Comparison of PD-L1, VISTA, LAG-3, and GAL-3 Expressions and Their Relationships to Mismatch Repair Protein and p53 Expression in 529 Cases of Endometrial Carcinoma.

The aim of this study is to evaluate the expressions of programmed death-ligand 1 (PD-L1), V-domain Ig suppressor of T-cell activation (VISTA), lymphocyte activation gene-3 (LAG-3), and galectin-3 (GAL-3), in mismatch repair-deficient (MMRd)/MMR-proficient and abnormal p53 expressing endometrial carcinomas and their relationship with clinical-histopathological features. Patients who underwent surgery for endometrial carcinoma between January 2008 and December 2018 were included in the study. Immunohistochemical analysis of MLH1, PMS2, MSH2, MSH6, p53, PD-L1, VISTA, LAG-3, and GAL-3 was performed on the tissue samples of microarray. A total of 529 patients were included. MMRd and p53-mutant tumors accounted for 31.5% and 11.5% of cases, respectively. PD-L1 and LAG-3 expressions in the MMRd and p53-mutant groups were higher than in the MMR-proficient group (P < 0.001). GAL-3 expression in the MMR-proficient group was statistically higher than in the MMRd and p53-mutant groups (P < 0.001). Mean age, grade, International Federation of Gynecology and Obstetrics stage, lymphovascular invasion, and lymph node metastasis were significantly higher in the p53-mutant group (P < 0.001). In the group with PD-L1 expression, nonendometrioid histologic type, tumor grade, and lymphovascular invasion were significantly higher (P < 0.001). Tumor grade, lymphovascular invasion, lymph node metastasis, and microcystic, elongated and fragmented pattern of invasion were significantly higher in the group with high VISTA expression (P < 0.05). Tumor grade was significantly higher in the group with LAG-3 expression (P < 0.001). Immunohistochemically determined subgroups and PD-L1, VISTA, LAG-3, and GAL-3 expression levels may be useful indicators of molecular features, and clinical outcomes also may have important implications for the development of targeted therapies in endometrial carcinoma.

Acquired Perforating Dermatosis: Clinical and Histopathological Analysis of 95 Patients From One Center.

INTRODUCTION: Acquired perforating dermatosis (APD) is a disease group characterized by transepidermal elimination of dermal connective tissue materials such as collagen, elastic fibers, and keratin through the epidermis and observed with pruritic skin lesions. OBJECTIVES: In this study, we aim to clarify the clinical, histopathological, and dermoscopic characteristics of APD, identify the associated systemic disease, and figure out treatment options. METHODS: This study was designed as a single-center retrospective, observational, cross-sectional study. We evaluated all accessible APD cases between January 2004 and June 2022 in a tertiary care hospital. RESULTS: A total of 95 patients with confirmed APD were included in the study. Sixty percent of the patients were women and 40% were men. The median age at diagnosis was 63.1 years (35-85 years). The most common site of lesions was the lower extremities which were detected in 86.31% of the patients. The concomitant systemic disease was identified in 84.21% of the patients. The most common systemic disease was type 2 diabetes mellitus (65.26%). Antihistamines and topical corticosteroids were the most commonly prescribed treatment agents. CONCLUSIONS: Transepidermal elimination of dermal connective tissue components is a feature of APD and the disease usually presents with pruritic papules and nodules with central keratotic crust or plug. The diagnosis of APD requires a clinical examination and histological investigation. APD is usually accompanied by systemic comorbidities. There are several topical and systemic medications available for APD, however, sometimes the therapy might be challenging.

Il-6 and MSH3 in colorectal carcinoma: Expression, relationship, and prognostic significance in 171 colorectal carcinoma cases.

