A randomised phase II study of extended pleurectomy/decortication preceded or followed by chemotherapy in patients with early-stage pleural mesothelioma: EORTC 1205.

BACKGROUND: The role of surgery in pleural mesothelioma remains controversial. It may be appropriate in highly selected patients as part of a multimodality treatment including chemotherapy. Recent years have seen a shift from extrapleural pleuropneumonectomy toward extended pleurectomy/decortication. The most optimal sequence of surgery and chemotherapy remains unknown. METHODS: EORTC-1205-LCG was a multicentric, noncomparative phase 2 trial, 1:1 randomising between immediate (arm A) and deferred surgery (arm B), followed or preceded by chemotherapy. Eligible patients (Eastern Cooperative Oncology Group 0-1) had treatment-naïve, borderline resectable T1-3 N0-1 M0 mesothelioma of any histology. Primary outcome was rate of success at 20 weeks, a composite end-point including 1) successfully completing both treatments within 20 weeks; 2) being alive with no signs of progressive disease; and 3) no residual grade 3-4 toxicity. Secondary end-points were toxicity, overall survival, progression-free survival and process indicators of surgical quality. FINDINGS: 69 patients were included in this trial. 56 (81%) patients completed three cycles of chemotherapy and 58 (84%) patients underwent surgery. Of the 64 patients in the primary analysis, 21 out of 30 patients in arm A (70.0%; 80% CI 56.8-81.0%) and 17 out of 34 patients (50.0%; 80% CI 37.8-62.2%) in arm B reached the statistical end-point for rate of success. Median progression-free survival and overall survival were 10.8 (95% CI 8.5-17.2) months and 27.1 (95% CI 22.6-64.3) months in arm A, and 8.0 (95% CI 7.2-21.9) months and 33.8 (95% CI 23.8-44.6) months in arm B. Macroscopic complete resection was obtained in 82.8% of patients. 30- and 90-day mortality were both 1.7%. No new safety signals were found, but treatment-related morbidity was high. INTERPRETATION: EORTC 1205 did not succeed in selecting a preferred sequence of pre- or post-operative chemotherapy. Either procedure is feasible with a low mortality, albeit consistent morbidity. A shared informed decision between surgeon and patient remains essential.

Peritoneal Dissemination in Patients with Recurrence After Post-pleurectomy/decortication for Pleural Mesothelioma.

BACKGROUND: In clinical practice, peritoneal dissemination after curative-intent surgery for pleural mesothelioma occasionally recurs. This study investigated the risk factors and prognosis associated with post-pleurectomy/decortication peritoneal dissemination in pleural mesothelioma, which are rarely reported. METHODS: This retrospective review included 160 patients who experienced recurrence after pleurectomy/decortication for pleural mesothelioma between January 2011 and December 2021. Patients with recurrence were classified according to the initial recurrence pattern. The P group experienced recurrence with peritoneal dissemination, and the non-P group experienced recurrence without peritoneal dissemination. The analysis determined the risk factors for peritoneal dissemination using multivariable logistic regression analysis. Survival was analyzed using the Kaplan-Meier method and the log-rank test. RESULTS: Of the 160 patients, 20 (12.5%) exhibited peritoneal dissemination and were assigned to the P group, whereas 140 (87.5%) had recurrence without peritoneal dissemination and were assigned to the non-P group. Multivariable logistic regression analysis showed that diaphragm reconstruction (odds ratio [OR], 2.8; 95% confidence interval [CI], 1.0-8.0; p = 0.048) and female sex (OR, 3.7; 95% CI 1.26-10.8; p = 0.017) were associated with the P group. Post-recurrence survival was worse in the P group than in the non-P group (1-year post-recurrence survival: 22.2% vs. 65.3%; median: 6.7 months vs. 19.4 months; p = 0.0013). CONCLUSIONS: Peritoneal dissemination occurred in approximately one of every eight patients with recurrence after pleurectomy/decortication for pleural mesothelioma, and the incidence was significantly higher among females and patients undergoing diaphragm reconstruction. Moreover, postoperative recurrence of peritoneal dissemination was associated with a poor prognosis.

