tbuckley/cabot-search huggingface dataset:
Radiogenomics in 332 metastatic non-small cell lung cancer (NSCLC) patients.
Authors: Jordi Remon, Laura Faivre, Francesco Facchinetti, Maria Virginia Bluthgen, Jean-Pierre Pignon, David Planchard, Ludovic Lacroix, Benjamin Besse, Jean-Charles Soria, Caroline Caramella
Journal: Journal of Clinical Oncology (2016)

11563 Background: Radiogenomics is focused on defining the relationship between image and molecular phenotypes. Therefore, we assess the association between metastatic sites at baseline CT and molecular abnormalities (MA) in NSCLC patients (pts). Methods: One senior radiologist reviewed retrospective basal CT scans of metastatic NSCLC pts from Gustave Roussy included in the MSN cohort. Tissue biopsy samples of these pts were collected for detecting the molecular profile by NGS platform (Ion-torrent) and/or Sanger sequencing molecular test as daily clinical practice. Radiological characteristics regarding metastatic sites were correlated with the molecular profile. Results: From 06/2009 to 06/2015, 332 metastatic NSCLC pts treated with first-line platinum-based chemotherapy were included (median age 59 years, 63% males, 14% never smokers, 76% adenocarcinoma, 11% with squamous cell carcinoma). Number of metastatic sites by patient was: one for 49%, 2 for 28%, 3 for 14%, > 4 for 9%. After 32.4 months of median follow-up, the median overall survival was of 15.3 months (95%CI: 12.9-17.8). Overall, 60% of NSCLC pts had a MA: 28% KRAS mutation, 14% EGFR mutation, 6% ALK rearrangement, 5% MET amplification or mutation, and 7% other mutations (BRAF and PI3K mutation, and HER2 mutation or amplification). Among pts with KRAS (n = 93), EGFR (n = 47), ALK (n = 21) and MET(n = 16) abnormalities, the respective percentages of brain, adrenal, metastatic pleural effusion, bone and lung metastases were: 39%/28%/18%/40%/33%; 45%/6%/36%/47%/49%; 52%14%/19%/43%/48%; and 44%/25%/0%/44%/25%. Among the 12 pts with peritoneal carcinomatosis, 5 had a mutation (3 with KRAS, 1 NRAS and 1 BRAF). Conclusions: Bone is the most common site of metastases in NSCLC pts. Baseline metastatic sites in molecular selected NSCLC pts are different according to the molecular abnormality. Among KRAS mutant tumours there are a higher percentage of adrenal metastases and a trend toward association with peritoneal carcinomatosis, whereas among ALK tumors exists higher percentage of brain metastases than pleural effusion. MET tumors have a tropism for the brain similar to the other molecular abnormalities, whereas lung metastases are especially frequent in EGFR and ALK tumours.
Mosaic <i>TP53</i> pathogenic variants on multi-gene hereditary cancer panel testing: Clinical characteristics and follow-up testing.
Authors: Sarah A. Jackson, Maegan Roberts, Jessica L. Mester, Megan L. Marshall, Kristen J. Vogel Postula, Amy R. Stettner, Kevin J. Arvai, Rachel T. Klein, Andrew F. Wagner, Kathleen S. Hruska
Journal: Journal of Clinical Oncology (2018)

