tbuckley/cabot-search huggingface dataset:
Change in bone alkaline phosphatase as an outcome predictor in men with hormone-refractory prostate cancer metastasized to bone
Authors: A. R. Allen, F. Saad, S. M. Hulting, J. D. Isaacson, D. J. Sleep
Journal: Journal of Clinical Oncology (2004)

4655 Background: Bone alkaline phosphatase (BAP) has been validated as a potential predictor of survival in hormone-refractory prostate cancer (HRPC) patients. Phase 2 results show that atrasentan, a potent, selective, oral endothelin A receptor antagonist, significantly attenuates BAP increase in men with metastatic HRPC. We tested the hypothesis that BAP change predicts time to disease progression (TTP) and survival in men with HRPC metastasized to bone. Methods: Data from 684* HRPC patients with bony metastases included in a phase 3, randomized, double-blind, placebo-controlled trial of atrasentan were stratified by the treatment-pooled median change in BAP from baseline at weeks 4, 8, and 12. Kaplan-Meier and Cox proportional hazard methodologies were used to compare TTP (a composite of radiographic and clinical measures) and survival in each group at each time point. Atrasentan treatment effect was analyzed using analysis of covariance comparing changes in BAP from baseline between treatment arms. Results: TTP was significantly delayed in patients whose change from baseline in BAP was lower than the pooled median change at that time point versus those whose change was higher than the median (table). Survival was also prolonged in patients with a BAP change from baseline below the median versus those above the median (week 4: HR = 1.29, 95% CI = 0.99–1.67, p=0.057; week 8: HR = 1.77, 95% CI = 1.34–2.34, p<0.001; week 12: HR = 1.77, 95% CI = 1.31–2.40, p<0.001). Atrasentan resulted in a significantly lower mean change in BAP from baseline at weeks 4, 8, and 12 versus placebo (p<0.001, p=0.006, p=0.001). Conclusion: These data support the hypothesis that change in BAP is predictive of TTP and survival in HRPC patients with bony metastases. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories Abbott Laboratories
SynthEx: a synthetic-normal-based DNA sequencing tool for copy number alteration detection and tumor heterogeneity profiling
Authors: Grace O. Silva, Marni B. Siegel, Lisle E. Mose, Joel S. Parker, Wei Sun, Charles M. Perou, Mengjie Chen
Journal: Genome biology (2017)

Changes in the quantity of genetic material, known as somatic copy number alterations (CNAs), can drive tumorigenesis. Many methods exist for assessing CNAs using microarrays, but considerable technical issues limit current CNA calling based upon DNA sequencing. We present SynthEx, a novel tool for detecting CNAs from whole exome and genome sequencing. SynthEx utilizes a "synthetic-normal" strategy to overcome technical and financial issues. In terms of accuracy and precision, SynthEx is highly comparable to array-based methods and outperforms sequencing-based CNA detection tools. SynthEx robustly identifies CNAs using sequencing data without the additional costs associated with matched normal specimens.
Phase I trial of hu3S193 in patients with advanced epithelial cancers which express the Lewis-y antigen
Authors: A. M. Scott, N. Tebbutt, F.-T. Lee, T. Cavicchiolo, Z. Liu, A. Poon, M. W. Brechbiel, E. Stockert, E. W. Hoffman, L. J. Old
Journal: Journal of Clinical Oncology (2004)

