tbuckley/cabot-search huggingface dataset:
BAP1 mutation-associated cholangiocarcinoma: An aggressive disease.
Authors: Deepa Anand, Chaitanya Churi, Asif Rashid, Rachna T. Shroff, Mingxin Zuo, Claudius Conrad, Jean-Nicolas Vauthey, Milind M. Javle
Journal: Journal of Clinical Oncology (2015)

420 Background: BRCA-associated protein-1 is a deubiquitylating enzyme encoded by the BAP1 gene, which is commonly mutated in uveal melanoma, mesothelioma and renal cancers. BAP1 mutations predict an aggressive disease course in these tumors. Recent data indicate that BAP1 mutation is also present in cholangiocarcinoma (CCA). The clinical phenotype of CCA with BAP1 mutations has not been defined. We investigated the clinico-pathologic features and treatment outcomes of these patients treated at a single center. Methods: A comprehensive chart review of CCA patients who had undergone genomic testing was performed. Data collected included clinical, pathological, genetic and radiological features and response to therapy. Results: Nine cases of BAP1 mutation associated CCA were diagnosed from January 2009 to May 2014 (Table). Seven patients had intrahepatic CCA and two had extra-hepatic CCA. Tumor size ranged from 6 to 14.7 cm (mean = 8.7 cm). Seven patients had poorly differentiated carcinoma whilst the other two had moderately differentiated tumors. Out of the nine patients, seven had nodal metastases and six had satellite lesions in liver. Six patients had distant metastases at presentation. Sites of metastases were bone, peritoneum, lung and abdominal wall. All nine patients showed progressive disease following primary therapy (primary chemotherapy or neoadjuvant chemotherapy after primary surgery). The average time to tumor progression after first therapy was 3 months. Conclusions: BAP1 mutation in CCA may be associated with an aggressive prognosis and poor response to standard therapies. [Table: see text]
The impact of number of cycles of targeted therapy on cost evaluation in metastatic colorectal cancers.
Authors: Helmy M. Guirgis
Journal: Journal of Clinical Oncology (2013)

359 Background: Increasing the number of cycles of cetuximab and bevacizumab in metastatic colorectal cancer might limit affordability and impact cost-effevctiveness. Methods: Average wholesale prices (AWPs) in U.S. dollars (US $) of cetuximab and bevacizumab were divided by reported median survival gain in days. Cost/survival of 90% of drugs was &lt;$750. A reference scale between 0% and 100% was constructed with 0% assigned to cost/overall survival (OS) &gt; $750, life threatening/fatal adverse events (AEs) and worsened quality of life (QoL). A plan was designed to correct for AEs and QoL. Results: Expressed as cost/overall survival (OS), crude and corrected scores (Table). Conclusions: Increasing number of cycles of cetuximab and bevacizumab increased the cost/survival and decreased scores. A limit on the purchase price of the entire treatment course of targeted therapy is recommended. [Table: see text]
Personalized dose monitoring of fluorouracil and metabolites of capecitabine (XELODA) in colorectal cancer patients (PersonaX).
Authors: Masato Nakamura, Katsuya Makihara, Toshihide Onikubo, Kumi Nakamura, Kazuya Uchibori, Sayaka Azuma, Kenta Murotani, Shigeyoshi Iwamoto, Hideyuki Mishima
Journal: Journal of Clinical Oncology (2016)

706 Background: Capecitabin is a prodrug converted into 5-FU via two phases of metabolites, 5' -DFCR and 5' -DFUR. In order to elucidate intra-individual variation of capecitabine, we have investigated pharmacodynamics and kinetics of fluoroprymidine in patients with colon cancer (UMIN000008852). Methods: A dose of 2000mg/m 2 /day of capecitabin were administered from day 1 to day 14 twice a day every 3 weeks with or without oxaliplatin and bevacizumab. Blood samples were collected on day 8 at 1 hour and 2 hour after morning meal in the first cycle. Concentrations of plasma 5-FU were measured by using ‘My5FU’, and concentrations of 5'-DFCR, 5'-DFUR and unchanged capecitabine were mesured by LC-MS. Results: A total of 34 patients with colorectal cancer were enrolled and evaluated. Although systemic 5FU are low after capecitabine intake, the concentrations of plasma 5FU were successfully measured by ‘My5FU’. Wide variation are shown in plasma 5FU, 5'-DFCR,5'-DFUR and unchanged capecitabine. There was a correlation between unchanged capecitabin and the AUC of their metabolites, 5' -DFCR and 5' -DFUR. The strongest correlation exists in 5FU and 5’DFUR (Spearmann correlation index: 0.82). Median and IQR (Interquartile Range) of 5FU was 175.1 (98.6-304) ug/mL. Conclusions: The monitoring of 5FU concentrations by ‘My5FU’ elucidated intra-individual variation of capecitabine. It will contribute to individual cancer treatment for patients administered capecitabine. The correlation between concentrations of capecitabine metabolites (5-FU, 5'-DFCR, 5'-DFUR,capecitabin) and their efficacy and toxicity are under examination. Clinical trial information: 000008852.
A phase II study of docetaxel and gemcitibine as neoadjuvant chemotherapy in stages IIIA & B breast cancer
Authors: J. D. Bitran, P. Kaiser
Journal: Journal of Clinical Oncology (2005)

