tbuckley/cabot-search huggingface dataset:
Non-interventional study OVATAR final report: Diagnostic and treatment approaches in Russian ovarian cancer population—BRCAm group analysis.
Authors: Alexandra Tyulyandina, Tatiana Kekeeva, Vera Gorbunova, Larisa Kolomiets, Galina Statsenko, Valeria Saevets, Svetlana Victorovna Khokhlova, Svetlana Tkachenko, Irina Koroleva, Alla Sergeevna Lisyanskaya, Oksana Bakashvili, Olga Novikova, Ludmila Krikunova, Ekaterina Solovieva, Dmitry Ponomarenko, Lyubov Zagumennova, Ilya Tsimafeyeu, Olga Vedrova, Vera Karaseva, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2019)

e13111 Background: First large Russian ovarian cancer observational study was conducted in 2014-2018. Methods: A total of 500 patients in 29 sites in Russia with newly diagnosed ovarian, peritoneal and fallopian tube cancer was enrolled (NCT02122588). The primary objective was to describe treatment approaches in the first line treatment. 141 patients (pts) with BRCA1/2 mutations (BRCA1/2mt) detected by NGS in blood and tissue were observed prospectively during at least 2 years. Results: Rate of BRCA1/2 mutations in Russian population is high – 28.4% (141 from 496 available for any testing). 77.6% (388/500) underwent biomarkers blood testing prior to treatment. CA-125 was positive in 99.7% (387/388), 15.2% (59/388) of pts had positive CA19-9, CA72-4 - in 2.3% (9/388). Positive CEA was presented in 15.2% (59/388). This marker was detected more frequently in BRCA2mt pts subgroup (28.0% (7/25)) than in BRCA1mt pts: 9.0% (8/90) (p = 0.05). 26.6% (133/500) of all study population had an oncology family history; 44.0% (62/141) BRCA1/2mt pts had relatives with oncological diseases and 19.7% (70/355) in BRCA wild type pts (p = 0.0001). 98.6% (139/141) of BRCA1/2mt pts received first line therapy. Objective response rate was registered in 79.8% (111/139) pts. Progression after platinum based regimens was observed in 53.6% (59/110) BRCA1mt pts and 44.8% (13/29) BRCA2mt pts. 35.6 % (21/59) of BRCA1mt pts had platinum-refractory and platinum-resistant relapses, while 15.4% in BRCA2mt subgroup (2/13) (p = 0.64). Platinum-sensitive relapses were in 64.4% (38/59) BRCA1mt pts and 84.6% BRCA2mt (11/13) (p = 0,64). Median PFS in BRCA1/2mt pts was 25.5 months. Among BRCA1/2mt pts underwent cytoreduction median PFS in subgroup without visible residual tumor was 36.4 months and in subgroup with residual tumor &lt; 1 cm 15.3 months. Conclusions: In this large-scale prospective non-interventional study diagnostics and treatment approaches in Russian ovarian cancer pts were evaluated and high frequency of BRCA1/2mt was observed. Pts with BRCA1/2mt had better prognosis and most of them had platinum-sensitive relapses after first line chemotherapy that allowed platinum-based regimen rechallenge.
Short versus long duration of adjuvant trastuzumab (T) in HER2+ breast cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).
Authors: Qurat Ul Ain Riaz Sipra, Irbaz Bin Riaz, Muhammad Husnain, Ammad Raina, Ahsan Khan, Maheen Akhtar, Zhen Wang, M. Hassan Murad, Roberto Antonio Leon-Ferre
Journal: Journal of Clinical Oncology (2019)

