tbuckley/cabot-search huggingface dataset:
Results of an Italian CORE-IMMUNO study: Safety and clinical-related biomarkers as predictors of immunotherapy (IT) benefit in real-world treatment of various advanced tumors (ATs).
Authors: Cristina Masini, Annalisa Berselli, Alessandra Romagnani, Candida Bonelli, Emanuela Fantinel, Maria Pagano, Maria Banzi, Giuseppe Prati, Elisa Gasparini, Gabriella Moretti, Erika Gervasi, Roberta Gnoni, Giovanna Stridi, Carmine Pinto
Journal: Journal of Clinical Oncology (2019)

e14156 Background: Checkpoint inhibitors in cancer therapy have shown survival benefits in the treatment of several ATs. However, the risk of serious side effects seems greater in certain types of tumors presenting reduced compliance with therapy. The aim of this study is to evaluate the safety profile and clinical benefits of IT, as appraised using clinically related biomarkers of pts outside clinical trials. Methods: In this retrospective study, data were evaluated on pts in the Reggio Emilia Provincial Oncology Network who were treated for ATs using Nivolumab, Pembrolizumab and Ipilimumab monotherapy in clinical practice. The pts included in the study had received at least 1 dose of IT by June 2018. LDH and neutrophil–lymphocyte ratio (NLR) were collected at baseline, antibiotic therapy (ATB) was considered during IT, and immunorelated adverse events (irAEs) were assessed with CTCAE v.4.1. Results: A total of 169 pts were examined: 78 with NSCLC, 57 with melanoma, 29 with kidney cancer, 3 with head-neck cancer and 2 with colorectal cancer. 123 pts (73%) were treated with Nivolumab, 36 (21%) with Pembrolizumab and 10 (6%) with Ipilimumab. Overall, 62 pts (37%) experienced irAES of any degree: 17/29 (59%) pts with kidney cancer presented irAES, while only 35% (20/57) and 31% (24/78) of pts with melanoma and lung cancer did, respectively. A total of 27/62 (43%) pts delayed IT due to toxicity, but only 7/62 (11%) pts discontinued treatment due to irAEs. Statistically significant increases in PFS (11 vs. 5 months, p = 0.002) and OS (19.9 vs. 8.7 months, p = 0.002) were found between pts who experienced irAEs and those who did not. As previously demonstrated in other groups of pts, in the Cox regression performed for OS, a baseline value of LDH≥1.5xULN and median NLR ≥2.93 correlates with poor prognosis. Unlike what is already known, the use of ATB during IT (35% of pts) correlates with increased survival (HR 0.59; IC95% 0.37-0.94, p = 0.028). Conclusions: These data confirm the tolerability of IT in an unselected real-world population. In particular, the development of irAEs could be considered a positive predictor of outcome, but with a different incidence among MTS.
Multicenter phase II trial of RRx-001 in previously treated SCLC.
Authors: Daniel Morgensztern, Michal G. Rose, John Charles Morris, Patrick C. Ma, Christina E. Brzezniak, Karen Grace Zeman, Arvinda Padmanabhan, JoAnn Hirth, Alexander I. Spira, Ellice Yuen-Ming Wong, Sukhmani Kaur Padda, Saiama Naheed Waqar
Journal: Journal of Clinical Oncology (2019)

e20104 Background: This exploratory single arm phase II study evaluated the efficacy and safety of RRx-001 followed by reintroduction of platinum plus etoposide in patients with previously treated small cell lung cancer (SCLC). Methods: Patients with SCLC that was platinum-resistant or received at least 2 prior lines were treated with RRx-001 4 mg IV on day 1 of each week of a 21-day cycle followed at progression by re-challenge with etoposide and cisplatin or carboplatin. The primary endpoints were overall survival (OS) and overall response rate to platinum therapy. Results: Between December 2016 and March 2018, 26 patients were enrolled and received at least one dose of RRx-001. The median number of prior lines of therapy was 2 (range 1-9) and 19 (73.1%) patients had platinum-resistant disease. In the intention-to-treat population, 1 (3.8%) achieved partial response (PR) and 7 (26.9%) had stable disease (SD) during treatment with RRx-001, whereas 1 patient (3.8%) had complete response and 6 (23.1%) had partial response on platinum plus etoposide. The estimated median and 12-month OS from enrollment were 8.6 months and 44.1%, respectively. The most common treatment-emergent adverse events from RRx-001 was mild discomfort at the infusion site (23%) and decreased appetite (15.3%). Conclusions: RRx-001 followed by re-challenge with platinum plus etoposide chemotherapy is feasible and associated with promising results. Clinical trial information: NCT02489903.
Elevated pretreatment serum IL-8 and PD-L1 and overall survival in a phase III randomized advanced pancreatic cancer clinical trial.
Authors: Ashok Maddukuri, Prashanth Reddy Moku, Hyma Vani Polimera, Vinod Nagabhairu, Suhail M. Ali, Kim Leitzel, Joseph J. Drabick, Scott Halstead, Todd Umstead, Daniel Mckeone, Aamnah Ali, Joyson Poulose, Neha Pancholy, Harry Menon, Howard Spiegel, Allan Lipton
Journal: Journal of Clinical Oncology (2019)

