Circulating cellular adhesion molecules and risk of diabetes: the Multi-Ethnic Study of Atherosclerosis (MESA).

AIMS: To test the hypothesis that soluble cellular adhesion molecules would be positively and independently associated with risk of diabetes. METHODS: Soluble levels of six cellular adhesion molecules (ICAM-1, E-selectin, VCAM-1, E-cadherin, L-selectin and P-selectin) were measured in participants in the Multi-Ethnic Study of Atherosclerosis, a prospective cohort study. Participants were then followed for up to 10 years to ascertain incident diabetes. RESULTS: Sample sizes ranged from 826 to 2185. After adjusting for age, sex, race/ethnicity, BMI and fasting glucose or HbA1c , four cellular adhesion molecules (ICAM-1, E-selectin, VCAM-1 and E-cadherin) were positively associated with incident diabetes and there was a statistically significant trend across quartiles. Comparing the incidence of diabetes in the highest and lowest quartiles of each cellular adhesion molecule, the magnitude of association was largest for E-selectin (hazard ratio 2.49; 95% CI 1.26-4.93) and ICAM-1 (hazard ratio 1.76; 95% CI 1.22-2.55) in fully adjusted models. Tests of effect modification by racial/ethnic group and sex were not statistically significant for any of the cellular adhesion molecules (P > 0.05). CONCLUSIONS: The finding of significant associations between multiple cellular adhesion molecules and incident diabetes may lend further support to the hypothesis that microvascular endothelial dysfunction contributes to risk of diabetes.

Accuracy of self-reported tobacco use status among hematopoietic SCT patients.

Tobacco use is a risk factor for adverse outcomes among hematopoietic SCT (HSCT) patients. Accurate identification of tobacco use offers a vital opportunity to treat this risk factor. The current study compared self-reported tobacco use status with serum cotinine levels among HSCT patients at the time of pre-transplant evaluation. A total of 444 participants completed both assessments; 44 participants (9.9%) were classified as tobacco users with serum cotinine concentrations >2 ng/mL vs 29 with self-reporting. Sensitivity and specificity of self-reporting were 65.9% and 100%, respectively. Positive and negative predictive values were 100% and 96.4%, respectively. Comparing tobacco use documented in the medical record with cotinine, sensitivity and specificity were 51.2% and 99.2%, respectively. Factors associated with tobacco use were male gender, single relationship status, less education and younger age. In summary, utilization of serum cotinine assays increased detection of tobacco use cases >50% over self-reporting. Results are discussed in the context of translation to care, including clinical and ethical implications, and current tobacco use treatment guidelines. When cotinine assays are not available, self-reporting of any tobacco use in the year before HSCT should trigger brief advice and cessation or relapse prevention counseling.

Phase II study of neoadjuvant therapy with docetaxel, cisplatin, panitumumab, and radiation therapy followed by surgery in patients with locally advanced adenocarcinoma of the distal esophagus (ACOSOG Z4051).

BACKGROUND: Preoperative chemoradiotherapy (CRT) improves outcomes in patients with locally advanced but resectable adenocarcinoma of the esophagus. ACOSOG Z4051 evaluated CRT with docetaxel, cisplatin, and panitumumab (DCP) in this patient group with a primary end point of a pathologic complete response (pCR) ≥35%. PATIENTS AND METHODS: From 15 January 2009 to 22 July 2011, 70 patients with locally advanced but resectable distal esophageal adenocarcinoma were enrolled. Patients received docetaxel (40 mg/m(2)), cisplatin (40 mg/m(2)), and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, and 9 with RT (5040 cGy, 180 cGy/day × 28 days) beginning week 5. Resection was planned after completing CRT. PCR was defined as no viable residual tumor cells. Secondary objectives included near-pCR (≤10% viable cancer cells), toxicity, and overall and disease-free survival. Adverse events were graded using the CTCAE Version 3.0. RESULTS: Five of 70 patients were ineligible. Of 65 eligible patients (59 M; median age 61), 11 did not undergo surgery, leaving 54 assessable. PCR rate was 33.3% and near-pCR was 20.4%. Secenty-three percent of patients completed DCP (n = 70) and 92% completed RT. 48.5% had toxicity ≥grade 4. Lymphopenia (43%) was most common. Operative mortality was 3.7%. Adult respiratory distress syndrome was encountered in two patients (3.7%). At median follow-up of 26.3 months, median overall survival was 19.4 months and 3-year overall survival was 38.6% (95% confidence interval 24.5% to 60.8%). CONCLUSIONS: Neoadjuvant CRT with DCP is active (pCR + near-pCR = 53.7%) but toxicity is significant. Further evaluation of this regimen in an unselected population is not recommended. CLINICALTRIALSGOV IDENTIFIER: NCT00757172.

