tbuckley/cabot-search huggingface dataset:
Association of baseline and on-study tumor biopsy markers with clinical activity in patients (pts) with advanced melanoma treated with ipilimumab
Authors: O. Hamid, S. D. Chasalow, Z. Tsuchihashi, S. Alaparthy, S. Galbraith, D. Berman
Journal: Journal of Clinical Oncology (2009)

9008 Background: Ipilimumab is a fully human monoclonal antibody to cytotoxic T-lymphocyte antigen-4. Identifying predictive markers may help select advanced melanoma pts most likely to benefit from ipilimumab therapy. Biomarkers in the tumor microenvironment are thought to be more relevant for predicting response than those in the peripheral blood. Methods: We examined tumor biopsy markers in a Phase II study CA184004 (ipilimumab 3 and 10 mg/kg). Ipilimumab was administered every 3 weeks (Q3W) x 4; eligible pts could receive ipilimumab Q12W starting Wk 24. Pre- and post-treatment (Wk 4) tumor biopsies were performed for hematoxylin and eosin analysis of tumor-infiltrating lymphocytes (TILs); immunohistochemistry of FOXP3 and indoleamine 2,3-dioxygenase (IDO); and mRNA expression profile analysis. Response was assessed with modified World Health Organization criteria. Associations between tumor biomarkers and clinical activity (complete response, partial response, or stable disease ≥ 24 wks) were assessed. Results: Ipilimumab 3 or 10 mg/kg was administered to 40 and 42 pts, respectively. In tumor biopsies, clinical activity was associated with high expression of FOXP3 (P = 0.014) and IDO (P = 0.012) at baseline and an increase from baseline in TILs (Wk 4) (P = 0.005) ( Table ). Tumor mRNA profiling identified genes with significant changes from baseline in expression, or with baseline expression levels that may be associated with clinical activity. These included various immune response genes and known melanoma antigens. Conclusions: Biomarkers in the tumor microenvironment have been demonstrated to be associated with clinical activity in pts treated with ipilimumab. [Table: see text] [Table: see text]
Abstract 15249: Prevalence of Nephrogenic Systemic Fibrosis in Dialysis Patients: Final Results of the Pro-FINEST Study
Authors: Sabine Amet, Vincent Launay-Vacher, Olivier Clement, Camille Frances, Aurore Tricotel, Jean-Yves Gauvrit, Nicolas Grenier, Genevieve M Reinhardt, Laurence Rouillon, Nicolas Janus, Maurice Laville, Choukroun Gabriel, Gilbert Deray
Journal: Circulation (2012)
Impact of prolongation of overall treatment time and timing of brachytherapy on outcome of radiation therapy in carcinoma of uterine cervix
Authors: V. Goel, J. K. Singh., M. K. Pandey
Journal: Journal of Clinical Oncology (2006)

15032 Background: Studies have described decreased pelvic control &amp; survival rates in invasive ca cervix when overall time in definitive RT is prolonged. We evaluated impact of timing of brachytherapy on outcome. Methods: Retrospective analysis of 338 patients of ca cervix treated with radical RT from Jan 2002 to Dec 2002 at Mahavir Cancer Sansthan Patna. The median age was 50 yrs (23–80 yrs). 73% patients were postmenopausal. Histopathology was Squamous Cell in 97% patients. Most common presenting complaints were bleeding P/V (92%) &amp; discharge P/V (82%); with stage I (3%), II (35%), III (43%), IV (5%), unknown stage in 14% cases. Results: Records of 338 patients (Stage IB to III) treated with definitive irradiation (combination of EBRT &amp; ICRT) were reviewed with reference to loco regional control, distant failure and its correlation with patient and tumor variables including OTT. Out of 302 patients who received complete RT, 24 received 60 Gy in 30 fractions as they were found to be unsuitable or were unwilling for ICRT. The rest received a dose of 50 Gy/25 Fr to 50.4 Gy/28 Fr over a median duration of 37 days. 30 patients received concomitant chemo radiation (cisplatin 40 mg/m 2 /4 cycles). 276 patients received ICRT (dose 21 Gy in 3 Fractions with a median gap of 43 days (range 5–111) after completion of ERT. The median OTT for completion of ERT &amp; ICRT was 75 days (range 54–177). At an average follow up of 18- 24 months residual disease was seen in 2 cases (0.6%), local recurrence in 14 cases (4%) &amp; distant failure in 14 cases (4%). Post RT complications were seen in 4.7% cases and included small bowel obstruction in 6 cases, VVF in 4 &amp; RVF in 6 cases. Significant correlation was seen between OTT and rate of loco regional recurrences. All local recurrences were seen when OTT was more than 75 days. No significant correlation could be drawn between age, Hemoglobin, tumor histology, &amp; bulky vs. non bulky tumor on loco regional and distant failure. Conclusions: Longer radiotherapy completion time was found to be associated with diminished survival outcomes for patients treated radically for carcinoma cervix. The significance of this observed association requires further investigation &amp; correction to keep OTT as short as possible. No significant financial relationships to disclose.
A phase I/II trial of BKM120 combined with vemurafenib (PLX4032) in BRAF<sup>V600E/k</sup> mutant advanced melanoma.
Authors: Andrea Kantor, Adil Daud, Pamela N. Munster, Roth Ea, Alain Patrick Algazi
Journal: Journal of Clinical Oncology (2012)

