Playing Hide-and-Seek in Beta-Globin Genes: Gene Conversion Transferring a Beneficial Mutation between Differentially Expressed Gene Duplicates.

Increasing evidence suggests that adaptation to diverse environments often involves selection on existing variation rather than new mutations. A previous study identified a nonsynonymous single nucleotide polymorphism (SNP) in exon 2 of two paralogous ß-globin genes of the bank vole (Clethrionomys glareolus) in Britain in which the ancestral serine (Ser) and the derived cysteine (Cys) allele represent geographically partitioned functional variation affecting the erythrocyte antioxidative capacity. Here we studied the geographical pattern of the two-locus Ser/Cys polymorphism throughout Europe and tested for the geographic correlation between environmental variables and allele frequency, expected if the polymorphism was under spatially heterogeneous environment-related selection. Although bank vole population history clearly is important in shaping the dispersal of the oxidative stress protective Cys allele, analyses correcting for population structure suggest the Europe-wide pattern is affected by geographical variation in environmental conditions. The ß-globin phenotype is encoded by the major paralog HBB-T1 but we found evidence of bidirectional gene conversion of exon 2 with the low-expression paralog HBB-T2. Our data support the model where gene conversion reshuffling genotypes between high- and low- expressed paralogs enables tuning of erythrocyte thiol levels, which may help maintain intracellular redox balance under fluctuating environmental conditions. Therefore, our study suggests a possible role for gene conversion between differentially expressed gene duplicates as a mechanism of physiological adaptation of populations to new or changing environments.

Computed Tomography Screening for Lung Cancer: Mediastinal Lymph Node Resection in Stage IA Nonsmall Cell Lung Cancer Manifesting as Subsolid and Solid Nodules.

OBJECTIVE: To compare long-term survival rates of patients with first, primary, clinical stage IA nonsmall cell lung cancer from a large cohort undergoing computed tomography screening with and without mediastinal lymph node resection (MLNR) under an Institutional Review Board-approved common protocol from 1992 to 2014. BACKGROUND: Assessing survival differences of patients with and without MLNR manifesting as solid and subsolid nodules. METHODS: Long-term Kaplan-Meier (K-M) survival rates for those with and without MLNR were compared and Cox regression analyses were used to adjust for demographic, computed tomography, and surgical covariates. RESULTS: The long-term K-M rates for 462 with and 145 without MLNR was 92% versus 96% (P = 0.19), respectively. For 203 patients with a subsolid nodule, 151 with and 52 without MLNR, the rate was 100%. For the 404 patients with a solid nodule, 311 with and 93 without MLNR, the rate was 87% versus 94% (P = 0.24) and Cox regression showed no statistically significant difference (P = 0.28) when adjusted for all covariates. Risk of dying increased significantly with increasing decades of age (hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.4-3.8), centrally located tumor (HR 2.5, 95% CI 1.2-5.2), tumor size 21 to 30 mm (HR 2.7, 95% CI 1.2-6.0), and invasion beyond the lung stroma (HR 3.0, 95% CI 1.4-6.1). For the 346 patients with MLNR, tumor size was 20 mm or less; K-M rates for the 269 patients with and 169 patients without MLNR were also not significantly different (HR 2.1, P = 0.24). CONCLUSIONS: It is not mandatory to perform MLNR when screen-diagnosed nonsmall cell lung cancer manifests as a subsolid nodule.

Sublobar resection is equivalent to lobectomy for clinical stage 1A lung cancer in solid nodules.

