bluuebunny/crossref_metadata_2025 huggingface dataset:
Bacterial communities in carnivorous pitcher plants colonize and persist in inquiline mosquitoes
Authors: Arellano Aldo A. , Coon Kerri L.
Published: February 2022

Background

The leaves of carnivorous pitcher plants harbor diverse communities of inquiline species, including bacteria and larvae of the pitcher plant mosquito (Wyeomyia smithii), which aid the plant by processing captured prey. Despite the growing appreciation for this microecosystem as a tractable model in which to study food web dynamics and the moniker ofW. smithiias a ‘keystone predator’, very little is known about microbiota acquisition and assembly inW. smithiimosquitoes or the impacts ofW. smithii-microbiota interactions on mosquito and/or plant fitness.

Results

In this study, we used high throughput sequencing of bacterial 16S rRNA gene amplicons to characterize and compare microbiota diversity in field- and laboratory-derivedW. smithiilarvae. We then conducted controlled experiments in the laboratory to better understand the factors shaping microbiota acquisition and persistence across theW. smithiilife cycle. Methods were also developed to produce axenic (microbiota-free)W. smithiilarvae that can be selectively recolonized with one or more known bacterial species in order to study microbiota function. Our results support a dominant role for the pitcher environment in shaping microbiota diversity inW. smithiilarvae, while also indicating that pitcher-associated microbiota can persist in and be dispersed by adultW. smithiimosquitoes. We also demonstrate the successful generation of axenicW. smithiilarvae and report variable fitness outcomes in gnotobiotic larvae monocolonized by individual bacterial isolates derived from naturally occurring pitchers in the field.

Conclusions

This study provides the first information on microbiota acquisition and assembly inW. smithiimosquitoes. This study also provides the first evidence for successful microbiota manipulation in this species. Altogether, our results highlight the value of such methods for studying host-microbiota interactions and lay the foundation for future studies to understand howW. smithii-microbiota interactions shape the structure and stability of this important model ecosystem.
Risk stratification of endometrial cancer and lymph node metastases prediction using 18F-FDG PET/CT: role of metabolic tumor volume and total lesion glycolysis
Authors: Abdelkawi Mostafa M. , Sweed Mohamed S. , Ali Mohamed A. , NasrElDin Eman A.
Published: February 2022

Background

Endometrial cancer is the commonest gynecologic malignancy. Pelvic lymph node metastasis is considered one of its most important prognostic factors. Surgery is considered the most important and effective treatment, still there is controversy about indication and necessity of pelvic lymph node dissection. 18F-fluorodeoxyglucose positron emission tomography/computed tomography is investigated in his study to evaluate its value in preoperative detection of lymph node metastases and risk stratification of endometrial cancer.

Results

Reviewing the records of 33 women with endometrial cancer, all 18F-FDG PET/CT studied indices, SUVmax, SUVmean, MTV and TLG, mean difference was statistically significant in all the studied risk categories (tumor grade, Myometrial invasion, lymphovascular space invasion, tumor stage, and risk stratification). SUVmax and TLG showed highest area under the curve for detection of Myometrial invasion > 50% (AUC = 0.911) with cut-off value of SUVmax > 14.55 showing 88.89% sensitivity and 86.67% specificity, and TLG > 192.653 having 88.89% sensitivity and 80% specificity. TLG showed highest AUC (0.889 and 0.921) for detection of LVSI and LNMs with 100% sensitivity and 66.67% specificity for cut-off value > 179.374 and 88.89% sensitivity and 83.33% specificity for cut-off value > 249.366, respectively. Concerning risk stratification of EC, SUVmax and TLG showed highest AUC (0.839) with cut-off value > 14.55 showing 77.27% sensitivity and 90.91% specificity, and > 192.653 having 77.27% sensitivity and 81.82% specificity, respectively.

Conclusion

The results of this study suggest that 18F-FDG PET/CT is a very valuable tool for prediction of lymph node metastases and risk stratification in endometrial cancer patients. Applying TLG cutoff values increases the accuracy and preoperative diagnosis of lymph node metastases which aids in sparing women with low-risk early stage EC unnecessary surgical risk and morbidity of lymphadenectomy.
A rule-based model for electricity theft prevention in advanced metering infrastructure
Authors: Otuoze Abdulrahaman Okino , Mustafa Mohd Wazir , Abioye Abiodun Emmanuel , Sultana Umbrin , Usman Ayinde Muhammed , Ibrahim Oladimeji , Omeiza Isaac Ozovehe Avazi , Abu-Saeed Abdallah
Published: February 2022

The deployment of smart electricity meter (SEM) via the advanced metering infrastructure (AMI) has come under cyber-attacks as adversaries continue to exploit the communication links for possible evasion of electricity bill payments. Various detection models relying on energy consumption data offer a disadvantage of delayed detection and consequent huge financial losses before frauds are detected. Moreover, existing techniques mostly concentrate on detection of electricity thefts and rely on energy consumption data alone as the basis of theft perpetration whereas other potential parameters which could be exploited for electricity theft prevention exist in AMI. In this study, AMI parameters, which are indicative of electricity thefts are preselected and modelled for electricity theft prevention. First, a given AMI network is sectioned into zones with the selected parameters modelled to define security risks by formulated set of rules based on real-time scenarios. Fuzzy inference system is then employed to model the security risks to ascertain the compromised state of the monitored parameters at the defined scenarios. The result of the developed model at 50% weight of each of the modelled parameters with interdependencies show clear indications of the modelled parameters and their interactions in the determination of risks. The decisions on monitored parameters evaluated at every timestep reveal varied dense velocity behaviours for every scenario. The result is suitable for monitoring the AMI in reporting and/or disconnecting any compromised SEM within a considerable timestep before huge losses are incurred. Implementation of this scheme will contribute a significant success in the attempt to prevent electricity theft perpetration via the AMI.
First randomized trial on adjuvant mitotane in adrenocortical carcinoma patients: The Adjuvo study.
Authors: Berruti Alfredo , Fassnacht Martin , Libè Rossella , Lacroix Andrè , Kastelan Darko , Haak Harm , Arlt Weibke , Decoudier Bénédict , Lasolle Hélène , Bancos Irina , Quinkler Markus , Barisson Villares Fragoso Maria Candida , Canu Letizia , Puglisi Soraya , Bourdeau Isabelle , Baudin Eric , Berchialla Paola , Beuschlein Felix , Bertherat Jerome , Terzolo Massimo
Published: February 2022

