tbuckley/cabot-search huggingface dataset:
Somatic tumor profiling of DNA mismatch repair deficient (MMR-D) colorectal cancers (CRC).
Authors: Karuna Ganesh, Sumit Middha, Jaclyn Frances Hechtman, Asad Ashraf, Christina Tran, Danylo Villano, Rona D. Yaeger, Neil Howard Segal, Andrea Cercek, Anna M. Varghese, Diane Lauren Reidy, Nancy E. Kemeny, Joseph Vijai, Mark E. Robson, Kenneth Offit, David B. Solit, Leonard Saltz, Michael F. Berger, Jinru Shia, Zsofia Kinga Stadler
Journal: Journal of Clinical Oncology (2016)

1528 Background: MMR-D in CRC may be caused by a somatic event, characterized by presence of BRAF V600E/MLH1-promoter hypermethylation (BRAF/HM+), or by a germline mutation in an MMR gene, diagnostic of Lynch syndrome (LS). In patients with Lynch-like syndrome (LLS), the etiology of the MMR-D remains unclear (LS germline-, BRAF/HM-) and these patients receive LS cancer screening recommendations. We sought to determine whether somatic tumor profiling of 1) BRAF/HM+, 2) LS and 3) LLS tumors may illuminate inherent biologic differences among MMR-D CRCs. Methods: We sequenced 410 genes in tumor and normal samples of 53 MMR-D patients who had undergone germline evaluation. Somatic mutation profiles were compared among subgroups. Results: Among 15 BRAF/HM+, 25 LS and 13 LLS cases, mean numbers of mutations were equivalent. Comparison of BRAF/HM+ and LS cases revealed differentially mutated genes with LS cases more frequently mutated in APC (80% vs 27%, p = 0.009), KRAS (60% vs 13%, p = 0.004) and MSH6 (36% vs 7%, p = 0.04). BRAF/HM+ cases were more frequently mutated in NOTCH3 (73% vs 32%, p = 0.01), GRIN2A (47% vs 12%, p = 0.01), MTOR (47% vs 16%, p = 0.04), PTPRD (47% vs 16%, p = 0.04), and ERBB4 (40% vs 16%, p = 0.04). Among LLS cases, 54% had > 1 somatic inactivating mutations in the gene corresponding to the immunohistochemical MMR defect, suggesting MMR-D was an acquired event. These tumors had infrequent APC and KRAS mutations, similar to BRAF/HM+ tumors. In the unexplained LLS cases, we found frequent mutations in chromatin remodeling genes (ARID1A, 83%; CREBBP, 50%; CTCF, 50%; KMT2C, 50%; KMT2D, 50%; MED12, 29%); PIK3CA hotspots (67%) and PTEN inactivation (67%), where mutation patterns suggested that these genetic aberrations may have arisen independently of microsatellite instability. Conclusions: MMR-D tumors have distinct mutation profiles depending on their molecular etiology. The LLS subgroup may be divided into those similar to the BRAF/HM+ group, and a unique LLS group consisting of tumors with increased mutation frequency in chromatin modifiers and PI3K signaling components. Improved molecular characterization may impact cancer screening recommendations, especially for LLS, where LS cancer screening may not always be necessary.
Chemotherapy tolerance and oncologic outcomes in colorectal cancer (CRC) patients with and without inflammatory bowel disease (IBD).
