tbuckley/cabot-search huggingface dataset:
The role of cellular immunity in the pathogenesis and treatment of patients with primary liver cancer.
Authors: Alexandre Tavartkiladze
Journal: Journal of Clinical Oncology (2016)

e14519 Background: The issues of etiogenesis and pathogenesis of Primary Liver Cancer have not been fully understood so far. The arsenal of medications for treatment of this disease has also been scarce. It is well known that certain percentage of Primary Liver Cancer is caused by Viral Hepatitis (B,C) and intoxication by Alfatoxins, but percentage of Primary Liver Cancer that is not associated with the above factors is not so low. Methods: The goal of our research was to study the results of cellular immunity activation in treatment of advanced cases of Primary Liver Cancer. 22 patients with advanced stages of Primary Liver Cancer which were not associated with viral hepatitis were used for observation. The patients received treatment according to the protocol of Doxorubicin and Cyclophosphamide combined therapy. In order to activate the cellular immunity we utilized Phytohaemagglutinin. The above substance (solution) were given to the patients according to the certain dosage regimen and the previously selected schedule (per os) for 3 months. The control group comprised of 15 patients with the advanced form of liver cancer which received treatment only by Doxorubicin and Cyclophosphamide combined therapy protocol. The values of the cellular immunity were assessed by means of Immuno-cyto-chemical research of blood lymphocytes: CD3+, CD4+ and CD8+ quantitative indicators of the cells. Results: The results of the study have shown that: a) before treatment, the cellular immunity of all the patients was suppressed by equal index; b)in 3 months after treatment, cellular immunity of the observed patients increased by 29% against the control group (p < 0,001). Conclusions: With the results of the study, we can conclude that the activation of cellular immunity plays the essential role in the regimen of the combined therapy of Primary Liver Cancer. In addition, the positively expressed dynamics with the cellular immunity activation during the therapy indicates to the essential role in pathogenesis and its possible etiological role in initiation, promotion and progression of Primary Liver Cancer.
Age-dependent changes in GI physiology and microbiota: time to reconsider?
Authors: Ran An, Ellen Wilms, Ad A M Masclee, Hauke Smidt, Erwin G Zoetendal, Daisy Jonkers
Journal: Gut (2018)

Our life expectancy is increasing, leading to a rise in the ageing population. Ageing is associated with a decline in physiological function and adaptive capacity. Altered GI physiology can affect the amount and types of nutrients digested and absorbed as well as impact the intestinal microbiota. The intestinal microbiota is considered a key player in our health, and a variety of studies have reported that microbiota composition is changing during ageing. Since ageing is associated with a decline in GI function and adaptive capacity, it is crucial to obtain insights into this decline and how this is related to the intestinal microbiota in the elderly. Hence, in this review we focus on age-related changes in GI physiology and function, changes of the intestinal microbiota with ageing and frailty, how these are associated and how intestinal microbiota-targeted interventions may counteract these changes.
Abstract B090: Personalized research: Establishment and characterization of prostate cancer patient-derived organoids and cells
Authors: Katia Anis Cheaito, Ola Hadadeh, Hisham Bahmad, Marwan El-Sabban, Albert El-Hajj, Deborah Mukherji, Wassim Abou-Kheir
Journal: Cancer Research (2018)

