tbuckley/cabot-search huggingface dataset:
A phase I trial for the use of intravesical cabazitaxel, gemcitabine, and cisplatin (CGC) in the treatment of BCG-refractory nonmuscle invasive urothelial carcinoma of the bladder.
Authors: Guarionex Joel DeCastro, Wilson Sui, Jamie S. Pak, Corinne T. Abate-Shen, Shing Mirn Lee, Christopher B. Anderson, Dara Holder, James M. McKiernan
Journal: Journal of Clinical Oncology (2017)

313 Background: Salvage intravesical chemotherapy has shown benefit in patients with high-risk non-muscle invasive bladder cancer who fail first line therapy. Our preclinical murine intravesical trial showed a combination therapy was superior to single-agents. Our objective was to investigate the safety of intravesical triple agent salvage chemotherapy consisting of cabazitaxel, gemcitabine and cisplatin (CGC). Methods: Patients with BCG refractory or recurrent high-risk non-muscle invasive bladder cancer who refused radical cystectomy were enrolled. All patients underwent a pre-treatment transurethral resection of bladder tumor and then received a 6-week regimen. All patients received the same dose of gemcitabine (2000mg) while the dose of cisplatin and cabazitaxel were escalated as shown in table 1. Toxicity was categorized according to CTC for Adverse Events v4 and included hematuria, dysuria, bladder spasm, urinary retention or frequency. A complete response (CR) was defined as a negative random bladder biopsy and negative cytology six weeks after treatment. Results: Median age of the 9 patients was 74 years (table 1) and the median number of prior intravesical therapies was 4 (range 2-5). All patients completed 6 weeks of induction CGC. Any local toxicity was found in 7 patients with 5 experiencing at least 1 grade 1 toxicity and 4 experiencing at least 1 grade 2 toxicity. Seven of eight patients were complete responders and initiated maintenance therapy. Conclusions: CGC appears to be a well-tolerated intravesical salvage chemotherapy regimen for the treatment of BCG-refractory NMIBC. Clinical trial information: NCT02202772. [Table: see text]
American BRCA outcomes and utilization of testing (ABOUT) study.
Authors: Rebecca Sutphen, Joseph E. Bauer, Katherine S. Virgo, Carolina Casares, Gregg Walker, Marc D Schwartz, Joanne Armstrong, Sue Friedman, Kristian Lynch, James Andrews, Claudia X Aguado Loi, Michele Toscano, Nancy Kotchko, Rachel Threet Teten, Matt R Kondoff, Lana Brand, Ashley Molina
Journal: Journal of Clinical Oncology (2012)

1608 Background: An estimated 100,000 individuals currently undergo genetic testing for hereditary susceptibility to breast and ovarian cancer annually in the U.S., yet little is known about their characteristics, testing experience or outcomes. Research in this high-risk group has been limited to patients recruited at academic medical centers where case ascertainment, health services delivery, decision-making and, quite likely, outcomes are different from those in the community setting where the majority of individuals currently receive healthcare services. Methods: Eligible subjects include 10,000 consecutive individuals requesting BRCA testing through the nation’s third-largest health insurer, Aetna, beginning in December, 2011. De-identified data are analyzed from each test request form submitted by the ordering provider. Each eligible subject is mailed a study packet inviting them to complete a questionnaire (by mail, online or telephone) designed to investigate informational and healthcare services, test results, knowledge, risk perception and medical intentions. Results: Of 442 subjects contacted during the first two weeks of accrual, 143 (32%) have completed the questionnaire to date. Similar to Aetna member demographics, 7% are African-American and 7% report Hispanic ethnicity. Based on Chi-Square tests, there were no differences between respondents and non-respondents with regard to age (51% under age 50), race, ethnicity or personal history of cancer (58%). Among respondents, deleterious mutations were identified in 8%. Testing for a known familial mutation was performed in 8%. Among women with breast cancer, 13% were undergoing testing prior to initial surgical treatment. Updated results from 3000 eligible subjects will be presented. Conclusions: This innovative, academic-industry collaboration enables an unprecedented investigation of significant issues surrounding individuals at increased risk for hereditary breast and ovarian cancer and undergoing genetic testing in the U.S. The results will guide the development and dissemination of more targeted decision-support tools and strategies to improve medical outcomes for such individuals.
Sorafenib treatment for advanced hepatocellular carcinoma: Effectiveness, safety, and controversial points.
Authors: Takayoshi Oikawa, Kei Sawara, Hidekatsu Kuroda, Yasuhiro Takikawa
Journal: Journal of Clinical Oncology (2017)

