tbuckley/cabot-search huggingface dataset:
Effect of downstaging without complete pathologic response after neoadjuvant treatment on cancer outcomes for cIII and cII rectal cancers
Authors: L. F. Lobato, L. Stocchi, A. da Luz Moreira, M. Kalady, D. Dietz, D. Geisler, I. Lavery, V. Fazio
Journal: Journal of Clinical Oncology (2009)

4108 Background: Neoadjuvant chemoradiation followed by surgery is standard of care for locally advanced rectal cancer. The impact of downstaging on prognosis when pathologic complete response (pCR) cannot be achieved remains unclear. The aim of this study was to evaluate whether downstaging impacts prognosis in patients with cII vs. cIII rectal cancer. Methods: We identified from our colorectal cancer database 233 patients with primary cII and cIII rectal cancer staged by CT and ERUS/MRI who received 5FU-based chemoradiation followed by R0 surgery after a median interval of 7 weeks during 1997–2007. Median radiotherapy dose was 5040 cGy. We excluded 58 patients with pCR and. Compared among the remaining 175 patients pathologic downstaging (cII to ypI, cIII to ypII or ypI) vs. No pathologic downstaging (c stage ≤ yp stage). Outcomes evaluated were 5-year overall survival, 3-year recurrence-free survival, overall recurrence, local recurrence and distant recurrence. Results: Median age was 58 years and median follow-up was 48 months. Patients with cII vs. cIII stage were statistically comparable regarding demographics, chemoradiation regimen, interval to surgery after neoadjuvant treatment, tumor distance from anal verge, operations performed and follow-up. The incidence of downstaging was increased in stage cIII vs. cII patients (68% vs. 21%, p &lt;0.001). With the exception of local recurrence rates, downstaging resulted in significantly improved cancer outcomes for cIII but not cII ( Table ). Conclusions: Downstaging without pCR is a significant prognostic factor for patients with stage cIII rectal cancer. A larger sample size is required to confirm lack of downstaging benefits in stage cII. [Table: see text] No significant financial relationships to disclose.
An outbreak of infection with Bacillus anthracis in injecting drug users in Scotland
Authors: C N Ramsay, A Stirling, J Smith, G Hawkins, T Brooks, J Hood, G Penrice, L  M Browning, S Ahmed, Collective on behalf of the NHS GGC, Collective on behalf of the Scottish National Outbreak Control Teams
Journal: Eurosurveillance (2010)

An investigation is currently underway to explore and control an outbreak of Bacillus anthracis among drug users (mainly injecting) in Scotland. Contaminated heroin or a contaminated cutting agent mixed with the heroin is considered to be the most likely source and vehicle of infection. Heroin users have been advised of the risk. The risk to the general public is regarded as very low.
Abstract 12390: Right Heart Failure Predicts Higher Mortality in Patients With Hypertrophic Cardiomyopathy
Authors: Stephen A McCullough, Yuichi J Shimada, Aaron L Baggish, Patricia A Lowry, Caitlin O’Callaghan, Richard D Rothman, Gus J Vlahakes, Michael A Fifer
Journal: Circulation (2014)

