C3 Hypocomplementemia Predicts the Progression of CKD towards End-Stage Kidney Disease in IgA Nephropathy, Irrespective of Histological Evidence of Thrombotic Microangiopathy.

Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgAN causes end-stage kidney disease (ESKD) in 30-40% of all cases. The activation of the complement system by pathological circulating IgAs, which is often associated with low serum C3 levels (LowC3), seems to play a crucial role. Previous studies have shown an association between histological evidence of TMA, which is the result of alternative complement activation, and poor outcomes. However, it is not known to what extent the decrease in serum C3 levels reflects ongoing TMA injury. Our study aimed at assessing the association between LowC3 and ESKD and whether this association reflects ongoing TMA. Methods: We enrolled all patients with biopsy-proven IgAN and followed-up patients until their last visit, ESKD, or death. Results: Of the 56 patients included in the study, 12 (21%) presented low serum C3 (LowC3) at the time of renal biopsy. TMA was significantly more frequent in the LowC3 group [7/12 (58%) vs. 9/44 (20%), p = 0.02]. After adjusting for potential confounders, LowC3 was strongly associated with an increased hazard of ESKD (hazard ratio [HR]: 5.84 [95%CI: 1.69, 20.15; p = 0.005). The association was not affected by adjusting for TMA. The estimated overall proportion of the relation between C3 and ESKD mediated by TMA was low and not statistically significant. Conclusions: Our study provides evidence that C3 hypocomplementemia is associated with an increased risk of ESKD through mechanisms that are largely independent from TMA.

Borderline rejection: To treat or not to treat?

INTRODUCTION: It is unclear whether kidney transplant recipients with a biopsy diagnosis as a "borderline" acute T-cell mediated rejection (TCMR) requires the treatment with intravenous (iv) steroids pulse plus/minus intensification of the maintenance therapy (TRT) in comparison with the simple clinical follow-up (F-UP). METHODS: We retrospectively followed a consecutive series of kidney transplant recipients diagnosed with a borderline acute TCMR at biopsy by surveillance or clinical indication for 12 months and compared TRT and F-UP groups. We evaluated trends in renal function by measuring estimated glomerular filtration rate (eGFR) using multiple regression models. Repeated eGFR measures (REML) were adjusted for potential confounding factors for 12 months. The difference in 12-month eGFR values were observed in the TRT vs F-UP groups, type of biopsy, as well as the surveillance vs. clinical outcomes. RESULTS: Out of 59 included patients, 37% of them were in the TRT group and remaining 63% in the F-UP group. As expected, the TRT group had, at the time of biopsy, lower eGFR value of 39.0 ml/min/m2 [16.5] in comparison to 49.6 [19.6] ml/min/m2 in the F-UP group (P = 0.043), Similarly, the TRT group required more frequent clinical biopsies vs. F-UP group (68% vs. 32%; P = 0.014). However, the TRT group recovered kidney function reaching the eGFR values of the F-UP group at 12 months; the increase being significant only in patients who received indication biopsies (P < 0.001). The estimated adjusted TRT effect on 12-month eGFR change after indication biopsy was improved by +15.8 ml/min/1.73m2 (95%CI: +0.1 to +31.4 ml/min/1.73 m2; P = 0.048 by three-way interaction term) compared to the F-UP group. CONCLUSION: Our preliminary study supports the indication for the treatment of acute borderline TCMR only in cases with biopsies performed by clinical indication.

Circulating Osteopontin Predicts Clinical and Radiological Response in First-Line Treatment of Advanced Non-Small Cell Lung Cancer.

PURPOSE: Pembrolizumab-based regimens are conditioned by the expression of PD-L1, but durable response rate is limited by innate and acquired resistance mechanisms. Here, we focus on osteopontin (OPN), an upfront biomarker of senescence, which closely associated with natural history of non-small cell lung cancer (NSCLC). METHODS: Seventy-nine patients eligible to pembrolizumab regimens-alone or in combination with chemotherapy-as first-line treatment of advanced NSCLC were enrolled. Predictive value of OPN toward iRECIST progression disease (PD) was set as first outcome. Secondary ones included performance status (ECOG) at baseline, early (first and best) responses, and overall survival (OS). RESULTS: High Serum OPN characterized patients with worse ECOG-PS (p = 0.015) at baseline and subjects experienced PD/death at first (OR 1.17 [1.02 to 1.35]; p = 0.030) and best responses (0.04 [0.00 to 0.81]; p = 0.035). OPN was associated with time-to-progression (B -2.74 [-4.46 to -1.01]) and time-to death (-0.13 [-0.20 to -0.05]). Cox regression models unveil a predictive value for iRECIST-PD (HR 1.01 [1.00 to 1.02]; p = -0.005), RECIST-PD (HR 1.01 [1.00 to 1.02]; p = 0.017), and OS (HR 1.02 [1.01 to 1.03]; p = 0.001). These models were internally validated through bootstrap resampling and characterized by relevant discrimination ability at ROC curve analyses. CONCLUSION: Baseline levels of serum OPN is closely associated with performance status and short/long term outcomes in patients with advanced NSCLC, which are candidate to pembrolizumab-based regimens. As upfront biomarker of senescence, OPN may pave the way for future studies focusing on senescence patterns in NSCLC.

