The prognostic role of preoperative neutrophil-to-lymphocyte ratio in upper tract urothelial carcinoma.

Introduction: The blood-based inflammatory marker, neutrophil-to-lymphocyte ratio (NLR), is a reliable prognostic biomarker for several cancers. Although the literature supports the correlation between preoperative NLR, clinicopathological characteristics, and oncological outcomes in upper tract urothelial carcinoma (UTUC), the cutoff of NLR is still debated. This study aimed to determine the prognostic value of NLR in patients with UTUC. Methods: This was a retrospective analysis of prospectively collected data from July 2012 to December 2022 evaluating patients with UTUC who underwent radical nephroureterectomy (RNU). NLR was calculated using the neutrophil and lymphocyte counts obtained a day before the surgery and the cutoff value was set as 2.5. Kaplan-Meier and Cox's proportional hazards regression were used to analyze the association between NLR and the oncological outcomes. Results: The study included 91 patients (78 males, 13 females) in the final analysis with a median follow-up of 49 months (8-130). The mean age of the patients with NLR <2.5 and NLR ≥2.5 was 56.88 years and 56.35 years, respectively, and the pathological stage was pT1 in 48%, pT2 in 20.88%, pT3 in 27.47%, and pT4 in 3.30% of the patients. Multivariable Cox regression analysis showed that the preoperative NLR ≥2.5 was significantly associated (Hz = 7.17) with higher T stage, lymphovascular invasion, necrosis, nodal involvement, adjuvant chemotherapy, and worse overall survival (OS) (Hz = 9.87). The Kaplan-Meier analysis revealed an improved OS in patients with NLR <2.5, but a statistically significant difference in the recurrence-free survival was not found. Conclusions: Preoperative NLR is an easily available, inexpensive, and important prognostic biomarker of survival in patients with UTUC and has a potential role in risk stratification by predicting adverse clinicopathological characteristics.

Advances, recognition, and interpretation of molecular heterogeneity among conventional and subtype histology of urothelial carcinoma (UC): a survey among urologic pathologists and comprehensive review of the literature.

AIMS: Urothelial carcinoma (UC) demonstrates significant molecular and histologic heterogeneity. The WHO 2022 classification has hinted at adding molecular signatures to the morphologic diagnosis. As morphology and associated molecular repertoire may potentially translate to choices of and response to therapy and relapse rate, broader acceptability of recognizing these key features among uropathologists is needed. This prompted an international survey to ascertain the practice patterns in classical/subtype UC among uropathologists across the globe. METHODS AND RESULTS: A survey instrument was shared among 98 uropathologists using SurveyMonkey software. Anonymized respondent data were analysed. The response rate was 85%. A majority were in concordance with the profiles of luminal (93%) and basal (82%) types. Opinion on the FGFR3 testing platform was variable. While 95% concurred that TERT promoter mutation is the key driver in UC, 72% had the opinion that APOBEC mutagenesis is the main signature in muscle invasive bladder cancer (MIBC). Uropathologists have divergent opinions on MIBC and ERCC2 mutations. Among the participants, 94% would quantify aggressive micropapillary and sarcomatoid histology, while 88% would reevaluate another transurethral resection of the bladder tumour specimen in nonmuscle invasive tumour with micropapillary, small cell, or sarcomatoid histology. A leading number agreed to specific molecular signatures of micropapillary (93%), plasmacytoid (97%), and small cell (86%) subtypes. Ninety-six percent of participants agreed that a small-cell component portends a more aggressive course and should be treated with neoadjuvant chemotherapy and 63% would perform HER2/neu testing only on oncologist's request in advanced tumours. Ninety percent agreed that microsatellite instability testing, although not a standard protocol, should be considered in young patients with upper tract UC. Eighty-six percent agreed that UC with high tumour mutational burden would be a better candidate for immunotherapy. CONCLUSION: In the era of precision medicine, enhanced understanding of molecular heterogeneity of UC will contribute to better therapeutic options, novel biomarker discovery, innovative management protocols, and outcomes. Our survey provides a broad perspective of pathologists' perceptions and experience regarding incorporation of histomolecular approaches to "personalize" therapy. Due to variable clinical adoption, there is a need for additional data using uniform study criteria. This will drive generation of best practice guidelines in this area for widespread and consistent clinical utility.

