Real-world use of oral versus subcutaneous semaglutide in a cohort of type 2 diabetic patients: which option to which patient?

PURPOSE: To evaluate the variables influencing the therapeutic choice toward oral versus subcutaneous semaglutide in a cohort of diabetic subjects. METHODS: We retrospectively collected data of 292 patients followed at the Diabetes Unit of the University Hospital of Siena and the Hospital of Grosseto, who were prescribed oral (n = 115) or subcutaneous (n = 177) semaglutide between October 2021 and October 2022. RESULTS: Oral semaglutide was preferentially prescribed in older subjects with longer disease duration in replacement of other antidiabetic drugs, while subcutaneous semaglutide was preferentially prescribed in add-on to metformin in subjects with higher body weight and BMI. After 6 months, both formulations significantly improved glycemic control and body weight, however injectable semaglutide showed a greater efficacy on A1c levels, weight loss, BMI and waist circumference reduction. No differences were found in terms of adverse events. CONCLUSION: In our experience, injectable semaglutide is preferred in patients with excess weight and shorter disease duration, while the oral formulation was used later and especially after therapeutic failure of previous therapies. Follow-up data indicate similar tolerability and efficacy of both formulations, despite subcutaneous semaglutide demonstrated greater efficacy.

Stroke-like events after brain radiotherapy: a large series with long-term follow-up.

BACKGROUND AND PURPOSE: Patients with a history of brain radiotherapy can experience acute stroke-like syndromes related to the delayed effects of brain radiation, including stroke-like migraine attacks after radiation therapy syndrome, peri-ictal pseudoprogression and acute late-onset encephalopathy after radiation therapy syndrome. The aim of this study was to collect evidence on the long-term outcome and treatment of these conditions, whose knowledge is undermined by their rarity and fragmented description. METHODS: Cases were collected, both prospectively and retrospectively, amongst six neuro-oncology departments. Inclusion criteria were as follows: (i) history of brain radiotherapy (completed at least 6 months before the acute episode); (ii) new onset of acute/subacute neurological symptoms; (iii) exclusion of all etiologies unrelated to brain irradiation. A review of current literature on stroke-like syndromes was performed to corroborate our findings. RESULTS: Thirty-two patients with acute neurological conditions attributed to the delayed effects of radiation were identified, including 26 patients with stroke-like syndromes. Patients with stroke-like syndromes commonly presented with a mosaic of symptoms, including focal deficits (77%), encephalopathy (50%), seizures (35%) and headache (35%). Seventy-three percent of them had acute consistent magnetic resonance imaging alterations. Treatment included high-dose steroids in 65% of cases. Twenty-two patients recovered completely (85%). Sixteen patients (62%) experienced relapses (median follow-up 3.5 years). A literature review identified 87 additional stroke-like cases with similar characteristics. CONCLUSIONS: Stroke-like events related to brain irradiation may be associated with permanent sequelae. Steroids are often administered on empirical grounds, as they are thought to accelerate recovery. Relapses are common, highlighting the need to elaborate adequate prevention strategies.

Neuropsychological evaluation and follow up in jcv- and non-jcv-related leukoencephalopathies in HIV infection.

The introduction of highly active antiretroviral therapy does not seem to have altered the incidence of progressive multifocal leukoencephalopathy (PML) in HIV infection. Moreover, the occurrence of a HIV-related leukoencephalopathy, called not determined leukoencephalopaties (NDLE), has been reported. As neuropsychological impairment remains highly prevalent in HIV infection, the aim of this study is to describe the neuropsychological profile of PML and NDLE patients, analyzing the time-related changes. Clinical and neuropsychological data from 32 patients (17 PML, 15 NDLE) were compared with two control groups: (1) asymptomatic HIV+ patients without magnetic resonance imaging evidence of leukoencephalopathy; (2) age-/gender-/education-matched healthy subjects. Patients with rapidly worsening PML were significantly impaired on all neuropsychological tests, while PML with more benign course and NDLE groups showed a dysexecutive pattern of impairment. Asymptomatic HIV+ subjects showed mild and isolated cognitive deficits, without functional impact. Cognitive impairment should therefore be considered a key feature from HIV infection diagnosis.

HIV-related acute inflammatory leukoencephalopathy of undetermined origin: review of the literature.

