Survival prediction models in motor neuron disease.

BACKGROUND AND PURPOSE: This study aimed to assess the predictive value of multimodal brain magnetic resonance imaging (MRI) on survival in a large cohort of patients with motor neuron disease (MND), in combination with clinical and cognitive features. METHODS: Two hundred MND patients were followed up prospectively for a median of 4.13 years. At baseline, subjects underwent neurological examination, cognitive assessment and brain MRI. Grey matter volumes of cortical and subcortical structures and diffusion tensor MRI metrics of white matter tracts were obtained. A multivariable Royston-Parmar survival model was created using clinical and cognitive variables. The increase of survival prediction accuracy provided by MRI variables was assessed. RESULTS: The multivariable clinical model included predominant upper or lower motor neuron presentations and diagnostic delay as significant prognostic predictors, reaching an area under the receiver operating characteristic curve (AUC) of a 4-year survival prediction of 0.79. The combined clinical and MRI model including selected grey matter fronto-temporal volumes and diffusion tensor MRI metrics of the corticospinal and extra-motor tracts reached an AUC of 0.89. Considering amyotrophic lateral sclerosis patients only, the clinical model including diagnostic delay and semantic fluency scores provided an AUC of 0.62, whereas the combined clinical and MRI model reached an AUC of 0.77. CONCLUSION: Our study demonstrated that brain MRI measures of motor and extra-motor structural damage, when combined with clinical and cognitive features, are useful predictors of survival in patients with MND, particularly when a diagnosis of amyotrophic lateral sclerosis is made.

Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. METHODS: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. RESULTS: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. CONCLUSIONS: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management.

Meditation training for people with amyotrophic lateral sclerosis: a randomized clinical trial.

BACKGROUND AND PURPOSE: Studies investigating psychological interventions for the promotion of well-being in people with amyotrophic lateral sclerosis (ALS) are lacking. The purpose of the current study was to examine the use of an ALS-specific mindfulness-based intervention for improving quality of life in this population. METHODS: A randomized, open-label and controlled clinical trial was conducted on the efficacy of an ALS-specific meditation programme in promoting quality of life. Adults who received a diagnosis of ALS within 18 months were randomly assigned either to usual care or to an 8-week meditation training based on the original mindfulness-based stress reduction programme and tailored for people with ALS. Quality of life, assessed with the ALS-Specific Quality of Life Revised scale, represented the primary outcome, whilst secondary outcomes included anxiety and depression, assessed with the Hospital Anxiety and Depression Scale, and specific quality of life domains. Participants were assessed at recruitment and after 2, 6 and 12 months. The efficacy of the treatment was assessed on an intention-to-treat basis of a linear mixed model. RESULTS: A hundred participants were recruited between November 2012 and December 2014. Over time, there was a significant difference between the two groups in terms of quality of life (ß = 0.24, P = 0.015, d = 0.89). Significant differences between groups over time were also found for anxiety, depression, negative emotions, and interaction with people and the environment. CONCLUSIONS: An ALS-specific meditation programme is beneficial for the quality of life and psychological well-being of people with ALS.

Novel FUS mutations identified through molecular screening in a large cohort of familial and sporadic amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Approximately 5%-10% of cases are familial (FALS) and the remaining are sporadic (SALS). To date FUS mutations are responsible for 4%-6% of familial cases as well as 0.7%-1.8% of sporadic cases. METHODS: The frequency of FUS mutations was investigated in an Italian cohort of 500 SALS and 40 FALS patients through direct sequencing of exons 5, 6, 13, 14 and 15. RESULTS: Eight FUS mutation carriers were identified in five SALS (1%) and three FALS (7.5%), five already known and three new mutations: a de novo mutation was identified in a sporadic subject as well as the co-presence of FUS/C9ORF72 mutations in a FALS subject. The molecular and clinical details of the three patients harbouring a novel mutation (G245V, G509D and R491C) are presented here. Moreover the co-presence of the R491C mutation and C9ORF72 pathological expansion was found according to the oligogenic disease model. CONCLUSIONS: In conclusion our results revealed a higher frequency of FUS mutation carriers (7.5%) in FALS compared to literature data together with a higher presence of female gender.

