tbuckley/cabot-search huggingface dataset:
KEYNOTE-240: Randomized phase III study of pembrolizumab versus best supportive care for second-line advanced hepatocellular carcinoma.
Authors: Richard S. Finn, Stephen L. Chan, Andrew X. Zhu, Jennifer J. Knox, Ann-Lii Cheng, Abby B. Siegel, Oliver Bautista, Pat Watson, Masatoshi Kudo
Journal: Journal of Clinical Oncology (2017)

TPS503 Background: There are no approved therapies for patients with hepatocellular carcinoma (HCC) after disease progression on sorafenib, or for patients with intolerance to sorafenib. HCC often arises in the background of chronic inflammation and is also associated with an immunosuppressed microenvironment, providing a strong rationale to evaluate immunotherapy in HCC. The randomized, double-blind, placebo-controlled phase 3 KEYNOTE-240 study (ClinicalTrials.gov, NCT02702401) was designed to compare the efficacy and safety of the anti–PD-1 antibody pembrolizumab + best supportive care (BSC) vs placebo + BSC in patients with previously treated advanced HCC. Methods: Eligibility criteria include age ≥18 years, confirmed diagnosis of Barcelona Clinic Liver Cancer (BCLC) stage C disease or BCLC stage B disease not amenable to or refractory to locoregional therapy, disease not amenable to a curative treatment approach (eg, transplantation, surgery, or ablation), documented progression after treatment with sorafenib or intolerance to sorafenib, Child-Pugh liver score A, and ECOG performance status 0-1. ~408 patients will be randomly assigned 2:1 to receive pembrolizumab 200 mg IV every 3 weeks (Q3W) + BSC or placebo Q3W + BSC for up to 35 cycles or until disease progression, unacceptable toxicity, patient withdrawal of consent, or investigator decision. Randomization will be stratified by geographic region, macrovascular invasion, and α-fetoprotein. BSC will be provided by the investigator per local treatment practices. Response will be assessed every 6 weeks per RECIST v1.1 by central imaging vendor review. Adverse events (AEs) will be assessed throughout treatment and for 30 days thereafter (90 days for serious AEs) and graded per NCI CTCAE v4.0. Primary objectives are comparison of progression-free survival per RECIST v1.1 by central imaging vendor review and overall survival between treatment arms. Secondary objectives are comparison of objective response rate, duration of response, disease control rate, and time to progression per RECIST v1.1 by central imaging vendor review, and evaluation of safety and tolerability. Enrollment in KEYNOTE-240 is ongoing. Clinical trial information: NCT02702401.
Response of chemoradiation therapy after induction chemotherapy failure in locally advanced head and neck squamous cell carcinoma (LA-HNSCC).
Authors: Yoojoo Lim, Bhumsuk Keam, Youngil Koh, Kyung-Hun Lee, Tae Min Kim, Se-Hoon Lee, Jeong-Hun Hah, Tack-Kyun Kwon, Dong-Wan Kim, Hong-Gyun Wu, Myung-Whun Sung, Dae Seog Heo, Kwang Hyun Kim
Journal: Journal of Clinical Oncology (2012)

5552 Background: Although induction chemotherapy (IC) for LA-HNSCC has shown high response rates, some patients do not respond to IC. Surgery has been the usual choice for the non-responding patients, but practically, not all of these patients are eligible for operation. The purpose of this study was to evaluate the efficacy of definitive radiation therapy (RT) for the HNSCC patients who failed IC. Methods: We have retrospectively analyzed the outcome of patients with LA-HNSCC who were initially treated with IC at Seoul National University Hospital between Jan. 2006 and Dec. 2010. Chemotherapeutic regimens used were 5-FU/cisplatin, docetaxel/5-FU/cisplatin, and docetaxel/cisplatin with or without cetuximab. After IC, patients were treated with RT, concurrent chemoradiation (CCRT), or surgery, either alone or with postoperative RT. Treatment modality was chosen on multi-disciplinary basis of our institution. Response was evaluated using RECIST criteria. Results: A total of 225 LA-HNSCC patients treated with IC were analyzed. Median age was 54 (range 24-77). Primary tumor locations were oral cavity (39.5%), nasal cavity/paranasal sinus (13.1%), oropharynx (13.1%), nasopharynx (13.1%), larynx (7.9%) and hypopharynx (13.1%). Among the 225 patients, 38 (16.9%) patients did not respond to IC [stable diseases (SD) = 23 (10.2%), progressive disease (PD) = 15 (6.7%)], and their median overall survival was 14.5 months. Among the 38 non-responders, 14 (36.8%) patients were undertaken surgery and 22 (57.8%) unresectable or inoperable patients were treated with either definitive RT or CCRT. Responses to subsequent definitive RT or CCRT for 20 evaluable patients were as follows: complete response = 6 (30.0%), partial response = 7 (35.0%), SD = 3 (15.0%), PD = 4 (20.0%) Overall response rate to definitive RT or CCRT in non-responder to IC was 65.0% (95%CI: 44.1%- 85.9%). Nine out of 15 patients who showed PD to IC received definitive RT or CCRT and interestingly, 3 (33.3%) patients responded to definitive RT or CCRT. Conclusions: A significant portion of HNSCC patients who failed to IC can benefit from subsequent definitive RT or CCRT. Further prospective study is warranted.
