[Expert Recommendation for the Implementation of Hyperthermic Intrathoracic Chemotherapy (HITOC) in Germany]. / Expertenempfehlung zur Anwendung der hyperthermen intrathorakalen Chemotherapie (HITOC) in Deutschland.

INTRODUCTION: During the last few years, hyperthermic intrathoracic chemotherapy (HITOC) has been performed in several departments for thoracic surgery in Germany. The objective of this expert recommendation is to provide elementary recommendations for a standardised HITOC treatment, which are based on clinical experiences and research data. METHODS: Between October and December 2018, a group of experts for thoracic surgery in five departments of thoracic surgery developed recommendations for the HITOC procedure in Germany. These experts were selected by the latest national survey for HITOC and had the most clinical experience with HITOC. All recommendations are based on clinical experience, the experts' research data and recent literature. RESULTS: All recommendations were evaluated by all participating departments in one consensus survey. Finally, a total of six main conclusions including a total of 17 recommendations were developed. For each recommendation, the strength of the consensus is presented in percentages. 100% agreement was established for nomenclature, technique, the chemotherapeutic agent, the perioperative management, the safety measures and the indications for HITOC. All experts recommended cisplatin as the first choice chemotherapeutic agent for HITOC. The dosage of cisplatin is specified in mg/m2 body surface area (BSA) and should be between 150 and 175 mg/m2 BSA. The volume of the perfusion fluid (approximately 4 - 5 l) seems to play a role for the concentration gradient of cisplatin and should therefore also be taken into account. CONCLUSIONS: These expert recommendations provide a standardised and consistent implementation of the HITOC procedure. On this basis, postoperative complications associated to HITOC should be reduced and comparison of the results should be improved.

Regional versus systemic analgesia in video-assisted thoracoscopic lobectomy: a retrospective analysis.

BACKGROUND: The optimal perioperative analgesic strategy in video-assisted thoracic surgery (VATS) for anatomic lung resections remains an open issue. Regional analgesic concepts as thoracic paravertebral or epidural analgesia were used as systemic opioid application. We hypothesized that regional anesthesia would provide improved analgesia compared to systemic analgesia with parenteral opioids in VATS lobectomy and would be associated with a lower incidence of pulmonary complications. METHODS: The study was approved by the local ethics committee (AZ 99/15) and registered (germanctr.de; DRKS00007529, 10th June 2015). A retrospective analysis of anesthetic and surgical records between July 2014 und February 2016 in a single university hospital with 103 who underwent VATS lobectomy. Comparison of regional anesthesia (i.e. thoracic paravertebral blockade (group TPVB) or thoracic epidural anesthesia (group TEA)) with a systemic opioid application (i.e. patient controlled analgesia (group PCA)). The primary endpoint was the postoperative pain level measured by Visual Analog Scale (VAS) at rest and during coughing during 120 h. Secondary endpoints were postoperative pulmonary complications (i.e. atelectasis, pneumonia), hemodynamic variables and postoperative nausea and vomiting (PONV). RESULTS: Mean VAS values in rest or during coughing were measured below 3.5 in all groups showing effective analgesic therapy throughout the observation period. The VAS values at rest were comparable between all groups, VAS level during coughing in patients with PCA was higher but comparable except after 8-16 h postoperatively (PCA vs. TEA; p < 0.004). There were no significant differences on secondary endpoints. Intraoperative Sufentanil consumption was significantly higher for patients without regional anesthesia (p < 0.0001 vs. TPVB and vs. TEA). The morphine equivalence postoperatively applicated until POD 5 was comparable in all groups (mean ± SD in mg: 32 ± 29 (TPVB), 30 ± 27 (TEA), 36 ± 30 (PCA); p = 0.6046). CONCLUSIONS: Analgesia with TEA, TPVB and PCA provided a comparable and effective pain relief after VATS anatomic resection without side effects. Our results indicate that PCA for VATS lobectomy may be a sufficient alternative compared to regional analgesia. TRIAL REGISTRATION: The study was registered (germanctr.de; DRKS00007529 ; 10th June, 2015).

[Postoperative Haemothorax Following Thoracic Surgery]. / Postoperative Blutung nach thoraxchirurgischen Eingriffen.

