tbuckley/cabot-search huggingface dataset:
Lactate response during acute exercise in cancer survivors undergoing exercise rehabilitation.
Authors: Nicholas Harman, Arjun Ramani, Benjamin Jacob George, Reid Hayward
Journal: Journal of Clinical Oncology (2019)

e23047 Background: Cancerous cells express a markedly different metabolic profile characterized by lactate production even when oxygen is plentiful. Lactate accumulation is a common marker for energy production and utilization, yet it is currently unclear how blood lactate responds during acute exercise to volitional fatigue in individuals with cancer and how this response is modified with exercise-based rehabilitation. The purpose of the current study is to assess the effect of an acute exercise bout to volitional fatigue on lactate accumulation before and after an exercise-based rehabilitation program for cancer survivors. Methods: 33 cancer survivors (female, n = 18; male, n = 15) were recruited to participate in a 12-week exercise-based rehabilitation program. All participants performed an initial assessment of physiological parameters, including blood lactate accumulation (LA) during a progressive treadmill protocol to volitional fatigue. LA was quantified every 2 minutes during treadmill testing via finger stick. The exercise intervention consisted of one hour sessions, three days per week, and included cardiovascular endurance, muscular strength, balance, and flexibility exercises. After 12 weeks of rehabilitation, participants completed a follow-up evaluation of physiological parameters. Results: There was a significant increase in LA at volitional fatigue after 12 weeks of training (Initial: 6.17 ± 2.61 mM, Post 12 Weeks: 7.26 ± 2.10 mM; p = 0.04), with no significant difference in resting blood lactate. The workload at which anaerobic lactate threshold presented was significantly increased after 12 weeks (Initial: 5.87 ± 1.59 METs, Post 12 weeks: 7.35 ± 1.85 METs; p = 0.02). Conclusions: Cancer survivors respond to acute exercise to volitional fatigue in a manner similar to healthy controls. Furthermore, similar to the response observed in healthy populations, cancer survivors exhibited an increase in lactate threshold and an increase in peak lactate accumulation at volitional fatigue after completing an exercise-based rehabilitation program. Thus, although many cancerous cells have a unique glycolytic profile, this does not appear to influence training-induced adaptations in blood lactate.
Germline mutations and onset of lung adenocarcinoma in smokers and nonsmokers.
Authors: Karen L. Reckamp, Thomas Paul Slavin, Stacy W. Gray, Carolyn E. Behrendt, Danielle Castillo, Marianna Koczywas, Mihaela C. Cristea, Kirsten Babski, Donna Stearns, Catherine A Marcum, Yeny Rodriguez, Amie Hass, Mary Vecchio, Analí Pamela Mora Alferez, Aleck Cervantes, Sharon Sand, Stephanie L Mach, Terrence Tsou, Ravi Salgia, Jeffrey N. Weitzel
Journal: Journal of Clinical Oncology (2019)

1518 Background: Eligibility for lung cancer screening is based largely on pack-years of smoking, missing many cases. To propose additional groups for screening, this observational study evaluated whether germline mutations associated with cancer risk accelerate onset of lung adenocarcinoma (LA) in ever- and never-smokers. Methods: Patients with LA and family history of cancer were recruited from our oncology clinic and the Clinical Cancer Genomics Community Research Network. With consent, blood samples were screened by large multi-gene panel for 4 categories of germline mutation [lung cancer-associated genes ( TP53, EGFR); BRCA2; other genes in Fanconi anemia (FA) pathway; other DNA repair genes]. Accelerated failure-time models of age at LA diagnosis, adjusted for sex, ethnicity, and packs per day, were constructed for never-smokers and ever-smokers. Statistical significance, at p&lt;0.05 limited the False Discovery Rate to 5% across 8 hypotheses. Results: In never-smokers with LA (n=104), mutated BRCA2, TP53 or EGFR were associated with younger age at diagnosis, while mutation in other FA or DNA repair gene was not. In ever-smokers with LA (n=65), mutated BRCA2 and other FA gene were associated with younger age at diagnosis, while other mutation categories were not (Table). Conclusions: Regardless of smoking history, BRCA2 mutation carriers experience accelerated onset of LA, as do never-smokers carrying TP53 or EGFR mutation and ever-smokers with mutation in FA gene other than BRCA2. With the exception of TP53 carriers (who merit whole body MRI), lung cancer screening with low-dose computed tomography, starting earlier in adulthood than usual, may be warranted for individuals with germline mutations in these genes. Age at Diagnosis of Lung Adenocarcinoma, by Germline Mutation and Smoking History, Adjusted for Sex, Ethnicity, and Packs per Day. [Table: see text]
Abstract 17957: Plasma Branched Chain Amino Acids Levels and Cardiovascular Mortality in Hemodialysis Patients
Authors: Shota Suzuki, Midori Shino, Tetsuya Fujikawa, Yoko Itoh, Koichiro Sumida, Koji Ohki, Eiko Ueda, Kazushi Uneda, Yuki Ohki, Kengo Azushima, Tatsuo Hashimoto, Hiromichi Wakkui, Tadashi KUji, Naoyuki Kobayashi, Toshimasa Ohnishi, Nobuhito Hirawa, Yoshiyuki Toya, Kouichi Tamura
Journal: Circulation (2017)

