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.

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.

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.

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.

Prostatic malakoplakia: clinicopathological assessment of a multi-institutional series of 49 patients.

Prostatic malakoplakia (MP) is rare, with only case reports and small series (< five patients) available in the literature. In this study we analysed an international multi-institutional series of 49 patients with prostatic MP to more clearly define its clinicopathological features. The median age was 67 years and the median serum prostate-specific antigen (PSA) was 7.5 ng/ml. MP was clinically manifest in most cases (28 of 45 patients with data available, 62%). Of 43 patients with detailed clinical history available, 21 (49%) had concurrent or metachronous malignancies (including prostate cancer). Diabetes or insulin resistance was present in 11 patients (26%). Additionally, three patients had a history of solid organ transplantation and one had HIV. Of note, six of 34 patients (18%) without concurrent prostate cancer had an abnormal digital rectal examination and/or lesions on magnetic resonance imaging (MRI) with prostate imaging reporting and data system (PIRADS) scores 4-5. The initial diagnosis was made on core biopsies (25 of 49, 51%), transurethal resection specimens (12 of 49, 24%), radical prostatectomies (10 of 49, 20%), Holmium-laser enucleation (one of 49, 2%) and cystoprostatectomy (one of 49, 2%). Tissue involvement was more commonly diffuse or multifocal (40 of 49, 82%). Von Kossa and periodic acid-Schiff stains were positive in 35 of 38 (92%) and 26 of 27 lesions (96%), respectively. Of note, two cases were received in consultation by the authors with a preliminary diagnosis of mesenchymal tumour/tumour of the specialised prostatic stroma. The present study suggests that prostatic MP is often associated with clinical findings that may mimic those of prostate cancer in a subset of patients. Moreover, MP may be found incidentally in patients with concurrent prostate cancer.

Autophagy-associated HMGB-1 as a novel potential circulating non-invasive diagnostic marker for detection of Urothelial Carcinoma of Bladder.

Urothelial carcinoma of bladder (UBC), a highly prevalent urological malignancy associated with high mortality and recurrence rate. Standard diagnostic method currently being used is cystoscopy but its invasive nature and low sensitivity stresses for identifying predictive diagnostic marker. Autophagy, a cellular homeostasis maintaining process, is usually dysregulated in cancer and its role is still enigmatic in UBC. In this study, 30 UBC patients and healthy controls were enrolled. Histopathologically confirmed tumor and adjacent normal tissue were acquired from patients. Molecular expression and tissue localization of autophagy-associated molecules (HMGB-1, RAGE, beclin, LC-3, and p62) were investigated. Serum HMGB-1 concentration was measured in UBC patients and healthy controls. ROC curves were plotted to evaluate diagnostic potential. Transcript, protein, and IHC expression of HMGB-1, RAGE, beclin, and LC-3 displayed upregulated expression, while p62 was downregulated in bladder tumor tissue. Serum HMGB-1 levels were elevated in UBC patients. Transcript and circulatory levels of HMGB-1 showed positive correlation and displayed a positive trend with disease severity. Upon comparison with clinicopathological parameters, HMGB-1 emerged as molecule of statistical significance to exhibit association. HMGB-1 exhibited optimum sensitivity and specificity in serum. The positive correlation between tissue and serum levels of HMGB-1 showcases serum as a representation of in situ scenario, suggesting its clinical applicability for non-invasive testing. Moreover, optimum sensitivity and specificity displayed by HMGB-1 along with significant association with clinicopathological parameters makes it a potential candidate to be used as diagnostic marker for early detection of UBC but requires further validation in larger cohort.

Association of human papillomavirus in penile cancer: A single-center analysis.

