Tumor microenvironment and immune effects of antineoplastic therapy in lymphoproliferative syndromes.

Lymphomas represent a wide group of heterogenic diseases with different biological and clinical behavior. The underlying microenvironment-specific composition seems to play an essential role in this scenario, harboring the ability to develop successful immune responses or, on the contrary, leading to immune evasion and even promotion of tumor growth. Depending on surrounding lymphoid infiltrates, lymphomas may have different prognosis. Moreover, recent evidences have emerged that confer a significant impact of main lymphoma's treatment over microenvironment, with clinical consequences. In this review, we summarize these concepts from a pathological and clinical perspective. Also, the state of the art of lymphoma's anti-idiotype vaccine development is revised, highlighting the situations where this strategy has proven to be successful and eventual clues to obtain better results in the future.

Acute coronary syndromes or myocarditis in young people: a difficult daily diagnostic challenge

Background: Chest pain (CP) represents about 5% of admissions to emergency departments (ED), even in young people. Acute coronary syndrome (ACS) and myocarditis are among the most important diagnoses to rule out. Clinical and ECG findings are not specific for either condition and separating both diagnoses is a challenge. Aim of the study: To evaluate the prevalence of ACS and myocarditis in young patients presenting with CP and elevated cardiac biomarkers to the ED and to determinate the differences in their clinical presentation. Methods: Retrospective study of all consecutive patients < 40 years old admitted to our ED from January 2009 to June 2011 for CP with elevated serum troponin concentration. All clinical, angiographic and cardiac magnetic resonance (CMR) data from the local database was reviewed. Clinical follow-up was obtained to assess all cause mortality, myocardial infarction and re-hospitalisation for CP. Results: 1588 patients < 40 years old were admitted to the ED with chest pain. 49 (3%) patients presenting with an elevated troponin I (> 0.09ug/l) were included in the study. 32.7% (16/49) were diagnosed with ACS (11 STEMI and 5 NSTEMI) and 59.2% (29/49) with myocarditis. Among the 29 patients with myocarditis, 17 presented with typical subepicardial late enhancement on CMR and 12 were diagnosed based on clinical presentation (6 had no complementary workup, 3 normal coronary angiogram and 3 inconclusive CMR). 8.1% (4/49) of patients had other diagnoses. Compared to patients with myocarditis, ACS patients were older (34.1±3.9 vs 26.9±6.4, p=0.0002) with significantly more cardiovascular risk factors (mean 2.06 vs 0.69, p<0.0001). Diabetes (18.8% vs 0%, p=0.004), dyslipidemia (56.3% vs 3.4%, p=0.0001) and family history of coronary artery disease (CAD) (37.5% vs 10.3%, p=0.050) were significantly associated with ACS. No significant association was found for smoking, hypertension and obesity. Fever (>38°C) or recent viral illness were present in 75.9% (22/29) of patients with myocarditis, and in 0% of ACS patients. During follow-up (mean 19.9 months ± 8.6), only 2 patients with myocarditis were re-admitted for chest pain. Conclusions: In this study, 32.7% of patients < 40 year old admitted to an ED with CP and elevated troponin had an ACS. Key clinical factors include diabetes, dyslipidemia, family history of CAD, fever or recent viral illness, and may help to differentiate ACS from myocarditis.

Neurological complications of infective endocarditis: risk factors, outcome, and impact of cardiac surgery: a multicenter observational study.

