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.

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.

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.

Short- and Mid-Term Changes in Lung Function after Bilateral Pulmonary Metastasectomy.

INTRODUCTION: The resection of pulmonary metastases is associated with a loss of lung function. The amount of functional impairment after bilateral metastasectomy remains unclear. Because only around 35% of those patients may expect long-term survival, it is important to preserve enough pulmonary function for an adequate quality of life. This analysis of 31 bilaterally operated patients was performed to describe the amount of pulmonary function loss. METHODS: This is a post-hoc subanalysis and comparison of a population that was published before. All pulmonary metastasectomies were performed through an anteroaxillary thoracotomy in all patients. Resections were performed with staplers, electrocautery, or laser. All patients had pulmonary function tests (PFTs) preoperative and after 3 months at the follow-up visit, including spirometry, diffusing capacity of lung for carbon monoxide (Dlco) and blood gases. Of the 31 bilaterally operated cases, 15 had additional PFTs after each staged operation before discharge from hospital. RESULTS: Altogether, 271 nodules (median 7, mean 8.2) were removed from the 31 patients with a lobectomy in 2, a segmentectomy in 8, and multiple wedge resections in 21 patients, with this being the largest resection. The mean loss of pulmonary function at follow-up visit was forced vital capacity (FVC) - 15.2%, total lung capacity (TLC) - 13.8%, forced expiratory volume in 1 second (FEV1) - 16.3%, and Dlco - 10.3%, all of which were significant (p = < 0.001). The 15 patients with PFTs after each operation showed a stepwise decrease of volume parameters and Dlco with deepest values after the second surgery of around - -40% from preoperative values. At this time, Po 2 was also significantly reduced by 10 mm Hg (p = 0.01). Comparing the bilateral group with 86 patients after unilateral metastasectomy, we found significantly more nodules removed in the bilateral group (8.2 vs. 3.1; p < 0.001) and that the loss of volume parameters was twice that of the unilateral group after metastasectomy. Dlco impairment did not differ between the groups (- 10.3 vs. - 9.5%; p = 0.868) after 3 months. CONCLUSION: Midterm pulmonary function impairment after bilateral pulmonary metastasectomy is 15% of spirometry values and 10% of Dlco. Reduction of spirometry values is almost twice compared with the group after unilateral surgery. Early functional loss after the second intervention causes FVC, TLC, and FEV1 reduction of around 40% and is associated with lower Po 2 (- 10 mm Hg). Therefore, bilateral metastasectomy can be offered to patients who do not have greater pulmonary limitations.

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.

Staging of lung cancer: the role of noninvasive, minimally invasive and invasive techniques.

Accurate staging and restaging of primary tumour and mediastinal nodes in patients with lung cancer is of significant importance. For primary tumours, computed tomography (CT) scans of the chest are recommended. Positron emission tomography (PET) imaging should be used in patients with curative intent treatment to evaluate metastatic disease. Diagnosis of the primary tumour should be performed using bronchoscopy or CT-guided transthoracic needle aspiration. In patients with enlarged mediastinal nodes and no distant metastasis, invasive staging of the mediastinum is required. For suspicious N2 or N3 disease, endoscopic needle techniques, such as endobronchial ultrasound and transbronchial needle aspiration, oesophageal ultrasound and fine needle aspiration, or a combination of both, are preferred to any surgical staging technique. In cases of suspicious nodes and negative results using needle aspiration techniques, invasive surgical staging using mediastinoscopy or video-assisted thoracic surgery should be performed. In central tumours or N1 nodes, preoperative invasive staging is indicated.Restaging after induction therapy remains a controversial topic. Today, neither CT, PET nor PET/CT scans are accurate enough to make final further therapeutic decisions for mediastinal nodal involvement. An invasive technique providing cytohistological information is still recommended.

Prognostic model for long-term survival of locally advanced non-small-cell lung cancer patients after neoadjuvant radiochemotherapy and resection integrating clinical and histopathologic factors.

BACKGROUND: Outcome of consecutive patients with locally advanced non-small cell lung cancer and histopathologically proven mediastional lymph node metastases treated with induction chemotherapy, neoadjuvant radiochemotherapy and thoracotomy at the West German Cancer Center between 08/2000 and 06/2012 was analysed. A clinico-pathological prognostic model for survival was built including partial or complete response according to computed tomography imaging (CT) as clinical parameters as well as pathologic complete remission (pCR) and mediastinal nodal clearance (MNC) as histopathologic factors. METHODS: Proportional hazard analysis (PHA) and recursive partitioning analysis (RPA) were used to identify prognostic factors for survival. Long-term survival was defined as survival ≥ 36 months. RESULTS: A total of 157 patients were treated, median follow-up was 97 months. Among these patients, pCR and MNC were observed in 41 and 85 patients, respectively. Overall survival was 56 ± 4% and 36 ± 4% at 24 and 60 months, respectively. Sensitivities of pCR and MNC to detect long-term survivors were 38% and 61%, specificities were 84% and 52%, respectively. Multivariable survival analysis revealed pCR, cN3 category, and gender, as prognostic factors at a level of α < 0.05. Considering only preoperative available parameters, CT response became significant. Classifying patients with a predicted hazard above the median as high risk group and the remaining as low risk patients yielded better separation of the survival curves by the inclusion of histopathologic factors than by preoperative factors alone (p < 0.0001, log rank test). Using RPA, pCR was identified as the top prognostic factor above clinical factors (p = 0.0006). No long term survivors were observed in patients with cT3-4 cN3 tumors without pCR. CONCLUSIONS: pCR is the dominant histopathologic response parameter and improves prognostic classifiers, based on clinical parameters. The validated prognostic model can be used to estimate individual prognosis and forms a basis for patient selection for treatment intensification.

