tbuckley/cabot-search huggingface dataset:
Initial reporting of NRG-LU001 (NCT02186847), randomized phase II trial of concurrent chemoradiotherapy (CRT) +/- metformin in locally advanced Non-Small Cell Lung Cancer (NSCLC).
Authors: Theodoros Tsakiridis, Chen Hu, Heath Devin Skinner, Rafael Santana-Davila, Bo Lu, Jeremy J. Erasmus, Anthony Doemer, Gregory M.M. Videtic, James Coster, Xuezhong Yang, Richard Lee, Maria Werner-Wasik, Philip E. Schaner, Steven Eric McCormack, Benjamin Esparaz, Ronald McGarry, Jose G. Bazan, Timothy Struve, Jeffrey D. Bradley
Journal: Journal of Clinical Oncology (2019)

8502 Background: Metformin, a diabetes agent that inhibits mitochondria complex I, enhances radiotherapy and chemotherapy responses in pre-clinical models of NSCLC. NRG-LU001 examined whether metformin can improve outcomes of curative CRT in locally advanced (LA)-NSCLC. Methods: The primary endpoint of this trial was 1-year progression free survival (PFS). Unresected, non-diabetic, stage IIIA/B NSCLC patients were randomized (1:1) to either carboplatin-paclitaxel chemotherapy concurrent with chest RT (60Gy), followed by consolidation carboplatin-paclitaxel chemotherapy (Control Arm) or the same and oral metformin (2000mg daily) during cytotoxic therapy (Experimental Arm). PFS and overall survival (OS) were estimated with the Kaplan-Meier method; time to local-regional progression (TTLRP), time to distant metastasis (TTDM) were estimated using the cumulative incidence method. Adverse events (AEs) were graded with CTCAE v.4.0. Results: Between Aug.2014 and Dec.2016, 170 patients were accrued. Analysis was planned at 102 PFS events (Feb. 2019). There was no significant difference in rates or grade of toxicity between the two arms. 1- and 2-year PFS was 60.4% (95% CI: 48.5, 70.4) and 40.1% (95% CI: 29.0, 51.0) in Control vs 51.3% (95% CI: 39.8, 61.7) and 34.5% (95% CI: 24.2, 45.1) in the Metformin arm (multivariable Cox proportional HR=1.20 (95% CI: 0.81, 1.78), p=0.36). OS at 2 years was 65.4% (95% CI: 53.5, 75.0) for Control vs 64.9% (95% CI: 53.1, 74.5) for the Metformin arm (HR=1.03 (95% CI: 0.64, 1.68)), while deaths due to disease were 90% vs 71%, respectively. No significant differences were found for TTLRP or TTDM. Conclusions: NRG-LU001 center reported outcomes show that oral daily metformin was well-tolerated in combination with CRT treatment for LA-NSCLC. However, metformin did not improve PFS and OS and did not alter the rates of local-regional failure or distant metastasis. Acknowledgements: TT and HS are Co-Principal Investigators. This project was supported by National Cancer Institute (NCI) grants: U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC). Clinical trial information: NCT02186847.
Genetic risk scores do not improve asthma prediction in childhood
Authors: F. Nicole Dijk, Charlotte Folkersma, Olena Gruzieva, Ashish Kumar, Alet H. Wijga, Ulrike Gehring, Inger Kull, Dirkje S. Postma, Judith M. Vonk, Erik Melén, Gerard H. Koppelman
Journal: Journal of Allergy and Clinical Immunology (2019)
Case 47-1992
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, A. Lebel, E.T. Hedley-Whyte
Journal: New England Journal of Medicine (1992)