1

Background: The ESE-ENSAT guidelines on ACC management suggest adjuvant mitotane for patients at high risk of recurrence. This indication has limited evidence base, lacking results from randomized controlled trials. No suggestion for or against adjuvant mitotane in low-risk patients was given, since studies did not stratify patients for prognosis. The randomized controlled study ADIUVO compared the efficacy of adjuvant mitotane treatment vs. observation in prolonging recurrence-free survival (RFS) in patients at low-intermediate risk of recurrence. Methods: The main inclusion criteria were: stage I-III ACC, R0 surgery, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane or observation. The primary endpoint of the study was RFS. Patients who refused randomization were eligible for the ADIUVO OBSERVATIONAL study. In this prospective, observational study, patients were managed as in ADIUVO except for randomization. A total of 91 patients were enrolled in ADIUVO, 45 in the mitotane and 46 in the observation arm. Baseline characteristics of patients were perfectly matched between the 2 arms: median age, 51 vs. 50.5 years; female, 73% vs. 67%; stage I, 20% vs. 26%; stage II, 67% vs. 63%, stage III, 13% vs. 11%; ACC secretion 44% vs. 36%; Weiss 5 vs. 5; respectively. In ADIUVO OBSERVATIONAL, 42 patients were treated with mitotane and 53 were untreated. Baseline characteristics of patients were matched between the 2 groups and with mitotane and observation groups in ADIUVO. Thus, the ADIUVO OBSERVATIONAL cohort was analyzed in parallel to deal with the lower than expected recruitment in ADIUVO. Results: In the ADIUVO study, recurrences were 8 in the MIT and 11 in the OBS arm, while deaths were 2 and 5, respectively. RFS and overall survival (OS) did not significantly differ between the 2 arms. In the OBS arm, the HR for recurrence was 1.321 (95%CI, 0.55-3.32, p = 0.54) and HR for death 2.171 (95%CI, 0.52-12.12, p = 0.29). The survival analysis in the ADIUVO OBSERVATIONAL study confirmed that of ADIUVO. Given the outcome of both studies, the NNT is 55. Conclusions: ACC patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected (5-yr RFS is 75%) and do not benefit significantly from adjuvant mitotane. The results of the ADIUVO study do not support routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment. This is an important step toward personalization of ACC care. Clinical trial information: NCT00777244.
Statin use and survival in men receiving androgen-ablative therapies for advanced prostate cancer: A systematic review and meta-analysis of cohort studies.
Authors: Jayalath Viranda Helitha , Clark Roderick , Lajkosz Katherine , Fleshner Neil E. , Hamilton Robert James
Published: February 2022

83

Background: Mounting evidence support a role for statins in improving survival in advanced prostate cancer (PC), particularly among men on androgen-ablative therapies. This study aimed to systemically review and meta-analyze the relationship between statin use and survival among men with PC on androgen deprivation therapy (ADT) or androgen receptor-axis-targeted therapies (ARATs). Methods: This review was conducted in accordance with the Cochrane Handbook for Systematic Reviews and reported in compliance with the MOOSE guidelines. Medline, Embase, Epub Ahead of Print, Cochrane CT, Cochrane SR, and Web of Science were searched from inception to May 18, 2021, for observational studies reporting associations of postdiagnostic statin use and survival outcomes (hazard ratios [HRs]). Two authors independently abstracted all data. Study quality was assessed using the Newcastle-Ottawa Scale. The primary outcomes included overall mortality (OM) and Prostate cancer-specific mortality (PCSM). Summary estimates pooled multivariable HRs with 95% confidence intervals (CIs) using the generic inverse variance method with random-effects modelling. Heterogeneity was assessed and quantified. A priori subgroup and sensitivity analyses were undertaken, and publication bias was evaluated. Confidence in the evidence was assessed using GRADE. Results: Twenty-five cohorts of 119,878 men (64,717 statin users [54%]) with over 74,416 mortality events were included. Postdiagnostic statin use was associated with a 27% reduction in the risk of OM (19 cohorts, HR 0.73 [95%CI: 0.66 to 0.82], I2= 83%) and a 35% reduction in the risk of PCSM (14 cohorts, HR 0.65 [95%CI: 0.58 to 0.73], I2= 74%), with significant heterogeneity in both estimates. Subgroup analyses identified a PCSM-advantage of statins for men on ARATs compared to ADT (HR 0.40 [95%CI: 0.30 to 0.55] vs HR 0.68 [95%CI: 0.60 to 0.76], p-difference < 0.01). Confidence in the overall evidence was “low” for both outcomes. Conclusions: Postdiagnostic statin use reduced both overall and prostate cancer-specific mortality in men on androgen-ablative therapies for advanced PC. Randomized controlled trials are warranted to validate these findings.
Evolving real-world patterns of practice in metastatic castration-sensitive prostate cancer (mCSPC): The genitourinary research consortium (GURC) national multicenter cohort study.
Authors: Yip Steven , Niazi Tamim , Hotte Sebastien J. , Lavallee Luke , Finelli Antonio , Kapoor Anil , Kolinsky Michael Paul , Ong Michael , Pouliot Frederic , Antebi Elie , Drachenberg Darrel , Gotto Geoffrey , Hamilton Robert James , Noonan Krista , Rendon Ricardo A. , Shayegan Bobby , Zardan Anousheh , Chi Kim N. , Saad Fred , Morash Chris
Published: February 2022

