Randomized open-label controlled study of cancer vaccine OSE2101 versus chemotherapy in HLA-A2-positive patients with advanced non-small-cell lung cancer with resistance to immunotherapy: ATALANTE-1.

BACKGROUND: Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients. PATIENTS AND METHODS: ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks. RESULTS: Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002). CONCLUSIONS: In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.

The importance of anthropology in psychiatry.

Anthropology is defined as "the study of humans", while psychiatric anthropology is a subfield of cultural anthropology which uses qualitative methodologies to explore the experience of mental illness. In a field that is often dominated by quantitative research, an anthropological approach allows us to understand experiences surrounding illness and the cultural context of mental illness. The articles presented in this issue of the Irish Journal of Psychological Medicine explore individual and group perspectives within a variety of cultural and historical contexts. This compilation of articles unearths fascinating insights into the lived experiences of distinct and vulnerable groups, including young people, migrants and members of the travelling community. Harnessing these insights can help us to tailor our services to the needs of societal populations, as well as improving therapeutic relationships with the ultimate goal of better treatment outcomes.

Lorlatinib for advanced ROS1+ non-small-cell lung cancer: results of the IFCT-1803 LORLATU study.

INTRODUCTION: ROS1-rearranged (ROS1+) non-small-cell lung cancer (NSCLC) is a rare lung cancer with limited treatment options. Phase I-II studies with ROS1-tyrosine kinase inhibitors (TKIs) included small numbers of patients and real-world data are lacking. We investigate the efficacy and safety of lorlatinib, a third-generation TKI targeting ALK and ROS1, in patients with ROS1+ NSCLC treated through an expanded access program. METHODS: Consecutive patients with advanced ROS1+ NSCLC treated with lorlatinib between October 2015 and June 2019 were included. Data were collected from medical records. The primary endpoint was progression-free survival. RESULTS: Out of the 80 patients included, 47(59%) were female, 49(62%) never smokers (less than 100 cigarettes over the lifetime), and 68(85%) had stage IV NSCLC at diagnosis. Most frequent histology was adenocarcinoma (95%) and median age was 58.2 years. At the time of lorlatinib initiation, 51(64%) patients had brain metastases and 55(81%) were PS 0-1. Lorlatinib was administered as second/third/fourth/fifth+ line in 29%/28%/18%/26% of patients. All patients previously received at least one ROS1 TKI, and 55(69%) previously received chemotherapy. Median follow-up from lorlatinib initiation was 22.2 months. Median progression-free survival and overall survival from lorlatinib initiation were 7.1 months [95% confidence interval (CI) 5.0-9.9 months] and 19.6 months (95% CI 12.3-27.5 months). Median duration of treatment with lorlatinib was 7.4 months (95% CI 6.5-13.1 months). Overall response and disease control rates were 45% and 82%, respectively. The central nervous system response rate was 72%. Treatment was stopped due to toxicity in 10 patients (13%). The safety profile was consistent with previously published data. CONCLUSIONS: Lorlatinib is a major treatment option for advanced refractory ROS1+ NSCLC in treatment strategy.

[Small cell lung cancer and immuno-oncologic agents: End of the cisplatin - etoposide era?] / Cancer bronchique à petites cellules et agent onco-immunologique : peut-on sortir de l'ère du tout cisplatine étoposide ?

In the setting of small cell lung cancer (SCLC), the development of immuno-oncological agents, particularly those targeting Programmed cell Death protein 1 (PD-1) and Programmed cell Death protein Ligand 1 (PD-L1), is still at an early stage. Two critical elements need to be considered : the current data are extracted from Phase I and Phase II trials and the level of evidence from phase III trials has not been reached as it has been for non-small cell lung cancer (NSCLC) or for malignant melanoma ; The second aspect is the slow development of predictive factors for response to the immuno-oncological agents targeting the PD-1 receptor and its ligand. The clinical data are still too fragmentary to produce recommendations, although the improvement in progression-free survival seen in different phase II studies is promising. The expectation of clinicians dealing withSCLC is an indication of the challenge that this disease currently poses to oncology and justifies a focused clinical research effort.

[What do chemotherapy specialists expect of lung cancer?] / Qu'attendent les médecins spécialistes de la chimiothérapie des cancers du poumon ?

