examined group, the histopathological diagnosis in the form of HT was found in 165 patients (54.8%), while CT in 136 (45.2%). It was proven that the larger the tonsils in the clinical picture, the more often the histopathological image responded to HT. Among clinical symptoms reported by patients qualified for tonsillectomy, the following were observed: recurring tonsil inflammation in 211 (70.1%), snoring and sleep apnea in 47 (15.6%), as well as sleep apnea in 33 (11%) patients. Primary bleeding occurred in 10 patients (3.34%), and secondary in 8 patients (2.66%). The most common comorbidities were cardiovascular burdens. <br><b>Conclusions:</b> For most cases, clinical symptoms were confirmed by adequate features of removed material in histopathological examination. The most common histopathological diagnosis was tonsillar hyperthrophy.

Selected protein expression in a new prognostic model for patients with non-muscle-invasive bladder cancer.

INTRODUCTION: After transurethral resection of a bladder tumor, patients frequently have a recurrence of the disease, thereby requiring adjuvant therapy. PURPOSE: The study aimed to determine the prognostic value of expression levels of p53, Ki-67, and survivin, and to develop a new prognostic model for patients with non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of a bladder tumor. METHODS: The study group consisted of 101 patients with primary NMIBC. Univariate followed by multivariate Cox proportional hazard regression analysis was performed to obtain a model including the smallest possible number of descriptive variables with the highest statistical significance and impact on risk. RESULTS: The RECINT model (RECurrence In Not Treated) including factors independently associated with cancer recurrence (tumor size [HR 1.148; p = 0.034], intensity of the color reaction for p53 [HR 1.716; p = 0.008], Ki-67 [HR 3.001; p = 0.022], and survivin [HR 1.461; p = 0.021]) adequately stratified recurrence free-survival (R2 = 0.341, p < 0.001) in patients with primary NMIBC. Patients with the lowest RECINT score (0-6) had the lowest probability of cancer recurrence (1- and 5-year recurrence of 16%) in comparison with other groups (p < 0.001). CONCLUSIONS: The RECINT model may be useful for stratifying the risk of recurrence in patients with non-muscle-invasive bladder cancer and may allow for identification of those who may benefit the most from adjuvant BCG immunotherapy.

Intensity of Nuclear Staining for Ki-67, p53 and Survivin as a New Prognostic Factor in Non-muscle Invasive Bladder Cancer.

The aim of the study was to determine the prognostic value of expression levels of biomarkers selected on the basis of the literature: p53, Ki-67, survivin, ß-catenin, E-cadherin and N-cadherin in patients with non-muscle invasive bladder cancer. Immunohistochemistry was performed on sections of primary papillary carcinoma of the bladder removed during transurethral resection of the tumor in 134 patients. The expression of ß-catenin and E-cadherin was found in all analyzed cases and N-cadherin expression was demonstrated in 3.73% of the tissues examined. The expression of the p53 protein was confirmed in 96.27% of tissues examined. The expression of the Ki-67 protein was demonstrated in all analyzed cases. Survivin expression was found in 95.52% of the study group. Multivariate analysis confirmed the relationship between the recurrence-free survival (RFS) and the intensity of the nuclear reaction for p53 (HR 1417, 95% CI 1.001-2.007, p = 0.049) and survivin (HR 1.451; 95% CI 1.078-1.955; p = 0.014), the expression level of the Ki-67 protein expressed by the TS index (HR 1.146, 95% CI 1.116-1.823, p = 0.005) and the use of adjuvant BCG therapy (HR 0.218, 95% CI 0.097-0.489, p = 0.0002). The evaluation of Ki-67 expression and the intensity of nuclear staining for survivin and p53 may provide additional information that will allow more accurate stratification of the risk of NMIBC recurrence after TURBT.

Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma.

