tbuckley/cabot-search huggingface dataset:
Predictors of overall survival in patients diagnosed with desmoplastic small round cell tumor (DSRCT).
Authors: Alexander Noor Shoushtari, Li-Xuan Qin, Deborah Kuk, Heather D. Magnan, Shakeel Modak, Suzanne L. Wolden, Eun Jung Cho, Valerie Pallos, Olivia Grubman, Aaron D. Viny, Richard D. Carvajal, Ping Chi, Sandra P. D'Angelo, Mark Andrew Dickson, Mary Louise Keohan, William D. Tap, Michael P. La Quaglia, Mrinal M. Gounder
Journal: Journal of Clinical Oncology (2014)

10582 Background: DSRCT is a rare, aggressive, and poorly understood neoplasm characterized by the EWS-WT1 translocation. Prognosis is poor despite upfront multimodality therapy with surgery, radiation (RT), and high-dose chemotherapy. We performed a retrospective review of patients (pts) with DSRCT at Memorial Sloan Kettering Cancer Center (MSKCC) to assess the association between overall survival (OS) and various clinical and therapeutic variables. Methods: We collected demographic/clinical data on pts diagnosed with DSRCT from 1995-2011 who had pathologic review and ≥1 oncologic consultation at MSKCC. Living pts were censored at time of last contact. First-line therapies were classified as follows: optimal (R0/R1) vs suboptimal (R2) surgery; consolidative RT; auto transplant; and chemotherapy: high-dose cyclophosphamide (HDCy) vs. standard Ewing's regimen [sER] vs other. Univariate (UVA) and multivariate (MVA) analyses were performed. Results: 191 patients were identified; 152 (80%) male, median age 22.6 years (yr) (range 4-62), 67% Caucasian. Most common primary site was abdomen and pelvis (A/P, 94%). Pts had disease (dz) present in A/P only (40%) or A/P plus: liver/spleen (21%), extra-abdominal (17%), or multiple distant sites (21%). Median OS (mOS) was 2.4 yr (range 0.04-12) with a median f/u 6.5 yr. UVA revealed mOS varied by site of dz, with A/P alone superior to A/P plus liver/spleen or multiple distant sites (2.8 vs 2.5 vs 2.3 yr, p=0.001). Age was not associated with mOS (p=0.90). MVA for mOS in 148 pts with complete covariates identified: optimal surgery vs suboptimal (3.2 vs 2.4 yr; HR 0.48, CI 0.29-0.78, p=0.003); consolidative RT vs no RT (3.2 vs 2.4 yr; HR 0.53, CI 0.31-0.91, p=0.021); and sER chemotherapy vs HDCy (2.7 vs 2.4 yr; HR 0.59, 0.38 – 0.93, p=0.024) as associated with improved OS. Conclusions: This is the largest DSRCT case series reported to date and represents the first MVA of the impact of multimodality therapy. Although overall prognosis remains dismal, R0/1 surgery and consolidative RT were associated with improved OS. sER was associated with improved OS over HDCy, but the magnitude of benefit was small. Further research and collaborations are needed to improve outcomes in these patients.
Use of HE4 and CA125 to predict surgical outcome and for prognostic value for progression-free survival (PFS) and overall survival (OS) in primary epithelial ovarian cancer (EOC) patients (pts).