879 Background: Phase II studies have demonstrated activity for the combination of docetaxel (D) and gemcitabine (G) in women with anthracycline resistant stage IV breast cancer. The Greek Breast Cancer Cooperative Group reported a 50% response rate to D&G in aforementioned patient population. Our objective was to determine the clinical and pathologic response rates, time to treatment failure (TTF) and survival of women with stages IIIA&B breast cancer who received D&G as neoajuvant chemotherapy. Methods: From 11/1/98 to 9/30/03 we enrolled 15 women with stage III breast cancer(12 with IIIA, 3 with IIIB, 5 ER/PR+, 10 ER/PR-, 10 Her2/neu overexpressive) in this phase II study. The median age was 48 yrs (range 37–75); the median PS was ECOG 0 (range 0–1). All patients received neoadjuvant G 725 mg/m.sq IVPB days 1 and 8 and D 75mg/m.sq IVPB day 8. Filigramstim 5 micrograms/kg/d was given sc on days 9–16. D&G cycles were repeated every 21 days. Dose modifications for D&G were permitted solely for Grade 3 or 4 neutropenia or thrombocytopenia.Four cycles of D&G were given prior to loco-regional therapy. Clinical responses were determined by the usual criteria. Pathologic responses were determined by the absence of microscopic breast cancer (pCR) or its presence (pPR). Results: The clinical response rate was 13/15 (87%[95% confidence limits59–98%]) with 6 clinical complete (cCR) and 7 clinical partial responses (cPR). Two patients failed to respond. Of the 13 patients who had cCR or cPR, there were 3pCR’s (23% [95% confidence limits 6–53%]) and 10pPR’s (77%). Toxicities were generally mild (alopecia, fatigue, arthalgias, diarrhea); there were no Grade 3 or 4 toxicities. 12 patients underwent modified radical mastectomy (9 stageIIIA and 3 IIIB) and 3 patients underwent lumpectomy, axillary sampling and breast irradiation. At a median followup of 48 months, the median TTF has not yet been reached. Conclusions: D&G is an active combination when used as neoadjuvant chometherapy in stage III breast cancer; comparative trials are warranted. Supported in part by Aventis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
Genotype-phenotype correlation of gastric cancer in familial adenomatous polyposis.
Authors: Tatsuhiro Ito, Moriya Iwaizumi, Hong Tao, Satoshi Osawa, Kiyotaka Kurachi, Yasushi Hamaya, Kosuke Takagaki, Takahisa Furuta, Ken Sugimoto, Haruhiko Sugimura, Masato Maekawa
Journal: Journal of Clinical Oncology (2016)

535 Background: Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary colorectal tumor syndrome characterized by the formation of a number of adenomatous polyps throughout the entire colon. Clinically, a precise family history together with surveillance of the colon as well as extra-colonic organs for people at risk is important to prevent cancer progression because of an almost 100% lifetime risk of colorectal cancer if the colon is not removed. Although there are fascinating correlations between the location of the APC mutation and the clinical phenotype, none has reported about genotype-phenotype correlation of gastric cancer in FAP, which occupies 2.1-4.2% in East Asia. Methods: Peripheral blood samples were obtained from 29 probands that was clinically diagnosed with FAP and DNA was extracted from the peripheral blood. All the coding exons of APC and their boundary regions were amplified using PCR and were directly sequenced. For large deletion/insertion analysis, an MLPA was performed using MLPA kit (P043 APC, MRC-Holland). Using results from the APC mutation analysis, we examined correlation between location of APCgermline mutation and clinical phenotype including gastric cancer. Results: Among 16 probands (3 cases were severe FAP, 12 cases classical FAP, and one case attenuated FAP) that were identified APC germline mutation, correlation between density of colonic adenomatous polypsosis and distribution of the APC mutation donated the same tendency of previous report. Among the 16 probands, 11 had fundic gland polyposis (FGPs) of the stomach and three had gastric adenocarcinoma (one case with FGPs and others without FGPs). Interestingly, all the three cases did not have severe adenomatous polyposis of the colon and their APC mutations were distributed at the location that is reported to be correlated with attenuated FAP. Conclusions: Patients with gastric cancer in FAP clinically have a tendency of having non-severe adenomatous polyposis of the colon and their location of APC mutation may be correlated to the hot spot location of attenuated FAP, suggesting that patient with non-severe colonic adenomatous polyp should have upper GI screening for gastric cancer prevention.
Antitumor activity of nanoparticle albumin-bound paclitaxel in experimental gastric cancer.
Authors: Changhua Zhang, Katherine T Ostapoff, Niranjan Awasthi, Margaret A. Schwarz, Roderich Schwarz
Journal: Journal of Clinical Oncology (2013)