HIV-related acute inflammatory leukoencephalopathy of undetermined origin (AIL) has been anecdotally described in literature as being responsible for cognitive and motor deficits. We carried out a review of all the cases of AIL published in literature. Articles were selected according to 2 criteria: acute onset of symptoms; undetermined aetiology and non-fulfilment of multiple sclerosis diagnostic criteria. They were then analyzed in terms of clinical, biological and instrumental features, therapy, diagnostic classification and prognosis. Although rare (21 patients out of about 4,000 publications), AIL is of particular interest, as the comprehension of its mechanisms could give some insight into the direct and immune-mediated actions of HIV within the brain. All the reported patients share several clinical, histopathological, radiological and CSF features, leading to hypothesize a similar aetiopathogenetic mechanism. Conversely, we observed a high heterogeneity of treatment and diagnostic classification, which could have conditioned the broad prognostic variability. The absence of a defined aetiology leads to consider these forms as a particular subgroup of not determined leucoencephalopathies (NDLE), with both MRI and histological pattern dominated by inflammation as distinctive feature.

NMO-IgG-negative relapsing myelitis.

OBJECTIVE: Idiopathic transverse myelitis (I-TM) is typically monophasic, while relapsing forms are usually referred to spinal cord-restricted neuromyelitis optica (NMO), atypical multiple sclerosis (MS), or myelitis during the course of infections and connectivitis. Our objective was to evaluate the frequency of recurrent I-TM; to clarify the nosology of these forms through comparison with NMO and post-infectious TM (P-TM). DESIGN: Prospective cohort study on patients presenting with I-TM was carried out inpatients of Infectious and Neurologic Disease Clinics, Italy. METHODS: Over an 8-year period, we recruited 13 patients with I-TM and 16 with P-TM. The patients were followed-up for at least 3 years with repeated brain and spinal cord magnetic resonance imaging (MRI) examinations, multimodal evoked potentials and serum screen for connectivitis. Relapses were defined on clinical and imaging criteria. RESULTS: Four patients with I-TM (31%) had a relapsing course . They were all males with age >50, and severe at-onset disability. The final outcome was poor in three out of four patients. Serum NMO-immunoglobulin G was undetectable in all patients. Longitudinally extensive myelitis was not predictive of relapses. I-TM and P-TM shared clinical, cerebrospinal fluid (CSF) and MRI features, as well as a similar rate (54 vs 38%) of peripheral nervous system involvement (polyradiculoneuritis), and an identical rate of relapses (31% for both forms). CONCLUSIONS: Our series support the existence of relapsing I-TM as a disease entity that does not appear related to NMO, nor to MS, cannot be further specified and shares many features with P-TM. The likelihood of relapses was unpredictable based on clinical, CSF and MRI findings.

Improvement in postoperative mortality in elective gastrectomy for gastric cancer: Analysis of predictive factors in 1066 patients from a single centre.

BACKGROUND: Gastrectomy represents the main treatment for gastric adenocarcinoma. This procedure is associated with substantial morbidity and mortality. The aim of this study was to evaluate the postoperative mortality changes across the study period and to identify predictive factors of 30-day mortality after elective gastrectomy for gastric cancer. METHODS: This was a retrospective cohort study of a prospective database from a single centre. Patients treated with an elective gastrectomy from 1996 to 2014 for gastric adenocarcinoma were included. We compared postoperative mortality between four time periods: 1996-2000, 2001-2005, 2006-2010, and 2011-2014. Univariate and multivariate analyses were applied to identify predictors of 30-day postoperative mortality. RESULTS: We included 1066 patients (median age 65 years; 67% male). The 30-day mortality rate was 4.7%. Mortality decreased across the four time periods; from 6.5% to 1.8% (P = 0.022). In the univariate analysis, age, ASA score, albumin <3.5, multivisceral resection, splenectomy, intrathoracic esophagojejunal anastomosis, R status, and T status were significantly associated with postoperative mortality. In the multivariate analysis, ASA class 3 (OR 10.06; CI 1.97-51.3; P = 0.005) and multivisceral resection (OR 1.6; CI 1.09-2.36; P = 0.016) were associated with higher postoperative 30-day mortality; surgery between 2011 and 2014 was associated with lower postoperative 30-day mortality (OR 0.55; CI 0.33-0.15; P = 0.030). CONCLUSION: There was a decrease in postoperative 30-day mortality during this 18-year period at our institution. We have identified ASA score and multivisceral resection as predictors of 30-day mortality for elective gastrectomy for cancer.

Minichromosome maintenance protein 7: a reliable tool for glioblastoma proliferation index.