496 Background: Sorafenib is only molecular target drug for hepatocellular carcinoma (HCC) in worldwide, however the effect and toxicity are different from cytotoxic anticancer agent. We evaluated that the efficacy and safety of sorafenib for unresectable HCC. Methods: This study population included fifty-eight patients that we can follow-up in 80 patients treated by sorafenib between May 2009 and May 2015 in our hospital. We evaluated the profile of sorafenib treatment (cause, initial dose, rate of changing dose), clinical response by mRECIST, adverse events by CTCAE v.4.0, Overall survival (OS) (total OS, median OS), conversion therapy and tumor response after progressive disease (PD). Results: HBV/HCV/alcohol/NBNC: 17/19/15/5, Child Pugh grade A/B: 54/4, cStage Ⅱ/Ⅲ/ⅣA/ⅣB: 1/17/15/23, extrahepatic spread(EHS) (lung /bone /adrenal gland /others): 9/5/2/7, prior treatment : 42/58 (72.4%). Cause of sorafenib treatment : TACE refractory (28%), vascular invasion or EHS (48%), initial dose 400mg (90%), changing dose :escalation (400→800); 15.5% reduction;10.3%. tumor response: objective response; 11.4%, disease control rate (DCR); 60.5%, OS: median OS 8.6 months, 3 year survival rate; 8.1%. There was significant difference in OS between Child Pugh score(CPS) (CPS:5, mOS 17.8 months, p &lt; 0.01). Adverse events: skin disorders (17.2%), gastrointestinal disorders (17.2%), hepatobilliary disorders (17.2%), respectively. In clinical course of after PD response, 10 patients (17.2%) received hepatic arterial infusion chemotherapy for conversion therapy from sorafenib, and had 40% of DCR. Conclusions: Sorafenib is good therapeutic drug for advanced HCC and TACE refractory patients. Taking 400mg dosage of sorafenib is good response which depends on liver function. After PD response by sofafenib, conversion therapy from sorafenib has possibilities of good response.
Is there a need for sentinel lymph node biopsy in microinvasive breast cancer?
Authors: Nimmi S. Kapoor, Jamie Shamonki, Jeong Lim Yoon, Cathie T. Chung, Armando E. Giuliano
Journal: Journal of Clinical Oncology (2012)

