tbuckley/cabot-search huggingface dataset:
Essential experimental steps and estimates of renal carcinoma initiating cells.
Authors: Craig Gedye, Danylo Sirskyj, Nazleen Carol Lobo, Ella Hyatt, Andrew Evans, Antonio Finelli, Neil Eric Fleshner, Robert James Hamilton, Girish S. Kulkarni, Michael Robinette, Alexandre Zlotta, Michael A.S. Jewett, Laurie Ailles
Journal: Journal of Clinical Oncology (2014)

11127 Background: Rare cancer stem cells (CSC), proposed to be solely responsible for tumor propagation and re-initiation, are functionally identified as tumor-initiating cells (TIC) from ex vivo tumors using xenotransplantation and clonogenic limiting dilution assays (LDA). TIC have not previously been described from ex vivohuman clear cell renal cell carcinoma (ccRCC). Methods: Primary human ccRCC samples (n=120) from patients undergoing nephrectomy were processed and implanted as subcapsular fragments or cell suspension injection LDAs with Matrigel in NOD/SCID/IL2Rγ -/- (NSG) mice, and observed for at least 6 months. In vitro clonogenic LDAs assays were performed from primary cell suspensions and ccRCC cell lines. LDAs were supplemented with human stromal cells and proteins, and the Y-26732 ROCK inhibitor. Multiparametric flow cytometry and immunofluorescence were used to investigate tumor heterogeneity and cell viability. Results: ccRCC TIC appeared rare from injected suspensions, but xenografts engrafted frequently from tiny fragments, and clonogenic frequencies were 10 3 -10 4 greater than TIC frequencies, suggesting that LDAs underestimated ccRCC tumor cell potential. We systematically identified multiple methodological steps that distort quantitation and identification of ccRCC TIC. For example cell viability was highly variable prior to processing, disaggregation itself destroyed up to 99% of tumor cells, standard assays substantially overestimated tumor cell viability in suspensions, and supplementation with human extracellular cells or proteins, or inhibition of anoikis by Y-26732 increased clonogenic and TIC frequencies in cell lines and primary ccRCC suspensions. Annexin-V staining revealed that tumor cells were more apoptotic then normal stromal cells, and that tumor cells positive for CD44 (a putative CSC marker) were more viable than CD44- tumor cells. Conclusions: We describe multiple, unappreciated and largely unavoidable observational errors in essential methods used to study TIC in ccRCC. ccRCC TIC may be more common than appreciated. Re-examination of the CSC hypothesis in other solid tumors is warranted in view of these previously unexplored methodological biases.
Panitumumab and pegylated liposomal doxorubicin in platinum-resistant epithelial ovarian cancer with KRAS wild-type: The PaLiDo study, a phase II nonrandomized multicenter study.
Authors: Karina Dahl Steffensen, Marianne Waldstrøm, Niels Pallisgaard, Bente Lund, Kjell Bergfeldt, Jessica Wihl, Nina Keldsen, Christian Marth, Ignace B. Vergote, Anders Kristian Moeller Jakobsen
Journal: Journal of Clinical Oncology (2012)

5052 Background: Ovarian cancer (OC) patients with platinum-resistant recurrent disease have few therapeutic options and the response rates are only 10-20% using non-cross-resistant chemotherapeutic agents. The increasing number of negative trials for OC treatment has prompted an evaluation of new biologic agents, which in combination with chemotherapy may result in improvement in survival. Panitumumab is a fully human monoclonal antibody specific to the epidermal growth factor receptor (EGFR). No previous studies have evaluated the effect of panitumumab in OC based on KRAS mutation status. The main purpose was to investigate the response rate in platinum-resistant, KRAS wild-type OC patients treated with pegylated liposomal doxorubicin (PLD) supplemented with panitumumab. Methods: Major eligibility criteria were confirmed stage I-IV primary epithelial ovarian/fallopian/peritoneal cancer patients with progression either during or within 6 months after end of first or second line platinum-based chemotherapy. Only patients with measurable disease by CA125 criteria and with KRAS wild type were eligible. Patients were treated with panitumumab 6 mg/kg day 1 and day 15 and with PLD 40 mg/m² day 1, every 4 weeks. Tumor assessment was performed at baseline and at every third cycle according to CA-125 criteria. Results: A total of 46 patients were enrolled by 6 study sites in this multi-institutional phase II trial. Within the population evaluable for response (N=33), there was 8 CA125 responders for an overall response rate of 24.3 %. Progression-free and overall survival in the intention-to-treat population (N=43) was 2.7 months (2.5-3.2 months, 95%CI) and 8.1 months (5.6-11.7 months, 95%CI), respectively. The most common treatment related grade 3 toxicities included skin toxicity (42%), fatigue (19%) and vomiting (12%). Conclusions: The combination of PLD and panitumumab demonstrates efficacy in platinum refractory/resistant patients although the dermatologic toxicity was considerable.
Updated overall survival analysis of patients with locally advanced or metastatic radioactive iodine-refractory differentiated thyroid cancer (RAI-rDTC) treated with sorafenib on the phase 3 DECISION trial.
Authors: Marcia S. Brose, Barbara Jarzab, Rossella Elisei, Salvatore Siena, Lars Bastholt, Christelle De La Fouchardiere, Furio Pacini, Ralf Paschke, Christopher Nutting, Young Kee Shong, Steven I. Sherman, Johannes WA Smit, John Woojune Chung, Christian Kappeler, Istvan Molnar, Martin Schlumberger
Journal: Journal of Clinical Oncology (2014)

