tbuckley/cabot-search huggingface dataset:
Open, phase II randomized trial of gefitinib alone versus olaparib (AZD2281) plus gefitinib in advanced non-small cell lung cancer (NSCLC) patients (P) with epidermal growth factor receptor (EGFR) mutations: Spanish Lung Cancer Group trial (NCT=1513174/GECP-GOAL).
Authors: Bartomeu Massuti, Rosario García Campelo, Delvys Rodriguez Abreu, Jordi Remon, Margarita Majem, Elisa Galvez, Jose Antonio Ortega, Francisco Aparisi, Noemi Reguart, María Ángeles Sala, Dolores Isla, Maria Sanchez Ronco, Ana Verdu, Miguel Angel Molina-Vila, Clara Mayo-de las Casas, Eva Pereira, Rosana Cajal, Maria Carmen Gonzalez-Arenas, Enric Carcereny, Rafael Rosell
Journal: Journal of Clinical Oncology (2014)

TPS8127 Background: EGFR tyrosine kinase inhibitors (TKIs) are considered the treatment of choice for p with advanced NSCLC harboring EGFR mutations, with higher response rate (RR) and longer progression free survival (PFS). However, the majority of p develop resistance to TKIs via several mechanisms. Our previous experience in the EURTAC trial showed that high BRCA1 mRNA expression levels cause shorter PFS for erlotinib-treated p. Olaparib, a PARP-inhibitor, can reduce BRCA1 expression and could improve PFS in this subset of patients when added to an EGFR TKI. A phase IB study confirmed activity and tolerance of olaparib plus gefitinib in the absence of pharmacokinetic interactions. Recommended dose for the combination was gefitinib 250 mg daily + olaparib 200 mg TDS. Methods: Stage IV EGFR-mutated NSCLC p, previously untreated for metastatic disease, with PS 0-2 and evaluable disease (RECIST criteria) are randomly assigned in a 1:1 ratio to single agent gefitinib or gefitinib+olaparib. Primary planned endpoint is PFS. Secondary endpoints: Overall survival (OS), RR, toxicity (CTC criteria), detection of initial presence of T790M resistant mutation, influence of BRCA1 and EGFR mutations on PFS, parallel analysis of EGFR mutations in serum, and ancillary molecular analyses. Statistical hypothesis: Median PFS of 10 months (m) in the gefinitib arm could be increased to 16 m in the combination arm; two-sided alpha error = 0.05 and power 80%. One hundred and sixteen events are required to test the superiority hypothesis. Total planned number of inclusions: 186 p. Pre-planned interim analysis at 58 PFS events (progression or death). Current status: Study opened on July 2013 in 38 Spanish centers; recruitment ongoing. Fifty-nine p screened; 14 included. Clinical trial information: NCT1513174.
DNA repair- and apoptosis-pathways to regulate response to chemo-radiotherapy (CRT) in patients (p) with locally advanced head and neck cancer (HNC).