Small Cell Carcinoma Prostate: A Case Report with Findings on 18-F FDG PET/CT.

Small-cell carcinoma of the prostate (SCCP) is a rare and very aggressive malignancy with neuroendocrine differentiation. In contrast to conventional prostate adenocarcinoma, SCCP is an aggressive carcinoma and portends to have a poor prognosis. Around 50% of these patients have metastatic disease at the first clinical presentation. We report the findings of 18-F fluorodeoxyglucose positron emission tomography/computed tomography in a case of histologically proven SCCP with an unusual finding of the left internal mammary lymph node.

Intravoxel incoherent motion and diffusion kurtosis imaging and their machine-learning-based texture analysis for detection and assessment of prostate cancer severity at 3 T.

OBJECTIVES: To evaluate the role of combined intravoxel incoherent motion and diffusion kurtosis imaging (IVIM-DKI) and their machine-learning-based texture analysis for the detection and assessment of severity in prostate cancer (PCa). MATERIALS AND METHODS: Eighty-eight patients underwent MRI on a 3 T scanner after giving informed consent. IVIM-DKI data were acquired using 13 b values (0-2000 s/mm2) and analyzed using the IVIM-DKI model with the total variation (TV) method. PCa patients were categorized into two groups: clinically insignificant prostate cancer (CISPCa) (Gleason grade ≤ 6) and clinically significant prostate cancer (CSPCa) (Gleason grade ≥ 7). One-way analysis-of-variance, t test, and receiver operating characteristic analysis was performed to measure the discriminative ability to detect PCa using IVIM-DKI parameters. A chi-square test was used to select important texture features of apparent diffusion coefficient (ADC) and IVIM-DKI parameters. These selected texture features were used in an artificial neural network for PCa detection. RESULTS: ADC and diffusion coefficient (D) were significantly lower (p < 0.001), and kurtosis (k) was significantly higher (p < 0.001), in PCa as compared with benign prostatic hyperplasia (BPH) and normal peripheral zone (PZ). ADC, D, and k showed high areas under the curves (AUCs) of 0.92, 0.89, and 0.88, respectively, in PCa detection. ADC and D were significantly lower (p < 0.05) as compared with CISPCa versus CSPCa. D for detecting CSPCa was high, with an AUC of 0.63. A negative correlation of ADC and D with GS (ADC, ρ = -0.33; D, ρ = -0.35, p < 0.05) and a positive correlation of k with GS (ρ = 0.22, p < 0.05) were observed. Combined IVIM-DKI texture showed high AUC of 0.83 for classification of PCa, BPH, and normal PZ. CONCLUSION: D, f, and k computed using the IVIM-DKI model with the TV method were able to differentiate PCa from BPH and normal PZ. Texture features of combined IVIM-DKI parameters showed high accuracy and AUC in PCa detection.

Carboplatin in Patients With Metastatic Castration-Resistant Prostate Cancer Harboring Somatic or Germline Homologous Recombination Repair Gene Mutations: Phase II Single-Arm Trial.