Authors: Celina Ang, Umut Ozbek, Anuja Kriplani, Jordan Axelrad, Noam Harpaz, Jean-Frederic Colombel, Stephen H. Itzkowitz, Randall F. Holcombe
Journal: Journal of Clinical Oncology (2016)

e15162 Background: IBD (Crohn's disease (CD) and ulcerative colitis (UC)) is a risk factor for CRC. Chemotherapy toxicity may exacerbate IBD symptoms and vice versa but data are limited. Methods: Medical records of CRC patients with and without IBD treated between 2008-2013 were reviewed. Where possible, patients were matched by age, sex, stage and diagnosis year. Chemotherapy tolerance and survival outcomes were compared. Results: Treatment characteristics and outcomes of the 158 patients identified are summarized in the table. Both IBD and non-IBD patients received fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, anti-EGFR agents and regional chemotherapy. Differences in stage-specific 5-year overall survival (OS) and recurrence-free survival (RFS) in IBD vs. non-IBD patients were not significant (NS), except for stage IV non-IBD patients who had significantly improved OS. Chemotherapy modifications were increased in IBD vs. non-IBD patients. Patients with histologically active IBD did not require more modifications than patients with inactive IBD. Conclusions: In this series, CRC patients with IBD experienced more treatment modifications (mostly delays) than those without IBD. IBD patients with stage IV CRC had shorter survival than non-IBD patients. These results must be interpreted cautiously given the retrospective nature of this review and relatively small sample size. IBD (N = 80; 25 CD, 55 UC) Non-IBD (N = 78) p- value Median age CRC diagnosis (range) 54 yrs (24-92) 57 yrs (27-93) NS Male/Female 48 (60%)/32 (40%) 47 (60%)/31 (40%) NS Histologically active IBD (yes/no/unknown) 51 (64%)/20 (25%)/9 (11%) CRC stage (I/II/III/IV/ unknown) 29 (36%)/17 (21%)/20 (25%)/ 12 (15%)/2 (3%) 24 (31%)/17 (22%)/24 (31%)/ 12 (15%)/1 (1%) NS Surgery 74 (93%) 75 (96%) NS Radiotherapy 13 (31%) 11 (26%) NS Chemotherapy 43 (70%) 40 (68%) NS 5-yr OS (I/II/III) IV 88%/83%/41% 19% 100%/100%/75% 50% NS 0.017 5-yr RFS (I/II/III) 89%/59%/60% 81%/83%/38% NS Chemotherapy modifications for toxicity N = 43 N = 40 Delay 8 (19%) 4 (10%) Discontinuation 7 (16%) 8 (20%) Hospitalization 6 (14%) 5 (13%) Known modification (yes/no) N = 31 23 (74%)/8 (26%) N = 27 12 (44%)/15 (56%) 0.03
Research on the diversity of T cell receptor repertoire in the process of malignant transformation of HBV chronic infection.
Authors: Henghui Zhang, Yanhui Chen, Guoli Li, Hui Zeng, Hongsong Chen
Journal: Journal of Clinical Oncology (2017)

e23086 Background: The progression of liver inflammation resulted from HBV infection is the main cause of HBV-related liver cancer. T cells play a central role in anti-HBV and anti-tumor specific immune response during disease progression, and the T cell receptor (TCR) repertoire can quantitatively reflect the immune function of T cells. The accurate information of TCR repertoire change in the progression from chronic hepatitis B to tumor was obtained in this study. Methods: CD4 + T cells from the spleens of mice and CD8 + T cells from 50ml peripheral blood of the patients with chronic hepatitis B and liver cancer were sorted by flow cytometry for establishing next generation sequencing (NGS) and the related bioinformatics research system of TCR repertoire. The sequence in V region of TCR was amplified bu using 5 'RACE technology with the mRNA as template. The sequences of TCRα and TCRβ were determined by the NGS technology, and the sequence data with 6Gb were obtained for each chain of each individual. Results: Acoording to analysis of TCR repertoire in mouse CD4 + T cells, the V-J pairing and diversity of CDR3 sequence in TCRβ were higher than TCRα; With the increasing of the recombination number in D gene fragments in the TCRβ chain, a higher diversity of V-J pairing could be introduced in TCRβ.Acoording to analysis of TCR repertoire in human CD8 + T cells, the effects of chronic hepatitis and HCC condition on the overall diversity of TCR receptor repertoire were not significant; The level of receptor repertoire in patients with chronic hepatitis and HCC showed major difference only at the level of low frequency ratio compared with healthy volunteers; the distinctive V-J paring and CDR3 could be detected in the group of patients with chronic hepatitis and HCC based on the above TCR clone at the level of low frequency. Conclusions: NGS sequencing and the related bioinformatics research system of mouse and human TCR repertoire were established. The level of receptor repertoire in patients with chronic hepatitis and HCC showed major difference only at the level of low frequency ratio compared with healthy volunteers.