Authors: Beatriz Cirauqui, Vanesa Quiroga, Imane Chaib, Belen Sanchez, Niki Karachaliou, Jose Luis Ramirez, Ariadna Quer, Ana Munoz, Ana Drozdowskyj, Carlos Pollan, Isabel Planas, Juan Verges, Patricia Cuadras, Ana Massuet, Clara Lezcano, Laia VilÃ Martinez, Maria de los Llanos Gil, Max Hardy, Rafael Rosell, Mireia Margeli
Journal: Journal of Clinical Oncology (2015)

e17025 Background: Platinum-based CRT is preferred standard of care for locally advanced HNC. However, survival benefit is small, with substantial toxicity and biomarkers of CRT resistance could guide treatment selection and spare morbidity. Increased DNA repair in solid tumors may contribute to cancer cells’ ability to survive in genotoxic stress environments afforded by therapy. Apoptosis may also play an important role in determining response to chemotherapy. Methods: We assessed mRNA expression levels of DNA-repair-related genes BRCA1, RAP80, 53BP1 and RNF8 as well as apoptosis-related genes BIM and Mcl-1. We correlated our findings with response and overall survival (OS) in 72 HNC p treated with weekly carboplatin AUC 2 and radiotherapy. Results: Median age 65; 70.2% male; 84.7% smokers and alcohol users; 97.2% squamous carcinoma; 90.3% stage IV; 44.4% complete response (CR) to CRT; 10.5 months (m) median OS. P with CR to CRT or with second primary tumors had significantly longer OS compared to p with no CR or secondary primary tumors (32 vs 8 m, p < 0.0001 and 46 vs 8 m, p 0.0007, respectively). Among the 32 p with CR to treatment and evaluable 53PB1 mRNA levels, 50% had low and 6.3% high levels of 53BP1 (P = 0.0059). 41.2% of high BRCA1 mRNA expressors had CR compared to 29.4% of low expressors (P = 0.0064). For a small group of p with low 53PB1 and either high BRCA1 or RAP80, CRs were 66.7% and 71.4% respectively. A trend for better OS was found for p with low 53BP1 compared to high 53BP1 (15 vs 8 m; P = 0.056). No significant differences were found according to expression of the other genes and response or OS. Conclusions: Our findings highlight the potential usefulness of 53BP1 mRNA as a predictive biomarker of response and OS in HNC p treated with CRT. Those with high 53BP1 expression could derive only a meager benefit from treatment. Analysis of BRCA1 and RAP80 could further reinforce the predictive value of 53BP1. Although this was a retrospective study with small sample size, it could inform larger translational studies in HNC.
Endoscopic dissection of a symptomatic giant gastric leiomyoma arising from the muscularis propria
Authors: Mauro Manno, Paola Soriani, Vincenzo Mirante, Giuseppe Grande, Flavia Pigò, Rita Conigliaro
Journal: Endoscopy (2017)

Gastrointestinal (GI) subepithelial masses represent a heterogeneous group of lesions, ranging from benign to malignant, for which management is sometimes challenging [1] [2]. We report the case of an 85-year-old woman, with a history of coronary artery disease and chronic atrial fibrillation being treated with anticoagulant therapy, who underwent urgent upper GI endoscopy for hemorrhagic shock and melena. During this procedure, a giant, 15-cm, non-pedunculated mass that was ulcerated on top was found at the greater curvature of the anterior wall of the stomach ([Fig. 1]).
Genomic characterization of non-small cell lung cancer by targeted massively parallel sequencing in African Americans.
Authors: Luiz H. Araujo, Cynthia Dawn Timmers, Tom Liu, Selen Ayse Yilmaz, Thanemozhi G. Natarajan, Konstantin Shilo, Weiqiang Zhao, Joseph Amann, Philip Edward Lammers, David Paul Carbone
Journal: Journal of Clinical Oncology (2014)

8086 Background: Technological advances have enabled the comprehensive analysis of genetic perturbations in non-small cell lung cancer (NSCLC), but African-Americans (AA) have often been underrepresented. This ethnic group presents higher lung cancer incidence and mortality, and some studies have suggested a lower incidence of EGFR mutations. Herein we used a targeted massively parallel sequencing approach to assess NSCLC samples resected from AAs. Methods: We designed and validated a NSCLC-specific panel comprising 80 genes of potential interest for therapy. Libraries were constructed using a custom Agilent Haloplex kit, and sequenced on an Illumina HiSeq 2500. Cell lines and clinical formalin-fixed paraffin-embedded samples with known mutation status were used for validation. NSCLC archival tissues derived from AAs were retrospective collected, and medical charts were reviewed to assess clinical data. ALK translocations were evaluated by fluorescence in situ hybridization (FISH). Results: Targeted capture probes covered 15,473 amplicons comprising 310,720 base pairs, with 99.29% coverage. Our platform successfully identified all known mutations in the validation samples. Ninety-nine AAs were included, with a median age of 61 years (41-76). Sixty-one percent were males, and 94% were current/former smokers. Sixty percent of samples had an adenocarcinoma component, and 31% were squamous cell carcinomas. We detected 1,465 non-silent variants in the coding sequence, after excluding known germline polymorphisms. Classic recurrent mutations were found in KRAS (16%), EGFR (5%), PIK3CA (1%), and NRAS (1%). We also identified known somatic mutations in TP53 (48%), BRAF (4%), KEAP1 (3%), PDGFRA, FBXW7, CDKN2A, and CTNNB1 (1% each). In addition, several variants of unknown significance were found and may deserve further investigation. One case was positive for ALK-FISH. EGFR and ALK-positive cases were adenocarcinomas, and no overlap was identified between major drivers. Conclusions: We demonstrated a relatively low frequency of classic driver mutations in NSCLC among AAs. This group may benefit from the identification of novel drivers through comprehensive genomic approaches.