Introduction: Human papillomavirus (HPV) is a known risk factor of penile cancer (PeCa). However, studies evaluating its true association are limited. In this study, we aimed to estimate HPV prevalence and its true association with PeCa in terms of molecular biological activities. Materials and Methods: This single-institutional prospective observational study was conducted between June 2016 and August 2019. We included 40 men with PeCa as a study group and 20 age-matched uncircumcised men who underwent circumcision for phimosis as a control group. Both the groups underwent deoxyribonucleic acid isolation for HPV subtyping followed by evaluation of relative E6/E7 messenger ribonucleic acid (mRNA) expression profile and relative telomerase activity in tissue samples. HPV-16 and -18 were categorized as high-risk, whereas HPV-6 and -11 were categorized as low-risk subtypes. Results: The mean (±standard deviation) age of PeCa was 51 ± 15.9 years. The majority of patients had stage II disease, and the most common procedure done was partial penectomy. The overall prevalence of HPV in PeCa was 42.5% (n = 17) as compared to 20% (n = 4) in controls. Among the subtypes, the most common subtype was HPV-16 noted in 33.3% (8/24) of cases, followed by HPV-18 in 29.2% (7/24) of cases. PeCa tissues had a significantly higher relative E7 mRNA expression for HPV-18 than the control group (P = 0.016). The mean relative telomerase activity was significantly higher in the PeCa tissues than the control group (138.66 vs. 14.46, P < 0.001). A significantly higher relative telomerase activity was noted in the PeCa tissues positive for high-risk HPV subtypes than controls (141.90 vs. 14.46, P = 0.0008), but not between high-risk HPV-positive and HPV-negative PeCa cases (141.90 vs. 137.03, P = 0.79). High-risk subtypes were not associated with tumor stage (P = 0.76) or lymph node metastasis (P = 0.816). Conclusions: HPV was associated in 42.5% of PeCa cases based on our experience from a single institution. PeCa tissues had a higher relative E7 mRNA expression for HPV-18 and relative telomerase activity as compared to controls suggesting their potential role as surrogate markers of virus-induced tumorigenesis.

The Genitourinary Pathology Society Update on Classification and Grading of Flat and Papillary Urothelial Neoplasia With New Reporting Recommendations and Approach to Lesions With Mixed and Early Patterns of Neoplasia.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder neoplasia with a focus on issues relevant to the practicing surgical pathologist for the understanding and effective reporting of bladder cancer, emphasizing particularly on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. The work is presented in 2 manuscripts. Here, in the first, we revisit the nomenclature and classification system used for grading flat and papillary urothelial lesions centering on clinical relevance, and on dilemmas related to application in routine reporting. As patients of noninvasive bladder cancer frequently undergo cystoscopy and biopsy in their typically prolonged clinical course and for surveillance of disease, we discuss morphologies presented in these scenarios which may not have readily applicable diagnostic terms in the WHO classification. The topic of inverted patterns in urothelial neoplasia, particularly when prominent or exclusive, and beyond inverted papilloma has not been addressed formally in the WHO classification. Herein we provide a through review and suggest guidelines for when and how to report such lesions. In promulgating these GUPS recommendations, we aim to provide clarity on the clinical application of these not so uncommon diagnostically challenging situations encountered in routine practice, while also importantly advocating consistent terminology which would inform future work.

The Genitourinary Pathology Society Update on Classification of Variant Histologies, T1 Substaging, Molecular Taxonomy, and Immunotherapy and PD-L1 Testing Implications of Urothelial Cancers.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in bladder cancer focusing on important topics of high interest for the practicing surgical pathologist and urologist. This review represents the second of 2 manuscripts ensuing from this effort. Herein, we address the effective reporting of bladder cancer, focusing particularly on newly published data since the last 2016 World Health Organization (WHO) classification. In addition, this review focuses on the importance of reporting bladder cancer with divergent differentiation and variant (subtypes of urothelial carcinoma) histologies and the potential impact on patient care. We provide new recommendations for reporting pT1 staging in diagnostic pathology. Furthermore, we explore molecular evolution and classification, emphasizing aspects that impact the understanding of important concepts relevant to reporting and management of patients.

Role of miRNA-182 and miRNA-187 as potential biomarkers in prostate cancer and its correlation with the staging of prostate cancer.

