Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: Results of a large international retrospective cohort study.

BACKGROUND: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. METHODS: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05. RESULTS: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS. CONCLUSIONS: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

Clinical and MRI measures to identify non-acute MOG-antibody disease in adults.

MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0-7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0-8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0-8)] and 152 healthy controls (91 females) were studied. In young patients (<34 years), with low disability (EDSS < 3), the absence of Dawson's fingers, temporal lobe lesions and longitudinally extensive lesions in the cervical cord pointed towards a diagnosis of MOG-antibody disease instead of the other two diseases (accuracy: 76%, sensitivity: 81%, specificity: 84%, P < 0.001). In these non-acute patients, the number of brain lesions < 6 predicted MOG-antibody disease versus multiple sclerosis (accuracy: 83%, sensitivity: 82%, specificity: 83%, P < 0.001). An EDSS < 3 and the absence of longitudinally extensive lesions in the cervical cord predicted MOG-antibody disease versus AQP4-neuromyelitis optica spectrum disorder (accuracy: 76%, sensitivity: 89%, specificity: 62%, P < 0.001). A workflow with sequential tests and supporting features is proposed to guide better identification of patients with MOG-antibody disease. Adult patients with non-acute MOG-antibody disease showed distinctive clinical and MRI features when compared to AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis. A careful inspection of the morphology of brain and cord lesions together with clinical information can guide further analyses towards the diagnosis of MOG-antibody disease in clinical practice.

Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.

OBJECTIVE: This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS). METHODS: We retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results. RESULTS: Of 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses. INTERPRETATION: This study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.

Capillaroscopic analysis of the microvascular status in mixed versus undifferentiated connective tissue disease.

INTRODUCTION: Raynaud phenomenon (RP), typically, precede the clinical onset of systemic manifestations in several connective tissue diseases (CTDs). These autoimmune disorders usually share a microvascular damage whose alterations can be detected by nailfold videocapillaroscopy (NVC). The aim of the study was to compare the NVC microvascular status in Mixed Connective Tissue Disease (MCTD) versus the Undifferentiated Connective Tissue Disease (UCTD), and to search correlations between NVC findings and specific autoantibodies in UCTD patients. METHODS: Clinical data and NCV patterns were retrospectively obtained from the files of 46 MCTD patients, 47 stable UCTD patients and 51 individuals with primary RP (PRP) as controls collected in a central database (VideoCap®, DS Medica, Milan, Italy). ANA and ENA Abs were tested respectively by indirect immunofluorescence and enzyme-linked immunosorbent assay. RESULTS: "Scleroderma-like" (SSc-like) NVC pattern was significantly more frequent in MCTD than in UCTD patients (48% vs 11%, p < 0.001). Giant capillaries, abnormal shapes (i.e. neoangiogenesis) and lower capillary density were predominantly detected among MCTD versus UCTD patients (48% vs 11%, 49% vs 13%, 52% vs 9%, respectively, p < 0.001). The absolute number of capillaries was significantly lower in MCTD versus UCTD patients (mean 7 ± 1.7 SD vs mean 9.2 ± 1.3 SD, respectively, p < 0.001). Fully normal NVC pattern and non-specific NVC alterations were respectively observed in 6% and 46% of MCTD and in 6% and 83% of UCTD. Moreover, PRP patients showed normal NVC pattern and non-specific capillary abnormalities in 23% and in 77%, respectively. No statistically significant correlations were observed between NVC patterns and ANA patterns/specific ENA-Abs among the UCTD patients. CONCLUSIONS: The significant presence of the SSc-like NVC pattern and reduced number of capillaries seem the most typical NVC findings in MCTD in comparison to UCTD patients, suggesting a reflection of more complex and severe disease in MCTD ones.

Full longitudinal nailfold videocapillaroscopy analysis of microvascular changes during normal pregnancy.