Analysis of prior malignancies in patients with cholangiocarcinoma.
Authors: Taryn Mary Boucher, Nancy E. Kemeny, Joanne F. Chou, Marinela Capanu, Maeve Aine Lowery, Andrea Cercek
Journal: Journal of Clinical Oncology (2017)

305 Background: Cholangiocarcinomas account for approximately 3% of gastrointestinal tumors. Our aim was to analyze types of prior malignancies in patients (pts) with cholangiocarcinoma, with a special interest in pts with prior breast cancer. Methods: An IRB waiver was obtained to retrospectively review female pts who presented with an initial diagnosis of cholangiocarcinoma to Memorial Sloan Kettering Cancer Center between January 2000 and August 2015. Results: Medical records of 804 female pts were reviewed. After excluding pts with limited records or without biopsy-proven cholangiocarcinoma, a total of 625 pts were analyzed. Of 625 pts with cholangiocarcinoma, 506 (81%) were intrahepatic (ICC), 85 (14%) hilar, 24 (4%) extrahepatic and 10 (2%) mixed ICC and hepatocellular carcinoma or rare variant. The median age at cholangiocarcinoma diagnosis was 63 years [range: 16-97 years] and 82.7% were white. Of the 625 pts, 105 (17%) had a history of another cancer: 44 (7.04%) breast, 9 (1.44%) colon, 9 (1.44%) melanoma and 5 (0.8%) ovarian. The remaining 38 pts with various prior cancers were grouped as Other. There was no association between the site of cholangiocarcinoma (intrahepatic versus extrahepatic) and type of prior cancer (p = 0.26). In pts with a prior cancer (n = 105), the median time from diagnosis of prior cancer to cholangiocarcinoma was 76 months [range: 2-624 months], which did not differ among types of prior malignancies (p = 0.25). The interval between diagnosis of breast cancer and cholangiocarcinoma was 82 months [range 4-526 months]. In pts with prior breast cancer, 21 (48%) received radiation and 25 (57%) received chemotherapy for their breast cancer. In 22 pts who had ER/PR testing, 16 were ER positive and 15 were PR positive. In 17 pts who had HER2 testing, 4 were HER2 positive. Conclusions: In 625 female pts with cholangiocarcinoma, 17% had a history of another cancer, with 44 (7%) having a history of breast cancer. The apparent increase in proportions of prior breast cancer compared to other cancers should be investigated further. An analysis of tumor mutations (MSK-IMPACT) and germline mutations in pts with cholangiocarcinoma and a history of breast cancer is underway to determine a potential association of molecular factors.
Phase II clinical trial evaluating CRLX101 in recurrent ovarian, tubal, and peritoneal cancer.
