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OBJECTIVES: The tendency for patients with primary focal hyperhidrosis (PFH), characterized by excessive sweating, to experience psycho-social deficits is well documented. In addition, although endoscopic thoracic sympathectomy (ETS) effectively corrects PFH, its role in the psycho-social management of these patients remains unclear. Here, we examined changes in psychiatric symptomatology and psychotropic medication usage in PFH patients following ETS. METHODS: In total, 106 PFH patients underwent ETS and were compared against 213 matched controls. Information on psychiatric diagnosis and prescription was obtained through a retrospective chart review. Prospectively, PFH patients completed Hyperhidrosis Impact Questionnaires, Leibowitz Social Anxiety Scales and Center for Epidemiological Studies Depression Scales to evaluate pre- and postoperative quality-of-life and psycho-social impairment. RESULTS: A significantly greater proportion of PFH patients had been prescribed psychotropic medication (37.7%) compared to controls (14.1%) despite no differences in the proportion of psychiatric diagnoses. Following ETS, 52.5% of the PFH patients who were using psychotropic medications reduced their prescription regimen, compared to only 10% of control patients (P

Background Obesity has increased dramatically in the American population during the past 2 decades. Approximately 35% of adults are obese. Although obesity represents a major health issue, the association between obesity and operative outcomes has been a subject of controversy. We queried the National Surgical Quality Improvement Program (NSQIP) database to determine whether an increased body mass index (BMI) affects the outcomes of pulmonary resection for lung cancer. Methods We identified 6,567 patients with a diagnosis of lung cancer who underwent pulmonary resection from 2005 to 2012 in the NSQIP database. We stratified this population into 6 BMI groups according to the World Health Organization classification. The primary outcome measured was 30-day mortality; secondary outcomes included length of stay (LOS), operative time, and NSQIP-measured postoperative complications. We performed both unadjusted analysis and adjusted multivariable analysis, controlling for statistically significant variables. Results Adjusted multivariable logistic regression showed no increase in 30-day mortality, overall morbidity, and serious morbidity among obese patients. Adjusted Poisson regression revealed greater operative times for both obese and underweight patients compared with normal weight patients. Overall, obese patients were younger and had a greater percentage of preoperative comorbidities, including diabetes, hypertension, dyspnea, renal disease, and history of previous cardiac surgery. The prevalence of active smokers was greater among patients with low and normal BMI. Underweight patients had a greater risk-adjusted LOS relative to normal weight patients, whereas overweight and mildly obese patients had lesser risk-adjusted LOS. Conclusion The results of our analysis suggest that obesity does not confer greater mortality and morbidity after lung resection.

Background The purpose of this study was to assess the effect of human immunodeficiency virus (HIV) infection on postoperative survival among non-small cell lung cancer (NSCLC) patients. Methods A retrospective cohort study compared 22 HIV-infected lung cancer patients to 2,430 lung cancer patients with HIV-unspecified status who underwent resection at Johns Hopkins Hospital from 1985 to 2009. Subcohort comparative analyses were performed using individual matching methods. Results Thirty-day mortality rates did not differ between HIV-infected and HIV-unspecified patients. Survival rates for HIV-infected lung cancer patients were significantly shorter than for HIV-unspecified patients (median, 26 versus 48 months; p = 0.001). After adjustment, the relative hazard of mortality among HIV-infected NSCLC patients was more than threefold that of HIV-unspecified patients (adjusted hazard ratio, 3.08; 95% confidence interval: 1.85 to 5.13). When additional surgical characteristics were modeled in a matched subcohort, the association remained statistically significant (adjusted hazard ratio, 2.31; 95% confidence interval: 1.11 to 4.81). Moreover, HIV-infected lung cancer patients with CD4 counts less than 200 cells/mm 3 had shortened median survival compared with patients whose CD4 counts were 200 cells/mm 3 or greater (8 versus 40 months; p = 0.031). Postoperative pulmonary and infectious complications were also elevated in the HIV-infected group ( p = 0.001 and p p = 0.061). Conclusions The HIV-infected NSCLC patients have more postoperative complications, rapid progression to disease recurrence, and poorer postoperative survival. Optimizing immune status before surgery and careful patient selection based on diffusion capacity of lung for carbon monoxide may improve patient outcomes.