BACKGROUND The purpose of this study was to assess the incidence of neurological complications in patients with infective endocarditis, the risk factors for their development, their influence on the clinical outcome, and the impact of cardiac surgery. METHODS AND RESULTS This was a retrospective analysis of prospectively collected data on a multicenter cohort of 1345 consecutive episodes of left-sided infective endocarditis from 8 centers in Spain. Cox regression models were developed to analyze variables predictive of neurological complications and associated mortality. Three hundred forty patients (25%) experienced such complications: 192 patients (14%) had ischemic events, 86 (6%) had encephalopathy/meningitis, 60 (4%) had hemorrhages, and 2 (1%) had brain abscesses. Independent risk factors associated with all neurological complications were vegetation size ≥3 cm (hazard ratio [HR] 1.91), Staphylococcus aureus as a cause (HR 2.47), mitral valve involvement (HR 1.29), and anticoagulant therapy (HR 1.31). This last variable was particularly related to a greater incidence of hemorrhagic events (HR 2.71). Overall mortality was 30%, and neurological complications had a negative impact on outcome (45% of deaths versus 24% in patients without these complications; P<0.01), although only moderate to severe ischemic stroke (HR 1.63) and brain hemorrhage (HR 1.73) were significantly associated with a poorer prognosis. Antimicrobial treatment reduced (by 33% to 75%) the risk of neurological complications. In patients with hemorrhage, mortality was higher when surgery was performed within 4 weeks of the hemorrhagic event (75% versus 40% in later surgery). CONCLUSIONS Moderate to severe ischemic stroke and brain hemorrhage were found to have a significant negative impact on the outcome of infective endocarditis. Early appropriate antimicrobial treatment is critical, and transitory discontinuation of anticoagulant therapy should be considered.

Increased blood glucose variability during therapeutic hypothermia and neurological recovery after cardiac arrest

INTRODUCTION. Recent studies suggest that increased blood glucose variability (BGV) is associated with ICU mortality1. Hypothermia is known to induce insulin resistance, thus potentially increasing BGV. No studies however have examined the effect of therapeutic hypothermia (TH) on insulin requirements and BGV. OBJECTIVES. To examine the effect of TH on BGV and its relationship to outcome in patients with coma after cardiac arrest (CA). METHODS. We prospectively studied 132 consecutive comatose CA patients treated with TH (target core temp 33_C for 24 h, using surface cooling). All patients were treated with intravenous insulin (blood glucose target 6-8 mM), according to a written algorithm, with nurse-driven adjustment of insulin dose. For each patient, standard deviation of repeated blood glucose samples was used to calculate BGV. Two time-points, comparable in duration, were studied: TH (stable maintenance phase, i.e. 6-24 h, core temp ± 33_C) vs. Normothermia (NT, i.e. after rewarming, stable normothermic phase, core temp ± 37_C). Mortality and neurological recovery (Glasgow-Pittsburgh Cerebral Performance Categories, CPC, dichotomized as good = CPC 1-2 vs. poor = CPC 3-5) were assessed at hospital discharge. Statistical analysis was performed with ANOVA for repeated measures. RESULTS. Compared to NT, TH was associated with increased intravenous insulin dose (0.8 ± 1.1 vs. 1.6 ± 2 U/h, P\0.0001), higher mean (6.9 ± 1.3 vs. 7.7 ± 1.8 mM, P\0.0001) and maximum (9.1 ± 3.7 vs. 10.9 ± 3.6 mM, P\0.0001) blood glucose, and increased BGV (1.3 ± 1.2 vs. 1.7 ± 1.1 mM, P = 0.004). Increased BGV was strongly associated with mortality (2.5 ± 1.5 mM in non-survivors vs. 1.6 ± 1 mM in survivors, P\0.001) and worse outcome (2.3 ± 1.4 mM in patients with poor vs. 1.5 ± 0.8 mM in those with good neurological recovery, P\0.0001). CONCLUSIONS. Therapeutic hypothermia is associated with increased insulin requirements and higher blood glucose variability,which in turn correlateswithworse prognosis in patientswith post- CA coma. Strategies aimed to maintain stable glycemic profile and avoid blood glucose variability might contribute to optimize the management of TH and may translate into better outcome.

Aptitude au volant: quelle conduite [Aptitude to drive: what road to take?].