86

Background: Treatment options for patients with mCSPC have rapidly evolved with the introduction of androgen receptor axis targeted therapies (ARATs) and chemotherapy. The GURC cohort study is a phase 4, multicentre, non-interventional, longitudinal cohort study of Canadian men with advanced prostate cancer. We prospectively examined the evolving real world management and treatment patterns of patients with mCSPC, with a focus on treatment intensification beyond ADT and germline DNA damage repair (DDR) testing. Methods: Clinical management patterns, baseline patient characteristics, germline DDR alteration status, treatment intensification with ARATs (abiraterone acetate [AA], apalutamide [Apa], enzalutamide [Enza]) and chemotherapy within the mCSPC cohort were analyzed. Results: 204 patients with mCSPC were enrolled from 2018 to 2021 across 25 Canadian sites. The median age was 71 (range 64 - 77), median PSA at study entry was 24, 88% (158/180) of patients had de novo mCSPC, 69% (110/204) of patients had a Gleason Score > 7, and 4% (2/49) of the patients who received a germline testing harbored a germline DDR alteration (BRCA2 = 1, MUTYH/MEN1 = 1). The distribution of high and low volume mCSPC at study entry was 62% (118/189) and 37% (71/189), respectively. Overall, patients received ADT alone 27% (51/189), AA 45% (86/189), apalutamide 17% (33/189), docetaxel 8% (15/189), and enzalutamide 3% (6/189). Treatment intensification with ARATs/docetaxel was administered to 69% [141/189]) of patients. Patients treated with ADT alone had a significantly lower volume of disease at treatment initiation (low volume rates of 49% [24/49] in ADT alone vs 33% [47/143] in treatment intensified patients, p = 0.044). Among those receiving treatment intensification with ARATs/docetaxel, time to intensification was ≤ 3 months in 78.5 % (113/144). Conclusions: This cohort study demonstrates that patients with mCSPC continue to receive ADT alone and docetaxel over time, despite an ever-increasing list of accessible ARATs. Patients receiving ADT alone appear to have lower volume of disease. Germline DDR testing is not yet comprehensively performed. This underlines the real world need to provide greater education and resources to encourage ARAT treatment and genetic testing in this setting.
Differential efficacy of PARP inhibitors in metastatic castration-resistant prostate cancer with DNA repair defects: A systematic review and meta-analysis.
Authors: Naqvi Syed Arsalan Ahmed , Bin Zafar Muhammad Daim , Islam Mahnoor , Ikram Waleed , Raina Ammad , Singh Parminder , Riaz Irbaz Bin , Bryce Alan Haruo
Published: February 2022

134

Background: Recent trials have suggested poly ADP-ribose polymerase inhibitors (PARPi) sensitivity in patients with treatment-refractory metastatic castration-resistant prostate cancer (mCRPC) harboring mutations in DNA damage and response repair genes (DDR). However, the efficacy profile might differ with different genes and is still being explored in multiple studies. Methods: We systematically searched several electronic databases (MEDLINE, EMBASE), and conference proceedings to include abstracts and full-text publications of phase II/III trials evaluating PARPi in treatment-refractory mCRPC with DDR gene alterations. Outcomes of interest included objective response rate (ORR), complete response (CR), prostate specific antigen (PSA) 50% response, circulating tumor cells conversion (CTCc) from ≥ 5 to < 5 cells, composite response (CoR) and risk of progression. Data was pooled using Inverse-variance approach. A DerSimonian and Laird random-effect meta-analysis was conducted to estimate pooled proportion (PP) of events using the Freeman-Tukey transformation in each gene. Clopper-Pearson method was used to estimate the associated 95% confidence intervals (CI). Results: This systematic review and meta-analysis included five unique trials with 648 patients and four PARPi (niraparib, olaparib, rucaparib, talazoparib). Objective response to PARPi was observed in 44.7% of patients with mutations in either BRCA1 or 2 or both (95% CI: 36.0%-53.6%; I2: 0%), 23.5% with ATM (95% CI: 3.91%-51.0%; I2: 65%), 25.0% with CDK12 (95% CI: 8.66%-49.1%), and 45.3% with PALB2 alterations (95% CI: 14.8%-77.5%; I2: 0%). Consistent results were observed for CR outcome. PSA50% response to PARPi was observed in 60.3% of patients with BRCA1/2 mutations (95% CI: 50.3%-70.0%; I2: 57%), 5.54% (95% CI: 0.01-16.6; I2: 0%) with ATM, and 70.1% (95% CI: 35.6%-96.6%; I2: 0%) with PALB2 mutations while no PSA 50% response was observed in patients with CDK12 mutations (PP: 0.00%; 95% CI: 0%-16.84%). Moreover, CTCc was observed in 68.3% of patients with BRCA1/2 mutations (95% CI: 45.0%-87.8%; I2: 77), 34.2% (95% CI: 11.2-61.3%; I2: 45%) with ATM, 41.7% (95% CI: 15.2%-72.3%) with CDK12, and 48.5% (95% CI: 6.39%-92.9%; I2: 49%) with PALB2. CoR was observed in 76.5% patients with BRCA1/2 mutations (95% CI: 65.4%-86.1%; I2: 22%), 30.4% (95% CI: 16.0%-46.9%) with ATM, 25% (95% CI: 8.66%-49.1%) with CDK12, and 63.9% (95% CI: 31.0%-91.8%; I2: 0%) with PALB2 mutations. Similarly, the risk of progression was 50.9% in patients with BRCA1/2 mutations (95% CI: 37.7%-63.9%), 70.9% (95% CI: 60.0%-80.40%; I2: 0%) with ATM, and 75% (95% CI: 19.4-99.3%) with PALB2. Conclusions: Current evidence is sparse regarding efficacy by specific genes. Limited data favors the use of PARPi in mCRPC patients harboring mutations in BRCA1/2 and PALB2 genes.
Pathologic and radiographic outcomes following prostate cancer diagnosis aided by IsoPSA testing.
Authors: Benidir Tarik , Hofmann Martin , Lone Zaeem M , Weight Christopher , Klein Eric A.
Published: February 2022

