Ki67 Tumor Expression Predicts Treatment Benefit Achieved by Macroscopic Radical Lung-Preserving Surgery in Pleural Mesothelioma-A Retrospective Multicenter Analysis.

Pleural mesothelioma (PM), linked to asbestos-induced inflammation, carries a poor prognosis. Therapy ranges from therapy limitation to aggressive multimodality treatment. Given the uncertainty about treatment benefits for patients, this study aimed to assess the role of Ki67 as a prognostic and predictive parameter in PM. Ki67 was measured in the specimens of 70 PM patients (17 female, 53 male) from two centers and correlated to overall survival (OS) and therapy outcome. The median OS was 16.1 months. The level of Ki67 expression was divided into low (≤15%) and high (>15%). A low value of Ki67 expression was associated with a longer OS (Ki67 ≤ 15%: 31.2 (95% CI 6.5-55.8) months vs. Ki67 > 15%: 11.1 (95% CI 7.7-14.6) months, p = 0.012). The 5-year survival represents 22% in the low Ki67 expression group, in contrast to 5% in the high Ki67 expression group. We found a significant interaction term of Ki67 with multimodality treatment (p = 0.031) translating to an OS of 48.1 months in the low expression Ki67 group compared to 24.3 months in the high Ki67 expression group when receiving surgery within multimodality therapy. Therefore, Ki67 stands out as a validated prognostic and, most importantly, novel predictive biomarker for treatment benefits, particularly regarding surgery within multimodality therapy.

Schwannoma of the phrenic nerve. A case report.

BACKGROUND: Neurogenic tumors are the third most common tumors occurring within the mediastinum. Predominantly completely asymptomatic, they are most often found in the posterior mediastinum, although they may also be located, albeit rarely, in the middle mediastinum. Thus, in the cases of tumors localized in the middle mediastinum, schwannomas of the phrenic nerve must always be considered. CASE REPORT: In this case, a male patient presented with a tumor of the middle mediastinum. PET/CT scan determined that it was a circumscribed tumor without signs of dissemination. However, due to the tumor's location, a preoperative biopsy of the tumor was not possible. Therefore, the patient underwent videothoracoscopic extirpation of the tumor, including the necessary resection of the phrenic nerve that passed through the centre of the tumor. Subsequent histological analysis definitively confirmed a schwannoma with low proliferative activity. CONCLUSIONS: Differential diagnosis of mediastinal tumours is very difficult; however, in the case of circumscribed tumours not invading the surrounding tissues, proceeding to surgical revision, with the complete removal of the tumour, is possible, even without determining the histological nature. Minimally invasive surgical techniques dominate the treatment of neurogenic tumors of the mediastinum; they are associated with minimal complications and allow a rapid return of the patient to their normal activities.

Clinical and prognostic significance of detecting CEA, EGFR, LunX, c-met and EpCAM mRNA-positive cells in the peripheral blood, tumor-draining blood and bone marrow of non-small cell lung cancer patients.

Background: Surgical treatment of early-stage non-small cell lung cancer (NSCLC) yields highest expectations for recovery. However, the frequency of further disease progression remains high since micro-metastatic disease may be undetected by conventional diagnostic methods. We test the presence and prognostic impact of circulating tumor cells (CTCs) in peripheral blood (PB), tumor-draining pulmonary blood (TDB) and bone marrow (BM) samples from NSCLC patients. Methods: The presence of circulating/disseminated tumor cells (CTCs/DTCs) was detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analysis in PB, TDB and BM samples before surgery in 119 stage IA-IIIA NSCLC patients (Clinical Trial NS10285). Results: NSCLC patients with the presence of carcinoembryonic antigen (CEA) mRNA-positive CTCs/DTCs in TDB and BM had significantly shorter cancer-specific survival (CSS) (P<0.013, resp. P<0.038). Patients with the presence of epithelial cellular adhesion molecule (EpCAM) mRNA-positive CTCs in TDB samples had significantly shorter CSS and disease-free survival (DFS) (P<0.031, resp. P<0.045). A multivariate analysis identified the presence of CEA mRNA-positive CTCs in the PB as an independent negative prognostic factor for DFS (P<0.005). No significant correlation of CTCs/DTCs presence and other prognostic factors was found. Conclusions: In NSCLC patients undergoing radical surgery, the presence of CEA and EpCAM mRNA-positive CTCs/DTCs is associated with poorer survival.

Lymph Node Log-Odds Ratio Accurately Defines Prognosis in Resectable Non-Small Cell Lung Cancer.

