tbuckley/cabot-search huggingface dataset:
A tale of two cohorts: Patients presenting for endoscopy in Kigali, Rwanda compared to an academic medical center in New Hampshire, U.S.
Authors: Mary D. Chamberlin, Angela Lee
Journal: Journal of Clinical Oncology (2017)

e18057 Background: Gastric cancer is the third leading cause of cancer death worldwide. In Rwanda and East Africs in general, gastric cancer is common in young men and women to the point where the region is known as the "stomach cancer region." Previously reported molecular profiling of Rwandan gastric cancer specimens indicate a lower mutation burden than expected based on historic western-based data; the corresponding database of endoscopy results suggests lsrge differences in access to care. This study compares a US endoscopy database to one from the University of Rwanda, to highlight the disparities of care in low and middle income countries (LMIC’s) compared to higher income countries. Methods: Retrospective pathology, demographic and radiographic data was collected from 164 Rwandan patients who presented for endoscopy at the Kigali University Teaching Hospital and compared with a matching cohort of patients at Dartmouth-Hitchcock Medical Center , Lebanon, NH (DHMC). Results: Approximately 85% of the Rwandan endoscopy cohort presented with gastric cancer, whereas none was seen in the DHMC cohort; the latter group was older than the Rwandan cohort (62.3 vs. 58.6 years). The most common indication for endoscopy among the DHMC cohort was gastroesophageal reflux disease (GERD) or anemia (72%) while the Rwandan cohort most commonly presented with pain or vomiting (68%). A matched US gastric cancer cohort revealed that 63% of US cases of gastric cancer receive treatment with curative intent compared to 7.4% of Rwandan cases. Conclusions: The Rwandan cohort presented with more severe symptoms and was more likely to be diagnosed with gastric cancer than the DHMC patients yet less likely to receive treatment with curative intent. These results highlight the disparities of care in LMIC’s and the need for improving access to early detection and curative treatments.
Clinical validity of electric field induced release and measurement (EFIRM) for <i>KRAS</i> mutation detection in circulating DNA associated with pancreatic ductal adenocarcinoma.
Authors: David T. Wong, Jason Hieu Tang, Wooil Kwon, Moonsoo Park, Xiaoqian Wang, Karolina Kaczor-Urbanowicz, Michael Tu, Fang Wei, Jin-Seok Heo, David Chia, Yong Kim
Journal: Journal of Clinical Oncology (2016)

e15702 Background: Incidence of pancreatic cancer has been significantly increasing over the years and likely to become 2nd most common cause of caner death as early as 2020. One of main reasons for the high mortality rate of pancreatic cancer is the lack of sensitive and specific tools to detect in early stages. Developing an effective and credible assay platform will fill an unmet need in cancer screening and early detection. We have recently demonstrated, in two blinded independent clinical studies, the clinical utility and performance of Electric Field Induced Release and Measurement (EFIRM)-based detection of actionable EGFR mutations in plasma and saliva from non-small cell lung carcinoma (NSCLC) patients with near 100% concordance with tissue biopsy-based genotyping. We hypothesize this novel and biopsy-concordant technology is translatable to the detection/risk assessment of pancreatic ductal adenocarcinoma (PDAC). Methods: We have developed EFIRM probes for the top four KRAS mutations (G12D, G12V, G12R and G12C with > 90% frequency in total) associated with PDAC. Detection efficiency of probes for mutated KRAS was verified and optimized and subsequently tested with genomic DNA harboring a respective mutation. Results: EFIRM KRAS probes were designed and efficiency in detecting a single base KRAS mutation was optimized by utilizing synthetic oligo DNAs. Specificity and sensitivity has been further optimized by hybridization conditions, particularly by applying different electric potentials. EFIRM KRAS mutation assay efficiently differentiated a single point KRAS mutation from a wild type in sheared cellular genomic DNA harboring each of the four KRAS mutations. EFIRM is a novel detection platform ready for clinical verification to detect KRAS mutations in resectable PDAC plasma/serum samples with matched tissues. Conclusions: We have developed novel EFIRM cell free DNA KRAS assays that has a promising clinical utility as a credible, sensitive and noninvasive clinical tool in screening the patients for endoscopic evaluation and for potential prognostic/management of PDAC.
VariantPlex panel to detect genomic aberrations in oncology patients with rare cancer type.
Authors: Su Jin Lee, Kyung Kim, Kyoung-Mee Kim, So Young Kang, Seung Tae Kim, Se Hoon Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Joon Oh Park, Jeeyun Lee
Journal: Journal of Clinical Oncology (2018)