REGOMA-OSS: a large, Italian, multicenter, prospective, observational study evaluating the efficacy and safety of regorafenib in patients with recurrent glioblastoma.

BACKGROUND: In the randomized phase II REGOMA trial, regorafenib showed promising activity in patients with recurrent glioblastoma. We conducted a large, multicenter, prospective, observational study to confirm the REGOMA data in a real-world setting. PATIENTS AND METHODS: The major inclusion criteria were histologically confirmed diagnosis of glioblastoma according to the World Health Organization (WHO) 2016 classification and relapse after radiotherapy with concurrent/adjuvant temozolomide treatment, good performance status [Eastern Cooperative Oncology Group performance status (ECOG PS 0-1)] and good liver function. Regorafenib was administered at the standard dose of 160 mg/day for 3 weeks on/1 week off. Brain magnetic resonance imaging was carried out within 14 days before starting regorafenib and every 8-12 weeks. The primary endpoint was overall survival (OS). The secondary endpoints were progression-free survival (PFS), objective response rate, disease control rate (DCR), safety and health-related quality of life. The Response Assessment in Neuro-Oncology (RANO) criteria were used for response evaluation and Common Terminology Criteria for Adverse Events (CTCAE) version 5 for assessment of adverse events (AEs). RESULTS: From September 2020 to October 2022, 190 patients with recurrent glioblastoma were enrolled from 30 cancer centers in Italy: their median age was 58.5 years [interquartile range (IQR) 53-67 years], 68% were male and 85 (44.7%) were in optimal clinical condition (ECOG PS 0). The number of patients taking steroids at baseline was 113 (60%); the second surgery was carried out in 39 (20.5%). O6-methylguanine-DNA methyltransferase (MGMT) was methylated in 80 patients (50.3%) and 147 (92.4%) of the patients analyzed had isocitrate dehydrogenase (IDH) wild type. The median follow-up period was 20 months (IQR 15.6-25.5 months). The median OS was 7.9 months ([95% confidence interval (CI) 6.5-9.2 months] and the median PFS was 2.6 months (95% CI 2.3-2.9 months). Radiological response was partial response and stable disease in 13 (7.3%) and 26 (14.6%) patients, respectively, with a DCR of 21.9%. The median number of regorafenib cycles per patient was 3 (IQR 2.0-4.0). Grade 3-4 drug-related adverse events were reported in 22.6% of patients. A dose reduction due to AEs was required in 36% of patients. No deaths were considered as treatment-related AEs. CONCLUSIONS: This large, real-world observational study showed similar OS with better tolerability of regorafenib in patients with relapsed glioblastoma compared with the REGOMA study.

Sensorimotor functional connectivity changes in amyotrophic lateral sclerosis.

We investigated whether the functional connections to the primary sensorimotor cortex (SMC) at rest are abnormal in 26 patients with amyotrophic lateral sclerosis (ALS) and whether such changes are related to the corticospinal tract (CST) damage, measured using diffusion tensor magnetic resonance imaging (DT MRI). ALS patients versus controls showed a significantly increased functional connectivity between the left SMC and the right cingulate cortex, parahippocampal gyrus, and cerebellum-crus II. No right SMC connectivity changes were found. The pattern of increased functional connectivity to the left SMC was more widespread when considering only patients with no CST DT MRI abnormalities than the whole group of patients. In this patient group, functional connectivity was also increased between the right SMC and the right parahippocampal gyrus. On the contrary, in ALS patients with CST damage (as assessed using DT MRI) versus controls, functional connectivity was increased between the left SMC and the right cingulate cortex only, while it was decreased between the right SMC and the right cerebellum-lobule VI. In ALS patients, disease severity correlated with reduced SMC functional connectivity. Functional brain changes do occur in ALS with mild disability. These changes might have a role in compensating for (limited) structural damage and might exhaust with increasing burden of disease pathology.

