tbuckley/cabot-search huggingface dataset:
Adjuvant taxane therapy for early-stage breast cancer: A real-world comparison of chemotherapy regimens in Ontario.
Authors: Sofia Torres, Maureen E. Trudeau, Andrea Eisen, Craig Earle, Kelvin K. Chan
Journal: Journal of Clinical Oncology (2014)

1081 Background: FEC-D (5-FU, epirubicin, cyclophosphamide - docetaxel) and dd (dose-dense) AC-P (doxorubicin-cyclophosphamide - paclitaxel) are considered equally effective regimens in the adjuvant treatment of breast cancer (BC), although never compared directly in a clinical trial. We compared the outcome of BC patients (pts) treated with FEC-D, dd AC-P and AC-P (q3 weekly). Methods: Retrospective study including all female BC pts diagnosed in 2003-2009 in Ontario, who received 1 of those regimens (ascertained from New Drug Funding Program and physician claims databases). Primary endpoint: overall survival (OS). Secondary endpoints: emergency room (ER) visits/admissions, risk of heart failure (HF). Analysis were conducted for OS and HF using Kaplan-Meier method and adjusted for confounders using proportional hazard models. Multivariable logistic regressions were performed for ER visits/admissions adjusting for confounders. FEC-D and ddAC-P were compared using propensity score (PS) matching. Results: 8,462 pts were identified, 4,710 (55.7%) received FEC-D, 2,065 (24.4%) AC-P and 1,687 (19.9%) dd AC-P. Patient characteristics were imbalanced between the arms. In unadjusted analyses, 5-year OS was 91.7% for FEC-D, 89.0% for dd AC-P and 87.4% for AC-P; after PS matching, it was 92% for FEC-D and 89% for ddAC-P. After adjusting for confounders, risk of death was lower for dd AC-P than AC-P (HR=0.76; 95% CI 0.61-0.96), and higher for dd AC-P than FEC-D (HR=1.24; 0.99-1.54) and for AC-P than FEC-D (HR=1.61; 1.26-2.06). ER visits / admissions during treatment, were higher for FEC-D (respectively, 50.5% and 23.7%), than AC-P (35.2% and 11.6%) and dd AC-P (30.5% and 8.4%); the differences persisted after PS matching (respectively, 48.2% and 23.5% for FEC-D, 31.1% and 8.7% for dd AC-P; p<0.0001). Risk of HF at 5 years for the PS matched groups was 1.37% for FEC-D and 1.49% for dd AC-P (p=0.71). Conclusions: OS was better for FEC-D and dd AC-P when compared with AC-P. This may be attributable to imbalances in patient characteristics. Propensity score matching for dd AC-P and FEC-D showed no difference in survival or HF risk between the arms but pts treated with FEC-D continued to have more ER visits/admissions.
miRNA profiling in resectable NSCLC by multiplex next-generation sequencing.
