New developments in the perioperative treatment of melanomas with locoregional advancement

Surgical intervention is the treatment of choice for patients with melanomas. However, the prognoses of the patients with melanomas at the IIC–IV stage, even after a complete resection of the lesions, is very diverse and, to a great degree, connected with a high risk of disease recurrence. The positive results of the studies in this area have resulted in systemic adjuvant therapy becoming the standard for patients in this group. New methods of systemic treatment – both the mo­lecularly targeted treatment with BRAF and MEK inhibitors (dabrafenib with trametinib) and anti-PD-1 immunotherapy (nivolumab or pembrolizumab) – are already registered in the United States and the European Union. Also the results of the studies concerning the use of preoperative systemic treatment in patients with loco-regionally advanced melanomas seem to be very promising

Progress in adjuvant treatment of melanoma patients

Surgery is therapy of choice in melanoma patients. However, prognosis of patients at stage IIC–IV even after radical resection is very heterogenous and related to high risk of disease relapse. Positive results of clinical trials indicate that in the nearest future systemic adjuvant therapy in high risk melanomas will become the standard of care. New treatment modalities, both molecular targeted therapy with BRAF+MEK inhibitors dabrafenib with trametinib and immunotherapy anti-PD-1 with nivolumab or pembrolizumab have been approved in US and EU

Calcium channel β subunits differentially modulate recovery of the channel from inactivation

AbstractWe examined the effects of calcium channel β subunits upon the recovery from inactivation of α1 subunits expressed in Xenopus oocytes. Recovery of the current carried by the L-type α1 subunit (cyCav1) from the jellyfish Cyanea capillata was accelerated by coexpression of any β subunit, but the degree of potentiation differed according to which β isoform was coexpressed. The Cyanea β subunit was most effective, followed by the mammalian b3, b4, and β2a subtypes. Recovery of the human Cav2.3 subunit was also modulated by β subunits, but was slowed instead. β3 was the most potent subunit tested, followed by β4, then β2a, which had virtually no effect. These results demonstrate that different β subunit isoforms can affect recovery of the channel to varying degrees, and provide an additional mechanism by which β subunits can differentially regulate α1 subunits

Tissue-type plasminogen activator-primed human iPSC-derived neural progenitor cells promote motor recovery after severe spinal cord injury.

The goal of stem cell therapy for spinal cord injury (SCI) is to restore motor function without exacerbating pain. Induced pluripotent stem cells (iPSC) may be administered by autologous transplantation, avoiding immunologic challenges. Identifying strategies to optimize iPSC-derived neural progenitor cells (hiNPC) for cell transplantation is an important objective. Herein, we report a method that takes advantage of the growth factor-like and anti-inflammatory activities of the fibrinolysis protease, tissue plasminogen activator tPA, without effects on hemostasis. We demonstrate that conditioning hiNPC with enzymatically-inactive tissue-type plasminogen activator (EI-tPA), prior to grafting into a T3 lesion site in a clinically relevant severe SCI model, significantly improves motor outcomes. EI-tPA-primed hiNPC grafted into lesion sites survived, differentiated, acquired markers of motor neuron maturation, and extended βIII-tubulin-positive axons several spinal segments below the lesion. Importantly, only SCI rats that received EI-tPA primed hiNPC demonstrated significantly improved motor function, without exacerbating pain. When hiNPC were treated with EI-tPA in culture, NMDA-R-dependent cell signaling was initiated, expression of genes associated with stemness (Nestin, Sox2) was regulated, and thrombin-induced cell death was prevented. EI-tPA emerges as a novel agent capable of improving the efficacy of stem cell therapy in SCI

Sentinel lymph node biopsies in patients with malignant melanoma — qualifying principles and histopathological assessment (2017)

  In 1999, the World Health Organisation (WHO) stated that sentinel lymph node biopsy should be the standard of management for those patients with melanomas without clinical signs of metastases to the regional lymph nodes. This procedure should include preoperative and intraoperative lymphoscintigraphy, combined with staining. Sentinel lymph node biopsies should be performed after excision biopsy of the melanoma and simultaneously with radical excision of the remaining scar after melanoma excision biopsy. Whenever sentinel lymph node(s) are found tumo­ur occupied, metastases are most likely to be located in one or more lymph nodes that were first occupied along lymphatic drainage from the primary focal point of the cancer. Detecting even single melanoma cells in the sentinel lymph node is usually used to determine the stage of the disseminating cancer and radically changes prognoses and further therapeutic decisions. Guidelines on lymph nodes examined during melanoma have been established by the College of American Pathologists (CAP), the European Society of Pathology (ESP) and the Polish Society of Pathologists in 2013. If melanoma metastases are found in sentinel lymph node(s) then: the number of lymph nodes should be specified as well as the number of those with metastases; microscopic features of sentinel lymph node(s) metastases should be defined as follows: the largest metastasis/ /metastases size, their location (subcapsular, intraparenchymal, mixed or extended), signs of possible infiltration and crossing the node capsule, penetration into adipose tissue and vasculature involvement

Derivation of the Supermolecular Interaction Energy from the Monomer Densities in the Density Functional Theory

The density functional theory (DFT) interaction energy of a dimer is rigorously derived from the monomer densities. To this end, the supermolecular energy bifunctional is formulated in terms of mutually orthogonal sets of orbitals of the constituent monomers. The orthogonality condition is preserved in the solution of the Kohn-Sham equations through the Pauli blockade method. Numerical implementation of the method provides interaction energies which agree with those obtained from standard supermolecular calculations within less than 0.1% error for three example functionals: Slater-Dirac, PBE0 and B3LYP, and for two model van der Waals dimers: Ne2 and (C2H4)2, and two model H-bond complexes: (HF)2 and (NH3)2.Comment: 6 pages, 1 figure, REVTeX

Postępy w leczeniu uzupełniającym chorych na czerniaki

Leczenie chirurgiczne jest postępowaniem z wyboru u chorych na czerniaki, jednak rokowanie chorych na czerniaki w stopniach zawansowania IIC–IV nawet po doszczętnej resekcji zmian jest niezwykle zróżnicowane i w dużej mierze związane z wysokim ryzykiem nawrotu choroby. Pozytywne wyniki badań wskazują, że w najbliższej przyszłości systemowe leczenie uzupełniające w omawianej grupie chorych na czerniaki będzie standardem podstępowania. Nowe sposoby leczenia systemowego — zarówno leczenie ukierunkowane molekularnie inhibitorami BRAF i MEK,dabrafenibem z trametynibem, lub immunoterapią anty-PD-1, niwolumabem lub pembrolizumabem, są już zarejestrowane w Stanach Zjednoczonych i Unii Europejskiej