Endoluminal management of bronchogenic carcinoma in 2010: diagnosis, staging, and therapy.

Endoluminal bronchogenic carcinoma, though a minority of lung cancer cases, presents a unique opportunity to utilize techniques for the diagnosis and therapy that are unavailable for more peripheral tumors. This review explores current techniques for the diagnosis, staging, and therapy of endoluminal central bronchogenic tumors and also introduces techniques currently under investigation as potential improvements or replacements for current techniques using recent literature. Additionally, the new staging criteria set forth in the 7th edition of the TMN staging system as a result of the American Joint Committee on Cancer (AJCC), International Union Against Cancer (IUCC), and the International Association for the Study of Lung Cancer (IASLC) are discussed with respect to endoluminal bronchogenic carcinoma.

An increased proportion of inflammatory cells express tumor necrosis factor alpha in idiopathic achalasia of the esophagus.

Achalasia is a motility disorder characterized by the absence of coordinated peristalsis and incomplete relaxation of the lower esophageal sphincter. The etiology remains unclear although dense inflammatory infiltrates within the myenteric plexus have been described. The nature of these infiltrating cells is unknown. The aim of this study was to evaluate the expression of proinflammatory cytokines - namely, tumor necrosis factor alpha and interleukin-2 - in the distal esophageal muscle in patients with achalasia. Lower esophageal sphincter muscle from eight patients undergoing myotomy or esophagectomy for achalasia of the esophagus were obtained at the time of surgery. Control specimens consisted of similar muscle taken from eight patients undergoing operation for cancer or Barrett's esophagus. The expression of tumor necrosis factor alpha and interleukin-2 were assessed by immunohistochemistry. The total number of inflammatory cells within the myenteric plexus were counted in five high power fields. The percentage of infiltrating cells expressing tumor necrosis factor alpha or interleukin-2 was calculated. Clinical data including demographics, preoperative lower esophageal sphincter pressure, duration of symptoms, and dysphagia score (1 = no dysphagia to 5 = dysphagia to saliva) were obtained through electronic medical records. Statistical comparisons between the groups were made using the unpaired t-test, Fisher's exact test, or Mann-Whitney U test, with a two-tailed P-value less than 0.05 being considered significant. The total number of inflammatory cells was found to be similar between the groups. A significantly higher proportion of inflammatory cells expressed tumor necrosis factor alpha in achalasia as compared with controls (22 vs. 11%; P= 0.02). A similar percentage of infiltrating cells expressed interleukin-2 (40 vs. 41%; P= 0.87). Age, gender, preoperative lower esophageal sphincter pressure, or dysphagia score were not correlated to expression of these cytokines. There was, however, a significant inverse correlation between duration of symptoms and the proportion of inflammatory cells expressing tumor necrosis factor alpha in achalasia (P= 0.007). In conclusion, a higher proportion of infiltrating inflammatory cells expressed tumor necrosis factor alpha in achalasia. Furthermore, this proportion appears to be highest early in the disease process. Further studies are required to more clearly delineate the role of tumor necrosis factor alpha in the pathogenesis of this idiopathic disease.

A pilot study of botulinum toxin injection for the treatment of delayed gastric emptying following esophagectomy.

OBJECTIVE: Esophagectomy may lead to impairment in gastric emptying, unless a pyloroplasty or pyloromyotomy is performed. These procedures may be technically challenging during minimally invasive esophagectomy, and they are associated with a small but definable morbidity, such as leakage and dumping syndrome. We sought to determine the results of our early experience with injecting the pylorus with botulinum toxin instead of conventional pyloric drainage. METHODS: Fifteen patients who had undergone esophagectomy and injection of the pylorus with botulinum toxin were identified. Twelve patients had undergone botulinum toxin injection at the time of minimally invasive esophagectomy, and the remaining three had been treated endoscopically after surgery. The latter three patients had undergone esophagectomy with either no pyloric drainage (n = 2) or an inadequate pyloromyotomy (n = 1), and they presented in the postoperative period with delayed gastric emptying. The adequacy of emptying after injection was assessed by the patients' ability to tolerate a regular diet, a barium swallow, and a nuclear gastric emptying study. RESULTS: No patient injected with botulinum toxin during esophagectomy developed delayed gastric emptying or aspiration pneumonia in the perioperative period. Eight of these patients underwent a nuclear emptying scan at a median of 4.2 months after surgery, which showed a mean emptying half-life of 100 min. With a median follow-up of 5.3 months, one patient (8%) required reintervention for symptoms of gastric stasis, presumably after the effect of the toxin subsided. All three patients injected postoperatively demonstrated an improvement in symptoms of gastric outlet obstruction and were able to resume a regular diet. CONCLUSIONS: Injection of the pylorus with botulinum toxin can be performed safely in patients undergoing esophagectomy. Longer-term studies are needed to clarify the efficacy and durability of this technique compared to the accepted procedures of pyloromyotomy or pyloroplasty.