BACKGROUND: Approximately 20%-25% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor a deleterious germline or somatic mutation in the homologous recombination repair (HRR) pathway genes, which is involved in the repair of double-stranded DNA damage. Half of these mutations are germline, while the remaining are exclusively somatic. While polyadenosine 5'diphosphoribose [poly (ADP-ribose)] polymerase inhibitors, such as olaparib and rucaparib, are effective in this subgroup, their widespread use is limited due to the associated high cost, especially in resource-constrained settings. Notably, platinum agents like carboplatin have exquisite sensitivity to cells with defective DNA repair machinery. Carboplatin, a conventional, inexpensive chemotherapeutic agent, offers a potential alternative treatment in such patients. Several retrospective small case series support this hypothesis. However, there are no prospective clinical trials of carboplatin in patients with mCRPC with HRR mutations. OBJECTIVE: The primary objective is to assess the objective response rate of 3 weekly carboplatin treatments in patients with mCRPC harboring deleterious mutations in the HRR pathway genes and previously treated with a taxane or a novel antiandrogen agent. The secondary objectives include progression-free survival, health-related quality of life, and safety profile of carboplatin. METHODS: Patients diagnosed with mCRPC harboring HRR pathway mutations previously treated with docetaxel or novel antiandrogen agents (abiraterone, enzalutamide, apalutamide, or darolutamide) or both will be eligible. Genes involved directly or indirectly in the HRR pathway will be tested. In this single-arm phase II study, we will screen approximately 200 patients to enroll 49 patients, and carboplatin (dosing at the area under curve=5) will be administered every 3 weeks until progression or intolerable side effects. The primary end point will be assessed as the proportion of patients with a reduction of serum prostate-specific antigen by more than 50% from enrollment. Secondary outcomes include progression-free survival-soft-tissue disease progression (by response evaluation criteria in solid tumors, version 1.1, and bone lesion progression using Prostate Cancer Clinical Trials Working Group 3 criteria), health-related quality of life during carboplatin treatment using the Functional Assessment of Cancer Therapy-Prostate questionnaire and the European Organisation for Research and Treatment of Cancer questionnaire and safety profile of carboplatin (National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0). RESULTS: The trial started enrollment in September 2023. This trial is ongoing, and 12 patients have been recruited to date. All 49 participants will be enrolled according to plan. CONCLUSIONS: This prospective phase II trial represents a critical step toward addressing the therapeutic gap in patients with mCRPC harboring HRR pathway mutations, particularly in demographic regions with limited access to poly (ADP-ribose) polymerase inhibitors. Outcomes from this study will inform clinical practice and guide future phase III randomized trials, ultimately improving patient outcomes globally. TRIAL REGISTRATION: Clinical Trials Registry of India CTRI/2023/04/051507; https://ctri.nic.in/Clinicaltrials/pmaindet2.php?EncHid=Njc0NjU=&Enc=&userName=. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54086.

Metastatic alveolar soft part sarcoma of the kidney in a young female.

A 19-year-old female presented with left flank discomfort and swelling. Imaging revealed a large mass arising from the left kidney, and radical nephrectomy confirmed the diagnosis of alveolar soft part sarcoma (ASPS) based on histopathological and ultrastructural examination. Postoperatively, positron emission tomography-computerized tomography showed lung metastasis and renal bed recurrence. Sunitinib was initiated for metastatic ASPS. This case underscores challenges in diagnosing and managing ASPS, highlighting the role of tyrosine kinase inhibitors. Multidisciplinary care and vigilant follow-up are crucial for rare tumors such as ASPS.

Clinical significance of blocking novel immune checkpoint B7-H4 in urothelial carcinoma of bladder as a potential therapeutic target.

Urothelial Carcinoma of Bladder is complex disease with high mortality and recurrence rates. Current standard regimes have exhibited anti-tumor activity but still, a proportion of patients are non-responsive or in-eligible to receive such treatments. Immune checkpoints have emerged as potential class of therapeutics to be tested in UCB patients. Clinical trials targeting PD-1/PD-L1 axis have been tested in UCB but still a proportion of patients are non-responsive to it which stresses upon identifying new targets. New immune checkpoint B7-H4 has been shown to negatively regulate T cell activity in cancer and is a poor prognostic factor in various solid tumors. In this study we assessed the novel immune checkpoint B7-H4 status in UCB patients. We observed elevated expression of B7-H4 and PD-L1 on CD8+ T cells in circulation of UCB patients. Relative mRNA expression and immunohistochemistry displayed upregulation in bladder tumor tissue. Increased expression of B7-H4 along with PD-L1 in periphery and tumor of UCB patients highlights involvement of B7-H4 in disease progression. Combinatorial blocking of B7-H4 and PD-L1 enhanced IFN-γ and granzyme B in CD8+ T cells functional T cell immune response in UCB patients. Also, B7-H4 was significantly associated with clinico-pathological parameters. Our findings highlight B7-H4 as potential therapeutic target for treatment of UCB patients in future after further validation.

Evaluation of programmed cell death ligand 1 expression in a contemporary cohort of penile squamous cell carcinoma and its correlation with clinicopathologic and survival parameters: A study of 134 patients.

