tbuckley/cabot-search huggingface dataset:
Risk of arterial thromboembolic events (ATEs) with tyrosine kinase inhibitors (TKIs) used in renal cell carcinoma: A systematic review and meta-analysis.
Authors: Muhammad Zain Farooq, Jessey Mathew, Saad Malik, V V Pavan Kedar Mukthinuthalapati, Noureen Asghar, Anum Riaz, Zarish Cheema, Irbaz Bin Riaz, Haris Zahoor
Journal: Journal of Clinical Oncology (2019)

e13119 Background: Tyrosine kinase inhibitors (TKIs) are routinely used in the treatment of metastatic RCC and Sunitinib is approved for the use in adjuvant setting. Arterial thromboembolic events (ATEs) have been described with these agents, although the overall risk remains unclear. We did a systematic review and meta-analysis to determine the incidence associated with the use of FDA approved TKIs used in treatment of RCC. Methods: PubMed, EMBASE, Cochrane Central and Scopus databases were searched to identify phase 2 and 3 RCTs of TKI therapy in RCC. Trials were included if they reported ATEs defined as arterial thrombosis, cerebral ischemia or infarction, myocardial ischemia and myocardial infarction. The DerSimonian-Laird random effects meta-analysis was performed using CMAv3 software to derive pooled estimates of incidence rates of ATEs with its 95% confidence interval (CI). I 2 statistic was computed to express the percentage of the total observed variability due to study heterogeneity. Risk for bias was assessed using the Cochrane Collaboration’s tool. Results: 1755 studies retrieved in the initial search, and 13 phase 2 and 3 clinical trials (n = 4983) were included in the quantitative analysis. The trials had open label design which can potentially result in bias. Risk of bias was low in all other domains. TKIs used for the treatment of RCC included sunitinib (n = 2632), sorafenib (n = 981), cabozantinib (n = 78), pazopanib (n = 844), axitinib (n = 189) and tivozanib (n = 259). The incidence of ATEs with the use of TKIs was 2.9% (95% CI: 2-3%). Cabozantinib was associated with the highest rate of ATEs (11.5%, 95% CI: 6-21%), followed by sunitinib (2.6%, 95% CI:2-3%) pazopanib (2.6%, 95% CI:2-4%) and axitinib (2.1%, 95% CI: 1-6%). The TKI with lowest event rate of ATE was tivozanib (0.8%, 95% CI:0.2-3%). Conclusions: The use of TKIs is associated with increased risk of developing ATEs. Clinicians should be aware of the possibility of increased ATEs and counsel the patients about this increased risk to enhance the process of informed decision making.
A phase I clinical trial using armored GPC3 CAR T cells for children with relapsed/refractory liver tumors.
Authors: David Henry Michael Steffin, Sai A Batra, Purva Rathi, Linjie Guo, Wenpeng Li, Amy N Courtney, Leonid S Metelitsa, Andras Heczey
Journal: Journal of Clinical Oncology (2019)

TPS2647 Background: CAR T therapies have been successful against hematologic malignancies, but have benefited only a handful of patients with solid cancers. Glypican 3 (GPC3) is an attractive immunotherapeutic target due to its preferential expression on multiple pediatric and adult solid cancers and lack of expression on non-malignant tissues. GPC3-CAR T cells were tested preclinically and inclusion of the 4-1BB costimulatory endodomain with IL-15 and IL-21 co-expression enabled CAR T cells to expand and persist the most in vitro and in vivo and led to robust antitumor activity in vivo. We are now testing GPC3-CAR T cells with IL15 and IL-21 for the first time in children with relapsed/refractory liver tumors. Methods: In this Phase 1 trial (GAP, NCT02932956), we are evaluating patients in 3 cohorts: 1) GPC3-CAR alone; 2) GPC3-CAR and IL-15; 3) GPC3-CAR with IL-15 and IL-21. We will 1) define the safety and establish the Recommended Phase 2 Dose (RP2D) of GPC3-CAR T cells co-expressing IL-15 and IL-21; 2) determine persistence and anti-tumor activity of GPC3-CAR T cells; 3) examine changes in gene and protein expression in the tumor microenvironment associated with potential immune escape mechanisms. Inclusion criteria are the following: age ≤18; histology proven, GPC3-positive tumor; life expectancy&gt;12 weeks; Child-Pugh-Turcotte score&lt;7; serum AST&lt;5 times ULN; total bilirubin&lt;3 times ULN for age; INR ≤1.7; absolute neutrophil count&gt;500/μl; platelet count&gt;20,000/μl; Hgb≥9.0 g/dl. Toxicity will be monitored using the Common Terminology Criteria of Adverse Events v4. The RP2D will be determined by the standard 3+3 dose escalation method using 5 dose levels. Persistence will be quantified using RT-PCR and flow cytometry. Antitumor activity will be defined by 3D imaging using RECIST 1.1 criteria and the immune-related response criteria. Immune-escape will be examined using single cell RNA sequencing and imaging of paraffin-embedded tissues using codetection by indexing to evaluate candidate proteins. Data will be analyzed via descriptive statistics. Cohort 1 of this study is now open for enrollment. Clinical trial information: NCT02932956.
Tumor growth rate as an early indicator of the efficacy of anti-PD-1 immunotherapy in advanced melanoma.
Authors: Bixia Tang, Zhihong Chi, Xinan Sheng, Lu Si, Chuanliang Cui, Yan Kong, Xieqiao Yan, Siming Li, Lili Mao, BIN LIAN, Xuan Wang, Xue Bai, Li Zhou, Jie Dai, Jun Guo
Journal: Journal of Clinical Oncology (2019)

