tbuckley/cabot-search huggingface dataset:
Abstract 16892: Cold Exposure Induces Drp1-Mediated Mitochondrial Elongation in Cardiomyocytes and is Associated With Sustained Respiratory Suppression
Authors: David Taylor, Stefanie Marek-Iannucci, Roberta A Gottlieb
Journal: Circulation (2018)

Introduction: The effects of cold exposure on the heart are poorly understood. Cardiac hypothermia arises exclusively in the context of coincident ischemia, either in out-of-hospital cardiac arrest, or in the setting of cardiac surgery. Our lab has recently described an intraoperative increase in mitochondrial protein expression in atria of patients undergoing coronary artery bypass graft surgery. We have been exploring the role of cold stimulus as a potential trigger for mitochondrial remodeling. Methods: The effects of cold exposure on mitochondrial morphology, fusion/fission protein expression and respiration were assessed in H9C2 cardiomyocytes and the Langendorff-perfused rat heart. Results: H9C2 cardiomyocytes were exposed to a range of hypothermic temperatures (25-32°C) under normoxic conditions for up to 24 hrs. Immunofluorescence imaging revealed elongated mitochondria under hypothermic conditions, which was associated with decreased levels of active pDrp1 (Ser616) and its receptor mitochondrial fission factor (MFF). Seahorse respirometry (conducted at 37°C) revealed depression of oxygen consumption in cells previously exposed to hypothermic temperatures. Both morphological and respiratory phenomena persisted when cells were rewarmed to 37°C for 2 hours. In Drp1 siRNA-treated H9C2 cardiomyocytes, mitochondria exhibited elongated morphology as well as depression of oxygen consumption. In Langendorff perfused rat hearts, 1 hour normoxic perfusion at 28 or 32°C gave rise to a reduction in pDrp1(Ser616). Furthermore, reductions in pDrp1 levels persisted following a subsequent 1 hour rewarming at 37°C. Conclusions: Hypothermia promoted elongation of cardiac mitochondria via reduced fission activity of Drp1, which was also associated with suppression of cellular oxygen consumption. The presence of mitochondrial elongation and suppressed oxygen consumption in Drp1 siRNA-treated cells suggests a link between Drp1 activity and respiratory function. In cardiomyocytes and Langendorff-perfused hearts, cold-induced Drp1 inhibition persisted following rewarming, suggesting that hypothermia may sustainably inhibit Drp1 activity.
Phase I trial of hyperthermic intraperitoneal chemoperfusion (HIPEC) with cisplatin, mitomycin, and paclitaxel in patients with gastric adenocarcinoma and carcinomatosis or positive cytology.
Authors: Brian D. Badgwell, Mariela A. Blum, Naruhiko Ikoma, Xuemei Wang, Jeannelyn Estrella, Sinchita Roy-Chowdhuri, Prajnan Das, Bruce D. Minsky, Shumei Song, Paul F. Mansfield, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2019)

