Survival outcomes in a prospective randomized multicenter Phase III trial comparing patients undergoing anatomical segmentectomy versus standard lobectomy for non-small cell lung cancer up to 2 cm.

OBJECTIVES: The oncological equivalence of anatomical segmentectomy for early stage non-small cell lung cancer (NSCLC) is still controversial. Primary aim of this study was survival outcomes in combination with improved quality of life after segmentectomy compared with lobectomy in patients with pathological stage Ia NSCLC (up to 2 cm, 7th edition) MATERIALS AND METHODS: We conducted a prospective, randomized, multicenter phase III trial to confirm the non-inferiority of segmentectomy to lobectomy in regard to prognosis (trial No. DRKS00004897). Patients were randomized to undergo either segmentectomy or lobectomy and followed up for 5-years survival and tumor recurrence. The 5-year hazard ratio comparing lobectomy with segmentectomy was required to remain above 0.5. RESULTS: Between October 2013 and June 2016, 108 patients with verified or suspected NSCLC up to 2 cm diameter were enrolled; 54 were assigned to lobectomy and 54 (1 drop-out) to segmentectomy. In-hospital and 90 days mortality was 0% in both groups. Overall survival at 5 years was 86.52% in the lobectomy compared to 78.21% in the segmentectomy group (HR = 0.61, (95% CI 0.23-1.66), p-value of non-inferiority test, p-ni = 0.687). Disease free survival was 77.29% for the lobectomy and 77.96% for the segmentectomy patients (HR = 1.50, (95% CI 0.60-3.76), p-ni = 0.019). At a median follow-up of 5 years, no differences were noted in either the locoregional or distant recurrent disease in both groups (9.4% vs 7.4%, p-ni = 0.506). CONCLUSION: Overall survival, locoregional and distant recurrences was not significantly difference for patients undergoing either segmentectomy or lobectomy for stage Ia NSCLC. The targeted non-inferiority of segmentectomy to lobectomy could not be proven for primary endpoint overall survival, but was significant for the secondary endpoint of disease free survival.

Long-term survival of patients with central or > 7 cm T4 N0/1 M0 non-small-cell lung cancer treated with definitive concurrent radiochemotherapy in comparison to trimodality treatment.

ABSTARCT: BACKGROUND: To examine long-term-survival of cT4 cN0/1 cM0 non-small-cell lung carcinoma (NSCLC) patients undergoing definitive radiochemotherapy (ccRTx/CTx) in comparison to the trimodality treatment, neoadjuvant radiochemotherapy followed by surgery, at a high volume lung cancer center. METHODS: All consecutive patients with histopathologically confirmed NSCLC (cT4 cN0/1 cM0) with a curative-intent-to-treat ccRTx/CTx were included between 01.01.2001 and 01.07.2019. Mediastinal involvement was excluded by systematic EBUS-TBNA or mediastinoscopy. Following updated T4-stage-defining-criteria initial staging was reassessed by an expert-radiologist according to UICC-guidelines [8th edition]. Outcomes were compared with previously reported results from patients of the same institution with identical inclusion criteria, who had been treated with neoadjuvant radiochemotherapy and resection. Factors for treatment selection were documented. Endpoints were overall-survival (OS), progression-free-survival (PFS), and cumulative incidences of isolated loco-regional failures, distant metastases, secondary tumors as well as non-cancer deaths within the first year. RESULTS: Altogether 46 consecutive patients with histopathologically confirmed NSCLC cT4 cN0/1 cM0 [cN0 in 34 and cN1 in 12 cases] underwent ccRTx/CTx after induction chemotherapy (iCTx). Median follow-up was 133 months. OS-rates at 3-, 5-, and 7-years were 74.9%, 57.4%, and 57.4%, respectively. Absolute OS-rate of ccRTx/CTx at 5 years were within 10% of the trimodality treatment reference group (Log-Rank p = 0.184). The cumulative incidence of loco-regional relapse was higher after iCTx + ccRT/CTx (15.2% vs. 0% at 3 years, p = 0.0012, Gray's test) while non-cancer deaths in the first year were lower than in the trimodality reference group (0% vs 9.1%, p = 0.0360, Gray's test). None of the multiple recorded prognostic parameters were significantly associated with survival after iCTx + ccRT/CTx: Propensity score weighting for adjustment of prognostic factors between iCTx + ccRT/CTx and trimodality treatment did not change the results of the comparisons. CONCLUSIONS: Patients with cT4 N0/1 M0 NSCLC have comparable OS with ccRTx/CTx and trimodality treatment. Loco-regional relapses were higher and non-cancer related deaths lower with ccRTx/CTx. Definitive radiochemotherapy is an adequate alternative for patients with an increased risk of surgery-related morbidity.

