Resection of the irradiated esophagus: the impact of lymph node yield on survival.

There is debate surrounding the appropriate threshold for lymph node harvest during esophagectomy in patients with esophageal cancer, specifically for those receiving preoperative radiation. The purpose of this study was to determine the impact of lymph node yield on survival in patients receiving preoperative chemoradiation for esophageal cancer. The National Cancer Database (NCDB) was utilized to identify patients with esophageal cancer that received preoperative radiation. The cohort was divided into patients undergoing minimal (<9) or extensive (≥9) lymph node yield. Demographic, operative, and postoperative outcomes were compared between the groups. Kaplan-Meier analysis with the log rank test was used to compare survival between the yield groups. Cox proportional hazards model was used to determine the association between lymph node yield and survival. In total, 886 cases were included: 349 (39%) belonging to the minimal node group and 537 (61%) to the extensive group. Unadjusted 5-year survival was similar between the minimal and extensive groups, respectively (37.3% vs. 38.8%; P > 0.05). After adjustment using Cox regression, extensive lymph node yield was associated with survival (hazard ratio 0.80, confidence interval 0.66-0.98, P = 0.03). This study suggests that extensive lymph node yield is advantageous for patients with esophageal cancer undergoing esophagectomy following induction therapy. This most likely reflects improved diagnosis and staging with extensive yield.

Induction chemoradiation therapy prior to esophagectomy is associated with superior long-term survival for esophageal cancer.

The purpose of this study was to examine the role of induction chemoradiation in the treatment of potentially resectable locally advanced (T2-3N0 and T1-3N+) esophageal cancer utilizing a large national database. The National Cancer Data Base (NCDB) was queried for all patients undergoing esophagectomy for clinical T2-3N0 and T1-3N+ esophageal cancer of the mid- or lower esophagus. Patients were stratified by the use of induction chemoradiation therapy versus surgery-first. Trends were assessed with the Cochran-Armitage test. Predictors of receiving induction therapy were evaluated with multivariable logistic regression. A propensity-matched analysis was conducted to compare outcomes between groups, and the Kaplan-Meier method was used to estimate long-term survival. Within the NCDB, 7921 patients were identified, of which 6103 (77.0%) were treated with chemoradiation prior to esophagectomy, while the remaining 1818 (23.0%) were managed with surgery-first. Use of induction therapy increased over time, with an absolute increase of 11.8% from 2003-2011 (P < 0.001). As revealed by the propensity model, induction therapy was associated with higher rates of negative margins and shorter hospital length of stay, but no differences in unplanned readmission and 30-day mortality rates. In unadjusted survival analysis, induction therapy was associated with better long-term survival compared to a strategy of surgery-first, with 5-year survival rates of 37.2% versus 28.6%, P < 0.001. Following propensity score matching analysis, the use of induction therapy maintained a significant survival advantage over surgery-first (5-year survival: 37.9% vs. 28.7%, P < 0.001). Treatment with induction chemoradiation therapy prior to surgical resection is associated with significant improvement in long-term survival, even after adjusting for confounders with a propensity model. Induction therapy should be considered in all medically appropriate patients with resectable cT2-3N0 and cT1-3N+ esophageal cancer, prior to esophagectomy.

Trends and outcomes in the use of surgery and radiation for the treatment of locally advanced esophageal cancer: a propensity score adjusted analysis of the surveillance, epidemiology, and end results registry from 1998 to 2008.

