tbuckley/cabot-search huggingface dataset:
Comparison of panendoscopy directed biopsies with percutaneous and image-guided biopsies during immune checkpoint inhibitor therapy.
Authors: Ahmad F Hashmi, Daniel Arnold Smith, Amir Ata Rahnemai-Azar, Pavitra Ravishankar, David Pfau, Ariel Ann Nelson, Christopher J. Hoimes, Nikhil H. Ramaiya
Journal: Journal of Clinical Oncology (2019)

e14084 Background: Immune checkpoint inhibitors (ICI) have been shown to be helpful in the treatment of a several cancers. Response to ICI therapy is varied. The goal of this study was to examine the role of pan-endoscopy guided biopsies as well as image-guided and percutaneous biopsies as a means to tailor treatment regimens for patients receiving ICI therapy. Methods: A retrospective chart review was performed on oncology patients at a single institution from 2010 from 2018 undergoing treatment with ICI (n = 1044). Patients undergoing biopsies within the treatment period and up to one month following conclusion of treatment were analyzed and separated into a pan-endoscopy guided biopsy cohort or image-guided/percutaneous biopsy cohort. Data regarding biopsy results and subsequent treatment plans was then gathered and compared. Results: 5.3% of patients underwent pan-endoscopy guided biopsy (n = 55). 6.0% of patients underwent image-guided/percutaneous biopsy (n = 63). The most common endoscopic procedures included EGD 42.6%, bronchoscopy 38.9%, and flexible sigmoidoscopy/colonoscopy 20.4%. The most common image/percutaneously sampled tissues included skin/soft tissue 24.6%, lymph nodes 19.7%, and liver 16.4%. Breakdown of treatment complications in the pan-endoscopy group included pneumonitis 3.2%, inflammatory or infectious esophagitis 6.4%, or colitis 4.3%. Treatment complications in the image guided/percutaneous group included skin reactions 2.2% and inflammatory mediastinal changes 1.1%. Conclusions: In our cohort, Pan endoscopy and image guided/percutaneous biopsies were successfully performed along multiple cancer cell lines and helped in the decision making process.[Table: see text]
Voltage: Investigator-initiated clinical trial of nivolumab monotherapy and subsequent radical surgery following preoperative chemoradiotherapy in patients with microsatellite stable locally advanced rectal cancer.
Authors: Takayuki Yoshino, Hideaki Bando, Yuichiro Tsukada, Koji Inamori, Satoshi Yuki, Yoshito Komatsu, Shigenori Homma, Mamoru Uemura, Takeshi Kato, Daisuke Kotani, Shota Fukuoka, Takeshi Sasaki, Yuji Nishizawa, Naoki Nakamura, Masashi Wakabayashi, Motohiro Kojima, Yosuke Togashi, Akihiro Sato, Hiroyoshi Nishikawa, Masaaki Ito
Journal: Journal of Clinical Oncology (2019)

3606 Background: Chemoradiotherapy (CRT) with surgery (S) is standard for patients (pts) with locally-advanced rectal cancer (LARC), and nivolumab (nivo) is active in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). We studied nivo and radical S following CRT (50.4 Gy with capecitabine 1,650 mg/m 2 ) in T 3–4 N any M 0 LARC. Methods: Phase I included testing of a recommended phase II dosing schedule (RP2S). Efficacy and safety were studied in phase II pts and those given RP2S in phase I. In Cohort A-1, for microsatellite stable (MSS) LARC pts, the primary endpoint was centrally confirmed pathologic complete response (pCR) rate using AJCC tumor regression grading. The estimated required sample size assuming null and alternative hypotheses pCR = 10% and 30% was 37 pts, with a 1-sided alpha of 5% and power of 90%. Cohort A-2 was exploratory and included a maximum of 5 MSI-H pts. Results: Nivo 240 mg q2 weeks x 5 cycles, following CRT but pre-S, was the RP2S. From 1/17 to 6/18, 37 pts were enrolled in Cohort A-1. Eleven pts (30%; 90% CI 18-44%) showed pCR (AJCC grade (gr) 0). Including the 3 pts (8%) graded AJCC 1, 14 (38%) had major pathologic responses. In addition, clinical CR was observed in 1 pt (3%) refusing S after nivo. Both MSI-H LARC Cohort A-2 pts showed pCRs. Immune-related severe adverse events were observed in 2 pts (gr 3 myasthenia and gr 2 interstitial nephritis); both fully recovered and had S. No treatment-related deaths were observed. pCR rates of 60% (6/10) and 19% (5/27) (p = 0.038, Fisher exact test) were seen in pts with tumor cells with PD-L1 ≥1% and &lt; 1% IHC staining, respectively, performed on biopsy samples taken pre-CRT. Rates of 62% (8/13) and 10% (1/10) (p = 0.029) were seen in 23 pts with samples analyzable by flow cytometry, according to CD8 + lymphocyte /regulatory T cell (CD8/T reg ) ratios ≥2 and &lt; 2, respectively. Conclusions: A promising pCR rate of 30%, with mild toxicity, was shown in MSS LARC pts treated with nivo plus radical S. PD-L1 expression and elevated CD8/T reg ratio may be better predictors of nivo benefit, warranting further study in a larger cohort. Clinical trial information: NCT02948348.
