tbuckley/cabot-search huggingface dataset:
Radiofrequency ablation of pathologically proven T1a renal tumors: 15 years follow up—A tertiary cancer center experience.
Authors: Mohamed E. Abdelsalam, Sharjeel H Sabir, Samuel B. Kusin, Surena F. Matin, Christopher G. Wood, Jose A. Karam, Kamran Ahrar
Journal: Journal of Clinical Oncology (2018)

4582 Background: To evaluate the long term oncologic efficacy and overall survival of radiofrequency ablation (RFA) for pathologically proven T1a Renal cell carcinoma (RCC). Methods: we retrospectively reviewed our renal ablation data base between January 2001 and December 2014, we included only patients with histologically diagnosed T1a RCC ( < 4 cm) who underwent RFA. Patient who underwent cryoablation, those with syndromes,and those with recurrent or bilateral RCC were excluded. For each patient, we recorded: Demographics, tumor size and histology, complications, recurrence at ablation site, development of metastases, history of another malignancy, survival/death and cause of death. Overall survival (OS) was estimated using Kaplan and Meier product-limit estimator. Results: Ninety four RFA procedures were performed for 92 lesions in 92 patients (54 males and 38 females, average age 68 years). Average tumor size was 2.7cm (range: 1-3.9 cm). The median follow-up for all subjects was 4.7 years (range: 0.16 – 14.4 years). Total of 7 patients developed complications (7.4%). Three, 1 and 3 patients developed Grades I, II and III (3.2%) complications respectively according to the Clavien-dindo classification. A total of 6 patients (6.4%) developed local recurrence at the ablation site, one patient underwent watchful observation, two underwent repeat ablation and 3 patients underwent partial nephrectomy. One patient had disease recurrence in the other kidney. Fifty four patients (56%) had another non-renal primary malignancy. None of the patients developed metastasis from RCC. The median overall survival was 8.31 years. The overall survival was 68 %, 34% and 21 % at 5, 10 and 14 years respectively. The cancer specific survival (CSS) was 100 %. Conclusions: Radiofrequency ablation is a safe and highly efficacious modality for treatment of small renal tumors. Fifteen-year follow up data reveals long standing oncologic control with low recurrence and complication rates.
FBI-1 expression in relation to clinicopathological variables in rectal cancers with a Swedish clinical trial of preoperative radiotherapy.
Authors: Chao-Jie Wang, Jian-Wei Zhou, Yun Zhou, Xiao-Feng Sun
Journal: Journal of Clinical Oncology (2017)

e15102 Background:FBI-1 is a recently characterized proto-oncoprotein of the POZ domain Krüppel-like (POK) family of transcription factors. Although several studies provide the evidence that FBI-1 is an important gene regulator in CRC, no analysis of any correlation between FBI-1 expression and preoperative radiotherapy (RT) has been studied in rectal cancers. Methods: This study included the patients with rectal cancer that participated in a Swedish clinical trial of preoperative RT between 1987 and 1990. Patients were divided into preoperative RT (62) and non-RT (77) groups. Applying immunohistochemstry, we detected FBI-1 expression in 118 normal mucosa, 139 primary rectal cancers, and 45 lymph node metastases, and analyzed its relationship with clinicopathological features and RT response. Results: FBI-1 was detected both in the cytoplasm and nucleus, and the cytoplasmic staining was up-regulated compared with normal mucosa both in non-RT and RT groups (74.0% vs. 17.7%, p &lt; 0.001; 69.4% vs. 41.1%, p = 0.002), however, the nuclear staining was down-regulated compared with normal mucosa both in non-RT and RT groups (22.1% vs. 75.8%, p &lt; 0.001; 35.5% vs. 83.9% p &lt; 0.001). Both cytoplasmic and nuclear staining were no difference between the non-RT and RT groups (74.0% vs. 69.4%, p = 0.542; 22.1% vs. 35.5%, p = 0.080, respectively). So we combined the non-RT and RT group together for further analysis. Nuclear staining of FBI-1 was positively with TNM stage and distance recurrence, it showed higher expression in III+ IV stage than that in I+II stage (41.0% vs. 17.9%, p = 0.003). The patients with distance recurrence showed higher FBI-1 expression than that with no distance recurrence (39.7% vs. 19.8%, p = 0.010). In stage I, II and III patients, higher nuclear FBI-1 in primary cancer showed worse disease free survival (HR: 1.934; 95%CI: 1.055-3.579, p = 0.033) and overall survival (HR: 2.174; 95%CI: 1.102-4.290; p = 0.025) independent of gender, age, growth pattern, differentiation and RT. Conclusions: Higher nuclear FBI-1 is related with later TNM stage, distance recurrence, and worse prognosis, it can be used as a potential diagnostic and prognostic biomarker in rectal cancer.
Development of predictors for PD-1/PD-L1-directed therapy of non-small cell lung cancer (NSCLC) by gene expression profiling of small diagnostic biopsies (DBX).
Authors: Fabian Dominik Mairinger, Marcel Wiesweg, Simon Bogner, Balazs Hegedues, Henning Reis, Moritz Goetz, Thomas Herold, Robert Walter, Thomas Hager, Kaid Darwiche, Martin Metzenmacher, Wilfried Ernst Erich Eberhardt, Ken Herrmann, Kurt Werner Schmid, Clemens Aigner, Martin H. Schuler
Journal: Journal of Clinical Oncology (2018)

