tbuckley/cabot-search huggingface dataset:
The impact of skeletal muscle and adipose tissue on long-term survival in patients with resectable colorectal cancer.
Authors: Michael B. Sawyer, Jessica Hopkins, Rebecca Reif, David Bigam, Vickie E. Baracos, Dean Eurich
Journal: Journal of Clinical Oncology (2018)

3585 Background: Computed tomography-derived body composition parameters are emerging prognostic factors in colorectal cancer. This study aimed to determine the roles of sarcopenia, myosteatosis and adiposity as independent and overlapping parameters in resectable colorectal cancer patients. Methods: This was a retrospective cohort study from a prospectively collected database. It included all adult patients with early-stage colorectal cancer, who underwent curative resection from 2007-09. All patients were seen in a tertiary care cancer center in Northern Alberta. Computed tomography-derived quantification of skeletal muscle and adipose tissues were used to determine cohort-specific cut-offs for sarcopenia, myosteatosis and total adiposity using an optimal stratification analysis. Multivariate cox proportional hazards models were performed to assess for associations between body composition parameters and overall, disease-free and cancer-specific survival. Results: In the 968 patients included, there were a total of 254 disease recurrences and 350 deaths. Body mass index and computed tomography-derived measures of adiposity did not result in worse survival outcomes. Sarcopenia was independently predictive of worse overall (HR 1.45; 95% CI 1.16, 1.84), recurrence-free (HR 1.32, 95% CI 1.00, 1.75) and cancer-specific survival (HR 1.46, 95% CI 1.09, 1.94) in a multivariate model. Myosteatosis was also independently predictive of overall survival (HR 1.53, 95% CI 1.19, 1.97). In a multivariate model considering joint effects of sarcopenia and myosteatosis, the presence of both parameters predicted the worst overall (HR 2.23, 95% CI 1.62, 3.06), recurrence-free (HR 1.53, 95% CI 1.06, 2.21) and cancer-specific survival (HR 2.40, 95% CI 1.69, 3.42). Conclusions: Sarcopenia and myosteatosis are independent predictors of worse survival in early-stage colorectal cancer. Their joint effect is highly predictive of reduced overall, recurrence-free and cancer specific survival. Sarcopenia and myosteatosis represent prognostic factors that may be easily integrated into clinical practice.
Comparison of SP142 (Ventana) and SP263 (Ventana) assays to test PD-L1 expression in metastatic cancer patients to be treated with immune checkpoint inhibitors.
Authors: Basak Oyan, Ozlem Sonmez, Aziz Yazar, Mehmet Teomete
Journal: Journal of Clinical Oncology (2018)

e24306 Background: PD-L1 expression is an important biomarker for prediction of response to anti-PD1 and Anti-PD-L1 immunotherapy. There are several immunohistochemistry (IHC) assays to determine the expression of PD-L1 in tumor cells. Most widely used assays are 22C3 (Dako), SP142 (Ventana) and SP263 (Ventana). In prior comparison trials, it was shown that 22C3 and SP263 were closely aligned in tumor cell staining, but SP142 stains less tumor cells. The aim of this trial was to retrospectively compare SP142 and SP263 staining in advanced stage cancer patients whose PD-L1 expression was done both with SP142 and SP263 assays on the same tissue. Methods: The PD-L1 expression results of advanced stage cancer patients were evaluated, retrospectively. 53 patients were found to be tested for PD-L1 between January 2016 and May 2017. Seven patients were tested with both SP142 and SP263 IHC assays. Results: In 6 patients, the percentage of positive tumor cells were higher with SP263 assay. The assays were compared at the clinically relevant cutoffs (≥50 % and ≥1%). At ≥1% cutoff, one of seven patients (14%) was PD-L1 negative with SP142, although PD-L1 expression was 30% with SP263 assay. At ≥50% cutoff, 3 of 7 patients (43%) was PD-L1 negative with SP142, although PD-L1 expression was positive with SP263 assay in these patients. Conclusions: Compared to SP263 assay, SP142 assay resulted in underestimation of PD-L1 expression in tumor cells. Especially at high cutoff levels like ≥50%, some patients may lose their chance to receive an effective treatment depending on the assay. The inconsistency in literature, regarding the association between PD-L1 expression and benefit achieved from anti-PD1 or Anti-PD-L1 immunotherapy may be related to the use of different assays for PD-L1 expression status. Patient Diagnosis SP263(% of positive tumor cells) SP142(% of positive tumor cells) 1 Lung-squamous cell 90% 40% 2 Lung- squamous cell 30% 0% 3 Lung- squamous cell 100% 30% 4 Lung-adenocarcinoma 40% 5% 5 Lung-adenocarcinoma 100% 80% 6 Triple negative breast cancer 60% 30% 7 Colon cancer 0% 0%
The MD CaREs initiative: Tailoring oncology education to ethnically and culturally diverse students.
Authors: Zuanel Diaz, Carla Lupi, Fernando Manuel Vargas Madueno, Barbra A. Roller, Cheryl Brewster, Alan Wells, Jessica Ordonez, Deborah Suarez, Michael Paez, Jeff Boyd, Carolyn D. Runowicz, Miguel Angel Villalona-Calero
Journal: Journal of Clinical Oncology (2018)