A randomized, open-label, phase II study of lapatinib / capecitabine, lapatinib / vinorelbine, or lapatinib / gemcitabine in patients with ErbB2-amplified metastatic breast cancer progressing after taxane treatment: Results of an interim analysis (GLICO-0801 / EGF111792).
Authors: Henry Leonidas Gomez, Silvia P. Neciosup, Celia Tosello, Patricia Xavier, Yeni Neron do Nascimento, Marcelo Fanelli, Gustavo Ismael, Jose Bines, Carlos Sampaio, Guillermo Luis Lerzo, Adolfo Miguel Capo, Max S. Mano, Luis Fein, Gustavo Werutsky, Carlos H. Barrios
Journal: Journal of Clinical Oncology (2012)

e11087 Background: Lapatinib-capecitabine is approved for the treatment of ErbB2-amplified metastatic breast cancer (MBC) after failure to anthracyclines, taxanes and trastuzumab. GLICO-0801 evaluates different lapatinib-based chemotherapy combinations as 1 st /2 nd line treatment for ErbB2 amplified MBC progressing after taxane treatment. We present the results of a planned safety interim analysis. Methods: This is an open-label, randomized, international, phase II trial exploring lapatinib (L) 1250mg qd in combination with capecitabine 2000mg/m 2 d 1-14 (Arm A) or vinorelbine 25mg/m 2 d 1 and 8 (Arm B) or gemcitabine 1000mg/m 2 d 1 and 8 (Arm C). Primary objective is to determine the clinical benefit rate (defined as CR+PR+SD for ≥24 weeks). This trial is registered at www.clinicaltrials.gov number: NCT01050322 Results: The first83 randomized patients (pts) (Arm A=29, B=28 and C=26) were included in this analysis. Of them, 65 (78%) have discontinued therapy with mean number of cycles of 4.7, 6.2 and 7.5 in arms A, B and C respectively. Eighteen (21%) pts are still on treatment. Median age was 52y (29-84); 80 pts (96%) had PS 0-1; 51 (61%) were postmenopausal. Fifty-six pts (67%) had visceral metastasis, 52 (63%) were treated as 2 nd line therapy and 36 (43%) had received prior trastuzumab. Most reported adverse events (AE) (87%) were grade 1-2. The most common AE (any grade) in arm A: diarrhea 72%, hand-foot syndrome 45%, vomiting 39%, anemia 36%; in arm B: diarrhea 75%, neutropenia 68%, nausea 43%, vomiting 39%; in arm C: diarrhea 72%, neutropenia 60%, anemia 44%, increase in ALT 44%. The most frequent serious AE reported in arm A: diarrhea in 3 pts (10%) and thrombocytopenia in 2 pts (7%); in arm B: febrile neutropenia in 2 pts (7%) and in arm C: sepsis in 1 pt (4%). There was one toxic death related to chemotherapy in arm C. Conclusions: There were no unexpected toxicities so far in this trial with most AEs being mild to moderate and manageable. This interim analysis supports the continuation of the study.