Authors: Ioana Braicu, Radoslav Chekerov, Rolf Richter, Ignace B. Vergote, Sven Mahner, Alain G Zeimet, Ram N. Ganapathi, Linn Lena Woelber, Dan Cacsire Castillo-Tong, Isabelle Cadron, Robert Zeillinger, Christina Fotopoulou, Jalid Sehouli
Journal: Journal of Clinical Oncology (2012)

5034 Background: Optimal surgical cytoreduction and response to platinum (P) based chemotherapy (ChTh) remain the cornerstones of therapeutic management of primary EOC. Aim of this study was to analyze the predictive role of HE4 and CA125 as biomarkers (BM) for clinical outcome in primary EOC pts at diagnosis and during subsequent follow-up. Methods: In the European OVCAD project 275 pts with primary EOC were enrolled. Pts were eligible if radical cytoreductive surgery and P-based ChTh were applied. Plasma collected at first diagnosis and 6 months after 1st line ChTh in P-sensitive pts was analyzed for HE4 and CA125 levels using ELISA and Luminex technique, respectively. Results: Complete cytoreduction with no residual tumor disease (RTD) was obtained in 69.9% pts. HE4 and CA125 expression in plasma at first diagnosis correlated with RTD, p = 0.002 and p=0.002, respectively. The sensitivity (SE) and specificity (SP) of the combinative use of both BM in predicting RTD was 64.8% and 73.5%, respectively. Pts having over-expression of both BM in plasma had a 6.1 greater risk for RTD (p&lt;0.001, OR: 6.107, 95% CI 2.41-15.46). P-resistance occurred more frequently when both BM were over-expressed (p=0.028, OR= 3.1, 95%CI 1.13-8.46). Elevated BM levels during follow-up predicted recurrence (SE 90% and SP 71% for CA125 ≥55U/ml; SE 72.7% and SP 81.4% for HE4 ≥150pM) and when HE4 or CA125 were positive, a SE of 86.4% and SP of 72.9% were achieved. Elevated CA125 and HE4 at 6 months following adjuvant therapy was associated with significantly poorer PFS (p&lt;0.001, HR 9.6, 95%CI 3.93-23.44 with elevated HE4 or CA125, and HR=50.52, 95%CI 14.44-176.78, with elevated HE4 and CA125) and OS (p&lt;0.001, HR=7.42 95%CI 1.43-38.42 with elevated HE4 or CA125 and HR=28.38 95%CI 6.50-123.97 with elevated HE4 and CA125). Conclusions: The combinative use of HE4 and CA125 appears to have a significant value in predicting optimal surgical outcome and development of P resistance disease in EOC pts. Elevated plasma levels 6 months after 1st line ChTh significantly correlate with OS and PFS in P-sensitive pts.
Impact of <i>RAS</i> testing on treatment duration among patients with metastatic colorectal cancer (mCRC).
Authors: Bruce A. Bach, Alexandra Christodoulopoulou, Andrew Klink, Guy Hechmati, Urvi Mujumdar, Bruce A. Feinberg, Marwan Fakih
Journal: Journal of Clinical Oncology (2017)

773 Background: Current clinical guidelines recommend that all patients with mCRC have tumor tissue genotyped for RAS mutations. Tumor RAS testing enables the widest range of treatment options, with potential impact on patient outcomes. The aim of this study was to estimate the impact of RAS testing on the duration of treatment, across multiple lines of chemotherapy in mCRC. Methods: Adults with a diagnosis of mCRC (ICD-9 codes 153.x, 154.0x, or 154.1x and 197.x–198.x) were identified from a database of US public and private insurance claims (129 million covered lives) from 2012–2014. Time to treatment discontinuation, overall and by line of chemotherapy, was compared through univariate analysis between patients who were tested for RAS mutations (identified by CPT codes) to those who were not tested. Multivariate Cox proportional hazard regression model was used to estimate the risk of discontinuation attributable to prior RAS testing (i.e., hazard ratio [HR]), adjusting for patient characteristics. Results: We identified 4,527 mCRC patients (mean age at diagnosis, 61.2 years; 54% male), 39% (n = 1,787) of whom had a claim for RAS testing during the study period. Patients tested for RAS mutations stayed on treatment significantly longer in first-line (1LD), second-line (2LD), and overall treatment (OTD) vs those who were not tested for RAS mutations (1LD: median, 245 days [95% confidence interval–CI: 232–251] vs 196 days [95% CI: 189–205]; 2LD: median, 189 days [95% CI: 168–203] vs 147 days [95% CI: 133–161]; OTD: median, 903 days [95% CI: 815–1,040] vs 305 days [95% CI: 281–337]; all P &lt; 0.01). Adjusting for patient characteristics, RAS testing significantly reduced the risk of discontinuation in 1LD, 2LD, and OTD (HRs: 0.83 [95% CI: 0.76–0.90], 0.80 [95% CI: 0.71–0.91], and 0.32 [95% CI: 0.27–0.37], respectively; all P&lt; 0.01). Conclusions: These observational data show that RAS testing is associated with significantly greater time on treatment for mCRC patients compared to not testing, suggesting that patients under the care of physicians who decide to test for RAS mutations, regardless of test result, are on therapy for a longer period of time than untested patients.