TPS8602 Background: Vemurafenib induces transient objective responses in half of BRAF V600E mutant melanoma patients and a median PFS of 5.3 months (NEJM. 2011;364:2507-2516). BRAF mutations are not sufficient to cause melanoma, but the combination of BRAF V600E mutation and PTEN loss is sufficient to recapitulate the malignant melanoma phenotype in vivo (Nat. Genet. 2009;41:544-552). PTEN loss and PI3K activation are common in BRAF mutant metastatic melanoma, and PI3K activation has been implicated as a cause acquired resistance to BRAF inhibitors (Cancer Cell. 2010;18:683-695) . This phase I/II study is the first trial to test the safety and efficacy of combining a potent BRAF inhibitor, vemurafenib, with a potent PI3K inhibitor, BKM120, in patients with metastatic BRAF mutant melanoma. Methods: Design: Phase I patients receive a single dose of oral BKM120 (d -7) then vemurafenib twice daily with BKM120 daily (starting on c1d1). PK analysis is performed for BKM120 alone and for both drugs in combination. Doses of both drugs will be escalated in 3+3 scheme. Phase II patients receive continuous dosing of vemurafenib twice daily and BKM120 daily. Serial biopsies for PD and mRNA expression analyses are required for patients with visible or palpable tumors. Reimaging will be performed every 8 weeks.Eligibility: This study is enrolling BRAF V600E/K mutant metastatic melanoma patients with no prior exposure to BRAF inhibitors or PI3K inhibitors, ECOG PS ≥ 2 and adequate organ function. Endpoints: The primary endpoint for phase 1 is the recommended phase 2 dose of the combination. The primary endpoint for phase II is the 6 month PFS rate. Secondary endpoints include median PFS and OS. Baseline PTEN expression and changes is pS6 protein levels will be examined as predictors of efficacy, and changes in gene expression profiles will be assessed. Summary: This is the first trial examining the safety and efficacy of combined BRAF/PI3K inhibition in BRAF mutant melanoma patients.
Health promotion in general practice
Authors: J K Cruickshank
Journal: BMJ (1994)

Health promotion in general practiceRefine the approach-don't abandon the principle EDrrOR,-The problem with interpreting both the Family Heart Study Group's report of its one year trial' and the result of the less interventionist OXCHECK study2 is that both studies tripped at the second hurdle for any clinical trial: after randomisation they failed to "screen" their controls in exactly the same way as they screened the intervention group.The Family Heart Study
Prognostic significance of plasma chromogranin A levels in hormone-refractory prostate cancer patients treated on Cancer and Leukemia Group B (CALGB) 9480
Authors: M.-E. Taplin, D. J. George, S. Halabi, W. R. Sellers, B. Sanford, K. T. Hennessy, C. G. Mihos, E. J. Small, P. W. Kantoff
Journal: Journal of Clinical Oncology (2004)