Significantly favourable outcome for patients with non-small-cell lung cancer stage IIIA/IIIB and single-station persistent N2 (skip or additionally N1) disease after multimodality treatment.

OBJECTIVES: Persistent lymph nodes infiltration after neoadjuvant treatment remains a controversial topic in the treatment of stage III non-small-cell lung cancer (NSCLC). The aim of this study is to identify subgroups with persistent N2 disease, who could experience survival benefit from the addition of surgery. METHODS: A retrospective mono-institutional study was conducted to analyse all patients with a final histopathology of NSCLC and persistent mediastinal disease after induction chemotherapy or chemoradiotherapy and surgery from January 1998 to June 2015. RESULTS: A total of 145 patients (93 men, 52 women) fulfilled the inclusion criteria. The median age was 60 years (range 38-78). A total of 82 (56.5%) patients received a lobectomy, 48 (33.1%) a pneumonectomy, 11 (7.6%) a bilobectomy and 4 (2.6%) an anatomical segmentectomy; 128 (88.3%) were completely resected (R0). Operative mortality was 2.6% (4 patients), and morbidity was 35.2% (51 patients). Overall survival at 5 years was 47.3% (n = 19) for single N2 (skip), 30.2% (n = 16) for single N2 and N1 lymph nodes and under 5% (n = 1) for multiple mediastinal stations disease. Overall survival at 5 years after lobectomy/bilobectomy was not statistically different than after pneumonectomy (33.5% vs 20.5%, P = 0.082). Disease-free survival at 5 years was 30.6% (n = 6) for ypN2a1, 23.4% (n = 7) for ypN2a2 and under 5% (n = 1) for ypN2b status. CONCLUSIONS: Lobectomy or bilobectomy has to be taken into account as a potentially curative option with promising long-term results for patients after induction treatment and persistent single-station N2 involvement (skip or additionally N1 status). TRIAL REGISTRY NUMBER: 14-6138-BO.

Potential Prognostic Value of Preoperative Leukocyte Count, Lactate Dehydrogenase and C-Reactive Protein in Thymic Epithelial Tumors.

Thymic epithelial tumors are the most common mediastinal tumors. Surgery is the mainstay of treatment and complete resection provides the best survival rate. However, advanced tumors often require multimodality treatment and thus we analyzed the prognostic potential of routine circulating biomarkers that might help to risk-stratify patients beyond tumor stage and histology. Preoperative values for white blood cell count (WBC), C-reactive protein (CRP) and lactate dehydrogenase (LDH) were analyzed in 220 thymic epithelial tumor patients operated between 1999 and 2018. Increased CRP levels (>1 mg/dl) were significantly more often measured in thymic carcinoma and neuroendocrine tumors when compared to thymoma. LDH serum activity was higher in thymic neuroendocrine tumors when compared to thymoma or thymic carcinoma. The median disease specific survival was significantly longer in thymoma cases than in thymic carcinoma and neuroendocrine tumors. Increased preoperative LDH level (>240 U/L) associated with shorter survival in thymus carcinoma (HR 4.76, p = 0.0299). In summary, higher CRP associated with carcinoma and neuroendocrine tumors, while LDH increased primarily in neuroendocrine tumors suggesting that biomarker analysis should be performed in a histology specific manner. Importantly, preoperative serum LDH might be a prognosticator in thymic carcinoma and may help to risk stratify surgically treated patients in multimodal treatment regimens.

PROGNOSTIC VALUE OF POST-INDUCTION CHEMOTHERAPY VOLUMETRIC PET/CT PARAMETERS FOR STAGE IIIA/B NON-SMALL CELL LUNG CANCER PATIENTS RECEIVING DEFINITIVE CHEMORADIOTHERAPY.

