tbuckley/cabot-search huggingface dataset:
AGENT: An open-label phase III study of arfolitixorin versus leucovorin in modified FOLFOX-6 for first-line treatment of metastatic colorectal cancer.
Authors: Heinz-Josef Lenz, Peter Gibbs, Sebastian Stintzing, Gerald W. Prager, Peter Nygren, Christos A. Papadimitriou, Roger Tell, Takayuki Yoshino, Derek J. Jonker, Aimery De Gramont, Josep Tabernero
Journal: Journal of Clinical Oncology (2020)

TPS268 Background: 5-fluorouracil (5FU), in combination with folates, is an established cornerstone of metastatic colorectal cancer (mCRC) treatment. All folates currently approved for mCRC need to be metabolically activated to [6R]-5,10-methylenetetrahydrofolic acid ([6R]-MTHF), the active thymidylate synthase co-substrate that potentiates the effect of 5FU. Arfolitixorin does not require multi-step metabolic activation, and may produce higher, and less inter- and intraindividually variable, concentrations of [6R]-MTHF than leucovorin. Methods: The phase III AGENT trial (NCT03750786) is a randomized, multicenter, parallel-group study comparing the efficacy of arfolitixorin versus leucovorin in mCRC patients treated with first-line 5FU, oxaliplatin, and bevacizumab. Patients are randomized (1:1) to the investigational arm (arfolitixorin + 5FU + oxaliplatin [ARFOX] + bevacizumab) or the comparator arm (leucovorin + 5FU + oxaliplatin [modified FOLFOX-6] + bevacizumab), and treated until disease progression based on RECIST 1.1 criteria. Recruitment is ongoing, and aims to randomize 440 patients in 18 months. Eligibility criteria include non-resectable mCRC; eligibility for 5FU, oxaliplatin, and bevacizumab therapy; ECOG PS 0 or 1. The study will be conducted across approximately 100 sites in Australia, Austria, Canada, France, Germany, Greece, Japan, Spain, Sweden, and USA. The primary endpoint is objective response rate. Key secondary endpoints are progression-free survival and duration of response. Additional secondary endpoints include overall survival, quality of life, safety and tolerability, and number of patients undergoing curative metastasis resection. A translational program will evaluate expression levels of several folate metabolism- and transportation-related genes in mCRC tumor biopsies to determine their relationship to treatment outcome. A broad array of genes will analyzed, including ATP-binding cassette C3 (ABCC3) transporter, methylenetetrahydrofolate dehydrogenase 2 (MTHFD2), proton-coupled folate transporter (PCFT), and serine hydroxymethyltransferase 1 (SHMT1). Interim data are expected in mid 2020. Clinical trial information: NCT03750786.
Survival impact on regorafenib (REG) and trifluridine/tipiracil hydrochloride (FTD/TPI) for patients with metastatic colorectal cancer: Single institutional experience.