e21050 Background: As immunotherapeutics take longer time to show clinical efficacy compared with chemotherapy and targeted therapy, it is critical to select patients with low tumor growth rate (TGR) prior immunotherapy as to get sufficient time for immunotherapeutics to play functions. However, which threshold of TGR before immunotherapy may be associated with good outcome remains unknown. Methods: Medical records from patients with advanced refractory melanoma prospectively treated in clinical trials (NCT02836795 and NCT03013101) of anti-PD-1 antibody toripalimab were analyzed. TGR was computed during the pretreatment period (reference) and the treatment period (treatment). Associations between TGR and objective response at the first evaluation, progression free survival (PFS), overall survival (OS) were computed. Results: We analyzed a total of 142 patients enrolled in these two clinical trials. Excluded for no measurable lesions in pretreatment period or incomplete imaging data through the pretreatment/treatment periods, a total of 90 patients could be explored for the relationship of TGR and the efficacy of anti-PD-1 antibody. TGR and hyperprogression were defined as Champiat S. used to make. The distribution of TGR is as follows: median 63.7 (range: -51~720). A total of 15 (16.7%), 41 (45.6%), 34 (37.8%) and 0 patients exhibited PR, SD, PD, CR, respectively. An association between lower TGR (TGR ≤55) and objective response was observed (P≤0.001). Among evaluable patients at week 8, 83.9% (13+34/56) and 26.5% (2+7/34) showed PR/SD from baseline tumor measurements for the group of TGR≤55 and TGR &gt; 55, respectively. Median PFS was 5.5 0.9m in the group of TGR≤55 compared 1.8 0.4m in the group of TGR &gt; 55 (P≤0.001). Median OS was not reached in the group of TGR≤55 group and was 15.9 1.8m in the group of TGR &gt; 55 (p = 0·02). Two patients were confirmed pseudoprogression in the follow-up. The TGR of these two patients was lower than 55. Five patients experienced hyperprogression. The TGR of each patient was 9, 12, 54, 56, 78, respectively. Conclusions: Melanoma patients with TGR≤55 prior anti-PD-1 antibody therapy are more likely to benefit from this regimen. However, it could not predict patients who may develop hyperprogression after anti-PD-1 antibody therapy. Clinical trial information: NCT02836795 and NCT03013101.
A retrospective study evaluating clinical predictors of duration of response to immune checkpoint inhibitors in patients with advanced non-small cell lung cancer.
Authors: Yahya Ibrahim, Keerthana Sankar, Hassan Mouzaihem, Seongho Kim, Amy Haddad, Hirva Mamdani
Journal: Journal of Clinical Oncology (2019)

