tbuckley/cabot-search huggingface dataset:
Multimodality treatment of synovialsarcoma: A single institution experience.
Authors: Daniela Greto, Camilla Delli Paoli, Giulio Francolini, Carlotta Becherini, Luca Dominici, Calogero Saieva, Vieri Scotti, Domenico Andrea Campanacci, Giovanni Beltrami, Guido Scoccianti, Mauro Loi, Isacco Desideri, Icro Meattini, Pierluigi Bonomo, Lorenzo Livi
Journal: Journal of Clinical Oncology (2017)

e22530 Background: Synovialsarcoma (SS) is a relatively rare cancer, accounting for 8% of all Soft-Tissue Sarcomas (STS). Identifying prognostic factors could allow to improve treatment strategy for this disease. Methods: Data of 52 patients treated at University of Florence between 1999 and 2016 were retrospectively analysed. Patients and treatment features (Table 1) were correlated with outcome. Results: At a median follow-up of 8.4 years, 9 deaths, 3 local recurrences (LR) and 19 distant metastases (DM) have occurred (17,3%, 5,8% and 36,5%, respectively). Survival Kaplan-Meier analysis showed that Overall survival (OS), Local recurrence disease free survival (DFS-LR) and Distant metastases disease free survival (DFS-DM) were 74,5%, 90% and 59,3%, respectively. Size&gt;10 cm was the only significant predictor of OS (p=0,004). Age&gt;40, size&gt;10 cm and G3 significantly influenced DFS-DM (p=0,043, p=0,002 and p=0,002, respectively). Cox univariate regression analysis confirmed the impact of size on OS (HR 5.8, 95% CI 1.37-24.43, p=0,017). Size (HR 5.06, 95% CI 1.73-14.79, p=0.003) and Grade (7.19, 95% CI 1.65-31.37, p=0.009) influenced DFS-DM. G3 was the only independent prognostic factor associated with DFS-DM. Conclusions: These data confirm that age, size and grade significantly influence outcome in patients affected by SS. Further studies are needed in order to develop tailored treatment strategies in this setting. [Table: see text]
Clinical utility of next-generation sequencing (NGS)-based genomic profiling of advanced solid tumors in routine clinical practice.
Authors: Pramod Kumar Julka, Harleen Kaur Nayyar, Shaikmaheboob Hussain, Tarun Mohindra, Amit Verma
Journal: Journal of Clinical Oncology (2018)

e24157 Background: Next-generation sequencing (NGS)-based genomic profiling of advanced solid tumors has given a new perspective to personalized patient care in oncology. In a single run, NGS allows the testing of all types of variants including single-nucleotide variations, insertions, deletions, exon duplications, gene copy number changes, and known translocations. Foundation One is a validated comprehensive genomic profile that interrogates the entire coding sequence of 315 cancer-related genes plus select introns from 28 genes. This study examined the clinical relevance of NGS-based genomic profiling in routine clinical practice at India’s first standalone daycare chemotherapy centre. Methods: Patients with histologically or cytologically confirmed locally advanced, metastatic or recurrent solid tumors having a measurable disease and ECOG performance status of ≤2 were included in the study. Blocks of the archival formalin-fixed paraffin-embedded tumor tissue was sent to Foundation Medicine for testing using a targeted NGS panel. Upon being notified of NGS results, treating physician prescribed the therapy to the individual patient as inferred from the test report. Results: There were 5 men and 7 women with a median age of 48 years (range 17-65 years). Type of cancer was lung and soft tissue sarcoma in 3 patients, breast in 2 patients and head and neck, colorectal, stomach and cholangiocarcinoma in 1 patient each respectively. Patients had received a median number of 2 prior systemic treatments (range 1-6). All the 12 patients had at least two genomic alterations and the average number of altered genes per patient was 5.5 (standard deviation 3.98). The median number of FDA approved therapies in patient’s tumor type or in another tumor type was 2 (range 2-8). TP53 (58.3%), PIK3CA (25%), CDKN2A (25%) and KRAS (16.7%) were the most frequently mutated genes in our study population. The medical oncologist’s pre-test to post-test treatment recommendation changed for 4 (33.3%) patients. Conclusions: The preliminary results of this study indicate the clinical utility of NGS-based genomic profiling in determining the most appropriate drug combination for a cancer patient.
Implementation of the genereader NGS system in a molecular pathology laboratory.
Authors: Andreas Bösl, Maria Pfisterer, Agnes Neugebauer, Constanze Nemes, Johanna Schneider, Christina Steger, Felix Offner
Journal: Journal of Clinical Oncology (2018)