Effect of oral cyclophosphamide on the immunogenicity of DPX-Survivac in ovarian cancer patients: Results of a phase I study.
Authors: Neil Lorne Berinstein, Amit M. Oza, Kunle Odunsi, Mohan Karkada, Jeannine A Villella, John J. Nemunaitis, Michael Morse, Tanja Pejovic, James Bentley, Rita Nigam, Genevieve Weir, Lisa MacDonald, Marianne Stanford, Tomasz Burzykowski, Marc Mansour
Journal: Journal of Clinical Oncology (2013)

3030 Background: Survivin, a protein involved in regulation of apoptosis, is highly expressed in many tumor types and has reported prognostic value. DPX-Survivac is a cocktail of survivin HLA class I peptides (A1, A2, A3, A24 and B7) formulated in the novel adjuvanting vaccine platform DepoVax. A phase I study examined the safety and immune potency of DPX-Survivac in combination with cyclophosphamide in ovarian cancer patients. Methods: 18 of 19 advanced ovarian cancer patients treated with platinum chemotherapy and showing no disease progression completed their vaccine therapy. Cohort A (6 pts) received three 0.5 mL vaccine injections 3 weeks apart; cohorts B and C (6 pts each) received three 0.1 mL or 0.5 mL vaccine injections in combination with metronomic low dose oral cyclophosphamide. Adverse events were assessed using CTCAE v4.0. Blood was collected to study immune function (MDSCs, T regs and B cells) and vaccine-induced T cell immunity (ELISpot, tetramer analysis and multi-parametric intracellular cytokine staining). Repeated measures of immunity at baseline and after 1, 2 and 3 injections were analyzed using a general linear model. Results: DPX-Survivac was well tolerated with no significant systemic AEs. Local injection AEs occured in all patients. Grade 3 local reactions occured in 3 patients (1 pt in B and 2 pts in C). 11 of 12 patients receiving the combination therapy produced immune responses by at least 2 assays, generally established with one or two vaccinations and increased or maintained with boosters. A dose response was observed, with cohort C patients producing significantly higher magnitude responses (C vs B, P=.013). Low dose cyclophosphamide significantly enhanced the 0.5 ml dose (C vs A, P=.015). Notably, antigen specific CD8 T cells were detected ex vivoi n PBL’s using tetramers and further characterized as polyfunctional by multi-parametric ICS, suggesting a robust immune response. Conclusions: DPX-Survivac is well tolerated and immunogenic. Immune modulation with low dose oral cyclophosphamide can dramatically enhance the immunogenicity of this vaccine. The efficacy of the proposed DPX-Survivac vaccine therapy needs to be tested in a randomized phase II study. Clinical trial information: NCT01416038.
An individual patient data meta-analysis of the immunochemotherapy using lentinan in patients with advanced gastric cancer
Authors: K. Oba, S. Morita, T. Matsui, M. Kobayashi, K. Kondo, J. Sakamoto
Journal: Journal of Clinical Oncology (2007)

15136 Background: An anti-tumor effect of lentinan (LNT), a non-specific immunomodulator, via an immunological response has been reported and combination immunochemotherapy has been examined. However, the survival benefit of LNT for patients with advanced or recurrent gastric cancer (AGC) was unclear in the world. We performed an individual patient data (IPD) meta-analysis in order to evaluate the survival effect of immunochemotherapy using LNT. Methods: A computerized and a manual search procedure were performed to identify all randomized clinical trial (RCT) for chemotherapy in patients (pts) with AGC. Inclusion criteria were RCTs for AGC and to compare any chemotherapy (control group) with the same plus LNT (LNT group). The primary endpoint was overall survival, secondary endpoints includes objective tumor response and toxicity. All analyses were based on IPD. Treatment effects were displayed as hazard ratios estimated by Cox proportional hazard model. A ratio less than unity indicated benefit from LNT. Results: We analyzed IPD of 5 randomized clinical trials for AGC, which met the predetermined inclusion criteria. These 5 trials had a combined total of 650 pts (LNT: 339 pts median age=63, control: 311 pts median age=63). The number of deaths was 83.8% (286/334) in LNT group and 84.8% (262/309) in control group. The overall hazard ratio was 0.83 (95%CI, 0.70–0.98; p=0.03) with no significant heterogeneity between the treatment effects in different trials (χ2 for heterogeneity=3.69; p=0.45). Three hundred and fifty five pts were evaluable for objective tumor response and the response rate was 18.4% (21/185) in LNT group (CR, 0 pts; PR, 21 pts) and 6.3% (5/173) in control (CR, 0 pts; PR, 5 pts). There were no significant differences in the toxicity. Conclusions: This IPD meta-analysis demonstrated that LNT significantly improves both OS and tumor response in pts with AGC. No significant financial relationships to disclose.
