Subcutaneous chronic implantable defibrillation systems in humans

The recent introduction of subcutaneous implantable cardioverter defibrillator (S-ICD) has raised attention about the potential of this technology for clinical use in daily clinical practice. We review the methods and results of the four studies conducted in humans for approval of this innovative technology for daily practice. Two studies using a temporary S-ICD system (acute human studies) were conducted to search for an appropriate lead configuration and energy requirements. For this purpose, 4 S-ICD configurations were tested in 78 patients at the time of transvenous (TV)-ICD implantation. The optimal configuration was tested in 49 more patients to comparatively assess the subcutaneous defibrillation threshold (S-DFT) versus the standard TV-ICD. Long-term implants were evaluated in 55 patients using an implanted system (chronic human study). The acute humans studies led to an optimal S-ICD configuration comprising a parasternal electrode and left anterolateral thoracic pulse generator. Both configurations successfully terminated 98% of induced ventricular fibrillation (VF), but significantly higher energy levels were required with S-ICD than with TV-ICD systems (36.6?±?19.8 J vs. 11.1?±?8.5 J). In the chronic study, all 137 VF episodes induced at time of implant were detected with a 98% conversion rate. Two pocket infections and four lead revisions were required during 10?±?1 months of follow-up. During this period, survival was 98%, and 12 spontaneous ventricular tachyarrhythmias were detected and treated by the device. These data show that the S-ICD systems here consistently detected and converted VF induced at time of implant as well as sustained ventricular tachyarrhythmias occurring during follow-up (248).     

Missing HLA C group 1 ligand in patients with AML and MDS is associated with reduced risk of relapse and better survival after allogeneic stem cell transplantation with fludarabine and treosulfan reduced toxicity conditioning

Reduced‐toxicity conditioning with fludarabine and treosulfan is a dose‐intensive regimen with enhanced anti‐leukemia effect and acceptable toxicity in AML/MDS. HLA‐C regulates natural‐killer (NK) cell function by inhibiting Killer immunoglobulin‐like receptors (KIR) and is divided into C1 and C2 epitopes. The missing‐ligand theory suggests that missing recipient KIR ligands drives NK‐alloreactivity after SCT, in the absence of HLA‐mismatch by activating unlicensed donor NK cells. We analyzed SCT outcomes in 203 patients with AML/MDS, median age 58 years, given SCT from matched‐siblings (n = 97) or matched‐unrelated donors (n = 106), using two treosulfan doses (total 36 or 42 g/m²). 34% expressed one HLA‐C group 1 allele (C1C1), 19% one HLA‐C group 2 allele (C2C2), and 48% both KIR ligands (C1C2). Median follow‐up was 48 months. 5‐year relapse, nonrelapse mortality (NRM) and leukemia‐free survival (LFS) rates were 38%, 27%, and 36%, respectively. Relapse rates were 43%, 45%, and 26% in patients expressing C1C1, C1C2, and C2C2 ligands, respectively (P = .03). Multivariate‐analysis identified chemo‐refractory disease (HR 3.1, P = .003), poor cytogenetics (HR 1.7, P = .08), female donor to male recipient (HR 0.4, P = .01) and C2C2 ligands (HR 0.4, P = .04) as independent factors predicting relapse. HLA‐C ligands were not associated with GVHD or NRM. LFS was 33%, 30%, and 46%, respectively (P = .07). Chemorefractory disease (HR 3.1, P = .0004) and C2C2 group ligand (HR 0.6, P = .06) independently predicted LFS. Treosulfan dose did not predict any SCT outcome. In conclusion, missing HLA‐C group 1 ligand is associated with reduced relapse risk, similar NRM and improved LFS, after HLA‐matched SCT with treosulfan conditioning in AML/MDS.     

Commotio Cordis and complete heart block: Where is the block level?

Ventricular fibrillation is typically the initial arrhythmia in commotio cordis following precordium impacts that occur within an electrically vulnerable period of the cardiac cycle. Conversely, complete heart block is very rare in this context, and its mechanism and temporal course are poorly understood. The presented case concerns a 12-year-old boy, athletic skier, who developed a transient complete heart block following commotio cordis. The electrocardiographic features, the proposed block level and mechanisms of complete heart block following commotio cordis are discussed.     

High rate of hematological responses to sorafenib in FLT3‐ITD acute myeloid leukemia relapsed after allogeneic hematopoietic stem cell transplantation

Relapse represents the most significant cause of failure of allogeneic hematopoietic stem cell transplantation (HSCT) for FLT3‐ITD‐positive acute myeloid leukemia (AML), and available therapies are largely unsatisfactory. In this study, we retrospectively collected data on the off‐label use of the tyrosine kinase inhibitor sorafenib, either alone or in association with hypomethylating agents and adoptive immunotherapy, in 13 patients with post‐transplantation FLT3‐ITD‐positive AML relapses. Hematological response was documented in 12 of 13 patients (92%), and five of 13 (38%) achieved complete bone marrow remission. Treatment was overall manageable in the outpatient setting, although all patients experienced significant adverse events, especially severe cytopenias (requiring a donor stem cell boost in five patients) and typical hand‐foot syndrome. None of the patients developed graft‐vs.‐host disease following sorafenib alone, whereas this was frequently observed when this was given in association with donor T‐cell infusions. Six patients are alive and in remission at the last follow‐up, and four could be bridged to a second allogeneic HSCT, configuring a 65 ± 14% overall survival at 100 d from relapse. Taken together, our data suggest that sorafenib might represent a valid treatment option for patients with FLT3‐ITD‐positive post‐transplantation relapses, manageable also in combination with other therapeutic strategies.     

