Impact of variant histology on upstaging and survival in patients with nonmuscle invasive bladder cancer undergoing radical cystectomy.

INTRODUCTION: Variant histology (VH) of urothelial carcinoma is uncommon and frequently presents at the muscle-invasive stage. VH is considering a significant risk factor for progression among patients with nonmuscle invasive bladder cancer (NMIBC). While there is some debate, expert opinion is generally that upfront radical cystectomy (RC) should be consider for these patients. Limited data exists to support this position. In this study, we sought to examine the rate of upstaging and overall survival for patients with VH NMIBC against patients with pure urothelial NMIBC who underwent RC, to help clarify the optimal treatment strategy for these patients. METHODS: The institutional REDCap database was utilized to identify all patients with T1 and Ta bladder cancer that underwent RC over the study period (2004-2022). Matched-pair analysis was performed between patients with VH and pure urothelial NMIBC; 42 pairs were matched on prior intravesical therapy, presence of muscularis propria on transurethral resection of bladder tumor (TURBT), any carcinoma in situ presence on prior TURBTs, and final tumor staging on TURBT. The primary outcomes of interest were pathologic tumor upstaging rate at RC and overall survival. Secondary outcomes of interest included association of demographic or pretreatment variables with upstaging, and upstaging rates for specific variant histologies. RESULTS: Patients with VH NMIBC undergoing RC were upstaged at a significantly higher rate than a matched cohort of patients with pure urothelial NMIBC (73.8% vs. 52.4%, P = 0.0244) and among those upstaged, had significantly higher rates of pT3 to pT4 (54.7% vs. 23.8%, P = 0.0088). Rate of node positivity at RC for VH NMIBC was also higher compared to pure urothelial NMIBC (40.5% vs. 21.4%, P = 0.0389). Among histologic variants, patients with plasmacytoid and sarcomatoid subtypes demonstrated the highest rates of upstaging; differences were not statistically significant. The overall median survival was 28.4 months for patients with VH after RC compared to 155.1 months for patients with pure urothelial NMIBC (P = 0.009). CONCLUSION: Patients with VH NMIBC undergoing RC are at significantly higher risk of upstaging at RC when compared to patients with pure urothelial NMIBC and have worse overall survival. While this study supports the concept of an aggressive treatment approach for patients with VH NMIBC, improvements in understanding of the disease are necessary to improve outcomes.

MRI Shrimp Sign in Cerebellar Progressive Multifocal Leukoencephalopathy: Description and Validation of a Novel Observation.

BACKGROUND AND PURPOSE: There are no validated imaging criteria for the diagnosis of progressive multifocal leukoencephalopathy in the cerebellum. Here we introduce the MR imaging shrimp sign, a cerebellar white matter lesion identifiable in patients with cerebellar progressive multifocal leukoencephalopathy, and we evaluate its sensitivity and specificity. MATERIALS AND METHODS: We first identified patients with progressive multifocal leukoencephalopathy seen at Massachusetts General Hospital between 1998 and 2019 whose radiology reports included the term "cerebellum." Drawing on a priori knowledge, 2 investigators developed preliminary diagnostic criteria for the shrimp sign. These criteria were revised and validated in 2 successive stages by 4 additional blinded investigators. After defining the MR imaging shrimp sign, we assessed its sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: We identified 20 patients with cerebellar progressive multifocal leukoencephalopathy: 16 with definite progressive multifocal leukoencephalopathy (mean, 46.4 [SD, 9.2] years of age; 5 women), and 4 with possible progressive multifocal leukoencephalopathy (mean, 45.8 [SD, 8.5] years of age; 1 woman). We studied 40 disease controls (mean, 43.6 [SD, 21.0] years of age; 16 women) with conditions known to affect the cerebellar white matter. We defined the MR imaging shrimp sign as a T2- and FLAIR-hyperintense, T1-hypointense, discrete cerebellar white matter lesion abutting-but-sparing the dentate nucleus. MR imaging shrimp sign sensitivity was 0.85; specificity, 1; positive predictive value, 1; and negative predictive value, 0.93. The shrimp sign was also seen in fragile X-associated tremor ataxia syndrome, but radiographic and clinical features distinguished it from progressive multifocal leukoencephalopathy. CONCLUSIONS: In the right clinical context, the MR imaging shrimp sign has excellent sensitivity and specificity for cerebellar progressive multifocal leukoencephalopathy, providing a new radiologic marker of the disease.

Efficacy and safety of rucaparib in previously treated, locally advanced or metastatic urothelial carcinoma from a phase 2, open-label trial (ATLAS).