DRENAJE VESICULAR POR ECOENDOSCOPIA CON PRÓTESIS METÁLICAS DE APOSCIÓN LUMINAL (PMAL) VS. COLECISTOSTOMÍA PERCUTÁNEA EN PACIENTES CON COLECISTITIS AGUDA NO CANDIDATOS A TRATAMIENTO QUIRÚRGICO
Authors: C De La Serna, A Yb Teoh, I Peñas, E Kw Nag, R Sanchez-Ocaña, Y Law James, P Diez, M Pérez-Miranda
Journal: Endoscopy (2015)

La colecistostomía percutánea (CP) es el tratamiento de elección en pacientes con colecistitis aguda (CA) no candidatos a cirugía. Recientemente, el drenaje vesicular por ecoendoscopia (DVE) con prótesis metálicas de aposición luminal (PMAL) ha surgido como alternativa terapéutica. Carecemos de estudios comparando eficacia, morbilidad y recidivas entre ambas técnicas
The frequencies and clinical implications of mutations in 33 kinase-related genes in locally advanced rectal cancer.
Authors: Khairun Izlinda Abdul Jalil, Katherine M Sheehan, Sinead Toomey, Jasmin Schmid, Anthony O'grady, Robert Cummins, Brian O'Neill, Deborah A McNamara, Joseph Deasy, William Grogan, Oscar S. Breathnach, Ailin Rogers, Glen Doherty, Des C Winter, David Gibbons, John Ryan, Kieran Sheahan, Peter Gillen, Elaine Kay, Bryan Hennessy
Journal: Journal of Clinical Oncology (2013)

3549 Background: Locally advanced rectal cancer, LARC (T3/4 and/or N+) is currently treated with pre-operative chemoradiotherapy (pCRT), but responses are not uniform. The phosphatidylinositol 3-kinase (PI3K), MAP-kinase (MAPK) and related pathways have been implicated in rectal cancer tumorigenesis. Here, we investigated the association between genetic variations in these pathways and clinical outcomes in LARC. Methods: We genotyped a total of 234 Single Nucleotide Polymorphisms (SNPs) including potentially clinically relevant mutations in 33 cancer related genes including PIK3CA, PIK3R1, AKT, STK11, KRAS, BRAF, MEK, CTNNB1, EGFR, MET and NRAS using the Sequenom platform. DNA samples utilized herein were extracted from pre-treatment rectal cancer biopsies of 201 patients who were then treated with long-course pCRT followed by surgical resection. Results: 62 different mutations were detected in 15 genes, with the highest frequencies occurring in KRAS (n=93, 47%), PIK3CA (n=29, 14%), MET (n=27, 13%), STK11 (n=13, 6.3%), CTNNB1 (n=12, 6%), BRAF (n=8, 4%) and NRAS (n=7, 3.5%). Mutations were also detected in AKT, PIK3R1, EGFR, GNAS, MEK1, PDGFRA, ALK and TNK2, but at frequencies of less than 2%. Pathologic complete response (pCR) was associated with excellent (97%) 5-year Recurrence-Free Survival (RFS) (Hazard ratio [HR], 0.076; 95% CI, 0.01-0.50, P=0.001). We found: 1) Mutations in PI3K pathway-related genes (PIK3CA, AKT, STK11) were significantly associated with absence of pCR (odd ratio [OR], 5.40; 95% CI, 1.24-23.54, P=0.024). However, mutations in MAPK pathway-related genes (KRAS, BRAF, NRAS, MEK) was not found to be significantly associated with pCR (P=0.805). 2) In contrast, in patients who did not achieve pCR (non-pCR), mutations in PI3K pathway-related genes were not associated with RFS. However, in these patients, codon 12 (G12D/G12V/G12S) and 13 mutations in KRAS were associated with poor RFS (HR, 0.336; 95% CI, 0.115-0.981, P=0.046). Conclusions: These results suggest that mutations in kinase signaling pathways may modulate treatment responsiveness and clinical outcomes in locally advanced rectal cancer and thus may constitute rational targets for novel therapies.
