tbuckley/cabot-search huggingface dataset:
Phase Ib/II with expansion of patients at the MTD study of olaparib plus weekly (metronomic) carboplatin and paclitaxel in relapsed ovarian cancer patients.
Authors: Saul E. Rivkin, Desiree Iriarte, Heather Sloan, Cara Wiseman, James Moon
Journal: Journal of Clinical Oncology (2014)

5527 Background: To establish the maximum-tolerated dose (MTD) and evaluate dose-limiting toxicities (DLTs) and response to therapy of combination therapy with carboplatin/paclitaxel and olaparib, an oral tablet inhibitor of poly ADP ribose polymerase (PARP) of BRCA 1 and 2, in advanced (Stage III or IV) relapsed ovarian cancer. Methods: Eligibility required measurable disease, adequate organ function and ECOG performance status of ≤ 2. Subjects had to have failed first line platinum containing chemotherapy. All subjects were tested for BRCA 1 and 2. Subjects received the metronomic therapy of paclitaxel 60mg/m2 IV and carboplatin AUC 2 IV weekly, 3 weeks out of 4 and increasing doses of olaparib until the maximum tolerated dose was obtained. Olaparib started at 50 mg bid administered orally for 3 consecutive days (D1-D3), every week for each cycle. Subjects were assessed for toxicity and response according to the protocol. Subjects received combination therapy until DLT or disease progression. Results: The MTD was found to be olaparib 150 mg bid, three (D1-D3) consecutive days of each week of each cycle. Total number of patients enrolled in the phase 1b part of this study was 14. Median age was 58. Median number of prior therapeutic regimens was 4. Median number of cycles on study to date is 9.3. There have been no deaths due to study regimen or grade 4 toxicities. The most common grade 3 toxicities were neutropenia, lymphopenia, anemia, fatigue, and MDS (1pt.). There was no evidence of GI, cardiac, hepatic, pulmonary or dermatologic toxicities in any of these patients. 4 subjects had a complete remission (CR), 3 had partial remissions (PR), 3 had stable disease (SD), 2 had progressive disease (PD) and 2 were not evaluable. Of the 4 CR’s three were BRCA positive Of the PR’s two were BRCA positive and one was variant. Of the SD’s there were 2 BRCA positive. Of the PD’s one was BRCA positive. Conclusions: Olaparib, an oral tablet can be safely administered with a weekly regimen of carboplatin and paclitaxel in heavily pretreated, ovarian cancer patients. This is the first successful combination of olaparib with carboplatin and paclitaxel that has been well tolerated with minimal toxicity. Clinical trial information: NCT01650376.
Altered retinoic acid signalling and its relationship to Cdx-2 in Barrett’s oesophagus and associated carcinogenesis
Authors: Chih-Long Chang, Guillermo De La Cueva-Mèndez, Pierre Lao-Sirieix, Ron Laskey, Rebecca Fitzgerald
Journal: Cancer Research (2005)

3918  Background Retinoic acid (RA) is a differentiation agent that acts via a number of cell signalling pathways involved in the determination of embryonic cell fate, including the homeobox gene Cdx2. During embryogenesis the oesophagus undergoes a columnar to squamous cell transition at 18 weeks gestation and recently up-regulation of Cdx2 has been implicated in the pathogenesis of intestinal metaplasia. We investigated whether the RA pathway has a role in the pre-malignant condition Barrett’s oesophagus and associated adenocarcinoma. Methods RA biosynthesis in cells and tissues from various stages of the Barrett’s metaplasia-dysplasia-adenocarcinoma sequence was measured using a stable reporter cell line transfected with a vector containing the RA responsive element and a downstream secretory alkaline phosphatase reporter. A Cdx2 expression vector was constructed by insertion of a full length coding sequence of Cdx2 into pCDNA3.1 myc-his. Human biopsies of squamous oesophagus were exposed to All Trans retinoic acid or the retinoic acid inhibitor citral for up to 72 h in organ culture. The morphological and molecular tissue characteristics were analysed using immunohistochemistry