We examined outcomes and trends in surgery and radiation use for patients with locally advanced esophageal cancer, for whom optimal treatment isn't clear. Trends in surgery and radiation for patients with T1-T3N1M0 squamous cell or adenocarcinoma of the mid or distal esophagus in the Surveillance, Epidemiology, and End Results database from 1998 to 2008 were analyzed using generalized linear models including year as predictor; Surveillance, Epidemiology, and End Results doesn't record chemotherapy data. Local treatment was unimodal if patients had only surgery or radiation and bimodal if they had both. Five-year cancer-specific survival (CSS) and overall survival (OS) were analyzed using propensity-score adjusted Cox proportional-hazard models. Overall 5-year survival for the 3295 patients identified (mean age 65.1 years, standard deviation 11.0) was 18.9% (95% confidence interval: 17.3-20.7). Local treatment was bimodal for 1274 (38.7%) and unimodal for 2021 (61.3%) patients; 1325 (40.2%) had radiation alone and 696 (21.1%) underwent only surgery. The use of bimodal therapy (32.8-42.5%, P = 0.01) and radiation alone (29.3-44.5%, P < 0.001) increased significantly from 1998 to 2008. Bimodal therapy predicted improved CSS (hazard ratios [HR]: 0.68, P < 0.001) and OS (HR: 0.58, P < 0.001) compared with unimodal therapy. For the first 7 months (before survival curve crossing), CSS after radiation therapy alone was similar to surgery alone (HR: 0.86, P = 0.12) while OS was worse for surgery only (HR: 0.70, P = 0.001). However, worse CSS (HR: 1.43, P < 0.001) and OS (HR: 1.46, P < 0.001) after that initial timeframe were found for radiation therapy only. The use of radiation to treat locally advanced mid and distal esophageal cancers increased from 1998 to 2008. Survival was best when both surgery and radiation were used.

A case of GH deficiency and beta-thalassemia.

A 23-year-old male patient, who suffers from beta-thalassemia major, came to us for an endocrine-metabolic evaluation. Medical history showed a diagnosis of heart disease with heart failure since the age of 16, type 1 diabetes mellitus diagnosed at the age of 18, treated with an intensive insulin therapy with a poor glycometabolic control. Patient performed regular blood transfusions and iron chelation with deferasirox. An echocardiogram revealed an enlarged left ventricle. Patient had undergone a comprehensive study of buoyancy both basal and hormone-stimulated and it was therefore carried out a diagnosis of GH deficiency and hypogonadotropic hypogonadism. A recombinant GH replacement therapy was then prescribed. After six months of therapy, the patient reported a net improvement of asthenic symptoms. Physical examination showed a reduction in abdominal adiposity in waist and an increase of 5 cm in stature. Laboratory tests showed an amelioration of glycometabolic control, such as to justify a reduction in daily insulin dose. The stature observed was thought appropriate to begin the administration of testosterone. Moreover, the cardiological framework showed a reduction of left ventricular dilatation, good ventricular motility, global minimum persistent tricuspid but not mitral regurgitation and no alteration on ECG.

Prevalence of celiac disease in patients with autoimmune thyroiditis.

AIM: Many autoimmune disorders are associated to celiac disease (CD) but the association with autoimmune thyroiditis has been more frequently documented; this is in part explained by a shared immunogenetic make-up, and in part caused to time gluten-exposition, as suggested by the significant correlation observed in celiac patients between the increase occurrence of autoimmune diseases and the length of exposure to gluten. The aim of this study was to establish the prevalence of celiac disease in a group of subjects with autoimmune thyroiditis newly diagnosed on the basis of antibodies anti-peroxidase (TPO). METHODS: A total of 113 untreated patients with TPO >70 IU/mL were enrolled. CD was screened by measuring anti-endomysial antibodies (EMA) both IgA and IgG; an high prevalence of positive serology was resulting in this group, justified, in part, from EMA IgG investigation. RESULTS: In fact 31/113 patients showed IgA and/or IgG positivity and were diagnosed as celiacs with jejunal biopsy. CONCLUSION: On the basis of this paper, such as in according to current research-setting studies, the greater frequency of CD in association to autoimmune thyroid disease suggests that all subjects with TPO should be routinely screened for CD, through EMA IgA and IgG. However, the performance of this screening has never been evaluated until now, even if it could, in fact, be valid in order to increment diagnosis of CD, today still undiagnosed.