6060^ Background: The phase 3 placebo-controlled DECISION trial established that sorafenib treatment significantly improves progression-free survival for patients with RAI-rDTC. Overall survival (OS) was immature at the time of primary analysis and possibly confounded by placebo crossing over to receive open-label sorafenib at progression. We report the OS results from a planned 9-month follow up as of May 31, 2013 and possible corrections for the crossover. Methods: Patients with locally advanced/metastatic progressive RAI-rDTC were randomized to receive sorafenib or placebo. Placebo patients were allowed to receive sorafenib open-label (OL) upon progression. OS data were analyzed using 2 correction methods for cross over: iterative parameter estimation (IPE) and rank preserving structural failure time (RPSFT). Results: A total of 417 patients were randomized (207 to sorafenib and 210 to placebo). Median OS had not been reached at the time of primary analysis (August 31, 2012) at which time 70% of placebo patients had started OL sorafenib and the difference across the two arms was not significant; HR: 0.80; 95% CI: 0.539, 1.194, p=0.138, one-sided. Correction for the effect of cross-over from the placebo to sorafenib treatment was performed using two methods: RPSFT (HR 0.61; 95% CI: 0.40, 0.94) and IPE (HR 0.70; 95% CI: 0.47, 1.04). As of the May 31, 2013 cutoff, 75% of placebo patients started OL sorafenib and there have been a total of 138 events (66 sorafenib and 72 placebo), with the median OS still not having been reached in the sorafenib arm and without statistically significant difference between arms; HR 0.88; 95% CI: 0.633, 1.236, p=0.2359. Correction for cross-over was performed using the RPSFT method (HR 0.69; 95% CI: 0.49, 0.99) and the IPE method (HR 0.79; 95% CI: 0.56, 1.11). Conclusions: The OS results from the DECISION trial are still immature 9 months following the primary analysis. OS analysis taking into account the crossover of placebo patients to the sorafenib arm are not conclusive, but nonetheless suggest that sorafenib may have an effect on OS. Long-term follow up of OS is on-going. Clinical trial information: NCT 00895674.
Use of systemic therapy in women with recurrent ovarian cancer—Development of a national clinical practice guideline
Authors: L. Elit, L. Zitzelberger, M. Fung Kee Fung, M. Brouwers, I. D. Graham, G. Browman
Journal: Journal of Clinical Oncology (2007)