2567 Background: The Lewis-y (Ley) antigen is a blood group related antigen that is expressed in a high proportion of epithelial cancers. We have generated a humanised antibody (hu3S193) against Ley, which has potent immune effector function, and efficacy in murine tumour models (Scott et al, Cancer Res 60: 3254–3261, 2000). Methods: An open label dose escalation Phase I trial of hu3S193 in patients (pts) with advanced Ley positive epithelial cancers has been conducted. Inclusion criteria included +ve Ley expression in tumour assessed prior to study entry. Pts received 4 infusions of hu3S193 at weekly intervals, with four dose levels (5, 10, 20 and 40 mg/m2). The first infusion of hu3S193 was trace labelled with 111In to evaluate targeting. Biodistribution, pharmacokinetics, and immune response were evaluated in all patients. Results: A total of 12 pts (6M:6F; age range 42–76 yrs; 5 breast, 7 colorectal cancer) have been accrued into the study, completing the 5 (3 pts), 10 (6 pts) and 20 (3 pts) mg/m2 dose levels. No infusion related AEs were observed. There was one episode of dose limiting toxicity, at the 10mg/m2 dose level, with Grade 3 liver enzyme rise observed in a pt with extensive liver metastases, which resolved following cessation of hu3S193 infusions. The biodistribution of 111In-hu3S193 showed no normal tissue uptake, and 111In-hu3S193 uptake was observed in cutaneous, lymph node and hepatic metastases. Pharmacokinetic analysis showed no dose dependence of 111In-hu3S193 serum clearance, with a (mean ± SD) T½α 6.2 ± 5.5 hrs, T½β 183.1 ± 66.4 hrs, CL 0.025 ± 0.014 L/hr, V1 3.43 ± 0.63 L. No immune responses (HAHA) were observed in any pt. Two pts had stable disease and 10 PD at restaging. Conclusions: Hu3S193 has promise for immunotherapy of Ley +ve tumours, and further Phase I/II clinical trials are planned. No significant financial relationships to disclose.
Single institution experience of post transplant lymphoproliferative disorder in liver transplant recipients.
Authors: Yasser Ged, Ahmed abu Shanab, Naeem Ullah, Aidan McCormick, David William Fennelly, Giuseppe Gullo, John Crown
Journal: Journal of Clinical Oncology (2015)

e19512 Background: Post transplant lymphoproliferative disorder (PTLD) is a rare complication of therapeutic immunosuppression in liver transplant patients and has a high mortality rate. Methods: Retrospective analysis of patients who had PTLD after liver transplantation at the national liver transplant centre in Ireland (1993 to 2013). Patients were identified from review of the liver transplant records. Results: 19 PTLD cases were diagnosed between 2000 and 2013 out of 710 liver transplant cases (2.7%). Patients characteristics are as follows: Median age at PTLD diagnosis 61 years (range 29-75),males (n = 16, 84%), median time from transplant to PTLD 76 months (range 19-173), most common indication for transplant was primary sclerosing cholangitis (PSC) (n = 7). Thirteen patients (68%) had intra abdominal disease, 6 patients (31.5%) had extra nodal disease including 2 with CNS involvement. PTLD histology consisted of 14 (74 %) monomorphic, 3 (16%) polymorphic disease and 2 (10%) Hodgkin lymphoma-like PTLD. Median follow up time was 17 months (range 1-166). All patients had initial reduction in immunosuppressive therapy, 17 patients had chemotherapy (CT) (Among these 12 had Rituximab with chemotherapy, 2 had surgery and 2 radiotherapy), 1 patient had single-agent Rituximab, 1 patient died before treatment. Complete Response (CR) was obtained in 10 patients (53%). At the last database cut-off, 11 patients had died : 5 were due to treatment-related complications and 3 due to progressive disease. 8 patients (7 treated with CT and 1 with Rituximab alone) are still alive and in CR with a median follow up of 64 months from diagnosis. Conclusions: Our incidence of PTLD was comparable to the reported literature. Higher PTLD rates were observed in PSC transplant recipients and male patients. Achieving durable CR is possible in PTLD patients with the appropriate use of CT and Rituximab. Special attention should be put in managing treatment toxicities in this group of patients with meaningful comorbidities.
Randomized phase II study of pemetrexed versus gefitinib in previously treated patients with advanced non-small cell lung cancer.
Authors: Young Saing Kim, Eun Kyung Cho, Sun Jin Sym, Junshik Hong, Inkeun Park, Hee Kyung Ahn, Jeong Woong Park, Sung Hwan Jung, Jinny Park, Jae Hoon Lee, Dong Bok Shin
Journal: Journal of Clinical Oncology (2014)