analysed by confocal microscopy and RT-PCR. Cell proliferation status was assessed by BrdU incorporation and immunohistochemical analysis of Ki67 and p21. Results The non-dysplastic Barrett’s oesophageal biopsies and cell lines had a significantly increased rate of RA biosynthesis compared with squamous and dysplastic tissues or cell lines. When Cdx2 was over-expressed in the squamous and non-dysplastic Barrett’s oesophageal cell lines, the RA synthesis was increased up to 10-fold. After 48 h of RA treatment in organ-culture, 8/31 (26%) squamous explants had a glandular phenotype with a villiform surface and mucosal glands. The immunohistochemical characteristics (increased expression of CK8/18, CK7, villin and TFF-1 with loss of CK13 expression) closely resembled the native Barrett’s tissue. Conversely, after 48 h of citral treatment 5/10 (50%) Barrett’s explants had a squamous phenotype, with reciprocal changes in immunohistochemical markers. Lack of BrdU incorporation and reduced Ki67 staining suggest that these phenotypic changes are proliferation independent. No phenotypic changes were observed in control tissues cultured without RA or citral. Interpretation Non-dysplastic Barrett’s columnar epithelium exhibits increased RA biosynthesis, which can also be induced by CDx2 over-expression in vitro. Furthermore, under conditions of altered retinoic acid activity the oesophageal phenotype can be altered independent of proliferation. The data suggests that alterations in RA signalling may have a role in Barrett’s carcinogenesis, which has the potential to be exploited therapeutically.
Long-term survival for patients with detectable metastatic melanoma at time of treatment with patient-specific tumor stem cell vaccines.
Authors: Robert Owen Dillman, Carol DePriest, Robin Anne Ellis
Journal: Journal of Clinical Oncology (2014)

3090 Background: Autologous, proliferating, self-renewing cancer cells (tumor stem cells) express numerous tumor-associated antigens including unique neoantigens. They are an excellent antigen-source for patient-specific polyvalent vaccines. Data from two single-arm phase II trials, (Cancer Biother Radiopharm 2007, 2009) and a 42-patient randomized trial, [J Immunother 2012] showed that metastatic melanoma patients treated with autologous dendritic cells loaded with antigens from autologous proliferating tumor cells (DC/TC) had better overall survival (OS) than patients injected with irradiated, proliferating, autologous tumor cells (TC). A survival benefit for DC/TC was seen in patients who had no evidence of disease (NED) at the time of treatment. [AACR 2014] In this study we addressed whether better survival was associated with DC/TC in NED- patients. Methods: To increase numbers for subset analyses, data for all 170 patients from the 3 trials were pooled. 27 TC-patients were excluded to decrease inter-patient differences associated with poor survival. Remaining patients were classified as NED or non-NED; this report focuses on the non-NED (n=73). Survival curves were generated for 39 treated with DC/TC and 34 treated with TC, and compared by log-rank test. Results: 5-year OS for all 73 non-NED patients was 27% (median 25.5 months). No patients were lost to follow up; 15/23 survivors had been followed for at least 5 years. Median ages were 54 and 53 years in the DC/TC and TC cohorts respectively; male gender accounted for 69% and 65%. M1c disease constituted a higher proportion of patients in the DC/TC cohort (44% vs 35%, p=0.071). OS was better in the DC/TC cohort (HR=0.65) with median survival 38.8 vs 14.7 months and 5-year OS 33% vs 20% (p=0.025). In patients with measurable disease by RECIST criteria, survival was better for DC/TC (p=0.035). Conclusions: This subset analysis suggests that active specific immunotherapy with DC/TC is associated with longer survivor than TC in patients who have detectable metastatic melanoma at the time of treatment. (NCI-V01-1646, NCT00436930) Supported by the Hoag Hospital Foundation and the Cancer Biotherapy Research Group.