Abstract Several attempts have been made to understand the exact mechanisms underlying the pathogenesis of prostate cancer (PC); however, the currently available cancer models fail to recapitulate the heterogeneity of this tumor, its metastasis, and progression to castration-resistant states. Moreover, many drug candidates that succeed in preclinical models fail to deliver a good outcome in clinical trials, resulting in ineffective patient treatment and misused resources. In this aspect, the development of three-dimensional (3D) organoid culture systems has rendered it feasible to recap the convolution of organogenesis in vitro, promoting the generation of novel and more representative cancer models. Thus, the aim of this study is to generate patient-specific 3D organoids and cell lines, then characterize these models to identify potential prognostic biomarkers and treatments for PC while correlating the outcome with the collected clinical parameters. In our study, we are employing the R-spondin-1-based organoids technology to generate PC organoids and primary cell lines derived from fresh normal and tumor tissues of patients undergoing radical prostatectomy. Consequently, molecular characterization of the different patient-derived PC organoids and cell lines will be performed, followed by using this model to assess different classical and in-clinical trials drugs. We succeeded in establishing 21 normal and 18 tumor patient-derived organoids, out of a total of 23 patients, and then propagated the established organoids for up to 6 generations. Interestingly, 2D cells were derived from these organoids using the same culture media and were continuously passaged for up to 20 passages so far (more than 3 months). Our newly patient-derived organoids and cells show a typical epithelial phenotype and express CK8 and CK14 (prostate epithelial markers). To the best of our knowledge, this is the first study to address the establishment of primary PC cell lines from organoids, which will likely lead to a comprehensive understanding of mechanisms exploited in PC. Moreover, molecular characterization of this model when combined with pharmacologic profiles can aid in predicting a patient’s drug response; thus, our study represents an attempt to inaugurate what can possibly lead to personalized treatment of PC. Citation Format: Katia Anis Cheaito, Ola Hadadeh, Hisham Bahmad, Marwan El-Sabban, Albert El-Hajj, Deborah Mukherji, Wassim Abou-Kheir. Personalized research: Establishment and characterization of prostate cancer patient-derived organoids and cells [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B090.
Phase II trial of SOM230 in patients with unresectable hepatocellular carcinoma (HCC).
Authors: Lynn G. Feun, Niramol Savaraj, Medhi Wangpaichitr, Stephen P. Richman, Deukwoo Kwon, Vy Dinh, Paul Martin
Journal: Journal of Clinical Oncology (2016)

e15588 Background: Standard therapy for unresectable HCC is sorafenib which is poorly tolerated by some patients (pts) with modest benefit in disease control rate (DCR). There is no established second line therapy. 40-50 % of HCC have somatostain receptors (SSTR), mainly 2 and 5. Somatostatin analog(octreotide) has been shown to possess antitumor activity both in vitro and in vivo. The antitumor effect is mediated by direct effect through these receptors resulting in growth inhibition and apoptosis. The indirect effects include decreased growth promoting factors such as IGF and growth hormone and antiangiogenesis. The new analog SOM230 has higher affinity to SSTR2,4 and 5 compared to octreotide and hence may have superior antitumor effect. Methods: Major eligibility criteria: KPS > 80,Child-Pugh score < 7 points or less, tumor progression on, intolerance to, or refuse sorafenib, < 3 systemic therapies SOM230 was given at starting dose of 60 mg IM q 28 days. CT/MRI scans q 2 mo. Blood for IGF-1 by ELISA at baseline and post treatment. Results: 26 pts were enrolled; so far 19 are evaluable for response/toxicity. Age range 52-81 (median 65). Sex: males 14 , female 5. Hepatitis B, C or B+C 12 (63%). Prior therapy 18 (95%). Multiple prior therapies 15 (79%) Prior sorafenib 13(68%). No pt stopped treatment due to toxicity and serious toxicity was uncommon(Grade 3 hyperglycemia 2 pts, grade 3 reversible elevation of AST/ALT one pt). For response, 9 pts had minor response/stable disease after 2 cycles and 5 pts had stable disease after 4 cycles. Confirmed DCR was 26%. Time to tumor progression ranged from 1 to 14+ mo (median 3 mo). Decreasing serum levels of IGF1 after SOM230 treatment by 2.5- 16 fold occurred in all patients who had minor response/stable disease . However, levels increased with disease progression. Baseline levels varied from 15 to 129ng/ml. Conclusions: In heavily pretreated patients, SOM230 given as second or third-line therapy showed modest benefit in DCR and accrual is continuing. Future trials may select patients most likely to benefit,such as using pretreatment octreotide image scanning and testing available tumor samples for SSTR expression. Serum IGF-1 levels may be useful in assessing tumor control. Supported by a grant from Novartis Clinical trial information: NCT01639352.
An international phase III randomized, non-inferiority trial comparing 3 vs 6 months of oxaliplatin-based adjuvant chemotherapy for colon cancer: Compliance and safety of the phase III Japanese ACHIEVE trial.
Authors: Tetsuya Eto, Masahito Kotaka, Dai Manaka, Junichi Hasegawa, Akinori Takagane, Masato Nakamura, Takeshi Kato, Yoshinori Munemoto, Fumitaka Nakamura, Hiroyuki Bandou, Hiroki Taniguchi, Makio Gamoh, Manabu Shiozawa, Takeharu Yamanaka, Tsunekazu Mizushima, Junichi Sakamoto, Shigetoyo Saji, Masaki Mori, Atsushi Ohtsu, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2016)

