[Thoracic insufficiency syndrome]. / Síndrome de insuficiencia torácica.

The compendium of disorders that affect the normal growth or function of the thorax will cause Thoracic Insufficiency Syndrome (TIS). TIS is defined as the inability of the chest to sustain normal breathing and/or lung growth. The etiology of the syndrome may be secondary to spinal deformities, global deformities of the chest, neuromuscular dysfunction or the combination of any these. Its manifestation is based on a history that highlights respiratory symptoms, a physical examination that demonstrates chest deformity, abnormal radiographic findings and/or computed tomography of the chest, accompanied by alterations in lung function or other studies of respiratory function. This syndrome must be treated with haste since it progressively worsens with the aggravation of the underlying condition(s) which is unfavorable to the irreversible physiological changes of the lung that occur during development, and are directly related to the respiratory insufficiencies. The vertical expandable prosthetic titanium rib (VEPTR) was developed as a treatment procedure that aims to restore the volume and function of the thorax with the purpose of enabling thoracic growth during the development of the child or adolescent. The treatment targets the components of the rib cage as a unit, in order to prevent or treat respiratory insufficiencies. Its indications include children with early development scoliosis who are prone to develop SIT. The proposed procedure entails a high incidence of complications and conflicting results that limit its efficacy as a treatment, which is why it is a subject of great controversy in the medical literature.

Los procesos que afecten el crecimiento normal o la función del tórax causarán el síndrome de insuficiencia torácica (SIT). Éste se define como la incapacidad del tórax de sostener una respiración normal y/o crecimiento pulmonar. La etiología del síndrome puede ser secundaria a deformidades de la columna, deformidades globales del tórax, disfunción neuromuscular o la combinación de éstas. Su manifestación se basa en un historial que resalta síntomas respiratorios, un examen físico que demuestra deformidad del tórax, hallazgos anormales radiográficos y/o tomografía computarizada del pecho, acompañados de alteración en la función pulmonar o de otros estudios de la función respiratoria. Este síndrome debe ser tratado con premura debido a que progresivamente empeora con el agravamiento de la condición subyacente, lo que resulta irreversiblemente desfavorable en los cambios fisiológicos del pulmón y se relaciona con insuficiencia respiratoria durante el desarrollo. El tratamiento expansor de costilla conocido en inglés como vertical expandable prosthetic titanium rib (VEPTR) propone restaurar el volumen y la función torácica con el propósito de permitir el crecimiento del tórax a través del desarrollo del paciente. El tratamiento se dirige a los componentes de la caja torácica como una unidad, con el fin de prevenir o tratar la insuficiencia respiratoria. Sus indicaciones incluyen niños con escoliosis de desarrollo temprano que sean propensos a desarrollar el SIT. El procedimiento propuesto conlleva una alta incidencia de complicaciones y resultados conflictivos que limitan su eficacia como tratamiento, por lo que es un tema de gran controversia en la literatura médica.

Genetic landscape of ultra-stable chronic lymphocytic leukemia patients.

Background: Chronic lymphocytic leukemia (CLL) has a heterogeneous clinical course. Beside patients requiring immediate treatment, others show an initial indolent phase followed by progression and others do not progress for decades. The latter two subgroups usually display mutated IGHV genes and a favorable FISH profile. Patients and methods: Patients with absence of disease progression for over 10 years (10-34) from diagnosis were defined as ultra-stable CLL (US-CLL). Forty US-CLL underwent extensive characterization including whole exome sequencing (WES), ultra-deep sequencing and copy number aberration (CNA) analysis to define their unexplored genetic landscape. Microarray analysis, comparing US-CLL with non-US-CLL with similar immunogenetic features (mutated IGHV/favorable FISH), was also carried out to recognize US-CLL at diagnosis. Results: WES was carried out in 20 US-CLL and 84 non-silent somatic mutations in 78 genes were found. When re-tested in a validation cohort of 20 further US-CLL, no recurrent lesion was identified. No clonal mutations of NOTCH1, BIRC3, SF3B1 and TP53 were found, including ATM and other potential progression driving mutations. CNA analysis identified 31 lesions, none with known poor prognostic impact. No novel recurrent lesion was identified: most cases showed no lesions (38%) or an isolated del(13q) (31%). The expression of 6 genes, selected from a gene expression profile analysis by microarray and quantified by droplet digital PCR on a cohort of 79 CLL (58 US-CLL and 21 non-US-CLL), allowed to build a decision-tree capable of recognizing at diagnosis US-CLL patients. Conclusions: The genetic landscape of US-CLL is characterized by the absence of known unfavorable driver mutations/CNA and of novel recurrent genetic lesions. Among CLL patients with favorable immunogenetics, a decision-tree based on the expression of 6 genes may identify at diagnosis patients who are likely to maintain an indolent disease for decades.

