tbuckley/cabot-search huggingface dataset:
Urokinase-type plasminogen activator gene (PLAU) to predict clinical outcome in invasive lobular carcinoma.
Authors: Otto Metzger, Stefan Michiels, Sandeep K. Singhal, François Bertucci, Christine Desmedt, Debora Fumagalli, Roberto Salgado, Christine Galant, Isabelle Veys, Kamal V.S. Saini, Denis Larsimont, Eric P. Winer, Martine J. Piccart-Gebhart, Christos Sotiriou
Journal: Journal of Clinical Oncology (2012)

e21010 Background: At the molecular level invasive lobular carcinoma (ILC) is mostly composed of luminal A (LA) (≈80%) followed by luminal B (≈15%) and a small fraction of HER2-positive (≈5%) tumors (Metzger et al SABCS2011). In ILC, Genomic Grade (GG) adds prognostic information to clinico-pathological (CP) characteristics (Metzger et al ASCO 2011). In this study we sought to evaluate the prognostic value of different gene signatures/modules in patients diagnosed with LA classic ILC. Methods: Gene expression data were generated from 184 consecutive frozen tumor samples using Affymetrix U133 Plus 2.0 arrays. ILC tumors were classified into molecular subtypes using the PAM50 classifier. ILC tumors characterized as classic ILC by pahtologists and as LA by PAM50 were selected for this analysis. Invasive disease free survival (IDFS) was defined as the interval between date of surgery and date of any invasive recurrence or death. Multivariate analyses for IDFS and overall survival (OS) adjusted for age, tumor size, nodal status and chemotherapy was performed for gene signatures/modules related to proliferation, invasion, immune response and signaling pathways (IGF1, PI3K, MAPK, Src, Wnt). Results: 125 LA classic ILC tumors were identified with a median follow-up of 6.6 years (95% CI 5.6-7.6). The addition of PLAU gene expression as continous variable to CP variables yielded a significant hazard ratio (HR) for IDFS (HR= 2.1 [1.1 – 4.1], Δx 2 = 4.5, likelihood ratio p = 0.03) and for OS (HR = 3.6 [1.4 – 9.6], Δx 2 = 6.9, likelihood ratio p = 0.009). GG as a continous variable yielded a significant HR for IDFS (HR= 2.6 [1.2 – 5.7], Δx 2 = 6.2, likelihood ratio p = 0.01), but not for OS (HR= 2.1 [0.8 – 5.5], Δx 2 = 2.5, likelihood ratio p = 0.11). In contrast, IGF1, PI3K, MAPK, Src, Wnt, immune response, gene-70 and gene-76 failed failed to add signficant independent prognostic value. Conclusions: In addition to GG, PLAU adds prognostic information to CP factors in LA classic ILC and may guide future drug development in this difficult to treat BC subset. Of interest, PLAU is involved in degradation of extracellular matrix contributing to cell migration and metastasis and is a major component of a validated breast cancer biomarker (UPA/PAI1).
Intervention to increase site activations for multicenter trials to improve accrual.