Endovascular repair of ascending aortic pathologies in patients unfit for open surgery: case series and literature review.

The number of vascular centers performing endovascular repair of ascending aortic disease is constantly increasing. Accordingly to the guidelines, open surgical repair remains the gold standard for these pathologies. However, approximately one quarter of patients are deemed unfit for open surgery. In this study, we describe three cases of ascending thoracic endovascular aortic repair (TEVAR) performed at our center. All the patients were deemed unfit for open surgery by the aortic team. Two patients had an ascending aortic pseudoaneurysm, and the third had a focal type A aortic dissection. In two cases, we used two abdominal aortic cuffs deployed from zone 0B to zone 0C, with no need for supra-aortic trunk debranching. In one case, we performed a "reverse" extrathoracic debranching, and we deployed a thoracic endograft from zone 0B to zone 2. Complications included one minor stroke and one inguinal hematoma. In one patient with an infected pseudoaneurysm, we performed ascending TEVAR as a bridge strategy for open repair. This patient developed a type Ia endoleak; however, clinical stabilization and infection control were obtained, and he was able to undergo heart surgery successfully. He underwent a second reintervention to treat superior mesenteric embolic occlusion. At 2 years of follow-up, all three patients were alive. Our preliminary experience demonstrates the technical feasibility and clinical appropriateness of ascending TEVAR using standard, commercially available endografts. However, no consensus has been reached regarding some critical aspects, such as the development of a standardized technique or the efficacy of the currently available devices. The improvements in graft design and the adoption of the "aortic team" approach could help in the near future to standardize the procedure, establish appropriate indications, and ensure good clinical outcomes.

Volumetric analysis in primary and residual type B aortic dissection treated with stented-assisted balloon-induced intimal disruption and relamination technique can predict aortic reintervention.

OBJECTIVE: The aim of this study was to investigate the mid-term results of stented-assisted balloon-induced intimal disruption and relamination (STABILISE) in patients with aortic dissection with the implementation of volumetric analysis. METHODS: This was a single-center retrospective analysis of prospectively collected data. From May 2017 to September 2022, 42 patients underwent STABILISE for acute complicated or subacute high-risk aortic dissection. STABILISE was completed with distal extended endovascular aortic repair in 24 patients. A computed tomography scan was performed at baseline, before hospital discharge, and at 1, 3, and 5 years. Perfused total aortic, true lumen, and false lumen volumes were assessed for thoracic, visceral, and aorto-iliac segment. The ratio between false lumen and total volume was named perfusion dissection index (PDI). Complete remodeling was defined as PDI = 0, and positive remodeling as PDI ≤0.1. RESULTS: Technical success was 97.6%. No 30-day deaths, spinal cord injuries, or retrograde dissections were observed. Mean follow-up was 44 ± 19.4 months. Thoracic diameter was lower at last available computed tomography scan (36.7 vs 33.0 mm; P = .01). Aortic growth >5 mm was observed in 9.5% of the patients. Thoracic and visceral aortic complete remodeling were 92.8% and 83.3%, respectively, with no difference between acute and subacute group. Distal extended endovascular aortic repair significantly increased complete remodeling in the aorto-iliac segment, compared with STABILISE alone (69.6% vs 21.4%; P < .001). Freedom from vascular reinterventions at 3 years was 83.1% (95% confidence interval, 71.5%-96.6%). Total PDI ≤0.1 at first postoperative control was a predictor of vascular reinterventions (P < .0001). CONCLUSIONS: STABILISE is a safe and feasible technique associated with high mid-term rates of complete remodeling in the thoracic and visceral aorta. Volumetric analysis allows the quantification of aortic remodeling and represents a predictor of aortic reinterventions.

Diagnostic Imaging of Agminated Blue Lesions and Blue Lesions with Satellitosis: Case Series with a Concise Review of the Current Literature.