Postoperative haemothorax following thoracic surgery is a rare complication, but associated with a high mortality. In the literature, this complication occurs in 0.6 to 4.6% of patients and with a mortality of 5.1 to 17.8%. In minor cases, chest tube placement, application of fresh frozen plasma (FFP) or transfusion can be sufficient to control the situation. In severe cases, re-thoracotomy is mandatory. The most frequent origin of bleeding is a bronchial or intercostal vessel (21 and 16%) or the area of pleural adhesions that were separated (10.5%). The pulmonal artery or vein were the origin of bleeding in 16% of cases while in most cases (37%) active bleeding could no longer be detected. A positive effect on postoperative outcome is observed after an early reoperation.

Mediastinal staging by videomediastinoscopy in clinical N1 non-small cell lung cancer: a prospective multicentre study.

A quarter of patients with clinical N1 (cN1) non-small cell lung cancer (NSCLC) based on positron emission tomography-computed tomography (PET-CT) imaging have occult mediastinal nodal involvement (N2 disease). In a prospective study, endosonography alone had an unsatisfactory sensitivity (38%) in detecting N2 disease. The current prospective multicentre trial investigated the sensitivity of preoperative mediastinal staging by video-assisted mediastinoscopy (VAM) or VAM-lymphadenectomy (VAMLA).Consecutive patients with operable and resectable (suspected) NSCLC and cN1 after PET-CT imaging underwent VAM(LA). The primary study outcome was sensitivity to detect N2 disease. Secondary endpoints were the prevalence of N2 disease, negative predictive value (NPV) and accuracy of VAM(LA).Out of 105 patients with cN1 on imaging, 26% eventually developed N2 disease. Invasive mediastinal staging with VAM(LA) had a sensitivity of 73% to detect N2 disease. The NPV was 92% and accuracy 93%. Median number of assessed lymph node stations during VAM(LA) was 4 (IQR 3-5), and in 96%, at least three stations were assessed.VAM(LA) has a satisfactory sensitivity of 73% to detect mediastinal nodal disease in cN1 lung cancer, and could be the technique of choice for pre-resection mediastinal lymph node assessment in this patient group with a one in four chance of occult-positive mediastinal nodes after negative PET-CT.

Prognostic factors in solitary fibrous tumors of the pleura.

BACKGROUND: Solitary fibrous tumors of the pleura (SFTP) are rare neoplasms originating from submesothelial mesenchymal cells with fibroblastic differentiation. The clinical behavior of SFTPs is mostly benign; however, up to 20% of patients develop local recurrence and/or distant metastasis. Although different risk-stratification models have been described, definitive criteria to predict a malignant clinical course of SFTP are still lacking. METHODS: In a retrospective analysis at a single-institution, 25 patients with histologically proven SFTP were identified. Clinicopathologic and survival data were collected and pathologic sections reviewed. Different markers and risk-stratification models were correlated with disease- and overall-free survival by Kaplan-Meier analysis. RESULTS: Of 25 SFTP, 8 tumors (32%) were classified as malignant according to the World Health Organization criteria. Three patients (12%) developed recurrence. Cohort median follow-up was 28 mo, and median overall survival was 160 mo. Comparison of proliferation markers showed higher mitosis count per high-power field and MIB-1 labeling index (MIB) in malignant compared with nonmalignant SFTP. MIB was identified as a predictor for disease-free survival. Applying the previously reported classifications to categorize SFTP according to the probability to show malignant behavior, significant differences in disease-free survival were also present in our cohort. CONCLUSIONS: In the present analysis of rare SFTP, previously proposed staging systems were applicable for prediction of disease-free survival. Independently of treatment, MIB was the only sole predictive marker. A prospective multi-institutional database could be helpful in establishing detailed predictive criteria in patients diagnosed with SFTP.

Author Correction: Intraoperative detection of circulating tumor cells in pulmonary venous blood during metastasectomy for colorectal lung metastases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Prognostic value of lymph node ratio after induction therapy in stage IIIA/N2 non-small cell lung cancer: a monocentric clinical study.