4131 Background: We previously reported the prognostic and predictive utility of pretreatment serum PD-L1 in the CCTG MA.31 serum bank (SABCS 2018, abstr PD3-10). IL-8 (CXCL8) is a pro-inflammatory cytokine that binds to CXCR1 and CXCR2 and promotes tumor immune escape and progression. High serum IL-8 levels are associated with poor prognosis in many cancers, and have recently been reported to predict for reduced OS to nivolumab in lung cancer and melanoma (ASCO 2018, abstr #3025). In this study, we retrospectively evaluated combined pretreatment serum IL-8 and PD-L1 on overall survival (OS) from a phase III randomized pancreatic cancer trial of first-line therapy (octreotide + 5-FU vs. 5-FU) that had reported no significant OS difference between treatment arms. Methods: This study had 147 patients with serum available for this retrospective biomarker analysis from an advanced pancreatic cancer phase III clinical trial.TheELLA immunoassay platform (ProteinSimple, San Jose, CA) was utilized to quantitate serum levels of IL-8 and PD-L1. Kaplan-Meier life table analysis was used to correlate serum biomarkers with overall survival (OS). Results: In univariate analysis, pretreatment serum IL-8 was a significant biomarker as a continuous variable (HR = 1.004; p = 0.012) and trended significant at the median cutpoint (HR = 1.379; p = 0.098) for OS, however serum PD-L1 was not significant at any cutpoint. When serum PD-L1 and IL-8 levels were analyzed as combined biomarkers (median cutpoints), the serum IL-8 high / PD-L1 high cohort had a significantly shorter OS vs the serum IL-8 low / PD-L1 low cohort (HR = 1.816; p = 0.017). Conclusions: In this phase III randomized clinical trial in advanced pancreatic cancer, pretreatment serum IL-8 was a significant biomarker for OS, but serum PD-L1 was not. Higher combined pretreatment serum levels of PD-L1 and IL-8 (both biomarkers high vs. both low) were prognostic for reduced OS in this phase III pancreatic cancer trial. Further study of circulating IL-8 and PD-L1 is warranted in pancreatic cancer for evaluation of targeted and investigational therapies, including the immune checkpoint inhibitors and anti-IL8 therapy.
Population-based cohort of prostate cancer patients on active surveillance (AS): guideline adherence, conversion to treatment and decisional regret.
Authors: Sabrina Peterson, Ramsankar Basak, Dominic Himchan Moon, Claire Liang, Ram S Basak, Sarah Walden, Aaron J Katz, Ronald C. Chen
Journal: Journal of Clinical Oncology (2019)