e15121 Background: Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 are standard second-line treatments of stage IV NSCLC and preferred first-line therapy in selected patients (pts). However, only a minority of pts respond. These can be only partially enriched by predictive biomarkers applicable to small DBX available in most pts with stage IV NSCLC such as PD-L1 expression and tumor mutational burden. Methods: Expression analysis of 770 immune-related genes in small surplus DBX using the NanoString nCounter platform was established following serial dilution experiments and adaptation. Clinical endpoints were best response (PD vs. SD/PR; PD vs. SD vs. PR), time-to-treatment-failure (TTF), and overall survival (OS) following ICI therapy. Predictive feature sets were selected by ensemble-based penalized linear or logistic regression. Prediction models for all endpoints were trained using support vector machine classification or regression. Scores of prediction quality were derived using 20-fold cross validation. The study was approved by the responsible IRB. Results: 127 pts with advanced NSCLC were enrolled at a single center. Extraction of qualitatively and quantitatively sufficient RNA was possible in 84 pts, of which 55 (33 adeno-, 21 squamous- and 1 adenosquamous carcinoma) generated admissible nCounter reads. Mean age at diagnosis was 62.6 years (37.1-84.7) with 22 females and 33 males. PD-L1 tumor proportion score was ≥1% in 57.1% and ≥50% in 16.3%. Median follow-up after start of ICI therapy was 11.9 months, and median OS since ICI therapy was 10.8 months. The best achieved cross-validated accuracy was 80% (based on the expression of 3 genes) for PD vs. SD/PR and 78% (5 genes) for PD vs. SD vs. PR. Best score (integrated area under the time-specific ROC curve) achieved for OS was 0.67 (5 genes) and 0.79 for TTF (3 genes). Validation in an independent cohort is ongoing. Conclusions: Comprehensive gene expression profiling is feasible in a proportion of routine DBX from NSCLC pts. Validation of more restricted gene panels is expected to expand the assessable pt population.
Predicting the failure of randomized clinical trials in radiation oncology: What can we learn?
Authors: Timothy K. Nguyen, Eric K Nguyen, Andrew Warner, Alexander V. Louie, David A. Palma
Journal: Journal of Clinical Oncology (2017)

e18241 Background: Although randomizedcontrolled trials (RCTs) are essential to evidence-based medicine, a significant proportion of cancer RCTs fail to complete. As RCT failure is not well understood in the field of radiation oncology, we sought to review radiotherapy RCTs to identify predictors of RCT failure. Methods: We undertook a review of the trial registry ClinicalTrials.gov to assess factors influencing the completion of RCTs involving radiotherapy. Eligible trials were registered in ClinicalTrials.gov between 09/27/2007 to 12/31/2010, included radiation (brachytherapy or external beam radiotherapy) in at least one study arm, and were closed due to either successful completion or failure to complete. Data was abstracted by two independent investigators, with discrepancies settled through consensus. Univariable and multivariable logistic regression analyses were performed to determine factors predictive of RCT failure. Results: The initial search yielded 460studies. After reviewing protocol details, 138 studies met inclusion criteria, of which 41 (30%) failed to complete. Most common reasons for RCT incompletion were: lack of accrual (59%), inadequate funding (15%), drug unavailability (7%) and interim data monitoring report recommendations (7%). The highest proportion of RCT failure was observed in the most recent era (p = 0.009), with rates increasing from 11% (1987-2006) to 39% (2009-2012). On univariable analysis, independent predictors of failure included RCTs with a surgical comparator (odds ratio [OR] of failure 6.45; p = 0.010), government sponsorship (OR 3.68; p = 0.024), inclusion of a safety endpoint (OR 3.03; p = 0.014) and study start year (OR 1.18; p = 0.030). On multivariate analysis, surgical RCTs were strongly predictive of failure (OR 7.90; p = 0.015), while behavioral RCTs were less likely to fail (OR 0.14; p = 0.047). Conclusions: Rates of RCT failure in radiation oncology are high. Trials with a surgical comparator are highly prone to failure, whereas behavioral trials are more likely to succeed. These factors can help to inform the design of future RCTs, and develop strategies to mitigate the risk of failure in future radiation RCTs that include a surgical comparator.
Novel formulation of cannabinoid analogues used in cancer therapy.
Authors: Tori Strong, Jana Rauvolfova, Elias Jackson, David Yang, E. Edmund Kim, Lan Pham, Jerry Bryant
Journal: Journal of Clinical Oncology (2018)

