A 1-year follow-up study on checkpoint inhibitor-induced colitis: results from a European consortium.

BACKGROUND: Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis. MATERIALS AND METHODS: This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed. RESULTS: Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis. CONCLUSIONS: Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.

Maternal Uterine Artery Adenoviral Vascular Endothelial Growth Factor (Ad.VEGF-A165) Gene Therapy Normalises Fetal Brain Growth and Microglial Activation in Nutrient Restricted Pregnant Guinea Pigs.

Fetal growth restriction (FGR) is associated with uteroplacental insufficiency, and neurodevelopmental and structural brain deficits in the infant. It is currently untreatable. We hypothesised that treating the maternal uterine artery with vascular endothelial growth factor adenoviral gene therapy (Ad.VEGF-A165) normalises offspring brain weight and prevents brain injury in a guinea pig model of FGR. Pregnant guinea pigs were fed a restricted diet before and after conception and received Ad.VEGF-A165 (1 × 1010 viral particles, n = 18) or vehicle (n = 18), delivered to the external surface of the uterine arteries, in mid-pregnancy. Pregnant, ad libitum-fed controls received vehicle only (n = 10). Offspring brain weight and histological indices of brain injury were assessed at term and 5-months postnatally. At term, maternal nutrient restriction reduced fetal brain weight and increased microglial ramification in all brain regions but did not alter indices of cell death, astrogliosis or myelination. Ad.VEGF-A165 increased brain weight and reduced microglial ramification in fetuses of nutrient restricted dams. In adult offspring, maternal nutrient restriction did not alter brain weight or markers of brain injury, whilst Ad.VEGF-A165 increased microglial ramification and astrogliosis in the hippocampus and thalamus, respectively. Ad.VEGF-A165 did not affect cell death or myelination in the fetal or offspring brain. Ad.VEGF-A165 normalises brain growth and markers of brain injury in guinea pig fetuses exposed to maternal nutrient restriction and may be a potential intervention to improve childhood neurodevelopmental outcomes in pregnancies complicated by FGR.

Eosinophil-associated diseases: the allergist's and clinical immunologist's perspective.

Summary: Eosinophil-associated diseases (EADs) refer to heterogeneous conditions in which eosinophils are believed to play critical pathological roles. They encompass common respiratory conditions, such as asthma, chronic rhinosinusitis with nasal polyps (CRSwNP), less common primary eosinophilic disorders of gastrointestinal tract, and rare conditions including eosinophilic granulomatosis with polyangiitis (EGPA) and hypereosinophilic syndrome (HES). A literature search was carried out in January 2024 in the MEDLINE and Scopus databases using the PubMed search engine (PubMed, National Library of Medicine, Bethesda, MD). We focused on blood eosinophilia and hypereosinophilia. A diagnostic workup is proposed. From allergist's point of view, we focused the review on 4 groups of eosinophilic disorders of specific interest. Our increased understanding of type 2 inflammation and biology has recently led to development of highly effective precision targeted therapies that are now approved for a growing number of eosinophilic disorders. Novel targeted biologics have a major impact on treatment strategies and have resulted in major advances in our understanding of the pathogenesis of these disorders. In the context of EADs, according to the heterogeneity of eosinophilic disorders a multidisciplinary approach should be adopted. Allergists and Clinical Immunologists play an important role as they have a clear understanding of the eosinophilic inflammation and the role of cytokines and are trained to recognize and characterize type 2 (T2) inflammation and its associated pathologies.

Tandem versus single haematopoietic stem cell transplant and BV maintenance in relapsed/refractory Hodgkin lymphoma: A matched cohort analysis from the LYSA.

Autologous hematopoietic stem cell transplant (ASCT) is the standard curative treatment for patients with high-risk relapsed/refractory Hodgkin lymphoma (R/R HL). The AETHERA study showed survival gain with Brentuximab Vedotin (BV) maintenance after ASCT in BV-naive patients, which was recently confirmed in the retrospective AMAHRELIS cohort, including a majority of BV-exposed patients. However, this approach has not been compared to intensive tandem auto/auto or auto/allo transplant strategies, which were used before BV approval. Here, we matched BV maintenance (AMAHRELIS) and tandem SCT (HR2009) cohorts, and observed that BV maintenance was associated with better survival outcome in patients with HR R/R HL.