33 Background: Gastric cancer is the second most common cause of cancer related death worldwide and lacks highly effective adjuvant or definitive systemic treatment for advanced disease. Nab-paclitaxel is a novel microtubule-targeting cytotoxic agent and not tested in gastric cancer as of yet. Methods: Human gastric cancer cell lines AGS, NCI-N87 and SNU16 were studied for treatment effects on cell proliferation, mitotic arrests and apoptosis in vitro and vivo. Tumor growth and survival studies were performed in murine xenografts. Results: Nab-paclitaxel inhibited cell proliferation with an IC50 of 2.01 nM in SNU16, 23.3 nM in AGS and 48.69 nM in NCI-N87 cells after 72-hour treatment, which was lower than that of oxaliplatin (1.05 μM to 1.51μM) and epirubicin (0.12 μM to 0.25 μM). Nab-paclitaxel treatment caused increased expression of the mitotic-spindle associated phospho-stathmin, nuclear fragmentation or karyopyknosis, and apoptotic events as confirmed through increased expression of cleaved-PARP and caspase-3. After a two-week nab-paclitaxel, oxaliplatin or epirubicin treatment, the local tumor growth inhibition rate was 77, 17.2 and 21.4 percent, respectively (p=0.002). Effects of therapy on tumoral proliferative and apoptotic indices corresponded with tumor growth inhibition data, while expression of phospho-stathmin also increased in tissues. There was an increase in median animal survival after nab-paclitaxel treatment (86 days) compared to controls (24 days, p=0.0004) or to oxaliplatin therapy (37.5 days, p=0.0005). Conclusions: The strong antitumor activity of nab-paclitaxel in experimental gastric cancer supports such microtubule-targeting therapy for clinical application. Nab-paclitaxel benefits were observed independent from phosphorylated stathmin expression at baseline, putting into question the consideration of nab-paclitaxel use in gastric cancer based on this putative biomarker.
Clinical outcome of concomitant chemoradiotherapy followed by adjuvant temozolomide (TMZ) therapy for high-grade gliomas (HGG) in Colombia (RedLANO registry).
Authors: L. D. Ortiz, A. F. Cardona, C. E. Fadul, A. Londono, H. A. Becerra, E. Jimenez-Hakim, C. J. Yepes, H. Carranza, R. E. Bruges Maya, C. J. Castro, C. A. Vargas
Journal: Journal of Clinical Oncology (2011)

2092 Background: The use of radiotherapy plus TMZ administered concomitantly with and after radiotherapy (Stupp platform; SP) for HGG was shown to improve median and 5-year survival. To compare these results with routine clinical practice a bidirectional registry was established by RedLANO. Methods: A total of 171 HGG patients treated with SP were included. Time to progression (TTP) and overall survival (OS) were estimated. Results: The median age was 56-yo (17-84 years) and 97 patients were male (56%). 82% had GB of which 62% were primary tumors; 55% of cases were treated with debulking surgery and 23% had undergone biopsy. 77% of patients completed the SP, with a median radiation dose of 58.2 Gy (r,18-64) and a mean number of TMZ cycles of 5 (SD + / -3). Pseudoprogression was documented in 20%, the median OS was 15.8-mo (IC95% 11.9-19.7 mo) and the TTP was 9.5-mo (IC95% 8.3-12.7 mo). The 1-y and 2-y survival rates were 69% and 31% respectively. In the retrospective analysis, the patients with a post-operative KPS over 70% showed more prolonged survival (p=0.05), as well as those with better RPA classification (p=0.04) and without multicentricity (p=0.049). Seventy-one patients (41%) were treated with second line therapy (Bev combos 32; metronomic or dose dense TMZ 24; BCNU 14; other 2) after the tumor had recurred. Conclusions: This study is the largest study of radiotherapy plus concomitant and adjuvant TMZ for HGG in Latin American patients. The median and 2-y survival outcomes in this study are comparable to previous reports.
End-of-life care decisions using Korean advance directives among cancer patient-caregiver dyads.
Authors: Su-Jin Koh, Shinmi Kim, JinShil Kim
Journal: Journal of Clinical Oncology (2016)

