Injectable Versus Oral First-Line Disease-Modifying Therapies: Results from the Italian MS Register

The current study aims to compare injectable and oral first-line disease-modifying therapies (DMTs) for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation using a cohort of relapsing remitting multiple sclerosis (RRMS) patients, with data extracted from the Italian MS Register. This multicenter, observational, retrospectively acquired, and propensity-adjusted cohort study utilized RRMS-naïve patients from the Italian MS Register who started either injectable or oral first-line DMTs between January 1, 2010, and December 31, 2017, to evaluate the impact on disability outcomes in patients. Enrolled patients were divided into two groups, namely the injectable group (IG) and the oral group (OG). Of a cohort of 11,416 patients, 4602 were enrolled (3919 in the IG and 683 in the OG). The IG had a higher rate of women (67.3% vs 63.4%, p < 0.05) and a lower mean age (36.1 ± 10.9 vs 38.9 ± 11.8, p < 0.001). The event time to first relapse demonstrated a lower risk in the OG (HR = 0.58; CI 95% 0.48–0.72, p < 0.001). However, no differences were found between the two groups with respect to the risk of CDP (HR = 0.94; CI 95% 0.76–1.29, p = 0.941), while a lower risk of DMT was found in the OG (HR = 0.72; CI 95% 0.58–0.88, p = 0.002) for the event time to discontinuation. Real-world data from the Italian MS Register suggests that first-line oral DMTs are associated with a lower risk of experiencing a new relapse and of therapy discontinuation compared to injectable DMTs.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-01001-6.Key Words: Multiple sclerosis, injectable DMTs, oral DMTs, real-world setting, EDSS score     

Preoperative sonographic evaluation of endometrial cancer

Preoperative sonography was performed in 93 patients with a histologic diagnosis of endometrial cancer. Uterine volume was enlarged (mean, 164 +/- 143.7 cm3; range, 25 to 800) but did not significantly correlate with the degree of myometrial invasion. Endometrial echoes were identified in 93.5% of the cases. A significant correlation (p less than 0.01, Newman-Keuls test) was found between endometrial echoes volume and myometrial invasion. Myometrial invasion was correctly predicted by sonography in 80% of the cases. Polypoid intraluminal growth was the most common factor affecting sonographic accuracy. Sonographic staging was accurate in 91% of the cases. Sonography appears to be an efficient, economic, and practical tool for clinical staging of endometrial cancer.     

Transvaginal sonographic findings in ambulatory patients with suspected pelvic inflammatory disease.

OBJECTIVE: To evaluate transvaginal sonographic findings in ambulatory patients with suspected pelvic inflammatory disease (PID). METHODS: We studied 51 outpatients with a mean age of 26.8 years (range 16-52) who had a history of low abdominal pain, negative pregnancy test, and no gynecologic procedures performed during the last month. Endometrial biopsy was used for the histopathologic diagnosis. The presence of plasma cell endometritis was used as the criterion standard for the diagnosis of PID. Sonography was performed before biopsy in a blinded fashion without knowledge of the clinical findings and laboratory results except for the pregnancy test. Repeat pelvic and ultrasound examinations were performed 4 weeks after antimicrobial therapy. RESULTS: Endometrial biopsy revealed plasma cell endometritis in 13 cases (25%). Thickened fluid-filled tubes were seen in 11 of 13 patients (85%) with plasma cell endometritis and in none of those without. Other sonographic findings associated with plasma cell endometritis were polycystic-like ovaries and free pelvic fluid. A sonogram suggestive of PID, ie, thickened fluid-filled tube with or without free pelvic fluid, had a sensitivity of 85% and a specificity of 100% for the diagnosis of plasma cell endometritis. None of the patients with a normal sonogram or simple cyst had plasma cell endometritis. Repeat examination after 4 weeks showed that the sonographic findings had resolved in 60% of the patients who had had histologic evidence of infection. CONCLUSION: Transvaginal sonography can facilitate the outpatient management of patients with suspected PID.     

