Genetic susceptibility to severe infection in families with invasive pneumococcal disease

Severe infections may be influenced by genetic constitution. The authors examined familial aggregation of invasive infections, using invasive pneumococcal disease (IPD) as the index condition to ascertain families at risk. From Danish national registers, they identified relatives of persons with IPD from 1977 through 2005. Risks of IPD, bacterial meningitis, septicemia, and any invasive infection were analyzed for relatives of IPD cases in a prospective cohort study (23 million person-years). In total, 43,134 persons were found to have an IPD case in the family. The authors observed an increased risk of invasive infections in relatives of IPD cases most likely sharing the same household (parents, offspring, siblings, half-siblings), but only regarding those events within 1 year of the index IPD diagnosis (rate ratio = 7.4, 95% confidence interval: 2.4, 23.0). After 1 year, there were no increased risks of severe infections, including IPD, in close relatives. For other relatives, no increased risks of severe infections were observed at any time. No aggregation of invasive infections in IPD relatives was found, other than for close events among relatives who most likely shared the same household. Thus, at the population level, genetic constitution appears of little importance in the development of IPD and other severe infections.     

Preterm Infants on Early Solid Foods and Iron Status in the First Year of Life—A Secondary Outcome Analysis of a Randomized Controlled Trial

Introduction of solid foods and iron status in the first year of life of preterm infants are highly discussed topics. The aim of this study was to examine whether two timepoints of introduction of standardized solid foods in preterm infants have an impact on ferritin and other hematologic parameters important for iron status in the first year of life. This is a secondary outcome analysis of a prospective, randomized intervention trial in very low birth weight (VLBW) infants randomized to an early (10–12th week corrected age) or a late (16–18th week corrected age) complementary feeding group. Iron status was assessed with blood samples taken at 6 weeks, 6 months, and 12 months corrected age. In total, 177 infants were randomized (early group: n = 89, late group: n = 88). Ferritin showed no differences between study groups throughout the first year of life, as did all other parameters associated with iron status. At 12 months corrected age, the incidence of iron deficiency was significantly higher in the early feeding group. There is room for improvement of iron status in VLBW preterm infants, regular blood checks should be introduced, and current recommendations may need to be a reconsidered.     

Aspergillus PCR testing: results from a prospective PCR study within the AmBiLoad trial

Objectives: Invasive fungal infection (IFI) is a major cause of morbidity and mortality in severely immunocompromised patients and is difficult to diagnose. The significance of molecular methods for diagnosis of IFI is still controversial. In a subset of patients treated within the AmBiLoad Trial, samples were investigated prospectively by a nested Aspergillus PCR assay to re‐evaluate the significance of PCR in this setting. Patients and methods: In the randomized, prospective multicenter AmBiLoad trial, patients with proven or probable IFI were randomized to receive liposomal amphotericin B (L‐AMB) 3 or 10 mg/kg QD for 14 d followed by L‐AMB 3 mg/kg QD. From 91 patients, 459 serial samples (98% blood samples) were investigated by a nested PCR assay for Aspergillus DNA. All samples were investigated in our laboratory with a previously described nested and a quantitative PCR assay. As required by the study protocol, serial Aspergillus antigen galactomannan was performed. IFI was defined according to modified EORTC/MSG 2002 criteria as applied in the AmBiLoad trial. Results: Seven and 52 patients had proven and probable IFI according to modified EORTC/MSG criteria, respectively. The median number of samples investigated per patient was 4. Seventy percent of samples were obtained during treatment with antifungal study medication. Forty‐three samples gave positive PCR results. Patients with an unfavorable outcome had a significantly higher rate of positive PCR results (48% versus 21%). Conclusions: The sensitivity of Aspergillus PCR testing is limited during antifungal therapy. The tendency for persistently positive PCR results to indicate a poor prognosis has to be confirmed in further studies.     

Cystic periventricular leukomalacia in preterm infants: an analysis of obstetric risk factors

Objective

To identify obstetric risk factors and to elucidate the effect of prolonged rupture of the membranes on the development of cystic periventricular leukomalacia (PVL) in preterm infants.

Methods

A retrospective case-control study of 95 preterm infants with the diagnosis of PVL and 245 healthy controls matched for gestational age. A total of 52 antenatal, intrapartum and neonatal characteristics were studied by univariate methods and logistic regression.

Results

Preterm premature rupture of membranes (PPROM) (odds ratio 2.1 [95% CI 1.3-3.4], P = .003), gestational age at PPROM (P = .025), prolonged rupture of membranes (P < .0001), administration of tocolytic agents (1.8 [1.1-3.0], P = .019) and antibiotics (1.9 [1.2-3.1], P = .008) were associated with PVL. The use of tocolytic agents > 24 h (P = .008), prolonged latency between the increase in maternal leukocyte count and birth (P = .034), spontaneous onset of labor (1.8 [1.0-2.9], P = .026), vaginal delivery (1.7 [1.1-2.8], P = .029) and male gender (1.5 [1.0-2.0], P = .04) were found more frequently in PVL cases. Preeclampsia (0.4 [0.1-0.9], P = .034), hypertension at booking (P = .009), sonographic IUGR (P = .020), abnormal blood flow of the umbilical artery (P = .032) and cesarean section without labor (0.5 [0.3-0.8], P = .006) were found less frequently. In logistic regression analysis, prolonged rupture of the membranes (P = .748), preeclampsia (P = .973), the use of antibiotics (P = .617) and beta-sympathomimetic tocolytic agents (P = .563) lost statistical significance, whereas birth weight (P = .036) became significant.