Authors: Sandra Gallach, Eloisa Jantus-Lewintre, David Montaner, Marta Usó, Elena Sanmartin, Rafael Sirera, Ana Blasco, Ricardo Guijarro, Miguel Martorell, Carlos Camps
Journal: Journal of Clinical Oncology (2012)

7060 Background: Early-stage NSCLC has a relapse rate around 40% within 5 years. With the advent of microRNA (miRNA), which seems to regulate many genes critical for tumorigenesis, there is a growing interest in the characterization of miRNAome in NSCLC specimens and to correlate them with prognosis. Next generation sequencing is a useful tool to study the miRNA content of solid tumors. Here, we applied high-throughput SOLiD transcriptome sequencing to study miRNAs expression in a cohort of early-stage NSCLC patients (tumor vs normal lung). Methods: RNA was isolated from frozen lung specimens (tumor and normal lung) from resectable NSCLC patients (n=35). Samples with a RIN ≥ 7 were analyzed and enriched in the miRNA fraction. miRNAs were sequencing using a bar-code multiplex SOLiD protocol. Data normalization was carried out by rescaling all data according to their counts. Readings were mapped against mature and no-mature miRNAs using miRBase. Statistical analysis was performed with CLCbio software and considered significant when p-adj&lt;0.005. Results: Using the SOLiD high throughput sequencing, we performed a systemic miRNA expression profiling analysis of paired samples (tumor vs normal lung). A total of 1268 miRNAs (mature and no-mature) have been detected in at least one sample. The differential expression between normal and tumor samples shown that 6 miRNAs (miR-193b, miR-182, miR-96, miR-148a, miR-299, miR-590) were upregulated and 7 (miR-145, miR-133a, miR-218, miR-125a, miR-30a, miR-126 and miR-139) were down-regulated significantly in tumor samples compared with normal lung tissues. We are performing studies using qRT-PCR in an independent cohort to further validate these findings. Conclusions: The deep sequencing technology used for differential miRNA expression is useful and novel. The use of barcoding allows multiplexing and lowers cost per sample. Several miRNAs were differentially expressed between tumor and normal tissue, but this point needs to be further validated in an independent cohort. Supported by grants TRA09-0132 (MICINN) and RD06/0020/1024 (ISCIII).
Meningococcal serogroup B strain coverage of the multicomponent 4CMenB vaccine with corresponding regional distribution and clinical characteristics in England, Wales, and Northern Ireland, 2007–08 and 2014–15: a qualitative and quantitative assessment
Authors: Sydel R Parikh, Lynne Newbold, Stephanie Slater, Maria Stella, Monica Moschioni, Jay Lucidarme, Rosita De Paola, Maria Giuliani, Laura Serino, Stephen J Gray, Stephen A Clark, Jamie Findlow, Mariagrazia Pizza, Mary E Ramsay, Shamez N Ladhani, Ray Borrow
Journal: The Lancet Infectious Diseases (2017)
Neoadjuvant treatment of locally advanced GIST: Results of APOLLON, a prospective, open label phase II study in KIT- or PDGFRA-positive tumors.
Authors: Peter Hohenberger, Claus Langer, Clemens Martin Wendtner, Werner Hohenberger, Annette Pustowka, Eva Wardelmann, Elisabeth Andre, Thomas Licht
Journal: Journal of Clinical Oncology (2012)

10031 Background: Imatinib may significantly downstage the metastatic GIST. This prospective, phase II, open-label trial of neoadjuvant imatinib evaluated the overall tumor response and progression rate of disease in locally advanced, non-metastic patients. Methods: Inclusion criteria were: KIT (n=39) or PDFRA (n=6) positive GIST, proven by biopsy and IHC. Tumors had to be locally advanced, potentially resectable, M0. Patients received 400 mg of imatinib daily (KIT exon 9 mutations: twice daily) for 6 months, in the absence of disease progression or unacceptable toxicity. At two months 18F-FDG-PET examination was performed to assess response in paralle to CT imaging. Adjuvant treatment postoperatively was not part of the study protocol (CST1571-BDE43, NCT00112632). Median follow-up is 36 months in 39 patients. Results: From 7/2005 to 10/ 2009, 41 patients (16f, 25 m, mean age 54 yrs) were recruited to the trial with an average tumor size of 10.8 cm. One patient died from myocardial infarction 3 weeks after start of treatment, all other patients completed the protocol. In two patients dose reduction/interruption due to toxicity was required. 34/41 patients underwent resection of the tumor after a median of 200 d (range 57-394), while two patients had to be operated early due to disease progression. R0 resections were performed in 30/34 patients, two patients showed M1 disease at resection. Five patients showed developed progression postop., resulting in a PFS rate at 3 years of 85.2%. No patient has died so far from the disease. Conclusions: Neoadjuvant treatment with imatinib for six months is a safe treatment in patients with locally advanced disease. The extent of the operation can be significantly downsized after pretreatment. Despite the fact that no adjuvant treatment was foreseen, the progression-free rate at 3 years postoperatively is promising.