1105 Background: There is limited data on the long-term outcome of patients with microinvasive breast cancer. Moreover, predictors of lymph node involvement and the impact of multifocal microinvasion are not well understood. We examined the occurrence of nodal metastasis and the significance of multifocality on disease recurrence. Methods: Patients with T1mic breast cancer, defined as tumors ≤1mm, surgically managed at our institute between 1995-2010 were identified. Specimen slides were independently reviewed. Multivariable analysis (MVA) was used to predict lymph node involvement and disease recurrence. Results: Fifty-two patients with T1mic breast cancers were identified. Median patient age was 53 (range 30-92), median size of in-situ disease was 3cm (range 0.1-12cm). Ten patients (19.2%) had multiple foci of microinvasion (range 2-7). The majority of tumors were high-grade (76.9%). When the invasive tumor component was evaluated, 31 of 41 (73.8%) were ER positive, 40.5% were HER2+(15/37), and only one was ER-/PR-/HER2-. Twenty-nine patients (55.8%) had breast conserving surgery and 23 had mastectomies. Lymph nodes were assessed in 48 patients; there was 1 macrometastasis (2.1%), 4 micrometastases (8.3%) and 4 (8.3%) with isolated tumor cells. Seven of 9 patients with lymph node involvement underwent adjuvant chemotherapy. Univariable analysis showed that ER(-) invasive disease and high-grade DCIS tumors were more likely to have involved lymph nodes. On MVA, only negative ER status was a significant predictor of lymph node metastasis (p&lt;0.02). At median follow-up of 83 months (range 6-172 months), 3 patients (6.3%) had disease recurrence (1 local, 1 distant, 1 local and distant) at 8, 17, and 130 months from presentation. All patients with recurrence had negative lymph nodes and only one focus of microinvasion. No factors predicted disease recurrence. Conclusions: Microinvasive breast cancer clearly has the ability to metastasize and recur, but in this series only 2% of patients presented with nodal macrometastasis. The evaluation of lymph nodes in T1mic cancer is unnecessary in the majority of patients. In our cohort, neither lymph node status nor multifocal microinvasion predicts recurrence.
Impact of BRCAness on the efficacy of oxaliplatin-based chemotherapy in patients with unresectable pancreatic cancer.
Authors: Tomohiro Kondo, Masashi Kanai, Tadayuki Kou, Tomohiro Sakuma, Hiroaki Mochizuki, Mayumi Kamada, Masahiko Nakatsui, Norimitsu Uza, Yuzo Kodama, Toshihiko Masui, Kyoichi Takaori, Shigemi Matsumoto, Hidehiko Miyake, Yasushi Okuno, Manabu Muto
Journal: Journal of Clinical Oncology (2017)

250 Background: Defects in individual genes that are involved in homologous recombination repair (HRR) is called “BRCAness” and several studies suggested that patients with BRCAness are more sensitive to platinum-based chemotherapy (Golan et al, 2014; Lowery et al, 2011; Vollebergh et al, 2014). We introduced the multiplex gene panel test into daily clinical practice since April 2015 at Kyoto University Hospital, in which we can monitor the entire coding region of 215 cancer-related genes and the rearrangement of 17 frequently rearranged genes. The purpose of this study was to evaluate the association between BRCAness status monitored by multiplex gene panel test and clinical outcome of patients with unresectable pancreatic ductal adenocarcinoma (PDAC) who received oxaliplatin-based chemotherapy. Methods: A total of consecutive 17 patients with histologically confirmed PDAC who underwent multiplex gene panel test were eligible. BRCAness status was determined according to the results of multiplex gene panel test. Oxaliplatin-based chemotherapy included FOLFIRINOX, GEMOX and SOX. We assessed the time to treatment failure (TTF) to evaluate the efficacy of oxaliplatin-based chemotherapy by log-rank test. Results: BRCAness-related mutations were detected in BRCA2 (n = 6), ATM (n = 4), ATR (n = 2), BRCA1 (n = 2), and PALB2 (n = 1). Based on these results, 11 patients were classified into non-BRCAness group and six patients were into BRCAness group. Seven and five patients received oxaliplatin-based chemotherapy in non-BRCAness and BRCAness group, respectively. Median TTF of oxaliplatin-based chemotherapy was 52 days (95% confidence interval [CI], 40–90 days) in non-BRCAness group and 294 days (95% CI, 56 days–NA) in BRCAness group. The difference was statistically significant (P = 0.027). Of note, two patients with BRCAness showed good response to FOLFIRINOX without disease progression &gt; 500 days. Conclusions: BRCAness-related mutations could be a promising predictive marker of the efficacy of oxaliplatin-based chemotherapy.
Hematopoietic Stem Cell Infected with HTLV-1 Functions As a Viral Reservoir In Vivo
Authors: Jun-ichirou Yasunaga, Rie Furuta, Michi Miura, Kenji Sugata, Akatsuki Saito, Akari Hirofumi, Takaharu Ueno, Norihiro Takenouchi, Jun-ichi Fujisawa, Masakazu Shimizu, Fumihiko Matsuda, Anat Melamed, Charles R. M. Bangham, Masao Matsuoka
Journal: Blood (2016)
A phase Ib safety and tolerability study of a pan class I PI3K inhibitor buparlisib (BKM120) and gefitinib (gef) in EGFR TKI-resistant NSCLC.
Authors: Daniel Shao-Weng Tan, Kiat Hon Lim, Wai Meng Tai, Aziah Ahmad, Summer Pan, Quan Sing Ng, Mei-Kim Ang, Apoorva Gogna, Yuen Li Ng, Bien Soo Tan, Haur Yueh Lee, Sakktee Sai Krisna, Dawn PX Lau, Liz Zhong, Gopal Iyer, Balram Chowbay, Alvin ST Lim, Angela Takano, Wan-Teck Lim, Eng-Huat Tan
Journal: Journal of Clinical Oncology (2013)

