The Landscape of the Anti-Kinase Activity of the IDH1 Inhibitors

Isocitrate dehydrogenases constitute a class of enzymes that are crucial for cellular metabolism. The overexpression or mutation of isocitrate dehydrogenases are often found in leukemias, glioblastomas, lung cancers, and ductal pancreatic cancer among others. Mutation R132H, which changes the functionality of an enzyme to produce mutagenic 2-hydroxyglutarate instead of a normal product, is particularly important in this field. A series of inhibitors were described for these enzymes of which ivosidenib was the first to be approved for treating leukemia and bile duct cancers in 2018. Here, we investigated the polypharmacological landscape of the activity for known sulfamoyl derivatives that are inhibitors, which are selective towards IDH1 R132H. These compounds appeared to be effective inhibitors of several non-receptor kinases at a similar level as imatinib and axitinib. The antiproliferative activity of these compounds against a panel of cancer cells was tested and is explained based on the relative expression levels of the investigated proteins. The multitargeted activity of these compounds makes them valuable agents against a wide range of cancers, regardless of the status of IDH1.

Evolution of surgery for pancreatic head and periampullary cancer

Development of surgical approach for pancreatic head and periampullary cancer at the Blokhin National Medical Research Center of Oncology over the past 30 years and global surgical tendencies of surgery for pancreatic cancer are demonstrated in the article. Over this period, gastropancreaticoduodenectomy has evolved from standard procedure without complete lymph node dissection and neurodissection and extended gastropancreaticoduodenectomy with obligatory circular skeletonization of superior mesenteric artery and para-aortic lymphadenectomy to standard gastropancreaticoduodenectomy. The last procedure implies mandatory skeletonization of the right semicircle of superior mesenteric artery, all tubular structures of hepatoduodenal ligament and possible resection of portal and superior mesenteric vein for suspected invasion. Surgical possibilities in the treatment of patients with pancreatic head and periampullary cancer are exhausted. The concept of “early diagnosis” is not applicable for patients with ductal pancreatic cancer. Further progress is exclusively associated with medicamentous combined treatment based on the molecular-biological characteristics of pancreatic and periampular cancer and, possibly, with primary prevention of pancreatic cancer.

Electrostatic precipitation Pressurized IntraPeritoneal Aerosol Chemotherapy (ePIPAC): first in-human application

Background: Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is a drug delivery technique with superior pharmacological properties for treating peritoneal metastasis (PM). Adding electrostatic loading (ePIPAC) as an adjunct to aerosol and artificial hydrostatic pressure improved tissue uptake in a preclinical model.Methods: We report the first ePIPAC use in 3 patients with PM of hepatobiliary-pancreatic (HBP) origin. All 3 patients received concomitant palliative systemic chemotherapy that was discontinued in two patients. PIPAC with cisplatin 7.5 mg/m2 and doxorubicin 1.5 mg/m2 was applied intraperitoneally at a pressure of 12 mmHg and a temperature of 37% °C for 30 min. Additionally, a voltage 7,500–9,500 V and a current≤10 µA were applied over a stainless steel brush electrode emitting a stream of electrons.Results: ePIPAC was technically feasible. No intraoperative complication was noted. The procedures were well tolerated with no adverse event CTCAE > 2. Patient 1 with PM of unknown origin (CUP with HBP phenotype) showed an objective histological and radiological response and survived 11 months. Patient 2 with ductal pancreatic cancer underwent secondary resection after ePIPAC with no residual PM; however, tumor recurred 5 months later. Patient 3 with adenocarcinoma of the gallbladder showed a radiological regression of liver infiltration and is alive after 22 months without histological evidence of PM.Conclusion: ePIPAC is technically feasible, is well tolerated and can induce tumor regression of PM in HBP cancers with and without concomitant systemic chemotherapy. These preliminary results justify prospective clinical studies with ePIPAC.