tbuckley/cabot-search huggingface dataset:
Topotecan plus carboplatin versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabin plus carboplatin (GC) or carboplatin plus pegylated doxorubicin (PLDC): A randomized phase III trial of the NOGGO-AGO-Germany-AGO Austria and GEICO-GCIG intergroup study (HECTOR).
Authors: Jalid Sehouli, Werner Meier, Pauline Wimberger, Radoslav Chekerov, Antje Belau, Sven Mahner, Christian Kurzeder, Felix Hilpert, Peter Klare, Steffen Doerfel, Hans-Georg Strauss, Ulrich Canzler, Christian Marth, Alexander Reinthaller, Edgar Petru, Rolf Richter, Maria Jesus Rubio, Isabel Bover, Antonio Gonzalez-Martin, Philipp Harter
Journal: Journal of Clinical Oncology (2012)

5031 Background: We present the efficacy data from a phase III study of topotecan (T) plus carboplatin (C) versus standard therapy with paclitaxel plus carboplatin (PC) or gemcitabine plus carboplatin (GC) or carboplatin plus pegylated doxorubicin (PLDC). Methods: From 02/07 to 12/09, 590 pts were screened and 550 pts were randomized to either T (0.75mg/m²/d1-3/q21d) + C (AUC 5/d1/q21d) or to standard therapy with CP or GC or PLDC based on patient preference. Progression free survival at 1 year was defined as primary endpoint. Results: Median number of cycles was 6 (range 0-9) in both arms. Most patients preferred GC (78%) in the standard therapy arm.. Best Response (CR+PR) was 73.1% (95%CI) and 75.1% (95%CI) for the CA. Median follow-up was 18 (0-52) months for TC and 20 (0-48) months for standard therapy. TC failed to show any advantage regarding 1-yr.-PFS or OAS. Conclusions: The combination of topotecan plus carboplatin failed to improve PFS or OAS in platinum sensitive relapsed ovarian cancer. In addition, carboplatin plus gemcitabine was well tolerated with lower rates of severe and long-lasting (neuropathy) toxicities compared to paclitaxel-carboplatin. [Table: see text]
Do patients with longstanding IBD have higher cancer risk compared to the general population? Results from the IBSEN study.
Authors: Milada Cvancarova, Oistein Hovde, Magnus Wanderaas, Bjorn Moum
Journal: Journal of Clinical Oncology (2015)

1573 Background: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic relapsing inflammatory bowel diseases (IBDs) that affect the gastrointestinal tract. The incidence and prevalence of IBD have increased worldwide. Involvement of extraintestinal organs is not uncommon; therefore many studies have focused on the risk of organ-specific cancers in IBD patients. In addition to longstanding disease, the presence of primary sclerosing cholangitis, a family history of colorectal cancer (CRC), the degree of inflammation of the bowel, and greater anatomic extension of colitis increase the risk of developing CRC. The aims of the present study were to determine the cancer prevalence in a well-defined population-based cohort of IBD pts 20 years after diagnosis and to compare the risk of cancer development in IBD pts to the general population. Methods: The IBSEN (Inflammatory Bowel South-Eastern Norway) study has prospectively followed all patients diagnosed with IBD from 1990 to 1994, in total 843 IBD pts followed regularly for 20 years. All IBD patients were age-and gender matched with 25 individuals from the general population (controls). Complete data on death and all cancers in the IBD cohort and in the controls were collected from the Norwegian Cancer Registry. Overall risk for cancer and CRC-specific risk was computed using Cox model. Results: In total we have analyzed 843 IBD pts and 20950 controls. There were 117 (14%) cancers in the IBD patients and 2095 (10%) in the controls. Overall, IBD pts had 1.5 times higher risk of cancer development compared to their matched controls (HR = 1.52 (95 % CI (1.26- 1.83) p < 0.001). There was no sex difference in all cancers risk. A total of 19 subjects in the IBD group developed CRC (17) or small bowel cancer (2). Males with IBD had a significantly increased risk of CRC-specific cancer compared to controls (HR = 2.54 (95% CI (1.40-4.63) p = 0.002), however this risk was not significant for women (HR = 1.31, 95%CI (0.58-2.98). Conclusions: Patients who have had IBD for 20 years have about 50 % higher cancer risk compared to the age- and gender matched controls from the general population. Most of this difference is caused by increased risk for bowel cancer in male IBD patients.