OBJECTIVE: In an attempt to understand physicians' expectations of chemotherapy, a group of lung cancer specialists was involved in an online survey investigating their opinions by a self-questionnaire. The questionnaire described five different chemotherapy prescription situations for lung cancer patients (stages IIIB or IV). METHOD: A total of 30 expert specialists were invited; 22 responded (73%). For each of the clinical situations, the expert was asked for his opinion on 3 items: cure, prolongation of survival and alleviation of symptoms. Each item was judged on a Likert scale with categories between -2 "not at all probable" and +2 "quite likely". RESULTS: For "cure", the percentage of -2 responses differed significantly according to the clinical situation (Fisher test: P<0.00001). The trend test showed a relationship between the percentage of -2 responses and the suspected order of the clinical situations (Cochran-Armitage trend test: P<0.0001). For symptom alleviation, the percentage of responses +2 and +1 differed significantly according to the clinical situation (Fisher test: P=0.00013, trend test: P<0.0001). CONCLUSION: What specialist physicians expect of chemotherapy in terms of curability and symptom relief differs according to the actual statistical prognosis of each situation as presented in the literature. The worst prognostic situation leads to the strongest expectation in terms of symptom relief and, conversely, the lowest for curability.

[Efficacy and safety of intravenous immunoglobulins in the management of neonatal hyperbilirubinemia due to ABO incompatibility: a meta-analysis]. / Efficacité et tolérance des immunoglobulines polyvalentes dans l'hyperbilirubinémie néonatale par incompatibilité ABO. Méta-analyse.

OBJECTIVES: ABO fetomaternal red blood cell incompatibility (ABO FMI) induces an immune hemolysis after fetal transfer of hemolyzing maternal anti-A or anti-B. ABO hemolytic disease (ABO HD) remains the most frequent cause of severe and early jaundice in newborns. High levels of unconjugated hyperbilirubinemia may induce acute and chronic neurological complications. Severe hyperbilirubinemia can be prevented by first-line phototherapy (PT) treatment, but exchange transfusion (ET) is required if treatment is not effective, even if ET is linked with high hemodynamic, infectious, gastrointestinal, and/or biological morbidity. Intravenous human polyclonal immunoglobulins (IVIg) have been proposed in concomitant use with PT in order to avoid the requirement for ET in ABO FMI. METHODS: Electronic databases of all published clinical trials in neonatal hyperbilirubinemia due to ABO incompatibility were systematically queried for randomized controlled clinical trials comparing PT alone to PT associated with IVIg based on the requirement for ET. Duration of PT and adverse events were optional criteria. A meta-analysis of the selected data was performed on six selected trials out of 28 found. RESULTS: IVIg doses ranged from 0.5 to 1.5 g/Kg in one to three administrations. Requirement for ET was lower in the IgIV+PT group, with a relative risk of 0.27 [CI 95% 0.17-0.42; P<0.00001], expressed as a number needed to treat of five neonates to avoid one ET. The mean duration of PT was 4 days in the PT group and association of PT with IVIg significantly reduced the duration of PT treatment by 0.84 days. The tolerance of the IVIg and PT association was good with no reported cases of ulcerative enterocolitis in 265 treated newborns. CONCLUSION: IVIG associated with PT reduces the need for ET and the duration of PT in newborns with hyperbilirubinemia due to ABO hemolytic disease. Their efficacy and good tolerance prompt consideration of IVIg as a therapeutic adjuvant to PT in severe hemolytic hyperbilirubinemia due to ABO incompatibility.

Morbidity and mortality in the antiphospholipid syndrome during a 5-year period: a multicentre prospective study of 1000 patients.

OBJECTIVES: To identify the main causes of morbidity and mortality in patients with antiphospholipid syndrome (APS) during a 5-year period and to determine clinical and immunological parameters with prognostic significance. METHODS: The clinical and immunological features of a cohort of 1000 patients with APS from 13 European countries who had been followed up from 1999 to 2004 were analysed. RESULTS: 200 (20%) patients developed APS-related manifestations during the 5-year study period. Recurrent thrombotic events appeared in 166 (16.6%) patients and the most common were strokes (2.4% of the total cohort), transient ischaemic attacks (2.3%), deep vein thromboses (2.1%) and pulmonary embolism (2.1%). When the thrombotic events occurred, 90 patients were receiving oral anticoagulants and 49 were using aspirin. 31/420 (7.4%) patients receiving oral anticoagulants presented with haemorrhage. 3/121 (2.5%) women with only obstetric APS manifestations at the start of the study developed a new thrombotic event. A total of 77 women (9.4% of the female patients) had one or more pregnancies and 63 (81.8% of pregnant patients) had one or more live births. The most common fetal complications were early pregnancy loss (17.1% of pregnancies) and premature birth (35% of live births). 53 (5.3% of the total cohort) patients died. The most common causes of death were bacterial infection (21% of deaths), myocardial infarction (19%) and stroke (13%). No clinical or immunological predictor of thrombotic events, pregnancy morbidity or mortality was detected. CONCLUSION: Patients with APS still develop significant morbidity and mortality despite current treatment (oral anticoagulants or antiaggregants, or both).

