Prognostic molecular assay might improve identification of patients at risk for recurrence in early-stage non-small-cell lung cancer.

INTRODUCTION: Adjuvant chemotherapy improves survival for some patients with NSCLC and is recommended in NCCN guidelines for stage Ib to IIa patients with certain "high-risk" characteristics. An internationally validated, 14-gene expression assay has been shown to better stratify mortality risk in nonsquamous NSCLC than either conventional staging or these high risk clinicopathologic features. PATIENTS AND METHODS: A blinded chart review of 52 patients with prospective molecular risk stratification using the 14-gene test compared recurrence outcomes with a mean follow-up of 15.2 ± 11.7 months of patients with high- or low-risk determined according to either NCCN criteria or the molecular assay. RESULTS: Molecular risk assessment was discordant from NCCN criteria in 14 of 23 patients in stages Ib and IIa (61%). Recurrence was not observed among any of 31 molecular intermediate- or low-risk patients, including 10 NCCN high-risk patients, whereas 2 of 6 recurrences (33%) occurred among NCCN low-risk patients. Recurrences in stages I or IIa were seen in 2 of 18 NCCN high-risk patients (11%; both were stage IIa and both received a high-risk molecular designation), and in 4 of 18 patients (22%) with a high-risk molecular score, including 1 stage Ia and 1 stage Ib patient. CONCLUSION: This small cohort study suggests that a 14-gene prognostic assay more accurately stratifies risk among early-stage NSCLC patients than current NCCN criteria. NCCN guidelines already advocate risk stratification within tumor, node, metastases stages. This molecular assay has clinical utility in better identifying high-risk patients and might improve NCCN adjuvant chemotherapy recommendations.

Lack of NKX2.2 expression in bronchopulmonary typical carcinoid tumors: implications for patients with neuroendocrine tumor metastases and unknown primary site.

BACKGROUND: Patients with neuroendocrine tumors (NETs) may have metastatic disease and unknown primary site. NETs commonly arise from the bronchopulmonary (BP) and gastrointestinal (GI) tract. The largest subgroups of well-differentiated BP-NETs are typical carcinoids (TCs). The homeodomain transcription factor NKX2.2 regulates development of gut serotonin cells and is a marker of GI-NETs. Previous work on a limited number of samples suggested that BP-TCs do not express NKX2.2. We hypothesized that lack of NKX2.2 expression in BP-TCs might be useful to distinguish BP- from GI-NETs, and evaluated NKX2.2 expression in a larger number of BP-TCs. METHODS: Archived formalin-fixed, paraffin-embedded tissues were obtained from 13 previously undescribed patients with BP-TCs. Expression of NKX2.2, serotonin, and the NE marker chromogranin A (CgA) were assessed by immunohistochemistry. RESULTS: CgA expression was robust in all 13 BP-TCs, confirming the NE phenotype. Serotonin expression was less frequent (9/13; 69%). Two patients with BP-TCs in which serotonin expression was absent exhibited Cushing's syndrome due to ectopic ACTH production. NKX2.2 expression was not observed in any of the 13 tumors. CONCLUSIONS: Bronchopulmonary TCs uniformly express CgA but not NKX2.2. Because most of these tumors express serotonin, our findings suggest that NKX2.2 may not be required for serotonin production by BP-TCs. We conclude that the presence or absence of NKX2.2 expression may assist in the determination of the primary tumor site in patients with NET metastases of unknown origin. NET metastases that are CgA-positive/NKX2.2-negative would suggest a BP primary, whereas those that are CgA-positive/NKX2.2-positive would suggest a GI primary.

Emergent management of malignancy-related acute airway obstruction.

Acute obstruction of the airway in the emergent situation results from a wide variety of malignant and benign disease processes. Acute management involves establishing a secure and patent route for adequate gas exchange. This requires rapid determination of the location of the obstruction and nature of the obstruction followed by a thoughtful management approach based on findings. Difficult anatomy, hemorrhage, dense secretions, inflammation, and bulky tumor mass can significantly complicate the task of clearing the airway. Obstruction of the central airways by malignant tumor is associated with poor prognosis, but quality of life is considerably improved by restoration of adequate central airways. For both the patient and the clinician, the presentation can be frightening, and advanced interventional pulmonary/endobronchial techniques are required to achieve prompt relief of symptoms. The alleviation of central airway obstruction by tumor is most often palliative, with improvement of quality of life the primary goal rather than cure. This review will cover covers an approach to the patient with airway obstruction that results from malignancy involving the trachea or proximal bronchial tree and affecting gas exchange.

