tbuckley/cabot-search huggingface dataset:
Impact of bladder cancer stage on work impairment and financial toxicity.
Authors: Pauline Filippou, Sean McCabe, Hannah McCloskey, Kathryn Gessner, Judy Hamad, Allison Mary Deal, Angela Smith, John L. Gore
Journal: Journal of Clinical Oncology (2020)

460 Background: Bladder cancer has been linked to financial toxicity with conflicting results regarding the impact of stage. Our objective was to evaluate financial toxicity and work impairment among bladder cancer patients in a large cross-sectional bladder cancer cohort. Methods: We surveyed bladder cancer patients in the Bladder Cancer Advocacy Network Patient Survey Network and Inspire platforms to determine financial toxicity and work impairment. We measured financial toxicity with the COST measure and Work Productivity and Activity Impairment General Health questionnaires. Patients were also queried regarding demographic, socioeconomic and clinical characteristics with specific attention to insurance status, income, and education. Results: 972 respondents self-identified as patients with bladder cancer. Among respondents, 41% were female and 97% were white. The mean age was 67.6 years, ranging from 29 to 93 years. Respondents were highly educated (67% completed college). Most patients identified as having non-invasive bladder cancer (NMIBC, n=578 [63%]); 30% (n=270) had MIBC, 7% (n=63) had metastatic cancer. Although patients with metastatic cancer had higher average COST scores (worse financial toxicity, Table below), stage was not significantly associated with COST on bivariable (p=0.07) or multivariable analysis (p=0.14). Patients with metastatic disease were more likely to report more work time missed and activity impairment due to health on bivariable analysis; only activity impairment was statistically associated with stage on multivariable analysis (p&lt;0.001) when controlling for age, gender, race, comorbidity, insurance, and education. Conclusions: Bladder cancer stage significantly impacts activity impairment but not percentage work time missed due to health nor financial toxicity. [Table: see text]
A Community-Based Intervention for Managing Hypertension in Rural South Asia
Authors: Tazeen H. Jafar, Mihir Gandhi, H. Asita de Silva, Imtiaz Jehan, Aliya Naheed, Eric A. Finkelstein, Elizabeth L. Turner, Donald Morisky, Anuradhani Kasturiratne, Aamir H. Khan, John D. Clemens, Shah Ebrahim, Pryseley N. Assam, Liang Feng
Journal: New England Journal of Medicine (2020)

The burden of hypertension is escalating, and control rates are poor in low- and middle-income countries. Cardiovascular mortality is high in rural areas.
A comparison of combined immune checkpoint inhibitors (IO) versus vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) in the treatment of advanced clear cell renal cell carcinoma.
Authors: Abigail Sy Chan, Gregory Russell Pond, Guru Sonpavde, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2020)

692 Background: IO and VEGFR/TKI are approved treatment options, either alone or combination, in advanced clear cell RCC. Currently, there is a lack of evidence comparing efficacy and safety outcomes amongst these therapies. We sought to compare the published data for the various options with respect to efficacy and safety. Methods: A literature search using PubMed, clinicaltrials.gov, ASCO and ESMO meeting abstract databases from January 1, 2015 to June 30, 2019 to identify eligible clinical trials in advanced clear cell RCC involving at least one immunotherapy agent was performed. Due to small sample sizes in the various cohorts, descriptive statistics were provided. Weighting of estimates was based on sample size of the intervention arms. Results: 14 studies involving 6,197 pts were identified. The median age was 62 years (54.8, 64), men constituting median of 75%, and prior TKI receipt in 63%. There were 7 studies in each treatment arm. The efficacy outcomes did not demonstrate statistical differences. In the safety analyses, IO + VEGFR/TKI demonstrated the highest serious adverse event rate, correlating with treatment discontinuation rates. Conclusions: IO + IO and IO + VEGFR/TKI showed comparable efficacy and toxicity outcomes in the treatment of advanced clear cell RCC. There is a non-significant trend towards increased efficacy in some outcomes with IO + VEGFR/TKI, with possibly increased adverse events. Further studies with patient level data, cross-comparative trials, and predictive biomarkers are needed to establish a therapeutic matrix for RCC pts.[Table: see text]
Detailed evaluation of hearing loss (HL) associated with high-dose (HD) carboplatin for salvage treatment of germ cell tumors (GCT).
Authors: Darren R. Feldman, Andrea Knezevic, Kaamilah Wilson, Maria Bromberg, Amy Budnick, Deaglan Joseph McHugh, Erik Larsen, Dean F. Bajorin, Robert J. Motzer, Emily S. Tonorezos, Sujata Patil, Samuel Aaron Funt
Journal: Journal of Clinical Oncology (2020)