Tout médecin de premier recours devrait pouvoir se prononcer sur l'aptitude à la conduite automobile de son patient. La problématique du conducteur âgé, dépendant soit de l'alcool ou de drogues, sous traitement de médicaments psychotropes, ou encore diabétique, est abordée à la lumière des dispositions légales et des récentes recommandations. Cet article aborde également les aspects relatifs aux problèmes neurologiques, cardiologiques et orthopédiques. Any primary care doctor should be able to decide on the fitness to drive of a given patient. The issue of an older driver, patients addicted to alcohol or drugs, under current psychotropic drug treatment, or diabetic, is discussed in the light of legal provisions and current recommendations. This article also discusses aspects associated with neurological, cardiac and orthopedic issues.

Inter-informant agreement and prevalence estimates for mood syndromes: Direct interview vs. family history method.

BACKGROUND: The use of the family history method is recommended in family studies as a type of proxy interview of non-participating relatives. However, using different sources of information can result in bias as direct interviews may provide a higher likelihood of assigning diagnoses than family history reports. The aims of the present study were to: 1) compare diagnoses for threshold and subthreshold mood syndromes from interviews to those relying on information from relatives; 2) test the appropriateness of lowering the diagnostic threshold and combining multiple reports from the family history method to obtain comparable prevalence estimates to the interviews; 3) identify factors that influence the likelihood of agreement and reporting of disorders by informants. METHODS: Within a family study, 1621 informant-index subject pairs were identified. DSM-5 diagnoses from direct interviews of index subjects were compared to those derived from family history information provided by their first-degree relatives. RESULTS: 1) Inter-informant agreement was acceptable for Mania, but low for all other mood syndromes. 2) Except for Mania and subthreshold depression, the family history method provided significantly lower prevalence estimates. The gap improved for all other syndromes after lowering the threshold of the family history method. 3) Individuals who had a history of depression themselves were more likely to report depression in their relatives. LIMITATIONS: Low proportion of affected individuals for manic syndromes and lack of independence of data. CONCLUSIONS: The higher likelihood of reporting disorders by affected informants entails the risk of overestimation of the size of familial aggregation of depression.

Reasons for discontinuation of recommended therapies according to the patients after acute coronary syndromes.

BACKGROUND: The prescription of recommended medical therapies is a key factor to improve prognosis after acute coronary syndromes (ACS). However, reasons for cardiovascular therapies discontinuation after hospital discharge are poorly reported in previous studies. METHODS: We enrolled 3055 consecutive patients hospitalized with a main diagnosis of ACS in four Swiss university hospitals with a prospective one-year follow-up. We assessed the self-reported use of recommended therapies and the reasons for medication discontinuation according to the patient interview performed at one-year follow-up. RESULTS: 3014 (99.3%) patients were discharged with aspirin, 2983 (98.4%) with statin, 2464 (81.2%) with beta-blocker, 2738 (90.3%) with ACE inhibitors/ARB and 2597 (100%) with P2Y12 inhibitors if treated with coronary stent. At the one-year follow-up, the discontinuation percentages were 2.9% for aspirin, 6.6% for statin, 11.6% for beta-blocker, 15.1% for ACE inhibitor/ARB and 17.8% for P2Y12 inhibitors. Most patients reported having discontinued their medication based on their physicians' decision: 64 (2.1%) for aspirin, 82 (2.7%) for statin, 212 (8.6%) for beta-blocker, 251 (9.1% for ACE inhibitor/ARB) and 293 (11.4%) for P2Y12 inhibitors, while side effect, perception that medication was unnecessary and medication costs were uncommon reported reasons (<2%) according to the patients. CONCLUSIONS: Discontinuation of recommended therapies after ACS differs according the class of medication with the lowest percentages for aspirin. According to patients, most stopped their cardiovascular medication based on their physician's decision, while spontaneous discontinuation was infrequent.

The cervico-thoracic outlet compression syndrome. Analysis of surgical treatment.