e19039 Background: Both pemetrexed and gefitinib have been shown to be efficacious and well tolerated in patients with pretreated advanced non-small cell lung cancer (NSCLC). We undertook a randomized phase II study to evaluate the efficacy and safety of pemetrexed versus gefitinib as second-line treatment in patients with advanced NSCLC. Methods: Patients with histologically or cytologically confirmed advanced (stage IIIB or IV) or recurrent NSCLC were randomly assigned to receive either 500 mg/m² of pemetrexed intravenously every 3 weeks or gefitinib 250 mg/day orally until disease progression, intolerable toxicity or withdrawal of consent. Patients were stratified by histology (adenocarcinoma vs. others), smoking history (present vs. never), and performance status (0-1 vs. 2). In the middle of the study, an amendment was implemented to exclude patients with EGFR mutations. Results: A total of 88 patients were enrolled (45 in pemetrexed arm and 43 in gefitinib arm). Most patients were male (69%) and 81% had non-squamous cell carcinoma. EGFR mutation status was known for 36 patients (41%); 34 patients had wild-type EGFR (pemetrexed, n = 13; gefitinib, n = 21) and one patient per each arm was positive for EGFR mutation. No significance differences between two arms were found in terms of the PFS (2.0 months per each arm, P = 0.942) or overall survival (OS) (8.5 months per each arm, P = 0.784). In EGFR wild-type patients, pemetrexed arm achieved numerically longer survival compared to gefitinib arm (median PFS: 6.6 vs. 3.1 months, P = 0.579; median OS: 20.9 vs. 12.7 months, P = 0.438). Frequently reported toxicities were anemia (51%) and fatigue (42%) for pemetrexed, and skin rash (49%) and anorexia (42%) for gefitinib. Grade 3 or 4 adverse events occurred in 18% with pemetrexed and 21% with gefitinib. Conclusions: Both pemetrexed and gefitinib showed comparable efficacy with excellent tolerability for second-line treatment in unselected patients with advanced NSCLC. Although not statistically significant, median PFS and OS favored the pemetrexed arm compared to the gefitinib arm in patients with wild-type EGFR. Clinical trial information: NCT01783834.
Network Analysis Reveals a Signaling Regulatory Loop in the <i>PIK3CA</i>-Mutated Breast Cancer Predicting Survival Outcome
Authors: Shauna R. McGee, Chabane Tibiche, Mark Trifiro, Edwin Wang
Journal: Genomics Proteomics & Bioinformatics (2017)

Mutated genes are rarely common even in the same pathological type between cancer patients and as such, it has been very challenging to interpret genome sequencing data and difficult to predict clinical outcomes. PIK3CA is one of a few genes whose mutations are relatively popular in tumors. For example, more than 46.6% of luminal-A breast cancer samples have PIK3CA mutated, whereas only 35.5% of all breast cancer samples contain PIK3CA mutations. To understand the function of PIK3CA mutations in luminal A breast cancer, we applied our recently-proposed Cancer Hallmark Network Framework to investigate the network motifs in the PIK3CA-mutated luminal A tumors. We found that more than 70% of the PIK3CA-mutated luminal A tumors contain a positive regulatory loop where a master regulator (PDGF-D), a second regulator (FLT1) and an output node (SHC1) work together. Importantly, we found the luminal A breast cancer patients harboring the PIK3CA mutation and this positive regulatory loop in their tumors have significantly longer survival than those harboring PIK3CA mutation only in their tumors. These findings suggest that the underlying molecular mechanism of PIK3CA mutations in luminal A patients can participate in a positive regulatory loop, and furthermore the positive regulatory loop (PDGF-D/FLT1/SHC1) has a predictive power for the survival of the PIK3CA-mutated luminal A patients.
Pemetrexed plus gemcitabine as front-line therapy for patients with advanced stage non-small cell lung cancer
Authors: J. Treat, M. McCleod, D. Mintzer, N. Christiansen, P. Bonomi, M. Monberg, L. Taylor, C. Obasaju
Journal: Journal of Clinical Oncology (2004)