Authors: Keigo Chida, Daisuke Kotani, Kentaro Sawada, Yoshiaki Nakamura, Akihito Kawazoe, Yasutoshi Kuboki, Kohei Shitara, Takashi Kojima, Hiroya Taniguchi, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2020)

43 Background: Regorafenib (REG) and trifluridine/tipiracil hydrochloride (FTD/TPI) demonstrated overall survival (OS) benefit in patients (pts) with metastatic colorectal cancer (mCRC) in the CORRECT and RECOURSE phase III trials. In Japan, REG and FTD/TPI have been approved in 2013 and 2014, respectively. However, little is known about survival impact on these agents in the real-world setting. Therefore, the aim of this retrospective study was to evaluate the effects of REG and FTD/TPI in pts with mCRC. Methods: We collected medical records from consecutive 1142 pts who had been initiated with first-line chemotherapy for mCRC from 2008 to 2016 at National Cancer Center Hospital East. The survival outcomes were compared between pts from 2008 to 2011 (cohort A) and those from 2012 to 2016 (cohort B). This study excluded pts who have not been refractory or intolerant to standard chemotherapy including fluoropyrimidine, oxaliplatin, irinotecan, and anti-EGFR antibody if KRAS exon 2/ RAS wild-type tumors. Results: A total of 590 pts were analyzed (cohort A; N = 236 and cohort B; N = 354). More patients received at least one of REG or FTD/TPI in cohort B (16.1% vs. 59.9%, p &lt; 0.001). The time from initiation to end of standard chemotherapy was comparable between the two cohort (20.0 vs. 17.5 months, p = 0.266). With a median follow-up period of 34.9 months, salvage-line OS (sOS) after standard chemotherapy was significantly longer in cohort B (4.8 vs. 6.6 months, p = 0.001), while there was only a favorable trend in cohort B in terms of OS from start of first-line treatment (27.3 vs. 28.5 months, p = 0.516). In cohort B, pts who sequentially received both of REG and FTD/TPI showed longest sOS (median, both of REG and FTD/TPI; 11.3 months, either REG or FTD/TPI; 7.0 months, neither REG nor FTD/TPI; 3.1 months). Conclusions: Our study showed that REG and FTD/TPI led to prolongation of sOS in the real-world setting, indicating the importance of strategies which make all active agents available to pts with mCRC.
The Longitudinal Influence of Social Determinants of Health on Glycemic Control in Elderly Adults With Diabetes
Authors: Rebekah J. Walker, Emma Garacci, Anna Palatnik, Mukoso N. Ozieh, Leonard E. Egede
Journal: Diabetes Care (2020)

OBJECTIVE This study aimed to understand the longitudinal relationship between financial, psychosocial, and neighborhood social determinants and glycemic control (HbA1c) in older adults with diabetes. RESEARCH DESIGN AND METHODS Data from 2,662 individuals with self-reported diabetes who participated in the Health and Retirement Study (HRS) were used. Participants were followed from 2006 through 2014. Financial hardship, psychosocial, and neighborhood-level social determinant factors were based on validated surveys from the biennial core interview and RAND data sets. All social determinant factors and measurements of HbA1c from the time period were used and treated as time varying in analyses. SAS PROC GLIMMIX was used to fit a series of hierarchical linear mixed models. Models controlled for nonindependence among the repeated observations using a random intercept and treating each individual participant as a random factor. Survey methods were used to apply HRS weighting. RESULTS Before adjustment for demographics, difficulty paying bills (β = 0.18 [95% CI 0.02, 0.24]) and medication cost nonadherence (0.15 [0.01, 0.29]) were independently associated with increasing HbA1c over time, and social cohesion (−0.05 [−0.10, −0.001]) was independently associated with decreasing HbA1c over time. After adjusting for both demographics and comorbidity count, difficulty paying bills (0.13 [0.03, 0.24]) and religiosity (0.04 [0.001, 0.08]) were independently associated with increasing HbA1c over time. CONCLUSIONS Using a longitudinal cohort of older adults with diabetes, this study found that financial hardship factors, such as difficulty paying bills, were more consistently associated with worsening glycemic control over time than psychosocial and neighborhood factors.
A phase III randomized controlled trial comparing surgery plus adjuvant chemotherapy with or without preoperative chemoradiotherapy for locally recurrent rectal cancer: A Japan Clinical Oncology Group study (JCOG1801).
