tbuckley/cabot-search huggingface dataset:
Pre-biopsy PSA and biopsy gleason sum; evaluating the independence of two independent variables
Authors: T. McCann, P. M. Pierorazio, R. Mitchell, M. Desai, C. A. Olsson, M. C. Benson, J. McKiernan
Journal: Journal of Clinical Oncology (2006)

14555 Background: Traditionally PSA, Gleason sum and Clinical Stage are considered independent predictors of outcome for prostate cancer. The purpose of this study is to investigate a codependence between prostate specific antigen (PSA) and Gleason sum and whether this relationship has evolved during the PSA era. Methods: The Columbia Urologic Oncology Database was reviewed and 2,522 patients were identified who underwent radical prostatectomy from 1988 to 2005; a retrospective cohort of 1,786 patients with complete data was included. Patients were stratified by Gleason sum into groups with Gleason sum &lt;7, =7 and &gt;7. PSA was correlated to Gleason sum to examine a possible relationship between the two variables. Two-sample t-tests with 95% confidence intervals were utilized to determine differences between groups and were confirmed by ANOVA techniques. A Cox regression model using an interaction term between PSA and Gleason sum was fit to determine if an interaction exists between the two variables. Patients were further stratified into two cohorts by median year of surgery (1998) and the PSA-Gleason sum relationship was evaluated over time. Results: Median patient age was 61.9 years. 1,081 patients were identified with Gleason sum &lt;7. 540 patients had a Gleason sum =7. 165 patients had a Gleason sum &gt;7. The mean PSA values were 6.05, 6.89 and 8.41 for &lt;7, =7 and &gt;7 groups respectively. Differences between the means were statistically significant and validated by the ANOVA technique (p &lt; 0.001). A Cox regression model validated PSA, Gleason sum and clinical stage as independent predictors of outcome. The addition of an interaction term into the Cox regression model between PSA and Gleason sum demonstrated a significant interaction effect between PSA and Gleason sum (p &lt; 0.001). The relationship remained between PSA and Gleason sum within the pre and post 1998 groups (p &lt; 0.001). Conclusions: PSA and Gleason sum are highly interrelated variables, although they each carry additional information that significantly contributes to the prediction of biochemical failure (PSA ≥0.2 ng/ml). For an individual patient, the higher the initial PSA the higher the risk of having a high Gleason sum on biopsy. This relationship has remained constant over the PSA era. No significant financial relationships to disclose.
Molecular biology from bench-to-bedside: Which colorectal cancer patients to refer for genetic counseling
Authors: L. H. Jensen, L. Dysager, J. Lindebjerg, S. Kølvraa, L. Byriel, D. G. Crüger
Journal: Journal of Clinical Oncology (2009)

4113 Background: The single most common cause of hereditary colorectal cancer is the Lynch syndrome, which is associated with deficiency of the mismatch repair genes MLH1, MSH2, or MSH6. Most MLH1 negative tumors are sporadic in origin, and they can be identified if harbouring a BRAF V600E mutation or hypermethylation of the MLH1 promoter. If Lynch syndrome is detected in a patient and its family, screening can prevent death from new colorectal cancer. A family history should always be obtained, but in small families or patients with de-novo mutations and mutations with late or low penetrance, this is not sufficient. The aim of this study was to validate our previously suggested clinically applicable strategy based on molecular characteristics for identifying which patients to refer for genetic counselling. Methods: The strategy was validated in an unselected cohort of 287 colorectal cancer patients. All tumors was tested for MLH1, MSH2, and MSH6 with immunohistochemistry. DNA from MLH1 negative tumors was sequenced for BRAF mutations. If wild-type, MLH1 promoter was analyzed with methylation specific multiplex ligation-dependent probe amplification (MLPA). MLH1 negative tumors were considered sporadic if BRAF V600E mutation or MLH1 promoter hypermethylation was found. A follow up was done on patients with MSH2 or MSH6 negative tumors and MLH1 negative cases not shown to be sporadic. Results: Most tumors, 251 (88%), stained positive for all three proteins. Six (2%) had negative MSH2 and one (&lt;1%) isolated loss of MSH6. MLH1 was negative in 29 cases (10%). DNA quality allowed BRAF analysis in 27 of these with 14 mutations and 13 wild-type. DNA quality allowed MLPA in four of the 13 BRAF wild-type, and all four were methylated. Subsequently, Lynch syndrome could not be ruled out in 18 patients. A follow-up at 8–10 years revealed four definite Lynch syndrome and four highly suspicious. Conclusions: An easy and clinically applicable step-wise approach with immunohistochemistry (100%), BRAF sequencing (10%), and methylation analysis (5%) identified several patients with hereditary cancer. The family history should be supplemented with a molecular screening for whom to send for genetic counselling. No significant financial relationships to disclose.
Advancement to the clinic of an RNAi therapeutic for solid tumors
Authors: D. Bumcrot, I. Toudjarska, A. Judge, J. Brodsky, E. Ambegia, T. Buck, T. Racie, L. Jeffs, I. MacLachlan, J. Gollob, D. W. Sah
Journal: Journal of Clinical Oncology (2009)

