Malliavin-Skorohod calculus and Paley-Wiener integral for covariance singular processes

We develop a stochastic analysis for a Gaussian process $X$ with singular covariance by an intrinsic procedure focusing on several examples such as covariance measure structure processes, bifractional Brownian motion, processes with stationary increments. We introduce some new spaces associated with the self-reproducing kernel space and we define the Paley-Wiener integral of first and second order even when $X$ is only a square integrable process continuous in $L^2$. If $X$ has stationary increments, we provide necessary and sufficient conditions so that its paths belong to the self-reproducing kernel space. We develop Skorohod calculus and its relation with symmetric-Stratonovich type integrals and two types of Itô's formula. One of Skorohod type, which works under very general (even very singular) conditions for the covariance; the second one of symmetric-Stratonovich type, which works, when the covariance is at least as regular as the one of a fractional Brownian motion of Hurst index equal to $H = \frac{1}{4}$

Wiener integrals, Malliavin calculus and covariance measure structure

We introduce the notion of {\em covariance measure structure} for square integrable stochastic processes. We define Wiener integral, we develop a suitable formalism for stochastic calculus of variations and we make Gaussian assumptions only when necessary. Our main examples are finite quadratric variation processes with stationary increments and the bifractional Brownian motion.Comment: 50 page

Congenital rhabdomyosarcoma: a different clinical presentation in two cases

Background: Rhabdomyosarcoma (RMS), one of the most common soft tissue sarcomas of childhood, is very rare in the neonatal period (0.4-2% of cases). In order to gain a deeper understanding of this disease at such age, patient and tumor features, as well as treatment modality and outcome need to be reported. Case presentation: We describe two cases with congenital RMS treated at Bambino Gesù Children's Hospital between 2000 and 2016. They represent only 2.24% of all RMS patients diagnosed during that period in our Institution; this data is in agreement with the incidence reported in the literature. They reflect the two different clinical forms in which the disease may manifest itself. One patient, with the alveolar subtype (positive for specific PAX3-FOXO1 fusion transcript) and disseminated disease, had a fatal outcome with central nervous system (CNS) progression despite conventional and high dose chemotherapy. The other child, with the localized embryonal subtype, was treated successfully with conservative surgery and conventional chemotherapy, including prolonged maintenance therapy. He is disease free at 7 years of follow-up. Conclusions: RMS can also be diagnosed during the neonatal period. Given the young age, disease management is often challenging, and especially for the alveolar subtype, the outcome is dismal despite intensified multimodality therapy. In fact, it characteristically manifests with multiple subcutaneous nodules and progression most commonly occurs in the CNS (Rodriguez-Galindo et al., Cancer 92(6):1613-20, 2001). In this context, CNS prophylaxis could play a role in preventing leptomeningeal dissemination, and molecular studies can allow a deeper tumor characterization, treatment stratification and identification of new potential therapeutic targets

Macrophage Autophagy and Oxidative Stress: An Ultrastructural and Immunoelectron Microscopical Study

The word autophagy broadly refers to the cellular catabolic processes that lead to the removal of damaged cytosolic proteins or cell organelles through lysosomes. Although autophagy is often observed during programmed cell death, it may also serve as a cell survival mechanism. Accumulation of reactive oxygen species within tissues and cells induces various defense mechanisms or programmed cell death. It has been shown that, besides inducing apoptosis, oxidative stress can also induce autophagy. To date, however, the regulation of autophagy in response to oxidative stress remains largely elusive and poorly understood. Therefore, the present study was designed to examine the ratio between oxidative stress and autophagy in macrophages after oxidant exposure (AAPH) and to investigate the ultrastructural localization of beclin-1, a protein essential for autophagy, under basal and stressful conditions. Our data provide evidence that oxidative stress induces autophagy in macrophages. We demonstrate, for the first time by immunoelectron microscopy, the subcellular localization of beclin-1 in autophagic cells

One shot NEPA plus dexamethasone to prevent multiple-day chemotherapy in sarcoma patients

