Is cigarette smoke associated with increased catabolism of gemcitabine in patients with advanced solid tumors?

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2602-2602
Author(s):  
Meaghan Working O'Malley ◽  
Stephanie Daignault ◽  
Patrick N. Healy ◽  
Lindsay A. Schmidt ◽  
Nithya Ramnath
Keyword(s):  
Logistic Regression ◽  
Cigarette Smoking ◽  
Small Sample Size ◽  
Plasma Concentrations ◽  
Small Sample ◽  
Stage Iii ◽  
Disease Stage ◽  
Smoking History ◽  
Unknown Primary ◽  
Never Smokers

2602 Background: Cigarette smoking can accelerate chemotherapy metabolism and result in lower plasma concentrations of the chemotherapeutic agent. Reduced drug levels may lead to undertreatment in smokers and, conversely, increased treatment-related neutropenia in nonsmokers. Methods: An IRB-approved retrospective chart review was performed on 151 patients with solid tumor malignancies who received gemcitabine alone or in combination with oral chemotherapy agents from July 1, 2009 to June 30, 2011 at the University of Michigan. Using logistic regression, we compared toxicity, including neutropenia, and smoking history measured in pack-years in smokers vs. nonsmokers to ascertain whether cigarette smoking is an independent factor predictive of toxicity to gemcitabine. Results: Tumor types included breast (9.3%), lung (4.6%), pancreatobiliary (70.9%), or other/unknown primary (15.2%). Most patients had advanced disease (stage III-IV; 78.1%); specifically, of the pancreatobiliary cohort (PB; n=107), 77.6% patients had stage III-IV disease. Within the PB cohort, most patients were “ever” smokers as compared to “never” smokers (60.7% vs. 39.3%). Logistic regression of this cohort showed that current smokers had decreased CTC-AE grade 3-4 neutropenia vs. never smokers (OR 0.667; 95% CI [0.156-2.859]). This effect was more pronounced with higher pack-year history: smokers with >50 pack-years had even less neutropenia as compared to never smokers (OR 0.333; 95% CI [0.065-1.699]). Further statistical analysis of subgroups was not performed due to small sample size. Conclusions: Smokers with pancreatobiliary malignancies receiving gemcitabine had less treatment-related neutropenia as compared to never smokers, a finding that was more pronounced as pack-years increased. Decreased toxicity, including neutropenia, may be due to increased metabolism and drug clearance as a result of smoking. This may lead to potential undertreatment of smokers and, conversely, increased treatment-related toxicity in never smokers. A prospective clinical trial is needed to further elucidate this correlation, and is currently being designed.

Smoking history and frequency of somatic KRAS mutations in adenocarcinoma of the lung

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7573-7573
Author(s):  
V. A. Miller ◽  
G. J. Riely ◽  
M. G. Kris ◽  
D. Rosenbaum ◽  
J. Marks ◽  
...  
Keyword(s):  
Cigarette Smoking ◽  
Mutational Analysis ◽  
Smoking History ◽  
Egfr Mutations ◽  
Molecular Testing ◽  
Kras Mutations ◽  
Exon 2 ◽  
Significant Difference ◽  
Never Smokers ◽  
Lung Adenocarcinomas

7573 Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are more common in patients with adenocarcinoma, especially those who smoked < 15 pack years (py). KRAS mutations are found in ∼25% of lung adenocarcinomas, most commonly in codons 12 and 13 of exon 2 (∼85%) and have been associated with poor prognosis in resected disease [Winton NEJM 2005] and resistance to EGFR tyrosine kinase inhibitors [Pao PLoS Med 2005]. KRAS mutations are uncommon in non-small cell lung cancer histologies other than adenocarcinoma. We sought to determine the association between quantitative measures of cigarette smoking and presence of KRAS mutations in lung adenocarcinomas. Methods: Standard direct sequencing techniques were used to identify KRAS codon 12 and 13 mutations in lung adenocarcinoma specimens from surgical resections between 2001 and 2006 and tumor specimens sent for KRAS molecular analysis in 2006. Surgical specimens were obtained from an institutional tumor bank. Detailed smoking history (age at first cigarette, packs per day, years smoked, years since quitting smoking) was obtained from the medical record and a patient-completed smoking questionnaire. Results: KRAS mutational analysis was performed on 408 lung adenocarcinomas from 242 women and 166 men. Median age was 68 (range 33–89). KRAS mutations were present in 19% (78/408, 95% CI 15 to 23%). The frequency of KRAS mutation was not associated with age or gender. The presence of KRAS mutations was not related to smoking history with 15% (9/61) of never smokers having KRAS mutations compared with 19% (51/275) of former smokers. When compared with never smokers, there was no significant difference in frequency of KRAS mutations for tumors from patients with 1–5 py (5%, p=0.44), 6- 10 py (12%, p=0.99), 11–15 py (25%, p=0.45), 16–25 py (16%, p=0.99), 26–50 py (25%, p=0.129), 51–75 py (20%, p=0.48), >75 py (20%, p=0.47) history of cigarette smoking. Conclusions: While the incidence of EGFR mutations has a strong inverse relationship with the amount of cigarettes smoked, allowing the selective molecular testing for EGFR mutations, the frequency of KRAS mutations cannot be predicted by age, gender, or smoking history. KRAS mutational analysis of all adenocarcinomas is required to reliably identify patients with KRAS mutations. No significant financial relationships to disclose.