276

Background: IsoPSA is a structure-based assay previously demonstrated to outperform prostate specific antigen (PSA) and free-to-total PSA ratio in detecting clinically significant prostate cancer at the time of biopsy (Stovsky, Klein 2019). Herein we report pathologic outcomes in patients treated via radical prostatectomy (RP) whom had undergone IsoPSA testing prior to their diagnostic biopsy. We also explore IsoPSA status in the context of MRI dependent findings, including PIRADS scores and PSA density. Methods: We conducted a retrospective review of patients whom had undergone IsoPSA testing prior to biopsy and RP at our institution between 2019-2021. We also identified subsets of patients with pre-operative prostate MRI’s. Exploratory analyses were performed to determine associations between IsoPSA and adverse histologic (cribiform, intraductal status (CB/ID), grade group status) pathologic (extraprostatic extension, seminal vesicle involvement, surgical margins) and radiographic (PSA density, PIRADS, location) features. We examined these data points in a randomly selected control group of RP patients whom had not had IsoPSA testing. Student’s T-test, Mann Whitney U, Kruskal Wallis, were used where appropriate. Results: A total of 83 patients underwent RP following IsoPSA testing, with 72.2% (60/83) also undergoing pre-operative prostate MRI. The mean total PSA was 10.3 ng/dL, IsoPSA index was 10.2 and prostate size 46.8 cc. IsoPSA was significantly associated with PSA density (median IsoPSA of 9.9 vs 7.8 for PSA density > 0.15, <0.15 respectively, p < 0.001). The median IsoPSA index was higher when the dominant tumor was found in the transitional zone versus peripheral zone (12.7 vs 8.8 p = 0.011). IsoPSA trended towards but was not associated with PIRADS-v2 score (1-2 vs 3 vs 4-5) (p = 0.1). IsoPSA was not selectively associated with adverse pathological or histological features. Conclusions: IsoPSA has been shown to predict clinically significant disease on biopsy, and as such may improve the selection of men for such intervention. In our initial cohort, IsoPSA reliably identified patients with clinically significant disease without selecting for unique adverse pathologic/histologic features when compared to a control group. Radiographically, IsoPSA was significantly associated with elevated PSA density ( > 0.15), tumor location (TZ vs PZ), and trended towards significance with PIRADS v.2 score (p = 0.1. Further work is encouraged to explore its adjunctive benefit in correlation to MRI features.
Health-related quality of life (HRQoL) in previously untreated patients with advanced renal cell carcinoma (aRCC) in CheckMate 214: Five-year follow-up results.
Authors: Cella David , Choueiri Toni K. , Hamilton Melissa , Ejzykowicz Flavia , Blum Steven I. , Ivanescu Cristina , Motzer Robert J.
Published: February 2022

307

Background: Nivolumab + ipilimumab (N+I) demonstrated durable, long-term survival in the phase 3 CheckMate 214 trial as first-line treatment for intermediate/poor (I/P)-risk patients (pts) with aRCC. After a minimum follow-up of 5 years, N+I maintained superior overall survival and response benefits vs sunitinib (S) in both I/P-risk pts and across all randomized pts. We report the HRQoL results from the 5-year follow-up. Methods: Pts were randomized 1:1 to receive N 3 mg/kg + I 1 mg/kg every 3 weeks (wks) for 4 cycles followed by N 3 mg/kg every 2 wks or S 50 mg/d orally for 4 wks (6-wk cycle). HRQoL was assessed using the FKSI-19, FACT-G, and EQ-5D-3L instruments at baseline (BL) and on day 1 of wks 1 and 4 of the first 2 cycles, on day 1 of wks 1 and 5 of the next 2 cycles, and on day 1 of wk 1 of subsequent cycles. The analyses included mixed-model repeated measures (MMRM) for change from BL across 59 months (while on-treatment) and time to confirmed deterioration (TCD). Bother with treatment side effects (item GP5 in FKSI-19) was assessed using a generalized estimating equations model with response dichotomized as minimal bother (“not at all” or “a little bit”) vs notable bother (“somewhat”, “quite a bit”, and “very much”). Results: 1096 pts were randomized to N+I (I/P-risk: 425; favorable [F]-risk: 125) and S (I/P-risk: 422; F-risk: 124). In the overall and I/P-risk populations, N+I pts reported improved mean FKSI-19 total scores over time compared with a decline observed with S. Overall changes from BL through 59 months favored N+I over S with significant differences between arms observed for all outcomes (Table). Median TCD was significantly longer with N+I vs S for all FKSI-19 scores, as well as FACT-G total and physical domains for both populations ( P < 0.05). Pts in the N+I arm were 76% (odds ratio [95% CI]: 0.24 [0.16–0.35]) and 73% (0.27 [0.18–0.40]) less likely to be notably bothered by side effects than pts in the S arm in the total and I/P-risk populations, respectively. Conclusions: Pts reported HRQoL benefits with N+I vs S. Treatment with N+I showed a decreased risk of being bothered by treatment side effects and of experiencing clinically meaningful deterioration in HRQoL in contrast with S. These results suggest that the superior efficacy of N+I over S comes with the additional benefit of improved long-term HRQoL. Clinical trial information: NCT02231749. [Table: see text]
Efficacy and safety of lenvatinib (LEN) plus pembrolizumab (PEMBRO) versus sunitinib (SUN) in the East Asian subset of patients with advanced renal cell carcinoma (aRCC) from the phase 3 CLEAR trial.
Authors: Rha Sun Young , Choueiri Toni K. , Matveev Vsevolod B. , Alyasova Anna , Hong Sung-Hoo , Alonso Gordoa Teresa , Gurney Howard , Bjarnason Georg A. , Buchler Tomas , Pedrazzoli Paolo , Takagi Toshio , Park Se Hoon , Lee Jae-Lyun , Perini Rodolfo F. , He Cixin , McKenzie Jodi A. , Eto Masatoshi
Published: February 2022

