Long-term and real-world safety and efficacy of retroviral gene therapy for adenosine deaminase deficiency.

Adenosine deaminase (ADA) deficiency leads to severe combined immunodeficiency (SCID). Previous clinical trials showed that autologous CD34+ cell gene therapy (GT) following busulfan reduced-intensity conditioning is a promising therapeutic approach for ADA-SCID, but long-term data are warranted. Here we report an analysis on long-term safety and efficacy data of 43 patients with ADA-SCID who received retroviral ex vivo bone marrow-derived hematopoietic stem cell GT. Twenty-two individuals (median follow-up 15.4 years) were treated in the context of clinical development or named patient program. Nineteen patients were treated post-marketing authorization (median follow-up 3.2 years), and two additional patients received mobilized peripheral blood CD34+ cell GT. At data cutoff, all 43 patients were alive, with a median follow-up of 5.0 years (interquartile range 2.4-15.4) and 2 years intervention-free survival (no need for long-term enzyme replacement therapy or allogeneic hematopoietic stem cell transplantation) of 88% (95% confidence interval 78.7-98.4%). Most adverse events/reactions were related to disease background, busulfan conditioning or immune reconstitution; the safety profile of the real world experience was in line with premarketing cohort. One patient from the named patient program developed a T cell leukemia related to treatment 4.7 years after GT and is currently in remission. Long-term persistence of multilineage gene-corrected cells, metabolic detoxification, immune reconstitution and decreased infection rates were observed. Estimated mixed-effects models showed that higher dose of CD34+ cells infused and younger age at GT affected positively the plateau of CD3+ transduced cells, lymphocytes and CD4+ CD45RA+ naive T cells, whereas the cell dose positively influenced the final plateau of CD15+ transduced cells. These long-term data suggest that the risk-benefit of GT in ADA remains favorable and warrant for continuing long-term safety monitoring. Clinical trial registration: NCT00598481 , NCT03478670 .

In vivo macrophage engineering reshapes the tumor microenvironment leading to eradication of liver metastases.

Liver metastases are associated with poor response to current pharmacological treatments, including immunotherapy. We describe a lentiviral vector (LV) platform to selectively engineer liver macrophages, including Kupffer cells and tumor-associated macrophages (TAMs), to deliver type I interferon (IFNα) to liver metastases. Gene-based IFNα delivery delays the growth of colorectal and pancreatic ductal adenocarcinoma liver metastases in mice. Response to IFNα is associated with TAM immune activation, enhanced MHC-II-restricted antigen presentation and reduced exhaustion of CD8+ T cells. Conversely, increased IL-10 signaling, expansion of Eomes CD4+ T cells, a cell type displaying features of type I regulatory T (Tr1) cells, and CTLA-4 expression are associated with resistance to therapy. Targeting regulatory T cell functions by combinatorial CTLA-4 immune checkpoint blockade and IFNα LV delivery expands tumor-reactive T cells, attaining complete response in most mice. These findings support a promising therapeutic strategy with feasible translation to patients with unmet medical need.

Modifiable risk factors of COVID-19 in patients with multiple sclerosis: a single-centre case-control study.

BACKGROUND: Disease and treatment-associated immune system abnormalities may confer higher risk of Coronavirus disease 2019 (COVID-19) to people with multiple sclerosis (PwMS). We assessed modifiable risk factors associated with COVID-19 in PwMS. METHODS: Among patients referring to our MS Center, we retrospectively collected epidemiological, clinical and laboratory data of PwMS with confirmed COVID-19 between March 2020 and March 2021 (MS-COVID, n = 149). We pursued a 1:2 matching of a control group by collecting data of PwMS without history of previous COVID-19 (MS-NCOVID, n = 292). MS-COVID and MS-NCOVID were matched for age, expanded disability status scale (EDSS) and line of treatment. We compared neurological examination, premorbid vitamin D levels, anthropometric variables, life-style habits, working activity, and living environment between the two groups. Logistic regression and Bayesian network analyses were used to evaluate the association with COVID-19. RESULTS: MS-COVID and MS-NCOVID were similar in terms of age, sex, disease duration, EDSS, clinical phenotype and treatment. At multiple logistic regression, higher levels of vitamin D (OR 0.93, p < 0.0001) and active smoking status (OR 0.27, p < 0.0001) emerged as protective factors against COVID-19. In contrast, higher number of cohabitants (OR 1.26, p = 0.02) and works requiring direct external contact (OR 2.61, p = 0.0002) or in the healthcare sector (OR 3.73, p = 0.0019) resulted risk factors for COVID-19. Bayesian network analysis showed that patients working in the healthcare sector, and therefore exposed to increased risk of COVID-19, were usually non-smokers, possibly explaining the protective association between active smoking and COVID-19. CONCLUSIONS: Higher Vitamin D levels and teleworking may prevent unnecessary risk of infection in PwMS.

