tbuckley/cabot-search huggingface dataset:
Detecting <i>NTRK</i>, <i>ROS1,</i> and <i>ALK</i> gene fusions in gastrointestinal tumor patients.
Authors: Steven James Potts, Emma Jane Dean, Jonathan Polikoff, Simon Pacey, E. Gabriela Chiorean, Cheng Ean Chee, Darren Sigal, Maria Aslam, Patrick Pauwels, Jason H. Christiansen, Pratik S. Multani, Jennifer Lamoureux, Danielle Murphy
Journal: Journal of Clinical Oncology (2017)

619 Background: The STARTRK-2 trial is a potentially registration-enabling Phase 2 global basket trial of the tyrosine kinase inhibitor entrectinib in patients with solid tumors harboring NTRK1, NTRK2, NTRK3, ROS1, or ALK gene fusions. Phase 1 studies of entrectinib reported a 79% ORR across multiple histologies in patients with gene fusions of these targets who were naïve to inhibitors of these targets, received an effective dose, and had extracranial disease. Patients harboring these fusions are typically rare in the cancer population ( &lt; 3%); however, they have been seen across a wide variety of GI tumors. In this presentation we report on the occurrence of these fusions in GI tumors, based on Ignyta’s internal and partner testing. We discuss the development of an assay for GI samples and immunohistochemistry (IHC) screening efficiency rates in a clinical cohort of 157 GI samples. Methods: The occurrence of NTRK, ROS1, and ALK gene fusions in GI tumors was studied from Ignyta internal and partner collaborations. We developed a 2-step diagnostic test to identify fusions in FFPE clinical specimens. IHC screening using a pan-receptor tyrosine kinase cocktail of antibodies precedes an RNA-based anchored multiplex PCR next generation sequencing (NGS) assay. Results: IHC positivity rates ranged from 0 to 24 percent depending on histology and averaging 8% positivity rate across 15 tumor locations. The screen is particularly effective in cholangiocarcinoma, colon, esophagus, gastric, peritoneum, rectum and small bowel. It was highest in pancreas (24%). Out of 157 GI samples, no instances were detected where the IHC was screened negative and gene fusions were observed by NGS. The IHC cocktail enriches detection of the patient population for gene fusions over 11-fold and has a 100% negative predictive value. Conclusions: This 2-step assay is an efficient method for detection of gene rearrangements in both high-volume clinical testing and studies of archival formalin-fixed paraffin-embedded specimens. Depending on how it is implemented in clinical trials, the staged approach can substantially decrease the costs and tissue expended for NGS. Screening efficiency may be improved even further as additional diagnostic antibodies become available. Clinical trial information: NCT02568267.
Just over half of doctors declare fees from drug companies
Authors: Ingrid Torjesen
Journal: BMJ (2017)

Only around half of doctors and other healthcare professionals are putting their names to payments and benefits they receive from drug companies in the register managed by the industry’s trade association—far fewer than previously claimed.

A new analysis of data submitted to the Association of the British Pharmaceutical Industry’s Disclosure UK database (www.disclosureuk.org.uk) has found that just 55% of doctors and other healthcare professionals are allowing their names to appear alongside the fees and expenses they receive from drug companies, not the 70% that was claimed in June 2016 when the scheme launched.1

The database lists details of the fees and benefits in kind paid by the industry to doctors, pharmacists, nurses, and healthcare organisations. Only those that consent to be identified are named, and the remainder of the information is published in aggregate form.

Mike Thompson, chief executive officer …
Effectiveness trial of a community-based supervised exercise program in cancer survivors.
Authors: Prue Cormie, Robert Usher Newton, Lani Valentine, Sandy McKiernan, Nigel Spry, David John Joseph, Dennis R Taaffe, Daniel Abido Galvao
Journal: Journal of Clinical Oncology (2014)

