tbuckley/cabot-search huggingface dataset:
A single-center retrospective cohort analysis of venetoclax in post-transplant, relapsed/refractory multiple myeloma.
Authors: Derek Galligan, Nina Shah, Jeffrey Lee Wolf, Sandy Wai Kuan Wong, Linda Abramovitz, Brenn Donnelly, Rupa Narayan, Gabriel N. Mannis, Shagun D. Arora, Thomas G. Martin
Journal: Journal of Clinical Oncology (2017)

e19514 Background: Despite recent advances, treatment of relapsed multiple myeloma (MM) remains a challenge. Pre-clinical studies suggest that bcl-2 inhibition can lead to MM cell death and may synergize with bortezomib. Methods: We performed a single-center, retrospective chart review of patients with relapsed MM following autologous stem cell transplantation (auto-HCT) who were treated with venetoclax, a bcl-2 inhibitor, with bortezomib. Results: 11 patients were identified. Median number of lines of prior therapy was 9 (range 5-13). 1 patient had documented high risk cytogenetics, defined as the presence of a 17p deletion, t(14;16), or t(14;20). In the 8 patients with cytogenetics/FISH available, no patients had t(11,14). 9/11 patients were refractory to bortezomib. 11/11 patients had progressed after carfilzomib, 9/11 after pomalidomide, and 11/11 after anti-CD38 antibody therapy. In all cases, patients were treated with venetoclax in combination with bortezomib. Patients were started at 400 mg daily for 7 days then increased to the median dose of 800mg daily. Overall patients received a median of 14.24 weeks of treatment (range 3-25.5). IMWG criteria were utilized to assess responses, including: 0/11 CR, 1/11 VGPR and 3/11 PR for an overall response rate of 36% (4/11). 1/11 had a minor response (light chain decrease by greater than 25% but less than 50%), 1/11 achieved stable disease, 5/11 had progressive disease. Median time to best response was 35 days (range 21-37) and median duration of response was 45 days (with several patients remaining on drug). All patients who responded had bortezomib-refractory disease. With median follow-up of 57 days, 4/11 patients have not progressed and 9/11 remain alive. The most common adverse effect was GI upset (bloating, nausea, vomiting, diarrhea) in 4/11 patients with no patients discontinuing due to side effects. There was no evidence of tumor lysis and there were no treatment-related deaths. Conclusions: Venetoclax is an active agent in relapsed multiple myeloma. Further efforts to study this therapy include prospective phase II trials and combination therapy with proteasome inhibitors and steroids.
Single-cell profiling of NSCLC tumor treated with Durvalumab and in combination with Tremelimumab.
Authors: Yashaswi Shrestha, Qu Zhang, Li Cheng, Rebecca Halpin, Brandon W. Higgs, Rajiv Raja, Katie Streicher
Journal: Journal of Clinical Oncology (2018)

12104 Background: Combination of anti-PD1/L1 and anti-CTLA4 is under investigation for treatment of multiple tumors. However, how this combination modifies the immune micro-environment of tumors is not well understood. Using single cell RNA sequencing (scRNAseq), we are systematically characterizing the ex vivo cellular and molecular effects of Durvalumab (D) and Tremelimumab (T) treatment on NSCLC tumors. Methods: Commercially available dissociated NSCLC tumor was treated with low dose interleukin-2 (IL-2) plus D, D+T or isotype control (IsoCtrl) at 20ug/ml each. For scRNAseq, T cells were isolated using αCD4 and αCD8 beads. Over 20,000 immune cells were profiled on D7 after treatment using 10X genomics. Exhausted T cells were defined based on the signature by Singer et al. (2016). Cell clustering and differential expression analyses were conducted using R package Seurat. Functional enrichment analyses, including KEGG and GO were performed by ClusterProfiler. Results: At D7 of D or D+T treatment, intracellular IFNG expression increased 60 and 80%, respectively. scRNAseq results were consistent with this functional data, showing 6% and 12% more IFNG expression in CD4+/CD8+ T cells following D and D+T, respectively. Checkpoint inhibitor expression (PDCD1, CTLA4, TIGIT, LAG3, HAVCR2) increased 4-9% and 7-15% upon D or D+T treatment, respectively. D and D+T treatment increased fraction of total CD4+ cells from 21% to 27% and 28%, respectively; however, there was a reduction in the specific CD4 subfraction of T regs (CD4+FOXP3+) in both treatments compared to IsoCtrl. D+T treatment shifted the molecular phenotype of exhausted T cells toward a more activated state by inducing a significant upregulation of PTPRCAP, ITGB1, and KLF2, genes important for T cell activation and/or reduced T reg function. Conclusions: Single-cell profiling of NSCLC tumor suggest that D+T treatment alters the molecular profile of exhausted T cells and T regs to generate a more active phenotype, which may contribute to clinical benefit for patients treated with this combination.
