KRAS G>A mutation favors poor tumor differentiation but may not be associated with prognosis in patients with curatively resected duodenal adenocarcinoma.

KRAS mutations have been found in duodenal adenocarcinomas and may have prognostic significance. The purpose of this study was to classify clinicopathological characteristics, microsatellite instability and KRAS mutations and identify possible prognostic role of KRAS mutations in duodenal adenocarcinomas. Demographics, tumor characteristics and survival were recorded for 78 patients with duodenal adenocarcinomas (Stages I-III). KRAS mutations were detected in 27 (34.6%) cases, of which the majority (74.1%) were G>A transitions. Multivariate logistic regression analysis showed that KRAS G>A mutation was significantly associated with late stage (p = 0.025) and poor tumor differentiation (p = 0.035), when compared with wild-type and other than G>A mutations. KRAS G>A mutation carriers were at increased risk for distant relapse (p = 0.022) and had significantly shorter overall survival (OS; log-rank p = 0.045) and a trend toward shorter relapse-free survival (RFS; log-rank p = 0.062) when compared with those who did not carry the KRAS G>A mutation. In multivariate analyses, there was a significant correlation between ≥ 3 positive lymph nodes and poor OS (p < 0.001) and RFS (p = 0.001) and KRAS G>A mutation carriers demonstrated no effect on clinical outcome. In conclusion, KRAS G>A mutation correlates significantly with late stage and poor tumor differentiation in duodenal adenocarcinoma. Among patients who undergo a curative resection of duodenal adenocarcinoma, KRAS G>A mutation carriers will more likely experience distant relapse but may not exhibit a poor prognosis. The number of positive lymph nodes should be incorporated in future staging systems.

Epithelioid sarcoma: one institution's experience with a rare sarcoma.

BACKGROUND: Epithelioid sarcomas (ES) are extremely rare soft tissue sarcomas. As such, their clinical behavior and response to treatment are poorly described in the literature. METHODS: We queried the centralized cancer registry and pathology archives at the Johns Hopkins Medical Institution and identified 22 patients with a diagnosis of ES. We excluded two patients because of inadequate data. A pathologist reviewed patient charts and reexamined available histological slides. This study was performed with institutional review board approval. RESULTS: The median age at diagnosis was 27.8 y; most patients (75%) were male. Regional lymph node metastases were present in 10% of patients at presentation. The majority of tumors (57.9%) recurred and 35% recurred more than once, although the number of recurrences did not affect survival (P = 0.48). Patients did not experience a decrease in time to recurrence with increasing number of resections. The median time between resection and recurrence was 1.23 y and the maximum was 18.8 y. Median overall survival was 56.2 mo and 5-y survival was 92%. CONCLUSIONS: Our study reveals that ES is an extremely rare tumor with a protracted and recurrent course, but overall survival may be more favorable than in the past. Patients benefit from aggressive and repeated resection. Epithelioid sarcoma is unique because it metastasizes to regional nodal basins. Extended surveillance is indicated, because recurrences can appear after decades of quiescence.

DNA methylation markers and early recurrence in stage I lung cancer.

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.

A murine xenograft model of spontaneous metastases of human lung adenocarcinoma.

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-Prkdc(scid)/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.

Promoter hypermethylation of hallmark cancer genes in atypical adenomatous hyperplasia of the lung.

PURPOSE: According to current models of tumorigenesis, the progression of phenotypic changes culminating in overtly malignant carcinoma is driven by genetic and epigenetic alterations. The recognition of an early form of glandular neoplasia termed atypical adenomatous hyperplasia (AAH), a precursor lesion from which lung adenocarcinomas arise, provides an opportunity for characterizing early epigenetic alterations involved in lung tumorigenesis. EXPERIMENTAL DESIGN: We evaluated AAHs, adjacent normal lung tissue, and synchronous lung adenocarcinomas for promoter hypermethylation of genes implicated in lung tumorigenesis (p16, TIMP3, DAPK, MGMT, RARbeta, RASSF1A, and hTERT). RESULTS: For individual genes and the number of genes methylated, we observed a significant increase in the frequency of promoter hypermethylation in the histologic progression from normal to AAH, with low-grade or high-grade atypia, and finally to adenocarcinoma (P(trend)

Thoracic Oncology Multidisciplinary Clinic Reduces Unnecessary Health Care Expenditure Used in the Workup of Patients With Non-small-cell Lung Cancer.