8107 Background: Overcoming EGFR TKI resistance (R) is a major clinical challenge; reported mechanisms include EGFR T790M mutation (mt), MET amplification (amp) and PIK3CA mt. As the PI3K pathway is a central convergent signaling node, we hypothesized that addition of buparlisib (BKM) could overcome EGFR TKI-R. Methods: Patients (pt) resistant to EGFR TKI (Jackman JCO 2010) were enrolled to determine safety, tolerability, pharmacokinetics (PK) and pharmacodynamics of BKM-gef. Using a “3+3” design, escalating doses of BKM were added to pt progressing on gef (Gp A). Pt not on gef preceding enrolment received a 2 wk run in (Gp B). Given the favorable CNS penetration of BKM, a CNS gp with brain metastases only was included. Pt had pretreatment biopsies and sequential PET-CT scans (baseline &amp; d28). Results: 15 pt have been treated at 3 dose levels: BKM 80 mg/d (n=6), 100 mg/d (n=6), 80 mg 5d on 2d off (5/2, n=3), with gef 250 mg/d. Gp A (n=9, 1 CNS), B (n=6, 1 CNS), F:M (9:6), median age 63 (47-73) and majority &gt;3 lines of therapy. DLT was G3 diarrhea observed in 2/6 pt at BKM100. Common adverse events (AE, all grades) include rash (80%), diarrhea (73%), fatigue (60%), anorexia (47%), mucositis (40%). Notably, 40% of pt had late (beyond DLT period) G3 toxicities such as rash and diarrhea. MTD is BKM 80/d and gef 250/d. To improve the overall safety profile, an intermittent schedule of BKM80 5/2 was also found to be feasible. In gp B, PET-CT done after 2 wk run-in of gef, 3/4 evaluable pt demonstrated reduction in SUV max of which 1 had PR. With addition of BKM, reduction in SUV max (&gt;25%) was seen in 4/10 pt (gp A &amp; B). Median PFS 2.8 m (95%CI 2.3 – 8.1), two pt in CNS gp had PFS of 2.8 and 10.7 m. Molecular analyses revealed 6/12 (50%) harbored T790M mt, 2/5 (40%) MET amp, 0/12 PI3KCA mt. In gp A, 4/9 pt (2 T790M; 1 MET amp) had clinical responses, including slight tumor shrinkage and reduced pleural effusion, but required dose reductions due to AE. PK profiles are being analyzed. Conclusions: MTD is gef 250-BKM 80/d. Antitumor activity has been observed with addition of BKM in EGFR TKI-R pt. In view of late toxicities and long t½ of BKM, exploring alternative schedules is warranted. A dose expansion cohort at MTD is currently ongoing. Clinical trial information: NCT01570296.
A pilot study of neoadjuvant cetuximab in locally advanced squamous cell carcinomas of skin (SCCS).
Authors: Kristen Renee Spencer, Amanda D. Kaveney, James Goydos, Sinae Kim, Vadim P Koshenkov, Sharad Goyal, Atif J. Khan, Elsie M Castrorao, Ann W. Silk, Howard Kaufman, Lien Huzzy, Megan L Ruppert, Shridar Ganesan, Janice M. Mehnert
Journal: Journal of Clinical Oncology (2015)