Targeted inducible delivery of immunoactivating cytokines reprograms glioblastoma microenvironment and inhibits growth in mouse models.

Glioblastoma multiforme (GBM) is the most common and lethal brain tumor characterized by a strongly immunosuppressive tumor microenvironment (TME) that represents a barrier also for the development of effective immunotherapies. The possibility to revert this hostile TME by immunoactivating cytokines is hampered by the severe toxicity associated with their systemic administration. Here, we exploited a lentiviral vector-based platform to engineer hematopoietic stem cells ex vivo with the aim of releasing, via their tumor-infiltrating monocyte/macrophage progeny, interferon-α (IFN-α) or interleukin-12 (IL-12) at the tumor site with spatial and temporal selectivity. Taking advantage of a syngeneic GBM mouse model, we showed that inducible release of IFN-α within the TME achieved robust tumor inhibition up to eradication and outperformed systemic treatment with the recombinant protein in terms of efficacy, tolerability, and specificity. Single-cell RNA sequencing of the tumor immune infiltrate revealed reprogramming of the immune microenvironment toward a proinflammatory and antitumoral state associated with loss of a macrophage subpopulation shown to be associated with poor prognosis in human GBM. The spatial and temporal control of IL-12 release was critical to overcome an otherwise lethal hematopoietic toxicity while allowing to fully exploit its antitumor activity. Overall, our findings demonstrate a potential therapeutic approach for GBM and set the bases for a recently launched first-in-human clinical trial in patients with GBM.

Socio-demographic and psychological factors associated with quality of life of women undergoing chemotherapy treatment for gynecological cancer.

PURPOSE: This research aimed to investigate the socio-demographic, clinical, and psychological variables predictive of a greater functioning and quality of life in patients with gynecological cancer after their first cycle of carboplatin and taxol-based chemotherapy. METHODS: The sample of the present research consisted of 104 patients. The European Organization on Research and Treatment of Cancer QLQ-C30, the State-Trait Anxiety Inventory-Form Y, and the Multidimensional Scale of Perceived Social Support were administered to each participant. RESULTS: The analyses showed that higher state anxiety levels predicted a lower role, emotional, and social functioning and a lower general quality of life. Higher trait anxiety levels and social support perceived from one's friends predicted a greater role functioning. Similarly, having a relationship predicted a greater physical, cognitive, and social functioning. On the contrary, the presence of relapsed cancer was negatively associated with these patients' quality of life. CONCLUSIONS: The present study highlighted the importance of identifying patients at higher risk of experiencing lower levels of functioning and worse general quality of life to implement tailored interventions from the beginning of treatment, thus improving the quality of life of these patients throughout the chemotherapy treatment.

Surgery for Intraductal Papillary Mucinous Neoplasms of the Pancreas: Preoperative Factors Tipping the Scale of Decision-Making.