4557 Background: The extent of neuroendocrine differentiation in prostate cancer correlates with aggressive disease and progression to hormone refractory prostate cancer (HRPC). Elevated plasma chromogranin A (CgA) levels in prostate cancer patients may reflect more extensive neuroendocrine phenotype. We therefore sought to test the hypothesis that CgA levels are of prognostic value in patients with HRPC. Methods: Pretreatment plasma was collected from 390 patients with metastatic HRPC enrolled in CALGB 9480, a study of 3 different dose levels of suramin. Plasma CgA levels were determined in 321 of the samples in duplicate using a quantitative sandwich immunoassay (DAKO Corp. Carpinteria, CA, Cat. No. K0025). The proportional hazards model was used to assess the prognostic significance of CgA in predicting overall survival. Results: Plasma CgA levels ranged from 7.7–19.3 U/L, with a median level of 12 U/L. In univariate analysis plasma CgA levels inversely correlated with survival times at the median CgA level, CgA ≤ 12 versus > 12 with survival 17 months (95% CI 14–19) compared to 11 months (95% CI 8–14, p = 0.014) and at all exploratory cut points including CgA ≤ 9.5 versus > 9.5 with survival 19 (95% CI= 16–20) months compared to 12 months (95% CI= 9–14, p = 0.002). In multivariate models adjusting for performance status, prostate specific antigen, lactate dehydrogenase (LDH), plasma CgA levels remained predictive of overall survival. The hazard ratio was 1.326 for patients whose CgA levels were above 9.5 compared to patients whose levels were < 9.5 (95% C.I. 1.045–1.68, p-value 0.020). Conclusion: These results support the hypothesis that plasma CgA levels can predict outcome in HRPC patients. No significant financial relationships to disclose.
Osteopontin (OPN) and interleukin-6 (IL-6) as predictive biomarkers in HCC receiving loco-regional treatment: Preliminary results.
Authors: Alessio Cubeddu, Giorgio Astara, Clelia Madeddu, Valeria Ruggiero, Carlo Cabula, Giancarlo Serra, Roberto Ganga, Luca Faloppi, Stefano Cascinu, Mario Scartozzi
Journal: Journal of Clinical Oncology (2015)

e13501 Background: OPN, a potential diagnostic biomarker and therapeutic target, is a multifunctional protein involved in the carcinogenesis, neoangiogenesis and metastasization in many solid neoplasms. IL-6 is a mediator of the immunologic response involved in the hepatocyte proliferation and carcinogenesis. The aim of our study was to analyse the potential correlation between blood levels of OPN, IL-6, IL-2, VEFG and clinical outcome in HCC patients receiving RFA. Methods: 14 patients diagnosed HCC and candidate to loco-regional treatment (RFA) with curative intent have been included in this study. Main inclusion criteria were: a solitary HCC smaller than 5 cm in diameter or multiple (no more than three) HCC smaller than 5 cm in total diameter; no extrahepatic metastasis; no radiologic evidence of invasion into the major portal/hepatic vein branches; good liver function with Child-Pugh Class A or B, with no history of encephalopathy, ascites refractory to diuretics or variceal bleeding; no previous treatment of HCC. Plasma levels of OPN, IL-6, IL-2, VEGF have been estimated through ELISA test in d0, before the loco-regional treatment and after 30 days. Patients with progressive disease at the first revaluation after RFA (15%), including local and new HCC sites in other hepatic segments, have been considered early progressors. Results: A statistically significant correlation between the basal levels of OPN and IL-6 (p = 0.001) has been observed, while there was no correlation between the IL-2 levels and VEGF. The levels of OPN and IL-6 resulted not significantly modified after the regional treatment compared to the basal. Levels of OPN and IL-6 increased significantly ( p = 0.022 and p = 0.013) in patients showing early progression after RFA. Conclusions: Although the limited sample size, we suggest that OPN IL-6 may be effective biomarkers for patients undergoing loco-regional treatment: OPN and IL-6 seemed in fact to able to predict response to treatment and to early identify the patients who may benefit from other anti-cancer treatments. Early Progressors NED p Delta OPN + 121 ± 57 -3 ± 62 0.022 Delta IL-6 + 48 ± 64 0.7 ±10.7 0.013
Long non-coding RNAs display higher natural expression variation than protein-coding genes in healthy humans
Authors: Aleksandra E. Kornienko, Christoph P. Dotter, Philipp M. Guenzl, Heinz Gisslinger, Bettina Gisslinger, Ciara Cleary, Robert Kralovics, Florian M. Pauler, Denise P. Barlow
Journal: Genome biology (2016)