AIMS: Colorectal cancer (CRC), the most common type of gastrointestinal cancer, mostly develops as a result of environmental factors. Inflammation is a relatively uncommon but crucial contributor to its etiology, and inflammation is also thought to pose a risk in patients without a clinical diagnosis of inflammatory bowel disease. In cell lines, the proinflammatory cytokine interleukin-6 (IL-6) causes a cytosolic shift in the mismatch repair protein MSH3, accompanied by functional loss. This study aimed to evaluate IL-6 and MSH3 expression in 171 sporadic CRC samples by immunohistochemistry (IHC). High levels of IL-6 are hypothesized to cause MSH3 expression loss. We also explored the clinical/pathological aspects of IHC-detected MSH3 loss and the relationship between MSH3 expression and tumor-infiltrating lymphocytes (TILs). MATERIALS AND METHODS: IL-6 and MSH3 IHC and H and E slides were evaluated by two pathologists. Clinical data were obtained from the institution's database. RESULTS: A relationship between MSH3 loss and IL-6 expression was not proven (P = 0.963). MSH3 staining was significantly reduced in the patient group with high TILs (P = 0.035). We observed 104 CRC cases (60.8%) with IL-6 expression and 85 cases (49.7%) with reduced MSH3 expression. CONCLUSION: This study did not demonstrate an association between IL-6 and MSH3 expression. As MSH3 is a relatively little-known protein, further large-scale studies are needed. The use of IHC to identify patients who may benefit from anti-IL-6 therapies in CRC in the future may be critical.

Immunohistochemical Approach to Mismatch Repair Deficiency in Pediatric High-Grade Glioma.

Knowledge of the molecular pathways of pediatric high-grade gliomas is increasing. Gliomas with mismatch repair deficiency do not currently comprise a distinct group, but data on this topic have been accumulating in recent publications. Immunohistochemistry can effectively determine mismatch repair status, indirectly suggesting the microsatellite instability of the tumor. This study aimed to determine the number of mismatch repair-deficient pediatric high-grade gliomas in a tertiary institution and assess the relationship between the survival and mismatch repair status of the patients. It also aimed to assess the potential for further clinical studies including immunotherapy. Of 24 patients with high-grade gliomas, 3 deceased patients were mismatch repair-deficient. Mismatch repair deficiency was significantly associated with shorter survival (P=0.004). Immunotherapy trials need to progress, and patients with mismatch repair-deficient pediatric high-grade gliomas are the most suitable candidates for such studies.

Ki67 Tumor Expression Predicts Treatment Benefit Achieved by Macroscopic Radical Lung-Preserving Surgery in Pleural Mesothelioma-A Retrospective Multicenter Analysis.

Pleural mesothelioma (PM), linked to asbestos-induced inflammation, carries a poor prognosis. Therapy ranges from therapy limitation to aggressive multimodality treatment. Given the uncertainty about treatment benefits for patients, this study aimed to assess the role of Ki67 as a prognostic and predictive parameter in PM. Ki67 was measured in the specimens of 70 PM patients (17 female, 53 male) from two centers and correlated to overall survival (OS) and therapy outcome. The median OS was 16.1 months. The level of Ki67 expression was divided into low (≤15%) and high (>15%). A low value of Ki67 expression was associated with a longer OS (Ki67 ≤ 15%: 31.2 (95% CI 6.5-55.8) months vs. Ki67 > 15%: 11.1 (95% CI 7.7-14.6) months, p = 0.012). The 5-year survival represents 22% in the low Ki67 expression group, in contrast to 5% in the high Ki67 expression group. We found a significant interaction term of Ki67 with multimodality treatment (p = 0.031) translating to an OS of 48.1 months in the low expression Ki67 group compared to 24.3 months in the high Ki67 expression group when receiving surgery within multimodality therapy. Therefore, Ki67 stands out as a validated prognostic and, most importantly, novel predictive biomarker for treatment benefits, particularly regarding surgery within multimodality therapy.

Postoperative Pyoderma Gangrenosum Following Carpal Tunnel Surgery: A Case Report and Review of the Literature.