BACKGROUND: Decision-making in intraductal papillary mucinous neoplasms (IPMNs) of the pancreas depends on scaling the risk of malignancy with the surgical burden of a pancreatectomy. This study aimed to develop a preoperative, disease-specific tool to predict surgical morbidity for IPMNs. METHODS: Based on preoperative variables of resected IPMNs at two high-volume institutions, classification tree analysis was applied to derive a predictive model identifying the risk factors for major morbidity (Clavien-Dindo ≥3) and postoperative pancreatic insufficiency. RESULTS: Among 524 patients, 289 (55.2%) underwent pancreaticoduodenectomy (PD), 144 (27.5%) underwent distal pancreatectomy (DP), and 91 (17.4%) underwent total pancreatectomy (TP) for main-duct (18.7%), branch-duct (12.6%), or mixed-type (68.7%) IPMN. For 98 (18.7%) of the patients, major morbidity developed. The classification tree distinguished different probabilities of major complications based on the type of surgery (area under the surve [AUC] 0.70; 95% confidence interval [CI], 0.63-0.77). Among the DP patients, the presence of preoperative diabetes identified two risk classes with respective probabilities of 5% and 25% for the development of major morbidity, whereas among the PD/TP patients, three different classes with respective probabilities of 15%, 20%, and 36% were identified according to age and body mass index (BMI). Overall, history of diabetes, age, and cyst size segregated three different risk classes for new-onset/worsening diabetes. CONCLUSIONS: In presumed IPMNs, the disease-specific risk of major morbidity and pancreatic insufficiency can be determined in the preoperative setting and used to personalize the possible surgical indication. Age and overweight status in case of PD/TP and diabetes in case of DP tip the scale toward less aggressive clinical management in the absence of features suggestive for malignancy.

Clinical and economic validation of grade B postoperative pancreatic fistula subclassification.

BACKGROUND: Grade B postoperative pancreatic fistula represents the largest fraction of postoperative pancreatic fistula. A subclassification of grade B postoperative pancreatic fistula has been recently proposed and seems to better stratify postoperative pancreatic fistula clinical and economic burden. Aim of this study was to validate, from a clinical and economic standpoint, grade B postoperative pancreatic fistula subclassification in patients submitted to pancreaticoduodenectomy. METHODS: All consecutive patients who underwent pancreaticoduodenectomy and developed biochemical leak or postoperative pancreatic fistula were included. Grade B postoperative pancreatic fistula was subclassified into 3 categories (B1: persistent drainage >21 days, B2: pharmacological treatments; B3: interventional procedures). Postoperative pancreatic fistula clinical and economic burden was assessed by evaluating postoperative complications, length of hospital stay, and overall hospital costs. RESULTS: Overall, 289 patients developed biochemical leak or postoperative pancreatic fistula. Of these, 34 had biochemical leak (12%), 25 had grade B1 postoperative pancreatic fistula (9%), 91 had grade B2 postoperative pancreatic fistula (31%), 94 had grade B3 postoperative pancreatic fistula (32%), and 45 experienced grade C postoperative pancreatic fistula (16%). The severity of postoperative complications significantly increased across biochemical leak and postoperative pancreatic fistula categories (P < .001), but it was comparable between biochemical leak and grade B1 postoperative pancreatic fistula. There was no significant difference in terms of length of hospital stay between patients with biochemical leak and those with grade B1 postoperative pancreatic fistula (P = 1.000). Overall hospital costs were similar for patients with biochemical leak and those with grade B1 postoperative pancreatic fistula (P = 1.000), whereas they significantly increased across all the other postoperative pancreatic fistula subgroups. CONCLUSION: A subclassification of grade B postoperative pancreatic fistula can better stratify the increasing clinical burden and economic impact of postoperative pancreatic fistula after pancreaticoduodenectomy. Grade B1 postoperative pancreatic fistula has minimal clinical and economic consequences and can be considered closer to a biochemical leak than to a grade B2 postoperative pancreatic fistula.

CXCL10 levels at hospital admission predict COVID-19 outcome: hierarchical assessment of 53 putative inflammatory biomarkers in an observational study.

