Joachim Schirren

Survival after trimodality therapy for malignant pleural mesothelioma: Radical Pleurectomy, chemotherapy with Cisplatin/Pemetrexed and radiotherapy

INTRODUCTION The role of surgery in the management of malignant pleural mesothelioma (MPM) is controversial and there are no established guidelines. We describe the feasibility and long-term outcomes associated with Radical Pleurectomy (RP) as surgical therapy modality in a standardized trimodality therapy concept of MPM. METHODS From November 2002 to October 2007, 35 out of 102 consecutive patients with MPM were enrolled in our prospective database. They underwent trimodality therapy, including RP followed by 4 cycles of chemotherapy with Cisplatin (75 mg/m(2))/Pemetrexed (500 mg/m(2)) and radiotherapy 4-6 weeks after operation. RESULTS Median age was 65 years. Nineteen patients were in advanced stages III and IV (54.3%). Tumor histology was epithelial in 27 patients (77.1%). Macroscopic complete resection could be achieved in 18 patients (51.4%). Surgical morbidity/mortality and trimodality treatment-related mortality were 20.0%, 2.9% and 5.8%, respectively. Thirty-three patients completed the trimodality therapy. Median follow-up was 21.7 months. Overall median survival was 30.0 months. One-, 2-, and 3-year-survival were 69%, 50% and 31%, respectively. Advanced stages III/IV (p=0.06), macroscopic incomplete resections (p=0.001), non-epithelial histology (p=0.55) and nodal metastases (p=0.19) were associated with poorer survival. CONCLUSIONS The trimodality therapy concept with RP demonstrates promising results in terms of long-term survival, morbidity and mortality. We propose that a surgical philosophy of limiting the procedure related morbidity while achieving comparable cytoreductive results allows patients to maintain physiological reserve to be eligible for multimodality treatment options in the long-term. The observed and theoretical benefits of this trimodality treatment approach warrant confirmation in larger RCT.

Environmental Isocyanate-Induced Asthma: Morphologic and Pathogenetic Aspects of an Increasing Occupational Disease

Occupational diseases affect more and more people every year. According to the International Labour Organization (ILO), in 2000 an estimated amount of at least 160 million people became ill as a result of occupational-related hazards or injuries. Globally, occupational deaths, diseases and injuries account for an estimated loss of 4% of the Gross Domestic Product. Important substances that are related to occupational diseases are isocyanates and their products. These substances, which are used in a lot of different industrial processes, are not only toxic and irritant, but also allergenic. Although the exposure to higher concentrations could be monitored and restricted by technical means, very low concentrations are difficult to monitor and may, over time, lead to allergic reactions in some workers, ending in an occupational disease. In order to prevent the people from sickening, the mechanisms underlying the disease, by patho-physiological and genetical means, have to be known and understood so that high risk groups and early signs in the development of an allergic reaction could be detected before the exposure to isocyanates leads to an occupational disease. Therefore, this paper reviews the so far known facts concerning the patho-physiologic appearance and mechanisms of isocyanate-associated toxic reactions and possible genetic involvement that might trigger the allergic reactions.

Primary tracheal tumors: experience with 14 resected patients

OBJECTIVE Primary tracheal tumors are rare. Management includes interventional endoscopy, surgery and radiotherapy. METHODS Between 1987 and 1996, 14 patients treated by resection and reconstruction of the trachea and bifurcation for primary tracheal tumors were retrospectively analyzed. RESULTS The most common histological finding was adenoid cystic carcinoma (n=7), followed by a squamous cell carcinoma (n=2), a mucoepidermoid carcinoma (n=2), a carcinoid tumor (n=1) and two benign tumors (xanthogranuloma, pleomorphic adenoma). Various reconstruction techniques were used and one prosthesis was implanted. Eight of the patients required preoperative Nd-YAG laser recanalisation. Six were treated by postoperative external beam radiotherapy, in three cases combined with endoluminal brachytherapy. Two major postoperative wound-healing impairment at the anastomosis occurred. Four minor wound-healing disorders were successfully treated by interventional endoscopy. Two patients died postoperatively with mediastinitis respectively with bilateral pneumonia. A local recurrence was observed in only two cases. At the last follow-up in January 1998, nine patients were still alive. We observed five long-term survivors (>6 years) with an adenoid cystic carcinoma or mucoepidermoid carcinoma. CONCLUSIONS Extensive segmental resection of the trachea is the treatment of choice for primary malignant and occasionally for benign tracheal tumors. Interventional endoscopy is a part of modern tracheal surgery.

