tbuckley/cabot-search huggingface dataset:
Once-daily oral afatinib (A) combined with pemetrexed (P) in patients (pts) with advanced solid tumors: A phase I dose escalation trial.
Authors: Quincy Chu, Randeep Sangha, Sebastien J. Hotte, Qiqi Deng, Steve Gyorffy, Vikram K. Chand, Hal W. Hirte
Journal: Journal of Clinical Oncology (2012)

e13011 Background: A is an oral, irreversible, ErbB Family Blocker with single-agent activity in a variety of solid tumors. Preclinical studies have demonstrated additive antitumor effects when combining A or erlotinib with P in non-small cell lung cancer cell lines with sensitizing or resistant EGFR mutations. We hypothesized that once-daily A given with P would be safe and feasible in pts with advanced solid tumors. Methods: This Phase I trial was a standard 3+3 dose escalation design where A was administered orally at a starting dose of 30 mg/day on days 2–21 and combined with IV P (500 mg/m 2 ) on Day 1 of a 21-day cycle. A was increased by 10 mg for each successive cohort until determination of the MTD, defined as the dose of A below which ≥2 of six pts experienced dose-limiting toxicity (DLT) in Cycle 1. MTD cohort was expanded to 18 pts and incidence and severity of AEs were graded according to CTCAE v3.0. Pts were treated to a maximum of 6 cycles with the option for A monotherapy thereafter. Results: 23 pts with advanced tumors were treated: 10 males, 13 females, ECOG 0/1/2 (30%/65%/4%), median age 58 yrs, and 57% received ≥3 prior chemotherapies. In Cycle 1, treatment-related DLTs were observed in six pts; two pts of three treated at 40 mg/day A dose and four pts of 20 treated at the MTD of 30 mg/day A dose. A and P were well tolerated, with the most frequent treatment-related AEs being diarrhea (91%; of which 86% were grade 1–2), stomatitis (65%) and rash (61%). Pts received a median of 2 cycles of treatment; five pts received &gt;4 cycles, including one patient with serous ovarian cancer who continues on trial treatment beyond 14 months. Best response of 21 available pts included two partial responses, 14 with stable disease, and three with progressive disease. Detailed response and PK data will be further analyzed. Conclusions: In pts with relapsed or refractory advanced solid tumors, oral A at 30 mg/day combined with standard dose P (500 mg/m 2 ) administered on Day 1 of a 21-day cycle, had an acceptable safety and tolerability profile. The study is currently evaluating an intercalated schedule of A on Days 2–6 with P based on preclinical synergy thought to arise from cell-cycle pharmacodynamic separation of A and P.
Incidence of venous thromboembolic events following major pelvic and abdominal surgery for cancer.
Authors: Pablo Emilio Serrano Aybar, Kavita Dhamanaskar, Laurie Elit, Sameer Parpia, Lori-Ann Linkins, Marko Simunovic, Leyo Ruo, Mohit Bhandari, Mark Norman Levine
Journal: Journal of Clinical Oncology (2017)

478 Background: The recommendation to administer extended-duration (28 days) venous thromboembolic events (VTE) prophylaxis with low molecular weight heparin in patients undergoing abdominal and pelvic surgery for cancer has not been widely implemented mainly because most studies focus on asymptomatic events with unknown clinical significance. The objective of this study was to determine the post-hospital discharge VTE incidence in these patients who do not receive post-hospital discharge prophylaxis. Methods: Prospective cohort study of patients undergoing abdominal and pelvic operations for cancer within the gastrointestinal tract, hepatobiliary (HPB) system or gynecological organs, with surgery lasting &gt; 1 hour, post-operative stay &lt; 28 days, and not undergoing anticoagulant therapy. Patients were evaluated at 1, 3 and 6 months from index operation for the presence of VTE by means of a screening ultrasound at 28 days and a questionnaire at each follow-up. The proportion with 95% confidence interval (CI) of VTE was calculated. Multivariable logistical regression was performed. Results: Of 284 patients, there were 79 (28%) colorectal, 97 (35%) HPB and 100 (35%) gynecology. All patients received pre- and post-operative in-patient prophylaxis. The proportion of VTE at 6 months was 7%, 95% CI 4.4-10.7 (20 events). Most events occurred between 3-6 months, 4.6%, 95% CI 2.46 – 7.7. Only one event occurred at one month after surgery (0.35%, 95% CI 0.06-1.97). 50% of the cohort had screening ultrasound, all of which were negative. Events were evenly distributed according to the type of surgery. The proportion of patients who died was 6.6%, 95% CI 3.5 – 9.4 (17 patients, 2 of which had a VTE-related death). In the multivariable analysis, post-operative chemotherapy was significantly associated with VTE, odds ratio (OR) 2.74, 95% CI 1.07-6.99. Caprini score was also associated with VTE but was not significant when included in the multivariable analysis, OR 1.19, 95% CI 0.99-1.42. Conclusions: Incidence of VTE following abdominal cancer surgery is low. Most events occur between 3-6 months from surgery. Post-operative chemotherapy is significantly associated with post-hospital discharge VTE.
Anastrozole in combination with fulvestrant in the first line treatment of hormone receptor positive advanced breast cancer: A meta-analysis.
Authors: Pui San Tan, Benjamin Haaland, Alberto J. Montero, Gilberto Lopes
Journal: Journal of Clinical Oncology (2013)

