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BACKGROUND: Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care. METHODS: We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping. RESULTS: Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and ß-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy. CONCLUSIONS: Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.

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Primary Acute Lung Injury (ALI) after lung resection (or "post-pneumonectomy pulmonary edema") is a rare form of acute respiratory failure characterized by dyspnea, hypoxemia, diffuse infiltrates on chest radiogram, and rapid evolution often unresponsive to therapy. ALI occurs almost exclusively following pneumonectomy, within 3 days from surgery and without a preceding cause. Factors implicated in its pathogenesis may include excessive fluid administration, alveolar injury during one-lung ventilation, pulmonary hypertension, and impaired lymph drainage. There is no specific therapy. Suggested measures in the perioperative care include the meticulous maintenance of physiological stability, judicious fluid restriction, and the limitation of ventilatory volumes and pressures.

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Paclitaxel is an active agent for adenocarcinomas and squamous cell carcinomas of the esophagus and is a radiation sensitizer. We sought to investigate the toxicity and complete response rate of paclitaxel, cisplatin, and concurrent radiation for esophageal cancer. Forty-one patients with esophageal cancer were studied, 29 with adenocarcinomas and 12 with squamous cell cancers. Twelve patients had tumor extension into the proximal stomach and/or abdominal adenopathy. Patients received paclitaxel 60 mg/m2 by 3-hour intravenous (i.v.) infusion, and cisplatin 25 mg/m2 weekly on days 1, 8, 15, and 22. Radiation was administered concurrently to a total dose of 39.60 Gy, in 1.80 Gy fractions, for 22 treatments. Patients with medical or surgical contraindications to esophagectomy received 2 additional weeks of paclitaxel with a radiation boost to 50.4 Gy. Neutropenia was the most common grade 3/4 toxicity occurring in 10 patients (24%). Only 2 patients (5%) had grade 4 esophagitis requiring parenteral nutrition. Twelve patients (29%) obtained a complete response. The 2-year progression-free and overall survival rates were 40% and 42%, respectively. Esophagitis was less severe than expected and prophylactic enteral feeding tubes were not necessary. Additional effective systemic treatments are needed to reduce the development of distant metastases.

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Pleural solitary fibrous tumors (SFTs) are uncommon tumors. Although these tumors have been well characterized, malignant pleural SFTs with liposarcomatous differentiation have not been reported. We report an unusual malignant pleural SFT intermixed with foci of well-differentiated liposarcoma. The patient was a 66-year-old, white man with a large, solid right pleural mass that measured 13.5 x 10.3 x 8.5 cm. The tumor was composed of spindle-shaped and plump cells embedded in dense collagenous stroma. The tumor cells were arranged in interlacing fascicles or in a patternless pattern. Marked nuclear atypia, a high mitotic rate (21 mitoses per 10 high-power fields), and areas of prominent necrosis were evident. In addition, numerous adipocytes mixed with typical lipoblasts were seen scattered throughout portions of the tumor. Immunohistochemistry revealed the tumor cells were strongly positive for CD34 and vimentin and negative for cytokeratin, desmin, smooth muscle actin (IA4), and S100. To the best of our knowledge, this case represents the first example of a malignant SFT with liposarcomatous differentiation.

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OBJECTIVE: To study the effects of proteolytic enzymes on mice hair follicles, particularly on cells of the bulge area regarded as follicle stem cells. BACKGROUND: Previous application by iontophoresis of proteolytic enzymes on guinea pig skin resulted in degenerative effects on hair follicles and the hypothesis was proposed that some of the affected cells could be stem cells. METHODS: To mark putative stem cells transgenic mice were produced carrying the lac-Z gene fused to the Upstream Regulatory Region (URR) of Human Papilloma Virus 11 (HPV11), as they express this gene specifically in the cells of the bulge area. Chymotrypsin and papain were applied on skin by iontophoresis, trypsin in the form of liposomes. RESULTS: Enzyme application, both by electrophoresis and as liposomes, led to intense degenerative effects of the hair follicle, such as detachment of the inner root sheath, cystic dilation of the hair shaft and presence of epithelial cells within the lumen. Some of these cells represent hair follicle stem cells expressing beta-galactosidase (beta-gal), having been detached from the bulge area as a result of enzyme treatment, implying impairment of their function.