AR nuclear localization and microtubule bundling as markers of docetaxel and cabazitaxel sensitivity in metastatic castration-resistant prostate cancer (mCRPC): Prospective biomarker analysis from TAXYNERGY.
Authors: Paraskevi Giannakakou, Emmanuel S. Antonarakis, Giuseppe Galletti, Daniel Worroll, John Stewart, Atef Zaher, Ted P. Szatrowski, Wei Zhou, Karla V. Ballman, Marie Vanhuyse, Ada Gjyrezi, Shinsuke Tasaki, Yang Bai, Luigi Portella, Brian J. Kirby, Guru Sonpavde, Mario A. Eisenberger, David M. Nanus, Fred Saad, Scott T. Tagawa
Journal: Journal of Clinical Oncology (2017)

134 Background: A better understanding of taxane sensitivity/resistance in mCRPC is needed to optimize treatment. Preclinically, taxane efficacy has been linked to the ability of microtubules (MT) to inhibit AR nuclear trafficking. In this prospective biomarker study, we used circulating tumor cells (CTCs) from patients (pts) in TAXYNERGY to perform real-time analysis of AR nuclear localization (ARNL) and MT stabilization (bundling; MTB) in order to predict taxane sensitivity. Methods: TAXYNERGY (NCT01718353) is a phase 2 trial randomizing chemo-naïve mCRPC pts 2:1 to docetaxel or cabazitaxel, with a switch to the alternative taxane in the absence of a ≥ 30% PSA drop by C4. Here we present the co-primary biomarker endpoints. CTCs at baseline (C1D1) were compared to CTCs after 1 week of taxane treatment (C1D8), and were analyzed by multiplex confocal microscopy for %ARNL (integrated AR intensity in the cell and nuclear areas) and MTB (assessed for increase compared to C1D1 on a scale from 0–3 from no to most MTB increase). Associations between %ARNL and MTB with clinical outcomes were sought. Results: Of 63 randomized pts, 26 had evaluable CTCs both at C1D1 and C1D8. At C1D8, mean %ARNL was significantly lower in pts achieving a ≥ 50% PSA drop by C4 vs those without (44% vs 64%; p = 0.004). A taxane-induced decrease in mean %ARNL (C1D8 vs C1D1) was associated with a higher rate of ≥ 50% PSA response (73% vs 13%; p = 0.009); mean %ARNL decreased by 18% in responders and increased by 2% in non-responders (p = 0.02). Finally, a taxane-induced increase in mean MTB trended higher in pts achieving a ≥ 30% PSA drop by C4 vs those without (0.69 vs 0.09; p = 0.09); increase in mean MTB score was indicative of response and observed in pts who did not require a taxane switch after C4 (0.75 vs 0.09; p = 0.06). Conclusions: We provide the first prospective data suggesting that taxane-induced shifts in ARNL and MTB (measured in CTCs) may serve as an early biomarker of taxane sensitivity. Consistent with preclinical data, AR nuclear exclusion caused by microtubule bundling may be a clinically-actionable marker of taxane efficacy. Funding: Sanofi Genzyme. Clinical trial information: NCT01718353.
What clinical factors influence advanced <i>BRCA1/2</i> mutant ovarian cancer patient (BMOC pt) outcomes to poly(ADP-ribose) polymerase inhibitor (PARPi) treatment?
