Focal laser ablation as clinical treatment of prostate cancer: report from a Delphi consensus project.

PURPOSE: To define the role of focal laser ablation (FLA) as clinical treatment of prostate cancer (PCa) using the Delphi consensus method. METHODS: A panel of international experts in the field of focal therapy (FT) in PCa conducted a collaborative consensus project using the Delphi method. Experts were invited to online questionnaires focusing on patient selection and treatment of PCa with FLA during four subsequent rounds. After each round, outcomes were displayed, and questionnaires were modified based on the comments provided by panelists. Results were finalized and discussed during face-to-face meetings. RESULTS: Thirty-seven experts agreed to participate, and consensus was achieved on 39/43 topics. Clinically significant PCa (csPCa) was defined as any volume Grade Group 2 [Gleason score (GS) 3+4]. Focal therapy was specified as treatment of all csPCa and can be considered primary treatment as an alternative to radical treatment in carefully selected patients. In patients with intermediate-risk PCa (GS 3+4) as well as patients with MRI-visible and biopsy-confirmed local recurrence, FLA is optimal for targeted ablation of a specific magnetic resonance imaging (MRI)-visible focus. However, FLA should not be applied to candidates for active surveillance and close follow-up is required. Suitability for FLA is based on tumor volume, location to vital structures, GS, MRI-visibility, and biopsy confirmation. CONCLUSION: Focal laser ablation is a promising technique for treatment of clinically localized PCa and should ideally be performed within approved clinical trials. So far, only few studies have reported on FLA and further validation with longer follow-up is mandatory before widespread clinical implementation is justified.

Aceruloplasminaemia: a family with a novel mutation and long-term therapy with deferasirox.

Ceruloplasmin is a member of the multicopper oxidase family that plays a major role in the transport of iron in the body. Aceruloplasminaemia (ACP) is a rare disease and is clinically identified by iron overload in liver, pancreas, brain, and other organs, and by microcytic anaemia. So far, the iron chelator deferasirox was given for therapy only up to 6 months due to side effects. Here, we describe a novel mutation leading to ACP and report for the first time a long-term therapy, that is, 2 years with deferasirox. ACP was diagnosed in 3 siblings using clinical and biochemical characteristics, HFE and ceruloplasmin mutational analysis, liver biopsy, brain-, liver-, and heart-MRI. For iron depletion, a starting dose of deferasirox 7.5 mg/kg/day was increased to 15 mg/kg/day and maintained at 4-7.5 mg/kg/day with a patient follow-up for 2 years. A novel homozygous mutation of the ceruloplasmin gene on chromosome 3 (3q23-q25, exon 12, G708S) was found. Iron was selectively and successfully removed by long-term therapy with deferasirox, as confirmed by follow-up liver biopsies, normalisation of serum ferritin concentrations, and improved glucose metabolism. Unexpectedly, iron depletion ameliorated anaemia. Low-dose deferasirox is an effective and safe long-term treatment option for patients with ACP.

Levels of cytokines in umbilical cord blood in small for gestational age preterm infants.

INTRODUCTION: Being born small for gestational age (SGA) can be a reference to intrauterine growth retardation (IUGR) and is associated with increased neonatal morbidity and mortality. In pregnancies complicated by IUGR placental insufficiency is thought to be one of the leading underlying pathogenetic mechanisms. As cytokines appear to be implicated in implantation and -placental development, imbalances in cytokine levels may contribute to pregnancy disorders i. e., IUGR. OBJECTIVE: Cord blood cytokine profiles were analyzed in order to characterize differences in cytokine profiles between SGA and appropriate for gestational age (AGA) preterm infants. METHODS: Cytokine concentrations were measured in venous cord blood of preterm infants delivered by caesarean section without previous labour activity and without signs of maternal or fetal infection. RESULTS: 93 preterm infants were enrolled, 29 SGA preterm infants (GA 31.0 (24.6-36.7) weeks; BW 1080 (315-2010) grams) and 63 AGA preterm infants (GA 33.3 (26.0-36.9) weeks; BW 1790 (760-3570) grams). In both groups multiple cytokines could be detected. Significant differences in cytokine levels between the groups were found for G-CSF, IL-12p40 and IL-8, while levels of IL-1a, IL-6, IL-10, IP-10, MCP-1, MCP-3, MIP-1a and TNF-a were not different. CONCLUSIONS: Alteration of cytokine levels in SGA preterm infants may be involved in the pathogenesis of reduced intrauterine growth as well as in the higher morbidity in these infants. Further studies are needed to get more comprehension of the complex function of cytokines in pregnancies complicated by IUGR.