Introduction: Plasma amino acids were reported to be associated with oxidative stress and cardiovascular disease (CVD) morbidity in patients with life-style related diseases. Among amino acids, rec...
Effect of body mass index and age on survival in patients with advanced lung cancer treated with anti-PD-1 immune checkpoint inhibitors.
Authors: Corentin Richard, Arielle Elkrief, Julie Malo, Lena Cvetkovic, Marie Florescu, Normand Blais, Mustapha Tehfe, Andréanne Gagné, Michèle Orain, Catherine Labbe, Philippe Joubert, François Ghiringhelli, Bertrand Routy
Journal: Journal of Clinical Oncology (2019)

e20676 Background: Age and body mass index (BMI) are important factors in patients treated with chemotherapy. However, in the era of immune checkpoint inhibitors (ICI), the importance of these baseline characteristics is unclear. For example, pooled analysis of age did not influence the clinical response to ICI, whereas patients with BMI &gt; 35 had better outcomes in melanoma and renal cell carcinoma. More data are needed to clarify the role of these two characteristics in non-small cell lung cancer (NSCLC) patients amenable ICI. Methods: We conducted a retrospective analysis of patients treated with anti-PD1 ICI for advanced NSCLC at the Dijon Cancer Center (n = 177), University of Montreal University Hospital (n = 106) and Quebec Heart and Lung Institute (n = 98). BMI and age were considered as continuous or categorical variables. Patients’ baseline characteristics were compared using the Chi-squared test. Survival curves were estimated by the Kaplan-Meier method and compared with the Log-rank test in a univariate analysis. Multivariate cox regression model was used to determine hazard ratios and 95% confidence intervals for progression-free survival (PFS) and overall survival (OS) between the groups, adjusting for other clinicopathologic features. Results: Among 381 patients included, the median BMI was 24.5 (range 16.2-43.4) and 32.7% and 13.6% were classified as overweight or obese respectively. The median age was 66 (range 37-89) and 29% were older than 70 years-of-age. Considering BMI and age as continuous or categorical variables, they were not associated with PFS or OS, with the exception of BMI in the Dijon cohort (continuous: HR = 0.95, 95%CI[0.91-0.99]; &lt; 25 vs &gt; 25: HR = 0.68, 95%CI[0.47-0.99]). Subgroup analysis and multivariate cox regression did not reveal significant interaction of these two factors with outcomes. There was no difference in toxicity between the groups. ECOG performance status was the only significant factor in the three cohorts. Conclusions: Unlike previously described in the era of chemotherapy, obesity and age were not associated with outcomes in NSCLC patients treated with ICI.
A phase II randomized study of avelumab plus entinostat versus avelumab plus placebo in patients (pts) with advanced epithelial ovarian cancer (EOC).
Authors: Karen Anne Cadoo, Michael L. Meyers, Robert Allen Burger, Deborah Kay Armstrong, Richard T. Penson, Michael S. Gordon, Gini F. Fleming, John William Moroney, Erika Paige Hamilton, Linda R. Duska, Robert Michael Wenham, Serap Sankoh, Susan Brouwer, Peter Ordentlich, Carol Aghajanian, Ursula A. Matulonis
Journal: Journal of Clinical Oncology (2019)