401 Background: HD carboplatin is an essential part of curative salvage high-dose chemotherapy (HDCT) for GCT. Although ototoxicity is a known side effect of HD carboplatin, data on severity and characteristics of HL in this population are limited. Methods: Eligible patients (pts) received salvage HD carboplatin for GCT at our center from 1993-2017 and had audiograms pre- and post-HDCT. All pts were planned for 3 sequential cycles of HD carboplatin; some had audiograms after each cycle. HL severity was classified by ASHA criteria (slight: 15-24dB; mild: 25-40dB; moderate: 41-55dB; moderately severe: 56-70dB; severe: 71-90dB; profound: &gt;90dB). Change in hearing threshold at each frequency (0.25 – 8 kHz) was analyzed by clinical and treatment variables using the Wilcoxon rank-sum test. The proportion of pts recommended for hearing aids was also recorded. Results: Of 115 pts (median age 31, 77% nonseminoma), 96 received TI-CE and 19 received TI-TIC on a clinical trial (Feldman CGUC 2015). Pts varied by prior cisplatin exposure (77% with ≤4 vs 23% with 5-9 cycles) and number of HD carboplatin cycles (89% had 3, 10% had 2, and 2% had 1). Carboplatin AUC was 21 in 23%, 24 in 75%, and 28 in 3%. Moderate to profound HL was present in 23% pre-HD carboplatin vs 82% post, preferentially at high frequencies (Table). Of 89 pts with normal to mild HL at baseline, 78% developed moderate or worse HL post-HD carboplatin, including 61% with moderately severe or severe HL. Higher AUC (24 vs 21) and number of HD carboplatin cycles were associated with greater HL with HD carboplatin whereas prior cisplatin exposure was not. Due to moderate or severe HL in the vital speech frequency range (2 – 4kHz), 20 (17%) pts were recommended for hearing aids post-HD carboplatin. Conclusions: In the largest series to detail ototoxicity in pts receiving salvage HD carboplatin for GCT, we show HL, particularly at high frequencies, is a major dose-dependent toxicity. Most pts will have at least moderate high frequency HL after HD carboplatin with approximately 1 in 6 recommended for hearing aids. [Table: see text]
Antibiotic Treatment and Immune Checkpoint Inhibitor Therapy in Patients With Cancer—Reply
Authors: David J. Pinato, Thomas Newsom-Davis, Mark Bower
Journal: JAMA Oncology (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Radiogenomic-Based Survival Risk Stratification of Tumor Habitat on Gd-T1w MRI Is Associated with Biological Processes in Glioblastoma
Authors: Niha Beig, Kaustav Bera, Prateek Prasanna, Jacob Antunes, Ramon Correa, Salendra Singh, Anas Saeed Bamashmos, Marwa Ismail, Nathaniel Braman, Ruchika Verma, Virginia B. Hill, Volodymyr Statsevych, Manmeet S. Ahluwalia, Vinay Varadan, Anant Madabhushi, Pallavi Tiwari
Journal: Clinical Cancer Research (2020)

Abstract Purpose: To (i) create a survival risk score using radiomic features from the tumor habitat on routine MRI to predict progression-free survival (PFS) in glioblastoma and (ii) obtain a biological basis for these prognostic radiomic features, by studying their radiogenomic associations with molecular signaling pathways. Experimental Design: Two hundred three patients with pretreatment Gd-T1w, T2w, T2w-FLAIR MRI were obtained from 3 cohorts: The Cancer Imaging Archive (TCIA; n = 130), Ivy GAP (n = 32), and Cleveland Clinic (n = 41). Gene-expression profiles of corresponding patients were obtained for TCIA cohort. For every study, following expert segmentation of tumor subcompartments (necrotic core, enhancing tumor, peritumoral edema), 936 3D radiomic features were extracted from each subcompartment across all MRI protocols. Using Cox regression model, radiomic risk score (RRS) was developed for every protocol to predict PFS on the training cohort (n = 130) and evaluated on the holdout cohort (n = 73). Further, Gene Ontology and single-sample gene set enrichment analysis were used to identify specific molecular signaling pathway networks associated with RRS features. Results: Twenty-five radiomic features from the tumor habitat yielded the RRS. A combination of RRS with clinical (age and gender) and molecular features (MGMT and IDH status) resulted in a concordance index of 0.81 (P &amp;lt; 0.0001) on training and 0.84 (P = 0.03) on the test set. Radiogenomic analysis revealed associations of RRS features with signaling pathways for cell differentiation, cell adhesion, and angiogenesis, which contribute to chemoresistance in GBM. Conclusions: Our findings suggest that prognostic radiomic features from routine Gd-T1w MRI may also be significantly associated with key biological processes that affect response to chemotherapy in GBM.
Dasatinib Is an Effective Treatment for Angioimmunoblastic T-cell Lymphoma
Authors: Tran B. Nguyen, Mamiko Sakata-Yanagimoto, Manabu Fujisawa, Sharna Tanzima Nuhat, Hiroaki Miyoshi, Yasuhito Nannya, Koichi Hashimoto, Kota Fukumoto, Olivier A. Bernard, Yusuke Kiyoki, Kantaro Ishitsuka, Haruka Momose, Shinichiro Sukegawa, Atsushi Shinagawa, Takuya Suyama, Yuji Sato, Hidekazu Nishikii, Naoshi Obara, Manabu Kusakabe, Shintaro Yanagimoto, Seishi Ogawa, Koichi Ohshima, Shigeru Chiba
Journal: Cancer Research (2020)