11 Background: The Korean advance directives (K-ADs) consist of a value statement, treatment directives (cardiopulmonary resuscitation [CPR], preferences for artificial ventilation, tube feeding, and hospice care). K-ADs can facilitate a patient’s decision-making for end-of-life (EOL) care. This study aims to examine the extent to which patient-caregiver dyads agreed on decisions for EOL care using the K-ADs. Methods: Using a descriptive study design, 81 cancer patients were invited to participate. The final sample consisted of 44 patient-caregiver dyads who completed K-ADs; 36 (44.4%) of the initial 81 patients declined to participate. Results: Patient participants had different cancerdiagnoses: 29.5% colorectal cancer, 29.5% breast, and 15.9% liver/biliary tract cancers; 59% of the sample had advanced stage cancer. Spouse (70.5%) and adult children of the patient (20.4%) were primary caregivers with perceived bonding rated as fair (31.8%) or good (65.9%). Rejection of K-ADs was mainly because of difficulty in deciding EOL care (50%). Comfort in dying was the most common theme of the value statement for patients (73.8%) and caregivers (66.7%). For treatment directives, dyads advocated for hospice care (66.7%) and reduced support for aggressive treatments of CPR or artificial ventilation, k = .43, p = .004 and k = .28, p = .046, respectively. These approaches showed significantly mild to moderate concordance among the dyads. Sixteen out of the 21 dyads identified their spouses as a proxy, with others designating their adult children. Conclusions: The findings of the study are exploratory but suggest the need for ongoing EOL discussion where patient-caregiver dyads are encouraged to participate in the decision-making for EOL care.
Phase II trial of S-1 combined with oxaliplatin (SOX) as neoadjuvant chemotherapy for locally advanced gastric cancer.
Authors: L. Chen
Journal: Journal of Clinical Oncology (2011)

122 Background: Previous phase II trial with combination therapy of S-1 plus oxaliplatin (SOX) demonstrated high response rate and well tolerability in patients with untreated advanced gastric cancer. The aim of this phase II trial was to evaluate the efficacy and safety of SOX as neoadjuvant chemotherapy for locally advanced gastric cancer (AGC). Methods: Eligibility criteria included a histologically proven AGC with stage IIIb, IIIc (AJCC 7th edition), at least 1 measurable lesion, no prior chemotherapy, ECOG 0∼2, adequate hepatic, renal, and bone marrow function. Enrolled patients were staged by EUS and CT. The neoadjuvant chemotherapy consisted of 3-4 cycles of oxaliplatin (130 mg/m 2 ) on day 1 and S-1 (80 mg/m 2 /day) for 14 days with 7 days rest. After chemotherapy, the patients underwent surgery. Results: From Dec 2009 to Sep 2010, 35 patients (IIIb; 19pts, IIIc; 16pts) were enrolled. The median age of the patients was 54.6 years (range; 20-72 y). All patients were available for evaluating the clinical responese and adverse events. The overall response rate was 68.5% (1CR, 23 PR, 9 SD, 2 PD). 32 patients underwent surgical resection. Of them, 27 patients underwent standard D2 surgery and 5 patients had palliative surgery. 25 patients had R0 resection. Postoperative pathological examination showed that most of the surgical patients were in T4a stage. According to Lauren classification, 71.9% patiens (23/32pts) were diffuse type, SOX showed higher respons rate (1CR, 20 PR, 2 SD, RR: 91.3%) among these patients. Major grade 3/4 hematological toxicities were anemia (5.7%), neutropenia (5.7%) and liver dysfunction (8.6%) and non-hematological toxicities were anorexia (5.7%) and vomiting (11.4%). But most of the adverse events were managable. Conclusions: Neoadjuvant chemotherapy with S-1 plus oxaliplatin (SOX) showed high response rate and and R0 resection rate for locally advanced GC, especially for diffuse type patients. All the patients did not have severe toxicity during the process of chemotherapy. This is the preliminary results, and the survival benefit in locally advanced GC patients that respond to SOX neoadjuvant chemotherapy needs to be addressed by a randomized-controlled trial. No significant financial relationships to disclose.
Regorafenib in metastatic colorectal cancer: An exploratory biomarker trial.
Authors: Mohamed E. Salem, Emanuel Petricoin, Anton Wellstein, Mariaelena Pierobon, Hongkun Wang, Sameh Mikhail, Marion L. Hartley, Brandon George Smaglo, Emil Lou, Angela Tatiana Alistar, Karen Dorsch-Vogel, Michael J. Pishvaian, Aiwu Ruth He, Alexander Y. Kim, Narayan Shivapurkar, Sandeep K. Reddy, John Marshall
Journal: Journal of Clinical Oncology (2016)

