tbuckley/cabot-search huggingface dataset:
The relationship between place of residence and child survival in Brazil.
Authors: Sastry N, Goldman N, Moreno L
Journal: BMJ (1993)

Hazards models were analyzed and revealed that selected covariates and child mortality were different between northeast Brazil and the rest of Brazil.  Simple urban and rural differences in child mortality were not apparent.  Analysis based on the northeast and the rest of Brazil proved to be the most discerning.  The confidence in selecting significant variables was limited by the small number of deaths (233 deaths out of 3477 live births).  5 different hazard models were presented.  The first model included demographic and reproductive covariates; the second contained location and migration covariates.  The third combined the first and second model covariates.  The fourth model included socioeconomic covariates to the first models covariates.  The final model included all covariates.  The results showed the importance of the effects of place of residence and migration status.  In the northeast a childs survival chances were related to community characteristics. For the rest of BrazIl urban residents did not have improved survival chances after controlling for demographic and socioeconomic characteristics and reproductive patterns.  Population size was a critical factor.  Mortality differences between the northeast and the rest of Brazil could be explained by differences in childbearing patterns.  Maternal age parity and birth spacing were found to be similar for the 2 regions.  High-risks births were associated with diminished socioeconomic status of women particularly in the northeast where disadvantaged circumstances and negative conditions were most severe.  Maternal education did not have the anticipated effect.  A detailed study of community characteristics is warranted; some preliminary notions from the results for the rest of Brazil suggest that modern medical services are beneficial only when women are able to take advantage of them.  This means targeting the disadvantaged with preventive or promotional measures as a useful health expenditure.  Data were obtained from the Brazil Demographic and Health Survey in 1986 on 5892 women aged 15-44 years.
Anti-Fungal Prophylaxis Using Intermediate Dose Ambisome Is Associated with Delayed Methotrexate Clearance in Pediatric Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Liora M. Schultz, Karan Kumar, Suzette Stone, Elizabeth Callard, Jessica Witkowski, Leigh Shinn, Lisa Pinner, Shizuka Franklin, Julianna Kula, Namrata Patel, Prianka Kumar, Kenneth I. Weinberg, Matthew Porteus, Rajni Agarwal, Ami Shah, Sandhya Kharbanda
Journal: Blood (2016)
A nomogram predicting disease-specific survival after nephrectomy for papillary renal cell carcinoma
Authors: T. Klatte, M. Remzi, J. W. Said, A. Haitel, F. F. Kabbinavar, M. Waldert, M. de Martino, M. Marberger, A. S. Belldegrun, A. J. Pantuck
Journal: Journal of Clinical Oncology (2009)

5091 Background: Whereas multiple nomograms have been developed to assess outcomes of patients with clear cell renal cell carcinoma, a model to assess prognosis of papillary renal cell carcinoma (PRCC) has not yet been developed. After data collection and slide review of a large cohort of patients, the aim of this study was to develop and to internally validate a nomogram for prediction of disease-specific survival for PRCC. Methods: Out of 2,687 patients who underwent surgery for a renal tumor between 1989 and 2008 at two institutions, 258 (10%) were found to have PRCC. H&amp;E slides were reviewed by one uro-pathologist at each institution for papillary sub-type, tumor grade, microvascular invasion, sarcomatoid features, collecting system invasion and presence and extent of tumor necrosis. A nomogram was constructed as a graphical representation of significant variables of disease-specific survival in multivariate Cox proportional hazards regression analysis. The discrimination and calibration of the nomogram were assessed, both utilizing bootstrapping to obtain relatively unbiased estimates. Results: After a median follow-up of 35 months, 49 PRCC-related deaths (19%) had occurred. In univariate analysis, incidental detection, T, N, M stage, grade, microvascular invasion, collecting system invasion, papillary sub-type, sarcomatoid features, and necrosis were all associated with prognosis. Multivariate Cox proportional hazards analysis, however, identified incidental detection, T stage, M stage, microvascular invasion, and necrosis, but not papillary sub-type as independent prognostic factors of disease-specific survival. These variables formed the basis of the nomogram that predicted 5-year disease-specific survival probability. The nomogram predicted well, with a bootstrapped corrected concordance index of 0.93, and showed good calibration. Conclusions: A highly accurate tool utilizing basic clinical and pathological information for predicting disease-specific survival was developed specifically for PRCC. This tool should be helpful for identification of the subset of PRCC patients with aggressive clinical behavior, and may contribute to the ability to individualize postoperative surveillance and therapy. No significant financial relationships to disclose.
Using a program that computes tumor decay (d) and regrowth (g) rates and the fraction (Φ) of tumor killed to assist in clinical trials and improve patient survival.
Authors: Julia Wilkerson, Susan Elaine Bates, Wilfred Donald Stein, Tito Fojo
Journal: Journal of Clinical Oncology (2013)