Oncogeriatric screening in patients with colorectal cancer: Is it a good tool for making decisions about their treatment?
Authors: Gemma Soler, Juan Antonio Marín, Raquel Legido, Juana Saldana, Mercedes Martinez Villacampa, Francisco Javier Perez, Idoia Morilla, Beatriz Pardo-Burdalo, Lucia Heras, Silvia Vazquez, Sabela Recalde, Maria Plana, Cristina Santos, Nuria Mulet, Alexandre Teule, Jose Carlos Ruffinelli, Ramon Salazar
Journal: Journal of Clinical Oncology (2018)

e22049 Background: Colorectal cancer (CRC) is the third most common cancer worldwide. It is mostly diagnosed in elderly people, with a median age at diagnostic of 70 years. The aim of this study is to explore whether oncogeriatric screening (OS) may be helpful in decision-making about treatment. Methods: From October 2015 to June 2017, we prospectively screened 137 ≥75-years-old patients diagnosed with CRC who were referred for chemotherapy. Our OS combines 4 scales, with a positive result in ≥85-years-old patients or 75-85-years-old patients with 2 of the following criteria: G8 scale < 14, Pfeiffer > 2, Barthel index < 90 and positive TIRS scale. In addition, age, comorbidity and ECOG functional status were taken into account for final treatment decision. Results: The median age was 80.44 years (75’1 – 88’9). The most frequent diagnosis was colon cancer (71´8%) versus rectal cancer (28´2%). 47´4% of patients had metastatic disease. Whilst the OS was positive in 32´1% of cases, vulnerability ( < 14 score in G8 scale) was detected in 62% of patients. Chemotherapy was more frequently dismissed in that vulnerable patients (45´9% of G8 < 14 patients vs 28´6% of G8≥14 patients). Finally, 67 patients received chemotherapy (capecitabine 70´1%, FOLFOX 19´4%, FOLFIRI 1´5%, clinical trial 9%). Interestingly, for those patients who initiated treatment at full-dose intensity, a dose reduction was needed in 76% of G8 < 14 patients vs 28.6% of G8≥14 patients. A dose-intensity of 100% could be maintained during the whole treatment (initial and subsequent cycles) in 13% vs 33% respectively. Tolerance of the treatment also differed, with grade 3 / 4 toxicity seen in 58´69% vs 26´66% and interruption of treatment due to toxicity in 15´2% vs 6´7%, respectively. There were no toxic deaths. Conclusions: In our cohort, patients who finally did not receive chemotherapy obtained a < 14 score in G8 scale in a higher proportion. This scale identifies patients who need dose-reduction or present relevant toxicity with a greater probability. For this reason, the G8 scale is considered a helpful screening tool for decision-making in treatment for CRC in elderly patients.