Background The flank is commonly used for primary xenografts in mice, but it is rare for these tumors to metastasize. Tail vein injection creates a pattern of metastases, but is artificial. We hypothesized that the liver is a convenient alternative xenograft site and that metastases would gradually proceed spontaneously. Materials and Methods Using 15 NOD.CB17-Prkdcscid/NcrCrl (NOD/SCID) mice, 10,000 A549 cells were xenografted into the liver while a second group of five mice were xenografted in the flank with 100,000 A549 cells as a control. Mice were euthanized and grossly dissected at 7 wk. A third group of seven mice received liver xenografts with A549 and a mouse each week was euthanized for 7 wk and evaluated. The liver, lung, and spleen were examined histologically. Results At 7 wk, 15/15 liver xenografted mice had gross primary tumor in the liver. Histologic review confirmed multiple microscopic foci of metastatic disease in all mice (15/15) throughout the lungs, mediastinal nodes, and spleen. The control group had primary tumor in the flank (4/5), but none had histologic evidence of metastases. Serially euthanized liver xenografted mice revealed evidence of a gradual spontaneous metastatic model system with the first histologic findings of micrometastases appearing in the lungs by wk 5, which became wide spread by wk 7. Splenic and mediastinal lymph node metastases developed in wk 6 and 7. Conclusions Liver xenografting of A549 cells into NOD/SCID mice is a reliable way of developing widespread micrometastases. This model allows the study of a gradually developing solid tumor with subsequent metastatic spread.

Methylation of tumor suppression genes (TSGs) is common in myeloid malignancies. However, application of this as a molecular marker for risk stratification in patients with AML is limited.To elucidate the impact of patterns of TSG methylation on outcome in cytogenetically normal patients, 106 samples from patients with having normal cytogenetic AML were evaluated for methylation of 12 genes by MSP. For sake of comparison, samples from patients with AML and abnormal cytogenetics (n = 63) were also evaluated.Methylation frequencies in the whole group (n = 169) were similar to previous reports for CDH1 (31%), ER (31%), FHIT (9%), p15 (INK4b) (44%), p73 (25%), and SOCS1 (75%). Methylation of CTNNA1 was observed in 10%, CEBP-α in16%, CEBP-δ in 2%, MLH1 in 24%, MGMT in 11% and DAPK in 2% of AML samples. We find that DNA methylation was more prevalent in patients with normal compared to karyotypically abnormal AML for most genes; CEBPα (20% vs 9%), CTNNA1 (14% vs 4%), and ER (41% vs 19%) (p0.05 for all comparisons). In contrast, p73 was more frequently methylated in patients with karyotypic abnormalities (17% vs 38%; p0.05), perhaps due to specific silencing of the pro-apoptotic promoter shifting p73 gene expression to the anti-apoptotic transcript. In AML patients with normal cytogenetics, TSG methylation was not associated with event free or overall survival in a multivariate analysis.In patients with AML, TSG methylation is more frequent in patients with normal karyotype than those with karyotypic abnormalities but does not confer independent prognostic information for patients with normal cytogenetics.

Background Survival outcomes of never smokers with non-small cell lung cancer (NSCLC) who undergo surgery are poorly characterized. This investigation compared surgical outcomes of never and current smokers with NSCLC. Methods This investigation was a single-institution retrospective study of never and current smokers with NSCLC from 1975 to 2004. From an analytic cohort of 4,546 patients with NSCLC, we identified 724 never smokers and 3,822 current smokers. Overall, 1,142 patients underwent surgery with curative intent. For survival analysis by smoking status, hazard ratios (HRs) were estimated using Cox proportional hazard modeling and then further adjusted by other covariates. Results Never smokers were significantly more likely than current smokers to be women (P Conclusions Our findings suggest that smoking status at time of lung cancer diagnosis has little impact on the long-term survival of patients with NSCLC, especially after curative surgery. Despite different etiologies between lung cancer in never and current smokers the prognosis is equally dismal.