Exploring the intra-patient <i>PIK3CA</i> mutational heterogeneity of circulating tumour cells by massive parallel sequencing in patients with metastatic hormone receptor-positive breast cancer.
Authors: Bram De Laere, Dieter J E Peeters, Roberto Salgado, Peter B Vermeulen, Peter A van Dam, Steven J Van Laere, Luc Yves Dirix
Journal: Journal of Clinical Oncology (2015)

11030 Background: Circulating tumour cells are a real-time reflection of the ad hoc relevant subpopulation in patients with progressive disease. The study comprises the clinical application of a liquid biopsy to assess the PIK3CA genotype at a single cell level. Methods: Using CellSearch and DEPArray we purified single and groups of CTCs and WBCs from peripheral blood in 29 patients with metastatic hormone receptor-positve breast cancer. Recovered cells were subjected to Ampli1 whole genome amplification (WGA). Temporally-matched circulating cell-free DNA (cfDNA) was purified from plasma. Additionally, gDNA from archival primary tumour (PT) tissue sections was extracted as comparator. Mutation analysis was performed via targeted amplicon sequencing (TAS) of exons 9 and 20. Results: Archival PT tissue section showed a high frequency of mutant PIK3CA (16/27 (59,2%)), with a poor and fair agreement with cfDNA (n = 21; 43% disparity; κ = 0,113) and CTCs (n = 22; 27% disparity; κ = 0,394), respectively. A concordant PIK3CA status between different compartments was observed in 10/18 (56%) samples. At the used sequencing depth, cfDNA failed to the detect PIK3CA mutations in 4 cases (22%), of which three were present in the respective PT and corresponding CTCs. Gain of mutation was observed in 4/18 patients (22%), with a wild type PT and mutant CTCs at progression (cfDNA confirmed the MT genotype in three cases). A wild-type PIK3CA sequence in recovered WBCs indicates a high specificity and tumorigenic nature of the picked up variants. Intra-CTC analysis reveals PIK3CA mutational heterogeneity with the presence of both mutant and wild-type CTCs. Additionally, unique double-mutated CTCs were detected in 10/26 (38%) cases as well. Conclusions: PIK3CA mutations are frequent in metastatic HR+ breast cancer. Intra-patient PIK3CA mutational heterogeneity was observed with cases of concordance and discordance when comparing early to advanced disease. The study presents the utilization of a liquid biopsy, thereby paving the way towards the application of a more personalized medicine in the management of patients with metastatic cancer.
The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity
Authors: Bo Shan, Xiaoxia Wang, Ying Wu, Chi Xu, Zhixiong Xia, Jianli Dai, Mengle Shao, Feng Zhao, Shengqi He, Liu Yang, Mingliang Zhang, Fajun Nan, Jia Li, Jianmiao Liu, Jianfeng Liu, Weiping Jia, Yifu Qiu, Baoliang Song, Jing-Dong J Han, Liangyou Rui, Sheng-Zhong Duan, Yong Liu
Journal: Nature Immunology (2017)
Association of hypertension and proteinuria with overall survival in solid-tumor patients treated with anti-VEGF drugs in the MARS study.