Authors: Saeed Rafii, Charlie Gourley, Joo Ern Ang, Rajiv Kumar, Elena Geuna, Tzyvia Rye, Linda Ashcroft, Bethan Powell, Ronnie Shapira-Frommer, Michael Friedlander, Lee-may Chen, Ursula Matulonis, Bella Kaufman, Jacques De Greve, Amit M. Oza, Susana N. Banerjee, Martin Eric Gore, L Rhoda Molife, Stanley B. Kaye, Timothy Anthony Yap
Journal: Journal of Clinical Oncology (2015)

5546 Background: The PARPi olaparib (Ola) was recently granted FDA accelerated approval in advanced BMOC. Despite impressive clinical activity in BMOC, the impact of baseline pt factors remains unclear. We hypothesized that the platinum chemotherapy (Plt chemo) to PARPi interval (PTPI) can be used to refine the conventional prediction of response to PARPi based on the clinical categorization of pts into Plt sensitive (Plt-S) and Plt resistant (Plt-R). Methods: Retrospective study of pt with advanced BMOC treated in relapsed setting with ≥ 200 mg bid Ola between 4/2006 – 8/2013 in multiple centers. Pearson Chi2, odds ratios (OR) and Fisher’s exact probability tests were used for statistical analyses. Results: 108 advanced BMOC pts were assessed; median age 55y (range 38-79); 83 (77%) pts had high grade serous carcinoma. BRCA1:BRCA2 mutations ratio 71:29. Median prior lines of chemo: 3 (range 1-10). 41 (38%) pts had prior breast cancer (BC). 64% had Plt-S disease and 36% had Plt-R disease prior to Ola. Median PTPI was 53 weeks (w) (range 4-244). Median PTPI was 68.7w for Plt-S pts versus (vs) 25.9w for Plt-R pts (p < 0.0001). RECIST complete or partial responses (CR/PR) were observed in 23/65 (35%) Plt-S pts vs 5/38 (13%) Plt-R pts (p < 0.02). Pts with > 52w PTPI had higher CR/PR rates than those with < 52w PTPI independent of their Plt status (37% vs 18%, respectively, p = 0.053). Pts who had only 1 prior line of chemo had higher CR/PR rates vs pts who had > 1 prior line (p < 0.005). No differences in CR/PR rates were noted between pts with BRCA1 vs pts with BRCA2 mutations, pts with prior BC vs pts without, or use of chemo for BC vs none. Median progression-free survival was 70w for pts with PR/CR vs 28w for pts without (log-rank, p = 0.0004). Median survival was 161w for pts with CR/PR and 64w for pts without (log-rank, p = 0.0005). Conclusions: These data suggest that prediction of response to PARPi in advanced BMOC based on conventional Plt-S/Plt-R categorization may be refined by PTPI. Treatment of Plt-R BMOC pts with a non-Plt agent prior to Ola in order to prolong PTPI may be an appropriate clinical strategy. These findings should be validated prospectively in a larger data set.
ABCG2 and TOP1 mRNA expression as predictive biomarkers for adjuvant FOLFIRI treatment in stage III colon cancer patients: Results from the PETAAC-3 prospective randomized clinical trial.
Authors: Nils Brunner, Sune Boris Nygaard, Eva Budinska, Jan Stenvang
Journal: Journal of Clinical Oncology (2017)

591 Background: FOLFIRI as adjuvant treatment in primary colon cancer was previously tested in two pivotal prospective randomized clinical trials (PETACC-3 and CALGB 89803), both of which failed to demonstrate significant beneficial effects when adding irinotecan to 5FU. As a consequence, FOLFIRI is presently not used as adjuvant treatment for colon cancer. Methods: The study included 580 patients with mRNA expression data performed on tumor samples (FFPE) from stage III colon cancer patients enrolled in the PETACC-3 study, which randomized the patients to 5FU plus Leucovorin +/- irinotecan. Primary end-points were disease free survival (DFS) and overall survival (OS). Median ABCG2 and the 75 percentile TOP-1 mRNA expression data were used to allocate the patients into one of two groups: One with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) (n = 167) and another group including all other combinations of these two genes. Kaplan Meier curves and Cox proportional hazards model were used to visualize differences between groups and calculate p-values (log-rank test). Results: The survival statistics showed a significant difference for both RFS (HR: 0.63 (0.44-0.92); p = 0.017) and OS (HR: 0.6 (0.39-0.93); p = 0.021) between the two groups when the patients received FOLFIRI. In contrast, no significant differences were observed between the groups when patients received 5FU and Leucovorin alone (RFS: 0.58; OS: 0.75). Conclusions: We here show that the combination of two independent gene expression abundance with a strong association to irinotecan treatment (high ABCG2 drug efflux pump and low TOP-1, which is the target for irinotecan) identified a group of stage III colon cancer patients who will not benefit from FOLFIRI adjuvant treatment while patients with other combinations of expression of these two genes appear to significantly benefit from adjuvant FOLFIRI treatment. The lack of a similar effect in patients receiving treatment with 5FU and Leucovorin only, points to a predictive value of ABCG2 and TOP-1 measurements.