Presentation of CaseA 25-year-old man was admitted to the hospital because of intermittent coccygeal pain throughout his life, with recent worsening.The patient was in good general health until one year earlier, when he underwent resection of a pilonidal sinus at another hospital. He was informed that the sinus was removed but that a large tumor was found, and no further operative procedure was performed. Thereafter the pain became worse, with radiation down the back of both legs, more prominently in the right leg, and was most severe in the buttocks and thighs; he also noticed numbness of both . . .
Dysfunction of Poly (ADP-Ribose) Glycohydrolase Induces a Synthetic Lethal Effect in Dual Specificity Phosphatase 22-Deficient Lung Cancer Cells
Authors: Yuka Sasaki, Hiroaki Fujimori, Miyuki Hozumi, Takae Onodera, Tadashige Nozaki, Yasufumi Murakami, Kazuto Ashizawa, Kengo Inoue, Fumiaki Koizumi, Mitsuko Masutani
Journal: Cancer Research (2019)

Poly (ADP-ribose) glycohydrolase (PARG) is the main enzyme responsible for catabolism of poly (ADP-ribose) (PAR), synthesized by PARP. PARG dysfunction sensitizes certain cancer cells to alkylating agents and cisplatin by perturbing the DNA damage response. The gene mutations that sensitize cancer cells to PARG dysfunction-induced death remain to be identified. Here, we performed a comprehensive analysis of synthetic lethal genes using inducible PARG knockdown cells and identified dual specificity phosphatase 22 (DUSP22) as a novel synthetic lethal gene related to PARG dysfunction. DUSP22 is considered a tumor suppressor and its mutation has been frequently reported in lung, colon, and other tumors. In the absence of DNA damage, dual depletion of PARG and DUSP22 in HeLa and lung cancer A549 cells reduced survival compared with single-knockdown counterparts. Dual depletion of PARG and DUSP22 increased the apoptotic sub-G1 fraction and upregulated PUMA in lung cancer A549, PC14, and SBC5 cells, and inhibited the PI3K/AKT/mTOR pathway in A549 cells, suggesting that dual depletion of PARG and DUSP22 induced apoptosis by upregulating PUMA and suppressing the PI3K/AKT/mTOR pathway. Consistently, the growth of tumors derived from double knockdown A549 cells was slower compared with those derived from control siRNA-transfected cells. Taken together, these results indicate that DUSP22 deficiency exerts a synthetic lethal effect when combined with PARG dysfunction, suggesting that DUSP22 dysfunction could be a useful biomarker for cancer therapy using PARG inhibitors. SIGNIFICANCE: This study identified DUSP22 as a novel synthetic lethal gene under the condition of PARG dysfunction and elucidated the mechanism of synthetic lethality in lung cancer cells.
NRG-GI002: A phase II clinical trial platform using total neoadjuvant therapy (TNT) in locally advanced rectal cancer (LARC)—First experimental arm (EA) initial results.
Authors: Thomas J. George, Greg Yothers, Theodore S. Hong, Marcia McGory Russell, Y. Nancy You, William Parker, Samuel A. Jacobs, Peter C. Lucas, Marc Jeffrey Gollub, William Adrian Hall, Lisa A. Kachnic, Namrata Vijayvergia, Norman Wolmark
Journal: Journal of Clinical Oncology (2019)