Background: Agmination and/or satellitosis in pigmented blue lesions is a phenomenon rarely mentioned in the literature and not well known. This phenomenon can be expressed by several benign and malignant pigmented blue lesions, such as blue nevi, Spitz nevi, melanocytoma and melanoma. On this spectrum, dermoscopy, reflectance confocal microscopy (RCM) and dynamic Optical coherence tomography (D-OCT) represent non-invasive imaging technologies, which may help clinicians in the diagnosis of melanoma and non-melanoma skin cancers in daily clinical practice. Methods: Currently, in the literature there is a lack of new data about agminated blue lesions and blues lesions with satellitosis, as well as the lack of a recent and updated review of the literature about this topic. Therefore, considering that clinicians must be confident with the diagnosis of these rare skin lesions, we decided to carry out this work. Results: In this paper, four new cases of agminated pigmented cutaneous lesions were described. Moreover, a review of the current literature on this topic was performed. Conclusions: A clinical-pathological correlation is often needed to reach a correct diagnosis; currently, dermoscopy and non-invasive diagnostic techniques, such as reflectance confocal microscopy and optical coherence tomography, due to the depth of these skin lesions in the dermis, can only make a partial and limited contribution.

Diagnosis of lung cancer following emergency admission: Examining care pathways, clinical outcomes, and advanced NSCLC treatment in an Italian cancer Center.

Background: Lung cancer patients diagnosed following emergency admission often present with advanced disease and poor performance status, leading to suboptimal treatment options and outcomes. This study aimed to investigate the clinical and molecular characteristics, treatment initiation, and survival outcomes of these patients. Methods: We retrospectively analyzed data from 124 patients diagnosed with lung cancer following emergency admission at a single institution. Clinical characteristics, results of molecular analyses for therapeutic purpose, systemic treatment initiation, and survival outcomes were assessed. Correlations between patients' characteristics and treatment initiation were analyzed. Results: Median age at admission was 73 years, and 79.0 % had at least one comorbidity. Most patients (87.1 %) were admitted due to cancer-related symptoms. Molecular analyses were performed in 89.5 % of advanced non-small cell lung cancer (NSCLC) cases. In this subgroup, two-thirds (66.2 %) received first-line therapy. Median overall survival (OS) was 3.9 months for the entire cohort, and 2.9 months for patients with metastatic lung cancer. Among patients with advanced NSCLC, OS was significantly longer for those with actionable oncogenic drivers and those who received first-line therapy. Improvement of performance status during hospitalization resulted in increased probability of receiving first-line systemic therapy. Discussion: Patients diagnosed with lung cancer following emergency admission demonstrated poor survival outcomes. Treatment initiation, particularly for patients with actionable oncogenic drivers, was associated with longer OS. These findings highlight the need for proactive medical approaches, including improving access to molecular diagnostics and targeted treatments, to optimize outcomes in this patient population.

Thrombotic microangiopathy due to primary antiphospholipid syndrome: successful treatment with eculizumab.

Antiphospholipid syndrome nephropathy includes a variety of histological lesions, including thrombotic microangiopathy, which is not included among the diagnostic criteria of antiphospholipid syndrome. Whereas in secondary antiphospholipid syndrome, e.g. to systemic lupus erythematosus, there is emerging evidence of a benefit from complement blockade with eculizumab, optimal treatment of primary antiphospholipid syndrome-associated thrombotic microangiopathy is currently unknown. We report the case of a 36-year-old male patient with primary antiphospholipid syndrome-associated thrombotic microangiopathy, presenting with a clinical picture of atypical hemolytic-uremic syndrome with frequent relapses, treated with eculizumab (four 900 mg weekly doses followed by 1200 mg fortnightly infusions) leading to resolution of hemolysis, long-term remission and partial kidney function recovery (peak serum creatinine 3.8 mg/dL, decreased and stabilized around 2.5 mg/dL) over a follow up period of over 2 years.

A functional role of Ephrin type-B receptor 6 (EPHB6) in T-cell acute lymphoblastic leukemia.

T-cell lymphoblastic acute leukemia (T-ALL) is an aggressive blood cancer, characterized by restricted cellular subsets with enriched leukemia initiating cells (LICs). Recently, Ephrin receptors (Eph) were described to be highly expressed in cancer stem cells. Here, using public RNA-Seq datasets of human T-ALL, we reported that EphB6 was the only member within the Eph family overexpressed in over 260 samples. We also found the highest level of EphB6 in a minor cell subpopulation within bulk tumors of patient-derived xenografts, obtained through the injection of primary patient biopsy material into immunocompromised NOD-Scid/IL2Rγc-/- (NSG) mice. Interestingly, this EphB6 positive (EphB6+) subset showed an enriched LIC activity after in vivo transplantation into NSG mice. Additionally, gene expression data at the single-cell level of primary patients' leukemic cells revealed that EphB6 + cells were significantly selected in minimal residual disease up to 30 days from the standard treatments and characterized by high levels of markers related to cell proliferation and poor clinical outcome, such as CCNB1 and KIF20A. Taken together, our data suggest that EphB6 supports LICs' maintenance and progression in T-ALL and, thus, targeting EphB6 + cells could be therapeutically relevant for the treatment of T-ALL patients.