Nuclear localization of non-phosphorylated, active beta-catenin is a measure of Wnt pathway activation and is associated with adverse outcome in patients with acute myeloid leukemia (AML). While genetic alterations of the Wnt pathway are infrequent in AML, inhibitors of this pathway are silenced by promoter methylation in other malignanices. Leukemia cell lines were examined for Wnt pathway inhibitor methylation and total beta-catenin levels, and had frequent methylation of Wnt inhibitors and upregulated beta-catenin by Western blot and immunofluorescence. One hundred sixty-nine AML samples were examined for methylation of Wnt inhibitor genes. Diagnostic samples from 72 patients with normal cytogenetics who received standard high-dose induction chemotherapy were evaluated for associations between methylation and event-free or overall survival. Extensive methylation of Wnt pathway inhibitor genes was observed in cell lines, and 89% of primary AML samples had at least one methylated gene: DKK1 (16%), DKK3 (8%), RUNX3 (27%), sFRP1 (34%), sFRP2 (66%), sFRP4 (9%), sFRP5 (54%), SOX17 (29%), and WIF1 (32%). In contrast to epithelial tumors, methylation of APC (2%) and RASSF1A (0%) was rare. In patients with AML with normal cytogenetics, sFRP2 and sFRP5 methylation at the time of diagnosis was associated with an increased risk of relapse, and sFRP2 methylation was associated with an increased risk for death. In patients with AML: (a) there is a high frequency of Wnt pathway inhibitor methylation; (b) Wnt pathway inhibitor methylation is distinct from that observed in epithelial malignancies; and (c) methylation of sFRP2 and sFRP5 may predict adverse clinical outcome in patients with normal karyotype AML.

Objective We hypothesized that most relapses in patients with esophageal cancer having neoadjuvant chemoradiation therapy would occur outside of the surgical and radiation fields. Methods Recurrence patterns, time to recurrence, and median survival were examined in 267 patients who had esophagectomy after neoadjuvant chemoradiation therapy at Johns Hopkins over 19 years. Results Of 267 patients, 82 (30.7%) showed complete response to neoadjuvant therapy, with 108 (40.4%) and 77 (28.8%) showing partial response or no response, respectively. Recurrence developed in 84 patients (patients with complete response 18/82, 21.4%; patients with partial response 39/108, 36.1%; patients with no response 27/77, 35.1%; P = .055, respectively). Most patients had recurrences at distant sites (65/84;77.4%) regardless of pathologic response, and subsequent survival was brief (median 8.37 months). Median disease-free survival was short (10 months) and did not differ based on recurrence site for patients with partial response or no response, but was longer for patients with complete response with distant recurrence, whose median disease-free survival was 27.3 months (P = .008). By multivariate analysis, no other factor except for pathologic response to neoadjuvant therapy was associated with disease recurrence or death. Patients with partial response or no response were 1.97 and 2.23 times more likely to have recurrence than patients with complete response (P = .024 and P = .012, respectively). Conclusions Most esophageal cancer recurrences after neoadjuvant therapy and surgery are distant, and survival time after recurrence is short regardless of pathologic response. Fewer patients achieving complete response had recurrences, and distant recurrences in these patients manifest later than in patients showing partial response and those showing no response. Only pathologic response is significantly associated with disease recurrence, suggesting that tumor biology and chemosensitivity are critical in long-term patient outcome.

Background: Despite optimal and early surgical treatment of non-small-cell lung cancer (NSCLC), many patients die of recurrent NSCLC. We investigated the association between gene methylation and recurrence of the tumor. Methods: Fifty-one patients with stage I NSCLC who underwent curative resection but who had a recurrence within 40 months after resection (case patients) were matched on the basis of age, NSCLC stage, sex, and date of surgery to 116 patients with stage I NSCLC who underwent curative resection but who did not have a recurrence within 40 months after resection (controls). We investigated whether the methylation of seven genes in tumor and lymph nodes was associated with tumor recurrence. Results: In a multivariate model, promoter methylation of the cyclin-dependent kinase inhibitor 2A gene p16, the H-cadherin gene CDH13, the Ras association domain family 1 gene RASSF1A, and the adenomatous polyposis coli gene APC in tumors and in histologically tumor-negative lymph nodes was associated with tumor recurrence, independently of NSCLC stage, age, sex, race, smoking history, and histologic characteristics of the tumor. Methylation of the promoter regions of p16 and CDH13 in both tumor and mediastinal lymph nodes was associated with an odds ratio of recurrent cancer of 15.50 in the original cohort and an odds ratio of 25.25 when the original cohort was combined with an independent validation cohort of 20 patients with stage I NSCLC. Conclusions: Methylation of the promoter region of the four genes in patients with stage I NSCLC treated with curative intent by means of surgery is associated with early recurrence. Copyright © 2008 Massachusetts Medical Society.