338

Background: In the phase 3 CLEAR trial that included patients with aRCC, LEN + PEMBRO demonstrated significant improvements in progression-free survival (PFS; hazard ratio [HR] 0.39; 95% CI 0.32, 0.49; P < 0.001), overall survival (OS; HR 0.66; 95% CI 0.49, 0.88; P = 0.005) and objective response rate (ORR; odds ratio 4.35; 95% CI 3.16, 5.97) vs SUN. Here we report the efficacy and safety results of the East Asian population subset of the CLEAR trial. Methods: Patients with aRCC and no prior systemic therapy were randomized (1:1:1) to receive 1 of 3 treatments including LEN 20 mg PO QD + PEMBRO 200 mg IV Q3W and SUN 50 mg PO QD (4 weeks on/2 weeks off). Randomization was stratified by geographic region and MSKCC prognostic groups. This analysis compares the efficacy and safety of LEN + PEMBRO vs SUN in the East Asian subset of the CLEAR trial including patients from Japan and the Republic of Korea. The primary endpoint was PFS; secondary endpoints included OS, ORR and safety. An independent review committee assessed tumors per RECIST v1.1. Median PFS and OS were calculated using the Kaplan-Meier method; HR and 95% CI were estimated by a stratified Cox model. Odds ratios were estimated by a stratified Cochran-Mantel-Haenszel test. Results: Of the 1069 patients randomized, 75 patients in the LEN + PEMBRO group and 65 patients in the SUN group were from East Asia. PFS was improved with LEN + PEMBRO vs SUN (median 22.1 vs 11.1 mo; HR 0.38, 95% CI 0.23, 0.62). Median OS was not reached for both arms; the HR for OS comparing LEN + PEMBRO vs SUN was 0.71, 95% CI 0.30, 1.71. ORR was improved with LEN + PEMBRO vs SUN (65.3% vs 49.2%; odds ratio 2.14, 95% CI 1.07, 4.28). Grade ≥3 treatment emergent adverse events (TEAEs) occurred in 88.0% of patients in the LEN + PEMBRO group and in 79.7% of patients in the SUN group. The incidences and types of TEAEs were generally similar to the overall CLEAR population and were manageable with dose adjustments and appropriate concomitant therapies. Conclusions: Efficacy results for patients in the East Asian subset of the CLEAR trial were consistent with the results of the overall population. The safety profile of LEN + PEMBRO in the East Asian subset was also generally consistent with that of the overall population. Clinical trial information: NCT02811861. [Table: see text]
A phase II study of talazoparib and avelumab in VHL deficient clear cell renal cell carcinoma.
Authors: Kotecha Ritesh , Lee Chung-Han , McHugh Deaglan Joseph , Dadoun Chloe , Knezevic Andrea , Carlo Maria Isabel , Feld Emily , Shapnik Natalie , Shah Neil J. , Feldman Darren R. , Motzer Robert J. , Voss Martin H
Published: February 2022

347

Background: VHL inactivation may lead to impairments in the DNA damage response pathway and increased replication stress, which consequently can increase the genomic instability of clear cell renal cell carcinoma (RCC). Other molecularly driven RCC subtypes including FH and SDH deficient RCC show impaired DNA repair through oncometabolite accumulation. Synthetic lethality with PARP inhibitors (PARPi) has been suggested in preclinical models, and PARPi may potentiate the effects of immune checkpoint blockade (ICB) therapy. Methods: We conducted a single center, investigator-initiated phase II trial to evaluate combined PARPi + PD-L1 inhibition in two genomically selected advanced RCC cohorts: 1) VHL altered RCC; 2) FH, SDH-RCC and renal medullary carcinoma. For Cohort 1, patients had to have previously been treated with VEGFR TKI and ICB therapy with maximum 3 prior lines of therapy. Patients received talazoparib 1mg daily plus avelumab 800mg IV every 14 days. The primary endpoint was objective response rate (ORR) by iRECIST, and secondary endpoints included progression-free survival (PFS), safety and tolerability. Results from Cohort 1 are reported here. Results: From 2019-2021, 10 advanced RCC patients were enrolled per the first stage of a Simon 2-stage design for cohort 1. The median age was 63 years (R: 42-71), and median number of prior therapies was 2 (R: 1-3). All patients had VHL loss detected by tissue NGS sequencing via MSK-IMPACT, and 3/10 (30%) of patients had co-occurring somatic or germline alterations in DDR specific genes. No objective tumor responses were seen, and the disease control rate was 60% (6/10) with those patients achieving stable disease as best response. All patients experienced disease progression and the median PFS was 3.6 months (95% CI 1.4-4.9). Adverse events were in keeping with reported toxicities for individual agents without emerging safety signals. Conclusions: This is the first clinical study of combination PARPi and ICB therapy in advanced clear cell RCC. In our cohort of VHL deficient TKI/ICB refractory RCC, the study did not meet its pre-defined efficacy threshold to continue enrollment, and our results do not support further study of this regimen in this population. Exploratory efforts to evaluate this treatment approach in other biomarker selected populations of RCC, including cohort 2 of this study, are ongoing. Clinical trial information: NCT04068831.
Final analysis of a non-interventional study on cabozantinib in patients with advanced renal cell carcinoma after prior checkpoint inhibitor therapy (CaboCHECK).
Authors: Grünwald Viktor , Boegemann Martin , Rafiyan Mohammad-Reza , Niegisch Guenter , Schnabel Marco Julius , Flörcken Anne , Maasberg Michael , Maintz Christoph , Zahn Mark-Oliver , Wortmann Anke , Hinkel Andreas , Casper Jochen , Darr Christopher , Hilser Thomas , Schulze Matthias , Sookthai Disorn , Schoenherr Caroline , Ivanyi Philipp
Published: February 2022