Benign thoracic disease in the elderly.

The spectrum of benign thoracic disease in the elderly includes structural abnormalities, infectious disease and their complications, benign neoplastic growths, and autoimmune disease. Differences in physiologic reserve in this population make diagnosis difficult, as elderly patients may not present in the classic fashion, as well as complicate treatment. Benign thoracic disease in the elderly can pose a challenging clinical problem. Older patients with comorbid diseases may have poor tolerance of unnecessary surgical interventions. However, benign disorders of the chest associated with symptoms attributable to effusion or obstruction of airways can limit quality of life. Minimally invasive techniques (eg, video-assisted thoracoscopic surgery) can limit the morbidity associated with intervention. Additionally, prompt intervention may spare the patient more invasive treatments. For example, early effusions can be managed with simple drainage rather than thoracotomy and decortication. With respect to suspected benign thoracic lesions in the elderly, guiding principles for management include avoiding unnecessary interventions while not overlooking potential malignancies. Close surveillance of progressive symptoms, ensuring no radiographic change in the size of the lesion over 2 years, and use of positron-emission tomography remain the diagnostic keys to accurate management.

Palliation of thoracic malignancies.

The sequelae of advanced malignancies of the chest, whether primary or metastatic, can be severely debilitating. In this review, we discuss the advances in palliative treatment for several intrathoracic complications of malignancy. The treatment of malignant pleural and pericardial effusions now includes a range of chemical sclerosants and percutaneous or surgical interventions. A new generation of promising stent and ablation technologies allows for the treatment of intrinsic or extrinsic airway obstruction. Similar techniques are being explored for esophageal obstruction, while the possible benefit of palliative radiation and chemotherapy continues to be investigated. Although their symptoms are often severe, patients with advanced thoracic malignancies have a growing number and variety of palliative treatment options to improve their quality of life.

Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation.

OBJECTIVES: The association between gastroesophageal reflux disease and idiopathic pulmonary fibrosis has not been fully characterized. The aims of this study were to determine in patients with idiopathic pulmonary fibrosis (1) the prevalence of reflux symptoms, (2) the esophageal manometric profile, and (3) the prevalence of proximal and distal esophageal reflux. METHODS: Between May 1999 and March 2006, 30 patients with idiopathic pulmonary fibrosis were referred to the Swallowing Center at the University of California San Francisco. Each patient underwent a structured symptom assessment, esophageal manometry, and 24-hour dual sensor ambulatory pH monitoring. RESULTS: Twenty (67%) patients had abnormal esophageal reflux. Typical reflux symptoms, although more common in those with reflux, were not reliable as a screening test (sensitivity 65%, specificity 71%). Sixty-five percent of patients with abnormal reflux had a hypotensive lower esophageal sphincter. Abnormal esophageal peristalsis was more common among those with reflux (50% vs 10%; P = .03). In 9 (30%) patients, acid refluxed into the proximal esophagus for over 1% of the study time. CONCLUSIONS: A majority of patients with idiopathic pulmonary fibrosis have pathologic reflux. Symptoms do not distinguish between those with and without reflux. In these patients, reflux is associated with a hypotensive lower esophageal sphincter and abnormal esophageal peristalsis, and often extends into the proximal esophagus.

Oklahoma prosthesis: resection of tumor of clavicle and chest wall reconstructed with a custom composite graft.

Tumors involving the clavicle by primary or metastatic growth may require clavicular resection often with rib resection. The resulting cosmetic and functional impairment of clavicular resection may be significant with a sloped appearing shoulder girdle and chronically impaired movement of the upper extremity. We report a 48-year-old woman presenting with a bulky metastatic renal cell mass of her left clavicle extending to the chest wall. We report en-bloc clavilculectomy and chest wall resection with a novel method of reconstruction using a single methyl methacrylate and prolene composite prosthesis in a configuration resembling the state of Oklahoma.

Stem cell activity of porcine c-kit+ hematopoietic cells.