Introduction: The clinical correlates of right heart failure (RHF) and its association with mortality in hypertrophic cardiomyopathy (HCM) have not been reported previously. Methods: We performed a retrospective cohort study of patients in our HCM program who underwent right heart catheterization between 1997 and 2012. RHF was assessed by right atrial pressure (RAP). Clinical correlates assessed were mean pulmonary artery pressure (PAP), mean pulmonary capillary wedge pressure (PCWP), atrial fibrillation (AF), ventricular tachycardia/fibrillation (VT/VF), and mortality. Data were analyzed with linear regression for PAP and PCWP, logistic regression for AF and VT/VF, and the Cox-proportional hazards model and the log-rank test for mortality. Results: 147 patients (age 68 ± 14 years, 54% women) were included in the study, with median follow-up for mortality 7.0 years. Median RAP was 6 mmHg [interquartile range, 4-9 mmHg]. Higher RAP was associated with higher PAP (+7.4 ± 0.8 mmHg per 5 mmHg increase, p &lt; 0.001) and PCWP (+5.0 ± 0.5 mmHg per 5 mmHg increase, p &lt; 0.001). Higher RAP was associated with prior AF (odds ratio [OR] = 1.6 [1.05 - 2.5] per 5 mmHg increase, p = 0.03) and prior VT/VF (OR = 1.6 [1.04 - 2.4] per 5 mmHg increase, p = 0.03). Higher RAP was found to predict overall mortality (hazard ratio [HR] = 2.5 [1.2 - 5.0] per 5 mmHg increase, p = 0.01). When data were dichotomized, RAP &gt; 10 mmHg was associated with increased mortality (p = 0.002, Figure). Conclusions: (1) As in other causes of heart failure, RHF in HCM is associated with higher PAP and PCWP. (2) RHF in HCM is associated with a higher prevalence of AF and VT/VF. (3) RHF in HCM is associated with increased mortality.
Pediatric phase I trial design using a pharmacodynamic marker as the primary endpoint
Authors: H. J. Meany, E. Fox, A. Aikin, P. Whitcomb, R. F. Murphy, B. C. Widemann, F. M. Balis
Journal: Journal of Clinical Oncology (2008)

10027 Background: The optimal dose of less toxic molecularly targeted agents should be defined by target modulation rather than toxicity. Talabostat is an inhibitor of dipeptidyl peptidase 4 (DPP-4) with minimal systemic toxicity in adults. We designed a dose finding trial of talabostat using serum DPP-4 inhibition as the primary endpoint. Methods: The cleavage rate of Ala-Pro-AFC to the fluorescent product, trifluoromethylcoumarin (AFC) was used to quantify plasma DPP-4 enzyme activity pre-dose and 1h and 24h after a daily oral dose of talabostat. The goal of the study was to identify a dose that inhibits DPP-4 continuously, throughout the 14 day dosing interval. Therefore, the optimal dose would inhibit >90% of pre-dose plasma DPP-4 activity at 24h. Talabostat (once daily × 14d) underwent intra- and inter-patient dose escalation by 70 to 100% over 4 dose levels with 2 patients enrolled per dose level. If <2 achieved >90% inhibition and neither had dose-limiting toxicity (DLT), the dose was escalated. If both achieved >90% inhibition, the cohort would expand to 6; and if ≥5/6 achieved >90% inhibition without DLT, the dose would be escalated 1 additional dose level to ensure that the optimal dose was on the plateau of the dose-response curve. If DLT occurred, the design would convert to a maximum tolerated dose primary endpoint with dose escalations in 40% increments. Results: Six patients (4.5–18 yr) were enrolled, 2 each at the first 3 dose levels, and 3 patients underwent intra-patient dose escalation. No DLTs were observed. DPP-4 activity was >90% inhibited 1h post-dose in 5/6 patients. Inhibition at 24h was dose-dependent, but Emax modeling of the dose-response curve predicted 90% inhibition would require doses >1,350 mcg/m2, which prompted a change to a twice daily dosing schedule. Conclusions: This trial design using a primary pharmacodynamic endpoint appeared to be feasible for determination of optimal drug dose and dosing schedule for talabostat. Subject Cycle Dose Level (mcg/m2/d) % DPP-IV inhibition 1h 24h 1 1 100 0 45 2 1 100 100 52 2 200 100 63 3 1 200 94 34 2 350 100 69 4 1 200 100 72 5 1 350 96 65 6 1 350 100 63 2 600 100 85 3 600 100 85 No significant financial relationships to disclose.
Treatable traits: toward precision medicine of chronic airway diseases
Authors: Alvar Agusti, Elisabeth Bel, Mike Thomas, Claus Vogelmeier, Guy Brusselle, Stephen Holgate, Marc Humbert, Paul Jones, Peter G. Gibson, Jørgen Vestbo, Richard Beasley, Ian D. Pavord
Journal: European Respiratory Journal (2016)