3585 Background: Malignancies of the liver, including primary (hepatocellular carcinoma) and secondary (metastatic) tumors, represent a significant unmet medical need. We are developing a therapeutic for solid tumors involving the liver that is comprised of lipid particle-formulated short interfering RNAs (siRNAs) targeting VEGF and the mitotic kinesin, KSP (Eg5). For each target, potent siRNA duplexes were selected following extensive screening in tissue culture cells. Efficacy was demonstrated in a mouse liver tumor model. Methods: To assess efficacy in vivo, a stable nucleic acid lipid particle (SNALP) formulation was developed based on similar formulations previously shown to silence liver-expressed genes via systemic administration in multiple species. A SNALP-formulated combination of the KSP and VEGF siRNAs (referred to as ALN-VSP01) was tested in an orthotopic liver tumor model in which human hepatoma cells (Hep3B) are implanted directly into the livers of immunocompromised mice. Results: Intravenous administration of ALN-VSP01 leads to dose-dependent inhibition of both KSP and VEGF expression in established liver tumors. This was accompanied by the formation of numerous aberrant mitotic figures (“monoasters”) in tumor cells indicative of the pharmacologic inhibition of KSP. In addition, tumor growth was significantly inhibited by a course of ALN-VSP01 treatment, and ALN-VSP01 treatment provided a clear survival benefit even when treatment was initiated in animals with a significant tumor burden. As a control, a SNALP-formulated siRNA targeting Luciferase was administered and shown to have no effect in these studies. Conclusions: Systemic administration of ALN-VSP01 exhibited clear efficacy in a mouse orthotopic liver tumor model. Clinical testing of ALN-VSP01 is expected to initiate in early 2009. [Table: see text]
Abstract 242: Subcutaneous and Visceral Adipose-Derived Stem Cells Have Similar Biological Properties and Both Improve Cardiac Function of Infarcted Rat Hearts
Authors: Chao Chi, Bo Xiang, Jixian Deng, Fei Wang, Kanmani Natarajan, Hung-Yu Lin, Hongyu Liu, Francis Lin, Darren H. Freed, Rakesh C. Arora, Ganghong Tian
Journal: Circulation Research (2014)

Background: Adipose stem cells (ASC) from subcutaneous and visceral adipose tissues have been studied individually. However, it is unclear whether ASC from the two sources have different biological properties and, more importantly, whether one sub-type of ASC is more effective in treatment of CHF. This study was designed to address these concerns. Methods: Morphology, yield, proliferation, surface markers, and cytokine secretion of rat subcutaneous ASC (S-ASC) and visceral ASC (V-ASC) were analyzed. A rat model of myocardial infarction (MI) was established by occlusion of the LAD. 7 days after MI, S-ASC (n = 11), V-ASC (n = 11), and cell culture medium (Control, n = 7) were injected into the infarct rim, respectively. Cardiac function of the infarcted hearts was monitored with MRI for 6 months. Results: Both S-ASC and V-ASC exhibited a fibroblast-like morphology and expressed stromal cell markers (CD29, CD90 and CD105). No significant expression of hematopoietic markers (CD11b, CD34 and CD45) was found. Under appropriate conditions, both cells could differentiate to adipocyte- and osteocyte-like cells. Both of them expressed a significant level of HGF, IGF-1 and VEGF. As to their differences, V-ASC had approximately 3-times greater cell yield and a lower colony-formation rate (9.8±1.0% vs.13.5±2.6%) relative to S-ASC. In contrast, S-ASC showed a significantly greater growth rate (Doubling Time: 17.9 h vs. 26.0 h) relative to V-ASC. Both S-ASC and V-ASC-treated hearts showed a significantly greater left ventricular ejection fraction (LVEF, 58.3% and 56.7%) than the control group (LVEF, 47.2%) at end of 6 months. LVEF between the two ASC-treated groups was not significantly different. Finally, the implanted stem cells were readily detected in vivo with MRI for at least 6 months. Myocardial tissue sections showed existence of ASC and their locations matched with MRI signals. Conclusions: S-ASC and V-ASC share several biological characteristics. Both provide comparable significant improvement on cardiac function. Moreover, these implanted cells can be reliably tracked for at least 6 months using MRI. We conclude that the S-ASC and V-ASC are equally effective for treatment of heart failure.
Obesity hypoventilation syndrome in the health area of the public company hospital Costa del Sol: Why do women have a higher prevalence?
Authors: Juan Antonio Piña Fernández, Ana Mochόn Doña, Juan Jose Santos Gonzalez, Mar Sánchez Jimenez, Pilar Fuentes Gala, José Joaquin Cebrián Gallardo, Luis Fernández de Rota, Francisco Linde de Luna, Alicia Padilla Galo, Ana Escribano Dueñas, Pilar Cuellar
Journal: European Respiratory Journal (2011)