Redirected T cell lysis in patients with metastatic uveal melanoma with gp100-directed TCR IMCgp100: Overall survival findings.
Authors: Takami Sato, Paul D. Nathan, Leonel Hernandez-Aya, Joseph J Sacco, Marlana M. Orloff, Jennifer Visich, Nicola Little, Ann-Marie Hulstine, Christina Marie Coughlin, Richard D. Carvajal
Journal: Journal of Clinical Oncology (2018)

9521 Background: IMCgp100 is a bispecific biologic comprised of a soluble T cell receptor recognizing the gp100 antigen fused to a scFV anti-CD3 and redirects T cell lysis of melanoma cells expressing gp100. Safety and preliminary efficacy of IMCgp100 were assessed in a Ph 1/2 study in metastatic UM (mUM). Methods: HLA-A*0201+ pts with mUM were treated with QW dosing of IMCgp100 iv at Cycle 1, Day 1 (C1D1, 20 mcg) and C1D8 (30 mcg), followed by the escalated dose administered at C1D15 and beyond. Results: Pts with mUM (n = 19), elevated LDH (87%), liver metastases (100%), and median of 4 prior therapies (0 – 8) were treated across 4 doses (54 to 73 mcg) in Ph 1; 23 pts were treated in the Ph 2 RP2D (68 mcg) expansion cohort. Related AE included pruritus (90%), pyrexia and fatigue (84%), and hypotension (74%). Gr 3/4 related AE include AST elevation, erythema and hypotension (all, 16%). Ten of the 19 pts in Ph 1 were treated at or above the RP2D. Objective PR by RECIST in Ph 1 were observed in 2 pts and minor responses in 4 pts (6/19 responses); median duration of response was 30.6 wk. One year PFS rate by irRC was 66% (95% CI [39, 83]). One year OS rate in Ph 1 was 74% (95% CI [48, 88]). Median OS in this cohort has not been reached (median follow up of 15.9 mo). The PKPD relationship of exposure was modeled with extent and duration of lymphocyte trafficking. The EC50 for lymphocyte extravasation to the periphery was estimated at 1.4 ng/mL. At high doses, maximal trafficking of 50% was observed compared to baseline. The extent of lymphocyte trafficking is saturable, however the duration was dose dependent. The EC90 represents the dose of 70 mcg, supporting the RP2D. In the full cohort (n = 42), rash of Gr ≥2 within the first 3 weeks of dosing is associated with prolonged OS when compared to pts with mild (G1) or no occurrence of rash (HR 0.122, 95% CI [0.03, 0.45], p = 0.0015). Conclusions: IMCgp100 is tolerable with the intra-patient escalation dosing regimen and leads to prolonged OS. A potential association of prolonged OS with rash severity was observed. PKPD modeling demonstrates a relationship between lymphocyte trafficking and exposure to IMCgp100. Pivotal trials in the setting of metastatic UM continue to enroll (NCT03070392, NCT02570308). Clinical trial information: NCT02570308.
Development of a novel algorithm to identify staging and lines of therapy for bladder cancer.
