Advancing Personalized Medicine in the Treatment of Locally Advanced Rectal Cancer.

Rectal cancer presents a significant burden globally, often requiring multimodal therapy for locally advanced cases. Long-course chemoradiotherapy (LCRT) and short-course radiotherapy (SCRT) followed by surgery have been conventional neoadjuvant approaches. Recent trials favor LCRT due to improved local control. However, distant tumor recurrence remains a concern, prompting the exploration of total neoadjuvant therapy (TNT) as a comprehensive treatment strategy. Immune checkpoint inhibitors (ICIs) show promise, particularly in mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) tumors, potentially revolutionizing neoadjuvant regimens. Nonoperative management (NOM) represents a viable alternative post-neoadjuvant therapy for selected patients achieving complete clinical response (cCR). Additionally, monitoring minimal residual disease (MRD) using circulating tumor DNA (ctDNA) emerges as a non-invasive method for the assessment of treatment response. This review synthesizes current evidence on TNT, ICIs, NOM, and ctDNA, elucidating their implications for rectal cancer management and highlighting avenues for future research and clinical application.

Correlation and Agreement Between the CO2 Gap Obtained From Peripheral Venous Blood and From Mixed Venous Blood in Mechanically Ventilated Septic Patients.

BACKGROUND: Venous-arterial CO2 difference (Pv-aCO2) is a valuable marker that can identify a subset of patients in shock with inadequate cardiac output to meet tissue metabolic requirements. Some authors have found that Pv-aCO2 levels calculated from mixed vs central venous blood demonstrate a linear relationship. The purpose of this study is to determine whether there is a linear relationship between Pv-aCO2 obtained with peripheral venous blood (Pv-aCO2p) and with mixed venous blood, and the agreement between the 2 measures. METHODS: This was a prospective, single-center, observational clinical study enrolling mechanically ventilated patients in septic shock during the first 24 hours following admission to the intensive care unit. RESULTS: The Bravais-Pearson r-coefficient between Pv-aCO2 and Pv-aCO2p was .70 in 38 determinations (95%CI .48-.83; P-value = 1.25 x 10^-6). The Bland-Altman bias was 4.11 mmHg (95%CI 2.82-5.39), and the repeatability coefficient was 11.05. Using the Taffe approach, the differential and proportional biases were 2.81 (95%CI .52-5.11) and 1.29 (95%CI .86-1.72), respectively. CONCLUSION: There was linear correlation between Pv-aCO2p and Pv-aCO2 in mechanically ventilated patients with septic shock. The bias showed a gradual increase in high Pv-aCO2 values in an upward trend.

Inflammatory indices as prognostic markers in metastatic colorectal cancer patients treated with chemotherapy plus Bevacizumab.

Background: Validated predictors of sensitivity or resistance to Bevacizumab (Bev) are not available, and Inflammatory Indexes (IIs) has been reported to be useful prognostic factors in various malignant solid tumours, including metastatic colorectal cancer (mCRC). Objectives: To explore the prognostic value of IIs in mCRC patients treated with first-line chemotherapy plus Bev. Design: One hundred and eighty-two patients diagnosed with mCRC and treated with first line chemotherapy plus Bev were considered for this prospective non-pharmacological study. Neutrophil, lymphocyte, platelet, aspartate transaminase (AST) and lactate dehydrogenase (LDH) tests were carried out at baseline and before each treatment cycle, according to clinical practice. Methods: Pre-treatment Systemic Immune-inflammation Index (SII), Colon Inflammatory Index (CII) and Aspartate aminotransferase-Lymphocyte Ratio Index (ALRI) were evaluated to assess a correlation with progression-free survival (PFS) and overall survival (OS). Results: In the overall population, PFS and OS were lower in patients with high SII (HR 1.64, p = 0.006 and HR 1.75, p = 0.004, respectively) and high ALRI (HR 2.13, p = 0.001 and HR 1.76, p = 0.02, respectively), but no difference was detected according to CII value. The multivariate analysis confirmed both SII and ALRI as independent prognostic factors for PFS (HR 1.64 and 2.82, respectively) and OS (HR 1.65 and 2.12, respectively). Conclusion: Our results demonstrate and confirm that IIs, and in particular SII and ALRI, are easy to measure prognostic markers for patient candidates to first line chemotherapy plus Bev for mCRC.