[Treatment of coronary three-vessel disease in patients above 75 years]. / Therapie der koronaren Dreigefäßerkrankung bei Patienten über 75 Jahren.

BACKGROUND: Chronic ischemic heart disease take the first place in cause of death in Germany. The proportion of patients aged 75 years or older amounts more than 80 %. Due to their growing part of population the medical care of older patients becomes increasingly important. In this investigation patients aged ≥ 75 years with coronary three-vessel disease were characterized and various treatment strategies were compared. PATIENTS AND METHODS: This analysis was retrospective. The data of patients aged 75 years or older with three-vessel disease diagnosed by coronary angiography at the Klinikum Lippe Detmold between 2005 and 2007 were collected. Depending on the received therapy they were parted in three groups: optimal drug therapy (OMT), interventional - (PCI) and surgical revascularization (CABG). Patient characteristics as well as survival- and MACCE-rates during follow up were ascertained. Subgroup analyzes were performed for acute coronary syndrom (ACS) and stable coronary artery disease( CAD). RESULTS: The data of 434 patients with an average age of 79 years were documented. 139 (32.0 %) were assigned to the OMT- 189 (43.6 %) to the PCI- and 106 (24.4 %) to the CABG-group. Overall there was no significant difference between the three groups regarding mortality. In the subgroup of patients wit ACS (n = 180) mortality significantly increased in the OMT-group compared to the two invasive therapies (PCI (p = 0.029), CABG (p = 0.045)). The subgroup of patients with stable CAD showed no significant differences in mortality between the three types of therapy. CONCLUSIONS: Older patients benefit from an interventional or surgical revascularization in the context of ACS. In contrast, in elderly with stable CAD optimal medical therapy provides a reasonable alternative to invasive therapy without increase in mortality.

Does ex vivo CD34+ positive selection influence outcome after autologous hematopoietic stem cell transplantation in systemic sclerosis patients?

This EBMT Autoimmune Disease Working Party study aimed to evaluate the influence of CD34+ positive graft selection (CD34+) on the outcome of systemic sclerosis (SSc) patients after autologous hematopoietic stem cell transplantation (AHSCT). Clinical and laboratory data from 138 SSc patients at diagnosis, before and after AHSCT were retrospectively analyzed. CD34+ selection was performed in 47.1% (n=65) patients. By multivariate analysis adjusting for all factors differing between the two groups (without or with CD34+), there was no statistically significant difference in terms of overall survival (hazard ratio (HR): 0.98, 95% confidence interval (CI) 0.40-2.39, P=0.96), PFS (HR: 1.55, 95% CI 0.83-2.88, P=0.17) and incidence of relapse or progression (HR: 1.70, 95% CI 0.85-3.38, P=0.13). We demonstrate that CD34+ does not add benefit to the outcome of SSc patient treated with AHSCT. These findings should be further confirmed by prospective randomized trials.

Differences among young adults, adults and elderly chronic myeloid leukemia patients.

BACKGROUND: The incidence of chronic myeloid leukemia (CML) increases with age, but it is unclear how the characteristics of the disease vary with age. In children, where CML is very rare, it presents with more aggressive features, including huge splenomegaly, higher cell count and higher blast cell percentage. PATIENTS AND METHODS: To investigate if after childhood the disease maintains or loses these characteristics of aggressiveness, we analyzed 2784 adult patients, at least 18 years old, registered by GIMEMA CML WP over a 40-year period. RESULTS: Young adults (YAs: 18-29 years old) significantly differed from adults (30-59 years old) and elderly patients (at least 60 years old) particularly for the frequency of splenomegaly (71%, 63% and 55%, P < 0.001), and the greater spleen size (median value: 4.5, 3.0 and 1.0 cm, P < 0.001). According to the EUTOS score, that is age-independent, high-risk patients were more frequent among YAs, than among adult and elderly patients (18%, 9% and 6%, P < 0.001). In tyrosine kinase inhibitors-treated patients, the rates of complete cytogenetic and major molecular response were lower in YAs, and the probability of transformation was higher (16%, 5% and 7%, P = 0.011). CONCLUSIONS: The characteristics of CML or the host response to leukemia differ with age. The knowledge of these differences and of their causes may help to refine the treatment and to improve the outcome. CLINICAL TRIAL NUMBERS: NCT00510926, NCT00514488, NCT00769327, NCT00481052.

Minimal morphological criteria for defining bone marrow dysplasia: a basis for clinical implementation of WHO classification of myelodysplastic syndromes.