Minimally invasive esophagectomy: state of the art.

Open esophagectomy is associated with significant mortality and morbidity, even in experienced centers. Two of the more frequent complications following esophagectomy are pneumonia and respiratory failure. Single-institution series have suggested that the incidence of these complications may be decreased with minimally invasive esophagectomy, with equivalent survival compared to open esophagectomy. However, this operation is technically challenging. In this review we detail the procedure as performed in our center, and also discuss some recent developments.

Circulating ghrelin is sensitive to changes in body weight during a diet and exercise program in normal-weight young women.

Ghrelin is directly involved with short-term regulation of energy balance. Although circulating levels of ghrelin are elevated in anorexia nervosa and reduced in obesity, the role of ghrelin in regulating long-term energy balance in healthy women has not been investigated. We examined the effects of a 3-month energy deficit-imposing diet and exercise intervention on circulating ghrelin in normal-weight, healthy women. Body composition, resting metabolic rate, and serum ghrelin were measured at pre-, mid-, and postintervention in controls (n = 7), who performed no exercise, and exercising women who remained weight stable (n = 5) or lost weight (n = 10). Exercise training occurred five times per week, and subjects were fed a specific diet. Ghrelin significantly increased over time (770 +/- 296 to 1322 +/- 664 pmol/liter) in the weight-loss group compared with the controls and the weight-stable group (P < 0.05). Changes in ghrelin were negatively correlated with changes in body weight (r = -0.61; P < 0.05). Body fat, body weight, and resting metabolic rate significantly decreased in the weight-loss group before the increase in ghrelin. These findings suggest that ghrelin responds in a compensatory manner to changes in energy homeostasis in healthy young women, and that ghrelin exhibits particular sensitivity to changes in body weight.

Nitric oxide induces angiogenesis and upregulates alpha(v)beta(3) integrin expression on endothelial cells.

Nitric oxide (NO) has been implicated as a mediator of angiogenesis. However, its precise role in angiogenesis and its mechanism of action have not been established. We performed in vivo and in vitro angiogenesis assays using NO donor S-nitroso-N-acetylpenicillamine (SNAP) and NO synthase inhibitor N-iminoethyl-l-ornithine (L-NIO). SNAP significantly increased and L-NIO significantly suppressed capillary ingrowth into subcutaneously implanted Matrigel plugs in mice. For the in vitro angiogenesis assay, human umbilical vein endothelial cells (HUVECs) (4 x 10(4) cells/well) were treated with placebo, SNAP (100 microM), or L-NIO (100 microM) and cultured on Matrigel for 18 h. The typical capillary networks formed on Matrigel by HUVECs as a result of cell migration and differentiation were quantified by computer-assisted image analysis as a measure of angiogenesis. Treatment of HUVECs with SNAP significantly increased the capillary network area compared with control, 8701 +/- 693 vs 6258 +/- 622 area units (P < 0.05), whereas L-NIO significantly decreased the capillary area (4540 +/- 342, P < 0.05). Furthermore, we have shown with a blocking monoclonal antibody that formation of capillary networks on Matrigel is mediated by the functional expression of the alpha(v)beta(3) integrin, which plays a role in facilitating endothelial cell adhesion to basement membrane matrix and endothelial cell migration. After an 18-h culture, flow cytometry revealed that SNAP significantly upregulated and L-NIO significantly downregulated in a concentration-dependent manner alpha(v)beta(3) integrin expression on endothelial cells. In conclusion, NO induces angiogenesis in vivo and in vitro by promoting endothelial cell migration and differentiation into capillaries. One possible mechanism might involve the upregulation of alpha(v)beta(3) integrin on endothelial cells, a critical mediator of cell-matrix adhesion and migration.

Characterization of a newly discovered T-cell receptor beta-chain heterodimer expressed on a CD8+ bone marrow subpopulation that promotes allogeneic stem cell engraftment.

The facilitating cell is a rare CD8+ bone marrow subpopulation that can enhance allogeneic hematopoietic stem cell engraftment across complete major histocompatibility complex barriers without inducing acute graft-versus-host disease. Here we describe a CD3epsilon-associated complex on the facilitating cell surface that consists of the T-cell receptor beta-chain disulfide-linked to a previously unknown 33-kilodalton glycoprotein. Provisionally called FCp33, this glycoprotein does not represent any of the known protein chains or surrogates associated with CD3-T-cell receptor beta. Expression of this CD3-T-cell receptor beta-FCp33 complex directly correlates with the facilitating cell's functional ability to enhance allogeneic stem cell engraftment in vivo.