e24234 Background: The purpose of the clinical sequencing project for refractory cancer patients was to route oncology patients to available biomarker-driven clinical trials. Here we focus on the sequencing results of the oncology patients with rare cancer type. Methods: From February 2017 through December 2017, 62 patients with rare cancers consented to participate in the clinical sequencing project at Samsung Medical Center (NCT#02593578). Of these patients, 59 passed the quality control process for the NGS-based targeted sequencing assay to detect copy number variations (CNVs), single nucleotide variations (SNVs), insertion and deletion (indels) in 31 cancer-implicated genes (Archer VariantPlex). Results: The median age of these patients was 55 years (range; 21-75 years) and male to female ratio was 29:33. Various cancer types were included in this study; 38 soft tissue sarcoma, 5 ovarian cancer, 4 melanoma, 4 brain tumor, 2 bone sarcoma, 2 uterine cervix cancer, 2 mesothelioma, 2 adenoid cystic carcinoma, 1 pheochromocytoma, 1 melanocytic schwannoma and 1 trichilemmal carcinoma. KRAS hotspot mutation was observed in 5 samples and PIK3CA mutation was in 3 samples. As for CNVs, copy number gain of ERBB2 was most frequently observed in 5 samples followed by MDM2 (N = 3), PDGFRα (N = 2) and STK11 (N = 2). Conclusions: Our study describes a single-center experience with targeted NGS for patients with rare cancer. VariantPlex was a feasible panel for detecting somatic mutations and CNVs in oncology patients. Clinical trial information: 02593578.
Efficacy and safety of apatinib in advanced soft tissue sarcoma: A multi-center, open-label phase II clinical trial.
Authors: Wenxi Yu, Zhengfu Fan, Jing Chen, Hong-Mei Zhang, Xing Zhang, Guofan Qu, Yong Chen, Gang Huang, Yang Yao
Journal: Journal of Clinical Oncology (2018)

11546 Background: Soft tissue sarcomas (STSs) are a heterogeneous group of mesenchymal tumors, accounting for < 1% of all adult malignancies. Although surgery combined with radiation results in high local control rates in localized STSs, high-risk patients (pts) have only 50% 5-year survival. Moreover, chemotherapy has been shown to be lack of consistent overall survival benefit in clinical trials. The vascular endothelial growth factor (VEGF) signaling mediated tumor growth plays an important role in the pathogenesis of several STSs subgroups. This study aimed to explore the efficacy and safety of apatinib, an oral tyrosine kinase inhibitor targeting VEFGR-2, in pts with advanced STS after failure of prior chemotherapy preliminarily. Methods: This is a prospective, open-label, single-arm, multi-center phase II study, with planned sample size of 53. All pts with histologically confirmed STSs experienced failure of prior chemotherapy in the last 6 months. Oral apatinib (500 mg) was given to pts daily in cycles of 28 days until disease progression, death or unacceptable toxicity. The primary outcome was 6-month progression-free survival (PFS) rate. Results: 35 pts were enrolled as of January 16, 2018. The top 3 subtypes of STSs were alveolar soft tissue sarcoma (20%), leiomyosarcoma (17%) and liposarcoma (12%). The 6-month PFS rate was not reached. Of 35 pts, 23 were available for response evaluation: 6 achieved partial response, 15 had stable disease, and 2 had progressive disease, resulting in an overall response rate of 26.1% and a disease control rate of 91.3%, at primary response. 33 pts were eligible for safety evaluation. The incidence of adverse events (AEs) was 93.9%. The most common AEs were hypertension (63.6%), proteinuria (60.6%), and hand-foot syndrome (54.6%). The incidence of Grade 3-4 AEs was 42.2%, and hypertension (30.0%) was the most common Grade 3-4 AEs. Conclusions: Current results demonstrated encouraging signs of anti-tumor activity, and well-tolerated toxicity of apatinib in previously treated advanced STSs. Clinical trial information: NCT03064243.
The clinical significance of the detection of chemotherapy drug sensitivity in patients with osteosarcoma and soft tissue sarcoma.
Authors: Qianrong Wang, Xiaowen Wang, Lei Wen, Jing Zhang, Jingyue Yang, Yan Chen, Hong-Mei Zhang
Journal: Journal of Clinical Oncology (2018)