BACKGROUND: Microvascular remodeling is one major responsible for vascular adaptation in pregnancy, still it is not routinely evaluated in the obstetric field. This pilot study aimed to explore the role of nailfold capillaroscopy (NCV) in detecting microvascular changes during normal pregnancy. METHODS: A population of 30 healthy pregnant women was longitudinally followed performing clinical assessment and NVC evaluation at each trimester and post-partum. Thirty non-pregnant age-matched healthy women having received at least two NVCs with a minimum 9 to 12-month interval were selected as controls. All NVC images were evaluated by a qualitative and semi-quantitative assessment using current standardised approach. Statistical analyses were conducted to assess NVC trend throughout gestation and its possible association with pregnancy course. RESULTS: A progressive significant increase of NVC neoangiogenesis and a specular reduction in capillary dilations was observed during pregnancy (p < 0.05). These variations were not found in age-matched controls, who showed stable NVC parameters over a similar time frame (p < 0.05). Additionally, a significant inverse correlation was found between NVC neoangiogenesis rate and maternal systemic BP (rho = -0.72, p < 0.005). CONCLUSION: This first comprehensive longitudinal NVC evaluation during normal pregnancy reports significant but physiological microvascular variations throughout gestation, suggesting NVC as a safe and promising technique for further investigate and define patterns of microvascular changes also in pathological pregnancies.

SARS-CoV-2 serology after COVID-19 in multiple sclerosis: An international cohort study.

BACKGROUND: The MuSC-19 project is an Italian cohort study open to international partners that collects data on multiple sclerosis (MS) patients with COVID-19. During the second wave of the pandemic, serological tests became routinely available. OBJECTIVE: To evaluate the seroprevalence of anti-SARS-CoV-2 antibodies according to the use of disease-modifying therapy (DMT) in a subset of patients included in the MuSC-19 data set who had undergone a serological test. METHODS: We evaluated the association between positive serological test results and time elapsed since infection onset, age, sex, Expanded Disability Status Scale score, comorbidities and DMT exposure using a multivariable logistic model. RESULTS: Data were collected from 423 patients (345 from Italy, 61 from Turkey and 17 from Brazil) with a serological test performed during follow-up. Overall, 325 out of 423 tested patients (76.8%) had a positive serological test. At multivariate analysis, therapy with anti-CD20 was significantly associated with a reduced probability of developing antibodies after COVID-19 (odds ratio (OR) = 0.20, p = 0.002). CONCLUSION: Patients with MS maintain the capacity to develop humoral immune response against SARS-COV-2, although to a lesser extent when treated with anti-CD20 drugs. Overall, our results are reassuring with respect to the possibility to achieve sufficient immunization with vaccination.

The effect of air pollution on COVID-19 severity in a sample of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Some studies have shown that air pollution, often assessed by thin particulate matter with diameter below 2.5 µg/m3 (PM2.5), may contribute to severe COVID-19 courses, as well as play a role in the onset and evolution of multiple sclerosis (MS). However, the impact of air pollution on COVID-19 has never been explored specifically amongst patients with MS (PwMS). This retrospective observational study aims to explore associations between PM2.5 and COVID-19 severity amongst PwMS. METHODS: Data were retrieved from an Italian web-based platform (MuSC-19) which includes PwMS with COVID-19. PM2.5 2016-2018 average concentrations were provided by the Copernicus Atmospheric Monitoring Service. Italian patients inserted in the platform from 15 January 2020 to 9 April 2021 with a COVID-19 positive test were included. Ordered logistic regression models were used to study associations between PM2.5 and COVID-19 severity. RESULTS: In all, 1087 patients, of whom 13% required hospitalization and 2% were admitted to an intensive care unit or died, were included. Based on the multivariate analysis, higher concentrations of PM2.5 increased the risk of worse COVID-19 course (odds ratio 1.90; p = 0.009). CONCLUSIONS: Even if several other factors explain the unfavourable course of COVID-19 in PwMS, the role of air pollutants must be considered and further investigated.

Signs and symptoms of COVID-19 in patients with multiple sclerosis.

