Anaesthesiologic Considerations for Intraoperative ECMO Anticoagulation During Lung Transplantation: A Single-Centre, Retrospective, Observational Study

Background: Extracorporeal membrane oxygenation (ECMO) is frequently used during lung transplantation. Unfractionated heparin (UFH) is mainly used as part of ECMO support for anticoagulation. One of the most common perioperative complications is bleeding, which high-dose UFH can aggravate.Methods: We retrospectively analyzed (n = 141) patients who underwent lung transplantation between 2020 and 2022. All subjects (n = 109) underwent central cannulated VA ECMO with successful intraoperative ECMO weaning. Patients on ECMO bridge, postoperative ECMO, heart-lung transplants and transplants without ECMO were excluded. The dose of UFH for the entire surgical procedure, blood loss and consumption of blood derivatives intraoperatively and 48 h after ICU admission were recorded. Surgical revision for postoperative bleeding were analyzed. Thrombotic complications, mortality and long-term survival were evaluated.Results: Lower doses of UFH administered for intraoperative ECMO anticoagulation contribute to a reduction in intraoperative blood derivates consumption and blood loss with no thrombotic complications related to the patient or the ECMO circuit. Lower doses of UFH may lead to a decreased incidence of surgical revision for hemothorax.Conclusion: Lower doses of UFH as part of intraoperative ECMO anticoagulation might reduce the incidence of complications and lead to better postoperative outcomes

The expression profiles of CD47 in the tumor microenvironment of salivary gland cancers: a next step in histology-driven immunotherapy

Background: Salivary gland carcinomas (SGC) are extremely rare malignancies with only limited treatment options for the metastatic phase of the disease. Treatment with anti-CD47 antibodies could represent a potent therapy for SGCs by promoting the phagocytic clearance of tumor cells through various mechanisms. However, the efficacy of anti-CD47 therapy is largely dependent on the expression of CD47 within the tumor microenvironment (TME). Materials and Methods: In 43 patients with SGC, we were the first to investigate the CD47 expression in both tumor cells and tumor-infiltrating immune cells (TIIC) in the center and periphery of primary tumors. We also correlated the data with the clinicopathological variables of the patients and offered novel insights into the potential effectiveness of anti-CD47 therapy in SGCs. Results: We observed that the CD47+ tumor cells are outnumbered by CD47+ TIICs in mucoepidermoid carcinoma. In the tumor center, the proportion of CD47+ tumor cells was comparable to the proportion of CD47+ TIICs in most histological subtypes. In low-grade tumors, significantly higher expression of CD47 was observed in TIICs in the periphery of the tumor as compared to the center of the tumor. Conclusion: The reason for a high expression of ‘don’t eat me’ signals in TIICs in the tumor periphery is unclear. However, we hypothesize that in the tumor periphery, upregulation of CD47 in TIICs could be a mechanism to protect newly recruited leukocytes from macrophage-mediated phagocytosis, while also allowing the removal of old or exhausted leukocytes in the tumor center

Lung transplantation following controlled hypothermic storage with a portable lung preservation device: first multicenter European experience

IntroductionCompared with traditional static ice storage, controlled hypothermic storage (CHS) at 4–10°C may attenuate cold-induced lung injury between procurement and implantation. In this study, we describe the first European lung transplant (LTx) experience with a portable CHS device.MethodsA prospective observational study was conducted of all consecutively performed LTx following CHS (11 November 2022 and 31 January 2024) at two European high-volume centers. The LUNGguard device was used for CHS. The preservation details, total ischemic time, and early postoperative outcomes are described. The data are presented as median (range: minimum–maximum) values.ResultsA total of 36 patients underwent LTx (i.e., 33 bilateral, 2 single LTx, and 1 lobar). The median age was 61 (15–68) years; 58% of the patients were male; 28% of the transplantations had high-urgency status; and 22% were indicated as donation after circulatory death. In 47% of the patients, extracorporeal membrane oxygenation (ECMO) was used for perioperative support. The indications for using the CHS device were overnight bridging (n = 26), remote procurement (n = 4), rescue allocation (n = 2), logistics (n = 2), feasibility (n = 1), and extended-criteria donor (n = 1). The CHS temperature was 6.5°C (3.7°C–9.3°C). The preservation times were 11 h 18 (2 h 42–17 h 9) and 13 h 40 (4 h 5–19 h 36) for the first and second implanted lungs, respectively, whereas the total ischemic times were 13 h 38 (4 h 51–19 h 44) and 15 h 41 (5 h 54–22 h 48), respectively. The primary graft dysfunction grade 3 (PGD3) incidence rates were 33.3% within 72 h and 2.8% at 72 h. Intensive care unit stay was 8 (4–62) days, and the hospital stay was 28 (13–87) days. At the last follow-up [139 (7–446) days], three patients were still hospitalized. One patient died on postoperative day 7 due to ECMO failure. In-hospital Clavien–Dindo complications of 3b were observed in six (17%) patients, and 4a in seven (19%).ConclusionCHS seems safe and feasible despite the high-risk recipient and donor profiles, as well as extended preservation times. PGD3 at 72 h was observed in 2.8% of the patients. This technology could postpone LTx to daytime working hours. Larger cohorts and longer-term outcomes are required to confirm these observations