Introduction:  After detecting in a previous study on the prevalence of obesity hypoventilation syndrome (OHS) in the health area of the public company Hospital costa del sol that the prevalence of OHS in women was almost twice the rate of OHS in men (men 22.2%, women 56.81%), we try to find out what could be the factor o factors that determine these results.   Material and methods:  Design: cross sectional. Subjects: patients treated with BiPAP Homecare. Scope: 2 nd Level Hospital (reference population 340,458 inhabitants). Sample: Patients in active treatment with non invasive ventilation (BiPAP) in November 2010. Variables: Sex, age, BMI, pathology, blood gas values.   Results:  We analyzed 51 patients. Sex: Male (15), Women (36). Mean age 68.70±34, Women 74±22 (OHS 72±19, OHS+ OSA 76±15), Men 55±13 (OHS 49±18, OHS + OSA 61±21); type VNI: Bipap (100%). pressure: inspiratory 13.5±2, expiratory 5±1.Gasometria: Ph: 7.38±0.10. PCO2: 50.48±10. PO2: 65.48±10. pathology: OHS 28 (54.90%) Women 75% - Men 25%; OHS + OSA 23 (45.09%) Women 65% - Men 35%. Middle BMI 37±12, Women 35±12 - Men 39±10   Conclusions:  Age is the factor that determines the high prevalence of OHS in women relative to men in our catchment area possibly due to menopause (99% of women> 49 years)  The average BMI is higher in male patients studied  Specific nursing consultation is required for adaptation and management of the patients with OHS in which the eating habits play a role in order to achieve weight control, which would benefit the prognosis of the disease.
Safety and efficacy of ledipasvir/sofosbuvir for the treatment of genotype 1 hepatitis C in subjects aged 65 years or older
Authors: Sammy Saab, Sarah H. Park, Masashi Mizokami, Masao Omata, Alessandra Mangia, Ed Eggleton, Yanni Zhu, Steven J. Knox, Phil Pang, Mani Subramanian, Kris Kowdley, Nezam H. Afdhal
Journal: Hepatology (2015)

Elderly subjects have been historically underrepresented in clinical trials involving antiviral hepatitis C therapies. The aim of this analysis was to retrospectively evaluate the safety and efficacy of ledipasvir/sofosbuvir (LDV/SOF) by age groups of &lt;65 years versus ≥65 years among subjects enrolled in phase 3 trials. Four open‐label phase 3 clinical trials evaluated the safety and efficacy of LDV/SOF with or without ribavirin (RBV) for the treatment of genotype 1 chronic hepatitis C virus. Sustained virological response at 12 weeks, treatment‐emergent adverse events (AEs), and graded laboratory abnormalities were analyzed according to age group. Of the 2293 subjects enrolled in four phase 3 trials, 264 (12%) were ≥65 years of age, of whom 24 were aged ≥75 years. Sustained virological response at 12 weeks was achieved by 97% (1965/2029) of subjects aged &lt;65 years and 98% (258/264) of subjects aged ≥65 years. The most common AEs in both LDV/SOF groups that occurred in ≥10% of subjects were headache and fatigue. The rate of study discontinuation due to AEs was similar in the two age cohorts. The use of RBV in 1042 (45%) subjects increased the number of AEs, treatment‐related AEs, and AEs leading to study drug modification/interruption, particularly among elderly subjects. Conclusions : LDV/SOF with or without RBV was highly effective for treatment of genotype 1 chronic hepatitis C virusin subjects aged 65 and older. Addition of RBV did not increase sustained virological response at 12 weeks rates but led to higher rates of AEs, especially in elderly subjects. (H epatology 2016;63:1112–1119)
The effect of anti TNF-alpha therapy on tuberculin skin test reaction
Authors: Ismail Hanta, Suleyman Ozbek, Oya Baydar, Sedat Kuleci
Journal: European Respiratory Journal (2011)