1580 Background: Li-Fraumeni Syndrome (LFS) is an autosomal dominant cancer susceptibility syndrome due to germline pathogenic variants in TP53 and is associated with a significant risk for sarcomas, female breast, and other cancers. A subset of individuals undergoing germline TP53 analysis will have a variant with an allele fraction (AF) less than that in heterozygous individuals, consistent with mosaicism. TP53 mosaicism may be limited to hematopoietic cells, such as in age-related hematopoietic expansion, or may be constitutional, in which case the variant exists in additional tissues and may increase LFS-associated cancer risks. This study aims to characterize the clinical characteristics and follow-up results of cases with a TP53 mosaic pathogenic or likely pathogenic variant (PV). Methods: We performed a retrospective review of all individuals undergoing multi-gene hereditary cancer panel testing at our diagnostic laboratory. Cases included those with mosaicism for one or more TP53 PV, characterized as an AF of < 35.0% on next-generation sequencing (NGS) on a blood or oral rinse specimen. Data were analyzed utilizing descriptive statistics and hypothesis tests, including Fisher’s exact test. Results: We identified 117 TP53 mosaic PV cases. Among 37 cases that had one or more relatives undergo testing for the mosaic PV, no relatives were positive. Among 21 cases that underwent subsequent fibroblast (FB) testing, 19.0% (4/21) correlated with the initial mosaic result, suggesting constitutional mosaicism. Of those that confirmed on FB, the mean AF for the original sample was 28.3% (n = 4; SD = 3.2%), whereas the mean for those negative on FB was 18.5% (n = 17; SD = 6.3%). Confirmation of mosaicism on FB was associated with an initial NGS AF ≥25.0% (p = 0.0276; FB Pos: 3/4, FB Neg: 2/17) and with a personal history of a breast cancer or sarcoma diagnosed < 46 years (p = 0.0276; FB Pos: 3/4, FB Neg: 2/17). Conclusions: Although NGS is not purely quantitative, apparent constitutional mosaicism appears to correlate with higher AF on NGS. In addition, phenotypes of cases with TP53 mosaicism confirmed via FB are more suggestive of LFS. Further studies are required to establish clinical correlation.
KEYNOTE-585: Phase 3 study of chemotherapy (chemo) + pembrolizumab (pembro) vs chemo + placebo as neoadjuvant/adjuvant treatment for patients (pts) with gastric or gastroesophageal junction (G/GEJ) cancer.
Authors: Yung-Jue Bang, Eric Van Cutsem, Charles S. Fuchs, Atsushi Ohtsu, Josep Tabernero, David H. Ilson, Woo Jin Hyung, Vivian E. Strong, Thorsten Oliver Goetze, Takaki Yoshikawa, Laura H. Tang, Peggy May Tan Hwang, Kohei Shitara
Journal: Journal of Clinical Oncology (2018)

TPS4136 Background: The FDA approved pembro for treating pts with recurrent locally advanced or metastatic G/GEJ adenocarcinoma whose disease has progressed on or after ≥2 prior therapies and whose tumors express PD-L1 (combined positive score ≥1). Combining chemo with pembro in the neoadjuvant/adjuvant setting may be beneficial for pts with locally advanced, resectable G/GEJ cancer. KEYNOTE-585 is a phase 3, randomized, double-blind study of chemo + pembro versus chemo + placebo as neoadjuvant/adjuvant treatment for locally advanced resectable G/GEJ cancer. Methods: Key eligibility criteria are age ≥18 years; previously untreated G/GEJ adenocarcinoma (Siewert type 2 or 3 tumor; Siewert type 1 tumor eligibility limited to those for whom planned treatment is perioperative chemo and resection), with no evidence of metastatic disease; planned surgery after preoperative chemo; ECOG performance status 0-1; adequate organ function; no active autoimmune disease. Pts will be randomly assigned 1:1 to receive chemo + pembro (arm 1) or chemo + placebo (arm 2). Pts will receive neoadjuvant (preoperative) chemo + pembro every 3 weeks (Q3W) for 3 cycles or chemo + placebo Q3W for 3 cycles followed by surgery, then adjuvant chemo + pembro Q3W for 3 cycles or chemo + placebo Q3W for 3 cycles, then monotherapy with pembro or placebo Q3W for 11 cycles; treatment will occur for up to 17 cycles. Chemo is cisplatin 80 mg/m2 IV + either capecitabine 1000 mg/m2 orally twice daily or 5-fluorouracil (5-FU) 800 mg/m2 IV (investigator's choice). Pembro 200 mg was administered by IV. Adjuvant monotherapy is pembro (arm 1) or placebo (arm 2). In a separate safety cohort, 5-FU 2600 mg/m2 IV + docetaxel 50 mg/m2 IV + oxaliplatin 85 mg/m2 IV + leucovorin 200 mg/m2 IV (FLOT) is being evaluated as a potential chemo option. Primary end points are overall survival, event-free survival per central review, and pathologic complete response (no invasive disease and histologically negative nodes) rate. Adverse events are graded per NCI CTCAE v4.0 and will be monitored for 30 or 90 days after treatment. Pts will be followed for survival. Planned enrollment is 800 pts. Clinical trial information: NCT03221426.
Alpha-2-macroglobulin as the marker for pancreatic cancer process direction.
Authors: Umar Muhmadovich Gaziev, Oleg Ivanovich Kit, Elena Mikhaylovna Frantsiyants, Larisa Kozlova, Stanislav Stanislavovich Mezentsev
Journal: Journal of Clinical Oncology (2016)