[Experience with the proseal laryngeal mask in ventriculoperitoneal shunting]. / Experiencia con el uso de la mascarilla laríngea Proseal en pacientes sometidos a cirugía de derivación ventrículo peritoneal.

OBJECTIVE: To describe the use, utility, safety, and effectiveness of the Proseal laryngeal mask for airway management in patients undergoing ventriculoperitonea shunting. PATIENTS AND METHODS: We retrospectively reviewed the records of all patients in whom the Proseal laryngeal mask was used during ventriculoperitoneal shunting between January 2006 and October 2009. Patient demographic characteristics, airway assessments, type of anesthesia, quality of ventilation, and perioperative complications were recorded. RESULTS: Of the 43 patients included, 8 (18.6%) had at least 1 difficult airway criterion. We were able to insert the Proseal laryngeal mask in all patients. Ventilation was optimal in 39 (91%) patients, with maintenance of end-expiratory carbon dioxide pressures between 35 and 40 mm Hg and airway pressures above 25 cm H2O throughout the procedures. Air leaks developed in 3 cases (7%) when the patient was placed in a lateral-cervical position for surgery; these patients required orotracheal intubation before surgery could begin. Mean duration of surgery was 53 minutes. Awakening occurred without incident in all cases. CONCLUSIONS: The Proseal laryngeal mask is useful for airway management in patients undergoing ventriculoperitoneal shunting. Due to the forced position of the neck, however, it may be necessary to reposition the mask or even proceed to orotracheal intubation in some cases. As is the case for other advanced uses, experience with the device is necessary. Material for managing a difficult airway should be on hand.

Resource use during systematic review production varies widely: a scoping review.

OBJECTIVE: We aimed to map the resource use during systematic review (SR) production and reasons why steps of the SR production are resource intensive to discover where the largest gain in improving efficiency might be possible. STUDY DESIGN AND SETTING: We conducted a scoping review. An information specialist searched multiple databases (e.g., Ovid MEDLINE, Scopus) and implemented citation-based and grey literature searching. We employed dual and independent screenings of records at the title/abstract and full-text levels and data extraction. RESULTS: We included 34 studies. Thirty-two reported on the resource use-mostly time; four described reasons why steps of the review process are resource intensive. Study selection, data extraction, and critical appraisal seem to be very resource intensive, while protocol development, literature search, or study retrieval take less time. Project management and administration required a large proportion of SR production time. Lack of experience, domain knowledge, use of collaborative and SR-tailored software, and good communication and management can be reasons why SR steps are resource intensive. CONCLUSION: Resource use during SR production varies widely. Areas with the largest resource use are administration and project management, study selection, data extraction, and critical appraisal of studies.

Age of HIV Acquisition Affects the Risk of Multi-Morbidity after 25 Years of Infection Exposure.

INTRODUCTION: Understanding the intersection of HIV, aging and health is crucial due to the increasing number of people aging with HIV. OBJECTIVE: The objective of the study was to assess the prevalence of, and risk factors for individual comorbidities and multi-morbidity in people living with HIV with similar duration of HIV infection, notwithstanding a 25-year difference at the time of HIV acquisition. METHODS: In a cross-sectional multicentre retrospective study, we compared three match-control age groups. The "Young" were selected from Romania and included HIV-positive patients prenatally infected and assessed at the age of 25-30 years. The "Old" and the "Geriatric" were selected from Italy. These respectively included subjects infected with HIV at the age of 25 years and assessed at the age of 50-55 years, and those infected at the age of 50 years and assessed at the age of 75-80 years. Each group was sex and age matched in a 1:5 ratio with controls selected from the CINECA ARNO database from Italy. We described non-infectious comorbidities (NICM), including cardiovascular disease, hypertension, dyslipidaemia, diabetes, chronic kidney disease, and multi-morbidity (MM≥ 3 NICM). RESULTS: MM prevalence in the "Young" group compared to controls was 6.2% vs 0%, while in the "Geriatric" was "68.2% vs 3.6%. Using "Young" as a reference, in multivariate analyses, predictors for MM were as follows: HIV serostatus (OR=47.75, IQR 14.78-154.25, p<0.01) and "Geriatric" vs "Young" (OR=30.32, IQR 5.89-155.98, p<0.01). CONCLUSION: These data suggest that age at acquisition of HIV should be considered as a risk factor for NICM and MM.