Rationale:  Tuberculin skin test (TST) reaction is still widely used to diagnosis of latent tuberculous infection (LTBI) before the anti TNF-alpha therapy. We aimed to evaluate the effect of anti TNF-alpha therapy on TST reaction.   Method:  Eighty-four ankylosing spondylitis patients (22 female, 62 male) before the anti TNF-alpha therapy were evaluated in this prospective study. TST was performed before the anti TNF-alpha therapy and on the 12 month visit. For those patients with a response of    Results:  Of 84 patients, 18 patients (21.4%) had a negative (0-4 mm) and 66 patients (78.6%) had a positive (≥5 mm) TST response at initial evaluation. The TST responses were converted from negative at initial visit to positive at 1-year repeat in only 4 (4.8%) patients. A significant decrease was observed in the diameters of TST that were repeated on the first year of TNF-a antagonist treatment (6.71±5.6 mm) compared to their initial diameters ((9.15±5.7 mm) (P   Conclusion:  We concluded that anti TNF-alpha therapy may be associated with suppression on TST reaction.
Independent review of E2100 progression-free survival (PFS) with the addition of bevacizumab (B) to paclitaxel (P) as initial chemotherapy for metastatic breast cancer (MBC)
Authors: B. J. Klencke, S. Bhattacharya, M. K. Samant, J. R. Gralow, M. N. Dickler, M. A. Cobleigh, E. A. Perez, T. N. Shenkier, N. E. Davidson, K. D. Miller
Journal: Journal of Clinical Oncology (2008)

1036 Background: E2100 was an open-label, multi-center, randomized, Phase III trial comparing P to P+B as initial chemotherapy for MBC. The original analysis based on investigator-assessed progression found a significant improvement in PFS (HR 0.498, p <0.001) (K. Miller, PASCO '05). A retrospective independent review of blinded radiological and clinical data was conducted to confirm the results. Methods: Radiographic images and physical exam findings were provided to the independent review facility (IRF; RadPharm Inc.) who reviewed these data in a blinded fashion, in accordance with a prespecified IRF charter following the RECIST criteria. PFS was reanalyzed as an intent-to-treat analysis of all 722 randomized subjects, and included on-study deaths and progression events assessed by the IRF that occurred on or before Feb 9, 2005 (consistent with the data cut-off for the original interim analysis). PFS was also reanalyzed using investigator assessments but otherwise following the same analysis methods. Results: Images were submitted for review for 89.9% of patients. Missing data were balanced between the two treatment arms. Eight planned sensitivity analyses that tested the impact of non-protocol therapy, missing data, and informative censoring in the assessment of progression for individual patients were conducted; all retained statistical significance for the addition of bevacizumab. Conclusions: The PFS risk was reduced by more than half and the ORR more than doubled with the addition of bevacizumab to weekly paclitaxel in both analyses, confirming the substantial and robust bevacizumab treatment effect. The strong consistency of the IRF and Investigator based PFS and ORR results validate original data reported by ECOG in this open-label trial. IRF Assessed Investigator Assessed P N=354 P+B N=368 P N=354 P+B N=368 Progression-free survival (HR) 0.483 0.421 p value (log-rank) <0.0001 <0.0001 Median (months) 5.8 11.3 5.8 11.4 Objective response in patients with measurable disease at baseline (%) 22.2 49.8 23.4 48.0 p value <0.0001 <0.0001 HR=hazard ratio Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc., Roche Amgen, Genentech, Inc., Gilead Sciences Genentech, Inc. Genentech, Inc.
Abstract 12292: GsMTx4-D is a Cardioprotectant Against Myocardial Infarction During Ischemia and Reperfusion
Authors: Jinli Wang, Wanqing Sun, George Techiryan, Frederick Sachs, Thomas Suchyna, Ji Li
Journal: Circulation (2014)