5511 Background: Preclinical evidence suggests that combining avelumab (A), a human anti-PD-L1 monoclonal antibody, and entinostat (E), a class I selective histone deacetylase (HDAC) inhibitor, may increase tumor immunogenicity and responsivity to checkpoint inhibition. This study evaluated whether A+E would lead to improved progression free survival (PFS) vs A in pts with advanced EOC. Methods: Pts with EOC which had progressed or recurred after 1st-line platinum-based chemotherapy and received 3- 6 lines of therapy were randomized 2:1 to receive A (10 mg/kg IV Q2W) plus E (5 mg PO QW) or A plus placebo (P). Treatment continued until disease progression (PD) or unacceptable toxicity. The primary endpoint was PFS (investigator-assessed, RECIST 1.1), stratifying on the presence/absence of bulky disease (tumor ≥ 50 mm) and platinum-refractory disease. The hypothesis was that the combination would reduce the hazard of PD or death by 43%, representing a 75% improvement in median PFS. 97 events (from 120 pts) provided 90% power with 1-sided significance level of 0.10. Secondary endpoints included ORR, duration and time to response, toxicity, clinical benefit rate, and OS. Results: 126 pts were enrolled, median age 63 yrs (range 43-82), median 4 prior lines, 83% serous histology. Median PFS was 1.64 and 1.51 mos for A+E and A+P, respectively (p = 0.31; HR 0.90, 95% CI: 0.58-1.39). No significant differences in ORR (6% vs 5%), or OS (NE vs 11.3 mos) were observed. 4 pts (3%) had clear cell EOC, with no responses observed. The incidence of related adverse events (AEs) was higher in the A+E arm compared to A+P (any grade: 93% vs 78%, Grade 3/4: 41% vs 10%), and the most frequent (≥20%) related AEs with A+E were fatigue (46%), nausea (31%), diarrhea (26%), anemia (26%), and chills (20%). Grade 3/4 related AEs occurring in ≥5% with A+E were fatigue (9%), and neutropenia (8%). 47% of pts in A+E arm required E dose holds/reductions. Discontinuations due to AEs were similar between arms (21% vs 17.5% for A+E and A+P, respectively), as was duration of study therapy (median 4 and 5 cycles started). Conclusions: In pts with heavily pretreated EOC, median PFS was not prolonged when E was added to A compared to A alone and the combination resulted in greater toxicity. Clinical trial information: NCT02915523.
Analysis of a neurosurgical directed acute spinal cord compression pathway at Michigan Medicine, a tertiary referral hospital.
Authors: John C. Krauss, Daniel Klarr
Journal: Journal of Clinical Oncology (2019)

e18285 Background: Spinal cord compression (SCC) is considered an oncologic emergency that is likely to severely impair patients’ quality of life if immediate action is not taken. Clinicians need a high suspicion to diagnose SCC, as the presenting symptoms are variable and nonspecific. To expedite the diagnosis and treatment of SCC, we instituted an emergent spine MRI imaging pathway that was led by the neurosurgeons and involved close collaboration with medical oncology and radiation oncology. Methods: The charts of all patients from July 2015 to June 2018 who underwent the “MR Spine Cord Compression Acute” imaging pathway at Michigan Medicine were reviewed. Electronic time stamps provided the time of the initial order, the time to scan completion, the time to scan reading, and the time to definitive intervention. The charts were reviewed for the initial neurosurgical physical exam, a presentation consistent with recent trauma, a previous diagnosis of malignancy, and a previous diagnosis of bone metastases. The type and timing of therapy, and survival following the imaging protocol were assessed. Results: 319 unique MRI exams were done over the three-year span, 155 of the patients had cancer, and 75 patients had SCC. The time from ordering of exam to performance is 2.91 hours (0 to 25.45), from performance to read 8.31 hours (0 to 75.25 hours). Time from MRI to intervention was 63.14 hours (0 to 432 hours) based on complex decision making around surgical vs. radiation vs. medical therapy. For the majority of patients who were diagnosed with SCC, the cause was secondary to tumor growth from contiguous spinal metastasis, and most had previously identified bone metastases. Degenerative disc extrusion was the most common cause of benign SCC. Conclusions: A neurosurgical directed standard imaging protocol is effective at rapidly diagnosing SCC. Malignant SCC is predominately treated surgically, but complex multi-disciplinary patient centered decision-making involving neurosurgery, radiation oncology, and medical oncology is frequently necessary to arrive at the appropriate treatment.
The prognostic value of patient-reported outcomes (PROs) for survival outcomes in cancer patients: A systematic review.
Authors: Francesco Cottone, Gary S. Collins, Johannes M. Giesinger, Kathrin Sommer, Nina Deliu, Marco Vignetti, Amelie Anota, Fabio Efficace
Journal: Journal of Clinical Oncology (2019)