7130 Background: Pemetrexed (ALIMTA), a multitargeted antifolate (MTA) and gemcitabine (GEM, GEMZAR) have demonstrated independent anti-tumor activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). The combination of these two therapies may produce synergistic anti-tumor effects. Previous studies of this combination have included a 90 min separation between the two drugs. More recent preclinical studies have suggested that this delay in administration might be unnecessary. This phase II study was designed to determine the objective tumor response rate and toxicity when pemetrexed is administered immediately after GEM on Day 8. Methods: Forty-six chemonaive patients Stage IIIB with pleural effusion or Stage IV NSCLC have been enrolled. Treatment consisted of GEM 1250mg/m2 (30-mins IV infusion on Days 1 and 8) and pemetrexed 500mg/m2, (10-minute IV infusion, immediately following GEM, on Day 1) q21 days. All patients received folic acid, vitamin B12, and steroid prophylaxis. Results: To date, results are available on 27 patients (18 M/9 F). Median age was 64.0 (range = 48–79) years, ECOG PS 0:1 = 25.9%:59.3%, Stage IIIB:IV = 11.1%:88.9%, Non-squamous (74%), squamous (26%). Cycle specific Grade 3/4 hematologic and non-hematologic toxicities consisted of neutropenia (15.8%), anemia (0%), thrombocytopenia (1.8%), asthenia (3.5%), renal insufficiency (1.8%), rash (5.3%). There were no patients experiencing grade 2 alopecia. Conclusions: This schedule of pemetrexed + GEM is very tolerable and offers the advantage of not requiring a 90 min delay between the two drugs. Complete toxicity, response and time to event results on all the 48 patients will be presented. Supported by a grant from Eli Lilly and Company, Indianapolis, IN. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eli Lilly & Co. Eli Lilly & Co.
DNA Methylation Divergence and Tissue Specialization in the Developing Mouse Placenta
Authors: Benjamin E. Decato, Jorge Lopez-Tello, Amanda N. Sferruzzi-Perri, Andrew D. Smith, Matthew D. Dean
Journal: Molecular Biology and Evolution (2017)

The placental epigenome plays a vital role in regulating mammalian growth and development. Aberrations in placental DNA methylation are linked to several disease states, including intrauterine growth restriction and preeclampsia. Studying the evolution and development of the placental epigenome is critical to understanding the origin and progression of such diseases. Although high-resolution studies have found substantial variation between placental methylomes of different species, the nature of methylome variation has yet to be characterized within any individual species. We conducted a study of placental DNA methylation at high resolution in multiple strains and closely related species of house mice (Mus musculus musculus, Mus m. domesticus, and M. spretus), across developmental timepoints (embryonic days 15-18), and between two distinct layers (labyrinthine transport and junctional endocrine). We observed substantial genome-wide methylation heterogeneity in mouse placenta compared with other differentiated tissues. Species-specific methylation profiles were concentrated in retrotransposon subfamilies, specifically RLTR10 and RLTR20 subfamilies. Regulatory regions such as gene promoters and CpG islands displayed cross-species conservation, but showed strong differences between layers and developmental timepoints. Partially methylated domains exist in the mouse placenta and widen during development. Taken together, our results characterize the mouse placental methylome as a highly heterogeneous and deregulated landscape globally, intermixed with actively regulated promoter and retrotransposon sequences.
Risk of tuberculosis among air passengers estimated by interferon gamma release assay: survey of contact investigations, Japan, 2012 to 2015
Authors: Masaki Ota, Seiya Kato
Journal: Eurosurveillance (2017)

Although the World Health Organization recommends contact investigations around air travel-associated sputum smear-positive tuberculosis (TB) patients, evidence suggests that the information thus obtained may have overestimated the risk of TB infection because it involved some contacts born in countries with high TB burden who were likely to have been infected with TB in the past, or because tuberculin skin tests were used, which are less specific than the interferon gamma release assay (IGRA) particularly in areas where Bacillus Calmette-Guérin (BCG) vaccination coverage is high. We conducted a questionnaire survey on air travel-associated TB contact investigations in local health offices of Japan from 2012 to 2015, focusing on IGRA positivity. Among 651 air travel-associated TB contacts, average positivity was 3.8% (95% confidence interval (CI): 2.5-5.6) with a statistically significant increasing trend with older age (p < 0.0094). Positivity among 0-34 year-old contacts was 1.0% (95% CI: 0.12-3.5%), suggesting their risk of TB infection is as small as among Japanese young adults with low risk of TB infection (positivity: 0.85-0.90%). Limiting the contact investigation to fewer passengers (within two seats surrounding the index case, rather than two rows) seems reasonable in the case of aircraft with many seats per row.
Immune Modulatory microRNAs Involved in Tumor Attack and Tumor Immune Escape
Authors: Stefan B. Eichmüller, Wolfram Osen, Ofer Mandelboim, Barbara Seliger
Journal: JNCI Journal of the National Cancer Institute (2017)