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We have generated transgenic mice carrying the URR of the human papillomavirus type 11 ligated in front of the Escherichia coli beta-galactosidase coding region sequence. Using X-Gal staining to demonstrate beta-galactosidase production, we observed a hair-specific transcription of the reporter gene. This transcription was limited to the epithelial cells of the hair bulge region. The transgene was developmentally regulated, as no LacZ staining was demonstrated during embryogenesis and specific staining was first observed after birth. Surprisingly, dexamethasone and ultraviolet B, but not phorbol myristate acetate or progesterone treatment of the animals resulted in an increase in number and intensity of hair follicles expressing the reporter gene.

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An effective locoregional therapy is needed for adenocarcinomas of the pancreas, stomach, and gastroesophageal junction. Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) may enhance the effect of radiation therapy (RT). Paclitaxel synchronizes cells at G2/M, a relatively radiosensitive phase of the cell cycle. We have shown that response to paclitaxel and concurrent RT (paclitaxel/RT) was not affected by p53 mutations in non-small cell lung cancer. This finding suggested that paclitaxel/RT was a rational treatment approach for other malignancies that frequently harbor p53 mutations, such as upper gastrointestinal malignancies. We completed a phase I study of paclitaxel/RT for locally advanced pancreatic and gastric cancer. The maximum tolerated dose of paclitaxel was 50 mg/m2/wk for 6 weeks with abdominal RT. The dose-limiting toxicities were abdominal pain within the radiation field, nausea, and anorexia. Phase II studies are now under way. Twenty-five patients with locally advanced pancreatic cancer have been entered at the phase II dose level of paclitaxel 50 mg/m2/wk with concurrent RT (total dose, 50 Gy). Thus far, the only grade 3/4 toxicities have been hypersensitivity reactions (n = 2), asymptomatic grade 4 neutropenia (n = 3), and nonneutropenic biliary sepsis (n = 1). Of the first 18 assessable patients with pancreatic cancer treated on the phase II study, six obtained a partial response, for a preliminary response rate of 33%. In the phase II study for locally advanced gastric cancer, 20 patients have been enrolled. Of the first 19 patients who have completed treatment, nine (47%) had grade 3/4 toxicities, including nausea, anorexia, esophagitis, and gastritis. Of the first 16 patients with gastric cancer, complete and partial responses have been observed in one and eight patients, respectively, for a preliminary response rate of 56%. We have also completed treatment on 24 patients with potentially resectable adenocarcinomas of the gastroesophageal junction with neoadjuvant paclitaxel 60 mg/m2 and cisplatin 25 mg/m2, weekly for 4 weeks, with concurrent RT (total dose, 40 Gy) followed by surgical resection. Ten patients (41%) had grade 3/4 toxicities, including neutropenia, nausea, and dehydration. Of 24 patients, four complete responses (17%) and 14 partial responses (58%) were observed, for an overall response rate of 75%. Severe esophagitis was uncommon, making this a well-tolerated outpatient regimen for adenocarcinomas of the distal esophagus. These findings demonstrate that paclitaxel-based chemoradiation for locally advanced upper gastrointestinal malignancies is well-tolerated with substantial activity.

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Invasive esophageal candidiasis produced transmural necrosis leading to perforation in 2 patients aged 10 and 27 years. Both patients survived after esophageal resection and complete diversion. One patient with acute leukemia and neutropenia experienced systemic candidiasis, which resolved after esophagectomy. Esophagectomy and diversion for yeast-induced necrosis may lead to complete recovery and resolution of disseminated candidiasis when combined with systemic antifungal therapy.

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The E5 open reading frame of the human papillomavirus type 16 encodes a transmembrane protein associated with the Golgi, ER, and plasma membranes. We have analyzed the effect of E5 expression on the activation of the EGF receptor family. We find that expression of the E5-protein strongly enhances EGFR activation in a ligand-dependent manner. This activation takes place immediately after addition of ligand, demonstrating that increased tyrosine phosphorylation cannot solely be due to an impaired downregulation of the receptors. Furthermore, this activation is not a result of impaired activity of EGFR-specific phosphatase through the E5-protein, as demonstrated by using inhibitors specifically blocking EGFR activation. In addition, treatment with EGF results in an enhanced activation of the ErbB2 receptor in E5-expressing cells. This superactivation must be a result of heterodimer formation between EGFR and ErbB2, since EGF is not a ligand for ErbB2. Finally, treatment of E5-expressing cells with HB-EGF shows no increased phosphorylation of the ErbB4 receptor, suggesting a specific effect of E5 on the activation of the different members of the EGFR family.