OBJECTIVES: Penile squamous cell carcinomas (PCs) are rare malignancies with a dismal prognosis in a metastatic setting; therefore, novel immunotherapeutic modalities are an unmet need. One such modality is the immune checkpoint molecule programmed cell death ligand 1 (PD-L1). We sought to analyze PD-L1 expression and its correlation with various clinicopathologic parameters in a contemporary cohort of 134 patients with PC. METHODS: A cohort of 134 patients with PC was studied for PD-L1 immunohistochemistry. The PD-L1 expression was evaluated using a combined proportion score with a cutoff of 1 or higher to define positivity. The results were correlated with various clinicopathologic parameters. RESULTS: Overall, 77 (57%) patients had positive PD-L1 expression. Significantly high PD-L1 expression was observed in high-grade tumors (P = .006). We found that 37% of human papillomavirus (HPV)-associated subtypes and 73% of other histotype tumors expressed PD-L1, while 63% of HPV-associated tumors and 27% of other histotype tumors did not (odds ratio, 1.35; P = .002 when compared for HPV-associated groups vs all others). Similarly, PD-L1-positive tumors had a 3.61-times higher chance of being node positive than PD-L1-negative tumors (P = .0009). In addition, PD-L1 high-positive tumors had a 5-times higher chance of being p16ink4a negative than PD-L1 low-positive tumors (P = .004). The PD-L1-positive tumors had a lower overall survival and cancer-specific survival than PD-L1-negative tumors. CONCLUSIONS: Overall, PD-L1 expression is associated with high-grade and metastatic tumors. Lower PD-L1 expression is observed more frequently in HPV-associated (warty or basaloid) subtypes than in other, predominantly HPV-independent types. As a result, PD-L1 positivity, including higher expression, portends lower overall and cancer-specific survival. These data provide a rational for further investigating PD-L1-based immunotherapeutics in PC.

Grossing and reporting of radical prostatectomy specimens: An evidence-based approach.

Radical prostatectomy (RP) constitutes the primary treatment option for patients with clinically localized, biopsy-proven prostate cancer that requires local treatment with curative intent. Accurate reporting of radical prostatectomy specimens is required to guide further risk stratification and management of patients. Hence, for the handling and reporting of RP specimens, a standardized protocol should be followed. Many general pathologists may not be well-versed with the guidelines for the handling of radical prostatectomy specimens. This article discusses a detailed approach to grossing techniques, including specimen description, fixation requirements, gross cut-up, and reporting of the grade and stage of RP specimens. This will enable the pathologist to aid in multidisciplinary management.

Association of heavy metals and trace elements in carcinoma urinary bladder: A case-controlled study.

Introduction: Abnormal levels of heavy metals (HM) and trace elements (TE) affect body metabolism and can induce carcinogenesis. This study aims to evaluate the role of HM and TE in carcinoma urinary bladder (CAUB). Methods: Patients with biopsy-proven CAUB (n = 100) were taken as the study group, while age-and sex-matched healthy volunteers were taken as control (n = 100). Blood and urine samples were compared for Arsenic (As), Copper (Cu), Manganese (Mn), Selenium (Se), Cadmium (Cd), Lead (Pb), and Mercury (Hg) levels. Serum glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and lipid peroxidation (LPO) levels were assessed to know the redox status between the two groups. Results: A significantly higher blood level of As, Mn, and Pb was observed in CAUB cases as compared to controls. Blood Se level was significantly lower in CAUB patients. On comparing urinary levels, CAUB patients had a higher As, Mn, and Pb levels compared to controls. Further, 68% and 59% of patients had their blood and urinary HM and TE levels above the permitted level, respectively. CAUB cases also had a lower GSH-Px (113.5 ± 44.7 vs. 163.9 ± 120.5, P = 0.0002), lower SOD levels (11.35 ± 5.6 vs. 13.75 ± 3.9, P = 0.008), and a higher LPO levels (15.5 ± 14.7 vs. 11.18 ± 11.2, P = 0.02) in the serum. Conclusions: A significantly higher concentration of As, Mn, and Pb was noted in the blood and urine of CAUB patients compared to controls. CAUB cases also had lower serum GSH-Px and SOD levels with a concomitant increased serum LPO assay suggesting underlying oxidative stress.

Perineural Invasion of Superior and Inferior Laryngeal Nerves in Advanced Stage Squamous Cell Carcinoma of the Larynx: A Case Series and Review.