Inflammatory Indexes can predict the efficacy of bevacizumab in metastatic colorectal cancer Bevacizumab (Bev) is a humanized monoclonal antibody with antiangiogenic activity, used in combination with chemotherapy as a standard first line treatment for many metastatic colorectal cancer patients. Validated predictors of sensitivity or resistance to Bevacizumab are not available, although several studies have investigated this issue in recent years. In this study, we investigated whether some selected baseline inflammatory indexes levels, namely Systemic Immune-inflammation Index (SII) and Aspartate aminotransferase-Lymphocyte Ratio Index (ALRI) could predict the survival in patients with metastatic colorectal cancer treated with Bevacizumab plus chemotherapy. We enrolled 182 patients diagnosed with mCRC and treated with first line chemotherapy plus Bev. For each patient we tested blood neutrophils, lymphocytes, platelets, aspartate transaminase (AST) and lactate dehydrogenase (LDH) before each treatment cycle, according to clinical practice. We calculated the SII value as platelet count × neutrophil count/lymphocyte count, and ALRI as AST/lymphocyte count. We found that patients with high SII and high ALRI values had lower survival as compared to those with low values. These parameters represent reproducible, inexpensive and easy to measure biomarkers to be used in both clinical practice and clinical trials, for patient selection.

Dynamic Monitoring of Circulating Tumor DNA in Patients With Metastatic Colorectal Cancer.

PURPOSE: Plasma circulating tumor DNA (ctDNA) is a valuable resource for tumor characterization and for monitoring of residual disease during treatment; however, it is not yet introduced in metastatic colorectal cancer (mCRC) routine clinical practice. In this retrospective exploratory study, we evaluated the role of ctDNA in patients with mCRC treated with chemotherapy plus bevacizumab. MATERIALS AND METHODS: Fifty-three patients were characterized for RAS and BRAF status on tumor tissue before the start of treatment. Plasma was collected at baseline, at first clinical evaluation, and at disease progression. ctDNA analysis was performed using Oncomine Colon cfDNA Assay on the Ion S5 XL instrument. RESULTS: At baseline, from a plasma sample, RAS, BRAF, or PIK3CA mutations were detected in 44 patients. A high correspondence was observed between ctDNA and tumor tissue mutations (KRAS 100%, NRAS 97.9%, BRAF 97.9%, PIK3CA 90%). Low baseline variant allele frequency (VAF) was found to be associated with longer median progression-free survival (PFS) compared with those with high VAF (15.9 v 12.2 months, P = .02). A higher PFS {12.29 months (95% CI, 9.03 to 17.9) v 8.15 months (95% CI, 2.76 to not available [NA]), P = .04} and overall survival (34.1 months [95% CI, 21.68 to NA] v 11.1 months [95% CI, 3.71 to NA], P = .003) were observed in patients with large decline in VAF at first evaluation. CONCLUSION: ctDNA analysis is useful for molecular characterization and tumor response monitoring in patients with mCRC. Quantitative variations of released ctDNA are associated with clinical outcomes.

Association between Pre-Treatment Biological Indicators and Compliance to Neoadjuvant/Perioperative Chemotherapy in Operable Gastric Cancer.