Abstract Recurrent hotspot (p.Gly17Val) mutations in RHOA encoding a small GTPase, together with loss-of-function mutations in TET2 encoding an epigenetic regulator, are genetic hallmarks of angioimmunoblastic T-cell lymphoma (AITL). Mice expressing the p.Gly17Val RHOA mutant on a Tet2-null background succumbed to AITL-like T-cell lymphomas due to deregulated T-cell receptor (TCR) signaling. Using these mice to investigate therapeutics for AITL, we found that dasatinib, a multikinase inhibitor prolonged their survival through inhibition of hyperactivated TCR signaling. A phase I clinical trial study of dasatinib monotherapy in 5 patients with relapsed/refractory AITL was performed. Dasatinib was started at a dose of 100 mg/body once a day and continued until days 10–78 (median day 58). All the evaluable patients achieved partial responses. Our findings suggest that AITL is highly dependent on TCR signaling and that dasatinib could be a promising candidate drug for AITL treatment. Significance: Deregulated T-cell receptor signaling is a critical molecular event in angioimmunoblastic T-cell lymphoma and can be targeted with dasatinib.
Selection of cancer-targeting ß-lactamase molecules for prodrug therapy using phage-displayed libraries
Authors: Girja Shukla, David Krag
Journal: Cancer Research (2008)

4073  Targeted prodrug therapy is based on a concept that a systemically administered non-toxic prodrug can be converted locally to high concentrations of a cytotoxic drug by an enzyme predominantly present at the tumor site. We have focused on the design of a bifunctional enzyme molecule that has both tumor binding property and prodrug enzyme activation property. s-lactamase has several desirable characteristics that make it an ideal candidate for targeted enzyme prodrug therapy. We have generated several filamentous bacteriophage-displayed peptide libraries embedded with enzyme s-lactamase (Enterobacter cloacae P99 cephalosporinase; PDB code 1BLS) molecules expressed as gene III fusion protein. Two types of s-lactamase libraries were prepared, loop and N-terminal fusion libraries. In the loop libraries a selected loop on the outer surface of s-lactamase molecule was randomized by replacing/inserting a heptapeptide loop. The randomizations of amino acids at positions 238-244, 275-278, 305-309 or 329-332 of s-lactamase molecule represent the loop-2, loop-3, loop-4 or loop-5 libraries, respectively. In the fusion libraries, a randomized linear dodecapeptide or cysteine constrained decapeptide (CysX10Cys) sequence was linked through a short linker (GGGS) to N-terminal position (-5 to -16) of s-lactamase molecule between the signal peptide and enzyme protein. The complexity of these libraries as determined by frequency and diversity of amino acids distributions in the randomized regions appears consistent with standards of other types of phage display library systems. However, the analysis of s-lactamase active clone numbers in various loop libraries demonstrated a higher tolerance of amino acid substitutions at loop-2 and loop-5 sites in comparison to those at loop-3 and loop-4. In addition, higher numbers of s-lactamase active primary clones in both, linear and cysteine constrained, N-terminal s-lactamase peptide fusion libraries were also observed. The loop-2, loop-5 and N-terminal fusion libraries were panned against erbB family of receptors and several breast cancer cell-lines. The clones from panning outcome were expressed to produce free s-lactamase protein, screened against the targets they were panned and identified several target-specific binders. The process of binding screening of different clones to their target(s) is simple and rapid in the presence a s-lactamase enzyme substrate. Since s-lactamase has been shown to convert a variety of cephalosporin-based anticancer prodrugs to cytotoxic drugs, the cancer target-specific s-lactamase enzyme molecules identified in this study and the phage-display approach that was used to generate and select these molecules should be useful in developing targeted enzyme prodrug therapy of cancer.
A randomized, double-blinded clinical trial of royal jelly intake for anticancer effects and suppressing adverse events in renal cell carcinoma patients treated with tyrosine kinase inhibitors.
Authors: Yasuyoshi Miyata, Kojiro Ohba, Tomohiro Matsuo, Kensuke Mitsunari, Hideki Sakai
Journal: Journal of Clinical Oncology (2020)