e12057 Background: Several RCTs have evaluated a shorter duration of T ( &lt; 12 months) with hopes of similar efficacy, reduced cardiotoxicity, cost and burden of treatment. Of the 5 major studies, PERSPHONE showed that 6 months was non-inferior compared to 12 months. However, four additional studies of shorter duration failed to demonstrate non-inferiority. Therefore, we performed an updated systematic review and a meta-analysis to assess the optimal duration of adjuvant T. Methods: MEDLINE, EMBASE, Cochrane, Scopus and conference proceedings were searched to identify RCTs comparing one year of adjuvant T with a shorter duration in early-stage HER2+ breast cancer. The DerSimonian-Laird random-effects Meta-Analysis was performed using CMAv3 software to derive pooled Hazard Ratio (HR) estimates for overall survival (OS, Disease-Free Survival (DFS) and Odds Ratio(OR) estimates of cardiac toxicity. Q-test was used to assess between-study heterogeneity; I 2 statistic was computed to express the percentage of the total observed variability due to study heterogeneity. The risk for bias was assessed using the Cochrane Collaboration’s tool. Results: We screened 1772 citations and identified 5 studies(n = 11,377) for analysis. 5691 patients were randomized to 12 months of adjuvant T while 5686 were randomized to a shorter duration (3 studies evaluated 6 vs 12 months, 2 studies evaluated 9 weeks vs 12 months). OS (HR, 1.16, 95% CI 1.03-1.31, P= 0.015,I 2 0.00, p= 0.837) and DFS (HR, 1.14, 95% CI 1.02-1.26 , P = 0.016,I 2 14.90, p= 0.319) were significantly worse in patients receiving shorter duration T as compared to 12 months. Cardiotoxicity was significantly higher in the 12 month group vs shorter duration (OR, 2.10, 95% CI 1.58-2.80, p = 0.000 ,I 2 51.182, p= 0.085). Grade 3/4 cardiac events and cardiac events leading to discontinuation of therapy were significantly higher in patients receiving 12 months (HR 2.06, 95% CI 1.60-2.63, P = 0.000, I 2 3.967, p= 0.384). There was no significant heterogeneity among studies. Risk of bias was low. Conclusions: Twelve months of adjuvant T is associated with significantly better DFS and OS compared to a shorter duration. As such, 12 months should remain the standard of care for most patients. There is an unmet need to identify lower risk groups which might do well with from shorter duration of HER2-directed therapy.
c-MYC regulates mRNA translation efficiency and start-site selection in lymphoma
Authors: Kamini Singh, Jianan Lin, Yi Zhong, Antonija Burčul, Prathibha Mohan, Man Jiang, Liping Sun, Vladimir Yong-Gonzalez, Agnes Viale, Justin R. Cross, Ronald C. Hendrickson, Gunnar Rätsch, Zhengqing Ouyang, Hans-Guido Wendel
Journal: The Journal of Experimental Medicine (2019)

The oncogenic c-MYC (MYC) transcription factor has broad effects on gene expression and cell behavior. We show that MYC alters the efficiency and quality of mRNA translation into functional proteins. Specifically, MYC drives the translation of most protein components of the electron transport chain in lymphoma cells, and many of these effects are independent from proliferation. Specific interactions of MYC-sensitive RNA-binding proteins (e.g., SRSF1/RBM42) with 5′UTR sequence motifs mediate many of these changes. Moreover, we observe a striking shift in translation initiation site usage. For example, in low-MYC conditions, lymphoma cells initiate translation of the CD19 mRNA from a site in exon 5. This results in the truncation of all extracellular CD19 domains and facilitates escape from CD19-directed CAR-T cell therapy. Together, our findings reveal MYC effects on the translation of key metabolic enzymes and immune receptors in lymphoma cells.
Who can benefit from a liver surgery for metastatic colorectal cancer in the era of modern chemotherapy? A post hoc analysis of the MIROX phase III trial.
Authors: Samira Makhloufi, Anthony Turpin, Thierry Andre, Francois-Rene Pruvot, Geoffrey Martinage, Stephanie Truant, Jean-Baptiste Bachet, Dewi Vernerey, Mohamed Hebbar
Journal: Journal of Clinical Oncology (2019)

