Preservation of Adrenoceptor and Endothelin Receptor Mediated Vasoconstriction and of Endothelium-Dependent Relaxation after Cold Storage of Explanted Blood Vessels for ex vivo Analyses.

INTRODUCTION: Adrenoceptor and endothelin (ET) receptor-mediated vasoconstriction as well as endothelium-dependent vasodilation of human saphenous veins were compared before and after 20 h of cold storage. METHODS: Contractile responses to potassium chloride (KCl), norepinephrine (NE), and ET-1 as well as vasodilator responses to acetylcholine (ACh) were evaluated. RESULTS: Storage in HEPES-supplemented Dulbecco's modified Eagle's medium (HDMEM) diminished KCl induced contractile forces to 71% (p = 0.002) and NE induced contractions to 80% (p = 0.037), in contrast to HEPES-supplemented Krebs-Henseleit solution (HKH) and TiProtec solution. KCl-normalized NE contractions were not affected by storage. NE EC50 values were slightly lower (7.1E-8 vs. 7.5E-8, p = 0.019) after storage in HKH, with no changes after storage in the other solutions. Endothelium-dependent responses to ACh were not affected by storage. ET-1 induced contractions were attenuated after storage in HDMEM (77%, p = 0.002), HKH (75%, p = 0.020), and TiProtec (73%, p = 0.010) with no changes in normalized constrictions. ET-1 EC50 values were not affected by storage. CONCLUSION: Loss of contractility after storage in HDMEM may reflect the lower content of dextrose. There was no specific attenuation of adrenoceptor, ET-receptor, or ACh receptor mediated signal transduction after storage in any of the media. HKH or TiProtec are equally suitable cold storage solutions for ex vivo measurements.

Exposure to cisplatin in the operating room during hyperthermic intrathoracic chemotherapy.

PURPOSE: Hyperthermic intrathoracic chemotherapy (HITOC) is an additive, intraoperative treatment for selected malignant pleural tumors. To improve local tumor control, the thoracic cavity is perfused with a cisplatin-containing solution after surgical cytoreduction. Since cisplatin is probably carcinogenic to humans, potential contamination of surfaces and pathways of exposure should be systematically investigated to enable risk assessments for medical staff and thus derive specific recommendations for occupational safety. METHODS: Wipe sampling was performed at pre-selected locations during and after ten HITOC procedures, including on the surgeon's gloves, for the quantitation of surface contaminations with cisplatin. After extraction of the samples with hydrochloric acid, platinum was determined as a marker for cisplatin by voltammetry. RESULTS: High median concentrations of cytostatic drugs were detected on the surgeons' (1.73 pg Cis-Pt/cm2, IQR: 9.36 pg Cis-Pt/cm2) and perfusionists' (0.69 pg Cis-Pt/cm2, IQR: 1.73 pg Cis-Pt/cm2) gloves. The display of the perfusion device showed partially elevated levels of cisplatin up to 4.92 pg Cis-Pt/cm2 and thus could represent an origin of cross-contamination. In contrast, cisplatin levels on the floor surfaces in the area of the surgeon and the perfusion device or in the endobronchial tube were relatively low. CONCLUSION: With a correct use of personal protective equipment and careful handling, intraoperative HITOC appears to be safe to perform with a low risk of occupational exposure to cisplatin.

Surgical Cytoreduction and HITOC for Thymic Malignancies with Pleural Dissemination.