scholarly journals Reversal of Rocuronium-induced Meeting Abstracts with Sugammadex in Pediatric and Adult Surgical Patients

2009 ◽  
Vol 110 (2) ◽  
pp. 284-294 ◽  
Author(s):  
Benoît Plaud ◽  
Olli Meretoja ◽  
Rainer Hofmockel ◽  
Julien Raft ◽  
Peter A. Stoddart ◽  
...  
Keyword(s):  
Neuromuscular Blockade ◽  
Small Sample Size ◽  
Dose Range ◽  
Plasma Concentrations ◽  
Age Groups ◽  
Small Sample ◽  
Reversal Agent ◽  
Adult Age ◽  
Class 1 ◽  
Train Of Four

Background Sugammadex reverses neuromuscular blockade by chemical encapsulation of rocuronium. This phase IIIA study explored efficacy and safety of sugammadex in infants (28 days to 23 months), children (2-11 yr), adolescents (12-17 yr), and adults (18-65 yr). Methods Anesthetized patients (American Society of Anesthesiologists class 1-2) received 0.6 mg/kg rocuronium and were randomized to receive sugammadex (0.5, 1.0, 2.0, or 4.0 mg/kg) or placebo at reappearance of T2. Neuromuscular monitoring was performed using acceleromyography. Primary endpoint was time from sugammadex/placebo administration to recovery of the train-of-four ratio to 0.9. Adverse events and electrocardiograms were recorded, and blood samples were collected for safety and determination of sugammadex and rocuronium plasma concentrations. Results A dose-response relation was demonstrated in children (n = 22), adolescents (n = 28), and adults (n = 26), but not infants because of the small sample size (n = 8). After placebo, median recovery time of train-of-four to 0.9 was 21.0, 19.0, 23.4, and 28.5 min in infants, children, adolescents, and adults, respectively. After 2.0 mg/kg sugammadex train-of-four 0.9 was attained in 0.6, 1.2, 1.1, and 1.2 min, respectively. The sugammadex plasma concentrations were similar for the children, adolescent, and adult age groups across the dose range. Sugammadex was well tolerated: No reoccurrence of blockade, inadequate reversal, significant QT prolongation, or other abnormalities were observed. Conclusions Sugammadex is a new reversal agent that rapidly, effectively, safely, and with similar recovery times reverses rocuronium-induced neuromuscular blockade in children, adolescents, adults, and the small number of infants studied.

scholarly journals Effects of Hypoxia on the Behaviour, Mortality and Plasma Electrolyte Concentrations of Goldlined Seabream, Rhabdosargus sarba

2008 ◽  
Vol 13 ◽  
pp. 73
Author(s):  
Hamed M. Al-Gheilani ◽  
Colin Waring ◽  
Abdulaziz Al-Kindi ◽  
Shehla Amer
Keyword(s):  
Treatment Time ◽  
Small Sample Size ◽  
Plasma Concentrations ◽  
Small Sample ◽  
Low Oxygen ◽  
Hypoxic Conditions ◽  
Plasma Electrolyte ◽  
Mean Size ◽  
And Gender ◽  
Ventilation Rates

The behaviour, mortality rates and plasma electrolyte concentrations of goldlined seabream Rhabdosargus sarba challenged with low dissolved oxygen (DO) conditions was studied in an experimental setup, comprising a control (7.9 ml/l DO) and two hypoxic (2 ml/l and 1 ml/l DO) treatments. Increased ventilation rates and decreased swimming activity were observed in hypoxic treatments, but some fish exhibited strenuous avoidance actions. No mortalities were observed after 3 h, 6 h, or 24 h, but 50% of males and 18% of females died in the 48 h treatment at 1 ml/l DO. The mean size of surviving fish (305± 32.1 g total weight) was significantly smaller than those that died (425 ± 33.1 g). The plasma concentrations of Na+, Cl- and Mg2+ did not vary significantly relative to treatment, exposure time, fish size and gender, or interactions among treatment, time and gender. Ca2+ concentrations increased significantly after 48 h at 1 ml/l, but this result may be artificial because of the small sample size. The results suggest that R. sarba is comparatively tolerant of the low oxygen or hypoxic conditions that often occur in the coastal waters of Oman, where seasonal upwellings and  high primary productivity have in the past caused mass mortalities of demersal fishes.  