At present there is increasing evidence concerning the value of minichromosome maintenance (MCM) protein expression as a novel indicator of proliferation. In the present study, 15 glioblastoma samples, classified according to WHO, were analysed to evaluate the expression of the principal proliferation markers. The samples examined were subdivided into 2 cytological subsets, small cell (SC) or multiforme cell (MC) glioblastoma, according to the predominant cell type defined in individual specimens. MCM7 detected more cells in the cycle than Ki67 and PCNA and all cases of SC glioblastoma, the most aggressive subset, displayed a significant increase of MCM7-stained nuclei versus those stained with Ki67. These results suggest that the cell cycle-associated proteins MCM are not only useful markers of proliferation, but also valid aids for diagnosis in cerebral glioblastoma.

Immunohistochemical evaluation of minichromosome maintenance protein 7 in astrocytoma grading.

The minichromosome maintenance (MCM) proteins, which play an important role in eukaryotic DNA replication, represent a group of proteins that are currently under investigation as novel diagnostic tumor markers. Several studies have proved a greater reliability of MCM proteins to stain proliferating cells compared to Ki67 protein, a routinely used proliferation marker in histopathology. In the present study, the expressions of MCM7 and Ki67 were estimated in 66 primary human astrocytomas in relation to tumor grade (Grade I-IV, WHO). MCM7 significantly stained more nuclei compared to Ki67 in all the histopathological grades investigated. In addition, a stronger increase of the MCM7 labelling index, in relation to the tumor aggressiveness, was observed.

A randomized phase III study: comparison between intravenous and intraarterial ACNU administration in newly diagnosed primary glioblastomas.

BACKGROUND: In this randomized phase III study, the effectiveness as well as the side-effects of intraarterial [i.a.] (17 patients) versus intravenous [i.v.] (16 patients) ACNU [Nimustine] administration in newly diagnosed glioblastoma, were compared. PATIENTS AND METHODS: All patients undenwent extensive surgical resection, and both groups were homogeneous for the other known risk factors. Thirty-three patients with glioblastoma were treated with ACNU at the dose of 80-100 mg/m2. Treatment was repeated every 5-8 weeks for a minimum of 2 and maximum of 14 cycles. Total survival time (TST) and to time to progression were chosen as outcome variables. RESULTS AND CONCLUSION: No significant differences in systemic and hematological toxicity between the i.a. and iv. ACNU administration routes were detected. In both groups, tolerance of the procedure was excellent. Analysis of the main outcome measured showed no significant differences between i.a. and i.v. ACNU administration: time to progression was 6 months for i.a. ACNU and 4 months for i.v. ACNU and total survival time was 17 months for i.a. ACNU and 20 months for i.v. ACNU. In spite of ACNU dose incrementation, obtained through i.a. route administration, and subsequent higher concentration in the tumor bed, no improvement could be achieved in effectiveness.

Postoperative adjuvant treatment for gastric cancer improves long-term survival after curative resection and D2 lymphadenectomy. Results from a Latin American Center.

BACKGROUND: The benefits of adjuvant treatment in the context of a D2 lymph node dissection are controversial. The aim was to investigate the effects of postoperative adjuvant treatment on the survival of patients with a curative resection for gastric cancer and a D2 lymph node dissection. METHODS: We performed a retrospective cohort study. Patients operated from 1996 to 2013 were selected. We compared long term survival of patients treated with surgery alone and those with surgery plus postoperative adjuvant treatment. A multivariate analysis for survival was applied in every stage. RESULTS: The study included 580 patients. Two-hundred and four patients received postoperative adjuvant treatment (AD) and 376 patients were treated only with surgery (SU). Patients in the AD group were younger (60 versus 68, p < 0.001), had a lower rate of multiple organ resection (21% versus 39%, p < 0.001) and had less postoperative complications (14% versus 32%, p < 0.001). In the AD group, patients had more advanced disease (stage III; 77% versus 66%, p < 0.001). No difference was found in lymph nodes resected (31 versus 30, p = ns). The median survival with adjuvant treatment was 33 months (39% 5 year survival) and 22 months (31% 5 year survival) for patients without adjuvant treatment (p = 0.003). On multivariate analysis, patients with stage IIIB and IIIC had significantly better overall and disease specific long-term survival with adjuvant treatment. CONCLUSIONS: These results suggest that there is a long-term survival benefit for patients treated with postoperative adjuvant treatment for stages IIIB and IIIC gastric cancer after D2 lymph node dissection.

Combined central and peripheral demyelination: Clinical features, diagnostic findings, and treatment.