Authors: Holly Massett, Kurt A. Jaeckle, Jenny R Hopkins, Bhupinder Singh Mann, Andrea Denicoff, David M. Dilts
Journal: Journal of Clinical Oncology (2012)

e16569 Background: The National Cancer Institute’s (NCI) Cancer Trials Support Unit (CTSU) provides access to NCI-sponsored trials. To participate in a multi-center trial, sites must first complete the trial’s Protocol Specific Requirements (PSRs); interested sites are listed as “pending” in the CTSU database until all PSRs are completed. The aim of this investigation was to examine site activation delays for a study with multiple start-up steps and evaluate an intervention directed at helping sites more rapidly open it to patient accrual. Methods: NCCTG N0577, an anaplastic glioma trial named CODEL, was identified as a slow accruing trial with many sites listed as pending activation in the CTSU’s database (&gt;85%; n=227 pending). Most N0577 pending sites had 1-2 incomplete PSRs (with 75% requiring only a neurocognitive certification), and we suspected that sites were not aware of these requirements. To accelerate site activation for N0577, we created an intervention using Awareness Theory. First, N0577 was amended to streamline the neurocognitive certification process. We then generated email lists of the 227 pending sites’ PIs (n=21; note: many were PIs of multiple sites) and their respective administrators (n=46), and created tailored email notices by PSR category explaining the necessary steps to complete N0577 activation at their site or to report their site as not planning to participate. Emails were sent to sites via the CTSU. Results: 31 sites (14%) registered activity for N0577 within 3 weeks of the intervention. Of these, 22 changed status to “approved,” 2 were disapproved, 1 withdrew, and 6 made changes but remained pending. This represents a marked increase (+520%) in site activity of the CTSU Regulatory Support Service (RSS) for N0577, compared with the monthly average (5 events/mo) during the preceding 6 months. Accrual is being monitored to observe for any increases and will be reported. Conclusions: Complicated and incomplete PSRs delay site activation of multi-center trials and may impact accrual. Streamlining PSR processes and early monitoring of CTSU site activation with notifications to sites of outstanding PSRs for trials can increase the timeliness of sites opening trials, with the potential to improve accrual.
Consistent benefit survival with cabazitaxel (CBZ) in metastatic castration resistant prostate cancer (mCRPC) in Spain: Updated results.
Authors: Iria Gonzalez, Daniel E. Castellano, Emilio Esteban, Quionia Pérez Arnillas, Javier Munarriz, Begona Campos Balea, Jose Maria Garcia-Bueno, M. Laura Villalobos Leon, Nuria Laínez, Gustavo Rubio, Carmen Santander, Jose David Cumplido Buron, Jose Garcia Sanchez, Almudena Martin, Beatriz Pelaez Lorenzo, Ana Reyes Garcia, Urbano Anido Herranz, Begoña Perez-Valderrama, Jose Maria Yglesias, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2014)

e16088 Background: New emerging therapies for mCRPC, such as CBZ, have prompted the need to identify appropriate patients (pts) for each specific treatment. Updated data on the experience with CBZ in mCRPC pts in Spain with longer follow-up is presented. Methods: Medical records from docetaxel-resistant mCRPC pts receiving CBZ at 19 centres in Spain were reviewed retrospectively. Baseline characteristics, PSA response, overall survival (OS), radiographic progression-free survival (rPFS), and toxicity were collected. Results: Data from 99 consecutive pts (median age 70 years) were reviewed: ECOG 0-1 (77.2%), Gleason score of 7-10 (83.6%), visceral involvement (24.5%), pain (72.7%) and radiological progression (69.7%) at CBZ initiation. Median duration of response to first-line androgen deprivation therapy (ADT) was 20.8 months (mo). Most pts received ≤2 hormonal lines (77.8%) and only one docetaxel line (76.8%) before CBZ. Forty-three (43.4 %) pts had progressed on docetaxel, 31 (31.3%) <6 mo and 25 (25.3%) >6 mo after docetaxel. Abiraterone or enzalutamide were given before CBZ in 5.1% of pts and after CBZ in 15.2%. Pts received a median of 6 cycles (interquartile range 4-9) of CBZ. CBZ dose-reductions or -delays for any cause occurred in 10 (10.1%) and 26 (26.3%) pts, respectively. Prophylactic G-CSF was given in 40 (40.4%) pts. A PSA decrease of ≥50% and ≥30% was reached in 38.1% and 46.4 % of pts treated with CBZ. Median OS from first CBZ cycle was 16.1 [CI: 11.4; 18.1] mo and median clinical and/or rPFS was 10.6 mo [CI: 7.5 ; 13.1]. Seventeen (17.2%) pts experienced at least one grade≥3 treatment-related AE, the most common being neutropenia (n=5), febrile neutropenia (n=2), asthenia (n=4), diarrhoea (n=2) and anemia (n=2). No grade ≥3 peripheral neuropathy was reported. An analysis of factors predicting outcome and the impact of gleason > 8 and time under ADT will be presented. Conclusions: CBZ administered in the adequate treatment setting in daily practice in Spain is associated with meaningful PFS and OS and an acceptable safety profile. Dose delays and reductions were low. Prophylactic G-CSF use in 40% pts may have contributed to these good results. Funding: Sanofi.