Authors: Carolyn N. Krasner, Michael J. Birrer, Suzanne T. Berlin, Neil S. Horowitz, Mary K. Buss, Scott Eliasof, Edward Graeme Garmey, Meliessa G. Hennessy, Panagiotis Konstantinopoulos, Ursula Matulonis
Journal: Journal of Clinical Oncology (2014)

5581 Background: Ovarian cancer (Ov.Ca.) is the leading cause of death among gyn malignancies in the United States with over 20,000 new cases diagnosed in 2013. Limited treatment options exist for women whose tumors have progressed after 1st-line platinum-based therapy. Current approved therapy for relapsed Ov.Ca. includes the topo-1 inhibitor topotecan, which provides limited survival benefit and remains compromised by toxicity. CRLX101 is a novel cyclodextrin-containing polymer conjugate of camptothecin (CPT) that self-assembles into nanoparticles and delivers sustained CPT into cancer cells while reducing systemic exposure. In vitro and in vivodata suggest superior activity of CRLX101 compared to approved agents in Ov.Ca. models. The monotherapy MTD of 15 mg/m2 IV q. 2 wks. has now been administered to over 200 solid tumor pts (pts.) across 7 clinical trials. Methods: This phase 2 clinical trial evaluated CRLX101 in pts. with relapsed Ov.Ca. progressing after 1-3 prior regimens of chemotherapy, and included platinum refractory, resistant and sensitive pts. Pts. received CRLX101 every 14 days on 28-day cycles and underwent CT-based tumor evaluation every 2 cycles. The primary endpoint is progression free survival at 6 mos (PFS6) and secondary objectives include tumor response rate and safety. Results: Enrollment is this clinical trial is complete with 30 pts. having received 1-13 cycles of therapy and 5 pts. remaining on study. CRLX101 appears well tolerated with no drug-related SAEs, treatment discontinuations, or deaths observed. Related grade 3/4 AEs include G3 vasovagal reaction (n=1), G3 pneumonia (n=1), and G3 pulmonary embolism (n=1) . The primary efficacy endpoint has been met with mPFS of 161 days and 6 pts. achieving PFS ≥ 6 mos. Among 19 platinum resistant pts. with evaluable scans, 3 pts. (16%) achieved durable RECIST partial responses and 14 pts. (74%) achieved net tumor reductions. Conclusions: CRLX101 administered to pretreated pts. with relapsed Ov.Ca. appears safe, well tolerated, and effective. As CRLX101 appears to durably inhibit HIF-1α and demonstrates elsewhere notable synergy in combination with VEGF inhibiting agents, the drug is currently being evaluated in combination with bevacizumab. Clinical trial information: NCT01652079.
Capecitabine plus bevacizumab (Cape-Bev) as a maintenance treatment after induction treatment with FOLFIRI plus bevacizumab (FOLFIRI-Bev) in metastatic colorectal cancer (mCRC).
Authors: Ali Murat Tatli, Hasan Senol Coskun, Mukremin Uysal, Sema Sezgin Goksu, Deniz Arslan, Seyda Gunduz, Mustafa Ozdogan, Hakan Sat Bozcuk, Burhan Savas
Journal: Journal of Clinical Oncology (2013)

e14683 Background: Bevacizumab is human monoclonal antibody that inhibits vascular endothelial growth factor and has been shown improvement progression-free survival and overall survival when combined with chemotherapy for treatment of mCRC in the first and second-line settings. The purpose of this study is to show the effectiveness of maintenance therapy with Cape-Bev in patients with mCRC who benefit of first-line (induction) chemotherapy with FOLFIRI-Bev. Methods: The study included patients with mCRC who received FOLFIRI-Bev as first-line chemotherapy. Maintenance therapy with Cape-Bev (Cape 1000 mg/m2 bid d1-14, Bev 7,5 mg/kg d1 q3w) was given until disease progression to patients who had achieved an objective response after 6-months FOLFIRI-Bev regimen. The time to disease