BACKGROUND: Objective of this study was to assess postoperative morbidity and mortality as well as recurrence-free and overall survival in patients with thymic malignancies and pleural dissemination undergoing surgical cytoreduction and hyperthermic intrathoracic chemotherapy (HITOC). METHODS: Retrospective study between September 2008 and December 2017 with follow-up analysis in May 2018. RESULTS: A total of 29 patients (male: n = 17) with thymic malignancies and pleural spread (primary stage IVa: n = 11; pleural recurrence: n = 18) were included. Surgical cytoreduction was performed via pleurectomy/decortication (P/D; n = 11), extended P/D (n = 15), and extrapleural pneumonectomy (EPP; n = 3). These procedures resulted in 25 (86%) patients with macroscopically complete (R0/R1) resection. Intraoperative HITOC was performed for 60 minutes at 42°C either with cisplatin (100 mg/m2 body surface area [BSA] n = 8; 150 mg/m2 BSA n = 6; 175 mg/m2 BSA n = 1) or with a combination of cisplatin (175 mg/m2 BSA)/doxorubicin (65 mg; n = 14). Postoperative complications occurred in nine patients (31%). Cytoprotective therapy resulted in lower postoperative creatinine levels (p = 0.036), and there was no need for temporary dialysis in these patients. The 90-day mortality rate was 3.4%, as one patient developed multiple organ failure. While recurrence-free 5-year survival was 54%, an overall 5-year survival rate of 80.1% was observed. Survival depended on histological subtype (p = 0.01). CONCLUSION: Surgical cytoreduction with HITOC is feasible in selected patients and offers encouraging survival rates. The application of cytoprotective agents appears to be effective for the prevention of postoperative renal insufficiency.

Protocol of a retrospective, multicentre observational study on hyperthermic intrathoracic chemotherapy in Germany.

INTRODUCTION: Objective of the 'German hyperthermic intrathoracic chemotherapy (HITOC) study' is to evaluate the HITOC as additional treatment after surgical cytoreduction for malignant pleural tumours. Even though HITOC is applied with increasing frequency, there is no standardised therapy protocol concerning the technique of HITOC, the selection as well as dosage of chemotherapeutic agents and perioperative management in order to provide a safe and comparable, standardised treatment regime. METHODS AND ANALYSIS: This trial is a retrospective, multicentre observational study, which is funded by the German Research Foundation. Approximately 300 patients will be included. Four departments of thoracic surgery, which are performing the most HITOC procedures in Germany, are contributing to this study: Center for Thoracic Surgery at the University Hospital Regensburg, Thoracic Clinic Heidelberg of the University of Heidelberg, Center for Thoracic Surgery of the Hospital University of Munich and the Department of Thoracic Surgery at the University Hospital Freiburg. All patients who underwent surgical cytoreduction and subsequent HITOC at one of the four centres between starting the HITOC programme in 2008 and December 2019 will be included. Information on the performed HITOC will be obtained, focusing on the technique as well as the applied perfusion solution including the chemotherapeutic agent. Furthermore, parameters of the patient's postoperative recovery will be analysed to determine 30-day morbidity and mortality. ETHICS AND DISSEMINATION: The approvals by the local ethics committee of the respective clinic and the three participating clinics have been obtained. The results will be presented in conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: German Clinical Trials Registry (DRKS00015012; Pre-results).

Adequate nephroprotection reduces renal complications after hyperthermic intrathoracic chemotherapy.

BACKGROUND AND OBJECTIVES: Hyperthermic intrathoracic chemotherapy (HITOC) is used for the treatment of malignant pleural tumors. Although HITOC proved to be safe, postoperative renal failure due to nephrotoxicity of intrapleural cisplatin remains a concern. METHODS: This single-center study was performed retrospectively in patients who underwent pleural tumor resection and HITOC between September 2008 and December 2018. RESULTS: A total of 84 patients (female n = 33; 39.3%) with malignant pleural tumors underwent surgical cytoreduction with subsequent HITOC (60 minutes; 42°C). During the study period, we gradually increased the dosage of cisplatin (100-150 mg/m2 BSA n = 36; 175 mg/m2 BSA n = 2) and finally added doxorubicin (cisplatin 175 mg/m2 BSA/doxorubicin 65 mg; n = 46). All patients had perioperative fluid balancing. The last 54 (64.3%) patients also received perioperative cytoprotection. Overall 29 patients (34.5%) experienced renal insufficiency. Despite higher cisplatin concentrations, patients with cytoprotection showed significantly lower postoperative serum creatinine levels after 1 week (P = .006) and at discharge (P = .020). Also, they showed less intermediate and severe renal insufficiencies (5.6% vs 13.3%). CONCLUSIONS: Adequate perioperative fluid management and cytoprotection seem to be effective in protecting renal function. This allows the administration of higher intracavitary cisplatin doses without raising the rate of renal insufficiencies.