Age-adjusted D-dimer to rule out deep vein thrombosis: findings from the PALLADIO algorithm.

Essentials The accuracy of the age-adjusted D-dimer in suspected venous thromboembolism is still debated. We assessed the performance of age-adjusted D-dimer combined with the PALLADIO algorithm. The age-adjusted threshold can reduce the need for imaging tests compared to the fixed cut-off. The safety of this approach should be confirmed in large management studies. SUMMARY: Background Age-adjusted D-dimer has been proposed to increase specificity for the diagnosis of venous thromboembolism (VTE). However, the accuracy of this threshold has been recently questioned. Objectives To assess the diagnostic performance of age-adjusted D-dimer combined with clinical pretest probability (PTP) in patients with suspected deep vein thrombosis (DVT). Methods PALLADIO (NCT01412242) was a multicenter management study that validated a new diagnostic algorithm, incorporating PTP, D-dimer (using the manufacturer's cut-off) and limited or extended compression ultrasonography (CUS) in outpatients with clinically suspected DVT. Patients with unlikely PTP and negative D-dimer had DVT ruled out without further testing (group 1); patients with likely PTP or positive D-dimer underwent limited CUS (group 2); patients with likely PTP and positive D-dimer underwent extended CUS (group 3). Patients with DVT ruled out at baseline had a 3-month follow-up. In this post-hoc analysis we evaluated age-adjusted D-dimer cut-off (defined as age times 10 µg L-1 , or age times 5 µg L-1 for D-dimers with a lower manufacturer's cut-off, in patients > 50 years). Results In total, 1162 patients were enrolled. At initial visit, DVT was detected in 4.0% of patients in group 2 and 53.0% in group 3. The age-adjusted D-dimer, compared with the fixed cut-off, resulted in 5.1% (95% CI, 4.0-6.5%) reduction of CUS. The incidence of symptomatic VTE during follow-up was: 0.24% (95% CI, 0.04-1.37) in group 1; 1.12% (95% CI, 0.44-2.85) in group 2; and 1.89% (95% CI, 0.64-5.40) in group 3. Conclusions The PALLADIO algorithm using age-adjusted D-dimer slightly decreased the number of required imaging tests, but this approach should be confirmed in large management studies.

[Clinical comparison of the reusable LMA Classic laryngeal mask and the disposable Soft Seal mask in adult patients]. / Comparación clínica de la mascarilla laríngea reutilizable LMS Classic y la desechable Soft Seal en paciente adultos.

OBJECTIVES: To compare the clinical behavior of the disposable Soft Seal laryngeal mask to the behavior of the reusable LMA Classic mask. METHODS: Patients were randomly assigned to 2 groups in which either the LMA Classic or the Soft Seal mask would be used. We assessed time required for positioning and number of attempts, seal pressure, fiberoptic bronchoscopic image, and complications. The masks were inserted by 2 anesthesiologists who were inexperienced in the use of laryngeal masks. We also compared compliance of the cuff in the laboratory. RESULTS: Sixty patients were enrolled. There were no differences in time required for insertion or number of attempts (first-try success, 83%). The mean (SD) seal pressure was greater in the Soft Seal group at 23 (4) cm H2O than in the LMA Classic group at 20 (4) cm H2O. There were no significant differences in the fiberoptic bronchoscopic images, ventilation, incidence of intraoperative complications, presence of blood on the cuff (LMA Classic, 6 out of 30 vs Soft Seal, 11 out of 29), or postoperative sore throat. In 3 patients in the Soft Seal group the laryngeal mask had to be replaced by an orotracheal tube. Cuff compliance in the laboratory was lower for the LMA Classic than for the disposable mask for all sizes assessed. CONCLUSIONS: Although the results suggest that the clinical behavior of the 2 masks is similar, the LMA Classic allowed for effective airway management in all of the cases assigned to it, whereas management was effective in 90% of the cases in which the Soft Seal mask was used. The inflatable cuff of the Soft Seal is more compliant in vitro and it provides a higher airway seal pressure than does the LMA Classic.