PURPOSE: The microRNAs expression has emerged as a potential biomarker for the diagnosis and prognosis of prostate cancer. This study investigated the expression of miRNA-182 and miRNA-187 in prostate cancer patients and established a correlation between miRNA expression and staging of prostate cancer. MATERIALS AND METHODS: This prospective observational study involved patients undergoing transrectal ultrasound-guided biopsy for suspicion of prostate cancer. Pre-biopsy urine samples and prostatic core tissue samples of the patients were preserved and the miRNA-182 and miRNA-187 were studied. RESULTS: Sixty-three patients were included in this study, thirty-three patients were diagnosed with prostate cancer and thirty patients having benign histopathology were considered as controls. The expression of miRNA-182 was significantly increased (p=0.002) and miRNA-187 significantly decreased (p<0.001) in prostate cancer tissue specimens. However, the expression of these miRNAs did not significantly differ in the urine of prostate cancer patients as compared to controls. Serum Prostatic Specific Antigen (PSA) inversely correlated with the median expression of miR-187 in prostatic tissue (p=0.002). Further, the expression of miRNA-187 in prostate cancer tissue was significantly decreased in metastatic prostate cancer (p=0.037). Using ROC analysis, miRNA-187 expression was able to distinguish the presence or absence of bone metastasis [area under ROC (AUROC) (±SD) was 0.873±0.061, p<0.001]. CONCLUSION: The miRNA-182 and miRNA-187 appear to be promising biomarkers in prostate cancer and miRNA-187 can serve as an important diagnostic marker of metastatic prostate cancer.

Immunoglobulin G4-related renal disease masquerading as renal pelvic tumor.

The recently recognized immunoglobulin G4 (IgG4)-related disease presenting as renal pelvic pseudotumor is rare. A definitive diagnosis is often difficult to obtain preoperatively, with patients being subjected to radical surgery due to suspicion of malignancy. We present a 64-year-old male with lower urinary tract symptoms, who, on evaluation had a right renal pelvic tumor on imaging and ureteroscopy. The patient underwent laparoscopic radical nephroureterectomy on clinical suspicion of upper tract urothelial carcinoma. The final histopathology revealed IgG4-related disease.

Cytological diagnosis of Langerhans cell histiocytosis: A series of 47 cases.

OBJECTIVE: Langerhans cell histiocytosis (LCH) is a rare disease affecting predominantly children and young adults but can be found in any age group. Diagnosis of LCH is often difficult and can be delayed because of its rarity. The present study highlights the cytomorphological features in a large cohort of cases. An accurate cytological diagnosis may avoid unnecessary biopsy and guide appropriate management. METHOD: Fourty seven (47) cases of LCH diagnosed on cytological material & fine-needle aspiration (FNA) over a period of 14 years (2003-2016) were retrieved from the archives. The cytological smears were evaluated and microscopic findings collected by semi-quantitative assessment done by two different pathologists RESULT: The age at the diagnosis of the patients ranged from 9 months to 28 years. The majority of cases were in the age group of 0-5 years. The most common site was head and neck region, which included cervical lymphadenopathy and scalp swelling. Two cases were diagnosed each from inguinal lymph node and bronchio-alveolar lavage (BAL). Cytological smears in the majority of the cases were moderate to highly cellular (58%) and showing abundant Langerhans cell in (72%) of cases. Areas of necrosis were seen in 38%, while 78% of cases showed giant cells. The majority of cases showed mild eosinophilia (61%), sparse lymphocytosis (83%) and mild neutrophilic infiltration (64%). There were 1-2 mitoses per 10 high power field in 12 cases (25.5%). No abnormal mitoses were identified. CONCLUSION: The presence of cells with features of Langerhans cells associated with the expression of selected immunohistochemical markers allow the diagnosis of LCH on cytological samples, sparing more invasive procedure as a biopsy.

Prognostic stratification of muscle invasive urothelial carcinomas using limited immunohistochemical panel of Gata3 and cytokeratins 5/6, 14 and 20.