Authors: Vincent Launay-Vacher, Nicolas Janus, Isabelle Laure Ray-Coquard, Philippe Beuzeboc, Catherine Daniel, Joseph Gligorov, Frédéric Selle, Francois Goldwasser, Olivier Mir, Jean-Philippe Spano, Jean Christophe Thery, Jean-Baptiste Rey, Christelle Jouannaud, Jean F. Morere, Stephane Oudard, Florian Scotte, Michel Azizi, Richard Dorent, Gilbert Deray
Journal: Journal of Clinical Oncology (2014)

2548 Background: MARS is a multicentric, noninterventional, prospective study which first reported the high prevalence of both baseline and de novo hypertension (HTN) and proteinuria (Pu) in patients receiving bevacizumab (Bev) or sunitinib (Su) (Gligorov J et al. SABCS 2013; Ray-Coquard I et al. ASCO GI 2014; Ray-Coquard I et al. ASCO GU 2014; Goldwasser F et al. ECC 2013; Launay-Vacher V et al. ASCO 2013). Methods: It included 1,124 patients, all naive of any previous anti-VEGF treatment. A First Renal Assessment was performed before the anti-VEGF was started with periodic follow-up for 1 year (Renal Follow-up Plan). Univariate (UA) and multivariate analyses (MA) tested the associations of HTN and Pu, at baseline or de novo, with overall survival (OS) (pre-planned). Results: De novo Pu was not associated with reduced OS, in any group. De novo Pu was a statistically significant prognostic factor for better OS in Bev-treated CRC, both in UA and MA. Baseline Pu was prognostic of reduced OS in Bev-treated LC, in UA but not in MA. HTN, either at baseline or de novo, was not found to be associated with OS, in any group. Conclusions: HTN was not associated with OS in our study, even in RCC Su-treated patients. De novo Pu, determined with a urinary dipstick, which is neither invasive nor costly, could be an easily accessible prognostic factor of better OS in Bev-treated CRC. Bev treatment in LC patients experiencing de novo Pu should be discussed since it can be prognostic of poorer OS. UA MA BC + Bev (n=402) CRC + Bev (n=195) RCC + Su (n=112) LC + Bev (n=101) OC + Bev (n=79) BC + Bev (n=402) CRC + Bev (n=195) RCC + Su (n=112) LC + Bev (n=101) OC + Bev (n=79) Baseline HTN NS NS NS NS NS NS NS NS NS NS Pu NS NS NS p=0.03 HR=2.46 [1.09-5.54] NS NS NS NS NS NS De novo HTN NS NS NS NS NS NS NS NS NS NS Pu NS p=0.004 HR=0.31 [0.14-0.67] NS NS NS NS p=0.01 HR=0.57 [0.39-0.83] NS NS NS Abbreviations: HTN: hypertension; Pu: proteinuria; BC: breast; CRC: colorectal; LC: lung; OC: ovarian cancers; RCC: renal cell carcinoma; Bev: bevacizumab; Su: sunitinib; NS: not significant (p>0.05).
Is tissue doppler imaging of tricuspid annular motion useful indetection of pulmonary hypertension and humoral response inchronic heart failure patients
Authors: Lenka Špinarová, Jiří Toman, Jaroslav Meluzín, Petr Hude, Jan Krejčí, Miroslav Souček, Jolana Müllerová, Marie Tomandlová
Journal: Journal of the American College of Cardiology (2002)
Genomic profiling of ampullary adenocarcinoma (AA): Insights from a comparative analysis of pancreatic and intestinal adenocarcinoma and opportunities for targeted therapies use.
Authors: Geraldine Perkins, Cecile Bouchet-Doumenq, Magali Svrcek, Orianne Colussi, Thibault Voron, Alain Sauvanet, Pascal Hammel, Jerome Cros, Francois Paye, Thierry Andre, Jean-Christophe Vaillant, Jean Baptiste Bachet, Armelle Bardier, Anne Berger, Tchao Meatchi, Bernard Nordlinger, Jean-Francois Emile, Isabelle Cojean-Zelek, Julien Taieb, Pierre Laurent-Puig
Journal: Journal of Clinical Oncology (2017)

300 Background: Ampullary adenocarcinoma (AA) is a rare entity. AA can originate from either intestinal or pancreaticobiliary ductal epithelium, and patients are often managed as those with pancreaticobiliary carcinomas. The study objectives were the genetic profiling of AA and the identification of specific molecular profiles according to these 2 pathological types. Methods: AA patients included in the AGEO retrospective multicenter cohort who underwent surgical resection of their tumor between 1999 and 2010 were selected. Formalin-fixed, paraffin-embedded (FFPE) archival tissue blocks were collected. Next generation sequencing (NGS) using a 50 gene panel (Ion AmpliSeq Cancer panel) on tumor DNA, and immunohistochemistry (IHC) panel including CK7, CK20, MUC1, MUC2 and CDX2, on tumor sections, were performed. Results: NGS was performed on 101 tumors from 6 hospitals, with 1 technical failure. In total, the most frequent gene mutations were: KRAS (45%), TP53 (40%), APC (15%), PIK3CA (12%), SMAD4 (9%), BRAF (8%), CDKN2A (6%). No mutation was found in 21% of tumors. According to IHC, the most common histological type was intestinal (51%), followed by pancreaticobiliary type (42%) and undetermined (7%). BRAF mutation was significantly associated with intestinal type (8 vs 0, p = 0.017). According to Cosmic database, similarities of molecular profiles exist between AA with intestinal type and colorectal adenocarcinoma, and between AA with pancreaticobiliary type and pancreas adenocarcinoma, respectively. Conclusions: This study shows that AA is a heterogeneous entity and that a large proportion of AA presents a molecular profile that is more similar to that of colorectal adenocarcinoma, compared to pancreatic adenocarcinoma. This important information could be interesting to guide treatment decision in patients with this rare disease.
