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Pleural mesothelioma (PM) is a rare but aggressive thoracic tumor with a poor prognosis. Multimodal treatment-including induction chemotherapy, aggressive surgical resection, radiotherapy and immunotherapy in selected cases-currently represents the best therapeutic option. Single-center studies advocate hyperthermic intrathoracic chemotherapy (HITHOC) during surgical resection as an additional therapeutic option, although its impact on post-operative morbidity and survival has not yet been evaluated on a larger scale. HITHOC can be applied not only in the case of mesothelioma, but also in the case of thymoma with pleural involvement or-in very selected cases-in patients with secondary pleural metastases. Despite favorable outcomes and reduced clinical risks, there is no uniform approach to HITHOC, and a wide variety of indications and technical applications are still reported. Based on available data, HITHOC seems to offer a clear benefit in regard to overall survival of all mesothelioma patients; however, multicenter randomized controlled trials are required to validate and standardize this approach. The aim of this review is to focus on the present role of HITHOC in thoracic tumors with pleural involvement as well as on future challenges, particularly in the light of possible combined therapy of thoracic tumors still presenting poor prognoses.

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BACKGROUND: Pleural neoplasms are rare and can be subdivided into pleural metastasis and primary pleural neoplasms. Non-mesothelioma primary pleural neoplasms are a diverse group of extremely rare pathologies. CASE PRESENTATION: In this case series, we describe the presentation and management of two rare primary pleural neoplasms. A first case describes a primary pleural yolk sac tumor treated with neoadjuvant chemotherapy, extended pleurectomy decortication, and hyperthermic intrathoracic chemotherapy. In a second case we describe the management of a primary pleural synovial sarcoma by neoadjuvant chemotherapy and extrapleural pneumonectomy. A complete resection was obtained in both cases and the post-operative course was uncomplicated. No signs of tumor recurrence were noted during follow-up in the first patient. In the second patient a local recurrence was diagnosed 6 months after surgery. CONCLUSION: Neo-adjuvant chemotherapy followed by extensive thoracic surgery, including hyperthermic intrathoracic chemotherapy, is a feasible treatment strategy for non-mesothelioma primary pleural neoplasms, but careful follow-up is required.

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Background: Cytoreductive surgery combined with hyperthermic intrathoracic chemotherapy (S-HITHOC) may be effective in treating thymic epithelial tumors (TETs) with pleural spread or recurrence. This study will evaluate the safety and efficacy of S-HITHOC in the treatment of TETs with pleural spread or recurrence. Methods: This study is an open, single-arm, prospective trial. Approximately 37 patients diagnosed with TETs with pleural spread or recurrence at the Zhongshan Hospital of Fudan University will be recruited and treated with S-HITHOC. The co-primary outcomes of the study are the length of postoperative hospital stay, complications, and overall quality of life (QoL). The secondary outcomes include drainage duration, volume, and cumulative pain scores. Discussion: This trial was approved by the Zhongshan Hospital Research Ethics Committee. The study findings will be actively disseminated through manuscript publications and conference presentations. Information sheets will be provided to each participant, and informed written consent will be obtained for each evaluation. This prospective study will evaluate the effectiveness of a surgical resection combined with the HITHOC procedure in treating TETs with pleural spread or recurrence in China and will support the standardization of the procedure. Registration: This trial was registered on Clinialtrial.gov (No. NCT05446935).

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Background: The role of cytoreductive surgery combined with hyperthermic intrathoracic chemotherapy (CRS+HITOC) for patients with secondary pleural metastases has scarcely been investigated. Patients and Methods: We conducted a retrospective, multicentre study investigating the outcome of CRS+HITOC for 31 patients with pleural metastases from different primary tumours in four high-volume departments of thoracic surgery in Germany. The primary endpoint was overall survival (OS). Secondary endpoints included postoperative complications and recurrence/progression-free survival (RFS/PFS). Results: The primary tumour was non-small cell lung cancer in 12 (39%), ovarian cancer in 5 (16%), sarcoma in 3 (10%), pseudomyxoma peritonei in 3 (10%), and others in 8 (26%) patients. A macroscopic complete resection (R/1) could be achieved in 28 (90%) patients. Major postoperative complications as classified by Clavien-Dindo (III-V) were observed in 11 (35%) patients. The postoperative mortality rate was 10% (n=3). A total of 13 patients received additive chemotherapy (42%). The median time of follow up was 30 months (95% CI = 17- 43). The median OS was 39 months (95% CI: 34-44 months) with 1-month, 3-month, 1-, 3-, and 5-year survival estimates of 97%, 89%, 77%, 66%, and 41%. There was a significantly prolonged OS in patients who received additive chemotherapy compared to patients with only CRS+HITOC (median OS 69 vs 38 months; p= 0.048). The median RFS was 14 months (95% CI: 7-21 months). Conclusions: We observed that CRS+HITOC is a feasible approach with reasonable complications and prolonged survival as a part of multimodal concept for highly selected patients with secondary pleural metastases.

