Effectiveness of delayed-release dimethyl fumarate on patient-reported outcomes and clinical measures in patients with relapsing-remitting multiple sclerosis in a real-world clinical setting: PROTEC.

BACKGROUND: Patient-reported outcomes (PRO) and clinical outcomes give a broad assessment of relapsing-remitting multiple sclerosis (RRMS) disease. OBJECTIVE: The aim is to evaluate the effectiveness of delayed-release dimethyl fumarate (DMF) on disease activity and PROs in patients with RRMS in the clinic. METHODS: PROTEC, a phase 4, open-label, 12-month observational study, assessed annualized relapse rate (ARR), proportion of patients relapsed, and changes in PROs. Newly diagnosed and early MS (≤3.5 EDSS and ≤1 relapse in the prior year) patient subgroups were evaluated. RESULTS: Unadjusted ARR at 12 months post-DMF versus 12 months before DMF initiation was 75% lower (0.161 vs. 0.643, p < 0.0001) overall (n = 1105) and 84%, 77%, and 71% lower in newly diagnosed, ≤3.5 EDSS, and ≤1 relapse subgroups, respectively. Overall, 88% of patients were relapse-free 12 months after DMF initiation (84%, newly diagnosed; 88%, ≤3.5 EDSS; 88%, ≤1 relapse). PRO measures for fatigue, treatment satisfaction, daily living, and work improved significantly over 12 months of DMF versus baseline. CONCLUSION: At 12 months after versus 12 months before DMF initiation, ARR was significantly lower, the majority of patients were relapse-free, and multiple PRO measures showed improvement (overall and for subgroups), suggesting that DMF is effective based on clinical outcomes and from a patient perspective.Clinical trial: A Study Evaluating the Effectiveness of Tecfidera (Dimethyl Fumarate) on Multiple Sclerosis (MS) Disease Activity and Patient-Reported Outcomes (PROTEC), NCT01930708, https://clinicaltrials.gov/ct2/show/NCT01930708.

Hearing and cognitive impairment: a functional evaluation of associative brain areas in patients affected by Alzheimer's disease.

Auditory dysfunction observed in patients with cognitive diseases is probably due to the alteration of some brain areas involved in sound stimulus processing. The present study aimed to investigate differences in such processing and in connectivity of the primary auditory cortex in patients affected by Alzheimer's disease (AD) and in normal subjects. We examined 131 diagnosed AD patients and a control group (CG) of 36 normal subjects. After a complete clinical investigation, focused on hearing function, all subjects underwent a brain FDG PET/CT. AD subjects vs CG showed reduced glucose consumption in BA 6,7,8,39, whereas we did not find differences in the primary auditory cortex. In AD, connectivity analyses showed a positive correlation of the primary auditory cortex with BA 6,8,21,31,39,40,42 and a negative correlation with BA 19, cerebellum and basal ganglia. Our findings suggest that neurological evaluation of patients with hearing loss might allow earlier (preclinical) identification of those affected by cognitive impairment.

Sapienza Global Bedside Evaluation of Swallowing after Stroke: the GLOBE-3S study.

BACKGROUND AND PURPOSE: Dysphagia occurs in up to 50% of all patients with acute stroke. There is debate regarding which is the most effective screening tool in identifying aspiration in patients with acute stroke. We assessed the accuracy of the Sapienza Global Bedside Evaluation of Swallowing after Stroke (GLOBE-3S), which combines the Toronto Bedside Swallowing Screening Test (TOR-BSST©) with oxygen desaturation and laryngeal elevation measurement during swallowing. METHODS: We prospectively enrolled consecutive patients with stroke within 72 h of symptom onset. All patients with stroke firstly underwent a standard neurological examination, then the GLOBE-3S evaluation and finally the fiberoptic endoscopic evaluation of swallowing (FEES). Two different assessors, a neurologist and a speech pathologist, blind to both the clinical data and each other's evaluation, administered the GLOBE-3S and FEES examination. We assessed the accuracy of the GLOBE-3S in detecting post-stroke swallow impairment with aspiration using the FEES as the standard. RESULTS: We enrolled 50 patients with acute stroke, 28 of whom (56%) had swallowing impairment with aspiration at FEES evaluation. A total of 33 patients (66%) failed the GLOBE-3S evaluation. The GLOBE-3S reached a sensitivity of 100% and a specificity of 77.3% (negative predictive value, 100%; positive likelihood ratio, 4.34). The median time required for the GLOBE-3S to be performed was 297 s. CONCLUSIONS: GLOBE-3S is quick to perform at the bedside and can accurately identify aspiration in patients with acute stroke. By including the measurement of laryngeal elevation and monitoring of oxygen desaturation, it could represent a highly sensitive instrument to avoid the misdiagnosis of silent aspirators.

