tbuckley/cabot-search huggingface dataset:
Phase 3 study of first line pevonedistat (PEV) + azacitidine (AZA) versus single-agent AZA in patients with higher-risk myelodysplastic syndromes (HR MDS), chronic myelomonocytic leukemia (CMML) or low-blast acute myelogenous leukemia (AML).
Authors: Mikkael A. Sekeres, Robert J. Fram, Zhaowei Hua, Lionel Ades
Journal: Journal of Clinical Oncology (2018)

TPS7077 Background: PEV is a first-in-class small molecule inhibitor of NEDD8-activating enzyme, with single-agent clinical activity in patients with relapsed/refractory AML (Swords et al. Br J Haematol 2015;169:534–43). In preclinical AML models, PEV in combination with AZA resulted in synergistic antitumor activity compared with either agent alone (Visconte et al. Leukemia 2016;30:1190–4). A phase 1b study reported that PEV+AZA was well tolerated and showed clinical activity in patients ≥60 years with untreated AML (Swords et al. Blood 2018; Epub). These results provided the rationale for this phase 3 study to compare the efficacy and safety of PEV+AZA versus single-agent AZA as first line treatment for patients with HR MDS, CMML, or low-blast AML. Methods: This is a global, multicenter, randomized, controlled, open-label, phase 3 study (NCT03268954). Eligible patients (N = ~450 planned) are adults with a confirmed diagnosis of HR MDS, CMML, or low-blast AML with no prior treatment, who are ineligible for intensive chemotherapy and/or allogeneic stem cell transplantation and do not have acute promyelocytic leukemia or a history of central nervous system involvement by AML. Patients are stratified by IPSS-R risk group (MDS/CMML) and low-blast AML, and randomized 1:1 to receive PEV 20 mg/m2 intravenously on days 1, 3, and 5, plus AZA 75 mg/m2 (intravenous or subcutaneous) on days 1–5, 8, and 9, or AZA alone, in 28-day cycles until progression, transformation to AML, or unacceptable toxicity. Primary endpoints are overall response rate by cycle 6 and event-free survival; overall survival is a key secondary endpoint. Other secondary endpoints include survival rates at 6 months and 1 year; rate/duration of response; time to AML transformation; rate of complete remission (CR); time to first CR or partial remission; rate of hematologic improvement; rate/duration of red blood cell and platelet transfusion independence; time to relapse, progression, or death; pharmacokinetics; and health-related quality of life. Recruitment is currently ongoing. Clinical trial information: NCT03268954.
Metabolic barriers to immunotherapy in renal cell carcinoma.
Authors: Katy Beckermann, Peter Siska, Frank Mason, Kimryn Rathmell, Jeffrey C Rathmell
Journal: Journal of Clinical Oncology (2017)

11560 Background: Cancer cells can inhibit effector T cells through both immunomodulatory receptors and alteration of the tumor microenvironment as a result of cancer metabolism. A majority of patients treated with immune checkpoint inhibitors recently approved by the FDA fail to exhibit a clinical response. The extent to which metabolic conditions within the tumor impede T cell activation and anti-tumor effector function in renal cell carcinoma (RCC) are unknown. Methods: Under the IACUC protocol M1600005-00, BALB/c or Rag mice were subcutaneously injected with 100,000 Renca cells obtained from ATCC and growth monitored by caliper measurements in 3 dimensions every 3 days. In vivoPD-1 blockade was performed by 200 mcg/i.p. injection every 3 days using purified mPD-1 (BioXcell, J43). Deidentified tissue donations from patients with RCC were collected under the IRB protocol #151549 and processed into single cell suspensions following mechanical dissociation for the functional assays indicated below. Results: Through work with Rag deficient mice lacking functional B and T cells, we have established that tumor growth is regulated in a T cell dependent manner as evidenced by earlier formation and faster tumor growth. In a syngeneic mouse model of RCC (RenCa), we find that inhibition of PD-1 delays tumor growth and size. Tumor infiltrating lymphocytes (TILs) were abundant in patient-derived RCC, but are phenotypically distinct and are impaired both functionally and metabolically from healthy control. Instead of efficient use of aerobic glycolysis, TILs fail to increase glucose metabolism, and instead display increased reactive oxygen species (ROS) and mitochondrial dysfunction. CD8 effector cells found in tumors have notable differences in mitochondrial morphology compared to healthy control CD8 T cells by electron microscopy and immunofluorescence where CD8 TIL are punctate and dispersed throughout the cell while healthy control CD8 mitochondria are fused in networks. Thus bypassing metabolic defects may partially restore TIL activation. Conclusions: Preclinical data suggests that improved understanding of metabolic dysfunction in TILs of RCC may allow for combined therapies to improve response rates of checkpoint inhibition in this disease.
Clinical significance of enterocyte-specific gene polymorphisms as candidate marker of oxaliplatin-based treatment for metastatic colorectal cancer.
Authors: Mitsukuni Suenaga, Marta Schirripa, Fotios Loupakis, Shu Cao, Wu Zhang, Chiara Cremolini, Sara Lonardi, Satoshi Okazaki, Martin D. Berger, Yuji Miyamoto, Shivani Soni, Afsaneh Barzi, Toshiharu Yamaguchi, Alfredo Falcone, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2018)