Purpose: Chemotherapy-induced nausea and vomiting (CINV) is one of the most feared and disturbing adverse events of cancer treatment associated with decreased adherence to effective chemotherapy regimens. For high-risk soft tissue sarcoma patients, receiving multiple-day chemotherapy (MD-CT), antiemetic guidelines recommend a combination of an NK 1 receptor antagonist (NK 1 -RA), a 5-HT 3 receptor antagonist (5HT 3 -RA), and dexamethasone on each day of the antineoplastic treatment. NEPA is the first oral fixed-dose combination of a highly selective NK 1 -RA, netupitant, and second-generation 5HT 3 -RA, palonosetron. So far, no data has been published in literature about the efficacy of a single dose of NEPA in MD-CT. Methods: We performed a prospective, non-comparative study to assess the efficacy of one shot of NEPA plus dexamethasone in sarcoma patients receiving MD-CT. The primary efficacy endpoint was a complete response (CR: no emesis, no rescue medication) during the overall phase (0–120 h) in cycle 1. The main secondary endpoints were CR during the overall phase of cycles 2 and 3. Results: The primary endpoint was reached in 88.9% of patients. Cycles 2 and 3 overall CR rates were 88.9% and 82.4%, respectively. The antiemetic regimen was well tolerated. Conclusions: This pilot study showed the benefit of one shot of NEPA to prevent CINV in sarcoma patients receiving MD-chemotherapy

A Single-Center, Randomized Controlled Trial to Test the Efficacy of Nurse-Led Motivational Interviewing for Enhancing Self-Care in Adults with Heart Failure

Background: The role of nurse-led motivational interviewing (MI) in improving self-care among patients with heart failure (HF) is promising, even if it still requires further empirical evidence to determine its efficacy. For this reason, this study tested its efficacy in enhancing self-care maintenance (primary endpoint), self-care management, and self-care confidence after three months from enrollment in adults with HF compared to usual care, and assessed changes in self-care over follow-up times (3, 6, 9, and 12 months). Methods: A single-center, randomized, controlled, parallel-group, superiority study with two experimental arms and a control group was performed. Allocation was in a 1:1:1 ratio between intervention groups and control. Results: MI was effective in improving self-care maintenance after three months when it was performed only for patients (arm 1) and for the patients-caregivers dyad (arm 2) (respectively, Cohen's d = 0.92, p-value < 0.001; Cohen's d = 0.68, p-value < 0.001). These effects were stable over the one-year follow-up. No effects were observed concerning self-care management, while MI moderately influenced self-care confidence. Conclusions: This study supported the adoption of nurse-led MI in the clinical management of adults with HF

Novel concepts and strategies in skull base reconstruction after endoscopic endonasal surgery

Recently, a variety of craniofacial approaches has been adopted to enter the skull base, among those, the endonasal endoscopic technique. An effective watertight thereafter: the reconstruction can be performed using different materials, both autologous and non-autologous, individually or combined in a multilayer fashion. The current study was focused on the development of new advanced devices and techniques, aiding in reducing postoperative CSF leak rate. Additive manufacturing allows the design of devices with tailored structural and functional features and, as well, injectable semi-IPNs and composites; therefore specific mechanical/rheological and injectability studies are valuable. Accordingly, we propose new additive-manufactured and injectable devices

Havep53 gene mutations and protein expression a different biological significance in colorectal cancer?

p53 alterations are considered the most common genetic events in many types of neoplasms, including colorectal carcinoma (CRC). These alterations include mutations of the gene and/or overexpression of the protein. The aim of our study was to assess whether in 160 patients undergoing resective surgery for primary operable CRC there was an association between p53 mutations and protein over-expression and between these and other biological variables, such as cell DNA content (DNA-ploidy) and S-phase fraction (SPF), and the traditional clinicopathological variables. p53 mutations, identified by PCR-SSCP-sequencing analysis, were found in 68/160 patients (43%) and positive staining for p53 protein, detected with the monoclonal antibody DO-7, was present in 48% (77/160) of the cases, with agreement of 57% (91/160). In particular, a significant association was found between increased p53 expression and genetic alterations localized in the conserved regions of the gene or in the L3 DNA-binding domain and the specific type of mutation. Furthermore, both overexpression of p53 and mutations in the conserved areas of the gene were found more frequently in distal than in proximal CRCs, suggesting that they might be "biologically different diseases." Although p53 mutations in conserved areas were associated with flow cytometric variables, overexpression of p53 and mutations in its L3 domain were only related respectively to DNA-aneuploidy and high SPF. These data may reflect the complex involvement of p53 in the different pathways regulating cell-cycle progression. In conclusion, the combination of the mutational status and immunohistochemistry of p53, and flow cytometric data may provide an important insight into the biological features of CRCs

Artificial Intelligence Predictive Models of Response to Cytotoxic Chemotherapy Alone or Combined to Targeted Therapy for Metastatic Colorectal Cancer Patients: A Systematic Review and Meta-Analysis