e23505 Background: Osteosarcoma and soft tissue sarcoma have low sensitivity to chemotherapy and are prone to recurrence and metastasis. In order to improve the efficacy of chemotherapy, we decided to investigate the expression of drug sensitive indicator genes in tumor tissue of patients. By analyzing the association between target gene expression and drug sensitivity results, we may establish a more accurate and effective chemotherapy guidance for clinical practice. Methods: This study included 20 patients with osteosarcoma and 36 patients with soft tissue sarcoma who were treated in the Department of Clinical Oncology of Xijing hospital from October 2014 to June 2016. Half of the patients from each tumor group received drug sensitivity test using liquid chip technology in tumor tissue specimens to predict genes indicating chemotherapy drug sensitivity (including platinum sensitivity index of ERCC1 and BRCA1; drug sensitivity index of TYMS and RRM1 for fluorine, pemetrexed, capecitabine and gemcitabine; docetaxel sensitivity index of TUBB3 and STMN1; etoposide and anthracycline sensitivity index of TOP2A). The patients were followed up to May 2017.Disease or progression free survival (DFS/PFS) was recorded after the application of the sensitive drugs. Results: Among 20 patients with osteosarcoma and 36 patients with soft tissue sarcomas, there is no difference in age, stage and tumor primary site between drug sensitivity test group and routine group(P > 0.05). In Osteosarcoma, DFS in drug sensitivity group was significantly higher than that in routine group (8.0±2.18 months and 4.0±1.31 months, P = 0.032). However, for soft tissue sarcomas, there is no statistical difference between the drug sensitivity group and routine group in DFS/PFS (13.0±2.64 months and 14±2.39 months respectively, P = 0.839). Conclusions: From the “one size fits all” treatment strategy to personalized precision medicine, it requires new strategies to predict drug sensitivity in individual. The drug sensitivity testwith gene expression profiling can provide an effective approach to improve the chemotherapeutic efficacy for mesenchymal malignant tumors, especially for osteosarcoma.
Profiling cancer-related needs and the role of physical, practical and psychological difficulties: A latent class analysis approach.
Authors: Alessandro Rossi, Maria Marconi, Stefania Mannarini, India Minelli, Chiara Rossini, Raffaella Morena, Giuseppe Di Lucca, Claudio Verusio
Journal: Journal of Clinical Oncology (2018)

e22161 Background: There was an increasing attention to the humanization of oncological cares that focused on patients’ needs – which have a strong impact on quality of life. Cancer-related needs seem to be related both to physical, practical and psychological difficulties as well as gender and age. Using a Latent Class Analysis (LCA) the aim of the study was to identify a latent structure accounting for the covariance between cancer-related needs. A one-factor model with two classes was hypothesized, which comprised needs as indicators and difficulties as external variables that moderate the latent structure. Methods: Patients (N = 171, 50.3% female, mean age = 64.6, SD = 12.7) were enrolled at the Department of Medical Oncology, “Presidio Ospedaliero” of Saronno, ASST Valle Olona, Italy. Using a standardized checklist patients were tested for physical issues, practical problems and distress (Psychological Distress Inventory: PDI; α = .88). Then, patients were tested with the Need Evaluation Questionnaire (NEQ) measuring: (A) communicative (α = .78) and (B) relational needs (α = .74); needs of information related to (C) the diagnosis (α = .72) and (D) treatments (α = .70). Results: A CFA was performed to confirm the original factorial structure of the NEQ (RMSEA = .059; CFI = .913) and the PDI (RMSEA = 0.72; CFI = .902). Then, the LCA (5000 bootstrap) shows the goodness-of-model fit [χ2 (6) = 9.06; p = .17; LRχ2 (6) = 10.64; p = .10] and the goodness-of-classification quality [Entropy = .84 ( > .7); Average-Latent-Class-Assignment-Probability: .950 and .964 for Class1 and Class2, respectively]. The LCA identified a latent variable with two classes (VLMR = 161.33; p < .001; Class1 = .54%; Class2 = .46%). In addition, interactions with the latent variable were found only for distress (β = .892; p = .019), practical (β = 1.26; p = .010) and physical (β = .983; p = .012) issues. Conclusions: These results provide a better understand of cancer-related needs: each class represents a specific “profile” that are moderated by physical, practical and psychological difficulties. These findings suggest paying more attention to the specific need expressed by the patient proposing new ways to improve quality of life.
P04.46 Variable RNA sequencing depth impacts gene signatures and target compound robustness - case study examining brain tumour (glioma) disease progression
Authors: A Stupnikov, C E McInerney, P G O’Reilly, A C Roddy, P D Dunne, A Gilmore, K Savage, S A McIntosh, T Flannery, E Healy, H P Ellis, K M Kurian, F Emmert-Streib, K M Prise, M Salto-Tellez, D G McArt
Journal: Neuro-Oncology (2018)