Pyoderma gangrenosum (PG) is a neutrophilic dermatosis characterized by painful ulcerated lesions. Postoperative PG, which typically begins with erythema and severe pain within two weeks after surgery, progresses into ulcerated lesions. It is often misdiagnosed as it resembles necrotizing skin infections, resulting in delayed treatment. Cases of postoperative PG located in the upper extremity are uncommon. In this case report, we discuss a male patient who developed postoperative PG after carpal tunnel surgery.

Allelic Variants of the Complement Genes in Acute Postinfectious Glomerulonephritis.

Acute postinfectious glomerulonephritis (APIGN) is one of the most common causes of acute glomerulonephritis in children. It may lead to inflammation and proliferation of glomerular tissue through immunologic mechanisms (Balasubramanian R, Paediatr Int Child Health 2017;37:240-247).

Retrospective Analysis of Paediatric Glial Tumours that Required Modern Molecular Techniques.

AIM: To determine if previous histological grading systems were sufficient or unreliable with a limited repository of modern techniques. MATERIAL AND METHODS: The pathology reports of pediatric neurosurgery patients between 2019-2022 were accessed. Data on patients that needed unattainable further molecular investigation were extracted. Data were noted from electronic archives, including their sex, age, histologic grade, location, resection type, survival, and therapy. RESULTS: Out of 61 surgeries, 17 patients needed further investigation for a proper 2022 World Health Organization (WHO) diagnosis. Seven were deceased, and nine were alive. Two of 10 patients with low-grade gliomas and five of six patients with highgrade gliomas were deceased. Data on one foreign patient with high-grade glioma was inaccessible. The average survival was 9 months for the deceased. CONCLUSION: Modern molecular techniques such as next-generation sequencing and methylation profiling are the state-ofthe- art methods, but it is hard for developing and underdeveloped countries to utilize such methods. The classification schemes, diagnostic key figures, and treatment modalities are developed using these techniques, but the less developed world is incapable of achieving these. We are trying to hybridize the modern and classic modalities, and the results of our study show that for overall survival, there is still not much difference. More economic and feasible techniques should be produced and summarized for the rest of the world.

Efficacy of radiological depth of invasion measurements on magnetic resonance images acquired at different magnetic field strengths and imaging sequences in predicting cervical lymph node metastasis and other outcomes in tongue cancer.

OBJECTIVES: We investigated the correlation between magnetic resonance imaging (MRI) parameters and tumor pathological depth of invasion (pDOI), between pDOI and radiological DOI (rDOI), between rDOI and duration between biopsy and MRI, and between rDOI and duration between MRI and surgery to determine the efficacy of rDOI in identifying small lesions and other conditions. STUDY DESIGN: We examined 36 adult patients who had been diagnosed histopathologically with cancer of the tongue and had undergone a glossectomy. Using 1.5 Tesla (T) and 3.0T MRI, we measured rDOI at the deepest infiltration point on 4 MRI sequences. We calculated the correlations between rDOI and the variables examined by Spearman rho analysis and evaluated the diagnostic performance of rDOI by receiver operating characteristic curve analysis. RESULTS: Axial T2-weighted images using 1.5T MRI provided the closest approximation of pDOI. Although the correlation between rDOI and pDOI was significant, rDOI showed poor or acceptable discrimination in identifying small lesions and other conditions. There were no significant correlations between rDOI and the time between biopsy and MRI or between MRI and surgery. CONCLUSIONS: The correlation between rDOI and pDOI is significant, but rDOI is ineffective in predicting malignancy and other conditions. Axial T2-weighted images using 1.5T MRI provide the closest approximation of pDOI.

Histopathologic Features for Overall Survival in Merkel Cell Carcinoma: A Case Series with Intact Mismatch Repair Protein Expression.