BACKGROUND: Genomic studies have delineated distinct molecular subgroups of urothelial carcinomas whose prognostic impact extends beyond traditional stage and grade groupings. The 'basal' subgroup shows increased gene expression levels of KRT5, KRT6, and KRT14 and low expression levels of GATA binding protein 3, and is associated with an extremely poor outcome. Identification of this subset is necessary for improved patient management and research on targeted therapies. We aimed to assess the prognostic utility of immunohistochemistry (IHC) for basal markers: cytokeratin 5/6 (CK5/6) and 14 (CK14), and luminal markers: cytokeratin 20 (CK20) and Gata3 in muscle invasive urothelial carcinomas (MIBC). MATERIALS AND METHODS: Study was of retrospective design (2014-2017). All chemotherapy naïve patients of MIBC undergoing radical cystectomy were included. IHC was performed on formalin fixed paraffin-embedded whole tumor sections. RESULTS: Among 40 cases of MIBC included, 45% (18/40) were positive for one or both basal markers, 37.5% (15/40) were positive for one or both luminal markers, while 15% (6/40) were positive for both basal and luminal markers. One case did not express any of the four markers. MIBCs expressing only basal markers presented at an advanced stage with frequent squamous differentiation and showed a trend towards shorter overall survival. Gata3+ MIBCs showed the best outcome irrespective of expression of other markers, while CK14+/Gata3- MIBCs were associated with worst outcomes. Gata3-/CK14- MIBCs showed intermediate survival outcomes. CK5/6, CK20 and p53 expression did not significantly correlate with outcome. CONCLUSION: IHC for Gata-3 and CK14 stratified MIBC into distinct prognostic subsets.

A clinicopathological study of primary central nervous system lymphomas & their association with Epstein-Barr virus.

BACKGROUND & OBJECTIVES: Primary central nervous system lymphomas (PCNSLs) are relatively uncommon, accounting for 2-3 per cent of primary brain tumours. Majority of these are diffuse large B cell lymphomas (DLBCL) occurring both in immunocompromised and immunocompetent patients. We undertook this study to classify PCNSL into germinal centre (GC) and non-germinal centre (NGC) type based on Hans classification and to find the role of Epstein-Barr virus (EBV) in pathogenesis both by conventional immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). METHODS: The consecutive cases of PCNSL during a 10 years period were analysed by IHC for CD45, CD20, CD3, B-cell lymphoma 2 and 6 (Bcl-2 and Bcl-6), B-cell specific octamer binding protein-1 (BOB-1), multiple myeloma oncogene-1 (MUM-1), EBV latent-membrane protein 1 (LMP-1), cyclin-D1, CD10, CD5 and CD23, as well as by CISH for EBV. RESULTS: During a period of 10 years, 65 PCNSL were diagnosed which comprised 0.69 per cent (65/9476) of all intracranial tumours. The mean age of presentation was 49 yr with sex ratio (M:F) of 1.4:1. Most common location was supratentorial region with predominant involvement of frontal lobe. Single lesions were seen in 38 (58.4%) and multifocal lesions in 27 (41.5%) patients. None of the patients were immunocompromised. All cases were B cell immunophenotype and were DLBCL except one case of follicular lymphoma. According to Hans classification, majority of them were NGC (n=51, 79.6%) and 13 (20.3%) were GC type. Bcl-2 expression was noted in 34 (52.3%) tumours. EBV was positive in three (4.6%) cases; two were detected both by IHC and CISH and one case by CISH only. INTERPRETATION & CONCLUSIONS: In Indian population, PCNSL occurs mainly in immunocompetent patients, and a decade earlier than in western population. Immunophenotyping revealed that all cases were DLBCL with predominance of NGC type. No prognostic difference was seen between GC and NGC DLBCL. Association of EBV was rare and this virus was possibly not involved in the pathogenesis of PCNSL in immunocompetent individuals. CISH was an easy, economical and less cumbersome method for detection of EBV in PCNSL.

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.

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.

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.

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.