Authors: Clint Cary, Anna Roberts, Abby K Church, George Eckert, Fangqian Ouyang, Jinghua He, David A Haggstrom
Journal: Journal of Clinical Oncology (2017)

e18235 Background: Large automated electronic medical record (EMR) databases have the potential to be valuable tools in studying the patterns and effectiveness of treatment. Therefore, the current study sought to develop novel tools to identify bladder cancer cases, their clinical stage, and the chemotherapy they receive in electronic medical records. Methods: EMR data were obtained from Indiana University Health hospitals from 2008 to 2015. We developed 2 novel algorithms using natural language processing on unstructured data to identify (a) bladder cancer cases and clinical stage, and (b) chemotherapy names and line of chemotherapy. Performance characteristics for each algorithm were assessed using sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Each algorithm’s performance for case ascertainment was measured against the gold standard of manual chart review. Results: A total of 2,559 unique bladder cancer patients were identified and stratified using the clinical staging algorithm, defined as metastatic, muscle invasive, or non-muscle invasive. We identified 657 metastatic cases, 567 muscle invasive cases, and 604 non-muscle invasive cases. Next, the treatment algorithm was applied to metastatic patients to identify the type of chemotherapy received and 1 st or 2 nd line of therapy. The sensitivity, specificity, PPV, and NPV for the clinical staging and treatment algorithm were calculated against the gold standard of manual chart review (Table). Conclusions: The performance of the staging algorithm demonstrates the strength of using innovative approaches. The poor performance of the treatment algorithm sets a framework from which to build upon in future work and suggests that structured approaches may still be the preferable approach. [Table: see text]
Clinical and molecular characteristics of NF1 mutations identified on hereditary cancer multi-gene panels.
Authors: Anton Mikhailovich Safonov, Virginia Speare, Jill S. Dolinsky, Amal Yussuf, Chia-Ling Gau, Katherine Nathanson
Journal: Journal of Clinical Oncology (2018)

e13612 Background: Somatic mutations to the NF1 gene have been shown to play a role in several tumor types. Evaluation of patients with Neurofibromatosis type 1 (NF1) has led to the longstanding clinical observation of a high rate of somatic mosaicism in NF1. We explored the clinical and genetic features of patients with NF1 mutations identified through cancer susceptibility testing. Methods: Results from a cohort of 118,768 patients who underwent multigene panel testing (MGPT) were queried to identify probands with a NF1 pathogenic/ likely pathogenic variant. Next generation sequencing was performed on panels of 2-67 hereditary cancer genes. Review of test requisition forms and available clinical history/pedigree was performed. NF1 cases were defined by concordance with NIH criteria. Additionally, we used a biphasic distribution to define a cutoff, dividing non-NF cases into normal and low variant allele frequency (VAF). Results: 158 total patients were identified; 89 patients had a reported clinical diagnosis of NF1; 69 had a mutation in NF1 but not reported as having NF1. Of the latter category, 2 Patients reported as having NF1 were diagnosed with cancer earlier (45.5 vs 54.8 years, p = 6.9 x 10^ - 5), without statistically significant difference in number or cancer type. However, sarcoma (p = 0.20), and ER+ breast cancer (OR 2.64, p = 0.08) approached significance as more common in patients with NF1. Patients with low VAF were diagnosed with cancer earlier (49.7 vs 58.9 yrs, p = 0.02). Mutations in other cancer susceptibility genes were present in 4.4% of clinical NF1 and 11.5% of NF1 mutation only cases; 75% of the latter category patients met NCCN 2016 family history guidelines for BRCA testing. Conclusions: Low VAF of the NF1 gene could result from somatic mosaicism, circulating tumor, or clonal hematopoiesis of indeterminant potential (CHIP). Our data show that patients with low VAF are diagnosed with cancer earlier, meaning that the observed low VAF is unlikely to be associated with CHIP, and more likely due to true somatic mosaicism. Additionally, our data suggests that the marginal utility of MPGT in breast cancer patients with clinically diagnosed NF may be low.
Adaptive dynamic artificial poly-ligand targeting (ADAPT) of low-abundance exosome-associated proteins in blood plasma.