e22213 Background: Clinical trials collect much data on tumor quantity as therapy proceeds. From this data progression endpoints and response rates are reported and used to evaluate efficacy. But there is much information contained therein that allows us to understand mechanisms of drug action and how to best administer therapies. Methods: We have developed mathematical equations that enable extraction of the rates of tumor decay (d) and regrowth (g) and also the fraction (Φ) of tumor killed. Results: We have analyzed data from &gt;3,000 cases of various tumor histologies including prostate, breast, renal, and medullary thyroid cancers as well as multiple myeloma (MM). These malignancies have been treated with “cytotoxic” and “targeted” therapeutics as well as vaccines. Across all treatment modalities, overall survival does not correlate with the rate of decay, d, but correlates strongly with the growth rate, g. In some drug/tumor combinations, Φ can also be extracted and its role in the drug’s action ascertained. Most therapies developed in metastatic cancers such as ixabepilone in breast cancer and sunitinib in renal cancer are “g therapies”. Such therapies reduce g, impact survival favorably and could further impact survival if administered beyond conventional endpoints for progression. In contrast, “Φ therapies”, such as bortezomib in MM and ATTP in prostate cancer kill a larger fraction of tumor and are proposed to be effective as adjuvant and neo-adjuvant treatments, with little benefit from extending treatment in the metastatic setting. Furthermore, the data suggest resistance in most is likely intrinsic since tumor growth rates on therapy do not change appreciably over time. Conclusions: We have developed an analytical method that characterizes a tumor’s response to a therapy and enables extraction of tumor decay (d) and regrowth (g) rates and the fraction (Φ) of tumor killed. Both g and Φ, but not d, determine the effectiveness of a therapy. Use of these parameters should allow for the conduct of smaller trials and may also help improve patient survival. A stand-alone computer program has been built, is available to the research community and will be demonstrated.
Phase II efficacy trial of pazopanib in non-clear cell metastatic renal cell carcinoma (PINCR trial).
Authors: Brian Addis Costello, Thai Huu Ho, Winston Tan, Bradley C. Leibovich, Erik P. Castle, Alexander S. Parker, Roxana Stefania Dronca, Rui Qin, Manish Kohli
Journal: Journal of Clinical Oncology (2014)