Machine learning to predict overall short-term mortality in cutaneous melanoma.

BACKGROUND: Cutaneous malignant melanoma (CMM) ranks among the ten most frequent malignancies, clinicopathological staging being of key importance to predict prognosis. Artificial intelligence (AI) has been recently applied to develop prognostically reliable staging systems for CMM. This study aims to provide a useful machine learning based tool to predict the overall CMM short-term survival. METHODS: CMM records as collected at the Veneto Cancer Registry (RTV) and at the Veneto regional health service were considered. A univariate Cox regression validated the strength and direction of each independent variable with overall mortality. A range of machine learning models (Logistic Regression classifier, Support-Vector Machine, Random Forest, Gradient Boosting, and k-Nearest Neighbors) and a Deep Neural Network were then trained to predict the 3-years mortality probability. Five-fold cross-validation and Grid Search were performed to test the best data preprocessing procedures, features selection, and to optimize models hyperparameters. A final evaluation was carried out on a separate test set in terms of balanced accuracy, precision, recall and F1 score. The best model was deployed as online tool. RESULTS: The univariate analysis confirmed the significant prognostic value of TNM staging. Adjunctive clinicopathological variables not included in the AJCC 8th melanoma staging system, i.e., sex, tumor site, histotype, growth phase, and age, were significantly linked to overall survival. Among the models, the Neural Network and the Random Forest models featured the best prognostic performance, achieving a balanced accuracy of 91% and 88%, respectively. According to the Gini importance score, age, T and M stages, mitotic count, and ulceration appeared to be the variables with the greatest impact on survival prediction. CONCLUSIONS: Using data from patients with CMM, we developed an AI algorithm with high staging reliability, on top of which a web tool was implemented ( unipd.link/melanomaprediction ). Being essentially based on routinely recorded clinicopathological variables, it can already be implemented with minimal effort and further tested in the current clinical practice, an essential phase for validating the model's accuracy beyond the original research context.

Parameters influencing renal response to SGLT2 inhibitors and GLP1 receptor agonists in type 2 diabetes patients with preserved renal function: a comparative, prospective study.

PURPOSE: SGLT2 inhibitors (SGLT2i) and GLP1 receptor agonists (GLP1-RA) protect the kidney in type 2 diabetes (T2DM) subjects. The role of patient's phenotype years before starting the treatment in determining the kidney response to these drugs has never been evaluated. SUBJECTS AND METHODS: Clinical and biochemical parameters were collected in 92 T2DM patients with preserved kidney function from year -4 (T-4) to year +3 (T+3) from the introduction of semaglutide or empagliflozin (T0). Glomerular filtration rate (eGFR) slopes were evaluated to identify eGFR changes (ΔGFR) and predictors of treatment response. Urinary markers of kidney impairment were measured at T0, including KIM-1, TNFR1 and L-FABP. RESULTS: Characteristics of patients on semaglutide (n = 46) or empagliflozin (n = 37) were similar at T-4 and T0. ΔGFR from T0 to T+3 was -5.5 [-10.0; -0.7] vs -2.6 [-102.4] ml/min/1.73 m2 for GLP1-RA and SGLT2i, respectively (p = ns). Compared with patients with a slower eGFR decline, those with ΔGFR > 5 ml/min/1.73 m2 from T0 to T+3 (49%) or ΔGFR > 10 ml/min/1.73 m2 from T-4 to T+3 (25%) had similar characteristics and urinary markers at T-4 and T0. The latter group showed greater eGFR decline from T-3 to T0, which tended to be delayed more by SGLT2i than GLP1-RA (p = 0.09). CONCLUSION: In our cohort, subjects with T2DM and preserved renal function show similar eGFR response to treatment with GLP1-RA or SGLT2i. Baseline urinary biomarkers or prior phenotyping do not predict treatment response. An early eGFR decline identifies patients prone to lose more eGFR over time, who may benefit more from SGLT2i treatment.

[Role of radiotherapy in haematology]. / Place de la radiothérapie en hématologie.