BACKGROUND AND PURPOSE: Clinical outcomes of multiple sclerosis (MS) patients affected by coronavirus disease 2019 (COVID-19) have been thoroughly investigated, but a further analysis on main signs and symptoms and their risk factors still needs attention. The objective of this study was to group together and describe based on similarity the most common signs and symptoms of COVID-19 in MS patients and identify all factors associated with their manifestation. METHOD: Logistic and linear regression models were run to recognize factors associated with each pooled group of symptoms and their total number. RESULTS: From March 2020 to November 2021, data were collected from 1354 MS patients with confirmed infection of COVID-19. Ageusia and anosmia was less frequent in older people (odds ratio [OR] 0.98; p = 0.005) and more in smoker patients (OR 1.39; p = 0.049). Smoke was also associated with an incremental number of symptoms (OR 1.24; p = 0.031), substance abuse (drugs or alcohol), conjunctivitis and rash (OR 5.20; p = 0.042) and the presence of at least one comorbidity with shortness of breath, tachycardia or chest pain (OR 1.24; p = 0.008). Some disease-modifying therapies were associated with greater frequencies of certain COVID-19 symptoms (association between anti-CD20 therapies and increment in the number of concomitant symptoms: OR 1.29; p = 0.05). Differences in frequencies between the three waves were found for flu-like symptoms (G1, p = 0.024), joint or muscle pain (G2, p = 0.013) and ageusia and anosmia (G5, p < 0.001). All cases should be referred to variants up to Delta. CONCLUSION: Several factors along with the choice of specific therapeutic approaches might have a different impact on the occurrence of some COVID-19 symptoms.

Microvascular capillaroscopic abnormalities and occurrence of antinuclear autoantibodies in patients with sarcoidosis.

We described nailfold videocapillaroscopy (NVC) findings and estimated the prevalence of serum anti-nuclear (ANA) and extractable nuclear antigen autoantibodies (ENA) in a cohort of sarcoidosis patients, comparing them with adequate healthy controls (HCs) and with primary Raynaud's phenomenon patients (PRPs). NVC findings were also correlated with the occurrence of autoantibodies, current treatment, laboratory parameters, variables of lung function and whole-body imaging data. Twenty-six patients with sarcoidosis were assessed through NVC, laboratory parameters, pulmonary function tests, chest-X ray and 18- fluorodeoxyglucose positron emission tomography/computed tomography. The NVC parameters and ANA/ENA dosage were recorded also in 30 PRPs and 30 HCs. Sarcoidosis patients showed a higher rate of capillary dilations and nonspecific abnormalities and a lower mean capillary absolute number than PRPs and HCs (p < 0.01 for all comparisons). The prevalence of ANA positivity was higher in patients with sarcoidosis compared with PRPs and HCs (p < 0.02 for both), whereas ENA positivity was detected in one sarcoidosis patient (Ro52). Among sarcoidosis patients, the mean capillary absolute number negatively correlated with the C-reactive protein concentrations and was positively associated with the forced vital capacity percentage. Instead, a negative correlation was detected between serum ACE levels and the presence of capillary dilations (all p < 0.05). Our findings suggest a microvascular involvement in sarcoidosis whose investigation by NVC might be useful for the follow-up of patients displaying RP. Autoantibody positivity in sarcoidosis might suggest autoimmune implications in the disease or the production of autoantibodies reactive to tissue damage.

Correlation between peri-operative complication in middle ear cholesteatoma surgery using STAMCO, ChOLE, and SAMEO-ATO classifications.

PURPOSE: To compare the relationship between the variable "complication" and the other variables of middle ear cholesteatoma classifications (STAMCO, ChOLE, and SAMEO-ATO). METHODS: Retrospective study of 110 patients that underwent 132 middle ear surgeries between the 1 January 2012 and the 31 December 2019 for chronic otitis with cholesteatoma classified according to STAMCO, ChOLE, and SAMEO-ATO classifications in a tertiary health care centre. RESULTS: Older age, male gender, STAMCO-T, and SAMEO-ATO [O1, T, O2, (s -)] and mastoid involvement (STAMCO-M and ChOLE-Ch) were associated with an increased risk of complication report. CONCLUSIONS: In our series, statistical analysis pointed out a relationship between surgical complications and age, gender, site, mastoidectomy type, and ossicular chain status at surgery. The choice of variables to be recorded for cholesteatoma staging should be carefully balanced, considering that "complication" variable could be a repetitive item.