TPS4606 Background: Seven treatments for metastatic renal cell carcinoma (mRCC) have been FDA approved since December, 2005. Most of the trials evaluating these agents excluded non-clear cell histologies and therefore the efficacy of these agents remains unclear in patients with metastatic non-clear cell RCC. One such agent is pazopanib, an oral tyrosine kinase inhibitor; its effects are being studied in patients with metastatic non-clear cell RCC in this trial. The primary endpoint is to determine the overall survival rate at 12 months in patients with metastatic non-clear cell RCC. Secondary endpoints are to determine best tumor response rates after two cycles, progression free survival and toxicity profile. Methods: Main eligibility criteria include: (1) age ³ 18 years old; (2) histologic confirmation of non-clear cell renal cancer; (3) ECOG Performance Status (PS) 0, 1, or 2; (4) up to one prior treatment for metastatic non-clear cell renal cell carcinoma is allowed as long as the agent was not pazopanib; (5) measurable or nonmeasurable metastatic disease as defined by RECIST criteria. This is a single arm Phase II study designed to determine the efficacy of pazopanib in metastatic non-clear cell RCC. Treatment is pazopanib 800 mg by mouth daily until progression or intolerability of treatment. Dose reductions are allowed for toxicity with dose level -1 being 600 mg daily and dose level -2, 400 mg daily. Cycles are 28 days. Routine evaluation includes history, examination, adverse events assessment, serum studies, and ECG with every cycle. Research blood and urine specimens are being collected for future correlative studies. All eligible patients will be followed until death or for a minimum of two years. The sample size will be 35 evaluable patients with accrual of 4 additional patients to account for ineligibility or other reasons. Full accrual is anticipated to take 24 months. Final analysis will begin approximately 36 months after the trial begins which is the time point at which the last patient enrolled can be observed for at least 12 months. The Mayo Clinic Cancer Center Data Safety Monitoring Board is responsible for reviewing accrual and safety data. Supported in part by GSK. Clinical trial information: NCT01767636.
The cell cycle checkpoint inhibitors in the treatment of leukemias
Authors: A. Ghelli Luserna di Rora’, I. Iacobucci, G. Martinelli
Journal: Journal of Hematology & Oncology (2017)

The inhibition of the DNA damage response (DDR) pathway in the treatment of cancers has recently reached an exciting stage with several cell cycle checkpoint inhibitors that are now being tested in several clinical trials in cancer patients. Although the great amount of pre-clinical and clinical data are from the solid tumor experience, only few studies have been done on leukemias using specific cell cycle checkpoint inhibitors. This review aims to summarize the most recent data found on the biological mechanisms of the response to DNA damages highlighting the role of the different elements of the DDR pathway in normal and cancer cells and focusing on the main genetic alteration or aberrant gene expression that has been found on acute and chronic leukemias. This review, for the first time, outlines the most important pre-clinical and clinical data available on the efficacy of cell cycle checkpoint inhibitors in single agent and in combination with different agents normally used for the treatment of acute and chronic leukemias.
QUANTITATIVE INVESTIGATIONS OF IDIOTYPIC ANTIBODIES
Authors: Harry Daugharty, John E. Hopper, A. Bruce MacDonald, Alfred Nisonoff
Journal: The Journal of Experimental Medicine (1969)

Specifically purified anti-p-azobenzoate antibodies of the IgG class from individual rabbits were used to elicit anti-idiotypic antibodies in recipient rabbits. Allotypes of each donor and recipient were matched. When polymerized antibodies were used for immunization, more than 80% of the recipients responded with the formation of antibodies that precipitated the monomeric donor antibody. Percentages of precipitable molecules in the donor antibody population (D) varied from 4 to 56. As little as 4% was readily detectable by the Ouchterlony method or precipitin test. Specificity of the reaction was tested by double diffusion in agar gel against a panel of purified antibenzoate antibodies from 14 heterologous rabbits and, quantitatively, in three systems by measurement of the extent of coprecipitation of heterologous, radiolabeled antibenzoate antibodies. No cross-reactions were observed. Reactions were shown to be attributable to antibenzoate antibodies in the donor serum, and contributions of allotypic reactions were excluded. In three systems investigated quantitatively, and in one studied qualitatively, two recipients of the same donor antibody produced anti-antibody that reacted with essentially the same subfraction of the donor antibody population. The findings that only a portion of the D population is immunogenic, and that the same subfraction is frequently immunogenic in different recipients, suggest that the immunogenic population comprises a limited number of homogeneous groups of antibody molecules. This is supported by the small number of bands usually observed by the Ouchterlony technique. Quantitative methods of analysis should provide an approach to the study of cell populations producing antibodies of a particular idiotype.
NF-κB p65 as a prognostic tool in prostate cancer: An immunohistochemical study from biopsy samples.
Authors: Ingrid Labouba, Philippe O. Gannon, Valerie Forest, Cécile Le Page, Cristina Storoz, Laurent Lessard, Anne-Marie Mes-Masson, Fred Saad
Journal: Journal of Clinical Oncology (2012)