Primary tumor resection in metastatic colorectal cancer (mCRC): A prospective cohort study.
Authors: Shu Fen Wong, Kathryn M Field, Suzanne Kosmider, Jeanne Tie, Hui-li Wong, Ben Tran, Mark Tacey, Jeremy Shapiro, Joseph McKendrick, Peter Gibbs
Journal: Journal of Clinical Oncology (2013)

3584 Background: The role of primary tumor resection in patients presenting with mCRC remains controversial. Previously reported survival benefits associated with primary tumor resection may not translate in the modern era of systemic therapies. We examined the impact of primary tumor resection on survival in a modern cohort of mCRC patients. Methods: Patients were identified using a clinician-designed mCRC registry involving 15 participating Australian sites from mid 2009. Patients were excluded if planned for curative metastasectomy or had incomplete data. Univariate logistic regression and multivariate cox regression was utilized to identify significant associations between resection, clinical variables and survival outcomes. Results: We identified 682 mCRC patients with median follow up 20 months. 40% (n = 275) had their primary in-situ. Rates of primary resection were higher for age &gt; 70 years (OR 1.66 95% CI [1.22 – 2.26], p = 0.001) and Charlson score ≥3 (OR 1.50 [1.10 – 2.06], p = 0.011). Lower resection rates were observed for rectal v colon primary (OR 0.39 [0.28 – 0.55], p &lt; 0.001), liver metastases (OR 0.59 [0.42 – 0.82], p = 0.002) and ECOG 2 - 4 (OR 0.64 [0.45 – 0.92], p = 0.015). There was a significant survival advantage for pts with primary tumor resection (median OS 21.3 vs 16.8 months; HR 0.63, p &lt; 0.001), even when adjusting for known prognostic factors in a multivariate analysis (HR 0.56 [0.44 – 0.72], p &lt; 0.001). Multivariate analyses also demonstrated that age &gt; 70 years (HR 1.32 [1.03 – 1.71], p = 0.031) and ECOG ≥ 2 (HR 3.17 [2.43 – 4.15], p &lt; 0.001) were significantly associated with poorer outcomes; whereas chemotherapy use (HR 0.61 [0.45 – 0.84], p = 0.002), bevacizumab use (HR 0.68 [0.52 – 0.89], p = 0.005) and rectal primary (HR 0.69 [0.53 – 0.91], p = 0.009) predicted improved survival. Conclusions: Our study suggests that primary tumor resection is associated with significant survival advantages for mCRC patients in the modern era of systemic therapies. The 40% of primary cancers in-situ is higher than previous mCRC studies and suggests a tendency for non-operative intervention in Australia. Further analysis aimed at examining the impact of other confounding variables such as tumor burden is ongoing and will be presented.
Clinicopathological features and prognostic factors of colorectal neuroendocrine neoplasms.