12066 Background: An enterocyte subtype of the Colorectal Cancer (CRC) Assigner classifier has shown to confer benefit from oxaliplatin in adjuvant treatment for stage III CRC. MS4A12 belongs to the enterocyte subtype-specific gene, whose expression is regulated by endogenous CDX2. We tested whether single nucleotide polymorphisms (SNPs) in enterocyte-related genes predict oxaliplatin efficacy in first-line treatment for metastatic CRC (mCRC). Methods: Three different cohorts of mCRC patients (pts) (total 603) were included in this study: discovery cohort receiving FOLFOX ± bevacizumab (BV) (n = 146, median age = 61, median follow-up = 45.0 mos); validation cohort receiving FOLFOXIRI + BV (n = 230, TRIBE arm B, median age = 60, median follow-up = 46.5 mos); and control cohort receiving FOLFIRI + BV (n = 228, TRIBE arm A, median age = 60, median follow-up = 49.3 mos). SNPs were analyzed by PCR-based direct sequencing. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier curves, log-rank test, and Cox proportional hazards regression. Results: Among the SNPs tested in the discovery cohort, MS4A12 rs4939378 and CDX2 rs3812863 were extracted as potential markers of efficacy. In the validation cohort, any G allele in MS4A12 rs4939378 was associated with longer PFS than the A/A variant in univariate analysis (12.4 vs. 10.9 mos, HR 0.70, 95%CI: 0.49-0.99, P= 0.033) and multivariable analysis (HR 0.65, 95%CI: 0.44-0.97, P= 0.035). The findings were more evident in the KRAS mutant than KRAS wild-type pts. In contrast, KRAS wild-type mCRC pts with the G/G variant in CDX2 rs3812863 had a longer PFS than those with any A allele (32.3 vs. 10.3 mos, HR 0.39, 95%CI: 0.19-0.81, P= 0.004), and the trend remained in multivariable analysis though without statistical significance (HR 0.48, 95%CI: 0.21-1.09, P= 0.08). These findings were not confirmed in the control cohort. Conclusions: The enterocyte subtype might affect the antitumor activity of oxaliplatin in not only early stage but also metastatic disease in CRC. Genetic variants in MS4A12 and CDX2 gene polymorphisms may serve as potential predictive marker of oxaliplatin-based treatment in mCRC pts.
Cardiologist Trades Stem Cells for Cell-Based Meat
Authors: Rebecca Voelker
Journal: JAMA (2018)

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Prognostic value of immune response gene expression in early stage curatively resected NSCLC: Data from the JBR.10 trial.
Authors: Wolfgang M. Brueckl, Akin Atmaca, Salah-Eddin Al-Batran, Joachim H Ficker, Ralph M Wirtz
Journal: Journal of Clinical Oncology (2016)

