tbuckley/cabot-search huggingface dataset:
CTEP #8850: A phase I trial of riluzole and sorafenib in patients with advanced solid tumors.
Authors: Kristen Renee Spencer, Janice M. Mehnert, Antoinette R. Tan, Rebecca Anne Moss, Kelly Levinson, Mark N. Stein, Lien Huzzy, Michael P. Kane, Darlene Gibbon, John Joseph Wright, Joseph Aisner, Robert S. DiPaola, Suzie Chen, Yvonne Wen, James Goydos
Journal: Journal of Clinical Oncology (2015)

11086 Background: Metabotropic glutamate receptor 1 (GRM1) activates MAPK and PI3K/AKT signaling and is implicated in multiple cancers including breast, prostate and melanoma. GRM1 overexpression stimulates tumor angiogenesis via enhanced microvesicle secretion to facilitate endothelial cell growth. Riluzole (R) is a clinically available inhibitor of GRM1 signaling. Sorafenib (S), a kinase inhibitor that inhibits MAPK and PI3K/AKT signaling through C-RAF and B-RAF inhibition with antiangiogenic effects, was identified in preclinical screens to have synergistic antitumor activity when combined with R. This phase I trial identified the maximum tolerated dose (MTD) of R combined with S in patients (pts) with advanced cancer. Methods: Pts with refractory solid tumors were enrolled utilizing a standard 3+3 dose-escalation design. R was given in 28 day cycles at the highest dose used in clinical practice (100 mg BID) in combination with S, beginning at 200 mg daily and escalating in 200 mg increments per cohort. Restaging evaluations were performed every 2 cycles using RECIST criteria. Results: 29 pts enrolled, median age 59 (22-85), 13F, 16M, PS 0 (48%), 1 (35%) or 2 (17%). The most common toxicities were nausea (31%), fatigue (62%) and diarrhea (41%), anorexia (31%), rash (27% PPE, 31% other), and hypophosphatemia (34%). Grade 3-4 toxicities included hypophosphatemia (10%), elevated lipase (10%), LFT abnormalities (10%), rash/PPE (14%), and fatigue (13%). The most frequent dose limiting toxicity (DLT) was rash, observed in 3 pts at the MTD, dose level (DL) 4 (R 200 mg bid/S 400 mg bid). Best responses were SD in 9 pts (31%), lasting > 3 months in 1 pt each with sarcoma, lung, colon, ovarian, and melanoma; and 1 GIST (9+ cycles with modest tumor reduction). Conclusions: R combined with S is safe with DLT of rash. While rash is a known side effect of sorafenib, its incidence and severity appeared increased in this study. An expansion cohort in pts with melanoma and sarcoma at DL3 (R 200 mg bid/S 400mg qam/200 mg qpm) is ongoing. Planned correlative assessments include circulating microvesicle quantification and immunohistochemical and western blotting to assess changes in activated signaling targets in pre and post treatment tumors. Clinical trial information: NCT01303341.
Erratum for the Research Article: “Interferon-λ restricts West Nile virus neuroinvasion by tightening the blood-brain barrier” by H. M. Lazear, B. P. Daniels, A. K. Pinto, A. C. Huang, S. C. Vick, S. E. Doyle, M. Gale Jr., R. S. Klein, M. S. Diamond
Journal: Science Translational Medicine (2015)
Combined inhibition of autophagy with mTOR inhibitor to enhance cell death in renal cell carcinoma.
