Relevance of Positron-Emission Therapy for Optimization of Treatment of Advanced Hodgkin’s Lymphoma Using Intensive ЕАСОРР-14 Program

Aim. To evaluate the relevance of the positron-emission therapy (PET) for optimization of the therapy of advanced Hodgkin’s lymphoma (HL) using the intensive EACOPP-14 program. Materials & Methods. 91 patients with advanced HL (IIX–IIE, III–IV) received the treatment according to the “ЛХМосква1-3” protocol over the period from November 2009 to February 2015, and then the treatment was analyzed. The median age was 29 years (range: 17–50); there were 42 men (46.3 %) and 49 (53.7 %) women. The treatment included 6 cycles of polychemotherapy according to the regimen ЕА(50)СОРР-14 ± radiation therapy. The radiation therapy was performed in 66 patients (72.5 %) after the completion of the chemotherapy. The cumulative focal dose was 30 Gy onto the areas of residual lesions and/or initially large tumor masses. Results. PET performed during the initial HL diagnosing permited to identify new areas of neoplastic lesions without changes in staging and treatment scheme, as well as specify areas and field size of planned radiation consolidation. The paper confirms the prognostic value of the intermediate PET in patients with advanced HL during the intensive first-line chemotherapy. The intensive therapy at the beginning of the treatment program is associated with higher chances for survival for patients with extremely unfavorable prognosis. After completion of the drug therapy, negative PET findings had a higher prognostic value, than the positive ones. The analysis of the relevance of residual tumor dimensions in the PET negative group demonstrated that the relapses were more common, if the residual tumor was more than 4.5 cm (according to CT findings). Conclusion. This study confirmed that it reasonable to discuss the discontinuation of the radiation therapy in patients with advanced HL, negative PET findings and small (< 2.5 cm) residual tumor after the intensive ЕАСОРР-14 program. This tactics permits avoiding a number of delayed complications

On the role of the mitochondrial 2-oxoglutarate dehydrogenase complex in amino acid metabolism

Mitochondria are tightly linked to cellular nutrient sensing, and provide not only energy, but also intermediates for the de novo synthesis of cellular compounds including amino acids. Mitochondrial metabolic enzymes as generators and/or targets of signals are therefore important players in the distribution of intermediates between catabolic and anabolic pathways. The highly regulated 2-oxoglutarate dehydrogenase complex (OGDHC) participates in glucose oxidation via the tricarboxylic acid cycle. It occupies an amphibolic branch point in the cycle, where the energy-producing reaction of the 2-oxoglutarate degradation competes with glutamate (Glu) synthesis via nitrogen incorporation into 2-oxoglutarate. To characterize the specific impact of the OGDHC inhibition on amino acid metabolism in both plant and animal mitochondria, a synthetic analog of 2-oxoglutarate, namely succinyl phosphonate (SP), was applied to living systems from different kingdoms, both in situ and in vivo. Using a high-throughput mass spectrometry-based approach, we showed that organisms possessing OGDHC respond to SP by significantly changing their amino acid pools. By contrast, cyanobacteria which lack OGDHC do not show perturbations in amino acids following SP treatment. Increases in Glu, 4-aminobutyrate and alanine represent the most universal change accompanying the 2-oxoglutarate accumulation upon OGDHC inhibition. Other amino acids were affected in a species-specific manner, suggesting specific metabolic rearrangements and substrate availability mediating secondary changes. Strong perturbation in the relative abundance of amino acids due to the OGDHC inhibition was accompanied by decreased protein content. Our results provide specific evidence of a considerable role of OGDHC in amino acid metabolism