Combined central and peripheral demyelination (CCPD) is rare, and current knowledge is based on case reports and small case series. The aim of our study was to describe the clinical features, diagnostic results, treatment and outcomes in a large cohort of patients with CCPD. Thirty-one patients entered this retrospective, observational, two-center study. In 20 patients (65%) CCPD presented, after an infection, as myeloradiculoneuropathy, encephalopathy, cranial neuropathy, length-dependent peripheral neuropathy, or pseudo-Guillain-Barré syndrome. Demyelinating features of peripheral nerve damage fulfilling European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria for CIDP were found in 23 patients (74%), and spatial dissemination of demyelinating lesions on brain MRI fulfilling the 2010 McDonald criteria for multiple sclerosis (MS) in 11 (46%). Two thirds of the patients had a relapsing or progressive disease course, usually related to the appearance of new spinal cord lesions or worsening of the peripheral neuropathy, and showed unsatisfactory responses to high-dose corticosteroids and intravenous immunoglobulins. The clinical presentation of CCPD was severe in 22 patients (71%), who were left significantly disabled. Our data suggest that CCPD has heterogeneous features and shows frequent post-infectious onset, primary peripheral nervous system or central nervous system involvement, a monophasic or chronic disease course, inadequate response to treatments, and a generally poor outcome. We therefore conclude that the current diagnostic criteria for MS and CIDP may not fully encompass the spectrum of possible manifestations of CCPD, whose pathogenesis remains largely unknown.

Amyotrophic lateral sclerosis: oxidative energy metabolism and calcium homeostasis in peripheral blood lymphocytes.

There is evidence of oxidative injury in postmortem brain, spinal cord, and CSF of patients with sporadic amyotrophic lateral sclerosis (SALS patients). We investigated the oxidative metabolism and calcium homeostasis in peripheral blood lymphocytes from such patients and did not find statistical differences in the basal oxygen consumption rate (QO2), cytochrome c oxidase activity, catalase activity, and lactate production. However the increase in QO2, induced by an uncoupler of oxidative phosphorylation, was depressed and the basal (resting) level of free cytosolic calcium ([Ca2+]in) was higher in lymphocytes from SALS patients (p < 0.01). Further increase in free [Ca2+]in challenged by a K+ channel blocker or by an uncoupler of oxidative phosphorylation was similar in SALS and control lymphocytes. The results show that systemic changes consistent with the presence of mitochondrial and of calcium metabolism dysfunction are present in SALS.

Scrapie infectivity and prion protein are distributed in the same pH range in agarose isoelectric focusing.

We separated lysed synaptosomal-microsomal membrane fraction from scrapie-infected hamster brain in preparative agarose isoelectric focusing. We also studied the distribution of PrP27-30 and scrapie infectivity in 13 regions of the gel in the range of pH 3.5 to 9.3. Most of the infectivity remained in the trough, where it had been placed at the beginning of the electrophoresis, along with PrP27-30. Scrapie infectious particles that encountered the gel demonstrated charge heterogeneity and were distributed in the range of pH 5.4 to 9.3. Analysis of charge heterogeneity of PrP27-30 after sodium dodecyl sulfate solubilization showed an isoelectric pattern in the same pH range as that for scrapie infectious particles. The similarity in charge heterogeneity between infectivity and PrP27-30, together with copurification, support the idea that PrP27-30 is an essential component of the scrapie infectious agent.

Scrapie-associated precursor proteins: antigenic relationship between species and immunocytochemical localization in normal, scrapie, and Creutzfeldt-Jakob disease brains.

We describe the antigenic properties and detection of a normal isoform of scrapie-associated precursor protein (PrP33-35C) in normal, and both normal and scrapie isoforms in scrapie- or Creutzfeldt-Jakob disease (CJD)-infected mouse, hamster, and human brains, using a variety of specific antibodies. Polyclonal antibodies raised against mouse and hamster PrP27-30 and against a synthetic peptide of the N-terminal sequence of this protein were used as immunologic probes. PrP27-30 purified as a primary immunogen corresponded to the lower molecular mass peptide, with Mr between 9.3 and 13.5 kd as estimated by size-exclusion high-pressure liquid chromatography. ELISA and immunoblot techniques demonstrated that antibodies recognized homologous antigens as well as precursor proteins from brains (PrP33-35C) and the scrapie isoform of scrapie-associated proteins (PrP33-35Sc/CJD and PrP27-30) from scrapie- and CJD-infected brains. The normal, scrapie, and CJD isoforms of scrapie-associated proteins share common epitopes with varying degrees of interspecies homology. Specific antigen detected in neurons indicated that these proteins are synthesized primarily in these cells. In infected brains, extracellular amyloid deposits formed by the scrapie isoform of PrP protein also strongly reacted with anti-PrP antibodies.

Immunohistochemical localization of prion protein in spongiform encephalopathies and normal brain tissue.