The management of myeloid and lymphoid disease is essentially based on chemotherapy and targeted therapies. Since radiotherapy could be responsible for severe late toxicities, essentially due to conventional bidimensional irradiation techniques, many trials have attempted to omit radiotherapy or to scale down the dose in their therapeutic strategy. Nevertheless, radiotherapy still plays a role for curative or symptomatic purposes.

Treatment of BRONJ with ozone/oxygen therapy and debridement with piezoelectric surgery.

OBJECTIVE: Bisphosphonate related osteonecrosis of the jaw (BRONJ) is progressive bone destruction in the maxillofacial region of patients under current or previous treatment with Bisphosphonates. The present case series study aimed to evaluate if ozone/oxygen therapy and debridement with piezoelectric surgery may improve the treatment of BRONJ. PATIENTS AND METHODS: The treatment modality of the patients included ozone/oxygen mixture from medical oxygen. The protocol for ozone/oxygen mixture therapy appointments was set as twice a week for 10 weeks, for a total of 20 applications for each patient. The evaluation of the lesions was based on the clinical and radiologic parameters. The primary outcome was the necrotic lesion reduction during ozone/oxygen therapy sessions and up to the end of follow up periods. The healing of the lesion was taken as a positive result. The level of significance was taken as p <0.05. RESULTS: A total of 14 patients affected by osteonecrosis were included. The mean follow-up of the patients was 14.3 months. The overall success rate after treatment was 64.2%. CONCLUSIONS: According to the results, ozone/oxygen therapy and debridement with Piezoelectric surgery for BRONJ treatment is a safe procedure with successful outcomes.

Branch pulmonary artery stent placement in a dog with heart base neoplasia.

A 7-year-old French bulldog was presented for evaluation of cardiac neoplasia. Two-dimensional transthoracic echocardiography revealed a mass on the base of the heart, compressing the right pulmonary artery. Computed tomography exam confirmed that a surgical approach to remove the mass would not be viable. Stent placement in the right pulmonary artery was performed to relieve external compression caused by the neoplasia. When surgery is not feasible, pulmonary artery stenting could be one aspect of a multidisciplinary approach to palliative management of heart base neoplasia.

Real-time three-dimensional echocardiographic study of a cardiac hemangiosarcoma in a dog.

A 7-year-old Golden Retriever was presented for a second opinion regarding a cardiac mass. Two-dimensional transthoracic echocardiography demonstrated presence of a mass in the area of the right atrium. The mass appeared adherent and possibly infiltrative to the external wall of the right atrium. Three-dimensional transthoracic echocardiography allowed better visualization of the neoplasia, suggesting that it was not infiltrative and contributed significantly to the decision to carry out the surgical resection of the cardiac tumor. This case report demonstrates the use of three-dimensional transthoracic echocardiography in the diagnostic evaluation of cardiac masses in dogs without the need for general anesthesia.

Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe.

OBJECTIVE: To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10 000 European Union (EU) population as part of an application for European Medicines Agency (EMA) orphan designation. DESIGN: Incidence estimation based on literature review and published national and EU statistics. SETTING AND POPULATION: European Union. METHODS: Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched. RESULTS: The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93-3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10 000 EU population (95% CI 3.07-3.60 per 10 000 EU population). This fell below the EMA threshold of 5 per 10 000 EU population. CONCLUSIONS: Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life-threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits. TWEETABLE ABSTRACT: Placental insufficiency meets the European Medicines Agency requirements for orphan disease designation.

Redo ileal pouch-anal anastomosis: outcomes from a case-controlled study.