BACKGROUND: ATLAS evaluated the efficacy and safety of the PARP inhibitor rucaparib in patients with previously treated locally advanced/unresectable or metastatic urothelial carcinoma (UC). METHODS: Patients with UC were enrolled independent of tumor homologous recombination deficiency (HRD) status and received rucaparib 600 mg BID. The primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (loss of genome-wide heterozygosity ≥10%) populations. Key secondary endpoints were progression-free survival (PFS) and safety. Disease control rate (DCR) was defined post-hoc as the proportion of patients with a confirmed complete or partial response (PR), or stable disease lasting ≥16 weeks. RESULTS: Of 97 enrolled patients, 20 (20.6%) were HRD-positive, 30 (30.9%) HRD-negative, and 47 (48.5%) HRD-indeterminate. Among 95 evaluable patients, there were no confirmed responses. However, reductions in the sum of target lesions were observed, including 6 (6.3%) patients with unconfirmed PR. DCR was 11.6%; median PFS was 1.8 months (95% CI, 1.6-1.9). No relationship was observed between HRD status and efficacy endpoints. Median treatment duration was 1.8 months (range, 0.1-10.1). Most frequent any-grade treatment-emergent adverse events were asthenia/fatigue (57.7%), nausea (42.3%), and anemia (36.1%). Of 64 patients with data from tumor tissue samples, 10 (15.6%) had a deleterious alteration in a DNA damage repair pathway gene, including four with a deleterious BRCA1 or BRCA2 alteration. CONCLUSIONS: Rucaparib did not show significant activity in unselected patients with advanced UC regardless of HRD status. The safety profile was consistent with that observed in patients with ovarian or prostate cancer. TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov (NCT03397394). Date of registration: 12 January 2018. This trial was registered in EudraCT (2017-004166-10).

Phase II trial of pembrolizumab in patients with platinum refractory germ-cell tumors: a Hoosier Cancer Research Network Study GU14-206.

Background: Despite remarkable results with salvage standard-dose or high-dose chemotherapy ∼15% of patients with relapsed germ-cell tumors (GCT) are incurable. Immune checkpoint inhibitors have produced significant remission in multiple tumor types. We report the first study of immunotherapy in patients with GCT. Patients and methods: Single arm phase II trial investigating pembrolizumab 200 mg i.v. Q3weeks until disease progression in patients with relapsed GCT and no curable options. Patients age ≥18 with GCT who progressed after first-line cisplatin-based chemotherapy and after at least one salvage regimen (high-dose or standard-dose chemotherapy) were eligible. Centrally assessed programmed death-ligand 1 (PD-L1) on tumor and infiltrating immune cells was scored. Primary end point was overall response rate using immune-related response criteria. Simon two-stage design with type I error 20% and power 80% was utilized. Results: Twelve male patients were enrolled. Median age was 38 years. All patients had nonseminoma. Primary site was testis (11) or mediastinum (1). Median AFP 615 (range 1-32, 760) and hCG 4 (range 0.6-37, 096). Six patients had late relapse (>2 years). Median number of previous chemotherapy regimens was 3. Six patients received prior high-dose chemotherapy. Two patients had positive PD-L1 staining (H-score 90 and 170). Median number of pembrolizumab doses was 2 (range 1-8). There were six grade 3 adverse events. No immune-related adverse events were reported. No partial or complete responses were observed. Two patients achieved radiographic stable disease for 28 and 19 weeks, respectively; both had continued rising AFP level despite radiographic stability and had negative PD-L1 staining. Conclusion: This is the first reported trial evaluating immune checkpoint inhibitors in GCT. Pembrolizumab is well tolerated but does not appear to have clinically meaningful single-agent activity in refractory GCT. Clinical trial information: NCT02499952.

Multidisciplinary clinic approach improves overall survival outcomes of patients with metastatic germ-cell tumors.

Background: To report our experience utilizing a multidisciplinary clinic (MDC) at Indiana University (IU) since the publication of the International Germ Cell Cancer Collaborative Group (IGCCCG), and to compare our overall survival (OS) to that of the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) Program. Patients and methods: We conducted a retrospective analysis of all patients with metastatic germ-cell tumor (GCT) seen at IU from 1998 to 2014. A total of 1611 consecutive patients were identified, of whom 704 patients received an initial evaluation by our MDC (including medical oncology, pathology, urology and thoracic surgery) and started first-line chemotherapy at IU. These 704 patients were eligible for analysis. All patients in this cohort were treated with cisplatin-etoposide-based combination chemotherapy. We compared the progression-free survival (PFS) and OS of patients treated at IU with that of the published IGCCCG cohort. OS of the IU testis cancer primary cohort (n = 622) was further compared with the SEER data of 1283 patients labeled with 'distant' disease. The Kaplan-Meier method was used to estimate PFS and OS. Results: With a median follow-up of 4.4 years, patients with good, intermediate, and poor risk disease by IGCCCG criteria treated at IU had 5-year PFS of 90%, 84%, and 54% and 5-year OS of 97%, 92%, and 73%, respectively. The 5-year PFS for all patients in the IU cohort was 79% [95% confidence interval (CI) 76% to 82%]. The 5-year OS for the IU cohort was 90% (95% CI 87% to 92%). IU testis cohort had 5-year OS 94% (95% CI 91% to 96%) versus 75% (95% CI 73% to 78%) for the SEER 'distant' cohort between 2000 and 2014, P-value <0.0001. Conclusion: The MDC approach to GCT at high-volume cancer center associated with improved OS outcomes in this contemporary dataset. OS is significantly higher in the IU cohort compared with the IGCCCG and SEER 'distant' cohort.