Authors: Mengjie Jiang, Hanguang Hu, Ying Yuan
Journal: Journal of Clinical Oncology (2017)

572 Background: Limited research is available regarding colorectal neuroendocrine neoplasms (NENs), especially in China. The prognostic factors of colorectal NENs remain controversial. Methods: A total of 68 patients with colorectal NENs were studied retrospectively. Clinical characteristics and prognosis between colonic and rectal NENs were compared. The Kaplan-Meier method and Cox regression models were used to evaluate the capacity of various factors to predict the outcome. Results: Of the 68 colorectal NENs patients, 43 (63.2%) had rectal NENs, and 25 (36.8%) had colonic NENs. Compared with rectal NENs, colonic NENs more frequently exhibited larger tumor size ( P &lt; 0.0001) and distant metastasis ( P &lt; 0.0001). Colonic NENs had a worse prognosis ( P= 0.027), with 5-year overall survival rates of 66.7% vs. 88.1% compared with rectal NENs. Neuroendocrine tumors, neuroendocrine carcinomas and mixed adenoendocrine carcinomaswere noted in 61.8%, 23.5% and 14.7% of patients, respectively. According to the available data (n = 49), Ki-67 index values were ≤ 2% in 27 (39.7%) patients, ranged from 3 to 20% in 6 patients (8.8%) and were &gt; 20% in 16 patients (23.5%). Multivariate analyses revealed that tumor location was not an independent prognostic factor ( P= 0.081), but tumor size ( P= 0.037) and pathological classification ( P= 0.012) were independent prognostic factors. Conclusions: Significant differences in clinicopathological feature and outcome exist between colonic and rectal NENs. Multivariate analysis indicated that tumor size and pathological classification were associated with the prognosis. However, tumor location was not an independent factor. The worse outcome of colonic NENs observed in clinical practice might be due not only to the biological differences, but also to larger tumor size in colonic NENs caused by the delayed diagnosis.
Avian influenza A in poultry stalls of Lahore District, Pakistan in 2009–2010
Authors: Mamoona Chaudhry, Hamad B. Rashid, Angélique Angot, Michael Thrusfield, Susan C. Welburn, Barend M. deC. Bronsvoort, Ilaria Capua, Giovanni Cattoli, Mark C. Eisler
Journal: Journal of Infection (2017)
Correlation between baseline variables and survival in the radium-223 dichloride (Ra-223) phase III ALSYMPCA trial with attention to total ALP changes.
Authors: A. Oliver Sartor, Roy Amariglio, Scott Wilhelm, Jose E. Garcia-Vargas, C. Gillies O'Bryan-Tear, Minghua Shan, Fang Fang, Chris Parker
Journal: Journal of Clinical Oncology (2013)

5080 Background: In patients (pts) with castration-resistant prostate cancer and bone metastases (mCRPC), total ALP (tALP) has been shown to be a prognostic marker for overall survival (OS) (Cook 2006). Here the prognostic value of tALP and other baseline clinical variables in Ra-223 pts is presented, along with the initial results of an exploratory analysis of changes in tALP seen with Ra-223. Methods: Study population included 921 pts (intent-to-treat population) from the ALSYMPCA trial. The Cox proportional hazards model was used to evaluate the prognostic potential of tALP and other baseline variables (albumin, Hb, LDH, ECOG performance status, PSA, and age). Log transformation was done for baseline variables (tALP, PSA, and LDH) with heavily skewed distributions. Baseline variables were assessed for interaction with treatment. To determine changes in tALP from baseline at 12 wk, 708 pts who had tALP measurements at both baseline and 12 wk were included. Results: The baseline variables in the Table were significantly associated with OS. Hb was not a significant factor when adjusting for all other covariates and was therefore removed from the final Cox regression model. No significant treatment-by-covariate interactions were detected. After controlling for other variables, higher baseline tALP was significantly associated with an increased risk of death (p &lt; 0.0001). At 12 wk, a decline in tALP relative to baseline was seen in 87% (433/497) of Ra-223 pts, compared to 23% (49/211) of placebo pts. The mean percentage change from baseline in tALP at 12 wk was a 32% decline for Ra-223 pts, in contrast to a 37% increase for placebo pts (p&lt; 0.001). Conclusions: In mCRPC pts, higher baseline levels of tALP were associated with an increased risk of death. With the majority of Ra-223 pts experiencing a decline in tALP at 12 wk, and the marked mean percentage tALP decline in these pts, further analysis to determine a correlation between tALP dynamics and survival is warranted. Clinical trial information: NCT00699751. [Table: see text]
Regarding Twitter as a Potential Data Source for Cardiovascular Disease Research
Authors: R. Jay Widmer, Suraj Kapa
Journal: JAMA Cardiology (2017)

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