progression, survival and toxic effects were analyzed from the beginning of bevacizumab-based chemotherapy. Results: We enrolled 30 patients, 16 men and 14 women. The mean age of the patients was 62 years. The patients who administered maintenance treatment received a median number of 11 cycles. The median progression-free and overall survivals were 22±4 months and 39±4 months, respectively. Significantly higher PFS and OS were seen among patients who complete or near-complete response to induction therapy with FOLFIRI-Bev (Table). Acceptable hand-foot syndrome was observed 14 patients (%51) treated with the Cape-Bev. No patient experienced severe toxicity. Conclusions: Cape-Bev regimen may be an effective maintenance treatment after response to first-line (induction) FOLFIRI plus bevacizumab treatment in selected mCRC with favorable safety profile. Further studies will be needed to demonstrate conclusively that. [Table: see text]
Prospective study of changes in spindle assembly checkpoint (SAC) to predict breast tumor response to taxanes
Authors: N. T. Ueno, S. Kim, W. F. Symmans, M. A. Detry, L. Pusztai, L. F. Sanchez, H. Ishihara, G. N. Hortobagyi, S. Noguchi
Journal: Journal of Clinical Oncology (2007)

586 Background: Increased cyclin-dependent kinase 1 (CDK1) and reduced CDK2 activity reflects taxane chemosensitivity via regulation of SAC. Novel C2P device (Sysmex Inc.) measures CDK1/2 activity in human tissue within a few hours. We hypothesized that SAC functionality in breast cancer predicts taxane sensitivity. Methods: Biopsy samples obtained before preoperative therapy from 69 pts with primary breast cancer (median age 52, St II, 56%, St III, 40%, HER2 36%, HR 52%) ex vivo with paclitaxel (100 nM) for 24 h, then measured for CDK1/2 activity. Tumors with CDK1/2 ratio &gt; 0.7 were denoted “responders” (CR, PR) based on preclinical testing. Clinical responses were evaluated with sonography. Results: 24 pts could not be evaluated because of unmeasurable or invalid CDK (n=3), no receipt of taxane (n=10), incomplete treatment/lack of imaging (n=10), or receipt of taxane as adjuvant therapy (n=1). Among the 45 evaluable pts, 30 obtained reading to determine the C2P-predicted response, which was significantly associated with the clinical response to preoperative therapy with paclitaxel, docetaxel, docetaxel/doxorubicin, paclitaxel/trastuzumab or lapatinib, or docetaxel/capecitabine (P=0.002; sensitivity 0.83; specificity 0.86; positive predictive value [PPV] 0.95; and negative predictive value [NPV] 0.60). For HER2- tumors, the sensitivity was 0.94; specificity 0.83; PPV 0.94; and NPV 0.83. We fit a series of logistic regression models to assess the relationship between C2P predicted response and clinical outcome. Each model included 1 clinical prognostic factor (HR status, stage, NG, histology, HER2) as well as the C2P prediction factor. In all 5 models C2P remained a statistically significant predictor of clinical response while adjusting for the other prognostic factor. Conclusions: CDK1/2 activity is a promising novel predictive marker to predict response to taxane- containing regimens for HER2- breast cancer. We could not predict taxane sensitivity in HER2+ tumors; this finding is consistent with preclinical findings that HER2 overexpression is involved in abnormal SAC functionality. Thus, the functional SAC reflects taxane sensitivity in HER2- tumors. We are planning a large prospective study to validate these findings. No significant financial relationships to disclose.
A phase I, first-in-human study to evaluate the tolerability, pharmacokinetics and preliminary efficacy of HuMax-tissue factor-ADC (TF-ADC) in patients with solid tumors.