4056 Background: This phase I trial evaluated the safety and toxicity of laparoscopic hyperthermic intraperitoneal perfusion with chemotherapy (HIPEC) combining mitomycin, cisplatin, and paclitaxel for patients with gastric cancer metastatic to the peritoneum. Methods: A Bayesian optimal interval design was used to identify the maximum tolerated dose (MTD) of escalating doses of paclitaxel (starting dose of 20 mg/m2 to maximum dose of 60 mg/m2) in combination with flat doses of mitomycin (30 mg) and cisplatin (200 mg) during laparoscopic HIPEC for patients with gastric adenocarcinoma metastatic to the peritoneum. The primary endpoint was MTD. Secondary endpoints included surgical complications and overall survival (OS). Results: A total of 27 patients were treated from November 2017 through November 2018. No dose-limiting toxicities were found. Treatment-related grade 1-2 side effects were leukopenia (11%), oral dysesthesia (4%), arthralgia (4%), and diarrhea (4%). Treatment-related grade 3-4 side effects included leukopenia (4%) and neutropenia (4%). The MTD was 60 mg/m2. Clavien-Dindo surgical complications were grade I (all representing electrolyte deficiencies requiring replacement) in 96% of patients, grade II in 4%, grade III in 0%, grade IV in 0%, and grade V in 4%. At a median follow-up of 15 months, the median OS from diagnosis of metastatic disease and the date of surgery has not been reached. One- and 2-year OS rates from the date of metastatic disease were 74% and 58%, respectively. The 1-year OS rate from the date of HIPEC was 51%. Conclusions: Laparoscopic HIPEC with mitomycin, cisplatin, and paclitaxel appears safe at intraperitoneal doses of 30 mg, 200 mg, and 60 mg/m2, respectively. Although electrolyte abnormalities are common, systemic toxicity of this therapy is modest. Survival rates are promising, supporting further research into intraperitoneal therapy for stage IV gastric cancer. Clinical trial information: NCT03330028.
Cathepsin B is one of a target molecule of Hedgehog signaling in pancreatic cancer
Authors: Yong-Tae Kim, Jin-Hyeok Hwang, Ji Kon Ryu, Yong Bum Yoon
Journal: Cancer Research (2007)

5367  Introduction: It is well known that the Hedgehog (Hh) signaling pathway regulates cell differentiation and organ formation during embryonic development. Recent reports showed that activation of Hh signal pathway has been associated with gastrointestinal tract cancers including pancreatic cancer as well as Gorlin’s syndrome tumors, and activation of HH signaling might be important for early and late stage of tumorigenesis in pancreatic cancer. However, there is few data available about target molecules of Hh signal in pancreatic cancer. Therefore, we investigated Hh-related target molecules in Hh ligand expressing pancreatic cancer cells. Materials and Methods: Two human pancreatic cancer cell lines, MiaPaCa-2 and Panc-1 were treated with cyclopamine (5 μM, 10 μM, 20 μM, and 40 μM) for Hh signal inhibition and tomatidine (5 μM), as a control. After 72 hours, we performed Western blot analysis against Hh signal components and apoptosis were measured by FACS. In order to find out possible Hh-related target molecules in pancreatic cancer, gene expression patterns were analyzed by microarray in Panc-1 after cyclopamine administration. Of 3 folds or more downregulated genes resulted from microarray data, expression of cathepsin B (CATB) was measured by Western blot and real-time PCR after inhibition of Hh signal pathway. In order to investigate expression of Hh signal components and CATB in pancreatic cancer tissues, immunohistochemical study of these proteins was carried out. Results: Cyclopamine did increase apoptosis in Panc-1 cells which expressed Shh, not in MiaPaCa-2. When Panc-1 cells were cultured in cyclopamine containing media, a total of 138 genes were 2 folds or more downregulated and 32 genes were 3 folds or more downregulated (of 22,746 human oligo). Whereas cyclopamine did not change the expression of Hh signal components such as Shh, Ptch, and Gli1, expression of CATB decreased after treatment of cyclopamine (p
Malignant pheochromocytoma (MP): A comprehensive genomic profiling (CGP) study.
Authors: Gennady Bratslavsky, Andrea Necchi, Oleg Shapiro, Joseph Jacob, Julia Andrea Elvin, Jo-Anne Vergilio, Jonathan Keith Killian, Nhu Ngo, Shakti Ramkissoon, Eric Allan Severson, Amanda Hemmerich, Siraj Mahamed Ali, Jon Chung, Prasanth Reddy, Vincent A. Miller, Brian Alexander, Alexa Betzig Schrock, Nick Liu, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2019)