The effect of anticoagulant therapy for idiopathic pulmonary fibrosis in real life practice.

BACKGROUND: IPF is a common form of interstitial lung disease for which there is no effective therapy and usually results in death. Two previous contradictory studies showed anticoagulant therapy  to be associated with both improved and worsened survival, respectively. OBJECTIVE: The objective of this retrospective cohort study was to evaluate the effect of anticoagulant therapy on the survival and disease progression of patients with idiopathic pulmonary fibrosis (IPF) in real clinical practice. METHODS: We compared the clinical characteristics, time to disease progression, incidence of acute exacerbation, and survival of 25 (20%) IPF patients receiving anticoagulant therapy to the remaining 97 IPF patients not receiving anticoagulant therapy. In addition we conducted a sensitivity analysis using as comparator a group of 25 patients matched by age, sex, functional impairment, cardiac comorbidities and pulmonary hypertension. RESULTS: Patients on anticoagulant therapy had a worse 1- and 3-year survival (84% and 53% versus 89% and 64% in the non-anticoagulant group, respectively), a difference that persisted after adjusting for age and comorbidities (hazard ratio 3.1 - 95% confidence interval, 1.4 to 7.0; p=0.006) and after comparison with the matched group (adjusted HR=4.8, 95% CI: 1.8-12.8; p=0.002). IPF patients on anticoagulant therapy had a shorter interval to disease progression ( 0.7 years versus 1.6 years, adjusted HR 2.2 -95% CI, 0.96 to 5.1; p=0.063) confirmed also in the analysis with matched subgroups (HR=2.7 (95% CI: 1.2-6.5); p=0.023). The incidence of acute exacerbations did not differ in the two groups (22% versus 23%). Two patients (8%) experienced anticoagulant treatment related complications and included an episode of hemorrhagic shock. CONCLUSION: In this retrospective study patients treated with anticoagulants had a worse survival and a shorter interval to disease progression. This support the recent finding that warfarin worsen the respiratory status and survival of IPF patients.

Transformation of low grade glioma and correlation with outcome: an NCCTG database analysis.

Glioblastomas (GBM) may originate de novo (primary), or following transformation from a lower grade glioma (secondary), and it has been postulated that these tumors may have different biological behaviors. We performed a correlative analysis involving 204 patients with glioma treated prospectively on NCCTG clinical trials. Central pathology review of tumor tissues taken at the time of initial diagnosis and at recurrence were performed in all patients. Tumors progressed from low (WHO grade 2) to high (grade 3-4) at recurrence in 45% low grade oligodendroglioma patients, in 70% with low grade oligoastrocytoma, and 74% with low grade astrocytoma (P = 0.031). Median overall survival (OS) from initial diagnosis varied by histology: oligodendroglioma, 8.8 years; (95% CI 5.7-10.2); oligoastrocytoma, 4.4 years (95% CI 3.5-5.6); astrocytoma grade 2 3.1 years (astrocytoma grade 2-4, 2.1 years) (95% CI 1.7-2.5, P < 0.001). Mean time to recurrence (TTR) also varied between patients with de novo GBM, those secondary GBM, and those that remained non-GBM at recurrence (1.1 ± 1.1 vs. 2.9 ± 1.8 vs. 4.0 ± 2.9 years, respectively, P < 0.001). Median OS from time of recurrence also varied between these three categories (0.7 years, 95% CI: 0.5-1.1 vs. 0.6 years, CI: 0.5-1.0 vs. 1.4 years, 95% CI: 1.1-2.0, respectively) (P < 0.001). At time of relapse, transformation to higher grade is frequent in low grade pure and mixed astrocytomas, but is observed in less than half of those with low grade oligodendroglioma. From time of recurrence, OS was not significantly different for those with primary versus secondary GBM, and it may thus be reasonable include patients with secondary GBM in clinical therapeutic trials for recurrent disease.