Authors: Hua Chen, Kyle Potts, Allan Murray, Mary Hitt, Ron Moore
Journal: Journal of Clinical Oncology (2017)

450 Background: mTOR (mammalian target of rapamycin) and autophagy are increasingly recognized as being a central cellular and pathological process for numerous human diseases, including renal cell carcinoma (RCC). Depending on the cellular context, autophagy may promote cancer cell survival or cell death. However, little is known about the mechanisms of regulating mTOR activity and autophagic function in RCC. We hypothesize that autophagy promotes cell survival via mTOR mediated-phosphatidylinositol 3-kinase (PI3K)/AKT pathway and is regulated by the von Hippel-Lindau (VHL) tumor suppressor. Methods: RCC cells were stably lentiviral transduced with expression of VHL or mCherry-EGFP tandemfluorescent-tagged LC3B for studying autophagic flux. Cell viability was evaluated by cytotoxic XTT and clonogenic assays and flow cytometry. The efficacy of PI3K/AKT/mTOR pathway inhibition by RAD001, PI-103, MK2206, AZD8055, and/or lysosomotropic inhibitors were evaluated by immunoblots and immunofluorescence for autophagy process of autophagosome and lysosome. Results: We show that mTOR is hyperactive in VHL-deficient cells compared to cells with wild-type VHL or VHL-expressing cells. AZD8055-induced toxicity occurs in a VHL-independent manner via cell cycle arrest and clonogenic senescent cell death, but results in significantly increased expression of autophagic marker LC3-II and the formation of autophagic vacuoles. Pharmacologic inhibition or siRNA silencing of autophagy pathway components promotes AZD8055-induced cell death in VHL-deficient cells. Interestingly, defective autophagy marked by the presence of sustained p62 expression in VHL-deficient cells appears to contribute to cell survival via mTOR signaling, which in turn influences autophagosome-lysosome fusion, and thus controls autophagic flux by acting at the termination stage of the process. Conclusions: These results support mTOR and autophagy pathways as potential targets of anticancer drugs and reveal VHL in control of the autophagic program in RCC. Further, this work suggests that combined inhibition of autophagy along with mTOR inhibitors could be a novel therapeutic strategy for the treatment of RCC.
Combined modality treatment for organ preservation in patients with invasive bladder cancer
Authors: M. N. Carrizo, J. P. Sade, M. V. Costanzo, M. Chacon, C. Chacon, M. Orlando, R. D. Chacon
Journal: Journal of Clinical Oncology (2009)

e16129 Purpose: To evaluate long term results of chemoradiation and organ preservation in invasive T2-T4a bladder carcinoma in a single institution with prolonged follow up. Methods: Sixty one patients with clinical stage II and III (T3N0) muscle invasive bladder carcinoma were treated between February 1991 and December 2007. Forty four received sequential treatment (chemo followed by radiation) and seventeen concurrent treatments. Chemotherapy was platinum based in all patients, fifth teen with Carboplatin. All underwent maximal citoreduction with TUR .First 20 patients received pelvic radiation (1991–1993),while the other 41 three-dimensional radiotherapy (median dose 60 Gy). Male/female 55/6: median age 64 (range 46–80); transitional type 58 and mixed-epidermoid 6. Grade II: 3, grade III: 48 and grade IV: 10. Clinical stage II:50 and III:11. Mean follow up 63 months. Results: The 5 year overall survival rate was 57%. Forty patients remained NED, with eight deaths due to second primary or cardiovascular disease. Twenty pts were treated more than 5 years ago, 16(80%) are alive, 14 NED,2 pts relapsed after 5 years. Of all predictive factors analyzed only clinical stage reached statistical significance for relapse (p=0.0029), and borderline significance for overall survival (p=0.064). Toxicity: Grade 3–4: 7%, with 3% of febrile neutropenia. No patient required cystectomy because of bladder morbidity. Conclusions: Trimodality treatment in selected patients offers rates of event free survival and overall survival similar to those reported for surgery with acceptable toxicity and no treatment related cystectomy. Relapse after 5 year is very uncommon. In this small group of patient results were similar with concurrent and sequential treatment. At present we treat our patients with concurrent chemoradiation with tridimensional technique. No significant financial relationships to disclose.
Predictive factors for plasma cell disorders in African American patients: A community practice perspective.
