Dean M. Donahue

POSTINTUBATION TRACHEAL STENOSIS. TREATMENT AND RESULTS

A total of 503 patients underwent 521 tracheal resections and reconstructions for postintubation stenosis from 1965 through 1992. Fifty-three had had prior attempts at surgical resection, 51 others had undergone various forms of tracheal or laryngeal repair, and 45 had had laser treatment. There were 251 cuff lesions, 178 stomal lesions, 38 at both levels, and 36 of indeterminate origin. Sixty-two patients with major laryngeal injuries required complete resection of anterior cricoid cartilage and anastomosis of trachea to thyroid cartilage, and 117 had tracheal anastomosis to the cricoid. A cervical approach was used in 350, cervicomediastinal in 145, and transthoracic in 8. Length of resection was 1.0 to 7.5 cm. Forty-nine had laryngeal release to reduce anastomotic tension. A total of 471 patients (93.7%) had good (87.5%) or satisfactory (6.2%) results. Eighteen of 37 whose operation failed underwent a second reconstruction. Eighteen required postoperative tracheostomy or T-tube insertion for extensive or multilevel disease. Twelve died (2.4%). The most common complication, suture line granulations (9.7%), has almost vanished with the use of absorbable sutures. Wound infection occurred in 15 (3%) and glottic dysfunction in 11 (2.2%). Five had postoperative innominate artery hemorrhage. Resection and reconstruction offer optimal treatment for postintubation tracheal stenosis.

Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice

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 β-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.

Vaccination With Irradiated Autologous Tumor Cells Engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor Augments Antitumor Immunity in Some Patients With Metastatic Non–Small-Cell Lung Carcinoma

PURPOSE We demonstrated that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting antitumor immunity in multiple murine models and patients with metastatic melanoma. To test whether this vaccination strategy enhances antitumor immunity in patients with metastatic non-small-cell lung cancer (NSCLC), we conducted a phase I clinical trial. PATIENTS AND METHODS Resected metastases were processed to single-cell suspension, infected with a replication-defective adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines consisted of 1 x 10(6), 4 x 10(6), or 1 x 10(7) cells, depending on overall yield, and were administered intradermally and subcutaneously at weekly and biweekly intervals. RESULTS Vaccines were successfully manufactured for 34 (97%) of 35 patients. The average GM-CSF secretion was 513 ng/10(6) cells/24 h. Toxicities were restricted to grade 1 to 2 local skin reactions. Nine patients were withdrawn early because of rapid disease progression. Vaccination elicited dendritic cell, macrophage, granulocyte, and lymphocyte infiltrates in 18 of 25 assessable patients. Immunization stimulated the development of delayed-type hypersensitivity reactions to irradiated, dissociated, autologous, nontransfected tumor cells in 18 of 22 patients. Metastatic lesions resected after vaccination showed T lymphocyte and plasma cell infiltrates with tumor necrosis in three of six patients. Two patients surgically rendered as having no evidence of disease at enrollment remain free of disease at 43 and 42 months. Five patients showed stable disease durations of 33, 19, 12, 10, and 3 months. One mixed response was observed. CONCLUSION Vaccination with irradiated autologous NSCLC cells engineered to secrete GM-CSF enhances antitumor immunity in some patients with metastatic NSCLC.

Complication of benign tracheobronchial strictures by self-expanding metal stents

OBJECTIVES Self-expanding metal stents are used to palliate benign strictures. We examined the complications of this approach. METHODS Between 1997 and 2002, we observed recurrent airway obstruction and extension of benign inflammatory strictures after the placement of tracheobronchial Microvasive Ultraflex stents and Wallstents (Boston Scientific Corp, Natick, Mass), in 10 patients with postintubation strictures and 5 with other indications; all but 1 patient were referred to us. Patients with tracheal (9), subglottic (1), combined tracheal and subglottic (3), and bronchial (2) strictures had been treated with covered and uncovered Wallstents (6) and Microvasive Ultraflex stents (9). RESULTS After stent insertion, stricture and granulations within previously normal airway were seen in all patients. New subglottic strictures resulting from the stent caused hoarseness in 4 patients. A bronchoesophageal fistula was found in 1 patient at presentation and a tracheoesophageal fistula in another during extraction of a Wallstent. Primary surgical reconstruction, judged to have been feasible before wire stent insertion in 10 patients, was possible after stenting in only 7 and failed in 2. Palliative tubes were placed in 60% (9/15). Self-expanding metal stents may lengthen luminal damage, incite subglottic strictures, and cause esophagorespiratory fistula in inflammatory airway strictures. The injury is severe, occurs after a short duration of stenting, and precludes definitive surgical treatment or requires more extensive tracheal resection. CONCLUSION The current generation of self-expanding metal stents should be avoided in benign strictures of trachea and bronchi.