The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia.

A paucity of research exists examining the potential impact of tobacco use on cancer treatment outcomes, especially among patients treated with hematopoietic SCT (HSCT). A retrospective cohort study design was used to examine the impact of smoking on duration of hospitalization and overall survival among 148 consecutive patients undergoing HSCT for treatment of acute leukemia from 1999 to 2005. Of the 148 patients, 15% reported current smoking, 30% former smoking, and 55% never used tobacco. Patients were followed for a median 3.5 years (interquartile range=2.1-5.5). Compared to no history of smoking, current smoking was associated with worse pre-HSCT pulmonary function tests (P<0.02 in each case), more days hospitalization (46.2 days versus 25.7 days, P=0.025), and poorer overall survival (hazard ratio (HR)=1.88; 95% CI 1.09-3.25). Results were similar after multivariate adjustment, although the association with overall survival attenuated slightly (HR=1.75; 95% CI 1.00-3.06). Current smoking appears to adversely affect the number of days hospitalized post HSCT and overall survival. Translational research focused on interventions to promote tobacco cessation may lead to improved HSCT outcomes.

Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5-fluorouracil, and interferon-alfa-2b-based chemoradiation: ACOSOG Trial Z05031.

BACKGROUND: The American College of Surgeons Oncology Group sought to confirm the efficacy of a novel interferon-based chemoradiation regimen in a multicenter phase II trial. PATIENTS AND METHODS: Patients with resected (R0/R1) adenocarcinoma of the pancreatic head were treated with adjuvant interferon-alfa-2b (3 million units s.c. on days 1, 3, and 5 of each week for 5.5 weeks), cisplatin (30 mg/m(2) i.v. weekly for 6 weeks), and continuous infusion 5-fluorouracil (5-FU; 175 mg·m(2)/day for 38 days) concurrently with external-beam radiation (50.4 Gy). Chemoradiation was followed by two 6-week courses of continuous infusion 5-FU (200 mg·m(2)/day). The primary study end point was 18-month overall survival from protocol enrollment (OS18); an OS18 ≥65% was considered a positive study outcome. RESULTS: Eighty-nine patients were enrolled. Eighty-four patients were assessable for toxicity. The all-cause grade ≥3 toxicity rate was 95% (80 patients) during therapy. No long-term toxicity or toxicity-related deaths were noted. At 36-month median follow-up, the OS18 was 69% [95% confidence interval (CI) 60% to 80%]; the median disease-free survival and overall survival were 14.1 months (95% CI 11.0-20.1 months) and 25.4 months (95% CI 23.4-34.1 months), respectively. CONCLUSIONS: Notwithstanding promising multi-institutional efficacy results, further development of this regimen will require additional modifications to mitigate toxic effects.

Haemosiderin-laden macrophages in the bronchoalveolar lavage fluid of patients with diffuse alveolar damage.

Quantification of haemosiderin-laden macrophages in bronchoalveolar lavage fluid (BALF) has been used to diagnose diffuse alveolar haemorrhage (DAH) but has not been assessed in patients with diffuse alveolar damage (DAD). The present study analysed BALF obtained from 21 patients with DAD diagnosed by surgical lung biopsy. The median age of 21 patients with DAD was 68 yrs (range 18-79 yrs); 14 (67%) were male and 12 (57%) were immunocompromised. The median proportion of haemosiderin-laden macrophages in BALF was 5% (range 0-90%), but was >or=20% in seven (33%) patients, fulfilling the commonly used BALF criterion for DAH. There was a trend toward a positive correlation between the percentage of haemosiderin-laden macrophages in BALF and parenchymal haemorrhage assessed semiquantitatively by histopathological analysis. Patients with >or=20% haemosiderin-laden macrophages in BALF showed a significantly increased mortality rate (p = 0.047) compared to those with <20%. In patients with an acute onset of diffuse lung infiltrates and respiratory distress, >or=20% haemosiderin-laden macrophages in BALF can occur with DAD, and is not necessarily diagnostic of DAH. The finding of >or=20% haemosiderin-laden macrophages in BALF is associated with a worse prognosis in patients with DAD.