Gene expression profiling can uncover biological mechanisms underlying disease and is important in drug development. RNA-seq is routinely used to assess gene expression but costs remain high. Sample multiplexing reduces RNA-seq costs, however, multiplexed samples have lower cDNA sequencing depth, which can hinder accurate differential gene expression detection. The impact of sequencing depth alteration on RNA-seq-based downstream analyses such as gene expression connectivity mapping is not known, where connectivity mapping can be used to identify potential therapeutic compounds for repurposing. In this study, published RNA-seq profiles from brain tumour (glioma) patients were assembled into two disease progression gene signature contrasts for astrocytoma. Available treatments for glioma have limited effectiveness rendering this a disease of poor clinical outcome. Gene signatures were subsampled to simulate sequencing alterations and analysed in connectivity mapping to investigate target compound robustness. Data loss to gene signatures led to the loss, gain and consistent identification of significant connections. The most accurate gene signature contrast with consistent patient gene expression profiles was more resilient to data loss and identified robust target compounds. Target compounds lost included candidate compounds of potential clinical utility in glioma (e.g. Suramin, Dasatinib). Lost connections may have been linked to low abundance genes in the gene signature that closely characterised the disease phenotype. Consistently identified connections may have been related to highly expressed abundant genes that were ever-present in gene signatures, despite data reductions. Potential noise surrounding findings included false positive connections that were gained as a result of gene signature modification with data loss. Findings highlight the necessity for gene signature accuracy for connectivity mapping, which should improve the clinical utility of future target compound discoveries.
Failure rate of standard rescue with leucovorin for high-dose methotrexate (HDMTX) in osteosarcoma.
Authors: Mikael Eriksson, Magdalena Rychlowska-Pruszynska, Mónika Csóka, Kirsten Sundby Hall, Jonas Karlén, Louise Kvistgaard, Pia Lisjö, Karin Ganlöv
Journal: Journal of Clinical Oncology (2017)

11028 Background: HDMTX followed by leucovorin rescue is well established as part of MAP chemotherapy for osteosarcoma. However, leucovorin rescue is not always effective as rescue, resulting in delays to subsequent courses of chemotherapy. Methods: This retrospective observational study involved patients ≥2 years of age with osteosarcoma treated with MAP during 2009 - 2014. Data was extracted from medical records from five clinics in Poland, Hungary, Norway and Sweden. The study objective was to determine to what extent patients treated with MAP encountered treatment delays due to MTX-related toxicity or delayed MTX elimination. Results: All patients fulfilling the inclusion criteria were included. Of 116 patients (ages 5-39 with a mean of 14 years; 59% males), 97% completed their first MAP cycle while only 48% completed six treatment cycles. The analysis of the primary endpoint included 114 evaluable patients. At least one treatment delay due to MTX toxicity or delayed MTX elimination was reported for 89 patients (78%) and only six patients (5%) completed the entire MAP treatment according to plan. Delay in subsequent treatment was observed following 183 of 369 evaluated MAP cycles (50%). About three quarters of the delays were found to be due to MTX-related toxicity while only a small number were related to delayed MTX elimination. The treatment related issues most commonly registered were increased liver enzymes, hematological disturbances, increased bilirubin and mucositis. Conclusions: We found at least one treatment delay due to MTX toxicity or delayed MTX elimination in 78% of all MAP-treated patients and that 50% of the administered MAP cycles resulted in a delay in subsequent treatment, mostly due to MTX toxicity. Only six patients (5%) completed the entire MAP treatment according to plan. The retrospective methodology with broad inclusion criteria implies that the results can be extrapolated to the entire target population. Thus, there appears to be an unmet need for a more effective HDMTX rescue that could reduce MTX toxicity and be expected to enable more patients to maintain planned MAP treatment intensity and duration, thereby improving the overall efficacy of the MAP regimen.
Matched pairs analysis of hematopoietic stem cell transplantation in acute leukemia patients treated with fludarabine and melphalan with or without total-marrow-lymphoid irradiation.
Authors: Lindsay Jensen, Tracey Stiller, Jeffrey Y.C. Wong, Tanya Paris, Joycelynne Palmer, Joseph Rosenthal
Journal: Journal of Clinical Oncology (2016)