Long-term safety and efficacy analysis of abiraterone acetate (AA) plus prednisone (P) in metastatic castration-resistant prostate cancer (mCRPC) without prior chemotherapy (COU-AA-302).
Authors: Dana E. Rathkopf, Matthew R. Smith, Johann Sebastian De Bono, Christopher Logothetis, Neal Shore, Paul L. De Souza, Karim Fizazi, Peter Mulders, Paul N. Mainwaring, John D Hainsworth, Tomasz M. Beer, Scott A. North, Yves Fradet, Thomas W. Griffin, Youn Choi Park, Thian San Kheoh, Eric Jay Small, Howard I. Scher, Arturo Molina, Charles J. Ryan
Journal: Journal of Clinical Oncology (2013)

5009 Background: AA, a CYP17 inhibitor, prolongs the lives of men with progressive pre- or post-chemotherapy treated mCRPC with a favorable safety profile (Rathkopf et al. ASCO-GU 2013. Abstr 5). This post hoc analysis examines the safety and tolerability of long-term treatment (≥ 24 mos) in study COU-AA-302. Methods: 1,088 pts were randomized 1:1 to AA 1000 mg + P 5 mg po BID vs placebo + P. Co-primary endpoints were radiographic progression-free survival (rPFS) and OS. Median times with 95% CI of the end points were estimated using the Kaplan-Meier (KM) method. Post hoc analysis of adverse events (AEs) was performed at pre-specified interim analysis (IA3) (55% OS events). Results: At a median follow-up = 27.1 mos (IA3): rPFS HR (95% CI) = 0.53 (0.45, 0.62), p &lt; 0.0001 and OS was improved over P [0.79 (0.66, 0.96), p = 0.0151]; the latter did not reach the pre-specified efficacy boundary (p = 0.0035). All secondary endpoints favored the AA arm (Rathkopf et al. ASCO-GU 2013. Abstr 5). The incidence rate of selected AEs by duration of exposure is shown below (Table). There was no clinically relevant increase in the incidence rate of AEs with longer exposure using AA + P versus P alone; although pts on treatment for ≥ 24 mos may have had greater tolerability. The percentage of patients who came off study due to an AE was 8% (AA) versus 6% (P). Conclusions: The updated IA3 of COU-AA-302 in pts without prior chemotherapy confirms the delay in progression and prolongation of life with a favorable safety profile including pts treated for ≥ 24 mos with AA + P or P. Clinical trial information: NCT00887198. [Table: see text]
RESECCIÓN ENDOSCÓPICA MUCOSA EN PÓLIPOS DE GRAN TAMAÑO. SEGURIDAD Y EFICACIA DE LA TÉCNICA EN NUESTRO CENTRO
Authors: A Álvarez Delgado, A Mora Soler, JM González Santiago, C Revilla Morato, D Pérez Corte, HM Marcos Prieto, C Piñero Pérez, A Velasco Guardado, A Rodriguez Pérez
Journal: Endoscopy (2015)

Introducción: Los pólipos de colon sésiles y/o planos de gran tamaño (mayores de 30 mms) son un desafió endoscópico, tanto para predecir la existencia de malignidad y/o invasión submucosa, como para su resecabilidad. La resección endoscópica mucosa (REM) es una técnica útil y aceptada para este tipo de lesiones.
Significance of plasma osteopontin (OPN) as a biomarker in squamous cell carcinoma of tongue.