L-DOPA biotransformation: correlations of dosage, erythrocyte catechol O-methyltransferase and platelet SULT1A3 activities with metabolic pathways in Parkinsonian patients.

The objectives of this study were to determine (1) the effects of dose and drug absorption on pathways of biotransformation of L-DOPA in Parkinsonian patients treated with Sinemet, and (2) the extent to which genetically-determined variations in the activities of erythrocyte catechol O-methyltransferase and/or platelet phenol sulfotransferase might be reflected in individual differences in L-DOPA metabolism. In the 19 patients studied, there were negative correlations between dosage or absorption and extent of O-methylation and of sulfation of L-DOPA or its metabolites. Levels of activity for erythrocyte COMT were also reflected in individual variation in the metabolism of L-DOPA. In contrast, differences in platelet phenol sulfotransferase were not reflected in differences in sulfation of L-DOPA or of its metabolites. If such a relationship did exist, it might have been obscured by the effects of high dosage of L-DOPA, effects which might have resulted from a deficiency of the sulfation cosubstrate 3'-phosphoadenosine 5'-phosphosulfate in patients taking higher doses of drug.

Critical appraisal of the application of carotid duplex scanning.

AIMS: To evaluate the indications for carotid arterial imaging in an open access vascular laboratory. To identify those symptoms predictive of > 50% stenosis of the carotid artery in order to reduce unnecessary imaging. To test the hypothesis that duplex scanning would not be of significant benefit in the management of those patients with ill defined symptoms. METHODS: We compared the outcome of carotid duplex scanning performed on 816 consecutive patients referred for a variety of clinical indications. The medical records of 816 patients were retrospectively analysed to identify the clinical indication for carotid duplex imaging over a three-year period (1997-9). RESULTS: The indications for duplex imaging were divided into two groups: definite carotid symptoms, n=350 (transient ischaemic attack n=205, cerebrovascular accident n=66, amaurosis fugax n=49, dysphasia n=30); and non-carotid symptoms, n=466 (dizziness n=63, syncope n=63, confusion n=20, vertigo n=10 and others n=310). Less than 5% of those with definite carotid symptoms and 2% of those with ill-defined symptoms had a stenosis > 80%. CONCLUSION: Regardless of symptoms, 14% and 2.9% of patients referred for carotid duplex imaging have a stenosis of > or = 50% and > or = 80%, respectively. Patients without definite carotid symptoms are of low priority for duplex imaging.

Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung.

BACKGROUND: The majority of lung carcinoma cases occur in current or former smokers. K-ras gene mutations are common in lung adenocarcinoma and have been associated with cigarette smoking, asbestos exposure, and female gender. METHODS: In the current study, the authors examined the contribution of cigarette smoking to K-ras gene mutations in patients with primary lung adenocarcinoma. Smoking histories were obtained from 106 prospectively enrolled patients with primary adenocarcinoma of the lung. RESULTS: K-ras mutations were detected in the primary tumor using an allele-specific ligation assay. Ninety-two of the 106 patients (87%) with lung adenocarcinoma were smokers. Nonsmokers with this tumor were more likely to be women (11 of 14; 79%), whereas the majority of smokers (57%) were men. K-ras mutations were detected in 40 of 106 tumors (38%) and were significantly more common in smokers compared with nonsmokers (43% vs. 0%; P = 0.001). CONCLUSIONS: The results of the current study confirm and extend previous observations that smokers with adenocarcinoma of the lung are more likely to have K-ras mutant tumors compared with nonsmokers. The strong link between cigarette smoking and K-ras mutations in adenocarcinoma of the lung supports the role of specific tobacco carcinogens in the etiology of this malignancy.