OBJECTIVES: The ratio of positive and resected lymph nodes (LN ratio) has been shown to be prognostic in non-small cell lung cancer (NSCLC). Contrary to the LN ratio, calculating the LN log-odds ratio (LN-LOR) additionally considers the total number of resected lymph nodes. We aim to evaluate LN-LOR between positive and resected lymph nodes as a prognostic factor in operable NSCLC. METHODS: Patients with NSCLC who underwent curative intent lobectomy treated at two high-volume centers were retrospectively studied. LN-LOR was dichotomized according to impact on OS and further combined with N descriptors and correlated with clinical variables and survival. RESULTS: 944 patients were included. Cut-off analysis revealed that an LN-LOR of -0.34 significantly discriminated patients according to OS (p < 0.001, chi-squared test 41.26). When combined with N1 and N2 descriptors, LN-LOR low risk (median OS not reached and 83 months) and LN-LOR high-risk patients (median OS 50 and 59 months) had similar survival irrespective of the anatomical location of the positive lymph nodes. Multivariable Cox regression analysis revealed that age (HR 1.02, 95% CI 1.001-1.032), sex (male, HR 1.65, 95% CI 1.25-2.19), histological subtype (HR 2.11, 95% CI 1.35-3.29), pathological stage (HR 1.23, 95% CI 1.01-1.45) and LN-LOR risk groups (low risk, HR 0.48, 95% CI 0.32-0.72) were independent prognostic factors for OS. CONCLUSIONS: This retrospective two-center analysis shows that LN-LOR is significantly associated with OS in resectable NSCLC and might better reflect the biological behavior of the disease, regardless of anatomical lymph node locations. This finding may additionally support the value of extensive LN dissection.

Biomarkers for Malignant Pleural Mesothelioma-A Novel View on Inflammation.

Malignant pleural mesothelioma (MPM) is an aggressive disease with limited treatment response and devastating prognosis. Exposure to asbestos and chronic inflammation are acknowledged as main risk factors. Since immune therapy evolved as a promising novel treatment modality, we want to reevaluate and summarize the role of the inflammatory system in MPM. This review focuses on local tumor associated inflammation on the one hand and systemic inflammatory markers, and their impact on MPM outcome, on the other hand. Identification of new biomarkers helps to select optimal patient tailored therapy, avoid ineffective treatment with its related side effects and consequently improves patient's outcome in this rare disease. Additionally, a better understanding of the tumor promoting and tumor suppressing inflammatory processes, influencing MPM pathogenesis and progression, might also reveal possible new targets for MPM treatment. After reviewing the currently available literature and according to our own research, it is concluded that the suppression of the specific immune system and the activation of its innate counterpart are crucial drivers of MPM aggressiveness translating to poor patient outcome.

Minimally invasive esophagectomy for esophageal cancer - results of surgical therapy.

INTRODUCTION: The indication for minimally invasive esophagectomy (MIE) in esophageal cancer has an increasing tendency. AIM: To present our cohort of patients operated on between 2006 and 2012. MATERIAL AND METHODS: A single centre study of 106 consecutive esophagectomies performed for esophageal cancer by a minimally invasive approach in 79 patients was performed. Transhiatal laparoscopic esophagectomy (THLE) was performed in 66 patients, transthoracic esophagectomy (TTE) in 13 patients, with histological findings of squamous cell carcinoma in 28 and adenocarcinoma in 51 patients. RESULTS: The MIE was completed in 76 (96.2%) patients. In cases of TTE, the operation was converted to an open procedure in 3 cases. Operation time ranged from 225 to 370 min (average 256 min). The number of lymph nodes removed was 7-16 (11 on average). The postoperative course was without any complications in 54 (68.3%) patients. Respiratory complications were observed in 14 (17.7%) patients (9 following THLE, 5 following TTE). Other serious complications included acute myocardial infarction (1 patient) and necrosis of the gastroplasty (1 patient). Anastomotic dehiscence was observed in 8 patients, left recurrent laryngeal nerve paralysis in 8 patients, intra-abdominal abscesses in 2 patients, and pleural empyema in 1 case. The overall morbidity of patients operated on by MIE was 31.6%. Thirty-day mortality was 10.1%. CONCLUSIONS: The MIE belongs to the therapeutic portfolio of surgical procedures performed for esophageal cancer. Successful performance requires erudition of the surgical team in both minimally invasive procedures as well as in classical surgical treatment of esophageal cancer; therefore centralization of patients is imperative.

Detection of minimal residual disease in lung cancer.