e19536 Background: Diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL) represent the most common and most aggressive forms of Non-Hodgkin lymphoma (NHL) respectively. Previous work has demonstrated CB1 antagonists as potential therapeutics for both DLBCL and MCL. Our drug formulation VYR-206 was developed from existing obesity treatment Rimonabant, a CB1 antagonist, by the addition of our tetraazacyclic (N4) conjugate derivative. The addition of N4 allows the potential for image guided theranostic application for diagnosis, precision and assessment of therapeutic response through radiotracer chelation. Our study is aimed at demonstrating the viability of our novel conjugate formulation VYR-206 and comparing it with its parent analogue Rimonabant in DLBCL and MCL cell lines for sensitivity or resistance. Methods: Cells from representative DLBCL and MCL cell lines were plated at 5,000 cells per well. The cells were incubated for 72 hours in 20 µL medium with 10% FBS and varied concentrations of experimental cannabinoid antagonist VYR-206, Rimonabant, or dimethylsulfoxide (DMSO) vehicle. Viability assays were conducted using Celltiter-Glo Luminescent Cell Viability Assay. Experiments were performed 2-3 times independently with each concentration tested in triplicate. Results: Drug effectiveness of compound VYR-206 was compared to CB1 antagonist Rimonabant with N4 as a control in both DLBCL and MCL cell lines. Drug VYR-206 follows closely to Rimonabant in VYR-206 sensitive DLBCL cell lines with reduction of viability at concentrations < 100μM and 0% of control at 200μM. In VYR-206 resistant DLBCL cell lines reduction of viability occurs at concentration of 100μM or more, still with 0% of control occurring at 200μM. Drug VYR-206 appears to show more effectiveness in VYR-206 sensitive MCL cell lines, showing a reduction in viability at concentrations < 50μM with 0% of control at 100μM. In VYR-206 resistant MCL cell line Rec-1, drug VYR-206 fails to decrease viability below 50% of control even at concentrations of 400μM. Conclusions: VYR-206 has the potential for both the treatment and assessment of the efficacy of cannabinoid therapy in malignant lymphoma cancer.
Dopaminergic precursors differentiated from human blood-derived induced neural stem cells improve symptoms of a mouse Parkinson's disease model
Authors: Yanpeng Yuan, Xihe Tang, Yun-Fei Bai, Shuyan Wang, Jing An, Yanchuan Wu, Zhi-Qing David Xu, Y. Alex Zhang, Zhiguo Chen
Journal: Theranostics (2018)