Authors: Ulrik Niels Lassen, David S. Hong, Nikolaos Diamantis, Vivek Subbiah, Rajiv Kumar, Morten Sorensen, Steen Lisby, Robert L. Coleman, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2015)

2570 Background: TF-ADC is an antibody drug conjugate composed of a TF-specific human IgG1 monoclonal antibody conjugated to a microtubule disrupting agent Monomethyl Auristatin E (MMAE). TF-ADC is presently being tested in an ongoing Phase I dose-escalation study (NCT02001623) in patients (pts) with locally advanced and/or metastatic solid tumors known to express TF. Methods: The primary study objective is to assess the tolerability of TF-ADC. In addition, maximum tolerated dose (MTD), pharmacokinetics and preliminary efficacy will be evaluated. Pts with cancer of the ovary, cervix, endometrium, bladder, prostate (CRPC), esophageal, SCCHN and lung (NSCLC) will be included. This is a classical 3+3 dose escalation study followed by cohort expansion. Responses are evaluated according to RECIST 1.1. Results: Eighteen pts have been enrolled across the first 6 dose cohorts (0.3-1.8 mg/kg). Mean number of prior lines of therapy is 3.7 (range 1-14). The most common AEs seen in ≥ 4 pts are fatigue, anemia, epistaxis, nasal congestion, pyrexia, and diarrhea. Elevation in liver enzymes was seen in 9 pts mainly grade (Gr) 1 including 2 pts with Gr 3 single events. One event of fatal pharyngeal hemorrhage in the 0.6 mg/kg cohort has been reported in a SCCHN pt with normal coagulation values previously treated with 3 lines of therapy including radical radiotherapy. Relationship with trial drug could not be excluded. Five pts experienced related AEs Gr ≥ 3. Seven SAEs were observed in 5 pts (transaminitis Gr 3, pharyngeal hemorrhage Gr 5, fever Gr 1, myalgia pain Gr 2, dyspnea Gr 2, hyponatremia Gr 3, gastritis Gr 3). No significant changes in coagulation parameters and no DLTs have been observed. Preliminary evidence of activity includes prolonged disease stabilization in 1 ovarian cancer pt (23 weeks), 2 CRPC pts (18 and 36 weeks) and a confirmed PR in an ongoing pt with cervical cancer. Conclusions: Preliminary data demonstrated manageable toxicity, with no DLTs observed and no changes in coagulation values up to 1.8 mg/kg. Preliminary evidence of anti-tumor efficacy is encouraging and study design allows for increased exposure to establish therapeutic window. Clinical trial information: NCT02001623.
Stem cell surface markers CD133 expression in hepatocellular carcinoma and as single prognostic factor for liver transplantation.
Authors: Yang Li, Nan Jiang, Dan-yun Ruan
Journal: Journal of Clinical Oncology (2015)

e15166 Background: Recent evidences indicate that CD133, a primitive haematopoietic and neuronal stem cell marker, is known to be present in cancer stem cells (CSCs) in hepatocellular carcinoma(HCC). However , the biological significance of CD133 in hepatocellular carcinoma is controversial. This study was undertaken to explore the expression and significance of stem cell marker CD133 in prognosis of liver transplantation after hepatocellular carcinoma. Methods: Real-time PCR and western blot analysis were performed to examine CD133 expression in human hepatoma cell lines, HCC tissue and normal hepatic tissue. Immunohistochemistry (IHC) assays assessed CD133 protein expression in paraffin-embedded clinical samples taken from 109 HCC patients. The correlation of CD133 expression with the clinicopathological parameters was evaluated along with the prognostic impact of CD133 expression in these HCC patients. Results: Our study showed that CD133 is expressed in human hepatoma cell lines and HCC tissue. CD133 positive HCC cells showed higher clonogenicity in vitro and tumorigenicity in vivo. Immunohistochemical analysis of 109 HCC tissue specimens revealed that CD133 positive immunostaining was found in 44 specimens (40.4%), but was not found in normal liver tissue. CD133 positive expression levels were correlated with tumour grade(P < 0.05) and tumor diameter(P < 0.05). Kaplan–Meier analysis indicated that patients with CD133 positive levels had shorter 1,3,5-year overall survival(OS) in compared with patients with CD133 negative expression(1,3,5-year OS of 92.6% ,71.5% and 36.7% vs. 100% , 82.6% and 76.3%, respectively, P < 0.001). Multivariate analyses revealed that CD133 positive expression was an independent prognostic factor for survival and tumour recurrence in patients with liver transplantation after HCC. Conclusions: Our findings suggest that CD133 positive cells are frequently present in HCC. Additionally, CD133 positive expression indicate a poor prognosis for patients.