Authors: Nay Min Tun, Gardith Joseph, Aye Min Soe
Journal: Journal of Clinical Oncology (2013)

e19508 Background: African Americans have over two-fold higher incidence of multiple myeloma (MM) compared to other ethnic groups in the United States. Screening tests for MM are most often done when patients present with features suggestive of anemia, renal impairment, hypercalcemia, hypergammaglobulinemia or lytic bone disease, although MM may present with other manifestations. We carried out a retrospective study to investigate the potential clinical variables predictive of plasma cell disorders (PCD) in African American population. Methods: We reviewed the charts of African American patients who had serum protein electrophoresis, immunofixation and serum free light chain levels from 2007 to 2012. We defined traditional triggers for MM workup as hemoglobin (Hb) &lt; 11 g/dL, serum creatinine (Cr) &gt; 1.3 mg/dL, corrected serum calcium (Ca) &gt; 10.5 mg/dL, albumin to globulin ratio (A:G ratio) &lt; 1, and osteopenia or lytic lesion on DEXA scan/X-ray. PCD was defined as monocloncal gammopathy of unknown significance (MGUS), smoldering MM, MM, light chain MGUS or light chain only MM. Results: 254 patients were eligible. Mean and range of age, Cr, Ca, A:G ratio, Hb, total white blood cell, absolute neutrophil and platelet counts were 60 years (21 - 95), 1.05 mg/dL (0.49 - 9.6), 9.5 mg/dL (8.5 - 11), 1.07 (0.31 - 3.08), 11.7 g/dL (5.7 - 16.5), 6 x 10 3 /mm 3 (1.9 - 26), 3675 x 10 3 /mm 3 (192 - 11765) and 237 x 10 3 /mm 3 (22 - 1262), respectively. Twelve (13%) out of 92 patients without traditional trigger variables had PCD. In contrast, 50 (31%) out of 162 patients with trigger variables had PCD (composed of 48% MGUS, 8% smoldering MM, 14% MM, 25% light chain MGUS and 2% light chain only MM). There is a significant association between the presence of trigger variables and PCD (χ 2 = 9.16, p = .002). The number of trigger variables is positively correlated with the likelihood of a PCD (Spearman’s rho = .22, p &lt; .001). So is increasing age (Spearman’s rho = .29, p &lt; .001) in patients with trigger variables. However, age is not predictive of PCD in patients without trigger variables (rho = .1, p = .34). Conclusions: The number of traditional trigger variables and increasing age (especially over 50 years) are predictive of PCD in African American population.
Improved Long-term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Compared With Reactive Monitoring of Serum Concentrations of Infliximab
Authors: Konstantinos Papamichael, Karen A. Chachu, Ravy K. Vajravelu, Byron P. Vaughn, Josephine Ni, Mark T. Osterman, Adam S. Cheifetz
Journal: Clinical Gastroenterology and Hepatology (2017)
Erratum: ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice (J Clin Invest. (2013) 123:5 (2332) 10.1172/JCI70042)
Authors: Mathew C. Casimiro, Marco Crosariol, Emanuele Loro, Adam Ertel, Zuoren Yu, William Dampier, Elizabeth A. Saria, Alex Papanikolaou, Timothy J. Stanek, Zhiping Li, Chenguang Wang, Paolo Fortina, Sankar Addya, Aydin Tozeren, Erik S. Knudsen, Andrew Arnold, Richard G. Pestell
Journal: Journal of Clinical Investigation (2013)
Outcomes after relapse from first autologous stem cell transplantation in multiple myeloma.