BACKGROUND: The optimal treatment modalities for patients with stage IIIA N2 non-small cell lung cancer (NSCLC) are still a matter of debate. To provide best outcome and to avoid unnecessary treatment patient selection for surgical therapy is crucial. In addition to mediastinal downstaging the lymph node ratio (LNR) has been suggested as a prognosticator in this patient group. METHODS: We retrospectively reviewed clinical and histopathologic data of 78 patients with stage IIIA N2 NSCLC, who underwent induction therapy with two cycles of platinum-based chemotherapy for intended surgery at our clinic between 2009 and 2016. To evaluate the prognostic value of the LNR the cut off was set at 0.33 as reported in prior literature. RESULTS: The median follow-up time was 30.1 months. In multivariate analysis mediastinal down staging was associated with a longer overall survival (OS): 52.2 (range, 5.9-89.7) months for ypN0 versus 24.6 (4.4-84.2) months for ypN1/2 (HR, 2.76; 95% CI, 1.07-7.1, P=0.0348). LNR ≤0.33 was linked to a better OS of 39.3 (range, 5.9-89.7) months compared to 14.7 (range, 4.4-66.2) months for a LNR >0.33 in univariate analysis (P=0.037). In multivariate analysis a statistical trend could be observed (HR, 2.82; 95% CI, 0.98-8.14, P=0.1). In patients with persistent lymph node involvement the LNR could also identify a subgroup of patients with a favorable prognosis (30.1 vs. 14.7 months, P=0.145). CONCLUSIONS: Mediastinal downstaging remains the best prognosticator in stage IIIA N2 NSCLC after induction therapy. However, using the LNR in patients with persistent mediastinal lymph node metastasis a subgroup with a favorable prognosis could be identified. The LNR could aid in finding the best treatment modalities for these patients.

Short veno-venous extracorporeal membrane oxygenation assisted segmentectomy for second primary lung tumor in a patient with insufficient respiratory function for one lung ventilation.

Advances in extracorporeal membrane oxygenation (ECMO) have allowed safe performance of complex thoracic surgical procedures that were impossible before. Application of ECMO in general thoracic surgery is extremely rare, but allows life-saving procedures in patients in whom one-lung ventilation cannot be carried out safely. We present the case of a 66 year old man who underwent a challenging veno-venous ECMO assisted segmentectomy for a second primary lung cancer. One-lung ventilation was not feasible due to previous lobectomy on the contralateral side and consequent lack of respiratory function. After the surgical procedure was completed the ECMO was removed and under stable conditions followed the immediate tracheal extubation.

Mucinous cystadenocarcinoma arising from mucinous cystadenoma of the lung: case report and review of the literature.

Mucinous cystadenoma is a benign tumor commonly found in the pancreas, the ovaries or the appendix. Only very few cases of these tumors originating from the lungs have been reported worldwide, with even less cases describing malignant transformation. We present the case of a 58-year-old woman with a history of recurrent pulmonary infections who underwent left upper lobectomy for lung abscess and was initially diagnosed with pulmonary mucinous cystadenoma (PMCA). Upon thorough immunohistochemical workup, especially due to carcinoembryonic antigen (CEA) positivity, intramucinous singlet cells were eventually diagnostic for invasive carcinoma, in this case a mucinous cystadenocarcinoma arising from a PCMA. PMCA is a rare benign tumor whose potential for malignant transformation has not yet been fully understood. Due to the low number of cases further studies are needed to evaluate if there is a benefit of complete oncologic resection, provided the general condition of the patient allows it. A review of the currently available literature serves to better understand the clinical, radiological and histological features of this rare tumor.

Pulmonary metastasectomy in sarcoma-experiences with laser-assisted resection.

BACKGROUND: Previous data suggest a survival benefit in well selected patients with extrathoracic sarcoma after pulmonary metastasectomy. Different techniques have been described for pulmonary metastasectomy; however laser-assisted surgery (LAS) was suggested to provide the best outcome in patients with higher numbers of metastases. METHODS: Data were extracted from a prospectively maintained institutional database and a total of 83 patients who underwent pulmonary metastasectomy at our clinic in the last 11 years were identified. RESULTS: We analyzed a total of 106 operations of which LAS was performed in 46 and conventional resection in 60 cases. Significantly more metastases were resected in the LAS group compared to the conventional group [median, interquartile range (IQR): 6.5 (2.0-11.0) vs. 1.0 (1.0-3.5); P<0.0001]. Despite this difference the number of tumor recurrences was similar in both groups [64% tumor recurrences in the LAS group and 58% in the conventional group, odds ratio (OR) =1.3, P=0.6]. Furthermore, overall survival (OS) was comparable with a median survival of 77.6 and 29.0 months and 2- and 5-year survival rates of 71% and 63% as well as 53% and 36% in the respective cohorts [hazard ratio (HR) =0.74, P=0.43]. CONCLUSIONS: Using LAS a significantly higher number of metastases were removed while producing similar long-term results as compared to patients treated by other techniques. Expectably, recurrence rates in metastasized sarcoma patients remain high with either surgical method. Future studies will have to evaluate possible advantages provided by LAS in a prospective manner.

