L3 skeletal muscle index (L3SMI) is a surrogate marker of sarcopenia and frailty in non-small cell lung cancer patients.

Background: Non-small cell lung cancer (NSCLC) is a common and highly lethal disease. As advanced treatment modalities are being developed, improved prognostication methods are sought. L3 skeletal muscle index (L3SMI) and alanine aminotransferase (ALT) levels are accepted surrogate markers of sarcopenia and related frailty. We aimed to evaluate the potential association of these markers with NSCLC patients' survival. Methods: A retrospective, single-center study of an NSCLC patients' cohort. L3SMI was calculated based on skeletal muscle area on computed tomography scans at the level of the L3 vertebra. Clinical data were extracted from clinical charts. Results: A total of 140 patients (56.4% males, median age 66 [range 37-86]) were included in this study, 32% were diagnosed at stage 3 and 45% at stage 4. During the follow-up duration (median of 1.9 years; range 1 month to 6.4 years), 102 patients (72.8%) died. Patients' characteristics that were found to be associated with increased mortality were performance status, albumin and tumor stage at diagnosis. Sarcopenia, defined as low L3SMI (lower than 41 cm2/m2 for women and lower than 53 cm2/m2 for men) was significantly associated with higher risk of mortality compared with patients with normal L3SMI values (77.2%, vs 64.6%, p=0.013) in univariate analysis, but not in a multiple regression analysis. Conclusion: Low L3SMI could serve as a surrogate marker for sarcopenia and frailty and, as such, facilitate the prognostication process of NSCLC patients.

An antibody to amphiregulin, an abundant growth factor in patients' fluids, inhibits ovarian tumors.

Growth factors of the epidermal growth factor (EGF)/neuregulin family are involved in tumor progression and, accordingly, antibodies that intercept a cognate receptor, epidermal growth factor receptor (EGFR)/ERBB1, or a co-receptor, HER2, have been approved for cancer therapy. Although they might improve safety and delay onset of chemoresistance, no anti-ligand antibodies have been clinically approved. To identify suitable ligands, we surveyed fluids from ovarian and lung cancer patients and found that amphiregulin (AREG) is the most abundant and generalized ligand secreted by advanced tumors. AREG is a low affinity EGFR ligand, which is upregulated following treatment with chemotherapeutic drugs. Because AREG depletion retarded growth of xenografted ovarian tumors in mice, we generated a neutralizing monoclonal anti-AREG antibody. The antibody inhibited growth of ovarian cancer xenografts and strongly enhanced chemotherapy efficacy. Taken together, these results raise the possibility that AREG and other low- or high-affinity binders of EGFR might serve as potential targets for cancer therapy.

Challenges in initiating and conducting personalized cancer therapy trials: perspectives from WINTHER, a Worldwide Innovative Network (WIN) Consortium trial.

Advances in 'omics' technology and targeted therapeutic molecules are together driving the incorporation of molecular-based diagnostics into the care of patients with cancer. There is an urgent need to assess the efficacy of therapy determined by molecular matching of patients with particular targeted therapies. WINTHER is a clinical trial that uses cutting edge genomic and transcriptomic assays to guide treatment decisions. Through the lens of this ambitious multinational trial (five countries, six sites) coordinated by the Worldwide Innovative Networking Consortium for personalized cancer therapy, we discovered key challenges in initiation and conduct of a prospective, omically driven study. To date, the time from study concept to activation has varied between 19 months at Gustave Roussy Cancer Campus in France to 30 months at the Segal Cancer Center, McGill University (Canada). It took 3+ years to be able to activate US sites due to national regulatory hurdles. Access to medications proposed by the molecular analysis remains a major challenge, since their availability through active clinical trials is highly variable over time within sites and across the network. Rules regarding the off-label use of drugs, or drugs not yet approved at all in some countries, pose a further challenge, and many biopharmaceutical companies lack a simple internal mechanism to supply the drugs even if they wish to do so. These various obstacles should be addressed to test and then implement precision medicine in cancer.

Outcome of alveolar hemorrhage in hematopoietic stem cell transplant recipients.

Alveolar hemorrhage (AH) is a frequent, serious complication of hematopoietic stem cell transplantation (HSCT). To study the incidence of AH, its clinical course and outcomes in HSCT patients, a retrospective review of the records of all adult patients who underwent bronchoscopy between January 1, 2002 and December 31, 2004 was carried out and those who underwent bronchoscopy after HSCT identified. A total of 223 patients underwent bronchoscopy after HSCT for diffuse pulmonary infiltrates with respiratory compromise. Eighty-seven (39%) patients had AH. Of these, 53 had AH without any identified organism while 34 had an organism along with hemorrhage on bronchoalveolar lavage (BAL). Six-month survival rate of patients with AH was 38% (95% confidence interval: 27-48%). In 95 of the 223 patients, an organism was isolated from BAL. These patients had poor outcomes compared to patients in whom no organism was identified. Patients with both AH and an organism had the worst prognosis. Mortality of patients with AH is improving and long-term survival of patients with AH is feasible. Isolation of a microbial organism in BAL is a strong predictor of poor outcome.