Frailty assessment, hip fracture and long-term clinical outcomes in older adults.

BACKGROUND: The primary aim of the study was determining the validation of the modified 19-item Frailty Index (mFI-19), based on the standard procedure for creating a frailty index scoring in the accumulation deficit theory of Rockwood and comparing it with the gold standard comprehensive geriatric assessment (CGA) in old age patients with hip fracture. As a secondary aim, we compared prognostic accuracies of mFI-19 and CGA in predicting long-term mortality after surgery. MATERIALS AND METHODS: A total of 364 older patients with hip fractures, each a candidate for surgery, were consecutively enrolled. All were subjected to CGA and mFI-19 at baseline and time to death (years from hip surgery) were collected prospectively. RESULTS: Mean patient age was 86.5 (SD: 5.65) years. The most common clinical phenotype (77%) was frail. Both CGA and mFI-19 performed similarly in predicting long-term mortality (Harrell's C-index: 0.66 and 0.68, respectively). CONCLUSIONS: The mFI-19 was validated, compared to the gold standard CGA, based on a systematic process for creating a frailty index in relation to the accumulation deficit. This is one of few prospective studies addressing long-term mortality in older adults with hip fractures, invoking a methodologically robust frailty screening assessment.

Is ultraviolet radiation avoidance affecting bone health in melanoma patients?

BACKGROUND: Ultraviolet (UV) radiation has numerous beneficial effects on human health, including stimulating vitamin D and serotonin production and immuno-regulatory activities. Conversely, UV radiation is also classified as a group one carcinogen by the International Agency for Research on Cancer. PURPOSE: To investigated the effects of UV radiation avoidance in melanoma patients in terms of vitamin D levels but also of bone mineral density and trabecular bone microarchitecture. METHODS: We conducted an observational study investigating the effects of UV radiation avoidance in 31 melanoma patients in terms of vitamin D levels but also of bone mineral density and trabecular bone microarchitecture by using dual-energy X-ray absorptiometry scan. Data were compared with two control groups of healthy subjects, who were chronically exposed or not exposed to UV radiation during their lifetime. RESULTS: Melanoma patients had on average slightly lower levels of vitamin D, without reaching statistical significance (P = .135). No significant difference was found across the three groups on T-scores of femoral neck (P = .544), of total hip (P = .617) and of lumbar spine P = .155). No significant difference was found on and trabecular bone score across exposure groups (P = .895). CONCLUSION: UV radiation avoidance does not seem to significantly impact vitamin D levels nor bone health in melanoma patients. Thus, UV protective behavior is advisable for all melanoma patients.

Diagnostic accuracy of biparametric versus multiparametric prostate MRI: assessment of contrast benefit in clinical practice.