BACKGROUND: National costs of lung cancer care exceed $12 billion. We investigate the resource-savings benefit of a single-day thoracic oncology multidisciplinary clinic (MDC) in the diagnostic period prior to non-small-cell lung cancer (NSCLC) treatment. MATERIALS AND METHODS: From July 2007 to January 2015, patients with NSCLC treated with multimodality therapy at a tertiary hospital-based cancer center in Maryland were identified. Patient and treatment details were collected. Health care resources utilized in the 90 days prior to receipt of first oncologic treatment were identified using billed activity codes. Associated total charges, including professional fees and hospital-based technical fees, were identified and inflated to 2014 dollars using the Consumer Price Index. Codes were categorized into provider visits, procedures, pathology/laboratory, radiology, and other tests. χ2, Student t, and Wilcoxon rank-sum tests compared charges of patients seen in and out of the MDC. RESULTS: Two-hundred ninety-seven (non-MDC = 161, 54%; MDC = 136, 46%) of 308 patients identified had total charges available. Patients seen through MDC had on average a 23% decrease in total charges per patient incurred ($5839 savings; range, $5213-$6464) compared with patients seen through non-MDC settings. Evaluation through MDC reduced the average number of provider visits per patient (non-MDC, 6.8 vs. MDC, 4.8; P < .01) prior to treatment start, which led to a 50% (average $3092; range, $2451-$3732) reduction in provider charges per patient (P < .01). CONCLUSIONS: Evaluation of patients with NSCLC through a coordinated single-day MDC reduced hospital charges per patient by 23% during the diagnostic period prior to treatment when compared with evaluation through traditional referral-based thoracic oncology clinics.

Epigenetic alteration of Wnt pathway antagonists in progressive glandular neoplasia of the lung.

BACKGROUND: Atypical adenomatous hyperplasia (AAH) is now recognized as a precursor lesion from which lung adenocarcinomas arise and thus represents an ideal target for studying the early genetic and epigenetic alterations associated with lung tumorigenesis such as alterations of the Wnt pathway. METHODS: We assessed the level of Wnt signaling activity in lung cancer cell lines by determining the level of active beta-catenin and determined the level of expression of Wnt antagonists APC, DKK1, DKK3, LKB1, SFRP1, 2, 4, 5, WIF1 and RUNX3 using reverse transcription-polymerase chain reaction. Using multiplex nested methylation-specific polymerase chain reaction, we analyzed promoter region methylation of these genes in resected lung tissue in the histopathologic sequence of glandular neoplasia (normal lung parenchyma, low-grade and high-grade AAH, adenocarcinoma). RESULTS: The majority of non-small cell lung cancer cell lines (11 of 16, 69%) have evidence of active Wnt signaling and silencing of Wnt antagonists correlated with promoter hypermethylation. Promoter region methylation of Wnt antagonists was common in primary lung adenocarcinoma and there was a significant increase in the frequency of methylation for Wnt antagonist genes and the number of genes methylated with each stage of tumorigenesis (test for rend P

A prospective cohort study of rectal cancer risk in relation to active cigarette smoking and passive smoke exposure.

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.

Hypermethylation of ASC/TMS1 is a sputum marker for late-stage lung cancer.