OBJECTIVE: In a study of Merkel cell carcinoma (MCC), a fusion transcript between MLH1 and SPATA4 was identified. This fusion has the potential to generate the inactive or dominant-negative form of the protein. Therefore, we aimed to investigate whether mismatch repair protein deficiency occurr in MCC cases or not, in addition to the overall survival association with histopathologic features. MATERIAL AND METHOD: A retrospective review of 15 patients diagnosed with a biopsy-proven Merkel Cell Carcinoma between 2012 and 2019 was performed. Mismatch repair (MMR) protein expressions were evaluated by immunohistochemistry. RESULTS: The median follow-up time was 36 months (mean 41, range 2-103 months). Six (40%) patients died during follow-up. The overall survival (OS) at 1 year, 2 years, 3 years, and 5 years were 87%, 80%, 62%, and 53%, respectively. The patients diagnosed at < 60 years had an improved OS compared to those ≥60 years of age (p=0.016). Patients in clinical stage I had better OS than patients in clinical stage IV (p=0.011). Cases with pathological tumor stage (pT) 1 had better OS than pT3 and pT4 (p=0.045). Adjuvant radiotherapy or adjuvant radiotherapy+chemotherapy treatment improved OS compared to adjuvant chemotherapy (p=0.003). MMR protein nuclear expression was intact in 12 cases available for immunohistochemical study. CONCLUSION: To the best of our knowledge, this is the second study that preferentially investigated the mismatch repair protein status of Merkel Cell Carcinoma. No mismatch repair protein deficiency of MCC cases was identified in the current study.

Association of Merkel Cell Polyomavirus Status With p53, RB1, and PD-L1 Expression and Patient Prognosis in Merkel Cell Carcinomas: Clinical, Morphologic, and Immunohistochemical Evaluation of 17 Cases.

BACKGROUND: Merkel cell carcinoma (MCC) is a rare, aggressive, primary neuroendocrine carcinoma of the skin whose main risk factors are immunosuppression, UV radiation exposure, and Merkel cell polyomavirus. Programmed death-1/programmed death ligand-1 (PD-L1)-based immunotherapy is currently the first choice for treating patients with metastatic MCC. METHODS: MCC biopsies (17) were evaluated for their nucleus and cytoplasm characteristics and growth patterns, as well as for intratumor lymphocytes, mitotic number, and lymphovascular invasion. Paraffin-embedded tissue samples of the biopsies were stained with MCPyV large T-antigen (LTag), RB1, p53, and PD-L1. RESULTS: We observed MCPyV LTag expression in 9 out of the 17 tumors, and all 9 cases were positive for RB1 ( P <0.000). p53 staining was not significantly correlated with MCPyV LTag. We observed no relationship between p53 expression and any other parameters, and PD-L1 expression was low in the MCC samples. We evaluated PD-L1 using both the combined positive score and tumor proportion score (TPS), and found that TPS was correlated with MCPyV LTag expression ( P =0.016). Tumors with tumor-infiltrating lymphocytes showed a better prognosis than those without these lymphocytes ( P =0.006). DISCUSSION: Our data demonstrated that RB1 was effective for immunohistochemically investigating the MCPyV status of tumors. TPS was superior to the combined positive score in evaluating PD-L1 in MCC. Tumor-infiltrating lymphocytes were the only parameters that were associated with survival. Further studies with larger series are required to confirm these results.

Comparison of PD-L1 and VISTA expression status in primary and recurrent/refractory tissue after (chemo)radiotherapy in head and neck cancer.

BACKGROUND: PD-L1 and VISTA are thought to play a role in escape from the immune system, tumor progression, and treatment response in tumoral tissue. The current study aimed to evaluate the effects of radiotherapy (RT) and chemoradiotherapy (CRT) on PD-L1 and VISTA expression in head and neck cancers. METHODS: PD-L1 and VISTA expression were compared between the primary biopsy taken at the time of diagnosis and refractory tissue biopsies of patients who received definitive CRT or recurrent tissue biopsies of patients who had surgery followed by adjuvant RT or CRT. RESULTS: In total, 47 patients were included. Radiotherapy had no effect on the expression levels of PD-L1 and VISTA in patients with head and neck cancer (p = 0.542 and p = 0.425, respectively). A positive correlation was found between PD-L1 and VISTA expression (p < 0.001; r = 0.560). PD-L1 and VISTA expression in the first biopsy were found to be significantly higher in clinical lymph node-positive patients compared to node-negative patients (PD-L1 p = 0.038; VISTA p = 0.018). The median overall survival of patients with ≥ 1% VISTA expression in the initial biopsy was significantly shorter than that of patients with < 1% VISTA expression (52.4 vs. 110.1 months, respectively; p = 0.048). CONCLUSION: It was found that PD-L1 and VISTA expression did not change with RT or CRT. Further studies are needed to evaluate the relationship of PD-L1 and VISTA expression with RT and CRT.