Postoperative early laboratory changes and follow-up process of patients underwent hyperthermic intrathoracic chemotherapy.

BACKGROUND: The aim of combining hyperthermic intrathoracic chemotherapy (HITHOC) with surgery is to achieve local control in patients with pleural malignancies. Liver and kidney dysfunction resulting from this procedure have been reported in the literature. The objective of the study is to examine whether the laboratory abnormalities observed during the initial period persist until day 30. METHODS: The study conducted a retrospective analysis of the blood glucose levels, renal function markers, and hepatic function markers of 30 patients who underwent pleurectomy-decortication and HITHOC for pleural mesothelioma from January 2010 to April 2022. The measurements were taken in the postoperative period on the first four and 30th days. The study analyzed the initial and final laboratory results caused by the procedure. RESULTS: Out of the total of 30 patients, 29, 28, 14, and 12 patients had elevated glucose levels on the first four days after the surgery, respectively. There was no association between glucose abnormalities and preoperative-postoperative diabetes mellitus. A minority of patients experienced atypical alterations in kidney and liver functions during the initial postoperative period. There was no apparent relationship between the renal and hepatic functions in the early and late periods after the surgery. CONCLUSION: Although there were fluctuations in glucose levels and renal and hepatic functions in the early period after surgery, there were no persistent alterations in these parameters by day 30. Elevated glucose levels during the early period were not associated with the development of newly diagnosed diabetes mellitus after surgery. The findings of our study provide evidence that HITHOC is a favorable and well-tolerated treatment option for mesothelioma.

Is extereme cytoreductive surgery beneficial to survival in malignant peritoneal mesothelioma?

INTRODUCTION: Malign peritoneal mesothelioma (MPM) is an uncommon disease that is difficult to treat. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) are the gold standards for treating MPM. Sometimes extreme cytoreductive surgery (eCRS) is required to achieve complete cytoreduction, which is one of the most important prognostic factors. There is limited information in the literature about the contribution of eCRS in patients with MPM. In this study, we aimed to investigate the impact of eCRS on survival and perioperative outcomes. METHODS: The Department of Surgical Oncology at Cumhuriyet University database was retrospectively reviewed for MPM patients who underwent CRS-HIPEC between January 2004 and December 2018. Patients who underwent CRS-HIPEC were divided into eCRS and less extensive CRS (leCRS) groups. A resection of ≥5 organs or ≥3 small bowel anastomoses were defined as eCRS. Both groups were compared regarding survival, demographic information, and perioperative outcomes. RESULTS: A total of 31 patients were included. eCRS-HIPEC was used in 15 patients. Complete cytoreduction (CC score 0/1) was achieved in all 31 patients. Compared to leCRS, the eCRS group had a longer median length of stay, longer intensive care unit stay, a higher median peritoneal cancer index (PCI), higher intraoperative blood loss, more frequent occurrence of any complication, and a longer operative time (all p values < 0.001). Clavien Dindo 3-4 complications, ASA, and gender were similar in both groups of patients (p > 0.05). It was found that there was no significant difference between the OS of the eCRS and leCRS groups (37.5 vs. 42.8 months, p = 0.895). CONCLUSIONS: Rates of serious complications and morbidity are similar in patients undergoing eCRS compared to leCRS. In patients with high PCI and multiorgan involvement, complete cytoreduction can be achieved by performing eCRS, and survival results equivalent to those with low PCI can be achieved.

Impact of Pleural Thickness on Occurrence of Postoperative Complications in Patients with Malignant Pleural Mesothelioma.