Examination of the additive value of CTC biomarkers of heterogeneity (Het) and chromosomal instability to nuclear-localized (nl) AR-V7+ CTCs in prediction of poor outcomes to androgen receptor signaling inhibitor (ARSi) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Howard I. Scher, Joseph Schonhoft, Ryon P Graf, Adam Jendrisak, Ethan Barnett, Anuradha Jayaram, Eric Winquist, Mark Landers, Yipeng Wang, Alison L Allan, Gerhardt Attard, Ryan Dittamore
Journal: Journal of Clinical Oncology (2019)

5075 Background: Prediction of ARSi benefit in mCRPC is an unmet medical need. Recently, the Epic Sciences CTC based nl AR-V7 test validated as a predictive biomarker in two multi-center validation studies and has received Medicare coverage for use in mCRPC. While the nl AR-V7 biomarker is highly specific to resistance and predictive of improved response with taxane Rx, it is a measure of just one mechanism of resistance to ARSis. CTC Het measured by the Shannon Index and CTC chromosomal instability measured by predicted number of Large Scale Transitions (pLST) have both been associated with poor OS to ARSis in previous analysis. Here we investigate the relationship of Het and pLST to nlAR-V7 in order to assess multi-clonal resistance and determine if these biomarkers can provide added sensitivity in the nlAR-V7 negative patient population. Methods: 275 blood samples from 2 nd + line mCRPC patients prior to treatment with ARSi (n=148) or taxanes (n=137) were obtained between 2012 and 2017 from 3 clinical centers. Detectable CTCs in each blood sample were assayed for nlAR-V7, Het, and pLST using the Epic Sciences platform. Biomarkers were analyzed in context of each other and outcomes including clinical co-variates. Results: 94% of samples had detectable CTCs, 84% were evaluable for Het analysis (&gt; 2 CTCs), and 76% were evaluable for pLST (&gt; 3 CTCs). Conclusions: Addition of CTC Het (Shannon Index) and CTC chromosomal instability (pLST) biomarkers to nlAR-V7 identifies an additional 15% of mCRPC pts (38% of total) that are predicted to have poor survival to AR signaling inhibitors. [Table: see text][Table: see text]
Immune-related adverse events for different age groups using the FDA Adverse Event Reporting System.