3550 Background: Oxaliplatin/Fluoropyrimidine chemotherapy is an established adjuvant treatment for colon cancer (CC). Neurotoxicity from oxaliplatin is cumulative, dose limiting, and potentially irreversible. The International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project was established to prospectively analyze data from several randomized trials to test whether 3-month (arm 3) of oxaliplatin-based adjuvant (FOLFOX4/ mFOLFOX6 or XELOX) is non-inferior in terms of disease-free survival to 6-month (arm 6) treatment in patients (pts) with stage III CC, with less toxicity. Methods: We present the compliance and safety of the phase III ACHIEVE trial (JFMC47) as one of the IDEA project. Results: From 2012 to 2014, 1,313 patients were randomized from 244 centers and 1,301 (651 in arm 3 and 650 in arm 6) included in the intention-to-treat (ITT) population. Baseline characteristics and proportion of mFOLFOX6 vs XELOX were well balanced (25.0% vs 75.0%). Among the safety population (N = 1,277, 98% of ITT population), there was a treatment-related death. Compliance was higher in arm 3 than in arm 6: treatment completion rate in pts receiving all the planned cycles were 86.3% in arm 3 and 61.4% in arm 6, and consistent higher rate either mFOLFOX6 or XELOX was observed in arm 3 than arm 6 (87.6% vs 69.6% in mFOLFOX6; 85.9% vs 58.7% in XELOX). Therapy was permanently interrupted due to toxicity in 11.5% in arm 3 and 28.7% in arm 6. The overall incidence of grade3-4 toxicity events was 28.7% in arm 3 and 42.8% in arm 6. Grade 2 or higher neuropathy was more frequent in arm 6 than in arm 3: 36.5 % vs 13.6%. However, toxicity events depended on the FU backbone with more grade 3-4 neutropenia on mFOLFOX6 (30.4% vs 12.4%), and more grade 3-4 anorexia (1.9% vs 5.1%) and grade 3-4 diarrhea (1.3% vs 5.5%) on XELOX. Conclusions: Both mFOLFOX6 and XELOX were safe and well tolerated. The grade3-4 main toxicities did vary according to FU backbone. Observed toxicity was significantly higher in the 6-month arm compared to that of the 3-month arm; compliance was lower in the standard 6-month arm. Clinical trial information: UMIN 000008543.
Assessment of treatment response to immunotherapy in melanoma patients with pathogenic mutations of NRAS, BRAF, CDKN2A and P53.
Authors: Thomas DeLeon, Benjamin Kipp, Blake Langlais, Thomas Flotte, Jennifer Winters, Heidi E. Kosiorek, Richard Wayne Joseph, Svetomir Markovic, Roxana Stefania Dronca, Matthew Stephen Block, Robert R. McWilliams, Lisa A. Kottschade, Mitesh J. Borad, Kandelaria M. Rumilla, Jesse S Voss, Alan H. Bryce
Journal: Journal of Clinical Oncology (2017)

e21057 Background: BRAF, NRAS, CDKN2A and P53 mutations are commonly observed pathogenic mutations in cutaneous melanoma. The influence of mutations such as BRAF, NRAS, CDKN2A and P53 on treatment response in the PD1 inhibitor era has not been well defined. Methods: This study included patients with melanoma with a cutaneous or unknown primary. All patients had genomic profiling with the Mayo Clinic 50-gene solid tumor mutation panel. Treatment response to first line immunotherapy with PD1, CTLA-4, or combination PD1/CTLA-4 inhibitors were assessed by response rate and time-to-progression (TTP) rate at 12 months. Each patient outcome was stratified by non-mutually exclusive gene mutation status into BRAF, NRAS, P53, CDKN2A, or quadruple negative (N4) groups. Results: Genomic profiling was performed on 208 patients, of whom 102 received first line immunotherapy. Most patients received a PD1 inhibitor (n = 62), followed by CTLA-4 inhibitor (n = 34), and combination therapy (n = 6). A trend towards improved outcomes was observed in CDKN2A and BRAF mutated patients with worse outcomes noted in P53, N4, and NRAS patients. The percent without progression at 12 months were BRAF 52.2%, CDKN2A 58.2%, NRAS 30.5%, P53 37.7%, and N4 26.7% (see table below). Response rates were BRAF 46.4%, CDKN2A 38.5%, NRAS 22.2%, P53 40.0%, and N4 33.3%. Conclusions: There is a trend towards improved outcomes with immunotherapy in BRAF and CDKN2A mutated patients while P53, NRAS and N4 patients have inferior outcomes. [Table: see text]
Reliable diagnosis of <i>BRCA1/2</i> germline mutations from tumor testing using a next-generation sequencing (NGS) platform.
Authors: Pei-Yi Ong, Song Ling Poon, Thomas Choudary Putti, Kien Thiam Tan, Samuel Guan Wei Ow, Shu-Jen Chen, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2018)