e15686 Background: Regular signs of tumor progression include destabilization of biological membranes and many other proteolysis-induced disorders. alpha-2-Macroglobulin (α2M) controls practically all of the known proteinases, regulating all proteolytic processes including immune reactions, as it has the broad spectrum of protection, including antitumor effect. Malignant tumors are able to synthesize and release proteins into the environment, including α2M that protects the tumor against immune system attacks. The purpose of the study was to measure α2M in the blood plasma (BP) and tumor tissue of patients with pancreatic cancer. Methods: BP of 103 pancreatic cancer (T3 N0 M0 ) patients was studied by ELISA before the surgery and at discharge. The results were compared to the normal values of 42 donors (N). Patients underwent pancreatoduodenal resection with bypass. Obtained tissues were divided into tumor focus (TF), perifocal zone (PZ) and conditionally healthy tissue of the resection line (RL); α2M was determined in 10% cytosolic fraction prepared using standard physiological solution. Results: α2M in BP before the surgery was increased in all 103 patients by 2 times in comparison with N. α2M in TF and PZ of all patients was increased by 3.9 and 1.8 times compared to RL (p < 0.001). Generalization (G) of pancreatic cancer was observed in 9 patients (8.7%) in 2 to 5 months. Before the discharge 9 patients with G showed α2M 2-2.7 times exceeding N, while in 94 patients without G it was similar to N. α2 М inhibitor from TF and PZ could penetrate into the surrounding tissues and blood depending on the status of regional microvessels, endogenous resistance, maturity state of tumor, etc. Conclusions: The data on α2M content in BP of patients with pancreatic cancer before the discharge is valuable for the prognosis of generalization in 93.6% of cases. α2M content in BP of pancreatic cancer patients is not associated with the type of surgery and anastomosis.
Treatment disparities between heterosexual and gay and bisexual men diagnosed with prostate cancer.
Authors: Darryl Mitteldorf
Journal: Journal of Clinical Oncology (2016)

e16548 Background: Prostate Cancer treatment types are varied, with choice making conducted within the doctor-patient dyad. This study is the first to identify which treatments heterosexual and Gay and Bisexual men (MsM) choose throughout the disease progression spectrum. Methods: 780 men (632 = Heterosexual, 148 = MsM) completed an online survey during summer of 2015. The men were randomly selected from a national Prostate Cancer support network. We asked about treatments they used during the prior six months and most recently. Combination treatments were treated as a single variable. Results: In general, heterosexual men use more advanced-stage treatments than MsM, while MsM use more early-stage treatments than heterosexuals. For treatments used 6 months prior to survey: 1. Heterosexuals reported a mean of 1.27 advanced-stage treatments, while MsM reported a mean of 0.48 (difference = 0.79). 2. MsM reported a mean of 0.38 early-stage treatments, while heterosexuals reported a mean of 0.24 (difference = 0.14). For most recent treatments: 1. Heterosexuals reported a mean of 1.19 advanced-stage treatments, while MsM reported a mean of 0.54 (difference = 0.65). 2. MsM reported a mean of 0.87 early-stage treatments, while heterosexuals reported a mean of 0.56 (difference = 0.31). Heterosexuals used an average of .65 more treatments during the prior 6 months (p < .0001, 95% Confidence interval: [.38, .91]) and an average of 34 more recent treatments (p = .00013, 95% Confidence interval: [.17, .52]), than did MsM. Regarding the proportion of participants who took both early- and advanced-stage treatments in the last 6 months: Of heterosexuals who reported using early-stage treatments, 39% also reported taking one or more advanced-stage treatment, compared to only 21% for MsM (p < .05). Additional demographics (age, race, etc) and HRQoL questions were asked but provided no significance. Conclusions: We found significant treatment utilization disparities between heterosexual and MsM. Most startling is that almost twice as many initially treated heterosexuals navigate towards advanced stage treatment as do MsM. Further investigation regarding all aspects of prostate cancer is indicated regarding this unique population.
Abstract MP91: Habitual Sleep Duration and Health: A Possible Role for Exercise
Authors: Christine M Hall, Sierra Forbush, Shawn Youngstedt, Scott Killgore, Holly Barilla, Jo-Ann Gehrels, Pamela Alfonso-Miller, William Palmer, Nancy Carrazco, Michael Grandner
Journal: Circulation (2016)