The abrogation of allosensitization following the induction of mixed allogeneic chimerism.

The association of preformed anti-donor Abs with the hyperacute rejection of bone marrow and solid organ allografts and the persistence of the anti-donor immune response secondary to immunologic memory make allosensitization an absolute contraindication to transplantation. Mixed allogeneic (A + B-->A) bone marrow chimerism has been demonstrated to confer donor-specific tolerance in nonsensitized recipients, but has not been evaluated in the setting of allosensitization. The current study documents that despite significant anti-donor sensitization, mixed allogeneic engraftment is possible and provides a marked advantage over fully allogeneic (B-->A) models. Moreover, the acceptance of donor skin grafts and loss of circulating anti-donor Abs suggest that allosensitization can be abrogated with the induction of stable mixed allogeneic chimerism.

The relationship between verbal abuse of medical students and their confidence in their clinical abilities.

PURPOSE: To explore the relationship between graduating students' self-reported experiences of verbal abuse during medical school and their confidence in their clinical skills. METHOD: Using data from the Association of American Medical Colleges Medical School Graduation Questionnaire and its Matriculating Student Questionnaire, the author determined the statistical relationships between students' experiences of verbal abuse and their levels of confidence upon graduating medical school. The author controlled for sex, race, age, academic ability (as measured by MCAT scores), and level of assuredness (as measured by levels of confidence upon matriculation). RESULTS: The relationship between verbal abuse and lower levels of confidence was significant for all demographic groups and for students with high and low abilities and high and low levels of assuredness. Although the statistical analysis does not prove causation between verbal abuse and lower confidence, the findings show a correlation between the two. CONCLUSION: Medical schools must understand that verbal abuse correlates with students' confidence, regardless of their sex, race, age, or levels of ability and assuredness. School policies must address the problem of verbal abuse of students to avoid lowering students' self-confidence.

On rising medical student debt: in for a penny, in for a pound.

Using national databases of the Association of American Medical Colleges, the authors have examined reasons for the rising indebtedness of U.S. medical students, looking across the past decade at the influence of tuition and fees (tuition-fees) alone and the total costs of attending school, the effects of the changing demographics of medical school enrollments and lengthened graduation times, the relationship between the availability of school-funded scholarships and the amount of student loan disbursements, the pattern of student financial aid, and the reliance on borrowing to cover the costs of medical education. In constant dollars, the average indebtedness of students graduating from public schools increased 59.2% between 1985 and 1995, and that for graduates of private schools increased 64.2%. The fraction of graduates bringing debt with them when they entered medical school declined from 42.1% in 1985 to 33.6% in 1995. Premedical debt as a fraction of total debt declined at public schools from 9% in 1985 to 7% in 1995, and at private schools from 7.8% in 1985 to 5.9% in 1995. For public schools, tuition-fees increased 60.1% between 1985 and 1995, and average medical school debt increased 60.9%; for private schools, tuition-fees increased 30.1% over that period, while average medical school debt increased 66.2%. On average, public school graduates accrued debt greater than their four-year tuition-fee payments, while the average debt accrued by private school graduates was less than tuition-fee amounts. In 1995, graduates of public schools had debt accumulations representing 62% of the average total cost of attendance (tuition, fees, books, supplies, equipment, and living expenses), and the indebtedness of private school graduates was 55% of the average total cost, findings suggesting that total costs were the stronger driver of the amounts borrowed. On a national scale, the influences on medical school debt of longer graduation times, the growing number of women students, greater racial-ethnic diversity, and the admission of more older students age were negligible or small. The average parental income, adjusted to constant dollars, actually increased between 1985 and 1995. For public schools, the aggregate amounts of student aid have climbed at a steeper rate than schools' tuition-fee revenues during the past decade. For public schools, tuition-fee revenues rose 66.7% between 1985 and 1995, while the amount of loans to students at public schools increased 92.7%. For private schools, tuition-fee revenues went up 36.5%, and the amount of loans to students rose 57.9% during the same period. Federal Stafford Loans represented the major financing source, increasing from 71.5% of public schools' tuition-fee revenue in 1985 to 92.2% in 1995, and from 23% of private schools' tuition-fee revenue in 1985 to 38% in 1995. Over the decade, scholarship support kept pace with tuition-fee increases at public schools, but lagged behind the increases at private schools. The recent escalation of student debt has coincided with the lifting of the federal loan borrowing limits under the Higher Education Act. In parallel, entering medical students have declared their intentions to rely more heavily on loans as a means of financing. These findings, although based on national data and trends, provide a framework for exploration of the factors affecting educational costs and financing at individual medical schools. The importance of doing so is mounting, as students may be throwing caution to the winds in the more favorable climate for borrowing, ignoring indicators of changing practice opportunities and incomes ahead.