Long non-coding RNAs (lncRNAs) are increasingly implicated as gene regulators and may ultimately be more numerous than protein-coding genes in the human genome. Despite large numbers of reported lncRNAs, reference annotations are likely incomplete due to their lower and tighter tissue-specific expression compared to mRNAs. An unexplored factor potentially confounding lncRNA identification is inter-individual expression variability. Here, we characterize lncRNA natural expression variability in human primary granulocytes. We annotate granulocyte lncRNAs and mRNAs in RNA-seq data from 10 healthy individuals, identifying multiple lncRNAs absent from reference annotations, and use this to investigate three known features (higher tissue-specificity, lower expression, and reduced splicing efficiency) of lncRNAs relative to mRNAs. Expression variability was examined in seven individuals sampled three times at 1- or more than 1-month intervals. We show that lncRNAs display significantly more inter-individual expression variability compared to mRNAs. We confirm this finding in two independent human datasets by analyzing multiple tissues from the GTEx project and lymphoblastoid cell lines from the GEUVADIS project. Using the latter dataset we also show that including more human donors into the transcriptome annotation pipeline allows identification of an increasing number of lncRNAs, but minimally affects mRNA gene number. A comprehensive annotation of lncRNAs is known to require an approach that is sensitive to low and tight tissue-specific expression. Here we show that increased inter-individual expression variability is an additional general lncRNA feature to consider when creating a comprehensive annotation of human lncRNAs or proposing their use as prognostic or disease markers.
5-FU plus leucovorin (Mayo Regimen) for concurrent chemoradiotherapy after surgery in patients with resectable locally advanced gastric carcinoma: Preliminary results of a phase II study
Authors: M. Altinbas, B. Kaplan, K. Ucar, M. Ozkan, E. Karahacioglu, O. Er, C. Kucuk, I. Soyuer
Journal: Journal of Clinical Oncology (2004)

4196 Background: Patients with locoregionally advanced carcinoma of the stomach have a grim outcome due to frequent local and systemic recurrences after surgery. To potentially increase the local control or survival rate and decrease relapses, we investigated a strategy of concurrent chemoradiotherapy and followed by consolidation chemotherapy after surgery. Methods: Operable 71 patients (Stage IB-IV, M0) underwent total or subtotal gastrectomy. Adjuvant chemotherapy (250 mg/m2 5-FU) was administered concurrently on the first day of every radiotherapy weeks [which was totally standart field radiotherapy (RT), or total abdominal field RT up to 20 Gy first, then returned to standart field RT], . After chemoradiotherapy regimen, consolidation chemotherapy consisted of 450 mg/mg 5-FU plus 20 mg/m2 Leucovorin was applied up to four cycles, q28 d. Results: Of 71 patients have been enrolled, 67 (94%) of 37 (55%) were randomized to standart field RT arm, and 30 (45%) were randomized to total abdominal irradiation arm. There were not significant difference between two arms according to the age, sex, surgical approach, tumor localization, and stages. Six patients in both arms did not get consolidation chemotherapy. The median follow-up was 7.5 months (range: 6–29 m). One-year progression-free survival was 53% and 65% on the first and second arm, respectively. The overall survival was 63% and 70% on the first and second arm, respectively. Nine patients (24%) on the first, and 12 (40%), and on the second arm were died. There was not a significant difference between the two groups. Commonest side effects during chemoradiotherapy were grade 3–4 neutropenia on the first arm (14%), diarrhea on the second arm (17%). There were no deaths related to chemotherapy, chemoradiotherapy, or surgery. Conclusions: Preliminary results suggest the feasibility of postoperative adjuvant chemoradiotherapy with 5-FU followed by consolidation chomotherapy with MAYO regimen in gastric cancer with acceptable toxicities. No significant financial relationships to disclose.
Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor GSK2118436 (GSK436).
Authors: K. L. Nathanson, A. Martin, R. Letrero, K. P. D'Andrea, S. O'Day, J. R. Infante, G. S. Falchook, M. Millward, C. M. Curtis, B. Ma, R. C. Gagnon, P. F. Lebowitz, G. V. Long, R. F. Kefford
Journal: Journal of Clinical Oncology (2011)