DNA hypermethylated gene promoter sequences are extremely promising cancer markers. Their use for risk assessment, early diagnosis, or prognosis depends on the timing of this gene change during tumor progression. We studied this for the proapoptotic gene ASC/TMS1 in lung cancer and used the findings to develop a sputum marker. ASC/TMS1 protein levels are reduced in all lung cancer types (30 of 40; 75%) but not in 10 preinvasive lesions. Hypermethylation of ASC/TMS1 is also associated with invasive cancers (41 of 152 or 27.0% of all lung cancer types) with variation in incidence between histopathologic types including 32.1% (26 of 81) of adenocarcinomas, 13.2% (7 of 53) of squamous cell carcinomas, 38.5% (5 of 13) of large-cell carcinomas, and 60% (3 of 5) of small-cell lung cancers. The hypermethylation is particularly correlated with late tumor stages being present in only 14% of stage I but 60% of later-stage tumors. The incidence of ASC/TMS1 hypermethylation in sputum DNA fully mimics the tissue findings being present in only 2% (2 of 85) of high-risk, cancer-free smokers, 15% (3 of 18) of patients with stage I non-small-cell lung cancer (NSCLC), but 41% of patients with stage III NSCLC (18 of 44), including 56% (10 of 18) of those with adenocarcinoma. Importantly, sputum is positive for this marker in 24% (10 of 42) of very high risk, clinically cancer-free individuals previously resected for stage I NSCLC. Thus, hypermethylation of ASC/TMS1 is a marker for late-stage lung cancer and, in sputum, could predict prognosis in patients resected for early-stage disease.

Endoscopic thoracic sympathectomy for primary focal hyperhidrosis: impact on psycho-social symptomatology and psychotropic medication use.

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 < 0.01). Additionally, scores improved dramatically in each Hyperhidrosis Impact Questionnaires category, and in both the Leibowitz Social Anxiety Scales and Center for Epidemiological Studies Depression Scales (P < 0.01). CONCLUSIONS: We demonstrate that in over half of PFH patients, psychotropic medication usage was discontinued after ETS, which is consistent with our findings on postoperative improvements in Hyperhidrosis Impact Questionnaires, Leibowitz Social Anxiety Scales and Center for Epidemiological Studies Depression Scales scores. Furthermore, our findings suggest that a considerable proportion of PFH patients who experience psychopathology may be doing so secondary to excessive sweating. Thus, improved awareness or recognition of these associations in the diagnosis and management of PFH patients is warranted.

Robotic Versus Thoracoscopic Resection for Lung Cancer: Early Results of a New Robotic Program.

BACKGROUND: Robot-assisted surgical techniques have been introduced in recent years as an alternative minimally invasive approach for lung surgery. While the advantage of video-assisted thoracoscopic surgery (VATS) over thoracotomy for anatomical lung resection has been extensively reported, the results of robotic video-assisted thoracoscopic surgery (RVATS) compared to VATS are still under investigation. METHODS: We performed a retrospective review of lung cancer patients, undergoing minimally invasive segmentectomy or lobectomy between December 2007 and May 2014. A robotic program was introduced in 2011. Relevant early surgical outcomes were compared between VATS and RVATS, including mortality, morbidity, conversion to thoracotomy, length of stay (LOS), and reoperation. RESULTS: Eighty (60.2%) patients underwent VATS resection, while 53 (39.8%) had a RVATS procedure. The two groups presented no meaningful differences at baseline, in terms of age, race, body mass index, and preoperative comorbidities. Adenocarcinoma was the most common histology in both groups. Patients in the RVATS group had significantly more segmentectomies (11.3% versus 1.2%, P = .016). There were no postoperative deaths. RVATS appeared to be associated with fewer conversions to open (13.2% versus 26.2%, P = .025) and more lymph nodes retrieved (9 versus 7, P = .049). We found no significant differences in terms of other individual complications, including tracheostomy, reintubation, pneumonia, pulmonary embolism, and cerebrovascular events. CONCLUSIONS: According to our results, the introduction of a robotic program did not negatively affect the early surgical outcomes of a well-established oncologic minimally invasive thoracic program. Potential advantages of RVATS still need to be explored in terms of long-term outcomes.