Authors: Madan Lal Brahma Bhatt, Vikas Kumar Srivastava, Durga Prasad Mishra, Madhu Mati Goel, Divya Mehrotra, Kirti Srivastava, Rishi Kumar Gara
Journal: Journal of Clinical Oncology (2013)

e17020 Background: Osteopontin (OPN) is an integrin-binding glycoprotein and its upregulation plays an important role in cancer progression. We analysed plasma OPN levels in squamous cell carcinoma of tongue (SCCT) patients, and healthy controls. We evaluated the relationship between plasma OPN level and outcome to therapy in the patients. Methods: Plasma OPN levels in 54 patients of SCCT and 18 healthy controls were measured by ELISA method. All participants gave written consent to participate in the study. Patients were subjected to chemo-radiotherapy using tele-cobalt radiotherapy machine (Theratron 780 C, AECL, Ottawa). A dose of 70 Gy of radiation was delivered to all the patients in 7 weeks with 2 Gy fraction size, 5 days a week by shrinking field technique. Chemotherapy was given in the form of Inj cisplatinum 30 mg/m2 IVI weekly, during the course of treatment with hydration, diuresis and anti-emetics. The data was analysed by using SPSS version 11.5 software. A value of p &lt; 0.05 was considered statistically significant. Results: The plasma OPN levels of the SCCT ranged from 29.53 ng/mL- 514.52 ng/mL (mean and SE; 229.94 ± 21.96 ng/mL), which were significantly higher (p &lt; 0.0001) than those of the controls which ranged from 12.45 ng/mL- 109.46 ng/mL (mean± SE; 50.69 ± 6.83 ng/mL). The patients with advanced T stage (T3/T4 vs.T1/T2) and positive N status (N +ve vs N-ve) had significantly higher plasma levels of OPN (p &lt; 0.0001 and 0.001 respectively). The Kalpan-Meier survival curves for overall survival of patients with advanced T stage, positive N status or advanced TNM stage were significantly lower than that of patients with early T stage, negative N status or early TNM stage, respectively. Multivariate Cox regression analysis showed that OPN may be a predictive biomarker for poor outcome to radio-chemotherapy (95% CI = 0.081–0.293, p &lt; 0.005). Conclusions: Our results suggested that the evaluation of plasma OPN levels may be a useful biomarker for diagnosis and prediction of response to radio-chemotherapy in SCCT.
Cost-effectiveness of everolimus plus exemestane in post-menopausal hormone receptor positive metastatic breast cancer.
Authors: Simon B. Zeichner, Kiran Kumar Venkata Raja Avancha, Gilberto Lopes, Stefan Gluck, Alberto J. Montero
Journal: Journal of Clinical Oncology (2013)

6548 Background: Everolimus in combination with exemestane is approved for the treatment of postmenopausal women with hormone-receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). The BOLERO-2, a randomized phase 3 trial, demonstrated a significantly improved progression free survival (PFS) with everolimus plus exemestane compared to exemestane alone in patients previously treated with non-steroidal aromatase inhibitors. In order to better inform U.S. policymakers, this study aimed to assess the cost-effectiveness, from a payer perspective, of everolimus in combination with exemestane. Methods: We created decision analytical and Markov models using published data from the BOLERO-2 trial. Utilities were derived from available literature. Costs were obtained from the Center for Medicare Services drug payment table and physician fee schedule and were represented in 2012 U.S. dollars. The quality-adjusted life-years (QALY) and incremental cost-effectiveness ratio (ICER) were calculated. One way and probabilistic sensitivity analyses were performed. Results: Everolimus added 0.42 years of progression-free survival (PFS) by central radiographic assessment with an incremental cost of $33,103, an overall cost of $62,751.54 per year of PFS gained, and an ICER of $79,376/QALY. By local assessment, everolimus added 0.29 years PFS years with an incremental cost of $31,873, an overall cost of $83,222 per year of PFS gained, and an ICER of $108,131/QALY. The results of the model were robust in sensitivity analyses. The primary drivers in this model were found to be: PFS duration, progression free probability on therapy, and overall everolimus cost. Conclusions: Everolimus plus exemestane appears to be cost-effective in the treatment of metastatic breast cancer. Based on efficacy and value, this newly approved combination should be considered to be a viable option in treating patients with HR+/HER2- MBC upon progression on non-steroidal aromatase inhibitors.