TPS9092 Background: The incidence of SCCS has increased over the past two decades, including a high risk subset with aggressive behavior. Due to a lack of high-quality clinical trials in this population, there is no standard systemic therapy for advanced SCCS. The epidermal growth factor receptor (EGFR), often highly expressed in SCCS, is implicated in UV-induced skin carcinogenesis and SCCS development. Cetuximab, a monoclonal antibody that competitively inhibits EGFR, improved disease control as first line therapy in unresectable SCCS in a single arm phase II trial. Despite impressive responses with cetuximab in some, most treated SCCS patients do not respond, and there is a need for predictive biomarkers. We hypothesize that the use of cetuximab will improve clinical outcomes in patients with advanced SCCS in the neoadjuvant setting, and that measures of antibody dependent cytotoxicity (ADCC) in tumor and/or specific genomic features of the tumor may predict response to therapy. Methods: In this pilot trial (NCT 02324608), we will enroll 20 patients with relapsed locally advanced SCCS or SCCS unamenable to definitive local therapy. The primary endpoint will measure response rate to cetuximab by RECIST criteria with secondary endpoints of progression free and overall survival, and conversion to resectability. Molecular tumor correlates include analyzing DNA mutations and measuring downstream activation of EGFR signaling and ADCC, correlating these with clinical benefit. Patients will receive cetuximab at 400mg/m2 Χ 1 followed by weekly doses of 250mg/m2 for 8 weeks prior to surgery. Patients will be evaluated for subsequent definitive surgical resection, or definitive radiotherapy if surgical resection is not possible. Postoperative adjuvant radiotherapy will be permitted. Patients will undergo pretreatment biopsies, and post-treatment tissue will be harvested at surgery or through a biopsy at the conclusion of cetuximab. Paired skin and tumor samples will be evaluated through partial DNA (FoundationOneΤΜ) and RNA sequencing, IHC analysis of EGFR signaling components, and measurement of ADCC. The trial is currently screening eligible subjects. Clinical trial information: 02324608.
Vasohibin 2 reduces chemosensitivity to gemcitabine in pancreatic cancer cells via Jun proto-oncogene dependent transactivation of ribonucleotide reductase regulatory subunit M2
Authors: Min Tu, Haifeng Li, Nan Lv, Chunhua Xi, Zipeng Lu, Jishu Wei, Jianmin Chen, Feng Guo, Kuirong Jiang, Guoxin Song, Wentao Gao, Yi Miao
Journal: Molecular Cancer (2017)

Vasohibin 2 (VASH2) has previously been identified as an agiogenenic factor and a cancer related protein. Here we investigated the association of VASH2 expression and chemoresistance in pancreatic cancer.Immunohistochemical staining for VASH2 was performed on 102 human pancreatic cancer samples. Pancreatic cancer cell line models exhibiting overexpression or knockdown of VASH2 were generated. Gene expression analyses were carried out to determine genes differentially regulated by VASH2. Putative transcription factors that are downstream mediators of gene expression regulated by VASH2 were queried bioinformatically. Dual-luciferase reporter assays and ChIP assays were performed to confirm transactivation of target genes following VASH2 overexpression or knockdown.VASH2 protein expression was higher in human pancreatic cancer than in paired adjacent tissues and elevated VASH2 levels were associated with gemcitabine chemoresistance. In cell line models of pancreatic cancer, VASH2 expression induced gemcitabine chemoresistance in vitro and in vivo. It was discovered that expression of ribonucleotide reductase regulatory subunit M2 (RRM2) is regulated by VASH2; immunohistochemical analysis demonstrated a positive association of VASH2 expression and RRM2 expression in human pancreatic cancer tissues. Bioinformatics analyses revealed that induction of the Jun proto-oncogene (JUN) by VASH2 is responsible for upregulation of RRM2 expression; this JUN-dependent regulation of RRM2 by VASH2 was confirmed by chromatin immunoprecipitation and dual luciferase reporter assays, which demonstrated that JUN directly binds with the RRM2 promoter to activate transcription.These data suggest that VASH2 reduces the chemosensitivity to gemcitabine in pancreatic cancer cells via JUN-dependent transactivation of RRM2.
Surge in child emergency admissions prompts new care standards
Authors: Adrian O’Dowd
Journal: BMJ (2017)