Complex Esophageal Reconstruction Procedures Have Acceptable Outcomes Compared With Routine Esophagectomy.

BACKGROUND: Complex esophageal reconstruction (CER) is defined as restoring esophageal continuity in a previously operated field, using a nongastric conduit, or after esophageal diversion. This study compares the outcomes of CER with non-CER (NCER), which uses an undisturbed stomach for reconstruction. METHODS: This single-institution retrospective cohort study compares 75 CERs with 75 NCERs from 1995 to 2014 that were matched for cancer versus benign disease. Distributions of demographic characteristics, comorbidities, and complications were compared between CER and NCER. Odds of mortality at 30 and 90 days were calculated with logistic regression. Overall survival was illustrated with Kaplan-Meier method and Cox proportional hazards regression. RESULTS: Although patients were similar in age, sex, and preoperative comorbidities, more non-white patients underwent CER (p = 0.04). Most NCER patients had adenocarcinoma (44%) or Barrett's high-grade dysplasia (39%); most CER patients had other benign disease (44%) or squamous cell carcinoma (24%, p < 0.01). CER had statistically significantly higher rates of reoperation, pneumonia, infection, and gastrointestinal complications, and longer median length of stay than NCER. Odds of mortality for CER and NCER at 30 days (odds ratio [OR] 1.0, 95% CI: 0.1 to 16.3), 90 days (OR 2.6, 95% CI: 0.5 to 13.9) and overall (adjusted hazard ratio 1.56, 95% CI: 0.9 to 2.7) were not statistically significantly different. CONCLUSIONS: Compared with NCER, CER patients had higher rates of return to the operating room, more postoperative infections and gastrointestinal complications, and longer length of stay. However, 30-day, 90-day, and overall survival were similar. CER should be offered to patients with acceptable risks and anticipated long-term survival.

Surgical resection of limited disease small cell lung cancer in the new era of platinum chemotherapy: Its time has come.

OBJECTIVE: Although resection is not the standard of care in treating small cell lung cancer, new platinum drugs and modern staging have allowed the role of surgery to be reevaluated. METHODS: We reviewed our institutional experience of 1415 patients with small cell lung cancer from 1976 to 2002 among whom 82 (6%) underwent surgery with curative intent. RESULTS: Median age at surgery was 62 years, and small cell lung cancer of mixed morphology represented 14 of 82 (17%). Treatment consisted of surgery alone in 11% of cases (9/82), surgery with neoadjuvant therapy in 22% (18/82), and surgery with adjuvant therapy in 55% (45/82). Prophylactic cranial irradiation was given to 23% (19/82). The 5-year survival of the entire cohort was 42%. The 5-year survival of patients receiving adjuvant chemotherapy (n = 41) was significantly different according to whether patients had received platinum or nonplatinum regimens (68% vs 32.2%, P = .04). Among patients with stage I disease who received adjuvant chemotherapy (n = 24), the 5-year survivals for patients receiving platinum and nonplatinum chemotherapy were 86% and 42%, respectively ( P < .02). If patients who received either neoadjuvant or adjuvant therapy (n = 56) were considered, the 5-year survival was significantly better for platinum than for nonplatinum chemotherapy (62% vs 36%, P = .05). The 5-year survival was also better for those undergoing lobectomies (n = 52) than for those with limited resections (n = 15, 50% vs 20%, P = .03). Survival outcomes also differed by gender, with female patients having a 5-year survival advantage over male patients (60% vs 28%, P = .004). CONCLUSION: These results support a reevaluation of the role of surgery in the multimodality therapy for small cell lung cancer, which currently includes only radiotherapy and chemotherapy.

Hypermethylation of the GATA genes in lung cancer.