BACKGROUND: Host inflammation contributes to determine whether SARS-CoV-2 infection causes mild or life-threatening disease. Tools are needed for early risk assessment. METHODS: We studied in 111 COVID-19 patients prospectively followed at a single reference Hospital fifty-three potential biomarkers including alarmins, cytokines, adipocytokines and growth factors, humoral innate immune and neuroendocrine molecules and regulators of iron metabolism. Biomarkers at hospital admission together with age, degree of hypoxia, neutrophil to lymphocyte ratio (NLR), lactate dehydrogenase (LDH), C-reactive protein (CRP) and creatinine were analysed within a data-driven approach to classify patients with respect to survival and ICU outcomes. Classification and regression tree (CART) models were used to identify prognostic biomarkers. RESULTS: Among the fifty-three potential biomarkers, the classification tree analysis selected CXCL10 at hospital admission, in combination with NLR and time from onset, as the best predictor of ICU transfer (AUC [95% CI] = 0.8374 [0.6233-0.8435]), while it was selected alone to predict death (AUC [95% CI] = 0.7334 [0.7547-0.9201]). CXCL10 concentration abated in COVID-19 survivors after healing and discharge from the hospital. CONCLUSIONS: CXCL10 results from a data-driven analysis, that accounts for presence of confounding factors, as the most robust predictive biomarker of patient outcome in COVID-19.

Altered Frequency and Phenotype of HLA-G-Expressing DC-10 in Type 1 Diabetes Patients at Onset and in Subjects at Risk to Develop the Disease.

Type 1 diabetes (T1D) is a chronic autoimmune disease resulting in progressive destruction of ß-cells. Several factors affecting lymphocyte and antigen-presenting cells, including dendritic cells (DCs), contribute to defective maintenance of tolerance in T1D. DC-10 are a subset of human DCs involved in IL-10-mediated tolerance. A precise monitoring of DC-10 in the peripheral blood is possible thanks to the discovery of specific biomarkers. DC-10, being cells that naturally express HLA-G, may be used for the appropriate staging of the disease. By enumerating and phenotypically characterizing DC-10 in the peripheral blood of subjects at different stages of T1D development-first-degree relatives (FDRs) of T1D patients, without (Abneg) or with (Abpos) autoantibodies, T1D patients at onset, and age-matched healthy controls (HCs)-we showed that DC-10 contain a high proportion of HLA-G-expressing cells as compared with monocytes. We reported that a low frequency of DC-10 during disease development is paralleled with the increased proportion of pro-inflammatory cDC2 cells. Moreover, DC-10 number and phenotype differ from Abneg FDRs, Abpos FDRs, and T1D patients compared with HCs, and DC-10 from T1D patients express low levels of CD83. Finally, multiple regression analysis, considering DC-10 and HLA-G-related parameters, showed that Abneg FDRs are more similar to subjects with autoimmunity than to HCs. This is the first demonstration that impairment in DC-10 number and phenotype, specifically CD83 expression, is associated with risk of developing T1D, suggesting a possible use of CD83+ DC-10 to stratify individuals at risk of T1D in conjunction with classical prognostic factors.

The role of acinar content at pancreatic resection margin in the development of postoperative pancreatic fistula and acute pancreatitis after pancreaticoduodenectomy.

BACKGROUND: A fatty infiltration of the pancreas has been traditionally regarded as the main histological risk factor for postoperative pancreatic fistula, whereas the role of the secreting acinar compartment has been poorly investigated. The aim of this study was to evaluate the role of acinar content at the pancreatic resection margin in the development of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis after pancreaticoduodenectomy. METHODS: Data from 388 consecutive patients who underwent pancreaticoduodenectomy (2018-2019) were analyzed. Pancreatic section margins were histologically assessed for acinar, fibrosis, and fat content. Acinar content was categorized using median and third quartile as cut-offs. Univariate and multivariable analysis of possible predictors of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis were performed. RESULTS: Acinar content was <60% in 166 patients (42.8%), ≥60% and ≤80% in 156 patients (40.2%), and >80% in 66 patients (17.0%). The rate of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis was significantly higher in patients with acinar content >80% (39.4% and 33.3%, respectively) as well as in those with acinar content ≥60% and ≤80% (36.5% and 35.3%, respectively), compared with patients with acinar content <60% (10.2% and 5.4%, respectively) (P < .001). Acinar content was identified as an independent predictor of clinically relevant postoperative pancreatic fistula (≥60% and ≤80%, odds ratio 2.51, P = .008; >80%, odds ratio 2.93, P = .010) and clinically relevant postoperative acute pancreatitis (≥60% and ≤80%, odds ratio 9.42, P < .001; >80%, odds ratio 10.16, P < .001). CONCLUSION: An acinar content at the pancreatic resection margin ≥60% is associated to an increased risk of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis. Fat content was associated neither with clinically relevant postoperative pancreatic fistula nor with clinically relevant postoperative acute pancreatitis.