INNV-03. SAFETY AND ADVERSE EVENT PROFILE OF TUMOR TREATING FIELDS USE IN THE EMEA REGION A REAL-WORLD DATA ANALYSIS
Authors: Sied Kebir, Martin Glas
Journal: Neuro-Oncology (2018)

Tumor Treating Fields (TTFields) is approved for the treatment of newly diagnosed and recurrent glioblastoma. The efficacy and safety of TTFields in newly diagnosed GBM was previously demonstrated in the EF-14 phase 3 trial (n=695). Optune + temozolomide significantly improved survival outcomes compared to temozolomide alone (median OS: 20.9 vs 16.0 months, p A review of global post-market surveillance data including patients treated with Optune in the EMEA region. Adverse events reported to the Novocure safety department were analyzed based on the MedDRA body system (system organ class) preferred terms. A total of 8025 patients were treated with Optune globally (newly diagnosed glioblastoma 46.1%, recurrent glioblastoma 46.2%, other 7.7%). Of these, 1496 patients were treated in the EMEA region (Israel, Switzerland, Germany and other European countries). In this cohort, as expected, skin reaction was the most prevalent adverse event affecting 25% of patients. Other adverse events included: General decline in health (24%), Nervous system disorders (18%), Injury at any location (5%), Gastrointestinal disorders (4%), and Musculoskeletal disorders (3%). This retrospective analysis demonstrates the safety profile of Optune in an EMEA patient cohort. The most common adverse event registered was skin reaction, which was also found in the phase 3 EF-11 trial for recurrent GBM and in the EF-14 trial for newly diagnosed GBM patients. No other device-related adverse events were reported. In summary, these results emphasize the safety of Optune in GBM treatment and its consequent adoption in the EMEA region.
Mucinous colorectal carcinoma: A single center experience.
Authors: Berna Oksuzoglu, Guliz Zengin, Ibrahim Turker, Umut Demirci
Journal: Journal of Clinical Oncology (2017)

e15116 Background: The aim of this study was to evaluate the clinical features and treatment outcomes of mucinous colorectal adenocarcinoma (MCA) followed in a single institution. Methods: Seventy-nine patients diagnosed with MCA admitted to our center between January 2003 and August 2016 included in this study. Demographic and clinico-pathologic characterictics of patients were analysed using patient medical records retrospectively. Results: Median age of the patients was 57 (24-83) with a male to female ratio of 1/3. Common symptoms were abdominal pain, rectal bleeding, abdominal distention, tenesmus and constipation in 44 (55.7%), 17 (21.5%), 7 (8.9%), 6 (7.6%), 5 (6.3%) of patients respectively. At the time of the diagnosis ECOG performance score was 0 or 1 in 74 (93.7%) of the patients. One (1.3%), 26 (32.9%), 37 (46.8%) and 15 (19%) of the patients had stage 1,2,3 and 4 disease respectively. Neoadjuvant chemo-radiotherapy with 5 FU and leucovorin (FUFA) was the treatment of choice in 11 (13.9%) of rectal MUC patients. The type of surgery was curative, palliative and emergent in 60 (76%), 9 (12.4%) and 9 (12.4%) respectively. Localisation of the primary tumor was right colon, left colon and rectum in 31 (39.2%), 30 (38%) and 18 (24.8) patients respectively. In the adjuvant setting, 59 (74.7%) of patients were received adjuvant chemotherapy. Only 6 patients had MSI, 26 patients had k-RAS, n-RAS and b-RAF mutation results. Metastatic sites were mostly visceral organ, intra-abdominal and local recurrence in 13 (16.5%), 12 (15.2%) and 6 (7.6%) of patients respectively. The median disease free survival, progression free survival and overall survival (OS), were 15.5 months, 17.5 months and 44.1 months, respectively. Conclusions: Survival rates were higher than literature in this study. This may be partly explained by better ECOG performance score of our patient group. We also found that better ECOG score, left sided tumor, younger age, were associated with better OS.
Collection of adverse events data for the supplemental indications in cancer clinical trials: Is it needed?