The influence of extracellular matrix proteins and mesenchymal stem cells on erythropoietic cell maturation.

BACKGROUND AND OBJECTIVES: As part of the bone marrow niche, cellular and acellular components like mesenchymal stem cells (MSCs) and extracellular matrix (ECM) proteins influence human haematopoiesis. To identify factors able to improve the in vitro generation of red blood cells (RBCs), we investigated the effect of these factors on proliferation and differentiation of human haematopoietic stem cells (HSCs) into erythroid cells. MATERIAL AND METHODS: Granulocyte colony-stimulating factor-mobilized CD34(+) HSCs were cultured for 16 days using an in vitro erythropoiesis assay as described previously (by our group). The HSCs were co-cultured with MSCs in either direct or indirect contact and with different ECM proteins (fibronectin, laminin, collagen and a mixture of ECM proteins, called ECM gel). RESULTS: Co-culturing of HSCs with ECM gel improved cell viability, and the presence of laminin slightly increased the maturation into enucleated RBCs. HSC expansion could not be improved by addition of any of the ECM proteins investigated. In contrast, fibronectin inhibited erythroid formation. Co-culturing of HSCs with MSCs generally stimulated cell viability and HSC proliferation, however, in favour of the myeloid lineage. In summary, of all investigated factors, only laminin and ECM gel had a supportive effect on RBC development under the described in vitro culture conditions.

Angiotensin II receptor blocker induced fetopathy: 7 cases.

BACKGROUND: During a period of 12 months 7 newborns with a partially severe fetopathy caused most probably by maternal sartan-intake in pregnancy were treated in 5 German teaching hospitals. Sartans antagonize the effect of angiotensin II at the AT1-receptor and are used to treat arterial hypertension. METHOD: We presented 2 cases at the yearly GNPI meeting 2010 and we were informed about similar cases in other German teaching hospitals which we brought together in this publication. RESULTS: In the presented cases, maternal sartan intake was noticed at different times in pregnancy and was in part discontinued some weeks before delivery. In all pregnancies oligohydramnios was present and fetal kidneys displayed a hyperechogenic structure on ultrasound. The newborns' postnatal course varied: oligohydramnios sequence with lung hypoplasia, arterial hypotension and renal insufficiency were the predominant problems of the first days of life. The majority (4/7) of infants did not survive this period, in other cases there was a complete (1/7) recovery of renal function whereas others survived with renal impairment (2/7), in part requiring chronic dialysis. Further distinctive features seen frequently were disturbances of cranial ossification and flaccid paralysis of hands and feet with deviations as well as sensorineural hearing loss. CONCLUSION: These case reports again underline the hazardousness of maternal sartan intake with potential fatal outcome for the newborn. Though the use of sartans in pregnancy is contraindicated and several case reports of sartan induced fetopathies exist, the risk of sartan treatment generally seems to be underestimated.

Image guidance for focal therapy of prostate cancer.

