Spliceosomic dysregulation in pancreatic cancer uncovers splicing factors PRPF8 and RBMX as novel candidate actionable targets.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, characterized by late diagnosis and poor treatment response. Surgery is the only curative approach, only available to early-diagnosed patients. Current therapies have limited effects, cause severe toxicities, and minimally improve overall survival. Understanding of splicing machinery alterations in PDAC remains incomplete. Here, we comprehensively examined 59 splicing machinery components, uncovering dysregulation in pre-mRNA processing factor 8 (PRPF8) and RNA-binding motif protein X-linked (RBMX). Their downregulated expression was linked to poor prognosis and malignancy features, including tumor stage, invasion and metastasis, and associated with poorer survival and the mutation of key PDAC genes. Experimental modulation of these splicing factors in pancreatic cancer cell lines reverted their expression to non-tumor levels and resulted in decreased key tumor-related features. These results provide evidence that the splicing machinery is altered in PDAC, wherein PRPF8 and RBMX emerge as candidate actionable therapeutic targets.

Intraoperative metabolic changes associated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) causes considerable hemodynamic, respiratory, and metabolic changes during the perioperative period. OBJECTIVES: To evaluate metabolic changes associated with this procedure. Understanding perioperative factors and their association with morbidity may improve the perioperative management of patients undergoing this treatment. METHODS: A retrospective review of a prospectively maintained database was performed. All consecutive unselected patients who underwent CRS plus HIPEC between January 2018 and December 2020 (n = 219) were included. RESULTS: The mean age was 58 ± 11.7 years and 167 (76.3%) were female. The most frequent histology diagnosis was serous ovarian carcinoma 49.3% (n = 108) and colon carcinoma 36.1% (n = 79). Mean peritoneal cancer index was 14.07 ± 10.47. There were significant variations in pH, lactic acid, sodium, potassium, glycemia, bicarbonate, excess bases, and temperature (p < 0.05) between the pre-HIPEC and post-HIPEC periods. The closed HIPEC technique resulted in higher levels of temperature than the open technique (p < 0.05). Age, potassium level post-HIPEC potassium level, and pre-HIPEC glycemia were identified as prognostic factors for morbidity in multivariate analysis. CONCLUSION: The administration of HIPEC after CRS causes significant changes in internal homeostasis. Although the closed technique causes a greater increase in temperature, it is not related to higher morbidity rates. The patient's age, post-HIPEC potassium level, and pre-HIPEC glycemia are predictive factors for morbidity.

The Role of Intraperitoneal Intraoperative Chemotherapy with Paclitaxel in the Surgical Treatment of Peritoneal Carcinomatosis from Ovarian Cancer-Hyperthermia versus Normothermia: A Randomized Controlled Trial.

BACKGROUND: The treatment of ovarian carcinomatosis with cytoreductive surgery and HIPEC is still controversial. The effect and pharmacokinetics of the chemotherapeutics used (especially taxanes) are currently under consideration. METHODS: A phase II, simple blind and randomized controlled trial (NTC02739698) was performed. The trial included 32 patients with primary or recurrent ovarian carcinomatosis undergoing cytoreductive surgery (CRS) and intraoperative intraperitoneal chemotherapy with paclitaxel (PTX): 16 in hyperthermic (42-43 °C) and 16 in normothermic (37 °C) conditions. Tissue, serum and plasma samples were taken in every patient before and after intraperitoneal chemotherapy to measure the concentration of PTX. To analyze the immunohistochemical profile of p53, p27, p21, ki67, PCNA and caspase-3 and the pathological response, a scale of intensity and percentage of expression and a grouped Miller and Payne system were used, respectively. Perioperative characteristics and morbi-mortality were also analyzed. RESULTS: The main characteristics of patients, surgical morbidity, hemotoxicity and nephrotoxicity were similar in both groups. The concentration of paclitaxel in the tissue was higher than that observed in plasma and serum, although no statistically significant differences were found between the two groups. No statistically significant association regarding pathological response and apoptosis (caspase-3) between both groups was proved. There were no statistically significant differences between the normothermic and the hyperthermic group for pathological response and apoptosis. CONCLUSIONS: The use of intraperitoneal PTX has proven adequate pharmacokinetics with reduction of cell cycle and proliferation markers globally without finding statistically significant differences between its administration under hyperthermia versus normothermia conditions.

Dysregulated splicing factor SF3B1 unveils a dual therapeutic vulnerability to target pancreatic cancer cells and cancer stem cells with an anti-splicing drug.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, requiring novel treatments to target both cancer cells and cancer stem cells (CSCs). Altered splicing is emerging as both a novel cancer hallmark and an attractive therapeutic target. The core splicing factor SF3B1 is heavily altered in cancer and can be inhibited by Pladienolide-B, but its actionability in PDAC is unknown. We explored the presence and role of SF3B1 in PDAC and interrogated its potential as an actionable target. METHODS: SF3B1 was analyzed in PDAC tissues, an RNA-seq dataset, and publicly available databases, examining associations with splicing alterations and key features/genes. Functional assays in PDAC cell lines and PDX-derived CSCs served to test Pladienolide-B treatment effects in vitro, and in vivo in zebrafish and mice. RESULTS: SF3B1 was overexpressed in human PDAC and associated with tumor grade and lymph-node involvement. SF3B1 levels closely associated with distinct splicing event profiles and expression of key PDAC players (KRAS, TP53). In PDAC cells, Pladienolide-B increased apoptosis and decreased multiple tumor-related features, including cell proliferation, migration, and colony/sphere formation, altering AKT and JNK signaling, and favoring proapoptotic splicing variants (BCL-XS/BCL-XL, KRASa/KRAS, Δ133TP53/TP53). Importantly, Pladienolide-B similarly impaired CSCs, reducing their stemness capacity and increasing their sensitivity to chemotherapy. Pladienolide-B also reduced PDAC/CSCs xenograft tumor growth in vivo in zebrafish and in mice. CONCLUSION: SF3B1 overexpression represents a therapeutic vulnerability in PDAC, as altered splicing can be targeted with Pladienolide-B both in cancer cells and CSCs, paving the way for novel therapies for this lethal cancer.

Emergency adrenalectomy due to acute heart failure secondary to complicated pheochromocytoma: a case report.

Pheochromocytomas are catecholamine producing tumors arising mostly from chromaffin cells of the adrenal medulla. The most common clinical presentation is hypertension, mainly in the form of paroxymal episodes. Cardiovascular manifestations include malignant arrhythmia and catecholamine cardiomyopathy, mimicking acute coronary syndromes and acute heart failure.There are reports of pheochromocytomas presenting as acute coronary syndrome and rapidly leading to cardiogenic shock; the failure of intensive medical treatment in these cases has prompted the need for emergency adrenalectomy as the only remaining option. We report on a case of complicated pheochromocytoma presenting as cardiogenic shock, in which emergency adrenalectomy was performed following a total lack of response to intensive medical treatment.