Polyglandular autoimmune endocrine insufficiency complicated by severe osteoporosis.

In literature different cases of polyglandular autoimmune type II syndrome (PGA II) are reported, where Addison's disease is associated with gonadal insufficiency. The lack in the production of sexual steroids causes a severe postmenopausal osteoporosis. The case we report is related to a 38-year-old woman we met in 1988 and who was suffering from deep asthenia, cramps, cutaneous hyperpigmentation, nausea, vomiting, abdominal pain, weight loss and hypotension. The biochemical data were indicative for autoimmune adrenal failure. Between 1988 and 1997 the patient developed a progressive insufficiency of other endocrine glands, leading to the classic feature of PGA II. In 1998, this clinical status was complicated by a severe osteoporosis. We thought that the sudden decrease in the bony mineral density was due to the lack of the protective role played by adrenal gland androgens in postmenopausal osteoporosis. They would directly act on the bony tissue, independently from oestrogens peripheral conversion, thus producing a stimulant effect on the bone formation. A new therapeutical approach, in case of osteoporosis, is today represented by DHEA replacement therapy in women showing low hormone levels.

The prognostic value of molecular marker analysis in patients treated with trimodality therapy for esophageal cancer.

The purpose of this study was to define the prognostic value of a group of molecular tumor markers in a well-staged population of patients treated with trimodality therapy for esophageal cancer. The original pretreatment paraffin-embedded endoscopic esophageal tumor biopsy material was obtained from 118 patients treated with concurrent cisplatin + 5-fluorouracil (5-FU) + 45 Gy radiation followed by resection from 1986 until 1997 at the Duke University Comprehensive Cancer Center. Three markers of possible platinum chemotherapy association [metallothionein (MT), glutathione S-transferase-pi (GST-pi), P-glycoprotein (P-gp or multidrug resistance)] and one marker of possible 5-FU association [thymidylate synthase (TS)] were measured using immunohistochemistry. The median cancer-free survival was 25.0 months, with a significantly improved survival for the 38 patients who had a complete response (P < 0.001). High-level expression of GST-pi, P-gp, and TS were associated with a decreased survival. MT was not significant in this population. Multivariate analysis identified high-level expression in two of the platinum markers (GST-pi and P-gp) and the 5-FU marker TS as independent predictors of early recurrence and death. In conclusion, this investigation measured three possible markers associated with platinum and one possible marker associated with 5-FU in a cohort of esophageal cancer patients. Independent prognostic significance was observed, which suggests that it may be possible to predict which patients may benefit most from trimodality therapy. These data need to be reproduced in a prospective investigation.

The impact of pre-radiotherapy surgery on radiation-induced lung injury.

AIMS: The use of postoperative radiation therapy (PORT) is predicated by an assessment of the potential benefits and risks, including radiation-induced lung injury. In this study, the risk of radiation-induced lung injury is assessed in patients who received PORT, and compared with a group of patients who received radiation without prior surgery, to determine if surgery increases the risk of radiation pneumonitis. MATERIALS AND METHODS: From 1991 to 2003, 251 patients with lung cancer were enrolled into a prospective study to assess radiation-induced lung injury. All patients received three-dimensional-planned, external-beam radiotherapy. One hundred and seventy-seven patients with over 6-months follow-up were eligible. For the current analysis, 49 patients (28%) had surgical intervention before radiotherapy. The rates of Grade 2 symptomatic pneumonitis in subgroups, based on the type of pre-radiation surgery, were computed and compared using Fisher's Exact Test. To consider the confounding factor of irradiated lung volume, patient subgroups were further defined on the basis of the mean lung dose. RESULTS: Surgical procedures included pneumonectomy (n=9), lobectomy (n=16), wedge resection (n=8) and exploration without resection (n=16). Radiation-induced lung injury occurred in 33 out of 177 (19%) patients, including 18% of the surgical group and 19% of the non-surgical group. Additionally, no statistically significant difference was found in the rate of radiation-induced lung injury based on the extent of resection. CONCLUSIONS: The incidence of pneumonitis is similar in the surgical and non-surgical groups. Thus, PORT may be safely given to selected patients after surgical exploration or resection.