PURPOSE: To assess the added value of dynamic contrast-enhanced (DCE) in prostate MR in clinical practice. METHODS: Two hundred sixty-four patients underwent prostate MRI, with T2 and DWI sequences initially interpreted, prior to full multiparametric magnetic resonance imaging (mpMRI) interpretation using a Likert 1-5 scale. A prospective opinion was given on likely benefit of contrast prior to review of the DCE sequence, and retrospectively following full mpMRI review. The final histology result following targeted and/or systematic biopsy of the prostate was used for outcome purposes. RESULTS: Biparametric magnetic resonance imaging (bpMRI) and mpMRI were assigned the same score in 86% of cases; when dichotomising to a negative or positive MRI (Likert score ≥ 3), concordance increased to 92.8%. At Likert score ≥ 3 bpMRI detected 89.9% of all cancers and 93.5% clinically significant prostate cancers (csPCa) and mpMRI 90.7% and 94.6%, respectively. mpMRI had fewer false positives than bpMRI (11.4% vs 18.9%) and a lower Likert 3 rate (8.3% vs 17%), conferring higher specificity (74% vs 67%), but similar sensitivity (95% versus 94%) and ROC-AUC (90% vs 89%). At a positive MRI threshold of Likert ≥ 4, mpMRI had a higher sensitivity than bpMRI (89% versus 80%) and detected more csPCa (89.2% versus 79.6%). DCE was prospectively considered of potential benefit in 27.3%, but readers would only recall 11% of patients for DCE sequences, mainly to assess score 3 peripheral zone lesions. Following full mpMRI review, DCE was considered helpful in 28.4% of cases; in 23/75 (30.6%) of these cases this only became apparent after reviewing the sequence, reasons included increased confidence, presence of "safety-net" lesions or inflammatory lesions. CONCLUSION: BpMRI has equivalent cancer detection rates to mpMRI; however, mpMRI had fewer Likert 3 call rates and increased specificity and was subjectively considered of benefit by readers in 28.4% of cases. KEY POINTS: • bpMRI has similar cancer detection rates to the full mpMRI protocol at a positive MRI threshold of Likert 3. • mpMRI had fewer intermediate category 3 calls (8.3%) than bpMRI (17%) and fewer false positives than bpMRI (11.4% vs 18.9%), conferring higher specificity (74% vs 67%). • Readers considered DCE beneficial in 28.4% of cases, but in a relatively high number (30.6%) this only became apparent after reviewing the sequence.

Biological therapy in genital psoriasis in women.

Genital psoriasis (GenPs) is a frequent manifestation of psoriasis, causing distress, especially in women. We prospectively studied a population of 74 psoriatic women with severe and generalized psoriasis eligible to biologic therapy, to examine which biologic therapy is more effective on GenPs and to study possible associations between PASI severity and GenPs. Overall, 25/74 (34%) had GenPs: 6 received Ixekizumab, 7 Ustekinumab, 8 Adalimumab, 2 Secukinumab, 1 Etanercept, 1 Certolizumab. Therapies were administered based on PASI severity, independently from the presence of GenPs. Side effects, PASI score, sPGA-G scale for GenPs were recorded at time 0 and after 6 month of therapy. The mean sPGA-G scale value was 2.8 before treatment. After biologic therapy, all patients except one, improved of at least one point. Mostly, patients treated with anti-IL17 (Secukinumab, Ixekizumab) and anti-IL12/23 (Ustekinumab) improved. Mean PASI ranged from 10 to 16.3 before treatment. After 6 months of therapy, 4 anti-TNFα patients, 6 anti-IL17 and 1 anti-IL12/23, reached PASI 90. At time 0, no correlation between PASI and sPGA-G was visible (Pearson r = 0.10, p = .620). From our data, GenPs apparently responds favorably to IL17A inhibitors, but further studies, based on larger numbers of patients, are needed.

Defining responders to therapies by a statistical modeling approach applied to randomized clinical trial data.

BACKGROUND: Personalized medicine is the tailoring of treatment to the individual characteristics of patients. Once a treatment has been tested in a clinical trial and its effect overall quantified, it would be of great value to be able to use the baseline patients' characteristics to identify patients with larger/lower benefits from treatment, for a more personalized approach to therapy. METHODS: We show here a previously published statistical method, aimed at identifying patients' profiles associated to larger treatment benefits applied to three identical randomized clinical trials in multiple sclerosis, testing laquinimod vs placebo (ALLEGRO, BRAVO, and CONCERTO). We identified on the ALLEGRO patients' specific linear combinations of baseline variables, predicting heterogeneous response to treatment on disability progression. We choose the best score on the BRAVO, based on its ability to identify responders to treatment in this dataset. We finally got an external validation on the CONCERTO, testing on this new dataset the performance of the score in defining responders and non-responders. RESULTS: The best response score defined on the ALLEGRO and the BRAVO was a linear combination of age, sex, previous relapses, brain volume, and MRI lesion activity. Splitting patients into responders and non-responders according to the score distribution, in the ALLEGRO, the hazard ratio (HR) for disability progression of laquinimod vs placebo was 0.38 for responders, HR = 1.31 for non-responders (interaction p = 0.0007). In the BRAVO, we had similar results: HR = 0.40 for responders and HR = 1.24 for non-responders (interaction p = 0.006). These findings were successfully replicated in the CONCERTO study, with HR = 0.44 for responders and HR=1.08 for non-responders (interaction p = 0.033). CONCLUSIONS: This study demonstrates the possibility to refine and personalize the treatment effect estimated in randomized studies by using the baseline demographic and clinical characteristics of the included patients. The method can be applied to any randomized trial in any medical condition to create a treatment-specific score associated to different levels of response to the treatment tested in the trial. This is an easy and affordable method toward therapy personalization, indicating patient profiles related to a larger benefit from a specific drug, which may have implications for taking clinical decisions in everyday clinical practice.

