[Checkpoint inhibitors-indications and application in melanoma patients]. / Checkpoint-Inhibitoren ­ Indikation und Verwendung bei Melanompatienten.

Since its introduction in 2011 the checkpoint inhibitor ipilimumab, has revolutionized the whole of oncology. After this first major step more checkpoint inhibitors, such as the PD­1 antibodies nivolumab and pembrolizumab have been developed. The results are groundbreaking, especially in advanced malignant melanoma, which only a few years ago led to certain death in most cases after only a few months. Currently, the application of checkpoint inhibitors has been extended to many more tumor entities, with very promising results.

[Aggressive primary cutaneous B-cell lymphomas and novel EBV+ entities]. / Aggressive primär kutane B-Zell-Lymphome und neue EBV-positive Entitäten.

Primary cutaneous large B­cell lymphomas (PCBLT), EBV-positive large B­cell lymphomas, not otherwise specified (EBV+ DLBCL, NOS), and primary cutaneous intravascular large B­cell lymphomas (PCIVLBL) are recognized as cutaneous lymphomas with intermediate to poor prognosis. Differentiation from indolent B­cell lymphomas or other pathologies of the skin can be complex, both clinically and histologically, but vital for the outcome of the patient. The combination of immunotherapy and polychemotherapy regimens, such as R­CHOP, has led to significant improvements in prognosis, especially in diffuse large B­cell lymphomas. Therapeutic decisions need to be individually made for each patient, ideally within an interdisciplinary tumor conference. Immunosenescence may be an important factor in the pathogenesis of EBV+ DLBCL, NOS in elderly individuals. Their prognosis is less favorable than that of patients with EBV-negative PCBLT, whereby this has been observed particularly in elderly patients. One third of patients with PCIVLBL progress to systemic disease. The occurrence of nodal manifestation is rarely observed. Symptoms may vary depending on the organ system involved. Currently there are no evidence-based therapy recommendations due to the rarity of the disease. EBV-positive mucocutaneous ulcer is a new provisional category in the current WHO classification for lymphoid neoplasms. It has been segregated from EBV+ DLBCL, NOS due to its self-limiting course and good response to conservative therapy.

Occurrence of an uncoupler-resistant intermediate type of phosphate-water oxygen exchange reaction catalyzed by heart submitochondrial particles.

The hydrolysis of ATP catalyzed by phosphorylating vesicles prepared from bovine heart mitochondria by ultrasonic disruption was studied in H218O. Provided that an ATP-generating system was included to prevent accumulation of ADP due to hydrolysis, the addition of 20 mM arsenate or 0.5 mM 2,4-dinitrophenol to the incubation mixture either singly or together, had little or no effect on the number of oxygen atoms from H2O incorporated (on the average) into each molecule of Pi formed by hydrolysis (the O:P ratio). As the ATP concentration was reduced from 2.0 to 0.05 mM, the O:P ratio increased from about 1.4 to over 2.0 and, although dinitrophenol significantly increased the ATPase activity, it did not significantly alter the O:P ratio for a given ATP level. This implies that the uncoupler does not act directly on the terminal transphosphorylation step. Companion experiments were performed in which 18O label was placed either initially in H2O or Pi. Under conditions where extensive exchange from H218O into Pi occurred, no 18O was lost from medium Pi under identical circumstances, thus showing that the exchange was intermediate and did not involve medium Pi. Kinetic plots of v vs. v/S were nonlinear with respect to ATPase activity. The kinetic data, as well as the Pi = H218O exchange data, are consistent with enzyme models having multiple forms of catalytic sites. Several models are evaluated and attempts are made to distinguish between some of the simpler cases of these models.

The effects of ADP on reverse electron flow and the oxygen exchange reactions catalyzed by bovine heart muscle submitochondrial particles.

1,N6-Ethenoadenosine diphosphate (epsilon-ADP) inhibits reverse electron flow (succinate leads to NAD+ driven by ATP) by competing with ATP, in contrast to ADP which we have shown previously to be a noncompetitive inhibitor. From these and other data it is concluded that the noncompetitive inhibition noted with ADP results from a combination of competitive inhibition plus non- or uncompetitive inhibition, the former occurring at a relatively nonspecific catalytic site and the latter at an extracatalytic site apparently quite specific for ADP. ADP, which stimulates ATP in equilibrium H2O and Pi in equilibrium H2O exchanges appears to be necessary for inhibition by arsenate of these exchanges. It is suggested that the ATP-supported Pi in equilibrium H2O exchange may be predominantly of the medium or intermediate type, depending on the concentrations of the Mg2+ complexes of ADP and Pi. Thus only exchanges involving medium ADP and Pi would be expected to show arsenate sensitivity.