Asthma and chronic obstructive pulmonary disease (COPD) are two prevalent chronic airway diseases that have a high personal and social impact. They likely represent a continuum of different diseases that may share biological mechanisms ( i.e. endotypes), and present similar clinical, functional, imaging and/or biological features that can be observed ( i.e. phenotypes) which require individualised treatment. Precision medicine is defined as “treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations”. In this Perspective, we propose a precision medicine strategy for chronic airway diseases in general, and asthma and COPD in particular.
Deep brain stimulation-associated brain tissue imprints: a new in vivo approach to biological research in human Parkinson’s disease
Authors: Affif Zaccaria, Ali Bouamrani, Stephan Chabardès, Michèle El Atifi, Eric Seigneuret, Johannes A. Lobrinus, Michel Dubois-Dauphin, François Berger, Pierre R. Burkhard
Journal: Molecular Neurodegeneration (2016)

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) or the internal segment of the globus pallidus (GPi) has been established as a highly effective symptomatic therapy for Parkinson’s disease (PD). An intriguing biological aspect related to the DBS procedure is that a temporary contact establishes between surgical instruments and the surrounding brain tissue. In this exploratory study, we took advantage of this unique context to harvest brain material adhering to the stylet routinely used during surgery, and to examine the biological value of these samples, here referred to as “brain tissue imprints” (BTIs). Nineteen BTIs from 12 STN- or GPi-electrode implanted patients were obtained in vivo during DBS surgery, without any modification of the surgical procedure. Immunofluorescence analyses confirmed that our approach allowed the harvesting of many neural cells including neurons harboring distinct neurotransmitter markers. Shotgun proteomic and transcriptomic analyses provided for the first time molecular information from DBS-associated brain samples, and confirmed the compatibility of this new type of sample with poly-omic approaches. The method appears to be safe and results consistent. We here propose BTIs as original and highly valuable brain samples, and DBS-related brain imprinting as a new conceptual approach to biological research in living patients with PD.
Natural Cytotoxicity of Peripheral Blood Lymphocytes and Regional Lymph Node Cells in Breast Cancer in Women&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="fn3"&gt;3&lt;/xref&gt;
Authors: S Cunningham-Rundles, D A Filippa, D W Braun, P Antonelli, H Ashikari
Journal: JNCI Journal of the National Cancer Institute (1981)

Natural cytotoxicity was studied before surgery or other treatment in 83 women with primary, untreated breast cancer. Peripheral blood lymphocytes (PBL) and cytotoxicity of regional lymph node cell(s) (RLNC) were examined in a 4-hour 51Cr release assay against the target cell K-562. Results indicated that greater than one-third of breast cancer patients have more negative lymphocyte cytotoxic activity toward K-562 than do the other two-thirds. Similar results were observed for PBL of 25 patients found to have benign breast lesions. Of these patients, 23 had fibrocystic disease. The difference between these findings and findings with normal control lymphocytes studied in parallel was highly significant (P less than 0.001). The study of RLNC cytotoxicity in patients with breast cancer showed that 25% of the patients' RLNC had significant natural cytotoxic activity toward K-562. Incubation of RLNC with interferon in vitro before addition of labeled K-562 cells did not induce cytotoxicity in RLNC that did not have this activity initially.
Clinical response of patients with advanced breast cancer treated with dendritic cell vaccine with and without thymalfasin
Authors: G. A. Moviglia, C. Gaeta, V. Gabriela, P. Farina, H. Costanzo, A. Paes de Lima, S. Merino, R. Moya, M. J. Veloso, A. Rudolph
Journal: Journal of Clinical Oncology (2005)