Authors: Valeriy Domenyuk, Zhenyu Zhong, Adam Stark, Xixi Wei, Patrick Kennedy, Brandon Toussaint, Radhika Santhanam, Symon Levenberg, Heather A. O'Neill, Teresa T. Tinder, Janet E. Duncan, Andrew William Hunter, Mark Robert Miglarese, David D Halbert, Gunter Mayer, Michael Famulok, David Spetzler
Journal: Journal of Clinical Oncology (2016)

e23070 Background: Tissue biopsies, required for definitive diagnosis of cancer, are risky and costly. We developed the non-invasive screening method ADAPT (Adaptive Dynamic Artificial Poly-ligand Targeting). Here we report the feasibility of aptamer library enrichment on blood plasma, which is primarily driven by exosome-associated proteins that may serve as biomarkers and drug targets. Methods: ssDNA libraries of ~10^12 oligodeoxynucleotides (ODNs) were enriched for associating with exosomes present in plasma. Specific interactions of enriched libraries and exosomes were evaluated by flow cytometry, NGS, qPCR and LC-MS/MS. Results: To validate the enrichment process is capable of identifying exosome specific ODNs in plasma, we titrated cancer cell line exosomes into human plasma and performed independent enrichments. qPCR and NGS revealed a linear relationship between exosomal input and the number of recovered unique ODNs. We then applied this enrichment scheme to human clinical samples of breast cancer/normal plasma. Flow cytometry showed that the enriched library bound preferentially to human plasma exosomes. Using NGS, this result was confirmed by comparing the binding profile of the enriched library recovered from unfractionated versus exosome depleted plasma from individual patients. Library mediated affinity purification of plasma exosomes and subsequent MS analysis revealed 96 exosome-associated proteins that were not detectable otherwise. Compared to the unenriched library, the breast cancer plasma enriched library showed higher binding to MCF7 breast cancer cells than to HS578Bst normal breast epithelial cells. This result shows that plasma-based enrichment trained the library towards recognizing proteins associated with the malignant phenotype. Conclusions: We have demonstrated that ADAPT applied to human plasma results in the enrichment and identification of ODNs with preferential binding to cancer exosomes. The detection of low-abundance proteins in human plasma suggests that ADAPT may be leveraged for biomarker and drug target identification.
Laparoscopic radical left hemicolectomy: Use of a bursa omentalis approach to ease splenic flexure mobilization.
Authors: Wei Wang, Wei Wang, Wenjun Xiong, Jin Wan
Journal: Journal of Clinical Oncology (2017)

e15071 Background: Laparoscopic splenic flexure mobilization was technically difficult for left colon cancer. This study was aimed to compare the safety and feasibility of laparoscopic radical left hemicolectomy using a bursa omentalis approach (BOA) versus medial-to-lateral approach (MtLA). Methods: BOA was entering the bursa omentalis prior to separating left Toldt’s fascia. We retrospectively analyzed data of 32 cases undergoing laparoscopic radical left hemicolectomy using BOA, matching with using MtLA from January 2013 and October 2016. The matching factors consisted of gender, age, ASA score, BMI, and TNM stage. Data of intraoperative and postoperative characteristics were reviewed. Splenic flexure mobilization time was defined as laparoscopic operation time minus left Toldt’s fascia separating time. Results: There was no significant difference in average time of ambulation, time to first flatus, hospital stay between two groups. The operative time was also similar between two groups (134.2±27.6 min vs 139.4±23.5 min. P = 0.42), but there are significantly shorter splenic flexure mobilization time in BOA group (25.9±12.3 min vs 35.5±22.5 min. P = 0.03). No entry to posterior pancreatic space was recorded in BOA group and 9.4% (3/32) were wrongly entering to posterior pancreatic space when separating left Toldt’s fascia in MtLA group. However, there was no significant difference in intra- or postoperative complication between groups. Conclusions: Our initial results suggest BOA for laparoscopic radical left hemicoletomy may be safe and feasible approach especially for unexperienced surgeons. The main advantages of present approach contain easy to identify pancreas and avoiding wrongly entering posterior pancreatic space when expanding the left Told’s fascia.
Prognostic significance of VEGF-A/VEGF-R and EGF in liver metastasis from colorectal cancer.