TPS773 Background: Treatment with Regorafenib (REGO) has shown significant clinical benefits in metastatic colorectal cancer (mCRC) patients (pts) as demonstrated in the CORRECT and CONCUR trials. Results from both studies suggest that subgroups have differential responses. Further research to identify these subgroups through the identification of molecular biomarkers is needed. Methods: Forty pts with refractory mCRC are being enrolled in this study. The primary objective is to prospectively identify tissue and serum-based biomarkers that can predict response to REGO. Secondary objectives are to determine molecular mechanisms by which REGO controls refractory mCRC, as well as molecular pathways involved in the acquisition of resistance. Tumor and blood samples are obtained prior to and 2 weeks after starting REGO. Blood samples are collected on day 1 of each cycle thereafter. Pts will receive 160 mg REGO daily for 3 weeks of each 4-week cycle until disease progression or unacceptable toxicity. Multi-omic based biomarker discovery approaches will be used to uncover predictive marker candidates with special attention to the tumor microenvironment. Laser capture microdissection will be used on tumor tissue to procure highly enriched populations of pt-matched epithelial and stromal/immune cell infiltrates. Each of these entities will be analyzed for RNA expression changes and protein signaling/drug target activation mapping. Protein signaling analysis will be performed by reverse phase protein array of key REGO-related proteins and phosphoproteins (e.g. phosphoVEGFR, Tie2, phosphoRET), as well as broad-scale mapping of mitogenic, survival, autophagy, inflammatory, motility, and signaling networks. Tumor profiling will include next-generation sequencing for 592 genes with 53 selected gene fusions, and IHC and FISH/CISH for selected biomarkers, including PDL1, HER2, MSI, TS, ERCC1, and TOPO1. Blood samples will undergo protein, miRNA, and mutated DNA analysis, as well as exosomal signature study via a proprietary synthetic polyligand multiplexed aptamer-based assay. Exploratory analysis of biomarkers will be used to determine correlations between the presence of, or change in, biomarker levels and clinical response. Clinical trial information: NCT01949194.
Impact of EGFR mutation status in patients with completely resected lung adenocarcinoma treated with adjuvant platinum-based chemotherapy.
Authors: K. Yoh, K. Goto, S. Niho, H. Ohmatsu, K. Nagai, Y. Ohe
Journal: Journal of Clinical Oncology (2011)

7036 Background: EGFR mutations are significantly related to a favorable clinical outcome among advanced or relapse lung adenocarcinoma patients treated with EGFR tyrosine kinase inhibitors (EGFR TKIs). We evaluated the prognostic value of EGFR mutation status in patients with completely resected lung adenocarcinoma treated with adjuvant platinum-based chemotherapy (ACT). Methods: From January 2005 to September 2009, 128 patients received complete resection followed by ACT for stage II-III non-small cell lung cancer (NSCLC) at our institution. Among these patients, the EGFR mutational status of 60 patients with lung adenocarcinoma was determined using a PCR-based assay for EGFR exons 18 to 21. Survival outcomes were evaluated by the EGFR TKIs-sensitive mutations status (either exon 19 deletion or L858R in exon 21). Results: Sensitive EGFR mutations were detected in 27 (45%) of all EGFR evaluable patients. 85% of patients received cisplatin and 15% received carboplatin-based adjuvant chemotherapy. Forty-six patients (77%) had developed recurrence at time of analysis. With a median follow-up of 31 months, 2-year disease-free survival (DFS) were 33% in mutation-positive patients, and 49% in negative patients, respectively (P = 0.11). By contrast, mutation-positive patients had longer overall survival (OS) than negative patients (P < 0.01). Based on the Kaplan-Meier method the estimated 2-year and 5-year OS in mutation-positive patients were 96% and 68%, respectively, as opposed to 71% and 36%, respectively, in negative patients. Multivariate analysis identified EGFR mutation status as an independent factor related to OS (P = 0.02). At the time of recurrence, 81% of EGFR mutation-positive patients were treated with EGFR TKIs. Conclusions: Our findings indicated that, even in patients with completely resected lung adenocarcinoma treated with ACT, EGFR mutation status was significantly associated with OS but not with DFS, if treated with EGFR TKIs after recurrence. EGFR mutation status should be considered as a stratification factor in randomized controlled trials for completely resected stage II-III NSCLC.