e13531 Background: Clinical genetic testing to diagnose germline mutations often requires blood sample, saliva or buccal smear from a cancer-affected individual. This rules out testing in families when cancer-affected individuals are deceased. Testing tumor for germline mutations may overcome this barrier but is not done routinely due to technical challenges. We explored the use of a next-generation sequencing (NGS) platform to diagnose germline pathogenic mutations from tumors. Methods: Tumors (breast = 17, ovarian = 26, others = 6) were retrieved from 49 cancer patients who have undergone multi-gene panel blood testing for hereditary cancer, including 19 patients with BRCA1/2 mutations and 30 patients without. Genomic DNA was extracted from tumor and sequenced for BRCA1/2 using a NGS platform. 30/49 specimens were sequenced for 5 other genes (APC, ATM, PALB2, PTEN, TP53). Variants with 30-70% mutant allele frequency are considered germline. Tumor testing and results interpretation was performed blinded to the blood test result. Results: All 30 patients with no BRCA1/2 mutations on blood testing were correctly tested negative on tumor. Tumor testing correctly diagnosed BRCA1/2 mutations in 12/19 patients while in 7/19 patients, the mutation was either detected but incorrectly classified as VUS (n = 4) or not detected at all (n = 3). Concordance rate for tumor and blood testing for BRCA1/2 mutations was 81.6%, with 0% false positive and 37% false negative rate. Of 30 specimens screened for 5 additional genes, tumor testing correctly diagnosed a pathogenic ATM mutation, and 7/9 VUS in the 5 genes. However, false positive mutations were diagnosed in 3/30 patients (PTEN= 2, TP53= 1), while no false positive findings were noted in APC, ATM or PALB2. Conclusions: Tumor testing for BRCA1/2 germline mutations using an NGS platform is fairly reliable with no false positive finding, and correctly identified almost two-thirds of pathogenic BRCA1/2 mutations, and may facilitate predictive testing in family members of some deceased mutation carriers. However, tumor testing may not be reliable to diagnose pathogenic mutations in genes frequently mutated in sporadic cancers, such as PTEN and TP53.
Regional differences in the utilization of active surveillance in localized prostate cancer.
Authors: Nickolas David Scherzer, Sudesh Srivastav, Steven J. DiBiase
Journal: Journal of Clinical Oncology (2018)

e17062 Background: Men with localized prostate cancer have various treatment options available in their management. In recent years, active surveillance (AS) has become more utilized in prostate cancer management. We sought this study to investigate the influence of geographic region in the United States on the utilization of AS for men with prostate cancer. Methods: Using the National Cancer Database Participant Use Data File, we identified men who were diagnosed with localized prostate cancer from 2004-2015. The United States was divided into nine regions based upon the US Census Divisions. The treatment status was recorded as either AS or not active surveillance (NAS). NAS consisted of patients that received treatment (radical prostatectomy, radiation, or hormone therapy), did not receive treatment, and those for which it was unknown whether they received treatment. Patients that received treatment after a period of active surveillance were removed from the study. A Chi-Square test was used with significance level of 1% to assess the association between region and frequency of AS. Results: This study included 645,535 men with localized prostate cancer treated in nine regions of the US, of whom 5.08% underwent AS. When comparing regional differences in AS, significant differences occurred (Chi-Square; p = < 0.0001) (Table 1). AS was utilized most commonly in the New England (8.16%) and Middle Atlantic (6.04%) regions, whereas AS was least utilized in the East South Central (2.93%) and Pacific (3.56%) regions. Conclusions: Regional differences exist in the U.S. regarding the utilization of AS in the management of localized prostate cancer. The etiology for these regional differences is likely multifactorial, involving physician and patient preference, hospital policy, and education. Additional research is required to further elucidate this relationship. Table 1: Utilization of Active Surveillance by U.S. Geographical Region Region Active Surveillance (%) New England 8.16 Middle Atlantic 6.04 East North Central 5.70 West North Central 5.55 West South Central 5.54 South Atlantic 3.93 Mountain 3.65 Pacific 3.56 East South Central 2.93
MicroRNA and erlotinib: possible correlation with the response in patients with metastatic lung cancer.
Authors: Maria Pagano, Francesca Zanelli, Alessandra Bisagni, Luca Braglia, Carmine Pinto
Journal: Journal of Clinical Oncology (2016)