Simple Summary Metastatic colorectal cancer (mCRC) has high incidence and mortality. Nevertheless, innovative biomarkers have been developed for predicting the response to therapy. We have examined the ability of learning methods to build prognostic and predictive models to predict response to chemotherapy, alone or combined with targeted therapy in mCRC patients, by targeting specific narrative publications. After a literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. We showed that all investigations conducted in this field provided generally promising results in predicting the response to therapy or toxic side-effects, using a meta-analytic approach. We found that radiomics and molecular biomarker signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Our study supports the use of computer science for developing personalized treatment decision processes for mCRC patients. Tailored treatments for metastatic colorectal cancer (mCRC) have not yet completely evolved due to the variety in response to drugs. Therefore, artificial intelligence has been recently used to develop prognostic and predictive models of treatment response (either activity/efficacy or toxicity) to aid in clinical decision making. In this systematic review, we have examined the ability of learning methods to predict response to chemotherapy alone or combined with targeted therapy in mCRC patients by targeting specific narrative publications in Medline up to April 2022 to identify appropriate original scientific articles. After the literature search, 26 original articles met inclusion and exclusion criteria and were included in the study. Our results show that all investigations conducted on this field have provided generally promising results in predicting the response to therapy or toxic side-effects. By a meta-analytic approach we found that the overall weighted means of the area under the receiver operating characteristic (ROC) curve (AUC) were 0.90, 95% C.I. 0.80-0.95 and 0.83, 95% C.I. 0.74-0.89 in training and validation sets, respectively, indicating a good classification performance in discriminating response vs. non-response. The calculation of overall HR indicates that learning models have strong ability to predict improved survival. Lastly, the delta-radiomics and the 74 gene signatures were able to discriminate response vs. non-response by correctly identifying up to 99% of mCRC patients who were responders and up to 100% of patients who were non-responders. Specifically, when we evaluated the predictive models with tests reaching 80% sensitivity (SE) and 90% specificity (SP), the delta radiomics showed an SE of 99% and an SP of 94% in the training set and an SE of 85% and SP of 92 in the test set, whereas for the 74 gene signatures the SE was 97.6% and the SP 100% in the training set

Evaluation of Endoglin (CD105) expression in pediatric rhabdomyosarcoma

BACKGROUND: The Intratumoral Microvessel Density (IMVD) is commonly used to quantify tumoral vascularization and is usually assessed by pan-endothelial markers, such as CD31. Endoglin (CD105) is a protein predominantly expressed in proliferating endothelium and the IMVD determined by this marker measures specifically the neovascularization. In this study, we investigated the CD105 expression in pediatric rhabdomyosarcoma and assessed the neovascularization by using the angiogenic ratio IMVD-CD105 to IMVD-CD31. METHODS: Paraffin-embedded archival tumor specimens were selected from 65 pediatric patients affected by rhabdomyosarcoma. The expression levels of CD105, CD31 and Vascular Endothelial Growth Factor (VEGF) were investigated in 30 cases (18 embryonal and 12 alveolar) available for this study. The IMVD-CD105 to IMVD-CD31 expression ratio was correlated with clinical and pathologic features of these patients. RESULTS: We found a specific expression of endoglin (CD105) in endothelial cells of all the rhabdomyosarcoma specimens analyzed. We observed a significant positive correlation between the IMVD individually measured by CD105 and CD31. The CD105/CD31 expression ratio was significantly higher in patients with lower survival and embryonal histology. Indeed, patients with a CD105/CD31 expression ratio < 1.3 had a significantly increased OS (88%, 95%CI, 60%-97%) compared to patients with higher values (40%, 95%CI, 12%-67%). We did not find any statistical correlation among VEGF and EFS, OS and CD105/CD31 expression ratio. CONCLUSION: CD105 is expressed on endothelial cells of rhabdomyosarcoma and represent a useful tool to quantify neovascularization in this tumor. If confirmed by further studies, these results will indicate that CD105 is a potential target for combined therapies in rhabdomyosarcoma.We thank Professor Franco Locatelli for critical reading this paper and for his suggestions. We would also like to thank the children ’ s parents, who gave their informed consent for publication and “Il cuore grande di Flavio ”Onlus. Dr. Marta Colletti is a post-doctoral fellow of the Umberto Veronesi Founda- tion. To Valentina Polcini for proofreading.S