6512 Background: AS is recommended for early-stage prostate cancer, for which over-treatment has been widely described. In published studies from large academic institutions and/or controlled clinical trials, where patients are monitored rigorously, AS is safe and results in low rates of cancer-specific mortality. However, active surveillance in the community setting has not been previously examined. Methods: In collaboration with the North Carolina state cancer registry, 346 men with newly-diagnosed low- or intermediate-risk prostate cancer throughout the state from 2011–13 who pursued active surveillance were enrolled in an observational cohort; medical records and patient-reported outcomes (validated measures of prostate cancer anxiety [MAX-PC] and Clark’s prostate cancer decision regret) were collected prospectively. Guideline-adherent monitoring during active surveillance was assessed using contemporary NCCN guidelines: PSA testing every 3–6 months and prostate biopsy within 18 months of initial diagnosis. Results: 58% of patients received adequate PSA testing and 45% prostate biopsy; overall, 32% of patients received guideline-adherent monitoring. Urology follow-up in Year 1 was 97% but dropped to 67% in Year 2. Within the first 2 years, 16% of patients converted to treatment. Multivariable analysis showed MAX-PC scores (OR 1.8, p = 0.008) and younger age were significantly associated with conversion; no other sociodemographic (race, education, marital status, rural/urban) or diagnostic variable (risk group) was associated. At 2 years, 94% expressed no regret. Conclusions: In a non-controlled setting of patients pursuing AS in the community, adherence to guideline-recommended monitoring was only 32%. Few patients expressed decisional regret. Conversion to treatment was likely driven by patient anxiety but not disease-related factors. While there are continued efforts to increase AS uptake, these results highlight the importance of behavioral interventions during active surveillance to reduce anxiety and improve monitoring adherence. Whether AS in non-controlled settings is safe and effective requires further study.
Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer
Authors: Vincent P. Groot, Stacy Mosier, Ammar A. Javed, Jonathan A. Teinor, Georgios Gemenetzis, Ding Ding, Lisa M. Haley, Jun Yu, Richard A. Burkhart, Alina Hasanain, Marija Debeljak, Hirohiko Kamiyama, Amol Narang, Daniel A. Laheru, Lei Zheng, Ming-Tseh Lin, Christopher D. Gocke, Elliot K. Fishman, Ralph H. Hruban, Michael G. Goggins, I. Quintus Molenaar, John L. Cameron, Matthew J. Weiss, Victor E. Velculescu, Jin He, Christopher L. Wolfgang, James R. Eshleman
Journal: Clinical Cancer Research (2019)

In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a KRAS ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology-certified clinical laboratory.Digital-droplet PCR was used to detect the major PDAC-associated somatic KRAS mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed.ctDNA was detected preoperatively in 29 (49%) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-naïve patients (21% vs. 69%; P < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90% (95% confidence interval (CI), 74%-98%), specificity 88% (95% CI, 62%-98%)] with a median lead time of 84 days (interquartile range, 25-146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA (P = 0.011).Measurement of KRAS ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.
A gene signature of response to radiotherapy in patients with grade II-III oligodendrogliomas.
Authors: Elizabeth Moyal, Julia Gilhodes, Guillaume Peyraga, Emmanuelle Uro-Coste, Damien Pouessel, Delphine Larrieu-Ciron, Catherine Carpentier, Francois Ducray, Caroline Dehais
Journal: Journal of Clinical Oncology (2019)

2041 Background: Grade II and III Oligodendroglioma associate mutations of isocitrate deshydrogenase 1 or 2 genes and the whole-arm chromosomal loss of 1p and 19q and have a better prognosis than other gliomas. However, even if the preferred treatment consists of a combination of radiotherapy (RT) and chemotherapy, some patients will less respond to this treatment and will relapse faster , in part because of an heterogeneity in the response to RT. In the aim to identify factors of response to RT, we analyzed clinical and molecular data of patients with grade II-III oligodendroglioma exclusively treated with RT in the POLA cohort. Methods: Gene expression profiles on Affymetrix expression arrays of patients from the POLA cohort with co-deleted 1p/19q grade II/II gliomas treated by exclusive RT were used to identify a gene expression set predictive of radiation sensitivity. The primary endpoint was the progression free survival (PFS), defined as the time from treatment start until progression or death. A supervised approach with penalized regression was applied to select most informative predictors, and then a risk score was created based on the linear predictor given by the multivariable model. Results: Forty-five patients corresponded to the study criteria, with a median age at diagnosis of 45 (range 23- 64). The supervised approach allowed identifying a three-gene prognostic set including Semaphorin -3C (SEMA3C), Neuronal Pentraxin 2 (NPTX2 ) and the Metabotropic Glutamate Receptor 5 (GRM5), involved in proliferation, migration and inflammation. The risk score associated to these three genes was statistically associated to PFS (HR = 2.72, p = 0.00005) and remains significant when adjusted on clinical covariates age at diagnosis, necrosis, endothelial proliferation and type of surgery (complete, partial or subtotal surgery) (HRadj = 2.36, p = 0.001). Conclusions: We report an independent three genes SEMA3C-NPTX2-GRM5 risk score signature of response to radiotherapy in patients with oligodendroglioma, which highlights the heterogeneous response in this reputed good prognosis population. This signature could help in determining the adapted treatment as well as potential new targets to address.
Feasibility of mobile-deployed care management based on standardized ePRO and computer-interpretable-guideline engine for lymphoma patients.
Authors: Tingting Zhang, Yuqin Song, Zhi Tao Ying, Lingyan Ping, Chen Zhang, Yan Xie, Weiping Liu, Ningjing Lin, Meifeng Tu, Lijuan Deng, Lingling Hong, Jun Zhu
Journal: Journal of Clinical Oncology (2019)