Authors: Zin Myint, Ayman Qasrawi, Richard O'Neal, Chris Z Thomas, Susanne M. Arnold, Peng Wang
Journal: Journal of Clinical Oncology (2019)

e14256 Background: Understanding immune-related adverse events (irAEs) for different age groups is crucial in the era of immunotherapy. The aim of our study is to assess the irAE profiles in different age groups (≤65 and &gt; 65 years) for drugs that target PD1/PDL1, CTLA4, and their combination. Methods: Data were obtained from the FDA Adverse Event Reporting System database from Jan 2014 to Sep 2018. We extracted the data based on reported irAEs and reviewed 30 different irAEs including, but not limited to colitis, pneumonitis, interstitial lung disease (ILD), myocarditis and pneumonitis. Cases with missing data, another drug reported with the PD1/PDL1 or CTLA4 combinations, and duplicate cases were excluded. We calculated the reporting odds ratio (ROR) for irAE associated with the use of PD1/PDL1, CTLA4 and combination, respectively. Results: A total of 6197 reported irAEs cases were included: 3140 cases from patients ≤65 years and 3057 from &gt; 65 years old. Colitis was the most common irAEs in both groups. The RORs (95% CI) in patients using CTLA4 alone, PD1/PDL1 alone or the combination were 4.17 (3.47-5.02), 0.6 (0.5-0.72), 1.98 (1.64-2.39) for colitis; 0.21 (0.09-0.52), 2.94 (1.97-4.38), 2.2 (1.46-3.3) for diabetic ketoacidosis; 0.29 (0.09-0.92), 16.5 (6.54-41.9), 0.18 (0.04-0.73) for rheumatoid arthritis in ≤65 age group. In &gt; 65 age group, the RORs (95% CI) in patients using CTLA4 alone, PD1/PDL1 alone or the combination were 4.79 (3.49-6.58), 0.56 (0.4-0.78), 2.84 (2.06-4) for hypophysitis; 0.12 (0.06-0.24), 28.53 (18.5-44), 0.17 (0.1-0.29) for interstitial lung disease (ILD); 0.38 (0.19-0.78), 2.87 (2.01-4.1), 2.41 (1.64-3.54) for myocarditis. When we compared all the studied irAEs between age groups (≤65 and &gt; 65) by ROR, the only statistically significant irAE was ILD. The RORs (95%CI) for ILD associated with PD1/PDL1 in age≤65 and &gt; 65 were 11.3 (7.65-16.8) &amp; 28.53 (18.49-44.02). Conclusions: There was no significant difference between irAEs in different age groups except with ILD, which is more commonly seen in the &gt; 65 age group. The ROR combination irAE profiles provide hypothesis generating information regarding association between irAEs and the use of various immune therapies.
A phase Ib study of pembrolizumab (Pem) in combination with stereotactic body radiotherapy (SBRT) for resectable liver metastatic MSS colorectal cancer (CRC): A postoperative safety analysis.
Authors: Michael Frederick Bassetti, Anita Ahmed Turk, Sam Joseph Lubner, Nataliya Volodymyrivna Uboha, Noelle K. LoConte, Daniel Mulkerin, David H. Kim, Kristina Matkowskyj, Sharon M. Weber, Daniel Abbott, Jens C. Eickhoff, Dustin A. Deming
Journal: Journal of Clinical Oncology (2019)

e15047 Background: Adjunctive therapies are essential to enhance the effect of anti-PD1 therapies for the treatment of microsatellite stable (MSS) colorectal cancer. SBRT is utilized to treat liver metastatic CRC, causing an increase in immunogenic intra-tumoral and intra-lymphatic antigen release and a rapid influx of responding immune cells. We hypothesize that radiation enhances the immunogenicity of MSS CRC and potentiates the effectiveness of PD-1 blockade. This phase Ib study examines the safety and efficacy of the sequential combination of SBRT and Pem in patients for whom the goal is to resect all sites of known disease. Methods: Key eligibility criteria include MSS CRC with liver-confined metastatic disease with the therapeutic goal of resection of all radiographic disease with one operation. Subjects must be a candidate for SBRT to 1-3 liver metastases. Prior surgery and systemic chemotherapy are allowed. Subjects receive sequential SBRT and cycle 1 of Pem prior to operative management. Postoperatively, patients complete cycles 2-9 of Pem followed by scheduled surveillance with imaging every 12 weeks. The primary objectives are to determine the safety/tolerability of this regimen and the recurrence rate at 1 year following clearance of metastatic disease. Secondary objectives include time to recurrence, DFS, and OS. Results: 10 patients (median age 61.5 [range 39-69]) have been enrolled and completed the intended neoadjuvant therapy, operative management and at least 4 adjuvant cycles of Pem. All patients had received prior FOLFOX. SBRT median dose was 50 Gy (40-60 Gy) to a single lesion targeted in all patients. Mean gross tumor size targeted was 19.1cc (2.3-80.4). Any-grade post-operative AEs (&gt;20%) attributable to Pem include diarrhea (30%), hyperbilirubinemia (20%%), and leukopenia (20%). Post-operative AEs included one case of biliary tract injury and biloma, not related to immunotherapy. No grade 3/4 immunotherapy AEs have occurred. Conclusions: The combination of SBRT with Pem and surgical resection is well tolerated with no signal of increased immunotherapy-related toxicity in the post-operative setting. Clinical trial information: NCT02837263.