Metachromatic leukodystrophy: A single-center longitudinal study of 45 patients.

In this study, we characterize the natural course of metachromatic leukodystrophy (MLD), explore intra/inter group differences, and identify biomarkers to monitor disease progression. This is a longitudinal observational study. Genotype and characteristics at disease onset were recorded. Time-to-event analyses were performed to assess time to major disease-related milestones in different subgroups. Longitudinal trajectories of nerve conduction velocities (NCV), brain MRI score, and brainstem auditory evoked responses (BAERs) were described. We recruited 22 late-infantile, 14 early-juvenile, 5 late-juvenile, and 4 adult MLD patients. Thirty-four were prospectively evaluated (median FU time 43 months). In late-infantile patients, the attainment of independent walking was associated with a later age at dysphagia. In early-juvenile, the presence of isolated cognitive impairment at onset was not a favorable prognostic factor. Late-infantile and early-juvenile subjects showed similar rapid loss of ambulation and onset of seizures, but late-infantile displayed earlier loss of trunk control, dysphagia, and death. We found significant differences in all major disease-related milestones (except death) between early-juvenile and late-juvenile patients. Late-juvenile and adult patients both presented with a predominant cognitive impairment, mild/no peripheral neuropathy, lower brain MRI score at plateau compared to LI/EJ, and later cerebellar involvement. NCV and BAER were consistently severely abnormal in late-infantile but not in older subjects, in whom both NCV and BAER were variably affected, with no deterioration over time in some cases. This study clarifies intra/inter group differences between MLD subtypes and provides additional indications regarding reliable clinical and instrumental tools to monitor disease progression and to serve as areference to evaluate the efficacy of future therapeutic interventions inthe different MLD variants.

Factors Associated With a High Motivation to Undergo Fertility Preservation in Female Cancer Patients.

Objective: Fertility loss due to cancer treatment can be a devastating experience for women and the couple. Undergoing fertility preservation can be a complex decision from both a medical and emotional point of view. The aim of the present study was to evaluate which socio-demographic and psychological factors predict a high motivation to undergo fertility preservation. Methods: Fifty-eight female cancer patients who accessed an Oncofertility Unit completed: a questionnaire to collect socio-demographic characteristics and the level of motivation, the Beck-Depression Inventory-II, the State-Trait Anxiety Inventory-Y, and the Fertility Problem Inventory. Results: Almost half of the sample (44.8%) declared a high motivation. At multiple logistic regression analysis only the "Need for parenthood" subscale of the FPI predicted a high motivation. We alternatively evaluated as possible predictor the construct "Representations about the importance of parenthood" (i.e., the sum of the "Need for Parenthood" and "Rejection of childfree lifestyle" subscales) in place of the two separate subscales. At multiple logistic regression analysis, only this variable predicted a high motivation to undergo fertility preservation. Conclusion: The most important predictor of a high motivation to undergo fertility preservation is the individual desire for parenthood. This implies that, regardless of socio-demographic characteristics, any woman of childbearing age should receive an appropriate counseling about fertility preservation.

Impact of molecular subtype on 1325 early-stage breast cancer patients homogeneously treated with hypofractionated radiotherapy without boost: Should the indications for radiotherapy be more personalized?