A comparative study using thrombin generation and three different INR methods in patients on Vitamin K antagonist treatment.

INTRODUCTION: Vitamin K antagonist (VKA) treatment requires routine monitoring using the international normalized ratio (INR). However, different INR assays may vary in their results. The aim of this study was to assess the agreement of three different INR methods, compared with thrombin generation, in patients on VKA treatment. METHODS: Sixty patients attending the Anticoagulation Clinic at Mater Dei Hospital (Msida, Malta) for VKA monitoring between August and September 2015 were enrolled. The INR was tested using a point-of-care (POC) device (CoaguChek XS Plus, Roche Diagnostics) for both capillary and venous blood samples, a photo-optical (Sysmex CS-2100i/CA-1500, Siemens) and a mechanical clot detection system (Thrombolyzer XRC, Behnk Elektronik). All assays used human recombinant thromboplastin as reagent. Thrombin generation was performed using the calibrated automated thrombogram. RESULTS: There was a negative curvilinear correlation between the endogenous thrombin potential and different INR assays (r≤-.75) and a strong positive linear correlation between the CoaguChek XS Plus on capillary samples and the other INR methodologies (r≥.96). CONCLUSION: All different INR assays showed good correlation with the thrombin generation potential. The POC INR showed one of the highest correlation coefficients with thrombin generation, confirming the POC devices as an accurate, valid alternative to laboratory INR in VKA patients.

Inefficient skeletal muscle oxidative function flanks impaired motor neuron recruitment in Amyotrophic Lateral Sclerosis during exercise.

This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O2 uptake ([Formula: see text]O2peak), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern ([Formula: see text]E peak). pALS displayed: (1) 44% lower [Formula: see text]O2peak vs. CTRL (p < 0.0001), paralleled by a 43% decreased peak skeletal muscle oxidative function (p < 0.01), with a linear regression between these two variables (r2 = 0.64, p < 0.0001); (2) 46% reduced [Formula: see text]Epeak vs. CTRL (p < 0.0001), achieved by using an inefficient breathing pattern (increasing respiratory frequency) from the onset until the end of exercise. Inefficient skeletal muscle O2 function, when flanking the impaired motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing individual impairments in the O2 transport and utilization chain.

Local treatment of malignant gliomas by direct infusion of specific monoclonal antibodies labeled with 131I: comparison of the results obtained in recurrent and newly diagnosed tumors.