A first-in-human phase I study of ER-α36 modifier icaritin in patients with advanced solid tumors.
Authors: Ying Fan, Binghe Xu, Xiaoyan Ding, Fei Ma, Jiayu Wang, Peng Yuan, Yang Luo, Qing Li, Pin Zhang, Ruigang Cai
Journal: Journal of Clinical Oncology (2013)

2614 Background: ER-α36 was recently identified to be expressed in varieties of cancers and may play important roles in carcinogenesis and tumor progression. Icaritin, a natural prenylflavonoid derived from the Chinese herb Epimedium, is a first of its kind ER-α36 modifier, which demonstrated potent anti-tumor effect in multiple cancer cell lines and their xenograft models. This study aims to determine its safety, tolerability, pharmacokinetics (PK), and potential antitumor activity. Methods: This phase I study comprises phase Ia and Ib. In phase Ia part, patients with advanced breast cancer (ABC) were treated with escalating doses of Icaritin orally once daily on a continuous 28-day dosing schedule. In phase Ib part, dosing was fixed to 600 or 800mg twice daily and expansion was made to other selected malignancies including hepatocellular cancer (HCC), colorectal cancer (CRC) and intrahepatic cholangiocarcinoma (ICC) to further explore PK parameters and efficacy. Results: 24 patients were enrolled to receive Icaritin at six dose levels ranging from 50mg to 1600mg per day in phase Ia. No dose limited toxicity (DLT) was found even in the highest dose defined in the protocol, thus the maximum tolerated dose (MTD) was not reached. Only grade 1 drug-related adverse events were observed including neutropenia, ALT elevation, hypercholesteremia, fatigue, anorexia, hypertriglyceridemia, proteinuria, myalgia, hot flash and rash. PK data from the fed dosing showed 3-fold increase of Cmax and AUC compared with the fast dosing. Half life was around 2-7 hours. Among 22 evaluable subjects, no complete or partial response (CR or PR) was detected, 5 patients had stable disease(SD)for 3 months or longer. For phase Ib study, 24 patients had been enrolled. One ABC, 2 CRC and 3 ICC patients progressed after 2 months of medication. Among 7 HCC patients already evaluated, 1 obtained PR and progressed after one year of treatment and 2 remained in the study, stable for 5 months. Similar drug related toxicity profile was noted in phase Ib. Conclusions: Icaritin was generally well-tolerated without DLT across tested dose levels. Evidence of promising antitumor activity was observed in ABC and HCC. Final results will be presented at the meeting. Clinical trial information: NCT01278810.
Investigation on relationships between reduction of cisplatin and anticancer effects in patients with bladder cancer.