Optical Coherence Tomography as a Valuable Tool for the Evaluation of Cutaneous Kaposi Sarcoma Treated with Imiquimod 5% Cream.

Kaposi sarcoma (KS) is a rare disease that was not frequently identified before the widespread occurrence of AIDS. Even today, it remains a challenge for physicians to diagnose, particularly in its early stages, often requiring referral to specialists and further investigations. Dermoscopy, a non-invasive imaging technique, reveals a distinctive rainbow pattern that strongly indicates KS. Moreover, advanced imaging tools like optical coherence tomography (OCT) can provide additional information though specific disease-related patterns have not been fully established yet. These emerging techniques show promise in facilitating early diagnosis of skin-related KS and monitoring the effectiveness of treatments. However, biopsy remains the definitive method for confirming the disease. In this study, we present two cases of cutaneous Kaposi sarcoma, documented using OCT, both before and after treatment with imiquimod 5% cream. The study highlights the potential of OCT in evaluating disease progression and treatment response, as well as the usefulness of dermoscopy in detecting early indicators of KS. By integrating these advanced imaging techniques, the diagnosis and management of cutaneous KS could be improved, leading to timely interventions and better patient outcomes.

Improvement in the Post-Processing of Wave Buoy Data Driven by the Needs of a National Coast and Sea Monitoring Agency.

Technological development in terms of the power requirement for data acquisition and processing opens new perspectives in the field of environmental monitoring. Near real-time data flow about the sea condition and a possible direct interface with applications and services devoted to marine weather networks would have a significant impact on several aspects, such as, for example, safety and efficiency. In this scenario, the needs of buoy networks have been analyzed, and the estimation of directional wave spectra from buoys' data has been deeply investigated. Two methods have been implemented, namely the truncated Fourier series and the weighted truncated Fourier series, and they have been tested by both simulated and real experimental data, representative of typical Mediterranean Sea conditions. From simulation, the second method proved to be more efficient. From the application to real case studies, it emerged that it works effectively in real conditions, as confirmed by parallel meteorological observations. The estimation of the main propagation direction was possible with a small uncertainty of a few degrees, yet the method exhibits a limited directional resolution, which suggests the need for undertaking further studies, briefly addressed in the conclusions.

A Case of Psoriatic Disease and Hidradenitis Suppurativa in a Child with Chromosome 17q21.31 Microduplication Syndrome.

Psoriatic disease is a chronic, relapsing inflammatory disorder, characterized mostly by cutaneous erythematous scaly plaques sometimes associated with arthritis. Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory disease of the apocrine glands, characterized clinically by painful abscesses, sinus tracts and scars. It typically occurs after puberty, affecting mainly intertriginous areas of the body. There is a strong association between HS and psoriasis since they share the same pathogenic inflammatory pathway. The patient presented: low birthweight, microcephaly, facial dysmorphisms, lumbar hyperlordosis, walking difficulties, global psychomotor developmental delay and learning disabilities. A genetic evaluation revealed a 2.5 Mb de novo microduplication in the 17q21.31 chromosomal region. Dermatological examination revealed HS (Hurley stage II-HS) distributed in the genital area and inguinal folds, psoriatic plaques on the retroauricolar folds, on the elbows bilaterally and on the lateral aspect of the right ankle and psoriatic arthritis. The patient was treated with adalimumab, with a marked improvement of both conditions. To our best knowledge, we report the first case of coexisting Psoriatic Arthritis Disease and Hidradenitis Suppurativa in a child with chromosome 17q21.31 microduplication syndrome. We hypothesize that gene CRHR1 duplication included in the 17q21.31 chromosomal region might be involved in the pathogenesis of both diseases.

Platelets and their derived extracellular vesicles: The new generation of markers in non-small cell lung cancer management.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death. Circulating elements have gained significant interest in the diagnosis and prognosis of NSCLC patients. Among these, platelets (PLTs) and their derived extracellular vesicles (P-EVs) are emerging eligible biosources both in terms of number and carriers of genetic materials (RNA, proteins, and lipids). PLTs are mainly produced by the shedding of megakaryocytes and together with P-EVs, participate in a variety of pathological processes including thrombosis, tumor progression, and metastasis. Here, we performed an extensive literature review focusing on PLTs and P-EVs as potential diagnostic, prognostic, and predictive markers for NSCLC patient management.