2593 Background: Advanced breast cancer patients resistant to chemo-, radio-, and hormonal therapy have low survival rates. Our institution has developed a protocol of autologous dendritic cell vaccine (DCV) (Annals of Oncology, 2004) that may improve patient outcomes. Thymalfasin (ZADAXIN) has been shown to enhance Th1 response, which is associated with tumor regression. This study was conducted to evaluate dendritic cell immunization and whether thymalfasin has a positive effect on the outcomes of advanced breast cancer patients who do not respond to this therapy. Methods: A retrospective observation of 18 patients with metastatic breast cancer was conducted. In Group 1 (n=7), patients received 6 dendritic cell immunizations (1 every 3 weeks) and had a lymphocyte proliferation index (LPI) >20 U (immune response) after the second vaccine. In Group 2 (n=6), patients received 6 dendritic cell immunizations and had an LPI <20 U (nonimmune response) after the second vaccine. In Group 3 (n=5), patients received 6 dendritic cell immunizations with an LPI <20 U (nonimmune response) after the second vaccine and they received thymalfasin (1.6 mg/twice a week). Immune response was measured by lymphocyte proliferation assay. Results: At 6 months, tumor reduction of >50% was seen in 100% of patients in Group 1 (responders), 50% in Group 2 (nonresponders), and 80% in Group 3 (nonresponders treated with thymalfasin). Patient survival at 12 months was 57% in Group 1, 0% in Group 2, and 80% in Group 3. Conclusions: An immune response (LPI > 20 U) to DCV therapy after the second vaccination was associated with reduction in tumor size and longer patient survival. Treatment with thymalfasin had a positive effect on advanced breast cancer patients who did not respond to dendritic cell immunization. Patient survival was higher in the thymalfasin-treated group compared with immune responders and nonimmune responders who did not receive thymalfasin. No significant financial relationships to disclose.
Mutational analysis of EGFR signaling pathway genes in lung adenocarcinomas
Authors: J. L. Marks, M. D. McLellan, Y. Kasai, L. A. Fulton, E. R. Mardis, R. K. Wilson, M. F. Zakowski, V. W. Rusch, H. E. Varmus, W. Pao
Journal: Journal of Clinical Oncology (2007)

7584 Background: About fifty percent of lung adenocarcinomas harbor somatic mutations in six genes that encode signaling proteins in the EGFR signaling pathway, i.e. EGFR, HER2/ERBB2, HER4/ERBB4, PIK3CA, BRAF, and KRAS. We performed mutational profiling of a large cohort of lung adenocarcinomas to uncover other somatic mutations that could contribute to lung tumorigenesis. Methods: We analyzed genomic DNA from 261 resected, clinically well-annotated non-small cell lung cancer (NSCLC) specimens. 90% of tumors were adenocarcinomas, and 10% were squamous cell carcinomas. The coding sequences of 39 genes, encoding proteins mostly in the EGFR signaling cascade and FGFR1–4, were screened for somatic mutations via high-throughput dideoxynucleotide sequencing of PCR-amplified gene products. Mutations were considered to be somatic only if they were found in an independent tumor-derived PCR product but not in matched normal tissue. Results: First-pass analysis of 9 MB of tumor sequence identified 199 distinct types of genetic variants that differed from published reference sequences. At least one variant was found in each gene analyzed. In addition to 6 variants found in RAS genes, we further examined the 94 variants localized to exons encoding the kinase domain of respective proteins. We have thus far identified known somatic mutations in EGFR, KRAS, BRAF, and PIK3CA, in addition to a number of previously unreported single nucleotide polymorphisms (SNPs). Conclusions: Mutational profiling of genes that encode for components of the EGFR signaling pathway has revealed multiple putative genetic variants in lung adenocarcinomas. Further analysis of potential somatic mutations is in progress. No significant financial relationships to disclose.
High-dose chemotherapy and autologous hematopoietic stem-cell transplantation for aggressive non-Hodgkin's lymphoma.
Authors: J M Vose, J R Anderson, A Kessinger, P J Bierman, P Coccia, E C Reed, B Gordon, J O Armitage
Journal: Journal of Clinical Oncology (1993)