8528 Background: Adjuvant chemotherapy (ACT) leads to a modest improvement in survival among patients with completely resected non-small cell lung cancer (NSCLC) but molecular predictors are still rare. Methods: Publicly available gene microarray, clinical and follow-up data from two different studies on early-stage NSCLC were used to determine the expression of T cells (CD3Z, CD4, FoxP3), B cells (IGHM) and macrophages (CD68, CD163) and PD-1 in the tissue of resected tumors. Expression values were calculated against clinical and survival data in a training set (n = 138) and a test set (subpopulation from the adjuvant JBR.10 study (N=90)) allowing the determination of the prognostic effect in the observational arm as well as the predictive effect regarding ACT. Results: Expression of T cells and PD-1 was of significant positive prognostic value in terms of survival in the training set (CD3Z: HR 0.50, 95%CI:0.29-0.83, p=0.008; PD-1: HR 0.57, 95%CI:0.34-0.96, p=0.03) and this could be confirmed in the test set cohort (CD3Z: HR 0.29, 95%CI:0.09-0.95, p=0.041; trend for PD1: HR 0.36, 95%CI:0.10-1.21, p=0.09). Additionally, CD3Z high expressing tumors showed a benefit from ACT in terms of 5-year survival with a trend for significance (HR 0.36, 95%CI:0.11-1.12, p=0.07). B cells and macrophages did not show consistent findings between test and training set cohorts. In multivariate analysis CD3Z was an independent positive prognostic factor for survival in early-stage NSCLC patients. Conclusions: CD3Z is a new marker with prognostic and possibly predictive value in curatively resected NSCLC. This data, when confirmed, might influence therapeutic decisions regarding ACT in the time of immunoncology.
TCT-254 Strut Impingement Phenomenon by a Bioresorbable Polymer Sirolimus-eluting Ultimaster Stent
Authors: Yutaka Tadano, Yoshifumi Kashima, Daisuke Hachinohe, Takuya Haraguchi, Hidemasa Shitan, Tomohiko Watanabe, Takuro Sugie, Umihiko Kaneko, Ken Kobayashi, Morio Enomoto, Daitaro Kanno, Katsuhiko Sato, Tsutomu Fujita
Journal: Journal of the American College of Cardiology (2018)
TCT-449 Trends in Utilization and Hospital Variation in the use of Mechanical Circulatory Support Devices in Patients Undergoing Percutaneous Coronary Intervention in Michigan: Insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2)
Authors: Thomas Earl, Milan Seth, Devraj Sukul, Nick Slocum, Louis Cannon, Hitinder Gurm
Journal: Journal of the American College of Cardiology (2018)
Promotion of proliferation and inhibition of apoptosis by diacylglycerol kinase zeta, a potential oncogene of osteosarcoma
Authors: Wenxi Yu, Lina Tang, Hongtao Li, Yonggang Wang, Feng Lin, Zan Shen
Journal: Journal of Clinical Oncology (2018)

e23503 Background: Osteosarcoma(OS) is the primary malignant bone tumor that most commonly affects children, adolescents, and young adults. However, survival rates continue to be unsatisfactory in the metastatic and relapse setting. Therefore, it is imperative to discover a novel target for more effective therapeutic interventions towards OS. Diacylglycerol kinase zeta (DGKζ) is a recently identified gene potentially associated with certain human carcinogenesis. However, the expressional correlation and functional importance of DGKζ in OS is still unclear. Methods: We analyzed DGKζ expression in OS cell lines,tumor samples and normal bone tissues. DGKζ expression was knocked down using siRNA then cell proliferation,apoptosis analyses and xenograft transplantation in nude mice were performed to evaluate impact of DGKζ depletion.Affymetrix GeneChip was performed to investigate expression of downstream targets after DGKζ knockdown. Results: Expression of DGKζ was confirmed in four OS cell lines then further confirmed in OS samples(37/80, 46.2%) while 24 normal bone samples demonstrated no DGKζ expression. Survival analysis showed that expression of DGKζ indicated a poor prognosis in OS patients. In vitro, depletion of DGKζ by siRNA inhibited OS cell proliferation and promoted cell apoptosis. In vivo, DGKζ silencing also suppressed xenograft tumor formation. Meanwhile, Affymetrix GeneChip and Ingenuity Pathway Analysis (IPA) demonstrated that DGKζ knockdown resulted in the dysregulation of a number of cell signaling pathways. CCND1,CDKN2B,CDK6,MYC,PCNA, EGR1 were identified and further validated by Western blot/qPCR as a direct downstream target of DGKζ. Conclusions: Our study shows that DGKζ acts an oncogene in OS via its regulation of several key downstream target and also suggests that targeting expression of DGKζ and its downstream signaling could be a potential strategy for management of osteosarcoma.
Randomized trial of a text messaging intervention for symptom distress in BCa patients undergoing chemotherapy.
Authors: Kuang-Yi Wen, Lori J. Goldstein, Suzanne M. Miller, Elias Obeid, Mary Beryl Daly
Journal: Journal of Clinical Oncology (2018)