The development of supernumerary teeth in the mandible in cases with a history of supernumeraries in the pre-maxillary region.

This article presents four cases in which delayed formation and late eruption of supernumerary teeth in the mandible occurred in patients with a history of supernumerary formation in the premaxilla region. In all cases, the premaxillary supernumeraries prevented eruption of the associated permanent incisor(s).

Treatment of non-small-cell lung cancer: a perspective on the recent advances and the experience with gefitinib.

Worldwide, non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related mortality and, until screening detects early disease, treatment for the majority of patients will consist of radiation therapy, chemotherapy or combinations thereof. Modern mono and doublet chemotherapy regimens have translated into modest increases in life expectancy and improved quality of life, but at the expense of systemic and pulmonary adverse events (AEs). There is a great unmet need to provide effective therapy for advanced NSCLC that does not have the toxicity burden of conventional chemotherapy and radiotherapy. Novel drugs that inhibit a range of growth factor receptors, such as the epidermal growth factor receptor tyrosine kinase inhibitors gefitinib ('Iressa') and erlotinib ('Tarceva') or the monoclonal antibody cetuximab ('Erbitux'), have recently been evaluated. Having demonstrated antitumour activity and rapid symptom improvement in pretreated patients with advanced NSCLC, gefitinib was approved in the USA, Japan and other countries. Gefitinib is well tolerated with a low incidence of grade 3/4 AEs. Interstitial lung disease has been reported in a small number of patients receiving gefitinib, although this may be attributed to other treatments and conditions. Nevertheless, although the use of novel treatments requires vigilance for unexpected AEs such as pulmonary toxicity, in this area of high unmet clinical need, the benefits outweigh the risks in patients for whom no other proven effective treatment exists.

The Lap-Band system in the United States: one surgeon's experience with 271 patients.

BACKGROUND: The LAP-BAND system is considered an important bariatric surgery procedure in many countries and is rapidly gaining acceptance in the United States. Outcomes data emerging in the United States parallel European and Australian experience. The purpose of this study was to examine our experience with this procedure in the United States. METHODS: Between November 2000 and September 2002, 271 patients (236 women) underwent LAP-BAND system placement. The mean age of patients was 40 years (18-63); preoperative mean body weight was 125 kg (93-192). Surgeries were performed using either the two-step (pars flaccida to perigastric) or the pars flaccida technique with three (1.1%) conversions to open procedures. Mean operative time was 42 min (23-86); average hospital stay was 1 day (4 h to 7 days). RESULTS: The mean body mass index (BMI) decreased from a baseline of 45.3 kg/m(2) (35-68) to 41.9 ( n = 178), 39.5 ( n = 101), 38.4 (n = 81), 36.5 (n = 72), 35.9 (n = 51), and 35.1 (n = 21) kg/m(2) at 3, 6, 9, 12, 18, and 24 months, respectively, after surgery. Mean excess weight loss was 40% at 12 months and 43% at 24 months. As patients lost weight, comorbid conditions improved. No deaths occurred, no bands had to be removed, and postoperative complications were minor: 20 (7.3%) access port problems, 18 (6.6%) gastric pouch dilatations, five (1.8%) gastric slippages, and five (1.8%) stoma obstructions. All were managed conservatively or repaired laparoscopically using the original bands. Additional complications included four cases of pneumonia and one case of pulmonary embolism. One patient required reoperation because of trocar site bleeding. CONCLUSIONS: The LAP-BAND system is a safe and effective bariatric procedure leading to considerable weight loss and reduction in comorbidity.

Eosinophil influx into the airways in patients with exercise-induced asthma.

Exercise-induced asthma is a common phenomenon, the mechanism of which is undetermined. Eosinophils have been suggested as playing a role in its occurrence. We studied the effect of exercise-induced asthma on the cellular and mediator composition of spontaneously obtained sputum. Twenty-five patients with bronchial asthma were investigated by studying sputum spontaneously obtained before and following challenge. One group with (n=9) and one without (n=9) exercise-induced asthma performed exercise challenge. A third group (n=7) performed methacholine challenge. The sputum was analysed using Giemsa staining for differential cell count, measuring eosinophil cationic proteins and mixtures of leukotrienes (D4, E4 and C4) in the liquid phase using ELISA. The group with exercise-induced asthma had a mean drop of 23.7+/-7.4% in FEV1, significantly (P=0.001) higher than the group without it. Following challenges, there were significant increases in sputum eosinophils only in the group with exercise-induced asthma (from 8.1+/-13.9% to 18.3+/-20.2%, P=0.0017) and not in control groups (from 0.9+/-0.9% to 1.5+/-15%) or in those who had methacholine challenge (from 23.6+/-27.2% to 22.3+/-23.8%). Eosinophil cationic proteins did not change significantly in any group. In the liquid phase of the sputum, the amount of leukotrienes increased following exercise in six of the seven patients with exercise-induced asthma in whom it was measured. The influx of eosinophils to the airway in patients who develop exercise-induced asthma can be partially explained by the leukotrienes in the airways of those patients.