9533 Background: The majority of cancer survivors (50-90%) do not participate in sufficient exercise and there is a paucity of research investigating the effectiveness of ‘real life’ exercise interventions. The aim of this trial was to determine if a supervised exercise program administered as it would be in a standard survivorship care setting improves patient outcomes. Methods: 430 survivors (301 female, 129 male; 61 ± 12 years; BMI: 27 ± 5) within 2 years of a cancer diagnosis participated in this investigation. Participants had been diagnosed with one of 40 different types of cancer, predominately breast – 41%, prostate – 13%, bowel – 10% & lymphomas – 8%. Between 2011-2013 participants self-enrolled in a 3-month community-based exercise program involving aerobic and resistance exercise supervised by accredited exercise physiologists across 12 fitness centres in Western Australia. Assessments were conducted at baseline, post-intervention and 6-months follow-up. Results: 306 participants (71%) completed the program attending an average 18 ± 5 out of a possible 24 sessions. No adverse events occurred during the exercise sessions. Significant (p ≤ 0.05) improvements were observed post-intervention in diastolic blood pressure (3%, -2.1 ± 9.9 mmHg), waist circumference (1%, -0.8 ± 4.6 cm), physical function (400m walk 6%, -15 ± 40 s; repeated chair rise 18%, -2.2 ± 2.5 s; strength 23%, 18 ± 19 kg [n=135]; balance 6%, 4 ± 8 [n=140]), quality of life (all domains of the SF-36 3-10%, 1.4-4.3 ± 5.5-8.7 NBS), fatigue (18%, -2.6 ± 8.1 FACIT-F) and psychological distress (13%, -1.1 ± 5.2 BSI-18). 57% of eligible participants completed the 6-month follow-up (questionnaires only). Significant improvements in all domains of quality of life (4-12%, 1.5-5.1 ± 6.4-10.4 NBS) and fatigue (30%, -4.7 ± 8.9) remained with a borderline improvement in psychological distress (11%, -1.0 ± 6.6 p = 0.053). The estimated monthly medical expenditure (SF-6D utility index) for participants was reduced significantly at post (12%, -$44 ± 114) and follow-up (14%, -$54 ± 139). Conclusions: A community-based exercise program of just 3 months in duration resulted in significant and sustained improvements in the physical, mental and social wellbeing of cancer survivors.
Staging for Intrahepatic Cholangiocarcinoma
Authors: Koji Tomiyama, Roberto Hernandez-Alejandro, David C. Linehan
Journal: JAMA Surgery (2017)

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Association of epithelial-mesenchymal transition with lapatinib resistance through multipe pathways activation in HER2-positive breast cancer.
Authors: Junjun Liu, Xiaosong Chen, Yan Mao, Qing Qu, Kunwei Shen
Journal: Journal of Clinical Oncology (2014)

e11579 Background: Lapatinib, an anti-HER2 kinase inhibitor, has improved clinical outcome for women with HER2 positive breast cancer. However, acquired resistance to lapatinib remains an important reason influencing its clinical efficacy. The epithelial-mesenchymal transition (EMT) is a key development program that is often associated with cancer progression and drug resistance. We wished to determine the relation of EMT and lapatinib resistance and define drug alternative that confer lapatinib-resistant cell proliferation through reversing EMT. Methods: Two HER2 positive breast cancer cell lines, SKBR3 and BT474 were continuously exposed to increasing doses of lapatinib to establish two stable cell lines resistant to lapatinib, SKBR3-R and BT474-R. Cell proliferation was determined by CCK8 assay and colony formation assay. Protein expression was determined by western-blotting. Invasion ability was analyzed by transwell assay. FITC staining flow cytometry (FCM) was conducted to observe the percentage of apoptosis. Results: Both two HER2 positive lapatinib resistant cell lines, SKBR3-R and BT474-R showed EMT phenomenon with E-cadherin down-regulated and snail,vimentin up-regulated. SKBR3-R and BT474-R had stronger capability of invasion. Moreover, BT474 lapatinib sensitive cell showed less sensitive to lapatinib after being induced EMT by cocultured with TGF-β. Also, EMT phenomenon of resistant and TGF-β induced cells was accompanied by NF-kB, MAPK, and Src pathways activation. NF-kB inhibitor bortezomib, ERK inhibitor U0126, Src inhibitor saracatinib all inhibited lapatinib-resistant cells' proliferation, induced apoptosis and partly reversed EMT phenomenon by blocking related pathways activation. Conclusions: Our data suggested that EMT was associated with the mechanism of lapatinib acquired resistance, which was accompanied by activating of NF-kB, MAPK, and Src pathways. Inhibiting these pathways could reverse EMT and induce cell apoptosis in lapatinib- resistant cells, serving as novel therapeutic ways for lapatinib-resistant breast cancer patients.
Phase I study to evaluate toxicity and feasibility of intratumoral injection of alpha-gal glycolipids in patients with advanced melanoma.
Authors: Mark R. Albertini, Erik Ranheim, Cindy Zuleger, Paul M. Sondel, Jacquelyn A Hank, Alan Bridges, Michael Newton, Thomas McFarland, Jennifer Collins, Erin Clements, MaryBeth Henry, Heather B. Neuman, Sharon M. Weber, Giles Francis Whalen, Uri Galili
Journal: Journal of Clinical Oncology (2014)