AIM: To assess short- and long-term outcomes of redo ileal pouch-anal anastomosis (redo-IPAA) for failed IPAA, comparing them with those of successful IPAA. METHOD: This was a case-control study. Data were collected retrospectively from prospectively maintained databases from two tertiary care centres. Patients who had a redo-IPAA between 1999 and 2016 were identified and matched (1:2) with patients who had a primary IPAA (p-IPAA), according to diagnosis, age and body mass index. RESULTS: Thirty-nine redo-IPAAs (16 transanal and 23 abdominal procedures) were identified, and were matched with 78 p-IPAAs. After a mean follow-up of 56 ± 51  (2.6-190) months, failure rates after transanal and abdominal approaches were 50% and 15%, respectively. Reoperation after the transanal approach was higher than after p-IPAA (69% vs 7%; P < 0.001). No differences were noted between the abdominal approach for redo-IPAA and p-IPAA in terms of morbidity (61% for redo-IPAA vs 38% for p-IPAA; P = 0.06), major morbidity (9% vs 8%; P = 0.96), anastomotic leakage (13% vs 10%; P = 0.74), mean daily bowel movements (6 vs 5.5; P = 0.68), night-time bowel movements (1.2 vs 1; P = 0.51), faecal incontinence (13% vs 7%; P = 0.40), urgency (31% vs 27%; P = 0.59), use of anti-diarrhoeal drugs (47% vs 37%; P = 0.70), mean Cleveland Global Quality-of-Life score (7 vs 7; P = 0.83) or sexual function. CONCLUSION: The abdominal approach for redo-IPAA is justified in cases of pouch failure because it achieves functional results comparable with those observed after p-IPAA, without higher postoperative morbidity. The transanal approach should be chosen sparingly.

DNA methylation of genes regulating appetite and prediction of weight loss after bariatric surgery in obese individuals.

PURPOSE: Epigenetic traits are influenced by clinical variables; interaction between DNA methylation (DNAmeth) and bariatric surgery-induced weight loss has been scarcely explored. We investigated whether DNAmeth of genes encoding for molecules/hormones regulating appetite, food intake or obesity could predict successful weight outcome following Roux-en-Y gastric bypass (RYGB). METHODS: Forty-five obese individuals with no known comorbidities were stratified accordingly to weight decrease one-year after RYGB (excess weight loss, EWL ≥ 50%: good responders, GR; EWL < 50%: worse responders, WR). DNAmeth of leptin (LEP), ghrelin (GHRL), ghrelin receptor (GHSR) and insulin-growth factor-2 (IGF2) was assessed before intervention. Single nucleotide polymorphisms of genes affecting DNAmeth, DNMT3A and DNMT3B, were also determined. RESULTS: At baseline, type 2 diabetes was diagnosed by OGTT in 13 patients. Post-operatively, GR (n = 23) and WR (n = 22) achieved an EWL of 67.7 ± 9.6 vs 38.2 ± 9.0%, respectively. Baseline DNAmeth did not differ between GR and WR for any tested genes, even when the analysis was restricted to subjects with no diabetes. A relationship between GHRL and LEP methylation profiles emerged (r = 0.47, p = 0.001). Searching for correlation between DNAmeth of the studied genes with demographic characteristics and baseline biochemical parameters of the studied population, we observed a correlation between IGF2 methylation and folate (r = 0.44, p = 0.003). Rs11683424 for DNMT3A and rs2424913 for DNMT3B did not correlate with DNAmeth of the studied genes. CONCLUSIONS: In severely obese subjects, the degree of DNAmeth of some genes affecting obesity and related conditions does not work as predictor of successful response to RYGB.

[New therapeutic strategies in non-Hodgkin lymphomas and Hodgkin lymphoma]. / Actualités thérapeutiques dans les lymphomes non hodgkiniens et le lymphome de Hodgkin.

In this review, we report the main advances of the last years in the four most common lymphomas in France, namely Hodgkin lymphoma, large cell diffuse B lymphoma, follicular lymphoma and mantle cell lymphoma. We have identified consensual practices in first line in France and then distinguished the targeting by new molecules. Thus, we wanted to highlight the problems for each of these four lymphomas and understand the tools used to find solutions. Finally, this review makes it possible to understand to what extent the new molecules (targeted therapies, immunotherapy) make it possible to continuously improve the management of patients with lymphomas. The global dynamics seems to reduce the place of conventional chemotherapies in favor of these new molecules. However, because of the increase in therapeutic possibilities, the challenge remains to find the combination associated with the best risk-benefit ratio.

Pseudoangiomatous stromal hyperplasia (PASH) presenting as axillary lump: case report and review of the literature.