Tumor-driven immune suppression is a major barrier to successful immunotherapy in ovarian carcinomas (OvCa). Among various mechanisms responsible for immune suppression, arginase-1 (ARG1)-carrying small extracellular vesicles (EVs) emerge as important contributors to tumor growth and tumor escape from the host immune system. Here, we report that small EVs found in the ascites and plasma of OvCa patients contain ARG1. EVs suppress proliferation of CD4+ and CD8+ T-cells in vitro and in vivo in OvCa mouse models. In mice, ARG1-containing EVs are transported to draining lymph nodes, taken up by dendritic cells and inhibit antigen-specific T-cell proliferation. Increased expression of ARG1 in mouse OvCa cells is associated with accelerated tumor progression that can be blocked by an arginase inhibitor. Altogether, our studies show that tumor cells use EVs as vehicles to carry over long distances and deliver to immune cells a metabolic checkpoint molecule - ARG1, mitigating anti-tumor immune responses.

Convolutional neural networks can accurately distinguish four histologic growth patterns of lung adenocarcinoma in digital slides.

During the diagnostic workup of lung adenocarcinomas (LAC), pathologists evaluate distinct histological tumor growth patterns. The percentage of each pattern on multiple slides bears prognostic significance. To assist with the quantification of growth patterns, we constructed a pipeline equipped with a convolutional neural network (CNN) and soft-voting as the decision function to recognize solid, micropapillary, acinar, and cribriform growth patterns, and non-tumor areas. Slides of primary LAC were obtained from Cedars-Sinai Medical Center (CSMC), the Military Institute of Medicine in Warsaw and the TCGA portal. Several CNN models trained with 19,924 image tiles extracted from 78 slides (MIMW and CSMC) were evaluated on 128 test slides from the three sites by F1-score and accuracy using manual tumor annotations by pathologist. The best CNN yielded F1-scores of 0.91 (solid), 0.76 (micropapillary), 0.74 (acinar), 0.6 (cribriform), and 0.96 (non-tumor) respectively. The overall accuracy of distinguishing the five tissue classes was 89.24%. Slide-based accuracy in the CSMC set (88.5%) was significantly better (p < 2.3E-4) than the accuracy in the MIMW (84.2%) and TCGA (84%) sets due to superior slide quality. Our model can work side-by-side with a pathologist to accurately quantify the percentages of growth patterns in tumors with mixed LAC patterns.

Role of WNT/ß-Catenin Pathway as Potential Prognostic and Predictive Factors in Renal Cell Cancer Patients Treated With Everolimus in the Second and Subsequent Lines.

BACKGROUND: The aim of the present study was to search for predictive and prognostic factors in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus among the components of the WNT/ß-catenin pathway. PATIENTS AND METHODS: In a prospective, single-arm, phase II study, patients with mRCC received everolimus (10 mg/d) in a 30-day cycle. We performed a prospectively planned evaluation of the potential biomarkers of the WNT/ß-catenin pathway. RESULTS: The serum level of soluble E-cadherin (sE-cadherin) in patients with RCC was significantly greater than that in the controls (71.62 ± 22.28 pg/mL vs. 54.26 ± 10.317 pg/mL; P = .0069). After 2 cycles of everolimus therapy, we observed a significance increase in sE-cadherin (from 71.81 ± 21.18 pg/mL to 77.50 ± 28.212 pg/mL; P = .0151). The Dickkopf-1 protein levels in the study and control groups were not significantly different (P = .2135). The favorable independent predictors for everolimus therapy were normal lactate dehydrogenase level before treatment (hazard ratio [HR], 0.52; 95% confidence interval [CI], 0.28-0.98; P = .0443) and low sE-cadherin level (HR, 0.54; 95% CI, 0.29-0.98; P = .0422). On multivariate analysis, we observed that worse overall survival was seen in patients with a lower regression coefficient of sE-cadherin after 2 cycles of treatment (HR, 2.60; 95% CI, 1.23-5.52; P = .0128), an increased corrected calcium level (HR, 3.09; 95% CI, 1.21-7.88; P = .0180), and an increased lactate dehydrogenase level before treatment (HR, 1.98; 95% CI, 1.02-3.83; P = .0426). CONCLUSION: WNT/ß-catenin component expression in patients with mRCC had no effect on progression-free survival or overall survival. However, we found that the sE-cadherin level might interact with response to everolimus therapy, although confirmation in future studies is needed.