3088 Background: Effective uptake of tumor cells by antigen-presenting cells is achieved pre-clinically by labeling them with α-gal glycolipids (α-gal) that bind the natural anti-Gal antibody. We aimed to evaluate toxicity and feasibility of intratumoral injections of α-gal as an autologous tumor vaccine in advanced melanoma patients (pts). Methods: Pts with unresectable metastatic melanoma, at least one readily resectable cutaneous, subcutaneous, or palpable lymph node metastasis, and serum anti-Gal titer ≥ 1:50 were eligible for treatment with 2 intratumoral injections of α-gal given 4 weeks apart on a 3x3 dose escalation schedule (Level I: 0.1 mg/injection; Level II: 1.0 mg/injection; Level III: 10 mg/injection). Monitoring included blood for clinical, autoimmune, and immunological analyses and core tumor biopsies. Overall treatment response was determined 8 weeks after the first α-gal injection. Results: Nine pts received 2 intratumoral injections of α-gal (3 pts/dose level). Vaccine site toxicity was mild, and no systemic toxicity could be attributed to the vaccine. Dose-limiting toxicity was not seen. There was no clinical autoimmunity and no induction of pathologic autoantibodies. Two pts (Level I (1 pt) and Level II (1 pt)) had stable disease by RECIST lasting 8 and 7 months, respectively. All other pts had progressive disease. Tumor nodule biopsies revealed minimal to no change in inflammatory infiltrate between pre and post-treatment biopsies with the exception of 1 pt in dose level III with a post-treatment inflammatory infiltrate. Pretreatment biopsies showed focal tumor cell necrosis in 2 of 9 pts. Two and 4 weeks post injection, target nodules (5 of 9 pts) exhibited tumor cell necrosis without neutrophilic or lymphocytic inflammatory response. Non-target tumor nodules (2 of 4 pts) showed necrosis, which was diffuse in 1 pt. Conclusions: Repeated intratumoral injections of α-gal are well tolerated, and tumor necrosis was seen in some melanoma pts after tumor injection with α-gal. If intratumoral injections of α-gal glycolipids can induce anti-melanoma immunity, subsequent investigation in combination with immune checkpoint inhibitors could be informative. Clinical trial information: nct00668382.
Phase II MMRC trial of extended treatment with carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (DEX) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM).
Authors: Todd M. Zimmerman, Kent A. Griffith, Jagoda Jasielec, Cara Ann Rosenbaum, Kathryn McDonnell, Jessica Waite-Marin, Jesus G. Berdeja, Noopur S. Raje, Donna Ellen Reece, Ravi Vij, Mattina Alonge, Shaun Rosebeck, Sandeep Gurbuxani, Malek Faham, Katherine A Kong, Joan Levy, Andrzej J. Jakubowiak
Journal: Journal of Clinical Oncology (2015)

