Search

Background & Aims Good outcomes after liver transplantation (LT) have been reported after successfully downstaging to Milan criteria in more advanced hepatocellular carcinoma (HCC). We aimed to compare post-LT outcomes in patients receiving locoregional therapies (LRT) before LT according to Milan criteria and University of California San Francisco downstaging (UCSF-DS) protocol and ‘all-comers’. Methods This multicentre cohort study included patients who received any LRT before LT from Europe and Latin America (2000–2018). We excluded patients with alpha-foetoprotein (AFP) above 1,000 ng/ml. Competing risk regression analysis for HCC recurrence was conducted, estimating subdistribution hazard ratios (SHRs) and corresponding 95% CIs. Results From 2,441 LT patients, 70.1% received LRT before LT (n = 1,711). Of these, 80.6% were within Milan, 12.0% within UCSF-DS, and 7.4% all-comers. Successful downstaging was achieved in 45.2% (CI 34.8–55.8) and 38.2% (CI 25.4–52.3) of the UCSF-DS group and all-comers, respectively. The risk of recurrence was higher for all-comers (SHR 6.01 [p, Graphical abstract, Highlights • Successful downstaging from UCSF criteria resulted in a similar outcome compared with the group initially within Milan criteria. • Patients within UCSF-DS criteria and with AFP values below or equal to 20 ng/ml at listing have excellent survival and recurrence rates. • All-comers have a higher recurrence after downstaging to Milan criteria, with frequent microvascular invasion in the explant.

Erectile dysfunction (ED) is defined as the inability to attain or maintain penile erection sufficient for successful sexual intercourse. ED carries a notable influence on quality of life, with significant implications for family and social relationships. Because atherosclerosis of penile arteries represents one of the most frequent causes of ED, patients presenting with it should always be investigated for potential coexistent coronary or peripheral disease. Up to 75% of patients with ED have a stenosis of the iliac-pudendal-penile arteries, supplying perfusion of the male genital organ. Recently the potential treatment of this pathological condition by percutaneous approaches has emerged with good angiographic results and with a significant improvement in symptoms and quality of life. This review will focus on the normal anatomy and physiology of erection, the pathophysiology of ED, the relation between ED and cardiovascular diseases and, lastly, on new treatment modalities aimed at restoration of normal erectile function.

H. Jokinen työryhmän jäsenenä. Introduction: Numerous diagnostic criteria have tried to tackle the variability in clinical manifestations and problematic diagnosis of vascular cognitive impairment (VCI) but none have been universally accepted. These criteria have not been readily comparable, impacting on clinical diagnosis rates and in turn prevalence estimates, research, and treatment. Methods: The Vascular Impairment of Cognition Classification Consensus Study (VICCCS) involved participants (81% academic researchers) from 27 countries in an online Delphi consensus study. Participants reviewed previously proposed concepts to develop new guidelines. Results: VICCCS had a mean of 122 (98-153) respondents across the study and a 67% threshold to represent consensus. VICCCS redefined VCI including classification of mild and major forms of VCI and subtypes. It proposes new standardized VCI-associated terminology and future research priorities to address gaps in current knowledge. Discussion: VICCCS proposes a consensus-based updated conceptualization of VCI intended to facilitate standardization in research. (C) 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Objective To report on a large multi-institutional series of laparoendoscopic single-site (LESS) partial nephrectomy (PN) and analyse renal function and short-term oncological outcomes. Material and Methods We conducted a retrospective analysis of consecutive cases of LESS-PN performed between November 2007 and March 2012 at 11 participating institutions. Demographic data and data on the main peri-operative outcomes and complications were gathered and analysed. Kidney function was evaluated by measuring serum creatinine concentration and estimated glomerular filtration rate (eGFR). Chronic kidney disease was defined in stages for each patient according to the National Kidney Foundation, Kidney Disease Outcomes Quality Initiative. Results A total of 190 cases were included in this analysis. The mean renal tumour size was 2.6 cm, and the mean PADUA score was 7.2. The median operating time was 170 min with a median estimated blood loss of 150 mL. A clampless technique was used in 70 cases (36.8%) and the median warm ischaemia time (WIT) was 16.5 min. PADUA score independently predicted the length of WIT (low vs high score: odds ratio 5.11, CI 1.50–17.41, P = 0.009; intermediate vs high score: odds ratio 5.13, CI 1.56–16.88, P = 0.007). The overall postoperative complication rate was 14.7%. Where a clamping technique was used, a significant increase in serum creatinine concentration and a significant decrease in eGFR were observed postoperatively and at 6 months. On multivariate analysis PADUA score was the only predicting factor. Overall survival rates were 99, 97 and 88% at 12-, 24- and 36-month follow-up, respectively, while disease-free survival rates were 98% at 12-month and 97% at 24- and 36-month follow-up. Conclusion The study showed that LESS-PN is effective in terms of renal function preservation and oncological control at short- and intermediate-term follow-up.

