Frank Walsh

Feasibility and Efficacy of Molecular Analysis-Directed Individualized Therapy in Advanced Non–Small-Cell Lung Cancer

PURPOSE The treatment of patients with advanced non-small-cell lung cancer (NSCLC) is based on clinical trials experience. Molecular characteristics that impact metabolism and efficacy of chemotherapeutic agents are not used for decision making. Ribonucleotide reductase subunit 1 (RRM1) is crucial for nucleotide metabolism, and it is the dominant molecular determinant of gemcitabine efficacy. Excision repair cross-complementing group 1 gene (ERCC1), a component of the nucleotide excision repair complex, is important for platinum-induced DNA adduct repair. We hypothesized that selection of double-agent chemotherapy based on tumoral RRM1 and ERCC1 expression would be feasible and beneficial for patients with advanced NSCLC. PATIENTS AND METHODS We conducted a prospective phase II clinical trial in patients with advanced NSCLC. Patients were required to have a dedicated tumor biopsy for determination of RRM1 and ERCC1 gene expression by real-time quantitative reverse transcriptase polymerase chain reaction. Double-agent chemotherapy consisting of carboplatin, gemcitabine, docetaxel, and vinorelbine was selected based on gene expression. Disease response and patient survival were monitored. RESULTS Eighty-five patients were registered, 75 had the required biopsy without significant complications, 60 fulfilled all eligibility criteria, and gene expression analysis was not feasible in five patients. RRM1 expression ranged from 0 to 1,637, ERCC1 expression ranged from 1 to 8,103, and their expression was correlated (Spearmans rho = 0.46; P < .01). Disease response was 44%. Overall survival was 59% and progression-free survival was 14% at 12 months, with a median of 13.3 and 6.6 months, respectively. CONCLUSION Therapeutic decision making based on RRM1 and ERCC1 gene expression for patients with advanced NSCLC is feasible and promising for improvement in patient outcome

Identification of an Emerging Pathogen, Mycobacterium massiliense, by rpoB Sequencing of Clinical Isolates Collected in the United States

ABSTRACT Mycobacterium massiliense is a rapidly growing mycobacterium that is indistinguishable from Mycobacterium chelonae/M. abscessus by partial 16S rRNA gene sequencing. We sequenced rpoB, sodA, and hsp65 genes from isolates previously identified as being M. chelonae/M. abscessus and identified M. massiliense from isolates from two patients with invasive disease representing the first reported cases in the United States.

Significant Tracheal Obstruction Causing Failure to Wean in Patients Requiring Prolonged Mechanical Ventilation: A Forgotten Complication of Long-term Mechanical Ventilation

INTRODUCTION Modern low-pressure, high-volume cuffed tracheotomy tubes have been shown to decrease tracheal injury. However, injury still occurs in patients requiring prolonged mechanical ventilation and prevents weaning, delays decannulation, prolongs hospitalization, and may totally obstruct the airway. We describe 37 patients, including the first reported case of failure to wean due to tracheal obstruction. METHODS Over a 3-year period, from September 1994 to August 1997, the hospital records of 37 patients requiring prolonged mechanical ventilation (> 4 weeks) and found to have tracheal obstruction were reviewed retrospectively. They were a subgroup of 756 patients admitted to hospitals during the same period. The average endotracheal/tracheostomy cannulation time was 3 weeks/12 weeks (range 2 to 4 weeks/8 to 14 weeks). Average age was 76 years (range, 34 to 81). Underlying diseases included COPD, postcoronary artery bypass graft surgery, postpneumonectomy, severe pneumonia, acute lung injury, and ischemic heart disease. RESULTS All 37 patients who initially failed to wean had difficulty in breathing and developed intermittent high peak airway pressures either early or during the weaning process or just on being ventilated. The insertion of a longer tracheal tube bypassed the obstruction, reestablished the airway, decreased peak airway pressures, and allowed the patient to breathe more easily. The obstruction was confirmed on bronchoscopy. Treatment consisted of either placement of a longer tracheal tube (34 of 37 patients) or placement of a tracheal stent. All but two of the patients (5.4%) were able to be weaned within a week. The two patients who still failed to be weaned were subsequently diagnosed as having amyotrophic lateral sclerosis. CONCLUSION Tracheal obstruction in patients requiring prolonged mechanical ventilation prevented weaning. Reestablishment of the airway with a longer tracheal tube or tracheal stent allowed most of the patients to be weaned.