Metastasectomy With Standardized Lymph Node Dissection for Metastatic Renal Cell Carcinoma: An 11-Year Single-Center Experience

BACKGROUND Pulmonary metastasectomy (PM) for metastatic renal cell carcinoma is an established method of treatment for selected patients. The incidence of intrathoracic lymph node metastases (ITLNM) and outcomes remain controversial. The purpose of this study was to determine the incidence of ITLNM and long-term outcome of PM for metastatic kidney cancer. METHODS From January 1999 to December 2009, 116 patients (82 men, age 61.7 ± 9.0 years) with metastases from kidney cancer underwent PM and systematic lymph node dissection with curative intent. Kaplan-Meier analyses, log-rank test, and Cox regression analyses were used to estimate survival and to determine prognosticators of survival. RESULTS Overall survival rates were 49% at 5 years and 21% at 10 years (median survival, 56.6 ± 9.2 months). Complete resections could be achieved in 108 patients (93.1%). Forty patients (34.5%) had systematic therapy before metastasectomy. Partial regression was observed in 11 patients (27.5%). Surgical morbidity and mortality rates were 13.8% (16 of 116) and 0.9% (1 of 116), respectively. ITLNM were found in 54 (46.6%). Patient age (≥ 70 years; p = 0.003), female gender (p = 0.016), and number of metastases (≥ 2 metastases; p = 0.012) were associated with inferior survival after PM in the univariate analysis. The presence of ITLNM and type of lung resection did not significantly affect survival. Patient age remained the only significant prognostic factor when a multivariate Cox proportional hazards model was applied. CONCLUSIONS PM and systematic lymph node dissection can be performed safely with low morbidity and mortality. Long-term survival is achievable in selected patients even with ITLNM. We recommend that systematic lymph node dissection should be demanded in every patient due to the high prevalence of ITLNM. Patients aged 70 years or older should be selected carefully for PM.

Prospective study on functional results after lung-sparing radical pleurectomy in the management of malignant pleural mesothelioma.

Introduction: Malignant pleural mesothelioma (MPM) can reduce lung function by entrapping lung parenchyma via a rind of tumor with or without concurrent effusion. Radical pleurectomy (RP) allows expansion of the trapped lung. The purpose of this study was to investigate changes in pulmonary function and lung perfusion in patients undergoing RP. Methods: In a prospective, nonrandomized study, all patients with histologically proven MPM were evaluated from January to December 2010 for trimodality therapy including RP as surgical procedure. Pulmonary-function tests and perfusion scans were obtained before and 2 months after RP. Primary end points were pulmonary function (forced vital capacity [FVC], forced expiratory volume in 1 second [FEV1]) and ipsilateral lung perfusion. Results: Sixteen out of 25 consecutive patients (age 68.8±8.9 years) were enrolled in the study. Macroscopic complete resection could be achieved in 13 patients (81.3%). Diaphragm resection was necessary in 5 patients. Significant postsurgical improvement of pulmonary function at 2 months was observed for FVC and FEV1 (both absolute and percentage of predicted values) and ipsilateral perfusion (p < 0.001). Avoidance of diaphragm resection was associated with greater increase in FVC (+34.6±17.0% versus +13.5±5.4%; p = 0.002) and FEV1 (+29.2±18.1% versus +12.1±6.4%; p = 0.015), respectively. Conclusions: Lung-sparing RP leads to significant improvement of pulmonary function and perfusion after a recovery time of 2 months. Functional results are better after preservation of the diaphragm. Preservation of physiological reserve via lung-sparing RP might allow patients with MPM to be eligible for further therapeutic options in the long term.