OBJECTIVES: The rates of postoperative mortality and morbidity are high in patients with malignant pleural mesothelioma (MPM). Therefore, it is important to identify variables that increase the risk of postoperative complications. Pleural thickness has recently been identified as a prognostic indicator in patients with MPM. The aim of this study was to investigate clinical variables, including pleural thickness, that contribute to postoperative complications in patients with MPM. PATIENTS AND METHODS: A total of 47 patients who underwent surgical excision of MPM between 2005 and 2021 were enrolled in this study. Correlations between postoperative complications within 90 days of surgery and preoperative clinical factors were investigated. RESULTS: A total of 27 patients underwent extrapleural pneumonectomy (EPP), and the remaining 20 underwent pleurectomy/decortication (P/D). Macroscopic complete resections were obtained in all but three patients. Of the 47 patients, 23 (49%) experienced postoperative complications of grade 3 or worse. The major complication in patients with EPP was respiratory failure (n = 6), whereas the major complication in patients with P/D was prolonged air leakage (n = 7). Univariate logistic regression analysis found a correlation between postoperative complications and age, surgical side, and pleural thickness, while multivariate logistic regression analysis found surgical side (p = 0.04, 95% Cl 1.10-21.71, OR 4.90) and pleural thickness (p = 0.03, 95% Cl 1.21-23.00, OR 5.26) to significantly influence the occurrence of postoperative complications. CONCLUSIONS: Pleural thickness has a significant effect on the occurrence of postoperative complications. Patients with thick pleura on the right side are at greater risk of postoperative complications.

Does mediastinal lymph node involvement influence the surgical outcome in malign pleural mesothelioma?

BACKGROUND: This study examined the effect of metastatic mediastinal lymph node involvement on the prognosis of patients with malignant pleural mesothelioma (MPM) who underwent extrapleural pneumonectomy (EPP) or extended pleurectomy (E/P) and also to assess the effect of metastatic mediastinal lymph node involvement on the prognosis of patients with MPM in these group of patients. METHODS: This retrospective study included 84 patients with MPM (66 men [78.6%] and 18 women [21.4%]) who underwent EPP (n = 44) or E/P (n = 40) at our institution between January 2001 and July 2019. Survival analyses were performed according to histopathology, nodal status, and surgical approach. RESULTS: In the EPP group, patients with T2-N2 status had a significantly better mean survival (17 ± 2.1 months) than patients with T3-N2 (7.3 ± 1.6 months) or T4-N2 (3.2 ± 1.1 months) status (p = .001). In the E/P group, patients with T2-N2 status had a mean survival of 18 ± 1.1 months, while patients with T3-N2 and T4-N2 status had mean survival durations of 6.6 ± 1.6 and 4.8 ± 1.2 months, respectively (p = .159). In both treatment groups, the survival rates of patients with epithelial tumors were better than those of patients with non-epithelial tumors, independent of N status. None of the patients with N2 disease survived until 5 years postoperatively. CONCLUSION: In summary, our results suggested that mediastinal lymph node metastasis negatively influenced the prognosis of patients with T3 MPM, regardless of treatment by EPP or E/P. Under these circumstances, preoperative cervical mediastinoscopy or endobronchial ultrasound-guided transbronchial needle aspiration may be considered for patients with high-stage MPM who are scheduled for surgery with curative intent. In our study, N2 status was spotted as a significant factor affecting survival, nevertheless its significance in survival of pleural mesothelioma patients should be analyzed in multi-centered studies.

[Diagnosis and treatment of malignant mesothelioma of the tunica vaginalis testis: a series of 7 cases].

Objective: To investigate the clinical features, diagnosis, prognosis of malignant mesothelioma of the tunica vaginalis testis (MMTVT). Methods: The clinicopathological data of 7 patients with MMTVT who treated at Sun Yat-sen University Cancer Center between January 2010 and October 2022 were retrospectively reviewed. Cases were first diagnosed at (M (IQR)) 49 (23) years old (range: 27 to 64 years old). The main clinical manifestations were scrotal enlargement (7 cases) and hydrocele (2 cases). Results: Three patients underwent radical orchiectomy as initial treatment, 2 cases underwent hydrocelectomy due to diagnosis of hydrocele, followed by radical orchiectomy at Sun Yat-sen University Cancer Center, and 2 cases underwent transscrotal orchiectomy. Common tumor markers of testicular cancer were not significantly elevated in MMTVT. The expression of tumor PD-L1 was positive in 2 out of the 3 cases. One patient received adjuvant chemotherapy and 2 patients received first-line chemotherapy after tumor recurrence. Chemotherapy regimens used include cisplatin+pemetrexed. Up to October 2022, 3 cases relapsed, of which 2 cases died. The median overall survival was 35 months (range: 4 to 87 months) and the median progression-free survival was 6 months (range: 2 to 87 months). Conclusions: MMTVT at early stage should be treated with early radical orchiectomy and followed up closely after surgery. The cisplatin+pemetrexed regimen is a common option for the treatment of metastatic MMTVT, while whether immune checkpoint inhibitors could serve as a second-line treatment option deserves further research.