357

Background: Data for cabozantinib after IO-combinations in metastatic renal cell carcinoma (mRCC) remain scarce. We therefore evaluated safety and effectiveness of cabozantinib after failure of IO-based therapies. Methods: Data from patients (pts) with mRCC and cabozantinib treatment after IO-based therapy was retrospectively collected from medical records. Primary endpoint was the incidence of serious adverse events (SAEs). Response rate was assessed clinically (CRR) and/or according to RECIST 1.1. Overall Survival (OS) and Progression Free Survival (PFS) were assessed from start of therapy and data were compared for pts with starting dose of 60 mg (cohort A) vs < 60 mg (cohort B) in a post-hoc analysis. Descriptive statistics and KM-plots were utilized, where appropriate. Results: This final analysis (cut off 08-Oct-21) assessed 56 eligible pts (71.4% male) with median age of 66 yrs. 87.5% (n = 49) had previous nephrectomy. 66.1% (n = 37) had clear cell RCC. 89.3% (n = 50) had ≥2 previous lines. ECOG ≤1 was 33.9% (n = 19). IMDC factors were 0 in 2 (3.6%), ≥1 in 21 (37.5%), missing in 31 pts (55.4%). 62.5% (n = 35) started at reduced dose. 55.4% (n = 31) required dose reductions and 1.8% (n = 1) discontinuation. Median treatment duration was 6.1 months (m). PR was 10.7% (n = 6), SD 19.6% (n = 11), PD 12.5% (n = 7) and missing in 57.1% (n = 32). Median OS and PFS were 15.34 m (95% CI 8.94, 20.93) and 6.34 m (95% CI 5.29, 8.25) in the ITT, 10.48 m (95% CI 6.01, 34.14) and 6.51 m (95% CI 2.99, 10.87) in cohort A and 16.46 m (95% CI 9.56, 23.33) and 6.34 m (95% CI 4.86, 8.71) in cohort B, respectively. All grade AEs and grade 3-5 AEs were 87.5% (n = 49) and 44.6% (n = 25) in the ITT, 95.0% (n = 19) and 55.0% (n = 11) in cohort A and 85.7% (n = 30) and 40.0% (n = 14) in cohort B. SAEs were reported in 21.4% (n = 12) of pts, which were 30.0% (n = 6) of cohort A and 17.1% (n = 6) of cohort B. Treatment related SAEs were reported in 10.7% (n = 6) of pts, which were 15.0% (n = 3) in cohort A and 8.6% (n = 3) in cohort B. Conclusions: Cabozantinib directly after IO therapy was safe and feasible. No new safety signals were reported. A reduced starting dose was frequently utilized and was not associated with adverse outcomes. Our data supports the use of cabozantinib after IO-failure. Major limitation was the retrospective nature of our study.[Table: see text]
Targeting an IL-6/JAK/STAT/PIM1 pathway in renal cell carcinoma.
Authors: Meza Kimberly Stephanie , Holder Sheldon L.
Published: February 2022

376

Background: Renal cell carcinoma (RCC) is the most common cancer of the kidney and accounts for over 430,000 new cases worldwide and 179,000 deaths each year. PIM1 overexpression is associated with poor clinical outcomes in patients with RCC. PIM1 is a constitutively active effector serine/threonine kinase with roles in tumor progression including cell proliferation, apoptosis, invasion, and migration. Yet, the mechanisms that underlie PIM1 expression and its function in RCC are not fully understood. Previous studies have implicated the cytokine IL-6 as an activator of STAT3 and stimulator of PIM1 expression in pancreatic cancer. The aim of the present study is to explore expression of PIM1 in RCC and identify potential signaling pathways that influence PIM1 expression. Methods: To evaluate the contribution of PIM1 expression in RCC we first established baseline PIM1 levels across four RCC cell lines (786-O, 769-P, CAKI-1, and RCC-4). Next, we quantified the presence of IL-6 in cell culture supernatants for each cell line using an ELISA assay. IL-6 signals through the JAK/STAT pathway, consequently we then used immunoblotting to determine whether ruxolitinib, a JAK1/2 inhibitor, would affect PIM1 expression. Finally, we examined cell viability post-ruxolitinib therapy using an MTS assay. Results: Our results show that 769-P, 786-O, and CAKI-1 but not RCC-4 cells overexpress PIM1 relative to normal renal proximal tubule epithelial cells. Results from the ELISA assay show that 786-O, CAKI-1, and to a lesser degree RCC-4 cells secrete IL-6 into their media. Interestingly, 769-P cells had little to no IL-6 present in their media. Based on these differences we sought to understand what effect inhibiting JAK may have on PIM1 expression. After treating cells with ruxolitinib, we found that 786-O and CAKI-1 cells show a time and dose dependent decrease in PIM1 levels whereas 769-P cells did not. To understand if these differences correlate with cell viability, we performed an MTS assay after treating cells with ruxolitinib. Preliminary results show that at 8hr post-treatment, CAKI-1 but not 769-P cells display a time and concentration dependent loss of cell viability. Conclusions: Our initial studies suggest that differential expression of PIM1 among RCC cell lines may be linked to autocrine IL-6 secretion. In CAKI-1 cells JAK inhibition decreases PIM1 expression and cell viability. In the context of 769-P cells with high PIM1 expression but low IL-6 secretion levels, JAK inhibition did not affect cell viability. These data suggest that in 769-P cells there exists a non-IL-6 dependent mechanism stimulating PIM1 expression. Further investigation is required to elucidate the contexts of these PIM1 regulatory pathways in order to develop IL-6/JAK/PIM1 targeted anti-cancer strategies in RCC.
Risk of secondary malignancies after pelvic radiation: A population-based analysis.
Authors: Salib Andrew , McPartland Connor , Mark James Ryan , Lallas Costas D. , Trabulsi Edouard John , Gomella Leonard G. , Chandrasekar Thenappan
Published: February 2022