Focal therapy is an appealing strategy for any tumor and in time may prove to be a valuable treatment option for low-risk, carefully selected prostate cancer (PCa) patients. In an era where active surveillance is now considered a viable option for low-risk PCa patients, it is conceivable that organ-sparing treatments could also become an established option. The aim of focal therapy is to achieve long-term cancer control with minimal morbidity yet without the side effects of radical therapy. Although lacking in evidence, it remains intuitive that if we treat the smallest possible region of the prostate where to ensure cancer control by ablation (laser, cryotherapy or another ablative source), then there is less potential for untoward side effects. Thus, we believe the ultimate goal in focal therapy is to target specifically the cancerous site while ablating it and the smallest zone of normal prostate tissue around it to obtain cancer control. To achieve this goal, one is dependent on high-quality imaging to: locate the cancerous lesion and have it assist in guiding the ablative modality toward the lesion; monitor the ablation in real time; accurately assess the extent and totality of the ablation post-treatment and finally be used to follow-up and monitor the prostate in search of a recurrence of cancer in the treated area or the development ion new zones. This review seeks to discuss such issues focusing on imaging modalities as they relate to focal therapy of PCa.

Image guided photothermal focal therapy for localized prostate cancer: phase I trial.

PURPOSE: We ascertained the feasibility and safety of image guided targeted photothermal focal therapy for localized prostate cancer. MATERIALS AND METHODS: Twelve patients with biopsy proven low risk prostate cancer underwent interstitial photothermal ablation of the cancer. The area of interest was confirmed and targeted using magnetic resonance imaging. Three-dimensional ultrasound was used to guide a laser to the magnetic resonance to ultrasound fused area of interest. Target ablation was monitored using thermal sensors and real-time Definity contrast enhanced ultrasound. Followup was performed with a combination of magnetic resonance imaging and prostate biopsy. Validated quality of life questionnaires were used to assess the effect on voiding symptoms and erectile function, and adverse events were solicited and recorded. RESULTS: Interstitial photothermal focal therapy was technically feasible to perform. Of the patients 75% were discharged home free from catheter the same day with the remainder discharged home the following day. The treatment created an identifiable hypovascular defect which coincided with the targeted prostatic lesion. There were no perioperative complications and minimal morbidity. All patients who were potent before the procedure maintained potency after the procedure. Continence levels were not compromised. Based on multicore total prostate biopsy at 6 months 67% of patients were free of tumor in the targeted area and 50% were free of disease. CONCLUSIONS: Image guided focal photothermal ablation of low risk and low volume prostate cancer is feasible. Early clinical, histological and magnetic resonance imaging responses suggest that the targeted region can be ablated with minimal adverse effects. It may represent an alternate treatment approach to observation or delayed standard therapy in carefully selected patients. Further trials are required to demonstrate the effectiveness of this treatment concept.

Increased intracranial pressure caused by non-space-occupying arachnoid cysts: report of two patients.

In this article we report on two patients with arachnoid cysts previously treated by shunt implantation presenting with clinical signs of an increased intracranial pressure i. e., papilledema, headache and nausea. Repeated MRI scans showed no alteration of the cerebrospinal fluid circulation and no space-occupying effect of the cysts. Although neuroimaging showed no signs of increased intracranial pressure, neurosurgical exploration was performed and revealed a distinctly increased pressure in both arachnoid cysts. After replacement of the shunt a prompt reduction of papilledema and relief of symptoms was observed.

Investigation of exercise stress by antihypertensive treatment with a combination containing beta-blocker/diuretic or reserpine.

The effects of a beta-blocker/diuretic combination and a reserpine-containing combination on exercise hypertension were compared in 20 patients suffering from mild hypertension with a diastolic pressure between 90 and 105 mmHg and a positive exercise test. This double-blind, randomized, within-patient, cross-over study involved two four-week phases, each preceded by a two-week wash-out period. The effect on the double product (tension-time index) and the physical working capacity at a heart rate of 170 bpm (PWC170) was also measured. The advantage of the preparation containing the beta-receptor blocker was apparent in both phases as physical work load increased. The PWC170 was twofold greater in the beta-receptor blocker group than in the reserpine group. The tension-time index was lowered in the normal range in both phases by the beta-blocker combination. The reserpine-containing preparation in the second phase did not further enhance the improvement produced by the beta-blocker in the first phase. These results suggest that it is worth questioning the traditional antihypertensive treatment in elderly patients, in whom mild hypertension is common, in order to better protect them from cardiovascular complications.