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Between 1962 and 1991, 72 patients (mean age 63.4 years) underwent sleeve lobectomy for primary lung cancer. Thirty-seven patients had adequate lung function and 35 were deemed unsuitable for pneumonectomy on the basis of inadequate pulmonary reserve (n = 31) or cardiac risk factors (n = 4). Squamous cell carcinomas (68%) and adenocarcinomas (26%) predominated. Upper lobectomy was performed in 48 patients, lower and middle lobectomy in 13, and right upper and middle bilobectomy in 11. Hospital mortality was 4% (3/72) and compares with a hospital mortality of 9% in 56 consecutive pneumonectomies between 1986 and 1990. Major complications occurred in 11% (bronchopleural fistula 1, persistent atelectasis 4, pneumonia 4). Adjusted actuarial survival after sleeve lobectomy at 1 and 5 years was 84% and 42%, compared with 76% and 44% after pneumonectomy. Five-year survival after lower and middle lobectomy in 13 patients (52%) was similar to that after upper lobectomy (46%), suggesting that in carefully selected patients the concept of sleeve lobectomy can be applied to all pulmonary lobes. N1 disease and compromised lung function were associated with lower survival (N1 38% vs N0 57%; compromised 20% vs adequate 55%). Comparison of preoperative and postoperative lung function and quantitative ventilation-perfusion isotope studies substantiated the preservation of pulmonary function in this group of patients. Sleeve lobectomy is the procedure of choice for anatomically suitable carcinomas or when reduced pulmonary reserve precludes extensive resection.

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BACKGROUND: Bilateral lung volume reduction is designed to improve pulmonary function in selected patients with severe emphysema by improving diaphragmatic and chest wall mechanics. Early results of lung volume reduction suggest significant improvement to selected patients with chronic obstructive pulmonary disease, some of whom might otherwise be considered for lung transplantation. The purpose of this review was to compare intermediate results of volume reduction with single and bilateral lung transplantation. METHODS: Functional performance and survival after volume reduction were compared with single and bilateral sequential lung transplantation. After evaluation, patients were enrolled in a supervised intensive preoperative and postoperative program of pulmonary rehabilitation. Functional assessment, including pulmonary function tests, room air arterial blood gas analysis, and 6-minute walk distance, was obtained before the operation and 3, 6, and 12 months after the operation. RESULTS: Thirty-three patients underwent volume reduction (mean age 57 years), 39 patients single lung transplantation (55 years), and 27 patients bilateral lung transplantation (49 years). Early mortality was 0, 1 of 39, and 2 of 25 and mortality at 12 months was 1 of 33, 4 of 39, and 4 of 25 in the volume reduction, single, and bilateral lung transplantation groups, respectively. At 6 months, mean forced expiratory volume in 1 second was improved by 79% (volume reduction), by 231% (single lung transplantation), and by 498% (bilateral lung transplantation) over preoperative values. Exercise endurance as measured by 6-minute walk distance increased by 28% (volume reduction), by 47% (single lung transplantation), and by 79% (bilateral lung transplantation) from baseline. At 6 months, all patients having single or bilateral lung transplantation and 26 of 33 patients having volume replacement were free of supplemental oxygen. CONCLUSIONS: Although single and bilateral lung transplantation result in superior lung function, volume reduction achieves satisfactory improvement of disabling symptoms early after operation while avoiding immunosuppression and transplant-specific complications. Our experience suggests that (1) volume reduction is a suitable alternative in selected patients eligible for transplantation; (2) volume reduction provides an earlier option for treatment in patients who may require transplantation at some future date; (3) volume reduction is the only surgical treatment available to the many patients who are not current or future transplant candidates. Conversely, in patients not suitable for volume reduction, transplantation remains the only choice for surgical therapy.

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Lung volume reduction (LVR) for advanced emphysema improves lung function and restores respiratory excursion of chest wall and diaphragm. Between January 1993 and February 1996, bilateral LVR via sternotomy was performed in 150 patients with an early mortality (< 60 days) of 2% (3/150). In 90 patients, FEV1 rose from 0.7 (24% pred.) preoperatively to 1.1 L (37% pred.) at 6 months (57% increase; p < 0.001). In the same interval, O2 requirements decreased during exercise from 95 to 46% of patients and from 50 to 16% of patients on continuous O2. After 1 (n = 54) and 2 (n = 15) years, the improvements in FEV1, pO2, 6-min walking distance, and dyspnea, and the reduction of TLC and RV remained stable. In selected patients, bilateral LVR results in marked improvement of emphysema-related disability and offers excellent palliation.