OBJECTIVE: A marker for hematopoietic stem cells (HSCs) of pigs, which are considered to be the most suitable donors for clinical xenotransplantation, has not yet been identified. In this study, we examined the HSC activity of porcine c-kit+ bone marrow cells (BMCs). METHODS: The HSC activity of porcine c-kit+ BMCs was evaluated both in vitro using colony-forming unit (CFU) and cobblestone area-forming cell (CAFC) assays and in vivo in nonobese diabetic/severe combined immunodeficiency transgenic (NOD/SCID-Tg) mice carrying porcine cytokine transgenes. RESULTS: Purified c-kit+ BMCs were substantially enriched for both CFUs and CAFCs in vitro and their transplantation led to long-term porcine hematopoiesis in vivo in mice. Although porcine chimerism was detectable in the peripheral blood of NOD/SCID-Tg mice receiving porcine c-kit- BMCs at early time points after transplantation, the levels were markedly lower than those in mice receiving purified c-kit+ BMCs (0.2%+/-0.14% vs 7.7%+/-1.6% and 0.17%+/-0.17% vs 5.6%+/-2.1% at weeks 3 and 6, respectively). Importantly, all mouse recipients of porcine c-kit+ BMCs showed durable multilineage chimerism (>19 weeks), whereas no recipients of porcine c-kit- BMCs sustained long-term engraftment. Moreover, porcine HSCs that had engrafted for 19 weeks in the recipients of porcine c-kit+ BMCs gave rise to clonogenic progenitors in vitro and reconstituted porcine hematopoiesis in secondary recipients. CONCLUSION: The present study demonstrates that c-kit is an essential marker of both long-term-repopulating HSCs and progenitor cells with early engraftment capacity.

Porcine mononuclear cells adhere to human fibronectin independently of very late antigen-5: implications for donor-specific tolerance induction in xenotransplantation.

To combat the shortage of donor organs, transplantation across species barriers has been proposed. Induction of tolerance would overcome the substantial immunologic barriers to xenotransplantation and would avoid the chronic use of immunosuppressive agents. Successful transplantation of hematopoietic cells induces robust specific tolerance to donor antigens in allogeneic and xenogeneic models. The beta1 integrin class of adhesion molecules and their interactions with extracellular matrix components are thought to be integral to the engraftment and maturation of hematopoietic stem cells. We therefore examined the efficacy of porcine very late antigen-5 (VLA-5) and VLA-4 interactions with the human extracellular matrix (ECM) protein, fibronectin. Peripheral blood mononuclear cells (PBMCs) from humans and miniature swine were flourochrome labeled and adhesion to plates coated with whole human fibronectin (whFN) or its 120 KDa fragment containing the VLA-5 binding region was determined. Flow cytometry and immuno- precipitation were used to identify a monoclonal antibody that cross-reacted on porcine VLA-5. Human and pig PBMC adhesion to human fibronectin (hFN) or 120 kDa fragment-coated plates was assessed following incubation with control ab, anti-VLA-4, anti-VLA-5, or soluble fibronectin. Using rabbit complement, cells expressing VLA-5 were purged from PBMC preparations before performing the adhesion assay. Porcine and human PBMC both adhered to hFN in a divalent cation-dependent and activation-dependent manner. Adhesion to hFN of human but not pig PBMC was blocked by anti-VLA-5 monoclonal antibody SAM-1, although this mAb immunoprecipitated a heterodimeric cell surface molecule (155/135 kDa) resembling VLA-5 from pig PBMC. Complement-mediated depletion of VLA-5-expressing cells ablated specific binding of human but not porcine cells to hFN and its 120 kDa fragment. Addition of soluble fibronectin was capable of blocking adhesion of PBMC of both species to hFN. Anti-VLA-4 reduced the binding of PBMC from both species to hFN to a similar extent. Human and pig cells can specifically adhere to hFN and its 120 kDa fragment, suggesting that this critical cell-ECM interaction is preserved across species. While human cells exclusively use VLA-5 for binding to the 120 kDa fragment, porcine cells could not be shown to adhere to whFN or its 120 kDa fragment via VLA-5. However, porcine VLA-4 is capable of mediating adhesion to human FN. We conclude that disparities in the adhesive interactions of beta1 integrins may be a barrier to the use of porcine hematopoietic stem cell transplantation as a means of inducing donor-specific tolerance in the pig to human species combination.