4584 Background: We CGP to characterize the genomic alterations (GA) in MP and to enable the search for potential therapy targets. Methods: From a series of 201,766 consecutive clinical cases, 44 cases of clinically advanced MP underwent CGP using a hybrid-capture based commercial assay to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and reported as mutations/Mb and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (DAKO 22C3 antibody). Results: All patients had clinically advanced recurrent and/or metastatic disease. 23 patients were females and 21 patients were males. There were 34 (77%) of MP known to have originated in the adrenal gland and 10 (23%) of the MP were sequenced from metastatic site where the exact primary site was unknown. The primary tumor was used for sequencing in 14 (32%) of the MP cases and a non-primary tumor metastatic site (liver, lung, bone, soft tissue, lymph node, kidney, peritoneal cavity, and chest wall) in 30 (68%) of the MP cases. There were 2.3 GA/tumor. The most frequent un-targetable GA were ATRX (25%), TP53 (21%), SDHB (13%), CTNNB1 (7%), VHL (7%), and CDKN2A/2B, PIK3R2, NOTCH2 and MEN1 (all 5%). The most frequent potentially targetable GA included RET (9%), NF1 (9%) and FGFR1 (5%). PBRM1 GA were found in 2% of MAP. Germline mutations in known cancer predisposition genes were predicted in 8 (18%) of cases involving SDHB (5 cases) and BRCA1, MEN1, and MSH2 (1 case each). The genomic signatures of primary MP were not significantly different from that obtained from sequencing of metastatic site biopsies. 0 (0%) of 5 MP stained positively for PD-L1 expression. The mean TMB was 2.95 mutations/Mb, the median TMB was 2.4 mutations/Mb. There 2 (5%) of MP with TMB ≥ 10 mutations/MB and 0 (0%) with TMB ≥ 20 mutations/Mb. 0 (0%) of 33 MP evaluated for MSI had a MSI-High status. Conclusions: Although the GA/tumor is relatively low for MP, CGP can reveal important potential therapy targets including RET, NF1 and FGFR1. MP do not reveal strong potential for immunotherapies with low TMB, absence of MSI-High status and low (2%) PBRM1 mutation frequencies.
Histone deacetylase 6-EGFR axis in recurrent hepatocellular carcinoma.
Authors: Yao-Tsung Yeh, Hong-Ying Dai, Shen-Nien Wang, Pin-Jou Chang-Chien
Journal: Journal of Clinical Oncology (2019)

e15638 Background: Alterations of histone deacetylases (HDACs) and related signaling have been increasingly associated with cancer development and treatment. Among those HDACs, HDAC6 uniquely functions in maintaining mRNA stability of certain genes. The aim of this study was to determine the clinical impacts and associated mechanisms of HDAC6 in hepatocellular carcinoma (HCC). Methods: Immunohistochemistry is firstly applied to analyze the distribution patterns of HDAC6 in 122 patients and the obtained results are statistically analyzed with clinicopathological characteristics and patient survival. XTT, flowcytometery, transwell assay, real-time PCR, IF, IB, immunoprecipitation (IP), and RNA-IP are used to determine the bio-impacts and underlying mechanisms of HDAC6 in liver cancer cells. Results: Both cytoplasmic and nuclear staining of HDAC6 proteins were mainly decreased in cancerous lesions. Nevertheless, increased cytoplasmic HDAC6 staining was positively correlated with disease recurrence (p = 0.002). Increased nuclear frequency, but not cytoplasmic intensity, of HDAC6 was associated with a poor survival rate in HCC patients (p = 0.041). Restoration of HDAC6 expression increased the proliferation, S phase, migration and invasion of the HepJ5, Huh7 and Mahlavu cells, lacking detectable HDAC6 expression. More interestingly, ectopic HDAC6 overexpression increased a ligand-independent expression of p-AKT, beta-catenin and cyclin D, and subsequently promoted the entry of beta-catenin into the nucleus. Both transcripts and proteins of the EGFR, a dominant trigger of AKT signaling, were unexpectedly increased upon HDAC6 restoration in HepJ5, Huh7 and Mahlavu cells. The expression of EGFR was not restored by treatment with MG132 (proteasome inhibitor) in HepJ5, Huh7 and Mahlavu cells, and HDAC6-specific siRNA decreased both HDAC6 and EGFR expression in Hep3B and SK-Hep1 cells, having detectable HDAC6 and EGFR expression. IP and RNA-IP analysis revealed that HDAC6 interacted with HuR and increased EGFR mRNA stability. Accordingly, the expression of HDAC6 and EGFR were positively correlated in cancerous lesions. Conclusions: Our results suggest that the contribution of HDAC6 to recurrent HCC may act through its maintenance of EGFR mRNA stability. HDAC6 may serve as a rational treatment target in recurrent HCC.
A phase II study of PD-1 inhibition for the prevention of colon adenomas in patients with Lynch syndrome and a history of partial colectomy.
Authors: Joanne M. Jeter, Heather Hampel, Peter Stanich, Rachel Pearlman, Alice Hinton, John L. Hays, Richard M. Goldberg
Journal: Journal of Clinical Oncology (2019)