Introduction: Habitual sleep duration is associated with cardiometabolic disease risk and poor mental health. Exercise has been shown to improve cardiometabolic disease risk and mental health. Further, insufficient/excessive sleep is associated with sedentary behavior. It is plausible that benefits of exercise may mitigate some negative effects of insufficient or excessive sleep. Methods: Data from the 2013 Behavioral Risk Factor Surveillance System, a phone-based survey conducted by the CDC, was used. All participants were asked to report habitual 24-hour sleep, which was recorded as whole numbers and categorized as Very Short (≤4h), Short (5-6h), Normal (7-8h, reference), and Long (≥9h). Participants reported their primary source of physical activity. For this analysis, the following groups were included: None (N=125314), Walking (N=179,996), Running (N=23,153), Gardening (N=26,637), and Yoga/Pilates (N=3370). Outcomes of interest were obesity, depressed mood, and history of hypertension and diabetes. Population-weighted binary logistic regression models evaluated relationships between sleep duration and these outcomes, stratified by activity group. Covariates included age, sex, race/ethnicity, and education. Results: See Table 1. Relationships between sleep duration and health outcomes differed by activity group. Associations with very short sleep were generally maintained across groups. However, relationships with short sleep were somewhat mitigated in running and yoga, and relationships with long sleep were seen less in running and gardening. Conclusions: The relationship between sleep duration and health may be modified by activity. It is possible that activities such as running and yoga may mitigate some of the negative health effects of insufficient or excessive sleep, as long as sleep duration is not extremely short. Also the obesity relationship was particularly unaffected by exercise.
A multicenter pilot study of nivolumab (NIVO) with drug eluting bead transarterial chemoembolization (deb-TACE) in patients (pts) with liver limited hepatocellular carcinoma (HCC).
Authors: James J. Harding, Joseph Patrick Erinjeri, Benjamin R. Tan, Kim Anna Reiss, Kabir Mody, Daniel Khalil, Hooman Yarmohammadi, Gregory Nadolski, Joseph Daniel Giardina, Marinela Capanu, Richard K. G. Do, Mikaela Bradley, Chayma Boussayoud, Emily Valentino, Taha Merghoub, William R. Jarnagin, Michael C. Soulen, Karen T. Brown, Ghassan K. Abou-Alfa
Journal: Journal of Clinical Oncology (2018)

TPS4146 Background: Emerging preclinical and clinical data indicate that regional therapies impact the immune microenvironment, induce a peripheral immune response, and may augment the effects of immune checkpoint blockade. Given the activity of NIVO in the metastatic setting, we propose to test the safety of NIVO at earlier stages of HCC (BCLC-B) as an adjuvant therapy to TACE. Methods: This is a multicenter phase 1 study of the combination of NIVO and deb-TACE in unresectable HCC pts (BCLC Stage B) who are not candidates for curative treatment and have Child Pugh A hepatic function (NCT03143270). The primary objectives are to assess the safety, tolerability, and to define the optimal dosing schedule of the combination. A modified 3 + 3 design will sequentially treat pts with differing schedules of NIVO relative to deb-TACE. For all cohorts, deb-TACE (loaded with 75mg of doxorubicin) is administered on Day 0. NIVO is dosed at 240mg IV every 14 days for 1 year. In Cohort 1, NIVO is administered beginning on day +14 after deb-TACE. In Cohort 2, interrupted NIVO dosing begins at Day -28 but is held on the Day 0 at the time of deb-TACE, then restarted on Day +14. In cohort 3, continuous NIVO dosing begins on Day -28 without interruption during deb-TACE. If limiting toxicities occur in ≤33% of each cohort; cohort 3 will be defined as the recommended schedule for this combination. This cohort will then be expanded to a total of 16 pts. Cross-sectional imaging is completed at baseline, 1 month post-embolization, and every 3 months until disease progression, intolerable toxicities, or consent withdrawal. Secondary endpoints include overall response rate by modified Response Evaluation Criteria in Solid Tumors (RECIST) and RECIST v1.1, time to progression, progression-free and overall survival. Correlative objectives include sequential whole blood sampling and biopsies (pretreatment, on-treatment, at progression) to define mechanisms of anti-PD-1 resistance and to explore the effect of different schedules of treatment on the immune environment. Up to 28 pts will enroll at 4 sites over a 2 year period. Cohorts 1 and 2 have completed enrollment as of February 2018. Clinical trial information: NCT03143270.
Antiplatelet Therapy After Coronary Artery Bypass Grafting—Reply
Authors: Yunpeng Zhu, Qiang Zhao
Journal: JAMA (2018)

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Can DNA methylation patterns be used as predictive biomarkers for chemotherapy response in osteosarcoma?
Authors: Sarbajit Mukherjee, Matlock Arizona Jeffries, Alexander Rivas, Reema Malik, Sami Ibrahimi, Kar-Ming Fung, Jeremy White, William H. Meyer, Sara Vesely, Donald A. Barkauskas, David Hall, Mohamad Ali Cherry
Journal: Journal of Clinical Oncology (2018)