AIM: We report molecular subtype impact on 1325 early breast cancer (BCa) patients treated with whole breast hypofractionated (WBH) adjuvant forward-planned intensity modulated radiotherapy (F-IMRT) without boost. METHODS AND MATERIALS: From 02/2009-05/2017 1325 patients with pTis-pT3, pNx-N1aM0 BCa who underwent breast conservation surgery were treated with WBHF-IMRT in our institute, to a total dose of 40 Gy/15 fractions, without boost. Median age: 62 (interquartile range-IQR-:51.14-70.53) years. HISTOLOGY: 8% in situ carcinoma (ISC), 92% invasive tumors. Molecular subtypes (invasive tumors): 49.9% Luminal A, 33.1% Luminal B Her2 negative (-), 6.2% Luminal B Her2 positive (+), 3.6% Hormone Receptor (HR)- Her2+, 7.1% Triple negative (TNBC), and 0.2% HR+. Chemotherapy (CT) was prescribed in 28% of patients, hormonal therapy in 80.3%, monoclonal antibodies (MAb) in 86.8% of Luminal B Her2+ and 97.7% of HR- Her2+ patients. RESULTS: Median follow up was 72.43 (IQR: 44.63-104.13) months. The 5-year Kaplan-Meier estimates of local relapse-free survival (LRFS) was 97.8%, regional-(RRFS) 98.6%, loco-regional- (LRRFS) 96.9%, distant- (DRFS) 96.6%, disease-free survival (DFS) 94.8% and overall survival (OS) 95.5%. Considering molecular subtypes, 5-year LRFS was: 99.8% for Luminal A, 96.7% for Luminal B Her2-, 94.1% for Luminal B Her2+, 87.9% for HR- Her2+, 95.1% for TNBC and 99.1% for in situ carcinoma. CONCLUSION: While the overall estimated probability of LR within 5 years after WBHF-IMRT without boost is good (2.2%), molecular subtypes have a strong impact, despite MAb therapy in Her2+ patients, and CT for TNBC patients, and could be used as a parameter in deciding the boost prescription.

Along-tract statistics of neurite orientation dispersion and density imaging diffusion metrics to enhance MR tractography quantitative analysis in healthy controls and in patients with brain tumors.

Along-tract statistics analysis enables the extraction of quantitative diffusion metrics along specific white matter fiber tracts. Besides quantitative metrics derived from classical diffusion tensor imaging (DTI), such as fractional anisotropy and diffusivities, new parameters reflecting the relative contribution of different diffusion compartments in the tissue can be estimated through advanced diffusion MRI methods as neurite orientation dispersion and density imaging (NODDI), leading to a more specific microstructural characterization. In this study, we extracted both DTI- and NODDI-derived quantitative microstructural diffusion metrics along the most eloquent fiber tracts in 15 healthy subjects and in 22 patients with brain tumors. We obtained a robust intraprotocol reference database of normative along-tract microstructural metrics, and their corresponding plots, from healthy fiber tracts. Each diffusion metric of individual patient's fiber tract was then plotted and statistically compared to the normative profile of the corresponding metric from the healthy fiber tracts. NODDI-derived metrics appeared to account for the pathological microstructural changes of the peritumoral tissue more accurately than DTI-derived ones. This approach may be useful for future studies that may compare healthy subjects to patients diagnosed with other pathological conditions.

Dual tracer 68Ga-DOTATOC and 18F-FDG PET/computed tomography radiomics in pancreatic neuroendocrine neoplasms: an endearing tool for preoperative risk assessment.