Fecundity of males after treatment for childhood cancer. A report from the Childhood Cancer Survivor Study (CCSS)
Authors: D. M. Green, T. Kawashima, W. Leisenring, M. Stovall, S. S. Donaldson, C. A. Sklar, J. Byrne, L. L. Robison
Journal: Journal of Clinical Oncology (2007)

9516 Background: Determine the proportion of male (M) survivors with impaired fecundity (IF). Methods: 6,555 CCSS M participants and 1,606 M siblings (S) were classified as surgically sterile (SS) for contraceptive purpose, SS for non-contraceptive purpose, IF (ongoing attempts to become pregnant for a period of one year without success or use of medication to help achieve a pregnancy), or fecund (F). Odds ratios (OR) were estimated using logistic regression, controlling for education level, marital status, age at baseline questionnaire, race/ethnicity and smoking status. Results: M were 6–29 years from cancer diagnosis (mean-16.3 years) and 15–44 years of age at the time of study (mean-25.4 years). 331 (5.0%) M or their partners were SS, 487 (7.4%) had IF and 5,737 (87.5%) were F. The OR (95% confidence interval (CI)) for being F was 0.66 (95% CI, 0.54–0.80) (p&lt;0.0001) compared to F MS. Among M, the OR for IF was 2.60 (95% CI, 1.97–3.42) (p&lt;0.0001) compared to F MS. The OR for IF was increased among those with a testicular (T) radiation dose (RD) of 0.1–499 cGy (OR=1.42; 95% CI 1.07–1.89; p=0.015), 500–599 cGy (OR=3.16; 95% CI 1.48–6.72; p=0.0028), 600–1,499 cGy (OR=2.53; 95% CI 1.26–5.09; p=0.009) and ≥ 2,400 cGy (OR=3.04; 95% CI 1.39–6.64; p=0.0054), pituitary (P) RD of 0.1–499 cGy (OR=1.89; 95% CI 1.41–2.55; p&lt;0.0001), CCNU (OR=2.14; 95% CI 1.25–3.66; p=0.0054), cyclophosphamide (OR=1.56;95% CI 1.23–1.97; p=0.0002), nitrogen mustard (OR=2.88;95% CI 2.08- 4.00; p&lt;0.0001), procarbazine (OR=2.97; 95% CI 2.24–3.93; p&lt;0.0001), vinblastine (OR=2.07;95% CI 1.41–3.04; p=0.00022), vincristine (OR=1.90; 95% CI 1.45–2.49; p&lt;0.0001) and melphalan (OR=2.43; 95% CI 1.09–5.43; p=0.03). The OR for IF increased with increasing alkylating agent score (AAS) (1 st tertile OR=1.70; 95% CI 1.19–2.43; p=0.0035; 2 nd tertile OR=2.63; 95% CI 1.82–3.81; p&lt;0.0001; 3 rd tertile OR=3.42; 95% CI 2.41–4.86; p&lt;0.0001). Multivariate analysis demonstrated that the combination of P ≥ 500 cGy and T ≥ 500 cGy (OR= 2.65; 95% CI 1.44–4.86; p=0.0017) and increasing AAS (1 st tertile OR=1.56; 95% CI 1.04–2.34; p=0.031; 2 nd tertile OR= 2.22; 95% CI 1.43–3.44; p=0.00036; 3 rd tertile OR=2.72;95% CI 1.74–4.25; p&lt;0.0001) were associated with IF. Conclusions: M have IF due in part to TRD and PRD and increasing AAS. No significant financial relationships to disclose.
