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.

Solitary Fibrous Tumor of the Kidney With Pure Round Cell Features: A Case Report With Review of Literature.

Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm known to occur at various soft tissue and visceral locations. Kidney is a rarely reported site for these tumors. Most of the SFTs described in the kidney exhibit a classical CD34-positive patternless spindle cell histology. Focal round cell morphology is seldom reported. Herein, we describe a 48-year-old male patient with renal SFT. This tumor had pure round cell morphology with a CD34-/STAT6+ immunophenotype. Fluorescent in situ hybridization and a multiplexed sequencing assay performed on an Illumina® HiSeq 4000 platform revealed NAB2 and STAT6 gene rearrangement. Renal tumors with round cell morphology are diagnostically challenging and SFT is not often considered in the differential diagnosis of a round cell tumor of the kidney. Moreover, a CD34-negative profile can be rather confounding while diagnosing such lesions. In such scenarios, a strong nuclear STAT6 immunostaining is extremely helpful in clinching the diagnosis. SFT should always be considered in the differential diagnosis of round cell tumors of the kidney due to significant diagnostic and therapeutic implications.

A localized hydrogel-mediated chemotherapy causes immunogenic cell death via activation of ceramide-mediated unfolded protein response.

Treatment of triple-negative breast cancer (TNBC) is challenging because of its "COLD" tumor immunosuppressive microenvironment (TIME). Here, we present a hydrogel-mediated localized delivery of a combination of docetaxel (DTX) and carboplatin (CPT) (called DTX-CPT-Gel therapy) that ensured enhanced anticancer effect and tumor regression on multiple murine syngeneic and xenograft tumor models. DTX-CPT-Gel therapy modulated the TIME by an increase of antitumorigenic M1 macrophages, attenuation of myeloid-derived suppressor cells, and increase of granzyme B+CD8+ T cells. DTX-CPT-Gel therapy elevated ceramide levels in tumor tissues that activated the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-mediated unfolded protein response (UPR). This UPR-mediated activation of apoptotic cell death led to release of damage-associated molecular patterns, thereby activating the immunogenic cell death that could even clear the metastatic tumors. This study provides a promising hydrogel-mediated platform for DTX-CPT therapy that induces tumor regression and effective immune modulation and, therefore, can be explored further for treatment of TNBC.

Gynecological morbidity and treatment-seeking among older adult (aged 45-59) women in India.

BACKGROUND: Women's gynecological health needs are not limited to the reproductive years of their life. Women are at risk of hormonal changes, gynecological malignancies, and various genitourinary conditions as they move toward menopause and beyond. Concerns about older women's sexual and reproductive health and rights (SRHR) continue to be taboo in many countries, of little interest to researchers and professionals in the field of healthcare, and a "blind spot" in discussions about policy as a whole. Despite the widespread agreement, the life course approach to addressing SRHR concerns has received minimal attention. The study estimates the prevalence, assesses the correlates, and treatment-seeking of gynecological morbidity (GM) among older adult women aged 45-59 years (N = 18,547) in India. METHOD: The analysis was based on the nationally representative Longitudinal Ageing Study (2016-2017) data that adopted a multistage stratified area probability cluster sampling to select respondents. The outcome variables used in this analysis were 'had any GM' and 'sought treatment for any GM.' Women with any morbidity such as per vaginal bleeding, foul-smelling vaginal discharge, uterus prolapses, mood swings/irritability, fibroid/cyst, and dry vagina causing painful intercourse were considered to have any GM. Of the respondents with GM, who sought a doctor's consultation or treatment were considered 'sought treatment for any GM.' Binary logistic regression was conducted to examine the adjusted effect of socioeconomic and demographic predictors of GM and treatment-seeking. Stata (V 16) was used for statistical analyses with a 5% significance level. RESULTS: Fifteen percent of the women had any GM, and only 41% of them sought treatment. Age, marital status, education, number of pregnancies, hysterectomy, involvement in household decision-making, social group, religion, wealth status, and region were significantly associated with GM. The odds of treatment-seeking were higher among women with 10+ years of schooling (OR 1.66, CI 1.23, 2.23), with hysterectomy (OR 7.36, CI 5.92, 9.14), with five-plus pregnancies (OR 1.25, CI 0.96, 1.64), and those from the richest (OR 1.91, CI 1.40, 2.60) households than their respective counterparts. CONCLUSION: Many older adult women experience GM, and treatment-seeking is inadequate. The GM prevalence and treatment-seeking vary considerably by socioeconomic and demographic characteristics. Results suggest community-level awareness generation and the inclusion of this otherwise ignored group in programs targeting better health and wellbeing of women.

Anion-responsive self-assembled hydrogels of a phenylalanine-TREN conjugate allow sequential release of propranolol and doxorubicin.

