TRAIL (tumor-necrosis factor related apoptosis-inducing ligand, CD253) and its death receptors TRAIL-R1 and TRAIL-R2 selectively trigger the apoptotic cell death in tumor cells. For that reason, ...TRAIL has been extensively studied as a target of cancer therapy. In spite of the promising preclinical observations, the TRAIL-based therapies in humans have certain limitations. The two main therapeutic approaches are based on either an administration of TRAIL-receptor (TRAIL-R) agonists or a recombinant TRAIL. These approaches, however, seem to elicit a limited therapeutic efficacy, and only a few drugs have entered the phase II clinical trials. To deliver TRAIL-based therapies with higher anti-tumor potential several novel TRAIL-derivates and modifications have been designed. These novel drugs are, however, mostly preclinical, and many problems continue to be unraveled. We have reviewed the current status of all TRAIL-based monotherapies and combination therapies that have reached phase II and phase III clinical trials in humans. We have also aimed to introduce all novel approaches of TRAIL utilization in cancer treatment and discussed the most promising drugs which are likely to enter clinical trials in humans. To date, different strategies were introduced in order to activate anti-tumor immune responses with the aim of achieving the highest efficacy and minimal toxicity.In this review, we discuss the most promising TRAIL-based clinical trials and their therapeutic strategies.
Lung transplant (LuTx) recipients are considered to be at higher risk of developing serious illness from COVID-19. COVID-19 vaccines were shown in randomized clinical trials to substantially reduce ...the severity of COVID-19, however, patients receiving immunosuppressants were excluded from these trials. Observational studies report a proportion of solid organ transplant (SOT) recipients being able to mount sufficient titers of SARS-CoV-2 specific IgG antibodies, however, other studies demonstrate that more than 90% of the SOT recipients elicit neither humoral nor cellular immune response after vaccination. Currently, the third booster dose of the COVID-19 vaccines was shown to elicit strong immune responses and may, thus, represent a potent tool in the prevention of severe COVID-19 infection in SOT recipients, including patients after lung transplantation. To address the main challenges of SARS-CoV-2 vaccination in LuTx recipients in the era of COVID-19, we have closely collected all available data on the immunogenicity, efficacy and safety of COVID-19 vaccines in LuTx recipients.
Introduction
Solitary fibrous tumor (SFT) is an extremely rare disease with a high misdiagnosis rate and a potentially malignant biologic nature. We have collected and analyzed data from 18 SFT ...patients to provide a deeper insight into this uncommon disease entity.
Methods
In our study, 18 patients who had undergone surgery between April 2014 and December 2021 for the diagnosis of SFT were evaluated. The collected data for each patient included the location of the SFT, the preoperative diagnosis, the definitive histological diagnosis, the presence of postoperative complications, the time of recurrence, the time of systemic progression, the type of treatment, and the survival rate. The median follow-up was 36 months.
Results
In three patients, the preoperative diagnosis did not correlate with the definitive histology of SFT. In patients with the limb location of SFT, no signs of recurrence nor distant metastases were seen within the study period. In total, 50% of the postsurgical complications were associated with the abdominal location of the SFT. In newly diagnosed SFT patients, two patients (20%) developed local recurrence, and the median time until recurrence was 22.5 months. Out of patients that were admitted and operated on for recurrent SFT, 67% relapsed, and the median time to relapse was 9.5 months. The systemic progression of the disease was observed in 33% of patients treated for recurrent SFT.
Conclusion
In our study, the misdiagnosis rate was high and correlated with previously published studies. Postsurgical complications were associated with the extrathoracic location of SFT. The mainstay of SFT treatment remains radical surgery, although radiotherapy alone can significantly improve overall survival. Clinical trials are urgently needed to evaluate the potential effect of other treatment modalities, such as immunotherapy and targeted therapy, in SFT patients.
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.
We retrospectively analyzed (
= 141) patients who underwent lung transplantation between 2020 and 2022. All subjects (
= 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.
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.
Lower doses of UFH as part of intraoperative ECMO anticoagulation might reduce the incidence of complications and lead to better postoperative outcomes.
Composite haemangioendothelioma is a rare vascular neoplasm with indolent to intermediate malignant potential. Diagnosis of this disease relays on histopathological identification of at least two ...different morphologically distinctive vascular components in proper clinical settings. Exceedingly rare cases of this neoplasm can exhibit areas resembling high-grade angiosarcoma, which does not change the biological behaviour. Such lesions tend to occur in the setting of chronic lymphoedema and thus, can mimic Stewart-Treves syndrome, which has a much worse clinical outcome and prognosis.
We present a case of 49 years old male suffering from chronic lymphoedema of the left lower extremity who had developed a composite haemangioendothelioma with high grade angiosarcoma-like areas mimicking the Stewart-Treves syndrome. Given the multifocality of the disease, the only potentially curable surgical treatment would be hemipelvectomy, which was refused by the patient. The patient has been followed-up, with no signs of local progression of the remaining disease, nor a distant spread outside the involved extremity for two years.