Expanded disability status scale progression assessment heterogeneity in multiple sclerosis according to geographical areas.

Using placebo data from 3 randomized multiple sclerosis (MS) trials with uniform inclusion criteria, we investigated heterogeneity of Expanded Disability Status Scale (EDSS) progression by geographical areas. Our analysis revealed a significantly lower EDSS progression in Eastern European countries (10.8%) compared with Western Europe (13.1%) or the USA/Canada (21.4%, p < 0.001); EDSS improvement behaved the same way. This heterogeneity is not explained by differences of baseline variables. No differences were detected on more easily quantifiable measures, the Timed 25-Foot Walk or the Multiple Sclerosis Functional Composite. At a time when disease progression represents the target for future interventions in MS, establishment of more quantitative and objective outcomes remains a key priority of MS research. Ann Neurol 2018;84:621-625.

Association of inflammatory markers with incident heart failure or cancer in the HUNT3 and Health ABC population studies.

AIMS: To investigate the relationship between chronic low-grade inflammation, as measured by high-sensitivity C-reactive protein (hsCRP) levels, and incident heart failure (HF) or cancer. METHODS: We assessed the relationship between baseline hsCRP concentrations and subsequent HF or cancer in two community-based cohorts, the Trøndelag Health Study (HUNT3) and the Health, Aging and Body Composition (ABC) study. In the latter, the analysis was replicated with interleukin (IL)-1, IL-6, or tumour necrosis factor (TNF)-α instead of hsCRP. RESULTS: In HUNT3, hsCRP was measured in 47,163 subjects (mean age 52.3 ± 15.8 years). During a median follow-up of 12.1 years, 2,034 (4.3%) individuals developed HF and 5,024 (10.7%) cancer, with 442 (0.9%) being diagnosed with both. After adjusting for age, male sex, diabetes, obesity, previous or current smoking, and comorbidities, elevated baseline hsCRP was associated with a higher risk of HF or cancer (HR 1.09; 95%CI, 1.07-1.10). In the Health ABC study, hsCRP levels were assessed in 2,803 participants, who had a mean age of 72.6 ± 2.9 years and a higher burden of comorbidities than in HUNT3. During a median follow-up of 8.2 years, HF and cancer were diagnosed in 346 (12.3%) and 776 (27.7%) subjects, respectively, with 77 (2.7%) having both conditions. After adjusting for the same variables used for the HUNT3 cohort, hsCRP remained significantly associated with incident HF or cancer (HR 1.11; 95%CI, 1.05-1.18), as were IL-1 (HR 1.15; 1.07-1.24), IL-6 (HR 1.09; 1.02-1.17), and TNF-α (HR 1.15; 1.07-1.24). CONCLUSIONS: A state of chronic, low-grade inflammation captured by an increase in hsCRP levels is associated with an increased risk of developing HF or cancer, with potential implications for clinical trials with anti-inflammatory therapies.