AIM: To explore the potentiality of radiomics analysis, performed on Ga-DOTATOC and fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) images, in predicting tumour aggressiveness and outcome in patients candidate to surgery for pancreatic neuroendocrine neoplasms (PanNENs). PATIENTS AND METHODS: Retrospective study including 61 patients who underwent Ga-DOTATOC and F-FDG PET/CT before surgery for PanNEN. Semiquantitative variables [SUVmax and somatostatin receptor density (SRD) for Ga-DOTATOC PET; SUVmax and MTV for F-FDG PET] and texture features [intensity variability, size zone variability (SZV), zone percentage, entropy; homogeneity, dissimilarity and coefficient of variation (Co-V)] have been analysed to evaluate their possible role in predicting tumour characteristics. Principal component analysis (PCA) was firstly performed and then multiple regression analyses were performed by using the extracted principal components. RESULTS: Regarding Ga-DOTATOC PET, SZV, entropy, intensity variability and SRD were predictive for tumour dimension. Regarding F-FDG PET, intensity variability, SZV, homogeneity, SUVmax and MTV were predictive for tumour dimension. Four principal components were extracted from PCA: PC1 correlated with all F-FDG variables, while PC2, PC3 and PC4 with Ga-DOTATOC variables. PC1 was the only significantly predicting angioinvasion (P = 0.0222); PC4 was the only one significantly predicting lymph nodal involvement (P = 0.0151). All principal components except PC4 significantly predicted tumour dimension (P <0.0001 for PC1, P = 0.0016 for PC2 and P < 0.0001 for PC3). Co-V from Ga-DOTATOC PET/CT was predictive of the outcome. CONCLUSION: Specific texture features derived from preoperative Ga-DOTATOC and F-FDG PET/CT could noninvasively predict specific tumour characteristics and patients' outcome, delineating the potential role of dual tracer technique and texture analysis in the risk assessment of patients with PanNENs.

Structural MRI outcomes and predictors of disease progression in amyotrophic lateral sclerosis.

BACKGROUND AND AIMS: Considering the great heterogeneity of amyotrophic lateral sclerosis (ALS), the identification of accurate prognostic predictors is fundamental for both the clinical practice and the design of treatment trials. This study aimed to explore the progression of clinical and structural brain changes in patients with ALS, and to assess magnetic resonance imaging (MRI) measures of brain damage as predictors of subsequent functional decline. METHODS: 50 ALS patients underwent clinical evaluations and 3 T MRI scans at regular intervals for a maximum of 2 years (total MRI scans = 164). MRI measures of cortical thickness, as well as diffusion tensor (DT) metrics of microstructural damage along white matter (WM) tracts were obtained. Voxel-wise regression models and longitudinal mixed-effects models were used to test the relationship between clinical decline and baseline and longitudinal MRI features. RESULTS: The rate of decline of the ALS Functional Rating Scale revised (ALSFRS-r) was significantly associated with the rate of fractional anisotropy (FA) decrease in the body of the corpus callosum (CC). Corticospinal tract (CST) and CC-body alterations had a faster progression in patients with higher baseline ALSFRS-r scores and greater CC-body disruption at baseline. Lower FA of the cerebral peduncle was associated with faster subsequent clinical progression. CONCLUSIONS: In this longitudinal study, we identified a significant association between measures of WM damage of the motor tracts and functional decline in ALS patients. Our data suggest that a multiparametric approach including DT MRI measures of brain damage would provide an optimal method for an accurate stratification of ALS patients into prognostic classes.

Preoperative predictive factors of laparoscopic distal pancreatectomy difficulty.

BACKGROUND: Laparoscopic distal pancreatectomy (LDP) is a challenging operation due to technical complexity and tumor-related factors. Aim of this study was to identify preoperative risk factors affecting LDP difficulty. METHODS: Consecutive patients who underwent LDP between 2015 and 2018 at San Raffaele Hospital and Policlinico S.Orsola-Malpighi Hospital were enrolled retrospectively. Three variables were used to define surgical difficulty: conversion to open, duration of surgery >3rd quartile and intraoperative blood loss >3rd quartile. The presence of ≥1 of these 3 variables was considered as another measure of difficulty. RESULTS: Overall, 191 patients were included. Conversion to open was required in 25 patients (13%). At multiple regression analysis, tumor proximity to major vessels was the only independent predictor of conversion from laparoscopic to open (p < 0.001). No variables independently predicted an excessive duration of surgery. Male gender (p = 0.033) and increasing parenchymal thickness at resection line (p = 0.018) were independent predictors of excessive blood loss. Increasing parenchymal thickness at resection line (p = 0.014) and tumor proximity to major vessels (p = 0.002) were significant risk factors for the presence of ≥1 outcome of surgical difficulty. CONCLUSION: Male gender, increasing parenchymal thickness at resection line and tumor proximity to major vessels represent preoperative risk factors of LDP difficulty.