To report the surgical outcomes of laparoscopic radical cystectomy (LRC) with extracorporeal orthotopic ileal neobladder (OIN) in patients with muscle-invasive urothelial carcinoma of the bladder (UCB). Between October 2009 and December 2011, 37 patients with muscle-invasive UCB underwent a LRC with OIN. Indications included (a) muscle-invasive UCB T2–4a, N0–Nx, M0; (b) high-risk and recurrent non-muscle-invasive tumors; (c) T1G3 plus CIS; and (d) extensive non-muscle-invasive disease that could not be controlled by transurethral resection and intravesical therapy. Demographic data, perioperative, and postoperative variables were recorded and analyzed. The median operating time was 330 min, with a median estimated blood loss of 410 ml. Median length of stay was 12 days, and the mean length of the skin incision to extract the specimen and for the configuration of the neobladder was 7 ± 1 cm. The complication rate was 21.6 % (Clavien II). No Clavien III–V complications were reported. Daytime and nocturnal continence were preserved in 95 and 78 %, respectively. No local recurrence or port site metastasis occurred. Median time to disease recurrence was 14 months (IQR 9–24), and 1-year cancer-specific survival was 91.9 %. Laparoscopic radical cystectomy with extracorporeal ileal neobladder is a challenging procedure but technically feasible, allowing low morbidity and oncological safety. Long-term oncological results are required to definitely recognize this procedure as a standard treatment for bladder cancer.

Sjögren syndrome (SS) is an autoimmune disease of the exocrine glands, characterized by focal lymphocytic infiltration and destruction of these glands. Neurologic complications are quite common, mainly involving the peripheral nervous system (PNS). The most common central nervous system (CNS) manifestations are myelopathy and microcirculation vasculitis. However, specific diagnostic criteria for CNS SS are still lacking. We report two cases of primary SS in which the revealing symptom was cerebral venous thrombosis (CVT) in the absence of genetic or acquired thrombophilias.

A cloned Thl cell line was isolated from pancreatic lymph nodes of NOD mice that carries a T-cell receptor encoding Vβ14 and proliferates in response to NOD islets, islet supernatant, and crystalline bovine and rat insulin, specifically to a B-chain peptide bound to IAg7. The response to islet supernatant was reduced by 75% by anti-insulin antibody treatment. The insulin-reactive clone reduced insulitis and totally blocked the development of spontaneous diabetes in NOD mice (n = 8) as well as the adoptive transfer of diabetes into irradiated NOD mice following the injection of splenocytes from diabetic mice (n = 13). Trafficking of the adoptively transferred cells was assessed by labeling the clone or diabetic splenocytes with a fluorescent marker (Dil). The labeled clone was detected in the islet periphery, whereas labeled splenocytes alone invaded the islets by 3 days. In contrast, the protective clone dramatically delayed and reduced the number of labeled diabetic splenocytes infiltrating the islet, although their appearance in the spleen was unaffected. In vitro, the clone as well as supernatant derived from the clone blocked the proliferation of diabetic NOD splenocytes to islets. This inhibitory effect was diminished by anti–transforming growth factor-β. In conclusion, an insulin-specific Thl cell was isolated from NOD mice that traffics to the islet and prevents the spontaneous development and the adoptive transfer of diabetes. It appears to act locally by releasing transforming growth factor-β and/or other factors that inhibit homing to and/or proliferation of diabetic splenocytes within the islet. These findings may provide insights into and suggest mechanisms for the protective effects of insulin therapy against diabetes.

Diagnosing pleural tuberculosis (plTB) might be difficult due to limited sensitivity of conventional microbiology tools. As M. tuberculosis (MTB)-specific T cells are recruited into pleural space in plTB, their detection may provide useful clinical information. To this aim, in addition to standard diagnostic tests, we used the QuantiFERON-TB Gold In-Tube (QFT-IT) test in blood and pleural effusion (PE) samples from 48 patients with clinical suspicion of plTB, 18 (37.5%) of whom had confirmed plTB. Four of them (22.2%) tested positive with a nucleic acid amplification test for MTB. The tuberculin skin test was positive in most confirmed plTB cases (88.9%). Positive QFT-IT tests were significantly more frequent in patients with confirmed plTB, as compared to patients with an alternative diagnosis, both in blood (77.7 vs 36.6%, p=0.006) and in PE samples (83.3% vs 46.6%, p=0.02). In addition, both blood and PE MTB-stimulated IFN-γ levels were significantly higher in plTB patients (p=0.03 and p=0.0049 vs non-plTB, respectively). In blood samples, QFT-IT had 77.8% sensitivity and 63.3% specificity, resulting in 56.0% positive (PPV) and 82.6% negative (NPV) predictive values. On PE, QFT-IT sensitivity was 83.3% and specificity 53.3% (PPV 51.7% and NPV 84.2%). The optimal AUC-derived cut-off for MTB-stimulated pleural IFN-γ level was 3.01 IU/mL (77.8% sensitivity, 80% specificity, PPV 68.4% and NPV 82.8%). These data suggest that QFT-IT might have a role in ruling out plTB in clinical practice.