[Recent Developments in the Regional Treatment of Peritoneal and Pleural Tumours (incl. HIPEC and HITOC)]. / Aktuelle Entwicklungen in der regionalen Behandlung von peritonealen und pleuralen Tumoren (inkl. HIPEC und HITOC).

The multimodal treatment of limited peritoneal metastases may improve prognosis in selected patients (pseudomyxoma peritonei, malignant peritoneal mesothelioma, colorectal, gastric and ovarian cancer) provided complete cytoreduction can be performed. Additive intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) is often performed. If the treatment is undertaken in experienced (and certified) centres, associated mortality is low. Intrapleural hyperthermic chemoperfusion (HITOC) can be performed in patients with pleural malignancies, mainly for malignant pleural mesothelioma or metastases from a thymoma. In single patients, pleural metastases from gastrointestinal malignancies might be an indication. Both therapies (HIPEC and HITOC) are complex and their exact role has to be defined within further prospective randomised trials.

[Implementation of Hyperthermic Intrathoracic Chemotherapy (HITHOC) in Germany]. / Anwendung der hyperthermen intrathorakalen Chemotherapie (HITHOC) in Deutschland.

INTRODUCTION: For several years, hyperthermic intrathoracic chemotherapy (HITHOC) has been performed in a few departments for thoracic surgery in a multimodality treatment regime in addition to surgical cytoreduction. Specific data about HITHOC in Germany are still lacking. METHODS: Survey in written form to all departments of thoracic surgery in Germany. The objective is the evaluation of HITHOC with respect to number, indications, technique, perioperative protection measure and complications. RESULTS: A total of 116 departments of thoracic surgery were contacted, with a return rate of 43% (n = 50). HITHOC was not performed in 33 departments, due to lack of resources or experience (n = 17), missing efficacy of the procedure (n = 8) and fear of excessive complication rates (n = 3). Since 2008, a total of 343 HITHOC procedures have been performed in 17 departments. Eight departments have their own perfusion machine, whereas the remaining departments borrow the perfusion machine. Indications were malignant pleural mesothelioma in all departments (n = 17), thymoma with pleural spread (n = 11) and secondary pleural carcinosis (n = 7). The HITHOC was performed in nearly all departments after closing the chest (n = 16), with a temperature of 42 °C (n = 12) and for 60 minutes (n = 15). Cisplatin was always used, either alone (n = 9) or in combination (n = 8). In all the participating departments, the aims of the HITHOC were improvement in local tumor control and prolonged recurrence-free and overall survival. Relevant HITHOC-associated complications were low. CONCLUSIONS: HITHOC is performed in at least 17 departments of thoracic surgery in Germany, and is widely standardised with protective measures and a low rate of complications. The aims of the HITHOC are improvement in local tumor control in pleural malignancies combined with prolonged overall survival and better quality of life.

Assessment of cisplatin concentration and depth of penetration in human lung tissue after hyperthermic exposure.