Resection of the thoracic wall in oncology

Based on our experience with 12 patients who underwent wide anterior chest wall resection in our institute, we attempt to define the indication of the different techniques for reconstruction by musculo-cutaneous flaps according to the extent of resection and location in the chest wall. The pectoralis major flaps are simple and important in the reconstruction of sternal defects; especially when dense retrosternal fibrosis has already developed after radiotherapy. The latissimus dorsi flaps are reliable and thick and suitable for coverage of major tissue loss. A new technique is also described for reconstruction of major anterolateral chest wall defects as well as sternal defects by a latissimus dorsi osteo-muscular flap. The external oblique musculo-cutaneous flaps are used to cover defects in the lateral chest wall below the 5th rib. Pedicled omental flaps are complementary flaps and can be used when muscle flaps are insufficient to replace significant tissue loss. Respiratory problems arising from paradoxical chest wall movement are temporary and may be encountered in the immediate post-operative period. Because of the development of fibrosis and of a better adaptation of the patient, this condition is well tolerated during the month following operation.     

Rectal carcinoma: CT staging with water as contrast medium

Computed tomography (CT) was used to study 42 patients with rectal carcinoma. Water was used as a contrast medium for studying the local extent of tumor in all patients. Scans were read prospectively without knowledge of the histologic staging and then compared with pathologic specimens. CT depicted the tumor in all patients. Comparison of CT and histologic results (following the Dukes classification) showed that disease was correctly staged as A in three of four patients, as B in eight of 12, as C in 15 of 17, and as D in nine of nine. Overall, carcinoma was correctly staged with CT in 35 of 42 patients (diagnostic accuracy, 83.3%). The accuracy in the assessment of local invasion was 97.6% (41 of 42). In the detection of lymph node involvement, the accuracy was 78.6% (sensitivity, 88%; specificity, 64.7%). CT is recommended in the preoperative staging of rectal carcinoma and as an aid in choosing the appropriate therapy. The use of water enema and complete distention of the rectum are reliable techniques for improving the accuracy of CT in the assessment of local invasion by cancer.     

Time-course of opioid and pituitary-adrenal hormone modifications during the immobility reaction in rabbits

A series of experiments in male rabbits examined the influence of tonic immobility (animal hypnosis) on the opioid and pituitary-adrenal hormones. The aims of the experiments were to follow the temporal modifications in hormone parameters and to discriminate the effects of immobility from those of the manipulative procedure to induce the reaction. Results show that immobility elicits increases in plasma ACTH and beta-EP, but no modifications in pituitary beta-EP. The effects of induction procedure were dissociable from those of immobility, the most marked effect being a prolonged, sustained increase of corticosterone plasma levels. Results support the hypothesis of the opioid involvement in the physiological control of immobility reaction and indicate different mechanisms underlying the immobility response and the procedure of induction.     

The effect of haptens on protein‐carrier immunogenicity

The immune response against hapten is T‐cell‐dependent, and so requires the uptake, processing and presentation of peptides on MHC class II molecules by antigen‐presenting cells to the specific T cell. Some haptens, following conjugation to the available free amines on the surface of the carrier protein, can reduce its immunogenicity. The purpose of this study was to explore the mechanism by which this occurs. Four proteins were tested as carriers and six molecules were used as haptens. The immune response to the carrier proteins was reduced > 100‐fold by some of the haptens (termed carrier immunogenicity reducing haptens – CIRH), whereas other haptens did not influence the protein immunogenicity (carrier immunogenicity non‐reducing haptens – nCIRH). Conjugation of the protein to a CIRH affected protein degradation by lysosomal cathepsins, leading to the generation of peptides that differ in length and sequence from those derived from the same native protein or that protein modified with nCIRH. Injection of CIRH‐conjugated protein into mice induced an increase in the population of regulatory T cells. The results of this study provide a putative mechanism of action for the reduction of immune response to haptenated proteins.     

Disseminated Rhinovirus C8 Infection with Infectious Virus in Blood and Fatal Outcome in a Child with Repeated Episodes of Bronchiolitis

We report a fatal case of acute lower respiratory tract disease with human rhinovirus C (HRV-C) as the unique cause in a 19-month-old girl with a history of repeated episodes of bronchiolitis. HRV-C type 8 nucleic acids were observed in respiratory, stool, and cerebrospinal fluid samples, and infectious virions were isolated from patient serum after inoculation onto reconstituted airway epithelia.     

Risks of nonchromosomal birth defects,small-for-gestational age birthweight,and prematurity with in vitro fertilization: effect of number of embryos transferred and plurality at conception versus at birth

Journal of Assisted Reproduction and Genetics - Excess embryos transferred (ET) (> plurality at birth) and fetal heartbeats (FHB) at 6 weeks’ gestation are associated with reductions...