Authors: Wilson I. Gonsalves, Morie A. Gertz, Angela Dispenzieri, Martha Lacy, Vinay Gupta, Preet Paul Singh, Suzanne R. Hayman, Francis Buadi, David Dingli, Prashant Kapoor, Vincent Rajkumar, Shaji Kumar
Journal: Journal of Clinical Oncology (2014)

8598 Background: Autologous stem cell transplant (ASCT) is an integral treatment for eligible patients (pts) with multiple myeloma (MM). However, disease relapse post-ASCT remains inevitable for many pts. We describe the natural course of the disease and its outcomes in MM pts relapsing post-ASCT. Methods: Pts were included if they met the following criteria: 1) ASCT at the Mayo Clinic within 12 months of diagnosis; AND relapse post-ASCT between 2000 to 2012. Pts were excluded if they received a tandem or an allogeneic transplant post first ASCT. Multivariate analysis was performed using a Cox proportional hazards model. Results: Median (range) age at ASCT was 59 yrs (29-74). The median time to ASCT was 6 mos (2-12). Pts were transplanted in the years of 1994-2012. The median time to relapse was 16 mos (2-184). The median follow-up (95% CI) from relapse was 79 mos (72-89). The median (range) number of regimens prior to ASCT and post relapse were 1 (0-3) and 2 (1-11), respectively. Of the 254 pts who had FISH testing, 28% were categorized as high risk. Seventy-nine pts (17%) had a prior diagnosis of MGUS or SMM. All pts received novel agent therapy during their disease course with 57% receiving them during induction. At Day 100 post-ASCT, a PR or better was seen in 416 (92%) pts, including a stringent CR in 10%, CR in 12% and VGPR in 36%. Only 9% of pts received maintenance therapy with immunomodulators or proteasome inhibitors. The median (95% CI) post-ASCT relapse survival (PRS) and overall survival from diagnosis was 40 (34-45) and 67 (62-75) mos, respectively. In a multivariate analysis, only shorter time to relapse, presence of CRAB symptoms or extramedullary disease at relapse, shorter time to initiating salvage therapy, higher pre-ASCT plasma cell labeling index and beta-2 microglobulin predicted for a shorter PRS. Prior history of MGUS/SMM, high-risk FISH, choice of salvage therapy and use of maintenance therapy did not affect PRS. Conclusions: In a population of mostly unmaintained pts who relapse post-ASCT, PRS is longer than PFS. Predictors for increased PRS include a longer duration of response to ASCT, biochemical progression (rather than CRAB symptoms or extramedullary disease at relapse) and a longer time to salvage therapy initiation.
Gene expression profiles of circulating tumor cells in metastatic breast cancer patients.
Authors: Bianca Mostert, Anieta M Sieuwerts, Jaco Kraan, Joan Bolt-de Vries, Dieter Peeters, Luc Dirix, Caroline M. Seynaeve, A. Jager, Felix E de Jongh, Paul Hamberg, Jacqueline Stouthard, Diederik F. S. Kehrer, Maxime P Look, Marcel Smid, Yuqiu Jiang, Yixin Wang, Jan W Gratama, John A Foekens, John W.M Martens, Stefan Sleijfer
Journal: Journal of Clinical Oncology (2012)

10504 Background: A circulating tumor cell (CTC) count is an established prognostic factor in metastatic breast cancer. Besides enumeration, CTC characterization promises to further improve outcome prediction and treatment guidance. We have previously shown the feasibility of measuring the expression of a panel of 96 clinically relevant genes in CTCs in a leukocyte background, and in the current study, we determined the prognostic value of CTC gene expression profiling in metastatic breast cancer. Methods: CTCs were isolated and enumerated from blood of 130 metastatic breast cancer patients prior to start of first-line systemic, endocrine or chemotherapeutic, therapy. Of these, 103 were evaluable for mRNA gene expression levels measured by quantitative RT-PCR in relation to time to treatment switch (TTS). Separate prognostic CTC gene profiles were generated by leave-one-out cross validation for all patients and for patients with ≥5 CTCs per 7.5 mL blood, and cut-offs were chosen to ensure optimal prediction of patients who might benefit from an early therapy switch. Results: In the total cohort, of whom 56% received chemotherapeutic and 44% endocrine therapy, baseline CTC count (≥5 versus &lt;5 CTCs/7.5 mL blood) predicted for TTS (Hazard Ratio (HR) 2.92 [95% Confidence Interval (CI) 1.71 – 4.95] P &lt;0.0001). A 16-gene CTC profile for all patients and a separate 9-gene CTC profile applicable for patients with ≥5 CTCs were identified, which distinguished those patients with TTS or death within 9 months from those with a more favorable outcome. Test performance for both profiles was favorable; the 16-gene profile had 90% sensitivity, 38% specificity, 50% positive predictive value (PPV) and 85% negative predictive value (NPV), and the 9-gene profile performed slightly better at 92% sensitivity, 52% specificity, 66% PPV and 87% NPV. In multivariate Cox regression analysis, the 16-gene profile was the only factor independently associated with TTS (HR 3.15 [95%CI 1.35 – 7.33] P 0.008). Conclusions: Two CTC gene expression profiles were discovered, which provide prognostic value in metastatic breast cancer patients. This study further underscores the potential of molecular characterization of CTCs.