Malignant Peritoneal Mesothelioma Associated With Endometriosis: A Clinicopathologic Study of 15 Cases.

Only a few cases of malignant peritoneal mesothelioma (MPeM) associated with endometriosis have been published; with chronic inflammation of the peritoneum associated with the latter being postulated as an inducing factor in the pathogenesis of this tumor. We assessed the clinicopathologic characteristics of MPeM associated with endometriosis to determine if there were other factors besides inflammation that may contribute to the pathogenesis in this patient population. Fifteen MPeM associated with endometriosis were retrieved from our files. Most presented with abdominal/pelvic pain, mass or distention; median age was 45 yr. Only 16% of patients had a history of asbestos exposure. In contrast, a third of the patients had a personal history of other neoplasms, and >80% had a family history of malignancies. Although most tumors had gross and microscopic features typical of MPeM, some had confounding features including "adhesion-like" appearance or gelatinous cysts/nodules, and signet ring cells. Tumors were epithelioid (9) and biphasic (6). MPeM was misdiagnosed as Müllerian carcinoma in 40% of cases. All patients (n=15) had cytoreductive surgery in addition to other therapies. Only 2/12 patients died of disease (17%). The 3- and 5-yr overall survival was 90%. MPeM associated with endometriosis tends to occur in patients with personal/familial history of malignancies, which may be a predisposing factor. In light of this finding, the role of endometriosis in the pathogenesis of MPeM is likely less relevant. The favorable outcome seen in these patients may be related to germline mutations or the hormonal milieu and needs further investigation.

Surgery for malignant pleural mesothelioma after radiotherapy (SMART): final results from a single-centre, phase 2 trial.

BACKGROUND: A novel approach for managing malignant pleural mesothelioma, surgery for mesothelioma after radiotherapy (SMART), consisting of a short accelerated course of high-dose, hemithoracic, intensity modulated radiotherapy (IMRT) followed by extrapleural pneumonectomy was developed. The aim of this study was to evaluate the clinical feasibility of the SMART protocol. METHODS: In this single-centre, phase 2 trial, patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-2, with histologically proven, resectable, cT1-3N0M0 disease who had previously untreated malignant pleural mesothelioma were eligible for inclusion. Patients received 25 Gy in five daily fractions over 1 week to the entire ipsilateral hemithorax with a concomitant 5 Gy boost to high risk areas followed by extrapleural pneumonectomy within 1 week. Adjuvant chemotherapy was offered to patients with ypN+ disease on final pathology. The primary endpoint was feasibility, which was defined as the number of patients with 30-day perioperative treatment-related death (grade 5 events) or morbidity (grade 3 or 4 events). A key secondary endpoint was cumulative incidence of distant recurrence. The final analysis was done on an intention-to-treat basis (including all eligible patients). This trial is registered with ClinicalTrials.gov, NCT00797719. FINDINGS: Between Nov 1, 2008, and Oct 31, 2019, 102 patients were enrolled onto the trial and 96 eligible patients were treated with SMART on protocol and included in the analysis. Extrapleural pneumonectomy was done at a median of 5 days (range 2-12) after completing IMRT. 47 (49%) patients had 30-day perioperative grade 3-4 events and one (1%) patient died within 30 days perioperatively (grade 5 event; pneumonia). After a median follow-up of 46·8 months (IQR 13·4-61·2), the 5-year cumulative incidence of distant recurrence was 62 (63·3% [95% CI 52·3-74·4]). The most common first sites of recurrence were the contralateral chest (33 [46%] of 72 patients) and the peritoneal cavity (32 [44%]). INTERPRETATION: Results from this study suggest that extrapleural pneumonectomy after radiotherapy can be done with good early and long-term results. However, minimising grade 4 events on the protocol is technically demanding and might affect survival beyond the post-operative period. FUNDING: Princess Margaret Hospital Foundation Mesothelioma Research Fund.

