Peristomal Skin Complications in Ileostomy and Colostomy Patients: What We Need to Know from a Public Health Perspective

Background: Peristomal skin complications (PSCs) are the most common skin problems seen after ostomy surgery. They have a considerable impact on a patient's quality of life and contribute to a higher cost of care. Methods: A systematic review was conducted, querying three databases. The analysis was performed on international studies focused on the clinical-epidemiological burden of PSCs in adult patients with ileostomy/colostomy. Results: Overall, 23 studies were considered. The main diseases associated with ostomy surgery were rectal, colon and gynecological cancers, inflammatory bowel diseases, diverticulitis, bowel obstruction and intestinal perforation. Erythema, papules, skin erosions, ulcers and vesicles were the most common PSCs for patients with an ostomy (or stoma). A PSCs incidence ranging from 36.3% to 73.4% was described. Skin complications increased length of stay (LOS) and rates of readmission within 120 days of surgery. Conclusions: PSCs data are still limited. A knowledge of their burden is essential to support health personnel and decision-makers in identifying the most appropriate responses to patients' needs. Proper management of these complications plays a fundamental role in improving the patient's quality of life. A multidisciplinary approach, as well as increased patient education and their empowerment, are priority measures to be implemented to foster a value-based healthcare

SARS-CoV-2 infection in cancer patients on active therapy after the booster dose of mRNA vaccines

The protective role against SARS-CoV-2 infection by the third booster dose of mRNA vaccines in cancer patients with solid malignancies is presently un- known. We prospectively investigated the occurrence of COVID-19 in cancer patients on active therapy after the booster vaccine dose. Methods: Cancer patients on treatment at the Center for Immuno-Oncology (CIO) of the University Hospital of Siena, Italy, and health care workers at CIO who had received a booster third dose of mRNA vaccine entered a systematic follow-up monitoring period to prospectively assess their potential risk of SARS-CoV-2 infection. Serological and microneu- tralization assay were utilized to assess levels of anti-spike IgG, and of neutralizing antibodies to the SARS-CoV-2 Wild Type, Delta and Omicron variants, respectively, after the booster dose and after negativization of the nasopharyngeal swab for those who had developed COV- ID-19. Results: Ninety cancer patients with solid tumors on active treatment (Cohort 1) and 30 health care workers (Cohort 2) underwent a booster third dose of mRNA vaccine. After the booster dose, the median value of anti-spike IgG was higher (p Z 0.009) in patients than in healthy subjects. Remarkably, 11/90 (12%) patients and 11/30 (37%) healthy subjects tested positive to SARS-CoV-2 infection during the monitoring period. Similar levels of anti-spike IgG and of neutralizing antibodies against all the investigated variants, with geometric mean titers of neutralizing antibodies against the Omicron being the lowest were detected after the booster dose and after COVID-19 in both Cohorts. Conclusions: The occurrence of SARS-CoV-2 infection we observed in a sizable proportion of booster-dosed cancer patients and in healthy subjects during the Omicron outbreak indicates that highly specific vaccines against SARS-CoV-2 variants are urgently required

T-Cell Receptor Repertoire Sequencing and Its Applications: Focus on Infectious Diseases and Cancer

The immune system is a dynamic feature of each individual and a footprint of our unique internal and external exposures. Indeed, the type and level of exposure to physical and biological agents shape the development and behavior of this complex and diffuse system. Many pathological conditions depend on how our immune system responds or does not respond to a pathogen or a disease or on how the regulation of immunity is altered by the disease itself. T-cells are important players in adaptive immunity and, together with B-cells, define specificity and monitor the internal and external signals that our organism perceives through its specific receptors, TCRs and BCRs, respectively. Today, high-throughput sequencing (HTS) applied to the TCR repertoire has opened a window of opportunity to disclose T-cell repertoire development and behavior down to the clonal level. Although TCR repertoire sequencing is easily accessible today, it is important to deeply understand the available technologies for choosing the best fit for the specific experimental needs and questions. Here, we provide an updated overview of TCR repertoire sequencing strategies, providers and applications to infectious diseases and cancer to guide researchers’ choice through the multitude of available options. The possibility of extending the TCR repertoire to HLA characterization will be of pivotal importance in the near future to understand how specific HLA genes shape T-cell responses in different pathological contexts and will add a level of comprehension that was unthinkable just a few years ago