3505 Background: This NCTN multi-arm randomized phase II modular clinical trial platform utilizes TNT with parallel EAs in LARC. EAs are not intended for direct comparison, but rather to test a variety of hypotheses in a consistent high-risk pt population with correlative biomarkers. Primary endpoint (EP) and available secondary EPs from the first EA using veliparib (a PARPi) are reported. NCT02921256. Methods: Stage II/III pts with LARC (with any ONE of the following: distal location [cT3-4 ≤5cm from anal verge, any N]; bulky [any cT4 or tumor within 3mm of mesorectal fascia]; high risk for metastatic disease [cN2]; or not a sphincter-sparing surgery [SSS] candidate) were randomized to neoadjuvant FOLFOX (x 4mo) → chemoRT (cape with 50.4Gy +/- veliparib 400mg PO BID) → surgery 8-12 wks later. Primary EP: 4 point reduction in Neoadjuvant Rectal Cancer (NAR) score with a one-sided α = 0.10 and 80% power. NAR compared by linear model controlling for stratification and possibly other factors. Secondary EPs: OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, and SSS. Binary EPs compared by Fisher’s exact test. Reported p-values are two-sided. Results: From 10/2016 - 2/2018, 178 pts were randomized (88 control, 90 veliparib). Baseline characteristics were balanced except for candidate for SSS at entry (39% control, 61% veliparib). 140 pts were evaluable for NAR (72 control, 68 veliparib). Mean NAR was 12.6 control (95% CI: 9.8–15.3) vs 13.7 for veliparib (CI: 10.2–17.2). Controlling for stratification (p = 0.69) or stratification and candidate for SSS (p = 0.78), NAR difference was not significant. pCR = 21.6% vs 33.8% (p = 0.14); cCR = 28.2% vs 33.3% (p = 0.60); and SSS = 52.5% vs 59.3% (p = 0.43). Most common grade 3/4 AEs were diarrhea and cytopenias. The EA had two deaths (cardiac arrest [FOLFOX]; enterocolitis [chemoRT]). Conclusions: Veliparib added to chemoRT as part of TNT was safe and without unexpected short-term toxicities but failed to improve the NAR score. Support: U10CA180868, -180822; UG1-189867; U24-196067; AbbVie. Clinical trial information: NCT02921256.
A phase II study of talazoparib (BMN 673) in patients with homologous recombination repair deficiency (HRRD) positive stage IV squamous cell lung cancer (Lung-MAP Sub-Study, S1400G).
Authors: Taofeek Kunle Owonikoko, Mary Weber Redman, Lauren Averett Byers, Fred R. Hirsch, Philip C. Mack, Lawrence Howard Schwartz, Jeffrey D. Bradley, Tom Stinchcombe, Natasha B. Leighl, Tareq Al Baghdadi, Primo Lara, Jieling Miao, Karen Kelly, Suresh S. Ramalingam, Roy S. Herbst, Vassiliki Papadimitrakopoulou, David R. Gandara
Journal: Journal of Clinical Oncology (2019)

9022 Background: This signal finding study was designed to evaluate the clinical efficacy of a PARP inhibitor, talazoparib, in advanced stage squamous cell lung cancer harboring HRRD. Methods: Eligible patients (pts) identified through the parent S1400 screening platform were required to have a deleterious mutation in any of the study-defined HRR genes [ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CHEK1, CHEK2, FANCA, FANCC, FANCD2, FANCF, FANCM, NBN (NBS1), PALB2, RAD51, RAD51B (RAD51L1), RAD54L, RPA1) defined as the full eligible population (FEP). The primary analysis population (PAP) is defined by a subset of genes [ATM, ATR, BRCA1, BRCA2, PALB2]. Pts have platinum sensitive disease (at least stable disease on platinum doublet) and progressed on most recent line of systemic therapy, a Zubrod performance status of 0-1, adequate organ function, and not have been previously exposed to a PARP inhibitor and not be on systemic therapy within 21 days of registration. A 2-stage design with exact 93% power and 1-sided 0.07 level type I error required enrollment of 40 patients in the PAP in order to rule out an ORR of 15% or less if the true ORR is 35% or greater. At least 3 or more responses were needed in the first 20 pts in order to proceed to full enrolment of 40 pts in the PAP. The total accrual goal was 60 FEP assuming 67% of patients would be in the PAP. Results: The study enrolled 51 patients of whom 47 are eligible and analyzable for response (FEP) with 24 in the PAP. In the FEP, median age 66.7 yrs; M/F 39/8 (83/17%); 85% White and 15% Black; 77% of the pts received at least 1 prior line of treatment for stage IV. The study was closed for futility with only one response in the PAP. In the PAP (n = 24, median age 68 yrs), ORR was 4% (95%CI: 0, 21) and DCR was 54% (95%CI: 33, 74); median PFS of 2.4 months (95%CI: 1.5-2.8) and median OS was 5.2 months (95%CI: 3.8-10, 7). There were five responders in the FEP with ORR of 11%; DCR of 53% and median DoR was 1.8 months (95% CI: 1.3, 4.2); median PFS was 2.5 months (95%CI: 1.6-3.0) and median OS was 5.7 months (95% CI: 4.5-8.7). The most frequent grade ≥3 adverse event in the FEP were: Anemia (14.9%), thrombocytopenia (12.8%); lymphopenia (8.5%) and nausea (6.4%). Conclusions: S1400G failed to show sufficient level of efficacy for talazoparib in a biomarker defined subset of squamous lung cancer with HRRD. There were no new safety signals and hematologic toxicities were the most frequent adverse events. Clinical trial information: NCT02154490.
Alteration of TGF-β signaling pathway predicts worse prognosis in pancreatic ductal adenocarcinoma.
Authors: Bole Tian, Mao Li, Dan Cao, Ang Li, Xiaochen Zhao, Shengzhong Hou, Shan Lu, Yu Mou, Xubao Liu, Shangli Cai
Journal: Journal of Clinical Oncology (2019)