To evaluate clinical and tumor characteristics in patients receiving high-dose chemotherapy and autologous peripheral stem-cell transplantation (PSCT) or bone marrow transplantation (ABMT) for relapsed or primary refractory non-Hodgkin's lymphoma (NHL).One hundred fifty-eight patients with NHL received high-dose chemotherapy and ABMT or PSCT. A multivariate analysis of characteristics was performed for comparison of the long-term failure-free survival (FFS) rate.Using a multivariate analysis, a prognostic model was constructed with patients in the good-prognosis group being those without a mass > or = 10 cm at the time of transplant, and no more than one of the following characteristics: three or more prior chemotherapy regimens, lactate dehydrogenase (LDH) level above normal, and chemotherapy resistance. Patients in the poor-prognosis group had a mass > or = 10 cm, or two of the other characteristics noted. The poor-prognosis group had a 3-year FFS rate of 10%, compared with a 45% 3-year FFS in the good-prognosis group (P < .001). Within the prognostic groups, there was no difference in the 3-year FFS rate of the poor-prognosis patients who received ABMT versus PSCT (10% v 12%; not significant). However, in the good-prognosis group, patients who received ABMT had a 3-year FFS rate of 32%, compared with 70% for those who received PSCT (P < .008).This prognostic model can identify patients with good and poor prognoses following high-dose chemotherapy and ABMT or PSCT for aggressive NHL. In good-prognosis patients, those who received PSCT had a superior FFS rate.
Dose-Response Studies of the Effect of Dietary Butylated Hydroxyanisole on Colon Carcinogenesis Induced by Methylazoxymethanol Acetate in Female CF1 Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: B S Reddy, Y Maeura
Journal: JNCI Journal of the National Cancer Institute (1984)

The effect of dietary butylated hydroxyanisole (BHA) on methylazoxymethanol acetate [(MAM AC) CAS: 592-62-1; methyl-ONN-azoxy)methanol acetate]-induced intestinal carcinogenesis was studied in female CF1 mice. BHA was added at levels of 0, 0.03, 0.1, 0.3, and 0.6% to the NIH-07 open-formula diet and at 0 and 0.6% to the AIN-76 semipurified diet and fed to mice, starting at 5 weeks of age until termination of the experiment. At 7 weeks of age, all animals except the vehicle-treated controls were given ip injections of MAM AC (15 mg/kg body wt for four times in 11 days for the low-dose group: total dose, 60 mg/kg body; 15 mg/kg body wt for eight times in 22 days for the high-dose group: total dose, 120 mg/kg body wt). With a low dose of carcinogen, the lung tumor incidence was inhibited in mice fed the NIH-07 diet containing 0.03-0.6% BHA and the AIN-76 diet containing 0.6% BHA compared to lung tumor incidence in those fed the diets without BHA; with a high dose of carcinogen, the inhibition was observed in mice fed the NIH-07 diet containing 0.1-0.6% BHA. Colon tumor incidence and colon tumor multiplicity (number of tumors per animal and number of tumors per tumor-bearing animal, respectively) were lower in mice fed the NIH-07 diets with 0.03-0.6% BHA or fed the AIN-76 diet with 0.6% BHA, as well as treated with a low dose of carcinogen, than in animals fed no BHA; with a high dose of carcinogen, colon tumor multiplicity and colon tumor incidence were inhibited in animals fed the NIH-07 diet containing 0.1-0.6% BHA. Consumption of the NIH-07 diets containing 0.03-0.6% BHA resulted in increased glutathione transferase activity of liver and small intestinal and colon mucosae in a dose-related manner.
Effects of Nonsteroidal Antiestrogens, Analog II and Tamoxifen, on a Metastatic Transplantable Rat Mammary Tumor&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: M M King, R A Magarian, J Terao, G L Brueggemann
Journal: JNCI Journal of the National Cancer Institute (1985)