Authors: Yuichiro Tsukada, Masaaki Ito, Naoki Nakamura, Yoshinori Ito, Hideaki Bando, Masahiko Ando, Hiroaki Onaya, Masataka Ikeda, Mitsugu Sekimoto, Tomohiro Kadota, Hiroshi Katayama, Junki Mizusawa, Haruhiko Fukuda, Yukihide Kanemitsu
Journal: Journal of Clinical Oncology (2020)

TPS263 Background: Local recurrence is one of the most common forms of recurrence after curative resection for primary rectal cancer. Surgical resection is recommended for locally recurrent rectal cancer (LRRC) to achieve radical cure if the tumor is judged as resectable with negative margins. However, a high local re-recurrent risk after surgery is a major problem due to the difficulty of re-resection and the serious symptoms, such as pain or fistula, resulting from re-recurrence. Preoperative chemoradiotherapy (preCRT) is expected to improve local control after radical surgery for radiation naïve LRRC; however, high frequency of surgical complications after preCRT cannot be ignored. Due to the refractory nature and rarity of LRRC, the true impact of preCRT on oncological and surgical outcomes has not been clarified by clinical trials. The purpose of this study is to confirm the superiority of preCRT followed by surgery plus adjuvant chemotherapy over surgery plus adjuvant chemotherapy alone, in terms of local relapse-free survival for resectable LRRC. Methods: Eligibility criteria include resectable LRRC without distant metastasis, no prior pelvic irradiation, no prior surgery for LRRC, aged 20-80 years, and sufficient organ function. Eligible patients are randomized into the surgery and adjuvant chemotherapy (arm A) or preCRT followed by surgery and adjuvant chemotherapy (arm B). PreCRT consists of the standard dose of capecitabine and radiotherapy (50.4Gy). Adjuvant chemotherapy consists of mFOLFOX6, CAPOX, capecitabine, or 5FU+l-LV. The primary endpoint is local relapse-free survival (LRFS), and the secondary endpoints include overall survival, relapse-free survival, %R0 resection, incidence of adverse events, and quality of life after surgery. The 3-year LRFS of arm A is assumed to be 60% with a 13% increase expected in arm B. The sample size was calculated as 106 (53 per arm) with a one-sided alpha of 10%, power of 70%, and accrual period of 6 years. This trial was initiated on 19 August 2019. Clinical trial information: jRCTs031190076.
Correlation of radiomics of metastatic lesions in gastroesophageal adenocarcinoma (GEA) with tumoral DKK1 mRNA expression and other immune biomarkers in patients (pts) treated with DKN-01.
Authors: Cynthia A. Sirard, Samuel J. Klempner, Girish S. Naik, Michael Kagey, Zak Nolte, Ziad Hindosh, Andre Burkett, Ronald Lee Korn
Journal: Journal of Clinical Oncology (2020)

429 Background: Dickkopf-1 (DKK1) modulates Wnt and PI3K/AKT signaling pathways and contributes to an immune suppressive tumor microenvironment. Recently, anti-DKK1 antibody (DKN-01) [D] plus pembrolizumab (P) in GEA tumors has demonstrated clinical activity. Radiomic Quantitative Texture Analysis (QTA) is a non-invasive method for imaging biomarker discovery that can predict molecular drivers of cancer from CT scans obtained during clinical trials. QTA may be a useful tool for predicting DKK1 expression and other immune biomarkers in metastatic lesions from GEA pts treated with DKN-01. Methods: 13 pts with GEA (12 M; 1F; age 37-81) enrolled in D+P Phase I/II trial with high vs low DKK1 RNA Scope H-Scores (H Score &gt; 35; n = 6 vs H-Score &lt; 35; n = 7) were identified. Metastatic Target lesions (TLs) from baseline CTs with IV contrast underwent additional QTA analysis (TexRAD, CE mark, Essex, UK) after RECIST analysis. ROIs were placed on the TLs and histogram frequency curves (HFC) of the metastatic tumor pixels were generated. First order tumor HFC statistical results (i.e. mean, Standard Deviation-SD, Skewness, Kurtosis, MPP) were correlated with tumoral DKK1 mRNA expression, baseline plasma DKK1 levels and other biomarkers (PD-L1 CPS and MDSCs) along with tumor shrinkage using Pearson’s r correlation (significance p &lt; 0.05). Results: Tumor derived QTA parameter (QTA SD) of the largest metastatic TL from each subject was positively correlated with DKK1 RNAscope H-score (r = 0.661, p value = .014) meaning larger SD texture scores had greater DKK1 expression. Also, tumor derived QTA parameter (QTA MPP) was correlated with baseline plasma DKK1 (r = -0.461, p = 0.005). Finally, QTA SD was correlated with PD-L1 expression (r = 0.630, p = 0.028) and TL shrinkage (r = -0.590, p = 0.034). Conclusions: Radiomics of GEA tumor metastasis using QTA showed significant correlations between tumor texture, tumor DKK1 mRNA expression and baseline plasma DKK1 suggesting that tumor textures may provide a non-invasive tool for assessing DKK1. Although promising as a imaging biomarker, further studies are required to validate these findings. Clinical trial information: NCT02013154.