The rising number of children attending emergency departments has prompted experts to produce new standards for specialist assessment units to deal with demand and help prevent children from being admitted to hospital inappropriately.

The Royal College of Paediatrics and Child Health published new standards for short stay paediatric assessment units (SSPAUs) on 23 March.1 The college said that the number of young people aged 15 and under seen in hospital emergency departments in England rose by 7.6% from 2014-15 to 2015-16, with 4.4 million attendances last year.

Some 1.1 million emergency admissions were recorded in 2015-16 among children and young people up to age 24, up 13% since 2006-07 overall and a rise of 28% in …
Phase III trial of non-pegylated liposomal doxorubicin (M) in combination with trastuzumab (T) and paclitaxel (P) in HER2+ metastatic breast cancer (MBC).
Authors: Lorena De La Pena, Javier Cortes, Alexey Manikhas, Laslo Roman, Vladimir Semiglazov, Mikhail Yu Biakhov, Lokanatha Dasappa, Antonio Llombart, Marcel Rozencweig, Salvatore Forenza, Ronald H. Goldfarb, Jeri Matera, Nozar Azarnia, Clifford Hudis, Jose Baselga
Journal: Journal of Clinical Oncology (2013)

517 Background: M in combination with T has shown promising activity and cardiac safety in MBC patients (pts). We conducted a randomized Phase III trial of first-line M plus T and P (MTP) versus T plus P (TP) in HER2+ MBC pts. Methods: Pts with HER2+ (by FISH) MBC ≥ 18 years and ECOG 0-1, who had received no prior chemotherapy for metastatic disease, were eligible. Left ventricular ejection fraction should be within normal institutional limits. Prior (neo-) adjuvant anthracyclines, T or P were permitted, if completed &gt;1 year before the start of the study. Pts received M 50 mg/m 2 q3w for 6 cycles, T 4 mg/kg loading dose followed by 2 mg/kg qw, and P 80 mg/m 2 qw, or T+P at the same doses until progression or toxicity. Primary outcome was progression-free survival (PFS). Enrollment of 332 pts would provide 80% power with a 5% significance to detect an improvement in PFS with MTP, assuming a median PFS of 8 months in TP and a hazard ratio (HR) of 0.70. Results: 363 pts enrolled (MTP 181, TP 183), 360 received treatment. The two groups were well balanced for demographics, pretreatment characteristics and extent of disease. One third of the pts had prior exposure to anthracyclines, but almost none to trastuzumab (1% and 2% in MTP and TP arms, respectively). Six cycles of M could be given to 72% of the pts. With a median follow-up of 31 months, median PFS was 16.1 and 14.5 months with MTP and TP, respectively (HR 0.84, P=0.174). In pts with ER and PR-negative tumors, PFS was 20.7 and 14.0 months, respectively (HR, 0.68; 95% CI 0.47–0.99). Median overall survival (OS) was 33.6 and 28.9 months, respectively (HR, 0.79, P=0.083). In ER and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR, 0.63; 95% CI 0.42–0.93). The incidence of NYHA Class III/IV congestive heart failure was 3% with MTP and there were 2 cardiac deaths with TP. The frequency of adverse events was higher with MTP, especially myelosuppression, stomatitis and gastrointestinal intolerance. Conclusions: The trial failed to demonstrate a significant clinical improvement with the addition of M to TP. The clinical benefit observed in an exploratory analysis in the ER and PR-negative population deserves consideration for further clinical trials. Clinical trial information: NCT00294996.