Purpose/Objective(s): The aim of this follow-up analysis of the ESPATUE phase-3 trial was to explore the prognostic value of post-induction chemotherapy PET metrics in patients with stage III non-small cell lung cancer (NSCLC) who were assigned to receive definitive chemoradiotherapy. Materials/Methods: All eligible patients stage IIIA (cN2) and stage IIIB of the trial received induction chemotherapy consisting of 3 cycles of cisplatin/paclitaxel and chemoradiotherapy up to 45 Gy/1.5 Gy per fraction twice-a-day, followed by a radiation-boost with 2 Gy once per day with concurrent cisplatin/vinorelbine. The protocol definition prescribed a total dose of 65-71 Gy. 18F-FDG-PET/CT (PETpre) was performed at study entry and before concurrent chemoradiotherapy (interim-PET; PETpost). Interim PETpost metrics and known prognostic clinical parameters were correlated in uni- and multivariable survival analyses. Leave-one-out cross-validation was used to show internal validity. Results: Ninety-two patients who underwent 18F-FDG-PET/CT after induction chemotherapy were enrolled. Median MTVpost value was 5.9 ml. Altogether 85 patients completed the whole chemoradiation with the planned total dose of 60-71 Gy. In univariable proportional hazard analysis, each of the parameters MTVpost, SUVmax(post) and TLGmax(post) was associated with overall survival (P < 0.05). Multivariable survival analysis, including clinical and post-induction PET parameters, found TLGmax(post) (hazard ratio: 1.032 (95%-CI: 1.013-1.052) per 100 ml increase) and total radiation dose (hazard ratio: 0.930 (0.902-0.959) per Gray increase) significantly related with overall survival in the whole group of patients, and also in patients receiving a total dose ≥ 60 Gy. The best leave-one-out cross-validated 2 parameter classifier contained TLGmax(post) and total radiation dose. TLGmax(post) was associated with time to distant metastases (P = 0.0018), and SUVmax(post) with time to loco-regional relapse (P = 0.039) in multivariable analysis of patients receiving a total dose ≥ 60 Gy. Conclusion: Post-induction chemotherapy PET parameters demonstrated prognostic significance. Therefore, an interim 18F-FDG-PET/CT is a promising diagnostic modality for guiding individualized treatment intensification.

Digital PCR for the Analysis of MYC Copy Number Variation in Lung Cancer.

BACKGROUND: MYC (v-myc avian myelocytomatosis viral oncogene homolog) is one of the most frequently amplified genes in lung tumors. For the analysis of gene copy number variations, dPCR (digital PCR) is an appropriate tool. The aim of our study was the assessment of dPCR for the detection of MYC copy number variations (CNV) in lung tissue considering clinicopathological parameters. Material and Methods. MYC status was analyzed with dPCR as well as qPCR (quantitative PCR) using gDNA (genomic DNA) from tumor and adjacent nontumor tissue samples of lung cancer patients. The performance of MYC was estimated based on the AUC (area under curve). RESULTS: The results of the MYC amplification correlated significantly between dPCR and qPCR (r S = 0.81, P < 0.0001). The MYC copy number revealed by dPCR showed statistically significant differences between tumor and adjacent nontumor tissues. For discrimination, a sensitivity of 43% and a specificity of 99% were calculated, representing 55 true-positive and one false-positive tests. No statistically significant differences could be observed for age, sex, and smoking status or the clinicopathological parameters (histological subtype, grade, and stage). CONCLUSION: The results of the study show that dPCR is an accurate and reliable method for the determination of MYC copy numbers. The application is characterized by high specificity and moderate sensitivity. MYC amplification is a common event in lung cancer patients, and it is indicated that the determination of the MYC status might be useful in clinical diagnostics.

Comparison of early tumour-associated versus late deaths in patients with central or >7 cm T4 N0/1 M0 non-small-cell lung-cancer undergoing trimodal treatment: Only few risks left to improve.

BACKGROUND: The optimal treatment for patients with locally advanced non-small-cell lung-cancer (NSCLC) cT4 cN0/1 cM0 is still under debate. The purpose of this study was to examine the long-term survival of cT4 cN0/1 cM0 NSCLC patients undergoing induction chemotherapy and concurrent radiochemotherapy before surgery. METHODS: All consecutive patients with confirmed NSCLC (cT4 cN0/1 cM0) treated with neoadjuvant chemotherapy, concurrent radiochemotherapy (RT/CTx) (45-46 Gy) and surgical resection between 2000 and 2015 were included. According to the UICC guidelines (8th edition), T4 stage was reanalysed by an expert radiologist. The mediastinal staging was performed by systematic EBUS-TBNA or mediastinoscopy. The primary end-point was overall-survival (OS). The power to detect an increase of early tumour-associated mortality (hazard ratio > 3.5) within the first 5 years after treatment in comparison to late deaths beyond 96 months was >80%. RESULTS: Overall, 67 patients were treated with concurrent RT/CTx. T4 criteria were fulfilled by all patients, and multiple T4 criteria by 53 patients. Seventy percent of patients had an initial PET/CT staging. The median follow-up period was 134 months. OS rates at 2, 5, 10 and 15 years were 83.6 ± 4.5%, 65.4 ± 5.9%, 53.3 ± 6.3% and 36.6 ± 6.8%, respectively. A total of 44.8% of patients achieved a pathologic complete response. In multivariable analysis, ypT category was the most predictive factor. OS at 5 years for ypT0 (n = 31) was 80.5%, and ypT1 (n = 11) was 62.5%. Main sites of failure were brain and pulmonary metastases in seven and three patients, respectively. The intercurrent annual death rate was estimated from the survival curve beyond 96 months and was found to be 4.75% (95% CI 2.40-9.27%). No significant increased mortality was observed during the first 5 years (annual death rate: 8.31% [95% CI 5.60-12.24%], hazard-ratio = 1.72 [95% CI 0.81-3.65]). CONCLUSIONS: The effectiveness of this trimodality schedule is high in patients with cT4 cN0/1 cM0 NSCLC with excellent local control rates. Considering the annual death rate beyond 8 years of survival as an intercurrent death rate due to comorbidity, this treatment schedule reduces annual mortality to background even in the first 5 years after therapy.