Authors: Sirisha Mushti, Sean Khozin, Huanyu Chen, Yun Wang, Virginia Ellen Maher, Rajeshwari Sridhara
Journal: Journal of Clinical Oncology (2016)

e18233 Background: Safety data collected for supplemental indications is usually similar to the safety data collected in support of the initial approval of the agent. It is unknown if comprehensive collection of safety data for supplemental indications adds any new information to the existing safety profile of the drug. In order to examine the redundancy in collecting exhaustive safety data from clinical trials in supplemental indications, we reviewed product labels of 14 approved drugs that had supplemental indications. Methods: Data, based on randomized clinical trials, from product labels of original and supplemental indications were collected to study the AE profiles. For each of the drugs, the number of unique AEs with a >5% difference in the incidence of AE rates (all grades) between the treatment and the control arm were identified. Data was then summarized into either: (1) observed only in original but not in supplemental indications; or (2) not observed in the original submissions but in supplemental indications. Results: The number of supplemental indications ranged from 2 to 4 for the each of the drugs listed below. The table below summarizes the unique number of AEs observed in the original and supplemental indications as presented in the product labels. Conclusions: Based on the number of new AEs that were reported in the product label for supplemental indications, it could be inferred that the safety data from the supplemental indications, in addition to the reported AEs in original indication widened the AE profile for the drug. Collecting comprehensive safety data for the supplemental indications can be useful in characterizing the safety profile of cancer agents. Class of Drugs Total # of AEs observed in original indication Total # of new AEs observed in supplemental indications but not in original indication Kinase Inhibitors: Everolimus 18 25 Imatinib 19 12 Sorafenib 10 19 Erlotinib 12 3 Lapatinib 13 14 Chemotherapeutic agents: Nab-Paclitaxel 3 23 Pemetrexed 14 5 Oxaliplatin 34 16 Monoclonal antibodies: Bevacizumab 27 11 Cetuximab 19 7 Trastuzumab 37 7 Hormonal agents: Letrozole 5 4 Abiraterone 2 2
PD-L1 expression of 742 newly diagnosed advanced respiratory and digestive system tumours in China based on SP142 assay.
Authors: Yanhui Chen, Yating Wang, Bohang Yang, Ying Hu, Hui Zeng, Henghui Zhang
Journal: Journal of Clinical Oncology (2018)

e24298 Background: Recent studies have proposed programmed cell death 1 ligand (PD-L1) expression as a distinct biomarker of response to anti-PD-1/PD-L1 therapies. The PD-L1 positive rates in newly diagnosed advanced common solid tumours in China were evaluated. Methods: 742 cases of advanced respiratory and digestive system tumour patients were included, including nasopharyngeal carcinoma (33), lung adenocarcinoma (243), lung squamous cell carcinoma (110), small cell lung cancer (20), esophageal cancer (34), gastric cancer (42), duodenal carcinoma (10), colon cancer (78), rectal cancer (31), hepatocellular carcinoma (31), cholangiocarcinoma (67), gallbladder cancer (10), and pancreatic cancer (33). Tumour tissue samples were collected to detect PD-L1 expression by immunohistochemistry (using the SP142 antibody). Results: According to PD-L1 strong positive ratio (≥50% in tumour cells (TC), or ≥10% in immune cells (IC)), in respiratory system tumours, nasopharyngeal carcinoma had the highest strong positive rates of PD-L1, 42% in TC and 21% in IC, followed by lung squamous cell carcinoma (26% in TC and 17% in IC) and lung adenocarcinoma (21% in TC and 12% in IC). Small cell lung cancer did not have PD-L1 strong positive cases. In digestive system tumours, the positive rates of PD-L1 in TC were higher in gallbladder, esophageal and pancreatic cancer, which were 10%, 6% and 6% respectively, followed by colon cancer (3%), gastric cancer (2%) and cholangiocarcinoma (1%). Duodenal carcinoma, rectal cancer and hepatocellular carcinoma did not have PD-L1 strong positive cases in TC. The positive rates of PD-L1 in IC were higher in rectal cancer, hepatocellular carcinoma, gallbladder cancer and cholangiocarcinoma, which were 23%, 23%, 20% and 18% respectively, followed by esophageal cancer (9%), gastric cancer (10%) and colon cancer (10%). Duodenal carcinoma and pancreatic cancer did not have PD-L1 strong positive cases in IC. Conclusions: The PD-L1 strong positive rates of respiratory system tumours were higher than the digestive system tumours. The role of PD-L1 as a predictor of efficacy of PD-1/PD-L1 inhibitors in different types of cancers needs further evaluation.