Highly Comprehensive Genomic Testing for CLL: WGS, One Key to CLL Patient Stratification
Authors: Kate E Ridout, Pauline Robbe, Doriane Cavalieri, Jennifer Becq, Miao He, Ruth Clifford, Niamh Appleby, Reem Alsolami, Adam Burns, Melanie Oates, Basile Stamatopoulos, Samantha Knight, Alona Sosinsky, Pavlos Antoniou, Mark Ross, David Bentley, Andrew Pettitt, Peter Hillmen, Mark Caulfield, Anna Schuh
Journal: Blood (2018)
Tumor bulk to predict clinical outcomes of anti-EGFR therapy in treatment refractory metastatic colorectal cancer independent of sidedness.
Authors: Jeremy D. Kratz, Noelle K. LoConte, Sam Joseph Lubner, Daniel Mulkerin, Nataliya Volodymyrivna Uboha, Dustin A. Deming
Journal: Journal of Clinical Oncology (2018)

795 Background: Epidermal growth factor receptor (EGFR) antibodies, cetuximab (C) and panitumumab (P) have shown improvement in clinical outcomes for distinct molecular profiles in metastatic colorectal cancer (mCRC). In the first line setting, EGFR targeting of left-sided tumors has shown favorable clinical outcomes when compared to right-sided tumors. Here we examined the efficacy of EGFR therapy in the treatment refractory setting as well as the impact of tumor bulk on clinical outcomes. Methods: A retrospective cohort of 72 patients (pts) with KRAS wild-type mCRC were identified who received either C or P in the late-line setting. Tumor measurements were performed per RECIST v1.1. Disease bulk was defined as single lesion with longest diameter or lymph node with short axis &gt; 3.5 cm. Right colon primary was defined proximal to splenic flexure. Results: In pts with treatment refractory right-sided disease the response rate (RR) was 16.7%, progression free survival (PFS) was 3.7 months (mo), and overall survival (OS) was 14.0 mo. This was compared to left sided disease with RR of 26.0%, PFS 6.2 mo (p &lt; 0.05), and OS 15.0 mo. In the non-bulky cohort the RR was 32.4%, PFS 7.9 mo, and OS 18.4 mo. In the bulky cohort the RR was 5.3% (p &lt; 0.01), PFS 4.0 mo (p &lt; 0.02), and OS 6.6 mo. In the right-sided non-bulky cohort there was a RR of 33% v. 0% in the right-sided bulky cohort. In the left-sided non-bulky cohort there was a RR of 32.3% v. 7.7% in the bulky cohort (p &lt; 0.05). Conclusions: These data indicate that tumor bulk can predict clinical outcomes for anti-EGFR targeting. In the late line setting, pts with left-sided cancers overall trended towards improvements in clinical outcomes, consistent with prior understanding in first line setting. Despite a limited cohort size, response was observed in pts with non-bulky right-sided disease. There was limited-to-no benefit of anti-EGFR targeting with right-sided bulky disease. Left-sided non-bulky patient received the greatest benefit from anti-EGFR targeting. Future prospective studies of targeted therapeutics should incorporate tumor bulk and sidedness when assessing clinical outcomes and tumor biology.
Senescence induction in human melanoma by the combined action of type II interferon and tumor necrosis factor.