3547 Background: Despite improvement in colorectal liver metastasis (CLM) treatment, survival after liver surgery remains highly variable. Several clinicopathologic prognostic factors have been reported whose validity in the era of modern chemotherapy remains to be defined. This study aimed to analyze the prognostic factors associated with survival after CLM resection. Methods: Clinicopathologic data of patients included in the MIROX phase III trial who underwent surgery for isolated CLMs were analyzed. The primary endpoints were 5-year overall survival (OS) and disease-free survival (DFS). Univariate Cox analysis was performed to identify associations with OS and DFS and select variables included in a multivariate model to determine their independent prognostic value. Results: A total of 181 patients were analyzed. The median follow-up period was 6.42 years (95% CI: 5.15-8.71), and the 5-year OS and DFS rates were 67.1% and 35.4%, respectively. On multivariate analysis, Fong's clinical risk score (CRS) as a categorical variable (CRS 0-1 vs 2-3 vs 4-5, p = 0.036) and polymorphonuclear neutrophil (PMN) count (&gt;6000/mm 3 vs ≤6000/mm 3 , p = 0.006) before chemotherapy were found to be independent prognostic factors for OS. However, only Fong's CRS remained significantly associated with DFS (p = 0.027). The final OS model was used to establish a nomogram that allows individual OS estimations at 1, 3, 5, and 10 years. Conclusions: Fong's CRS and PMN count were independently associated with poor OS after CLM resection. Fong's CRS was also associated with DFS. The established prognostic nomogram could predict OS more accurately before CLM treatment.
Profiling of genomic alterations in MAPK/ERK signaling in a large cohort of metastatic prostate cancer (mPC) patients.
Authors: Edwin Lin, Andrew W Hahn, Guru Sonpavde, Michael B. Lilly, Roberto Nussenzveig, Elisa Ledet, Sumanta K. Pal, Petros Grivas, Thereasa A. Rich, Victoria M. Raymond, A. Oliver Sartor, Mark Yandell, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2019)

5032 Background: All mPC patients eventually progress on current treatments and prognosis remains poor. In vitro models and small patient cohorts have shown that mPC progression is associated with increased MAPK/ERK signaling. However, in clinical mPC, the genomic alterations that cause aberrant MAPK/ERK signaling and their frequency are poorly defined. We hypothesize that profiling of genomic alterations in MAPK/ERK in a large cohort of heavily pretreated progressive mPC patients will provide a robust measure of importance, and reveal recurrent patterns of alteration. Given the large number of drugs that target MAPK/ERK, these may be incorporated into novel combinatorial treatments for mPC. Methods: 2,679 plasma samples from 2,309 men with mPC were assessed by a validated ctDNA NGS panel that sequences 73 clinically relevant cancer genes (Guardant360, Redwood City, CA) and profiles indels, amplifications, and fusions with high sensitivity and specificity. Genes were assigned to gene sets corresponding to biological pathways and molecular functional classes using the REACTOME database, followed by calculation of summary statistics. Interdependencies between genetic alterations at inter- and intra-gene set levels were discovered by a Bayesian network approach. Results: 56% of mPC samples harbored alterations in MAPK/ERK signaling genes. These included receptor tyrosine kinases (RTKs), MAP kinase cascade, and cell cycle control genes. Gene amplifications were the most frequent alterations in RTK, RAF, and cell cycle control genes, a novel finding. Bayesian network analysis revealed positive interdependencies between all MAPK/ERK genes. In RTK genes, co-amplifications were especially frequent between MET &amp; EGFR and PDGFRA &amp; KIT. Conclusions: In a large cohort of mPC patients, we show that MAPK/ERK gene alterations are present in over half of mPC patients. RTKs, BRAF, and CDK4/6 amplifications are among the most frequent events, display recurrent patterns of co-alteration, and are targetable by existing drugs. Future work to assess the biological and clinical significance of these recurrent patterns of alteration will pave the way for novel combinatorial treatments.
Dietary Fuels in Athletic Performance
Authors: Andreas Mæchel Fritzen, Anne-Marie Lundsgaard, Bente Kiens
Journal: Annual Review of Nutrition (2019)