scholarly journals Sequencing Alpha-1 MZ Individuals Shows Frequent Biallelic Mutations

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Kimberly E. Foil ◽  
M. Gwen Blanton ◽  
Chris Sanders ◽  
Joannah Kim ◽  
Haitham S. Al Ashry ◽  
...  
Keyword(s):  
Severity Score ◽  
Small Sample Size ◽  
Genetic Counselor ◽  
Familial Risk ◽  
Small Sample ◽  
Smoking History ◽  
Augmentation Therapy ◽  
Clinical Trial Registration ◽  
Increased Risk ◽  
Severity Scores

Rationale. Individuals with a single Z mutation in the SERPINA1 gene that codes for alpha-1 antitrypsin (AAT) are at increased risk for COPD if they have ever-smoked. Whether additional variants alter the risk for COPD in this population remains unknown. Objectives. To determine whether additional SERPINA1 variants impact COPD development in a previously identified MZ (carrier) cohort. Methods. Individuals with prior MZ results and AAT serum level <16uM were recruited from the Alpha-1 Coded Testing study and Alpha-1 Foundation Research Registry. Participants completed smoking history, demographics, and COPD Severity Score (Range 0-33) using REDCap data capture. At-home finger-stick tests were performed for next generation sequencing (NGS) at the Biocerna LLC laboratory. A genetic counselor reviewed records and interviewed participants with additional variants by NGS. A Wilcoxon Rank Sum test was used to assess correlation between variants and the COPD severity score. Results. A second SERPINA1 variant of known or possible significance was identified in 6 (5.8%) participants. One each of ZZ, SZ, FZ, ZSmunich, ZM2obernburg, and Z/c.922G>T genotypes were identified. ZZ, SZ, and FZ are known pathogenic genotypes. Smunich is a likely pathogenic variant. M2obernburg and c.922G>T are variants of uncertain significance. The ZZ individual was on augmentation therapy when determined MZ by protease inhibitor (Pi) phenotyping; the others had limited targeted genotyping with MZ results. These six participants with biallelic variants had positive COPD severity scores >1. Presence of additional variants was not significantly associated with COPD symptoms in this small sample size. Conclusions. Some diagnosed MZ individuals instead have biallelic variants. Larger studies are needed to determine COPD-risk liability of variants. Accurate diagnosis impacts medical management and familial risk assessment. Pi phenotyping can be confounded by augmentation therapy and liver transplantation. Because a normal M allele may be reported in the absence of tested mutation(s) in AATD genotyping, clinicians should consider clinical circumstances and laboratory methods when selecting and interpreting AATD tests. Advanced testing, including NGS, may be beneficial for select individuals with prior MZ results. Clinical Trial Registration. This study was registered with clinicaltrials.gov (NCT NCT02810327).

Exploring phosphatase and tensin homolog (PTEN) loss via immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) as a potential predictive marker for response to everolimus in patients (pts) with neuroendocrine tumors (NET).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 333-333
Author(s):  
Moh'd M. Khushman ◽  
Alexandra Gomez Arteaga ◽  
Liege Diaz ◽  
Gabriel Tinoco ◽  
Richa Dawar ◽  
...  
Keyword(s):  
Small Sample Size ◽  
Mammalian Target Of Rapamycin ◽  
Predictive Marker ◽  
Suppressor Gene ◽  
Small Sample ◽  
Mtor Pathway ◽  
Negative Regulator ◽  
Unknown Primary ◽  
Pten Loss