Autologous neural stem cells (NSCs) may offer a promising source for deriving dopaminergic (DA) cells for treatment of Parkinson's disease (PD). Methods: By using Sendai virus, human peripheral blood mononuclear cells (PBMNCs) were reprogrammed to induced NSCs (iNSCs), which were then differentiated to dopaminergic neurons in vitro. Whole-genome deep sequencing was performed to search for mutations that had accumulated during the reprogramming and expansion processes. To find the optimal differentiation stage of cells for transplantation, DA precursors obtained at various differentiation time points were tested by engraftment into brains of naïve immunodeficient mice. At last, the safety and efficacy of iNSC-derived DA precursors were tested by transplantation into the striatum of immunodeficient PD mouse models. Results: PBMNC-derived iNSCs showed similar characteristics to fetal NSCs, and were able to specifically differentiate to DA neurons with high efficiency in vitro. The sequencing data proved that no harmful SNVs, Indels and CNVs were generated during the reprogramming and expansion processes. DA precursors obtained between differentiation day 10 to 13 in vitro were most suitable for transplantation when a balanced graft survival and maturation were taken into account. Two weeks after transplantation of DA precursors into mouse PD models, the motor functions of PD mice started to improve, and continued to improve until the end of the experiments. No graft overgrowth or tumor was observed, and a significant number of A9-specific midbrain DA neurons were surviving in the striatum. Conclusion: This study confirmed the efficacy of iNSC-derived DA precursors in a mouse PD model, and emphasized the necessity of genomic sequencing and vigorous safety assessment before any clinical translation using iNSCs.
Large-scale analyses of tumor mutation burdens (TMBs) across various advanced gastrointestinal (GI) malignancies in the nationwide cancer genome screening project, SCRUM-Japan GI-SCREEN.
Authors: Yoshiaki Nakamura, Wataru Okamoto, Kohei Shitara, Takashi Kojima, Chigusa Morizane, Yoichi Naito, Satoshi Yuki, Yoshinori Kagawa, Yukiya Narita, Yuichiro Nakashima, Hideaki Takahashi, Makoto Ueno, Ken Kato, Yoshito Komatsu, Atsushi Ohtsu, Kiwamu Akagi, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2018)

12094 Background: Tumor mutation burdens (TMBs) in advanced gastrointestinal (GI) malignancies have not been well-characterized. We analyzed TMB in tissue samples from advanced GI malignancies using the Oncomine Cancer Research Panel (OCP), a targeted next-generation sequencing panel, as part of the Nationwide Cancer Genome Screening Project (SCRUM-Japan GI-SCREEN). Methods: The performance of the OCP panel for TMB analysis was assessed using whole-exome sequencing (WES) data from 10,183 samples in the Cancer Genome Atlas (TCGA). Then, TMBs were calculated based on somatic non-synonymous mutations in the following 1,759 GI tumors: colorectal cancer (CRC, n = 751), gastric cancer (GC, n = 509), esophageal cancer (EC, n = 143), pancreatic cancer (PC, n = 136), biliary tract cancer (BTC, n = 92), small intestinal cancer (SIC, n = 30), gastrointestinal stromal tumor (GIST, n = 29), hepatocellular carcinoma (HCC, n = 27), neuroendocrine tumor/cancer (NET/NEC, n = 27), appendiceal cancer (AC, n = 12), and anal canal cancer (ACC, n = 3). High TMB was defined as more than 20 mutations per megabase (mt/Mb). CRC microsatellite instability (MSI) status was assessed using a PCR-based method. Results: TMBs estimated from the OCP-targeted region based on TCGA data were strongly correlated with those from TCGA whole-exome sequencing data (R2 = 0.720). TMBs in the GI-SCREEN ranged from 0 to 103.6 mt/Mb across various tumor subtypes. In CRC, 75% of MSI-high (MSI-H) and 17% of non-MSI-H tumors had high TMB. In non-CRC, high TMB was identified in 13% of GC, 17% of EC, 28% of PC, 26% of BTC, 30% of SIC, 7% of GIST, 7% of HCC, 15% of NET/NEC, 25% of AC, and 33% of ACC tissues. TMB was not associated with sex, age, histology (adenocarcinoma vs. squamous cell carcinoma), prior chemotherapy, or radiotherapy. Tumors with mutations in DNA damage response (DDR) genes (ATM, BRCA1, BRCA2, MLH1, and MSH2) had higher TMB than those with wild-type DDR genes (p < 0.001). Conclusions: TMB varied widely across various advanced GI malignancies. TMB analysis may be used as an agnostic histologic indicator to identify patients with GI malignancies who can benefit from immunotherapy. Clinical trial information: UMIN000016343.
Randomized trial comparing a web-mediated follow-up via patient-reported outcomes (PRO) vs. routine surveillance in lung cancer patients: Final results.
Authors: Fabrice Denis, Ethan M. Basch, Claire Lethrosne, Nicolas Pourel, Olivier Molinier, Yoann Pointreau, Julien Domont, Hugues Pierre Bourgeois, Helene Senellart, Jaafar Bennouna, Thierry Urban, Anne-Lise Septans, Magal Balavoine, Philippe Solal-Celigny, Amylou C. Dueck, Christophe Letellier
Journal: Journal of Clinical Oncology (2018)