Objective: To evaluate bilateral superior and recurrent laryngeal nerves for tumor spread in patients of advanced-stage laryngeal carcinoma undergoing surgical resection. Methods: A prospective study was conducted including biopsy-proven cases of laryngeal squamous cell carcinoma (SCC) that were planned for total laryngectomy. Patients with metachronous or synchronous SCC were excluded from the study. All patients underwent total laryngectomy, where both superior and recurrent laryngeal nerves were harvested along with the specimen, and the proximal ends of the nerves were marked for reference. Perineural invasion (PNI) was assessed in nerves within the tumor and in bilateral extra-laryngeal nerves. Results: The study included 22 patients with a mean age of 58 years. Intra-tumoral PNI was found in 7 of the 22 cases (32%). The free nerve margins of superior and recurrent laryngeal nerves, which were examined from proximal to distal orientation, showed no tumor infiltration in any of the cases. Conclusion: Perineural invasion of minor nerves constitutes a major pathway of spread. On the contrary, invasion of superior or recurrent laryngeal nerves does not constitute a route for tumor spread. Hence, there is no need to extend the surgical boundary for total laryngectomy to include these major nerves separately.

Castleman disease masquerading as a paraganglioma showing uptake on DOTATATE PET.

A man in his 50s presented with shortness of breath and was found to have a large paracaval mass, which on further evaluation with CT, showed a large heterogeneously enhancing mass lesion adjacent to right renal hilum. His 24-hour urinary metanephrines and nor-metanephrines were normal. In view of location and features on CT, paraganglioma was considered as a possibility. A 68Ga-DOTATATE positron emission tomography/CT demonstrated avidity in the lesion with maximum standardised uptake value of 16.5. He underwent right laparoscopic converted to open mass excision along with nephrectomy. Histopathological examination was suggestive of hyaline vascular Castleman disease.

Quality of life assessment in testicular non-seminomatous germ cell tumour survivors.

PURPOSE: Patients with Germ cell tumours (GCT) are at risk of long-term toxicities due to multimodality therapy. It is debatable whether there is an impact on the quality of life(QoL) of GCT survivors. METHODS: A case-control study was conducted at a tertiary care centre in India, using the EORTC QLQ C30 questionnaire, to compare the QoL between GCT survivors(disease free > 2 years) and healthy matched controls. A multivariate regression model was used to identify factors affecting QoL. RESULTS: A total of 55 cases and 100 controls were recruited. Cases had a median age of 32 years (interquartile range, IQR 28-40 years), ECOG PS of 0-1(75%), advanced stage III (58%), chemotherapy (94%) and 66% were > 5 years from diagnosis. The median age of controls: 35 years (IQR 28-43 years). A statistically significant difference was seen for emotional (85.8 ± 14.2 vs 91.7 ± 10.4, p 0.005), social(83.0 ± 22.0 vs 95.2 ± 9.6, p < 0.001) and global scales (80.4 ± 21.1 vs 91.3 ± 9.7, p < 0.001). Cases had more nausea and vomiting(3.3 ± 7.4 vs 1.0 ± 3.9, p 0.015), pain(13.9 ± 13.9 vs 4.8 ± 9.8, p < 0.001), dyspnea(7.9 + 14.3 vs 2.7 ± 9.1, p 0.007), and appetite loss(6.7 ± 14.9 vs 1.9 ± 7.9, p 0.016) and greater financial toxicity(31.5 ± 32.3 vs 9.0 ± 16.3, p < 0.001). Adjusting for age, performance status, BMI, stage, chemotherapy, RPLND, recurrent disease, and time since diagnosis, no predictive variables were significant. CONCLUSION: There is a detrimental impact of history of GCT in long term survivors of GCT.

Sclerosing epithelioid fibrosarcoma of the kidney.

A woman in her 20s presented with headache and back pain and was found to have a left renal mass with bony metastases. She underwent nephrectomy, and on histopathology was initially diagnosed with stage 4 clear cell sarcoma of the kidney. She underwent palliative radiation and chemotherapy; however, the disease progressed and she came to our centre. We started her on second-line chemotherapy and submitted her tissue blocks for review. Due to her age and lack of sclerotic stroma in the tissue, we had our doubts about the diagnosis and hence, tissue sample was submitted for next-generation sequencing (NGS). NGS detected an EWSR1::CREBL1 fusion, clinching the final diagnosis of sclerosing epithelioid fibrosarcoma of the kidney, a singular diagnosis rarely reported in the literature. Currently, the patient is post her third line of chemotherapy, is on maintenance, and is doing well and has resumed her daily activities.