The hump columellar strut: a reliable technique for correction of nasal tip underprojection.

Nasal tip under projection is often found in rhinoplasty cases both for congenital or post-traumatic deformity. Nasal trauma may result in alteration of the external and internal nasal structures with following aesthetic impairment and difficulties in breathing. Post-traumatic surgery is frequent, but restoration of pre-traumatic form and function remains a challenge. The present paper describes a new method to increase tip projection by a columellar strut harvested from the autologous nasal bone and cartilage of the resected hump. A total of 15 cases (11 women/4 men, mean age 32.6 ± 12.3 years) of major tip projection/misalignment abnormalities to be corrected by increased nasal tip projection were drawn, and all underwent closed or open rhinoplasty with the placement of a bony columellar strut harvested from the resected hump of the patient. Short and long-term advantages of this procedure are to be underlined. Harvesting is routinely performed during dorsal resection and preparation of the graft is easy. Differently from bone of the vomer or the inferior turbinate, this is cortical bone straight in shape and rigid in framework, and therefore ideal to gain reliable tip support overtime. No additional harvesting areas are needed. Placement of this bony strut is carried out in the standard fashion without additional dissection or further procedures. Long-term follow-up shows maintained projection over time. This graft can be combined with various grafting or suturing techniques usually applied according to each surgeon's experience and the needs of each patient.

Approach to the correction of drooping tip: common problems and solutions.

The drooping tip deformity is both a bothersome aesthetic feature and functional impairment of the nose. Both static and dynamic factors may affect tip appearance and it seems logical to take into account these factors when planning correction of drooping tip. Many studies have examined this topic, but its treatment remains controversial. In order to make nasal tip surgery successful, it is useful to identify the keystone anatomical characteristics of the tip itself. Naso-labial angle, nostril axis, tip rotation angle according to Frankfort plane and columellar-facial angle may be measured to assess nasal tip position. The present study focuses on the authors' personal experience on the key anatomic changes of the nose that deserve correction and on the main surgical steps needed to achieve consistent results when dealing with a drooping tip. Pre- and post-operative nasal tip rotation and projection were studied. Correction of the drooping tip was accomplished by an open or closed septorhinoplasty approach according to patient's needs. The surgical techniques mostly employed for tip repositioning was septum straightening (41/41) and tongue-in-groove (36/41 cases) (87.8%). A columellar strut was used in 8/41 (19.51%) cases. LLC cephalic resection was applied in 29/41 patients (70.73%), LLC re-orienting sutures were made in 18/41 cases (43.9%) and lateral crural overlay was needed in 2/41 (4.8%). The key anatomic changes of the nose that deserve correction and the surgical steps needed to ease the often intriguing pre-operative decision-making process are reviewed.

Radiological and clinical difficulties in the management of chronic maxillary sinusitis in ß Thalassemic paediatric patients.

INTRODUCTION: Beta thalassemia is a blood dyscrasia that caused a marked expansion of active marrow spaces and extramedullary haematopoiesis results. In these patients various alterations and abnormalities affects different body areas, including increased risk of sinusitis. The marrow expansion in the facial bones results in delay in pneumatisation of the sinuses, overgrowth of the maxillae, and forward displacement of the upper incisors with skeletal deformities. In current literature, maxillary sinuses are not deeply evaluated by CT scan studies in these kind of patients. The aim of our study was to investigate the presence of maxillary sinuses abnormalities by the use of CT in patients with beta-thalassemia major and to compare these findings with a control group free from this disease. MATERIALS AND METHODS: A retrospective analysis of 22 paediatric patients with beta-thalassemia major and 22 control subjects without sinonasal diseases was performed. CT was done using a 64-multidetector-row CT scanner without contrast injection, obtained in axial plane using thin-slice technique. Evaluated parameters were: bone thickness of the lateral and anterior wall, density and volume of the maxillary sinuses. RESULTS: Significant difference was found between the study group and control group in the evaluation of all the parameters examined. The maxillary sinus of ß thalassemic patients was smaller respect of controls, the bone was more dense and thick in the side and anterior wall. Beta-thalassemic patients have a relative risk of 2.87 to develop a maxillary sinusitis. DISCUSSION: In these patients there is an increased incidence of sinonasal infections due to the abnormal development of cranio facial skeleton. These bone alterations might confuse the physicians and lead to an increased rate of sinusitis diagnoses.