Normal early pregnancy: serum hCG levels and vaginal ultrasonography findings

Vaginal sonography and determination of serum hCG levels were carried out in 22 healthy pregnant women every 2 to 4 days after the first positive pregnancy test until a living fetus was observed. Gestational age was calculated from the day of ovulation, assessed by LH surge or hCG administration, plus 14 days. A gestational sac of 1-3 mm was detected at a mean (SEM) of 31.2 (0.2) days of gestation (range 30-33 days). The corresponding mean hCG level was 730 iu/l (30) and the range 467-935 iu/l (International Reference Preparation). The yolk sac was detected at a mean of 36.0 (0.2) days, range 34-38 days, at a mean hCG level of 4130 iu/l (370), range 1120-7280 iu/l. Fetal heart motion was visible at a mean of 41.1 (0.3) days, range 39-43 days and the corresponding mean hCG level was 12,050 iu/l (1240), range 5280-22,950, iu/l. The yolk sac and the fetal heart motion were always seen when the sac exceeded 10 and 18 mm in mean diameter, respectively.     

Efficacy and tolerability profile of etoricoxib in patients with osteoarthritis: A randomized,double-blind,placebo and active-comparator controlled 12-week efficacy trial

OBJECTIVE: To evaluate the efficacy of 12 weeks of treatment with etoricoxib, a selective COX-2 inhibitor, in patients with osteoarthritis (OA) of the knee or hip. METHODS: In the 12-week placebo- and active comparator-controlled period of a randomized, double-blind study, eligible patients were treated with etoricoxib 60 mg once daily (n = 224), naproxen 500 mg twice daily (n = 221), or placebo (n = 56). Western Ontario McMaster's Osteoarthritis Index (WOMAC) pain and physical function subscales and patient's global assessment of disease status were primary end points. Key secondary and other end points were patient's and investigator's global assessment of response to therapy, WOMAC stiffness subscale, investigator's global assessment of disease status, rescue paracetamol use, proportion of patients discontinuing due to lack of efficacy, and study joint tenderness. RESULTS: Etoricoxib 60 mg demonstrated efficacy significantly superior to placebo (p < or = 0.005) and comparable to naproxen 500 mg twice daily as assessed by the primary efficacy end points. Secondary and other end points confirmed these results. Treatment effects were evident by day 2, maximal by week 2, and sustained over the entire 12 weeks. Etoricoxib was well tolerated for 12 weeks. CONCLUSIONS: Etoricoxib showed rapid and durable treatment effects in patients with OA of the knee or hip. Etoricoxib was generally well tolerated.     

Failure of estrogen to protect the substantia nigra pars compacta of female rats from lesion induced by 6-hydroxydopamine

The immunostaining for tyrosine hydroxylase (TH) in the substantia nigra pars compacta (SNpc) and in the ventral tegmental area (VTA) after intranigral infusion of 6-hydroxydopamine (6-OHDA, 6 microg/side) was analyzed in ovariectomized adult female Wistar rats. Estrogen replacement for 52 days (400-microg 17-beta-estradiol capsules) did not prevent the loss of TH-immunoreactive cells induced by 6-OHDA in the SNpc. This result indicates that the neuroprotective effect of dopaminergic mesencephalic cells is not observed with long-term estrogen replacement.     

Induction of a brainstem correlate of conditioned taste aversion expression: role of the pontine parabrachial nucleus

Increases in Fos-like immunoreactivity (FLI) in the intermediate division of the nucleus of the solitary tract (iNTS) are seen following the expression of a conditioned taste aversion (CTA). In studies limited to behavioral assessment, the pontine parabrachial nucleus (PBN) has been demonstrated to play a critical role in the acquisition, but not the expression, of CTAs. To better define the role of the PBN in taste aversion learning, the present study examined the effects of PBN lesions on FLI in iNTS in animals with lesions placed either before or after CTA training. As is the case with behavioral expression of a CTA, timing of PBN lesions was found to be critical. Lesions placed prior to conditioning blocked evidence of conditioning, including both taste rejection and FLI in iNTS. Lesions placed after conditioning, but before testing, did not interfere with either taste rejection or FLI. These results support and extend prior claims that PBN is critical for CTA acquisition but not expression. They also demonstrate that input from PBN to iNTS is not necessary for the FLI seen there during CTA expression.     