Authors: Cristina Boß, Simone Kayser, Claus Garbe, Tobias Feuchtinger, Martin Röcken
Journal: Journal of Clinical Oncology (2014)

e22213 Background: Adoptive T-cell transfer is a promising therapeutic option for patients with metastatic malignant melanoma. Recent evidence suggests that CD4+ T helper (Th1) lymphocytes are of great importance for those therapeutic strategies as they orchestrate the response of cytotoxic T lymphocytes and can impair tumor growth through cytokine signaling. The secretion of interferon-γ (IFN-γ) and tumor necrosis factor (TNF) by Th1 lymphocytes seems to be crucial for efficient tumor control. Methods: We treated a panel of melanoma cell lines with IFN-γ and TNF. Analysis of cell cycle arrest was performed by FACS. To generate tumor-antigen specific Th1 lymphocytes, we primed peripheral blood mononuclear cells with peptide pools from different tumor-antigens. After stimulation with IL-2 und IL-7, we enriched IFN-γ producing cells with the IFN-γ capture technique. Subsequently we expanded the Th1 cells over 2 weeks. Results: Here we show first that IFN-γ and TNF induce various types of cell cycle arrest, including a predominant G0/G1 arrest. In some melanomas the cell cycle arrest remained stable over 7 passages after withdrawal of IFN-γ and TNF, while it was of shorter duration in others. As this suggested that the G0/G1 growth arrest may be reverted in melanomas, we repeatedly pulsed the cancer cells every 3 weeks. This treatment induced in human melanoma cells senescence, as defined by stable growth arrest and induction of the senescence associated secretory phenotype. Moreover, we established a culture method that allows to generate melanoma-antigen specific Th1 lymphocytes with a GMP conform protocol. The supernatants of such tumor-specific Th1 cells also induced a G0/G1 cell cycle arrest and senescence, like the combined action of IFN-γ and TNF. Conclusions: The Th1 cytokines IFN-γ and TNF induce senescence in a large spectrum of human melanomas. In order to establish a therapeutically applicable treatment approach, we are currently developing devices for the GMP-conform generation of tumor-antigen specific Th1 lymphocytes.
Medical and socioeconomic factors associated with triple-negative breast cancer (TNBC) in women with health care disparities.
Authors: Tarek N. Elrafei, Devika Prassana, Maria Castaldi, Pavlos Msaouel, Marianna Strakhan, Karenza M. Alexis, Richard J. Gralla
Journal: Journal of Clinical Oncology (2014)

e17512 Background: TNBC accounts for approximately 15-20% of breast cancer diagnoses. Several factors prompted this analysis of factors associated with TNBC in a population with health care disparities. First, cancer care disparities affecting low income and minority women are well documented. Second, multiple studies have indicated that African American and Hispanic women have a higher risk of TNBC and generally have poorer therapeutic outcomes.. We examined social, economic and other demographic factors affecting diagnosis and care in patients with TNBC in an urban safety net hospital. Methods: We reviewed multiple aspects of patients with breast cancer diagnosed at our institution between 2007 and 2013. We analyzed data on the presence of a screening mammogram, access to genetic testing, time from detection to mammogram, mammogram to biopsy, biopsy to therapy, and time to progression, and clinical parameters including age, race, stage, and receptor status. Results: A total of 502 diagnoses of breast cancer were made over that period. Of these patients, 58 (12%) were found to have TNBC. Full demographic data were available for about 95% of all demographic parameters. Median age was 52 (range 32-79). Race: 39 black, 13 hispanic, 5 white, 1 other. 29% of patients were uninsured, and 35% of patients were immigrants. Initial clinical suspicion for the breast was by detection of a lump in 61%, with 31% found on mammogram, and 8% by other means. The median interval of lump detection to biopsy was 81 days (range 15-1418). 50 patients (86%) met criteria for genetic testing for BRCA. Of those, only 52% underwent BRCA testing. No significant difference was found in BRCA testing between insured vs uninsured, immigrant vs non-immigrant (p=0.377) women. Conclusions: These findings indicate several areas of need in this population with TNBC and health care disparities. The nearly 3 month interval between detection of a lump and pathologic diagnosis and 66% of cases found as a mass, likely affect survival outcomes. Significant challenges remain in screening, reducing intervals to diagnosis, and access to genetic testing for minority patients with TNBC independent of insurance and immigration status.