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The aim of lung volume reduction surgery is to alleviate the symptoms of severe emphysema and to improve the life quality of the patient. The appropriate candidates (approximately 20% of all emphysematic patients examined in our clinic) had considerable dyspnea, an increased lung capacity, and a heterogenous dissemination of the emphysema with regional destruction of the parenchyma, hyperinflation and poor perfusion. After preoperative physiotherapie with a specified rehabilitation aim, a resection of 20 to 30% of the total lung volume was performed via sternotomy. From January 1993 to February 1996, 150 patients underwent bilateral lung volume reduction (age range = 36 to 77 years). The mean forced expiratory volume in 1 s (FEV1) was preoperatively 25% of the predicted value, the total lung capacity (TLC) 142% and the residual volume (RV) 283%, 94% of these patients necessitated oxygen supply at rest or during exercise. The 90-day mortality was 4%. All patients except 1 were extubated immediately after operation. The median hospital stay was 10 days in the first 100 patients and 7 days in the last 50. An increase of the FEV1 by 51% and a decrease of the RV by 28% was observed 6 months after operation. The mean PaO2 was improved by 8 mm Hg while the percentage of oxygen dependent patients went down from 50 to 16%. In addition a raise of the perseverance capacity, a clear decrease of dyspnea and an improvement of the life quality were achieved. These results persist after 1 (n = 56) and 2 (n = 20) years after operation. Lung volume reduction leads to an improvement of the lung function, symptoms and the quality of life, which is superior to that achieved by maximal clinical intervention.

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While resection of tracheobronchial segments has become a standard operation in adults, lesions of the carina in children are rare and their treatment is technically more demanding. Since 1980, 8 patients aged 8 to 19 years underwent surgical reconstruction of the carina. The indications were tumors in 5 and non-neoplastic lesions in 3. In 3 patients with tumor (2) and advanced histoplasmosis (1), resection of the carina was combined with parenchymal resection. The principles of operative repair include complete resection, with frozen section confirmation in tumors, particular emphasis on adequate mobilization of the airway in children to reduce anastomotic tension, and use of anesthetic techniques that facilitate early extubation. One patient (12.5%) died after complex airway reconstruction for extensive mediastinal fibrosis. Residual malacia in a patient with postpneumonectomy syndrome required successful re-resection. Seven patients remain free of anastomotic stricture and tumor recurrence during a mean follow-up of 62 months (range 5 to 132 months), with expected preservation of lung function. Late bronchoscopy in 5 patients 6 months to 11 years after operation demonstrated growth of the luminal diameter and patent anastomoses. Carinal reconstruction in children is occasionally required, succeeds in general, and does not result in late problems at the anastomosis.

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The advantages of the tracheal T-tube compared with a regular tracheostomy tube are a physiologic direction of air flow, preservation of laryngeal phonation, and superior patient acceptance. Between 1968 and 1991, 140 patients aged 7 months to 95 years underwent placement of T-, TY- (n = 7), or a modified extended T-tube (n = 4). Primary diagnosis was postintubation stenosis in 86 patients, burn injury in 13 patients, malignant airway tumors in 12 patients, and various disorders in 29 patients. Stenting with a silicone rubber tube was temporary in 31 patients and 14 underwent later operative reconstruction. Definitive permanent insertion was performed in 49 patients. A modified tube was used in 4 patients with left main bronchial stenosis with effective long-term palliation in 3. Postoperative airway obstruction prompted placement in 32 patients. Positioning of the T-tube above the vocal cords in 12 patients for subglottic stenosis was effective in 10. The T-tube was not tolerated in 28 patients (20%) because of obstruction of the upper limb or aspiration. Five of 10 patients under the age of 10 years had airway obstruction necessitating tube removal. Long-term intubation in 112 patients exceeded 1 year in 49 patients and 5 years in 12 patients. Only 5 patients required tube removal for obstructive problems more than 2 months after placement. The tracheal T-tube restores airway patency reliably with excellent long-term results and represents the preferred management of chronic airway obstruction not amenable to surgical reconstruction.