e11591 Background: Emerging resistance to single agent aromatase inhibitors (AI) or fulvestrant as first line treatment for postmenopausal women with advanced hormonal receptor positive breast cancer calls for alternative therapeutic options. This meta-analysis studies the effectiveness of combination therapy with fulvestrant and an AI, as compared to an AI alone in first line treatment of postmenopausal patients with hormonal receptor positive relapsed or metastatic breast cancer. Methods: Literature search was performed using PubMed, Google Scholar, Embase, ASCO and ESMO to search for studies published during the last 10 years using relevant keywords. Two prospective randomized clinical trials were found to fulfill the search criteria for combination of fulvestrant + AI vs. AI alone (both studied anastrozole in combination with fulvestrant). Meta-estimates were calculated by combining study estimates using the DerSimonian and Laird random effects model. The linear mixed-effects model was used to generate 95% prediction intervals for study-specific hazard and odds ratios. Results: Pooled hazard ratio for progression free survival was 0.88 (95% CI 0.72-1.09, 95% prediction interval [PI] 0.65-1.21). Pooled HR for overall survival was 0.88 (95% CI 0.72-1.08, 95% PI 0.68-1.14). Pooled odds ratio for response rate was 1.13 (95% CI 0.79-1.63, 95% PI 0.78-1.65). Conclusions: Pooled results showed a small, non-statistically significant, improvement in progression-free and overall survival. These results do not support the use of combination therapy with fulvestrant and anastrozole in the first line treatment of postmenopausal patients with hormonal receptor positive relapsed or metastatic breast cancer.
Predictive Accuracy of Serial Transvaginal Cervical Lengths and Quantitative Vaginal Fetal Fibronectin Levels for Spontaneous Preterm Birth Among Nulliparous Women
Authors: M. Sean Esplin, Michal A. Elovitz, Jay D. Iams, Corette B. Parker, Ronald J. Wapner, William A. Grobman, Hyagriv N. Simhan, Deborah A. Wing, David M. Haas, Robert M. Silver, Matthew K. Hoffman, Alan M. Peaceman, Steve N. Caritis, Samuel Parry, Pathik Wadhwa, Tatiana Foroud, Brian M. Mercer, Shannon M. Hunter, George R. Saade, Uma M. Reddy
Journal: JAMA (2017)