Candidate predictive biomarkers for response to olaparib in advanced gastric cancer (AGC).
Authors: Darren R Hodgson, Zhongwu Lai, Brian Andrew Dougherty, Ambar Ahmed, Gershon Y. Locker, Alan Sharpe, Tony Weishiu Ho, Seock-Ah Im, Woo Ho Kim, J Carl Barrett, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2016)

4041 Background: A Phase II trial in 124 patients (pts) with AGC (NCT01063517; Study 39) showed that, as 2nd-line therapy, the PARP inhibitor olaparib (Lynparza; tablets) plus paclitaxel, followed by maintenance olaparib (O/P arm), significantly improved overall survival (OS) vs paclitaxel alone (P arm) both in the overall population and in pts with low ATM protein levels (ATMlow), for whom the trial was enriched (Bang et al JCO 2015). The current study explored the relationship of other candidate biomarkers with ATM levels and clinical outcomes. Methods: Next-generation DNA sequencing (Foundation Medicine) of tumor samples from Study 39 pts was performed, followed by comprehensive genomic analysis. Candidate biomarkers included microsatellite instability (MSI)-like status (overall mutation load), ATM mutations, mutations in other genes involved in homologous recombination repair (HRRm), and TP53 and ARID1A mutations. ATM levels were determined by IHC at study entry. Associations between genetic markers were assessed by contingency table analysis, while associations between individual genetic markers and clinical outcome were assessed by Cox proportional hazards modeling. Results: 55/124 pts (ATMlow , n = 28; ATM positive [+ve], n = 27) had ≥ 1 sample evaluable for tumor genetics (EFTG): 6 pts (11%) had loss-of-function ATM mutations (all in ATMlow pts) and 35 pts (64%) had a TP53 mutation (TP53m). HRRm (including in ATM), ARID1A mutations and MSI-like profiles were found in 11, 19 and 7 pts, respectively, most of whom were ATMlow . OS HRs (95% CI) for O/P vs P in the EFTG population, ATMlow pts, ATM +ve pts and TP53m pts were 0.34 (0.16–0.74), 0.17 (0.05–0.65), 0.65 (0.24–1.73) and 0.515 (0.21–1.29), respectively. Pt numbers were small, but these exploratory analyses suggest that 1) ATMlow pts who receive O/P have the longest OS, regardless of TP53m status; 2) the OS HR in ATMlow pts is lower than for subsets of pts with other candidate biomarkers; and 3) an OS benefit is seen with O/P for pts without ATM mutations. Conclusions: For pts with AGC, ATM level remains the leading predictive biomarker for determining response to olaparib treatment. Clinical trial information: NCT01063517.