Focusing on daily nutrition is important for athletes to perform and adapt optimally to exercise training. The major roles of an athlete's daily diet are to supply the substrates needed to cover the energy demands for exercise, to ensure quick recovery between exercise bouts, to optimize adaptations to exercise training, and to stay healthy. The major energy substrates for exercising skeletal muscles are carbohydrate and fat stores. Optimizing the timing and type of energy intake and the amount of dietary macronutrients is essential to ensure peak training and competition performance, and these strategies play important roles in modulating skeletal muscle adaptations to endurance and resistance training. In this review, recent advances in nutritional strategies designed to optimize exercise-induced adaptations in skeletal muscle are discussed, with an emphasis on mechanistic approaches, by describing the physiological mechanisms that provide the basis for different nutrition regimens.
Effect of tumor cell-derived debris and IgG on metastasis of pancreatic cancer and inflammation through tumor-associated macrophages.
Authors: Qi Zhang, Qi Chen, Xueli Bai, Jianxin Wang, Tingbo Liang
Journal: Journal of Clinical Oncology (2019)

e15764 Background: The progression and metastasis of pancreatic ductal adenocarcinoma (PDAC) is highly dependent on the tumor microenvironment. Most tumor-associated macrophages (TAMs) are M2 phenotypic macrophages, which normally show anti-inflammatory functions in numerous disorders. We previously found that alternatively activated macrophages showed pro-inflammatory characteristics upon stimulation of hepatoma cell-derived debris, but the molecular mechanism was unclear. Methods: Macrophages were induced using tumor cell debris. Xenograft mouse model was established. Immunoblotting and immunochemistry were used to test protein expression. Results: The M2 macrophages-derived inflammation also existed in PDAC. We proved that the necrotic debris of PDAC cells induced potent IL-1β release by M2 macrophages via TLR4/TRIF/NF-κB signaling, and this effect was further boosted by IgG that also derived from PDAC cells. We further revealed that increased IL-1β promoted epithelial-mesenchymal transition (EMT) and consequent metastasis of PDAC cells. Using a selective COX-2 inhibitor celecoxib, we enhanced the anti-tumoral efficacy of gemcitabine. Conclusions: These data revealed a special pro-inflammatory phenomenon and mechanism in PDAC, and indicated that IL-1β and COX-2 can be therapeutic targets of anti-inflammatory strategy in PDAC treatment.
Bortezomib Stabilizes and Activates p53 in Proliferative Compartments of Both Normal and Tumor Tissues <i>In Vivo</i>
Authors: Yuezhen Xue, Nick Barker, Shawn Hoon, Pingping He, Teena Thakur, Shifana Raja Abdeen, Priadarsini Maruthappan, Farid J. Ghadessy, David P. Lane
Journal: Cancer Research (2019)