11525 Background: Response to neoadjuvant chemotherapy correlates with a positive outcome in localized osteosarcoma patients. However, there are no reliable predictors of chemotherapy response. We investigated the role of DNA methylation patterns as a biomarker to chemotherapy response. Methods: We obtained 26 diagnostic biopsy specimens from the Children’s Oncology Group tissue biobank: 13 with a good (≥ 90% necrosis in the post-chemotherapy resected tumor specimen) and 13 with a poor chemotherapy response ( < 90% necrosis). Patient characteristics were similar between these groups. DNA was isolated from tissue and loaded onto Illumina arrays. Machine learning was used to discriminate responders from non-responders. Samples were randomly split into a development (70%) and a validation (30%) set. A GLMnet model optimized within the development set then tested on previously unseen data within the validation set. The random split, model development, and testing were then repeated for a total of 40 cycles. CpG sites used in at least 3 cycles were selected for further testing (n = 16). An optimized, supervised GLMnet predictive algorithm model was generated using the same procedure (40 cycles) based on these 16 CpG sites, and final performance metrics were recorded. Results: During initial algorithm development utilizing all methylation sites, the machine learning algorithms performed with an average 74.7% accuracy on previously-unseen data, corresponding to a receiver operator characteristic (ROC) area-under-the-curve (AUC) value of 0.76. The final optimized algorithms, based on 16 CpG highly discriminant CpG sites, improved to an average 91.87% accuracy to discriminate chemotherapy responders from non-responders, with a corresponding ROC-AUC of 0.97 (2x2 table: Fisher’s p = 0.03). Conclusions: Based on distinct epigenomic patterns in osteosarcoma patients, we developed an algorithm which accurately differentiates chemotherapy responders from non-responders at the time of initial diagnostic biopsy. These findings have the potential to improve both prognostic accuracy and personalized therapy in osteosarcoma, pending confirmatory studies.
The effect of doxorubicin on the cancer-testis antigens transcription.
Authors: Denis S. Kutilin, Dmitry I. Vodolazhsky, Kristina I. Soldatova, Hava Mogushkova, Vladimir Trifanov, Evgeniy N. Kolesnikov, Mikhail A Kozhushko, Leonid V. Kharin, Oleg Ivanovich Kit
Journal: Journal of Clinical Oncology (2018)

e24117 Background: Cancer-testis antigens (CTA) can be used as immunotherapy targets of cervical cancer. However, immunotherapy is often used in combination with anthracycline antibiotics chemotherapy, in particular doxorubicin(DXR), whose effects on the expression of CTA genes have not been studied. Therefore, the effect of different concentrations of DXR and exposure time on the cancer-testis (CT) genes expression of HeLa cells was studied. Methods: Cultivation of HeLa CCL-2 cells (cervical cancer) was performed in CB 150 incubatorin RPMI-1640 medium with various concentrations of DXR: 0 (control), 2 and 4 μg/ml. The cell lines were removed from the vial substrate after 1, 5 and 24 hours of cultivation. The relative expression of 16 genes (MAGE-A1, -A2, -A3, -A4, MAGE-B1, -B2, GAGE-1, -3, -4, MAGEC1, BAGE, XAGE3, NY-ESO1, SSX2, SYCP1, PRAME1) were determined by RTqPCR. Statistical analysis was carried out using a two-way repeated measures ANOVA (influence of factors A-time of cultivation and B-concentration of DXR) and the Newman-Keuls test in the Statistica 8.0. Results: The factors A and B together influenced the expression of 75% of investigated genes (p < 0.005): MAGE(A1, A3, A4), MAGE(B1, B2), GAGE(1, 3), BAGE, XAGE3, NY-ESO1, PRAME1 and SYCP1. At the same time, these factors did not significantly affect the expression of SSX2, MAGEA2, GAGE4 and MAGEC1, factor B alone did not statistically significantly affect the expression of MAGE (B1, B2) (factor A influenced, p < 0.05), and the factor A did not affect the expression of the PRAME1 (factor B influenced, p < 0.05). Pairwise comparison of 9 groups of 2 factors (Newman-Keuls test) revealed the following (p < 0.002): 1) After 1 hour, increased expression of MAGE (A1, A4, A3) and SYCP1 , NY-ESO1 , inhibition of GAGE1 and BAGE expression; 2) After 5 hours, decrease in BAGE expression ; 3) After 24 hours, decreased expression of GAGE1, BAGE and increased expression of XAGE3. Conclusions: The factors A and B influenced the expression of MAGE (A1, A3, A4), MAGE (B1, B2), GAGE(1,3), BAGE, XAGE3, NY-ESO1, PRAME1 and SYCP1 genes in the HeLa cells, but did not affect the expression of SSX2, MAGEA2, GAGE4 and MAGEC1, which allowed us to recommend these 4 CTA as a target for immunotherapy.