Current therapies against cancer utilize the patient's immune system for tumor eradication. However, tumor cells can evade immune surveillance of CD8+ T and/or natural killer (NK) cells by various strategies. These include the aberrant expression of human leukocyte antigen (HLA) class I antigens, co-inhibitory or costimulatory molecules, and components of the interferon (IFN) signal transduction pathway. In addition, alterations of the tumor microenvironment could interfere with efficient antitumor immune responses by downregulating or inhibiting the frequency and/or functional activity of immune effector cells and professional antigen-presenting cells. Recently, microRNAs (miRNAs) have been identified as major players in the post-transcriptional regulation of gene expression, thereby controlling many physiological and also pathophysiological processes including neoplastic transformation. Indeed, the cellular miRNA expression pattern is frequently altered in many tumors of distinct origin, demonstrating the tumor suppressive or oncogenic potential of miRNAs. Furthermore, there is increasing evidence that miRNAs could also influence antitumor immune responses by affecting the expression of immune modulatory molecules in tumor and immune cells. Apart from their important role in tumor immune escape and altered tumor-host interaction, immune modulatory miRNAs often exert neoplastic properties, thus representing promising targets for future combined immunotherapy approaches. This review focuses on the characterization of miRNAs involved in the regulation of immune surveillance or immune escape of tumors and their potential use as diagnostic and prognostic biomarkers or as therapeutic targets.
Explaining the Coincidence Rule for Estimating Respiratory Compensation in Metabolic Acid–Base Disorders
Authors: George S. Liu, Vivek Bhalla
Journal: Annals of Internal Medicine (2017)

Letters18 April 2017Explaining the Coincidence Rule for Estimating Respiratory Compensation in Metabolic Acid–Base DisordersGeorge S. Liu, AB and Vivek Bhalla, MDGeorge S. Liu, ABFrom Stanford University School of Medicine, Stanford, California.Search for more papers by this author and Vivek Bhalla, MDFrom Stanford University School of Medicine, Stanford, California.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L16-0470 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Background: Acid–base homeostasis is an important yet nonintuitive part of medical training. One aid is the coincidence rule (1), which applies to patients with metabolic acid–base disorders and respiratory systems that are able to compensate normally for their metabolic disorder. It states that when arterial blood gas is measured, the first 2 digits of the pH after the decimal point approximate the expected Paco2. The logic behind this rule remains poorly understood.Objective: To explain why the coincidence rule works.Methods and Findings: The equation for the coincidence rule for pH values between 7.00 and 7.99 is as follows: Download figure Download PowerPoint ... References1. Fulop M. A guide for predicting arterial CO2 tension in metabolic acidosis. Am J Nephrol. 1997;17:421-4. [PMID: 9382159] CrossrefMedlineGoogle Scholar2. Albert MS, Dell RB, Winters RW. Quantitative displacement of acid–base equilibrium in metabolic acidosis. Ann Intern Med. 1967;66:312-22. [PMID: 6016545] LinkGoogle Scholar3. Hasan A. Handbook of Blood Gas/Acid–Base Interpretation. 2nd ed. London: Springer-Verlag; 2013. doi:10.1007/978-1-4471-4315-4 CrossrefGoogle Scholar Author, Article, and Disclosure InformationAffiliations: From Stanford University School of Medicine, Stanford, California.Acknowledgment: The authors thank Drs. Timothy Meyer and Alan Pao (Stanford University) for critical discussions and their commitment to teaching acid–base homeostasis to medical trainees.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L16-0470.This article was published at Annals.org on 4 April 2017. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 18 April 2017Volume 166, Issue 8Page: 610KeywordsAcidosisArterial blood gasAttentionBicarbonatesBloodConflicts of interestDisclosureMetabolic disordersRespiratory system ePublished: 4 April 2017 Issue Published: 18 April 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...