Extracorporeal photopheresis vs. systemic immunosuppression for immune-related adverse events: Interim analysis of a prospective two-arm study.

BACKGROUND: Checkpoint inhibitor-induced steroid-refractory (sr) and steroid-dependent (sd) immune-related adverse events (irAE) account for about 11 % of irAE. Although these patients face worse outcomes due to irAE mortality and/or sustained immunosuppression, which impairs anti-tumor response, there is no established second-line treatment based on prospective trial data. METHODS: This prospective comparative study investigates outcomes of extracorporeal photopheresis (ECP), an immunomodulating therapy, versus second-line immunosuppressants (SLI) in sr/sd-irAE. The primary endpoint was longitudinal change in immunophenotype; secondary endpoints were outcome of irAE and tumor response. Patient demographics, quality of life (EORTC QLQ-C30; global health status (GHS/QoL)) and longitudinal blood samples were analyzed at baseline; in weeks 1, 4, 8, and 12. RESULTS: At interim analysis, 21 patients (11 ECP, 10 SLI) with 7 different sr/sd-irAE were included. Compared with the SLI group, the ECP group demonstrated a higher clinical response rate of irAE (93 % vs. 80 %; 95 % CI 0.83-1.92; P = 0.54) and a better GHS/QoL score throughout all follow-up visits. ECP patients showed a numerically higher overall survival (23 vs. 12 months; 95 % CI 0.02-3.02; P = 0.27) and lower cancer progression rates (33 % vs. 67 %; 95 % CI 0.09-1.60; P = 0.52). Immunophenotyping revealed changes in immune cell populations and the regulation of immune checkpoints. There were no significant safety issues in either treatment group. CONCLUSION: This prospective comparative study supports the clinical efficacy of ECP in the treatment of sr/sd-irAE in comparison to the SLI cohort. Thus, ECP represents a potential treatment option for this indication, given its good safety profile while maintaining anti-tumor response. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05700565, https://classic. CLINICALTRIALS: gov/ct2/show/NCT05700565.

Four-year overall survival update from the phase III HIMALAYA study of tremelimumab plus durvalumab in unresectable hepatocellular carcinoma.

BACKGROUND: In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA. PATIENTS AND METHODS: Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization). RESULTS: For STRIDE, durvalumab, and sorafenib, median [95% confidence interval (CI)] follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified. CONCLUSIONS: These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.

The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects.

Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.

Pre-therapeutic factors for predicting survival after radioembolization: a single-center experience in 389 patients.

PURPOSE: To determine pre-therapeutic predictive factors for overall survival (OS) after yttrium (Y)-90 radioembolization (RE). METHODS: We retrospectively analyzed the pre-therapeutic characteristics (sex, age, tumor entity, hepatic tumor burden, extrahepatic disease [EHD] and liver function [with focus on bilirubin and cholinesterase level]) of 389 consecutive patients with various refractory liver-dominant tumors (hepatocellular carcinoma [HCC], cholangiocarcinoma [CCC], neuroendocrine tumor [NET], colorectal cancer [CRC] and metastatic breast cancer [MBC]), who received Y-90 radioembolization for predicting survival. Predictive factors were selected by univariate Cox regression analysis and subsequently tested by multivariate analysis for predicting patient survival. RESULTS: The median OS was 356 days (95% CI 285-427 days). Stable disease was observed in 132 patients, an objective response in 71 (one of which was complete remission) and progressive disease in 122. The best survival rate was observed in patients with NET, and the worst in patients with MBC. In the univariate analyses, extrahepatic disease (P < 0.001), large tumor burden (P = 0.001), high bilirubin levels (>1.9 mg/dL, P < 0.001) and low cholinesterase levels (CHE <4.62 U/I, P < 0.001) at baseline were significantly associated with poor survival. Tumor entity, tumor burden, extrahepatic disease and CHE were confirmed in the multivariate analysis as independent predictors of survival. Sex, applied RE dose and age had no significant influence on OS. CONCLUSIONS: Pre-therapeutic baseline bilirubin and CHE levels, extrahepatic disease and hepatic tumor burden are associated with patient survival after RE. Such parameters may be used to improve patient selection for RE of primary or metastatic liver tumors.

STAT3 inhibition reduces toxicity of oncolytic VSV and provides a potentially synergistic combination therapy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a refractory malignancy with a high mortality and increasing worldwide incidence rates, including the United States and central Europe. In this study, we demonstrate that a specific inhibitor of signal transducer and activator of transcription 3 (STAT3), NSC74859, efficiently reduces HCC cell proliferation and can be successfully combined with oncolytic virotherapy using vesicular stomatitis virus (VSV). The potential benefits of this combination treatment are strengthened by the ability of NSC74859 to protect primary hepatocytes and nervous system cells against virus-induced cytotoxicity, with an elevation of the VSV maximum tolerated dose in mice. Hereby we propose a strategy for improving the current regimen for HCC treatment and seek to further explore the molecular mechanisms underlying selective oncolytic specificity of VSV.

JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand.