CNS involvement in patients with AIDS-related lymphomas.
Authors: Jitesh Joshi, Nicolas Mounier, Xiaonan Xue, Dan Wang, Josep-Maria Ribera, Christoph Wyen, Kieron Dunleavy, Richard F. Little, Wyndham Hopkins Wilson, Ariela Noy, Joseph A. Sparano, Stefan K. Barta
Journal: Journal of Clinical Oncology (2014)

8570 Background: CNS involvement (CNSi) at baseline and CNS relapse (CNSr) appears increased in pts with AIDS-related lymphomas (ARL) although this has not been systematically examined. The aim of our study was to better describe factors and outcomes associated with CNSi at baseline and relapse in patients with ARL. Methods: We used an existing database of patients with newly diagnosed ARL (Barta et al, Blood 2013) and identified 886 pts with complete information on CNSi at baseline and relapse. We used descriptive statistics to define the prevalence of baseline CNSi and incidence of CNSr. We used Cox-proportional hazard models to assess associations of baseline characteristics (age, sex, time of enrollment, CD4 count, viral load, hx of prior AIDS, concurrent cART, lymphoma subtype, IPI, type of initial chemotherapy, rituximab use) with CNSr, and the Kaplan-Meier method to assess overall survival (OS) for patients with baseline CNSi or CNSr. Results: 69% of the pts (n=607) were treated in the post-cART era; 31% (n=276) received rituximab-containing induction chemoimmunotherapy. All included 880 pts received either intrathecal (IT) therapy for CNSi or IT prophylaxis (ppx) with 1- or 3-agent regimens. CNSi at diagnosis was found in 13 % (BL/BLL 27%; DLBCL 6%; p < 0.001). There was no difference in the prevalence of baseline CNSi between pre- and post-cART era (13% each). 5.3% of pts experienced CNSr at a median of 4.2 mo (0.3-19.3) after diagnosis (12% if CNSi at baseline; 4% if not). Median OS after CNSr was 1.6 mo (0-86.4). On multivariate analysis, only baseline CNSi was significantly associated with frequency of CNSr (HR 2.9, p=0.01), but no other baseline characteristic. When restricted to pts with no CNSi at diagnosis, IT CNS ppx with 3 vs. 1 agent did not significantly impact the frequency of CNSr (HR 0.33, p= 0.38). CNSi vs. no CNSi at diagnosis was not associated with reduced OS (HR 0.85, p= 0.32). Conclusions: 5% of patients with ARL treated with IT CNS-directed therapy experience CNS relapse; it occurs early and has a poor outcome. We did not find a reduced frequency of CNSr with the use of cART, rituximab, or 1- vs. 3-agent IT CNS ppx. Although CNSi at diagnosis confers a 2.9-fold higher risk for CNSr, it does not appear to impact OS, likely because of the low overall frequency of CNSr.