Widespread Expression of Hedgehog Pathway Components in a Large Panel of Human Tumor Cells and Inhibition of Tumor Growth by GANT61: Implications for Cancer Therapy

The sonic Hedgehog/GLI signaling pathway (HH) is critical for maintaining tissue polarity in development and contributes to tumor stemness. Transcription factors GLI1–3 are the downstream effectors of HH and activate oncogenic targets. To explore the completeness of the expression of HH components in tumor cells, we performed a screen for all HH proteins in a wide spectrum of 56 tumor cell lines of various origin using Western blot analysis. Generally, all HH proteins were expressed. Important factors GLI1 and GLI2 were always expressed, only exceptionally one of them was lowered, suggesting the functionality of HH in all tumors tested. We determined the effect of a GLI inhibitor GANT61 on proliferation in 16 chosen cell lines. More than half of tumor cells were sensitive to GANT61 to various extents. GANT61 killed the sensitive cells through apoptosis. The inhibition of reporter activity containing 12xGLI consensus sites by GANT61 and cyclopamine roughly correlated with cell proliferation influenced by GANT61. Our results recognize the sensitivity of tumor cell types to GANT61 in cell culture and support a critical role for GLI factors in tumor progression through restraining apoptosis. The use of GANT61 in combined targeted therapy of sensitive tumors, such as melanomas, seems to be immensely helpful

Many Distinct Ways Lead to Drug Resistance in BRAF- and NRAS-Mutated Melanomas

Advanced melanoma is a relentless tumor with a high metastatic potential. The combat of melanoma by using the targeted therapy is impeded because several major driver mutations fuel its growth (predominantly BRAF and NRAS). Both these mutated oncogenes strongly activate the MAPK (MEK/ERK) pathway. Therefore, specific inhibitors of these oncoproteins or MAPK pathway components or their combination have been used for tumor eradication. After a good initial response, resistant cells develop almost universally and need the drug for further expansion. Multiple mechanisms, sometimes very distant from the MAPK pathway, are responsible for the development of resistance. Here, we review many of the mechanisms causing resistance and leading to the dismal final outcome of mutated BRAF and NRAS therapy. Very heterogeneous events lead to drug resistance. Due to this, each individual mechanism would be in fact needed to be determined for a personalized therapy to treat patients more efficiently and causally according to molecular findings. This procedure is practically impossible in the clinic. Other approaches are therefore needed, such as combined treatment with more drugs simultaneously from the beginning of the therapy. This could eradicate tumor cells more rapidly and greatly diminish the possibility of emerging mechanisms that allow the evolution of drug resistance

Esophageal bypass surgery as a definitive repair of recurrent acquired benign bronchoesophageal fistula

Abstract Background Acquired benign bronchoesophageal fistula (BEF) is rare and develops as a complication of other diseases, mostly of inflammatory processes and traumas of the chest. The treatment of choice is a surgical repair, which is considered definitive and leads to successful outcomes. However, incidence of recurrence after the primary repair based on limited data is up to 10% and its treatment is challenging. We report a surgical case of a patient with recurrent acquired benign BEF after primary resection and ensuing successful definitive repair with esophageal bypass surgery after temporary esophageal stenting. Case report A 46-year-old male was referred to our department with a symptomatic left-sided bronchoesophageal fistula as a complication of severe acute necrotizing mediastinitis that originated from odontogenic abscess. Previously, several cervicotomies and bilateral thoracotomy were performed at an external medical facility to manage the acute condition. We performed resection of the fistula through re-thoracotomy. Postprocedural esophagography demonstrated a recurrence of bronchoesophageal communication. Postinflammatory adhesions excluded further repair through thoracotomy, therefore a stent was introduced in the esophagus for 12 weeks. Thereafter, an esophageal bypass surgery using a substernaly interposed gastric conduit was performed and resulted in an excellent long-term outcome. Conclusions Esophageal bypass surgery using a substernaly interposed gastric conduit may be considered if the standard surgical repair of acquired benign bronchoesophageal fistula is not successful or feasible