Evaluation of trans-sphenoidal surgery in pituitary GH-secreting micro- and macroadenomas: a comparison between microsurgical and endoscopic approach.

AIM: Acromegaly is caused by a GH-secreting pituitary adenoma, associated with many comorbidities and increased risk of mortality. Surgery is the first-line therapy. Success of therapy is measured by symptomatic improvement, preservation of pituitary function and biochemical control. Trans-sphenoidal surgery (TSS), endoscopic or microscopic, is the preferred treatment. To evaluate surgery effectiveness and individuate the technique associated with a higher remission rate, patients undergoing TSS were retrospectively selected. METHODS: Thirty-seven consecutive patients underwent surgery between 1996 and 2006. Tumors were classified into macroadenomas or microadenomas and into intrasellar, extrasellar and extrasellar with cavernous sinus invasion. Surgery was performed in 22 patients with endoscopic technique, in 15 patients with microsurgical approach. The hormonal assays were performed 6 months and yearly after surgery for an average of 5 years. RESULTS: Ten patients were affected by microadenoma, 27 by macroadenoma. In microadenomas remission rate was independent of the used technique. Within macroadenomas, remission percentage in endoscopic approach (68.75%) was significantly higher than in microscopic approach (18.18%) (P=0.018). Postsurgical biochemical remission was calculated combining the surgical technique and tumor extension: the endoscopic approach was associated with a significantly higher remission rate in extrasellar than both in intrasellar and extrasellar with cavernous sinus invasion. In the latter group, any technique had not reached biochemical remission. CONCLUSION: TSS is able to induce a long-term remission of acromegaly, with low risk of recurrence and complications. Endoscopic approach is more suitable than microscopic technique in macroadenomas and adenomas with suprasellar extension.

The chemokine interleukin-8 regulates parathyroid secretion.

Interleukin-8 (IL-8) is a chemokine important in inflammatory processes. Homology cloning experiments performed using bovine parathyroid cDNA and degenerate primers encoding transmembrane regions III and VI of peptide and protein hormone G-protein coupled receptors identified a set of known receptors not previously identified in the parathyroid. Among these was the IL-8 type B receptor. Incubation of freshly isolated bovine parathyroid cells with recombinant IL-8 for 6-48 h produced an increase in the levels of mRNA for parathyroid hormone (PTH). The levels of PTH secreted in response to nanomolar amounts of IL-8 were also elevated in cells incubated for 1 h with IL-8. Differential display analysis of mRNA from parathyroid cells, incubated in the presence and absence of IL-8, permitted the identification of cDNA clones for RNA species whose expression was either elevated or suppressed. These experiments suggest that IL-8 and inflammatory events play a role in bone homeostasis through actions on the parathyroid gland.

Thymopoiesis in HIV-infected adults after highly active antiretroviral therapy.

The thymus of HIV-seropositive patients can enlarge as CD4+ T cell counts increase on highly active anti-retroviral therapy (HAART). This may indicate development of new T cells or represent mature peripheral T cells recirculating to the thymus. To define the etiology of the enlargement, the thymuses of two HIV-infected individuals on HAART were biopsied. For more than 3 years before initiation of HAART, both patients (38 and 41 years of age) had documented CD4+ T lymphopenia. Peripheral blood samples were obtained to assess circulating CD4+ CD45RA+ CD62L+ T cells, which were thought to have recently developed in the thymus. Peripheral blood T cells from both patients and thymocytes from the second patient were also tested for levels of DNA episomes formed during T cell receptor gene rearrangement (T cell receptor rearrangement excision circles, TRECs). With HAART, peripheral blood CD4+ T cell counts increased from approximately 60/mm(3) to 552/mm(3) and 750/mm(3) for patients 1 and 2, respectively. Thymic biopsies from both patients showed normal thymus histology with active thymopoiesis. Percentages of peripheral blood CD4+ CD45RA+ CD62L+ T cells and quantitation of T cell TRECs also reflected active thymopoiesis in both patients. Thus, in these two HIV-seropositive adults examined after initiation of HAART, thymic enlargement represented active thymopoiesis. Thymopoiesis in adult AIDS patients may contribute to immune reconstitution even after prolonged CD4+ T lymphopenia.