Plasma Circulating Tumor HPV DNA for the Surveillance of Cancer Recurrence in HPV-Associated Oropharyngeal Cancer
Authors: Bhishamjit S. Chera, Sunil Kumar, Colette Shen, Robert Amdur, Roi Dagan, Rebecca Green, Emily Goldman, Jared Weiss, Juneko Grilley-Olson, Shetal Patel, Adam Zanation, Trevor Hackman, Jeff Blumberg, Samip Patel, Brian Thorp, Mark Weissler, Wendell Yarbrough, Nathan Sheets, William Mendenhall, Xianming M. Tan, Gaorav P. Gupta
Journal: Journal of Clinical Oncology (2020)

PURPOSE Plasma circulating tumor human papillomavirus DNA (ctHPVDNA) is a sensitive and specific biomarker of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). We investigated whether longitudinal monitoring of ctHPVDNA during post-treatment surveillance could accurately detect clinical disease recurrence. METHODS AND MATERIALS A prospective biomarker clinical trial was conducted among patients with nonmetastatic HPV-associated (p16-positive) OPSCC. All patients were treated with curative-intent chemoradiotherapy (CRT). Patients underwent a 3-month post-CRT positron emission tomography/computed tomography scan and were thereafter clinically evaluated every 2-4 months (years 1-2), then every 6 months (years 3-5). Chest imaging was performed every 6 months. Blood specimens were collected every 6-9 months for analysis of plasma ctHPVDNA using a multianalyte digital polymerase chain reaction assay. The primary endpoint was to estimate the negative predictive value (NPV) and positive predictive value (PPV) of ctHPVDNA surveillance. RESULTS Forty-five patients were enrolled, and 509 blood samples were analyzed. After a median follow-up time of 19.2 months (range, 14.1-30.6 months), 4 patients (9%) developed disease recurrence. Thirty-seven patients had undetectable ctHPVDNA at all post-treatment time points, and none developed recurrence (NPV, 100%; 95% CI, 91% to 100%). Eight patients developed a positive ctHPVDNA during post-treatment surveillance, 4 of whom were diagnosed with biopsy-proven recurrence. Four patients had 2 consecutively positive ctHPVDNA blood tests, all 4 of whom developed biopsy-proven recurrence. Two consecutively positive ctHPVDNA blood tests had a PPV of 100% (95% CI, 51% to 100%). Median lead time between ctHPVDNA positivity and biopsy-proven recurrence was 6.6 months (range, 3.3-12.9 months). CONCLUSION Detection of ctHPVDNA in two consecutive plasma samples during post-treatment surveillance has high PPV and NPV for identifying disease recurrence in patients with HPV-associated oropharyngeal cancer and may facilitate earlier initiation of salvage therapy.