Interpreting therapeutic effect in multiple sclerosis via MRI contrast enhancing lesions: now you see them, now you don't.

Gadolinium (Gd) enhancement of multiple sclerosis (MS) lesions on MRI scans is a commonly used outcome measure in therapeutic trials. However, enhancement depends on MRI acquisition parameters that might significantly alter detectability. We investigated how the difference in blood-brain barrier (BBB) permeability threshold between MRI protocols affects lesion detection and apparent enhancement time using dynamic-contrast-enhanced (DCE) MRI. We examined fourty-four relapsing-remitting MS patients with two MRI protocols: 'standard sensitivity' (SS) (1.5 T, single-dose Gd) and 'high sensitivity' (HS) (3 T, triple-dose Gd, delayed acquisition). Eleven patients had at least one enhancing lesion and completed the 1-month follow-up. We acquired DCE-MRI during the HS protocol and calculated BBB permeability. Sixty-five lesions were enhanced with the SS vs. 135 with the HS protocol. The detection threshold of the HS was significantly lower than that of the SS protocol (K trans = 2.64 vs. 4.00E-3 min(-1), p < 0.01). Most lesions (74 %) were in the recovery phase; none were in the onset phase and 26 % were at the peak of enhancement. The estimated duration of detectability with the HS protocol was significantly longer than for the SS protocol (6-12 weeks vs. 3 weeks). Our observations on the protocol-dependent threshold for detection and time-course help explain discrepancies in the observed effects of anti-inflammatory therapies on MS lesions.

Innovative technique for large septal perforation repair and radiological evaluation.

PERFORATION OF THE NASAL SEPTUM MAY HAVE MULTIPLE CAUSES: traumatic, iatrogenic, infectious, degenerative, overuse of vasoconstrictors, abuse of cocaine and more recently chemotherapy agents. Perforations are also classified according to their size and type of cartilaginous or osteocartilaginous deficit, as well as location (front, middle and rear). Many surgical techniques have been proposed to repair the perforation, although the results are often unsatisfactory for perforations of small and medium size; in large perforations permanent obliteration of the defect cannot always be ensured. It is often necessary to use tissues from inside the nasal turbinates or cartilage from other donor sites such as the ear or rib, and various techniques are discussed in light of the recent literature. The perforations observed in the last eight years and surgical approaches performed in open or closed approaches are taken into account. The authors propose a new technique that has been used with success in many types of septal perforation regardless of aetiology, and in particular large perforations, which allows for the use of the osteocartilaginous donor site as a hump. It is also useful in reductive rhinoseptoplasty, which targets selection to easily obtain mucopericondral flaps with an extramucosal technique and to obtain also an aesthetic improvement.

Sneddon's Syndrome presenting with topographic disorientation.

A 32-year-old woman was admitted to our department for a progressive difficulty in topographic orientation, confirmed by an extensive battery of neuropsychological tests. All biochemical and immunological examinations of blood and cerebrospinal fluid and a cerebral MRI were normal, but a technetium-99m-ethyl cysteinate dimer-single photon emission CT (Tc-99m ECD-SPECT) scan showed bilateral parietal hypoperfusion. The patient refused to undergo other examinations, but 14 months later she returned to hospital for diffuse cutaneous livedo reticularis over her trunk and legs. This time the MRI showed small frontoparietal cortical-subcortical abnormalities suggestive of arterial ischemic infarctions. We made a diagnosis of Sneddon's Syndrome (SNS). SNS is characterized by the association of livedo reticularis and cerebrovascular disease; non-dermatological onset is extremely uncommon. To our knowledge, this is the first description of a patient presenting with cognitive impairment only and observed at such an early stage of the disease that a cerebral MRI was normal.