Prognostic factors in patients with poor-risk germ-cell tumors: a retrospective analysis of the Indiana University experience from 1990 to 2014.

BACKGROUND: Based on the risk stratification from the International Germ Cell Cancer Collaborative Group (IGCCCG), only 14% of patients with metastatic germ-cell tumors (GCT) had poor-risk disease with a 5-year progression-free survival (PFS) rate of 41% and a 5-year overall survival (OS) rate of only 48%. This analysis attempts to identify prognostic factors for patients with poor-risk disease. PATIENTS AND METHODS: We conducted a retrospective analysis of all patients with GCT diagnosed and treated at Indiana University from 1990 to 2014. Clinical and pathological characteristics were available for all patients and all of them were treated with cisplatin-etoposide-based chemotherapy. Cox proportional hazards models were used to target significant predictors of disease progression and mortality. A significance level of 5% was used in the analysis. RESULTS: We identified 273 consecutive patients with poor-risk GCT (PRGCT). Median follow-up time was 8 years (range 0.03-24.5). The 5-year PFS and OS rates were 58% [95% confidence interval (CI) 51% to 63%] and 73% (95% CI 67% to 78%), respectively. In multivariate survival analyses, multiple risk factors were associated with disease progression, including liver metastasis, brain metastasis, primary mediastinal nonseminomatous GCT (PMNSGCT), and elevation in logarithmic ß-hCG. Significant predictors of mortality were PMNSGCT [hazard ratio (HR) 4.63, 95% CI 2.25-9.56; P < 0.001], brain metastasis (HR 3.30, 95% CI 1.74-6.23; P < 0.001), and increasing age (HR 1.03, 95% CI 1.01-1.06; P = 0.02). CONCLUSIONS: Patients with PMNSGCT, brain metastasis, or with increasing age are at higher risk of death than their counterparts. This contemporary cohort (1990-2014) of 273 patients with PRGCT had improved PFS and OS outcomes than those from the historical IGCCCG group of patients (1975-1990).

Association between dietary patterns and the risk of metabolic syndrome among Lebanese adults.

PURPOSE: The main objective of this study was to evaluate the association between dietary patterns and the metabolic syndrome (MetS) and its metabolic abnormalities among Lebanese adults, using data from a national nutrition survey. METHODS: A cross-sectional analysis involving adults aged ≥ 18 years (n = 323) with no prior history of chronic diseases was conducted. Participants completed a brief sociodemographic and 61-item food frequency questionnaire. Anthropometric measurements and fasting blood samples were also obtained. The International Diabetes Federation criteria were used to classify study participants with the metabolic syndrome. Dietary patterns were identified by factor analysis. Multivariate logistic regression analysis was used to evaluate the associations of extracted patterns with MetS and its metabolic abnormalities. RESULTS: Out of 323 participants, 112 (34.6%) were classified as having MetS. Three dietary patterns were identified: "Fast Food/Dessert," "Traditional Lebanese," and "High Protein." Compared with participants in the lowest quintile of the Fast Food/Dessert pattern, those in the highest quintile had significantly higher odds for MetS (OR, 3.13; 95% CI: 1.36-7.22) and hyperglycemia (OR, 3.81; 95% CI: 159-9.14). Subjects with the highest intake of the High Protein pattern had an increased risk for hypertension (OR, 2.98; 95% CI: 1.26-7.02). The Traditional Lebanese pattern showed no association with MetS or its components. CONCLUSIONS: The findings of this study demonstrate a positive association of the Fast Food/Dessert pattern with MetS and hyperglycemia among Lebanese adults. These results may guide the development of improved preventive nutrition interventions in this adult population.

Metabolic syndrome and insulin resistance in obese prepubertal children in Lebanon: a primary health concern.