IFN-α/IFN-λ responses to respiratory viruses in paediatric asthma
Authors: Simonetta Baraldo, Alberto Papi, Marina Saetta, Marco Contoli
Journal: European Respiratory Journal (2017)

We read with interest the paper by Bergauer et al. [1] on innate immune responses to viral infection in paediatric asthma. The paper confirms previous reports on impaired interferon responses in stable asthma [2–4], but describes a hyperactive interferon production during asthma exacerbations associated with rhinovirus infection. The authors conclude that, despite impaired immune condition at stable state, the ability to upregulate type I interferons during the acute phase is preserved in asthmatic children. However, what is lacking from this study is the information on interferon production during acute rhinovirus infection in an age-matched group of non-asthmatics. Thus, how can it be conclusively excluded that the production of interferon is impaired during the rhinovirus-induced acute phase of asthma in the absence of such a comparative control group? A study which examined nasal washes of children during acute episodes of wheezing or rhinitis, reported lower levels of IFN-λ in children with wheezing than in those with acute rhinitis, even if the differences were not statistically significant [5]. The fact that asthmatic patients, once infected, have more severe manifestations of the infectious diseases [6] could possibly suggest an impaired response also in the acute phase, but conclusive data are lacking. Does impaired interferon production in stable asthma also occur during rhinovirus-induced acute asthma attacks? <http://ow.ly/kgVe309GazS>
Prognostic reclassification of patients with intermediate risk metastatic germ cell tumors (IRGCT): implications for clinical practice, trial design, and molecular interrogation.
Authors: Daniele Raggi, Luigi Mariani, Patrizia Giannatempo, Salvatore Lo Vullo, Daniele Giardiello, Nicola Nicolai, Luigi Piva, Davide Biasoni, Mario Catanzaro, Tullio Torelli, Silvia Stagni, Massimo Maffezzini, Giuseppina Calareso, Elena Verzoni, Paolo Grassi, Giuseppe Procopio, Filippo G. De Braud, Giorgio Pizzocaro, Roberto Salvioni, Andrea Necchi
Journal: Journal of Clinical Oncology (2015)

e15572 Background: About one third of patients with metastatic GCT are classified as IRGCT, and available guidelines recommend the same treatment of poor risk cases. Yet the prognosis of these patients is heterogeneous and consequently refining the intensity of treatment is warranted. We aimed to address the heterogeneity of this category by providing a proof-of-principle for reclassification attempt. Methods: Data on consecutive patients with IRGCT and who received treatment at Fondazione INT Milano in the time-frame 02/1980-03/2014 were collected. Cox regression analyses were done evaluating potential prognostic factors for overall survival (OS, primary endpoint) to first-line therapy. Each factor was evaluated in a multivariable model. Recursive partitioning was performed to define prognostic risk groups. Results: 224 patients were suitable for present analysis. Median age was 26 years (IQR: 22-31), 11 (4.9%) had a retroperitoneal (RP) primary, 6 yielded seminomatous histology. 85 (37.9%) had lung metastases and 58 (25.9%) bulky (i.e. ≥ 10cm) RP lymph-nodes (LN). Patients received cisplatin, bleomycin and etoposide (PEB, n = 199) or vinblastine (PVB, n = 23), 2 other treatments. Median follow up was 135 months (IQR: 81-223). Globally, 5-year progression-free survival (PFS) and OS were 72.8% (95%CI: 67.1-79.0) and 86.2% (81.7-91.0). In the multivariable model for OS, elevated alfa fetoprotein level (AFP) was the only significant prognostic factor (HR: 1.48, 95%CI: 1.12-1.96). Two separate prognostic groups with differential OS outcomes were identified based on the cut-off level of 6,200 IU/ml. Ten-year OS was 55.6% (95%CI: 36.6-84.3) and 86.7% (95%CI: 82.0-91.7) for those with AFP above (n = 19, 8.5%,) and below (n = 205, 91.5%) the cut-off, respectively. Conclusions: A small fraction of patients with highly elevated AFP have an OS approximating the poor prognostic category, while the vast majority are close to good risk cases. This might have implications to select outlier patients for clinical trials and molecular characterization.