Risk Factors for Lymph Node Metastases and Prognosticators of Survival in Patients Undergoing Pulmonary Metastasectomy for Colorectal Cancer

BACKGROUND Systematic lymph node dissection is not routinely performed in patients undergoing pulmonary metastasectomy (PM) of colorectal cancer. The aim of the study was to identify risk factors for lymph node metastases (LNM) and to determine prognosticators for survival in colorectal cancer patients with pulmonary metastases. METHODS We retrospectively reviewed our prospective database of 165 patients with colorectal cancer undergoing PM and systematic lymph node dissection with curative intent from 1999 to 2009. The χ(2) test, regression analyses, Kaplan-Meier analyses, log rank tests, and Cox regression analyses were used to determine prognosticators for LNM and survival. RESULTS The prevalence of LNM was 22.4%. Lymph node metastases were more often detected in case of rectal cancer and if anatomic resections in term of segmentectomy or lobectomy had to be performed for PM. The number of pulmonary metastases showed a nonlinear association with the risk of positive postoperative LNM. For 1 to 10 pulmonary metastases, each additional pulmonary metastasis conferred a 16% increase in risk for LNM. Rectal cancer, M-status of the primary tumor, number of pulmonary metastases, and disease progression during pre-PM chemotherapy were independent prognosticators for survival. Lymph node metastases were not an independent prognosticator. CONCLUSIONS Rectal cancer, required anatomic resections, and multiple metastases were risk factors for LNM. Rectal cancer, M-status of the primary tumor, number of pulmonary metastasis, and disease progression during pre-PM chemotherapy were independent negative predictors of survival, stratifying patients with poor prognosis who may benefit from chemotherapy before or after PM.

Factors predicting poor survival after lung-sparing radical pleurectomy of IMIG stage III malignant pleural mesothelioma

OBJECTIVES The role of radical pleurectomy (RP) in the management of IMIG stage III in malignant pleural mesothelioma (MPM) remains controversial. The aim of the study was to investigate the feasibility and outcome as well as to determine factors predicting poor survival. METHODS Patients having IMIG stage III MPM were identified within a prospective multimodality treatment study (RP followed by chemoradiation) between 2002 and 2010 at a single institution. Kaplan-Meier analyses, log-rank test and Cox regression analyses were used to estimate survival and to determine predictors of survival. RESULTS A total of 78 patients (66.3 ± 2.5 years, 65 males) underwent RP followed by chemoradiation. A total of 42 (54%) had IMIG stage III. Mortality and morbidity were 4.8 and 31%, respectively. Median survival and 5-year survival were 21 months and 28%, respectively, for stage III patients. Progression-free survival was 11 months. The sites of failure were predominantly locoregional (20/42, 47.6%). Pathological detection of tumour spread at the resected thoracoscopy incisions (median survival 12 vs 35 months, P < 0.001), incomplete resections (median survival 13 vs 35 months, P = 0.01) and male gender (median survival 18 vs 68 months, P < 0.039) were associated with inferior survival in the univariate analyses. Histology, lymph node metastases, laterality and age had no significant impact on survival. The tumour spread at the resected previous incisions remained the only significant prognostic factor (hazard ratio (HR) = 4.3; P = 0.027) in the multivariate analysis. Patients having tumour spread had survival comparable to that of patients at stage IV in the complete patient cohort (median survival 12 vs 8 months; P = 0.39). CONCLUSIONS Lung-sparing RP for IMIG stage III MPM is feasible and offers promising long-term survival. The tumour spread at the resected previous incisions is associated with more incomplete resections and was a negative prognosticator for long-term survival. The tumour spread at the resected previous incisions or chest tube sites should be considered as T4 or stage IV according to the IMIG staging system.

The role of residual tumor resection in the management of nonseminomatous germ cell cancer of testicular origin.

OBJECTIVE To assess the outcome of patients with testicular nonseminomatous germ cell tumors (TNSGCT) undergoing intrathoracic residual tumor resection (RTR) after previous chemotherapy (CT) at a single institution. METHODS The office records of all patients who underwent intrathoracic RTR for TNSGCT after CT at a single institution from January 2000 through December 2006 were reviewed. RESULTS There were 124 consecutive patients (age 33.1 ± 8.4 years) with residual masses who underwent 189 surgical procedures. Morbidity and mortality rates were 12.7 and 0.5%, respectively. Complete resections could be achieved in 121 patients (97.6%). In the resected lung masses, necrosis was the predominant histology, (44.4 vs. 29% in mediastinal masses p = 0.018). Mature teratoma was the leading histology in the mediastinum (62.1 vs. 39.5% in lung masses, p = 0.0006). Fifty-nine out of 124 patients (47.6%) required interventions at both lungs and had discordant histological results in 20.3% (12/59) of the cases. Mean survival was 86.6 ± 2.6 months. The overall 5-year-survival and 10-year survival rates were 87 and 85%, respectively. Viable cancer, incomplete resections, age ≥ 34 years, and major pulmonary resections were associated with inferior survival in a univariate Cox proportional hazards model. In a multivariable Cox proportional hazards model, viable cancer, incomplete resections, and major pulmonary resections remained significant prognostic factors. CONCLUSIONS In selected TNSGCT patients with residual masses, RTR can be performed safely after CT. RTR should be attempted at all sites because of possible discordant histological differentiation. Complete and parenchyma-sparing resections are associated with excellent long-term survival, which can be influenced by the surgeon.