Does the preoperative fasting period affect the liver in a distant organ model of renal ischaemia reperfusion?

OBJECTIVES: To experimentally evaluate the effects of preoperative fasting duration on distant organ liver in renal ischaemia-reperfusion (IR) injury. METHODS: This is an experimental study. In the study, 3 groups were formed. In Group A, abdominal laparotomy was carried out after 12 hours of preoperative fasting without any IR damage. In Group B, IR injury was carried out after 12 hours of preoperative fasting, and abdominal laparotomy was carried out, in Group C after 2 hours of fasting after IR injury. Apoptosis, congestion, balloon degeneration, nuclear pleomorphism, and leukocyte infiltration were examined histopathologically and tumor necrosis factor-alpha (TNF-α), interleukin (IL) -1 beta, IL-6, and IL-10 were evaluated biochemically. RESULTS: A statistically significant difference was determined between the groups in respect of postoperative IL-10 levels (p=0.020) with significantly lower levels determined in Group C than in Groups A and B (p=0.021). Similar rates of mild nuclear polymorphism were seen with no statistically significant difference determined between the groups (p>0.167). A statistically significant difference was determined between the groups in respect of the congestion scores (p<0.001), with a lower score in Group C than in Groups A and B, where the scores were similar (p<0.001, p=0.017). CONCLUSION: With this result, it would be correct to say that the short preoperative fasting period has protective effects on the liver tissue.

Validation of Inflammatory Prognostic Biomarkers in Pleural Mesothelioma.

Evoked from asbestos-induced inflammation, pleural mesothelioma represents a fatal diagnosis. Therapy ranges from nihilism to aggressive multimodality regimens. However, it is still unclear who ultimately benefits from which treatment. We aimed to re-challenge inflammatory-related biomarkers' prognostic value in times of modern immune-oncology and lung-sparing surgery. The biomarkers (leukocytes, hemoglobin, platelets, neutrophils, lymphocytes, monocytes, neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR), C-reactive protein (CRP)) and clinical characteristics (age, sex, histology, therapy) of 98 PM patients were correlated to overall survival (OS). The median OS was 19.4 months. Significant OS advantages (Log-Rank) were observed in multimodal treatment vs. others (26.1 vs. 7.2 months, p < 0.001), surgery (pleurectomy/decortication) vs. no surgery (25.5 vs. 3.8 months, p < 0.001), a high hemoglobin level (cut-off 12 g/dL, 15 vs. 24.2 months, p = 0.021), a low platelet count (cut-off 280 G/L, 26.1 vs. 11.7 months, p < 0.001), and a low PLR (cut-off 194.5, 25.5 vs. 12.3 months, p = 0.023). Histology (epithelioid vs. non-epithelioid, p = 0.002), surgery (p = 0.004), CRP (cut-off 1 mg/dL, p = 0.039), and platelets (p = 0.025) were identified as independent prognostic variables for this cohort in multivariate analysis (Cox regression, covariates: age, sex, histology, stage, CRP, platelets). Our data verified the previously shown prognostic role of systemic inflammatory parameters in patients treated with lung-sparing surgery within multimodality therapy.

Metastatic melanoma: clinicopathologic features and overall survival comparison.