OBJECTIVES: The effects of cisplatin on the lung parenchyma during hyperthermic intrathoracic chemotherapy perfusion have not been analysed in detail. The objective of this study was to evaluate both the concentration and depth of the penetration of cisplatin in human lung tissue after hyperthermic exposure under ex vivo conditions. METHODS: This experimental study was approved by the local ethics committee. Twelve patients underwent pulmonary wedge resections after elective thoracic lobectomies were performed (resected lobe), and the lung tissue (approximately 1-2 cm(3)) was incubated (in vitro) with cisplatin (0.05 mg/ml; 60 min, 42°C). Subsequent tissue beds (depth, 0.5 mm; median weight, 70-92 mg) were prepared from the outside to the middle, and the amount of cisplatin per tissue weight was analysed using atomic absorption spectrometry. Afterwards, the penetration of cisplatin depth was calculated and related to the different concentrations per tissue. RESULTS: Cisplatin penetrated into the human lung tissue after ex vivo hyperthermic exposure. The median amount of platinum [nmol cisplatin/g lung tissue] decreased significantly (P ≤ 0.05) depending on the penetration depth: 32 nmol/g (1 mm), 20 nmol/g (2 mm) and 6.8 nmol/g (4 mm). The calculated median concentrations of cisplatin (µg/ml) were 2.4 µg/ml (1 mm), 1.4 µg/ml (2 mm) and 0.5 µg/ml (4 mm), respectively. CONCLUSIONS: Under ex vivo hyperthermic conditions, cisplatin diffused into human lung tissue. The median penetration depth of the cisplatin was approximately 3-4 mm. The penetration of cisplatin into lung tissue may affect the local therapy of residual tumour cells on the lung surface using hyperthermic intrathoracic chemotherapy perfusion in patients with malignant pleural tumours.

Anaesthetic management of cytoreductive surgery followed by hyperthermic intrathoracic chemotherapy perfusion.

BACKGROUND: Macroscopic cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion (HITHOC) is a new multimodal approach for selected patients with primary and secondary pleural tumors, which may provide the patient with better local tumor control and increased overall survival rate. METHODS: We present a single-center study including 20 patients undergoing cytoreductive surgery and HITHOC between September 2008 and April 2013 at the University Medical Center Regensburg, Germany. Objective of the study was to describe the perioperative, anaesthetic management with special respect to pain and complication management. RESULTS: Anaesthesia during this procedure is characterized by increased intrathoracic airway and central venous pressure, hemodynamic alterations and the risk of systemic hypo- and hyperthermia. Securing an adequate intravascular volume is one of the primary goals to prevent decreased cardiac output as well as pulmonary edema. Transfusion of packed red blood cells (PRBC) was necessary in seven of 20 (35%) patients. Only two patients (10%) showed an impairment of coagulation in postoperative laboratory analysis. Perioperative forced diuresis is recommended to prevent postoperative renal insufficiency. Supplementary thoracic epidural analgesia in 13 patients (65%) showed a significant reduction of post-operative pain compared with peroral administration of opioid and non-opioid analgesics. CONCLUSION: This article summarizes important experiences of the anaesthesiological and intensive care management in patients undergoing HITHOC.

Cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion for malignant pleural tumours: perioperative management and clinical experience.

OBJECTIVES: A combination of cytoreductive surgery and hyperthermic intrathoracic chemotherapy perfusion (HITHOC) was performed for the treatment of primary and secondary pleural malignancies. We describe the perioperative management and our clinical experience. METHODS: Between September 2008 and August 2011, eight patients with pleural manifestation of thymoma (Masaoka stage IVa) and eight patients with malignant pleural mesothelioma (MPM) were prospectively enrolled. Postoperative morbidity, recurrence and survival rates were analysed. RESULTS: All the patients received multimodality therapy, including chemotherapy, radiation and surgical resection (pleurectomy/decortication) followed by the HITHOC procedure. Chemotherapy perfusion was performed with cisplatin (100-150 mg/m(2)) at 42°C for 1 h. Severe chemotherapy-related complications were not observed. Reoperation was necessary in two patients. There was no 30-day mortality. The median stay on the intensive care unit was 1 day, and the median duration of hospitalization was 15 days. Pleural recurrence of thymoma was evident in one thymoma patient 6 months after HITHOC. At mean follow-up of 22 months, seven thymoma patients (7/8; 88%) are alive without recurrence. Tumour progression was present in six mesothelioma patients (6/8; 75%). Four patients (50%) with MPM are alive, including two with no evidence of mesothelioma, and the median survival is 18 months. CONCLUSIONS: Cytoreductive surgery in combination with HITHOC can be performed with acceptable morbidity and mortality rates in selected patients. Patients should be evaluated by an interdisciplinary team to determine their eligibility for this therapeutic alternative. Early clinical results may encourage the use of this surgical option to provide better local tumour control in a multimodality treatment setting.