Perioperative course and quality of life in a prospective randomized multicenter phase III trial, comparing standard lobectomy versus anatomical segmentectomy in patients with non-small cell lung cancer up to 2 cm, stage IA (7th edition of TNM staging system).

OBJECTIVES: For early stage non-small cell lung cancer (NSCLC) retrospective data of functionally compromised patients undergoing segmentectomy showed equal outcomes for perioperative complications and quality of life (QoL) compared with lobectomy patients. However no prospectively randomized data comparing patients eligible for both procedures are available. MATERIALS AND METHODS: We conducted a prospective, randomized, multicenter phase III trial and investigated perioperative complications and QoL in patients with NSCLC stage IA (7th edition) undergoing segmentectomy versus lobectomy. The EORTC Questionnaire Core-30 (QLQ C-30) supplemented by thirteen-item lung cancer-specific module (LC13) was assessed before surgery, at discharge, 6 weeks, 3, 6 and 12 months post-surgery. RESULTS: 108 patients with verified or suspected NSCLC up to 2 cm diameter were enrolled, whereby 54 were assigned to lobectomy and 54 to segmentectomy. Due to nodal disease, tumor size and surgical reasons estimated during the operation, eight patients of the segmentectomy group received a lobectomy. In hospital and 90 days mortality was 0% in both groups. Perioperative complications were observed in 6 (11.3%) patients after segmentectomy and in 8 patients (14.8%) after lobectomy (p = 0.563), while the 90-day morbidity were 17% and 25.9% (9 and 14 patients), respectively (p = 0.452). Twelve months after surgery, there was a significant deterioration to the baselines of physical (p < 0.001) and cognitive functioning (p = 0.025), dyspnea (p < 0.001) and fatigue (p = 0.003) in the lobectomy group. Dyspnea showed a faster recovery in the segmentectomy compared to lobectomy group with statistical significance (p = 0.016 after 12 months). CONCLUSION: In patients with early-stage NSCLC, segmentectomy is associated with a statistically not significant lower perioperative morbidity and appears to provide a superior recovery in QoL compared with lobectomy patients.

Pretreatment metabolic tumour volume in stage IIIA/B non-small-cell lung cancer uncovers differences in effectiveness of definitive radiochemotherapy schedules: analysis of the ESPATUE randomized phase 3 trial.

PURPOSE: According to the ACRIN 6668/RTOG 0235 trial, pretreatment metabolic tumour volume (MTV) as detected by 18F-fluorodeoxyglucose PET/CT is a prognostic factor in patients with stage III non-small-cell lung cancer (NSCLC) after definitive radiochemotherapy (RCT). To validate the prognostic value of MTV in patients with stage III NSCLC after RCT, we analysed mature survival data from the German phase III trial ESPATUE. METHODS: This analysis included patients who were staged by PET/CT and who were enrolled in the ESPATUE trial, a randomized study comparing definitive RCT (arm A) with surgery (arm B) after induction chemotherapy and RCT in patients with resectable stage IIIA/IIIB NSCLC. Patients refusing surgery and those with nonresectable disease were scheduled to receive definitive RCT. MTV was measured using a fixed threshold-based approach and a model-based iterative volume thresholding approach. Data were analysed using proportional hazards models and Kaplan-Meier survival functions. RESULTS: MTV as a continuous variable did not reveal differences in survival between the 117 patients scheduled to receive definitive RCT and all 169 enrolled patients who underwent pretreatment PET/CT (p > 0.5). Five-year survival rates were 33% (95% CI 17-49%) in patients scheduled for definitive RCT with a high MTV (>95.4 ml) and 32% (95% CI: 22-42%) in those with a low MTV. The hazard ratio for survival was 0.997 (95% CI 0.973-1.022) per 10-ml increase in MTV and the slope was significantly shallower than that in the ACRIN 6668/RTOG 0235 trial (random effects model, p = 0.002). There were no differences in MTV size distributions between the ACRIN and ESPATUE trials (p = 0.97). CONCLUSION: Patients with stage III NSCLC and a large MTV in whom definitive RCT had a particularly good survival in the ESPATUE trial. Treatment individualization according to MTV is not supported by this study. The ESPATUE and ACRIN trials differed by the use of cisplatin-containing induction chemotherapy and an intensified radiotherapy regimen that were particularly effective in patients with large MTV disease.