ECLS for Life-Threatening Complications in Mesothelioma Surgery: Is It Worthwhile?

Extracorporeal life support (ECLS) is an effective method for bridging patients to recovery in cases of respiratory and/or cardiac failure that are potentially reversible and unresponsive to conventional management. Nevertheless, there have been only few reports about the use of ECLS in oncological patients with complications due to their neoplasm or its treatment. We report the use of veno-arterial extracorporeal membrane oxygenation in three cases of severe perioperative complications following surgery for mesothelioma after induction chemotherapy at our Institution.

The role of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in the treatment of peritoneal carcinomatosis: a systematic review including evidence from Japan.

The prognosis of peritoneal carcinomatosis is poor. However, the emergence of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) as a treatment option has prolonged survival and it can even potentially cure patients with peritoneal carcinomatosis. Randomized controlled studies and other observational studies indicated that this combined therapy potentially improved the prognosis of patients with colon, gastric, and ovarian cancers with acceptable morbidity and mortality rates. Even in rarer diseases, such as pseudomyxoma peritonei and malignant peritoneal mesothelioma, CRS + HIPEC markedly improved the prognoses over those with conventional treatment. Based on the accumulated evidence, clinical guidelines recommend CRS + HIPEC for selected patients with peritoneal carcinomatosis. However, several issues still need to be overcome. A standard method for HIPEC has not yet been established. Furthermore, the criteria employed for patient selection need to be clarified to achieve real benefits. The peritoneal cancer index, chemo-sensitivity and several biological markers are considered to be key factors.

Interobserver variation in the assessment of the sarcomatoid and transitional components in biphasic mesotheliomas.

The percentage of sarcomatoid component has an impact on prognosis in patients with biphasic malignant pleural mesothelioma. Recent study showed that the transitional pattern similar to sarcomatoid component of malignant mesothelioma has negative prognostic significance. Practice guidelines recommend quantification of sarcomatoid component despite poor diagnostic reproducibility of biphasic mesothelioma among thoracic pathologists. The aim of this study was to determine the interobserver agreement in the quantification of sarcomatoid component, and in the diagnosis of a transitional component in the biphasic malignant mesothelioma. Thirteen experts in thoracic pathology reviewed the representative H&E and cytokeratin whole-slide images of the 54 biphasic mesotheliomas, without knowledge of BAP1 or p16 deletion status, and completed the survey of 25 questions. The overall interobserver agreement in the assessment of the percentage of the sarcomatoid component in 25% increments was good (wK = 0.62). Excellent agreement was present in 14 of 54 cases (26%), and 3 cases were unanimously scored. Excellent agreement was reached for the cases with 0-24% and > 75% of the sarcomatoid component.The most commonly used criteria for the diagnosis of sarcomatoid component were malignant spindle cells, frank sarcomatoid features and high N/C ratio. The overall interobserver agreement for transitional pattern was fair (wK = 0.40). Unanimous opinion about the absence of transitional pattern was observed in only one case. At least 70% agreement regarding the presence of transitional pattern was observed in 12 cases, with the rest of the cases showing a wide range of disagreement. Morphologic characteristics that favor transitional pattern over non-transitional include sheet-like growth of cohesive, plump, elongated epithelioid cells with well-defined cell borders and a tendency to transition into spindle cells. Our study defined precise morphologic criteria that may be used in the differential diagnosis between transitional pattern and other mesothelioma subtypes including sarcomatoid and epithelioid.

Localized biphasic malignant mesothelioma presenting as a giant pelvic wall mass: a rare case report and literature review.