Cystatin C as a predictor factor in patients with renal cell carcinoma treated by everolimus.

BACKGROUND: We evaluated the influence of serum cystatin C (CysC) with respect to other glomerular filtration rate (GFR) markers on the treatment effect of everolimus in a phase II study in patients with metastatic renal cell carcinoma (mRCC). MATERIALS AND METHODS: Outcomes were from the study's primary analysis. GFR was calculated according to CKD-EPI-sCr equation, CKD-EPI-CysC equation and CKD-EPI-sCr-CysC equation, Modification of Diet in Renal Disease (MDRD) equation and Cockcroft-Gault (CG) equation, serum levels of creatinine (sCr) and CysC before the treatment. RESULTS: We observed in 56 patients analysed patients high correlation (R Spearman from ±0.69 to ±1.00; P < 0.0001) between CysC level and GFR markers: sCr, CKD-EPI-sCr, CKD-EPI-CysC, CKD-EPI-sCr-CysC, MDRD, GFR (CG) before everolimus therapy. We observed that the adverse independent predictors for everolimus therapy were increased CysC level [HR: 2.85 (95 % CI 1.34-6.05), P = 0.0065], histologic grade G1/2 [HR: 3.38 (95 % CI 1.59-7.20), P = 0.0016] and increased LDH level [HR: 5.59 (95 % CI 2.52-12.40), P < 0.0001]. Worse OS was seen in multivariate analysis in patients with increased cystatin C level before treatment [HR: 2.60 (1.03-2.60), P = 0.0428], increased corrected calcium level [HR: 2.78 (95 % CI 1.03-7.54), P = 0.0441] and increased LDH level before treatment [HR: 2.34 (95 % CI 1.11-4.97), P = 0.0262]. CONCLUSION: Increased serum CysC level in contrast to other studied GFR markers had predictive significance in patients with mRCC.

Functional Assessment of Synoptic Pathology Reporting for Ovarian Cancer.

BACKGROUND: Ovarian cancer has one of the highest death/incidence rates and is commonly diagnosed at an advanced stage. In the recent WHO classification, new histotypes were classified which respond differently to chemotherapy. The e-standardized synoptic cancer pathology reports offer the clinicians essential and reliable information. The aim of our project was to develop an e-template for the standardized synoptic pathology reporting of ovarian carcinoma [based on the checklist of the College of American Pathologists (CAP) and the recent WHO/FIGO classification] to introduce a uniform and improved quality of cancer pathology reports. A functional and qualitative evaluation of the synoptic reporting was performed. METHODS: An indispensable module for e-synoptic reporting was developed and integrated into the Hospital Information System (HIS). The electronic pathology system used a standardized structure with drop-down lists of defined elements to ensure completeness and consistency of reporting practices with the required guidelines. All ovarian cancer pathology reports (partial and final) with the corresponding glass slides selected from a 1-year current workflow were revised for the standard structured reports, and 42 tumors [13 borderline tumors and 29 carcinomas (mainly serous)] were included in the study. RESULTS: Analysis of the reports for completeness against the CAP checklist standard showed a lack of pTNM staging in 80% of the partial or final unstructured reports; ICD-O coding was missing in 83%. Much less frequently missed or unstated data were: ovarian capsule infiltration, angioinvasion and implant evaluation. The e-records of ovarian tumors were supplemented with digital macro- and micro-images and whole-slide images. CONCLUSIONS: The e-module developed for synoptic ovarian cancer pathology reporting was easily incorporated into HIS.CGM CliniNet and facilitated comprehensive reporting; it also provided open access to the database for concerned recipients. The e-synoptic pathology reports appeared more accurate, clear and conclusive than traditional narrative reports. Standardizing structured reporting and electronic tools allows open access and downstream utilization of pathology data for clinicians and tumor registries.

Minimally invasive transnasal approach for primary ectopic meningioma of the paranasal sinuses.