Phase I study of TH-302, investigational hypoxia-targeted drug, in combination with sunitinib.
Authors: Alexander Starodub, Mohammed M. Milhem, Kenneth Lee Pennington, Ebenezer A. Kio, Daniel Bruetman, Tracy Thorne, Barbara Hickingbottom, Stew Kroll
Journal: Journal of Clinical Oncology (2013)

e15557 Background: Tumors often consist of highly hypoxic subregions known to be resistant to chemotherapy and radiotherapy. TH-302 is an investigational hypoxia-targeted drug with a 2-nitroimidazole trigger designed to release the DNA alkylator bromo-isophosphoramide mustard (Br-IPM) when reduced in severe hypoxia. Preclinical models demonstrate that treatment with sunitinib increased the tumor hypoxic fraction, the therapeutic target of TH-302. Initiating TH-302 following sunitinib significantly increased the efficacy of sunitinib in these models. In this phase 1 dose escalation study, TH-302 was combined with standard dose sunitinib. Methods: Eligible patients (pts) for the study (NCT01381822) had advanced RCC, GIST or PNET tumors, evaluable disease by RECIST, ECOG ≤2 and acceptable hematologic, hepatic and renal function. Pts received TH-302 in combination with standard full doses of 50 mg PO sunitinib daily from Day 1 to Day 28 of a 6 week cycle. TH-302 was administered IV on Days 8, 15 and 22. TH-302 starting dose was 240 mg/m 2 . The study objectives were to determine the MTD, DLTs and RP2D and to evaluate the safety and preliminary efficacy of TH-302 when used in combination with sunitinib. Results: Ten pts were enrolled. Median age: 63 (range 27-72); Female (5)/ Male (5); ECOG 0 (5); ECOG 1 (5); Primary tumor: RCC (6), GIST (4). Median prior chemotherapies: 3 (range: 0-3) including prior sunitinib in 7 pts. No DLTs were observed in the 3 pts at the 240 mg/m 2 cohort and 1 pt of 5 DLT evaluable in the 340 mg/m 2 cohort had a DLT of stomatitis. Eight pts discontinued (progressive disease (6), pursued other treatment options, adverse event unrelated to study drugs). Three pts had a study drug related SAE (neutropenic sepsis, anemia, hyperthyroidism). Common TH-302 related AEs were nausea and mucosal toxicity and were mostly grade 1 or 2. Grade 3/4 thrombocytopenia and neutropenia were reported in 4 pts and 3 pts, respectively. One of 4 (25%) pts with GIST had a confirmed PR and 3 of 4 (75%) pts with RCC had PRs including 2 with confirmed PRs. Conclusions: TH-302 can be administered in combination with full dose sunitinib. Mucositis was dose limiting. There is preliminary evidence of activity of TH-302 in combination with sunitinib in RCC. Clinical trial information: NCT01381822.