Radiofrequency ablation for treatment of medically inoperable stage I non–small cell lung cancer

OBJECTIVE This study evaluated long-term results of radiofrequency ablation for medically inoperable early-stage lung cancer. METHODS Thirty-one consecutive patients with biopsy-proven non-small cell lung cancer underwent 38 treatments of computed tomographically guided radiofrequency ablation in a 4.5-year period. All patients were carefully selected and deemed medically ineligible for resection by a multidisciplinary team. Radiofrequency ablation was performed with curative intent with a single or cluster cool-tip electrode. Patients were hospitalized for 23-hour observation. RESULTS Treatment was complete in all cases, with no 30-day mortality. Local recurrence was confirmed radiographically by computed tomography, positron emission tomography, or both after 31.5% of treatments (12/38). Two patients were successfully retreated for technical failures related to pneumothorax; 3 underwent radiotherapy with stable disease. Mean maximal diameter of 38 tumors treated was 2.0 +/- 1.0 cm (range 0.8-4.4 cm). After median follow-up of 17 +/- 11 months, 74% of patients (23/31) were alive. Three patients died of metastatic disease; 5 died of pneumonia remote from treatment. The 2- and 4-year survivals were 78% and 47%, respectively. Median overall survival was 30 months. Pneumothorax (13%), pneumonia (16%), and pleural effusion (21%), were the most common complications. CONCLUSIONS Radiofrequency ablation of medically inoperable early-stage lung cancer in carefully selected patients yields encouraging midterm results without significant loss of pulmonary function. Local tumor progression appears related to lung tumors larger than 3 cm. Computed tomography and positron emission tomography need further validation for the early identification of local tumor progression following radiofrequency ablation.

Clinical experience with carinal resection

OBJECTIVE Pathologic processes that involve the carina pose a tremendous challenge to thoracic surgeons. Although techniques have been developed to allow primary resection and reconstruction, few institutions have accumulated sufficient experience to allow meaningful conclusions about the indications and the morbidity and mortality rates for this type of surgery. METHODS Since 1962, 135 patients have undergone 143 carinal resections (134 primary resection, 9 re-resection) at our institution. Indications for carinal resection included bronchogenic cancer (58 patients), other airway neoplasms (60 patients), and benign or inflammatory strictures (16 patients). Thirty-seven patients (28%) had a history of prior lung or airway surgery not involving the carina. Carinal resection without pulmonary resection was accomplished in 52 patients; 57 patients had carinal pneumonectomy (44 right, 13 left); 14 patients had carinal plus lobar resection, and 11 patients had carinal resection after pneumonectomy (9 left, 2 right). There were 15 different modes of reconstruction, based on the type and extent of resection. Techniques were used to reduce anastomotic tension. RESULTS The operative mortality rate in the 134 patients after primary carinal resection was 12.7%. Adult respiratory distress syndrome was responsible for 9 early deaths. Predominant predictors of operative death included postoperative mechanical ventilation (P =.001), length of resected airway (P =.03), and development of anastomotic complications (P =.04). Mortality rates varied by the type of procedure and the indication for resection. Left carinal pneumonectomy was associated with a high operative mortality rate (31%). Complications were noted in 52 patients (39%), including atrial arrhythmias (20 patients) and pneumonia (11 patients). Anastomotic complications, both early and late, were seen in a total of 23 patients (17%) and resulted in death or surgical reintervention in 21 patients (91%). The operative mortality rate for carinal re-resection was 11.1%. CONCLUSIONS Carinal resection with primary reconstruction may be accomplished with acceptable mortality rates, but the underlying pathologic process and chance for long-term survival must be carefully considered before the operation is recommended, especially in the case of left carinal pneumonectomy. Anastomotic complications exact a heavy toll on involved patients. Careful patient selection and meticulous anesthetic and surgical technique remain the key to minimizing morbidity and mortality rates.

Adjuvant radiation therapy for stage II thymoma.

BACKGROUND Thymoma is difficult to study because of its indolent natural history. The criteria for administration of adjuvant radiation therapy remain controversial, and it is unclear whether patients with Masaoka stage II thymoma benefit from adjuvant radiation. The goal of this report was to determine whether or not this group benefits from radiation therapy in terms of disease-specific survival and tumor recurrence. METHODS Case records of the Massachusetts General Hospital were retrospectively reviewed from 1972 to 1999. One hundred fifty-five patients underwent resection for thymoma, of which, 49 had stage II disease. The world literature was reviewed using a Medline search (1966 to 2001), and a secondary review of referenced works was performed. RESULTS Fourteen stage II patients underwent radiation therapy. Thirty-five did not receive radiation therapy. Baseline prognostic factors between radiated and nonradiated groups were similar. All patients underwent complete resection. The addition of adjuvant radiotherapy did not significantly alter local or distant recurrence rates in stage II thymoma. Disease-specific survival at 10 years in stage II patients was 100% with radiotherapy and without radiotherapy (p = 0.87). There was one recurrence in the nonradiated group at 180 months, which was outside the usual radiation portal. CONCLUSIONS Most stage II patients do not require adjuvant radiation therapy and can be observed after complete resection.