Purpose The present investigation prospectively examined active cigarette smoking and household passive smoke exposure and the risk of developing rectal cancer. Methods Cigarette smoking data were collected on all household members during two private censuses in Washington County, Maryland. These two cohorts were followed up, one cohort from 1963–1978 and the other from 1975–1994 for first-time diagnoses of rectal cancer. We identified 148 and 169 rectal cancer cases in the 1963 and 1975 cohorts, respectively. Relative risks were estimated by means of Poisson regression models. Results In men, the adjusted relative risks (aRR) and 95% confidence intervals (CI) for the association between current smoking and rectal cancer were 3.1 (1.2–7.8) in the 1963 cohort and 1.8 (0.9–3.7) in the 1975 cohort; the corresponding aRRs in women were 0.9 (0.5–1.8) and 1.6 (0.9–3.8) in the 1963 and 1975 cohorts, respectively. In nonsmokers, household passive smoke exposure was strongly associated with rectal cancer among men in the 1963 cohort (aRR = 5.8; 1.8–18.4) but not the 1975 cohort (aRR = 1.1; 0.2–5.0). In women, household passive exposure was not strongly associated with rectal cancer in either cohort. Conclusions The results of our study suggest that active cigarette smoking may contribute to rectal cancer risk, but inconsistencies in the findings preclude drawing strong, clear-cut inferences.

Purpose People with HIV infection in the United States frequently smoke tobacco. We sought to characterize lung cancer incidence among HIV-infected individuals, examine whether cancer risk was related to HIV-induced immunosuppression, and assess whether the high prevalence of smoking explained elevated risk. Methods We conducted a retrospective cohort study at an HIV specialty clinic in Baltimore, MD (1989-2003). Incident lung cancers were identified using hospital records. We used negative binomial regression to compare incidence across subgroups defined by demographics, use of highly active antiretroviral therapy (HAART), and HIV markers. Standardized incidence ratios (SIRs) compared incidence with an urban reference population (Detroit, MI). We adjusted SIRs for the effect of smoking, using smoking prevalences estimated from part of the cohort and the general population. 95% CIs and P values were two sided. Results Thirty-three lung cancers were observed among 5,238 HIV-infected patients (incidence: 170 per 100,000 person-years). Incidence increased with age (P < .0001), but did not differ by sex, race, or CD4 count. Incidence tended to increase with calendar year (P = .09) and HAART use (P = .10), and was inversely related to HIV viral load (P = .03), but these associations were attenuated with age adjustment. The SIR was 4.7 (95% CI, 3.2 to 6.5) versus the general population. Twenty-eight lung cancer patients (85%) and 69% of the cohort were smokers. After smoking adjustment, risk remained elevated (SIR, 2.5; 95% CI, 1.6 to 3.5). Conclusion Lung cancer risk was substantially elevated in HIV-infected individuals. Incidence was unrelated to HIV-induced immunosuppression. Notably, incidence remained high after adjustment for smoking, suggesting the involvement of additional factors.