Clinical Profile and Predictors of Survival in Carcinoma Penis Patients.

BACKGROUND: Carcinoma penis is a rare neoplasm, and the literature is scarce on long-term survival and its predictors. The aim of the study was to determine the clinical profile and management patterns, identify predictors of survival, and the impact of education and rural/urban dwelling on survival. METHODS: Patients with a histological diagnosis of carcinoma penis from January 2015 to December 2019 were included in the study. Demographics, clinical profile, education status, primary residence address, and outcomes were obtained from the case records. Distance from the treatment centre was obtained from the postal code. The primary objectives were to assess relapse-free survival (RFS) and overall survival (OS). The secondary objectives were to identify the predictors of RFS and OS and to determine the clinical profile and treatment patterns in patients with carcinoma penis in India. Time-to-event was calculated by Kaplan-Meir analysis and survival was compared by the log-rank test. Univariate and multivariable Cox regression analyses were used to find independent predictors of relapse and mortality. Logistic regression analyses to examine the associations of rural residence, education status, and distance from the treatment centre with the relapse adjusting for measured confounding variables. RESULTS: Case records of 102 patients treated during the above period were retrieved. The median age was 55.5 (interquartile range [IQR] 42-65 years). Ulcero-proliferative growth (65%), pain (57%), and dysuria (36%) were the most common presenting features. Clinical examination or imaging revealed inguinal lymphadenopathy in 70.6% of patients, however, only 42% of these lesions were pathologically involved. A total of 58.8% of patients were from rural areas, 46.9% had no formal education, and 50.9% had a primary residence ≥100 km from the hospital. Patients with lower education and rural households had higher TNM stages and nodal involvement. Median RFS and OS were 57.6 months (15.8 months to not reached) and 83.9 months (32.5 months to not reached), respectively. On univariate analysis tumor stage, involvement of lymph nodes, T stage, performance status, and albumin was predictive for relapse and survival. However, on multivariate analysis, the stage remained the only predictor of RFS and nodal involvement, and metastatic disease was a predictor of OS. Education status, rural habitation, and distance from the treatment centre were not predictors for relapse or survival. CONCLUSIONS: Patients with carcinoma have locally advanced disease at presentation. Rural dwellings and lower education were associated with the advanced stage but did not have a significant bearing on the survival outcomes. The stage at diagnosis and nodal involvement is the most important predictor of RFS and OS.

The study of miRNA-200c expression and epithelial-to-mesenchymal transition-related transcription factors in the primary bladder urothelial carcinoma.

Background: Epithelial-mesenchymal transition (EMT) plays an important role in bladder carcinoma (BC) invasiveness and metastasis. Studies have shown that muscle-invasive BC (MIBC) and non-MIBC (NMIBC) are different at the molecular level owing to different EMT-related programming. Recent studies suggest that dysregulation of specific miRNAs is linked to EMT in BC. With this background, we aimed to study the immunoexpression of EMT-markers and its correlation with miRNA-200c expression in a series of MIBCs and NMIBCs. Materials and Methods: Quantitative real-time-polymerase chain reaction for the quantification of miR-200c expression was performed on 50 cases of urinary BC obtained from transurethral resection of bladder tumor (TURBT), cystectomy specimens, and ten peritumoral bladder tissue. Immunohistochemistry for ZEB1, ZEB2, TWIST, E-cadherin, and ß-catenin was performed on tumor and peritumoral bladder tissue. Results: Thirty-five TURBT and 15 cystectomy specimens were assessed. Among MIBC, loss of expression of E-cadherin (72.3%), ß-catenin (66.7%), and ZEB1, ZEB2, and TWIST2 immunoreactivity was noted in 53.3%, 86.7%, and 73.3% of cases, respectively. Among NMIBC, loss of expression of E-cadherin (22.5%), ß-catenin (17.1%) and ZEB1, ZEB2, and TWIST immunoreactivity was noted in 11.5%, 51.4%, and 91.4% of cases, respectively. Upregulation of miRNA-200c was noted in cases with retained E-cadherin and negative TWIST expression. Downregulation of miRNA-200c expression was noted in all the cases showing loss of E-cadherin, ß-catenin, and in cases immunoreactive for ZEB1, ZEB2, and TWIST in MIBC. Downregulation of miRNA-200c expression was also noted in cases of MIBC with retained ß-catenin and those immunonegative for ZEB1 and ZEB2. A similar trend was noted in NMIBC. Median miRNA-200c expression was low in both high-grade and low-grade NMIBC compared to peritumoral bladder tissue and was not statistically significant. Conclusion: This study for the first time explores the relation of miR200C with E-cadherin, b-catenin, and its direct transcriptional regulators, namely Zeb1, Zeb2, and Twist in the same cohort of BC. We observed that miRNA-200c is downregulated in both MIBC and NMIBC. We identified novel expression of TWIST in cases of BC showing downregulation of miR200Cs suggesting that it is one of the protein targets of altered miRNA-200c expression contributing to EMT and can serve as a promising diagnostic marker and therapeutic target. Loss of E-cadherin and ZEB1 immunoexpression in high-grade NMIBC suggests an aggressive clinical behavior. However, ZEB2 heterogeneous expression in BC limits its diagnostic and prognostic utility.