10085 Background: Chemotherapy is often associated with treatment side-effects that negatively affect HRQOL. The aim of this study was to examine the feasibility and preliminary efficacy of a novel mobile text messaging (TXT) intervention to help breast cancer (BCa) patients coping with chemotherapy. Methods: Through an iterative patient-centered formative evaluation process, we developed an automatic bidirectional theory-guided and evidence-informed TXT intervention that sent two daily proactive messages addressing education, symptom management and support with options for patients to request more texts. In a RCT study, 100 BCa patients undergoing chemotherapy were assigned to either the TXT group or a control group that received an ACS chemotherapy booklet. Measures were administered at baseline, 1-month, 2-month, 3-month and 4-month. A satisfaction interview was conducted following the intervention. Acceptability and feasibility were examined. Primary outcomes were symptom distress and HRQOL. Secondary outcomes were depressive symptoms, self-efficacy and doctor-patient communication. Results: The majority of the sample was white (70%) with a mean age of 59 years. Both study groups reported significant increase in symptom distress and decline in HQROL from baseline to follow-ups. Symptom distress was found significantly lower and HRQOL was higher in the intervention group at month 1 and month 3 than the control (p-value ≤ 0.05). Intervention group reported significant improvement in self-efficacy and doctor-patient communication (p-value ≤ 0.05). No difference was found in depressive symptoms between two groups. Regarding acceptability, 70% of eligible participants consented and 90% of the TXT group participants were satisfied with the intervention. Intervention participants texted back to the system a total of 2388 times requesting additional texts with a mean range of 3-58 requests. Conclusions: Feasibility, satisfaction, and preliminary efficacy of a TXT intervention to promote better outcomes for BCa patients undergoing chemotherapy were established. Further research is needed to develop additional tailoring and personalization per participants’ feedback.
Effect of circulating tumor cells (CTCs) on overall survival in metastatic medullary thyroid cancer (metMTC).
Authors: Jian Yu Xu, Beverly Carol Handy, Steven G. Waguespack, Mimi I-Nan Hu, Naifa Lamki Busaidy, Camilo Jimenez, Maria E. Cabanillas, Gilbert J Cote, Steven I. Sherman
Journal: Journal of Clinical Oncology (2016)

e17547 Background: CTCs have been shown to be a valuable prognostic marker for breast, colon and prostate cancers. We have previously reported that ≥ 5 CTCs per tube can be detected using the Veridex CellSearch system in blood from a subset of patients with metMTC. We now update the survival data and evaluate whether elevated CTCs are associated with worse survival in metMTC. Methods: Two 7.5 mL tubes of whole blood were obtained from 18 subjects (M:F 9:9) with distant metastatic MTC. CTCs were enumerated by the CellSearch system, which identifies CTCs by immunomagnetic cell selection using EpCAM as a capture antigen, followed by immunohistochemical characterization for detection of epithelial-derived cells that stain positive for cytokeratin and DAPI and negative for the lymphocyte marker CD45. Captured cells are visually confirmed and counted by microscope. Results: Patients’ characteristics: mean age at diagnosis was 43 yrs and at sampling was 52 yrs; mean and median calcitonin levels were 55,591 and 3240 ng/mL, respectively; metastatic disease noted in liver, lungs, and bones in 89%, 72% and 67% of patients, respectively. Six patients had ≥ 5 CTCs per tube. With a median follow-up of 32.6 months after sampling, 14 patients had died, including all 6 with ≥ 5 CTCs per tube compared with 67% of those with < 5 CTCs. Calcitonin doubling times did not significantly differ between those who died and those alive at last follow-up. Median survival was 13 months for those with ≥ 5 CTCs, and 51.5 months for those with < 5 CTCs. Kaplan-Meier analysis demonstrated significantly shorter survival for those with ≥ 5 CTCs (P = 0.0116). The hazard ratio for mortality of ≥ 5 CTCs compared with < 5 CTCs was 3.42 (P = 0.0577) while for calcitonin doubling time < 6 months compared with ≥ 6 months was 1.42 (P = 0.543). Conclusions: The presence of ≥ 5 CTCs per tube detected by CellSearch in blood from patients with metMTC is associated with worse overall survival and may be more predictive than calcitonin doubling time. Larger cohorts are required to validate this observation, and to determine if reduction in CTCs could predict response to treatment and better outcome.
LUNA: A randomized phase II trial of liver resection plus chemotherapy or chemotherapy alone in patients with unresectable lung and resectable liver metastases from colorectal adenocarcinoma.
Authors: Yun Shin Chun, Reza J. Mehran, Ching-Wei David Tzeng, Bryan K. Kee, A. Dasari, Boris Sepesi, Claudius Conrad, Thomas A. Aloia, Scott Kopetz, Jean-Nicolas Vauthey
Journal: Journal of Clinical Oncology (2017)