BACKGROUND AND AIMS: Perioperative treatment is currently the gold standard approach in Europe for locally advanced gastric cancer (GC). Unfortunately, the phenomenon of patients dropping out of treatment has been frequently observed. The primary aims of this study were to verify if routine blood parameters, inflammatory response markers, sarcopenia, and the depletion of adipose tissues were associated with compliance to neoadjuvant/perioperative chemotherapy. METHODS AND STUDY DESIGN: Blood samples were considered before the first and second cycles of chemotherapy. Sarcopenia and adipose indices were calculated with a CT scan before starting chemotherapy and before surgery. Odds ratios (OR) from univariable and multivariable models were calculated with a 95% confidence interval (95% CI). RESULTS: A total of 84 patients with locally advanced GC were identified between September 2010 and January 2021. Forty-four patients (52.4%) did not complete the treatment according to the number of cycles planned/performed. Eight patients (9.5%) decided to suspend chemotherapy, seven patients (8.3%) discontinued because of clinical decisions, fourteen patients (16.7%) discontinued because of toxicity and fifteen patients (17.9%) discontinued for miscellaneous causes. Seventy-nine (94%) out of eighty-four patients underwent gastrectomy, with four patients having surgical complications, which led to a suspension of treatment. Sarcopenia was present in 38 patients (50.7%) before chemotherapy began, while it was present in 47 patients (60%) at the CT scan before the gastrectomy. At the univariable analysis, patients with basal platelet to lymphocyte ratio (PLR) ≥ 152 (p = 0.017) and a second value of PLR ≥ 131 (p = 0.007) were more frequently associated with an interruption of chemotherapy. Patients with increased PLR (p = 0.034) compared to the cut-off were associated with an interruption of chemotherapy, while patients with increased monocytes between the first and second cycles were associated with a lower risk of treatment interruption (p = 0.006); patients who underwent 5-fluorouracil plus cisplatin or oxaliplatin had a higher risk of interruption (p = 0.016) compared to patients who underwent a 5-fluorouracil plus leucovorin, oxaliplatin and docetaxel (FLOT) regimen. The multivariable analysis showed a higher risk of interruption for patients who had higher values of PLR compared to the identified cut-off both at pretreatment and second-cycle evaluation (OR: 5.03; 95% CI: 1.34-18.89; p = 0.017) as well as for patients who had a lower PLR than the identified cut-off at pretreatment evaluation and had a higher PLR value than the cut-off at the second cycle (OR: 4.64; 95% CI: 1.02-21.02; p = 0.047). Becker regression was neither affected by a decrease of sarcopenia ≥ 5% (p = 0.867) nor by incomplete compliance with chemotherapy (p = 0.281). CONCLUSIONS: Changes in PLR values which tend to increase more than the cut-off seem to be an immediate indicator of incomplete compliance with neoadjuvant/perioperative treatment. Fat loss and sarcopenia do not appear to be related to compliance. More information is needed to reduce the causes of interruption.

Prospective validation of VEGF and eNOS polymorphisms as predictors of first-line bevacizumab efficacy in patients with metastatic colorectal cancer.

Bevacizumab (Bev) plus chemotherapy is a standard first-line treatment in metastatic colorectal cancer (mCRC), however to date no predictive factors of response have been identified. Results of our previous analysis on patients enrolled in a randomized prospective phase III multicenter study (ITACa study) showed a predictive value of Vascular Endothelial Growth Factor (VEGF) polymorphism (VEGF + 936), a 27-nucleotide variable number tandem repeat (VNTR) of the endothelial nitric oxide synthase (eNOS) gene and eNOS + 894 polymorphism. mCRC patients, treated with Bev plus chemotherapy, were included in this prospective validation trial. eNOS + 894G > T was analyzed by Real time PCR, while the eNOS VNTR and VEGF + 936C > T were determined by standard PCR and direct sequencing analysis. These polymorphisms were assessed in relation to progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). These three polymorphisms were not predictive of PFS (p 0.91, 0.59 and 0.09, respectively), and OS (p 0.95, 0.32 and 0.46, respectively). Moreover, the haplotype analyses did not confirm what was found in our previous study; patients bearing a specific haplotype of eNOS had not significantly improved outcomes. This prospective study failed to validate the predictive impact of eNOS and VEGF polymorphisms for response to Bev plus first-line chemotherapy in mCRC patients.