Pulmonary metastasectomy for thyroid cancer as salvage therapy for radioactive iodine-refractory metastases.

OBJECTIVES: Distant metastasis arising from thyroid cancer is rare but has been associated with significantly reduced long-term survival, especially when refractory to radioactive iodine ablation. We provide one of the largest studies worldwide reporting the outcome after salvage pulmonary metastasectomy for this entity, aiming to identify prognostic factors and to analyse surgical indication. METHODS: We retrospectively analysed the medical records of 43 patients who had undergone pulmonary metastasectomy for radioactive iodine-refractory thyroid cancer from 1985 to 2016. RESULTS: The median follow-up period was 77 (95% confidence interval 41-113) months. Twenty-three (53%) patients were alive at the time of analysis. The majority of tumours were follicular thyroid cancer by histology, with 23% identified as Hurthle cell subtype. Five- and 10-year disease-specific (DS) survival was 84% and 59%, respectively. Thirty-one (72%) patients underwent R0-resection with a 5- and 10-year DS survival of 100% and 77%, respectively. This was significantly reduced to 62% and 22% (P = 0.013) in case of incomplete resection, respectively. Ten years after R0-metastasectomy, 17 (55%) patients were recurrence-free. Systematic mediastinal lymphadenectomy was performed in 16 (37%) patients and was associated with improved long-term DS survival (10 years 88% vs 46%, P = 0.034). Moreover, a reduction of > 80% in serum thyroglobulin levels post-metastasectomy correlates with better long-term DS survival (10 years 81% vs 36%, P = 0.007). CONCLUSIONS: Pulmonary metastasectomy is associated with good survival for selected patients with radioactive iodine-refractory metastases of differentiated thyroid cancer, especially if R0-resection can be achieved. Moreover, it is worth considering whether a significant reduction of tumour load, as indicated by thyroglobulin serum levels, seems possible.

Intraoperative detection of circulating tumor cells in pulmonary venous blood during metastasectomy for colorectal lung metastases.

Circulating tumor cells (CTC) have been studied extensively in various tumor types and are a well-established prognosticator in colorectal cancer (CRC). This is the first study to isolate CTC directly from the tumor outflow in secondary lung tumors. For this purpose in 24 patients with CRC who underwent pulmonary metastasectomy in curative intent blood was drawn intraoperatively from the pulmonary vein (tumor outflow). In 22 samples CTC-enumeration was performed using CellSieve-microfilters and immunohistochemical- and Giemsa-staining. Additionally 10 blood samples were analyzed using the CellSearch-System. We could isolate more CTC in pulmonary venous blood (total 41, range 0-15) than in samples taken from the periphery at the same time (total 6, range 0-5, p = 0.09). Tumor positive lymph nodes correlated with presence of CTC in pulmonary venous blood as in all cases CTC were present (p = 0.006). Our findings suggest a tumor cell release from pulmonary metastases in CRC and a correlation of CTC isolated from the tumor outflow with established negative prognostic markers in metastasized CRC. The presented data warrant further investigations regarding the significance of local tumor compartments when analyzing circulating markers and the possibility of tumor cell shedding from secondary lung tumors.

Intrapulmonary Castleman's Disease Pretending to Be a Lung Cancer-Work Up of an Intrapulmonary Tumour.

A 24 year old male presented with a history of recurrent bronchopulmonal infections. Chest computed tomography was performed, revealing a right central mass. In the following bronchoscopy and ultrasound guided needle aspiration of the tumour no specific diagnosis could be obtained. Due to the central location of the tumour thoracotomy and middle lobe resection was performed. Histopathological analysis revealed an intrapulmonary, subpleural located Morbus Castleman of the hyaline-vascular type.Castleman's disease is a very rare disorder of the lymphatic tissue that is differentiated into two clinical subtypes. The localized type presents histologically almost always as the hyaline-vascular form. Findings have been reported in mediastinal lymph nodes, the abdomen and peripheral lymphnodes. Intrapulmonary development is very rare and only 9 cases have previously been described in literature.On the other hand the multicentric type accounts for approximately 10%-15% of cases and histologically usually presents as the plasma cell variant. It is accompanied by fatigue and general weakness and often requires systemic steroid or chemotherapy.The localized type develops less clinical symptoms and is curable by complete surgical resection.