Psychological Interventions for Patients With Advanced Disease: Implications for Oncology and Palliative Care
Authors: Gary Rodin, Ekaterina An, Joanna Shnall, Carmine Malfitano
Journal: Journal of Clinical Oncology (2020)

A growing body of research demonstrates the feasibility and efficacy of psychological interventions for adult patients with advanced cancer. Findings from quantitative studies of psychotherapeutic interventions with primary psychological outcomes for such patients are reviewed here and recommendations for best practice are made. We consider these interventions according to three broad phases in which they are most commonly applied: soon after diagnosis of advanced cancer, when living with the disease, and at or near the end of life. Cumulative evidence from well-designed studies demonstrates the efficacy of psychosocial interventions for patients with advanced disease to relieve and prevent depression, anxiety, and distress related to dying and death, as well as to enhance the sense of meaning and preparation for end of life. Individual and couple-based interventions have been proven to be most feasible, and the development and use of tailored and validated measures has enhanced the rigor of research and clinical care. Palliative care nurses and physicians can be trained to deliver many such interventions, but a core of psychosocial clinicians, including social workers, psychologists, and psychiatrists, is usually required to train other health professionals in their delivery and to ensure their quality. Few of the interventions for which there is evidence of effectiveness have been routinely incorporated into oncology or palliative care. Advocacy on the basis of this evidence is required to build psychosocial resources in cancer treatment settings and to ensure that psychological care receives the same priority as other aspects of palliative care in oncology.
The development of therapeutic cancer vaccine for pancreatic cancer.
Authors: Hiroki Yamaue, Motoki Miyazawa, Masahiro Katsuda, Manabu Kawai, Seiko Hirono, Ken-Ichi Okada, Yuji Kitahata, Masaki Ueno, Shinya Hayami
Journal: Journal of Clinical Oncology (2020)

707 Background: A previous phase II/III trial using a single cancer peptide vaccine derived from vascular endothelial growth factor receptor (VEGFR)2 for patients with advanced pancreatic cancer did not demonstrate the overall survival (OS) benefit (Yamaue et al. Cancer Sci 2015). However, for the next trial, we conducted a multicenter phase II study using multipeptide cocktail vaccine named OCV-C01 derived from a novel higher immunogenic antigen KIF20A, VEGFR1 and VEGFR2 combined with gemcitabine in postoperative adjuvant setting. Methods: A single-arm multicenter phase II study was performed on 30 patients with pancreatic ductal carcinoma who underwent pancreatectomy. At each 28-day treatment cycle, patients received weekly subcutaneous injection of OCV-C01 for 48 weeks, and gemcitabine was administered intravenously at 1,000 mg/m2 on days 1, 8, and 15 for 24 weeks. Patients were followed for 18 months. The primary endpoint was disease-free survival (DFS) and secondary endpoints included safety, OS and immunological assays on peptide-specific cytotoxic T lymphocyte (CTL) activity and KIF20A expression in resected pancreatic cancer. Results: The median DFS was 15.8 months (95% confidence interval (CI), 11.1-20.6), and the DFS rate at 18 months was 34.6% (95% CI, 18.3-51.6). The median OS was not reached and the OS rate at 18 months was 69.0% (95% CI, 48.8-82.5). The administration of OCV-C01 was well tolerated. In the per protocol set, there were significant differences in DFS between patients with and without KIF20A-specific CTL responses (p = 0.027), and between patients with and without KIF20A expression in resected pancreatic cancer tissues (p = 0.014). In addition, all four patients who underwent R0 resection with KIF20A expression had no recurrence of pancreatic cancer with KIF20A-specific CTL responses. Conclusions: OCV-C01 combined with gemcitabine was tolerable with a favorable median DFS of 15.8 months. In cancer vaccine treatment, positive expression of targeted antigen was essential, and postoperative adjuvant setting was more suitable than advanced state of cancer. Clinical trial information: UMIN000007991.
Primary versus metastatic intrahepatic cholangiocarcinoma: A comparative comprehensive genomic profiling (CGP) study.