TPS3625 Background: Liver resection for metastatic colorectal cancer is associated with 5-year overall survival (OS) of 58% and accepted as standard of care. However, the role of liver resection with unresectable low-volume lung metastases is unknown. A recent retrospective study showed that resection of liver metastases was associated with statistically improved OS compared to a matched group of patients treated with systemic therapy alone for lung and liver metastases (3-year OS 43% vs. 14%; Mise Y, Ann Surg Oncol 2015). LUNA is a single-institution phase 2 randomized trial designed to determine the overall survival benefit of liver resection in patients with unresectable lung metastases and to integrate biological surrogates to risk stratify patients and optimize patient selection for hepatectomy. Methods: Eligibility criteria include resectable liver metastases, defined as sufficient liver remnant volume, adequate vascular inflow and outflow, and preservation of 2 contiguous liver segments. Low-volume lung metastases are defined as solid pulmonary nodules &lt; 2 cm in size and &lt; 15 in number. Chest computed tomography is reviewed by an attending thoracic surgeon, and lung metastases are deemed unresectable due to anatomic location, distribution, or patients’ comorbidities. Previous treatment with systemic chemotherapy and/or biologic agents is permitted. After stratification by KRAS status and primary tumor location in the colon vs. rectum, patients are randomized 1:1 to liver resection plus chemotherapy or no liver resection with chemotherapy at the discretion of the treating oncologist as routine standard of care. Patients are restaged every 3‒6 months until 3 years after randomization or death. The primary endpoint is OS. Secondary endpoints include quality of life and identification of biological surrogates in blood and resected liver tissue associated with response to chemotherapy, time to tumor progression, and survival. Targeting an effect size of extending median OS from 17 to 34 months will provide 80% power with 0.05 one-sided alpha with a sample size of 80 patients. Clinical trial information: NCT02738606.
Significance of monitoring vascular endothelial growth factor signals in blood during treatment of colorectal cancer patients.
Authors: Nao Kakizawa, Koichi Suzuki, Hideki Ishikawa, Fumiaki Watanabe, Fumi Hasegawa, Rina Kikugawa, Shingo Tsujinaka, Yasuyuki Miyakura, Hiroshi Noda, Toshiki Rikiyama
Journal: Journal of Clinical Oncology (2018)

e15563 Background: Vascular endothelial growth factor (VEGF) signals may change during colorectal cancer (CRC) treatment, but monitoring real time changes has not been conducted. Methods: Blood monitoring was carried out to track changes in the status of VEGF ligands (A, C, and D) in CRC patients. Expression was determined by ELISA. Results: VEGF-C and -D monitoring was performed in 48 metastatic CRC patients treated with bevacizumab. Mean VEGF-D expression was 440 pg/ml which was set as the cutoff value. Patients with high VEGF-D had a significantly worse prognosis than those with low VEGF-D (8.0 vs.14.7 months, p = 0.0314). No significant difference in prognosis was seen between patients with high and low VEGF-D in first-line treatment, but patients with high VEGF-D had a significantly worse prognosis when treated with second-line bevacizumab than those with low VEGF-D (2.0 vs.10.8 months, p = 0.0049). VEGF-C showed no significant correlation with prognosis. VEGF monitoring were carried out in 75 CRC patients preoperatively. Mean VEGF-A expression in patients with recurrence (n = 8) was twice that in those without (1431.9 vs.662.5 pg/ml, p = 0.0006) but no difference was seen in levels of VEGF-C or D. Patients with high VEGF-A showed a significantly worse relapse-free survival than those with low VEGF-A (p = 0.0091). Conclusions: The RAISE trial showed that patients with high VEGF-D had a better prognosis when treated with ramucirumab, suggesting VEGF-D could be a useful biomarker to identify optimal second-line VEGF inhibitors. Patients with high VEGF-A expression exhibit similar features to CRC patients defined with consensus molecular subtype 4 harboring mesenchymal features and VEGF signal activation, suggesting some CRC patients are likely to relapse through VEGF signal activation. These patients are potential candidates for VEGF inhibitor treatment post-surgery. The AVANT trial showed no benefit of VEGF inhibitors in adjuvant therapy but our data cast light on strategies of adjuvant therapy using VEGF inhibitors in selected patients with activation of VEGF signals. Monitoring VEGF signals could provide useful information to evaluate treatment response and optimal drug selection.