Predictive Value of QT Dispersion for Ventricular Tachyarrhythmias in Patients with Implantable Cardioverter Defibrillator

Background: QT dispersion, measured as interlead variability of QT intervals in the surface electrocardiogram, has been demonstrated to provide an indirect measurement of the inhomogeneity of myocardial repolarization as a potential substrate for ventricular arrhythmias. Methods: QT dispersion was measured in the standard 12-lead ECG in 51 patients at the time of implantation of a third generation implantable cardioverter defibrillator (ICD) with automatic electrogram storage capability for electrical events triggering device therapy. In addition, QT dispersion was measured in 100 age- and sex-matched healthy controls. All 5 1 study patients with ICD were prospectively followed to determine possible associations between QT dispersion at implant and subsequent spontaneous ICD shocks for ventricular tachyarrhythmias (VT). Results: Rate-corrected QT dispersion and adjusted QTc dispersion, which takes account of the number of leads measured, were significantly greater in ICD patients compared to controls (76 ± 25 ms vs 46 ± 11 ms, and 24 ± 7 ms vs 14 ± 3 ms respectively, P < 0.0 1). During 15 ± 8 months follow-up, ventricular tachyarrhythmias occurred in 23 (45%) of 51 ICD patients. QTc dispersion and adjusted QTc dispersion were not significantly different between ICD patients with ventricular tachyarrhythmias and ICD patients without ventricular tachyarrhythmias during follow-up (74 ± 19 ms versus 77 ± 29 ms, and 23 ± 6 ms vs 25 ± 8 ms respectively). Conclusion: Increased QT dispersion measured in the 12-lead standard ECG does not appear to be a useful marker for future arrhythmic events in a mixed patient population with ICD.     

Peripheral blood progenitor cells mobilized by chemotherapy plus granulocyte-colony stimulating factor accelerate both neutrophil and platelet recovery after high-dose VP16, ifosfamide and cisplatin

Summary. We report on the chemotherapy plus granulocyte colony-stimulating factor (G-CSF) induced mobilization of peripheral blood progenitor cells (PBPCs) and their impact on haematopoietic recovery following high-dose chemotherapy. Twenty-four patients with advanced solid tumours or lymphomas received standard-dose chemotherapy with VP16, ifosfamide and cisplatin (VIP) followed by filgrastim (G-CSF; 5 μg/kg s.c. daily for 14 d) for the prevention of chemotherapy induced neutropenia and for the simultaneous mobilization of PBPCs. Maximal numbers of progenitors of different lineages were reached at day 11 (range 9–14) after VIP chemotherapy. A median of 0·415 × 10⁹/1 CD34⁺ cells (range 0·11–1·98), 9000 CFU-GM/ml (range 2800–17700). 3500 BFU-E/ml (range 400–10800) and 200 CFU-GEMM/ml (range 0–4400) were recruited. One single apheresis yielded a median of 1·6 × 10⁸ mononuclear cells/kg (range 0·2–5·4) or 5·4 × 10⁶ CD34⁺ cells/kg body weight (range 0·2–24·2). Fourteen patients who showed at least a partial remission after two cycles of the standard-dose chemotherapy regimen were subjected to high-dose VIP chemotherapy (cumulative doses of 1500 mg/m² VP16, 12 g/m² ifosfamide and 150 mg/m² cisplatin) with or without PBPC support. The first six patients were treated with growth factors only (IL-3/GM-CSF) and did not receive PBPCs, whereas the following eight patients were supported with PBPCs in addition to IL-3 and GM-CSF. Neutrophil recovery as well as platelet recovery were significantly faster in patients receiving PBPCs with a median of 6·5 d below 0·1 × 10⁹ neutrophils/1 and 3 d below 20 × 10⁹ platelets/1 as compared to 10·5 d and 8 d in control patients receiving growth factors only. The accelerated platelet recovery in patients supported with PBPCs might be explained—in the absence of detectable colony-forming units megakaryocyte—by the presence of glycoprotein IIb/IIIa⁺, non-proliferating endomitotic megakaryocytic precursor cells within G-CSF mobilized PBPCs. Our data demonstrate that chemotherapy plus G-CSF mobilized PBPCs accelerate both neutrophil and platelet recovery after high-dose VIP chemotherapy in patients with solid tumours or lymphomas.     