Authors: Jeffrey S. Ross, Ethan Sokol, Jo-Anne Vergilio, Keith Killian, Douglas I. Lin, Erik Williams, Natalie Danziger, Shakti H. Ramkissoon, Eric Allan Severson, Amanda Hemmerich, Claire I. Edgerly, Richard Huang, Siraj Mahamed Ali, Russell Madison, Brian M Alexander, Jeffrey Michael Venstrom, Venkataprasanth P. Reddy, Kimberly McGregor, Julia Andrea Elvin, Alexa Betzig Schrock
Journal: Journal of Clinical Oncology (2020)

578 Background: Genomic alterations (GA) characteristic of IHCC are well known. We queried whether the GA of IHCC from primary tumor biopsies (p-bx) would differ from IHCC metastasis biopsies (m-bx). Methods: CGP was performed on 1,268 cases of advanced stage IHCC using p-bx in 1,048 cases and m-bx from 220 cases. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC. Results: M-bx sites included: lymph nodes (63), soft tissues (47), peritoneum (34), lung/pleura (27), omentum (15), bone (10), GYN tract (5), brain (2), Upper GI (2), colon (2), bladder (1), abdomen (1) and adrenal (1). The GA per sample were similar as were biomarkers of immuno-oncology (IO) drug response. The KRAS mutation frequency was doubled in the m-bx compared to the p-bx (p &lt; 0.001), and enrichment of the potentially targetable KRAS G12C was also observed. Frequencies of untargetable GA were similar overall. IDH1 (p &lt; 0.001) and FGFR2 GA known to be enriched in IHCC were less frequent in the m-bx cohort. GA in STK11 were more frequently identified in m-bx. Conclusions: GA found in p-bx vs m-bx in IHCC are significantly different; the m-bx cohort featuring greater KRAS and lower IDH1 and FGFR2 GA. This suggests that the m-bx group may contain a significant number of non-IHCC cases whose metastatic lesions were actually derived from other primary sites incorrectly assigned the diagnosis of IHCC. [Table: see text]
Development and Progression of Radiologic Abnormalities in Individuals at Risk for Familial Interstitial Lung Disease
Authors: Margaret L. Salisbury, Justin C. Hewlett, Guixiao Ding, Cheryl R. Markin, Katrina Douglas, Wendi Mason, Adam Guttentag, John A. Phillips, Joy D. Cogan, Sara Reiss, Daphne B. Mitchell, Pingsheng Wu, Lisa R. Young, Lisa H. Lancaster, James E. Loyd, Stephen M. Humphries, David A. Lynch, Jonathan A. Kropski, Timothy S. Blackwell
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: The preclinical natural history of progressive lung fibrosis is poorly understood.Objectives: Our goals were to identify risk factors for interstitial lung abnormalities (ILA) on high-resolution computed tomography (HRCT) scans and to determine progression toward clinical interstitial lung disease (ILD) among subjects in a longitudinal cohort of self-reported unaffected first-degree relatives of patients with familial interstitial pneumonia.Methods: Enrollment evaluation included a health history and exposure questionnaire and HRCT scans, which were categorized by visual assessment as no ILA, early/mild ILA, or extensive ILA. The study endpoint was met when ILA were extensive or when ILD was diagnosed clinically. Among subjects with adequate study time to complete 5-year follow-up HRCT, the proportion with ILD events (endpoint met or radiographic ILA progression) was calculated.Measurements and Main Results: Among 336 subjects, the mean age was 53.1 (SD, 9.9) years. Those with ILA (early/mild [n = 74] or extensive [n = 3]) were older, were more likely to be ever smokers, had shorter peripheral blood mononuclear cell telomeres, and were more likely to carry the MUC5B risk allele. Self-reported occupational or environmental exposures, including aluminum smelting, lead, birds, and mold, were independently associated with ILA. Among 129 subjects with sufficient study time, 25 (19.4%) had an ILD event by 5 years after enrollment; of these, 12 met the study endpoint and another 13 had radiologic progression of ILA. ILD events were more common among those with early/mild ILA at enrollment (63.3% vs. 6.1%; P < 0.0001).Conclusions: Rare and common environmental exposures are independent risk factors for radiologic abnormalities. In 5 years, progression of ILA occurred in most individuals with early ILA detected at enrollment.