e18223 Background: Several studies have indicated that PROs may independently predict survival outcomes across various cancer populations. We aimed to synthesize current evidence in this research area and to investigate methodological quality of these studies. Methods: We conducted a systematic review of published studies (from January 2016 to December 2017) in oncology, which included at least one PRO domain in a multivariable prognostic model for survival outcomes. We used absolute and relative frequencies to assess the main characteristics of the studies, including tumor site, type of PRO questionnaire, type of PROs assessed (e.g., symptoms or functional scales) and their statistical significance for survival outcomes. As such studies pose important statistical challenges, we also investigated methodological issues based on a comprehensive set of predefined criteria. Results: Out of 385 candidate articles, 65 studies met eligibility criteria. Out of these, n = 56 (86%) reported at least one PRO as a statistically significant prognostic factor in a multivariable prognostic model and thirty-two studies (49%) were done with patients with metastatic/advanced cancer. Overall, the most used instrument to assess PROs was the EORTC QLQ-C30 questionnaire (n = 29, 45%) and the most frequent tumors were lung (n = 18, 28%), esophagogastric (EG) and gynaecological (GY) cancer (each n = 11, 17%). Among these, statistically significant prognostic PRO scales from the EORTC-QLQC30 included fatigue, pain and appetite loss for lung; nausea/vomiting, pain, dyspnea, appetite loss and constipation for EG and physical and role functioning for GY. With respect to methodological quality, we found important drawbacks. For example, only 24% assessed multicollinearity among PRO scales and only 29% assessed performance of the prognostic multivariable model (e.g., evaluating discrimination and calibration). Conclusions: In recent years, a remarkable number of studies has found that PROs provide prognostic information beyond well-established clinical and socio-demographic factors. However, some key methodological limitations have been found, which deserve special attention in future studies.
Clinical pharmacogenomic testing impacts therapy decisions and supportive medication choices in breast cancer.
Authors: Kathleen Kiernan Harnden, John F. Deeken, Matthew Stankowicz, Arielle Stafford, Costanza Cocilovo, Alina Khromykh, Ramaswamy K Iyer, Scott Barnett, Grace Lawrence, Franziska Moeckel, Brittany Vogt, Sheila Philips, Andrea Solares, Kirsten H. Edmiston
Journal: Journal of Clinical Oncology (2019)

569 Background: Pharmacogenomics, the study of the interaction between the patient’s genome and therapeutic drug response, evaluates the associations between efficacy and toxicity through analysis of drug metabolizing enzymes. As personalized medicine advances to the forefront of cancer care, pharmacogenomics can evaluate the individual’s ability to metabolize key medications in breast cancer treatment including anti-emetics, opioids, and tamoxifen. Women who do not achieve optimal levels of the active metabolites of tamoxifen are at higher risk of recurrence. Patients on chemotherapy who do not respond to anti-emetics can suffer from nausea and vomiting resulting in dehydration and hospitalization. This project evaluates the feasibility and therapeutic impact of real time pharmacogenomics in a selection of patients at the Inova Schar Cancer Institute (ISCI). Methods: An interdisciplinary team was created through the ISCI and the Inova Translational Medicine Institute to implement cheek swab based pharmacogenomic testing in 50 new patients undergoing mastectomy or neoadjuvant chemotherapy for breast cancer. Study patients were assessed for genotypic variability of key CYP enzymes and resulting impact on anti-emetic choices, perioperative pain control, and tamoxifen use. Results: Data was collected in a RedCap database. The 50 women enrolled were ages 28-83. Cheek swabs were performed in clinic and median turn around time was 7 days. 24 distinct genotypes were found in the 50 patients. 20% had abnormal CYP2D6 phenotypes indicating abnormalities in tamoxifen metabolism. 28% of patients had results leading to changes in dose or medication choice of perioperative pain control. 6% of patients had a CYP2D6 ultra-rapid metabolizer phenotype and were given granisetron in lieu of ondansetron. These patients had no documented nausea or vomiting requiring dose adjustments to the treatment plan or medical intervention. 40% of patients had results recommending avoidance of tamoxifen, 75% of which have ER+ breast cancer. 25% of patients had recommended changes to the dose of tamoxifen. Conclusions: Pharmacogenomic testing is feasible and available real-time for immediate use in the clinic. CYP mutations impact treatment decisions in a significant proportion of patients. Individualized treatment plans tailored to pharmacogenomic recommendations can be created in the multi-disciplinary setting and may decrease side effects of treatment and improve efficacy of curative therapy.
Effective Cancer Genotyping—Many Means to One End
Authors: Catherine B. Meador, Geoffrey R. Oxnard
Journal: Clinical Cancer Research (2019)