Response to crizotinib and cabozantinib in stage IV lung adenocarcinoma patients with mutations that cause <i>MET </i>exon 14 skipping.
Authors: Paul K. Paik, Alexander E. Drilon, Helena Alexandra Yu, Lee M. Krug, Natasha Rekhtman, Laetitia Borsu, Michelle S. Ginsberg, Michael F. Berger, Marc Ladanyi, Charles M. Rudin
Journal: Journal of Clinical Oncology (2015)

8021 Background: Mutations in the MET exon 14 RNA splice acceptor and donor sites, which lead to exon skipping, deletion of the juxtamembrane domain, and loss of Cbl E3-ligase binding to the resultant aberrant MET protein, were previously reported to be oncogenic in preclinical models (Kong-Beltran, Cancer Res 2006). These mutations occur in 4% of lung adenocarcinomas but have not been clinically assessed (TCGA 2014). We now report responses to the MET inhibitors crizotinib and cabozantinib in patients with stage IV lung adenocarcinomas harboring mutations leading to MET exon 14 skipping. Methods: Patients with stage IV lung adenocarcinomas harboring MET exon 14 splice site mutations (N=6) or a mutation deleting Y1003 in exon 14 (N=1) were identified through a clinical assay based on hybrid capture/next-generation sequencing of 341 oncogenes and tumor suppressors (MSK-IMPACT). MET IHC was performed on archival FFPE tissue. RNA skipping was confirmed by NanoString. Radiographic response to MET inhibition was assessed using RECIST 1.1 and PERCIST criteria. Results: Clinicopathologic data for those treated are in the table below. To date, 3 patients have been treated with off-label crizotinib and 1 with cabozantinib (NCT01639508). 3 of 4 patients (75%) developed a PR to treatment. The remaining patient had SD by RECIST, with PET imaging demonstrating a complete PERCIST response. Conclusions: MET exon 14 skipping is a novel oncogenic target that predicts for response to MET inhibitors. This appears to be a substantially better predictor of response than either protein expression or gene amplification. Patients with these splice site mutations should be treated on a clinical trial of a MET inhibitor. For those without access to a trial, use of off-label crizotinib should be considered. ID Age Sex Smoking status (pack years) MET exon 14 variant MET therapy Response MET IHC (H-score) 1 65 M C (20) MET p.V1001_F1007del (c.3001_3021delGTAGACTACCGAGCTACTTTT) crizotinib (3rd line) PR (-31%) NA 2 80 M F (20) MET c.3024_3028delAGAAGGTATATT crizotinib (3rd line) PR (-30%) 300 3 90 F N MET c.3028G>C crizotinib (3rd line) PR (-47%) NA 4 80 F N MET c.3028G>C cabozantinib (3rd line) SD (0%), CR (PERCIST) 300
Ponatinib in Chronic-Phase Chronic Myeloid Leukemia Patients: Final Report from a Phase 1 Trial
Authors: Michael J. Mauro, Jorge E. Cortes, Hagop M. Kantarjian, Neil P. Shah, Dale L. Bixby, Ian W. Flinn, Thomas O'Hare, Victor M. Rivera, Stephanie Lustgarten, Sergio Santillana, Michael C. Heinrich, Brian J. Druker, Michael W. Deininger, Moshe Talpaz
Journal: Blood (2016)
Identification, characterization, and chemotherapy utilization in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) using real-world data: Retrospective U.S. claims database analysis.
