Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma: Canadian practices and outcomes.

INTRODUCTION: Peritoneal mesothelioma (PM) is a rare malignancy originating from the peritoneal lining. Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is the standard-of-care for patients with isolated PM. Due to a paucity of prospective data there are several different HIPEC protocols. The aims of this study are to describe the CRS and HIPEC protocols for PM and patient outcomes across Canada. METHODS: A multicenter retrospective study was performed on patients diagnosed and treated for PM with CRS and HIPEC in four major peritoneal disease centers in Canada between 2000 and 2021. Data on patient characteristics, treatment patterns, postoperative morbidity, recurrence, and survival were collected. RESULTS: A total of 72 patients were identified. Mean age was 52 years (17-75) and 37.5% were male. Epithelioid (70.1%) and multicystic (13%) mesothelioma were the most common subtypes. Twenty-one patients (30%) were treated with neoadjuvant chemotherapy. CRS and HIPEC was performed in 64 patients (91.4%). Of these, the mean PCI was 22 (2-39) and cisplatin+doxorubicin was the most common HIPEC regimen (n = 33, 51.6%). A semi-closed coliseum technique was used in 68.8% of HIPECs and the mean duration of surgery was 486 min (90-1052). Clavien-Dindo III or IV complications occurred in 12 patients (16.9%). With a median follow-up of 24 months (0.2-104.4), we found a 5-year overall survival of 61% and a 5-year recurrence-free survival of 35%. CONCLUSION: CRS and HIPEC is a safe and effective treatment modality for well-selected patients with PM, with some achieving prolonged survival.

Citral reduces breast tumor growth by inhibiting the cancer stem cell marker ALDH1A3.

Breast cancer stem cells (CSCs) can be identified by increased Aldefluor fluorescence caused by increased expression of aldehyde dehydrogenase 1A3 (ALDH1A3), as well as ALDH1A1 and ALDH2. In addition to being a CSC marker, ALDH1A3 regulates gene expression via retinoic acid (RA) signaling and plays a key role in the progression and chemotherapy resistance of cancer. Therefore, ALDH1A3 represents a druggable anti-cancer target of interest. Since to date, there are no characterized ALDH1A3 isoform inhibitors, drugs that were previously described as inhibiting the activity of other ALDH isoforms were tested for anti-ALDH1A3 activity. Twelve drugs (3-hydroxy-dl-kynurenine, benomyl, citral, chloral hydrate, cyanamide, daidzin, DEAB, disulfiram, gossypol, kynurenic acid, molinate, and pargyline) were compared for their efficacy in inducing apoptosis and reducing ALDH1A3, ALDH1A1 and ALDH2-associated Aldefluor fluorescence in breast cancer cells. Citral was identified as the best inhibitor of ALDH1A3, reducing the Aldefluor fluorescence in breast cancer cell lines and in a patient-derived tumor xenograft. Nanoparticle encapsulated citral specifically reduced the enhanced tumor growth of MDA-MB-231 cells overexpressing ALDH1A3. To determine the potential mechanisms of citral-mediated tumor growth inhibition, we performed cell proliferation, clonogenic, and gene expression assays. Citral reduced ALDH1A3-mediated colony formation and expression of ALDH1A3-inducible genes. In conclusion, citral is an effective ALDH1A3 inhibitor and is able to block ALDH1A3-mediated breast tumor growth, potentially via blocking its colony forming and gene expression regulation activity. The promise of ALDH1A3 inhibitors as adjuvant therapies for patients with tumors that have a large population of high-ALDH1A3 CSCs is discussed.