8510 Background: In a phase I/II study of combination treatment with CFZ, LEN, and DEX (KRd) without ASCT, KRd provided a high rate of sCR (55%) in NDMM patients (pts) and 3-year progression-free survival and OS rates of 79% and 96% (Jakubowiak et al. Blood 2012;120:1801-9; Jasielec et al. Blood 2013;122:3220). To further improve response and outcomes, we designed a phase II study to assess activity of extended treatment with KRd and ASCT. Methods: Pts received 28-day (d) cycles of CFZ 20/36 mg/m2IV (d1, 2, 8, 9, 15, 16), LEN 25mg PO (d1–21), and DEX 40/20 mg PO wkly (cycles1–4 induction/5–8 consolidation) with ASCT after cycle 4. For cycles 8–18, KRd was given with a modified CFZ schedule (d1, 2, 15, 16) and then LEN alone after cycle 18. Response was assessed by IMWG plus nCR. The primary endpoint is the rate of stringent complete response (sCR) at the end of cycle 8, with statistical hypothesis that the improvement of sCR from 30% (KRd without ASCT) to >50% will represent added benefit of ASCT. Results: As of December 31, 2014 the study accrual goal of 53 pts has been met; median age 62 yr (range 40-76), ISS stage II/III 53%, high-risk cytogenetics 27%, as per IMWG. To date, 49 pts completed induction, 41 transplant, 23 consolidation, and 7 have completed 18 cycles of KRd. A median 9.79x106/kg CD34+ cells were collected (range 3.89-16.79). Response improved with each phase of treatment (Table). At the end of 8 cycles, 15/17 evaluable pts (88%) were MRD-negative. After a median follow-up of 9.7 months (range 1.6-23), all pts were alive and 52 of 53 progression free. KRd was well tolerated during induction with no new or unexpected events. After ASCT, KRd-related AEs were mostly Grade (G) 1/; the, most common G3/4 AEs were lymphopenia (50%), leukopenia (14%), and neutropenia (21%). Conclusions: KRd with ASCT for NDMM resulted in higher sCR rates than KRd without ASCT and high rate of MRD-negative disease, suggestive of benefit of adding ASCT to KRd treatment. The results to date compare favorably to any prior treatment of NDMM. Clinical trial information: NCT01816971. Post-Induction Post-Transplant Post-Consolidation Post-KRd ≥ PR % 98 100 100 100 ≥ VGPR % 78 97 100 100 ≥ nCR % 14 44 91 100 sCR % 10 25 70 86
Attractiveness biases are the tip of the iceberg in biological markets
Authors: Pat Barclay
Journal: Behavioral and Brain Sciences (2017)

Abstract Physical attractiveness affects how one gets treated, but it is just a single component of one's overall “market value.” One's treatment depends on other markers of market value, including social status, competence, warmth, and any other cues of one's ability or willingness to confer benefits on partners. To completely understand biased treatment, we must also incorporate these other factors.
Effect of sex on treatment outcomes in rectal cancer patients after neoadjuvant radiotherapy or chemoradiation: A combined analysis of Polish-1 and Polish-2 studies.
Authors: Lucjan Wyrwicz, Mateusz Spalek, Wojciech Michalski, Jacek Krynski, Wojciech Polkowski, Andrzej Rutkowski
Journal: Journal of Clinical Oncology (2017)

656 Background: Two independent studies have previously reported the equivalence of short-course radiotherapy (SCRT) and chemoradiation (CRT) in stage II/III rectal cancer patients (Bujko 2006 – Polish-1, Ngan 2012). Recently, in tumors with resection margin at risk (cT4 and fixed cT3), SCRT and chemotherapy when compared with CRT was associated with similar R0 resection rates, but improved overall survival (OS; Polish-2 study; Bujko 2016). The differences in pelvis anatomy and access to surgical field provide the rational for analysis of patients’ sex on treatment outcomes in locally advanced rectal cancers. Methods: We performed individual patients data analysis of Polish-1 (n = 312) and Polish-2 (n = 515) cohorts. The male-to-female ratio was similar in both studies (Polish-1: 65.1%; Polish-2: 65.8%). No major differences in treatment allocation, toxicities, complience to study procedures between males and females were observed. Results: In the combined cohort the prognostic effect of sex on survival was observed (74.5% female and 66.9% of male patients alive at the cut-off time; HR 0.72; p = 0.018). No differences in post-operative mortality were observed with 3-4% of patients dying in 6 months from randomization in each analyzed stratum. When analyzing the treatment outcomes by sex, male patients benefited more from SCRT than CRT. This effect was observed in more advanced tumors from Polish-2 (HR 0.65; 95% CI 0.45-0.95; p = 0.026), while it did not reached the significance in Polish-1 (HR 0.67; 95% CI 0.34-1.33). Conclusions: This individual patients data analysis indicates that female patients with locally advanced rectal has better prognosis than males. This observation is valid either for SCRT or CRT. In the future, rectal cancer studies should be stratified for sex in order to minimize the risk of bias. Although it should be confirmed by other studies, it is very likely that efficancy of SCRT is higher in male patients. Clinical trial information: NCT00833131.
Targeting AXL for the treatment of pancreatic cancer.
Authors: Kathleen Ludwig, Rolf A. Brekken
Journal: Journal of Clinical Oncology (2015)