p53 protein, activated and stabilized by posttranslational modifications, performs its major functions by inducing DNA repair, cell-cycle arrest, or apoptosis through transcriptional activation. Here, we determined the ability of p53 protein stabilized via proteasome inhibition to perform similar functions as p53 induced by stresses such as DNA damage. Treating mice with the proteasome inhibitor bortezomib stabilized p53 in stem/progenitor cells of the intestine and stomach, in other proliferating tissues, and in intestinal tumors. Robust basal p53 mRNA levels were observed in the same compartments where p53 was stabilized. Spatial activation of p53 target genes in response to bortezomib in the small intestine demonstrated that CDKN1A and BAX were upregulated in the proliferative crypts but not in the differentiated villi of the small intestine; PUMA was specifically activated at the crypt base of p53 wild-type mice. Thus, cellular context determines the p53 transcriptional target selection. p53-dependent apoptosis was induced in Lgr5-expressing stem cells of the small intestine and high p53 transcriptional activity and apoptosis was induced in intestinal adenomas and in xenograft tumors. Bortezomib inhibited the growth of intestinal adenomas and xenograft tumors with wild-type p53, indicating the importance of p53 in the response to proteasome inhibitors in tissue homeostasis and in cancer therapy. SIGNIFICANCE: These findings show that bortezomib is less active in p53-defective tumors, yet its success in treating multiple myeloma suggests its use can be extended to p53-proficient solid tumors.
Nurse Navigators telephone and web application follow-up intervention for patients treated with oral anticancer medication: an optimization of oncologists' medical time.
Authors: Marie Ferrua, FATIMA YATIM, Aude Fourcade, Marilène Guillet Lacaze, Olivier Mir, Etienne Minvielle
Journal: Journal of Clinical Oncology (2019)

6544 Background: Many interventions to improve safety and quality of oral anti-cancer medication have occurred the past few years. Frequently, these systems involve Nurse Navigators (NN) but rather limited data is actually available describing their activities and quantifying which intervention could have been performed without an oncologist's expertise. This is a major issue in optimizing the workload of oncologists statewide. Methods: The study was conducted at Gustave Roussy (Villejuif, France) as part of an assessment program of an intervention combining NN and mobile app dedicated to patients receiving oral cancer medication (cytotoxic, targeted therapies). A coding grid was developed to classify the NNs' activities from the intervention reports. NN interventions consist in regular follow-up calls and requests from patients and their relatives (via phone calls or mobile app). NN interventions recorded over a 24-month period were all encoded by two researchers. Results: 2395 interventions were analyzed concerning 236 patients, 1880 of which were regular follow-ups, and 515 patient requests. The majority of contacts were carried by phone conversation (94%). 52% of the interventions were followed-up upon by at least one additional action by the NN (n = 1250). In 25% (n = 318) of the interventions, the oncologist's expertise was required mainly because of the presence or aggravation of symptoms and/or toxicities or concerning oncological treatment (therapeutic protocol, biological assessment). 75% (n = 932) of the interventions have been processed successfully by NN by themselves. The principal actions carried out by the NN were: A. Contact or provide referral to a health professional or institution 24%, B. Advice to the patient 43%, C. Management of medical documents and appointments 6%; D. Administrative management 2%. Conclusions: Patients' needs for oral cancer drugs are mainly related to advice, information and coordination of the care pathway. In the majority of interventions, the NNs were able to manage these situations by themselves, which could optimize the workload of oncologists.
Haematological biomarkers of pathological response on neo-adjuvant chemo-immunotherapy treatment for resectable stage IIIA non-small cell lung cancer (NSCLC) patients.
Authors: Raquel Laza Briviesca, Alberto Cruz Bermudez, Miguel Barquin, Ernest Nadal, Amelia Insa, Rosario Garcia-Campelo, Noemi De Dios Alvarez, Manuel Domine, Bartomeu Massuti, Margarita Majem, Delvys Rodriguez-Abreu, Alex Martinez Marti, Manuel Cobo, Guillermo Lopez-Vivanco, Elvira del Barco, Reyes Bernabé, Nuria Vinolas, Isidoro Barneto, Santiago Viteri, Mariano Provencio-Pulla
Journal: Journal of Clinical Oncology (2019)