The PCBP1 gene encoding poly(rc) binding protein i is recurrently mutated in Burkitt lymphoma

The genetic hallmark of Burkitt lymphoma is the translocation t(8;14)(q24;q32), or one of its light chain variants, resulting in IG‐MYC juxtaposition. However, these translocations alone are insufficient to drive lymphomagenesis, which requires additional genetic changes for malignant transformation. Recent studies of Burkitt lymphoma using next generation sequencing approaches have identified various recurrently mutated genes including ID3, TCF3, CCND3, and TP53. Here, by using similar approaches, we show that PCBP1 is a recurrently mutated gene in Burkitt lymphoma. By whole‐genome sequencing, we identified somatic mutations in PCBP1 in 3/17 (18%) Burkitt lymphomas. We confirmed the recurrence of PCBP1 mutations by Sanger sequencing in an independent validation cohort, finding mutations in 3/28 (11%) Burkitt lymphomas and in 6/16 (38%) Burkitt lymphoma cell lines. PCBP1 is an intron‐less gene encoding the 356 amino acid poly(rC) binding protein 1, which contains three K‐Homology (KH) domains and two nuclear localization signals. The mutations predominantly (10/12, 83%) affect the KH III domain, either by complete domain loss or amino acid changes. Thus, these changes are predicted to alter the various functions of PCBP1, including nuclear trafficking and pre‐mRNA splicing. Remarkably, all six primary Burkitt lymphomas with a PCBP1 mutation expressed MUM1/IRF4, which is otherwise detected in around 20–40% of Burkitt lymphomas. We conclude that PCBP1 mutations are recurrent in Burkitt lymphomas and might contribute, in cooperation with other mutations, to its pathogenesis. © 2015 Wiley Periodicals, Inc.     

Second malignancies after treatment of childhood non-Hodgkin lymphoma – a report of the Berlin-Frankfurt-Muenster study group

Second malignant neoplasms (SMN) pose a concern for survivors of childhood cancer. We evaluated incidence, type and risk factors for SMN in patients included in Berlin-Frankfurt-Muenster protocols for childhood non-Hodgkin lymphoma.3,590 patients <15 years of age at diagnosis, registered between 01/1981 and 06/2010, were analyzed. SMN were reported by the treating institutions and the German Childhood Cancer Registry. After a median follow-up of 9.4 years (quartile [Q] range, Q1 6.7 and Q3 12.1) 95 SMN were registered (26 carcinomas including nine basal cell carcinomas, 21 acute myeloid leukemias/myelodysplastic syndromes, 20 lymphoid malignancies, 12 central nervous system [CNS]-tumors, and 16 others). Cumulative incidence at 20 years was 5.7±0.7%, standard incidence ratio, excluding basal cell carcinomas, was 19.8 (95% Confidence Interval [CI]: 14.5-26.5). Median time from initial diagnosis to second malignancy was 8.7 years (range, 0.2-30.3 years). Acute-lymphoblasticleukemia- type therapy, cumulative anthracycline dose, and cranial radiotherapy for brain tumor-development were significant risk factors in univariate analysis only. In multivariate analysis including risk factors significant in univariate analysis, female sex (hazard ratio [HR] 1.87, 95% CI: 1.23-2.86, P=0.004), CNS-involvement (HR 2.24, 95% CI: 1.03-4.88, P=0.042), lymphoblastic lymphoma (HR 2.60, 95% CI: 1.69-3.97, P<0.001), and cancer-predisposing condition (HR 11.2, 95% CI: 5.52-22.75, P<0.001) retained an independent risk. Carcinomas were the most frequent SMN after non-Hodgkin lymphoma in childhood followed by acute myeloid leukemia and lymphoid malignancies. Female sex, lymphoblastic lymphoma, CNS-involvement, or/and known cancer-predisposing condition were risk factors for SMN-development. Our findings set the basis for individualized long-term follow-up and risk assessment of new therapies.     

Surgical treatment of piles

PURPOSE: The present prospective, randomized clinical trial compares the outcome of surgical hemorrhoidectomy according to Parks and Milligan-Morgan in terms of hospital stay, duration of incapacity to work, symptom relief, length of morbidity, and patient convenience. METHODS: Thirty-four consecutive patients with third or fourth degree internal hemorrhoids were randomly allocated to the two groups. Before surgery, all patients were interviewed using a standard questionnaire, followed by rectal examination. All patients underwent a follow-up interview and examinations 1, 2, 4, 8, and 12 weeks after the operation. RESULTS: No serious postoperative complications were seen. Length of hospital stay (3.2 days for Parks hemorrhoidectomyvs. 4.6 days for Milligan-Morgan hemorrhoidectomy; 95 percent confidence interval, 0.2 and 2.6, respectively;P=0.02) and mean duration of incapacity to work (12.3 days for Parks hemorrhoidectomyvs. 20.2 days for Milligan-Morgan hemorrhoidectomy; 95 percent confidence interval, 5.7 and 10.2, respectively;P<0.001) differed significantly between the Milligan-Morgan and Parks patients. Until two weeks after the operation, Milligan-Morgan hemorrhoidectomy patients experienced significantly more pain. CONCLUSIONS: Our study confirms that both operations are safe, easy to perform, and lead to satisfactory results. However, the Parks procedure is the preferred option, because it minimizes patients' postoperative discomfort, is more economic, has a significantly reduced hospital stay, and has a shorter time for return to work.     