Stimuli-responsive self-assembled and supramolecular hydrogels derived from peptide amphiphiles have opened exciting new avenues in biomedicine and drug delivery. Herein, we screened a series of phenylalanine-amphiphiles possessing polyamine and oxyethylene appendages for their self-assembly and anion-responsiveness and found that the tris(aminoethyl)amine (TREN) containing amphiphile NapF-TREN formed injectable hydrogels that could be disrupted upon the addition of stoichiometric amounts of tetrahedral monovalent anions such as H2PO4- and HSO4-, while the addition of other anions such as Cl-, HPO42-, CO32-, HCO3- or SO42- did not affect the gel stability. The anion-gelator interaction was investigated by 1H and 31P NMR spectroscopy as well as by Isothermal Titration Calorimetry (ITC). These studies confirmed a 1 : 1 stoichiometry and revealed negative enthalpy and negative entropy for the binding of H2PO4- with NapF-TREN. Microscopic investigations by TEM, AFM, and SAXS revealed that H2PO4- anions induced a nanofiber-to-nanoglobule morphological change in the aqueous self-assemblies of NapF-TREN. However, upon ageing the samples, slow reformation of the nanofibers was also observed, reflecting the reversibility of the anion-gelator interaction. The anion- and pH-responsive nature of the NapF-TREN hydrogels was exploited to program sequential release of entrapped drugs propranolol and doxorubicin.

p53 and p16ink4a As Predictive and Prognostic Biomarkers for Nodal metastasis and Survival in A Contemporary Cohort of Penile Squamous Cell Carcinoma.

BACKGROUND: Human papilloma virus (HPV) infection is implicated in a proportion of invasive squamous cell carcinoma of the penis (PC). A subset of PC involves dysregulation of the p53 pathway. HPV in situ hybridization (ISH) and p16ink4a positivity are surrogate markers for HPV infection, and p53 immunohistochemistry (IHC) denotes abnormality in the p53 pathway. There remains an ambiguity with regard to the contribution of both the pathways in the prognosis of PC. We sought to analyze the clinicopathologic characteristics of a cohort of Indian PC patients with respect to p16 ink4a and p53 expression. PATIENTS AND METHODS: A cohort of 123 PC patients was studied for p16ink4aand p53IHC and HPVISH. The results of these biomarkers were correlated with various clinicopathologic parameters. RESULTS: p16ink4a and HPV ISH were positive in 47% and 53% of the tumors, respectively. The proportion of warty, basaloid, or mixed warty-basaloid tumor subtypes showed significant p16ink4apositivity (P < .0001) compared to other subtypes. Twenty-eight patients were dual negative (p53- /p16ink4a-), 32 were dual positive (p53+/p16ink4a+), 38 were p53+/p16ink4a-, and 25 were p53-/p16ink4a +. In patients where p16ink4a was negative, a p53-positive phenotype had a higher propensity for lymph node metastases (OR, 5.42; 95% CI, 1.75-16.80; P = .003). Similarly, p53 positivity dictates nodal involvement in the p16ink4a-positive subset of tumors (OR, 5.00; 95% CI, 1.23-20.17; P = .024). On multivariate analyses, pathologic subtypes (warty, warty-basaloid, and basaloid) (P < .0001), p16ink4aexpression (P < .0001), and absence of nodal metastasis (P < .0001) were significant predictors of improved overall (OS) and cancer specific survival (CSS). In Kaplan-Meier analysis, the OS was significantly longer in patients with p16ink4a + tumors (P < .0001), as was the CSS (P < .0001). Patients with dual positive tumors had a significantly higher OS (P < .001) and CSS (P = .012), in the entire cohort. In the node positive patients, dual positivity was associated with significantly higher OS (P < .0001); however, the median CSS for p53+/p16ink4a+tumors were not significantly different compared to p53- /p16ink4a- tumors (P = .064), although there was a trend towards improved CSS. CONCLUSIONS: There is a strong concordance between p16ink4aIHC and HPV ISH results. p16ink4a status is an independent predictor of survival (OS and CSS) in our cohort of PCs. p53 is a predictor of nodal metastasis irrespective of p16 status. Dual positive tumors have a significantly better outcome in comparison to dual negative tumors.

Reappraisal of HER2 Amplification in High-Grade Urothelial Carcinoma Based on 2018 ASCO/CAP Clinical Practice Guidelines.