Precision cancer medicine requires effective genotyping of every patient's tumor to optimally design treatment plans. Despite its imperfect sensitivity, the rapidity and convenience of cell-free DNA sequencing makes it an essential complement to tumor genotyping, which, when used appropriately, can aid the pursuit of effective genotyping for all patients.See related article by Leighl et al., p. 4691.
The prognostic value of KRAS mutation subtypes and PD-L1 expression in patients with lung adenocarcinoma.
Authors: Luwei Tao, Jingxin Sun, Tarek Mekhail, Lingbin Meng, Cheng Fang, Yuan Du, Mark A. Socinski, Amanda Allen, Brenda L. Rzeszutko, Chung-Che Chang
Journal: Journal of Clinical Oncology (2019)

e20022 Background: KRAS gene mutations are found in 20-30% of non-small cell lung cancer (NSCLC), especially in adenocarcinoma. Compared to EGFR and ALK mutations, KRAS mutation in NSCLC may be associated with poorer prognosis. However, prognostic value of different KRAS mutation subtypes in NSCLC remains unknown. The goal of this study is to evaluate the association of KRAS mutation subtypes, PD-L1 expression and clinical outcome in patients diagnosed with primary lung adenocarcinoma. Methods: A total of 256 patients diagnosed with KRAS mutated (determined by pyrosequencing) lung adenocarcinoma between 2011 and 2015 in AdventHealth-Orlando were evaluated for their cancer staging, Relapse-free survival (RFS) and overall survival (OS). PD-L1 staining was performed in a subgroup of 95 patients from the same cohort. PD-L1 expression was determined with immunohistochemistry staining using Ventana PD-L1 (SP263) assay. Results: In this cohort of patients, 65 had stage I disease, 29 stage II, 49 stage III, 110 stage IV and 3 with no clinical stage information; 104 male, 152 female; median age 67. All patients received standard surgical/chemo/radio therapy according to the disease stages. Only one single patient received immunotherapy. Nine subtypes of KRAS mutation were detected, predominantly in codon 12. Three major subtypes account for 83.6% KRAS mutations, namely G12C (45.7%), G12V (21.9%) and G12D (16.0%). We found that these three major subtypes had no difference in cancer stages (P = 0.58) or brain metastasis at diagnosis (P = 0.78). Kaplan Meier analysis also showed similar OS and RFS among all KRAS subtype. 34% of KRAS mutated patients were found to be PD-L1 positive with tumor proportion score of greater than or equal to 1. PD-L1 expression status was indistinct among the three major mutation subtypes (P = 0.38). Of interest, among patients with G12C mutation, positive PD-L1 expression was associated with significantly shorter OS (5.7 vs 12.8 months; P = 0.007). In contrast, for patients with other KRAS mutation subtypes, PD-L1 expression status had no impact on OS (P = 0.63). Conclusions: The clinical courses, including tumor stage at diagnosis, presence of brain metastasis, OS and RFS, are similar among lung adenocarcinoma patients with different KRAS mutation subtypes. Additionally, PD-L1 expression status appears to be independent of KRAS mutation subtypes. Of note, concurrent PD-L1 expression and G12C mutation is associated with particularly poorer prognosis. Further study is needed to see if PD1/PD-L1 block may improve outcome of this group of patients.