11019 Background: Although more than 23,000 oncologists are practicing in the United States, a markedly small number of these are Hispanic/Latino. Related perhaps are statistics reflecting the poor representation of minorities in clinical trials, even for tumors from which minority outcomes are disproportionately poor compared to non-minority patients. Methods: To address these issues, we establish a partnership between a hybrid academic-community cancer center and a college of medicine, both with a history of addressing the needs of Hispanics/Latinos, a minority and typically underserved population. This partnership aims to increase participation of minority undergraduate, medical and graduate students in cancer research through a novel educational approach. Its curriculum concentrates on emerging fields in oncology, features research experiences, participation in execution of clinical trials and incorporates an outreach program to underserved populations. Results: Departing from well-established programs, we injected innovative education elements. We created a competency-based mixed modality course that includes an on-line interactive sessions for medical students to expand their skills in cancer screening and prevention at the individual, community, and health systems levels, with an emphasis on breast and cervical cancer, disparities and underserved populations. We also created an advanced Multidisciplinary Oncology Clinical Elective for 4th year medical students that introduces biospecimen banking science, tumor molecular profiling, medical physics, clinical research, and clinical cancer genetics. Finally, we enriched two long-standing programs which target undergraduate minority students, aimed at increasing the number of underrepresented candidates accepted to medical school, by providing opportunities to learn cutting-edge methodologies. Conclusions: A strong partnership that focuses on cancer research, education and training should contribute to a more diverse clinical and research workforce, an initiative that is ideally implemented in South Florida.
Analysis of a large patient cohort with nivolumab: Predictive clinical factors for continued benefit after an immune-related adverse event.
Authors: Diaa Osman, Khine Zar Win, Morgan Wong, Alexandria T. Phan
Journal: Journal of Clinical Oncology (2017)

e14600 Background: Nivolumab (NIVO), a PD-1 inhibitor, is used in various advanced malignancies with meaningful and durable outcomes. However, its use can be limited by severe immune-related adverse events (irAEs). We analyzed our large single institution patient cohort who have been treated with NIVO to risk stratify and identify clinical factors associated with continued benefit after irAEs. Methods: 125 patients with advanced malignancies, treated with NIVO during 2011-2016 at the University of New Mexico Comprehensive Cancer Center, were evaluated. Inclusion criteria included a minimum of 1 completed treatment of NIVO (1 or 3mg/kg). Stratifying factors including age, gender, BMI, ethnicity, co-morbidities, pretreatment WBC and albumin, number of treatments received, type of malignancy, number of metastatic sites, overall tumor response rate (ORR), irAEs, and tumor response rates after irAE were identified. Results: Primary sites of cancer for the 125 patients who received NIVO were lung (44, 35%), melanoma (43, 34%), head-neck (8, 6%), renal (14, 11%), Hodgkin’s (16, 13%), 2 patients with more than one malignancy (1 with lung and head-neck, and 1 with lung and melanoma), and other non-approved indications (16, 13%). The overall tumor response rate was 34.4%. Total All CTCAE v4 grades irAEs experienced were 32% (40/125), and 33% (13/40) were severe (grade &gt; 3). Eighteen (18/40, 45%) patients continued to have tumor response after experiencing any grade irAE. The mean age of those experiencing an irAE with subsequent tumor control (CR, PR, or SD) was 72.3 years, mean BMI 28.2 kg/m 2 , 38.9% were female, 11.1% were non-Caucasian, 61.1% had &gt; 2 co-morbidities, 72.2% with &gt; 2 metastatic sites and the mean albumin was 3.4 g/dl. Conclusions: Patients who had a tumor response after being re-challenged with NIVO, despite experiencing an irAE, were found to be older, had a higher BMI, an increased number of co-morbidities, higher tumor burden, and mean albumin &gt; 3.0g/dl. Risk stratifying these patients prior to starting treatment is possible and can be helpful in anticipating which patients should be re-challenged or will have continued benefit with NIVO after experiencing an irAE.
A Model to Predict 1‐Month Risk of Transplant or Death in Hepatitis A–Related Acute Liver Failure
Authors: Jin Dong Kim, Eun Ju Cho, Choonghyun Ahn, Sue K. Park, Jong Young Choi, Han Chu Lee, Do Young Kim, Moon Seok Choi, Hee Jung Wang, In Hee Kim, Jong Eun Yeon, Yeon Seok Seo, Won Young Tak, Moon Young Kim, Heon Ju Lee, Yun Soo Kim, Dae Won Jun, Joo Hyun Sohn, So Young Kwon, Sang Hoon Park, Jeong Heo, Sook‐Hyang Jeong, Jeong‐Hoon Lee, Nobuaki Nakayama, Satoshi Mochida, Akio Ido, Hirohito Tsubouchi, Hazime Takikawa, None Shalimar, Subrat Kumar Acharya, William Bernal, John O’Grady, Yoon Jun Kim
Journal: Hepatology (2018)

