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Pittsburgh, PA, United States
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Mehta R.S.,University of Pittsburgh | Mehta R.S.,150 Center Avenue | Liman A.D.,VA Pittsburgh Healthcare System | Passero V.A.,University of Pittsburgh | And 2 more authors.
Cancer Microenvironment | Year: 2013

Approximately 1 in 14 men and women during their lifetime will be diagnosed with lung cancer, which is the leading cause of cancer-related mortality in the world. As of January 1, 2008, there were about 373,500 men and women living with lung cancer in the United States. Fewer than 60,000 of these are estimated to be alive by January 2013, reflecting a poor overall 5-year relative survival rate of under 16 %. With metastatic cancer, the overall 5-year survival is meager 4 %. On the other hand, the overall five-year survival is over 50 % when the cancer is still in the localized stage. However, unfortunately, more than half of cases of lung cancer are diagnosed at an advanced stage Howlader et al. (2010). Cancer metastasis, the single most critical prognostic factor, is still poorly understood and a highly complex phenomenon. The most common sites of lung cancer metastasis are the lymph nodes, liver, adrenals, brain and bones. The gastrointestinal (GI) tract is an exceptionally rare site of metastasis; with only a handful of cases reported in the literature Centeno et al. (Lung Cancer, 18: 101-105, 1997); Hirasaki et al. (World J Gastroenterol, 14: 5481-5483, 2008); Carr and Boulos (Br J Surg, 83: 647, 1996); Otera et al. (Eur Respir Rev, 19: 248-252, 2010); Antler et al. (Cancer, 49: 170-172, 1982); Fujiwara et al. (Gen Thorac Cardiovasc Surg, 59: 748-752, 2011); Stinchcombe et al. (J Clin Oncol, 24: 4939-4940, 2006); John et al. (J Postgrad Med, 48: 199-200, 2002); Carroll and Rajesh (Eur J Cardiothorac Surg, 19: 719-720, 2001); Brown et al. (Dis Colon Rectum, 23: 343-345, 1980). We report three cases of non-small cell (squamous cell) lung cancer with GI tract metastasis - two in the colon and one in the jejunum. Then we present a review of literature exploring various theories of metastasis, as an attempt to understand the reason of preferential tumor metastasis. © 2013 Springer Science+Business Media Dordrecht.

Bauman J.E.,University of Pittsburgh | Bauman J.E.,University of New Mexico | Bauman J.E.,150 Center Avenue | Arias-Pulido H.,University of New Mexico | And 11 more authors.
Oral Oncology | Year: 2013

Objectives: The epidermal growth factor receptor (EGFR) is a validated target in head and neck squamous cell carcinoma (HNSCC). In recurrent and/or metastatic (R/M) HNSCC, resistance to anti-EGFR therapy inevitably occurs. Downstream activation of the PI3K/Akt/mTOR pathway is an established resistance mechanism. Concurrent mTOR blockade may improve efficacy of anti-EGFR therapy. Materials and methods: Erlotinib 150 mg daily and temsirolimus 15 mg weekly were administered to patients with platinum-refractory R/M HNSCC and ECOG performance status 0-2. The primary endpoint was progression-free survival (PFS). Correlative studies determined PIK3CA and HRAS mutation status; p16, EGFR, pS6K, pAkt and PTEN expression; and pre- and post-treatment plasma levels of 20 immunomodulatory cytokines. Results: Twelve patients enrolled; six withdrew within 6 weeks due to toxicity or death, prompting early closure of the trial. Grade ≥ 3 toxicities included fatigue, diarrhea, gastrostomy tube infection, peritonitis, pneumonia, dyspnea, and HN edema. Median PFS was 1.9 months. Median overall survival was 4.0 months. Six/12 tumors were p16(+), 9/11 lacked measurable PTEN expression, and 1/12 harbored a PIK3CA mutation. On exploratory analysis, high baseline plasma VEGF and interferon-gamma levels marginally associated with tumor progression. Conclusions: The combination of erlotinib and temsirolimus was poorly tolerated. Low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in R/M disease. Investigation of more tolerable combinations of EGFR and PI3K/Akt/mTOR pathway inhibitors in selected HNSCC patients is warranted. © 2012 Elsevier Ltd. All rights reserved.