Shared cross-cultural principles underlie human prosocial behavior at the smallest scale.

Prosociality and cooperation are key to what makes us human. But different cultural norms can shape our evolved capacities for interaction, leading to differences in social relations. How people share resources has been found to vary across cultures, particularly when stakes are high and when interactions are anonymous. Here we examine prosocial behavior among familiars (both kin and non-kin) in eight cultures on five continents, using video recordings of spontaneous requests for immediate, low-cost assistance (e.g., to pass a utensil). We find that, at the smallest scale of human interaction, prosocial behavior follows cross-culturally shared principles: requests for assistance are very frequent and mostly successful; and when people decline to give help, they normally give a reason. Although there are differences in the rates at which such requests are ignored, or require verbal acceptance, cultural variation is limited, pointing to a common foundation for everyday cooperation around the world.

Dynamic Compensation of a Piezoelectric Accelerometer Obtained through a General Probabilistic Approach.

Dynamic compensation is the (partial) correction of the measurement signals for the effects due to bandwidth limitations of measurement systems and constitutes a research topic in dynamic measurement. The dynamic compensation of an accelerometer is here considered, as obtained by a method that directly comes from a general probabilistic model of the measurement process. Although the application of the method is simple, the analytical development of the corresponding compensation filter is quite complex and had been previously developed only for first-order systems, whilst here a second-order system is considered, thus moving from a scalar to a vector problem. The effectiveness of the method has been tested both through simulation and by a dedicated experiment. Both tests have shown the capability of the method of significantly improve the performance of the measurement system when dynamic effects are more prevalent than additive observation noise.

Co-Occurrence of Beckwith-Wiedemann Syndrome and Early-Onset Colorectal Cancer.

CRC is an adult-onset carcinoma representing the third most common cancer and the second leading cause of cancer-related deaths in the world. EO-CRC (<45 years of age) accounts for 5% of the CRC cases and is associated with cancer-predisposing genetic factors in half of them. Here, we describe the case of a woman affected by BWSp who developed EO-CRC at age 27. To look for a possible molecular link between BWSp and EO-CRC, we analysed her whole-genome genetic and epigenetic profiles in blood, and peri-neoplastic and neoplastic colon tissues. The results revealed a general instability of the tumor genome, including copy number and methylation changes affecting genes of the WNT signaling pathway, CRC biomarkers and imprinted loci. At the germline level, two missense mutations predicted to be likely pathogenic were found in compound heterozygosity affecting the Cystic Fibrosis (CF) gene CFTR that has been recently classified as a tumor suppressor gene, whose dysregulation represents a severe risk factor for developing CRC. We also detected constitutional loss of methylation of the KCNQ1OT1:TSS-DMR that leads to bi-allelic expression of the lncRNA KCNQ1OT1 and BWSp. Our results support the hypothesis that the inherited CFTR mutations, together with constitutional loss of methylation of the KCNQ1OT1:TSS-DMR, initiate the tumorigenesis process. Further somatic genetic and epigenetic changes enhancing the activation of the WNT/beta-catenin pathway likely contributed to increase the growth advantage of cancer cells. Although this study does not provide any conclusive cause-effect relationship between BWSp and CRC, it is tempting to speculate that the imprinting defect of BWSp might accelerate tumorigenesis in adult cancer in the presence of predisposing genetic variants.

Germline Variants in MLH1 and ATM Genes in a Young Patient with MSI-H in a Precancerous Colonic Lesion.

Lynch syndrome (LS) is an autosomal dominant inherited disorder that primarily predisposes individuals to colorectal and endometrial cancer. It is associated with pathogenic variants in DNA mismatch repair (MMR) genes. In this study, we report the case of a 16-year-old boy who developed a precancerous colonic lesion and had a clinical suspicion of LS. The proband was found to have a somatic MSI-H status. Analysis of the coding sequences and flanking introns of the MLH1 and MSH2 genes by Sanger sequencing led to the identification of the variant of uncertain significance, namely, c.589-9_589-6delGTTT in the MLH1 gene. Further investigation revealed that this variant was likely pathogenetic. Subsequent next-generation sequencing panel analysis revealed the presence of two variants of uncertain significance in the ATM gene. We conclude that the phenotype of our index case is likely the result of a synergistic effect of these identified variants. Future studies will allow us to understand how risk alleles in different colorectal-cancer-prone genes interact with each other to increase an individual's risk of developing cancer.