e20665 Background: Immune Checkpoint Inhibitors (ICI) with/without chemotherapy has become the standard of care for the treatment of advanced/metastatic non-small cell lung cancer (NSCLC). Similar to the response rate, durability of response to ICI is quite variable. While programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) have been described to predict response to ICI, little is known about the clinical predictors of duration of response (DoR). Methods: A retrospective chart review of patients (pts) with advanced NSCLC treated with ICI based therapy at Karmanos Cancer Institute was conducted. Data were collected on demographics, clinical characteristics, and tumor characteristics. Univariable and multivariable cox regression analyses were performed for six pre-chosen covariates (histology, prior radiation therapy, brain metastasis, occurrence of immune-related adverse events (irAEs), statin use and smoking status) to see the associations with the DoR to ICI. Results: One hundred thirty-one pts were included in the analysis (68% adenocarcinoma, 60% received prior radiation, 20% had brain metastasis, 26% developed irAEs, 33% were on a statin, 69% former smokers, 12% current smokers and 19% never smokers). Overall median DoR was 149 days (range, 14-1934 days). On multivariable analysis, longer DoR to ICI was observed in pts with non-adenocarcinoma histology (HR: 0.65; p = 0.050; CI: 0.42-1.00, median DoR 242.5 days) and current smokers (HR: 0.53; p = 0.031; CI: 0.30-0.95, median DoR 206.5 days). Other variables, including the presence of brain metastasis, prior radiation therapy, occurrence of irAEs and statin use had no significant relationship with the DoR. Conclusions: Tumor histology and smoking status were statistically and clinically significant predictors of durability of response to ICI in advanced NSCLC, presumably secondary to higher tumor mutational burden. Presence of brain metastasis did not adversely impact DoR to ICI.
Long Noncoding RNA p53‐Stabilizing and Activating RNA Promotes p53 Signaling by Inhibiting Heterogeneous Nuclear Ribonucleoprotein K deSUMOylation and Suppresses Hepatocellular Carcinoma
Authors: Geng Qin, Xinyi Tu, Haibei Li, Pengbo Cao, Xi Chen, Jin Song, Hui Han, Yuanfeng Li, Bingqian Guo, Liting Yang, Pandeng Yan, Peiyao Li, Chengming Gao, Jinxu Zhang, Ying Yang, Jian Zheng, Huai‐qiang Ju, Lei Lu, Xuan Wang, Chaohui Yu, Yi Sun, Baocai Xing, Hongzan Ji, Dongxin Lin, Fuchu He, Gangqiao Zhou
Journal: Hepatology (2019)

To identify hepatocellular carcinoma (HCC)‐implicated long noncoding RNAs (lncRNAs), we performed an integrative omics analysis by integrating mRNA and lncRNA expression profiles in HCC tissues. We identified a collection of candidate HCC‐implicated lncRNAs. Among them, we demonstrated that an lncRNA, which is named as p53‐stabilizing and activating RNA ( PSTAR ), inhibits HCC cell proliferation and tumorigenicity through inducing p53‐mediated cell cycle arrest. We further revealed that PSTAR can bind to heterogeneous nuclear ribonucleoprotein K (hnRNP K) and enhance its SUMOylation and thereby strengthen the interaction between hnRNP K and p53, which ultimately leads to the accumulation and transactivation of p53. PSTAR is down‐regulated in HCC tissues, and the low PSTAR expression predicts poor prognosis in patients with HCC, especially those with wild‐type p53. Conclusion: This study sheds light on the tumor suppressor role of lncRNA PSTAR , a modulator of the p53 pathway, in HCC.
Prostate carcinoma in African-Americans has miRNA expression and biological markers for aggressive disease.
Authors: Malhaar Agrawal, Zaheer Bukhari, Aksiniya Stevasarova, Martin Tenniswood, Raavi Gupta
Journal: Journal of Clinical Oncology (2019)