Gastric signet ring cell in a Moroccan medical oncology unit.
Authors: Sami Aziz Brahmi, Nezar Bouyahia, Amine Mohammed Chad, Khaoula Daoudi, Fatima Zahra Hijri, Samia Arifi, Mellas Nawfel, Omar El Mesbahi
Journal: Journal of Clinical Oncology (2012)

e14725 Background: Signet ring cell carcinoma (SRC) of the stomach is a histological type based on microscopic characteristics, and its clinicopathologic characteristics and treatment are still controversial. Methods: In this retrospective study, we reviewed the records of 68 patients diagnosed with gastric SRC treated between January 2007 and July 2011. The aim of this study is to identify the epidemiological, clinical and therapeutic features of this type cancer in a Moroccan population Results: In our study, SRC of the stomach represents 39 % of the gastric cancer and 11 % of all the digestif tract cancer. The mean age at the diagnosis was 46 years ranged from 25 to 80 years, 68 % were female. The clinical symptoms were vomiting (72%), epigastric pain (70%) and deterioration of Performans Status (93%). 73% of the patients were metastatic at the diagnosis, sites of metastasis were: peritoneum (85 %), lymphatic nodes (43 %), liver (35%), lung (28 %), ovaries (7 %), adrenal glands (7 %), bone (4 %) and the kidney (2 %). 23% of the patients had a localized disease and locally advanced 8%. Among the 64 patients, 27% were treated with curative intent by total gastrectomy followed by adjuvant concomittant chemoradiotherapy (n=6), adjuvant chemotherapy (n = 4) or perioperative chemotherapy (n=7). For the metastatic patients, chemotherapy regimens were distributed as following: ECC (Epirubicine 50 mg/m 2 , Cisplatine 60 mg/m 2 , Capecitabine 625 mg/m 2 /12h) was administred to 45 % of the cases, cisplatine-5FU to 18 % of the cases, capecitabine as monotherapy for 16 %; FUFOL Mayo clinic regimen for 9 % and EOX (Epirubicine 50 mg/m 2 , oxaliplatine 130 mg/m 2 , capecitabine 625 mg/m 2 /12h) for 5%. 7% of the patients were oriented to supportive care. A second line of chemotherapy was administed to 4 patients based on XELIRI (irinotecan 250 mg/m 2 and capecitabine 2000mg/d for 14 days) in 3 patients and XELOX (oxaliplatine 85 mg/m 2 and capecitabine 2,000mg/d for 14 days) in one patient (n = 1). Conclusions: The gastric Signet ring cell carcinoma represents an entity with specific characteristics, which tends more toward tumor invasion depth, with nodal and peritoneal metastases. Our results are consistent with those of the literature concerning the epidemiological finding and diagnosis aspects.
Biologic pathways associated with breast cancer metastases to the brain.