Conclusion

PPROM and prolonged rupture of the membranes may provoke adverse effects on the neurodevelopmental outcome of the preterm fetus. These findings may have implications on the obstetric management of PPROM beyond 30 weeks of gestation. Cesarean section without labor was less likely associated with the diagnosis of PVL.     

The Effect of Evolving Strategies in the Surgical Management of Organ-Confined Prostate Cancer: Comparison of Data from 2005 to 2014 in a Multicenter Setting

Introduction

The objective of this study was to evaluate changes of patient characteristics and surgical techniques in radical prostatectomy in Germany within the last decade.

Methods

Data from 44 German prostate cancer centers were included in the study. Patients’ characteristics (age, initial PSA value), surgical techniques (open vs. minimally invasive approaches), perioperative parameters (operating time, rate of nerve-sparing (NS) radical prostatectomies (RPs), hospitalization time, catheter indwelling time, surgical margin status, number of dissected lymph nodes (LN)), and pathological findings (tumor stage, Gleason score) were analyzed.

Results

Data from 11,675 patients who underwent RP between 2005 and 2014 were analyzed. The rate of open RP approaches decreased by 1.7% (p = 0.0164), the rate of minimally invasive approaches increased by 1.8% (p = 0.0164). Robot-assisted RPs (RARP) increased by 4.6% (p < 0.0001). The number of NS procedures and pelvic lymphadenectomy (LA) increased by 4.5% (p < 0.0001) and 4.7% (p < 0.0001), respectively. Catheter indwelling time and hospitalization time decreased by 1 day (p < 0.0001). No change in the rate of positive surgical margins (p = 0.5061) and the ratio of positive lymph nodes removed (p = 0.4628) was observed. The number of Gleason ≤6 tumors decreased significantly (p < 0.0001).

Conclusions

The number of RARP has significantly increased over the past decade and there is a trend towards surgeries on more advanced tumors with higher yields of lymph nodes dissected. At the same time, the rate of nerve-sparing procedures has significantly increased.

     

Autologous stem-cell transplantation in progressing amyloidosis is associated with severe transplant-related toxicity

BACKGROUND: Amyloid light-chain (AL) amyloidosis is a disorder of plasma cells in which depositions of immunoglobulin light-chain fragments cause progressive organ failure and death with a median survival of one year, but autologous stem-cell transplantation can induce high response rates, especially in isolated renal involvement. METHODS: Six patients aged between 43 and 59 years were diagnosed with AL-amyloidosis and had stem cells mobilized with either recombinant human granulocyte colony-stimulating factor (rhG-CSF) alone (n = 2) or cyclophosphamide (2-4 g/m(2)) and rhG-CSF (n = 4). All six patients had kidney involvement and nephrotic syndrome, four had cardiac involvement and two involvement of the vascular, nervous and gastrointestinal systems. Five of the patients received high-dose melphalan (200 mg/m(2)) and autologous blood stem-cell support. RESULTS: One patient died as a result of sepsis after stem-cell mobilization. The other five patients received high-dose melphalan but experienced severe toxicity. One patient died as the result of gastrointestinal perforation on day 6, one presented with hyperfibrinolysis and spontaneous rupture of the spleen, and another experienced severe bleeding of the gastrointestine, tachyarrhythmia and hemolytic anemia. Four patients had acute renal failure: three required hemodialysis and one underwent renal transplant 21 months later. Restaging after a follow-up of 31-52 months revealed reversal of nephrotic syndrome in all three patients who regained adequate renal function. With respect to cardiac involvement (n = 2), one patient showed a decrease in NYHA class from II to I but baseline wall thickness remained stable. CONCLUSION: Treatment of selected patients with AL-amyloidosis by high-dose melphalan and stem-cell support results in reversal of amyloid-related disease in a substantial proportion of patients and improved survival.     

Activating NOTCH1 mutations predict favorable early treatment response and long-term outcome in childhood precursor T-cell lymphoblastic leukemia

Activating mutations of the transmembrane receptor NOTCH1 are common in precursor T-cell lymphoblastic leukemia (T-ALL). We systematically analyzed the impact of activating NOTCH1 mutations on early treatment response and long-term outcome in 157 patients with T-ALL of the pediatric ALL-Berlin-Frankfurt-Munster (BFM) 2000 study. We confirm previous results that NOTCH1 mutations occur in more than 50% of T-ALL in children. In 82 patients (82/157; 52.2%), activating NOTCH1 mutations were identified either in the heterodimerization (55/82; 67.1%), in the PEST (13/82; 15.9%), or in both domains (14/82; 17.0%). The presence of NOTCH1 mutations was significantly correlated with a good prednisone response and favorable minimal residual disease (MRD) kinetics, which was independent from sex, age, white blood cell count, and T-cell immunophenotype at the time of diagnosis. Furthermore, activating NOTCH1 mutations specified a large subgroup of patients with an excellent prognosis. These findings indicate that in the context of the ALL-BFM 2000 treatment strategy, NOTCH1 mutations predict a more rapid early treatment response and a favorable long-term outcome in children with T-ALL.