e15202 Background: Our previous immunohistochemical studies of NF-κB p65 in prostate cancer (PCa) highlight its clinical potential as a prognostic marker in different cohorts of Canadian and European men. However these studies are essentially based on tissue microarrays (TMAs) built from samples obtained from radical prostatectomy specimens where other prognostic parameters, such as pathologic stage, Gleason score, and margin status are also available. However, limited prognostic parameters are available to clinicians at the time of diagnosis. The current study aims to assess whether the immunohistochemical staining of p65 could offer prognostic information at the time of diagnosis and help risk stratify patients. Methods: Prostatebiopsies were obtained from a cohort of 328 prostate cancer patients who were further treated by radical prostatectomy. NF-κB p65 was stained by immunochemistry on biopsy samples containing malignant tissue. The nuclear frequency was quantified as a percentage of positive p65 nuclear cells. Results: Our first statistical analyses revealed that the nuclear frequency of NF-κB p65 on biopsy samples was correlated with clinical paramaters as final Gleason score and BCR. Patients with Gleason score post-prostatectomy of 7 or more had a higher NF-κB p65 nuclear frequency in biopsy samples (p&lt;0.05, Student test). NF-κB p65 nuclear frequency was also higher in patients developing a BCR and bone metastasis (p&lt;0.05, Student test). Conclusions: These preliminary results show an association between NF-κB p65 nuclear distribution in biopsy samples and PCa aggressivity. We showed that NF-κB p65 immunohistochemical staining on biopsies was predictive of BCR. NFkB p65 may be prognostic marker at the time of diagnosis and could eventually be useful in clinical decision making.
Association of downregulation of toll-like receptor 3 (TLR3) expression with aggressive breast cancer (BC).
Authors: Elias Obeid, Rita Nanda, Terri Li, Bifeng Zhang, Jeffrey Mueller, Olufunmilayo I. Olopade
Journal: Journal of Clinical Oncology (2013)

11035 Background: Inflammation in the tumor microenvironment plays a key role in human breast cancer. We previously showed that a high proportion of alternatively-activated, tumor-associated macrophages (M2) are associated with increased microvessel density (MVD) and worse outcomes in BC. The anti-tumor effect of TLR3 is well recognized. To our knowledge, there are no studies evaluating TLR3 expression and characteristics of inflammation in primary breast tumors. Methods: 48 breast tumors were obtained from the University of Chicago Breast Cancer SPORE tissue bank under IRB approved protocols. Tissue microarrays were constructed and molecular subtypes assigned based on immunohistochemical (IHC) staining into: luminal A, luminal B, HER2-like, and basal-like. Macrophage density was determined using double staining with CD68/CD163. MVD was measured by IHC using anti-CD34. Staining quantification was done by a pathologist. To evaluate the association between M2 macrophages, TLR3 and MVD, Spearman's rho correlation coefficients were calculated. Survival comparison analysis was done using Wilcoxon statistic. Results: Of the tumors studied, 46% were LumA, 38% basal-like, 4% HER2-like, 2% LumB. We found a significant association between high MVD and high M2 content in tumors (p&lt;0.000). Tumors with high MVD exhibited shorter survival (Wilcoxon statistic 4.845, p=0.028). Spearman’s rho nonparametric correlations showed low TLR3 expression correlated with higher MVD (p=0.014), advanced pathologic tumor stage (p=0.046) and a trend for nodal disease (p=0.069). There was no statistically significant association between TLR3 expression and number of M2 macrophages (p=0.21). Conclusions: Neovascularization is promoted by tumor-associated macrophages and in turn poorer prognosis in BC. Our results suggest that reduced TLR3 expression is associated with more aggressive breast cancer. Future studies are needed to elucidate a mechanism by which TLR3 is downregulated in highly angiogenic BC. Thus, activation of TLR3 with TLR3-ligands such as poly (A:U) can potentially be coupled with anti-angiogenic therapies in patients with BC exhibiting low TLR3 expression and high MVD to improve treatment outcomes.
Relationship between quality of life and overall survival in metastatic castration-resistant prostate cancer (mCRPC) patients in ALSYMPCA.
Authors: Sten Nilsson, A. Oliver Sartor, Nicholas J. Vogelzang, Robert E. Coleman, Joe M. O'Sullivan, Neal D. Shore, Daniel Heinrich, David Bottomley, Peter Hoskin, Lars Franzen, Arne Solberg, Jonathan D. Reuning-Scherer, Lin Zhan, Chris Parker
Journal: Journal of Clinical Oncology (2017)