Lymph Node Involvement and the Surgical Treatment of Thymic Epithelial and Neuroendocrine Carcinoma.

BACKGROUND: Thymic epithelial and neuroendocrine carcinomas are rare malignancies, and only a few prognosticators are defined. Surgery is the mainstay of treatment, and complete resection contributes to superior outcome. Systematic lymph node dissection is not routinely performed in thymic malignancies. The aim of this study was to assess the impact of histologically confirmed lymph node metastases on the outcome after thymectomy. METHODS: We identified 53 patients with thymic epithelial or neuroendocrine carcinomas who underwent surgical resection at our center between 1999 and 2016. The clinical follow-up was retrospectively collected, and the impact of clinicopathologic factors on overall survival was analyzed. RESULTS: Ninety-one percent of the patients were treated taking a multimodal approach. Median overall survival was 11.3 years. Lymph node metastases were identified in 16 patients (30.2%; 11 pN1 and 5 pN2). Lymph node metastasis was associated with inferior overall survival (hazard ratio [HR] 3.03, 95% confidence interval [CI]: 1.03 to 8.87, p = 0.044). Masaoka-Koga stage (4 versus 1 to 3) was another significant prognosticator (HR 7.01, 95% CI: 2.52 to 19.50, p = 0.0002). Organ metastases were present in 18 patients at the time of thymectomy and were associated with inferior outcome (HR 5.8, 95% CI: 2.04 to 16.79, p = 0.001). CONCLUSIONS: This retrospective, single-center analysis demonstrates a high rate of lymph node metastasis in resectable thymic neuroendocrine tumors or carcinomas. Positive lymph nodes are associated with an inferior outcome. Prospective studies are warranted to explore whether this outcome can be improved by systematic lymphadenectomy and adjuvant therapies. Nevertheless, lymphadenectomy provides optimal staging and should be a routine part of surgery for patients with thymic malignancies.

Effectiveness of Robotic Lobectomy-Outcome and Learning Curve in a High Volume Center.

BACKGROUND: Robotic surgery has been developed as a sophisticated tool to expand possibilities in minimal invasive surgery. The learning curve for this method is short in various surgical fields; however, limited data exist on the learning curve in robotic thoracic surgery. METHODS: This study analyzes a single center experience of robotic lobectomies using a prospectively kept database. Perioperative data and outcome of patients during the learning curve were compared with patients operated with increased institutional experience. The learning curve was defined as the initial 20 lobectomies. RESULTS: Sixty-four robotic lobectomies were performed between January 2014 and February 2017. Indications, preoperative lung functions, comorbidities, patient age, and tumor stage were comparable between patients operated during the learning curve and thereafter. The mean operative time could be significantly reduced after the learning curve (286 ± 86 vs. 211 ± 62 minutes; p = 0.0003). The conversion rate dropped from 4 of 20 (20%) during the learning curve to 2 of 44 (4.5%, p = 0.07) thereafter. Chest tube duration (4.3 ± 2.9 vs. 3.8 ± 2.1 days) and hospital stay (8.3 ± 3.4 vs. 7.9 ± 4.5 days) were not different in the two phases. The number of resected lymph nodes increased from 11.2 ± 6.8 to 13.9 ± 6.5 (p = 0.0797). Lymph node upstaging was achieved in 8 (12.9%) cases. Ninety-day mortality was 0%, and 2-year overall survival was 83%. CONCLUSIONS: Robotic thoracic surgery can be safely performed and trained with low complication rates and contributes to the extension of minimal invasive thoracic surgery. The initial learning curve in our experience is overcome after 20 cases. However, to become proficient in more advanced procedures and to further reduce operative time, additional training is required. Prospective studies are required to clearly determine the role of robotic surgery in comparison to the video-assisted thoracoscopic surgery (VATS) procedures.

Pulmonary metastasectomy for sarcoma-Essen experience.