[Hyperuricemia and gout: diagnosis and therapy]. / Hyperurikämie und Gicht : Diagnostik und Therapie.

In our modern society hyperuricemia is one of the most frequent metabolism disturbances. So far, every fourth man and every tenth woman suffer from an asymptomatic or a symptomatic hyperuricemia named gout. Mostly, over nutrition and malnutrition as well as other secondary factors with a genetically determined renal secretion disturbance of uric acid lead to an increase of serum uric acid. By deposition of uric acid crystals in tissues with intermittent immunologic activation of inflammation cells a manifestation of gout can be seen. The clinical image of gout varies widely. It may manifest as acute or chronic arthritis, tophi on the skin, subcutaneous tissue and the skeletal system as well as urate nephropathy. To eliminate the consequences of hyperuricemia in the long term, apart from a thorough anamnesis of nutritional habits a general examination of metabolic parameters is necessary to exclude a metabolic syndrome and other causes for a secondarily caused hyperuricemia. As gout is very often primarily caused by a renal secretion disturbance of uric acid special diagnostics should be done. Basing on literature research and inclusion of experts opinions this article represents the therapeutically options in treatment of hyperuricemia and gout with their resulting side effects and contraindications.

[Oxidatively modified lipoproteins and their antibodies in patients with antiphospholipid syndromeand systemic lupus erythematosus]. / Oxidativ modifizierte Lipoproteine und deren Antikörper bei Patienten mit Antiphospholipidsyndrom und Systemischem Lupus erythematodes.

The antiphospholipid syndrome (APS) with its typical clinical manifestations of recurrent thrombosis and fetal loss is biochemically defined by the presence of circulating antiphospholipid antibodies (aPL). The disease pattern has raised special interest as a possible link between autoimmunity and atherosclerosis. aPL, oxidized low density lipoproteins (oxLDL), and antibodies to oxLDL (Anti-oxLDL) are suggested to play an important role in atherogenesis. In the present study we compared the serum levels of oxLDL and Anti-oxLDL in APS patients (20 subjects with primary APS; 14 subjects with secondary APS) and nonAPS subjects (24 phenotypically healthy controls samples and 12 patients with systemic lupus erythematosus [SLE]) and investigated associations of the above mentioned parameters with the intima-media thickness (IMT), a clinical surrogate parameter of atherosclerosis.SLE patients with and without APS showed significantly increased levels of Anti-oxLDL as compared to the controls group (p = 0.038 and p = 0.007, respectively). In contrast, oxLDL levels were not significantly different between the controls group and patients. The Anti-oxLDL levels correlated significantly with anticardiolipin (p = 0.002) and beta(2)-glycoprotein I antibodies (p < 0.048), both from IgG isotype. Only SLE patients without APS revealed a significantly elevated production of reactive oxygen species indicating an increased proatherogenic oxidative stress in the circulation (p < 0.002). In the patient groups, the circulating levels of oxLDL and Anti-oxLDL showed no association with atherosclerosis as estimated by IMT. In conclusion, our experimental data do not support the concept of oxidative stress-induced accelerated atherosclerosis in APS patients.

A dependency model for patients with Alzheimer's disease: its validation and relationship to the costs of care--the LASER-AD Study.

