Endovenous laser ablation: the role of intraluminal blood

AbstractObjectiveIn this histological study, the role of the intraluminal blood during endovenous laser ablation was assessed.MethodsIn 12 goats, 24 lateral saphenous veins were treated with a 1500-nm diode laser. Four goats were treated in an anti-Trendelenburg position (group 1). The next four goats were treated in a Trendelenburg position (group 2) and the remaining four goats in the Trendelenburg position with additional injection of tumescent liquid (group 3). Postoperatively, the veins were removed after 1 week and sent for histological examination. We measured the number of perforations. Vein wall necrosis and the perivenous tissue destruction were quantified using a graded scale.ResultsThe ‘calculated total vein wall destruction’ was significantly higher in the third group (81.83%), as compared with groups one (61.25%) (p < 0.001) and two (65.92%) (p < 0.001). All three groups showed a significant difference in the perivenous tissue destruction scale (p < 0.001) with the lowest score occurring in the third group. Vein wall perforations were significantly more frequent in groups one and two as compared with the third group (T-test respectively p < 0.001, p = 0.02).ConclusionA higher intraluminal blood volume results in reduced total vein wall destruction. Injection of tumescent liquid prevents the perivenous tissue destruction and minimises the number of perforations

Mechanisms of local immunosuppression in cutaneous melanoma

Cutaneous melanoma is highly immunogenic, yet primary melanomas and metastases develop successfully in otherwise immunocompetent patients. To investigate the local immunosuppressive microenvironment, we examined the presence of suppressor T lymphocytes and tolerising dendritic cells (DCs), the expression of immunosuppressive cytokines (IL-10, TGFβ1 and TGFβ2) and the enzyme indoleamine 2,3-dioxygenase (IDO) using qRT–PCR and immunohistochemistry in primary skin melanomas, negative and positive sentinel lymph nodes (SLN), and lymph nodes with advanced metastases. Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. They express transforming growth factor β receptor 1 (TGFβR1), and are therefore susceptible to TGFβ1 and TGFβ2 specifically expressed by primary melanoma. We found that expression of IDO and interleukin 10 (IL-10) increased with melanoma progression, with the highest concentration in positive SLN. We suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenic DCs migrating from the primary melanoma site to the SLN. In primary melanoma, TGFβ2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFβ1 may have a major effect. This mechanism of tumour-associated immunosuppression may inhibit the immune response to the tumour and may explain the discrepancy between the induction of systemic immunity by anti-melanoma vaccines and their poor performance in the clinic

The impact of viral mutations on recognition by SARS-CoV-2 specific T cells.

We identify amino acid variants within dominant SARS-CoV-2 T cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T cells assessed by IFN-γ and cytotoxic killing assays. Complete loss of T cell responsiveness was seen due to Q213K in the A∗01:01-restricted CD8+ ORF3a epitope FTSDYYQLY207-215; due to P13L, P13S, and P13T in the B∗27:05-restricted CD8+ nucleocapsid epitope QRNAPRITF9-17; and due to T362I and P365S in the A∗03:01/A∗11:01-restricted CD8+ nucleocapsid epitope KTFPPTEPK361-369. CD8+ T cell lines unable to recognize variant epitopes have diverse T cell receptor repertoires. These data demonstrate the potential for T cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T cell as well as humoral immunity.This work is supported by the UK Medical Research Council (MRC); Chinese Academy of Medical Sciences(CAMS) Innovation Fund for Medical Sciences (CIFMS), China; National Institute for Health Research (NIHR)Oxford Biomedical Research Centre, and UK Researchand Innovation (UKRI)/NIHR through the UK Coro-navirus Immunology Consortium (UK-CIC). Sequencing of SARS-CoV-2 samples and collation of data wasundertaken by the COG-UK CONSORTIUM. COG-UK is supported by funding from the Medical ResearchCouncil (MRC) part of UK Research & Innovation (UKRI),the National Institute of Health Research (NIHR),and Genome Research Limited, operating as the Wellcome Sanger Institute. T.I.d.S. is supported by a Well-come Trust Intermediate Clinical Fellowship (110058/Z/15/Z). L.T. is supported by the Wellcome Trust(grant number 205228/Z/16/Z) and by theUniversity of Liverpool Centre for Excellence in Infectious DiseaseResearch (CEIDR). S.D. is funded by an NIHR GlobalResearch Professorship (NIHR300791). L.T. and S.C.M.are also supported by the U.S. Food and Drug Administration Medical Countermeasures Initiative contract75F40120C00085 and the National Institute for Health Research Health Protection Research Unit (HPRU) inEmerging and Zoonotic Infections (NIHR200907) at University of Liverpool inpartnership with Public HealthEngland (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford.L.T. is based at the University of Liverpool. M.D.P. is funded by the NIHR Sheffield Biomedical ResearchCentre (BRC – IS-BRC-1215-20017). ISARIC4C is supported by the MRC (grant no MC_PC_19059). J.C.K.is a Wellcome Investigator (WT204969/Z/16/Z) and supported by NIHR Oxford Biomedical Research Centreand CIFMS. The views expressed are those of the authors and not necessarily those of the NIHR or MRC