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Hyperthermic intrathoracic chemotherapy (HITOC) is an additional intraoperative treatment option within the multimodality therapy of pleural malignancies. A chemotherapy perfusion with high-dose cisplatin is performed over a period of 60 min after surgical cytoreduction to improve local tumour control through the eradication of residual tumour cells. Although HITOC is increasingly used, there is only little scientific evidence about the necessary safety measures after HITOC. Therefore, the objective of this study was an analysis of cisplatin excretion via various body fluids after HITOC, with the aim of providing recommendations on occupational health and safety. Five patients undergoing HITOC were included. Before and after the HITOC, as well as during the following days, serum, urine, and bronchial secretion, as well as pleural effusion, were sampled. The platinum levels in the samples were measured using ICP-MS (inductively coupled plasma-mass spectrometry). Immediately after the HITOC, the mean levels of cisplatin increased dramatically in the serum (from 0.79 to 1349 µg/L), urine (from 3.48 to 10,528 µg/g creatinine), and bronchial secretion (from 0.11 to 156 µg/L). Thereafter, the cisplatin levels dropped to 133 µg/L in the serum and 994 µg/g creatinine in the urine within nine days after the HITOC. The AUC ratio shows 59% of the cisplatin being excreted via the urine after 48 h. The sampling of pleural effusion started 24 h after the HITOC, and the cisplatin levels decreased from 618 to 93 µg/L within nine days. Although the cisplatin levels in the body fluids of HITOC patients are much lower compared to patients receiving intravenous chemotherapy, a significant amount of cisplatin is excreted via these body fluids. Consequently, safety precautions must be implemented in the post-HITOC care of patients to avoid occupational exposure to cisplatin.

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OBJECTIVE: To compare the efficacy and safety of hyperthermic intrathoracic/intraperitoneal chemotherapy versus conventional intrapleural/intraperitoneal chemotherapy in the treatment of malignant pleural or peritoneal effusion. METHODS: A randomized clinical trial was carried out in 8 cancer centers across China. Patients with malignant pleural or peritoneal effusion were randomly assigned to the study group or control group. Patients in the study group were treated with cisplatin-based hyperthermic intrathoracic chemotherapy (HITHOC) or hyperthermic intraperitoneal chemotherapy (HIPEC), while the control group was treated with conventional intrapleural or intraperitoneal chemotherapy using same chemotherapeutic regime as the study group. The objective response rate (ORR) was analyzed as primary outcome. Quality-of-life (QOL) score was recorded as secondary outcome using the questionnaire 30 (QLQ-C30) of the European Organization for Research and Treatment of Cancer (EORTC). The efficacy and safety of the two treatments were compared. RESULTS: Total 135 patients were recruited and randomized in this study, with 67 patients in the study group and 68 patients in the control group. The ORR in the study group (80.70%) was significantly higher than that in the control group (31.03%, p < 0.001). However, neither changes of QOL scores, nor incidence rates of adverse events were significantly different between the two groups (p = 0.076 and 0.197, respectively). CONCLUSION: Efficacy of HITHOC or HIPEC is superior to that of conventional modality for the treatment of malignant effusion with comparable side effects.

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Hyperthermic intrathoracic chemotherapy (HITHOC) adjunct to surgery for Malignant Pleural Mesothelioma (MPM) has no definite role. The primary objective of this pilot-trial was to evaluate the feasibility for future large studies. The study design was a prospective randomized three-centric pilot trial. We recruited patients diagnosed with MPM and prospectively assigned them to two groups: Group A: Video Assisted Thoracic Surgery (VATS) talc pleurodesis or Group B: Video-assisted P/D plus HITHOC. From November-2011 to July-2017 24 males and 3 females, with a median age of 68-years were enrolled (recruitment rate 5 patients/year). Preoperative stage was I-II, and 18 had epithelioid type. 14 patients were in the Group A. Operative mortality was 0. Follow-up ranged 6-80 months. The median overall survival time started to diverge at 20 months, being 19 months (95% CI 12-25) in Group A and 28 months (95% CI 0-56) in Group B. Survival rate for the epithelioid type was 15 months (95% CI 0-34) in Group A and 45 months (95% CI 0-107) in the Group B. These findings suggest that video-assisted P/D plus HITHOC may improve survival time in MPM patients undergoing surgical treatment and support the need for a larger multicenter randomized clinical trial.