INTRODUCTION: Five-year survival for melanoma with distant metastasis has been reported as 25%. This study evaluates the relationship between known and uncertain clinicopathologic parameters and overall survival (OS) for metastatic melanoma patients. METHODS: Metastatic melanoma cases (n = 122, 45 female, 77 male) that were metastatic at the time of diagnosis or referred for molecular pathological analysis were included. Survival was analyzed using the Kaplan-Meier method with comparisons performed by the log-rank test. RESULTS: The mean age of diagnosis at the time of metastasis was 56 years (range 19-89). The 1-year, 2-year, and 5-year OS rates were 44%, 27%, and 17%, respectively. Cox multiple regression analysis identified the following as independent poor prognostic factors for OS: perivascular pseudorosette formation (hazard ratio [HR]: 12.821, p = 0.045), lung compared to skin and subcutaneous soft tissue and to lymph node, specific cytologic features such as clear cytoplasm (p = 0.043), and hyperchromatic nuclei (HR: 98.605, p = 0.005) compared to vesicular chromatin pattern. At the end of the study, 26 (21%) of the patients were alive, and 96 (79%) were deceased. CONCLUSIONS: In conclusion, perivascular pseudorosette formation, first described as a case report in primary and metastatic melanoma, may represent a new prognostic and diagnostic histopathological finding for metastatic melanoma.

Effect of neoadjuvant therapy on tumor tissue PD-L1 and VISTA expression levels in non-small-cell lung cancer.

Background: PD-L1 and VISTA are important checkpoint control stations and play an immunomodulatory role in patients with non-small-cell lung cancer. Method: The expression levels of PD-L1 and VISTA between pre- and post-treatment tumor tissue were compared. Results: While PD-L1 expression was >1% in 35% of patients before neoadjuvant therapy, PD-L1 expression was >1% in 65% of patients after treatment (p = 0.004). VISTA expression was >1% in 41% of patients before treatment, and this rate was 65% after treatment (p = 0.025). Conclusion: Chemotherapy and chemoradiotherapy can be used as immunizers by increasing PD-L1 and VISTA expression levels.

Clinicopathologic features and survival outcomes of ocular melanoma: a series of 31 cases from a tertiary university hospital.

BACKGROUND: We aimed to determine the effect of clinicopathologic features on overall survival among Caucasian ocular melanoma patients in the Central Anatolia region of Turkey. METHODS: This single-center study included conjunctival (n = 12) and uveal (n = 19) melanoma patients diagnosed between January 2008 and March 2020. Clinicopathologic features and outcomes were reviewed retrospectively. Five cases were tested for BRAF V600 mutations with real-time polymerase chain reaction, and one case was tested with nextgeneration sequencing. Survival was calculated using the Kaplan-Meier method. RESULTS: Thirty-one patients had a mean initial age of 58.32 years (median, 61 years; range 25 to 78 years). There were 13 male and 18 female patients. The median follow-up time was 43.5 months (range, 6 to 155 months) for conjunctival melanoma and 35 months (range, 8 to 151 months) for uveal melanoma. When this study ended, eight of the 12 conjunctival melanoma patients (66.7%) and nine of the 19 uveal melanoma patients (47.4%) had died. The presence of tumor-infiltrating lymphocytes was related to improved overall survival in conjunctival melanoma (p = .014), whereas the presence of ulceration (p = .030), lymphovascular invasion (p = .051), tumor in the left eye (p = .012), tumor thickness of > 2 mm (p = .012), and mitotic count of >1/mm² (p = .012) reduced the overall survival in conjunctival melanoma. Uveal melanoma tumors with the largest diameter of 9.1-15 mm led to the lowest overall survival among subgroups (p = .035). Involvement of the conjunctiva (p=.005) and lens (p = .003) diminished overall survival in uveal melanoma. BRAF V600 mutation was present in one case of conjunctival melanoma, GNAQ R183Q mutation was present in one case of uveal melanoma. Patients with uveal melanoma presented with an advanced pathological tumor stage compared to those with conjunctival melanoma (p = .019). CONCLUSIONS: This study confirmed the presence of tumor-infiltrating lymphocytes as a favorable factor in conjunctival melanoma and conjunctival and lens involvement as unfavorable prognostic factors in uveal melanoma for overall survival, respectively.