BACKGROUND: cJun terminal kinase (JNK) is constitutively activated in most hepatocellular carcinomas (HCCs), yet its exact role in carcinogenesis remains controversial. While tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a major mediator of acquired immune tumour surveillance, and is currently being tested in clinical trials as a novel cancer therapy, the resistance of many tumours to TRAIL and concerns about its toxicity in vivo represent obstacles to its clinical application. In this study we investigated whether JNK activity in HCC could contribute to the resistance to apoptosis in these tumours. METHODS: The effect of JNK/Jun inhibition on receptor-mediated apoptosis was analysed by pharmacological inhibition or RNA interference in cancer cells and non-tumour cells isolated from human liver or transgenic mice lacking a phosphorylation site for Jun. RESULTS: JNK inhibition caused cell cycle arrest, enhanced caspase recruitment, and greatly sensitised HCC cells but not normal hepatocytes to TRAIL. TRAIL-induced activation of JNK could be effectively interrupted by administration of the JNK inhibitor SP600125. CONCLUSIONS: Expression and TRAIL-dependent feedback activation of JNK likely represent a mechanism by which cancer cells escape TRAIL-mediated tumour surveillance. JNK inhibition might represent a novel strategy for specifically sensitising HCC cells to TRAIL thus opening promising therapeutic perspectives for safe and effective use of TRAIL in cancer treatment.

The role of the novel Th17 cytokine IL-26 in intestinal inflammation.

BACKGROUND AND AIMS: Interleukin 26 (IL-26), a novel IL-10-like cytokine without a murine homologue, is expressed in T helper 1 (Th1) and Th17 cells. Currently, its function in human disease is completely unknown. The aim of this study was to analyse its role in intestinal inflammation. METHODS: Expression studies were performed by reverse transcription-PCR (RT-PCR), quantitative PCR, western blot and immunohistochemistry. Signal transduction was analysed by western blot experiments and ELISA. Cell proliferation was measured by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. IL-26 serum levels were determined by an immunoluminometric assay (ILMA). RESULTS: All examined intestinal epithelial cell (IEC) lines express both IL-26 receptor subunits IL-20R1 and IL-10R2. IL-26 activates extracellular signal-related kinase (ERK)-1/2 and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) mitogen-activated protein (MAP) kinases, Akt and signal transducers and activators of transcription (STAT) 1/3. IL-26 stimulation increases the mRNA expression of proinflammatory cytokines but decreases cell proliferation. In inflamed colonic lesions of patients with Crohn's disease, an elevated IL-26 mRNA expression was found that correlated highly with the IL-8 and IL-22 expression. Immunohistochemical analysis demonstrated IL-26 protein expression in colonic T cells including Th17 cells expressing the orphan nuclear receptor RORgammat, with an increased number of colonic IL-26-expressing cells in active Crohn's disease. CONCLUSION: Intestinal cells express the functional IL-26 receptor complex. IL-26 modulates IEC proliferation and proinflammatory gene expression and its expression is upregulated in active Crohn's disease, indicating a role for this cytokine system in the innate host cell response during intestinal inflammation. For the first time, IL-26 expression is demonstrated in colonic RORgammat-expressing Th17 cells in situ, supporting a role for this cell type in the pathogenesis of Crohn's disease.

Inhibition of Src tyrosine kinase reverts chemoresistance toward 5-fluorouracil in human pancreatic carcinoma cells: an involvement of epidermal growth factor receptor signaling.

Resistance to chemotherapy is believed to be a major cause of treatment failure in pancreatic cancer. Thus, it is necessary to explore alternative therapeutic modalities to overcome drug resistance in pancreatic cancer treatment. We tested the hypothesis that Src tyrosine kinase inhibition could augment the chemosensitivity of 5-fluorouracil (5-FU)-resistant human pancreatic cancer cells to 5-FU. As detected by MTT proliferation assay, propidium iodide and annexin V staining, a combination of 5-FU+Src kinase inhibitor PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine) reflected the chemotherapeutic sensitivity and restored the 5-FU-induced apoptosis in 5-FU-resistant cells. Furthermore, when small-interfering RNA approach to silence Src gene expression was applied, the degree of 5-FU-induced apoptosis was increased in all cell lines independently of the chemoresistance status. Western blotting and RT-PCR analysis revealed that the expression of thymidylate synthase (TS) was higher in 5-FU-resistant cells, however, decreased significantly after pretreatment with PP2. Furthermore, the combination of 5-FU+PP2 decreased the 5-FU-induced activation of epidermal growth factor receptor (EGFR)-AKT pathway. Finally, PP2 in combination with 5-FU substantially decreased the in vivo tumor growth and inhibited distant metastases. Taken together, 5-FU chemoresistance can be reversed through indirect TS regulation by inhibiting Src tyrosine kinase. A potential mechanism of action of Src kinase inhibitors on 5-FU chemosensitivity might be linked to the inhibition of 5-FU-induced EGFR-AKT activation.

Unconventional medicine teaching at the Universities of the European Union.