We used polyclonal antibodies raised against hamster and mouse PrP27-30 as immunologic probes to study the localization of intracellular and extracellular deposits of prion protein in normal and scrapie-infected mouse and hamster brains and in Creutzfeldt-Jakob disease (CJD)-infected mouse brains. In addition, we examined normal human brain and brain tissues from patients with CJD, kuru, Alzheimer's disease, and idiopathic chronic encephalitis. There was positive staining in the cytoplasm of neurons of normal and scrapie- and CJD-infected mice, and in the neurons of normal and scrapie-infected hamsters. The staining pattern suggests the localization of PrP in an intracellular membrane compartment, most likely the rough endoplasmic reticulum or Golgi apparatus. Antibodies raised against a 15-amino-acid synthetic peptide of the N-terminal of hamster PrP27-30 displayed a similar pattern of staining in mouse brain sections. We observed no intracellular staining in human brain sections obtained at autopsy. Antibodies prepared against mouse and hamster PrP27-30 reacted with amyloid plaques in scrapie-infected mouse and kuru- and CJD-infected human brain sections but not with amyloid plaques in the brain of a patient with Alzheimer's disease.

Detection of HTLV-III-specific IgG bands in the CSF from a patient with AIDS and encephalitis.

Recent evidence would suggest that HTLV-III may be neurotropic. We have found oligoclonal IgG bands by isoelectric focusing in the CSF of a homosexual man with AIDS and encephalitis. Subsequent analysis revealed that such bands contained anti-HTLV-III activity, suggesting that neurologic symptoms in AIDS patients may be caused by replication of HTLV-III inside the CNS.

Migraine with aura and white matter abnormalities: Notch3 mutation.

The authors report on an Italian family with eight affected members who show autosomal dominant migraine with prolonged visual, sensory, motor, and aphasic aura. These symptoms are associated with white matter abnormalities on brain MRI. All living affected members carry a Notch3 mutation (Arg153Cys) previously reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). White matter abnormalities occur in a variable percentage of the general migraine population; CADASIL should be suspected in migraineurs with prolonged atypical aura and white matter abnormalities.

Clustering of ALS patients in central Italy due to the occurrence of the L84F SOD1 gene mutation.

OBJECTIVE: To study three new apparently unrelated Italian families with ALS and several sporadic ALS patients living in the same rural area. BACKGROUND: One Italian family with ALS carrying a superoxide dismutase 1 (SOD1) gene mutation (G41S) and no regional ALS clustering has been reported in Italy. METHODS: Genetic analysis was performed by automated and manual sequencing of the SOD1 gene in 13 family members and in 6 of 10 unrelated patients with sporadic cases of ALS living in the same area. The authors also determined SOD1 activity in erythrocytes and lymphocytes. RESULTS: The three families included a total of 28 affected members distributed over six generations. Despite a wide variability in age at onset and disease duration, the clinical pattern is uniform, with onset in the lower limbs, ascending progression, and predominant lower motor neuron involvement in all subjects. Generational anticipation is evident in the last two generations. All familial ALS patients and one of the six sporadic patients carry the same L84F missense point mutation in exon 4 of the SOD1 gene. SOD1 enzyme activity and SOD1 protein levels were not decreased significantly in the L84F patients. CONCLUSION: The ALS patients carrying the L84F mutation derive from a common ancestor. This mutation is responsible for ALS clustering in the area. The L84F mutation does not modify SOD1-specific activity.

Subcellular distribution and physicochemical properties of scrapie-associated precursor protein and relationship with scrapie agent.

We studied the biologic properties of hamster-adapted scrapie (strain 263K) and its relationship to the precursor protein of scrapie (PrP33-35Sc). The highest titer of infectious material and the greatest concentration of PrP33-35Sc were in the fractions containing microsomal and synaptosomal membranes. We found traces of infectivity in the absence of PrP33-35Sc associated with matrix protein. Partitioning of membranes with neutral chloroform-methanol resulted in concentration of PrP33-35Sc and infectivity within the interphase layer. Recombination of membrane glycoproteins (interphase) with lipids extracted from homologous brains decreased infectivity greater than or equal to 4 logs. Temperature-dependent phase separation of infected synaptosomal and microsomal membranes with Triton X-114 yielded a phospholipid-rich phase containing a high concentration of PrP33-35Sc and greatest infectivity titers. This material spontaneously formed liposomes, indicating that PrP33-35Sc and PrP33-35C precursor proteins are highly hydrophobic intrinsic membrane components integrated with phospholipids. Homologous membrane phospholipids appear to prevent aggregation of the scrapie isoform of PrP and maintain high levels of infectivity.