Marker-free automated histopathological annotation of lung tumour subtypes by FTIR imaging.

By integration of FTIR imaging and a novel trained random forest classifier, lung tumour classes and subtypes of adenocarcinoma are identified in fresh-frozen tissue slides automated and marker-free. The tissue slices are collected under standard operation procedures within our consortium and characterized by current gold standards in histopathology. In addition, meta data of the patients are taken. The improved standards on sample collection and characterization results in higher accuracy and reproducibility as compared to former studies and allows here for the first time the identification of adenocarcinoma subtypes by this approach. The differentiation of subtypes is especially important for prognosis and therapeutic decision.

Controlled-Release Oxycodone as "Gold Standard" for Postoperative Pain Therapy in Patients Undergoing Video-Assisted Thoracic Surgery or Thoracoscopy: A Retrospective Evaluation of 788 Cases.

BACKGROUND: To assess the clinical efficacy of controlled-release oxycodone for postoperative analgesia after video-assisted thoracic surgery (VATS) or thoracoscopy. METHODS: Pain therapy is standardized in our thoracic center throughout the complete postoperative stay. Patients receive immediately postoperative standardized oral analgesic protocol with controlled-released oxycodone (Oxy Group) or oxycodone with naloxone (Targin Group) and nonopioid every 6 h. We switched the opioid protocol from controlled-release oxycodone to Targin in January 2012. All patients are visited daily by a pain specialist throughout the whole stay. RESULTS: Data of 788 patients undergoing VATS (n = 367) or thoracoscopy (n = 421) during January 2011 until March 2013 were analyzed. In VATS, patients with Targin had higher pain scores at rest (p < 0.02) and on coughing (p < 0.001) than patients with oxycodone alone and more patients with Targin were dismissed with oral opioid dose than patients with oxycodone alone (p < 0.001). No differences in pain scores on POD 5 and 6, or in length of hospital stay, incidence of nausea, time to first dejection or opioid dose after dismission were found between controlled-release oxycodone and Targin. After conventional thoracoscopy, 209 patients received controlled-release oxycodone and 212 Targin. Patients with Targin had higher pain scores at rest (p < 0.004) and on coughing (p < 0.01) than patients with oxycodone alone and more patients with Targin were dismissed with oral opioid dose than patients with oxycodone alone (p < 0.004). There were no differences in pain scores on POD 5 and 6, or in length of hospital stay, incidence of nausea, time to first dejection or opioid dose after dismission. CONCLUSION: Oral opioid analgesia with controlled-release oxycodone is an effective postoperative regimen after VATS and thoracoscopies. Our retrospective data indicate that Targin might be less effective analgesic than oxycodone after VATS and thoracoscopies with no improvement in bowel function in the immediate postoperative period. STUDY LIMITATIONS: The study design is retrospective in nature.

Surgery of primary lung cancer with oligometastatic m1b synchronous single brain metastasis: analysis of 37 cases.

BACKGROUND: At the time of diagnosis, lung cancer has often metastasized already. Brain metastases, however, are associated with a poor prognosis (median survival of less than 1 year). We evaluated the changes of the median survival after resection of the cerebral metastases and primary non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Between January 1999 and December 2009, 37 patients (22 men, 15 women; median age: 55.64 years; age range: 38-72 years) underwent surgery for primary NSCLC after craniotomy and removal of the synchronous single brain metastasis. The overall survival was evaluated and risk factors identified. RESULTS: Mediastinal lymph node involvement was excluded with mediastinoscopy in 26 of the 37 patients. Postoperative N-stage was N0, N1, and N2 in 16 (43%), 10 (27%), and 11 (30%) patients, respectively. Histology was squamous cell carcinoma in 10 (27%), adenocarcinoma in 20 (54%), and large cell carcinoma in 7 (19%). The employed type of resection was anatomical segmentectomy in 6 and lobectomy in 31 patients. The 30-day mortality was 0% and postoperative complications occurred in 12 patients only (32%). The overall 1 and 2 years survival were 62 and 24%, respectively. None of the factors age, sex, tumor histology, primary location of the tumor, type of resection, adjuvant chemotherapy, or nodal status affected survival in the univariate analysis. CONCLUSIONS: The oncologic lung resection of NSCLC after the resection of a single brain metastasis can be implemented without an increased risk of complications or mortality. Despite the stage IV disease, the median survival appears encouraging.

Experimental respiratory syncytial virus infection of human peribronchial gland cells in vitro.

Respiratory syncytial virus (RSV) is a relevant agent of respiratory tract infections, especially in exacerbations of chronic lung diseases. Peribronchial submucosal glands are the main source of tracheobronchial mucus and therefore of major interest. The authors isolated and cultured human peribronchial gland cells and infected them with RSV. The course of infection was monitored by transmission electron, immuno-, and lectin fluorescence microscopy. Morphology shows virus factories with budding particles within cytoplasmatic vacuoles and virus release after 44 h of infection. Experimental infection of human peribronchial gland cells in primary culture appears to be a suitable model in pulmonary research.

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.

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.

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.