e18507 Background: Reduced intensity conditioning regimens (RIC) for hematopoietic stem cell transplantation (HCT) can reduce morbidity and mortality, but patients with advanced disease may require alternate approaches. In a previous report of RIC (Fludarabine (FLU) and Melphalan (MEL)) with total-marrow-lymphoid irradiation (TMLI) in HCT for advanced hematological malignancies, we found the addition of TMLI to RIC was feasible and safe. Here we compare outcomes of patients treated with RIC with or without TMLI. Methods: The matched pair analysis included 50 patients treated with TMLI to a dose of 12 Gy (1.5 Gy BID x 4 days), FLU (25 mg/m2/d x 5 days), and MEL (140 mg/m2/d x 1 day) (Group 1) and 50 patients treated with FLU/MEL alone (Group 2). Match criteria included: sex, age (±10 years), diagnosis, disease risk, donor type, and material type. Overall survival (OS), event free survival (EFS), relapse/progression rate (RPR) and non-relapse mortality (NRM) were measured from date of HCT. Survival outcomes were analyzed using Kaplan-Meier analysis. Results: Median follow-up was 5.8 years in both groups. The majority of patients had acute myelogenous leukemia (80%), high risk disease (56%), unrelated donors (54%) and were male (52%). Median age was 59 (range: 19-70). There was no difference between the two groups in OS (p = 0.33), EFS (p = 0.49), RPR (p = 0.26) and NRM (p = 0.09). OS at 2 years in Group 1 vs. 2 was 50 (95% CI: 36-63) vs. 59% (44-71). EFS at 2 years was 48 (34-61) vs. 53% (39-66). RPR at 2 years was 16 (7-28) vs. 28% (16-41). NRM at 2 years was 36 (23-49) vs.18% (9-30). The most common types of grade ≥ 3 toxicity were mucositis and infection, but this was not statistically significantly different between groups (Table 1, p > 0.1). Conclusions: TMLI/FLU/MEL patients had similar outcomes to patients treated with FLU/MEL alone, with comparable toxicity. Dose escalation of TMLI or other modification may be required to improve disease control. CTCAE Toxicity Bearman Toxicity Mucositis Infection Bladder CNS Cardiac GI Hepatic Pulmonary Renal Stomatitis Grade 3 4 5 3 4 5 3 3 3 3 3 3 3 3 Group 1 (n) 17 0 0 13 2 3 1 0 2 4 0 2 5 0 Group 2 (n) 10 1 0 21 3 1 0 0 0 1 0 1 2 1
Risk and types of secondary primary malignancies in DLBCL survivors changes over time based on stage at diagnosis.
Authors: Ajay Major, Derek Smith, Debashis Ghosh, Rachel Rabinovitch, Bradley Haverkos, Manali K. Kamdar
Journal: Journal of Clinical Oncology (2018)

e19540 Background: Previous studies have shown increased risk of second primary malignancies (SPM) after DLBCL treatment. Risk factors for and types of SPM that occur, stratified by stage of DLBCL at diagnosis, have not been previously described. Methods: The Surveillance, Epidemiology, and End Results database was queried for patients (pts) aged > 18 years (y) with primary DLBCL from 1973-2010 and categorized by early-stage (1-2; ES) or advanced-stage (3-4; AS). Differences in overall and location-specific SPM incidence by stage and time since diagnosis were assessed in 5-year intervals by Fine-Gray hazards model. Logistic regression was used to assess differences in cause of death. Overall survival (OS) was compared by log-rank test. All models were adjusted for age, race, sex and diagnosis in the post-rituximab era after 2001. Results: We identified 26,038 DLBCL pts, 14,724 with ES and 11,314 with AS disease. Median follow-up was 6y (IQR 1.6-11.4y). Median age was 63. Overall 14.9% of pts developed SPM. Cumulative 5, 10 and 15y incidence of SPM for ES/AS was 6.6%/6.0%, 11.0%/9.8%, and 14.7%/13.3%, respectively. Over the entire study period, SPM incidence was not significantly different between ES and AS (p = .14). However, in 0-5y period after diagnosis, ES had higher risk of SPM than AS, specifically colorectal, pancreas, breast and prostate SPM. In 5-10y period, there was no overall difference in SPM risk by stage, although AS pts had significantly higher risk of hematologic SPM. In 10-15y period, AS had higher risk of SPM than ES, specifically hematologic SPM. In > 15y period, there was no difference in SPM risk by stage. There was no difference in odds of developing SPM between pts who died of cancer and pts who were still alive or died from non-cancer causes. OS was significantly higher in ES than AS (p < .0001) regardless of pre- or post-rituximab era. Conclusions: In this large population-based study of risk and types of SPM in DLBCL, ES pts were more likely to develop SPM in first 5y, and AS pts were more likely to develop SPM 10-15y after diagnosis. We identified distinctly different types of SPM based on stage of DLBCL. Our study merits site-specific surveillance for DLBCL pts according to stage and time since diagnosis.