<h3>Importance</h3> Spontaneous preterm birth is a leading cause of infant mortality. Prediction, largely based on prior pregnancy outcomes, is not possible in women pregnant for the first time. <h3>Objective</h3> To assess the accuracy of universal screening to predict spontaneous preterm birth in nulliparous women using serial measurements of vaginal fetal fibronectin levels and cervical length. <h3>Design, Settings, and Participants</h3> A prospective observational cohort study of nulliparous women with singleton pregnancies, from 8 clinical sites across the United States between October 2010 and May 2014. Women and clinicians were blinded to results unless cervical shortening less than 15 mm was identified. <h3>Exposures</h3> Transvaginal cervical length and quantitative vaginal fetal fibronectin levels were reviewed at 2 study visits 4 or more weeks apart. <h3>Main Outcomes and Measures</h3> Spontaneous preterm birth at less than 37 weeks was the primary outcome. Cervical length and quantitative fetal fibronectin were considered independently and together at each visit. Measurement distributions were compared for spontaneous preterm birth vs all other births. Spontaneous preterm birth before 32 weeks was a secondary outcome. <h3>Results</h3> The study included 9410 women (median age, 27.0 [interquartile range, 9.0] years; 60.7% non-Hispanic white, 13.8% non-Hispanic black, 16.5% Hispanic, 4.0% Asian, and 5.1% other), of whom 474 (5.0%) had spontaneous preterm births, 335 (3.6%) had medically indicated preterm births, and 8601 (91.4%) had term births. Among women with spontaneous preterm birth, cervical length of 25 mm or less occurred in 35 of 439 (8.0%) at 16 to 22 weeks' gestation and in 94 of 403 (23.3%) at 22 to 30 weeks' gestation. Fetal fibronectin levels of 50 ng/mL or greater at 16 to 22 weeks identified 30 of 410 women (7.3%) with spontaneous preterm birth and 31 of 384 (8.1%) at 22 to 30 weeks. The area under the receiver operating characteristic curve for screening between 22 and 30 weeks for fetal fibronectin level alone was 0.59 (95% CI, 0.56-0.62), for transvaginal cervical length alone was 0.67 (95% CI, 0.64-0.70), and for the combination as continuous variables was 0.67 (95% CI, 0.64-0.70). <h3>Conclusions and Relevance</h3> Among nulliparous women with singleton pregnancies, quantitative vaginal fetal fibronectin and serial transvaginal ultrasound cervical length had low predictive accuracy for spontaneous preterm birth. These findings do not support routine use of these tests in such women.
Impact of nodal metastasis on survival of stage IV colon cancer: Analysis of National Cancer Data Base (NCDB).
Authors: Mohammed Shaik, Alpesh K. Korant, Supriya Kumar Saha, Gregory Johnston, Vikrom K. Dhar, Benjamin Abadeer, David Wiese, Madan L. Arora, Andrew Stewart, Sukamal Saha
Journal: Journal of Clinical Oncology (2013)

3582 Background: Nodal metastasis (mets) is an important prognostic factor in the staging of colon cancer (CCa). However, the significance of nodal mets in stage IV CCa remains undetermined. Therefore, we investigated the impact of nodal mets on 5 year overall survival (5-yr OS) in stage IV CCa. Methods: Patients (pts) from the NCDB who had been diagnosed with histologically confirmed Stage IVCCa from 1998-2010 were divided into two groups: with(+ve) or without(-ve) nodal mets and the 5 yr OS was compared using the Kaplan Meier Curves. Multivariate analysis was performed using CoxProportional regression model. An adjusted hazard ratio(aHR) was calculated for pts with nodal mets compared to those without nodal mets after adjusting for age, grade and tumor size. Results: 70,387 pts from the NCDB with stage IV CCa were included in our analysis. Of these, 12,363(17.5%) had no nodal mets (TN0M1), 23,052(32.7%) had 1-3 nodal mets (TN1M1), and 34,972 (49.69%) had 4 or more nodal mets (TN2M1) involved at the time of diagnosis (Table 1a).The overall nodal positivity was 82.4%. The 5-yrOS of all stage IV pts was 10.7% (Table 1b); 5 yr OS for node -ve pts was 18.4% versus 9.2% for node +ve pts (p&lt;0.0001)(Table1b). The 5 yr OS of N1 and N2 was 12% and 7.2%, respectively. The aHR of pts with nodal mets versus without nodal mets was 1.8 (95% CI of 1.7-1.9), after adjusting other prognostic covariates. Conclusions: Stage IV CCa with nodal mets is associated with an increased risk of death compared to node-negative disease. The number of positive lymph nodes at the time of diagnosis is also an important risk factor. [Table: see text]
Fibroblast-Specific Genetic Manipulation of p38 Mitogen-Activated Protein Kinase In Vivo Reveals Its Central Regulatory Role in Fibrosis
Authors: Jeffery D. Molkentin, Darrian Bugg, Natasha Ghearing, Lisa E. Dorn, Peter Kim, Michelle A. Sargent, Jagadambika Gunaje, Kinya Otsu, Jennifer Davis
Journal: Circulation (2017)