Stability Program in Dendritic Cell Vaccines: A “Real-World” Experience in the Immuno-Gene Therapy Factory of Romagna Cancer Center

Advanced therapy medical products (ATMPs) are rapidly growing as innovative medicines for the treatment of several diseases. Hence, the role of quality analytical tests to ensure consistent product safety and quality has become highly relevant. Several clinical trials involving dendritic cell (DC)-based vaccines for cancer treatment are ongoing at our institute. The DC-based vaccine is prepared via CD14+ monocyte differentiation. A fresh dose of 10 million DCs is administered to the patient, while the remaining DCs are aliquoted, frozen, and stored in nitrogen vapor for subsequent treatment doses. To evaluate the maintenance of quality parameters and to establish a shelf life of frozen vaccine aliquots, a stability program was developed. Several parameters of the DC final product at 0, 6, 12, 18, and 24 months were evaluated. Our results reveal that after 24 months of storage in nitrogen vapor, the cell viability is in a range between 82% and 99%, the expression of maturation markers remains inside the criteria for batch release, the sterility tests are compliant, and the cell costimulatory capacity unchanged. Thus, the data collected demonstrate that freezing and thawing do not perturb the DC vaccine product maintaining over time its functional and quality characteristics

Primary Analysis and 4-Year Follow-Up of the Phase III NIBIT-M2 Trial in Melanoma Patients With Brain Metastases

Purpose: Phase II trials have shown encouraging activity with ipilimumab plus fotemustine and ipilimumab plus nivolumab in melanoma brain metastases. We report the primary analysis and 4-year follow-up of the NIBIT-M2 study, the first phase III trial comparing these regimens with fotemustine in patients with melanoma with brain metastases. Patients and methods: This phase III study recruited patients 18 years of age and older with BRAF wild-type or mutant melanoma, and active, untreated, asymptomatic brain metastases from nine centers, randomized (1:1:1) to fotemustine, ipilimumab plus fotemustine, or ipilimumab plus nivolumab. The primary endpoint was overall survival (OS). Results: From January, 2013 to September, 2018, 27, 26, and 27 patients received fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab. Median OS was 8.5 months [95% confidence interval (CI), 4.8-12.2] in the fotemustine arm, 8.2 months (95% CI, 2.2-14.3) in the ipilimumab plus fotemustine arm (HR vs. fotemustine, 1.09; 95% CI, 0.59-1.99; P = 0.78), and 29.2 months (95% CI, 0-65.1) in the ipilimumab plus nivolumab arm (HR vs. fotemustine, 0.44; 95% CI, 0.22-0.87; P = 0.017). Four-year survival rate was significantly higher for ipilimumab plus nivolumab than fotemustine [(41.0%; 95% CI, 20.6-61.4) vs. 10.9% (95% CI, 0-24.4; P = 0.015)], and was 10.3% (95% CI, 0-22.6) for ipilimumab plus fotemustine. In the fotemustine, ipilimumab plus fotemustine, and ipilimumab plus nivolumab arms, respectively, 11 (48%), 18 (69%), and eight (30%) patients had treatment-related grade 3 or 4 adverse events, without treatment-related deaths. Conclusions: Compared with fotemustine, ipilimumab plus nivolumab significantly improved overall and long-term survival of patients with melanoma with asymptomatic brain metastases

Epigenetic Immune Remodeling of Mesothelioma Cells: A New Strategy to Improve the Efficacy of Immunotherapy