Unknown primary tumors.

An unknown primary tumor (UPT) is defined by the presence of a metastatic cancer without a known primary site of origin despite a standardized diagnostic workup. Clinically, UPTs show rapid progression and early dissemination, with signs and symptoms related to the metastatic site. The molecular bases of their biology remain largely unknown, with no evidence as to whether they represent a distinct biological entity. Immunohistochemistry remain the best diagnostic tool in term of cost-effectiveness, but the time-consuming "algorithmic process" it relies on has led to the application of new molecular techniques for the identification of the primary site of UPTs. For example, several microarray or miRNA classifications of UPTs have been used, with an accuracy in the prediction of the primary site as high as 90%. It should be noted that validating a prediction of tissue origin is challenging in these patients, since most of them will never have a primary site identified. Moreover, prospective studies to determine whether selection of treatment options based on such profiling methods actually improves patient outcome are still missing. In the last few years functional imaging (i.e. FDG-PET/CT) has gained a main role in the detection of the site of origin of UPTs and is currently recommended by the European Association of Nuclear Medicine. However, despite recent refinements in the diagnostic workup, the site of origin of UPT often remains elusive. As a consequence, treatment of patients with UPT is still empirical and inadequate.

Gene variants associated to malignant thyroid disease in familial adenomatous polyposis: a novel APC germline mutation.

BACKGROUND AND AIM: Familial adenomatous polyposis (FAP) is an autosomal inherited syndrome characterized by hundreds to thousands colorectal adenomatous polyps with oncological transformation lifetime risk of 100%. FAP is mainly associated with mutations in APC (autosomal dominant inheritance) or MUTYH (autosomal recessive inheritance) genes. Affected individuals are at increased risk of developing extra-intestinal tumors. Lifetime risk of developing thyroid carcinoma has been described in previous reports of about 2-12%, mainly in females, and the mean age is below 30 yr. About 95% of cancers are papillary thyroid carcinomas (PTC), mostly multifocal. The aim of this study was to evaluate the frequency of PTC among our series of FAP patients and to assess the type of gene mutation associated with the disease. METHODS: Fifty-four subjects from 36 FAP families were selected (29 females/25 males) and the mean age (±SD) at diagnosis was 28.8±10.8 yr. All patients underwent blood examination for thyroid hormones and antibodies, germline mutational analysis of APC and/or MUTYH genes, thyroid ultrasound, and endocrinological evaluation. RESULTS: In 13/54 (24.1%) subjects, an eumetabolic thyroid disease was found: plurinodular disease in 7/54 (13.0%); single nodule in 4/54 (7.4%); in 2/54 patients (3.7%), we found a malignant nodule characterized after total thyroidectomy as a classical PTC. Both patients were female and showed a classic FAP phenotype. Mutational analysis revealed in the first patient the APC germline mutation 3183_87del ACAAA and in the second patient the del9-10 (del9080dup11) novel APC variant; the first mutation has been already reported in association with PTC; to our knowledge the second mutation has never been previously reported in association with FAP. CONCLUSIONS: In the population examined, the estimated prevalence of thyroid malignant diseases was 3.7%. In both patients, the identified APC gene pathogenetic variants mapped within the 5' region of the gene, previously reported as a PTC-associated mutational hot spot. Both patients had classic FAP phenotype and genetic analysis revealed two pathogenetic APC mutations: c.3183_87delACAAA, a recurrent pathogenetic variant and del9-10 (del9080dup11), a novel, not previously described genomic rearrangement. In agreement with previous studies, the morpho-functional surveillance of thyroid in FAP series should be recommended. A better insight into the overall genotype-phenotype correlation of APC gene mutations would be helpful for the identification of at-risk individuals.

Hyperthermic isolated perfusion with tumor necrosis factor-alpha and doxorubicin for the treatment of limb-threatening soft tissue sarcoma: the experience of the Italian Society of Integrated Locoregional Treatment in Oncology (SITILO).