Polymyositis-dermatomyositis-associated interstitial lung disease.

We report findings in 70 patients with both diffuse interstitial lung disease and either polymyositis (PM) or dermatomyositis (DM). Initial presentations were most commonly either musculoskeletal (arthralgias, myalgias, and weakness) or pulmonary (cough, dyspnea, and fever) symptoms alone; in only 15 patients (21.4%) did both occur simultaneously. Pulmonary disease usually took the form of acute to subacute antibiotic-resistant community-acquired pneumonia. Chest radiographs and computed tomography most commonly demonstrated bilateral irregular linear opacities involving the lung bases; occasionally consolidation was present. Jo-1 antibody was present in 19 (38%) of 50 patients tested. Synchronous associated malignancy was present in 4 of 70 patients (5.7%). Surgical lung biopsies disclosed nonspecific interstitial pneumonia (NSIP) in 18 of 22 patients (81.8%), organizing diffuse alveolar damage (DAD) in 2, bronchiolitis obliterans organizing pneumonia (BOOP) in 1, and usual interstitial pneumonia (UIP) in 1. Treatment usually included prednisone in 40-60 mg/d dosages for initial control, followed by lower dose prednisone plus an immunosuppressive agent such as azathioprine or methotrexate for disease suppression. Survival was significantly better than that observed for historical control subjects with idiopathic UIP, and was more consistent with survival previously reported in idiopathic NSIP. There was no difference in survival between Jo-1 positive and Jo-1 negative groups.

Subtotal parathyroidectomy in renal failure: still needed after all these years.

There are scant data on the frequency of parathyroidectomy (PTX) for end-stage renal disease (ESRD). Medical therapy for ESRD and secondary hyperparathyroidism has evolved to include better dialytic urea removal and the use of calcitriol. The aim of this study was to determine whether medical therapy has changed the frequency or indications for PTX in the management of renal failure. Hospital and clinic records were analyzed to gather information on all patients undergoing PTX for secondary hyperparathyroidism (2HPT) (n = 48) and tertiary hyperparathyroidism (3HPT) (n = 26) from 1986 through 1998 at our institution. Prospective computer databases were queried for information concerning both chronic dialysis and renal transplant patients at our center. The patients were divided based on date of operation before or after 1991, a divider that separated the patients into groups before or after the widespread adoption of intravenous calcitriol treatment during hemodialysis at our institution. Over the 12 year period, the proportion of our chronic dialysis patients undergoing PTX did not change significantly, ranging from 0% to 2.5% per year. Comparing all patients undergoing PTX for 2HPT during 1986-1991 versus 1992-1998, there was no significant difference in time on dialysis [7.0 +/- 4.2 (n = 11) vs. 7.5 +/- 4.6 (n = 36) years, mean +/- SD]. The later group had higher intact parathyroid hormone (iPTH) levels [765 +/- 415 (n = 6) vs. 1377 +/- 636 (n = 28) pg/ml; p = 0.03], lower serum calcium [11.2 +/- 1.0 (n = 12) vs. 9.9 +/- 1.5 (n = 34) mg/dl; p = 0.006], and higher serum phosphate [5.7 +/- 1.6 (n = 12) vs. 7.2 +/- 2.3 (n = 31) mg/dl; p = 0.042]. Among the population of patients with transplants undergoing PTX for 3HPT, the average percent per year undergoing PTX ranged from 0% to 4.2% and did not change during the study period. Comparing the 1986-1991 group to the 1992-1998 group, the time from transplantation to PTX did not change during the study period (3.3 +/- 2.3 vs. 2.9 +/- 3.0 years; p = 0.391), and there were no significant differences between preoperative calcium levels or iPTH levels. Despite advances in dialysis technique and pharmacologic therapy, there has been no change in the proportion of dialysis patients requiring PTX for 2HPT or 3HPT. There was also no change in the time on dialysis for patients with 2HPT or the time from transplant to PTX for patients with 3HPT. Analysis of preoperative biochemical markers as evidence of disease severity suggests there was no change in indications for PTX during our study. From this information we conclude that parathyroid pathophysiology is incompletely understood and medical therapy is not optimal, resulting in a continuing need for PTX in some patients.