Authors: Yasuyoshi Miyata, Tomohiro Matsuo, Kojiro Ohba, Hideki Sakai
Journal: Journal of Clinical Oncology (2017)

306 Background: Cisplatin (CDDP)-based chemotherapy is recognized as standard treatment for patients with advanced urothelial cancer (UC). In patients having lowered renal function, dosage of CDDP must be decreased for prevention of adverse events. However, relationship between reduction of CDDP and anti-cancer effects is not fully understood. The main aim is to clarify the influence of pathological anti-cancer effects by decreasing of CDDP in muscle invasive bladder cancer (MIBC). In addition, anti-cancer effects of radiation therapy in patients with decreased dosage of CDDP are also investigated. Methods: One hundred thirty three patients with MIBC selected CDDP-based intra-arterial chemotherapy. Biopsy was performed before intra-arterial chemotherapy, and then complete resection by trans-urethral resection was done after the therapy. Decreased dosage was defined as reduction ratio is over 20%, and 34 patients were judged as decreased dosage group. Two courses of chemotherapy with CDDP (70 mg/m 2 ) and doxorubicin (30 mg/m 2 / epirubicin (30 mg/m 2 ) were administered, and each course of chemotherapy was repeated approximately every 4 weeks. In 78 patients (58.6%), radiation therapy (total 40 – 60 Gy) began the day after chemotherapy administration. Results: The rate of down-stage after the chemotherapy in standard dosage group (63 of 99, 63.6%) was significantly higher (P=0.046) than that in decreased dosage one (15 of 35, 50.5%). In regard to pathological complete response (p-CR), patients with p-CR in decreased dosage group (n=9, 26.5%) were significantly lower (P=0.015) than those in standard dosage one (n=50, 50.5%). When similar analysis were performed in patients without radiation therapy, rate of p-CR in decreased dosage group was just 10.0%. On the other hand, p-CR was achieved in 33.3% in patients with radiotherapy of decreased dosage group. Conclusions: Reduction of CDDP may decrease its anti-cancer effects in patients with MIBC. On the other hand, combination of radiotherapy can increase the rate of p-CR in patients who treated with decreased dosage of CDDP. We believe our results are useful for discussion on treatment strategies in UC patients having lowered renal function.
Imatinib mesylate in the treatment of paediatric chronic myeloid leukaemia (CML): A study of 30 cases from a regional cancer centre in western India
Authors: S. K. Parikh AP, S. N. Shukla, P. M. Shah, K. M. Patel, B. J. Parikh, A. S. Anand Addl, S. S. Talati Asso, S. A. Shah, H. P. Panchal, A. A. Patel
Journal: Journal of Clinical Oncology (2007)

20021 Background: CML is a very rare disease in childhood. There are scant data available concerning the use of Imatinib in the paediatric patients. Methods: Thirty cases of paediatric CML (25 males, 5 females; median age-11, range: 4–14 years, 23 Interferon naive, 1 interferon resistant) during the period of September 2003 to October 2006 were analyzed. Results: There were 28 patients in chronic phase (CP), 1 accelerated phase (AP) and 1 with blast crisis (BC). All patients were Philadelphia positive (Ph+) (20 by G-banding, 10 by fluorescence in situ hybridization [FISH]) and treated with imatinib using 260 mg/m 2 daily for CP and 340 mg/m 2 for AP/BC. The median time from diagnosis to imatinib therapy was 4 months (range: 0.5–91 months). Twenty-five (92.5%) of 27 evaluable patients achieved complete haematological remission (CHR) (World literature 95% in adult) at a median duration of 60 days (range: 25–150 days). Two patients did not respond; one of them with BC died due to progressive disease and three patients were not evaluable (2 patients loss to follow up and in 1 patient imatinib started recently). Complete cytogenetic response (CyGR) was achieved in 7 of 15 patients studied; 2 patients had partial CyGR while 4 had no CyGR while in 2 patients result was inconclusive. In 2 patients molecular remission was studied with RT-PCR, had attained it at 12 months. Overall, the drug was well tolerated and none of the patients had to permanently discontinue the drug. There were no treatment related deaths. The common adverse events were thrombocytopenia (6.6%), neutropenia (16.6%), skin rash (6.6%), anaemia (3.3%), superficial oedema (6.6%), weight gain (6.6%) and muscle cramps (3.3%). Severe (grade III-IV) events were infrequent except 1 patient with grade IV febrile neutropenia. At median follow up of 24 months (range: 1–35 months, 11 patients followed &gt;24 months), one patient has haematological relapse while one patient has disease progression in form of myeloblastic crisis. Conclusions: The Imatinib mesylate treatment is safe and it achieves rapid and higher CHR in paediatric CML. No significant financial relationships to disclose.