e16558 Background: African American (AA) men have twice the incidence and mortality in Prostate Cancer (PCa) as compared to non-Hispanic Whites. The identification of a biological basis for this disparity is crucial in providing focused treatment. In this study, we have characterized the pathological features and molecular markers of PCa in AA men. Methods: 91 proctectomies for primary PCa and 23 biopsies for metastatic PCa with their pathological data were retrieved. Tissue microarrays were constructed and the expression of Programmed Cell Death 1 (PD-1), Programmed Death Ligand 1 (PD-L1) and Mismatch Repair (MMR) (MLH1, MSH2, MSH6 and PMS2) proteins was assessed by immunohistochemistry. miRNA expression of 24 cases of primary PCa and adjacent normal prostate tissue from proctectomies was identified by microarray in situ hybridization. Spearman’s rank-correlation was used to correlate variables and p &lt; .05 was considered significant. TargetScan and DIANA analysis software were used to identify modulation in miRNA expression. Results: In a supervised heat map, overall the downregulation of microRNA was more than upregulation in tumor tissue; 11 miRNA were upregulated and 12 were downregulated, with a log fold change of 1.5. miR-345, a component of the mismatch repair and DNA Replication pathway, showed significant up-regulation (p = 9.4E-02); has been linked to more aggressive PCa. PD-L1 expression was lower in primary PCa (16%) than in metastatic PCa (35%). PD-1 expression was high in almost half of primary and metastatic PCa patients. MMR protein expression was largely intact in both primary and metastatic PCa cases. Both of these protein markers have been associated with biochemical recurrence and low survival. Conclusions: The biological characteristics (low expression of PD-L1, high expression of PD-1, intact MMR and distinct miRNA signature) identified in our cohort of exclusively AA men are indicators of aggressive PCa. These results explain the biological basis of widely documented poor prognosis of PCa in AA men.
Changes in Albuminuria But Not GFR are Associated with Early Changes in Kidney Structure in Type 2 Diabetes
Authors: Helen C. Looker, Michael Mauer, Pierre-Jean Saulnier, Jennifer L. Harder, Viji Nair, Carine M. Boustany-Kari, Paolo Guarnieri, Jon Hill, Cordell A. Esplin, Matthias Kretzler, Robert G. Nelson, Behzad Najafian
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Although diabetic nephropathy is assessed clinically by measuring eGFR and albuminuria, structural kidney damage typically precedes these clinical manifestations. Previous studies have assessed early structural change in type 1 diabetes but not in type 2. In a study of American Indian patients with type 2 diabetes and generally preserved kidney function, the authors found changes in kidney structure over an average of 9 years, as determined by quantitative morphometric analysis of kidney biopsy specimens. They also found that these kidney structure changes were more consistently associated with changes in albuminuria than with changes in measured GFR. This finding suggests that for people with normal or elevated GFR, increasing albuminuria may better than early GFR decline in reflecting the risk of progressive type 2 diabetic nephropathy. Background In type 1 diabetes, changes in the GFR and urine albumin-to-creatinine ratio (ACR) are related to changes in kidney structure that reflect disease progression. However, such changes have not been studied in type 2 diabetes. Methods Participants were American Indians with type 2 diabetes enrolled in a clinical trial of losartan versus placebo. We followed a subset who underwent kidney biopsy at the end of the 6-year trial, with annual measurements of GFR (by urinary clearance of iothalamate) and ACR. Participants had a second kidney biopsy after a mean follow-up of 9.3 years. We used quantitative morphometric analyses to evaluate both biopsy specimens. Results Baseline measures for 48 participants (12 men and 36 women, mean age 45.6 years) who completed the study included diabetes duration (14.6 years), GFR (156 ml/min), and ACR (15 mg/g). During follow-up, glomerular basement membrane (GBM) width, mesangial fractional volume, and ACR increased, and surface density of peripheral GBM and GFR decreased. After adjustment for sex, age, ACR, and each morphometric variable at baseline, an increase in ACR during follow-up was significantly associated with increases in GBM width, mesangial fractional volume, and mean glomerular volume, and a decrease in surface density of peripheral GBM. Decline in GFR was not associated with changes in these morphometric variables after additionally adjusting for baseline GFR. Conclusions In American Indians with type 2 diabetes and preserved GFR at baseline, increasing ACR reflects the progression of earlier structural glomerular lesions, whereas early GFR decline may not accurately reflect such lesions.
A phase II study of apatinib combined with S-1 in previously treated refractory metastatic colorectal cancer.
Authors: Ning Li, Wenying Deng, Guifang Zhang, Yanwei Guo, Yijie Ma, Qiong Wu, Xinyi Yang, Suxia Luo
Journal: Journal of Clinical Oncology (2019)

e15016 Background: Although regorafenib and fruquintinib have been recommended as the third-line treatment for patients with refractory metastatic colorectal cancer (mCRC), the median survival time of mCRC is still only for 4-8 months and the low response rate and unpleasant side effects limit their use in Chinese patients. Apatinib, an oral VEGFR-2 inhibitor, has been approved as a third line treatment in metastatic gastric cancer. In addition, apatinib has demonstrated good safety, tolerability, and efficacy in the treatment of advanced solid tumors. The aim of this study was to assess the efficacy and safety of apatinib combined with S-1 in the treatment of refractory mCRC. Methods: In this prospective, open-label, single-arm, multicenter, phase II study, patients after failure of second-line chemotherapy were enrolled and took apatinib (250mg, daily) combined with S-1 (standard dose). The primary endpoint was progression free survival (PFS) and the second endpoint was response rate and overall survival time. Results: From December 2017, 22 patients (14 male) with a median age of 56y (range: 34-71 y) were enrolled and eligible for evaluation of the PFS, response rate and safety. The median PFS was 105d (95% CI: 79.01-130.98). two patients (9%) achieved partial response, 15 (68.18%) achieved stable disease, and 5 (22.72%) were progressive disease. The objective response rate and the disease control rate were 9% and 77.27%, respectively. Median overall survival was not reached. The common adverse effects were abnormal liver function (7/22; 31.81%), leukopenia (5/22; 22.72%) and thrombocytopenia (4/22; 18.18%). The incidence for grade 3-4 side effect was very low. One patient experienced grade 3 proteinuria and there were no toxic deaths. Conclusions: This preliminary result indicated that apatinib combined with S-1 may extend the PFS in mCRC, with well-tolerated toxicities, making it a promising therapeutic target for mCRC treatment. Clinical trial information: NCT03397199 .
Genomic predictors of benefit of docetaxel (D) and next-generation hormonal therapy (NHT) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Anis Hamid, Himisha Beltran, Atish Dipankar Choudhury, Christopher Sweeney
Journal: Journal of Clinical Oncology (2019)