OBJECTIVES: A single randomized trial established lobectomy as the standard of care for the surgical treatment of early-stage non-small cell lung cancer. Recent advances in imaging/staging modalities and detection of smaller tumors have once again rekindled interest in sublobar resection for early-stage disease. The objective of this study was to compare lung cancer survival in patients with non-small cell lung cancer with a diameter of 30 mm or less with clinical stage 1 disease who underwent lobectomy or sublobar resection. METHODS: We identified 347 patients diagnosed with lung cancer who underwent lobectomy (n = 294) or sublobar resection (n = 53) for non-small cell lung cancer manifesting as a solid nodule in the International Early Lung Cancer Action Program from 1993 to 2011. Differences in the distribution of the presurgical covariates between sublobar resection and lobectomy were assessed using unadjusted P values determined by logistic regression analysis. Propensity scoring was performed using the same covariates. Differences in the distribution of the same covariates between sublobar resection and lobectomy were assessed using adjusted P values determined by logistic regression analysis with adjustment for the propensity scores. Lung cancer-specific survival was determined by the Kaplan-Meier method. Cox survival regression analysis was used to compare sublobar resection with lobectomy, adjusted for the propensity scores, surgical, and pathology findings, when adjusted and stratified by propensity quintiles. RESULTS: Among 347 patients, 10-year Kaplan-Meier for 53 patients treated by sublobar resection compared with 294 patients treated by lobectomy was 85% (95% confidence interval, 80-91) versus 86% (confidence interval, 75-96) (P = .86). Cox survival analysis showed no significant difference between sublobar resection and lobectomy when adjusted for propensity scores or when using propensity quintiles (P = .62 and P = .79, respectively). For those with cancers 20 mm or less in diameter, the 10-year rates were 88% (95% confidence interval, 82-93) versus 84% (95% confidence interval, 73-96) (P = .45), and Cox survival analysis showed no significant difference between sublobar resection and lobectomy using either approach (P = .42 and P = .52, respectively). CONCLUSIONS: Sublobar resection and lobectomy have equivalent survival for patients with clinical stage IA non-small cell lung cancer in the context of computed tomography screening for lung cancer.

Balancing curability and unnecessary surgery in the context of computed tomography screening for lung cancer.

OBJECTIVE: Surgical management is a critical component of computed tomography (CT) screening for lung cancer. We report the results for US sites in a large ongoing screening program, the International Early Lung Cancer Action Program (I-ELCAP). METHODS: We identified all patients who underwent surgical resection. We compared the results before (1993-2005) and after (2006-2011) termination of the National Lung Screening Trial to identify emerging trends. RESULTS: Among 31,646 baseline and 37,861 annual repeat CT screenings, 492 patients underwent surgical resection; 437 (89%) were diagnosed with lung cancer; 396 (91%) had clinical stage I disease. In the 54 (11%) patients with nonmalignant disease, resection was sublobar in 48 and lobectomy in 6. The estimated cure rate based on the 15-year Kaplan-Meier survival for all 428 patients (excluding 9 typical carcinoids) with lung cancer was 84% (95% confidence interval [CI], 80%-88%) and 88% (95% CI, 83%-92%) for clinical stage I disease resected within 1 month of diagnosis. Video-assisted thoracoscopic surgery and sublobar resection increased significantly, from 10% to 34% (P < .0001) and 22% to 34% (P = .01) respectively; there were no significant differences in the percentage of malignant diagnoses (90% vs 87%, P = .36), clinical stage I (92% vs 89%, P = .33), pathologic stage I (85% vs 82%, P = .44), tumor size (P = .61), or cell type (P = .81). CONCLUSIONS: The frequency and extent of surgery for nonmalignant disease can be minimized in a CT screening program and provide a high cure rate for those diagnosed with lung cancer and undergoing surgical resection.

The role of minimal access surgery for metastasectomy and cytoreduction.

This article summarizes findings about the applicability of minimal-access techniques for thoracic and upper gastrointestinal cancers, including those affecting the lung, liver, stomach, and adrenal gland. If metastasectomy and cytoreductive surgery are rapidly evolving, minimal-access surgery in this setting is in its introductory stages. Nevertheless, minimal-access metastasectomy and cytoreductive surgery harbor great potential for selected patients, but further clinical studies are needed.