BACKGROUND: Pulmonary metastasectomy is an established treatment modality for patients with soft as well as bone tissue sarcomas. Aim of this study is to describe the Essen experience in the surgical management of patients with pulmonary sarcoma metastases. METHODS: This is a retrospective single center analysis of perioperative outcome of patients undergoing pulmonary metastasectomy for sarcoma metastases from 1997-2017 and a summary of published papers on this topic. RESULTS: During the observation period 327 patients (49.23% female) underwent pulmonary metastasectomy for metastases of extrathoracic sarcomas in curative intent. The number of resected metastases was 1-3 in 283 cases (86.54%), 4-9 in 31 cases (9.48%) and 10 or more lesions in 14 cases (4.28%). Wedge resections or precision excisions with laser or electrocautery were performed in 278 cases (85.02%), anatomical segmental resections in 16 patients (4.89%) and lobectomies in 33 patients (10.09%). Bilateral procedures were performed in 98 cases (29.96%). Lymphadenectomy was performed in 122 patients. Positive lymph nodes were found only in 6 cases. All of these cases were patients with soft tissue sarcoma as primary tumor. Preoperative neoadjuvant treatment was performed in 79 patients (24.15%) with chemotherapy, in 54 patients (16.51%) with radiochemotherapy and in 10 patients (3.05%) with radiotherapy. Major postoperative complications were observed in 2.75% of all patients. Thirty-day mortality was 0%. CONCLUSIONS: Pulmonary metastasectomy in sarcoma patients is a feasible and safe treatment strategy even in patients with bilateral metastases and multiple lesions. Thoracic lymph node metastases are rare and did not influence survival in our cohort.

Resection of the Tracheobronchial Bifurcation With Complete Preservation of Lung Parenchyma.

BACKGROUND: The resection of the tracheobronchial bifurcation with complete preservation of lung parenchyma remains a challenge owing to the limited indications for surgery, anesthesiologic management, operative technique, and postoperative course. The aim of this retrospective study was to evaluate factors influencing the perioperative course and long-term survival. METHODS: Between 1989 and 2014, 19 patients underwent a resection of the distal trachea and carina with complete preservation of lung tissue, 16 for malignant tumors (7 adenoid cystic carcinomas, 3 carcinoid tumors, 3 mucoepidermoid tumors, 2 squamous cell carcinomas, and 1 small cell carcinomas), 2 for inflammatory stenosis, and 1 after a complex traumatic rupture. RESULTS: Surgical approach was posterolateral thoracotomy in 17 patients and median sternotomy in 2. In 16 patients, end-to-end anastomosis was performed, and in 3 patients, combined end-to-end and side-to-end anastomosis were performed. The operative mortality was 0%, the perioperative complication rate was 26.3%. Six patients with adenoid cystic carcinoma and all patients with lung carcinoma received adjuvant radiotherapy; only 1 patient with small cell lung cancer had chemotherapy before surgery. Long-term results are excellent in patients with benign disease, typical and atypical carcinoid tumor, mucoepidermoid carcinoma, and in most patients with adenoid cystic carcinoma. Two patients with lung cancer died 28 and 45 months after surgery, and 1 patient with adenoid cystic carcinoma died 75 months after surgery. CONCLUSIONS: Resection of the tracheobronchial bifurcation with complete preservation of lung indicated for selected patients with local tumor growth at the distal trachea and carina provides low perioperative mortality and complications and results in long-term survival rates.

Definitive radiochemotherapy versus surgery within multimodality treatment in stage III non-small cell lung cancer (NSCLC) - a cumulative meta-analysis of the randomized evidence.

Randomized trials were analyzed comparing surgery with definitive radiotherapy as local curative treatment options within the framework of different multimodality treatments for patients with locally advanced non-small cell lung cancer (NSCLC). Endpoints for comparison of treatment results were overall survival, progression-free survival, and toxicity.Hazard ratios (HR) were taken to measure treatment effects and pooled using a random effects model.Overall survival was not significantly different between surgical and definitive radiotherapy arms (HR=0.92 [95%CI 0.82-1.04], p=0.19, χ2-test). There was heterogeneity with respect to survival at 2 years (p<0.0001, Cochran Mantel Haenszel (CMH)-test). Latter trials using concurrent radiochemotherapy (ccRT/CT) showed better survival at 2 years (risk ratio of death=0.80 [95%CI 0.73-0.88], p<0.0001, CMH-test). In the ccRT/CT trials, survival in the surgical arms tended to have an excess early mortality before 6 months of follow-up and a lesser hazard rate in comparison to definitive ccRT/CT thereafter (HR=0.78 [95%CI 0.63-0.98]). Over all trials, treatment associated mortality was higher in the surgical arms (risk ratio=3.56 [95% CI: 1.65-7.72], p=0.0005, CMH test). With respect to progression-free survival, no significant differences were found (HR=0.91 [95%CI: 0.73 - 1.13]), although the largest conducted trial found an advantage for the surgical arm (HR=0.77 [95%CI: 0.62-0.96]).Induction therapy followed by resection or definitive radiochemotherapy represent valuable curative treatment options for patients with stage III NSCLC, the individual treatment choice deserves careful interdisciplinary evaluation and counseling. Based on the broad heterogeneity of patient groups in these stages further research on predictive factors supporting individual therapy selection is necessary.