Abstract 13700: High Affinity CaM, but Not Normal Affinity CaM Can Prevent Arrhythmias in CPVT Which Mutation is Located at CaM-like Domain of RyR2
Authors: Shigehiko Nishimura, Takeshi Yamamoto, Go Fukui, Takako Maeda, Akihiro Hino, Takeshi Suetomi, Makoto Ono, Mamoru Mochizuki, Tetsuro Oda, Shinichi Okuda, Shigeki Kobayashi, Masafumi Yano
Journal: Circulation (2015)

Introduction: We have been previously reported that calmodulin (CaM) binding affinity to RyR2 decreases upon beta stimulation in catecholaminergic polymorphic ventricular tachycardia (CPVT) type knock-in mice with mutation at central domain (R2474S-KI). Meanwhile, amino acid residues from 4026 to 4172 of RyR2 have EF hand motifs and are called CaM-like domain (CaMLD). Some of the human CPVT mutations were reported in this CaMLD. In the present study we investigated the molecular mechanism of arrhythmogenesis of CPVT with mutation at CaMLD using N4103K KI mice. Methods and Results: VT and/or Vf were frequently observed after 120 mg/kg caffeine plus 1 mg/kg epinephrine infusion in KI mice, but not in WT mice (WT: 0%, KI: 43%). CaM binding affinity to RyR2 was assessed by incorporation of exogenous CaM labeled with HiLyte Fluor® in isolated saponin-permeabilized cardiomyocytes. The binding affinity of CaM decreased in KI cells (Kd: 161 nM) compared with WT cells (Kd: 89 nM). Addition of 1μM cAMP did not change the affinity of CaM to RyR2 in both KI and WT cells, while it decreased the affinity in R2474S-KI. Frequency of the Ca 2+ sparks was measured in isolated saponin-permeabilized cells. The Ca 2+ spark frequency (SpF: s -1 100μm -1 ) was much higher in KI than in WT cells {KI (n=79): 21.5±6.3; WT (n=34): 10.6±4.1; p&lt;0.01}. Addition of 100 nM CaM to KI cells did not decrease SpF {(n=87): 22.4±6.5}, however, significant decrease was observed by HA-CaM (modified CaM which has higher affinity to RyR2). Spontaneous Ca 2+ transient (SCaT) was measured during sequential pacing from 1 to 5 Hz in isolated intact cardiomyocytes. The SCaT was rarely observed in WT cells even with 10 nM isoproterenol and 5 Hz pacing, whereas that was observed in 33% of KI cells. Incorporation of CaM to intact KI cells using protein delivery kit (BioPORTER®) did not decrease incidence of SCaT (34% of KI cells), however, significantly decreased by HA-CaM incorporation. Conclusions: Different from R2474S-KI mice, CaM binding affinity to RyR2 is decreased without beta stimulation in KI mice with CaMLD mutation. Conformational change of CaMLD might affect CaM-binding domain (CaMBD) and decrease the affinity of CaM to CaMBD. The CaMLD-CaMBD interaction may be a novel therapeutic target of lethal arrhythmias.
Efficacy of a single-dose injection of CLR 131 (1-131-CLR1404) in a Caki-2 athymic nude mouse model.
Authors: Jarrod Longcor, Katherine Oliver, Irawati Kandela
Journal: Journal of Clinical Oncology (2017)

e14087 Background: CLR 131 is a novel radioiodinated therapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Study was to evaluate the therapeutic effect of CLR 131 when administered as a single dose intravenous injection in Caki-2 tumor bearing mice. Caki-2 cells are a human clear cell renal cell carcinoma (CCRCC). Methods: The Caki-2 cell line (human clear cell carcinoma) was purchased from American Type Culture Collection (ATCC, Rockville, MD) and maintained in McCoy’s 5a media supplemented with 10% fetal bovine serum. Female athymic nude mice (Hsd: Athymic Nude-Foxn1nu); 4-5 weeks of age, 16-18 g (Harlan, Indianapolis, IN) were injected subcutaneously with 1x10 6 viable cells (in 100 µL Dulbecco’s PBS) into the right flank. The study was initiated when tumor size had reached a pre-determined size (100-250 mm 3 ). The mice were given potassium iodide at a concentration of 0.1% in their drinking water to block possible free iodide in the drug formulation. A single dose of ~110µCi of CLR 131 was given at Day 0 (N = 6 per group). A control dose of I-127-CLR1404 was given at ~110 µCi dose and was injected via tail vein on Day 0. Results: Tumor growth of the treatment group was significantly inhibited. The control group showed exponential growth after day 20 post-injection while the treatment group maintained the initial tumor volume up to day 75 post injection. By day 65, the control group increased 10.75-fold compared to the treatment group in average tumor volume. CLR 131 provides survival benefit for Caki-2 bearing mice. Kaplan Meier survival showed significant survival benefit with this model. Conclusions: The results of the study indicate that a single dose of CLR 131 on Caki-2 tumor bearing model showed a significant inhibition of tumor growth as well as significant survival benefit.