Myxoid liposarcoma of the supraclavicular fossa.

Liposarcomas generally originate most often in the extremities or retroperitoneum, less frequently in the head and neck, and rarely in the thorax. We describe a particularly rare presentation of myxoid liposarcoma originating in the supraclavicular fossa. The mass was resected and has not recurred. We searched our pathology database for other soft-tissue tumors of the supraclavicular fossa and found no other case of sarcoma originating in this site. In addition, we performed a literature review of thoracic and neck liposarcomas to identify similar cases and discuss their clinical course.

A biologic risk model for stage I lung cancer: immunohistochemical analysis of 408 patients with the use of ten molecular markers.

OBJECTIVE: The standard treatment of patients with stage I non-small cell lung cancer is resection of the primary tumor; however, the recurrence rate is 28% to 45%. This study evaluates a panel of molecular markers in a large population of patients with stage I non-small cell lung cancer to determine the prognostic value of each marker and to create a biologic risk model. METHODS: Pathologic specimens were collected from 408 consecutive patients after complete resection for stage I non-small cell lung cancer at a single institution, with follow-up of at least 5 years. A panel of 10 molecular markers was chosen for immunohistochemical analysis of the primary tumor on the basis of differing oncogenic mechanisms. Local tumor expansion requires growth regulating proteins (epidermal growth factor receptor, the protooncogene erb-b2); apoptosis proteins (p53, bcl-2); and cell cycle regulating proteins (retinoblastoma recessive oncogene, KI-67). Local tumor invasion requires angiogenesis (factor viii). The development of distant metastases involves the expression of adhesion proteins (CD-44, sialyl-Tn, blood group A). Cox proportional hazards regression analysis was used to construct an independent risk model for cancer recurrence and death. RESULTS: Multivariable analysis demonstrated significantly elevated risk for the following molecular markers: p53 (hazard ratio, 1.68; P =.004); factor viii (hazard ratio, 1.47 P =. 033); erb-b2 (hazard ratio, 1.43; P =.044); CD-44 (hazard ratio, 1. 40; P =.050); and retinoblastoma recessive oncogene (hazard ratio, 0. 747; P =.084). CONCLUSIONS: Five molecular markers were associated with the risk of recurrence and death, representing independent metastatic pathways: apoptosis (p53), angiogenesis (factor viii), growth regulation (erb-b2), adhesion (CD-44), and cell cycle regulation (retinoblastoma recessive oncogene). This study demonstrates the validity of this molecular biologic risk model in patients with stage I non- small cell lung cancer.

Desensitization of myocardial beta-adrenergic receptors and deterioration of left ventricular function after brain death.

Brain death often results in a series of hemodynamic alterations that complicate the treatment of potential organ donors before transplantation. The deterioration of myocardial performance after brain death has been described; however, the pathophysiologic process of the myocardial dysfunction that occurs after brain death has not been elucidated. This study was designed to analyze the function of the myocardial beta-adrenergic receptor and the development of left ventricular dysfunction in a porcine model of experimental brain death. Analysis of the beta-receptor included determination of receptor density and adenylate cyclase activity after stimulation independently at the receptor protein, the G protein, and the adenylate cyclase moiety. Myocardial beta-receptor density did not change after the induction of brain death. A decrease in stimulated adenylate cyclase activity was observed within the first hour after brain death at the level of the beta-receptor, the G protein, and the adenylate cyclase moiety, which suggests the occurrence of rapid desensitization of beta-receptor function. Significant deterioration of myocardial performance also occurred within the first hour after brain death, represented by a decrease in preload-recruitable stroke work compared with the baseline value. The deterioration of myocardial performance after brain death correlates temporally with desensitization of the myocardial beta-receptor signal transduction system. The mechanism of impairment appears to be localized to the adenylate cyclase moiety itself.