Detection of a Novel MSI2-C17orf64 Transcript in a Patient with Aggressive Adenocarcinoma of the Gastroesophageal Junction: A Case Report.

Adenocarcinoma of the esophagus (EAC) and gastroesophageal junction (GEJ-AC) is associated with poor prognosis, treatment resistance and limited systemic therapeutic options. To deeply understand the genomic landscape of this cancer type, and potentially identify a therapeutic target in a neoadjuvant chemotherapy non-responder 48-year-old man, we adopted a multi-omic approach. We simultaneously evaluated gene rearrangements, mutations, copy number status, microsatellite instability and tumor mutation burden. The patient displayed pathogenic mutations of the TP53 and ATM genes and variants of uncertain significance of three kinases genes (ERBB3, CSNK1A1 and RPS6KB2), along with FGFR2 and KRAS high copy number amplification. Interestingly, transcriptomic analysis revealed the Musashi-2 (MSI2)-C17orf64 fusion that has never been reported before. Rearrangements of the RNA-binding protein MSI2 with a number of partner genes have been described across solid and hematological tumors. MSI2 regulates several biological processes involved in cancer initiation, development and resistance to treatment, and deserves further investigation as a potential therapeutic target. In conclusion, our extensive genomic characterization of a gastroesophageal tumor refractory to all therapeutic approaches led to the discovery of the MSI2-C17orf64 fusion. The results underlie the importance of deep molecular analyses enabling the identification of novel patient-specific markers to be monitored during therapy or even targeted at disease evolution.

Genetic determinants of type 1 diabetes in individuals with weak evidence of islet autoimmunity at disease onset.

AIMS/HYPOTHESIS: Islet autoantibodies (AAbs) are detected in >90% of individuals with clinically suspected type 1 diabetes at disease onset. A single AAb, sometimes at low titre, is often detected in some individuals, making their diagnosis uncertain. Type 1 diabetes genetic risk scores (GRS) are a useful tool for discriminating polygenic autoimmune type 1 diabetes from other types of diabetes, particularly the monogenic forms, but testing is not routinely performed in the clinic. Here, we used a type 1 diabetes GRS to screen for monogenic diabetes in individuals with weak evidence of autoimmunity, i.e. with a single AAb at disease onset. METHODS: In a pilot study, we genetically screened 142 individuals with suspected type 1 diabetes, 42 of whom were AAb-negative, 27 of whom had a single AAb (single AAb-positive) and 73 of whom had multiple AAbs (multiple AAb-positive) at disease onset. Next-generation sequencing (NGS) was performed in 41 AAb-negative participants, 26 single AAb-positive participants and 60 multiple AAb-positive participants using an analysis pipeline of more than 200 diabetes-associated genes. RESULTS: The type 1 diabetes GRS was significantly lower in AAb-negative individuals than in those with a single and multiple AAbs. Pathogenetic class 4/5 variants in MODY or monogenic diabetes genes were identified in 15/41 (36.6%) AAb-negative individuals, while class 3 variants of unknown significance were identified in 17/41 (41.5%). Residual C-peptide levels at diagnosis were higher in individuals with mutations compared to those without pathogenetic variants. Class 3 variants of unknown significance were found in 11/26 (42.3%) single AAb-positive individuals, and pathogenetic class 4/5 variants were present in 2/26 (7.7%) single AAb-positive individuals. No pathogenetic class 4/5 variants were identified in multiple AAb-positive individuals, but class 3 variants of unknown significance were identified in 19/60 (31.7%) patients. Several patients across the three groups had more than one class 3 variant. CONCLUSIONS/INTERPRETATION: These findings provide insights into the genetic makeup of patients who show weak evidence of autoimmunity at disease onset. Absence of islet AAbs or the presence of a single AAb together with a low type 1 diabetes GRS may be indicative of a monogenic form of diabetes, and use of NGS may improve the accuracy of diagnosis.