e13006 Background: Transforming growth factor beta (TGF-β) signaling pathway is one of the core pathways involved in tumor initiation and progression. The prognostic value of TGF-β pathway genes as a functionally related group in pancreatic ductal adenocarcinoma (PDAC) is rarely studied. Methods: 72 PDAC patients who underwent surgery between November 30, 2015 and September 13, 2017 in West China Hospital, Sichuan University were identified and included in this study. Whole-exome sequencing (WES) or targeted next-generation sequencing was performed with tumor tissue from all the participants. Clinical data was retrospectively collected. Clinicopathologic characteristics and overall survival (OS) were analyzed. Results: Genetic alterations were detected in 71 patients (98.6%). While 1 patient (1.4%) had only one genetic alteration, 33 patients (45.8%) had 2-4 genetic alterations and 37 patients (51.4%) had ≥5 genetic alterations. Overall, 25 patients (34.7%) with alteration of TGF-β pathway and 47 patients (65.3%) with wild type of TGF-β pathway were identified as TGF-βm+ group and TGF-βm- group respectively. Mutation of TGF-β pathway was independently associated with inferior OS in present cohort (HR, 2.22; 95% CI, 1.05-4.70; P = 0.04), adjusted for tumor stage, metastasis, surgery method and comorbidity. Subgroup analysis showed that patients with mutation of TGF-β pathway had shorter OS after radical surgery (HR, 3.25, 95% CI: 1.01–10.49; P = 0.04). While in the subgroup of patients who underwent palliative surgery, OS was not statistically different (HR, 0.93, 95% CI: 0.41–2.09; P = 0.86). Conclusions: Inferior prognosis was observed in PDACs with mutations of TGF-β pathway. Genomic information could help screen out patients at risk after surgery and adjuvant therapy might benefit this subgroup of PDACs.
To balloon or to suture, that is the question
Authors: Reem Z. Sharaiha
Journal: Endoscopy (2019)

Obesity is major health concern in the USA, affecting more than 90 million Americans [1]. Because of obesity-related comorbidities, including but not limited to diabetes, heart disease, and cancer, the healthcare costs associated with obesity may account for up to 21 % of US healthcare expenditure [2] [3].
WHO teams arrive in Pakistan to establish source of HIV infections
Authors: Ashfaq Yusufzai
Journal: BMJ (2019)

World Health Organization officials have arrived in Pakistan to try to establish how more than 700 people, many of them children, have become infected with HIV in the past 40 days.