OBJECTIVES: To examine and compare human epidermal growth factor receptor 2 (HER2) amplification status in high-grade urothelial carcinoma (HGUCa), using both 2013 and 2018 HER2 reporting guidelines for breast carcinoma from the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP). METHODS: HER2 status by fluorescence in situ hybridization (FISH) assay in 78 cases of HGUCa was compared using 2013 and 2018 HER2 reporting guidelines. RESULTS: HER2 amplification was observed in 22 (28.2%) of 78 tumors, of which 17 were in group 1, 1 in group 2, and 2 each in groups 3 and 4 (FISH assay, 2018). The remaining 14 HER2-amplified tumors (FISH assay, 2013) became negative, falling into group 2 (FISH assay, 2018) and were either negative or equivocal on immunohistochemistry (IHC, 2018). All FISH-negative tumors (n = 37) using 2013 criteria remained negative (group 5, 2018). FISH-equivocal tumors (2013) were further categorized into HER2 amplified (n = 1) and HER2 negative (n = 4) (2018). Overall, 20 (25.6%) tumors had discordant HER2 FISH results (2018 vs 2013). CONCLUSIONS: Implementing 2018 guidelines, HER2 amplification decreased from 36 to 22 cases. The group with a HER2/CEP17 ratio of 2 or more and average HER2 copy number less than 4 (group 2) were predominantly negative by IHC, suggesting a biologically distinct group of HGUCa that is different from HER2-amplified tumors, which may not respond to HER2-targeted therapy.

Correlates of tobacco quit attempts and missed opportunity for tobacco cessation among the adult population in India.

INTRODUCTION: Tobacco cessation is crucial to reduce tobacco-related diseases and premature deaths. Quitting efforts can be enhanced through brief routine interventions at health facilities because healthcare providers are highly trusted, resulting in stronger adherence to their advice. MATERIALS AND METHODS: This study used data on tobacco users aged 15-49 years (n = 93,522) collected as part of the fourth round of the National Family Health Survey (NFHS) 2015-16. Bivariate and multivariate analyses were carried out using STATA (version 13) to understand the socioeconomic and demographic correlates of tobacco quit attempts and advice to quit by healthcare providers. GIS map has been used to show inter-state variations in quit attempts and advice. RESULTS: Thirty per cent of the tobacco users were found to have attempted to quit tobacco. Education, mass media exposure, economic status, and chronic disease emerged as enablers, while alcohol use and social backwardness came out as barriers to quit attempts. Quit advice from the healthcare providers was found not to be given frequently (51%) and varied significantly by the socioeconomic and demographic profile of the users. Not all of the tobacco users attempting to quit had been advised to quit, indicating a missed opportunity to intervene and reinforce quitting at a health facility. CONCLUSIONS: Fewer attempts to quit among the adolescents, the less educated, and the users from the poorest households may increase the burden of tobacco-attributable diseases unless timely interventions are made. Better training of the healthcare providers in administering and recommending tobacco cessation and emphasizing on the value of cessation counselling is urgently required to enhance quitting practices and improve health.

Cytomorphologic and Immunophenotypic Profile of a Cohort of Small Cell Carcinoma of the Urinary Bladder.

BACKGROUND: The incidence of primary small cell carcinoma (SCC) of the urinary bladder is extremely rare. We sought to analyze the cytologic and immunophenotypic features of SCC of the urinary bladder in urine and reassert the importance of cytologic examination of urine specimens for diagnosis of this tumor. METHODS: We studied the clinical and cytomorphologic features in the presurgical urine specimens (4 voided urine and 2 bladder-washing specimens) of histopathologically and immunohistochemically proven cases of SCC of the urinary bladder. RESULTS: There were 6 cases, all males, with an age range of 61-81 years. On cytologic and histopathologic examination, typical SCC morphology was present in all cases. On immunohistochemistry, synaptophysin and CD56 were positive in all 6 cases, while chromogranin was positive in only 3. The Ki-67 labeling index ranged from 30 to 100%. CONCLUSIONS: SCC should be kept in the differential diagnosis, when high-grade urothelial carcinoma is suspected in a urine cytology specimen, as this distinction has important therapeutic and prognostic implications. Therefore, a careful observation and, if required, the use of an appropriate immunocytochemical panel on the presurgical urine specimens can lead to a correct diagnosis.

Inflammatory myofibroblastic tumor of the urinary bladder managed by laparoscopic partial cystectomy.

Inflammatory myofibroblastic tumor of the urinary bladder is a rare mesenchymal tumor with uncertain malignant potential. It often mimics soft tissue sarcomas both clinically and radiologically. Surgical resection in the form of partial cystectomy or transurethral resection remains the mainstay of treatment. Herein we report the case of an inflammatory myofibroblastic tumor in a young girl, which was managed by laparoscopic partial cystectomy. To the best of our knowledge, this is the first reported case of laparoscopic management of an inflammatory myofibroblastic tumor of the urinary bladder.

Preputial/penile skin flap, as a dorsal onlay or tubularized flap: a versatile substitute for complex anterior urethral stricture.