Hu J.,Johnnie chran Jr Brain Tumor Center | Wen P.Y.,Dana-Farber Cancer Institute | Abrey L.E.,University of Zürich | Fadul C.E.,Dartmouth Hitchcock Medical Center | And 4 more authors.
Journal of Neuro-Oncology | Year: 2013

Gimatecan is a lipophilic oral camptothecin analogue with preclinical activity in glioma models. We conducted a multicenter phase II trial to evaluate the efficacy of gimatecan in adults with recurrent glioblastoma. Eligibility criteria included ≤1 prior treatment for recurrent disease, age ≥18, Eastern Cooperative Oncology Group performance status 0-1, and normal organ function. Patients taking enzyme-inducing anti-seizure medications were excluded. Gimatecan 1.22 mg/m2 was given orally once daily for 5 consecutive days during each 28-day cycle. The primary endpoint was progression-free survival at 6 months. A Simon 2-stage optimal design was used in which 19 patients were evaluated in the 1st stage, with an additional 36 patients accrued if >4 patients in stage 1 achieved PFS at 6 months. 29 patients were enrolled in the study, with median age of 58 years (range, 25-77 years); 58.6 % female. All patients received prior surgery, radiation therapy, and at least one chemotherapy regimen. The daily dose was reduced to 1.0 mg/m2 after four of the first 10 patients experienced grade 4 hematologic toxicity. Treatment-related grade 3/4 toxicities included thrombocytopenia (17.2 %), leukopenia (17.2 %) and neutropenia (10.3 %). None of the 19 patients treated at 1.0 mg/m2/day experienced grade 4 hematologic toxicity. One patient had a partial radiographic response by modified Macdonald criteria. Only 3 patients (12 %) were progression-free at 6 months. Median time to progression was 12.0 weeks (7.0, 17.0).Treatment with gimatecan 1.0 mg/m2/day for 5 days, repeated every 28-days showed minimal efficacy. © 2012 Springer Science+Business Media New York.

Ducey M.J.,University of New Hampshire | Williams M.S.,150 Center Avenue | Gove J.H.,U.S. Department of Agriculture | Roberge S.,University of New Hampshire | Kenning R.S.,Salish Kootenai College
Forestry | Year: 2013

Coarse woody debris (CWD) has been identified as an important component in many forest ecosystem processes. Perpendicular distance sampling (PDS) is one of the several efficient new methods that have been proposed for CWD inventory. One drawback of PDS is that the maximum search distance can be very large, especially if CWD diameters are large or the volume factor chosen is small. Here, we propose a modified method, which we call distance-limited PDS, that addresses this limitation. We describe the field procedures, develop new a new estimator, and provide a proof of unbiasedness of that estimator. The new method is compared with line intersect sampling (LIS) and PDS in a field trial in the northeastern United States. The results of the field trial show that this new method requires as little as the sampling effort of LIS in order to achieve comparable variance of the estimates. © 2012 Published by Oxford University Press on behalf of the Institute of Chartered Foresters, 2012.

Tarhini A.,150 Center Avenue | Kotsakis A.,150 Center Avenue | Gooding W.,150 Center Avenue | Shuai Y.,150 Center Avenue | And 5 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Mammalian target of rapamycin (mTOR) is a promising target in small cell lung cancer (SCLC). We designed a phase II study of everolimus, an mTOR inhibitor, in previously treated, relapsed SCLC. Experimental Design: Patients were treated with everolimus 10 mg orally daily until disease progression. The primary endpoint was disease control rate (DCR) at 6 weeks. PI3K/Akt signaling pathway biomarkers were evaluated on baseline tumor tissue. Results: A total of 40 patients were treated: 23 had 1 prior regimen/sensitive relapse, 4 had 1 prior regimen/refractory, and 13 had 2 prior regimens. Twenty-eight patients received 2 or more cycles of everolimus, 7 received 1 cycle, and 5 did not complete the first cycle. Best response in 35 evaluable patients: 1 (3%) partial response (in sensitive relapse), 8 (23%) stable disease, and 26 (74%) progression; DCR at 6 weeks was 26% (95% CI = 11-40). Median survival was 6.7 months and median time to progression was 1.3 months. Grade 3 toxicities included thrombocytopenia (n = 2), neutropenia (n = 2), infection (n = 2), pneumonitis (n = 1), fatigue (n = 1), elevated transaminases (n = 1), diarrhea (n = 2), and acute renal failure (n = 1). High phosphorylated AKT expression was modestly associated with overall survival (HR = 2.07; 95% CI = 0.97-4.43). Baseline S6 kinase protein expression was significantly higher in patients with disease control versus patients with progression (P = 0.0093). Conclusions: Everolimus was well tolerated but had limited single-agent antitumor activity in unselected previously treated patients with relapsed SCLC. Further evaluation in combination regimens for patients with sensitive relapse may be considered. ©2010 AACR.