BACKGROUND: Loss of independence becomes more marked as Alzheimer's disease (AD) progresses and contributes significantly to its societal and economic burden. Existing measures of functional disability focus either on basic or on instrumental activities of daily living (ADL). It would be more appropriate to combine these but, using existing assessment tools, this would involve considerable quantitative analysis. Recently, a qualitative and pragmatic system of classifying AD patients according to levels of dependency has been developed in a Belgian cohort. OBJECTIVES: To validate independently, in a UK community setting, a functional classification model of AD patients and to explore the relationship between dependency and costs of care using this model. RESEARCH DESIGN AND METHODS: Longitudinal epidemiological study of 224 AD patients. Data were collected at baseline and at 6 months on ADL, global state, cognition, behavioural dimensions, depression, quality of life and resource utilisation using validated instruments. An automatic classification algorithm was performed to allow identification of dependency clusters. The scheme was tested for validity against other simultaneously collected data including health and social care costs. The relationship between dependency and costs of care was explored using ANOVA models. RESULTS: Analysis of the ADL assessment instruments produced three ADL sub-scores by which patients could be classified into one of three disability clusters: ('non-dependent', 'non-dependent with instrumental functional disability', and 'dependent'). Good external validity of the classification scheme was demonstrated by correlation with simultaneously collected data. After a backward selection process on ANOVA model (at a 5% level), institutionalisation and the most dependent status were the most significant cost drivers. CONCLUSIONS: Qualitative classification of AD patients using dependency levels is a simple and validated approach. Applying this approach showed that institutionalisation and the most 'dependent' status were independently and significantly associated with high care cost.

Multiple antiphospholipid tests do not increase the diagnostic yield in antiphospholipid syndrome.

The family of antiphospholipid antibodies (aPL) includes a heterogeneous population of autoantibodies whose specificity is directed against not only phospholipids, but their complex with plasma proteins. Anticardiolipin antibodies (aCL) and lupus anticoagulant (LA) tests are widely performed to screen the aPL family which is associated with thrombotic complications in patients with systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS). The clinical significance of other aPL tests, including antibodies against phosphatidylserine (aPS), phosphatidylinositol (aPI), phosphatidic acid (aPA), phosphatidylcholine (aPC) and phosphatidylethanolamine (aPE), has not been established. The purpose of this study was to evaluate whether multiple aPL tests have enhanced diagnostic value for APS. We tested IgG/M/A aPS, aPI, aPA, aPC and aPE by ELISA using 10% bovine serum as blocking and sample diluent in 26 SLE patients with clinical manifestations of APS, but negative for both aCL and LA (Group 1). The results were compared with 32 SLE patients without any features of APS (Group 2) and 24 SLE patients with APS (aCL and/or LA positive) (Group 3). In Group 1, 1/26 (4%) was positive for IgA aPE, less frequent than in other groups, and none of the patients had any other aPL. In Group 2, 1/32 (3%) was positive for aPS, two (6%) for aPI, one (3%) for aPA and four (12.5%) for aPE. None was positive for aPC. In the third group, 13/24 (54%) were positive for aPS, 11 (46%) for aPI, 15 (63%) for aPA, four (17%) for aPC and seven (29%) for aPE. Since aPE was found in some patients, we extended the study, including 207 SLE patients, and tested aPE. IgG/M/A aPE was found in six (3%), 10(5%) and 21 (10%), respectively, but no association was found between aPE and any clinical features of APS. This study suggests that screening by multiple aPL tests does not increase the diagnostic yield in APS.

[The antiphospholipid syndrome]. / Das Phospholipid-Antikörpersyndrom.

Antiphospholipid syndrome (APS) is a thrombophilic disorder, which embraces almost all specialities. This article includes information about the history, classification, epidemiology, clinical manifestations and treatment of the APS. It is the aim of this article to introduce the APS with clinical features of all medical specialities to show the actuality of the syndrome which is not known everywhere.

The pathogenic 16/6 idiotype in patients with silica associated systemic lupus erythematosus (SLE) and uranium miners with increased risk for development of SLE.