Induction chemoradiation compared with induction radiation for lung cancer involving the superior sulcus

BACKGROUND The usual approach of induction radiation therapy (RT) followed by resection of superior sulcus tumors results in many incomplete resections, a high local recurrence rate, and suboptimal survival. Induction chemoradiotherapy (CT/RT) has been shown to reduce local and distant recurrences and improve survival in stage III lung cancer. We investigated the role of induction CT/RT in superior sulcus patients. METHODS This was a single-institution, retrospective study. RESULTS From 1985 to 2000, 35 consecutive patients underwent induction treatment followed by resection of a superior sulcus tumor. All patients had mediastinoscopy first to exclude N2 disease, and all were N0 at final pathologic examination. Twenty patients had induction RT (mean, 39 Gy), and 15 had induction CT/RT (mean, 51 Gy) with concurrent cisplatin-based chemotherapy. There was no treatment mortality. Complete resection was performed in 16 of 20 (80%) of the RT patients and in 14 of 15 (93%) of the CT/RT patients (p = 0.15). The pathologic response from the induction treatment was complete or near complete in 7 of 20 (35%) of the RT patients and in 13 of 15 (87%) of the CT/RT patients (p = 0.001). The median follow-up was 167 months in the RT patients and 51 months in the CT/RT patients. Two-year and 4-year survival was 49% and 49% (95% confidence interval, 26% to 71%) in the RT patients and 93% and 84% (95% confidence interval, 63% to 100%) in the CT/RT patients, respectively (p = 0.01). The local recurrence rate was 6 of 20 (30%) in the RT patients and 0 in the CT/RT patients (p = 0.02). CONCLUSIONS Induction CT/RT for superior sulcus tumors appears to offer improved survival compared with induction RT alone.

Surgical treatment of primary pulmonary sarcomas

OBJECTIVE We sought to identify the long-term prognosis after surgical treatment for primary pulmonary sarcoma. METHODS Twenty-three patients were retrospectively identified as having been treated surgically for primary pulmonary sarcoma between 1981 and 1996. The records of all patients were reviewed, and the histopathology reexamined by a pathologist. RESULTS Fifteen patients were male and eight female; their ages ranged from 20 to 78 (mean 51) years. Tumors measured between 0.9 and 12.0 (mean 5.2) cm across the greatest diameter. The histologic diagnoses were malignant fibrous histiocytoma (8, three grade 1 or 2, two grade 3), synovial sarcoma (4), malignant schwannoma (3), leiomyosarcoma (3), and one case each of angiosarcoma, intimal sarcoma, epitheloid hemangioendothelioma, fibrosarcoma and primitive neuroectodermal tumor. Three patients were found to be unresectable. All three underwent radiation and chemotherapy. Lobectomies or bilobectomies were performed in 13 patients including two sleeve resections, one carinal resection, and one chest wall resection. Four patients underwent radical pneumonectomies. Three patients with invasion of the pulmonary artery, pulmonary veins or atrial wall underwent extended resections with the use of cardiopulmonary bypass. In two, a homograft was used to reconstruct the right ventricular outflow tract. Of the resected patients, six had a positive resection margin, and four had at least one positive lymph node in the specimen. Three patients underwent repeat pulmonary resections for recurrences. Eleven patients received postoperative chemotherapy and eight had radiation therapy. Follow-up was available on 22 patients, and ranged from 2 to 183 (mean 48) months; 14 patients are disease free, six died of disease, one died of surgical complications (operative mortality 5%), and two are alive with disease. Actuarial 3- and 5-year survival of the resected patients was 69%. Size and grade were not found to be correlated with significantly increased survival, but completeness of resection was (P<0.05). CONCLUSIONS Resection of primary pulmonary sarcomas can produce an acceptable survival rate if the resection is complete. Cardiopulmonary bypass can be a useful adjunct when tumors involve a resectable area of the heart or great vessels.

Reoperative tracheal resection and reconstruction for unsuccessful repair of postintubation stenosis

OBJECTIVE Our objective was to analyze characteristics and results of redo tracheal resection and reconstruction. METHODS Seventy-five patients were operated on between 1966 and 1997 after unsuccessful initial repairs for postintubation tracheal stenosis. RESULTS Sixteen of these patients came from a group of 32 patients with unsuccessful repair among the 450 primary resections and reconstructions performed at our institution. Fifty-nine patients were referred to us after unsuccessful initial repair elsewhere. Initial management was a T-tube or tracheotomy in 39 patients. The length of repeat resection ranged from 1.0 cm to 5.5 cm (mean 3.5 cm). A laryngeal release was used in 19 patients (25%) to reduce anastomotic tension. Complications occurred in 29 patients (39%) and were most frequent in the group requiring laryngeal release (12/19, 63.2%). Overall outcome was good in 59 patients (78.6%) and satisfactory in 10 (13.3%). The repair was unsuccessful in four patients (5.3%), and two patients died (2.6%). CONCLUSIONS Despite difficulties encountered in reoperative surgery after failed tracheal reconstruction for postintubation stenosis, successful outcome may be achieved in a large number of cases.