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Bronchoplastic techniques preserving lung parenchyma allow resection and reconstruction of the major bronchi and carina and are widely used in adults. The smaller and more delicate airways of children make such operations more demanding, but successful outcome can still be achieved with particular attention to technique. The authors treated 12 patients age 8 to 19 years (mean, 13.8 years) over a 12-year period. Ten patients had tumors of the airway: carcinoid (4), mucoepidermoid (2), malignant fibrous histiocytoma (1), adenocarcinoma (1), granular cell (1), and invasive fibrous tumor (1); and 2 had nonneoplastic strictures. Previous operative treatment included incomplete local excision in 2 and laser ablation in 1. Carinal resection and reconstruction was performed in 6 patients, main-stem bronchial resection in 3, and sleeve lobectomy in 3. There was one death after a complex airway reconstruction for extensive mediastinal fibrosis involving the airway. Postoperative morbidity consisted of prolonged atelectasis in 3 patients. Residual malacia in 1 patient with postpneumonectomy syndrome required further tracheobronchial resection. Follow-up is complete (mean, 64 months; range, 7 to 130). There has been no anastomotic stenosis or tumor recurrence. Preservation of lung function is expected in all patients. In 7 patients, bronchoscopy 4 months to 11 years postoperatively confirmed anastomotic patency and growth. The understanding of bronchoplastic techniques and precise attention to technical detail should allow these procedures to be successfully performed in pediatric patients.

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OBJECTIVE: Strictures of the upper airway caused by burns have features distinct from other benign stenoses. The authors reviewed their experience with burn-related stenoses to define the principles of treatment. SUMMARY BACKGROUND DATA: The combined effects of inhaled gases and heat in burn victims produce an intense, often transmural, inflammation of the airway, further complicated by intubation. The incidence of laryngotracheal strictures in survivors of inhalation injury is high, but the reported experience with their treatment is limited and often unduly separated into injuries of larynx and trachea. METHODS: Presentation, treatment, and long-term follow-up are reviewed in 9 women and 9 men age 9 to 63 years, who were evaluated over a 22 year period for chronic airway compromise after inhalation injury. There were 18 tracheal stenoses, 14 subglottic strictures, and 2 main bronchial stenoses. Laryngotracheal strictures stenosis. T-tubes were placed in 15 patients, in low subglottic or tracheal stenosis below the vocal cords, in high subglottic stenosis through the vocal cords, and as a stent after resection of subglottic stenosis. RESULTS: There were two deaths during follow-up, one from respiratory failure and one from an unrelated cause. Two patients underwent evaluation only. Early in this series, one tracheal and one laryngotracheal resection resulted in prompt restenosis. Of the remaining 14 patients, 9 are without airway support from 2 to 20 years later. Four have permanent tracheal tubes. One patient required tracheostomy 8 years after successful subglottic reconstruction. CONCLUSIONS: Strictures of the upper airway related to inhalation injury are associated with prolonged inflammation and involve larynx and trachea in a majority of patients. These complex injuries respond to prolonged tracheal stenting (mean, 28 months) and resection or stenting of subglottic stenoses with recovery of a functional airway and voice in most patients. Early tracheal resection should be avoided.

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The upstream regulatory region (URR) of human papillomavirus type 18 (HPV-18) harbors transcriptional promoter and enhancer elements which are thought to determine the cell-type specificity of the virus. In order to study the regulation of HPV-18 expression in vivo, we constructed transgenic mice carrying the bacterial lacZ gene under the control of the HPV-18 URR. Analysis of beta-galactosidase activity by histochemical staining of tissue sections of four independent transgenic mice showed that the viral promoter was specifically active in epithelial cells within a variety of organs (e.g., tongue, ovary, uterus, testis, and small intestine). Very strong staining was observed in newborn transgenic mice in contrast to a weak activity found during fetal life. Determination of beta-galactosidase activity in crude extracts from tissues of three lines of transgenic mice proved to be a useful tool for a quantitative analysis of transgene expression. In mice from two different transgenic lines treated with dexamethasone such measurements revealed a biphasic effect of the hormone on the activity of the enzyme in the stratified epithelium of the tongue (transient increase followed by a decrease). Northern (RNA) blot analysis showed similar changes in beta-galactosidase mRNA in that tissue. Treatment with tetradecanoyl phorbol acetate (TPA) led to a twofold increase in both enzymatic activity and mRNA levels. Finally, combined treatments with dexamethasone and TPA showed that both factors interfered with each other in their respective effects on transgene expression, suggesting that a cross-talk mechanism between transcription factors could be involved in the regulation of the HPV-18 URR.

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