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with a severe progno- sis, and with a long-standing need for more effective therapeutic approaches. However, treatment with immune checkpoint inhibitors is becoming an increasingly effective strategy for MPM pa- tients. In this scenario, epigenetic modifications may negatively regulate the interplay between immune and malignant cells within the tumor microenvironment, thus contributing to the highly immunosuppressive contexture of MPM that may limit the efficacy of immunotherapy. Aiming to further improve prospectively the clinical efficacy of immunotherapeutic approaches in MPM, we investigated the immunomodulatory potential of different classes of epigenetic drugs (i.e., DNA hypomethylating agent (DHA) guadecitabine, histone deacetylase inhibitors VPA and SAHA, or EZH2 inhibitors EPZ-6438) in epithelioid, biphasic, and sarcomatoid MPM cell lines, by cytofluo- rimetric and real-time PCR analyses. We also characterized the effects of the DHA, guadecitabine, on the gene expression profiles (GEP) of the investigated MPM cell lines by the nCounter platform. Among investigated drugs, exposure of MPM cells to guadecitabine, either alone or in combination with VPA, SAHA and EPZ-6438 demonstrated to be the main driver of the induction/upregulation of immune molecules functionally crucial in host-tumor interaction (i.e., HLA class I, ICAM-1 and cancer testis antigens) in all three MPM subtypes investigated. Additionally, GEP demonstrated that treatment with guadecitabine led to the activation of genes involved in several immune-related func- tional classes mainly in the sarcomatoid subtype. Furthermore, among investigated MPM subtypes, DHA-induced CDH1 expression that contributes to restoring the epithelial phenotype was highest in sarcomatoid cells. Altogether, our results contribute to providing the rationale to develop new epigenetically-based immunotherapeutic approaches for MPM patients, potentially tailored to the specific histologic subtypes

Fragile histidine triad gene inactivation in lung cancer: the European Early Lung Cancer project.

Rationale: Fragile histidine triad (FHIT) is a tumor suppressor gene involved in the pathogenesis of lung cancer. Objectives: The purpose of this study was to investigate the different molecular alterations leading to the inactivation of FHIT gene function and to validate their use as biomarkers of risk for progression of the disease in patients belonging to the multicentric European study for the Early detection of Lung Cancer (EUELC) who were resected for early-stage lung tumors. Methods: FHIT immunostaining was performed on 305 tumor samples. Themethylation status of FHIT promoterwas assessed by nested methylation-specific polymerase chain reaction (MSP-PCR) in 232 tumor and 225 normal lung samples ofwhich a subset of 187 patients had available normal/tumorDNA pairs. Loss of heterozygosity (LOH) at the FHIT locus was analyzed in 202 informative cases by D3S1300 and D3S1234 microsatellite markers. Measurements and Main Results: Lost or reduced FHIT expression was found in 36.7 and 75.7% of the tumor samples, respectively. Methylation of the FHIT promoter was found in 36.7%of tumor and 32.7% of normal lung samples, whereas LOH was detected in 61.9% of the tumors. A strong association with complete loss of FHIT expression was presentwhenmethylation and LOHwere analyzed together (P5 0.0064). Loss of FHIT protein expression was significantly more frequent in squamous cell carcinoma histotype (P , 0.0001) and in smokers (P5 0.008). FHIT methylation in normal lung was associated with an increased risk of progressive disease (OR, 2.27; P 5 0.0415). Conclusions:Our results indicate thatdifferentmolecularmechanisms interplay to inactivate FHIT expression and support the proposition that FHIT methylation in normal lung tissue could represent a prognostic marker for progressive disease

Proteoglycans and glycosaminoglycan fine structure in the mouse tail tendon fascicle