Disruption in networking of KCMF1 linked ubiquitin ligase impairs autophagy in CD8+ memory T cells of patients with renal cell carcinoma.

Metastatic Renal Cell Carcinoma (mRCC) remains incurable, despite the current checkpoint-blockade-driven, limited overall response rate. The CD8+ memory T cells can mount a rapid and an effective response. The ubiquitin ligase RAD6-KCMF1-UBR4-mediated regulation of autophagy in CD8+ memory T cells in patients with renal cell carcinoma (RCC) remains unexplored. Consequently, flow cytometry was used to study memory T cells, and their subsets, including activation and regulatory phenotypes in peripheral blood mononuclear cells (PBMCs). Expression of the ubiquitin ligase and autophagy was measured both at the cellular and molecular levels in memory T cells of patients with RCC. JC.1 staining and Annexin/PI assays were used to evaluate the memory T cells depolarization and apoptosis rates. The results indicated that the disruption of Ub-E2-E3 complex and impaired autophagy in memory T cells diminished their ability to survive and combat against tumor cells. Inhibition of memory T cells apoptosis by targeting E3 ubiquitin ligase or autophagy pathways can be explored as a potential therapeutic strategy to improve the long-term survival of memory T cells in RCC.

Primary Mediastinal Germ Cell Tumors (PMGCT): A Real-world Analysis From A Tertiary Cancer Care Center in India.

BACKGROUND: Primary mediastinal GCT (PMGCT) is a rare entity and comprises 10-15% of all mediastinal tumors. We present our institutional experience of MGCT treated with multimodality management. MATERIALS AND METHODS: We conducted a retrospective analysis between 2010 to 2020 of all mediastinal germ cell tumors registered at our center. Data on patient demographics, treatments received, treatment toxicities and response were recorded. Overall survival and relapse free survival were estimated using Kaplan-Meier methods. RESULTS: A total of 30 patients were identified. The median age was 25.5 (range, 18-45) years. Common presenting features included cough (70%) and shortness of breath (70%). Histology wise, 60% patients were non seminomatous histology, whereas 33.3% patients were Seminoma. Twenty-seven (90%) patients received chemotherapy as the first-line treatment, of whom five patients (16.6%) underwent surgery and radiation therapy subsequently. Median follow-up was 26.9 months. Thirteen patients (43.3%) had complete response (43.3%) and eight patients had partial response (26.7%), while three patients (5.5%) had progressive disease. Three-year relapse-free survival rate was 69.6% (95% confidence interval [CI], 42.8-85.6%). Overall survival (OS) at 3 years was 73.4% (95% CI, 49.4-87.3%). Patients with seminoma had a 3 year OS of 90.0% (95% CI, 47.3-98.5%) compared to those with non-seminoma (63.53% [95% CI, 32.3-83.3%]). CONCLUSIONS: Multiagent chemotherapy is the backbone of treatment in PMGCT. Seminomatous PMGCT have excellent prognosis, while further improvement is needed in those with nonseminomatous tumor.