GLI inhibitor GANT61 kills melanoma cells and acts in synergy with obatoclax

MEK kinase inhibitors (trametinib and selumetinib) or kinase inhibitors directed against mutated BRAF(V600E) (vemurafenib and dabrafenib) have initial encouraging effects in the treatment of melanoma but acquired resistance appears almost invariably after some months. Studies revealed mutually exclusive NRAS and BRAF activating mutations driving the MAPK/ERK pathway among human melanomas. Although combination therapy exerts significantly better antitumor cell efficacy, complete remission is rarely achieved. To employ an alternative approach, we have targeted the Hedgehog/GLI pathway, which is deregulated in melanomas through the GLI1/2 inhibitor GANT61, alone or accompanied with the treatment by the BCL2 family inhibitor obatoclax in 9 melanoma cell lines. Thus, we targeted melanoma cells irrespective of their NRAS or BRAF mutational status. After GANT61 treatment, the cell viability was drastically diminished via apoptosis, as substantial nuclear DNA fragmentation was detected. In all tested melanoma cell lines, the combined treatment was more efficient than the application of each drug alone at the end of the cell growth with inhibitors. GANT61 was efficient also alone in most cell lines without the addition of obatoclax, which had only a limited effect when used as a single drug. In most cell lines, tumor cells were eradicated after 5-9 days of combined treatment in colony outgrowth assay. To conclude, GANT61 treatment might become a hopeful and effective anti-melanoma targeted therapy, especially when combined with the BCL2 family inhibitor obatoclax.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Novel Insights into the Immunotherapy of Soft Tissue Sarcomas: Do We Need a Change of Perspective?

Soft tissue sarcomas (STSs) are rare mesenchymal tumors. With more than 80 histological subtypes of STSs, data regarding novel biomarkers of strong prognostic and therapeutic value are very limited. To date, the most important prognostic factor is the tumor grade, and approximately 50% of patients that are diagnosed with high-grade STSs die of metastatic disease within five years. Systemic chemotherapy represents the mainstay of metastatic STSs treatment for decades but induces response in only 15–35% of the patients, irrespective of the histological subtype. In the era of immunotherapy, deciphering the immune cell signatures within the STSs tumors may discriminate immunotherapy responders from non-responders and different immunotherapeutic approaches could be combined based on the predominant cell subpopulations infiltrating the STS tumors. Furthermore, understanding the immune diversity of the STS tumor microenvironment (TME) in different histological subtypes may provide a rationale for stratifying patients according to the TME immune parameters. In this review, we introduce the most important immune cell types infiltrating the STSs tumors and discuss different immunotherapies, as well as promising clinical trials, that would target these immune cells to enhance the antitumor immune responses and improve the prognosis of metastatic STSs patients

How COVID-19 Affects Lung Transplantation: A Comprehensive Review

Lung transplant (LuTx) recipients are at a higher risk of developing serious illnesses from COVID-19, and thus, we have closely reviewed the consequences of the COVID-19 pandemic on lung transplantation. In most transplant centers, the overall LuTx activity significantly declined and led to a specific period of restricting lung transplantation to urgent cases. Moreover, several transplant centers reported difficulties due to the shortage of ICU capacities. The fear of donor-derived transmission generated extensive screening programs. Nevertheless, reasonable concerns about the unnecessary losses of viable organs were also raised. The overall donor shortage resulted in increased waiting-list mortality, and COVID-19-associated ARDS became an indication of lung transplantation. The impact of specific immunosuppressive agents on the severity of COVID-19 varied. Corticosteroid discontinuation was not found to be beneficial for LuTx patients. Tacrolimus concentrations were reported to increase during the SARS-CoV-2 infection, and in combination with remdesivir, tacrolimus may clinically impact renal functions. Monoclonal antibodies were shown to reduce the risk of hospitalization in SOT recipients. However, understanding the pharmacological interactions between the anti-COVID-19 drugs and the immunosuppressive drugs requires further research