e20618 Background: Lung cancer is a leading cause of cancer mortality worldwide. Several molecular pathways underlying mechanisms of this disease have been partly elucidated, among which the epidermal growth factor receptor (EGFR) pathway is one of the well-known signaling cascades that plays a critical role in tumorigenesis. MiRNAs (microRNAs) involved in regulating gene expression in the transcription level. More studies have found that miRNAs are correlated with EGFR-tyrosine Kinase inhibitors (EGFR-TKIs) secondary resistance. We explore the expression levels of the miR-133b, miR-7, miR-21 and miR146a in 33 patients with NSCLC metastatic who received erlotinib. The patients with disease stabilization on erlotinib for at least 6 months were considered responders (8 responder and 25 non-responder). This project aims to determine the possible association between miRNAs expression and response to erlotinib treatment in patients with metastatic lung cancer that progressing after at least one line of chemotherapy and identify miRNAs predictive of response Methods: We analyzed a series of 33 patients (19 female and 14 male) with NSCLC who received a second- or third-line erlotinib treatment. EGFR were mutated in 15% of patients, in only 1 case ALK was rearranged. The levels of miRNAs were correlated with responses to erlotinib treatment. Total RNA was isolated from formalin-fixed paraffin embedded (FFPE) sample of NSCLC by High Pure miRNA Isolation Kit (Roche) using the manufacturer’s instructions. MiRNA levels were quantified using TaqMan microRNA Assay (Applied Biosystem) Results: The expression levels of miR-7 in responders resulted significantly lower than in non-responders (Mann-Whitney, p < 0.05), in contrast the expression levels of miR-133b and -146a in responders resulted significantly higher than in non-responders (Mann-Whitney respectively, p < 0.01 and p < 0.05). MiR-21 expression levels were not significantly different (Mann-Whitney, p > 0.05). Conclusions: Based on these preliminary data it appears that miR133b miR-7, and -146a are involved in the response to erlotinib treatment. However, the study sample is too small and other studies are needed to confirm the data
Survival Patterns for Patients with Resected N2 Non–Small Cell Lung Cancer and Postoperative Radiotherapy: A Prognostic Scoring Model and Heat Map Approach
Authors: Weiye Deng, Ting Xu, Yujin Xu, Yifan Wang, Xiangyu Liu, Yu Zhao, Pei Yang, Zhongxing Liao
Journal: Journal of Thoracic Oncology (2018)

IntroductionThe positive-to-resected lymph node ratio (LNR) predicts survival in many cancers, but little information is available on its value for patients with N2 NSCLC who receive postoperative radiotherapy (PORT) after resection. We tested the applicability of prognostic scoring models and heat mapping to predict overall survival (OS) and cancer-specific survival (CSS) in patients with resected N2 NSCLC and PORT.MethodsOur test cohort comprised patients identified from the Surveillance, Epidemiology, and End Results database with N2 NSCLC who received resection and PORT in 2000–2014. Prognostic scoring models were developed to predict OS and CSS using Cox regression; heat maps were constructed with corresponding survival probabilities. Recursive partitioning analysis was applied to the Surveillance, Epidemiology, and End Results data to identify the optimal LNR cutoff point. Models and cutoff points were further tested in 183 similar patients treated at The University of Texas M. D. Anderson Cancer Center in 2000–2015.ResultsMultivariate analyses revealed that low LNR independently predicted better OS and CSS in patients with resected N2 NSCLC who received PORT.ConclusionsLNR can be used to predict survival of patients with resected N2 NSCLC followed by PORT. This approach, which to our knowledge is the first application of heat mapping of positive and negative lymph nodes, was effective in estimating 3-, 5-, and 10-year OS probabilities.
Compared descriptive analysis of immunologic landscape in soft tissue sarcoma and GIST.
Authors: Armelle Dufresne, Tom Lesluyes, Mehdi Brahmi, Christine Menetrier-Caux, Christophe Caux, Jean-Yves Blay, Frederic Chibon
Journal: Journal of Clinical Oncology (2018)

11517Background: Development of immune therapy in sarcoma faces a high heterogeneity of the different histological subtypes, molecular subtypes and immune infiltrate. This is likely to account for ...