UNLABELLED: Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? For long complex anterior urethral stricture augmentation urethroplasty is considered the standard procedure but the best substitute material is still to be ascertained. Preputial/penile skin is a very good substitute especially when used as a dorsal onlay. It demonstrates exceptional functional and cosmetic results even in patients with unsuitable oral mucosa. OBJECTIVE: • To present our experience of single-stage reconstruction of urethral stricture with preputial/penile skin flap, as a dorsal onlay flap (DOF) where there is an adequate urethral plate and as a tubularized flap (TF) where there is a compromised urethral plate, in cases of complex anterior urethral strictures. MATERIALS AND METHODS: • We retrospectively reviewed 144 patients, who underwent single-stage repair of pendular /bulbar urethral strictures with preputial/penile flap as either a DOF or a TF, between January 2001 and December 2008. • Patients were divided into three groups: Group 1 consisted of patients who underwent transverse preputial DOF; Group 2 consisted of those who underwent tube urethroplasty; and Group 3 consisted of those patients who were circumcised and for whom the penile skin was used as a DOF (circumpenile flap). • Patients were followed up by physical examination, retrograde urethrography, uroflowmetry and post-void residual urine measurement. RESULTS: • The mean follow-up was 40.1 months (range 36-84 months). • The primary success rates at 1 year follow-up were 90, 85 and 93.3% for Groups1, 2 and 3, respectively, and at 3-years follow-up they were 85, 75 and 86.7%, respectively. • Half of the recurrences were successfully managed with a single visual internal urethrotomy or dilatation. • The secondary success rate was defined as recurrent stricture managed by a single endoscopic procedure and was 5, 10 and 6.8% in Groups 1, 2 and 3, respectively. The overall success rate was 90.85 and 93.3%, respectively. • A total of 75% of the patients in the study completed 60 months of follow-up with no additional recurrence. CONCLUSIONS: • A preputial/penile flap for complex anterior urethral stricture is a good treatment option, with results similar to other techniques, has acceptable donor site morbidity and is effective even in circumcised patients and for those patients with unsuitable oral mucosa. • A DOF is less likely to lead to diverticula formation and post-void dribbling. TFs have a higher failure rate than DOFs but, when combined judiciously with secondary endoscopic procedures, can provide good results.

Isolated renal zygomycosis: novel diagnostic and prognostic criteria with experience of a tertiary care center.

BACKGROUND: Isolated renal zygomycosis is a life-threatening infection and difficult to diagnose ante mortem due to varied presentations. Most reports in the literature are case reports. We are presenting our experience of 10 patients. MATERIALS AND METHODS: Retrospective data of 10 consecutive patients with primary renal zygomycosis, including 2 post-transplant patients, in our tertiary care center was analyzed. Epidemiological characteristics, predisposing conditions, clinical presentation, diagnostic findings and treatment outcomes were recorded. Characteristic radiological findings were recorded. Localized disease was managed by supportive treatment or percutaneous drainage and extensive disease with unilateral or bilateral nephrectomy. Renal involvement was confirmed in all patients by histopathology. RESULTS: The mean age of presentation was 35 years. Five patients who had bilateral renal involvement presented with oliguric acute renal failure, hematuria and abdominal pain. Three had unilateral renal disease and presented with flank pain and fever. The two post-transplant patients presented with fever and graft dysfunction. Even after aggressive treatment 5 patients died, accounting for a mortality rate of 50%. CONCLUSION: Isolated renal zygomycosis can be diagnosed with typical radiological findings, combined with clinical, laboratory and histopathological features. This study describes the newer ante mortem radiological diagnostic criteria and prognostic predictors of the disease.

Bone densitometric assessment and management of fracture risk in Indian men of prostate cancer on androgen deprivation therapy: Does practice pattern match the guidelines?

OBJECTIVE: Estimation of baseline bone mineral density (BMD) at the time of instituting androgen deprivation therapy (ADT) for metastatic prostate cancer is recommended by several specialty groups and expert panels. The present study was carried out to analyze the practice pattern of Indian urologists with regard to bone densitometric assessment and management of fracture risk in men of prostate cancer on ADT, and their degree of adherence to currently available guidelines. MATERIALS AND METHODS: Telephonic interviews of 108 qualified urologists, randomly selected from the member database of Urological Society of India was carried out with a predefined questionnaire. The responses were analyzed and compared with the available evidences and recommendations. RESULTS: Only 19.4% urologists routinely perform a baseline BMD before starting ADT. Although majority of them prescribe calcium and vitamin D supplementation, only few tell regarding fracture risk and life-style modification to their patients. While 59.6% of the respondents use Zoledronic acid (ZA) in their patients on ADT, half of them prescribe it without knowing the BMD status, which may lead to overuse of ZA. CONCLUSION: Majority of the urologists in India do not follow the guidelines for BMD measurement in prostate cancer. A baseline BMD may help in reducing the unnecessary use of ZA.