e15276 Background: Pancreatic cancer is a highly aggressive and deadly disease. Local invasion and metastasis contribute significantly to the poor survival of patients with pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that expression of the receptor tyrosine kinase (RTK) AXL contributes to tumor cell invasion and metastasis. The ligand for AXL is Gas6 (Growth arrest-specific protein) promotes cell proliferation, survival and migration through activation of the PI-3K/AKT/S6K and ERK/MAPK pathways. Preliminary data has shown that targeting the AXL pathway offers a potential therapeutic approach to inhibit PDAC growth Methods: Multiple strategies to inhibit AXL activity were evaluated including direct inhibition with BGB 324, a first in class oral receptor tyrosine inhibitor, and inhibition of its Gas6, a vitamin K-dependent protein, with oral warfarin. In-vitro analysis of basal AXL and Gas6 expression in multiple pancreatic cell lines were determined by flow cytometry and PCR. The efficacy of AXL inhibition with BGB 324 or warfarin was measured by evaluating AXL-dependent tumor cell migration, invasiveness and proliferation. In-vivo efficacy of AXL inhibition by BGB 324 or warfarin was evaluated in multiple murine models including genetic, syngenic and xenograft mouse models Results: Here we document that inhibiting Gas6-mediated Axl activation with low dose warfarin blocks pancreatic cancer progression and spread. Warfarin and other Axl-targeting agents inhibit tumor progression and block spontaneous metastasis in multiple murine models of pancreatic cancer. Warfarin and BGB324 inhibited AXL-dependent tumor cell migration, invasiveness and proliferation while increasing apoptosis and sensitivity to chemotherapy. Conclusions: We demonstrate that AXL signaling is necessary for pancreatic tumor cell epithelial plasticity, which is potently reversed by warfarin or selective AXL inhibition in vitro and in vivo. We anticipate Axl is a critical driver of pancreatic cancer progression and its inhibition with low dose warfarin or Axl-selective targeting agents may significantly improve outcome in patients.
A randomized trial of prophylactic cranial irradiation versus observation in patients with fully resected stage IIIA N2 non-small cell lung cancer and high risk of cerebral metastases after adjuvant chemotherapy.
Authors: Si-Yu Wang, Ning Li, Wei Ou, Xiong Ye, Bin-Bin Zhang, Hua Yang, Hai-Bo Sun, Qin Fang, Song-Liang Zhang
Journal: Journal of Clinical Oncology (2014)

7508 Background: Prophylactic cranial irradiation (PCI) significantly decreases the incidence of brain metastases in patients with non-small cell lung cancer (NSCLC), but its impact on survival is uncertain. Previously, we built a mathematical model to predict the risk of developing cerebral metastases in patients with locally advanced NSCLC. The purpose of this study is to evaluate if PCI improves survival in patients with resected stage IIIA N2 NSCLC and high risk of cerebral metastases after adjuvant chemotherapy. Methods: In this open-label, randomized trial, patients with fully resected stage IIIA N2 NSCLC and high cerebral metastases risk without recurrence after postoperative adjuvant chemotherapy were randomly assigned to receive PCI (30 Gy in 10 fractions) or observation. The primary end point was disease-free survival (DFS). The secondary end points included the incidence of brain metastases, overall survival (OS) and toxicity. Results: From January 2005 to January 2009, 156 eligible patients were randomized (81 in PCI group and 75 in control group). This study was terminated early as a result of slow accrual. The PCI group had significantly lengthened DFS compared with the control group, with a median DFS of 28.5 months versus 21.2 months (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.46-0.98; P=0.037). The 3-year and 5-year DFS were respectively 42.0% and 26.1% with PCI, and 29.8% and 18.5% with observation. PCI was associated with a decrease in risk of brain metastases (5-year brain relapse rate, 13.6% vs 41.3%; odds ratio, 0.223; 95% CI, 0.102-0.489; P<0.001). The median OS was 31.2 months in the PCI group and 27.4 months in the control group (HR, 0.81; 95% CI, 0.56-1.16; P=0.310). The 3-year and 5-year OS were respectively 44.5% and 27.4% with PCI, and 38.7% and 22.8% with observation. While main toxicities were headache, nausea/vomiting and fatigue in the PCI group, they were generally mild. Conclusions: In patients with fully resected stage IIIA N2 NSCLC and high risk of cerebral metastases after adjuvant chemotherapy, PCI prolongs DFS and decreases the incidence of brain metastases.