Kang R.,University of Pittsburgh | Tang D.,University of Pittsburgh | Livesey K.M.,University of Pittsburgh | Schapiro N.E.,University of Pittsburgh | And 3 more authors.
Antioxidants and Redox Signaling | Year: 2011

Reactive oxygen species, including hydrogen peroxide (H 2O 2), can cause toxicity and act as signaling molecules in various pathways regulating both cell survival and cell death. However, the sequence of events between the oxidative insult and cell damage remains unclear. In the current study, we investigated the effect of oxidative stress on activation of the Receptor for Advanced Glycation End-products (RAGE) and subsequent protection against H 2O 2-induced pancreatic tumor cell damage. We found that exposure of pancreatic tumor cells to H 2O 2 provoked a nuclear factor kappa B (NF-κB)-dependent increase in RAGE expression. Further, suppression of RAGE expression by RNA interference increased the sensitivity of pancreatic tumor cells to oxidative injury. Furthermore, targeted knockdown of RAGE led to increased cell death by apoptosis and diminished cell survival by autophagy during H 2O 2-induced oxidative injury. Moreover, we demonstrate that RAGE is a positive feedback regulator for NF-κB as knockdown of RAGE decreased H 2O 2-induced activity of NF-κB. Taken together, these results suggest that RAGE is an important regulator of oxidative injury. © 2011 Mary Ann Liebert, Inc.

Williams M.S.,150 Center Avenue | Ebel E.D.,150 Center Avenue
Environmental Science and Technology | Year: 2014

The fitting of statistical distributions to chemical and microbial contamination data is a common application in risk assessment. These distributions are used to make inferences regarding even the most pedestrian of statistics, such as the population mean. The reason for the heavy reliance on a fitted distribution is the presence of left-, right-, and interval-censored observations in the data sets, with censored observations being the result of nondetects in an assay, the use of screening tests, and other practical limitations. Considerable effort has been expended to develop statistical distributions and fitting techniques for a wide variety of applications. Of the various fitting methods, Markov Chain Monte Carlo methods are common. An underlying assumption for many of the proposed Markov Chain Monte Carlo methods is that the data represent independent and identically distributed (iid) observations from an assumed distribution. This condition is satisfied when samples are collected using a simple random sampling design. Unfortunately, samples of food commodities are generally not collected in accordance with a strict probability design. Nevertheless, pseudosystematic sampling efforts (e.g., collection of a sample hourly or weekly) from a single location in the farm-to-table continuum are reasonable approximations of a simple random sample. The assumption that the data represent an iid sample from a single distribution is more difficult to defend if samples are collected at multiple locations in the farm-to-table continuum or risk-based sampling methods are employed to preferentially select samples that are more likely to be contaminated. This paper develops a weighted bootstrap estimation framework that is appropriate for fitting a distribution to microbiological samples that are collected with unequal probabilities of selection. An example based on microbial data, derived by the Most Probable Number technique, demonstrates the method and highlights the magnitude of biases in an estimator that ignores the effects of an unequal probability sample design. © This article not subject to U.S. Copyright. Published 2014 by the American Chemical Society.

Berhane H.,University of Pittsburgh | Shinde A.,University of Pittsburgh | Kalash R.,University of Pittsburgh | Xu K.,University of Pittsburgh | And 11 more authors.
Radiation Research | Year: 2014

The altered DNA damage response pathway in patients with Fanconi anemia (FA) may increase the toxicity of clinical radiotherapy. We quantitated oral cavity mucositis in irradiated Fanconi anemia Fancd2-/- mice, comparing this to Fancd2+/- and Fancd2+/+ mice, and we measured distant bone marrow suppression and quantitated the effect of the intraoral radioprotector GS-nitroxide, JP4-039 in F15 emulsion. We found that FA mice were more susceptible to radiation injury and that protection from radiation injury by JP4-039/F15 was observed at all radiation doses. Adult 10-12-week-old mice, of FVB/N background Fancd2-/-, Fancd2 +/- and Fancd2+/+ were head and neck irradiated with 24, 26, 28 or 30 Gy (large fraction sizes typical of stereotactic radiosurgery treatments) and subgroups received intraoral JP4-039 (0.4 mg/mouse in 100 μL F15 liposome emulsion) preirradiation. On day 2 or 5 postirradiation, mice were sacrificed, tongue tissue and femur marrow were excised for quantitation of radiation-induced stress response, inflammatory and antioxidant gene transcripts, histopathology and assay for femur marrow colony-forming hematopoietic progenitor cells. Fancd2-/- mice had a significantly higher percentage of oral mucosal ulceration at day 5 after 26 Gy irradiation (59.4 ± 8.2%) compared to control Fancd2+/+ mice (21.7 ± 2.9%, P = 0.0063). After 24 Gy irradiation, Fancd2-/- mice had a higher oral cavity percentage of tongue ulceration compared to Fancd2 +/+ mice irradiated with higher doses of 26 Gy (P = 0.0123). Baseline and postirradiation oral cavity gene transcripts were altered in Fancd2 -/- mice compared to Fancd2+/+ controls. Fancd2 -/- mice had decreased baseline femur marrow CFU-GM, BFUe and CFU-GEMM, which further decreased after 24 or 26 Gy head and neck irradiation. These changes were not seen in head-and neck-irradiated Fancd2+/+ mice. In radiosensitive Fancd2-/- mice, biomarkers of both local oral cavity and distant marrow radiation toxicity were ameliorated by intraoral JP4-039/F15. We propose that Fancd2-/- mice are a valuable radiosensitive animal model system, which can be used to evaluate potential radioprotective agents. © 2014 by Radiation Research Society.