Clinical Investigations in Critical CareSignificant Tracheal Obstruction Causing Failure to Wean in Patients Requiring Prolonged Mechanical Ventilation: A Forgotten Complication of Long-term Mechanical Ventilation

INTRODUCTION Modern low-pressure, high-volume cuffed tracheotomy tubes have been shown to decrease tracheal injury. However, injury still occurs in patients requiring prolonged mechanical ventilation and prevents weaning, delays decannulation, prolongs hospitalization, and may totally obstruct the airway. We describe 37 patients, including the first reported case of failure to wean due to tracheal obstruction. METHODS Over a 3-year period, from September 1994 to August 1997, the hospital records of 37 patients requiring prolonged mechanical ventilation (> 4 weeks) and found to have tracheal obstruction were reviewed retrospectively. They were a subgroup of 756 patients admitted to hospitals during the same period. The average endotracheal/tracheostomy cannulation time was 3 weeks/12 weeks (range 2 to 4 weeks/8 to 14 weeks). Average age was 76 years (range, 34 to 81). Underlying diseases included COPD, postcoronary artery bypass graft surgery, postpneumonectomy, severe pneumonia, acute lung injury, and ischemic heart disease. RESULTS All 37 patients who initially failed to wean had difficulty in breathing and developed intermittent high peak airway pressures either early or during the weaning process or just on being ventilated. The insertion of a longer tracheal tube bypassed the obstruction, reestablished the airway, decreased peak airway pressures, and allowed the patient to breathe more easily. The obstruction was confirmed on bronchoscopy. Treatment consisted of either placement of a longer tracheal tube (34 of 37 patients) or placement of a tracheal stent. All but two of the patients (5.4%) were able to be weaned within a week. The two patients who still failed to be weaned were subsequently diagnosed as having amyotrophic lateral sclerosis. CONCLUSION Tracheal obstruction in patients requiring prolonged mechanical ventilation prevented weaning. Reestablishment of the airway with a longer tracheal tube or tracheal stent allowed most of the patients to be weaned.

Tracheostomy tube occlusion protocol predicts significant tracheal obstruction to air flow in patients requiring prolonged mechanical ventilation

OBJECTIVE This study was undertaken to test the hypothesis that a tracheal tube occlusion protocol predicts clinically important obstruction to air flow in patients requiring prolonged mechanical ventilation, making routine bronchoscopy unnecessary. DESIGN A prospective evaluation of 75 patients who were clinically ready to be decannulated. All patients underwent the tracheal tube occlusion protocol followed by bronchoscopy. SETTING Three hospitals affiliated with a college of medicine. PATIENTS Over a 24-month period, 52 males and 23 females were enrolled in the study. Mean age was 55 yrs (range 25 to 85). Mean endotracheal/tracheostomy time was 2.4/8.9 wks (range 1 to 4/5 to 14). All patients were mechanically ventilated for at least 4 wks and were successfully weaned from the mechanical ventilator for at least 48 hrs. During spontaneous breathing, these data were observed: minute ventilation of < 10 L/min; resting respiratory rate of < 18 breaths/min; and arterial oxygen saturation of > 90% on 40% oxygen tracheal collar mask. The tracheal tube occlusion protocol consisted of deflating the cuff on the fenestrated tracheal tube and occluding the tube. INTERVENTIONS Patients who developed respiratory distress when the tracheal tube was occluded were deemed to have failed the protocol. At bronchoscopy, the patients were asked to cough and hyperventilate in an attempt to forcibly reduce the cross-sectional area of the trachea. A sustained, subjectively assessed decrease of > or = 50% of the effective cross-sectional area of the trachea was considered to be an indication for intervention. MEASUREMENTS AND MAIN RESULTS Sixty-three (84%) of 75 patients tolerated the tracheal tube occlusion protocol. Twelve (16%) of 75 patients developed signs of respiratory distress and showed decreased oxygen saturation values necessitating uncapping of the tracheal tube. All patients had some degree of tracheal injury. However, those patients who failed to tolerate the tracheal tube occlusion protocol had clinically important tracheal obstruction to air flow. CONCLUSION A tracheal tube occlusion protocol can predict clinically important obstruction to air flow after prolonged mechanical ventilation.

Phase 2 randomized study of enzastaurin (LY317615) for lung cancer prevention in former smokers

Chemoprevention for lung cancer with nutraceutical or anti‐inflammatory agents has had mixed clinical benefit. Novel targeted agents hold the promise of greater efficacy and selectivity. The authors of this report evaluated enzastaurin, a selective protein kinase C‐β (PKC‐β) inhibitor with antiproliferative and proapoptotic properties, in former smokers.