e24175 Background: The goal of this study was to evaluate and implement an NGS System, the GeneReader (Qiagen, Hilden, Germany) in a routine molecular laboratory, to compare its performance to other methodologies, and to use the system in the identification of key tumor mutations for personalized cancer care. Methods: Reference standards (n = 2), FFPE tumor (n = 50; colorectal cancer (CRC) n = 29; lung cancer n = 10; melanoma n = 11) and liquid biopsies (n = 20; CRC n = 15, lung n = 5) samples with known mutations in various cancer driver genes (BRAF, EGFR, KRAS and NRAS) were used in this study. All samples were processed following the manufacturer’s instructions, and their mutational status compared with previous results. Furthermore, interpretation of the variant findings was performed using the QIAGEN Clinical Insight Interpret (QCII) software, to provide actionable recommendations for each sample based on its mutational profile. Results: All previously known mutations were correctly confirmed with the GeneReader NGS workflow, making it a reliable system for routine cancer mutational analysis. Importantly, in 6% (3/50) of the samples, NGS identified additional pathogenic mutations previously missed by single-analyte pyrosequencing. These results suggest an NGS approach can more sensitively and accurately detect mutations and potentially broaden clinical options. Furthermore, 50% (10/20) of liquid biopsies harbored pathogenic mutations, 30% (3/10) of which were not found in tumor mass analysis from the same individuals. As such, liquid biopsy not only provides an additional sample source for analysis, but also additional insights into full cancer mutational profile. Conclusions: The GeneReader NGS system provides a solution for cancer testing with low hands-on time and high accuracy. Such NGS approach also allows a more sensitive way of detecting critical cancer mutations. Additionally, the application of this technology in liquid biopsies enables a more accurate and comprehensive understanding of the cancer molecular profile, supporting individualized clinical therapeutic decisions.
CDK8 Selectively Promotes the Growth of Colon Cancer Metastases in the Liver by Regulating Gene Expression of TIMP3 and Matrix Metalloproteinases
Authors: Jiaxin Liang, Mengqian Chen, Daniel Hughes, Alexander A. Chumanevich, Serena Altilia, Vimala Kaza, Chang-Uk Lim, Hippokratis Kiaris, Karthikeyan Mythreye, Maria Marjorette Pena, Eugenia V. Broude, Igor B. Roninson
Journal: Cancer Research (2018)

Abstract Unresectable hepatic metastases of colon cancer respond poorly to existing therapies and are a major cause of colon cancer lethality. In this study, we evaluated the therapeutic viability of targeting the mediator kinase CDK8, an early clinical stage drug target, as a means to suppress metastasis of colon cancer. CDK8 was amplified or overexpressed in many colon cancers and CDK8 expression correlated with shorter patient survival. Knockdown or inhibition of CDK8 had little effect on colon cancer cell growth but suppressed metastatic growth of mouse and human colon cancer cells in the liver. This effect was due in part to inhibition of already established hepatic metastases, indicating therapeutic potential of CDK8 inhibitors in the metastatic setting. In contrast, knockdown or inhibition of CDK8 had no significant effect on the growth of tumors implanted subcutaneously, intrasplenically, or orthotopically in the cecum. CDK8 mediated colon cancer growth in the liver through downregulation of matrix metalloproteinase (MMP) inhibitor TIMP3 via TGFβ/SMAD-driven expression of a TIMP3-targeting microRNA, miR-181b, along with induction of Mmp3 in murine or MMP9 in human colon cancer cells via Wnt/β-catenin-driven transcription. These findings reveal a new mechanism for negative regulation of gene expression by CDK8 and a site-specific role for CDK8 in colon cancer hepatic metastasis. Our results indicate the utility of CDK8 inhibitors for the treatment of colon cancer metastases in the liver and suggest that CDK8 inhibitors may be considered in other therapeutic settings involving TGFβ/SMAD or Wnt/β-catenin pathway activation. Significance: These findings demonstrate that inhibition of the transcription-regulating kinase CDK8 exerts a site-specific tumor-suppressive effect on colon cancer growth in the liver, representing a unique therapeutic opportunity for the treatment of advanced colon cancer.
Post-transplant head and neck cancers: A prospective analysis of clinical factors for risk stratification.
Authors: Joanne Soo, Joseph Schroers-Martin, Andrea Garofalo, David Matthew Kurtz, Nathan D'Emilio, David Robert Grimm, Helen Luikart, Maximilian Diehn, John B. Sunwoo, Kiran K Khush, Ash A. Alizadeh
Journal: Journal of Clinical Oncology (2018)