Composite haemangioendothelioma represents a rare malignant vascular tumour, with significantly more favourable biological behaviour than angiosarcoma, even in cases where angiosarcoma-like areas are present. For that reason, composite haemangioendothelioma can be easily misdiagnosed as true angiosarcoma. The rarity of this disease unfortunately hampers the development of clinical practice guidelines and the implementation of treatment recommendations. Most of the patients with localized tumour are treated by wide surgical resection, without neo- or adjuvant radiotherapy or chemotherapy. However, in the case of this diagnosis, the watch-and-wait approach is better than mutilating procedure, highlighting the necessity of establishing of the correct diagnosis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
High hydrostatic pressure (HHP) induces immunogenic death of tumor cells which confer protective anti-tumor immunity in vivo. Moreover, DC pulsed with HHP-treated tumor cells induced therapeutic ...effect in mouse cancer model. In this study, we tested the immunogenicity, stability and T cell stimulatory activity of human monocyte-derived dendritic cell (DC)-based HHP lung cancer vaccine generated in GMP compliant serum free medium using HHP 250 MPa. DC pulsed with HHP-killed lung cancer cells and poly(I:C) enhanced DC maturation, chemotactic migration and production of pro-inflammatory cytokines after 24h. Moreover, DC-based HHP lung cancer vaccine showed functional plasticity after transfer into serum-containing media and stimulation with LPS or CD40L after additional 24h. LPS and CD40L stimulation further differentially enhanced the expression of costimulatory molecules and production of IL-12p70. DC-based HHP lung cancer vaccine decreased the number of CD4+CD25+Foxp3+ T regulatory cells and stimulated IFN-γ-producing tumor antigen-specific CD4+ and CD8+ T cells from non-small cell lung cancer (NSCLC) patients. Tumor antigen specific CD8+ and CD4+ T cell responses were detected in NSCLC patient's against a selected tumor antigens expressed by lung cancer cell lines used for the vaccine generation. We also showed for the first time that protein antigen from HHP-killed lung cancer cells is processed and presented by DC to CD8+ T cells. Our results represent important preclinical data for ongoing NSCLC Phase I/II clinical trial using DC-based active cellular immunotherapy (DCVAC/LuCa) in combination with chemotherapy and immune enhancers.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Primary graft dysfunction (PGD) after lung transplantation (LuTx) contributes substantially to early postoperative morbidity. Both intraoperative transfusion of a large amount of blood products ...during the surgery and ischemia-reperfusion injury after allograft implantation play an important role in subsequent PGD development.
We have previously reported a randomized clinical trial of 67 patients where point of care (POC) targeted coagulopathy management and intraoperative administration of 5% albumin led to significant reduction of blood loss and blood product consumption during the lung transplantation surgery. A secondary analysis of the randomized clinical trial evaluating the effect of targeted coagulopathy management and intraoperative administration of 5% albumin on early lung allograft function after LuTx and 1-year survival was performed.
Compared to the patients in the control (non-POC) group, those in study (POC) group showed significantly superior graft function, represented by the Horowitz index (at 72 h after transplantation 402.87 vs 308.03 with p < 0.001, difference between means: 94.84, 95% CI: 60.18-129.51). Furthermore, the maximum doses of norepinephrine administered during first 24 h were significantly lower in the POC group (0.193 vs 0.379 with p < 0.001, difference between the means: 0.186, 95% CI: 0.105-0.267). After dichotomization of PGD (0-1 vs 2-3), significant difference between the non-POC and POC group occurred only at time point 72, when PGD grade 2-3 developed in 25% (n = 9) and 3.2% (n = 1), respectively (p = 0.003). The difference in 1-year survival was not statistically significant (10 patients died in non-POC group vs. 4 patients died in POC group; p = 0.17).
Utilization of a POC targeted coagulopathy management combined with Albumin 5% as primary resuscitative fluid may improve early lung allograft function, provide better circulatory stability during the early post-operative period, and have potential to decrease the incidence of PGD without negative effect on 1-year survival.
This clinical trial was registered at ClinicalTrials.gov (NCT03598907).
The aim of this study was to compare the efficacy, consumption and safety after piritramide administered either intramuscularly (IM) on demand or via patient-controlled intravenous analgesia (PCA) ...and to examine the impact of OPRM1 and ABCB1 gene polymorphisms on the drug efficacy/safety in both regimens.
One hundred and four patients scheduled for elective inguinal hernioplasty received piritramide with PCA or IM for postoperative pain management. We evaluated piritramide consumption, pain intensity using visual analogue scale (VAS) and adverse effects.
Median (IQR) piritramide consumption was 18.5 (13.5-31.2) and 15.0 (15.0-15.0) mg in the PCA and IM groups, respectively (P=0.0092). The respective values of area under the VAS
-time curve were 40 and 280 mm.h (P=0.0027). Opioid-induced adverse effects were more frequent in the PCA than in the IM group. Variant OPRM1 allele was associated with decreased pain relief, increased opioid consumption and increased incidence of adverse effects, while ABCB1 polymorphisms showed no impact on the observed parameters.
We observed higher piritramide consumption, better pain relief and slightly worse safety profile in the PCA group compared with IM administration. Variant OPRM1 118G allele carriers required higher opioid dosing and suffered from more adverse effects, however, the differences between genotypes have been less pronounced in the PCA patients likely due to improved pain management via PCA.
Mucormycosis is a rare invasive fungal disease diagnosed in immunocompromised patients, including those with diabetes or iron overload, and in patients treated for hematological malignancies or after ...transplantation. Isavuconazole is a triazole antifungal effective against Mucorales with good tolerability, but with potential for relatively high interindividual variability in pharmacokinetics. This report demonstrates the case of a lung transplant recipient treated with isavuconasole that exhibits a very long elimination half-life of 159 hours, and discusses the practical implications of this finding for dosage adjustment and need for therapeutic drug monitoring.
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