Purpose Small-cell lung cancer (SCLC) is increasingly diagnosed in elderly patients, who are at higher risk of treatment-related morbidity and mortality. We conducted a randomized two-stage phase II study to assess the therapeutic index of two different platinum/etoposide regimens, attenuated-dose (AD) and full-dose (FD) plus prophylactic lenograstim. Patients and Methods SCLC patients older than 70 years were randomized to receive four courses of cisplatin 25 mg/m2 on days 1 and 2, and etoposide 60 mg/m2 on days 1, 2, and 3 every 3 weeks (AD); or cisplatin 40 mg/m2 on days 1 and 2, and etoposide 100 mg/m2 on days 1, 2, and 3 every 3 weeks, plus lenograstim 5 mg/kg days 5 through 12, every 3 weeks (FD). A combined primary end point named therapeutic success (TS), which took into account activity, toxicity, and compliance, was used. Results Ninety-five patients were enrolled. Seventy-five percent and 72% of the patients in the AD and FD arms, respectively, completed the treatment as per protocol. Response rate was 39% and 69% in the AD and FD arms, respectively, and 1-year survival probability was 18% and 39%, respectively. Treatment was well tolerated in both groups, with no grade 3 to 4 myelotoxicity in the AD arm, and 12% myelotoxicity in the FD arm. Overall, the observed TSs were 10 (36%) of 28 patients and 42 (63%) of 67 patients for AD and FD treatments, respectively. Conclusion In elderly patients with SCLC a full-dose cisplatin/etoposide regimen combined with prophylactic lenograstim is active and feasible, while attenuated doses of the same regimen are associated with a poor therapeutic outcome.

Objective: To determine whether TIAs have a neuroprotective effect.Background: Ischemic tolerance or preconditioning, which protects the brain against stroke, has been demonstrated in animal models of cerebral ischemia. Because TIA may represent a clinical model of ischemic tolerance, patients with TIA before cerebral infarction (CI) may therefore have a better outcome than patients without TIA before CI.Methods: A total of 2,490 patients admitted consecutively to a primary care center for first-ever CI in the anterior circulation were divided into two groups on the basis of the presence or absence of prior ipsilateral TIAs. Duration of TIA was classified into three groups (20 minutes). The severity of the neurologic picture on admission and functional disability after stroke were compared between patients with and without TIAs.Results: A total of 293 (12%) of the 2,490 patients had prior ipsilateral TIAs before CI. Risk factors did not differ between patients with or without TIAs, whereas the topography and etiology of ischemic stroke did differ (p < 0.001). Patients without prior TIAs had a more severe clinical picture on admission, with a greater reduction of consciousness (p = 0.009). Patients with previous TIAs had a more favorable outcome than those without TIAs (67% versus 58%, p = 0.004). After adjustment for confounding variables, TIAs lasting 10 to 20 minutes were still associated with a favorable outcome (odds ratio, 1.98; 95% confidence interval, 1.27 to 3.08; p = 0.002). The interval between TIA and CI influenced the outcome (p = 0.007).Conclusions: This study suggests that ischemic tolerance may play a role in patients with ipsilateral TIAs before CI, allowing better recovery from a subsequent ischemic stroke.

The capability of diffusion-weighted (DW) magnetic resonance imaging (MRI) to identify very early ischemic brain injury better than conventional MRI is well known. This technique, which successfully discriminates acute from old infarcts, is particularly useful in patients with multiple brain infarcts (MBI). Among 142 patients with acute stroke consecutively admitted to our primary care center, we selected 43 patients with two or more brain infarcts on conventional MRI. All patients presented with clinical deficits consistent with acute cerebral ischemia and underwent conventional spin echo for T1 (T1-WI) and T2-weighted images (T2-WI), T1-W gadolinium-enhanced images, and echo-planar technique for DW MRI sequences. Patients underwent DW MRI examinations within 15 days of stroke onset (mean ± SD: 3 ± 3 days). In all but 1 case, the infarcts detected on DW MRI were also visible on T2-WI. The different signal pattern on DW MRI, compared with T2-WI, facilitated the detection of acute infarcts in all patients. T1-WI with gadolinium enhancement was only helpful in 5 (11.6%) patients. DW MRI enabled precise clinicotopographic correlations in 79% of our patients and provided additional clinically relevant findings in 72% of the patients. Based on the neuroradiological findings, patients were divided into three clinicotopographic types of MBI as follows: 13 patients (30.2%) presented with multiple acute infarcts, 24 patients (55.8%) with a single acute infarct and multiple old infarcts, and 6 patients (13.9%) with multiple acute and old infarcts. In conclusion, DW MRI can easily be added to conventional MRI in order to be able to distinguish acute from old infarcts, and to identify acute multiple lesions. Therefore, a better correlation between clinical symptoms and the site of lesions can be obtained, considerably improving patient care.