The Influence of Type of Anesthesia, Perioperative Pain, and Preoperative Health Status on Chronic Pain Six Months After Thoracotomy-A Prospective Cohort Study.

BACKGROUND: Chronic post-thoracotomy pain (CPP) has a high incidence. However, less is known about risk factors and the influence of different analgesia therapies. METHODS: In this prospective cohort study, patients either received standardized epidural analgesia or began an oral analgesic protocol with controlled-release oxycodone immediately postoperatively. Patients answered a baseline questionnaire on the day before surgery and a follow-up questionnaire six months postoperatively. The questionnaire included Short-Form 12, the Neuropathic Pain Scale, and descriptive questions for CPP. Pain protocols of all patients were examined. Logistic regression was used to analyze the risk factors related to CPP. RESULTS: One hundred seventy-four patients were enrolled; data of 131 patients were available after the six-month follow-up period. Fifty-one patients (39%) had CPP six months postoperatively. Of these, more than 80% had impaired daily activity or ability to work, or reported sleeping disturbance due to CPP. The strongest predictive factors for the development of CPP were: thoracic pain for three months preoperatively (odds ratio [OR] = 3.54, 95% confidence interval [CI] = 1.69-7.40, P = 0.001), thoracic pain for 12 months preoperatively (OR = 2.73, 95% CI = 1.28-5.83, P = 0.009), and higher pain scores at rest in the first five postoperative days compared with patients without CPP (OR = 1.79, 95% CI = 1.24-2.57, P = 0.002). Neuropathic pain was present in 4.8% of patients. Patients with CPP had a reduced physical (P = 0.005) and mental health status (P = 0.03) six months after surgery compared with patients without CPP. CONCLUSIONS: Preoperative thoracic pain and higher pain scores in the first five postoperative days seem to be the strongest risk factors for the development of CPP. CPP patients reported poorer mental and physical health before and six months after surgery.

Hydrogeochemical investigations in a drained lake area: the case of Xynias basin (Central Greece).

In Xynias drained Lake Basin's area, central Greece, a hydrogeochemical research took place including groundwater sampling from 30 sampling sites, chemical analysis, and statistical analysis. Groundwaters present Ca-Mg-HCO3 as the dominant hydrochemical type, while their majority is mixed waters with non-dominant ion. They are classified as moderately hard to hard and are characterized by oxidizing conditions. They are undersaturated with respect to gypsum, anhydrite, fluorite, siderite, and magnesite and oversaturated in respect to calcite, aragonite, and dolomite. Nitrate concentration ranges from 4.4 to 107.4 mg/L, meanwhile 13.3 % of the samples exceed the European Community (E.C.) drinking water permissible limit. The trace elements Fe, Ni, Cr, and Cd present values of 30, 80, 57, and 50 %, respectively, above the maximum permissible limit set by E.C. Accordingly, the majority of the groundwaters are considered unsuitable for drinking water needs. Sodium adsorption ratio values (0.04-3.98) and the electrical conductivity (227-1200 µS/cm) classify groundwaters as suitable for irrigation uses, presenting low risk and medium soil alkalization risk. Factor analysis shows that geogenic processes associated with the former lacustrine environment and anthropogenic influences with the use of fertilizers are the major factors that characterized the chemical composition of the groundwaters.

Standardized Uptake Decrease on [18F]-Fluorodeoxyglucose Positron Emission Tomography After Neoadjuvant Chemotherapy Is a Prognostic Classifier for Long-Term Outcome After Multimodality Treatment: Secondary Analysis of a Randomized Trial for Resectable Stage IIIA/B Non-Small-Cell Lung Cancer.