Authors: Thomas W. Flaig, Maneesha Mehra, Robert Stellhorn, Yvette Ng, Mary Beth Todd
Journal: Journal of Clinical Oncology (2013)

e17510 Background: Limited data are available characterizing the progression of newly diagnosed PC to mCRPC and the use of different treatments in the mCRPC population. Real world longitudinal pt-level data were used to define, profile, and characterize treatment of pts with mCRPC. Methods: The PharMetrics database (2000-2011), a nationally representative, nonpayer–owned, integrated, commercial US claims database, was used to identify pts with an index PC diagnosis (dx) (ICD-9 codes 185.x or 233.4) and confirmation of ≥ 3 PSA test values in their claim history (n = 7402). An algorithm was developed to identify progression of PC from index dx to mCRPC by 1) evaluating the presence or absence of a secondary malignancy dx (ICD-9 codes 198.5, 199.1, and 198.82) to determine metastatic status, and 2) evaluating PSA increases with concurrent medical/surgical castration to determine castration-resistant status (Alemayehu et al, J Med Econ. 2010;13:351). Results: Mean follow-up duration was 50.7 ± 35.5 (SD) months. 271 pts (3.7%) had PC with metastases (mets) at dx. 2836 (38.3%) had medical/surgical/both castration during follow-up. 779 (11%) pts developed CRPC and 299 (4.0%) were defined as having mCRPC. Median age at PC dx and mCRPC dx was 73.5 and 76.7 years, respectively. Duration from initial PC dx to mCRPC was 28 ± 20.7 (SD) months. Prior to mCRPC dx (&gt; 3 months), &lt; 10% of pts were exposed to chemotherapy. Chemotherapy exposure (docetaxel, vinorelbine, estramustine, mitoxantrone) upon mCRPC dx (±3 mos) was 24%. Any docetaxel exposure after mCRPC dx was 42.8% (excluding pts with dx/follow-up pre-2004 docetaxel approval year). Other treatments in mCRPC pts at dx included opioids (n = 174, 58%) and bisphosphonates (n = 58, 19%). Conclusions: This effort identifies a methodology of using a retrospective US claims database to identify mCRPC, which accounts for less than 5% of pts with PC. 24% of pts presented with mets at initial PC dx while 76% developed mets over time. The moderate rate of opioid use and incomplete penetration of chemotherapy in mCRPC emphasizes the need for improved treatment alternatives.
Differences in comorbidity at diagnosis and receipt of adjuvant chemotherapy among older women by race and ethnicity.
Authors: Gregory Sampang Calip, Ernest Law, Wan-Ju Lee, Stephen Schwartz, Naomi Ko
Journal: Journal of Clinical Oncology (2015)

e17599 Background: Differences in comorbidity at diagnosis and utilization of appropriate adjuvant breast cancer treatments could potentially contribute to disparities in breast cancer outcomes between racial and ethnic groups. We investigated the influences of race/ethnicity and comorbidity on receipt of adjuvant chemotherapy. Among women treated with chemotherapy, we described how chemotherapy regimens varied by these factors. Methods: We identified women ages 65-74 years diagnosed with incident, stage II or III, operable lymph node-positive breast cancer from the Surveillance, Epidemiology and End Results-Medicare linked database between 2001 and 2009. Comparing Black, Asian/Pacific Islander (API) and Hispanic women to Non-Hispanic White (NHW) women, multivariable logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for receiving adjuvant chemotherapy and specific regimens. Results: Among 6,002 NHW, 865 Black, 296 API and 469 Hispanic women, 45% received adjuvant chemotherapy. Black and Hispanic women had higher Charlson comorbidity scores (2+) at diagnosis. In multivariable models adjusting for breast cancer characteristics and Charlson score, Black (OR = 0.57; 95% CI 0.48-0.66) and Hispanic (OR = 0.72; 0.58-0.88) women were less likely be treated with chemotherapy compared to NHW women, whereas API women were similar (OR = 0.83; 0.65-1.06). Among women that received chemotherapy, Black women (OR = 0.70; 0.52-0.94) were less likely to be treated with taxanes; Hispanic women (OR = 0.60; 0.38-0.95) were less likely to be treated with anthracyclines. Black and Hispanic women were also less likely to receive granulocyte colony-stimulating factors with chemotherapy (OR = 0.78; 0.61-0.99; and OR = 0.59; 0.41-0.84 respectively). Conclusions: Treatment with adjuvant chemotherapy for lymph node-positive breast cancer differs by race/ethnicity and these differences persist after accounting for other breast cancer characteristics and comorbidity. Further research on patient preferences and factors that support treatment decision-making within these groups may help in addressing breast cancer health disparities.