Association between molecular subtype of esophageal squamous cell carcinoma and survival of patients.
Authors: Denis S. Kutilin, Oleg Ivanovich Kit, Aleksey Yurievich Maksimov, Natalia A. Petrusenko, Tatiana Yu. Myagkova, Mikhail A Kozhushko, Sergey V. Sanamyants, Evgeniy N. Kolesnikov
Journal: Journal of Clinical Oncology (2019)

e15520 Background: Esophageal squamous cell carcinoma (ESCC) comprises a group of heterogeneous tumors with various prognoses which does not depend on clinical signatures (TNM, tumor location). In recent years, different molecular subtypes of ESCC have been identified in different populations; however, such studies have not been conducted in the population of Southern Russia. The purpose of the study was the molecular typing of ESCC in patients of the Southern Russia, and the assessment of survival of patients with different molecular subtypes of ESCC. Methods: Tissue sections from FFPE blocks from 124 ESCC patients were studied. Tumor and normal cells were isolated using laser microdissection (Palm MicroBeam, Carl Zeiss). Molecular typing of ESCC was performed by the determination of copy number variation (CNV) of 8 genes ( CUL3, ATG7, SOX2, TP63, YAP1, VGLL4, CDK6, KDM6А) using Real-Time qPCR and 7 somatic mutations (SNP) ( NFE2L2 (c.85G &gt; A), NOTCH1 (c.1379C &gt; T), NOTCH1 (c.1451G &gt; T), ZNF750 (c.414C &gt; A), ZNF750 (c.1621G &gt; A), SMARCA4 (p.Q758*, c.2272C &gt; T), KMT2D (Q5170* , c.15508C &gt; T)) using Sanger direct sequencing method. The differences were assessed by the Mann-Whitney test. For the cluster analysis (Hierarchical Clustering, Euclidean distance), we used R scripts. Survival of patients was analyzed by the Kaplan–Meier method, and differences between survivals in groups were assessed by the log-rank test. Results: Cluster analysis allowed determination of 3 clusters of ESCC samples different in CNV (p &lt; 0.005): cluster 1 (n = 39) demonstrated increased CNV of SOX2, TP63, YAP1 and decreased CNV of CUL3, ATG7 and VGLL4, cluster 2 (n = 82) – increased CNV of CDK6 and decreased CNV of KDM6А, cluster 3 (n = 3) – decreased CNV of ATG7. Samples of cluster 1 showed c.85G &gt; A mutation in the NFE2L2 gene, cluster 2 - c.1379C &gt; T and c.1451G &gt; T in NOTCH1, c.414C &gt; A and c.1621G &gt; A in ZNF750, and cluster 3 - p.Q758* and Q5170* in SMARCA4 and KMT2D, respectively. Thus, we differentiated 3 molecular subtypes of ESCC (1,2,3). Overall survival rates were higher in ESCC2 (16.1±2.0 months), the lowest ones – in ESCC3 (0.88±0.56 months), with intermediate values in ESCC1 (4.6±0.74 months). Differences between the groups were statistically significant (p = 0.00001). Conclusions: Based on the differential distinctions in SNP and CNV of the genes, we verified 3 molecular subtypes of ESCC with different overall survival of patients.
Comparative gene expression analysis in gliomas with different IDH1/2 status.