Authors: Vinay Varadan, Aditi Palkar, Kristy L. S. Miskimen, Nicole Olivia Williams, Matthew Morton, Steve Maximuk, Shaveta Vinayak, Lisa R. Rogers, Andrew E. Sloan, Jill Barnholtz-Sloan, Hannah L. Gilmore, Lyndsay Harris
Journal: Journal of Clinical Oncology (2014)

11038 Background: Brain metastases (BM) associated with breast cancer are difficult to treat, with a median survival less than 1 year for these patients. While basal-like and HER2+ breast cancers are at higher risk of developing brain metastases, no effective treatments exist for these patients. Comprehensive characterization of the transcriptome of matched primary breast (PB) tumors and BM allows for discovery of pathways mediating BM in breast cancer to improve treatment for this deadly disease. Methods: Pathology records were searched for patients who underwent surgical resection of BM from PB and archival FFPE material was obtained along with clinical data from the medical record and tumor registry. TMA sections were stained with ER, PR and HER2 to confirm receptor status. Tumor DNA/RNA was extracted from macrodissected 2 mm cores from FFPE. Gene expression profiling was performed using Affymetrix HTA 2.0 arrays on 96 FFPE samples for whom sufficient RNA was available. PAM50 subtypes were derived and differential gene expression between BM and PB was estimated using the Mann-Whitney-Wilcoxon test followed by multiple testing correction. Pathway enrichment analysis was performed using the KEGG and NCI Pathway Interaction Databases. Results: Differential gene expression analysis between the 46 BM and 26 PB showed enrichment (p<0.05;FDR<0.1) of B1 and B3 integrin, IL8 and CXCL2/4, UPA/PAI, Osteopontin, RAC1, BMP, TGFβ, PI3K and Ras pathways in KEGG and NCI-PID. The matched subset of 27 BM and PB samples showed persistent enrichment for all these pathways and showed differential expression of angiogenesis (PDGFR, c-MET, Angiopoetin) lymphangiogenesis (VEGFR-3) and HIF-1-alpha and Jak-STAT signaling pathways. Differential expression of non-genomic ER signaling was seen in both cohort-level and matched PB/BM pairs and Androgen receptor signaling was modulated in paired samples. A subset of BM showed upregulation of the Creighton AKT geneset, which was confirmed using a predefined AKT activity signature. Conclusions: Our study shows significant modulation of driver pathways in brain metastases when compared with matched primary breast tumors. Orthogonal validation of these findings using IHC and functional studies will be presented.
Effects of entinostat onresistance to cetuximab and EGFR TKIs in non-small cell lung cancer.
Authors: Samir E. Witta, Dan Chan, Luc Girard, Di Zheng, Veronica Franekova, Michael Peyton, Zhi-Yong Zhang, Zoe Kline, John D. Minna, Paul A. Bunn, Fred R. Hirsch
Journal: Journal of Clinical Oncology (2012)

e18077 Background: Cetuximab, a monoclonal antibody targeting the epidermal growth factor (EGFR) is active in patients with NSCLC. Gate keeper mutations in EGFR, such as T790M and activation of alternative driven pathways such as Met amplification are known mechanisms of acquired resistance to EGFR TKI. Here we evaluated the effects of the class I histone deacetylase inhibitors (HDACi), entinostat with cetuximab or EGFR TKIs in NSCLC cell lines with 3 potential mechanisms of intrinsic and acquired EGFR inhibitor resistance: RAS mutation according to E-cadherin expression, T790M EGFR mutation, and amplified MET. Methods: In vivo efficacy of entinostat alone or in combination with cetuximab or gefitinib was tested in athymic nude mice bearing RAS mutant, E-cadherin positive (A549) and E-cadherin negative (NCI-H460) NSCLC xenograft tumors. NSCLC cell lines were treated with various dilutions of cetuximab, entinostat or erlotinib. The NCI-H1975 and NCI-H1993 cell lines harboring the EGFR-L858R/T790M mutation and MET amplification, respectively, were treated with the combination of entinostat and erlotinib. Cell growth was analyzed by the MTT assay. Expression of e-cadherin was evaluated using affymetix microarrays. Results: When entinostat (E; 5mg/kg) was combined with cetuximab (C; 25mg/kg) in nude mice bearing the E-cadherin positive A549 xenograft, tumor growth inhibition was higher than each drug alone in (C: 65%; E: 70%; E+C: 88%; p=0.001) or what is detected in the E-cadherin negative H460 xenografts (C: 3%, E: 64%, E+C: 75%). Synergistic effects were detected when entinostat was combined with erlotinib in the NCI-H1975 or NCI-H1993 cell lines (combination index, CI&lt;1). Conclusions: Entinostat enhances the effect of Cetuximab in vivo in Ras mutant, E-cadherin positive NSCLC cell lines, or erlotinib in cell lines harboring the EGFR mutation T790M or amplified MET. The combination of entinostat and EGFR inhibitors could provide the rational for developing clinical trials in patients with NSCLC with tumors resistant to EGFR inhibitors.