333 Background: Identification of pts with exquisite sensitivity and/or durable responses to targeted therapies may lead to improved patient selection and allow for more rational treatment designs. Exceptional responders to everolimus in NET including pancreatic (PNET) were observed in our cohort of pts. PTEN is a key negative regulator of the phosphatidylinositol 3-kinase(PI3K)/Akt and mammalian target of rapamycin (mTOR) pathway. Loss of PTEN tumor suppressor gene function, usually due to deletion, leads to PI3K/Akt/mTOR pathway activation. Inthis study, we explored the role of PTEN as a potential predictive marker of everolimus in pts with NET including PNET. Methods: Between 2010 and 2014, pts with well-differentiated unresectable and metastatic gastrointestinal NET treated at our institution with everolimus were identified. 17 patients had pathology specimens available for testing. PTEN loss detection by FISH was carried out using a commercially available probe for cytoband 10q23, and by IHC using a commercially available antibody. Patients’ response to everolimus was evaluated through August 2014. The primary outcome was PFS and PTEN status was correlated with PFS for any potential association. Results: The median age was 59 years (range 45-78); 7 were male; 8 had PNET (2 gastrinomas, 1 insulinoma and 5 non-functional); 7 had small bowel NET and 2 unknown primary. All pts received everolimus starting at 10mg daily and octreotide LAR. Of the pts with PNETs, 3 had PTEN loss by FISH. Of those, one did not tolerate everolimus. The PFS for the other two pts was 8 and 24 months respectively. Among the 4 pts with intact PTEN; PFS was 14, 26, 3 and 12 months. 1 patient had insufficient tumor for testing. PTEN FISH is ongoing in the 9 non-pancreatic NET pts. PTEN expression by IHC is also ongoing and will be reported at the meeting. Conclusions: Testing for PTEN loss by FISH is feasible. Due to the small sample size, the role of PTEN loss could not be defined as a predictive marker in PNET. Testing on additional cases is ongoing and will be presented at the meeting.

Effects of the leucovorin shortage: Pilot study investigating cost, efficacy, and toxicity comparison of low fixed-dose versus body surface area-adjusted leucovorin dosing in patients with resectable colon or metastatic colorectal cancer

2016 ◽  
Vol 23 (3) ◽  
pp. 163-172 ◽  
Author(s):  
Brandon R Shank ◽  
Amy H Seung ◽  
Katharine Kinsman ◽  
Matthew J Newman ◽  
Ross C Donehower ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Event ◽  
Pilot Study ◽  
Metastatic Colorectal Cancer ◽  
Small Sample Size ◽  
Small Sample ◽  
Disease Stage ◽  
Fixed Dose ◽  
Dosing Strategies ◽  
Event Rates

Purpose As a result of the leucovorin shortage, we switched from BSA-adjusted to low fixed-dose leucovorin in patients with colon cancer receiving fluorouracil-containing therapy. Methods A retrospective, pilot study of adults receiving intravenous leucovorin as part of a fluorouracil-containing treatment was conducted including individuals with stage II or III colon or newly diagnosed metastatic colorectal cancer. One low fixed-dose (leucovorin 50 mg) patient was matched by the investigator to one BSA-adjusted (leucovorin 200–500 mg/m2/dose) patient on disease stage and age. The objectives were to compare cost of alternative dosing strategies as well as efficacy and adverse event rates. Only patients being treated in the first-line metastatic colorectal cancer setting were included in the efficacy analysis. Results Fifty-eight patients were included. Leucovorin cost was reduced by 7- to 14-fold, and we were able to conserve a total of 1580–3400 doses of leucovorin by changing to fixed-dose (estimated from 200 mg/m2 or 400 mg/m2 dosing strategies, respectively). No statistically significant differences in progression-free survival ( p = 0.254), overall survival ( p = 0.923), or complications resulted. Conclusion Our decision to reduce the dose of leucovorin allowed us to conserve supply and control cost. The small sample size did not allow us to detect differences in efficacy or adverse event rates, and thus a larger study would be required to confirm our findings that efficacy was not compromised nor adverse effects greater.

scholarly journals Identification of Small Grains Genotypes Resistant to Soilborne wheat mosaic virus

Plant Disease ◽  
2006 ◽  
Vol 90 (8) ◽  
pp. 1039-1044 ◽  
Author(s):  
L. Cadle-Davidson ◽  
M. E. Sorrells ◽  
S. M. Gray ◽  
G. C. Bergstrom
Keyword(s):  
New York ◽  
Logistic Regression ◽  
Sample Size ◽  
Mosaic Virus ◽  
Small Sample Size ◽  
Disease Incidence ◽  
Small Sample ◽  
Distribution Data ◽  
Incidence Data ◽  
Small Grains