Total Pancreatectomy With Islet Autotransplantation as an Alternative to High-risk Pancreatojejunostomy After Pancreaticoduodenectomy: A Prospective Randomized Trial.

OBJECTIVE: To compare pancreaticoduodenectomy (PD) and total pancreatectomy (TP) with islet autotransplantation (IAT) in patients at high risk of postoperative pancreatic fistula (POPF). BACKGROUND: Criteria to predict the risk of POPF occurrence after PD are available. However, even when a high risk of POPF is predicted, TP is not currently accepted as an alternative to PD, because of its severe consequences on glycaemic control. Combining IAT with TP may mitigate such consequences. METHODS: Randomized, open-label, controlled, bicentric trial (NCT01346098). Candidates for PD at high-risk pancreatic anastomosis (ie, soft pancreas and duct diameter ≤3 mm) were randomly assigned (1:1) to undergo either PD or TP-IAT. The primary endpoint was the incidence of complications within 90 days after surgery. RESULTS: Between 2010 and 2019, 61 patients were assigned to PD (n=31) or TP-IAT (n=30). In the intention-to-treat analysis, morbidity rate was 90·3% after PD and 60% after TP-IAT ( P =0.008). According to complications' severity, PD was associated with an increased risk of grade ≥2 [odds ratio (OR)=7.64 (95% CI: 1.35-43.3), P =0.022], while the OR for grade ≥3 complications was 2.82 (95% CI: 0.86-9.24, P =0.086). After TP-IAT, the postoperative stay was shorter [median: 10.5 vs 16.0 days; P <0.001). No differences were observed in disease-free survival, site of recurrence, disease-specific survival, and overall survival. TP-IAT was associated with a higher risk of diabetes [hazard ratio=9.1 (95% CI: 3.76-21.9), P <0.0001], but most patients maintained good metabolic control and showed sustained C-peptide production over time. CONCLUSIONS: TP-IAT may become the standard treatment in candidates for PD, when a high risk of POPF is predicted.

Ceramisation of hazardous elements: Benefits and pitfalls of the inertisation through silicate ceramics.

The addition of wastes to silicate ceramics can considerably expand the compositional spectrum of raw materials with a possible inclusion of hazardous components. The present work quantitatively examines relevant literature to determine whether the benefits of incorporating hazardous elements (HEs) into silicate ceramics outweigh the pitfalls. The mobility of various HEs (Ba, Zn, Cu, Cr, Mo, As, Pb, Ni, and Cd) has been parameterised by three descriptors (immobilisation efficiency, mobilised fraction, and hazard quotient) using leaching data. HEs can be incorporated into both crystalline and glassy phases, depending on the ceramic body type. Moreover, silicate ceramics exhibit a remarkably high immobilisation efficiency (often exceeding 99.9%), as accomplished for Ba, Cd, Ni, and Zn elements. The pitfalls of the inertization process include an insufficient stabilisation of incorporated HEs, as indicated by the high hazard quotients (beyond the permissible limits established for inert materials) obtained in some cases for Mo, As, Cr, Pb, and Cu elements. Such behaviour is related to oxy-anionic complexes (Mo, As, Cr) that can form their own phases or are not linked to the tetrahedral framework of aluminosilicate glass. Pb and Cu elements are preferentially partitioned to glass with a low coordination number, while As and especially Mo are not always stabilised in silicate ceramics. These drawbacks necessitate conducting additional studies to develop appropriate inertisation strategies for these elements.

No Evidence of Long-Term Disruption of Glycometabolic Control After SARS-CoV-2 Infection.