Authors: Natalya N. Timoshkina, Oleg I. Kit, Anton Pushkin, Anna V. Antonets, Eduard Evgenevich Rostorguev, David H. Porksheyan, Sergey E. Kavitskiy, Natalya S. Kuznetsova
Journal: Journal of Clinical Oncology (2019)

e13008 Background: The new 2016 WHO classification of tumors of the central nervous system takes into consideration mutational status of IDH genes. Research of molecular changes in gliomas remain to be an actual issue. We analyzed the gene expression of some significant pathways in gliomas. Methods: 27 patients (12 females, 15 males) aged from 27 to 76 years with verified brain tumors (glioblastomas (G4) – 67%, anaplastic astrocytomas and oligoastrocytomas (G3) – 11%, astrocytomas (G2) – 22%) were investigated. 7 mutations in the IDH1 gene and 5 ones in IDH2 in fresh frozen tumor tissues were detected by RT-qPCR with Therascreen IDH1/2 RGQPCR kit (Qiagen). The expressions of EGFR, SMAD4, SMAD7, SMO, NOTCH1, NOTCH2, HBP1, HIF1A, EGLN1, EGLIN3, KDM1B, KDM1A, MSI1, MSI2, TET1 genes in tumor and normal brain tissue obtained while surgical access were assessed with RT-qPCR. PSMC, TBP and RPLO were used as reference genes. Results: Analysis of IDH1/2 status revealed only R132H mutation of IDH1 in 6 patients. The ratio of the relative expression of genes in tumor tissue with mutation and wild-type and the significance of the differences in the Mann-Whitney test are presented in the table below . Conclusions: Expression of SMAD7, EGLN1, EGLN3 as an activating factor of TGF-b-signaling pathway potentially may be used as an additional prognostic marker of gliomas progression.[Table: see text]
Metal-Organic Framework Nanoparticle-Based Biomineralization: A New Strategy toward Cancer Treatment
Authors: Chengchao Chu, Min Su, Jing Zhu, Dongsheng Li, Hongwei Cheng, Xiaoyuan Chen, Gang Liu
Journal: Theranostics (2019)

Cancer treatment using functional proteins, DNA/RNA, or complex bio-entities is important in both preclinical and clinical studies. With the help of nano-delivery systems, these biomacromolecules can enrich cancer tissues to match the clinical requirements. Biomineralization
FOLFOXIRI versus doublet-regimens in the first-line therapy of MSI-S right-sided (RS) metastatic colorectal cancer (mCRC): A survival analysis.
Authors: Alexandre A Jacome, Bryan K. Kee, David R. Fogelman, Imad Shureiqi, Arvind Dasari, Kanwal Pratap Singh Raghav, Van K. Morris, Benny Johnson, Robert A. Wolff, Michael J. Overman, Scott Kopetz, Jane Rogers, Shahab U. Ahmed, Amir Mehdizadeh, Cathy Eng
Journal: Journal of Clinical Oncology (2019)

e15060 Background: Microsatellite stable (MSI-S) RS mCRC patients (pts) have a worse prognosis relative to left sided tumors for overall survival (OS). The present analysis aims to test the hypothesis that a triplet-regimen is superior compared to doublet-regimens (DR; FOLFOX or FOLFIRI) for OS. Methods: Pts with treatment-naive RS mCRC at MD Anderson Cancer Center between January/2011 to December/2018 were selected. We compared the progression-free survival (PFS) and OS of mCRC pts treated with FOLFOXIRI versus DR. Pts treated with anti-EGFR therapy were excluded. Results: A total of 37 pts were treated with FOLFOXIRI and 111 pts with DR. There were no statistical difference between groups regarding gender, KRAS and BRAF mutations, peritoneal metastasis and bevacizumab use. There were statistical difference in age (median: 46y vs 59y) and metastasectomy rates (14% vs 32%) (p &lt; 0.001). KRAS mutation was found in 65% of the population. Median follow-up was 55.3m. Median PFS was 6.5m vs 11.2m (HR: 1.30 95% CI 0.85 – 1.99) and median OS was 17.0m vs 26.3m (HR: 1.01 95% CI 0.60 – 1.68). By univariate analysis, pts who have undergone metastasectomy had superior PFS (14.9m vs 9.2m; p&lt;0.001) and OS (32.4m vs 22.9m; p=0.003). By multivariate analysis adjusted for age, BRAF mutation, metastasectomy, bevacizumab use and, treatment regimen, only age and metastasectomy had prognostic influence for PFS (p=0.039 and p=0.026, respectively). Conclusions: Despite RS having a poor prognosis for OS, our study does not suggest that RS mCRC pts benefit from intensive treatment. Randomized clinical trials may suggest more individualized therapies.