Association of time to leukemia (TTL) in NOD/SCID mice with expression of apoptosis regulators in pediatric ALL
Authors: L. H. Meyer, A. Zangrando, S. M. Eckhoff, M. Queudeville, E. Vendramini, G. Basso, G. te Kronnie, K. Debatin
Journal: Journal of Clinical Oncology (2009)

10042 Background: Acute lymphoblastic leukemia (ALL) is the most frequent malignant disease in childhood. Although advances in therapy have led to improved long term survival, relapse remains a major challenge. In a recent study we transplanted pediatric leukemia samples from newly diagnosed BCP-ALL patients into NOD/SCID mice. Time to leukemia (TTL) was analyzed for each patient sample as time from transplant to overt leukemia in the recipients. Patients whose leukemia cells engrafted rapidly showed a clearly inferior relapse free survival in contrast to patient samples with prolonged in vivo growth. Multivariate analysis showed an almost 45- fold increased risk for relapse in patients with short TTL. Methods: Gene expression profiles of ALL samples (N = 14) with short versus long TTL in the xenograft model were analyzed using a human whole genome array (Affymetrix U133 Plus 2.0) correlating gene expression values (relative expression) to the time from transplant to manifestation of leukemia in the NOD/SCID mice (TTL, in weeks) by quantitative traits analysis (QTA). Results: Among 5 genes significantly correlated (Spearman correlation, P &lt; .0001) XIAP-associated factor 1 (XAF1) was found to be up-regulated in patients with long TTL. XAF1 abrogates the inhibitory effect of XIAP on caspase-3 thereby sensitizing for apoptosis. In accordance to this caspase-3 activation was also found to be up-regulated in patients with long TTL. Patient samples exhibiting a short time to overt leukemia in the xenotransplant model associated with poor relapse free survival showed down-regulated XAF1 and impaired caspase-3 activation leading to decreased apoptosis of the leukemia cells. Conclusions: Taken together, we used a novel approach directly correlating gene expression values to time from transplant to overt leukemia (TTL) identifying the apoptosis regulator XAF1 to be associated with poor outcome of patients. Small XIAP-inhibiting molecules can be used to substitute the lacking inhibitory effect of down-regulated XAF1 in these poor responding pediatric ALL patients. No significant financial relationships to disclose.
Urinary metabolite profiling by nuclear magnetic resonance spectroscopy to distinguish control patients from Wilms tumor (WT) and WT tumor by stage.
Authors: Dawn MacLellan, Tobias Karakach, Arlene Naranjo, Conrad Vincent Fernandez
Journal: Journal of Clinical Oncology (2014)

e21013 Background: Accurate risk stratification of pediatric renal tumors is essential in optimal management. Urine metabolic profiling may enhance accurate categorization. We determined if the urinary metabolite signature of favourable histology WT is distinct from normal controls, and if these signatures vary between stages, histology and relapse. Methods: Urine was collected from 10 healthy male controls (average age 65 (range 25 to 95) months). 91 frozen urine samples from the Children's Oncology Group biobank were obtained from Stage 1 (n=20), Stage 2 (n=27), Stage 3 (n=28), and Stage 4 (n=16) patients with anaplastic histology (n=15) and favorable histology (n=76). Relapse occurred in 38. Samples were matched for age, gender, and race. Urine samples (200 μL) were mixed with an internal reference standard in heavy water. For each sample, 600 μL of the solution was drawn and 1D 1H-NMR spectral data were acquired. The spectra underwent standard analysis before being exported to MATLAB R2008b (MathWorks, Natick, MA) for advanced statistical processing. Results: Separation of the metabolite signatures of control and WT tumor urine samples was demonstrated by a validated partial least squares discriminant analysis (PLS-DA). Urine levels of creatine, creatinine, acetate and citrate were decreased in WT tumor compared to controls. The urine of WT tumor patients demonstrated elevated levels of amino acids, sugars, dimethylamine, 2-oxoglutarate, alanine, and branched chain amino acids versus controls. The branched chain amino acids that were noted to be altered included: leucine, isoleucine, iso-valerate, 2-hydroxybutyrate, and 2-oxoisovalerate. Urinary metabolomic profiles among different stages of WT tumor showed distinct profiles and separation by PLS-DA. Group clustering was noted among control, different stages, relapse, and non-relapse samples, with some overlap. Conclusions: Metabolomic profiling of urine by NMR demonstrates distinct, but not completely separable, patterns that distinguish between controls, WT stage and histology, and relapse. Determining how distinct these findings are from other cancers and the pathways responsible is needed.