Increased loss of chromosome 9p21 but not p16 inactivation in primary non-small cell lung cancer from smokers.

Epidemiological studies have demonstrated a causal association between tobacco use and carcinoma of the lung, and some genetic targets of the carcinogens in cigarette smoke have been defined recently. We further examined the effect of cigarette smoking on the frequency of allelic losses on chromosome 9p21 and the incidence of p16 inactivation. Chromosomal loss at 9p21-24 was determined by microsatellite analysis using 14 markers in 47 patients with non-small cell lung cancer. In addition, p16 gene inactivation was determined by DNA sequence analysis, methylation-specific PCR, and immunohistochemistry. Tumors from a group of nonsmokers (n = 14) were compared with tumors from a group of smokers (n = 33) matched for cell type, tumor stage, and gender. Allelic loss encompassing the p16 locus was present significantly (P = 0.01) more often in smokers (23 of 33 smokers, 70%) than in nonsmokers (4 of 14 nonsmokers, 28%). No significant differences in the frequency of p16 inactivation were observed between smokers and nonsmokers (45% versus 36%). However, homozygous deletion of the p16 gene locus and point mutation of p16 gene were only observed in tumors from smokers, whereas the p16 gene was inactivated in tumors from nonsmokers only through promoter hypermethylation. Thus, inactivation of the p16 gene is a common event in all non-small cell lung cancer, but the mechanism of gene alteration differs between smokers and nonsmokers. The significant link between tobacco and loss of the p16 locus identifies additional genetic targets of smoking in the pathogenesis of lung cancer.

Microsatellite instability at selected tetranucleotide repeats is associated with p53 mutations in non-small cell lung cancer.

Microsatellite alterations are useful clonal markers for the early detection of cancer. An increase in microsatellite instability has been observed at certain tetranucleotide repeat markers (AAAGn) in lung, head and neck, and bladder cancer. However, the genetic mechanism underlying these elevated microsatellite alterations at selected tetranucleotide repeat (EMAST) tumors is still unknown. The p53 gene plays an important role in maintaining genome integrity by repairing damaged DNA. Therefore, we tested 88 non-small cell lung cancers with a panel of 13 microsatellite markers previously shown to exhibit frequent instability and also performed p53 sequence analysis in these tumors. Thirty-one of these 88 cancers (35%) demonstrated a novel allele [EMAST(+)] in > or =1 of these 13 microsatellite markers. p53 mutations were detected in 50 of 88 (57%) cancers and were significantly (P = 0.001) more common in EMAST(+) tumors (25 of 31; 81%) than in EMAST(-) tumors (25 of 57; 44%). Among squamous cell cancers, p53 mutations were detected significantly (P = 0.04) more frequently in EMAST(+) tumors (17 of 19; 89%) than in EMAST(-) tumors (10 of 18; 55%). Similarly, among primary adenocarcinomas, p53 mutations were present in 67% of the EMAST(+) tumors and in 35% of EMAST(-) adenocarcinomas. None of the 31 EMAST(+) tumors demonstrated high frequency microsatellite instability when examined with a reference panel of five mono- and dinucleotide markers. Primary lung cancers with microsatellite alterations at selected tetranucleotide repeats have a high frequency of p53 mutations and do not display a phenotype consistent with defects in mismatch repair.

Iron deficiency diminishes gallbladder neuronal nitric oxide synthase.