Resection of multifocal non-small cell lung cancer when the bronchioloalveolar subtype is involved.

OBJECTIVE: Bronchioloalveolar lung cancer is commonly multifocal and can also present with other non-small cell types. The staging and treatment of multifocal non-small cell cancer are controversial. We evaluated the current staging of multifocal bronchioloalveolar carcinoma and the therapeutic effectiveness of resection when this tumor type is involved. METHODS: We reviewed our experience between 1992 and 2000 with complete pulmonary resections for bronchioloalveolar carcinoma. Kaplan-Meier survival curves were calculated from the dates of pulmonary resection. RESULTS: Among 73 patients with bronchioloalveolar carcinoma, 14 patients, 7 male and 7 female with a mean age of 65 years (51-87 years), had multifocal lesions without lymph node metastases. Follow-up was 100% for a median of 5 years (range 2.6-8.5 years). Tumor distribution was unilateral in 9 patients and bilateral in 5 patients. The multifocal nature of the disease was discovered intraoperatively in 4 patients. Nine patients had 2 lesions, 4 patients had 3 lesions, and 1 patient had innumerable discrete foci in a single lobe. Operative mortality was 0. Postoperatively, 10 patients were staged pIIIB or pIV on the basis of multiple foci of similar morphology; 4 patients had some differences in histology (implying multiple stage 1 primaries). The median survival time to death from cancer was 14 months (141 days-5.6 years). The overall 5-year survival after resection of multifocal bronchioloalveolar carcinoma was 64%. Unilateral or bilateral distribution had no impact on survival. CONCLUSIONS: The current staging system is not prognostic for multifocal bronchioloalveolar carcinoma without lymph node metastases. Complete resection of multifocal non-small cell lung cancer when bronchioloalveolar carcinoma is a component may achieve survivals similar to that of stage I and II unifocal non-small cell lung cancer. When bronchioloalveolar carcinoma is believed to be one of the cell types in multifocal disease without lymph node metastases, consideration should be given to surgical resection.

Aggressive management of lung donors classified as unacceptable: excellent recipient survival one year after transplantation.

OBJECTIVE: A dire shortage of lungs for transplantation exists. We hypothesized that aggressive organ procurement organization management of lungs usually rated as unacceptable (ratio of Pao(2) to inspired oxygen fraction <150) might make them acceptable for transplantation. We also hypothesized that lungs from donors who died of trauma could be used for transplantation with recipient survival comparable with that seen with lungs from donors who died of nontraumatic causes. METHODS: From January, 1, 1995, through August 31, 2000, a total of 194 donors resulted in 228 lung transplants. Of these, 27 donors were deemed unacceptable for lung transplantation according to organ procurement organization protocol. We used the California Transplant Donor Network database to conduct a retrospective review of all 194 donors, including the 27 supposedly unacceptable donors who were treated with invasive monitoring (central venous pressure), methylprednisolone, fluid restriction, inotropic agents, bronchoscopy, and diuresis. We evaluated survivals at 30 days and 1 year of patients who received lungs rated as unacceptable and acceptable. In addition, we compiled data on recipient survival for a subgroup of 122 recipients with lungs from donors who died of trauma and compared these data with those of recipients who received lungs from donors who died of nontraumatic causes to see whether the donor's death by trauma resulted in higher recipient mortality. RESULTS: After aggressive organ procurement organization management, ratios of Pao(2) to inspired oxygen fraction, central venous pressures, fluid balances, dopamine requirements, and chest radiographs of unacceptable donors according to organ procurement organization criteria were comparable with those of acceptable donors. There were no significant differences in recipient mortality between groups at 30 days or 1 year after transplantation. Moreover, no significant difference was found in mortalities of recipients who received lungs from donors who died of traumatic and nontraumatic causes. CONCLUSION: Aggressive organ procurement organization management of donors initially considered unacceptable may increase the number of lungs available for transplantation.