e18010 Background: To effectively assist lymphoma patients and their care-givers after their hospital discharge, a standard follow-up guideline for lymphoma patients was designed and encoded through a computer-interpret-able-guideline (CiG) engine and deployed through mobile-Web and mobile-Apps to ensure continuous care throughout the treatment and recovery processes. Methods: Scheduled tasks including ePRO questionnaires and requests for test results were sent for completion, and a virtual care management team was assigned to ensure compliance and respond to automatic triggered alerts. Attending oncologists also were given mobile-Apps to access the patients’ securely uploaded records and consult remotely to manage side-effects manifested after discharge. The out-of-hospital record management and care coordination enabled the adjustment of individual treatment plans and the optimization of clinical resources utilization. Results: During 2018, 1012 patients or their caregivers interacted with our team through the mobile platform after discharge. Out of these, 856 individual patients uploaded enough information to be initiated in the mobile follow-up program. Approximately 30% of these patients were Beijing residents while the rest came from all over China. Close to half of these patients had follow-up tests done in other 387 hospitals or 52 clinics. Based on ePRO questionnaires submitted, 218 patients had 616 side-effect-symptom alerts triggered and followed up, in addition to patient-initiated mobile consultation with their attending oncologists. Lab results especially white blood cell counts, platelet counts, and neutrophil counts, contributed to the majority of test alerts managed by our team. Analysis of the thousands anonymized questions identified clinical processes in need of optimization. A new patient education manual addressing frequently asked questions, and new processes such as chemo-regime scheduling were put in place. Conclusions: We have demonstrated the feasibility of a mobile-deployed care management process after discharge for lymphoma patients and their caregivers. We have initiated retrospective studies of impacts on our patients’ treatment compliance and quality of life. A randomized clinical trial in six cancer types assessing the value of such an approach is also under planning.
A dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of mTORC1/2 inhibitor XP-105 (BI 860585) as monotherapy and in combination with exemestane or paclitaxel in patients (pts) with advanced solid tumors.
Authors: Filippo G. De Braud, Wentao Jason Wu
Journal: Journal of Clinical Oncology (2019)

3127 Background: Resistance to mTORC1 inhibition may develop through feedback loop leading to upregulation of mTORC2. XP-105, also known as BI 860585, is a potent dual mTORC1/2 inhibitor designed to overcome such resistance. This Phase 1 trial (NCT01938846) was performed to determine the MTD and activity of XP-105 alone or in combination with exemestane or paclitaxel in pts with advanced solid tumors. Methods: A 3+3 escalation design was used; Pts received XP-105 (5–300 mg/day) monotherapy or (40–220 mg/day) combined with fixed-dose exemestane 25 mg/day, or 80–160 mg/day combined with paclitaxel 60 or 80 mg/m 2 /week. A reduction of pAKT/total AKT ratio was used as a PD marker of target inhibition. Results: 90 pts were treated (41 with monotherapy, 25 and 24 in combination with exemestane, or paclitaxel respectively). XP-105 MTD was defined as 220 mg daily for monotherapy, and 160mg daily with exemestane 25 mg/d or paclitaxel 80 mg/m 2 /week. In the monotherapy arm, stable disease (SD) was reported in 8 pts (20%), with a median duration of 11 months. In the exemestane combination arm, 4 (16%) partial responses (PR) were reported. In the paclitaxel combination arm, 1 complete response (CR) and 4 PRs were reported (OR rate 21%). Disease control rate (CR/PR/SD) was 20%, 28%, and 58% in the monotherapy, XP-105/exemestane, and XP-105/paclitaxel arms, respectively. A sustained reduction in pAKT/total AKT to &lt; 50% of baseline levels was observed with XP-105 ≥120mg daily. Overall, XP-105 was well tolerated; in the XP-105/paclitaxel combination the most frequent drug-related AEs were diarrhea and fatigue (58.3% each), hyperglycaemia (54.2%), anaemia (50%). Grade ≥3 AEs were hyperglycaemia, fatigue, diarrhea, anaemia, leukopenia. No PK interaction was observed. Conclusions: The MTD for XP-105 monotherapy and in combination with exemestane or paclitaxel was defined as 220 mg and 160mg once daily, respectively. Combination regimens showed higher activity as compared to monotherapy with durable OR in about 20% of pts. The observed safety profile of XP-105 compared favorably to those reported from other mTOR inhibitors. Clinical trial information: NCT01938846.
USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance
Authors: Yu Zhang, Rong-bei Liu, Qian Cao, Ke-qi Fan, Ling-jie Huang, Jian-shuai Yu, Zheng-jun Gao, Tao Huang, Jiang-yan Zhong, Xin-tao Mao, Fei Wang, Peng Xiao, Yuan Zhao, Xin-hua Feng, Yi-yuan Li, Jin Jin
Journal: Journal of Clinical Investigation (2019)