Functional Repair Assay for the Diagnosis of Constitutional Mismatch Repair Deficiency From Non-Neoplastic Tissue
Authors: Andrew Y. Shuen, Stella Lanni, Gagan B. Panigrahi, Melissa Edwards, Lisa Yu, Brittany B. Campbell, Ariane Mandel, Cindy Zhang, Nataliya Zhukova, Musa Alharbi, Mark Bernstein, Daniel C. Bowers, Sara Carroll, Kristina A. Cole, Shlomi Constantini, Bruce Crooks, Rina Dvir, Roula Farah, Nobuko Hijiya, Ben George, Theodore W. Laetsch, Valerie Larouche, Scott Lindhorst, Rebecca C. Luiten, Vanan Magimairajan, Gary Mason, Warren Mason, Oz Mordechai, Naureen Mushtaq, Garth Nicholas, Michael Oren, Laura Palma, Luis Alberto Pedroza, Jagadeesh Ramdas, David Samuel, Kami Wolfe Schneider, Andrea Seeley, Kara Semotiuk, Ashraf Shamvil, David Sumerauer, Helen Toledano, Patrick Tomboc, Margaret Wierman, An Van Damme, Yi-Yen Lee, Michal Zapotocky, Eric Bouffet, Carol Durno, Melyssa Aronson, Steve Gallinger, William D. Foulkes, David Malkin, Uri Tabori, Christopher E. Pearson
Journal: Journal of Clinical Oncology (2019)

Constitutional mismatch repair deficiency (CMMRD) is a highly penetrant cancer predisposition syndrome caused by biallelic mutations in mismatch repair (MMR) genes. As several cancer syndromes are clinically similar, accurate diagnosis is critical to cancer screening and treatment. As genetic diagnosis is confounded by 15 or more pseudogenes and variants of uncertain significance, a robust diagnostic assay is urgently needed. We sought to determine whether an assay that directly measures MMR activity could accurately diagnose CMMRD.In vitro MMR activity was quantified using a 3'-nicked G-T mismatched DNA substrate, which requires MSH2-MSH6 and MLH1-PMS2 for repair. We quantified MMR activity from 20 Epstein-Barr virus-transformed lymphoblastoid cell lines from patients with confirmed CMMRD. We also tested 20 lymphoblastoid cell lines from patients who were suspected for CMMRD. We also characterized MMR activity from patients with neurofibromatosis type 1, Li-Fraumeni syndrome, polymerase proofreading-associated cancer syndrome, and Lynch syndrome.All CMMRD cell lines had low MMR activity (n = 20; mean, 4.14 ± 1.56%) relative to controls (n = 6; mean, 44.00 ± 8.65%; P < .001). Repair was restored by complementation with the missing protein, which confirmed MMR deficiency. All cases of patients with suspected CMMRD were accurately diagnosed. Individuals with Lynch syndrome (n = 28), neurofibromatosis type 1 (n = 5), Li-Fraumeni syndrome (n = 5), and polymerase proofreading-associated cancer syndrome (n = 3) had MMR activity that was comparable to controls. To accelerate testing, we measured MMR activity directly from fresh lymphocytes, which yielded results in 8 days.On the basis of the current data set, the in vitro G-T repair assay was able to diagnose CMMRD with 100% specificity and sensitivity. Rapid diagnosis before surgery in non-neoplastic tissues could speed proper therapeutic management.
Diagnosis of Myelodysplastic Syndromes and Related Conditions: Rates of Discordance between Local and Central Review in the NHLBI MDS Natural History Study
Authors: Ling Zhang, Donald M Stablein, Pearlie Epling-Burnette, Alexandra M. Harrington, Lynn C. Moscinski, Steven Kroft, Amy E. DeZern, Tareq Al Baghdadi, Jane Jijun Liu, Matthew J. Walter, Rafael Bejar, Edward J. Gorak, Rami S. Komrokji, Gregory A. Abel, Bart L Scott, Steven D. Gore, Mikkael A. Sekeres
Journal: Blood (2018)
Abstract 13556: Elderly Patients Receiving Durable LVAD Support: Insights and Outcomes
Authors: Palak Shah, Francis D Pagani, Shashank S Desai, Anthony Rongione, Simon Maltais, Nicholas A Haglund, Shannon M Dunlay, Keith D Aaronson, John M Stulak, Mary Beth Davis, Christoper Salerno, Jennifer A Cowger
Journal: Circulation (2015)