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OBJECTIVES: Cytoreductive surgery and hyperthermic intrathoracic chemotherapy (HITOC) is effective on survival for patients with pleural metastatic thymic tumours. METHODS: Multicentre, retrospective analysis of patients with stage IVa thymic tumours treated with surgical resection and HITOC. Primary end point was overall survival, secondary end points were recurrence-/progression-free survival and morbidity/mortality. RESULTS: A total of n = 58 patients (thymoma, n = 42; thymic carcinoma, n = 15; atypical carcinoid of the thymus, n = 1) were included, who had primary pleural metastases (n = 50; 86%) or pleural recurrence (n = 8; 14%). Lung-preserving resection (n = 56; 97%) was the preferred approach. Macroscopically complete tumour resection was achieved in n = 49 patients (85%). HITOC was performed with cisplatin alone (n = 38; 66%) or in combination with doxorubicin (n = 20; 34%). Almost half of the patients (n = 28; 48%) received high-dose cisplatin > 125 mg/m2 body surface area. Surgical revision was required in 8 (14%) patients. In-hospital mortality rate was 2%. During follow-up, tumour recurrence/progression was evident in n = 31 (53%) patients. Median follow-up time was 59 months. The 1-, 3- and 5-year survival rates were 95%, 83% and 77%, respectively. Recurrence/progression-free survival rates were 89%, 54% and 44%, respectively. Patients with thymoma had significantly better survival compared to patients with thymic carcinoma (P-value ≤0.001). CONCLUSIONS: Promising survival rates in patients with pleural metastatic stage IVa in thymoma (94%) and even in thymic carcinoma (41%) were achieved. Surgical resection and HITOC is safe and effective for treatment of patients with pleural metastatic thymic tumours stage IVa.

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BACKGROUND: For decades, both intraperitoneal and pleural chemotherapy (IPC) have been delivered as a liquid solution. Recent studies suggest that foam carriers outperform liquid carriers for locoregional chemotherapy. For the first time, this study aims to evaluate the feasibility, safety, and characteristics of foam-based intrathoracic chemotherapy (FBiTC) in an in vivo setting. METHODS: In this study, contrast-enhanced FBiTC with doxorubicin was delivered via video-assisted thoracoscopy (VAT) in three swine under general anesthesia. Intraoperative and postoperative parameters, blood analyses, vital signs, and anesthesiologic data were collected. Additionally, an intraoperative computer tomography (CT) scan was performed, and histological tissue sections were collected and further analyzed using fluorescence microscopy. RESULTS: FBiTC was delivered without major complications. End-tidal capnometry detected increased CO2 levels with reduced peripheral oxygen saturation and increased blood pressure and heart rate. No major intra- or postoperative complications were observed. CT scans confirmed a multidirectional distribution pattern of foam. Postoperative laboratory workup did not reveal any critical changes in hemoglobin, white blood count, or platelets. There was no evidence of critical kidney impairment or liver function. Fluorescence microscopy of tissue specimen detected doxorubicin in pleural tissues. DISCUSSION: Our preliminary results are encouraging and indicate that FBiTC is feasible. However, to consider a possible clinical application, further studies are required to investigate the pharmacologic, pharmacodynamic, and physical properties of FBiTC and to ensure the safety of the overall procedure regarding oxygenation levels and capnography parameters.