Long-term survival of a patient with congenital central hypoventilation syndrome despite the lack of continuous ventilatory support

Untreated idiopathic congenital central hypoventilation syndrome (CCHS) is thought to cause infant death within 1-2 months. Here we present an adult patient with CCHS who survived without continuous ventilatory support, despite hypoventilation from early childhood onward. The diagnosis was confirmed at the age of 22 years, when the patient presented with hypoventilation during the night (PaCO2 60 mm Hg, PaO2 56 mm Hg, pH 7.32 HCO3- 30 mmol/l) but hyperventilation when awake (PaCO2 26 mm Hg, PaO2 81 mm Hg, pH 7.56, HCO3- 23 mmol/l). The maximal hematocrit was 77%. Despite mental retardation, noninvasive positive pressure ventilation (NPPV) could be successfully established. NPPV-supported ventilation during the night (PaCO2 36, PaO2 84 mm Hg, pH 7.47, HCO3- 25 mmol/l) reduced hematocrit values (40.6 to 36.8%) over a period of 4 years. In conclusion, long-term survival with CCHS is possible without continuous ventilatory support. Spontaneous improvement of hypoventilation during sleep throughout childhood is possible and hyperventilation during wakefulness may occur in patients with CCHS. CCHS can be managed with NPPV despite mental retardation, even over a long-term period.     

High resolution copy number analysis of IRF4 translocation‐positive diffuse large B‐cell and follicular lymphomas

Translocations affecting chromosome subband 6p25.3 containing the IRF4 gene have been recently described as characteristic alterations in a molecularly distinct subset of germinal center B‐cell‐derived lymphomas. Secondary changes have yet only been described in few of these lymphomas. Here, we performed array‐comparative genomic hybridization and molecular inversion probe microarray analyses on DNA from 12 formalin‐fixed paraffin‐embedded and two fresh‐frozen IRF4 translocation‐positive lymphomas, which together with the previously published data on nine cases allowed the extension of copy number analyses to a total of 23 of these lymphomas. All except one case carried chromosomal imbalances, most frequently gains in Xq28, 11q22.3‐qter, and 7q32.1‐qter and losses in 6q13‐16.1, 15q14‐22.31, and 17p. No recurrent copy‐neutral losses of heterozygosity were observed. TP53 point mutations were detected in three of six cases with loss of 17p. Overall this study unravels a recurrent pattern of secondary genetic alterations in IRF4 translocation‐positive lymphomas. © 2012 Wiley Periodicals, Inc.     

Finite element analysis on the biomechanical stability of open porous titanium scaffolds for large segmental bone defects under physiological load conditions

Repairing large segmental defects in long bones caused by fracture, tumour or infection is still a challenging problem in orthopaedic surgery. Artificial materials, i.e. titanium and its alloys performed well in clinical applications, are plenary available, and can be manufactured in a wide range of scaffold designs. Although the mechanical properties are determined, studies about the biomechanical behaviour under physiological loading conditions are rare. The goal of our numerical study was to determine the suitability of open-porous titanium scaffolds to act as bone scaffolds. Hence, the mechanical stability of fourteen different scaffold designs was characterized under both axial compression and biomechanical loading within a large segmental distal femoral defect of 30 mm. This defect was stabilized with an osteosynthesis plate and physiological hip reaction forces as well as additional muscle forces were implemented to the femoral bone. Material properties of titanium scaffolds were evaluated from experimental testing. Scaffold porosity was varied between 64 and 80%. Furthermore, the amount of material was reduced up to 50%. Uniaxial compression testing revealed a structural modulus for the scaffolds between 3.5 GPa and 19.1 GPa depending on porosity and material consumption. The biomechanical testing showed defect gap alterations between 0.03 mm and 0.22 mm for the applied scaffolds and 0.09 mm for the intact bone. Our results revealed that minimizing the amount of material of the inner core has a smaller influence than increasing the porosity when the scaffolds are loaded under biomechanical loading. Furthermore, an advanced scaffold design was found acting similar as the intact bone.