Introduction: Age ≥ 70 is used to exclude patients from cardiac transplantation. Elderly patients may be offered left ventricular assist device (LVAD) therapy as an alternative. It remains poorly defined how they respond to LVAD support. Hypothesis: Elderly patients have LVAD outcomes that are non-inferior to younger patients. Methods: Data on 1,149 continuous-flow LVAD recipients from May 2004 to May 2015 was pooled from the Mechanical Circulatory Support Research Network (MCSRN). Groups were assigned based on Age ≥ 70 (n = 163) and &lt; 70 (n = 986). Results: Patients age ≥ 70 were more likely to be male (91%), have an ischemic cardiomyopathy (71%), atrial fibrillation (41%), hypertension (66%), diabetes (38%) and prior sternotomy (45%). Older patients also had a lower BMI and higher creatinine, 26.7 ± 0.4 v. 29.9 ± 0.5 and 1.46 ± 0.04 v. 1.35 ± 0.02, p &lt; 0.05. The hazard ratio for mortality was highest in elderly patients in the early post-operative period and stabilized over time with no long-term differences in survival, p = 0.18, Figure 1a. Elderly patients had equivalent rates of device thrombosis and stroke, p = 0.47 and 0.44, Figures 1b-c. Survival free of gastrointestinal bleeding (GIB) at 1-year was 58% in elderly patients compared to 69% in younger patients, Figure 1d, p &lt; 0.01. Multivariate cox regression revealed that age ≥ 70 was not a significant predictor of mortality (HR 0.93, 95% CI 0.69 - 1.25, p = 0.62), but pre-operative creatinine (HR 1.54, 95% CI 1.28 - 1.86, p &lt; 0.01) and bilirubin (HR 1.2, 95% CI 1.03 - 1.4, p = 0.02) were. When age was considered a continuous variable, the HR was 1.2 (95% CI 1.07 - 1.3 per 10y, p &lt; 0.01). Conclusions: Elderly patients, age ≥ 70, have equivalent long-term survival after LVAD implantation with similar rates of device thrombosis and stroke. Rates of GIB were higher in the elderly and this finding warrants caution when choosing anti-coagulation protocols in the elderly. Overall age ≥ 70 does not portend a poorer survival after LVAD implant.
Association of RhoGDI2 with HGF-mediated tumor invasion through VEGF in stomach cancer.
Authors: Sung Ae Koh, Kyung Hee Lee, Eun Young Choi, Min Kyoung Kim, Jae-Ryong Kim, Sang Woon Kim
Journal: Journal of Clinical Oncology (2014)

e22007 Background: Rho GDP dissociation inhibitor 2 (Rho GDI2) has been identified as a regulator of tumor metastasis, but its role in cancer remains controversial. The aims of this study were to analyze RhoGDI2 on gastric cancer growth and metastasis, and to determine its possible signaling pathway Methods: Genes induced by HGF were screened using cDNA microarray technology in the stomach cancer cell lines, NUGC3 and MKN28. The level of expression of Rho GDI2 was further confirmed by real time RT-RCR and Western blot analysis. The role of Rho GDI2 in the level of HGF-induced up-regulation of VEGF was measured by knockdown of Rho GDI2 with Rho GDI2 shRNA and a chromatic immuno-precipitation assay. Results: The levels of Rho GDI2 and VEGF were up-regulated in cells treated with HGF in a dose-dependent manner, but Rac-1 was down-regulated. HGF-induced up-regulation of VEGF was repressed by Rho GDI2 knockdown. The level of Rac-1was increased in cell of Rho GDI2 knockdown without HGF. HGH-induced up regulation of pERK and pP38 was inhibited in Rho GDI2 knockdown cells. HGF enhanced the binding activity of Rho GDI2 to the VEGF promoter in control cells, but not in the Rho GDI2-shRNA cells. Transfection with Rho GDI2 -shRNA results in no effects of cell proliferation, as determined with MTT assays. In an in vitro invasion assay, significantly fewer cells transfected with Rho GDI2 shRNA than control cells were able to invade across a Matrigel membrane barrier. We also found that the serum level of Rho GDI2 decreased after curative surgery at stomach cancer patients. Conclusions: In conclusion, Rho GDI2 appears to play an important role in the up-regulation of VEGF induced by HGF and contributes to HGF-mediated tumor invasion and metastasis, which may serve as a promising target for gastric cancer therapy.