TPS1587 Background: Colon cancers and adenomas that are associated with Lynch syndrome (LS) often display microsatellite instability (MSI), a characteristic that is associated with increased response to treatment with PD-1 inhibitors. Because LS patients with a history of colon cancer are at increased risk of having a second primary colon cancer or high-risk adenoma, preventive measures are of particular interest in this population. We hypothesize that a maintenance schedule of nivolumab can be safely administered to LS patients with a history of treated colon cancer with remaining colon at risk in order to decrease the incidence of adenomas, advanced adenomas and second primary colon cancers. Methods: OSU 17198 is a phase II multi-center, single-arm study of nivolumab in patients with germline MLH1 or MSH2 mutations and a history of hemicolectomy for colon cancer at least one year prior to study entry. Subjects must have completed any adjuvant therapy at least 6 months prior to study participation and may not have received prior therapy with a PD-1 inhibitor. Nivolumab is given at 240mg IV every 3 months for two years, and colonoscopies will be performed prior to study entry, after the fourth dose, after the eighth dose, and one year after the eighth dose. Subjects will be monitored for auto-immune adverse effects. The primary endpoint is incidence of adenomas at three years, and secondary endpoints are safety, incidence of advanced adenomas, and incidence of colon and non-colon cancers at three years. Approximately 104 subjects will be enrolled to obtain 94 evaluable subjects. This study is currently open for enrollment at the Ohio State University and at various stages of activation at seven additional sites in the United States. Enrollment of this study is anticipated to be completed in 2020, and data collection is anticipated to be complete in 2023. This study has undergone safety review by the FDA and the Ohio State University Institutional Review Board. Clinical trial information: NCT03631641.
An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.
Authors: Mark R. Middleton, Joseph J. Sacco, Jaime R. Merchan, Brendan D. Curti, Ari M. Vanderwalde, Anna Claire Olsson-Brown, Francesca Aroldi, Nicos Fotiadis, Scott Baum, Robert S. Coffin, Howard Kaufman, Kevin J. Harrington
Journal: Journal of Clinical Oncology (2019)

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.
Predicting response to neoadjuvant chemotherapy in nonmetastatic hormone receptor-positive breast cancer using 21-gene Breast Recurrence Score test.
Authors: Romy Jose Thekkekara, Sushma Bharadwaj, Udit Yadav, Anmol Baranwal, David Peace, Wendy Rogowski, Marin Sekosan, Thomas E. Lad, Elizabeth A. Marcus, Karen Ferrer, Mousami Shah, Susan H. McDunn
Journal: Journal of Clinical Oncology (2019)