In the heart, acute injury induces a fibrotic healing response that generates collagen-rich scarring that is at first protective but if inappropriately sustained can worsen heart disease. The fibrotic process is initiated by cytokines, neuroendocrine effectors, and mechanical strain that promote resident fibroblast differentiation into contractile and extracellular matrix-producing myofibroblasts. The mitogen-activated protein kinase p38α (Mapk14 gene) is known to influence the cardiac injury response, but its direct role in orchestrating programmed fibroblast differentiation and fibrosis in vivo is unknown.A conditional Mapk14 allele was used to delete the p38α encoding gene specifically in cardiac fibroblasts or myofibroblasts with 2 different tamoxifen-inducible Cre recombinase-expressing gene-targeted mouse lines. Mice were subjected to ischemic injury or chronic neurohumoral stimulation and monitored for survival, cardiac function, and fibrotic remodeling. Antithetically, mice with fibroblast-specific transgenic overexpression of activated mitogen-activated protein kinase kinase 6, a direct inducer of p38, were generated to investigate whether this pathway can directly drive myofibroblast formation and the cardiac fibrotic response.In mice, loss of Mapk14 blocked cardiac fibroblast differentiation into myofibroblasts and ensuing fibrosis in response to ischemic injury or chronic neurohumoral stimulation. A similar inhibition of myofibroblast formation and healing was also observed in a dermal wounding model with deletion of Mapk14. Transgenic mice with fibroblast-specific activation of mitogen-activated protein kinase kinase 6-p38 developed interstitial and perivascular fibrosis in the heart, lung, and kidney as a result of enhanced myofibroblast numbers. Mechanistic experiments show that p38 transduces cytokine and mechanical signals into myofibroblast differentiation through the transcription factor serum response factor and the signaling effector calcineurin.These findings suggest that signals from diverse modes of injury converge on p38α mitogen-activated protein kinase within the fibroblast to program the fibrotic response and myofibroblast formation in vivo, suggesting a novel therapeutic approach with p38 inhibitors for future clinical application.
Should culture affect practice? Prognostic discussions with immigrants.
Authors: Phyllis Noemi Butow, Ming Sze, Maurice Eisenbruch, Melanie Bell, Lynley Aldridge, Janette L. Vardy, Rina Hui, Frances Boyle, Winston S. Liauw, David Goldstein
Journal: Journal of Clinical Oncology (2013)

6556 Background: Poor prognosis is difficult to impart, particularly across a cultural divide. This study is the first to compare prognostic communication with immigrants (with and without interpreters) versus native–born patients in audio-taped oncology consultations. Methods: Ten oncologists, 78 patients (31 Australian-born, 47 immigrants) and 115 family members participated. The first two consultations after diagnosis of incurable disease were audiotaped, transcribed and coded. 142 consultations were included in the analysis. Results: Fifty percent of doctor and 59% of patient prognostic speech units were notinterpreted or interpreted non-equivalently when an interpreter was present. Immigrant status predicted few, and oncologist characteristics no, prognostic facts disclosed. Oncologists were significantly less likely to convey hope to immigrants, and more likely to use medical jargon (p = 0.009) than with Australian-born patients. Incurable disease status and a limited life span were commonly acknowledged, generally with no timeframe provided. Physical issues were discussed more commonly than emotional aspects. Conclusions: While culture did not appear to influence doctor speech, interpreters filtered or blocked much prognostic communication. Initiatives to empower all patients to attain needed information, optimise communication when an interpreter is present and train cancer health professionals in culturally appropriate care, are urgently required.
Clinical Activity of the γ-Secretase Inhibitor PF-03084014 in Adults With Desmoid Tumors (Aggressive Fibromatosis)
Authors: Shivaani Kummar, Geraldine O'Sullivan Coyne, Khanh T. Do, Baris Turkbey, Paul S. Meltzer, Eric Polley, Peter L. Choyke, Robert Meehan, Rasa Vilimas, Yvonne Horneffer, Lamin Juwara, Ann Lih, Amul Choudhary, Sandra A. Mitchell, Lee J. Helman, James H. Doroshow, Alice P. Chen
Journal: Journal of Clinical Oncology (2017)