5018 Background: Predictive genomic biomarkers in mCRPC remain elusive. Prior studies suggest that tumor suppressor (TS) loss is prognostic, and may result in less benefit from NHT, but no impact on D efficacy. We assessed genomic predictors of differential benefit of androgen receptor-targeted therapy and chemotherapy for mCRPC. Methods: Patients with mCRPC and targeted exome sequencing of biopsies obtained after metastatic diagnosis were identified (n=109). Patients with pure small cell histology (n=6) were excluded. Time from NHT or D start to clinical/radiographic progression (time to treatment failure, TTTF) was estimated by Kaplan-Meier method, with censoring at next therapy or last follow-up for non-progressors. Results: 80.1% of patients had bone and/or lymph node-only metastases at mCRPC diagnosis. In total, 87/103 (84.5%) and 61/103 (59.2%) received NHT and D for mCRPC, respectively. Median overall survival was 4.5 years from first mCRPC. The frequency and predictive association of selected recurrently-altered genes are detailed in the table. PTEN alterations (alts) were associated with worse TTTF on NHT, but not D, and a similar trend was observed with BRCA2. Biallelic RB1 loss was strongly predictive, conferring significantly shorter TTTF on both NHT and D. A score based on presence of tumor PTEN alt (1) and/or biallelic RB1 alt (1) was predictive of TTTF on NHT (median TTTF of score 0 vs 1 vs 2: 14.7 vs 12 vs 3.8 months; log rank p=0.003). Conclusions: The presence of single or compound PTEN and RB1 alts predict poorer outcomes with NHT for mCRPC. Chemotherapy may be a preferred therapeutic strategy for this patient population. [Table: see text]
Treatment outcome for primary cervix large B-cell lymphoma: A clinical analysis of thirty-seven cases.
Authors: Xiaojian LIU
Journal: Journal of Clinical Oncology (2019)

e17025 Background: Cervical lymphoma is a rare condition and may be difficult to diagnose and treatment. Large B-cell lymphoma is among the most common sub-type of Cervical Lymphoma.No standard treatments for patients with primary cervix large B-cell lymphoma have been introduced currently. Only case reports published in the literature and indicated the R-CHOP regimens in combination with involved field radiation therapy (RT) are effective. Shanghai Cancer Center is one of the top pathological consultant center in China. We retrospectively analyse the 37 patients with primary cervix large B-cell lymphoma and outcome after R-CHOP in combination with RT. Methods: Thirty-seven untreated primary cervix large B-cell lymphoma patients received R-CHOP like regimens. Fourteen of them underwent subsequent RT. Thirteen of them received subsequent salvage chemotherapy. Results: Of 37 patients underwent R-CHOP chemotherapy, only 3 patients received the radical surgery. An overall response rate (ORR) was 78.3% after completion of chemotherapy.The PFS and OS rate at 5 years were 58% and 69%, respectively. For 14 patients who received RT after R-CHOP, an estimated ORR were 89.2%. For all patients, The PFS reached the platform after 2 years follow up and the OS after 3 years according to the survival curve analysis. The international prognostic index (IPI) score were the only predictor of worse outcome. Conclusions: R-CHOP regimens plus involved field radiation therapy led high response rate in primary cervix large B-cell lymphoma. Patients with high IPI had a trend of less satisfied with R-CHOP regimens plus IFRT. Future prospective and multicenter studies are needed. By the way, we are conducting a gene expression profile between DLBCL-unspecified and primary cervix large B-cell lymphoma by NGS in order to get the valuable information to improve the treatment outcome even by using some targeted drugs. The data will be show in the next few months.