e18051 Background: Transplant recipients experience a 2 to 10-fold increased risk of head and neck cancers (HNC) compared to the general population, with about 10-15% of transplant recipients developing a HNC. Retrospective studies have identified level of immunosuppression, chronic HPV infection, and alcohol and tobacco use as risk factors for the development of HNC after transplant. We sought to prospectively assess the utility of clinical risk factors for prediction of HNC in the transplant population. Methods: We prospectively followed 330 patients who received a heart or lung transplant at Stanford from 2010 to 2016. Positive smoking history, alcohol use > 1 oz per week, age at transplant > 60, and high level of immunosuppression were used to stratify patients in low- (0-1 factors) and high- (2+ factors) risk categories. Disease course was evaluated in patients who developed HNC. Mean follow-up time was 3.6 years ± 2.1 years. Results: Eighty patients were categorized as high risk. There was no significant difference in follow-up time between high- and low-risk groups. In total, 32 patients (9.7%) developed a HNC, with a mean time of 841 days between transplantation and diagnosis. Two low-stage resectable non-cutaneous SCC cases and one parotid SCC occurred exclusively in the high-risk category. There was a significant difference in cancer incidence between the two risk categories (6% in low-risk v. 21.3% in high-risk; OR = 4.23; p < 0.0001). The use of a combined risk score improved risk stratification compared to the use of smoking history (OR = 2.79), level of immunosuppression (OR = 2.82) and alcohol use (OR = 1.18). While age was the most important risk factor for developing HNC (OR = 6.76), this was largely due to the increase in cutaneous malignancies with age. Use of a combined risk category was able to identify 25 at-risk patients < 60 years of age, of which 2 (8%) developed a HNC. Conclusions: While transplant patients regularly undergo clinical follow-up, clinical risk factors can be used to identify patients who may benefit from additional screening. The utility of biomarkers such as HPV titers and circulating tumor DNA for early detection of HNC, particularly in high-risk patients, should be evaluated.
Use of statins and the risk of prostate cancer biochemical recurrence in men treated with radical prostatectomy.
Authors: Luke Trapp, Irene B. Helenowski, Michael Gurley, Robin Leikin, William Catalona, Borko Jovanovic, Timothy Kuzel
Journal: Journal of Clinical Oncology (2016)

5048 Background: Retrospective cohort studies disagree as to the correlation between the use of statin medications and favorable progression free and overall survival in men with prostate cancer. The purpose of this study is to determine whether use of statins is associated with higher rates of biochemical recurrence free (BCRF) survival for patients with prostate cancer (PCa) who undergo radical prostatectomy (RP). Methods: We reviewed data from a cohort of 3311 patients who consented to the SPORE in Prostate Cancer at the Robert H. Lurie Comprehensive Cancer Center at Northwestern University and were treated with RP with curative intent between 2002 and 2015. Subjects were grouped based on prescription of statin medication within two years prior or any time subsequent to RP. Wilcoxon rank-sum and Fisher’s exact tests were used to examine age, race, Gleason score, clinical stage, and pathological stage between statin users and non-users where appropriate. The log-rank test was used to compare the Kaplan-Meier estimated BCRF survival between the two groups. Subjects in the cohort will be excluded from the final analysis in the case of (neo/)adjuvant therapies, insufficient pathology data, or insufficient follow-up data. Results: We identified 1023 (30.9%) statins users and 2288 (69.1%) non-users. Race, Gleason score, clinical stage, and pathological stage were not significantly different between the two groups. The median age for all patients at RP was 68 (range 29-81). After a median follow-up time of 49.0 months (range 1-150 months) among all patients, the 5-year BCRF survival rate was 58.2% (CI95% 54-62) among statin users and only 52.7% (CI95% 50-55) among non-users (log-rank p < 0.01). The 5-year overall survival rate was 100% in both groups. Conclusions: Preliminary analysis suggests that use of statin medication in men diagnosed with prostate cancer correlates with an increased rate of BCRF survival. Final analysis of the cohort will provide updated information and survival estimates.
Outcomes in metastatic cancer patients who develop spinal cord compression.
Authors: Achuta Kumar Guddati, Gagan Kumar, Iuliana Shapira
Journal: Journal of Clinical Oncology (2016)