Two murine monoclonal antibodies, BC-2 and BC-4, raised against tenascin and labeled with 131I were infused locally in the site of neoplastic disease by means of a removable (16 patients) or indwelling (34 patients) catheter. Fifty patients bearing a malignant glioma were treated. Twenty-six of these were suffering from recurrent disease; their tumors relapsed within 9 months (median) after treatment. The remaining 24 cases had a newly diagnosed tumor, and local radioimmunotherapy (RIT) was given immediately after surgery and radiochemotherapy. All efforts were made to reduce the tumor before the infusion of the radiopharmaceutical. Therefore, 22 cases with relapsing glioma underwent additional debulking surgery, which led to total or subtotal removal of tumor in 9 of the patients. Altogether, 28 patients had intralesional RIT when the disease was minimal or microscopic. Conversely, 22 cases underwent local RIT with a tumor the diameter of which was > 2 cm. In many cases, the infusions were repeated up to six times to achieve complete destruction of the neoplastic tissue. The local treatment did not give rise to systemic or to cerebral adverse effects. The labeled monoclonal antibodies, given directly in the site of the lesion, concentrated in very high amount in the neoplastic tissue and remained fixed in the target for a long period of time. For these reasons, the radiation dose to the tumor was remarkable (on average > 30,000 cGy/cycle) and consequently led to promising results. The median survival was, in total, 20 months (18 in recurrent tumors and 23 in newly diagnosed lesions). Moreover, median survival was 17 months in patients with bulky tumors (both recurrent and newly diagnosed tumors) and 26 months in patients with minimal or microscopic disease. The median time to progression was 3 months in recurrent and 7 months in newly diagnosed gliomas. Finally, RIT produced 3 CRs (all in recurrent tumors), 6 PRs (4 in recurrent and 2 in newly diagnosed), and 11 stabilizations of disease (4 in recurrent and 7 in newly diagnosed). In 19 cases (13 recurrent and 6 newly diagnosed) the progression of tumor was recorded. Eleven patients (2 recurrent and 9 newly diagnosed) who were treated by RIT when their disease was minimal and nondetectable by radiological methods remained disease-free and were classified as NED. The overall response rate (NED plus CR plus PR) was 40% (34.6% recurrent and 45.8% newly diagnosed).(ABSTRACT TRUNCATED AT 400 WORDS)

Weed control in rice with metham-sodium.

Metam-sodium is a soil fumigant with herbicidal properties. A field experiment was conducted in 2000 at Copiano (Pavia, Italy) to determine the efficacy of three rates of metam-sodium (300, 450 and 600 l/ha) at three different planting times (5, 12 and 18 days after chemical treatments) for the control of weeds in rice cultivation. The study mainly focused on the control of red rice (Oryza sativa var. selvatica), a weed which is worldwide distributed in rice fields and difficult to eradicate Test design was a split-plot with four replications. The main plot size was 13, 5 by 15 m and the subplot size was 13, 5 by 5 m. The chemical treatments were carried out as pre-sowing. Two days after chemical treatments, all field plots were flooded with 10 cm of water as practiced locally. An early variety of rice (Loto) was sown at 150 kg/ha. Weed control was visually evaluated as a percentage of ground covering by all weeds and by each weed individually at three, four and five weeks after treatments. Observations were made also on rice selectivity, and rice grain yield was assessed at the end. Metam-sodium did not injure the rice plants. Metam-sodium at 450 l/ha controlled 100%, 97% and 92% of red rice at the first, second and third observations, respectively. Good results were also obtained with metam-sodium at 300 and 600 l/ha, which controlled 94 to 82% of red rice during the season. Echinochloa crus-galli was better controlled with the higher rates of metam-sodium, particularly in the early part of the season. Metam-sodium did not show enough efficacy in this study against Heteranthera reniformis, Bulboschoenus maritimus and Lindernia spp. The best rice grain yield was obtained with all rates of metam-sodium, when rice was sown 5 days after treatment.

Benefits and challenges of going abroad for research or clinical training.

Research or clinical experience abroad is often encouraged for early career professionals to enhance their future career prospects. If resources are available to facilitate this, we believe that a fellowship abroad should definitely be considered. It can be a great asset, but also an exciting and scary experience at the same time. We, Nicoletta and Mandy, medical doctors in Italy and the Netherlands, respectively, have been fortunate enough to gain abroad experience: Nicoletta in Birmingham, United Kingdom, for 12 months, doing a clinical research fellowship in the field of anticoagulation and atrial fibrillation, working with Prof. Gregory Lip, and Mandy in Hamilton, ON, Canada, for 13 months, undertaking a clinical research fellowship in the field of anticoagulation, stroke and atrial fibrillation, with Dr John Eikelboom, Prof. Jack Hirsh, Prof. Jeff Weitz and, Prof. Stuart Connolly. As we have both experienced the benefits but also the challenges resulting from these encounters, we hope that this forum piece will provide other early career professionals with helpful suggestions and, above all, fill them with excitement about an international training opportunity.