BACKGROUND: Even after successful radical treatment of lung cancer, patients in stages I and II of the TNM system very frequently suffer recurrence, which end lethally. Detection of subclinical residual disease after surgery is thus one of the most important emerging diagnostic methods. Minimal residual disease (MRD) is defined as the presence of isolated tumor cells or circulating cells in a patient after curative primary tumor removal and at the same time, no clinical signs of cancer. Conventional methods cannot detect minimal residual disease and hence there is a need for detection using new molecular biological methods. METHODS: We searched the PubMed database for original and review articles on minimal residual disease in lung cancer. Search words were "lung cancer", "minimal residual disease" and "detection of minimal residual disease". The publications we found were compared with the results of our own studies on the detection of minimal residual disease in lung cancer and the personal experiences are described. Examination of blood samples from 98 healthy volunteers and bone marrow from 12 patients with non inflammatory and non tumour illness, were used to determine cut-off values for specific markers in the compartments. Subsequently, expression of selected markers in tumor tissue was analysed in a pilot sample of 50 patients with lung cancer and the presence of MRD was measured as expression of values of the tested markers correlated with clinico-pathological characteristics. CONCLUSIONS: Recent studies on other malignancies apart from lung cancer have shown the importance of MRD detection in the determination of disease progression and prognosis. The methods of MRD diagnostics are based on detection of specific tumor markers. Of these, the most specific for lung cancer, appears to be the LunX protein. The best method for determining MRD is probably RT-PCR. Further studies should expand knowledge in this area: to refine understanding of the importance of tumor markers for prognosis, as well as to confirm the significance of these findings in clinical practice.

Videothoracoscopic identification of chondromatous hamartoma of the lung.

INTRODUCTION: The main disadvantage of a videothoracoscopic procedure is the lack of touch sensation. The probability of easily finding the lesion is usually estimated according to computed tomography (CT). AIM: To find useful parameters of location of chondromatous hamartoma of the lung parenchyma in relation to its size to assess the probability of successful search via a videothoracoscopic approach only. MATERIAL AND METHODS: A group of 55 patients operated on for chondromatous hamartoma of the lung at the First Department of Surgery in Olomouc from January 2006 to June 2011 was analyzed. Initially, the tumor's longest diameter and its nearest distance to the pleural surface were measured on CT scans. Subsequently, the surgery began using the videothoracoscopic approach. A short thoracotomy with direct palpation followed when videothoracoscopy failed. RESULTS: No significant differences in age, sex and side of localization between the group with and without successful videothoracoscopic detection were found. A significant difference was found in the median size (p = 0.026) and the depth of the tumor (p < 0.0001) and in the calculated index "tumor size/depth" (p < 0.0001). Deeper analysis revealed that the parameters "depth" and "index size/depth" are considered to be good predictors but the parameter "size" is not a suitable predictor. CONCLUSIONS: The main predictors of successful videothoracoscopic detection of lung chondromatous hamartoma are considered to be the depth of the tumor in the lung parenchyma with a cut-off value ≤ 7.5 mm and the index "size/depth" with a cut-off value ≥ 1.54; the tumor size is not considered to be a good predictor.

Thoracoscopic treatment of benign esophageal tumors.

INTRODUCTION: Gastrointestinal stromal tumors are among the most frequent mesenchymal tumors of the gastrointestinal tract; the incidence of these tumors in the esophagus is less than 5%. Prognosis depends on localization, size, mitotic activity and possible invasion of surrounding structures. Minimally invasive surgery may be maximally utilized for removal of these tumors from the esophageal wall. This operation is usually performed thoracoscopically or laparoscopically and using the "rendez-vous" method - with endoscopic navigation. AIM: To evaluate a set of patients with benign tumor of the esophagus who were operated on at the First Department of Surgery from 2006 to 2011. MATERIAL AND METHODS: In the years 2006-2011 a total of 11 patients with benign tumors of the esophagus underwent operation. RESULTS: Of the 11 patients with esophageal tumor, 5 were diagnosed with gastrointestinal stromal tumor, 5 with leiomyoma and in one patient the lesion was described as heterotopy of the pancreas. We used the minimally invasive rendez-vous method with endoscopic navigation in 9 cases. All patients healed primarily and were released from hospital on the 4(th)-7(th) day. These patients are being followed up as outpatients and recurrence of the tumor has not been observed in any of them. CONCLUSIONS: Minimally invasive treatment of benign tumors of the esophageal wall is considered to the method of choice. Due to possible complications and the need for subsequent therapy in some patients, these procedures should be centralized to departments with experience in esophageal, thoracic and minimally invasive surgery.

Video-assisted laparoscopic resection of the esophagus for carcinoma after neoadjuvant therapy.