The World Health Organization classification of myelodysplastic syndromes (MDS) is based on morphological evaluation of marrow dysplasia. We performed a systematic review of cytological and histological data from 1150 patients with peripheral blood cytopenia. We analyzed the frequency and discriminant power of single morphological abnormalities. A score to define minimal morphological criteria associated to the presence of marrow dysplasia was developed. This score showed high sensitivity/specificity (>90%), acceptable reproducibility and was independently validated. The severity of granulocytic and megakaryocytic dysplasia significantly affected survival. A close association was found between ring sideroblasts and SF3B1 mutations, and between severe granulocytic dysplasia and mutation of ASXL1, RUNX1, TP53 and SRSF2 genes. In myeloid neoplasms with fibrosis, multilineage dysplasia, hypolobulated/multinucleated megakaryocytes and increased CD34+ progenitors in the absence of JAK2, MPL and CALR gene mutations were significantly associated with a myelodysplastic phenotype. In myeloid disorders with marrow hypoplasia, granulocytic and/or megakaryocytic dysplasia, increased CD34+ progenitors and chromosomal abnormalities are consistent with a diagnosis of MDS. The proposed morphological score may be useful to evaluate the presence of dysplasia in cases without a clearly objective myelodysplastic phenotype. The integration of cytological and histological parameters improves the identification of MDS cases among myeloid disorders with fibrosis and hypocellularity.

Bendamustine in combination with ofatumumab in relapsed or refractory chronic lymphocytic leukemia: a GIMEMA Multicenter Phase II Trial.

We conducted a phase II, noncomparative, open-label, multicenter GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) study (CLL0809) to assess the efficacy and safety of bendamustine in combination with ofatumumab (BendOfa) in relapsed/refractory chronic lymphocytic leukemia (CLL). Forty-seven patients from 14 centers were evaluated. Therapy consisted of bendamustine (70 mg/m(2)) for 2 consecutive days every 28 days, and ofatumumab 300 mg on day 1 and 1000 mg on day 8 during the first cycle, and 1000 mg on day 1 subsequently. Treatment was administered up to six cycles. The overall response rate (ORR), as per intention-to-treat analysis, was 72.3% (95% confidence of interval (CI), 57-84%), with 17% complete responses. After a median follow-up of 24.2 months, the overall survival was 83.6% (95% CI, 73.0-95.7%) and the progression-free survival (PFS) was 49.6% (95% CI, 35.9-68.6%). The median PFS was 23.6 months. Univariate and multivariate analyses were used to identify clinical and biological characteristics associated with ORR and PFS. Myelosuppression was the most common toxicity; grade ≥3 neutropenia was observed in 61.7% of patients; however, grade ≥3 infections occurred in 6% of patients. BendOfa is feasible and effective in relapsed/refractory CLL patients, including patients with high-risk clinical and biological features.

[Acute hepatic failure after ingestion of mushrooms]. / Akutes Leberversagen nach Pilzingestion.

This report is about a married couple who were admitted to hospital suffering from gastrointestinal complaints after eating mushrooms. With the suspicion of poisoning with Amanita phalloides treatment started with elimination of the toxins, symptomatic therapy and specific therapy with silibinin. After quantitative determination of the Amanita toxins the patients were immediately transferred to a university hospital.Poisoning by the death cap mushroom is responsible for acute hepatic and often also renal failure and is accompanied by a high mortality. Clinical symptoms follow a three-phase course with gastrointestinal complaints, an asymptomatic interval and finally the hepatorenal phase. Even in suspected cases of intoxication, treatment should be started by antidote therapy with silibinin.

Proliferation centers in chronic lymphocytic leukemia: correlation with cytogenetic and clinicobiological features in consecutive patients analyzed on tissue microarrays.

To better define the significance of proliferation centers (PCs), the morphological hallmark of chronic lymphocytic leukemia (CLL), lymph node biopsies taken from 183 patients were submitted to histopathologic and fluorescence in situ hybridization (FISH) studies using a 5-probe panel on tissue microarrays. Seventy-five cases (40.9%) with confluent PCs were classified as 'PCs-rich' and 108 cases (59.1%) with scattered PCs were classified as 'typical'. Complete FISH data were obtained in 101 cases (55.1%), 79 of which (78.2%) displayed at least one chromosomal aberration. The incidence of each aberration was: 13q- 36,7%, 14q32 translocations 30.8%, 11q- 24.7%, trisomy 12 19.5% and 17p- 15.6%. Five cases showed extra copies of the 14q32 region. The 'PCs-rich' group was associated with 17p-, 14q32/IgH translocation, +12, Ki-67>30%. The median survival from the time of tissue biopsy for PCs-rich and typical groups was 11 and 64 months, respectively (P=0.00001). The PCs-rich pattern was the only predictive factor of an inferior survival at multivariate analysis (P=0.022). These findings establish an association between cytogenetic profile and the amount of PC in CLL, and show that this histopathologic characteristic is of value for risk assessment in patients with clinically significant adenopathy.