Suppressive activity of bronchial macrophages recovered by induced sputum.

BACKGROUND: The immunomodulatory activity of macrophages was shown to be a crucial mechanism in the pathogenesis of asthma. METHODS: Induced sputum (IS) and methacholine challenge (MC) were carried out in 21 atopic subjects. Suppressive activity (SA) of sputum macrophages (SMO) was investigated on autologous peripheral lymphocytes (APL) proliferation in 12 of these patients and compared to the MC. RESULTS: In 10 of the 21 patients, the FEV1 was >80%; five of these had a nonreactive MC. Eosinophils and metachromatic cells correlated well (r=0.6442; P=0.0029), but not with the MC. The SA of SMO correlated (P=0.0152) with the MC: SMO enhanced APL proliferation in five patients with a positive MC, while SMO showed SA in five with a negative MC. Only two patients with suppressive SMO had a positive MC. Cytokine profiles from five patients showed that two patients with a negative MC had interleukin (IL)-1alpha and beta, IL-6, and transforming growth factor (TGF)-beta transcripts, while two patients with a positive MC transcripted IL-4 and IL-5. One patient with a borderline MC transcripted IL-5, but not IL-4. CONCLUSIONS: These data support the theory that patients with reduced suppressive bronchial macrophages display clinical bronchial hyperreactivity.

Hemophilus influenzae biotype III cellulitis in an adult.

The case of a patient with systemic lupus erythematosus presenting with severe leg cellulitis caused by Hemophilus influenzae non-B biotype III is reported. Skin infections caused by H. influenzae in general, and of the extremities in particular, seem to be rare in adults. This is the first reported case of cellulitis caused by H. influenzae biotype III. The infection was treated successfully with antibiotics. This case highlights the importance of blood cultures and prompt antimicrobial treatment in febrile adults with cellulitis, especially immunocompromised patients.

Nedocromil and exercise-induced asthma: acute and chronic effects.

BACKGROUND: Nedocromil sodium confers both acute and chronic protective effects in patients with bronchial asthma, the interactions of which are unknown. OBJECTIVE: To examine to what extent and for how long nedocromil sodium prevents exercise-induced asthma when given immediately before exertion compared to chronic administration. PATIENTS AND METHODS: Eighteen asthmatic patients were given 4 mg NS at 30 min or 3.5 hours before exertion. We compared the resultant effect with that of the same protocol measured after 2 and 4 weeks of continuous treatment with the drug. RESULTS: Nedocromil sodium decreased exercise-induced asthma similarly at both points when given acutely. Chronic treatment of up to 4 weeks did not improve this protective effect at either interval following the inhalation. CONCLUSION: Nedocromil sodium most likely reaches its maximal effect on exercise-induced asthma upon the first administration, although treatment for longer than 4 weeks might be required to prove a chronic effect of the drug.

The in vitro and in vivo effect of corticosteroids on basophil releasability in patients with mild and severe bronchial asthma.

BACKGROUND: While inhalation of corticosteroids (CST) is considered very effective in most asthmatic patients, some require a high dose of oral prednisone to control the disease. Basophils, which participate in inflammation, are responsive to corticosteroids by suppressing histamine release. OBJECTIVES: We investigated the in vivo (oral prednisone) and in vitro (dexamethasone, DEX) effect on basophil histamine release in mild and steroid-dependent asthmatics. METHODS: Histamine release from basophils to anti-IgE and anti-IgE + IL3 was evaluated following five days of prednisone given 20 mg twice daily in eight subjects with mild disease and 2 h following their daily prednisone ingestion in eight subjects with severe disease, as well as after in vitro DEX was added to the cells. RESULTS: Histamine release from basophils was seen following anti-IgE as well as anti-IgE + IL-3. The same amount of release was seen in the mild and severe asthmatics. In vivo prednisone suppressed histamine release to both stimuli and DEX added to the suppression in the mild asthmatics. In the severe ones, DEX showed no inhibitory effect on histamine release. CONCLUSION: Oral and in-vitro CST suppressed histamine release from basophils of mild but not severe CST-dependent asthmatics. Suppression of basophil releasability can be a reflection of asthma severity.