This study was designed to determine whether treatment with the nonsteroidal antiestrogens analog II and tamoxifen given three times per week, 2 weeks before and 2 weeks after tumor cell transplantation, influenced the metastasis of a transplantable, metastatic rat mammary tumor, DMBA-4. Following transplantation of 2,000 viable tumor cells into the fifth and sixth mammary fat pads of 50-day-old inbred, female WF rats, all rats in all 3 groups displayed primary tumors by 5 weeks post tumor transplant. Analog II delayed the primary tumor development when compared to the time of the primary tumor development in either the control (untreated) or tamoxifen-treated groups. No metastatic tumors were found in the analog II-treated group 5 weeks after tumor transplantation, and only 1 animal in the tamoxifen-treated group had a secondary tumor, whereas 50% of the control animals had metastatic tumors. Six weeks after tumor implantation, palpable secondary tumors had developed in 40% of the analog II-treated group and 80% of the tamoxifen-treated group, whereas 60% of the control animals had developed secondary tumors. By the end of the study (7 wk) no differences existed between primary or secondary tumor incidences or between control and antiestrogen-treated groups. Both antiestrogens were effective in delaying the development of secondary tumors, especially during the time of treatment. Following cessation of treatment, analog II prevented metastatic tumor development for up to a month and tamoxifen, for 3 weeks. Further studies are indicated to determine if continuous treatment can effectively inhibit metastatic tumor development indefinitely.
Benefit from bevacizumab (BV) is independent of pretreatment plasma vascular endothelial growth factor-A (pl-VEGF) in patients (pts) with metastatic colorectal cancer (mCRC)
Authors: S. N. Holden, E. Ryan, A. Kearns, E. Holmgren, H. Hurwitz
Journal: Journal of Clinical Oncology (2005)

3555 Background: BV (Avastin™) is a monoclonal antibody to VEGF; in the pivotal trial in mCRC, addition of BV to first-line irinotecan, 5-fluorouracil and leucovorin (IFL) significantly prolonged progression-free survival (PFS) and overall survival (OS). pl-VEGF has been shown to be prognostic in mCRC. We developed a highly sensitive pl-VEGF enzyme-linked immunosorbent assay (ELISA) to correlate pretreatment pl-VEGF concentration with PFS and OS for both overall prognosis and prediction of response to BV. Methods: In the pivotal trial, pretreatment pl-VEGF samples were collected in the first 398 pts randomized to IFL plus either BV or placebo; 384 pts (193 BV, 191 placebo) consented for non-pharmacokinetic studies of these samples. Citrated pl-VEGF was measured by an indirect ELISA with upper and lower limits of quantitation of 889 and 12.5 pg/mL, respectively, and treated as a continuous variable in these analyses. Median OS and PFS were estimated from Kaplan-Meier curves and hazard ratios (HRs) by Cox regression. Results: Comparison of the 95% confidence intervals (CIs) around the HRs for PFS and OS between this subgroup and the overall trial population show that survival outcomes are similar. pl-VEGF was detected in 337 of 384 samples; 47 samples (12%) were < 12.5 pg/mL, 4 (1%) were >889 pg/mL (median 44 pg/mL). The HR for OS in all subgroup pts with respect to pl-VEGF (prognostic analysis) is significantly >1, suggesting an increasing risk of death with increasing pl-VEGF. The HRs comparing PFS and OS between BV-treated pts and controls with respect to pl-VEGF (predictive analyses) are not significantly different from 1, suggesting no relationship. Conclusion: This retrospective subset analysis suggests that the survival benefit associated with BV is independent of pretreatment pl-VEGF. These data support previous reports that increasing pl-VEGF is negatively prognostic in mCRC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech, GlaxoSmithKline, Pfizer Genentech Genentech