Early T1 Myocardial MRI Mapping: Value in Detecting Myocardial Hyperemia in Acute Myocarditis.

Background Hyperemia is a key component of acute myocarditis (AM). Early gadolinium uptake because of myocardial hyperemia may be quantified by using T1 mapping. Purpose To evaluate the value of early enhanced T1 shortening for the diagnosis of acute myocarditis. Materials and Methods Study participants suspected of having AM and healthy control (HC) participants were prospectively enrolled from September 2016 to May 2019. Participants underwent 1.5-T cardiac MRI including Lake Louise criteria, T2 mapping, native T1, and extracellular volume, with the addition of early enhanced T1 mapping (2 minutes after intravenous administration of 0.15 mmol/kg gadobutrol). Color-coded maps of the percentage of T1 shortening from precontrast to early postcontrast were generated. Optimal early T1 shortening cut-off value and its diagnostic performance in the identification of acute myocarditis were calculated. Results Forty-five study participants with AM (median age, 40 years; interquartile range [IQR], 20-46 years; 22 women) diagnosed according to multidisciplinary clinical evaluation, electrocardiography, laboratory test, echocardiography, cardiac MRI, and coronary CT and/or invasive angiography. Findings were confirmed by endomyocardial biopsy in 64% (29 of 45) of participants. MRI parameters were compared with 19 HC participants (median age, 39 years; IQR, 28-46 years; seven women). Median early T1 shortening was 75% (IQR, 72%-78%) in participants with AM versus 65% (IQR, 61%-66%) in HC participants (P < .001). Early T1 shortening showed high diagnostic performance (area under the receiver operating characteristic curve [AUC], 0.97; 95% confidence interval [CI]: 0.94, 1.00) and excellent interobserver reproducibility (intraclass correlation coefficient: 0.98; 95% CI: 0.96, 1.00). Early T1 shortening of 70% or greater identified acute myocarditis with 93% sensitivity, 100% specificity, and 95% diagnostic accuracy. Early T1 shortening had better diagnostic performance than late percentage T1 shortening (AUC, 0.97 vs 0.90, respectively; P = .03) and extracellular volume (AUC, 0.97 vs 0.88, respectively; P = .046), and similar to native T1 (AUC, 0.97 vs 0.93, respectively; P = .63) and T2 mapping (AUC, 0.97 vs 0.97, respectively; P > .99). Conclusion In this proof-of-concept study, percentage of T1 shortening at early enhanced T1 mapping showed high accuracy for the diagnosis of acute myocarditis. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by De Cecco and Monti in this issue.

Chemotherapy-induced nausea in a sample of gynaecological cancer patients: assessment issues and personal risk factors evaluation.

PURPOSE: Chemotherapy-induced nausea (CIN) is a relevant problem for gynaecological cancer patients. The evaluation of CIN is a key aspect in its management, along with the identification of associated risk factors. The objective of the study was to compare different measurements of nausea and to investigate personal risk factors in CIN development. METHOD: Eighty-one women treated for gynaecological cancers took part. The presence of CIN was evaluated using the MASCC Antiemesis Tool (MAT) and a patient's report to clinicians at the subsequent chemotherapy cycle. Personal risk factors were assessed using the State-Trait Anxiety Inventory and a self-report questionnaire. RESULTS: The study shows that the agreement between patients' assessment of CIN with MAT and what they referred to clinicians was only moderate for acute nausea (Cohen's Kappa = 0.55; p < 0.001), while good for delayed nausea (Cohen's Kappa = 0.68; p < 0.001). At multiple logistic regression analysis, younger age, anticipatory nausea, patient medium-high expectations of CIN, and parity emerged as risk factors for the development of acute nausea (p = 0.0087, 0.0080, 0.0122 and 0.0021, respectively). Patient medium-high expectations of CIN and being single resulted to be risk factors for delayed nausea (p = 0.0397 and 0.0024, respectively). CONCLUSIONS: Our findings confirm that personal factors contribute to individual differences in the development of CIN; moreover, we highlight the importance of CIN evaluation by clinicians, underlining the need to use reliable instruments.