BACKGROUND: Iron deficiency has been demonstrated in the prairie dog to result in cholesterol crystal formation and altered biliary motility. Gallbladder filling and emptying are influenced by both inhibitory and excitatory stimuli, with nitric oxide (NO) playing a key role in normal relaxation. Iron is a cofactor for nitric oxide synthase. Therefore, we tested the hypothesis that iron deficiency would result in diminished levels of gallbladder neuronal nitric oxide synthase (nNOS) but would not influence the gallbladder's response to excitatory stimuli. MATERIALS AND METHODS: Twenty adult female prairie dogs were fed either an iron-supplemented (Fe(+)) (200 ppm) control diet (n = 10) or an iron-deficient (Fe-) (8 ppm) diet (n = 10) for 8 weeks. Fasting gallbladder volume was measured. Gallbladder muscle strips were harvested for response to excitatory stimuli and measurement of nNOS protein levels by Western blotting. Muscle strip response to a spectrum of doses of cholecystokinin, acetylcholine, and electrical field stimuli was determined, and the areas under the response curves were calculated. RESULTS: Gallbladder volume increased in the iron-deficient prairie dogs compared with the iron-supplemented group (1.45 +/- 0.27 mL vs 0.80 +/- 0.13 mL, P < 0.05). Iron deficiency diminished the ratio of gallbladder nNOS to beta-actin protein levels (0.05 +/- 0.01 vs 3.48 +/- 1.02, P < 0.05) but resulted in a normal response to excitatory stimuli. CONCLUSIONS: We conclude that diminished gallbladder neuronal nitric oxide synthase contributes to the gallbladder stasis that occurs with iron deficiency. This phenomenon may contribute to the increased incidence of gallstones in premenopausal women.

Laparoscopic diagnosis and management of ovarian torsion in the newborn.

BACKGROUND AND OBJECTIVES: The application of laparoscopic techniques in the surgical management of neonatal ovarian cysts is proving valuable both as a diagnostic tool and a potential therapeutic intervention. We report the successful management of a prenatally diagnosed ovarian cyst in a newborn female and provide operative evidence for the presumptive etiology of the cyst. METHODS AND RESULTS: A prenatally diagnosed ovarian cyst was managed using 5 mm laparoscopic instruments in a newborn female. The prenatal ultrasonographic and operative findings are consistent with in utero adnexal torsion with subsequent autoamputation and cystic degeneration of the ovary. The orphaned ovarian cyst was removed from the infant's abdominal cavity by enlarging the camera port incision. DISCUSSION: The application of laparoendoscopic procedures in infants and children continues to evolve with the availability, of microinstrumentation and increasing experience among pediatric surgeons. This approach may prove valuable in the diagnosis and management of prenatally diagnosed ovarian cysts. In addition, further insight into the etiology of congenital ovarian cysts may be obtained. The safety and efficacy of this approach in these infants remains to be fully evaluated.

Molecular detection of tumor cells in bronchoalveolar lavage fluid from patients with early stage lung cancer.

BACKGROUND: Conventional cytologic analysis of sputum is an insensitive test for the diagnosis of non-small-cell lung cancer (NSCLC). We have recently demonstrated that polymerase chain reaction (PCR)-based molecular methods are more sensitive than cytologic analysis in diagnosing bladder cancer. In this study, we examined whether molecular assays could identify cancer cells in bronchoalveolar lavage (BAL) fluid. METHODS: Tumor-specific oncogene mutations, CpG-island methylation status, and microsatellite alterations in the DNA of cells in BAL fluid from 50 consecutive patients with resectable (stages I through IIIa) NSCLC were assessed by use of four PCR-based techniques. RESULTS: Of 50 tumors, 28 contained a p53 mutation, and the identical mutation was detected with a plaque hybridization assay in the BAL fluid of 39% (11 of 28) of the corresponding patients. Eight of 19 adenocarcinomas contained a K-ras mutation, and the identical mutation was detected with a mutation ligation assay in the BAL fluid of 50% (four of eight) of the corresponding patients. The p16 gene was methylated in 19 of 50 tumors, and methylated p16 alleles were detected in the BAL fluid of 63% (12 of 19) of the corresponding patients. Microsatellite instability in at least one marker was detected with a panel of 15 markers frequently altered in NSCLC in 23 of 50 tumors; the identical alteration was detected in the BAL fluid of 14% (three of 22) of the corresponding patients. When all four techniques were used, mutations or microsatellite instability was detected in the paired BAL fluid of 23 (53%) of the 43 patients with tumors carrying a genetic alteration. CONCLUSION: Although still limited by sensitivity, molecular diagnostic strategies can detect the presence of neoplastic cells in the proximal airway of patients with surgically resectable NSCLC.