6538 Background: Metastatic spinal cord compression (MSCC) is one of the dreaded complications of cancer. Early recognition and intervention is crucial for favorable outcomes. A database with nationwide representation was utilized to examine the outcomes of hospitalization in these patients over a 12-year period. Methods: Nationwide Inpatient Sample (NIS) from 2000 to 2011was utilized to extract data for all in-hospital stays of patients with MSCC using ICD-9-CM codes. NIS variables were used to identify in-hospital mortality, discharge dispositions and length of stay (LOS). The usage and timing of radiation therapy and surgical interventions were also identified using ICD-9-M codes. These interventions were defined as ‘early intervention’ if they were provided within the first 48 hours of hospitalization. Multivariable logistic regression was used to examine the factors associated with delays in ‘early intervention’. We also examined whether delays in treatment led to worse outcomes in terms of mortality and morbidity. Chi square test and Wilcoxon rank test were used to compare categorical and continuous variables respectively. Results: 13,457 patients were admitted with MSCC from 2000 to 2011 who received one or more modalities of treatment. Of these, 5035 (37%) received early intervention. The percent of patients receiving early intervention has not changed significantly from 2000 to 2011 (p = 0.15). Female gender, private for-profit hospitals and higher co-morbidity index were associated with lower use of early intervention. In-hospital mortality was lower in the early intervention group (5.0% vs. 6.9%, p = 0.04). Patients receiving early intervention were discharged home more often (44.2% vs. 36.4%, p < 0.001) along with lower need of home health services (14.6% vs 18.8%, p = 0.004). The LOS was significantly shorter and hospital charges lower in those who received early intervention (LOS: median 6 days vs. 11 days, p < 0.001) (charges: $34,354 vs $50,062; p < 0.001). Conclusions: The rate of care delivery by early intervention in MSCC is suboptimal. Early treatment results in lower mortality, shorter length of stay and higher rates of discharges to home along with lower hospital charges and decreased usage of home healthcare.
Patient attitudes towards biobanks and preferences for use of archived biospecimens.
Authors: Jeffrey M. Peppercorn, Nora Horrick, Julia Rabin, Katharine M. Quain, Fay J. Hlubocky, Deborah Collyar, Lecia V. Sequist, Aditya Bardia, Steven J. Isakoff, Eric Campbell, Debra Mathews
Journal: Journal of Clinical Oncology (2018)

e18612 Background: Novel cancer research frequently involves storage of biospecimens for future use. However, ethical questions related to collection, control, and use of stored tissue persist. We sought to understand attitudes and preferences regarding biobanks and archived tissue research among patients with cancer. Methods: We conducted a cross-sectional study among patients presenting for routine cancer care. Survey questions addressed: interest in biobank participation, preferences for stored tissue use, concerns regarding harms to participants, and biobank governance. Differences in response by sociodemographic and clinical characteristics were analyzed with Fisher’s exact test. Results: Among 240 participants (348 approached, response rate 69%), median age was 59y (range 24 to 91), 88% were white, 79% female, 81% college educated, 67% had breast cancer, 30% metastatic disease, 30% prior clinical trial participation and 27% prior tissue donation. Overall, 89% supported use of their tissue for cancer research. Many also supported use of their tissue to study non-cancer diseases (79%), mental health (75%), or addiction (74%). Despite high personal interest in biobanks, only 50% endorsed routine biospecimen collection from all cancer patients. Ethical concerns varied, with 47% supporting use of excess blood/tissue for research without consent while 13% reported concerns with potential harms from storage and use of tissue for research. 28% believed that biospecimens were controlled by the hospital and 40% felt they should control their own tissue after removal. Younger patients ( < 50y) were more likely than older patients to support universal biospecimen collection (73% vs. 45%, p < 0.001) and to believe they should control how their excess blood/tissue is used (58% vs. 37%, p = 0.02). Non-white patients were more concerned with potential harm from biobanks than whites (38% vs. 10%, p < 0.001), and less supportive of using their biospecimens for addiction research (59% vs. 78%, p = 0.06). Conclusions: Biobanking is strongly supported among cancer patients, particularly use of their own biospecimens for research. Concerns about potential harms must be addressed to promote diverse racial/ethnic biobank participation.
Landscape of EGFR-dependent and independent mechanisms of osimertinib resistance in EGFR-mutant NSCLC patients.
Authors: Xiuning Le, Sonam Puri, Marcelo Vailati Negrao, Monique B. Nilsson, Jacqulyne Ponville Robichaux, Theresa A. Boyle, James Kevin Hicks, Emily Roarty, Waree Rinsurongkawong, Bonnie S. Glisson, Jianjun Zhang, Vassiliki Papadimitrakopoulou, Jhanelle Elaine Gray, John Heymach
Journal: Journal of Clinical Oncology (2018)