697 Background: Royal jelly (RJ) is a honey bee product secreted from the mandibular glands and hypopharyngeal glands of worker honeybees. RJ has anti-allergy, anti-inflammatory, and immunomodulatory effects. RJ has been reported to improve the anti-cancer effects and suppress the adverse effects of chemotherapeutic agents. The main aim is to clarify the clinical effects of oral intake of RJ in renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKIs). Methods: A randomized, controlled, double-blinded clinical trial with reduction of tumor size and frequencies of adverse events as endpoints was performed in 33 RCC patients who received TKIs in Nagasaki University Hospital. Patients were divided into RJ (n = 16) and placebo (n = 17) groups, and there was no significant difference in all clinical and pathological parameters between the two groups. RJ and placebo were orally administered for 3 months. Results: In this study, 21, 8, and 3 patients were treated with sunitinib, pazopanib, and axitinib, respectively; only 1 patient was treated with sorafenib. Frequencies and severities of fatigue and anorexia in the RJ group was significantly lower than those in the placebo group ( P = 0.003 and 0.015, respectively). Such significant differences between the 2 groups were detected in patients treated with sunitinib, but not in those treated with other TKIs. The number of patients who were given an initial dose of TKIs in the RJ and placebo groups were 7 (43.8%) and 2 (11.8%), respectively, and the relative dose intensity (RDI) of the RJ group (88.6%) was significantly higher ( P = 0.016) than that in the placebo group (68.6%). Regarding anti-cancer effects, the frequency of partial response in the RJ group (n = 5; 41.7%) was higher than that in the placebo group (2; 18.2%); however, such difference was not significant ( P = 0.056). Conclusions: RJ intake can increase RDI. Although a significant difference was not observed, RJ intake observed a trend for improving anti-cancer effects by increasing RDI and maintaining quality of life.
Review of the real-world prevalence of mHSPC, nmCRPC, mCRPC, and gene alterations associated with HRR in prostate cancer (PC).
Authors: Neal D. Shore, Louisa Oliver, Irene Shui, Alicia Gayle, On Yee Wong, Jeri Kim, Sarah Payne, Sameer R. Ghate
Journal: Journal of Clinical Oncology (2020)

229 Background: The clinical journey of PC is evolving rapidly. New hormonal agents (NHA) have demonstrated clinical efficacy in metastatic hormone sensitive prostate cancer (mHSPC), non-metastatic castrate-resistant prostate cancer (nmCRPC) and metastatic castrate-resistant prostate cancer (mCRPC). A shift in the treatment landscape considering precision medicine, recently supported by the phase III PROFOUND study, suggests updates to the currently limited clinical guideline recommendations for genomic testing. Better understanding of the patient pathway and respective proportion of patients to support patient care is needed. The objective of this SLR was to summarize published literature on the prevalence of mHSPC, nmCRPC, mCRPC and HRR gene alterations. Methods: An SLR was conducted across nine databases in OVID to capture English language studies published 01/2009–05/2019 on global epidemiology and clinical practice trends for mHSPC, nmCRPC, mCRPC and HRRm. 4,732 papers were identified which were systematically screened for inclusion. Grey literature searches included 10 conference proceedings from 2014–2019. Results: In total, 244 observational publications met the inclusion criteria - 4 studies reported the prevalence of mCRPC, 3 on nmCRPC and 0 on mHSPC. From these, the estimated prevalence of mCRPC and nmCRPC is 1.6–2.1 and 1.1–2.1 per 100 PC cases, respectively. HRRm were investigated in 13 publications with next generation sequencing of tissue and blood samples being reported as the most frequent method. Of the HRR gene alterations examined, BRCA2 were found to have the highest prevalence with a range of 4.5–9.3 and 1.1–15.1 per 100 overall PC cases for germline and somatic gene alterations, respectively. Other prevalent HRR gene alterations included germline ATM, BRCA1 and CHEK2. Conclusions: Limited data are available evaluating the prevalence of mHSPC, nmCRPC and mCRPC required to quantify the burden of these populations suggesting a lag in the published literature following updates to US treatment guidelines. Our review also shows that HRR gene alterations, specifically BRCA2, are prevalent in PC consistent with recently published data on PROFOUND population.
Randomized phase II study of olaparib with or without cediranib in men with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Joseph W. Kim, Rana R. McKay, Mary-Ellen Taplin, Nancy B. Davis, Paul Monk, Leonard Joseph Appleman, Primo Lara, Ulka N. Vaishampayan, Jingsong Zhang, Asit K. Paul, Glenn Bubley, Eliezer Mendel Van Allen, Ying Huang, Zhenwei Zhang, Massimo Loda, Geoffrey Shapiro, Patricia LoRusso, S. Percy Ivy, Daniel Peter Petrylak
Journal: Journal of Clinical Oncology (2020)