Acute liver failure (ALF) caused by hepatitis A is a rare but fatal disease. Here, we developed a model to predict outcome in patients with ALF caused by hepatitis A. The derivation set consisted of 294 patients diagnosed with hepatitis A–related ALF (ALFA) from Korea, and a validation set of 56 patients from Japan, India, and United Kingdom. Using a multivariate proportional hazard model, a risk‐prediction model (ALFA score) consisting of age, international normalized ratio, bilirubin, ammonia, creatinine, and hemoglobin levels acquired on the day of ALF diagnosis was developed. The ALFA score showed the highest discrimination in the prediction of liver transplant or death at 1 month (c‐statistic, 0.87; 95% confidence interval [CI], 0.84‐0.92) versus King’s College criteria (KCC; c‐statistic, 0.56; 95% CI, 0.53‐0.59), U.S. Acute Liver Failure Study Group index specific for hepatitis A virus (HAV‐ALFSG; c‐statistic, 0.70; 95% CI, 0.65‐0.76), the new ALFSG index (c‐statistic, 0.79; 95% CI, 0.74‐0.84), Model for End‐Stage Liver Disease (MELD; c‐statistic, 0.79; 95% CI, 0.74‐0.84), and MELD including sodium (MELD‐Na; c‐statistic, 0.78; 95% CI, 0.73‐0.84) in the derivation set (all P &lt; 0.01). In the validation set, the performance of the ALFA score (c‐statistic, 0.84; 95% CI, 0.74‐0.94) was significantly better than that of KCC (c‐statistic, 0.65; 95% CI, 0.52‐0.79), MELD (c‐statistic, 0.74; 95% CI, 0.61‐0.87), and MELD‐Na (c‐statistic, 0.72; 95% CI, 0.58‐0.85) (all P &lt; 0.05), and better, but not statistically significant, than that of the HAV‐ALFSG (c‐statistic, 0.76; 95% CI, 0.61‐0.90; P = 0.28) and new ALFSG indices (c‐statistic, 0.79; 95% CI, 0.65‐0.93; P = 0.41). The model was well‐calibrated in both sets. Conclusion: Our disease‐specific score provides refined prediction of outcome in patients with ALF caused by hepatitis A.
DNA repair deficiency, genomic instability and immune profiling in a phase 1 study of locally advanced pancreatic cancer patients treated with veliparib, gemcitabine and radiotherapy.
Authors: Richard Tuli, Nicholas N. Nissen, Simon Lo, Miranda Bryant, Arsen Osipov, Andre Rogatko, Mourad Tighiouart, Zhenqiu Liu, Nan Deng, Andrew Eugene Hendifar, Stephen Lawrence Shiao
Journal: Journal of Clinical Oncology (2018)