Boone B.A.,University of Pittsburgh | Steve J.,University of Pittsburgh | Krasinskas A.M.,University of Pittsburgh | Zureikat A.H.,University of Pittsburgh | And 5 more authors.
Journal of Surgical Oncology | Year: 2013

Background Trials examining FOLFIRINOX in metastatic pancreatic cancer demonstrate higher response rates compared to gemcitabine-based regimens. There is currently limited experience with neoadjuvant FOLFIRINOX in pancreatic cancer. Methods Retrospective review of outcomes of patients with borderline resectable or locally unresectable pancreatic cancer who were recommended to undergo neoadjuvant treatment with FOLFIRINOX. Results FOLFIRINOX was recommended for 25 patients with pancreatic cancer, 13 (52%) unresectable and 12 (48%) borderline resectable. Four patients (16%) refused treatment or were lost to follow-up. Twenty-one patients (84%) were treated with a median of 4.7 cycles. Six patients (29%) required dose reductions secondary to toxicity. Two patients (9%) were unable to tolerate treatment and three patients (14%) had disease progression on treatment. Seven patients (33%) underwent surgical resection following treatment with FOLFIRINOX alone, 2 (10%) of which were initially unresectable. Two patients underwent resection following FOLFIRINOX + stereotactic body radiation therapy (SBRT). The R0 resection rate for patients treated with FOLFIRINOX ± SBRT was 33% (55% borderline resectable, 10% unresectable). A total of five patients (24%) demonstrated a significant pathologic response. Conclusions FOLFIRINOX is a biologically active regimen in borderline resectable and locally unresectable pancreatic cancer with encouraging R0 resection and pathologic response rates. J. Surg. Oncol. 2013 108:236-241. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.

Ransom J.I.,U.S. Geological Survey | Roelle J.E.,U.S. Geological Survey | Cade B.S.,U.S. Geological Survey | Coates-Markle L.,United States Bureau of Land Management | Kane A.J.,150 Center Avenue
Wildlife Society Bulletin | Year: 2011

Locally abundant feral horses (Equus caballus) can rapidly deplete available resources. Fertility control agents present promising nonlethal tools for reducing their population growth rates. We tested the effect of 2 forms of the immunocontraceptive porcine zona pellucida (PZP) on foaling rates in 3 populations of feral horses in the western United States. A liquid form requiring annual boosters was administered at Little Book Cliffs Wild Horse Range, Mesa County (CO), and Pryor Mountain Wild Horse Range, Bighorn County (WY) and Carbon County (MT), and a time-release pellet form designed to produce 2 yr of infertility was administered at McCullough Peaks Herd Management Area, Park County (WY). Average foaling rates (foals born/mare-yr) from direct observation of untreated and treated female horses (mares), 2004-2008, were 60.1% (n = 153 mare-yr) versus 6.6% (n = 91 mare-yr) at Little Book Cliffs, and 62.8% (n = 129 mare-yr) versus 17.7% (n = 79 mare-yr) at Pryor Mountain, respectively. At McCullough Peaks, mean annual foaling rates from 2006 to 2008 were 75.0% (n = 48 mare-yr) for untreated mares and 31.7% (n = 101 mare-yr) for treated mares. Controlling for age of mares and pretreatment differences in fertility, PZP reduced foaling rates in all 3 herds. The pellets used at McCullough Peaks (produced by cold evaporation) were less effective than pellets used in a previous trial and produced by heat extrusion. Immunocontraception with PZP may be a useful tool in reducing fertility rates in some western United States feral horse herds, but population growth reduction will depend on timely access to mares for inoculation and the proportion of mares that can be successfully treated. © 2011 The Wildlife Society.

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