BACKGROUND: Localized biphasic MPeM is rare in clinical practice, we reviewed 8 cases of localized biphasic MPeM (including our present case), and summarized the clinical and imaging features of the disease. CASE PRESENTATION: We reported a 79-year-old man with chief complaint of a narrowing in the caliber of the stool for one year. A soft tissue shadow was occasionally found by CT examination in the right pelvic wall, and it was diagnosed as localized biphasic malignant peritoneal mesothelioma (MPeM) by postoperative pathology. Radical excision was performed and no radio-chemotherapy was applied. Nearly six years after surgery, the mass was significantly enlarged, and the neighboring tissues including rectum, prostate, seminal vesicle, and right ischial ramus were all infiltrated. The patient was in the end stage of cancer with poor prognosis. CONCLUSIONS: The localized biphasic MPeM may show following characteristics: (1) with heterogeneous low-density and obscure margin; (2) with low incidence rate of ascites; (3) with few central hemorrhage and necrosis; (4) with few calcified structures; (5) with mild to moderate heterogeneous delayed enhancement on contrast-enhanced CT. The imaging characteristics can provide further information for the diagnosis of localized biphasic MPeM in the future.

Long-Term Survival Analysis of Pleural Mesothelioma Patients Undergoing Surgery: Brief Report From a Tertiary Referral Centre.

OBJECTIVES: to date, no consensus has been reached on the surgical gold-standard in pleural mesothelioma (PM). We retrospectively reviewed our experience as a tertiary referral centre, to compare short- and long-term survival of PM patients undergoing different types of surgery. METHODS: in retrospective, observational, single-centre study, we analysed all the patients histologically diagnosed with PM undergoing surgical procedures with palliative or curative intent at IRCCS Istituto Nazionale dei Tumori of Milan, Italy, from January 2003 to December 2020. The primary study endpoint was 10-year overall survival (OS) in three different types of resections: extra-pleural-pneumonectomy (EPP), pleurectomy/decortication (P/D), partial-pleurectomy/pleural-biopsy (PP/B). Secondary endpoints were postoperative hospital stay and postoperative 30-day and 90-day mortality rates. The survival function was estimated using Kaplan-Meier, and the Log-rank test was used for testing differences. Univariable and Multivariable Cox regression models were implemented to estimate Hazard Ratio (HR) for all variables of interest. RESULTS: 243 consecutive patients were enrolled, EPP was performed in 49 (20.2%), P/D in 58 (23.8%), PP/B in 136 (56.0%) patients. The median follow-up time was 19.8 months. 10-year OS was significantly better for P/D group (16%, Log-Rank test p<0.0001) compared to PP/B (1.8%) and EPP (0%). No statistically significant differences were found among the 3 surgical groups in 30- and 90-day mortality rates. At multivariable analysis, gender (male, HR=1.58), type of resection (P/D, HR=0.55) and surgery date (recent years, HR=0.61) were found to be independent prognostic factors for OS. CONCLUSIONS: in PM, lung-sparing curative approach (e.g. P/D) should be preferred in highly selected patients and in highly experienced centres, whenever appropriate. Anyway, when P/D is not indicated, adopting palliative/conservative management (e.g. PP/B) could ensure comparable results as extremely aggressive surgeries (e.g. EPP). The aim of surgery in PM should not be reaching complete resection, but rather accomplishing significant resection allowing to complete the multimodality treatment in highly selected patients in experienced centers.

Malignant pleural mesothelioma: Description of pleural decortication and hyperthermic chemotherapy technique in multimodal therapy.

The current treatment for mesothelioma, in selected cases, consists of extended pleurodecortication and intrathoracic hyperthermic chemotherapy. This technique is laborious and detailed and must be followed step by step to achieve good results. We present the case of a patient with epithelioid mesothelioma meeting surgical criteria who underwent the mentioned technique, experiencing an adequate postoperative period and an early discharge. This experience demonstrates that the technique is safe when performed in centres with experience and the means to address this complex pathology.