There is an increasing recognition that cardiovascular (CV) risk factors portend an increased risk of both heart failure (HF) and cancer. Chronic, low-grade inflammation might represent a shared pathogenic pathway underlying the association between these risk factors, HF, and malignancy. The biomarker high-sensitivity C-reactive protein (hsCRP) might add prognostic information on CV and cancer risk by capturing this inflammatory state. In this study we analysed the association of inflammation, as assessed by baseline measurement of hsCRP, and the risk of developing HF and cancer in two community-based prospective studies, the Trøndelag Health Study (HUNT3) and the Health, Aging and Body Composition (Health ABC) study.In these cohorts, comprising more than 50,000 individuals, inflammation at baseline was associated with an increased risk of incident HF or cancer during a median follow-up of 8-12 years, after adjusting for traditional risk factors and comorbidities.In the Health ABC study sample, three inflammatory markers other than hsCRP, namely interleukin (IL)-1, IL-6, or tumour necrosis factor α, performed similarly to hsCRP in predicting the risk of incident HF or cancer. These results provide insights into the interconnection between HF and cancer and reinforce the concept that low-grade, chronic inflammation promotes the development of both HF and cancer and, thereby, might be targeted for prevention of either condition. Furthermore, our findings confirm the reliability of hsCRP as a biomarker to select individuals who may benefit from anti-inflammatory treatments to reduce CV and cancer events.

MRI assessment of seminal vesicle involvement by prostate cancer using T2 signal intensity and volume.

BACKGROUND: Seminal vesicle involvement (SVI) in patients with newly diagnosed prostate cancer is associated with high rates of treatment failure and tumor recurrence; correct identification of SVI allows for effective management decisions and surgical planning. METHODS: This single-center retrospective study analyzed MR images of the seminal vesicles from patients undergoing radical prostatectomy with confirmed T3b disease, comparing them to a control group without SVI matched for age and Gleason grade with a final stage of T2 or T3a. Seminal vesicles were segmented by an experienced uroradiologist, "raw" and bladder-normalized T2 signal intensity, as well as SV volume, were obtained. RESULTS: Among the 82 patients with SVI, 34 (41.6%) had unilateral invasion, and 48 (58.4%) had bilateral disease. There was no statistically significant difference in the degree of distension between normal and involved seminal vesicles (P = 0.08). Similarly, no statistically significant difference was identified in the raw SV T2 signal intensity (P = 0.09) between the groups. In the 159 patients analyzed, SVI was prospectively suspected in 10 of 82 patients (specificity, 100%; sensitivity, 12.2%). In all these cases, lesions macroscopically invaded the seminal vesicle, and the raw T2 signal intensity was significantly lower than that in the SVI and control groups (P = 0.02 and 0.01). CONCLUSION: While signal intensity measurements in T2-weighted images may provide insight into T3b disease, our findings suggest that this data alone is insufficient to reliably predict SVI, indicating the need for further investigation and complementary diagnostic approaches.

Biometry extraction and probabilistic anatomical atlas of the anterior Visual Pathway using dedicated high-resolution 3-D MRI.

Anterior Visual Pathway (aVP) damage may be linked to diverse inflammatory, degenerative and/or vascular conditions. Currently however, a standardized methodological framework for extracting MRI biomarkers of the aVP is not available. We used high-resolution, 3-D MRI data to generate a probabilistic anatomical atlas of the normal aVP and its intraorbital (iOrb), intracanalicular (iCan), intracranial (iCran), optic chiasm (OC), and tract (OT) subdivisions. We acquired 0.6 mm3 steady-state free-precession images from 24 healthy participants using a 3 T scanner. aVP masks were obtained by manual segmentation of each aVP subdivision. Mask straightening and normalization with cross-sectional area (CSA) preservation were obtained using scripts developed in-house. A probabilistic atlas ("aVP-24") was generated by averaging left and right sides of all subjects. Leave-one-out cross-validation with respect to interindividual variability was performed employing the Dice Similarity Index (DSI). Spatially normalized representations of the aVP subdivisions were generated. Overlapping CSA values before and after normalization demonstrate preservation of the aVP cross-section. Volume, length, CSA, and ellipticity index (ε) biometrics were extracted. The aVP-24 morphology followed previous descriptions from the gross anatomy. Atlas spatial validation DSI scores of 0.85 in 50% and 0.77 in 95% of participants indicated good generalizability across the subjects. The proposed MRI standardization framework allows for previously unavailable, geometrically unbiased biometric data of the entire aVP and provides the base for future spatial-resolved, group-level investigations.