OBJECTIVE: To investigate the prevalence of the 16/6 idiotype (16/6 Id), a major cross reactive idiotype of anti-DNA antibodies involved in the pathogenesis of experimental lupus, in subjects with an exogenous risk for the development of systemic lupus erythematosus (SLE). METHODS: The titer of 16/6 Id was determined by ELISA in sera of uranium miners exposed to heavy quartz dust: 15 developed definite and 12 probable SLE, 34 had clinical symptoms, and 27 had only serological signs (medium to high titer anti-dsDNA antibodies) of possible connective tissue disease (CTD) development. RESULTS: The prevalence of 16/6 Id was higher in all groups compared to healthy blood donors. It was 18.5% in miners with SLE (definite and probable) and 22.2-26.5% in miners with clinical and/or serological signs for developing CTD. All 16/6 Id positive miners were positive for anti-dsDNA antibodies and other autoantibodies associated with CTD. The prevalence of 16/6 Id in anti-dsDNA positive miners correlated slightly with CTD/SLE symptoms: 55.6% in patients with SLE, 47.4% in miners with possible CTD/SLE, and 22.2% in miners without CTD symptoms. Further, at short term followup, disease progressed in 2 miners of the 16/6 Id positive, but not in 16/6 Id negative miners. CONCLUSION: The detection of 16/6 Id in miners exposed to quartz dust may indicate a higher risk for development of SLE, warranting further studies of the role of 16/6 Id in the development of SLE in a cohort with the same sex, ethnicity, geographic region, and occupation.

[Distal vascular access for chronic hemodialysis in patients over 65 years of age. Surgical results]. / Abords vascularies distaux pour hémodialyse chronique après 65 ans. Résultats chirurgicaux.

OBJECTIVE: To evaluate the results of vascular accesses for chronic haemodialysis in elderly patients. MATERIAL AND METHODS: 56 consecutive vascular accesses for haemodialysis were performed from November 1993 to December 1995 in patients over the age of 65 years. The policy adopted was to prefer distal accesses: only forearm accesses, primary arteriovenous fistula (AVF) or radio-M venous bioprosthesis shunt (AVS) were performed. Surgical or interventional radiological reoperation rates and abandonment rates were evaluated. RESULTS: 13 AVF (mean age: 74.5 years) and 43 AVS (mean age: 73.8 years) were analysed. The mean number of reoperations was significantly higher in the shunt group. 1 out of 13 AVF was abandoned versus 9 out of 43 AVS (no significant difference). DISCUSSION: AVS gave poor results in terms of reoperation rate, inducing a high cost and impairment of the quality of life of these patients. Their survival in this population was comparable to that of AVF. Several teams prefer to perform first-line humero-cephalic or humero-basilic arteriovenous fistulas whenever a simple fistula in the forearm cannot be performed. They appear to give better results, but their use in the elderly is poorly evaluated. Peritoneal dialysis may be preferable to haemodialysis in the elderly. As vascular accesses are increasingly performed in elderly subjects with a reduced life expectancy, protection of the proximal venous capital does not appear to be a sufficient argument to justify the use of AVS in this population. CONCLUSION: This study encouraged us to abandon the use of prostheses in the forearm in favour of direct accesses in the arms.

ATP-sensitive K+ channels regulated by intracellular Ca2+ and phosphorylation in normal (T84) and cystic fibrosis (CFPAC-1) epithelial cells.

The elementary K+ conductance activated by the cAMP or the Ca2+ second messenger pathways was investigated in the model salt-secreting epithelium, the human T84 cell line. Under Cl(-)-free conditions, an inwardly rectifying whole-cell K+ current was evoked by either forskolin 10 (mumol/l) or acetylcholine 1 (mumol/l) and blocked by extracellular charybdotoxin 10 (nmol/l). In the cell-attached mode, both secretory agonists induced the opening of a channel showing inward rectification with a unitary chord conductance of 36.8 +/- 2.5 pS (n = 26) for inward currents. In inside-out patches, a 35-pS inwardly rectifying K+ channel that corresponded to the channel recorded in the cell-attached configuration was recorded in the presence of 0.3 mumol/l free Ca2+ at the inner side of the membrane. This channel was blocked by Ba2+ (5 mumol/l) and by charybdotoxin (50 nmol/l). Its open probability was enhanced by intracellular Ca2+ with and EC50 of 0.25 mumol/l and strongly reduced by intracellular MgATP with an IC50 of 600 mumol/l. In the continuous presence of ATP, the channel activity was consistently increased by 125 kU/l catalytic subunit of cAMP-dependent protein kinase. In the cystic fibrosis pancreatic duct cell line CFPAC-1, a K+ channel was also recorded, with similar characteristics and regulation as the 35-pS channel in T84 cells. We conclude that an ATP-sensitive K+ channel regulated by intracellular Ca2+ and phosphorylation supports the main K+ current activated by secretory agonists in normal cystic fibrosis cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)