Drug utilisation in very preterm infants: any changes during the past decade?

BACKGROUND: Improved standards of perinatal care for preterm infants led to decreased hospital mortality rates during the past decade. However, studies investigating changes in drug utilisation in neonatal intensive care units (NICU) during this period are missing. OBJECTIVE: The aim of the present study therefore was to evaluate the most frequently used groups of drugs in preterm infants treated in NICUs and to analyse potential changes in drug utilisation over a period of ten years. METHODS: Drug utilisation patterns in 164 preterm infants born between 1989 and 1990 (group I; gestational age 27.2+/-1.2 weeks, birth weight 970+/-145 g) were compared to those in 113 preterm infants born between 2001 and 2004 (group II; gestational age 26.9+/-1.65 weeks, birth weight 930+/-253 g, mean and standard deviation each) with need for postnatal mechanical ventilation. RESULTS: Significant changes in drug utilisation patterns were observed for complete courses of antenatal corticosteroids (40 vs. 51.5%), diuretics (78 vs. 36.6%), surfactant (63.3 vs. 75%), methylxanthines (89.9 vs. 56.7%), sedatives/analgesics (82.4 vs. 91.5%) and catecholamines (38.3 vs. 52.4%) (group II vs. group I each). Postnatal corticosteroids were applied more often in group II (17.4 vs. 13.4%). However, duration of postnatal corticosteroid treatment has decreased (6 d vs. 13 d). The use of antibiotics remained unchanged (100 vs. 98.9%). Comparison of clinical outcome variables showed a decreased duration of mechanical ventilation and a significantly increased survival rate. CONCLUSION: Drug utilisation patterns in preterms have changed considerably during the past decade. Improved standards of care and shorter duration of mechanical ventilation may be operative.

In vivo matrix-guided human mesenchymal stem cells.

Microfracture of subchondral bone results in intrinsic repair of cartilage defects. Stem or progenitor cells from bone marrow have been proposed to be involved in this regenerative process. Here, we demonstrate for the first time that mesenchymal stem (MS) cells can in fact be recovered from matrix material saturated with cells from bone marrow after microfracture. This also introduces a new technique for MS cell isolation during arthroscopic treatment. MS cells were phenotyped using specific cell surface antibodies. Differentiation of the MS cells into the adipogenic, chondrogenic and osteogenic lineage could be demonstrated by cultivation of MS cells as a monolayer, as micromass bodies or mesenchymal microspheres. This study demonstrates that MS cells can be attracted to a cartilage defect by guidance of a collagenous matrix after perforating subchondral bone. Protocols for application of MS cells in restoration of cartilage tissue include an initial invasive biopsy to obtain the MS cells and time-wasting in vitro proliferation and possibly differentiation of the cells before implantation. The new technique already includes attraction of MS cells to sites of cartilage defects and therefore may overcome the necessity of in vitro proliferation and differentiation of MS cells prior to transplantation.

[Therapy of hypertensive coronary patients. Open long-term study with a combination of atenolol and nifedipine]. / Therapie hypertensiver Koronarpatienten. Offene Langzeitstudie mit der Kombination Atenolol plus Nifedipin.

In the present study, 20 patients with both hypertension and stabile angina pectoris were treated twice daily for 6 months with 50 mg atenolol and 20 mg retard-formulation nifedipine. The effect of this treatment on blood pressure and heart rate was investigated at rest and under standardized ergometric conditions, and by means of a 24 h Holter ECG. The frequency of angina pectoris episodes in 6-week periods was reduced by 34% over 6 months. The initial decrease in systolic and diastolic blood pressure (by 25%) was maintained over the long term at rest and under exercise. Patient exercise tolerance with reduced oxygen utilization, as represented by the product of pressure x rate, showed a lasting improvement. After 6 months, monotopic ventricular premature beats in particular were reduced significantly (46%) as compared with the initial situation.