Authors: Elena Alekseevna Nikipelova, Oleg I. Kit, Elena Mikhaylovna Frantsiyants, Valeria Bandovkina, Irina V. Kaplieva, Lidia K. Trepitaki, Lyudmila Dmitriyevna Tkalya, Evgeniy N. Kolesnikov, Alexander V. Snezhko, Michail Averkin, Mikhail Anatolievich Kozhushko, Sergey Vladimirovich Sanamyanc, Roman E. Myagkov, Leonid Kharin, Vladimir Trifanov
Journal: Journal of Clinical Oncology (2017)

e15128 Background: Liver metastasis from colorectal cancer dramatically reduces the treatment effectiveness and affects survival. Early detection of metastasis allows increasing the median survival and improving the quality of life of patients. The purpose of the study was to reveal factors significant for the prognosis of liver metastasis from colorectal cancer. Methods: Levels of VEGF-A, VEGF-R and EGF were studied by ELISA in tumors and resection line tissues of 113 patients with colorectal cancer (rectal cancer n = 43, colon cancer n = 70). Results: VEGF-A and VEGF-R levels in all tumors were increased compared to the resection line. VEGF-A levels in 46.5% patients with rectal tumors and in 29% patients with colon tumors were 2.5 times higher than in other patients; the VEGF-A/VEGF-R ratio was 2.9 times higher as well. Besides, these patients showed an increase in EGF levels in tumors by 3.9 times (rectal cancer) and 4.2 times (colon cancer), compared to the resection line. The follow-up demonstrated that the patient cohort developed liver metastases during next 3 months. Conclusions: Neoangiogenesis is activated in rectal and sigmoid tumors, and increasing VEGF-А and EGF contribute to tumor progression and metastasis. The VEGF-A/VEGF-R ratio in tumor tissues in comparison with the resection line value can be a reliable factor for the prognosis of liver metastasis.
The place and role of Skype consultancies among palliative patients and the impact of this type of care on a quality of life, pain, anxiety and depression symptoms assessment in home hospice care patient.
Authors: Anna Kieszkowska-Grudny, Jerzy Jarosz, Zbigniew Kaczmarek, Anna Siwy-Hudowska, Dorota Jasinska
Journal: Journal of Clinical Oncology (2016)

e21512 Background: The increasing number of home hospice pts and their expectations calls for intensified surveillance and monitoring quality of life (QoL). The subject of the study was to define the directions of telemedicine techniques development as a complementary element in of home palliative care. Methods: 252 palliative pts took part in this 2 stages study. In 1st stage, 143 pts (63%F),age 18 to 100 (M = 68,92,SD = 13,53) were interviewed based on a specially designed questionnaire. This stage was to find out needs and barriers to hospice pts in access to telemedicine via Internet or phone. In 2nd stage were 109 pts (56%F),age 38 to 95 (M = 69,36;SD = 11,57). This group was divided to: non-Skype /NSG - with standard palliative consultancies, Skype /SG - with 2 additional Skype consultancies per week based on structured interview. QoL (EORTC-PAL15), pain, anxiety and depression (HADS) were assessed twice, before and after 1month observation (1m). Results: Only ¼ pts were able to use the Internet and 1/10 smartphone apps in daily communication, but 71% pts expected regular contacts with doctors and 61% with other personnel. 64%pts reported that phone consultancies are sufficient enough in regular contact with professionals and no need of the Internet consultancies. There was negative correlation (p < 0,05) with pts age and their confidence to technical solutions and needs to extra contact with the doctor via e-Hospice. The 2nd stage results showed that after 1m overall QoL is higher in SG, and physical functioning (p < 0,05) is worse in NSG. No differences were found in level of anxiety between groups, but in SG higher depression were reported after 1m (p < 0,05). SG felt higher pain in the evening, and strongest and average pain after 1m in comparison to NSG (p < 0,05). Conclusions: However, telemedicine seem to be novel way for delivery high quality health care, and can support better quality of life among palliative pts, it is crucial to create new e-Hospice services in more suitable way, taking into account age, medical conditions, and confidence to use this kind of tool.