Surgical treatment of the thoracic outlet compression syndrome is being presently reconsidered. Until these last few years, there was the choice between two interventions only: scalenotomy, a simple operation entailing no complication, but with a 60% recurrence rate--or the resection of the first rib through an axillary approach, an efficacious intervention which caused, however, serious nervous complications in 14% of treated cases. The follow-up of 75 cases operated for a TOCS reveals to the authors that--all techniques taken into account--results are unsatisfactory in 33% of cases. These failures are due either to technical deficiencies, or to a complication arising in the course of the operation, or to an erroneous diagnosis. The authors resort to surgery only to treat serious vascular syndromes (absolute indication) or invalidating neurological compression syndromes, after failure of physical therapy (relative indication). They propose a cervical approach--the only one enabling a safe dissection of the brachial plexus--a partial scalenectomy, resection of all fibrous bands pressing on nervous trunks, or the resection of a cervical rib. Should the costo-clavicular space appear anatomically too narrow, the first rib, already partially freed by the cervical approach, will be resected through the axillary route.

Prenatal diagnosis of dysmorphic syndromes by routine fetal ultrasound examination across Europe.

OBJECTIVES: Ultrasound scan in the mid-trimester of pregnancy is now a routine part of prenatal care in most European countries. The objective of this study was to evaluate the prenatal diagnosis of dysmorphic syndromes by fetal ultrasound examination. METHODS: Data from 20 registries of congenital malformations in 12 European countries were included in the study. RESULTS: There were 2454 cases with congenital heart diseases, 479 of which were recognized syndromes, including 375 chromosomal anomalies and 104 syndromes without chromosomal anomalies. Fifty-one of the 104 were detected prenatally (49.0%). One hundred and ninety-two of 1130 cases with renal anomalies were recognized syndromes, including 128 chromosomal anomalies and 64 syndromes without chromosomal anomalies; 162 of them (84.4%) were diagnosed prenatally, including 109 chromosomal anomalies and 53 non-chromosomal syndromes. Fifty-four of the 250 cases with limb defects were recognized syndromes, including 16 chromosomal syndromes and 38 syndromes without chromosomal anomalies; 21 of these 54 syndromes were diagnosed prenatally (38.9%), including 9 chromosomal syndromes. There were 243 cases of abdominal wall defects including 57 recognizable syndromes, 48 with omphalocele and 9 with gastroschisis; 48 were diagnosed prenatally (84.2%). Twenty-six of the 187 cases with diaphragmatic hernia had recognized syndromes, including 20 chromosomal aberrations and 6 syndromes without chromosomal anomalies. Twenty-two of them (84.6%) were detected prenatally. Sixty-four of 349 cases with intestinal anomalies were recognized syndromes; 24 were diagnosed prenatally (37.5%). There were 553 cases of cleft lip and palate (CL(P)) and 198 of cleft palate (CP) including 74 chromosomal anomalies and 73 recognized non-chromosomal syndromes. Prenatal diagnosis was made in 51 cases of CL(P) (53.7%) and 7 of CP (13.7%). Twenty-two of 188 anencephalic cases were syndromic and all were diagnosed prenatally. Of 290 cases with spina bifida, 18 were recognized syndromes, and of them 17 were diagnosed prenatally. All 11 syndromic encephaloceles were diagnosed prenatally. CONCLUSIONS: Around 50% of the recognized syndromes which are associated with major congenital anomalies (cardiac, renal, intestinal, limb defects, abdominal wall defects and oral clefts) can be detected prenatally by the anomaly scan. However the detection rate varies with the type of syndrome and with the different countries' policies of prenatal screening.

High cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function.