PURPOSE: To assess whether dysglycemia diagnosed during severe acute respiratory syndrome coronavirus 2 pneumonia may become a potential public health problem after resolution of the infection. In an adult cohort with suspected coronavirus disease 2019 (COVID-19) pneumonia, we integrated glucose data upon hospital admission with fasting blood glucose (FBG) in the year prior to COVID-19 and during postdischarge follow-up. METHODS: From February 25 to May 15, 2020, 660 adults with suspected COVID-19 pneumonia were admitted to the San Raffaele Hospital (Milan, Italy). Through structured interviews/ medical record reviews, we collected demographics, clinical features, and laboratory tests upon admission and additional data during hospitalization or after discharge and in the previous year. Upon admission, we classified participants according to American Diabetes Association criteria as having (1) preexisting diabetes, (2) newly diagnosed diabetes, (3) hyperglycemia not in the diabetes range, or (4) normoglycemia. FBG prior to admission and during follow-up were classified as normal or impaired fasting glucose and fasting glucose in the diabetes range. RESULTS: In patients with confirmed COVID (n = 589), the proportion with preexisting or newly diagnosed diabetes, hyperglycemia not in the diabetes range and normoglycemia was 19.6%, 6.7%, 43.7%, and 30.0%, respectively. Patients with dysglycemia associated to COVID-19 had increased markers of inflammation and organs' injury and poorer clinical outcome compared to those with normoglycemia. After the infection resolved, the prevalence of dysglycemia reverted to preadmission frequency. CONCLUSIONS: COVID-19-associated dysglycemia is unlikely to become a lasting public health problem. Alarmist claims on the diabetes risk after COVID-19 pneumonia should be interpreted with caution.

Porcelain versus Porcelain Stoneware: So Close, So Different. Sintering Kinetics, Phase Evolution, and Vitrification Paths.

Five porcelain and porcelain stoneware bodies were investigated to compare sintering mechanisms and kinetics, phase and microstructure evolution, and high temperature stability. All batches were designed with the same raw materials and processing conditions, and characterized by optical dilatometry, XRF, XRPD-Rietveld, FEG-SEM and technological properties. Porcelain and porcelain stoneware behave distinctly during sintering, with the convolution of completely different phase evolution and melt composition/structure. The firing behavior of porcelain is essentially controlled by microstructural features. Changes in mullitization create conditions for a relatively fast densification rate at lower temperature (depolymerized melt, lower solid load) then to contrast deformations at high temperature (enhanced effective viscosity by increasing solid load, mullite aspect ratio, and melt polymerization). In porcelain stoneware, the sintering behavior is basically governed by physical and chemical properties of the melt, which depend on the stability of quartz and mullite at high temperature. A buffering effect ensures adequate effective viscosity to counteract deformation, either by preserving a sufficient skeleton or by increasing melt viscosity if quartz is melted. When a large amount of soda-lime glass is used, no buffering effect occurs with melting of feldspars, as both solid load and melt viscosity decrease. In this batch, the persistence of a feldspathic skeleton plays a key role to control pyroplasticity.

Case Report: The Added Value of Liquid Biopsy in Advanced Colorectal Cancer From Clinical Case Experiences.

Liquid biopsy represents a valid strategy for tumor molecular characterization. It gives the opportunity to bypass tumor heterogeneity, to monitor tumor characteristics during the course of treatment, and to perform the analysis even when tumor tissue is not available or inadequate. In the clinical practice of metastatic colorectal cancer, tumor molecular characterization is crucial for patient management, as RAS and BRAF status could influence the treatment choice. Although for this type of cancer tumor tissue is usually available at diagnosis, liquid biopsy could give complementary information and could permit monitoring of the mutation status during the course of treatment. At present, there are no clinical indications for its use in clinical practice. However, we report four clinical cases for which liquid biopsy analysis gave integrative information with respect to tumor tissue characterization, which permits us to understand the unresponsiveness of patients to treatment, with potential implications in patient's management.

Pre-Existing Diabetes and COVID-Associated Hyperglycaemia in Patients with COVID-19 Pneumonia.