Introduction: Reperfusion of ischemic cardiac tissue by percutaneous coronary intervention has become a routine treatment for acute ST-elevation myocardial infarction. However, restoring blood flow to ischemic cardiac tissue can injure myocytes that were viable prior to reperfusion. The putative causes of ischemia/reperfusion (I/R) injury are varied, though cation imbalance has long been known to be a significant contributor. GsMTx4 peptide is a selective inhibitor of cation selective mechanosensitive ion channels (MSCs) and has helped establish the role of MSCs in cardiac physiology. However, the role of MSCs in ischemic reperfusion injury remain uncertain. Hypothesis: Pathological stresses from swelling and hypercontracture during I/R can activate cationic MSCs, the D enantiomer of GsMTx4 can act as a cardioprotectant during I/R. Methods: GsMTx4-D pharmacokinetics in the plasma and heart was monitored over 24 h using an LCMSMS assay. The cardioprotective activities of GsMTx4 were monitored in a mouse model of ischemia/reperfusion (I/R) injury in which the left anterior descending coronary artery (LAD) was occluded and then released. The influence of GsMTx4 on contractile function and transient calcium signaling of cardiomyocyte were assessed by SoftEdge MyoCam system. Results: GsMTx4-D reduced infarct area by &gt;40% for both acute and pretreated animals relative to vehicle injected animals (p&lt;0.01). Cardiac output was significantly improved in GsMTx4-D pretreatment group, and arrhythmias were also significantly reduced by intravenous injections of GsMTx4-D. The further studies with isolated cardiomyocytes revealed that GsMTx4-D improved contractility and intracellular transient calcium signaling of cardiomyocytes under hypoxia/reoxygenation conditions. The immunoblotting data demonstrated that administration of GsMTx4-D attenuated I/R-induced inflammatory c-Jun N-terminal protein kinase (JNK) and NF-κB signaling pathways in the hearts. Conclusions: GsMTx4-D is a potent cardioprotectant that decreases infarct area, improves heart function, reduces arrhythmias and attenuates inflammatory signaling pathways that are caused by I/R. Thus GsMTx4-D could be a useful therapy in treating cardiac I/R injury.
Phase II trial of cetuximab and erlotinib in patients with lung adenocarcinoma and acquired resistance to erlotinib.
Authors: G. J. Riely, Y. Y. Janjigian, C. G. Azzoli, M. Pietanza, L. M. Krug, N. A. Rizvi, M. G. Kris, V. A. Miller, W. Pao, M. S. Ginsberg
Journal: Journal of Clinical Oncology (2010)

7557 Background: The most common mechanism of acquired resistance to erlotinib (initial response followed by progressive disease) is development of a secondary mutation in the epidermal growth factor receptor (EGFR), suggesting that these tumors continue to depend upon EGFR signaling. We hypothesized that combined EGFR blockade would overcome acquired resistance to erlotinib in patients with lung adenocarcinoma. A prior phase I trial demonstrated the MTD of cetuximab given every 2 weeks in combination with erlotinib was 500 mg/m2. We conducted this phase II trial to determine the efficacy of cetuximab and erlotinib in patients with acquired resistance to erlotinib. Methods: Eligible patients had metastatic lung adenocarcinoma with either radiographic response (RECIST) to treatment with erlotinib or a documented EGFR mutation. All patients had previous treatment with erlotinib for more than 3 months, radiographic progression by RECIST during treatment with erlotinib, and continuous treatment with erlotinib for 1 month prior to initiating treatment. All patients met consensus definition of acquired resistance (Jackman JCO 28:357). Patients with grade 2 or greater skin toxicity on erlotinib monotherapy were not eligible. All patients received erlotinib 100 mg daily along with cetuximab 500 mg/m2 every two weeks. Results: Between December 2008 and July 2009, 13 patients were enrolled and treated. Median age was 60 (range 50-69), 9 women/4 men. The median time from beginning erlotinib was 19 months (range 5-72 months). Baseline EGFR mutations: exon 19 deletions (9), L858R (2), unknown (2). Acquired resistance T790M: present (7), absent (1), unknown (5). The median number of cycles received was 2 (range 1-7). Most common grade 3 and grade 4 toxicities were rash and hypomagnesemia. Response rate (CR+PR) was 0% (0/13, 95% CI 0-25%). Median progression-free and overall survival were 3 months and not reached (> 6 months). Conclusions: Combined EGFR inhibition with cetuximab 500 mg/m2 every 2 weeks and erlotinib 100 mg daily had no significant activity in patients with acquired resistance to erlotinib. Supported, in part, by Bristol-Myers Squibb and Imclone. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb, Genentech, ImClone Systems