Some controversies in endovenous laser ablation of varicose veins addressed by optical-thermal mathematical modeling

Minimally invasive treatment of varicose veins by endovenous laser ablation (EVLA) becomes more and more popular. However, despite significant research efforts performed during the last years, there is still a lack of agreement regarding EVLA mechanisms and therapeutic strategies. The aim of this article is to address some of these controversies by utilizing optical–thermal mathematical modeling. Our model combines Mordon's light absorption-based optical–thermal model with the thermal consequences of the thin carbonized blood layer on the laser fiber tip that is heated up to temperatures of around 1,000 °C due to the absorption of about 45 % of the laser light. Computations were made in MATLAB. Laser wavelengths included were 810, 840, 940, 980, 1,064, 1,320, 1,470, and 1,950 nm. We addressed (a) the effect of direct light absorption by the vein wall on temperature behavior, comparing computations by using normal and zero wall absorption; (b) the prediction of the influence of wavelength on the temperature behavior; (c) the effect of the hot carbonized blood layer surrounding the fiber tip on temperature behavior, comparing wall temperatures from using a hot fiber tip and one kept at room temperature; (d) the effect of blood emptying the vein, simulated by reducing the inside vein diameter from 3 down to 0.8 mm; (e) the contribution of absorbed light energy to the increase in total energy at the inner vein wall in the time period where the highest inner wall temperature was reached; (f) the effect of laser power and pullback velocity on wall temperature of a 2-mm inner diameter vein, at a power/velocity ratio of 30 J/cm at 1,470 nm; (g) a comparison of model outcomes and clinical findings of EVLA procedures at 810 nm, 11 W, and 1.25 mm/s, and 1,470 nm, 6 W, and 1 mm/s, respectively. Interestingly, our model predicts that the dominating mechanism for heating up the vein wall is not direct absorption of the laser light by the vein wall but, rather, heat flow to the vein wall and its subsequent temperature increase from two independent heat sources. The first is the exceedingly hot carbonized layer covering the fiber tip; the second is the hot blood surrounding the fiber tip, heated up by direct absorption of the laser light. Both mechanisms are about equally effective for all laser wavelengths. Therefore, our model concurs the finding of Vuylsteke and Mordon (Ann Vasc Surg 26:424–433, 2012) of more circumferential vein wall injury in veins (nearly) devoid of blood, but it does not support their proposed explanation of direct light absorption by the vein wall. Furthermore, EVLA appears to be a more efficient therapy by the combination of higher laser power and faster pullback velocity than by the inverse combination. Our findings suggest that 1,470 nm achieves the highest EVLA efficacy compared to the shorter wavelengths at all vein diameters considered. However, 1,950 nm of EVLA is more efficacious than 1,470 nm albeit only at very small inner vein diameters (smaller than about 1 mm, i.e., veins quite devoid of blood). Our model confirms the efficacy of both clinical procedures at 810 and 1,470 nm. In conclusion, our model simulations suggest that direct light absorption by the vein wall is relatively unimportant, despite being the supposed mechanism of action of EVLA that drove the introduction of new lasers with different wavelengths. Consequently, the presumed advantage of wavelengths targeting water rather than hemoglobin is flawed. Finally, the model predicts that EVLA therapy may be optimized by using 1,470 nm of laser light, emptying of the vein before treatment, and combining a higher laser power with a greater fiber tip pullback velocity