Stability of the beta-adrenergic receptor/adenylyl cyclase pathway of pediatric myocardium after brain death.

Our previous work in the adult porcine model shows that brain death results in a rapid decline in left ventricular systolic function as measured by the preload recruitable stroke work method to 8% of the baseline slope within 6 hours; this process is accompanied by functional uncoupling of the beta-adrenergic receptor at the level of the adenylyl cyclase moiety within 1 hour. In contrast, the pediatric porcine myocardium displays no change in left ventricular systolic function from baseline within 6 hours of brain death. This work investigates whether the beta-adrenergic receptor/adenylyl cyclase pathway remains intact after induction of brain death in the pediatric porcine model. Thirteen 1-month-old swine (7 to 10 kg) were anesthetized and underwent median sternotomy, and baseline transmural left ventricular biopsy specimens were obtained before ligation of head vessels to induce brain death in six piglets, with the remaining seven serving as controls. Baseline left ventricular biopsy specimens were obtained just before and 1 and 3 hours after brain death or at matched time points without brain death in the control group. Myocardial tissue was then analyzed for beta-adrenergic receptor density with the use of saturation [125I]-iodocyanopindolol binding in the absence and presence of propranolol 1 mumol/L. Coupling of the beta-adrenergic receptor to its signal transduction system (stimulation of adenylyl cyclase) was tested at three levels: beta-adrenergic receptor (isoproterenol 100 mumol/L), stimulatory G protein Gs (sodium fluoride 10 mmol/L), and the adenylyl cyclase moiety itself (forskolin 100 mumol/L).(ABSTRACT TRUNCATED AT 250 WORDS)

Improved tolerance of the pediatric myocardium to brain death.

The occurrence of brain death has been shown to significantly diminish left ventricular function in the adult porcine model. This study examined whether the pediatric myocardium is as sensitive as the adult myocardium to the detrimental effects of brain death in the porcine model. Left ventricular intracavitary pressure and major and minor axis epicardial dimensions were measured in eleven 1-month old pigs (7.5 to 10 kg) during a vena caval occlusion. Brain death was induced in six pigs by acutely ligating the brachiocephalic and left subclavian arteries. The remaining five pigs served as controls. Data were then collected every hour for 6 hours. The plot of the stroke work versus the end diastolic volume, called the preload recruitable stroke work relationship, was determined from the measured pressure and calculated intracavitary volume data. The slope of this linear relationship is an index of contractility, and the x intercept (Vo) is an index of diastolic mechanics. At each hour after instrumentation two vena caval occlusions were performed, and the mean slope of the preload recruitable stroke work line was calculated as a percentage of the baseline slope in both the brain-dead and control group. The mean values from the brain-dead pigs were 118%, 138%, 126%, 154%, 123%, and 87% of the baseline value for the 6 hours after brain death. The mean control values were 128%, 117%, 133%, 123%, 114%, and 111% of baseline for the 6 hours after instrumentation alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of triiodothyronine and vasopressin on cardiac function and myocardial blood flow after brain death.