PURPOSE: In lung cancer, DNA hypermethylation is known to be a common event. EXPERIMENTAL DESIGN: Gene expression and methylation status of GATA-4, GATA-5, and GATA-6 were analyzed with cell lines and primary human lung cancers. Methylation profiles of primary lung cancers were analyzed and correlated with clinical as well as histopathological data. RESULTS: Complete methylation was detected by methylation-specific PCR for both GATA-4 and GATA-5 in four cell lines (H358, DMS-53, A549, and H1299), all of which had no expression by reverse transcription-PCR analysis. Demethylation with 5-aza-2'deoxycytidine restored expression in each case. GATA-6 was ubiquitously expressed in all of the six cell lines. GATA-4 bisulfite sequencing revealed complete methylation of the GATA-4 promoter in H358 cells, correlating well with its lack of expression at the mRNA level. Only a few CpG sites showed methylation by bisulfite sequencing within the GATA-4 promoter in a cell line that expressed the gene. In 63 cases of primary lung cancers, GATA-4 and GATA-5 promoter methylation was detected in (42 of 63) 67% and (26 of 63) 41%, respectively. GATA-6 remained unmethylated both in cell lines and primary tumors. Six autopsy specimens of normal lung tissue showed no aberrant promoter hypermethylation for the GATA genes. Correlation of concomitant GATA-4 and GATA-5 methylation with clinicopathological parameters only found a statistically significant increase in methylation frequency with increasing patient age (P < 0.001). CONCLUSIONS: These epigenetic changes in the GATA genes in lung cancer are tumor-specific, relate to the loss of GATA gene expression, and occur increasingly in the elderly.

Why are patients being readmitted after surgery for esophageal cancer?

OBJECTIVE: Readmission after surgery is an unwanted adverse event that is costly to the healthcare system. We sought to evaluate factors associated with increased risk of readmission and to characterize the nature of these readmissions in patients who have esophageal cancer. METHODS: A retrospective cohort study was performed in 306 patients with esophageal carcinoma who underwent neoadjuvant chemoradiation followed by esophagectomy at Johns Hopkins Hospital between 1993 and 2011. Logistic regression was used to identify factors associated with 30-day readmission. Readmissions were defined as inpatient admissions to our institution within 30 days of discharge. RESULTS: The median age at surgery was 61 years; the median postoperative length of stay was 9 days; and 48% of patients had ≥1 postoperative complication (POC). The 30-day readmission rate was 13.7% (42 of 306). In univariate analysis, length of stay and having ≥1 POC were significantly associated with readmission. In multivariate analysis, having ≥1 POC was significantly associated with a >2-fold increase in risk for 30-day readmission (odds ratio 2.35, with 95% confidence interval [1.08-5.09], P = .031) when controlling for age at diagnosis and length of stay. Of the 42 patients who were readmitted, 67% experienced POCs after surgery; 50% of patients who experienced POCs were readmitted for reasons related to their postoperative complication. The most common reasons for readmission were pulmonary issues (29%), anastomotic complications (20%), gastrointestinal concerns (17%), and venous thromboembolism (14%). CONCLUSIONS: Complications not adequately managed before discharge may lead to readmission. Quality improvement efforts surrounding venous thromboembolism prophylaxis, and discharging patients nothing-by-mouth, may be warranted.

Does obesity affect the outcomes of pulmonary resections for lung cancer? A National Surgical Quality Improvement Program analysis.

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.

Epigenetic silencing of neurofilament genes promotes an aggressive phenotype in breast cancer.