Mice lacking liver-specific β-catenin develop steatohepatitis and fibrosis after iron overload
Authors: Morgan E. Preziosi, Sucha Singh, Erika V. Valore, Grace Jung, Branimir Popovic, Minakshi Poddar, Shanmugam Nagarajan, Tomas Ganz, Satdarshan P. Monga
Journal: Journal of Hepatology (2017)
Prospective comparison of open and thoracoscopic lobectomy techniques: Thoracoscopic lobectomy is an equivalent cancer operation for early lung cancer
Authors: J. R. Roberts
Journal: Journal of Clinical Oncology (2006)

7225 Background: Minimally invasive pulmonary lobectomy is less painful than classical techniques, and thus potentially safer. Much research has demonstrated that the surgery is at least as safe as standard techniques. However, though the techniques are decades old, they are still not widely practiced. Opponents to these techniques argue that minimally invasive pulmonary surgery has not been demonstrated to be equivalent cancer surgery. Methods: We compared our patients stage by stage undergoing open and minimally invasive resections (case-control). All patients who underwent elective anatomic lobectomy were compared with respect to demographic parameters, hospital stay, and survival, by stage. Means were compared using two-tailed student’s t test, proportions, with chi-square, and survival by nonparametric statistics. p values less than 0.05 were accepted as significant. Results: Four hundred fifty-three patients (453)underwent lobectomy over a seven year period (317 were open (OL), and 146 were thoracoscopic (TL)). No differences were seen between the ages, functional vital capacity (FVC%) and residual volume (RV%). However, TL patients had poorer FEV1% (open-69%, TL-60%, p = 0.0245) and poorer diffusing capacity (open-87%, TL-64%, p = 0.000906). Further, the open lobectomies had longer length of stays (open-9.5 dyas, TL–7.3 days, p = 0.001), longer intensive care unit stays (open-1.6 days, TL-0.129 days, p = 0.00013), and higher perioperative mortality (open open-3%, TL-0%). The survival values for stage I NSCLC patients are shown below. No differences in survival between the two techniques was seen. Conclusions: Thoracoscopic or minimally invasive lobectomy is an established technique that has been refined for more than a decade. Several studies suggest an earlier recovery from thoracoscopic lobectomy. This study demonstrates that the two approaches are equivalent cancer operations. [Table: see text] No significant financial relationships to disclose.
Association of KRAS mutation with worse recurrence-free survival and site of metastatic progression after resection of hepatic colorectal metastases.
Authors: Nancy E. Kemeny, Joanne F. Chou, Marinela Capanu, Alexandra N. Gewirtz, Andrea Cercek, T. Peter Kingham, William R. Jarnagin, Yuman Fong, Ronald P. DeMatteo, Peter J. Allen, Jinru Shia, Celina Ang, Efsevia Vakiani, Michael Ian D'Angelica
Journal: Journal of Clinical Oncology (2013)

3609 Background: There are conflicting results regarding the influence of KRAS mutation status and outcome in patients (pts) with colorectal cancer. A recent report suggested worse outcome in KRAS mutated (MUT) pts who underwent resection of hepatic metastases (Karagkounis et al, ASCO 2012). Methods: Recurrence patterns and survival were evaluated in 169 patients who had undergone resection of liver metastases, then received adjuvant hepatic arterial infusion and systemic chemotherapy, and for whom KRAS data were available. Kaplan-Meier methods were used to estimate recurrence free survival (RFS) and overall survival (OS). Log-rank test was used to determine whether survival functions differed by KRAS mutation status. Cumulative incidence function was used to estimate the probability of time from adjuvant therapy to bone, brain, lung and liver metastases separately. Mutations in KRAS (codons 12, 13) were detected using the iPLEX assay (Sequenom, Inc). Results: Median follow-up for the entire cohort was 38.8 months. 118 were KRAS wildtype (WT), and 51 were KRAS MUT (45 G12, 5 G13, 1 K117N). The 3 year RFS was 48% [95%CI: 37-58%] for KRAS WT pts and 30% [15-44%] for MUT pts (p&lt;0.01). OS at 3 years was 96% [88-98%] for KRAS WT and 80% [61-90%] for MUT pts (p=0.08). Cumulative incidence of developing bone, brain, lung, and liver metastases by 2 years is presented in Table 1. The cumulative incidence of metastases to bone at 2 years was 0% and 13.7% in KRAS WT versus MUT pts (p&lt;0.01), to brain 0% versus 4.6% for KRAS WT versus MUT (p=0.05), and to lung 27% versus 47.5% in KRAS WT versus MUT pts (p&lt;0.01). Conclusions: In pts who have had liver resection followed by adjuvant therapy, those with KRAS MUT have a worse RFS and seemingly worse OS than those who are KRAS WT. Also, patients with KRAS MUT appear more likely to develop bone, brain, and lung metastases. Further investigation of a larger number of patients is warranted. [Table: see text]