The willingness of Chinese cancer patients toward participating in medical decision-making.
Authors: Yu Jiang, Jie Zhang, Yang Dan
Journal: Journal of Clinical Oncology (2014)

e20575 Background: Due to the influence of Confucianism, medical decision-making in China is complicated. In addition to doctors, family members usually play an important role in the process of decision-making. The purpose of this study is to explore the willingness and actual extent of involvement of cancer patient in the decision-making process. Methods: Questionnaires were administrated to 247 cancer patients. All participants had been informed of the cancer diagnosis, at least 18 years old, and were able to read and understand the questionnaires. Results: The effective response rate was 72.9% (180 out of 247). Over half of patients were willing to take part in the process of medical decision-making. Only seven patients (3.9%) preferred to make decision themselves. More than one third patients (36.1%) thought that doctors, patients and family members should discuss together to make the final decision. As for whose opinion should be consider first, 17 patients (9.4%) preferred to their own opinions, 153 patients (85.0%) preferred to doctors’ opinions, while 10 patients (5.6%) preferred to family members’ opinions. Actually, only 35.0% of patients involved in the process of medical decision-making. Three patients (1.7%) made the decision by themselves alone. Seventy-eight (43.3%) medical decisions were made solely by their doctors. Thirty-seven final decisions (20.6%) were made by doctors, patients, and family members together. The proportion of patients participating into the actual decision-making process is lower than their expectation (p = 0.001). Conclusions: Although more than half of Chinese cancer patients wanted to take part in medical decision-making, only one third of them actually involved in this process.
Phase 1/1b study of the FAK inhibitor defactinib (VS-6063) in combination with weekly paclitaxel for advanced ovarian cancer.