BACKGROUND: Tumor necrosis factor-alpha (TNFalpha)-based hyperthermic isolated limb perfusion (HILP) is routinely carried out at most oncological institutions in the treatment of locally advanced soft tissue limb sarcoma (STS), employing high TNFalpha dosages. After a phase I-II study, the SITILO (Italian Society of Integrated Locoregional Therapies in Oncology) centers began to employ the lower dose of 1 mg of TNFalpha. The aim of this paper is to report on the results obtained in 75 patients with limb-threatening STS treated with a low TNFalpha dose and doxorubicin (Dx). PATIENTS AND METHODS: HILP with TNFalpha (at a dosage of either 1 mg) and Dx was administered to 75 patients with limb-threatening STS: 37 males and 38 females; median age 50 years; tumor in the lower and upper limbs in 58 and 17 patients, respectively; primary and recurrent tumors in 45 and 30 patients, respectively. Most tumors (77%) were high grade. Tumor resection was carried out 6 to 8 weeks after HILP. RESULTS: The grade of limb toxicity was mild to moderate in the vast majority of patients (76%). Grades IV and V were observed, but only when high muscle temperatures were recorded and high TNFalpha dosages were employed. Systemic toxicity was also mild to moderate and there were no postoperative deaths. Complete and partial tumor responses were 34% and 48%, respectively, with an overall response of 82% . Limb sparing surgery was carried out in 85.3% of patients. At a median follow-up of 28 months, 16 recurrences (21.3%) were recorded, with a 5-year locoregional disease-free survival of 63% . The 5-year disease-free survival and overall survival were 36.7% and 61.6%, respectively. CONCLUSION: HILP with 1 mg of TNFalpha is an effective neoadjuvant therapy resulting in a high rate of limb sparing in limb-threatening STS, with acceptable local reactions and negligible systemic toxicity.

Prognostic factors influencing tumor response, locoregional control and survival, in melanoma patients with multiple limb in-transit metastases treated with TNFalpha-based isolated limb perfusion.

BACKGROUND: In isolated limb perfusion (ILP) with tumor necrosis factor-alpha (TNFalpha) and interferon (IFN)-gamma, pioneered by Lienard and Lejenne in 1988, TNFalpha was empirically employed at a dosage (3-4 mg) ten times higher than the systemic maximum tolerable dose (MTD). We previously conducted a phase I/II study in 20 patients with in-transit melanoma metastases, using a combination of melphalan and TNFalpha at dosages ranging from 0.5 to 3.3 mg. The dose of 1 mg of TNFalpha was identified as optimal in terms of both efficacy and toxicity. The aim of the present study was to describe our experience with 113 stage IIIA/IIIAB melanoma patients treated with a TNFalpha-based ILP and identify prognostic factors for response, locoregional control and survival. PATIENTS AND METHODS: Patients at stage IIIA-IIIAB (presence of in-transit metastases and/or regional node involvement) were considered eligible. The disease was bulky (>or=10 nodules3 cm) in 42.5% of the patients and unresectable in 33% . Forty patients were treated with a TNFalpha dosage of >1 mg and 73 with 1 mg. Patients with tumors in the upper and lower limbs were submitted to ILP via axillary and iliac vessels, respectively. TNFalpha was injected in the arterial line of an extracorporeal circuit at the pre-established dose, followed by melphalan (13 and 10 mg/l of limb volume for the upper and lower limbs, respectively) 30 minutes later. RESULTS: Complete responses (CR) and partial responses (PR) were 63% and 24.5%, respectively, with an objective response (OR) of 87.5%. No change (NC) was observed in only 12.5% of the patients. Upon multivariate analysis, only bulky disease maintained its independent value for tumor response with an odds ratio of 4.07 and a p-value of 0.02. The 5-year locoregional disease-free survival was 42.7%. Upon multivariate analysis, the only prognostic factors were stage, age and bulky disease. The 5-year overall survival was 49%. Multivariate analysis showed that only sex, stage and CR maintained their independent values. CONCLUSION: TNFalpha-based ILP was proven to be an effective treatment for melanoma patients with in-transit metastases. The TNFalpha dosage of 1 mg was as effective as 3-4 mg, with lower toxicity and cost. We propose that TNFalpha and melphalan-based ILP should be employed for bulky tumors or after failure of melphalan-based ILP.

Functional outcome of auditory implants in hearing loss.