Determinants of the generalist career intentions of 1995 graduating medical students.

Using national databases of the Association of American Medical College, the authors employed logistic regression analysis to show the relative predictive influences of selected demographic, structural, attitudinal, and educational variables on the specialty careers choices of 1995 U.S. medical school graduates. Plans to pursue certification in family practice or an unspecified generalist career could be predicted with moderate success, while choices of general internal medicine and general pediatrics could not. The intentions of the 1995 graduates to pursue generalist specialty, were significantly associated with demographic factors such as female gender, older student age, and rural hometown; early interest in the generalist specialties; attitudes favoring helping people over seeking opportunities for leadership, intellectual challenge, or research; the presence of a department of family medicine in the medical school; and ambulatory care experiences in the third and fourth years. In the multiple-regression models used in this study, a number of factors widely touted as important to the cultivation of generalism were not significant predictors of generalist decisions; an institutional mission statement expressly addressing the cultivation of generalist careers; giving admission preferences to applicants who vowed an interest in generalism; public (versus private) school sponsorship; discrete organization units for general internal medical or general pediatrics; the proportion of institutional faculty in the general specialty of medicine and pediatrics; the level of educational debt; the students; clinical experiences in the first and second years of medical school. The authors acknowledge the danger of inferring causal relationships from analyses of this kind, and described how the power of previous associations--e.g., that between a required third-year clerkship in family medicine and graduates' family practice career choices--may be weakened when the independent variable spreads across institutional cultures that at present are less conductive to primary care. The findings of this analysis add to the evidence that generalist career intentions are largely carried on the tide of students' interests and experiences in family medicine and ambulatory primary care. In terms of the predictive values of the input variable in this study, career decisions for the other two generalist specialties--general internal medicine and general pediatrics--were essentially a crapshoot, either because the tactics to promote interest in these fields were ineffective (or confounded), or because the efforts were underdeveloped. Moreover, the statistical models of this study employed quantifiable variables that can be discerned and manipulated to guide the result, whereas medical students tend to identify less tangible elements as more powerful factors influencing their career choices. The results sharpen the strategic focus, but must be combined with those of other, descriptive analysis for a more complete understanding of graduating students' career decisions.

A nonlethal conditioning approach to achieve durable multilineage mixed chimerism and tolerance across major, minor, and hematopoietic histocompatibility barriers.

Reconstitution of lethally irradiated mice with a mixture of syngeneic and allogeneic (A+B-->A) bone marrow results in multilineage mixed allogeneic chimerism, donor-specific transplantation tolerance, superior immunocompetence and resistance to graft-vs-host disease. However, the morbidity and mortality associated with lethal irradiation would be a major limitation to the clinical application of chimerism to induce tolerance for solid organ grafts or treat other nonmalignant hematologic diseases. We report here that durable multilineage mixed allogeneic chimerism and donor-specific transplantation tolerance for skin and primarily vascularized allografts can be achieved across multiple histocompatibility barriers using a nonmyeloablative radiation-based approach. The percentage of B10 mouse recipients that engrafted directly correlated with the degree of disparity between donor and recipient and the dose of total body irradiation administered. Although the occurrence of engraftment following conditioning with doses of total body irradiation of > or = 600 cGy was similar for animals receiving bone marrow disparate at MHC or MHC, minor and hematopoietic (Hh-1) loci (67% vs 78%), the level of donor chimerism was significantly less when multiple histocompatibility barriers were present (94.6 +/- 3.8% vs 37.5 +/- 12.5%). Treatment of the recipient with cyclophosphamide 2 days following allogeneic bone marrow transplantation reduced the dose of radiation sufficient for reliable engraftment to only 500 cGy of total body irradiation, regardless of MHC and Hh-1 disparity. Donor chimerism was stable and present in all lineages, with production of lymphoid (T and B cell), NK, and myeloid (erythrocyte, platelet, granulocyte, and macrophage) cells. Mixed chimeras exhibited donor-specific tolerance in vitro, as assessed by mixed lymphocyte culture (MLR) and cytotoxicity (CML) assays, and in vivo to skin and primarily vascularized cardiac allografts. The observation that engraftment and tolerance can be achieved across multiple histocompatibility barriers using nonmyeloablative recipient conditioning may allow allogeneic bone marrow transplantation to be applied to nonmalignant disease states in which lethal conditioning cannot be justified, including the induction of donor-specific tolerance for solid organ transplantation and the treatment of hemoglobinopathies and enzyme deficiency states.