Local Concentrations of CC-Chemokine-Ligand 18 Correlate with Tumor Size in Non-small Cell Lung Cancer and Are Elevated in Lymph Node-positive Disease.

BACKGROUND: The tumor microenvironment plays a critical role in tumor growth and spreading. Tumor-associated macrophages (TAM) make up a large proportion of the tumor mass and are one of the main producers of CC-chemokine ligand 18 (CCL18), which is believed to carry out important functions in the immunological interactions that promote tumor progression. MATERIALS AND METHODS: Cytokines/chemokines were measured in bronchoalveolar lavage (BAL) from the tumor site and serum before and after resection in patients with proven non-small cell lung cancer (NSCLC). RESULTS: CCL18 concentrations in BAL positively correlated with the radiologically determined tumor volume (r=0.72, p=0.0003) in NSCLC. In addition, tumors with lymph-node metastasis exhibited significantly higher CCL18 concentrations in BAL (p=0.049) than those without. Serum CCL18 concentrations did not differ significantly before and after tumor resection. CONCLUSION: The increased release of CCL18 with greater tumor size is most likely due to the accompanied growth of leukocyte infiltrate. With previous findings taken into account, this could be one factor contributing to tumor invasiveness and particularly lymphatic spread in patients with larger tumors.

Altered purinergic signaling in the tumor associated immunologic microenvironment in metastasized non-small-cell lung cancer.

OBJECTIVES: Purines are well-known as intracellular sources for energy but they also act as extracellular signaling molecules. In the recent years, there has been a growing interest in the therapeutic potential of purinergic signaling for cancer treatment. This is the first study to analyze lung purine levels and purinergic receptors in non-small-cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: In this prospective clinical trial we enrolled 26 patients with NSCLC and 21 patients with chronic obstructive pulmonary disease (COPD) without signs of malignancy. The purine concentrations were analyzed in bronchoalveolar lavage fluid (BALF) using fluorescent/luminescent assays. Expression of purinergic receptors and ectonucleotidases were analyzed using real time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Patients with NSCLC have significantly lower ATP and ADP concentrations in BALF than patients with COPD (p=0.006 and p=0.009). Expression of the ectonucleotidase CD39 is significantly higher in BAL cells from cancer patients compared to COPD (p=0.001) as well as in metastasized tumors compared to non-metastasized tumors (p=0.009). Receptor-analysis revealed a higher expression of P2X4 (p=0.03), P2X7 (p=0.001) and P2Y1 (p=0.003) in BAL cells of tumors with distant metastasis. CONCLUSION: Our data suggests a role for CD39 in lung cancer tumor microenvironment, influencing tumor invasiveness and metastasization. Potentially the increased degradation of ATP and ADP leads to a subversion of their anti-neoplastic effects. Furthermore P2Y1, P2X4 and P2X7 receptors are upregulated in BAL cells in metastatic disease. Our findings might facilitate the identification of new therapeutic targets for cancer immunotherapy.

Impact of different hold time before addition of platelet additive solution on the in vitro quality of apheresis platelets.

BACKGROUND: The quality of platelets (PLTs) stored in PLT additive solution (PAS) is dependent on the type and proportion of the used PAS. No data are available as to whether a different hold time before the addition of PAS to hyperconcentrated PLT suspensions has an impact on PLT quality. The in vitro quality between single-donor PLT concentrates was compared with two different hold times with two PASs. STUDY DESIGN AND METHODS: On two occasions, 6x10(11) PLTs in 150 mL of plasma were collected from 20 blood donors. The units were split into two equal parts, and 140 mL of PAS-II or PAS-IIIM (randomized sequence) was added after 2 or 8 hours resulting in a PAS proportion of 65 percent. On Days 1, 5, and 7, glucose and lactate concentration, pH value, PLTs' P-selectin expression, response to hypotonic shock, and release of transforming growth factor-beta1 were determined. RESULTS: On all days, the lactate concentrations were higher and pH values were lower in units with an 8-hour hold time, whereas the results of in vitro tests relating to the in vivo viability and activation of PLTs were similar for both groups. PAS-IIIM-stored PLTs showed a lower glycolytic activity and better results in all performed in vitro tests than PAS-II-stored PLTs. CONCLUSIONS: Although the metabolism of glucose was enhanced during hold time, the differences between both hold time groups are not meaningful from a biological viewpoint. Therefore, an 8-hour hold time is feasible. PLT storage in PAS-IIIM results in a PLT in vitro quality superior to that of PLTs stored in PAS-II.