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INTRODUCTION: Stage IVa thymoma is a rare disease without a standard of care. Subtotal pleurectomy and HITHOC introduced in highly selected patients may provide interesting oncologic results. The purpose of this study was to distinguish de novo stage IVa tumors (DNT) from distant relapse (DR) with respect to post-operative and long-term outcomes to provide the procedure efficacy. METHODS: From July 1997-December 2021, 40 patients with IVa pleural involvement were retrospectively analyzed. The surgical procedure was subtotal pleurectomy and HITHOC (cisplatin 50 mg/m2, mitomycin 25 mg/m2, 42 °C, 90 min). The post-operative outcome, disease-free interval (DFI) and overall survival (OS) were analyzed. RESULTS: Mean age was 52 ± 12 years. B2 and B3 thymomas were preponderant (27; 67.5%). The median number of pleural nodes were nine (4-81) vs. five (1-36); p = 0.004 * in DNT and DR, respectively. Hospital mortality rate was 2.5%. There were four specific HITHOC complications (10%). DFI were 49 and 85 months (p = 0.02 *), OS were 94 and 118 months (NS), in DNT and DR, respectively. CONCLUSIONS: Subtotal pleurectomy with HITHOC in IVa offers satisfying results in highly selected patients, for both DNT and DR. Due to the disease rarity, multicentric studies are needed to define HITHOC as a standard of care.

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OBJECTIVES: Breast and ovarian cancer account for over 30% of malignant pleural effusions (MPEs). Treatment of the metastatic disease requires control of the MPE. Even though primarily symptomatic, the treatment of the MPE can potentially affect the oncological course of the disease. The aim of this review is to analyze the effectiveness of intrathoracic chemotherapy in the treatment of MPE caused by breast and ovarian cancer. METHODS: A systematic literature research was conducted up until May 2021. Studies published in English on patients undergoing either surgical or interventional intrapleural chemotherapy were included. RESULTS: Thirteen studies with a total of 497 patients were included. Analysis was performed on 169 patients with MPE due to breast cancer and eight patients with MPE secondary to ovarian cancer. The pooled success rates of intrathoracic chemotherapy for controlling the MPE were 59.1% and 87.5%, respectively. A survival analysis was not possible with the available data. The overall toxicity of the treatment was low. CONCLUSIONS: Intrathoracic chemotherapy achieves symptomatic control of the MPE in 59.1% of patients with metastatic breast cancer and 87.5% of patients with metastatic ovarian cancer. This is inferior to other forms of surgical pleurodesis. Data from small case series and studies on intraperitoneal chemotherapy show promising results. However, formal oncological studies on the use of intrathoracic chemotherapy for metastatic breast or ovarian cancer are lacking. Further prospective pilot studies are needed to assess the therapeutic oncological effects of this treatment.

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Mediastinal malignant pleural mesothelioma with signs of tamponade is rare. Indication for reoperation for recurrent malignant pleural mesothelioma is a controversial but viable option in selected patients. We report a case of a 68-year-old man presenting with epithelioid malignant pleural mesothelioma who underwent a total of three debulking surgeries (pleurectomy/decortication) combined with hyperthermic intrathoracic chemotherapy. Five years after the first procedure, a third urgent operation was performed for recurrence of a large mediastinal mesothelioma causing acute symptoms of pericardial constriction and tamponade. The patient was alive for eight years since the first treatment and 36 months after the second reoperation.

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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.

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A complete resection of thymic tumors is known to be the most important prognostic factor, but it is often difficult to perform, especially in advanced stages. In this study, 73 patients with advanced thymic tumors of UICC stages III and IV who underwent radical resection were examined retrospectively. The primary endpoint was defined as the postoperative resection status. Secondary endpoints included postoperative morbidity, mortality, recurrence/progression-free, and overall survival. In total, 31.5% of patients were assigned to stage IIIa, 9.6% to stage IIIb, 47.9% to stage IVa, and 11% to stage IVb. In stages III a R0 resection was achieved in 53.3% of patients. In stages IV a R0/R1 resection was documented in 76.7% of patients. Surgical revision was necessary in 17.8% of patients. In-hospital mortality was 2.7%. Median recurrence/progression-free interval was 43 months (p = 0.19) with an overall survival of 79 months. The 5-year survival rate was 61.3%, respectively. Median survival after R2 resection was 25 months, significantly shorter than after R0 or R1 resection (115 months; p = 0.004). Advanced thymic tumors can be resected with an acceptable risk of complications and low mortality. In stage III as well as in stage IV the promising survival rates are dependent on the resection-status.