4128 Background: A phase I trial of veliparib (V), gemcitabine (G) and radiotherapy (RT) was conducted to determine the maximum tolerated dose (MTD) and clinical activity in patients with and without DNA damage repair (DDR) defects. Methods: LA patients were treated with weekly G (1000 mg/m2), daily RT (36 Gy/15 fractions) and daily V 20 mg BID for 3 weeks escalated per Bayesian method followed by standard chemotherapy. DAVID was used to interpret differential gene expression. Cox regression model was used to identify DDR pathways associated with survival. Next generation sequencing (NGS) identified genetic mutations involved in DDR, tumor mutation burden (TMB) and microsatellite instability (MSI) status. Blood samples were interrogated for PAR protein and cytokines using an ELISA and electrochemiluminescent array, respectively. The log-rank test was used to evaluate differences in PFS and OS. Results: 34 patients were enrolled from 2013 to 2016. MTD of veliparib was 40 mg BID with gemcitabine 400 mg/m2 and RT (36 Gy/15). 12 patients experienced DLT (83.3% lymphopenia, 8.3% neutropenia). Median PFS and OS were 10 and 15 months, respectively. Gene expression analysis identified DDR defects in 50% of patients. Median PFS and OS were significantly higher for these biomarker positive patients (17 vs. 8 mos, p < .01; 22 vs. 12 mos, p < .001, respectively). NGS identified 10 DDR mutations which were not prognostic of outcome. median TMB was 1.8 mut/Mb. A single MSI high patient was identified who was also TMB high ( > 20 mut/MB) and harbored DDR deficiency by NGS. Lower PAR levels were associated with borderline statistically significant improvements in both PFS and OS (p < .06). Higher levels of IL2 and IL12 and lower levels of FLT1 were associated with improved PFS and OS (p < .05). Conclusions: The combination of V, G and RT was well tolerated. DDR alterations were identified in a large proportion of patients and were associated with improved PFS and OS. Whereas most patients were MSS and had low TMB, those with higher levels of pro-inflammatory cytokines were likely to harbor DDR alterations which were associated with improved outcomes. Clinical trial information: NCT03245541.
A multi-gene risk signature for improved identification of cutaneous squamous cell carcinoma (cSCC) patients with a high risk of recurrence.
Authors: Chrysalyne Schmults, Sarah T Arron, Ashley Wysong, Kyle R. Covington, Robert W. Cook, Jason Newman
Journal: Journal of Clinical Oncology (2018)

9577 Background: cSCC is rivaled only by basal cell carcinoma as the most common cancer in the U.S. Though most cases are cured by excision, a subset recur and become incurable with number of deaths approximating melanoma (Karia et al., JAAD, 2012). Identifying the subset at risk of recurrence is critical for development of clinical trials in cSCC which has no FDA-approved treatments and very few phase II trials. Therefore, we set out to develop a gene expression-based biomarker associated with disease recurrence/metastasis in cSCC. Methods: According to an IRB approved multicenter protocol, 230 primary cSCC tumors were analyzed for mRNA expression of 73 candidate genes reported to be associated with cSCC metastasis. After quality filtering, 63 genes and 212 samples were included in the predictive model construction. Multiple machine learning algorithm approaches were applied with 75% of the specimens used for training and the remaining 25% used for validation. Results: Six genes demonstrated consistent expression across all samples tested and were used as controls to normalize expression values of the remaining genes. Eighteen genes were differentially expressed between recurrent and non-recurrent cases. Evaluation of the genes with multiple predictive modeling methods identified an optimal model that was 71% sensitive, 90% specific, had a 50% positive predictive value (PPV), and a 96% negative predictive value (NPV) for recurrence. Conclusions: This study developed a predictive model for risk of recurrence with a much higher PPV than staging criteria developed by Brigham and Women’s Hospital and the American Joint Committee on Cancer (50% vs. approximately 24% and 18% respectively) while maintaining a high NPV (Karia et al., JCO 2014; Karia et al., JAMA Dermatology, 2017). Clinical application of such a prognostic test with a robust PPV (50% risk of recurrence) will enable identification of cSCC patients who may be appropriate for therapeutic intervention beyond surgical clearance (e.g. nodal staging and/or adjuvant radiation) and enrollment in clinical trials evaluating contemporary therapies.
Assessment of clinical, radiological and radiomic predictive factors of bevacizumab efficacy in brain metastases radionecrosis treatment.
Authors: Aurelien Gobert, Roger Sun, Lizza Hendriks, Sylvain Reuzé, Samy Ammari, Jean-Philippe Spano, Benjamin Besse
Journal: Journal of Clinical Oncology (2018)