Loco-regional radioimmunotherapy of high-grade malignant gliomas using specific monoclonal antibodies labeled with 90Y: a phase I study.

A Phase I radioimmunotherapy trial was conducted in which radioconjugated monoclonal antibody (MAb) was directly infused into the tumor or postoperative tumoral bed in patients with high-grade malignant glioma. BC-4, a murine MAb that recognizes tenascin, was used in these studies. The MAb was labeled with 90Y, a pure beta emitter with maximum energy of 2.284 MeV, which can penetrate into tissue up to 0.5-0.7 cm. Stable 90Y-labeled MAb conjugates were prepared using the chelator p-isothiocyanatobenzyl derivative of diethylenetriaminepentaacetic acid (ITC-Bz-DTPA), obtaining >95% labeling efficiency and conserving the antibodies' immunoreactivity (>85%). Twenty patients, 2 with anaplastic astrocytoma and 18 with glioblastoma, were included in the study. All of the patients had been treated previously with conventional therapies (surgery, external radiotherapy, and chemotherapy) and presented with progressive disease not amenable to further treatment. A dose-escalation study was performed using doses ranging from 5-30 mCi (185-1110 MBq) of 90Y-labeled MAb BC-4. The protein dose of MAb was always 1 mg. Three patients were treated at the 5, 10, 15, and 20 mCi levels, and the 25- and 30-mCi doses were each administered to 4 patients. Systemic toxicity was completely absent in all of the patients. The maximum tolerated dose to the brain was 25 mCi (925 MBq). The average dose to the tumor was 3200 cGy/mCi. Doses to the liver, bone marrow, and kidneys were below 10 cGy/mCi in all of the cases. Biodistribution studies demonstrated that the 90Y-labeled MAb accreted exclusively in the neoplastic area without any diffusion into the normal brain or other normal organs. No clinical responses were recorded because of the very advanced stage of disease at the time of radioimmunotherapy.

Safety of vitamin K antagonist treatment for splanchnic vein thrombosis: a multicenter cohort study.

BACKGROUND: The treatment of splanchnic vein thrombosis (SVT) is challenging, due to the increased risk of bleeding and potentially life-threatening complications. Current recommendations are based on evidence from the treatment of venous thrombosis in usual sites, but small observational studies in SVT population suggest that the bleeding risk may offset the benefit of anticoagulant treatment in this setting. The aim of this study was to evaluate the safety of vitamin K antagonists (VKAs) in SVT patients. METHODS: We retrospectively included SVT patients treated with VKAs followed by 37 Italian anticoagulation clinics, until June 2013. The primary outcome was the incidence of major bleeding (MB), according to the ISTH definition, during VKA treatment. Vascular events, including both arterial and venous thrombosis, and mortality were also documented. RESULTS: Three hundred and seventy-five patients were included (median age 53 years; 54.7% males). During a median VKA treatment duration of 1.98 years, 15 MB events occurred, corresponding to an incidence rate of 1.24 (95% confidence interval [CI], 0.75-2.06) per 100 patient-years. Gastrointestinal bleeding represented 40% of all MB events. At multivariate analysis, the presence of esophageal varices emerged as independent predictor of MB (hazard ratio 5.4; 95% CI, 1.4-21.1). The incidence rate of vascular events on treatment was 1.37 (95% CI, 0.84-2.23) per 100 patient-years and the mortality rate was 0.83 (95% CI, 0.44-1.54) per 100 patient-years. CONCLUSIONS: Selected SVT patients followed by anticoagulation clinics for the management of VKA treatment show a low rate of major bleeding and vascular events.