CONTEXT: The recent rapid increase in demand for and use of unconventional medicine requires an adequate medical education. In the United States, 64% of medical schools offer undergraduate courses. No information is available about similar courses at European universities. OBJECTIVES: To document the incidence of educational courses on unconventional medicine offered by the European universities and their topic content. DESIGN: Mail survey, which consisted of two questionnaires and was conducted in 1999 (January-June). The first questionnaire was sent to the universities' Rectorats, the second one to the faculties or lecturers indicated by the replies to the first questionnaire. PARTICIPANTS: The Universities listed by the Confederation of European Union Rectors' Conference. MAIN OUTCOME MEASURES: Courses offered at European Universities, both at medical faculties and at other faculties. RESULTS: Five hundred and fifty (550) universities were contacted. Replies were received from 326 (59%); 141 have a faculty of medicine and 107 (76%) of them replied. We also received answers from 29 faculties of health sciences. In addition we received 190 (50%) answers from 380 other miscellaneous universities. Courses on unconventional medicine were offered by 43 (40%) medical schools, 21 (72%) health sciences faculties, and by 15 (8%) other faculties. Topics covered encompassed a wide range of techniques (33), from homeopathy to shamanism. CONCLUSIONS: Unconventional medicine courses are widely represented at European universities. They cover a wide range of therapies. Many of them are used clinically. Research work is underway at several faculties.

Haemolysis during cardiopulmonary bypass: how to reduce the free haemoglobin by managing the suctioned blood separately.

During cardiopulmonary bypass (CPB) the collection of the patient's blood from the operating area is of fundamental importance. This blood is collected in the cardiotomy reservoir using field suckers and can be managed in different ways. It can be filtered in the cardiotomy reservoir and redirected to the venous reservoir, then oxygenated and returned to the patient, or it can be managed separately: collected in the cardiotomy reservoir, treated at the end of the operation and only after this, returned to the patient. The aim of this study is to determine in vivo the effect of a separate management of the suction blood from the operative field, using the Avant D903 oxygenator (Dideco, Mirandola, Italy). Twenty-one patients undergoing coronary artery bypass graft surgery with CPB were selected and put into two groups at random. In the control group (n = 10) the suction blood in the cardiotomy reservoir was filtered and immediately redirected into the venous reservoir, oxygenated and returned to the patient. In the study group (n = 11) the suctioned blood was collected in the D903 Avant's (Dideco) cardiotomy reservoir and returned to the patient only after having been washed at the end of the operation, using a Compact Advanced (Dideco), as required. Clinical data demonstrated that while in the study group it was possible to keep the free plasma haemoglobin (FPH) concentrations the same as at the beginning, in the control group there was a significant increase in FPH from 5.0 +/- 3.5 mg/dl (baseline) to 37 +/- 16.7mg/dl (120min after CPB).

Purines and pyrimidines determination in urine using high-performance liquid chromatography.

Single purine and pyrimidine bases are involved in two fundamental metabolic pathways that lead to formation of the building stones of DNA and RNA. Purine and pyrimidine nucleotides are also critically important metabolites in many cellular functions. The main breakdown of purines and pyrimidines produces uric acid and B-minoacids, respectively. Therefore, the study of purine and pyrimidine compounds in body fluid has high clinical relevance. We report, in this work, our experience in purines and pyrimidines determination in urine from children presenting with a clinical picture suggesting an inborn these pathways.

Predictors of perinatal outcome in intrauterine growth retardation: a long term study.

UNLABELLED: Fifty-three intrauterine retarded fetuses (IUGR) and seventy-five healthy pregnancies were monitored by neurobehavioural profile (quiet state or S1F and activity state or S2F percentages) and umbilical artery Doppler velocimetry (UA RI) on two occasions between the 27th-32nd and the 33rd-36th week of gestation. The aims of the present study were the following 1) to relate S1F, S2F and RI to mild and severe IUGR 2) to relate behavioural state analysis and UA Doppler velocimetry to the following perinatal outcomes: Cesarean section (CS); Preterm delivery (PD); small for gestational age (SGA); Apgar score at 1st and 5th min < 7; Respiratory Distress Syndrome (RDS); Neurological Injury (NI) (evaluated at the birth, the 4th, the 8th and the 12th month of life). 3) to establish the best predictors of perinatal outcome with these monitoring parameters by a stepwise computerized processing. Our results suggest: 1) mild IUGR, characterized by a progressive increase in peripheral vascular resistances, positive diastolic peak flow (RI: 0.72 +/- 0.01; mean +/- SD), is associated with gradual increase in S1F (12.51 +/- 2.84; mean +/- SD) and a decrease in S2F (27.51 +/- 2.81; mean +/- SD) percentages; 2) severe IUGR, characterized by zero or negative diastolic peak flow (UA RI-->1), is associated with a significant increase in S1F (21.32 +/- 12.11; mean +/- SD) and a decrease in S2F percentages (30.93 +/- 20.35; mean +/- SD). IN CONCLUSION: S1F is the best predictor of severe IUGR and significant for all the perinatal outcomes selected; S2F is the best predictor of mild IUGR and significant for SGA; UA RI is the best parameter for recognizing mild IUGR and evolution to severe IUGR.