On 29 May technical teams arrived in Rotadero village in Sindh province in the southeast of the country at the request of the government, to support the response to an outbreak first reported on …
KEYNOTE-630: Phase 3 study of adjuvant pembrolizumab versus placebo in patients with high-risk, locally advanced cutaneous squamous cell carcinoma.
Authors: Jessica Lyn Geiger, Gregory A. Daniels, Ezra E.W. Cohen, Joy Yang Ge, Burak Gumuscu, Ramona F. Swaby, Anne Lynn S. Chang
Journal: Journal of Clinical Oncology (2019)

TPS9597 Background: Among patients with high-risk, locally advanced (LA) cutaneous squamous cell carcinoma (cSCC) who receive current standard-of-care surgical resection and adjuvant radiotherapy, ~40-50% develop local recurrence and regional metastasis ( J Clin Oncol. 2018;36:1275-1283). Recent data suggest that programmed death 1 inhibitors such as pembrolizumab may provide a well-tolerated, effective, and durable response in patients with LA or metastatic cSCC. To evaluate the efficacy and safety of adjuvant pembrolizumab in patients with high-risk LA cSCC, the randomized, double-blind, placebo-controlled phase 3 KEYNOTE-630 trial (NCT03833167) will be conducted. Methods: After surgical resection and radiotherapy for high-risk LA cSCC, eligible patients will be randomly assigned 1:1 to intravenous pembrolizumab (400 mg Q6W) or placebo for up to 9 cycles (~1 year), with radiographic imaging at least every 12 weeks until year 2 and then every 6 months until the end of year 5 to assess treatment response. Eligibility criteria will include age ≥18 years, histologically confirmed LA cSCC with ≥1 high-risk feature at the primary site of malignancy, macroscopic resection with or without microscopic positive margins, completed adjuvant radiotherapy, disease free ≤28 days from randomization, and ECOG performance status 0-1. Treatment will be discontinued at disease recurrence, start of new anticancer treatment, unacceptable toxicity, intercurrent illness that prevents treatment, pregnancy, investigator or patient decision to withdraw, or administrative reasons that require treatment cessation. After the first disease recurrence, all patients who meet crossover or retreatment criteria may receive pembrolizumab 400 mg Q6W for up to 18 cycles. Adverse events will be monitored throughout the study and graded according to the NCI CTCAE, version 4.0. The primary efficacy end point will be investigator-assessed and biopsy-confirmed recurrence-free survival. Secondary end points will be overall survival, health-related quality of life, and safety. Recruitment is ongoing in 19 countries and will continue until approximately 570 patients are enrolled. Clinical trial information: NCT03833167.
Risk of subsequent cancer diagnosis in patients treated with 3D conformal, intensity modulated, or proton beam radiation therapy.
Authors: Michael H. Xiang, Daniel Tandel Chang, Erqi L. Pollom
Journal: Journal of Clinical Oncology (2019)

1503 Background: Approximately half of cancer patients receive radiation therapy (RT). Modern RT modalities (3D conformal [3DCRT], intensity modulated [IMRT], proton beam [PBRT]) have been theorized to pose different risks of second cancers, but the relationship between RT modality and subsequent cancers has been unclear due to their rarity. Methods: Pediatric and adult patients with a first cancer diagnosis who received 3DCRT, IMRT, or PBRT were identified in the National Cancer Database. To analyze a more uniform population, cases were required to be non-metastatic and have at least 2 years of follow-up time. Ten cancer types were included: head/neck, upper gastrointestinal (GI), lower GI, gynecological, lymphoma, non-small cell lung, prostate, breast, bone/soft tissue, and brain/central nervous system. Diagnosis of a subsequent cancer was determined using a variable denoting the sequence of malignant neoplasms over the lifetime of the patient. The risk of subsequent cancer diagnosis was modeled using multivariable logistic regression adjusting for age, follow-up time, cancer type, RT dose, chemotherapy, and other factors. Propensity score matching was additionally used to balance baseline characteristics. Results: In total, 430,866 patients were included (33.4% 3DCRT, 65.1% IMRT, 1.5% PBRT) with median follow-up of 5.0 years and total follow-up period of 2.35 million person-years. In the comparison of IMRT relative to 3DCRT, there was no difference in the risk of subsequent cancer diagnosis (adjusted odds ratio [OR] 1.01; 95% confidence interval [CI] 0.98-1.03; p = 0.62). In contrast, recipients of PBRT had significantly lower risk of subsequent cancer diagnosis relative to IMRT (adjusted OR 0.31; 95% CI 0.26-0.37; p &lt; 0.0001). The benefit associated with PBRT persisted in sensitivity analyses that excluded patients with prostate cancer (71.6% of the PBRT cases), receipt of chemotherapy, and/or follow-up time less than 5 years. Conclusions: Risk of subsequent cancer diagnosis was similar between IMRT and 3DCRT and significantly lower for PBRT. PBRT may be preferred in situations where avoidance of second cancers is paramount, such as pediatrics and young adults.
Relacorilant (RELA) with nab-paclitaxel (NP): Safety and activity in patients with pancreatic ductal adenocarcinoma (PDAC) and ovarian cancer (OvCA).
Authors: Pamela N. Munster, Jasgit C. Sachdev, Gini F. Fleming, Erkut Hasan Borazanci, Jennifer A. Grabowsky, Manish Sharma, Joseph Custodio, Andrew Greenstein, Lawrence Lu, Dat Nguyen, Stacie Peacock Shepherd
Journal: Journal of Clinical Oncology (2019)