16033 Background: To develop a national guideline on the use of systemic therapy for women with recurrent ovarian cancer. Methods: In March 2005, the Society of Gynecologic Oncologists of Canada (GOC) held a workshop with clinicians and methodologists to begin the process of defining specific recommendations for the management of recurrent ovarian cancer in the Canadian context. An adaptation process developed by the Canadian Strategy for Cancer Control (CSCC) Clinical practice Guidelines Action Group (CPG-AG) was used. Guideline adaptation modifies existing guidelines to fit a local organizational and cultural context. A draft guideline was developed and sent to practitioners from across Canada for feedback. Relevant comments were incorporated. Results: A literature review identified seven guidelines which were assessed for quality by six reviewers using the AGREE instrument. Data on guideline quality, currency and content (recommendations) was used by the pan-Canadian panel in an informal consensus process which resulted in the initial draft of a guideline. A sub-panel reviewed the draft and made further edits to ensure the guideline's appropriateness for a national context. Practitioner feedback was requested from 165 health care providers who treat ovarian cancer from across Canada. Overall response rate was 37%. Respondents included gynecologic oncologists (62.5%), medical oncologists (25%), radiation oncologists (3%), internal medicine (3%), gynecologists (1%) and psychosocial oncology (1%). Overall response to the guideline was positive. All comments were reviewed by the sub-panel and the guideline was edited appropriately. Conclusions: This was the first undertaking of the creation of an interdisciplinary guideline in gynecologic oncology with input from health care providers from across Canada. Feedback from the panel and external practitioners indicated that this was a worthwhile process. Our goal was to vet this work in the Canadian context so as to inform provincial decision-makers concerning access to expensive systemic therapy. The guideline has been endorsed by the national organization and will be available to practitioners and decision makers on the organization's website. No significant financial relationships to disclose.
Induction mFOLFOX6 with or without aflibercept followed by chemoradiation (CRT) and surgery in high risk rectal cancer: Phase II randomized, multicenter, openlabel trial—The GEMCAD RIA study.
Authors: Carlos Fernandez-Martos, Vicente Alonso, Isabel Busquier, Jaume Capdevila, Antonio Cubillo Gracian, Javier Gallego Plazas, Inmaculada Guasch, Laura Layos, Ferran Losa, Juan Maurel, Marta Martin-Richard, Mercedes Martinez Villacampa, Bartomeu Massuti, Clara Montagut Viladot, Miquel Nogue, Carles Pericay, Maria Jose Safont, Nuria Salas, Antonieta Salud Salvia, Ruth Vera
Journal: Journal of Clinical Oncology (2015)

TPS3626 Background: Induction chemotherapy (CT) before CRT and surgery is now considered a new treatment alternative for patients with locally advanced rectal (LAR) cancer. Willet et al. (Nat Rev 2004) demonstrated that Induction treatment with anti VEGF therapy bevacizumab (BEV) before CRT, decreased tumor interstitial fluid pressure and blood flow, suggesting normalization of the tumor vasculature. The AVCROSS phase II trial (Nogue, The Oncologist 2011) showed that BEV combined with induction CT followed by BEV combined with CRT and surgery produced high pCR rates (36%) but with an unacceptable rate of surgical reoperations. Aflibercept (Afli) (ziv-aflibercept in the US) is a novel anti-angiogenic agent that acts as a soluble receptor that binds to human VEGF-A, VEGF-B, PlGF. We hypothesized that administering induction Afli/FOLFOX followed by CRT will improve pCR rate without compromise wound healing. Methods: We will conduct a multicenter phase II randomized trial, stratified by mrT stage and institution, with 2:1 allocation, comparing preoperative induction mFOLFOX6 with or without Afli prior to standard CRT (capecitabine with 50.4 Gy) and surgery. Primary endpoint: pathological complete response (pCR). 180 patients (p) will be recruited (120 p for mFOLFOX6 + Aflibercept group and 60 p for mFOLFOX6). Assumptions: 10% of dropouts, 0.10% one-sided type-I error, 80% power to detect a 15% difference in pCR. 2 interim analyses for safety, efficacy/futility (Lan de Mets, O’brien-Fleming). Major eligibility criteria: High-risk rectal cancer with 1 of the following criteria on high resolution MRI: Extramural vascular invasion or extramural extension > 5 mms into perirectal fat or mesorectal fascia threatened or involved in middle T3 tumors. mrT3 distal and mrT4 or N2 middle or distal tumors. Enrollment began in January 2015. ClinicalTrials.gov Identifier: NCT02340949 Clinical trial information: 02340949.
High β-III tubulin expression in triple-negative (TN) breast cancer (BC) subtype and correlation to ixabepilone response: A retrospective analysis
Authors: C. E. Horak, F. Y. Lee, L. Xu, S. Galbraith, J. Baselga
Journal: Journal of Clinical Oncology (2009)