AIM: The aim of the current study was to compare clinical characteristics, laboratory findings, and major outcomes of patients hospitalized for COVID-19 pneumonia with COVID-associated hyperglycaemia or pre-existing diabetes. METHODS: A cohort of 176 adult patients with a diagnosis of pre-existing diabetes (n = 112) or COVID-associated hyperglycaemia (n = 55) was studied. RESULTS: Patients with COVID-associated hyperglycaemia had lower BMI, significantly less comorbidities, and higher levels of inflammatory markers and indicators of multi-organ injury than those with pre-existing diabetes. No differences between pre-existing diabetes and COVID-associated hyperglycaemia were evident for symptoms at admission, the humoral response against SARS-CoV-2, or autoantibodies to glutamic acid decarboxylase or interferon alpha-4. COVID-associated hyperglycaemia was independently associated with the risk of adverse clinical outcome, which was defined as ICU admission or death (HR 2.11, 95% CI 1.34-3.31; p = 0.001), even after adjustment for age, sex, and other selected variables associated with COVID-19 severity. Furthermore, at the same time, we documented a negative association (HR 0.661, 95% CI 0.43-1.02; p = 0.063) between COVID-associated hyperglycaemia to swab negativization. CONCLUSIONS: Recognizing hyperglycaemia as a specific clinical entity associated with COVID-19 pneumonia is relevant for early and appropriate patient management and close monitoring for the progression of disease severity.

Type 1 Diabetes Patients' Practice, Knowledge and Attitudes towards Influenza Immunization.

Diabetic patients are at higher risk of developing infectious diseases and severe complications, compared to the general population. Almost no data is available in the literature on influenza immunization in people with type 1 diabetes mellitus (T1DM). As part of a broader project on immunization in diabetic patients, we conducted a cross-sectional study to: (i) report on seasonal influenza coverage rates in T1DM patients, (ii) explore knowledge, attitudes, and practices (KAPs) towards seasonal influenza in this population, and (iii) identify factors associated with vaccine uptake, including the role of family doctors and diabetologists. A survey was administered to 251 T1DM patients attending the Diabetes Clinic at San Raffaele Research Hospital in Milan, Italy and individual-level coverage data were retrieved from immunization registries. Self-reported seasonal influenza immunization coverage was 36%, which decreased to 21.7% when considering regional immunization registries, far below coverage target of 75%. More than a third (36.2%) of T1DM patients were classified as pro-vaccine, 30.7% as hesitant, 17.9% as uninformed, and 15.1% as anti-vaccine. Diabetologists resulted to be the most trusted source of information on vaccines' benefits and risks (85.3%) and should be more actively involved in preventive interventions. Our study highlights the importance of developing tailored vaccination campaigns for people with diabetes, including hospital-based programs involving diabetes specialists.

Genetic and Epigenetic Alterations of CDH1 Regulatory Regions in Hereditary and Sporadic Gastric Cancer.

E-cadherin is a key player in gastric cancer (GC) and germline alterations of CDH1, its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of CDH1 promoter and enhancers in the regulation of gene expression. For this purpose, we analyzed genetic variants of the CDH1 gene through Next-Generation Sequencing (NGS) in a series of GC cell lines (NCI-N87, KATO-III, SNU-1, SNU-5, GK2, AKG, KKP) and the corresponding CDH1 expression levels. By bisulfite genomic sequencing, we analyzed the methylation status of CDH1 regulatory regions in 8 GC cell lines, in a series of 13 sporadic GC tissues and in a group of 20 HDGC CDH1-negative patients and 6 healthy controls. The NGS analysis on CDH1 coding and regulatory regions detected genetic alterations in 3 out of 5 GC cell lines lacking functional E-cadherin. CDH1 regulatory regions showed different methylation patterns in patients and controls, GC cell lines and GC tissues, expressing different E-cadherin levels. Our results showed that alterations in terms of genetic variants and DNA methylation patterns of both promoter and enhancers are associated with CDH1 expression levels and have a role in its regulation.

Dysglycemia after COVID-19 pneumonia: a six-month cohort study.