PURPOSE: A confirmatory analysis was performed to determine the prognostic value of metabolic response during induction chemotherapy followed by bimodality/trimodality treatment of patients with operable locally advanced non-small-cell lung cancer. PATIENTS AND METHODS: Patients with potentially operable stage IIIA(N2) or selected stage IIIB non-small-cell lung cancer received three cycles of cisplatin/paclitaxel (induction chemotherapy) followed by neoadjuvant radiochemotherapy (RCT) to 45 Gy (1.5 Gy twice per day concurrent cisplatin/vinorelbine) within the ESPATUE (Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA[N2] and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy) trial. Positron emission tomography scans were recommended before (t0) and after (t2) induction chemotherapy. Patients who were eligible for surgery after neoadjuvant RCT were randomly assigned to definitive RCT or surgery. The prognostic value of percentage of maximum standardized uptake value (%SUVmax) remaining in the primary tumor after induction chemotherapy-%SUVremaining = SUVmax(t2)/SUVmax(t0)-was assessed by proportional hazard analysis and receiver operating characteristic analysis. RESULTS: Overall, 161 patients were randomly assigned (155 from the Essen and Tübingen centers), and 124 of these received positron emission tomography scans at t0 and t2. %SUVremaining as a continuous variable was prognostic for the three end points of overall survival, progression-free survival, and freedom from extracerebral progression in univariable and multivariable analysis (P < .016). The respective hazard ratios per 50% increase in %SUVremaining from multivariable analysis were 2.3 (95% CI, 1.5 to 3.4; P < .001), 1.8 (95% CI, 1.3 to 2.5; P < .001), and 1.8 (95% CI, 1.2 to 2.7; P = .006) for the three end points. %SUVremaining dichotomized at a cut point of maximum sum of sensitivity and specificity from receiver operating characteristic analysis at 36 months was also prognostic. Exploratory analysis revealed that %SUVremaining was likewise prognostic for overall survival in both treatment arms and was more closely associated with extracerebral distant metastases (P = .016) than with isolated locoregional relapses (P = .97). CONCLUSION: %SUVremaining is a predictor for survival and other end points after multimodality treatment and can serve as a parameter for treatment stratification after induction chemotherapy or for evaluation of adjuvant new systemic treatment options for high-risk patients.

A Single-Institution Analysis of the Surgical Management of Pulmonary Large Cell Neuroendocrine Carcinomas.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) is an uncommon tumor of the lung and represents approximately 3% of all lung cancers. LCNEC displays biological behaviors resembling those of small cell lung carcinomas and features of high-grade neuroendocrine tumors. LCNEC of the lung are considered aggressive. Reported prognoses are heterogeneous, and the optimum treatment remains undefined. METHODS: We conducted a retrospective study of all patients who were treated for LCNEC in our Department of Thoracic Surgery between May 2005 and December 2013. Primary outcomes of interest were patient survival and prognostic factors. Kaplan-Meier analysis was performed to determine the significant predictors of overall survival. RESULTS: Within the prescribed period, 127 patients were treated for LCNEC, and 125 underwent surgical resection with curative intent. Induction chemotherapy or radiochemotherapy was given to 9 patients, and 63 patients received postoperative chemotherapy. Complete resection was achieved in 99.2%. The overall 1-, 3- and 5-year survival rates were 83.7%, 63.2%, and 53.8% of all patients, and the 5-year survival in patients at stages I, II, and III was 64.5%, 40%, and 29.7%. There was a significant survival difference at 5 years between pT1/2 (58.5%) and pT3 tumors (22.4%; p = 0.043) and for patients with lymphatic involvement (L0 vs L1, p = 0.001; pN1 or pN2 vs pN0, p = 0.04). CONCLUSIONS: Surgical treatment can achieve satisfactory results in early tumor stages, which are comparable with other non-small cell lung cancers, with a low perioperative mortality rate.

Three-Year Follow-Up of a Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (the TREAT Study).

INTRODUCTION: Adjuvant chemotherapy in non-small cell lung cancer (NSCLC) improves survival but is associated with significant toxicity. The Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (TREAT study) was designed to test the hypothesis that a protocol with reduced toxicity might improve feasibility of postoperative delivery of adjuvant chemotherapy drugs to patients with NSCLC, thereby improving compliance and, potentially, survival. METHODS: Two adjuvant regimens were evaluated for feasibility in 132 patients with NSCLC: the standard regimen of cisplatin and vinorelbine (CVb) (cisplatin 50 mg/m(2) on day 1 and day 8 and vinorelbine 25 mg/m(2) on days 1, 8, 15, and 22 every 4 weeks) and a regimen consisting of cisplatin and pemetrexed (CPx) (cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 every 3 weeks). The primary end-point analysis showing that CPx is safe and feasible with dose delivery superior to that of CVb has already been published. Here we report the 3-year follow-up results of the secondary efficacy end points-overall, relapse-free, distant metastasis-free, and local relapse-free survival-also with regard to histologic diagnosis. RESULTS: After a median of 39 months, no significant differences in any of the outcome parameters between CVb and CPx were observed. Also, histologic diagnosis and tumor size in stage IB did not influence survival in the CPx-treated patients. Yet, Cox regression analyses showed that overall survival at 3 years was significantly correlated with feasibility and the occurrence of dose-limiting toxicity. CONCLUSIONS: Although adjuvant chemotherapy with CPx is safe and characterized by less toxicity and better dose delivery than CVb, overall survival was not influenced by treatment arm in the context of this phase II trial.