3587 Background: High βIII-tubulin (βIII) expression confers resistance to many anti-microtubule agents (Sève, Lancet 2008; 9: 168). The anti-microtubule agent ixabepilone (Ixa) demonstrates efficacy in βIII over-expressing tumor models resistant to taxanes and has clinical activity in patients with TN BC. The incidence and expression of βIII by BC subtype have not been delineated. Methods: Retrospective analyses of βIII mRNA expression were conducted in two microarray datasets of BC cohorts. Using intrinsic gene clustering, BC tumors from the Ixa neoadjuvant study CA163–080 (080) and the International Genome Consortium (IGC) were defined as basal-like (BL), luminal-like, Her2-overexpressing (Her2+) or normal-like subtypes. For study 080, IHC status subtyping defined TN, Her2+ and Her2-ER+PR+ patients. Mean expression of TUBB3, the gene encoding for βIII, was determined for each subtype. Clinical responses for 080 patients were compared to βIII expression levels. Results: For both cohorts, mean expression of TUBB3 was higher in BL and Her2+ tumors (one-way ANOVA and Tukey's HSD test; both p &lt; 0.001). TUBB3 expression was rank-ordered: low, medium and high. In 080 and IGC cohorts, high expressors represent &gt;50% of patients in BL and Her2+ subtypes and ∼20% of other BC subtypes. Subtyping 080 patients by receptor expression status demonstrated mean TUBB3 expression was higher for TN compared to Her2+ and Her2-ER+PR+ patients (t-test; p = 0.009). TN patients (n = 11/46) in study 080 had a trend to higher pCR rate than the overall population (n = 29/161), 26 vs. 18%. Receiver operating characteristics (ROC) analysis with AUC=0.66 demonstrates that high TUBB3 expression may predict for Ixa response in the overall 080 population. Conclusions: BC patients with TN, BL and Her2+ tumors have higher βIII expression. For the 080 study, responses to Ixa were higher for TN BC patients, and ROC analysis correlated response to βIII levels in the overall population. These data suggest high βIII in BL and TN BC may contribute to the aggressiveness of these subtypes and predict for Ixa clinical response. Additional studies are needed to address the activity of taxanes relative to βIII expression in TN BC. [Table: see text]
<i>BRAF</i> exon 15 (7q34) mutation heterogeneity in metastatic and primary melanomas.
Authors: Daiane Pereira Guimaraes, Mariana Fernandes, Andreia Neves Comodo, Lais de Sousa Moraes, Denise Barcelos, Fernando Cintra Lopes Carapeto, Andressa Germano, Edna Sadayo Miazato Iwamura, Janete Maria Cerutti, Gilles Landman
Journal: Journal of Clinical Oncology (2015)

e20092 Background: Cutaneous melanoma (CM) is the skin malignancy with the highest potential of mortality. The MAPK pathway is constitutively activated in the majority of melanomas and it is the main focus of novel targeted therapies for metastatic melanoma (MM), together with KIT, BRAF and MEK inhibitors. Approximately half CM have BRAF V600 mutation and benefits with fast tumor regression from treatment with BRAF and MEK inhibitors. However, most of these patients relapse within 6 to 12 months. Several mechanisms of resistance to BRAF inhibition have been described, as a result of MAPK pathway reactivation or independent MAPK-signaling activation. Methods: This is a retrospective study with 84 samples in paraffin blocks of 56 patients, filed at the Department of Pathology of Universidade Federal de São Paulo, treated from 1996 to 2012. DNA extracted from 4 different areas of each sample was sequenced for BRAF exon 15 to test heterogeneity. Different blocks from the same patients were also compared. Results: 40 out of 84 samples (47.6%) had, at least, 2 sequenced areas. 16 (40%) had a mutation in BRAF exon 15 and 20% were V600E. 35% of these samples were heterogeneous. 13 pacients had 2 or more metastasis. Comparing patient’s own metastatic samples 12 (84.6%) were heterogeneous. 36.9% of the analyzed samples were acral melanomas (AM), and of these, 25% had exon 15 mutated. 5 samples presented intratumoral heterogeneity. 41.6% of acral MM had their primary tumor samples analyzed by the same method, so that in 7 primary AM had 1 or 2 corresponding metastasis. Of all detected mutations (n = 16), 4 were silent, 11 missense and 1 was nonsense type. 4 mutations were never described. Conclusions: BRAF exon 15 mutation status is heterogeneous within MM samples, between metastatic samples of the same patient and also among metastasis and their primary site melanoma. Moreover, the mutation status evaluation of a single metastatic sample might be insufficient to establish a targeted therapy, for resistance to novel drugs could be related to tumor heterogeneity.
Association of delayed commencement of adjuvant chemotherapy (AC) with inferior survival in colon cancer patients with stage II and III diseases: A national population-based cohort study.
Authors: Ik Yong Kim, Young Wan Kim
Journal: Journal of Clinical Oncology (2017)