Soilborne wheat mosaic virus (SBWMV) was detected in New York in 1998 for the first time and has been associated with yield loss where identified. We assessed 115 regionally adapted small grains genotypes for resistance to SBWMV over four growing seasons. Resistance to SBWMV reduces the percentage of plants that develop detectable viral titer and symptoms. Logistic regression was used to analyze disease incidence data and was compared with a general linear model for categorizing relative resistance to SBWMV. Logistic regression facilitated assessment of the effects of small sample size, low disease incidence, and nonuniform disease distribution. By increasing sample size from 20 to 30 stems per replicate, the number of resistance categories was increased through improved resolution of intermediate resistance classes. In environments with low disease incidence, the number of genotypes categorized as susceptible decreased while intermediate genotypes appeared to be resistant in the analysis. Inclusion of disease distribution data as covariates in a spatially balanced experiment did not increase the power of the logistic analysis. No genotype assessed in multiple years was immune to infection. However, 41 of the regionally adapted genotypes tested repeatedly expressed strong resistance to SBWMV, providing growers a choice of cultivars resistant to SBWMV.

Evaluation of potential gastrointestinal carcinogenicity associated with the ingestion of asbestos

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Thales J. Cheng ◽  
Sharlee L. More ◽  
Mark A. Maddaloni ◽  
Ernest S. Fung
Keyword(s):  
Animal Studies ◽  
Distribution Systems ◽  
Fiber Type ◽  
Small Sample Size ◽  
Small Sample ◽  
Smoking History ◽  
Weight Of Evidence ◽  
Critical Study ◽  
Asbestos Fibers ◽  
Gi Cancers

AbstractThe inhalation of asbestos, depending on the fiber type and dose, may be associated with the development of mesothelioma and other asbestos-related diseases. However, little is known about the potential adverse effects associated with the ingestion of asbestos. Evidence of asbestos fibers released from asbestos-cement pipes used in water distribution systems has led to concerns of potentially contaminated drinking water. The purpose of this study is to determine whether ingestion of asbestos fibers may lead to cancerous effects on the gastrointestinal (GI) tract. Data from animal and human studies were analyzed using a weight-of-evidence approach to evaluate the potential risk of GI cancers associated with asbestos ingestion. Seventeen human and 23 animal studies were identified and evaluated in this study. Animal studies were conducted in multiple species with inconsistent dosing protocols. Overall, animal studies reported that the asbestos fibers, irrespective of fiber type and dose, failed to produce any definitive GI carcinogenic effect. The 17 identified human epidemiological studies reported the ingestion of asbestos-contaminated water with concentrations from 1 to 71,350 million fibers per liter (MFL). A majority of the epidemiology studies reported statistically significant increases in multiple GI-specific cancers. However, these findings are confounded due to several critical study limitations including flawed study design, small sample size, selection bias, lack of individual exposure history, lack of adequate latency, and the inability to account for confounders including occupational history, diet, and smoking history. Based on our weight-of-evidence assessment, there is insufficient evidence of causality between the ingestion of asbestos and an increased incidence of GI cancers.

scholarly journals Fat Graft in Surgical Treatment of Medication-Related Osteonecrosis of the Jaws (MRONJ)

2021 ◽  
Vol 11 (23) ◽  
pp. 11195
Author(s):  
Davide De Cicco ◽  
Gianpaolo Tartaro ◽  
Giuseppe Colella ◽  
Giovanni Dell’Aversana Orabona ◽  
Mario Santagata ◽  
...  
Keyword(s):  
Surgical Treatment ◽  
Small Sample Size ◽  
Small Sample ◽  
Disease Stage ◽  
Fat Graft ◽  
Adipose Derived Stem Cells ◽  
Osteonecrosis Of The Jaws ◽  
Evolution Pattern ◽  
Group A ◽  
Cost Efficient

Background: Although the published literature has grown exponentially during the last few decades, managing medication-related osteonecrosis of the jaws (MRONJ) remains challenging. Since the first description of adipose-derived stem cells, cell therapy showed promising perspectives in surgical treatment of MRONJ. In this study, the beneficial effect of fat graft in surgical treatment of stage 2 and 3 MRONJ patients was assessed. Methods: A retrospective analysis of the evolution pattern of the disease was conducted comparing the outcomes of MRONJ patients who underwent sequestrectomy followed by fat graft (n = 9) and those who received sequestrectomy alone (n = 12). Results: Improvement of the disease stage was observed in 77.8% vs. 22.2% cases in group A and B, respectively (p = 0.030); disease stability was documented in 11.1% vs. 25.0% cases in group A and B, respectively (p = 0.603); worsening of MRONJ stage was observed in 11.1% vs. 50.0% cases in group A and B, respectively (p = 0.159). Conclusions: Despite the small sample size, this study suggests that fat graft may represent a promising low-risk and cost-efficient adjunctive therapy in the surgical treatment of MRONJ patients.

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