Purpose Desmoid tumors (aggressive fibromatosis) arise from connective tissue cells or fibroblasts. In general, they are slow growing and do not metastasize; however, locally aggressive desmoid tumors can cause severe morbidity and loss of function. Disease recurrence after surgery and/or radiation and diagnosis of multifocal desmoid tumors highlight the need to develop effective systemic treatments for this disease. In this study, we evaluate objective response rate after therapy with the γ-secretase inhibitor PF-03084014 in patients with recurrent, refractory, progressive desmoid tumors. Patients and Methods Seventeen patients with desmoid tumors received PF-03084014 150 mg orally twice a day in 3-week cycles. Response to treatment was evaluated at cycle 1 and every six cycles, that is, 18 weeks, by RECIST (Response Evaluation Criteria in Solid Tumors) version 1.1. Patient-reported outcomes were measured at baseline and at every restaging visit by using the MD Anderson Symptoms Inventory. Archival tumor and blood samples were genotyped for somatic and germline mutations in APC and CTNNB1. Results Of 17 patients accrued to the study, 15 had mutations in APC or CTNNB1 genes. Sixteen patients (94%) were evaluable for response; five (29%) experienced a confirmed partial response and have been on study for more than 2 years. Another five patients with prolonged stable disease as their best response remain on study. Patient-reported outcomes confirmed clinician reporting that the investigational agent was well tolerated and, in subgroup analyses, participants who demonstrated partial response also experienced clinically meaningful and statistically significant improvements in symptom burden. Conclusion PF-03084014 was well tolerated and demonstrated promising clinical benefit in patients with refractory, progressive desmoid tumors who receive long-term treatment.
Detecting circulating tumor cells (CTCs) in patients with high-risk, localized prostate cancer using the CellSearch platform.
Authors: Sumanta Kumar Pal, Clayton Lau, Miaoling He, Przemyslaw Twardowski, Timothy G. Wilson, Mark H. Kawachi, Alejandra Torres, Courtney Carmichael, Yun Yen, Marcin Kortylewski, Jeremy Jones
Journal: Journal of Clinical Oncology (2012)

e15178 Background: Enumeration of circulating tumor cells (CTCs) using the CellSearch platform has prognostic value in patients with metastatic castration resistant prostate cancer. However, the prognostic value of CTC enumeration in high-risk, localized prostate cancer (HRLPC) remains undefined. Methods: Patients with HRLPC (defined by ≥1 of the following criteria: ≥ cT3a disease, Gleason score 8-10, or PSA &gt; 20 ng/mL) who have chosen prostatectomy for their definitive management were prospectively identified. Patients were consented to receive 4 sequential 30 mL blood draws, each collected in 3 separate 10 mL EDTA tubes. The first 2 blood draws were conducted 2 weeks prior and immediately prior to surgery, while the second 2 blood draws were conducted 4-6 weeks and 3 months following surgery. Within 4 hrs of blood collection, the white blood cell (WBC) fraction was pooled and Ficoll purified. The WBC fraction was transferred to a CellSave tube, and CTCs were enumerated using the CellSearch system. Expression of CD133 and E-cadherin was characterized using the CellSearch system in patients with detectable CTCs. Results: Within 3 monthsof study initiation in Nov 2011, 19 of a planned 37 patients have been accrued. Median age in the cohort was 65 (range, 51-74), and the number of patients with Gleason score 8-10, ≥ cT3a disease, or PSA &gt; 20 ng/mL was 16, 4, and 2, respectively. The majority of patients (17/19, or 89%) had only one high-risk feature. Mean baseline PSA for the cohort was 11.4 (range, 3.4-37). CTCs were detectable in 67% of patients prior to surgery, 27% of patients at 1 month following surgery and 67% of patients at 3 months following surgery. Amongst those patients with detectable CTCs, the median count was 3 (range, 1-7). Further, in these patients, CD133 and E-cadherin were detected in 44% and 46% of specimens assessed, respectively. Full details of these analyses will be provided at the time of the meeting. Conclusions: Using a modified methodology, CTC enumeration using the CellSearch platform is feasible in patients with HRLPC. Interestingly, markers of epithelial-mesenchymal transition and stem cell lineage are detectable in a proportion of patients with localized disease.
Reply to Moreels et al.
Authors: Kei Yane, Akio Katanuma, Hiroyuki Maguchi, Kuniyuki Takahashi, Toshifumi Kin
Journal: Endoscopy (2017)

We appreciate Mouradides et al. for their valuable comments regarding our recent study that described the usefulness of short-type single-balloon enteroscope (short SBE)-assisted endoscopic retrograde cholangiopancreatography (ERCP) and potential factors affecting procedural failure [1]. It is our pleasure to share our opinion regarding their comments and to provide further insight into the role of passive bending in our recently published series.