Pancreatic endocrine neoplasms (PENs), commonly referred to as islet cell tumors, are a unique group of malignancies often characterized by a clinical neuroendocrine syndrome attributable to the selective overproduction and humoral circulation of pancreas-specific hormones. Approximately 2000 new cases of PENs are diagnosed each year in the United States; of these cases, 60-70% are associated with a clinical syndrome resulting from the secretion of a single functional hormone.1 The remaining one third of PENs secrete no clinically detectable biologically active hormones and most often present as space occupying lesions causing obstructive jaundice, upper gastrointestinal luminal obstruction, bleeding, or abdominal pain. While many functional PENs follow an indolent course, a substantial proportion of functional and nonfunctional tumors are defined by aggressive biology, resulting in early locoregional invasion of lymph node basins and adjacent organs, as well as metastases to the liver and beyond.2,3 Although histologic characteristics, including tumor size, pleomorphism, neurovascular invasion, and metastases to the regional lymph nodes or liver, have been used for predicting long-term survival, these factors have not proven to be entirely reliable prognostic markers for PENs after surgical resection.3-6 In recent years, several studies have reported a number of genes with important implications in the tumorigenesis of the pancreatic islets. These have included deletional mutations in the MEN1 gene on chromosome 11q, activation of the HER-2/neu proto-oncogene, overexpression of cyclin D1, point mutations in the DPC4/Smad4 gene, and deletion of a putative tumor suppressor gene on chromosome 3p.7-11 In addition to the genetic mutations of MEN1, molecular alterations of the cell cycle control gene, INK4a/p16, appear to be particularly important contributors to the pathogenesis of PENs.12-15 While homozygous deletions of INK4a/p16 have been found to variable degrees in PENs, the presence of epigenetic alterations, namely aberrant hypermethylation involving the promoter region of this locus, has been reported in PENs regardless of functional status.12-14 The combination of genetic and epigenetic alterations involving tumor suppressor genes contributes to the biology of several solid human tumors. Of the several epigenetic mechanisms that play a role in tumorigenesis (including chromosomal histone deacetylation and loss of genomic imprinting), DNA methylation of tumor suppressor gene promoter sites has been studied most extensively for its potential to predict tumor behavior.16-18 Silencing of tumor suppressor gene expression by promoter hypermethylation at CpG-rich islands is common among several human malignancies.19 Several reports have validated that the hypermethylation of promoter regions for such genes as INK4a/p16, E-cadherin, and hMLH1 correlates directly with the loss of transcription of these tumor suppressor genes in a variety of tumors.19-22 The purpose of this investigation was to determine the methylation status of several tumor suppressor genes to gain insight into the heterogeneous biology affiliated with nonfunctional PENs. The unique methylation pattern associated with each PEN in our study was analyzed for its ability to predict clinical outcomes after surgical resection.

Background Recent reports indicate that age is not a contraindication to pulmonary resection for octogenarians with nonsmall cell lung cancer (NSCLC), but other data are lacking. The purpose of this study was to determine outcomes in these patients, particularly short- and long-term survival with stage I disease. Methods A retrospective cohort of 68 octogenarians with NSCLC who underwent curative resection from 1980 to 2002 was followed-up for outcomes. Results Median age was 82 years old (range, 80–87 years old) consisting of 44 males (65%), with a mean follow-up of 32 months (range, 1–178 months). Operations included: 47 lobectomies (69%), 11 wedge resections (16%), 5 segmentectomies (8%), 4 bilobectomies (6%), and 1 pneumonectomy (1%). There were 31 adenocarcinomas (46%), 18 squamous carcinomas (26%), 12 bronchioalveolar carcinomas (18%), 4 large cell carcinomas (6%), and 3 miscellaneous malignant neoplasms (4%). Median hospital stay was 7 days (range, 3–53 days). Thirty-day mortality was 8.8% (n = 6) with 83% developing cardiopulmonary complications. Overall actuarial survival at 1, 3, and 5 years was 73%, 51%, and 34%, respectively. Of 41 patients (60%) with stage I disease, 23 were T1 lesions. Five-year survival was significantly different between stages Ia and Ib patients (61% and 10%, respectively, p = 0.001). Patients in more advanced stages had a 5-year survival of 3/27 (11%). Multivariate analysis identified advanced tumor stage, lower ASA physical status, and low FEV 1 as factors associated with poorer long-term survival. Conclusions The 5-year survival, particularly in patients with stage Ia tumors with favorable ASA and FEV 1 , supports the notion that health status and tumor stage outweigh chronologic age in determining surgical candidates.