Although glutamic acid decarboxylase (GAD) has been implicated in IDDM, there is no direct evidence showing GAD-reactive T cells are diabetogenic in vivo. To address this issue, 3-wk-old NOD mice received two injections of purified rat brain GAD; one mouse rapidly developed diabetes 3 wk later. Splenocytes from this mouse showed a proliferative response to purified GAD, and were used to generate a CD4+ T cell line, designated 5A, that expresses TCRs encoding Vbeta2 and Vbeta12. 5A T cells exhibit a MHC restricted proliferative response to purified GAD, as well as GAD65 peptide 524-543. After antigen-specific stimulation, 5A T cells secrete IFNgamma and TNFalpha/beta, but not IL-4. They are also cytotoxic against NOD-derived hybridoma cells (expressing I-Ag7) that were transfected with rat GAD65, but not nontransfected hybridoma cells. Adoptive transfer of 5A cells into NOD/SCID mice produced insulitis in all mice. Diabetes occurred in 83% of the mice. We conclude that GAD injection in young NOD mice may, in some cases, provoke diabetes due to the activation of diabetogenic T cells reactive to GAD65 peptides. Our data provide direct evidence that GAD65 autoimmunity may be a critical event in the pathogenesis of IDDM.

PTL after solid organ transplantation are a serious complication occuring in 1–18% of patients. Between 1978 and february 1994, 1000 transplantations were performed and eleven secondary lymphoproliferative disorders were observed (1.1%). Seven of them were high-grade lymphoma and required chemotherapy.

Objective:To assess the predictivity of predefined variables with respect to long-term mortality in a cohort of patients with chronic critical leg ischaemia (CLI).Design:Prospective observational study.Methods:Census offices were asked to release information on survival or death status of 574 patients with CLI 2 years after their recruitment in the study.Results:Of 522 patients with available information, 165 (31.6%) died within 2 years of hospital admission, mostly from vascular causes as expected. Among the variables considered, male sex, current smoking, arterial hypertension, diabetes mellitus, hypercholesterolaemia, obesity, history of myocardial infarction and low ankle systolic pressure showed no univariate association with mortality. The multivariate analysis also excluded revascularisation procedures and the Fontaine stage as prognostic factors in terms of mortality. Besides age ≥ 70 years (relative risk, RR 1.94; 95% confidence interval (CI) 1.37–2.70), only a history of stroke (RR 1.82; 95% CI 1.19–2.79) and major amputation (RR 1.90; 95% CI 1.30–2.80) were significantly associated with mortality.Conclusions:CLI is a clinical condition of such severity that most of the recognised cardiovascular risk factors cannot further influence the fate of the patients, one-third of whom die within 2 years.

Objective:To draw a picture of the different practices adopted for the diagnosis, specific treatment and general care of critical leg ischaemia (CLI) in the light of the recommendations of the recent Consensus Document.Design:Prospective observational study.Setting:A representative sample of vascular and general surgery, angiology, general medicine departments of the Italian National Health Service.Subjects:Patients with leg ischaemia considered as chronic and critical according to the definition and diagnostic criteria adopted in each centre.Chief outcome measures:Epidemiological profile of the standard population; prevalence of definition criteria and of diagnostic and therapeutic procedures; short and medium-term clinical outcome as well as of the general vascular morbidity and mortality.Main results:Over a 3 month period, 574 patients were recruited in 69 centres mainly on the basis of clinical findings of CLI (rest pain and/or trophic lesions). They had an adequate diagnostic assessment of their vascular lesions and a high cardiovascular risk in terms of prior morbidity and presence of risk factors. Over half of the patients underwent revascularisation and three quarters were given pharmacological treatments. At the end of the observation period, 50 patients had died (8.7%), three had had a myocardial infarction (0.5%), six a stroke (1.0%), 70 a major amputation (12.2%) and 103 had persistent CLI (17.9%).Conclusions:This survey confirms the dramatic prognosis of patients with CLI and provides an appropriate background and setting to conduct experimental clinical studies in this field.

Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host’s metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host’s immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.