Growing Region Segmentation Software (GRES) for quantitative magnetic resonance imaging of multiple sclerosis: intra- and inter-observer agreement variability: a comparison with manual contouring method

Lesion area measurement in multiple sclerosis (MS) is one of the key points in evaluating the natural history and in monitoring the efficacy of treatments. This study was performed to check the intra- and inter-observer agreement variability of a locally developed Growing Region Segmentation Software (GRES), comparing them to those obtained using manual contouring (MC). From routine 1.5-T MRI study of clinically definite multiple sclerosis patients, 36 lesions seen on proton-density-weighted images (PDWI) and 36 enhancing lesion on Gd-DTPA-BMA-enhanced T1-weighted images (Gd-T1WI) were randomly chosen and were evaluated by three observers. The mean range of lesion size was 9.9-536.0 mm(2) on PDWI and 3.6-57.2 mm(2) on Gd-T1WI. The median intra- and inter-observer agreement were, respectively, 97.1 and 90.0% using GRES on PDWI, 81.0 and 70.0% using MC on PDWI, 88.8 and 80.0% using GRES on Gd-T1WI, and 85.8 and 70.0% using MC on Gd-T1WI. The intra- and inter-observer agreements were significantly greater for GRES compared with MC ( P<0.0001 and P=0.0023, respectively) for PDWI, while no difference was found between GRES an MC for Gd-T1WI. The intra-observer variability for GRES was significantly lower on both PDWI ( P=0.0001) and Gd-T1WI ( P=0.0067), whereas for MC the same result was found only for PDWI ( P=0.0147). These data indicate that GRES reduces both the intra- and the inter-observer variability in assessing the area of MS lesions on PDWI and may prove useful in multicentre studies.     

Local staging of pancreatic carcinoma with multi-detector row CT: use of curved planar reformations initial experience

PURPOSE: To evaluate the utility of curved planar reformations compared with standard transverse images in the assessment of pancreatic tumors. MATERIALS AND METHODS: Forty-three patients suspected of having pancreatic tumors underwent contrast material-enhanced biphasic multi-detector row computed tomography (CT). Curved planar reformations were generated along the pancreatic duct, common bile duct, and major mesenteric vessels. Three blinded independent readers assessed the curved planar reformations and transverse images separately for the presence of tumor, resectability, and vascular involvement. The results were compared with those of a consensus panel who evaluated the curved planar reformations and transverse images together along with clinical data and surgical findings. RESULTS: Of 43 patients, 20 had pancreatic malignancies as judged by the consensus panel and proven at biopsy and/or clinical follow-up. For tumor detection, transverse images and curved planar reformations had an average sensitivity of 95.0% and 98.4% (P >.05), respectively, and an average specificity of 90.9% and 91.3% (P >.05), respectively. For tumor resectability, transverse images and curved planar reformations had an average sensitivity of 85.7% and 71.4% (P >.05), respectively, and an average specificity of 85.2% and 84.3% (P >.05), respectively. Average interpretation time was 6.4 minutes with transverse images and 4.1 minutes with curved planar reformations. CONCLUSION: Curved planar reformations are equivalent to transverse images in the detection of pancreatic tumors and determination of surgical resectability.     

Lateral parabrachial lesions disrupt paraoxon-induced conditioned flavor avoidance.

Preliminary clinical evidence obtained in Gulf War veterans and patients suffering multiple chemical sensitivity points to the existence of a potential link between environmental exposure to organosphosphates (OPs) and the emergence of unspecific sickness syndromes in which associative Pavlovian conditioning might be partly involved. A laboratory animal model might be a useful tool for analyzing the involvement of conditioning in sickness syndromes potentially linked to OP poisoning. The first objective in the present study was to determine if paraoxon (PX), the neuroactive metabolite of the OP parathion, elicits a conditioned avoidance response to a novel stimulus (a taste-odor compound) in a conditioned flavor aversion procedure. Data obtained in Experiment 1 show conditioned flavor avoidance, demonstrative of the associative nature of the sickness properties of PX. The second objective was to characterize the nature of the specific physiological cue serving as the unconditioned stimulus in PX-induced conditioned avoidance. Despite PX administration did induce cholinergic hyperactivity, as measured by body hypothermia and increased jaw movements, lesions of the lateral parabrachial area (lPB) disrupted PX-elicited flavor avoidance responses, indicating that cholinergic signs were not sufficient as unconditioned stimuli supporting avoidance responses. Given that lPB neural integrity is necessary to process aversive interoceptive information, disruption of conditioned flavor avoidance as a result of lPB lesions is consistent with a central interruption of interoceptive processing in PX-poisoned animals. Data are discussed under the light of the hypothesis claiming the importance of associative processes and noncholinesterase targets in sickness syndromes potentially induced by OP exposure.