e12093 Background: The Recurrence Score (RS) result based on the 21-gene Oncotype DX Breast Recurrence Score assay is standard of care in deciding adjuvant chemo-hormonal therapy versus hormone therapy alone in hormone-receptor positive (HR+), HER 2 negative, node–negative breast cancer. This study explores the role of RS result in predicting the response to neoadjuvant chemotherapy (NACT). Methods: In this retrospective single institution cohort study, electronic medical records of 148 women with HR+, HER 2 negative, non-metastatic breast cancer who received NACT from 2006 onward were screened. 38 patients were excluded due to lack of tissue for testing. Pretreatment biopsy blocks were sent to Genomic Health, Inc. for Oncotype Dx testing. Low RS result was defined as ≤25. Pathologic complete response (pCR) was defined as no residual tumor. Partial response (PR) was residual tumor with &gt; 25% decrease in the largest dimension. No response (NR) was defined as &lt; 25% decrease in the tumor post NACT. Progression (PD) was defined as increase in size of original tumor or new site(s) of disease. Results: Of the 110 patients studied, 58% were postmenopausal women. Fifty percent were African American, 12% were Caucasian and 27% were Hispanic. Invasive ductal carcinoma was the predominant histology (86%). Most patients had &gt; T2 disease (97%) with 73% being clinically node positive. Adriamycin based NACT regimen was used in treating 86.3% of the women. Forty patients (36.4%) had tumor with RS≤25. NR/PD was significantly higher in tumors with RS≤25 (27/40) vs RS &gt; 25 (13/70) (OR: 9.1, 95% CI: 3.7-22.2, P&lt; 0.001). pCR was seen in 16% with RS &gt; 25 and 0% with RS ≤25. Response to NACT (pCR/PR) was 32.5% in RS≤25 vs 81.4% in RS &gt; 25. In tumors with response, RS &gt; 25 was associated with a greater percent decrease in the tumor size compared to RS≤25 (median decrease of 71% vs 52%, P= 0.033). Conclusions: HR+, HER 2 negative, RS≤25 breast cancer is associated with increased rates of NR/PD and is unlikely to respond to NACT. Recurrence Score result determination in pretreatment breast cancer biopsy samples can be an effective tool to select patients with non-metastatic breast cancer for NACT. Studies are needed to determine novel neoadjuvant therapeutic approaches in patients who are candidates for neoadjuvant therapy but are unlikely to benefit from NACT.
Prognosis of ovarian cancer in the United States during 1973 to 2015.
Authors: Jianfeng Zhang, Yingying Lu, Yuzi Zhang, Zhenghua Zhang, Shangli Cai
Journal: Journal of Clinical Oncology (2019)

e17072 Background: Ovarian cancer is the first leading cause of cancer death among gynecologic malignancies. Despite significant efforts to improve treatment strategies, the prognosis of patients with ovarian cancer remains poor. Different diagnostic period and the occurrence of distant metastases may have different impacts on prognosis. In this study, we sought to describe the impact of distant metastases and different diagnostic period on prognosis of ovarian cancer. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with ovarian cancer from year 1973 to year 2015. Kaplan-Meier method was used to estimate the overall survival (OS) and Log-Rank test was used to compare the difference between groups. Results: Total 152729 patients with ovarian cancer were included. Median age was 62 years. The overall rates of distant lymph node metastases, bone, brain, liver and lung were 2.9%, 1.0%, 0.2%, 6.6% and 5.6%. Median overall survival (OS) was 30 months, 6 months, 9 months, 20 months and 20 months for pure distant lymph node metastases, brain metastases, bone metastases, lung metastases and liver metastases, respectively. Patients who were diagnosed from year 2010 to year 2015 had significantly improved OS compared with patients who were diagnosed from year 1973 to year 2009 (54 months vs. 47 months, P &lt; 0.0001). Patients with pure distant lymph node metastases who were diagnosed from year 2010 to year 2015 also had significantly improved OS compared with patients who were diagnosed from year 1973 to year 2009 (30 months vs. 24 months, P = 0.0002). In addition, we also observed a trend of longer OS in patients with bone metastases diagnosed from year 2014 to year 2015 compared with patients who were diagnosed year 2010 to year 2013 (10 months vs. 7 months, P = 0.05). Conclusions: The results of this analysis indicated an improved prognosis in patients with ovarian cancer from 2010 to 2014, especially for patients with distant lymph node metastases. In addition, novel treatment strategies are needed for patients with distant visceral metastases.