Neurofilament heavy polypeptide (NEFH) has recently been identified as a candidate DNA hypermethylated gene within the functional breast cancer hypermethylome. NEFH exists in a complex with neurofilament medium polypeptide (NEFM) and neurofilament light polypeptide (NEFL) to form neurofilaments, which are structural components of the cytoskeleton in mature neurons. Recent studies reported the deregulation of these proteins in several malignancies, suggesting that neurofilaments may have a role in other cell types as well. Using a comprehensive approach, we studied the epigenetic inactivation of neurofilament genes in breast cancer and the functional significance of this event. We report that DNA methylation-associated silencing of NEFH, NEFL, and NEFM in breast cancer is frequent, cancer-specific, and correlates with clinical features of disease progression. DNA methylation-mediated inactivation of these genes occurs also in multiple other cancer histologies including pancreas, gastric, and colon. Restoration of NEFH function, the major subunit of the neurofilament complex, reduces proliferation and growth of breast cancer cells and arrests them in Go/G1 phase of the cell cycle along with a reduction in migration and invasion. These findings suggest that DNA methylation-mediated silencing of the neurofilament genes NEFH, NEFM, and NEFL are frequent events that may contribute to the progression of breast cancer and possibly other malignancies.

Risk of subsequent primary neoplasms developing in lung cancer patients with prior malignancies.

BACKGROUND: This study was performed to test the hypothesis that a history of other primary neoplasms before a lung cancer diagnosis increases the risk of subsequent malignancy. METHODS: Of 8363 lung cancer patients seen from 1978 to 2002, 881 (11%) had at least 1 previous nonlung primary malignancy. Charts were analyzed for the occurrence of subsequent malignancies. RESULTS: Lung cancer diagnosis in 881 patients consisted of 75% non-small cell, 12% small cell, and 13% other histologies. The median age was 66 years, with 56% male, 76% white, and 86% smokers. Of the 881 patients, 92% had no subsequent cancer (group 1), and 8% went on to experience the development of a new primary neoplasm (including lung) after their lung cancer (group 2). After adequate follow-up, the cumulative probability of developing a subsequent cancer did not differ markedly between those with and without a prior non-lung cancer diagnosis at 2 years (12% vs 10%) or 5 years (16% vs 15%). Group 1 patients had a significantly lower 1- and 5-year survival than group 2 patients (59% vs 48% and 29% vs 17%, respectively; P =.008). Although multivariate analysis suggested that stage, history of tobacco-associated neoplasm, and history of definitive surgical resection were important determinants in predicting long-term survival, a prior malignancy was not an independent risk factor in the development of subsequent malignancy. CONCLUSIONS: The risk of developing a subsequent malignancy is very high in lung cancer patients with prior primary malignancies, but it is not markedly different from the risks experienced by patients with no prior malignancies.

Prognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms.

BACKGROUND: The aberrant promoter methylation of the mismatch repair gene, hMLH1, is associated with microsatellite instability (MSI) in cancer cells and often is associated with a favorable prognosis. METHODS: Pancreatic endocrine neoplasms (PENs) were obtained from 48 patients who underwent surgical resection. Methylation-specific polymerase chain reaction was used to detect methylation in the hMLH1 promoter. Tumor MSI at loci BAT26, BAT25, D2S123, D5S346, and D17S250 was determined with microsatellite polymerase chain reaction. RESULTS: Hypermethylation of the hMLH1 promoter was present in 11 of 48 PENs (23%). Five of the 11 hMLH1-methylated PENs were found to be microsatellite unstable, and MSI was restricted to PENs with hMLH1 hypermethylation. Tumor recurrence at 2 years after surgical resection was significantly less common among the hMLH1-methylated PENs (11%), compared with the unmethylated PENs (35%; P=.038). Patients with hMLH1-methylated PENs experienced improved 5-year survival (100%) compared with patients with unmethylated tumors (56%; P=.010). Likewise, MSI-positive PENs were associated with improved survival compared with MSI-negative tumors (100% vs 59%; P=.017) at 5 years. CONCLUSION: As in hereditary nonpolyposis colorectal cancer in which MSI is associated with improved survival, methylation of hMLH1 leads to MSI in PENs and affords a favorable prognosis.

Pulmonary resection in octogenarians with stage I nonsmall cell lung cancer: a 22-year experience.

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.