9087 Background: Osimertinib is a third generation EGFR TKI, however, the mechanisms of resistance to osimertinib have been incompletely described, and there are currently no targeted regimens known to be effective for these patients. We evaluated clinical and genetic characteristics of patients who received osimertinib for EGFR-mutant NSCLC. We also provide treatment experience after progression on osimertinib. Methods: Using the MD Anderson GEMINI database and Moffitt Cancer Center dataset, we identified patients treated with osimertinib and performed clinical outcome analysis. Molecular profiling analysis was performed at the time of progression when available. Results: 118 patients were identified. Median PFS on osimertinib was 8.8 months (95% CI, 6.5 to 11). Overall survival from diagnosis was 76.7 months (95% CI, 42.5 to 111). 71 patients had disease progression. Upon progression, osimertinib was continued in 44 of 71 patients with 21 (48%) received local consolidation radiation. The osimertinib continued patients had longer second PFS compared to the ones discontinued. For patients who progressed on osimertinib, 42 had molecular profiling upon progression. A total of 22 genes/pathways were observed to have recurrent alterations. In addition to two cases with germline T790M, 19 cases retained and 21 cases lost detectable T790M mutation. Among T790M-retained cases, tertiary EGFR mutations of C797S/G and L792H (11 cases) in EGFR gene, and MET amplification (5 cases), were the most common mechanisms of resistance. In T790M-lost cases, PIK3CA mutation (2 cases), MET amplification, and small cell transformation, but not additional EGFR resistance mutations, were observed. Other resistance- associated alterations included FGFR amplification and RET fusion. Preclinical studies verified that osimertinib resistance could be reversed by targeting a subset of these alterations. Conclusions: We found continuation of osimertinib beyond first progression may offer clinical benefit. Osimertinib resistance is associated with diverse mechanisms. The loss of T790M was common, and the majority of resistance was associated with EGFR-independent, as in some cases targetable, mechanisms.
Eradication of soft-tissue sarcoma in a patient-derived orthotopic xenograft (PDOX) model by tumor-targeting Salmonella typhimurium A1-R in combination with doxorubicin.
Authors: Takashi Murakami, Jonathan DeLong, Frederick C. Eilber, Ming Zhao, Yong Zhang, Nan Zhang, Arun S. Singh, Tara Russell, Kuniya Tanaka, Itaru Endo, Robert M. Hoffman
Journal: Journal of Clinical Oncology (2016)

11068 Background: Soft-tissue sarcoma (STS) is a recalcitrant cancer with frequent failures after first-line therapy such as doxorubicin (DOX). More effective therapy and better mouse models to test this therapy are needed. The present study used a patient-derived orthotopic xenograft (PDOX) model of STS to test the combination of tumor-targeting Salmonella typhimurium A1-R in combination with DOX. Methods: A patient undifferentiated pleomorphic STS from the thigh muscle was grown orthotopically in the right biceps femoris muscle of mice to establish a PDOX model. Twenty PDOX mice were divided into 4 groups: G1, control without treatment; G2, Salmonella typhimurium A1-R administered by intratumoral (i.t.) injection once a week for 4 weeks; G3, DOX administered by intraperitoneal (i.p.) injection once a week for 4 weeks; G4, S. typhimurium A1-R (i.t.) administered once a week for 2 weeks followed by i.p. DOX once a week for 2 weeks. Results: On day 25 from the initiation of treatment, tumor volume in G2, G3, and G4 was significantly lower than G1. Mice found without gross tumor included one mouse (20%) in G2; one mouse (20%) in G3; and 3 mice (60%) in G4. Body weight loss did not significantly differ between the 3 treated groups or from the untreated control. Histological examination demonstrated eradication of tumor only in G4 where mice were treated with S. typhimurium A1-R followed by DOX. Conclusions: Our present study indicates future clinical potential of combining S. typhimurium A1-R with first-line chemotherapy such as DOX for patients with metastatic STS.