Endoscopic sinus surgery is a standard procedure in the treatment of various pathologies such as chronic sinusitis or some types of neoplasms. The transnasal approach to tumours of paranasal sinuses is favourable due to functional and aesthetic reasons. We report a rare case of a large primary ectopic meningioma of the paranasal sinuses in a 48-year-old woman referred to the Otolaryngology Clinic due to the incidental finding of a pathologic mass visualised on the orthopantomography picture. After diagnosis, the patient was successfully treated with radical transnasal surgery performed under endoscopic vision. In a 1-year follow-up there were no signs of tumour recurrence.

Survivin expression as a prognostic factor in patients with epithelial ovarian cancer or primary peritoneal cancer treated with neoadjuvant chemotherapy.

BACKGROUND: The aim of this study was to evaluate association of expression of survivin and p53 with the effects of neoadjuvant chemotherapy (NAC) in patients with advanced ovarian cancer (AOC). METHODS: We retrospectively evaluated 60 consecutive patients with AOC (International Federation of Gynecology and Obstetrics stage IIIC-IV) treated with NAC. The expression of p53 and survivin was assessed immunohistochemically. The median of expression total score survivin equals 2 was adopted to dichotomize the group. The positive and negative expression of p53 was used to dichotomize the group. RESULTS: The expression of survivin in tumor tissue taken before and after NAC was a significant difference in the percentage of stained nuclei (P = 0.0002), the intensity of staining (P = 0.0003), and total score (P = 0.0001). There was a significant difference in p53 expression in tumor tissue before and after NAC in the percentage of stained nuclei (P = 0.0424). Survivin expression, in contrast to p53 expression, was a prognostic factor in patients with AOC treated with NAC (P = 0.0484). The expression of survivin and p53 was not a predictive factor. Independent adverse predictor factors were as follows: lack of optimal interval debulking surgery and the lack of an objective response (the respective hazard ratio was 3.93 [95% confidence interval, 2.07-7.46; P < 0.0001] and 2.36 [95% confidence interval,1.25-4.47; P = 0.0080]). The suboptimal range of interval debulking surgery, resistance to platinum, and the lack of paclitaxel in the NAC were adverse prognostic factors (the respective hazard ratio was 2.61 [95% confidence interval, 1.17-5.83], 2.72 [95% confidence interval, 1.07-6.89], and 2.56 [95% confidence interval, 1.06-6.18]; P < 0.05]). CONCLUSIONS: High expression of survivin could be a prognostic factor in patients treated with NAC for AOC.

Wnt/ß-catenin pathway as a potential prognostic and predictive marker in patients with advanced ovarian cancer.

BACKGROUND: ß-catenin is the key protein in the WNT signalling pathway and it forms adherent junctions together with E-cadherin. In ovarian carcinoma, abnormal expression of ß-catenin, E-cadherin and WNT-1 was observed, but their prognostic and predictive role is unclear. The aim of this study was to clarify the prognostic and predictive role of E-cadherin, ß-catenin and WNT-1 in advanced epithelial ovarian carcinoma (AEOC). METHODS: The expression of E-cadherin, ß-catenin and WNT-1 was determined by immunohistochemistry in AEOC. The correlation between expression of these proteins and progression-free survival (PFS) and overall survival (OS) was evaluated. Statistical analyses included Kaplan-Meier estimation, log-rank test, Spearman correlation and Cox proportional-hazards model. RESULTS: In ovarian cancer, intense expression of E-cadherin, ß-catenin and WNT-1 was found. In multivariate analysis, strong membrane ß-catenin expression was an independent unfavourable predictor for PFS (HR 2.19, 95% CI 1.09-4.39; p = 0.028), while in univariate analysis, strong membrane ß-catenin expression was a prognostic factor for OS in patients with AOC (p = 0.039). In multivariate analysis, only resistance to first-line chemotherapy was an adverse independent prognostic factor for OS (HR 16.84; 95% CI 5.07-55.98; p < 0.0001). Additionally, strong membranous ß-catenin expression was associated with resistance to platinum-based chemotherapy (p = 0.027). CONCLUSIONS: These findings support that WNT/ß-catenin pathway and E-cadherin are important factors in advanced epithelial ovarian cancer.