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In the context of quality assurance, the objectives were to describe the surgical treatment and postoperative morbidity (particularly renal insufficiency). A retrospective, multicentre study of patients who underwent cytoreductive surgery (CRS) with cisplatin-based HITOC was performed. The study was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation (GZ: RI 2905/3-1)). Patients (n = 350) with malignant pleural mesothelioma (n = 261; 75%) and thymic tumours with pleural spread (n = 58; 17%) or pleural metastases (n = 31; 9%) were analyzed. CRS was accomplished by pleurectomy/decortication (P/D: n = 77; 22%), extended P/D (eP/D: n = 263; 75%) or extrapleural pneumonectomy (EPP: n = 10; 3%). Patients received cisplatin alone (n = 212; 61%) or cisplatin plus doxorubicin (n = 138; 39%). Low-dose cisplatin (≤125 mg/m2 BSA) was given in 67% of patients (n = 234), and high-dose cisplatin (>125 mg/m2 BSA) was given in 33% of patients (n = 116). Postoperative renal insufficiency appeared in 12% of the patients (n = 41), and 1.4% (n = 5) required temporary dialysis. Surgical revision was necessary in 51 patients (15%). In-hospital mortality was 3.7% (n = 13). Patients receiving high-dose cisplatin were 2.7 times more likely to suffer from renal insufficiency than patients receiving low-dose cisplatin (p = 0.006). The risk for postoperative renal failure is dependent on the intrathoracic cisplatin dosage but was within an acceptable range.

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Although the method of hyperthermic intrathoracic chemotherapy (HITHOC) after cytoreductive surgery is known for more than 20 years now, the interest of the scientific community has been growing especially in recent years with annually increasing numbers of publications. The feasibility and safety of HITHOC has already been demonstrated. The primary objective now is to reach a consent about the optimal implementation and standardization of the procedure. In the international clinical practice of HITHOC the parameters of temperature, duration, type and number of chemotherapeutic agents vary, making a comparison of the short- and long-term results difficult. For about ten years, the combination of surgical cytoreduction and HITHOC has been performed more routinely in several departments of thoracic surgery in Germany, especially in university hospitals. Recently, a group of experts for thoracic surgery of five departments of thoracic surgery elaborated recommendations for the HITHOC procedure in Germany. These recommendations represent a standardized and consistent implementation of HITHOC. Through this, postoperative complications associated to HITHOC should be reduced and a better comparison of the results should be enabled. This article is intended to give a brief overview of the literature, current recommendations in the implementation of HITHOC and also aims to show future perspectives of this procedure.

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Historically, patients with pleural malignant mesothelioma have had a poor prognosis and survival rate. Recently, new surgical approaches and chemotherapy delivery techniques have been developed. One of this treatment options is thoracic cytoreductive surgery and HITHOC (hyperthermic intrathoracic chemotherapy perfusion), a promising strategy in selected patients, offering significantly longer median survival length and tumour-free survival rate. However, there is little experience and little is known regarding the optimal perioperative management of this patients. Given that they usually present with poor preoperative status and the surgery is aggressive, prolonged and associated with significant hemodynamic repercussions, this procedure poses a true challenge to the anaesthesiologist. We will discuss optimal patient selection and optimization, as well as premedication, recommended monitoring aspects on top of the usual for any anaesthetic procedure, induction and anaesthetic agents, blood management and one lung ventilation. Also, we expose the importance of adequate pain control during the surgery and postoperatively, the hemodynamic disturbances that occur during the procedure and the potential complications that could occur afterwards. In a few words, this review intends to offer recommendations for the management of patients undergoing cytoreductive surgery and HITHOC for the perioperative care, based on the scarce evidence and our clinical experience.

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The traditional treatment of stage IV lung cancer is predominantly supportive or palliative. No current standardized guidelines promote the use of hyperthermic intrathoracic chemotherapy (HITHOC) in the treatment of advanced lung cancer with pleural involvement. Several small studies have examined the safety and utilization of HITHOC for this population, though the data is extremely limited. A review of the literature is presented in accordance with the Narrative Review checklist. The MEDLINE electronic database was searched for articles published in English from January 1999 - August 2020 using relevant keywords such as "hyperthermic intrathoracic chemotherapy", "hyperthermic intrapleural chemotherapy" and "HITHOC". This was supplemented by review and hand search of the reference lists. While data suggest a potential though controversial role for HITHOC for certain intrathoracic tumors such as malignant pleural mesothelioma and thymoma, there is insufficient evidence to confidently promote a role for hyperthermic intrathoracic chemotherapy in the treatment of advanced lung cancers. Existing studies are small, nonrandomized, and prone to bias. Hyperthermic intrathoracic chemotherapy is not a standardized treatment for advanced lung cancer, and is characterized by potentially serious side effects with little clinical benefit. Recent developments in targeted therapy and immunotherapy are unlikely to leave room for the development of large randomized controlled trials.