Pseudoangiomatous stromal hyperplasia (PASH) is an uncommon benign mesenchymal breast lesion. There are extremely rare reports of PASH arising in accessory breast tissue. To date, in literature, fewer than 10 cases of PASH occurring in axillary region have been described. We report a case presenting as axillary lump in a young woman. A 20-year-old female presented to our surgical unit for a progressively growing and painful palpable mass of the right axilla for about a year. Before surgery an ultrasound was performed. The patient underwent local excision of the lesion under local anaesthesia. Through histological and immunohistochemical examination a pseudoangiomatous stromal hyperplasia (PASH) was diagnosed. At 6 months of followup the patient is free of disease. It is important to include PASH also in the differential diagnosis of axillary lumps. Histological examination of the surgical specimen and surgery represent, respectively, the mainstay for diagnosis and therapy.

[HPV vaccination in boys and men : update and recommendations]. / Vaccination contre le papillomavirus humain (HPV) chez les garçons et les hommes : actualités et recommandations.

High-risk oncogenic HPVs (HR-HPV) are associated in men with pre-cancerous anal dysplasia, oropharyngeal, anal and penile cancer. Anogenital warts are induced by low-risk HPVs. These manifestations are increasing among men, and especially in some high-risk groups as men who have sex with men (MSM). This review targets HPV-associated disease epidemiology as well as safety, immunogenicity, and efficacy level of HPV vaccine in men. Obstacle and cost-effectiveness analysis of HPV vaccination are discussed. Three HPV vaccines are currently available in Belgium with the 9-valent (" 9HPV " - 6/11/16/18/31/33/45/52/58) offering protection against most of HPVassociated diseases. The safe 9-valent vaccine is efficient to prevent genital warts, anal dysplasia and it decreases the recurrence of genital warts and high grade anal neoplasia in MSM with or without HIV infection. In Europe, the 9-valent vaccine could prevent in men more than 350,000 genital warts, 5,485 oropharyngeal cancers, 2,303 anal cancers et 852 grade 2/3 intraepithelial neoplasia as well as 1,113 penile cancers per year. In the Federation Wallonie-Bruxelles, the vaccine coverage reaches currently 30 % in girls and is very low in boys and men.The Superior Health Council of Belgium (CSS) recommends since 2017 the gender-neutral HPV vaccination for people up to 26 years old and to immunocompromised patients. The implementation of the CSS HPV vaccine program and its acceptability among boys and men are discussed on the basis of the most recent epidemiologic data and available costeffectiveness analysis. Ways to overcome barriers to gender-neutral HPV vaccination are suggested.

Chez l'homme, l'infection chronique par les HPV à haut risque oncogénique cause des lésions dysplasiques précancéreuses anales, des cancers oropha-ryngés, anaux et du pénis. Les HPV à bas risque oncogénique provoquent des condylomes ano-génitaux. Ces manifestations sont en augmenta-tion, notamment dans certains groupes, comme les hommes ayant des relations sexuelles avec des hommes (HSH). Cette revue de la littérature cible, l'épidémiologie des affections associées à l'HPV, la sécurité et l'efficacité des vaccins anti-HPV chez l'homme, ainsi que l'analyse des barrières à la vaccination et des études " coût-efficacité ". Des trois vaccins contre le HPV disponibles en Belgique, le Nonavalent (" 9HPV " - 6/11/16/18/31/ 33/45/52/58) offre la plus large protection. Le vaccin 9HPV est sécuritaire et prévient l'apparition de condylomes et de dysplasies anales ; il est efficace dans la prévention secondaire de condylomes et de lésions anales précancéreuses chez les HSH, qu'ils soient ou non infectés par le VIH. En Europe, chez l'homme, le 9HPV pourrait prévenir par an plus de 350.000 condylomes, 5.485 cancers oropharyngés, 2.303 cancers anaux et 852 néoplasies intra-épithéliales de grade 2/3 ainsi que 1.113 cancers du pénis. En Fédération Wallonie-Bruxelles, la couverture vaccinale est actuellement de 30 % chez les filles et anecdotique chez les garçons et les hommes. En 2017, le Conseil supérieur de la Santé (CSS) a élargi la vaccination aux deux sexes jusqu'à 26 ans et aux patients immunocompromis. L'application de ce programme de vaccination et son acceptation parmi les garçons et les hommes sont discutées sur base des données épidémiologiques récentes et des études coût-efficacité disponibles, afin d'encourager cette implémentation.