Previous studies have documented decreases in serum-free triiodothyronine (T3) after brain death and improved hemodynamics with its replacement, suggesting its controversial, but promising, clinical utility for managing potential organ donors. Vasopressin is also commonly used clinically as a pressor agent after brain death. A load-independent analysis of cardiac function and an assessment of myocardial blood flow (MBF) with these agents have not been reported, however. Eighteen pigs were instrumented with left ventricular epicardial dimension transducers and a left ventricular micromanometer. MBF was assessed by standard microsphere techniques. Baseline left ventricular pressure-dimension data were collected, and brain death was induced by ligating the innominate and left subclavian arteries. Left ventricular function data were collected every 30 minutes after brain death to 6 hours or until the animal died. Microsphere injections were performed before brain death and hourly thereafter to 4 hours. At 90 minutes after brain death, animals were assigned to a vasopressin (2 units/hr, intravenously, n = 6), T3 (0.05 microgram/kg/hr, intravenously, n = 6), or control (n = 6) treatment group. Preload recruitable stroke work (PRSW), a load-independent index of left ventricular function, was derived from the pressure-dimension data. MBF was calculated by conventional methods. At 4 hours after brain death, PRSW and MBF decreased significantly in the control, vasopressin, and T3 groups relative to the baseline, pre-brain dead state (PRSW: -36% +/- 12%, -48 +/- 7%, -52% +/- 5%; MBF: -27% +/- 15%, -38% +/- 5%, -78% +/- 2%, respectively). Neither vasopressin nor T3, however, showed any advantage over the control group in terms of preserving left ventricular function or prolonging survival. Furthermore, these data show a marked decrease in MBF in the T3 group (p < 0.01 versus control and vasopressin groups) without a significant change in cardiac function. Analysis of endocardial to epicardial flow ratios disclosed no significant differences between groups at any time. In summary, animals treated with T3 had a greater decline in MBF than the control group at 4 hours, without any benefit to cardiac function. Further studies examining the mechanism responsible for the deterioration of MBF and cardiac dysfunction will be necessary to optimally manage the brain dead patient before organ harvest, especially regarding the precise role of T3.

Malignant melanoma presenting as a mediastinal mass.

A case of malignant melanoma presenting as a mediastinal mass without an extrathoracic primary is reported. Microscopically the tumor appeared consistent with malignant melanoma, with the presence of focal melanin pigment in large epithelioid cells. Fontana stain confirmed the presence of melanin pigment. Immunohistochemical staining further suggested melanoma, with the tumor cells expressing a HMB45+, S100+ and cytokeratin-phenotype. Electron microscopy showed an abundance of melanosomes confirming the diagnosis of malignant melanoma.

Molecular biologic substaging of stage I lung cancer according to gender and histology.

BACKGROUND: This study is designed to assess molecular biologic substaging according to gender and histology in patients with stage I non-small cell lung cancer (NSCLC). METHODS: Pathologic specimens were collected from 408 consecutive patients after complete resection for stage I NSCLC, with follow-up of at least 5 years. A panel of nine molecular markers was chosen for immunohistochemical analysis of the tumor: recessive oncogenes p53 and bcl-2, the protooncogene erbB-2, KI-67 proliferation index, retinoblastoma oncogene (Rb), epidermal growth factor receptor (EGFr), angiogenesis factor viii, sialyl-Tn antigen (STN), and CD-44. Cox proportional hazards regression analysis was used to construct a risk model for cancer-specific survival according to marker status, gender, and histologic subtype. RESULTS: Among men, the only molecular marker associated with decreased cancer-specific survival is erbB-2; among women, there are four markers: p53, Rb, CD-44, and factor viii. Among patients with squamous cell carcinoma, the only molecular marker associated with decreased cancer-specific survival is erbB-2; among patients with adenocarcinoma (AC), there are three markers: p53, CD-44, and factor viii. Multivariable analysis of interactions among molecular markers, gender, and histology demonstrates two important relationships (hazard ratio): p53+/women (2.269) and CD-44+/AC (2.266). CONCLUSIONS: Molecular biologic substaging of patients with stage I NSCLC demonstrates differential cancer-specific survival according to marker expression, gender, and histologic subtype.