111 Background: Cediranib, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, suppresses expression of BRCA1, BRCA2, and RAD51 and increases sensitivity of tumors to poly (ADP-ribose) polymerase (PARP) inhibitors in vitro. Olaparib, a PARP inhibitor, demonstrates clinical efficacy in men with DNA repair deficient, mCRPC. We therefore performed a randomized phase 2 trial comparing olaparib with or without cediranib in men with mCRPC. Methods: Men with a minimum of one prior line of systemic therapy for mCRPC were randomized 1:1 to receive cediranib 30mg po daily plus olaparib 200mg po BID (Arm A) or olaparib 300mg BID alone (Arm B). At radiographic progression, patients (pts) in Arm B could crossover to Arm A. The primary endpoint was radiographic progression-free survival (rPFS). Secondary endpoints were objective response rate (ORR) and PSA50 decline rate (PSA50). Tumor biopsy specimens were obtained for biomarker analyses pre- and on-treatment. Results: Baseline characteristics of the 90 pts enrolled are summarized below. The median rPFS was 11.1 versus 4.0 months in Arm A and Arm B, respectively (Hazard Ratio 0.54, 95% CI 0.317, 0.928, p=0.026). Trends toward a higher ORR (19% and 12%), Disease Control Rate (Stable Disease + Partial Response) (77% and 64%,) and PSA50 (29% and 17%) were observed in Arm A compared to Arm B, respectively. Thirteen pts in Arm B crossed over to Arm A. One pt had a PR after crossover. Grade 3/4 adverse events (G3/4 AEs), irrespective of attribution, occurred in 77% and 58% of Arm A and Arm B pts, respectively. G3/4 AEs occurring in &gt;10% of pts were hypertension (32%), fatigue (23%) and diarrhea (11%) in Arm A, and anemia (16%) and lymphopenia (11%) in Arm B. Conclusions: The cediranib/olaparib combination significantly improves rPFS in unselected, mCRPC pts. AEs were manageable. Analyses of mutation status in homologous recombination DNA repair genes are pending and will be key in interpreting the data. Clinical trial information: NCT02893917. [Table: see text]
On the mechanism of anti-CD39 immune checkpoint therapy
Authors: David Allard, Bertrand Allard, John Stagg
Journal: Journal for ImmunoTherapy of Cancer (2020)

With the coming of age of cancer immunotherapy, the search for new therapeutic targets has led to the identification of immunosuppressive adenosine as an important regulator of antitumor immunity. This resulted in the development of selective inhibitors targeting various components of the adenosinergic pathway, including small molecules antagonists targeting the high affinity A2A adenosine receptor and low affinity A2B receptor, therapeutic monoclonal antibodies (mAbs) and small molecules targeting CD73 and therapeutic mAbs targeting CD39. As each regulator of the adenosinergic pathway present non-overlapping biologic functions, a better understanding of the mechanisms of action of each targeted approach should accelerate clinical translation and improve rational design of combination treatments. In this review, we discuss the potential mechanisms-of-action of anti-CD39 cancer therapy and potential toxicities that may emerge from sustained CD39 inhibition. Caution should be taken, however, in extrapolating data from gene-targeted mice to patients treated with blocking anti-CD39 agents. As phase I clinical trials are now underway, further insights into the mechanism of action and potential adverse events associated with anti-CD39 therapy are anticipated in coming years.