A prospective survey of febrile events in hematological malignancies.

The Hema e-Chart prospectively collected data on febrile events (FEs) in hematological malignancy patients (HMs). The aim of the study was to assess the number, causes and outcome of HM-related FEs. Data were collected in a computerized registry that systematically approached the study and the evolution of FEs developing in a cohort of adult HMs who were admitted to 19 hematology departments in Italy from March 2007 to December 2008. A total of 869 FEs in 3,197 patients with newly diagnosed HMs were recorded. Fever of unidentified origin (FUO) was observed in 386 cases (44.4%). The other causes of FE were identified as noninfectious in 48 cases (5.5%) and infectious in 435 cases (50.1%). Bacteria were the most common cause of infectious FEs (301 cases), followed by fungi (95 cases), and viruses (7 cases). Mixed agents were isolated in 32 episodes. The attributable mortality rate was 6.7% (58 FEs). No deaths were observed in viral infection or in the noninfectious groups, while 25 deaths were due to FUO, 16 to bacterial infections, 14 to fungal infections, and three to mixed infections. The Hema e-Chart provided a complete system for the epidemiological study of infectious complications in HMs.

Leisure sport activity as a trigger for acute coronary events in men without known coronary artery disease : a single-center case study.

INTRODUCTION: Leisure sport activity (LSA) is gaining in importance among middle-aged and senior men in the German population. There is a consensus that regular aerobic exercise at moderate intensities and increased physical fitness are associated with a reduced risk of fatal and nonfatal acute cardiac events (ACE) in middle-aged individuals. However, vigorous exercise (VE) can acutely and transiently increase the risk of an ACE in susceptible individuals. There is an ongoing discussion as to whether preparticipation screening may prevent such events. This case study characterizes patients participating in LSA who had not been involved in preparticipation screening prior to their ACE. METHODS: In the period between June 2003 and July 2009, all consecutive patients with an ACE presenting at the catheter laboratory were retrospectively screened for VE that had occurred during LSA. All 13 men with previously unknown coronary artery disease (CAD) had exercised regularly. All patients underwent coronary angiography. This study characterized clinical parameters, duration of LSA, coronary diagnostic procedure, as well as therapeutic intervention. RESULTS: In seven patients, cardiovascular (CV) risk factors comprised arterial hypertension in seven, hyperlipidemia in seven, smoking or former smoking in two, family history of CV disease in four, and previous peripheral atherosclerotic disease in two. The culprit lesion was identified in seven patients in the left anterior descending artery, in four in the right coronary artery, and in two in the circumflex artery. The mean left ventricular ejection fraction was 65% (45-84). The mean complexity of the lesions using the syntax score was 17 (2-36). PCI was performed in 12 patients, while one patient was transferred for coronary artery bypass grafts. All patients survived their ACE. CONCLUSION: This case study supports the data indicating that ACE in men with previously unknown CAD is not uncommon during LSA. This patient cohort provides data on a group of patients who might benefit from preparticipation screening.

[Renal artery stenosis: angioplasty or drug treatment?]. / Nierenarterienstenose: Intervention oder medikamentöse Behandlung?

BACKGROUND AND OBJECTIVE: Angioplasty in patients with renal artery stenosis aims at reducing blood pressure and at improving kidney function. Its efficacy has however been questioned by recent published data. It was the aim of this retrospective study to compare angioplasty with medical treatment in an unselected patient population. METHODS: Data on 109 patients were retrospectively analysed. This cohort included all those patients admitted to the Lippe-Detmold Hospital between 1992 and 2008 for renal artery stenosis. The data included blood pressure, creatinine-based calculated glomerular filtration rate (cGFR), any renal dialysis, cardiovascular risk factors, events and survival time after transluminal renal angioplasty or drug treatment, respectively. RESULTS: Patients who had undergone angioplasty were younger (p = 0.04), had less cardiovascular co-morbidity (p < 0.01), but a higher degree of stenosis (p < 0.01). After a median follow-up of 32.5 (angioplasty) and 36.0 months (drug treatment), respectively, a significant decrease of cGFR was recorded in drug treated patients (- 16.2 ml/min, 95 %, CI - 25.7 to - 6.7) but not in the angioplasty group (- 4.5 ml/min, 95 %, CI - 13.5 to 4.5). There were no other significant differences were not observed. CONCLUSION: Younger patients with a high degree of renal artery stenosis but without generalized atherosclerosis more frequently underwent angioplasty in clinical practice. The smaller post-angioplasty reduction in the loss of renal function in this group needs to be validated in a prospective, randomized study.