BACKGROUND/AIMS: Classical operation approaches, used for decades during subtotal esophageal resection for esophageal carcinoma, have certain disadvantages. The transhiatal "blind" approach according to Orringer lacks sufficient radicality, the thoracotomic approach is burdened by serious postoperative complications, primarily respiratory. These disadvantages are eliminated to a great extent by use of the video-assisted laparoscopic transhiatal approach, which is presented in our study. METHODOLOGY: Between 2000-2006 forty-three patients with esophageal cancer underwent video-laparoscopic transhiatal esophagectomy. In all patients passage was renewed by esophagogastroplasty, constructed by placing the neoesophagus in the posterior mediastinum, anastomosis with the cervical esophagus from a laparotomy. Prior to the operation, 27 patients underwent neoadjuvant radio-chemotherapy. Chemotherapy consisted of 5 fluorouracil and cisplatinum, and radiotherapy with a total dose of 50 Gy. RESULTS: The extirpation phase was completed laparoscopically in all patients. Right-sided pneumothorax was seen in 27 patients, in six cases postoperative manifestation of left vocal chord paresis due to damage to the recurrent laryngeal nerve was observed, in 2 patients a fistula developed in the cervical anastomosis, which in all cases healed spontaneously. The operation time ranged between 225-370 minutes, the average time being 256 minutes. The mini-invasive phase took an average of 40 minutes. One patient died 57 days after the operation due to respiratory insufficiency. The average hospital stay was 12.2 days. CONCLUSIONS: The video-assisted laparoscopic transhiatal approach proved to be very useful during subtotal esophageal resection. In tumors localized in the lower portion of the esophagus, it completely replaces the transhiatal "blind" approach according to Orringer and, in comparison, eliminates operative hemorrhagic complications, which are more frequent in "blind" extirpations, especially in patients after neoadjuvant therapy. It also enables performing a lymphadenectomy, which is not possible using the "blind" approach. In tumors of the middle thoracic esophagus, which are inaccessible by the original Orringer's approach, it eliminates the need for a thoracotomy, which significantly contributes to the decrease of respiratory complications.

p53--prognostic factor of malignant transformation of Barrett's esophagus.

The most significant precancerosis in the esophageal cancer is Barrett's esophagus. The risk of malignant transformation is determined primarily in accordance with the degree of dysplastic alterations of the mucosa. Indication of "preventive" extirpation of the esophagus should be supported by other factors, for example by detection of p53 mutation or expression. The study reports on the evaluation of a group of 20 patients with Barrett's esophagus treated at the 1st Department of Surgery, the p53 level and its correlation with histological findings evaluated in these patients. A good correlation was found between the grade of Barrett's esophagus dysplasia and high p53 positivity. This correlation was also confirmed by detection of early carcinoma in patients with "preventive" extirpation of the esophagus due to a high-grade dysplasia. Preliminary results show that examination of p53 level in specimens taken from the esophageal mucosa may be helpful for the estimation of malignant potential of the dysplastic mucosa.

Sentinel lymph node in esophageal cancer before neoadjuvant therapy.

UNLABELLED: The technique of sentinel lymph node identification and biopsy has become a new popular technique for surgeon to improve staging of malignant diseases. It may also reduce the risk of complication related to standard lymphadenectomy. The method is still in experimental phase in case of esophageal cancer. A possible complication for employment of the method in this tumor is neoadjuvant therapy. The authors developed the technique for identifying and obtaining the sentinel lymph node in esophageal cancer using minimally invasive surgical technique before neoadjuvant therapy. The sentinel lymph node is detected using 99mTc-labelled nanocolloid. The authors report and discuss possible difficulties of the method in the case of a patient with detected sentinel lymph node in this way. CONCLUSION: It is possible to identify and obtain a sentinel lymph node before neoadjuvant therapy in esophageal cancer. On the other hand, the clinical significance and applicability of the method of sentinel lymph node still remains controversial in this kind of a tumor.

Five-year survival after sleeve pneumonectomy combined with the superior vena cava replacement for lung cancer.

The authors report an excellent long-term survival after sleeve pneumonectomy combined with the superior vena cava (SVC) replacement for T4N2M0 non-small cell lung cancer. N2 disease was objectified by mediastinoscopy before an inductive treatment. After three cycles of platinum-paclitaxel combination a partial response was proved. Right pneumonectomy with ePTFE graft replacement of directly invaded SVC was performed. The carinal resection was forced intraoperatively, because of the positive resection margins of the right main bronchus. The direct invasion into SVC, residual N2 disease and definitive free resection margins were confirmed histologically. This patient has survived for 5 years after combined extended lung resection without any relapse; the SVC graft still remains functional.