High-dose cefepime therapy is recommended for febrile neutropenia. Safety issues have been raised in a recent meta-analysis reporting an increased risk of mortality during cefepime therapy. Cefepime-related neurological toxicity has been associated with overdosing due to severe renal dysfunction. This study aimed to investigate the association between cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients. Cefepime trough concentrations (by high-performance liquid chromatography) were retrospectively analyzed for 30 adult febrile neutropenic patients receiving the recommended high-dose regimen (6 g/day for a glomerular filtration rate [GFR] of >50 ml/min). The dose adjustment to renal function was evaluated by the ratio of the cefepime daily dose per 100 ml/min of glomerular filtration. The association between cefepime plasma concentrations and neurological toxicity was assessed on the basis of consistent neurological symptoms and/or signs (by NCI criteria). The median cefepime concentration was 8.7 mg/liter (range, 2.1 to 38 mg/liter) at a median of 4 days (range, 2 to 15 days) after the start of therapy. Neurological toxicity (altered mental status, hallucinations, or myoclonia) was attributed to cefepime in 6/30 (20%) patients (median GFR, 45 ml/min; range, 41 to 65 ml/min) receiving a median dose of 13.2 g/day per 100 ml/min GFR (range, 9.2 to 14.3 g/day per 100 ml/min GFR). Cefepime discontinuation resulted in complete neurological recovery for five patients and improvement for one patient. A multivariate logistic regression model confirmed high cefepime concentrations as an independent predictor of neurological toxicity, with a 50% probability threshold at ≥22 mg/liter (P = 0.05). High cefepime plasma concentrations are associated with neurological toxicity in febrile neutropenic patients with mild renal dysfunction. Careful adherence to normalized dosing per 100 ml/min GFR is crucial. Monitoring of plasma concentrations may contribute to preventing neurological toxicity of high-dose therapy for this life-threatening condition.

Early neurological impairment and severe anemia in a newborn with Pearson syndrome

BACKGROUND: Pearson marrow-pancreas syndrome (PS) is usually a fatal mitochondrial disease, mostly diagnosed during infancy or postmortem. PS is caused by the deletions or duplications of mitochondrial DNA (mtDNA). The tissue distribution and relative proportions of expressed abnormal mtDNA determine the phenotype and the clinical course. MATERIALS AND METHODS: We describe the case of a term baby boy who was diagnosed with PS early in the neonatal period due to severe aregenerative anemia and persistent lactic acidosis. RESULTS: His neurological examination was abnormal since birth. Brain magnetic resonance imaging (MRI) at term was abnormal, indicating that mitochondrial encephalopathy in PS can be already manifested in the neonatal period. To our knowledge, neonatal encephalopathy in PS has not been previously described. CONCLUSION: PS is a rare condition diagnosed in the newborn. It should be suspected in the presence of severe anemia and persistent lactic acidosis, and may manifest with early encephalopathy.

Systematic molecular and cytogenetic screening of 100 patients with marfanoid syndromes and intellectual disability.

The association of marfanoid habitus (MH) and intellectual disability (ID) has been reported in the literature, with overlapping presentations and genetic heterogeneity. A hundred patients (71 males and 29 females) with a MH and ID were recruited. Custom-designed 244K array-CGH (Agilent®; Agilent Technologies Inc., Santa Clara, CA) and MED12, ZDHHC9, UPF3B, FBN1, TGFBR1 and TGFBR2 sequencing analyses were performed. Eighty patients could be classified as isolated MH and ID: 12 chromosomal imbalances, 1 FBN1 mutation and 1 possibly pathogenic MED12 mutation were found (17%). Twenty patients could be classified as ID with other extra-skeletal features of the Marfan syndrome (MFS) spectrum: 4 pathogenic FBN1 mutations and 4 chromosomal imbalances were found (2 patients with both FBN1 mutation and chromosomal rearrangement) (29%). These results suggest either that there are more loci with genes yet to be discovered or that MH can also be a relatively non-specific feature of patients with ID. The search for aortic complications is mandatory even if MH is associated with ID since FBN1 mutations or rearrangements were found in some patients. The excess of males is in favour of the involvement of other X-linked genes. Although it was impossible to make a diagnosis in 80% of patients, these results will improve genetic counselling in families.