8501 Background: GSK436 is a highly potent, selective ATP-competitive BRAF inhibitor. BRF112680, a first in human study, assessed safety, pharmacokinetics, pharmacodynamics, and efficacy. Efficacy of single-agent GSK436 was demonstrated in BRAF V600 mutation-positive (mut+) metastatic melanoma patients (pts), with an unconfirmed response rate (RR) of 77% in V600E mut+ pts and 44% in V600K mut+ pts (based on October 2010 data cut). This study evaluates the relationship of genetic alterations in target genes to RR. Methods: To date, samples from 38 pts have been evaluated; 5 pts had samples at pre-treatment (preTx) and progression, 32 pts had a preTx sample only, and 1 pt had a progression sample only. Tumor DNA was evaluated by Sequenom (SEQ) for a targeted panel of mutations in 11 genes (AKT1, BRAF, CDK4, CDKN2A, CTNNB1, GNAQ, GNA11, KIT, MEK1, MEK2, NRAS). PTEN mutation and copy number were derived by sequencing and array CGH (Agilent 1M) or MPLA, respectively. Results: BRAF mutation status was confirmed in all pt samples via SEQ. At preTx, 30 tumors were BRAF V600E, and 7 were V600K. The BRAF mut was retained in the 5 pts with both preTx and progression samples; in 3/5 the ratio of mut:wt decreased in the progression sample. To date, a PTEN alteration (mutation, hemizygous or homozygous deletion) was observed in 9/37 preTx sample pts (24%); 8 of which were V600E+. Pts with a PTEN alteration had lower RR (1/9=11%) compared with pts in which no PTEN alteration was observed (15/28=54%). In addition to the BRAF mutation, we observed in separate preTx samples mutations in MEK2 and CDK4; both patients had SD. An additional pt with a BRAF and β-catenin mutation had PR. Conclusions: These data support genetic characterization of melanomas for mutations outside of BRAF as predictors of RR to BRAF inhibition; the V600 mutation type itself is strongly predictive. Our data suggest that alterations in PTEN may be associated with a decrease in RR to GSK436. Mutations in the MAPK signaling pathway (MEK2) and outside it (CDK4) have been identified, which may also be associated with RR. Additional analyses are being performed to identify further predictors of response to BRAF inhibition.
Paradox radiologic progression despite appropriate antituberculosis therapy
Authors: Ugur Gonlugur, Sule Kosar, Arzu Mirici
Journal: European Respiratory Journal (2011)

In this study we report a HIV negative case who got worse paradoxically in the course of antituberculosis therapy. A 68-year old male patient applied with complaints of cough, chest pain, and weight loss. Chest computed tomography revealed an irregular nonhomogenous opacity involving the apical and posterior segments of superior lobe of right lung.  At the end of the first month of therapy radiological lesions increased.  There was no endobronchial lesion on bronchoscopy, and no acid-fast bacilli in bronchial lavage fluid. Therapy protocol was not changed but radiological lesions regressed gradually. In conclusion, temporary deteriorations can occur in previous pulmonary infiltrates in patients who are under appropriate antituberculosis therapy. The gold standard for monitorization is microbiological methods but not radiological ones. Comorbid conditions, drug reaction and treatment failure is important in the differential diagnosis.
Which is better in patients with curatively resected extrahepatic biliary tract cancer? Adjuvant concurrent chemoradiation (CCRT) alone versus CCRT followed by maintenance chemotherapy
Authors: K. Lim, D. Oh, E. Chie, J. Jang, S. Im, T. Kim, S. Kim, S. Ha, Y. Bang
Journal: Journal of Clinical Oncology (2008)

15659 Background: There is currently no standard adjuvant therapy for patients (pts) with curatively resected extrahepatic biliary tract cancer (EHBTC). The role of adjuvant concurrent chemoradiation (CCRT) alone or CCRT followed by maintenance chemotherapy (MC) is not yet established. Methods: We enrolled pts with EHBTC who received curative resection and then received adjuvant CCRT with or without MC between 2000 and 2006 at Seoul National University Hospital. 5-fluorouracil (5-FU) was administered at a dose of 500mg/m2 on D1,2,3 and D28, 29, 30 along with 40–50 Gy of external beam radiation. MC was delivered with 5-FU based regimen for 6–12 months. We retrospectively analyzed the clinical features, disease free survival (DFS) and overall survival (OS) between adjuvant CCRT alone and CCRT followed by MC. Results: Total 91 pts were enrolled. The median age was 63 years (range 42–87) and male was 66. Sixty seven pts received R0 resection (pathologically negative margins) and 24 pts R1 resection (microscopically positive margins). The median follow-up duration for all pts was 22 months. 3-year DFS and 3-year OS rate were 48.4% and 65.7%, respectively. Out of 91 pts, 24 received CCRT alone and 67 received CCRT followed by MC. Baseline characteristics were comparable between the two groups. 3- year DFS rates for the CCRT alone and CCRT followed by MC were 28.2 and 55.1% (p=0.02) and 3-year OS rates were 34.8% and 75.6% (p=0.001) respectively. There was no statistical difference between both groups in the pattern of treatment failure such as local and systemic recurrence (p=0.396). For subgroups with R0 or R1 resection, CCRT followed by MC led to longer OS and DFS than CCRT alone, except DFS in R0 resection. Also, CCRT followed by MC showed more prolonged OS and DFS than CCRT alone in negative nodal state, but not in positive nodal state. Conclusions: In patients with curatively resected EHBTC, adjuvant CCRT followed by MC had significant prognostic impact on DFS and OS compared with CCRT alone. No significant financial relationships to disclose.