177 Background: Radium-223 improved overall survival (OS) with meaningful improvements vs placebo in health-related quality of life (HRQoL) in phase 3 ALSYMPCA (Parker NEJM 2013; Nilsson Ann Oncol 2016). We examined the relationship of OS to HRQoL scores at baseline or change from baseline. Methods: HRQoL in ALSYMPCA was assessed by FACT-P questionnaire at baseline, during treatment (wk 16, 24), and follow-up. Cox proportional hazards model for OS was fitted using HRQoL baseline scores and included previously identified covariates: treatment (radium-223 vs placebo); log 10 baseline LDH, ALP, and PSA; age; baseline ECOG-PS; and albumin. A time-dependent model also included change from baseline HRQoL scores. Results: Analysis includedbetween 810-836 patients with baseline HRQoL scores for various FACT-P metrics. Significant associations were seen between OS and FACT-P total score at baseline or change from baseline. Every 10-point increase in FACT-P total score (ie, improvement) was associated with 7% decreased risk of death (Table). Results for FACT-P subscales were similar, except social well-being. Conclusions: This analysis of ALSYMPCA data shows that baseline HRQoL and changes in HRQoL are prognostic of OS in mCRPC. Clinical trial information: NCT00699751. [Table: see text]
Predicting response to irinotecan/5-fluorouracil (5-FU) chemotherapy for advanced colorectal cancer based on gene expression in primary tumour
Authors: V. Coyle, W. Allen, P. Jithesh, D. McManus, M. Stevenson, R. Harte, M. Eatock, R. Wilson, P. Johnston
Journal: Journal of Clinical Oncology (2009)

e14558 Background: Despite improvements in the treatment of advanced colorectal cancer (CRC), there remains a subset of patients who fail to benefit from chemotherapy. The identification of predictive response markers has been limited by the relative scarcity of metastatic tumour samples for molecular analysis, prompting a need to consider surrogate models for generation of predictive markers. Methods: We performed gene expression profiling of archived formalin fixed paraffin-embedded (FFPE) colorectal primary tumours (dating from 2001–2007) from 40 patients who received irinotecan/5-FU chemotherapy as first line treatment for advanced disease. Patients were classified as responders/non-responders based on radiological response. Gene expression profiling was performed using the Almac Diagnostics Colorectal Disease Specific Array (DSA). Data was analysed using Genespring GX v7.3. Principal Components Analysis (PCA) was used to separate responding and non-responding patients based on the tumour- derived expression data. Predictive classifiers were constructed using several class prediction methods. The performance of the classifiers was assessed by leave-one-out cross-validation. Results: 37 samples passed data QC assessments for inclusion in predictive analysis. PCA using genes passing a t-test and 1.5-fold change filter demonstrated clear separation between responding and non-responding patients. Predictive modelling using the k-nearest neighbour and Support Vector Machine (SVM) algorithms with Fishers exact test as feature selection method each generated seven different predictive classifiers containing 5 to 35 genes; these had an average predictive accuracy of 80%. Predictive modelling of this dataset is ongoing and these encouraging initial results will be extended to a larger patient cohort. Conclusions: DNA microarray profiling has been used to generate gene signatures predictive of response to irinotecan/5-FU therapy in advanced CRC; importantly, these predictive signatures have been generated from FFPE colorectal primary tumour facilitating their independent validation in large patient cohorts and potential clinical implementation in the event of successful validation. [Table: see text]