6500 Background: In a previous interim analysis, we found a 7-month median overall survival (OS) benefit (p = 0.002) associated with web-based monitoring to detect recurrence in lung cancer patients after initial treatment, vs. scheduled imaging. We hypothesized that benefit was due to earlier detection of symptoms and relapses, prompting earlier treatment and supportive care. Final results with 2-year follow-up is presented. Methods: Advanced-stage lung cancer patients without evidence of disease progression after initial treatment were randomly assigned to compare a web-mediated follow-up (experimental arm) based on weekly self-scoring of 13 common patient symptoms with a routine follow-up (control arm) with 3-6 months repeated CT-scans. In the experimental arm, an alert email was sent to the oncologist when self-scored symptoms matched predefined criteria. The IRB protocol-specified primary outcome was OS. After a pre-planned interim analysis in which OS improvement was observed, the IDMC suggested a cessation of further recruitment in 1-2016 and recommended to offer eligible patients in the control arm to cross over to the intervention. Results: From 6-2014 to 1-2016, 121 patients were included in the intent-to-test survival (ITT) analysis. Ten out of 34 living patients in the control arm were eligible to cross over following the interim analysis. With 2 years of follow-up and 70 deaths observed, the median OS was 23.0 months in the experimental arm and 14.8 months without adjustment for crossover in the control arm (HR 0.62, 95% CI 0.39 to 0.995, p= 0.048). Censoring crossover resulted in a hazard ratio of 0.53 (95% CI 0.33 to 0.85, p = 0.009) with consistent results also observed based on a rank-preserving structural failure time model (psi = -0.55, 95% CI -1.09 to -0.03). Conclusions: With a longer follow-up and although eligible patients from the control arm crossed over to receive intervention after the preplanned interim analysis, the OS remained significantly larger with the web-mediated follow-up based on PRO than with routine disease follow-up by CT scans alone. This is the first study to show the benefits of PROs during surveillance in cancer patients. Clinical trial information: NCT02361099.
Evaluation of cytomegalovirus (CMV) reactivation, relapse, and survival after allogeneic hematopoietic stem cell transplantation (allo-HSCT) using two T cell depletion strategies.
Authors: Talal Hilal, Shawn Peterson, Charles Bodine, Stacey A. Slone, Gerhard Hildebrandt, Zartash Gul
Journal: Journal of Clinical Oncology (2016)

7047 Background: CMV reactivation after allo-HSCT has been shown to be associated with decreased risk of early relapse. We sought to evaluate the effects of two T cell depletion strategies on the incidence of CMV reactivation, risk of relapse, and survival data between the two cohorts. Methods: We retrospectively evaluated all charts of patients (pts) who underwent allo-HSCT between 2005-2015. Data were collected and the two cohorts divided into alemtuzumab (A) vs. anti-thymocyte globulin (ATG). Results: There were 55 pts in ATG group and 38 in A. Both groups were similar with respect to age, gender, intensity of conditioning regimens, diagnosis, remission status at transplant, aGVHD and HLA mismatch. CMV positivity in donor, recipient or both was present in 81% of cases in ATG group and 62% of cases in A (P = 0.04). There was no difference in ATG and A groups with respect to CMV reactivation (P = 0.86), or relapse at 1 year (yr) (P = 0.34). There was no difference in CMV reactivation between myeloablative (MAC) and reduced intensity conditioning (RIC). There was more CMV reactivation at 100 days in pts with myeloid malignancies (P = 0.036). Of pts without CMV reactivation at 100 days, 36% relapsed at 1 yr vs. 12% with CMV reactivation at 100 days (P = 0.02). Consequently there was an improvement in relapse free survival (RFS) with CMV reactivation (P = 0.02). There was no impact of the T cell depletion strategy, nor the intensity of conditioning regimen on RFS. Overall survival (OS) was better with A than with ATG (P = 0.004) but was not impacted by CMV reactivation or intensity of conditioning regimen. The hazard of CMV reactivation was decreased by 16% in ATG arm but was not statistically significant. Nonrelapse mortality (NRM) was significantly higher in ATG group compared to the A group (P = 0.02), and in the MAC group compared to the RIC group (P = 0.047). Conclusions: CMV reactivation at 100 days significantly decreased the risk of relapse at 1 year thereby improving RFS. However, the use of ATG vs. A did not impact the risk of CMV reactivation or relapse. Interestingly, OS was improved with A and NRM was higher with ATG, warranting further prospective evaluation.