The auditory implant provides a new mechanism for hearing when a hearing aid is not enough. It is the only medical technology able to functionally restore a human sense i.e. hearing. The auditory implant is very different from a hearing aid. Hearing aids amplify sound. Auditory implants compensate for damaged or non-working parts of the inner ear because they can directly stimulate the acoustic nerve. There are two principal types of auditory implant: the cochlear implant and the auditory brainstem implant. They have common basic characteristics, but different applications. A cochlear implant attempts to replace a function lost by the cochlea, usually due to an absence of functioning hair cells; the auditory brainstem implant (ABI) is a modification of the cochlear implant, in which the electrode array is placed directly into the brain when the acoustic nerve is not anymore able to carry the auditory signal. Different types of deaf or severely hearing-impaired patients choose auditory implants. Both children and adults can be candidates for implants. The best age for implantation is still being debated, but most children who receive implants are between 2 and 6 years old. Earlier implantation seems to perform better thanks to neural plasticity. The decision to receive an implant should involve a discussion with many medical specialists and an experienced surgeon.

Effect of cabergoline added to levodopa treatment on sleep-wake cycle in idiopathic Parkinson's disease: an open label 24-hour polysomnographic study.

Few studies focused on the effects of cabergoline on sleep-wake cycle in PD. Twelve patients affected by PD treated with levodopa as monotherapy underwent two 24-hour ambulatory polysomnographic (A-PSG) sessions twice: in baseline condition (levodopa as monotherapy) and after addition of cabergoline. In each condition, a subjective evaluation of sleep quality and daytime sleepiness was obtained by means of Parkinson's disease Sleep Scale (PDSS) and the Epworth Sleepiness Scale. The statistical analysis of sleep parameters revealed a significant increase of sleep efficiency and slow wave sleep under cabergoline. The PDSS total score showed a significant improvement of overall sleep quality after cabergoline. No significant changes in daytime sleepiness were observed. No patient referred and/or showed sleep attacks before and after addition of cabergoline. We hypothesize that the long-lasting effect of cabergoline may improve the objective quality of nocturnal sleep in PD patients complaining nocturnal motor disability without inducing daytime sleepiness.

Evaluation of abnormalities of orthostatic postural control in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a multi-systemic disease of unknown etiology characterized by damage to the small arteries, arterioles and capillaries. The documented occurrence of various neuropathies in SSs patients led us to hypothesize that there is a potential for postural control impairments in such disease. This study was aimed at evaluating the orthostatic postural control of SSc patients who do not manifest balance or hearing symptoms. METHODS: Postural stability was assessed in 36 female SSc patients by means of a static computerized posturography technique. Their immunological and microvascular condition were evaluated by means of blood tests and microcapillaroscopy of the digital vessels. Posturography and microcapillaroscopy were performed before and after treating the patients with Iloprost. In order to compare results, posturography was also carried out on a control group composed of 10 healthy women of similar age. Both groups were studied in two different sensory conditions, i.e. with eyes opened and with eyes closed. RESULTS: Posturography results showed relevant differences in body sway between patients and control subjects. Fourier spectral analysis of body sway showed that, independently from visual control, SSc patients exhibit a higher level of low/middle frequency oscillations (both on the lateral and the anteroposterior axis). No relationship was established between disease stage and postural performance. CONCLUSION: This study seems to indicate a subtle neurophysiological dysfunction in the orthostatic postural control of female SSc patients. Further tests on the somatosensory neurological function of SSc patients may help support the above mentioned findings.

Expression of single-chain antibodies in transgenic plants.

There is an ever-growing interest in plant molecular farming as a system for producing valuable recombinant pharmaceutical molecules, such as single-chain variable fragments, on an industrial/agricultural scale and it appears that it is going to become a reality. Human epidermal growth factor receptor-2 (HER2) is an oncogene involved in abnormal cell growth in breast cancer and is considered for the development of new cancer therapies. We describe here the cloning and expression of a scFv-alpha HER2 that has been produced in Escherichia coli and in plants using both stable and transient systems in tobacco and Nicotiana benthamiana. Single-chain antibodies (ScFvs) extracted and purified from E. coli and plant tissues were tested for functionality and specificity by flow cytometry analysis on several cell lines and showed positive results when used on breast cancer slides coming from human frozen tissues. As a result, scFv-alpha HER2 represents a good opportunity for application and use in diagnosis and therapy.