669 Background: To evaluate factors affecting the delay ( ≥ 8 weeks) of AC and the impact of chemotherapy delay on survival in patients with colon cancer(CC). Methods: The study cohort consisted of patients with stage II and III colon cancer, diagnosed between January 1, 2011 and December 31, 2012, who underwent curative resection and AC at all hospitals registered in the Korean Health Insurance Review and Assessment Service (HIRA). Detailed clinical data are from monitoring and evaluation of quality of colon cancer care. Results: Among 5355 patients, 154 (2.9%) received AC more than 8 weeks after surgery. Based on multivariate analysis, risk factors associated with AC delay ≥ 8 weeks were: older age [65 to 74 years (hazard ratio, HR = 1.48) and 75 years (HR = 1.69), p = 0.0354], medical aid status in health security system (HR = 1.76, p = 0.0345), emergency surgery (HR = 2.43, p = 0.0002), and chemotherapy with fluoropyrimidine (HR = 1.49, p = 0.0373). Independent prognostic factors for inferior OS included AC delay ≥ 8 weeks (HR = 1.49, p = 0.0365), older age [65 to 74 years (HR = 1.94) and 75 years (HR = 3.41), p &lt; 0.0001], TNM III stage (HR = 2.46, p &lt; 0.0001), emergency surgery (HR = 1.89, p &lt; 0.0001), ASA score with 3 or higher (HR = 1.50, p &lt; 0.0001), and higher transfusion amount (HR = 1.09, p = 0.0392). OS rates in patients with stage II / III CCs according to delay of AC using 8 weeks cutoff showed inferior OS in the delayed chemotherapy group (p = 0.008).Detailed OS rates were 97.81% at 1 year, 93.77% at 2 year, 89.62% at 3 year, and 85.79% at 4 year in the chemotherapy group within 8weeks. In the delayed chemotherapy group ≥ 8 weeks, OS rates were 96.1% at 1 year, 87.66% at 2 year, 80.98% at 3 year, and 80.2% at 4 year. Conclusions: This national population-based cohort study shows that delayed commencement of AC, defined as ≥ 8 weeks, is associated with inferior OS in CC patients with stage II / III. To reduce the proportion of patients receiving delayed AC, multidimensional aspects such as health insurance status or age should be considered. Based on our results, the time of commencement of chemotherapy can be incorporated as another quality indicator for colon cancer care.
Reply:
Authors: Guadalupe Garcia‐Tsao, Juan G. Abraldes, Annalisa Berzigotti, Jaime Bosch
Journal: Hepatology (2017)

Potential conflict of interest: Dr. Bosch consults for, advises for, and received grants from Conatus. He consults for and advises for Actelion and Exalenz. He consults for and received grants from Gilead. He consults for Novo. 1 We thank Kumar et al. for supporting our recommendations regarding the dose of traditional nonselective beta‐blockers (NSBBs; propranolol, nadolol) in patients with cirrhosis and ascites. Specifically, we recommend that in patients with ascites (refractory or not) NSBBs be titrated to a maximal dose of propranolol of 160 mg (80 mg twice/day) and a maximal dose of nadolol of 80 mg/day.1 This is half the maximal dosage that had been previously recommended (irrespective of presence of ascites)2 and that is currently recommended for patients without ascites.1 The rationale for limiting the maximal dose of NSBBs to only patients with ascites stems from some evidence showing higher mortality in patients with refractory ascites on NSBBs. This effect appears to be dose related given that doses of propranolol lower than 160 mg/day are associated with a better survival.3 NSBBs could be potentially deleterious in patients with refractory ascites because, in these patients, vasodilatation and a relative reduction in cardiac index are more pronounced and, a further reduction induced by NSBBs, could exacerbate fluid retention and lead to renal dysfunction.4 Because vasodilatation and systemic hypotension are already present in patients with ascites, we limited the dose of NSBB to all patients with ascites, not only those with refractory ascites. Additionally, a more pronounced liver dysfunction in patients with ascites can lead to decreased NSBB metabolism and lower effective doses. Kumar et al. suggest that fixed doses of NSBBs should be used in all patients irrespective of the presence of ascites; however, there is no evidence to support this approach. In the absence of a deleterious effect, there is no rationale for limiting the dose of NSBBs in patients without ascites. Regarding carvedilol, this not only has a NSBB effect, but it also has a vasodilatory effect that leads to a greater decrease in mean arterial pressure than propranolol,5 with doses >25 mg/day being associated with worsening fluid retention. Therefore, clinical trials have used maximal doses of carvedilol of 12. 5 mg/day, irrespective of the presence of ascites, and our recommendations are aligned with this approach. The theoretical "optimal" doses of carvedilol quoted by Kumar et al. cannot be recommended given that they are based on pharmacokinetic modeling and have not been related to portal pressure reduction or to a clinical outcome. Practitioners should titrate the dose of NSBBs/carvedilol, starting at the lowest dose and capping the maximal doses, particularly in patients with ascites. Any decrease in systolic blood pressure levels below 90 mm Hg should lead to dose reduction or drug discontinuation.1