Calcineurin acts as a calcium-activated phosphatase that dephosphorylates various substrates, including members of the nuclear factor of activated T cells (NFAT) family, to trigger their nuclear translocation and transcriptional activity. However, the detailed mechanism regulating the recruitment of NFATs to calcineurin remains poorly understood. Here, we report that calcineurin A (CNA), encoded by PPP3CB or PPP3CC, is constitutively ubiquitinated on lysine 327, and this polyubiquitin chain is rapidly removed by ubiquitin carboxyl-terminal hydrolase 16 (USP16) in response to intracellular calcium stimulation. The K29-linked ubiquitination of CNA impairs NFAT recruitment and transcription of NFAT-targeted genes. USP16 deficiency prevents calcium-triggered deubiquitination of CNA in a manner consistent with defective maintenance and proliferation of peripheral T cells. T cell-specific USP16 knockout mice exhibit reduced severity of experimental autoimmune encephalitis and inflammatory bowel disease. Our data reveal the physiological function of CNA ubiquitination and its deubiquitinase USP16 in peripheral T cells. Notably, our results highlight a critical mechanism for the regulation of calcineurin activity and a novel immunosuppressive drug target for the treatment of autoimmune diseases.
A novel mechanism of miRNA-mediated CBX8 associated with tumorigenesis in head and neck squamous cell carcinoma.
Authors: Shine-Gwo Shiah, Sung-Tau Chou, Ching-Chuan Kuo, Ya-Hui Chi
Journal: Journal of Clinical Oncology (2019)

e17534 Background: Polycomb group (PcG) proteins influence the development and progression of cancer. However, the mechanism that contributes to tumorigenesis have not been fully understood in head and neck squamous cell carcinoma (HNSCC). Methods: The expression of chromobox 8 (CBX8), a member of the polycomb group (PcG) of proteins, on OSCC patients was determine by quantitative real-time PCR (qRT-PCR) and immunohistochemistry. Specific targeting by miRNAs was determined by software prediction, luciferase reporter assay, and correlation with target protein expression. The functions of miR-410-3p and CBX8 were accessed by transwell migration and invasion analyses using gain- and loss-of-function approaches. Results: Here we found that CBX8 is upregulated in HNSCC tissues and cell lines. Using CBX8 knockdown cDNA microarray, we identify a CBX8-mediated target gene MIPOL1 which is inversely correlated with CBX8 expression in HNSCC tissues. Ectopic expression of MIPOL1 could inhibit tumor invasion and migration, whereas MIPOL1 silencing suppressed these effects in CBX8-knockdown HNSCC cells. Otherwise, depletion of CBX8 also induced p53 activity and increased the expression level of p21 and p27 through MIPOL1-independent manner, which result in cell cycle arrest in G2M phase. Silencing of p53 could inhibit p21 and p27 accumulation in CBX8 knockdown cells. Furthermore, we demonstrated that down-regulation of miR-410-3p promoted HNSCC cells migration and invasion through directly targeting CBX8. Overexpression of miR-410-3p decreased CBX8 expression and reduced migration and invasion, while ectopic expression of CBX8 rescued the miR-410-3p-reduced migration and invasion. In clinical samples, miR-410-3p level closely inversely correlated with CBX8 and positively correlated with MIPOL1. Conclusions: Collectively, our findings indicate that miR-410-3p may act as a tumor suppressor via negatively regulating CBX8. The newly identified miR-410-3p/CBX8/MIPOL1 and miR-410-3p/CBX8/p53 signaling axes may suggest new therapeutic strategies against HNSCC.
Endoscopic grading of gastric intestinal metaplasia: can we do it without pathologists?
Authors: Manon C. W. Spaander
Journal: Endoscopy (2019)

The introduction of narrow-band imaging (NBI) had led to a major step forward in the endoscopic identification of lesions in the gastrointestinal tract. This endoscopic improvement puts in doubt the conventional way of assessing gastrointestinal lesions. For the esophagus and colon, this is already a matter of debate: do we still need to take random biopsies in Barrett’s esophagus and in inflammatory bowel disease surveillance? Do we still need to send every colorectal polyp to pathology or can we resect and discard? The same discussion can also be held for premalignant lesions of the stomach when using NBI.