Short-term effects of inhalative tiotropium/formoterol/budenoside versus tiotropium/formoterol in patients with newly diagnosed chronic obstructive pulmonary disease requiring surgery for lung cancer: a prospective randomized trial.

OBJECTIVE A new diagnosis of chronic obstructive pulmonary disease (COPD) is often made during the evaluation of patients requiring a surgical intervention for lung cancer. Based on initial impaired lung function, these untreated patients are often considered not fit for lung surgery. There is limited information on the short-term effectiveness of preoperative pharmacologic treatment strategies in patients with newly diagnosed COPD before lung surgery. METHODS A prospective randomized study was conducted comparing 1-week-treatment periods of tiotropium/formoterol/budenoside (GR1) with tiotropium/formoterol (GR2) in conjunction with smoking cessation and chest physiotherapy. No patients had been previously treated for COPD. The primary end point was body plethysmography (forced expiratory volume in 1s (FEV1), forced vital capacity (FVC), and airway resistance (RAW)) at the end of each treatment period. Secondary end points were improvement of ≥ 10% in FEV1 (% predicted) and improvement of the severity of COPD after the 1-week treatment, as well as the rate of pulmonary complications after surgery. RESULTS A total of 46 patients were randomized in GR1 (n=24) and GR2 (n=22). Both groups were comparable with regard to age, height, weight, smoking history, baseline body plethysmography (FVC, FEV1, and RAW), and the severity of COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) staging, respectively. However, the short-term effects of the treatment with regard to FEV1 (2.0 l vs 1.7 l; p=0.031) and increase of FEV1 (0.31 l vs 0.10 l; p=0.02) were better in GR1. More patients in GR1 had an improvement of ≥ 10% in FEV1 (p=0.004) and improvement of the severity of COPD (p=0.012) after the 1-week treatment. Fewer pulmonary complications (11.1% vs 42.9%, p=0.04) were observed in GR1 after surgery. CONCLUSIONS Both therapies resulted in an improvement of lung function. There is benefit from adding inhalative budenoside to tiotropium and formoterol in terms of an improvement in FEV1 and the severity of COPD. These beneficial results might lead to less pulmonary complications in the postoperative period.

Prospective study on perioperative risks and functional results in bronchial and bronchovascular sleeve resections.

BACKGROUND Most reports on sleeve resections are based on a retrospective analysis over a long period of many decades. This prospective study addresses the challenging questions associated with sleeve resection. METHODS In a prospective study, 100 consecutive patients undergoing bronchial or bronchovascular sleeve resection with systematic lymph node dissection were analyzed: operative procedures, extended lymph node dissection, bronchial and vascular complications, functional results, recurrence and survival were recorded. RESULTS 100 patients (male 78, female 22, age 60.0 +/- 11.9) were enrolled in this study. A R0 resection rate of 99 % could be achieved and pneumonectomies avoided using 9 different surgical techniques. The average number of dissected lymph nodes was 30 on the right side and 33 on the left side. Morbidity and mortality were 39 % and 2 %, respectively. The main indication was non-small cell lung cancer (74 %). The local and distant recurrence rates were 1 % and 16 %, respectively. The overall 5-year survival rate was 87 %. Long-term survival differed significantly between N0 and N1 status ( P = 0.027) and N0 and N2 status ( P = 0.029), but not between N1 and N2 status ( P = 0.754). There were no relevant differences in pre- and postoperative perfusion scans and FEV (1) at 6 months after surgery. CONCLUSIONS In the hands of experienced surgeons bronchial and bronchovascular sleeve resections are safe operations for high-risk patients. There is no statistical significance between N1 and N2 disease with regard to long-term survival. Systematic lymph node dissection does not lead to increased perioperative risk. Sleeve resections have little effect on pulmonary function. Preoperative FEV (1) and lung perfusion can be achieved by 6 months after surgery.