e20026 Background: PD1/PDL1 treatments have become the main therapy in advanced stages of NSCLC due to its significant increase in overall survival (OS), but recently, combination with chemotherapy in locally advanced stages is showing promising results. Many studies have described the neutrophil-to-lymphocyte ratio (NLR) and platelets-to-lymphocyte ratio (PLR) as indicator of systemic inflammation, that could be use as biomarker of response to immunotherapy. In our study, we described the effect of neoadjuvant chemo-immunotherapy in Complete Blood Count (CBC) parameters and evaluated their relationship with pathological responses. Methods: Immune cell populations of 46 resectable stage IIIA NSCLC patients treated with neo-adjuvant chemo-immunotherapy from NADIM clinical trial were analysed. Samples were extracted before initiating the neo-adjuvant treatment with nivolumab plus carboplatin and at the third cycle before patients underwent surgery. We classified patients in 3 subgroups of pathological response assessed in the resection specimen: complete response (pCR), mayor response (&lt; 10% viable tumour) and incomplete response (&gt; 10% viable tumour). Wilcoxon and Mann-Whitney U statistic test were used to evaluated differences between pre and post treatment and between pathological responses groups respectively. Results: From 46 patients, 5 patients did not undergo surgery, so they were excluded from the analysis. Absolute numbers (x103cells/µl) of CBC were significantly reduced after neo-adjuvant treatment in patients, leucocytes (8.80 vs 6.64), Eosinophil (0.22 vs 0.15), Monocytes (0.72 vs 0.62), Neutrophils (5.53 vs 3.53), Haemoglobin (35.82 vs 29.68), Platelets (292.44 vs 227.22), NLR (2.73 vs 1.71) and PLR (143.34 vs 115.85) except Lymphocytes (2.22 vs 2.25) and Basophils (0.06 vs 0.05). Moreover, when the analysis was done by subgroups of pathological responses, PLR variation was significantly different between pCR and incomplete response (-21.33 vs -76.98) whereas NLR and the rest of the immune populations were no different between subgroups. Conclusions: In our study, NLR is not associated to chemo-immune neo-adjuvant treatment response. Nevertheless, in our cohort a higher decrease on PLR post neo-adjuvant treatment is associated to an incomplete pathological response.
Patient-reported experience of diagnosis, management, and burden of renal cell carcinomas: Results from a global patient survey in forty-three countries.
Authors: Rachel H Giles, Deb Maskens, Robert Bick, Robin Martinez, Malcolm Packer, Daniel Yick Chin Heng, James M. G. Larkin, Axel Bex, Sara Jane Maclennan, Michael A.S. Jewett, Eric Jonasch
Journal: Journal of Clinical Oncology (2019)

e16091 Background: The International Kidney Cancer Coalition (IKCC) is a federation of 38 affiliated patient organizations representing 1.2 million patients worldwide that is committed to reduce the global burden of kidney cancer. A large-scale global survey of RCC patients to capture real world experiences (RWE) has never been undertaken. Methods: The 35-question survey was designed to identify geographic variations in patient education, experience and awareness, access to care, best practices, quality of life, involvement in clinical trials and to highlight unmet needs. The survey was conducted online or in paper form in Sept-Oct 2018 by kidney cancer patients and /or their caregivers identified by IKCC’s Affiliate Organizations and through social media in 14 languages. Results: 1,983 responses were recorded from 43 countries. Analysis revealed that at diagnosis, 43% of all respondents had no understanding of their RCC sub-type; patients with clear cell carcinoma (64%) had a notably poorer understanding of their RCC subtype than did patients with rarer RCC subtypes. While 96% of respondents reported psychosocial impacts, surprisingly, only 50% disclosed them to their healthcare team. Of the 70% of patients who were never asked to participate in a clinical trial, 89% responded they would have “fairly likely” done so if asked. RCC patients &lt; 45 years old reported nearly twice as many barriers to treatment as patients &gt; 45 at diagnosis. Females reported longer delays to diagnosis than males. Shared decision making remains aspirational across major cancer centers and community hospitals: globally 29% of all patients reported no involvement in their treatment decision, responding ‘my doctor decided for me’. Conclusions: This exploratory research sheds light on the unmet needs in the RCC patient experience and warrants further analysis. This first-ever global survey serves as a benchmark for longitudinal data collection. RWE indicates opportunities to improve communication about diagnosis, psychosocial impacts, and clinical trials. [Table: see text]