e14003 Background: The incidence of brain metastases increases with frequent use of stereotactic radiotherapy. The main complication is radionecrosis (RN), which is difficult to diagnose with tumor progression, as both are frequently associated. In a retrospective study, we assessed the efficacy and safety of bevacizumab in the RN treatment of brain metastases. The aim of our study was to search for clinico-radiological and radiomic prognostic and / or predictive factors for response to bevacizumab. Methods: Demographic and efficacy (overall survival and progression-free survival) data were retrospectively collected from patients treated with bevacizumab for brain metastases RN at Gustave Roussy center. Available MRI were processed, and texture data were extracted (P = 41 image features). From radiometric data on radionecrosis lesions, a random survival forest was used to construct a global survival prognostic model using R randomForestRSC software. Results: From October 2011 and September 2017, 20 patients (12 females, 8 males) were treated with bevacizumab for brain metastases necrosis, with 29 MRI lesions. The variable selection algorithm, as a function of the minimum depth threshold, identified 17 characteristics of interest among the 41 characteristics of the image resulting from the segmentation of the RN lesions. Each RN lesion was stratified between low risk and high risk, with a threshold value corresponding to the cut-off determined by the Youden formula with AUC = 92.2 at time t = 6 months. In univariate analyses, a radiomic signature from texture analyzes correlates significantly with progression-free survival (p = 0.0414) and overall survival (p = 0.0029). Conclusions: Radionecrosis of brain metastases is difficult to distinguish from brain progression and represent a critical clinical issue. Interestingly, we found a radiomic signature correlated with overall survival and progression-free survival. Due to the small cohort size, the statistical power was not sufficient to perform a multivariate analysis, nor to have an independent validation cohort. This preliminary data should be confirmed and a multicenter expansion cohort is still in progress.
Transcriptional and post-transcriptional regulation of ribonucleotide reductase (RRM2) control its oncogenic role in prostate cancer progression.
Authors: Ying Zhang Mazzu, Joshua Armenia, Goutam Chakraborty, Yuki Yoshikawa, Travis A. Gerke, Mohammad Omar Atiq, Konrad Hermann Stopsack, Kazumasa Komura, Gwo-Shu Mary Lee, Lorelei A. Mucci, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2018)

5044 Background: The role of DNA repair pathways has been recognized in prostate cancer (PC) progression. Ribonucleotide reductase (RNR) is essential for DNA synthesis and repair. The subunit of RNR complex, RRM2, can regulate tumor initiation, progression and drug resistance in multiple cancer types. There is limited knowledge of RRM2 function in PC. Methods: The clinical cohort was analyzed for the correlation of RRM2 and clinical outcomes. RNA-seq and protein array were applied for the mechanism studies. ChIP and reporter assays were used for transcriptional study. Results: High level of RRM2 was associated with lethal disease, independent from Gleason grade (odds ratio:3.54; 95% CI, 1.76-7.4) in a cohort of men in the Physicians' Health Study and the Health Professionals’ Follow-up Study (n = 404). Transcriptomic analysis revealed that multiple oncogenic transcription factor networks were inhibited by inhibition of RRM2, while p53 signaling was strongly activated. Phosphoproteomic analysis showed inhibition of RRM2 could repress multiple oncogenic signals including SFK, STAT, and Akt/mTOR signaling. Intriguingly, inhibition of RRM2 by siRRM2 and the inhibitor (COH29) could specially target gene profiling of poor-prognosis subtypes (PCS1 and PAM50) in PC. In an in vivo PC xenograft model, COH29 strongly inhibited tumor growth. Amplification of RRM2 is rarely observed in PC, thus, transcription and post transcription may largely contribute to overexpression of RRM2. A bioinformatics strategy was developed to search the putative RRM2-targeting transcription factors (TFs). Among 13 TFs candidates, FoxM1 and E2F1 were validated to target the RRM2 promoter. Additionally, we found that methylation-induced silencing of miR-193b could release the inhibition control of FoxM1 and RRM2 in PC cells. DNMTs inhibitor (5-Aza) restored miR-193b expression, leading to the upregulation of RRM2 and FoxM1 in PC cells. Conclusions: We reveal the function of RRM2 in PC and unravel the mechanism of dysregulation of RRM2 in PC. Our findings suggest that RRM2 may serve as a key regulator of PC growth and a possible therapeutic target for PC therapy.