The isolated mouse tail tendon fascicle, a functional and homogenous volume of tendon extracellular matrix, was utilized as an experimental system to examine the structure–function relationships in tendon. Our previous work using this model system demonstrated relationships between mean collagen fibril diameter and fascicle mechanical properties in isolated tail tendon fascicles from three different groups of mice (3-week and 8-week control and 8-week Mov13 transgenic) K.A. Derwin, L.J. Soslowsky, J. Biomech. Eng. 121 (1999) 598–604. These groups of mice were chosen to obtain tendon tissues with varying collagen fibril structure and/or biochemistry, such that relationships with material properties could be investigated. To further investigate the molecular details of matrix composition and organization underlying tendon function, we report now on the preparation, characterization, and quantitation of fascicle PGs (proteoglycans) from these three groups. The chondroitin sulfate/dermatan sulfate (CS/DS)-substituted PGs, biglycan and decorin, which are the abundant proteoglycans of whole tendons, were also shown to be the predominant PGs in isolated fascicles. Furthermore, similar to the postnatal maturation changes in matrix composition previously reported for whole tendons, isolated fascicles from 8-week mice had lower CS/DS PG contents (both decorin and biglycan) and a higher collagen content than 3-week mice. In addition, CS/DS chains substituted on PGs from 8-week fascicles were shorter (based on a number average) and richer in disulfated disaccharide residues than chains from 3-week mice. Fascicles from 8-week Mov13 transgenic mice were found to contain similar amounts of total collagen and total CS/DS PG as age-matched controls, and CS/DS chain lengths and sulfation also appeared normal. However, both decorin and biglycan in Mov13 tissue migrated slightly faster on sodium dodecyl sulfate polyacrylamide gel electorphoresis (SDS-PAGE) than the corresponding species from 8-week control, and biglycan from the 8-week Mov13 fascicles appeared to migrate as a more polydisperse band, suggesting the presence of a unique PG population in the transgenic tissue. These observations, together with our biomechanical data [Derwin and Soslowsky, 1999] suggest that compensatory pathways of extracellular matrix assembly and maturation may exist, and that tissue mechanical properties may not be simply determined by the contents of individual matrix components or collagen fibril size. © 2001 Orthopaedic Research Society. Published by Elsevier Science Ltd. All rights reserved.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34919/1/1100190216_ftp.pd

Finalised dependability framework and evaluation results

The ambitious aim of CONNECT is to achieve universal interoperability between heterogeneous Networked Systems by means of on-the-fly synthesis of the CONNECTors through which they communicate. The goal of WP5 within CONNECT is to ensure that the non-functional properties required at each side of the connection going to be established are fulfilled, including dependability, performance, security and trust, or, in one overarching term, CONNECTability. To model such properties, we have introduced the CPMM meta-model which establishes the relevant concepts and their relations, and also includes a Complex Event language to express the behaviour associated with the specified properties. Along the four years of project duration, we have developed approaches for assuring CONNECTability both at synthesis time and at run-time. Within CONNECT architecture, these approaches are supported via the following enablers: the Dependability and Performance analysis Enabler, which is implemented in a modular architecture supporting stochastic verification and state-based analysis. Dependability and performance analysis also relies on approaches for incremental verification to adjust CONNECTor parameters at run-time; the Security Enabler, which implements a Security-by-Contract-with-Trust framework to guarantee the expected security policies and enforce them accordingly to the level of trust; the Trust Manager that implements a model-based approach to mediate between different trust models and ensure interoperable trust management. The enablers have been integrated within the CONNECT architecture, and in particular can interact with the CONNECT event-based monitoring enabler (GLIMPSE Enabler released within WP4) for run-time analysis and verification. To support a Model-driven approach in the interaction with the monitor, we have developed a CPMM editor and a translator from CPMM to the GLIMPSE native language (Drools). In this document that is the final deliverable from WP5 we first present the latest advances in the fourth year concerning CPMM, Dependability&Performance Analysis, Incremental Verification and Security. Then, we make an overall summary of main achievements for the whole project lifecycle. In appendix we also include some relevant articles specifically focussing on CONNECTability that have been prepared in the last period

Design of Approaches for Dependability and Initial Prototypes

The aim of CONNECT is to achieve universal interoperability between heterogeneous Networked Systems. For this, the non-functional properties required at each side of the connection going to be established must be fulfilled. By the one inclusive term "CONNECTability" we comprehend properties belonging to all four non-functional concerns of interest for CONNECT, namely dependability, performance, security and trust. We model such properties in conformance with a meta-model which establishes the relevant concepts and their relations. Then, building on the conceptual models proposed in the first year in Deliverable D5.1, in this document we present the approaches developed for assuring CONNECTability both at synthesis time and at runtime. The contributions include: the Dependability&Performance analysis Enabler, for which we release a modular architecture supporting stochastic verification and state-based analysis; incremental verification and event-based monitoring for runtime analysis; a model-based approach to interoperable trust management; the Security-by-Contract-with-Trust framework, which guarantees and enforces the expected trust levels and security policies