Authors: Manish R. Patel, Jeffrey R. Infante, Kathleen N. Moore, Mitchell Keegan, Anne Poli, Mahesh Padval, Suzanne Fields Jones, Joanna Horobin, Howard A. Burris
Journal: Journal of Clinical Oncology (2014)

5521 Background: Defactinib (VS-6063) is an oral inhibitor of focal adhesion kinase (FAK). Blockade of FAK has been shown to reduce tumor growth and metastasis through inhibition of tumor cell survival, proliferation, invasion and tumor angiogenesis. FAK inhibitors also reduce the proportion of cancer stem cells (CSCs) while paclitaxel (PTX) treatment enriches for CSCs. This multicenter study investigated the safety/tolerability and activity of defactinib in combination with weekly PTX. Methods: Pts with advanced or refractory ovarian cancer were enrolled. In the Phase 1, defactinib was administered at either 200mg or 400mg BID with PTX 80 mg/m2 on days 1, 8, and 15, every 28 days. In the Phase 1b, an additional 12 pts were enrolled at a dose of 400 mg BID defactinib with 80 mg/m2 PTX. In pts with biopsiable disease, paired tumor biopsies were collected following a 10-day run-in with defactinib alone. Results: Eighteen pts were enrolled (6 in phase I and 12 in phase Ib): median age was 67.5 years (50-77); ECOG PS was 0 or 1. Pts received a median of 3 (1-9) prior regimens of therapy. All patients had prior taxane exposure and 15/18 (83%) were platinum resistant. The combination therapy was well tolerated with no DLT observed. The recommended dose was determined to be defactinib 400 mg BID with PTX 80 mg/m2. Reported treatment related grade 3 toxicities included: neutropenia (n=5), hyperbilirubinemia (3), thrombocytopenia (1), anemia (1), leukopenia (1), nausea (1), vomiting (1), increased alanine aminotransferase (1). No grade 4/5 drug related toxicities were observed. Defactinib did not alter PTX exposure. A decrease of p-FAK was observed in all 3 patients who underwent paired biopsies. One pt had a CR by RECIST, 1 pt has an ongoing PR of >6 months and 1 pt has ongoing SD of >8 months. Nine of the 18 pts remain on study. Conclusions: Defactinib was generally well tolerated in combination with weekly PTX, and further analysis of PD and biomarkers is ongoing. Radiographic tumor changes, normalization of serum markers, and tumor reductions in pFAK support further development of this combination. Clinical trial information: NCT01778803.
Suppression of apoptosis by BRAF inhibitors through off-target inhibition of JNK signaling.
Authors: Kenneth Yee Tsai, Harina Vin, Marco Leung, Vida Chitsazzadeh, Sandra Ojeda, David Dwyer, Kristen Richards, Larissa Stewart, Jonathan Curry, Kevin B. Kim, Ana Ciurea, Madeleine Duvic, Victor Prieto, Stephen Ullrich, Elsa Flores
Journal: Journal of Clinical Oncology (2012)

8537 Background: The advent of targeted therapy has revolutionized the treatment of cancer. The mutant BRAF V600E protein is found in over 50% of melanomas and thyroid carcinomas, resulting in elevated kinase activity, increased mitogen-activated protein kinase (MAPK) pathway signaling, and cell proliferation. Vemurafenib and PLX4720 were designed to selectively inhibit the BRAF kinase, and clinical trials of vemurafenib in metastatic melanoma have demonstrated a response rate of over 50% and an overall survival advantage over standard dacarbazine therapy. Approximately 20-30% of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma (cSCC) highlighting the importance of understanding toxicities associated with this drug. Paradoxical ERK activation in BRAF wild-type, RAS-mutant cells is thought to be the major mechanism by which this occurs, as evidenced by the presence of RAS mutations in 60% of such lesions. Methods: Using a combination of BRAF-wild-type cSCC cell lines, primary human keratinocytes, as well as a UV mouse model of cSCC and human cSCC samples, we identified novel effects of BRAFi on apoptosis. Results: Here we show an unexpected and novel effect of vemurafenib and PLX4720 in suppressing apoptosis through the inhibition of multiple off-target kinases. JNK signaling and apoptosis are suppressed in cSCC lesions arising in vemurafenib-treated patients as well as in irradiated mouse skin. This occurs independently of paradoxical ERK signaling and in the presence of MEK inhibitor. Treatment with PLX4720 greatly accelerates the development of UV-induced cSCC in mice without Ras mutations. Kinome screening identified ZAK and MKK4 (MEK4 / MAP2K4) kinases as inhibited by vemurafenib, leading to suppression of MKK4 and MKK7 (MAP2K7) phosphorylation. Knockdown of inhibited off-target kinases recapitulates these anti-apoptotic effects of vemurafenib. Conclusions: Our results implicate suppression of JNK signaling, independent of ERK activation, as an additional, complementary mechanism of adverse effects of vemurafenib. This has broad implications for combination therapies with other modalities that induce apoptosis and for the long-term use of vemurafenib in the adjuvant setting.