478

Background: Radiation therapy (RT) is an integral component of the multimodal therapy of pelvic malignancies, either as primary treatment or in combination with surgical resection. In addition to local treatment effects on nearby pelvic organs, RT has been established to be a risk factor for delayed secondary malignancies. In this study, we examine the rate of any secondary malignancies following RT for primary pelvic malignancies, with a specific emphasis on secondary pelvic malignancies Methods: Using the SEER (Surveillance, Epidemiology, and Ends Results) database, we retrospectively examined 2,102,192 patients with primary pelvic malignancies (prostate, bladder, uterine, rectal, cervical). For each disease site, we compared the rate of all secondary malignancies in radiated patients to non-radiated patients. Secondary malignancies were then stratified as pelvic and non-pelvic, in order to determine the local effect of RT on malignancy risk. Results: A total of 2,102,192 patients were examined (1,189,108 prostate, 315,026 bladder, 88,809 cervical, 249,535 uterine, 259,714 rectal). A total of 113,322 patients developed secondary malignancies after RT (Table), with 26,299 developing secondary pelvic malignancies after RT (18,411 prostate, 1,026 bladder, 1,410 cervical, 2,179 uterine, 3,273 rectal) (Table). The overall relative risk (RR) of RT on developing a secondary malignancy was 1.79 (1.77-1.80 CI, P<0.0001), particularly in patients with prostate (RR 2.57), uterine (RR 1.24) and cervical cancer (1.09). The overall RR of RT on developing a secondary pelvic malignancy was 2.09 (2.06-2.13 CI, P<0.0001), particularly in patients with bladder (RR 6.90), prostate (RR 2.74), and uterine cancer (RR 1.21). Conclusions: Radiation treatment for pelvic malignancies increases the risk of developing secondary malignancies over the patient’s lifetime. Further work needs to done to identify at risk populations.[Table: see text]
A prospective phase II trial of neoadjuvant nivolumab plus gemcitabine/cisplatin chemotherapy in muscle-invasive urothelial carcinoma of bladder.
Authors: Kim Hongsik , Kim Ryul , Hong Joohyun , Kwon Ghee Young , Kim Chan Kyo , Park Won , Song Wan , Sung Hyun Hwan , Jeong Byong Chang , Hong Jung Yong , Park Se Hoon
Published: February 2022

494

Background: To assess the efficacy and safety of the combination of nivolumab plus gemcitabine/cisplatin in neoadjuvant setting of muscle-invasive urothelial carcinoma of bladder (MIBC). Methods: In this prospective phase II trial (CRIS, KCT0003804), eligible patients had cT2-T4a N0 MIBC, cisplatin-eligible, and to be planned radical cystectomy. Patients received nivolumab 3 mg/kg on days 1 and 15, cisplatin 70 mg/m2 on day 1, and gemcitabine 1,000 mg/m2 on days 1, 8 and 15. Study treatment was repeated every 28 days up to 3 or 4 cycles, depending on the surgery schedules. The primary endpoint was pathologic complete response (pCR, ypT0). Secondary endpoints included pathologic downstaging (<ypT1), disease-free survival (DFS) and safety. Results: Between Sep 2019 and Oct 2020, 51 patients were enrolled. The majority of patients (96%) completed the planned (median, 3; range 1 to 4) cycles of nivolumab plus gemcitabine/cisplatin without significant toxicities. The most commonly observed adverse events included fatigue, nausea and pruritus. Among the 49 patients who completed study treatment, 12 patients refused surgery but were treated with concurrent chemoradiotherapy. Radical cystectomy was performed in 34 (69%) patients. Pathologic results revealed 12 pCR (ypT0, 35%), 4 ypTis, 3 ypTa, 3 ypT1, and 12 ypT2/T3. Preoperative PD-L1 (22C3 TPS>1%) did not correlate with pCR or pathologic downstaging rates. With a median follow-up of 19 months (95% CI, 17 to 20), 12 patients experienced disease recurrence and median DFS was not reached. Conclusions: Neoadjuvant nivolumab plus gemcitabine/cisplatin was feasible and provided meaningful pathologic responses in patients with MIBC. Clinical trial information: KCT0003804.
ABLE: Phase 2, single-arm, two-stage study of nabpaclitaxel with anti-PD1/PDL1 in advanced urothelial cancer.
Authors: Tsung Irene , Green Edward , Palmbos Phillip Lee , Reichert Zachery R , Vaishampayan Ulka N. , Smith David C. , Caram Megan Veresh , Yentz Sarah Elizabeth , Daignault-Newton Stephanie , Sloan Zachery , Hurley Laura , Alva Ajjai Shivaram
Published: February 2022

502

Background: Anti-PD/PDL1 immune checkpoint inhibitor monotherapy is standard in select PDL1 expressing advanced urothelial cancer (aUC) and platinum-refractory aUC. Nab-paclitaxel (NAB) previously showed encouraging activity in platinum-refractory aUC. We conducted a single-arm trial of the combination of NAB and pembrolizumab in platinum-refractory or cisplatin-ineligible aUC. Methods: Eligible patients (pts) had RECIST 1.1 measurable urothelial cancer, grade ≤1 neuropathy, and ECOG PS 0-2. Study therapy consisted of NAB at starting dose of 125 mg/m2 IV on days 1 and 8 and pembrolizumab 200 mg IV on day 1 in 21-day cycles until progression, intolerable toxicity, death, or consent withdrawal. Continuing NAB after 6 cycles was optional. NAB starting dose was reduced to 100 mg/m2 after planned interim analysis on the first 17 subjects. Primary endpoint was overall response rate (ORR) by RECIST 1.1. Secondary endpoints included safety/toxicity, progression free survival (PFS), overall survival, complete response proportion, duration of response (DOR), and duration of therapy (DOT). Results: Between 2/2018 and 4/2021, 36 response evaluable pts were enrolled; 11 of upper tract origin, 32 men, mean age 71.5 years (range 52 – 88), 25 pure urothelial, 15 platinum-refractory, 21 cisplatin-ineligible by Galsky criteria, and ECOG PS was 0, 1 or 2 in 9, 20, and 7 pts, respectively. Unconfirmed best ORR was 58.3% (95% CI: 42-74) including 3 CR and 18 PR, confirmed ORR 50% (18/36); 31/36 pts experienced some tumor shrinkage. Median DOR was 19 weeks (95% CI: 15.6-34.8), and median PFS 5.4 months (95% CI: 4.6-7.9). Pts received a median of 6 cycles (range 1-14) with median DOT 4.2 months (range 0.6-9.6). Grade ≥3 adverse events (AE) occurred in 25 pts including fatigue (n = 6), anemia (n = 6), peripheral neuropathy (n = 3), and oral mucositis (n = 3); 6 discontinued treatment due to AEs. Ten pts had immune mediated AEs including 1 with encephalitis. Archival tumor NGS revealed TMB ≥10 in 5/21 available. Conclusions: The combination of NAB and pembrolizumab exhibited promising activity in advanced urothelial cancer with no unexpected toxicity. Clinical trial information: NCT03240016.
NEXT: A single-arm, phase 2, open-label study of adjuvant nivolumab after completion of chemo-radiation therapy in patients with localized muscle-invasive bladder cancer.
Authors: Gupta Sumati , Grass G. Daniel , Maughan Benjamin L. , Jain Rohit K. , Dechet Christopher B. , Sanchez Alejandro , O Neil Brock , Poch Michael Adam , Li Roger , Lloyd Shane , Tward Jonathan David , Phunrab Tenzin Kunsang , Hawks Josiah , Swami Umang , Boucher Kenneth M , Agarwal Neeraj
Published: February 2022