AIM: The aim of this study was to understand whether the dysglycemia associated with SARS-CoV-2 infection persists or reverts when the viral infection resolves. METHODS: We analyzed fasting blood glucose (FBG) after hospital discharge in a cohort of 621 adult cases with suspected COVID-19 pneumonia. RESULTS: At admission, 18.8% of the patients in our cohort had pre-existing diabetes, 9.3% fasting glucose in the diabetes range without a prior diagnosis (DFG), 26% impaired fasting glucose (IFG), 44.9% normal fasting glucose (NFG), while 2% had no FBG available. FBG categories were similarly distributed in the 71 patients without confirmed COVID-19 pneumonia. During follow-up (median time 6 month) FBG was available for 321 out of the 453 (70.9%) surviving patients and showed a trend to a marginal increase [from 97 (87-116) to 100 (92-114) mg/dL; p = 0.071]. Transitions between FBG categories were analyzed in subjects without pre-existing diabetes (265 out of 321). We identified three groups: (i) patients who maintained or improved FBG during follow-up [Group A, n = 185; from 100 (86-109) to 94 (88-99) mg/dL; p < 0.001]; (ii) patients who moved from the NFG to IFG category [Group B, n = 66: from 89 (85-96) to 106 (102-113) mg/dl; p < 0.001]; (iii) patients who maintained or reached DFG during follow-up [Group C, n = 14: from 114 (94-138) to 134 (126-143) mg/dl; p = 0.035]. Male sex and ICU admission during the hospitalization were more prevalent in Group C compared to Group A or B. CONCLUSIONS: Six months after the SARS-CoV-2 infection DFG was evident in only few patients who experienced severe COVID-19 pneumonia.

Mutational Analysis in Urinary Cell-Free DNA: KRAS in Colorectal Cancer.

Urinary cell-free DNA offers an important noninvasive source of material for genomic testing also for nonurological tumors. Its clinical utility in monitoring tumor evolution and treatment failure is promising. Here we describe a method to detect cancer mutations into urine from patients affected by colorectal cancer.

Rapamycin Plus Vildagliptin to Recover ß-Cell Function in Long-Standing Type 1 Diabetes: A Double-Blind, Randomized Trial.

AIM: The aim of this study was to investigate whether treatment with rapamycin plus vildagliptin restores ß-cell function in patients with long-standing type 1 diabetes. METHODS: A phase 2, single-center, randomized, double-blind, placebo-controlled study was conducted in long-standing type 1 diabetes patients randomly assigned (1:1:1) to 4 weeks of rapamycin (group 2), 4 weeks of rapamycin plus 12 weeks of vildagliptin (group 3), or double placebo (group 1). The primary outcome was the proportion of participants with a positive response to the Mixed-Meal Tolerance Test (C-peptide at 90 minutes > 0.2 nmol/L) at weeks 4 and 12. Secondary end points included insulin requirement, standard measures of glycemic control, and hormonal and immunological profile. RESULTS: Fifty-five patients were randomly assigned to group 1 (n = 18), group 2 (n = 19), or group 3 (n = 18). No patient in any group showed a positive C-peptide response, and there was no significant difference at 4 and 12 weeks for the primary outcome. At 4 weeks, insulin requirement decreased from 0.54 to 0.48 U/kg/day in group 2 (P = .013), from 0.59 to 0.51 U/kg/day in group 3 (P < .001), whereas it did not change in group 1. At 12 weeks, glycated hemoglobin significantly decreased both in group 2 (from 7.3% [56 mmol/mol] to 7% [53 mmol/mol]; P = .045] and in group 3 (from 7.2% [55.5 mmol/mol] to 6.9% [52 mmol/mol]; P = .001]. Rapamycin treatment was associated with a decrease in insulin antibody titer and changes in hormonal/immunological profile. CONCLUSIONS: Rapamycin reduced insulin requirement, but did not restore ß-cell function in patients with long-standing type 1 diabetes.