4130 Background: Glucocorticoid receptor (GR) pathway activation has been linked with chemotherapy resistance (CTR). RELA (formerly CORT125134, Corcept Therapeutics), a potent selective GR modulator, in combination with paclitaxel reduced CTR and enhanced activity against tumor growth in preclinical models of solid tumors. Methods: Patients (pts) with advanced solid tumors, ≤3 prior lines of cytotoxic therapy, ECOG status 0-1, and adequate marrow function received RELA (100, 150, or 200mg) + NP (60, 80, or 100mg/m 2 ). Once daily RELA was given either continuously (CON) or intermittently (INT) (day before, of, and after NP). NP was dosed weekly for 3 of 4 weeks (wks) of a 28-day cycle. Prior NP therapy was allowed. Results: 72 pts have been enrolled [mean age 60 (range 18-81), mean number of prior therapies 3, prior taxane (TXN) treatment 54/72 (75%)]. 61 pts received ≥1 dose of RELA. Grade ≥3 AE ≥10% for CON: neutropenia (6/43, 14%); INT: neutropenia (6/18, 33%), anemia (2/18, 11%), and mucosal inflammation (2/18, 11%). Prophylactic G-CSF became mandatory in later cohorts. Recommended Phase 2 Dose: RELA 100mg-CON/150mg-INT + NP 80mg/m 2 (exposures similar to NP 100mg/m 2 due to CYP3A4 inhibition by RELA). Disease control (DC) &gt; 24 wks was noted in 5/27 (19%) PDAC pts: 3 PR, 2 SD (27-50 wks). 3 pts achieved benefit despite progression on prior TXN with time to progression (TTP) 1.9-3.6x longer than prior TXN. 4/13 (31%) OvCA pts had DC &gt; 24 wks: 1 CR, 1 PR, 2 SD (33-54+ wks). 1 pt had TTP 4.4x longer than prior TXN. 3 additional PRs were observed: acinar pancreatic cancer, TTP 31 wks (4.4x prior TXN); vulvar SCC HPV+, TTP 55 wks (3.9x prior TXN); cholangiocarcinoma, DC 29+ wks. Expression of GR-regulated genes involved in inflammation, apoptosis, and CTR distinguished pts with DC from pts without DC, providing proof of mechanism. Conclusions: RELA+NP resulted in durable disease control in pts with metastatic PDAC, OvCA, and other solid tumors, including those that have progressed on prior TXN. TTP was often several-fold longer than previously achieved on TXN therapy. Toxicities are manageable with prophylaxis for neutropenia. Further evaluation in OvCA NCT03776812, PDAC, and others are planned. Clinical trial information: NCT02762981.