BACKGROUND/AIMS: Ethnic-based associations between obesity and the metabolic syndrome (MS) have been suggested. The prevalence of MS in obese children was found to range between 13.9 and 48.8%, depending on the country of origin. This study was conducted to investigate the relationship between obesity and various components of MS in prepubertal children in Lebanon. METHODS: Eighty-seven obese children (Tanner stage 1), 25 overweight and 28 normal-weight controls were recruited from private and public schools. Anthropometric, biochemical and blood pressure measurements were performed. RESULTS: According to the modified Adult Treatment Panel III definition, the MS was identified in 26.4 and 4% of obese and overweight children, respectively, with a higher prevalence among girls than boys. The most common abnormalities among subjects with MS were elevated waist circumference (WC) (100.0%), high triglyceride (91.7%) and low high-density lipoprotein cholesterol (66.7%) levels. Insulin resistance was identified in 70% of obese children and 75% of those having the MS. Body mass index, WC and homeostasis model assessment of insulin resistance were significant determinants of the MS in this age group. CONCLUSION: MS was found in 26.4% of obese Lebanese children, thus underscoring the importance of early screening of obesity and its associated metabolic abnormalities and of developing successful multicomponent interventions addressing pediatric obesity and MS.

Adolescent obesity in Syria: prevalence and associated factors.

Abstract Background Data on the prevalence of overweight and obesity in Eastern Mediterranean countries remain scarce, particularly for children and adolescents. The objective of this study is to estimate the prevalence of obesity and examine associated factors and covariates amongst school adolescents in Syria. Methods A cross-sectional survey of a representative sample of 776 adolescents (386 males and 390 females), aged 15-18 years, was conducted in six randomly chosen secondary schools in Damascus, the capital city of Syria. Anthropometric measurements and dietary assessment data were collected using standard methods and techniques. Overweight and obesity were defined according to World Health Organization 2007 child growth standards. Results The prevalence rates of overweight and obesity were estimated at 18.9 and 8.6%, respectively. Carbohydrate and saturated fatty acid intakes were significantly higher amongst overweight and obese (250.66 and 32.82 g/day, respectively) as compared with normal weight adolescents (218.12 and 26.10 g/day, respectively). Regression analysis showed that the likelihood of obesity was significantly greater amongst adolescent boys than girls (OR = 2.30, P < 0.05) and amongst subjects reporting family history of obesity (OR = 2.98, P < 0.05). The odds of obesity increased consistently with increasing educational attainment of both parents and was higher (OR = 1.63) amongst adolescents reporting lower crowding index than their counterparts. Conclusion Our findings of a positive association between obesity and socio-economic status measured by parental education and crowding index call for intervention strategies for the promotion of healthy dietary practices not only amongst school adolescents but also parents, targeting families as the unit of intervention. Further studies are needed to examine nutritional habits and food choices amongst families of different socio-economic strata.

Nutritional status of Bedouin children aged 6-10 years in Lebanon and Syria under different nomadic pastoral systems.

PIP: During April-July 1993, anthropometric measurements of 296 children aged 6-10 years from four different Bedouin groups of Lebanon and Syria and interviews with their caretakers were conducted to determine child nutritional status and to examine the association between their diet and nutritional status. The children were from the semi-settled Bedouins of the Beqa'a valley in Lebanon, who practice livestock production and seasonal labor; the transhumant Bedouins of the Akkar area of Lebanon, who follow traditional migration routes between winter quarters in valleys to summer mountain grazing areas; true nomadic groups in Syria with limited access to markets and agricultural produce; and settled Bedouins herding governmental livestock in exchange for food and pay in Syria's Aleppo dessert. The Bedouin children in the Beqa'a valley were less likely to be malnourished than those in the other groups. 6.8% of Beqa'a valley children were severely stunted (2 Z-scores below the reference population) compared to 14.8% of those from the Akkar, 24% from the Palmyra, and 41.1% from the Aleppo. 41.8% of Beqa'a valley children were mildly stunted (1 Z-score below the reference population) compared to their counterparts (43.2%, 69%, and 70.5%, respectively). 3.9% of the Beqa'a valley children were severely underweight compared to 5.7% of the Akkar, 7% of the Palmyra, and 14.7% of the Aleppo. Proportion of mildly underweight children was 26.3% for Beqa'a valley children, 48.9% for Akkar children, 67.5% for Palmyra children, and 64.7% for Aleppo children. The children in the Beqa'a valley had higher intakes of important macronutrients and micronutrients than those from the other groups, confirming that diet and food availability contribute to stunting and underweight in Bedouin children. The arid region with frequent droughts, difficult living conditions, scarcity of fruits and vegetables, and lack of extra income sources likely contributed to the poor nutritional status of the true nomads of Palmyra. Very low intake of nutrients among the Aleppo and Palmyra groups explained their very low nutritional status.^ieng