506

Background: Nivolumab has known efficacy as adjuvant therapy after radical cystectomy in localized muscle invasive bladder cancer (MIBC). We are evaluating the efficacy of nivolumab adjuvant to definitive chemo-radiation therapy (CRT) in MIBC. Methods: In the NEXT study, we are currently enrolling patients with localized MIBC undergoing standard CRT. Participants are started on nivolumab 480 mg IV every 4 weeks (up to 12 doses) within 90 days of completion of CRT. Cystoscopic and scan-based assessments are done every 3 months for the first two years (yrs). The primary endpoint is failure-free survival (FFS) at 2 yrs from the start of CRT, with failure defined as local or systemic disease recurrence. Secondary endpoints include toxicity and quality of life (QOL) assessments. We have planned correlative studies on peripheral blood and tumor tissue. We performed a protocol-defined interim safety and efficacy analysis to assess the 6-month FFS rate with CRT and adjuvant nivolumab. Results: From 8/03/2017 to 9/28/2021, 20 patients were enrolled at two centers; median age is 76 yrs, clinical stage range is T2-T4b, N0-N+, M0; the median number of nivolumab cycles is 6.5, and the median follow-up is 8.9 months. The estimated 6-month FFS rate is 88.2% (95% CI 74.2% - 100%). Disease has progressed in 9 patients, of which 4 have local bladder recurrence (T1 in 3/4) and 5 have distant metastases. The estimated median FFS is 17.1 months (95% CI 8.71 months - infinity). Grade ≥3 treatment-related adverse events (AEs) are noted in 3/20 patients (15%): elevated transaminases, diarrhea, and polymyalgia rheumatica. Grade 3 radiation therapy oncology group (RTOG) AEs occurred in 2 patients. QOL measures are serially evaluable in 13 patients for the first 3 months of adjuvant nivolumab, and are stable in the domains of disease-related physical symptoms, treatment side effects, and function/well-being, while are significantly improved (p=0.023) in the domain of disease-related emotional symptoms. Conclusions: In this first report of the role of immunotherapy adjuvant to CRT for localized bladder cancer, adjuvant nivolumab is well tolerated and has promising efficacy. Clinical trial information: NCT03171025.
Impact of different HER2 expression levels on the outcomes of second-line immunotherapy for metastatic urothelial carcinoma.
Authors: Li Siming , Wu Xiaowen , Yan Xieqiao , Zhou Li , Xu Huayan , Li Juan , Liu Yiqiang , Tang Bixia , Chi Zhihong , Si Lu , Cui Chuanliang , Guo Jun , Sheng Xinan
Published: February 2022

524

Background: Immunotherapy has become an option of second-line treatment for metastatic urothelial carcinoma (mUC) after the failure of platinum-containing chemotherapy. HER2 expression is an adverse prognostic factor of urothelial carcinoma (UC) while the predictive value of HER2 expression in UC treatment remains unknown. This study attempts to explore the impact of different HER2 expression and gene amplification levels on the outcomes of second-line immunotherapy in metastatic UC. Methods: The baseline clinical data and the outcomes after second-line anti-PD-1 immunotherapy from 2017 to 2021 in 79 patients with metastatic UC who failed to the first-line platinum-containing chemotherapy were reviewed. The expression level of HER2 was detected by immunohistochemistry (IHC) staining ( Anti-Her2/neu, Cat.4B5, Ventana ) from formalin-fixed paraffin-embedded (FFPE) tumor tissue of patients. The copy number amplification level of HER2 gene was detected by second-generation sequencing (NGS) from FFPE tumor tissue of patients. The correlation between HER2 expression and objective response rate (ORR), median progression-free survival (PFS) and overall survival (OS) were analyzed. Results: HER2 expression levels by IHC were performed in 77 patients and the copy number (CN) amplification level of 20 patients with HER2 IHC 2+ were detected by NGS. The median PFS of HER2 negative (IHC 0), low expression (IHC 2 +/ CN - and IHC 1 +) and overexpression (IHC 3 + and IHC 2 +/ CN +) patients were 11.0 months (95% confidence interval [CI]: 1.4-20.6 months), 3.7 months (95% CI: 1.3-6.1 months) and 1.8 months (95% CI: 0.8-2.8 months), respectively, with significant difference in the overall comparison ( P = 0.001) and in the each two comparisons. ORR had a trend to decrease gradually with the increase of HER2 expression level from negative to overexpression (42.4% vs. 31.6% vs. 0%, P = 0.08). However, no correlation between HER2 expression and OS after anti-PD-1 immunotherapy was observed. Conclusions: Different HER2 expression levels have a significant impact on the PFS of the second-line anti-PD-1 immunotherapy in patients with metastatic urothelial carcinoma. The overexpression of HER2 (IHC 3 + and IHC 2 +/ CN +) may be an adverse factor, while the HER2-negative status may be a favorable factor. HER2 expression have potential value in predicting the efficacy of second-line immunotherapy for advanced urothelial carcinoma, which needs further research.