Multidrug-resistant neuroblastoma cells are responsive to arsenic trioxide at both normoxia and hypoxia

Despite intensive treatment, the outcome of high-risk neuroblastoma patients is poor with acquired multidrug resistance as an important cause. Previously, our group has shown that arsenic trioxide (As(2)O(3)) kills multidrug-resistant neuroblastoma cells in vitro and in vivo at clinically tolerable doses. Regions of tissue hypoxia often arise in aggressive solid tumors, and hypoxic tumors exhibit augmented invasiveness and metastatic ability in several malignancies. Furthermore, hypoxia may impair the treatment efficiency; therefore, we have studied the cytotoxic effect of As(2)O(3) on neuroblastoma cells grown under normoxic as well as hypoxic (1% oxygen) conditions. At both normoxia and hypoxia, 2 and 4 mumol/L As(2)O(3) induced evident cell death in the drug-sensitive SH-SY5Y and IMR-32 cells as well as in the multidrug-resistant SK-N-BE(2)c (with a mutated p53) and SK-N-FI cells after 72 hours of exposure. In contrast, the conventional chemotherapeutic drug etoposide showed lowered efficiency in hypoxic IMR-32 cells. In accordance with our previously published results, although not to the same extent as in their normoxic counterparts, Bax is proteolytically cleaved also in neuroblastoma cells exposed to As(2)O(3) at hypoxia. This suggests that similar molecular mechanisms are involved in As(2)O(3)-induced neuroblastoma cell death during hypoxia compared with normoxia. Together, our results support As(2)O(3) as a potential candidate drug as a complement to conventional treatments for high-risk neuroblastoma patients and perhaps also for patients with other multidrug-resistant solid tumors.     

Soluble TNF Receptors and Kidney Dysfunction in the Elderly

The importance of TNF-α and its soluble receptors (sTNFR1 and sTNFR2) in the development of kidney disease is being unraveled. Yet, community-based data regarding the role of sTNFRs are lacking. We assessed serum sTNFRs and aspects of kidney damage cross-sectionally in two independent community-based cohorts of elderly participants: Prospective Investigation of the Vasculature in Uppsala Seniors (n=815; mean age, 75 years; 51% women) and Uppsala Longitudinal Study of Adult Men (n=778; mean age, 78 years). Serum sTNFR1 correlated substantially with different aspects of kidney pathology in the Uppsala Longitudinal Study of Adult Men cohort (R=−0.52 for estimated GFR, R=0.22 for urinary albumin-to-creatinine ratio, and R=0.17 for urinary kidney injury molecule-1; P<0.001 for all), with similar correlations in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort. These associations remained significant after adjustment for age, sex, inflammatory markers, and cardiovascular risk factors and were also evident in participants without diabetes. Serum sTNFR2 was associated with all three markers in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort (P<0.001 for all). Our findings from two independent community-based cohorts confirm and extend results of previous studies supporting circulating sTNFRs as relevant biomarkers for kidney damage and dysfunction in elderly individuals, even in the absence of diabetes.     

Predictors associated with nonunion and symptomatic malunion following non-operative treatment of displaced midshaft clavicle fractures—a systematic review of the literature

Purpose

The aim of this study was to survey existing literature in order to identify all reported predictors associated with nonunion or symptomatic malunion in adult patients with displaced midshaft clavicle fractures treated non-operatively.

Method

A systematic literature search in Medline was carried out in order to identify publications in English, reporting on predictors for nonunion and malunion in adults with displaced midshaft clavicle fractures. After applying inclusion and exclusion criteria, eight publications were included in this systematic review.

Results

A total of 2,117 midshaft clavicle fractures were included in the eight publications. All publications reported on predictors for nonunion but none were found to report on predictors for malunion. The studies were characterized by different definitions for nonunion and symptomatic malunion if at all present. A total of 13 potential factors associated with nonunion were identified, six of these (displacement, comminution, shortening, age, gender and smoking) were reported as predictors for nonunion. Outcome definitions varied among the studies.

Conclusion

The included publications varied greatly in design, sample size, and quality. Based on the present literature most of the predictors were found to be of limited evidence, however displacement seems to be the most likely factor that can be used to predict for nonunion. Treating all clavicle fractures with displacement surgically would inevitably lead to overtreatment, which is why future studies need to focus on predictive factors in order to differentiate between patients that would benefit from surgery and those who would not.     

Degarelix as an Intermittent Androgen Deprivation Therapy for One or More Treatment Cycles in Patients with Prostate Cancer

Background

Guidelines for prostate cancer treatment suggest that intermittent androgen deprivation (IAD) can be considered for certain patients.

Objective

To evaluate the efficacy and safety of degarelix as IAD for one or more treatment cycle(s) in prostate cancer patients requiring androgen deprivation.

Design, setting, and participants

This open-label uncontrolled multicenter study included patients with prostate-specific antigen (PSA) >4 to 50 ng/ml or PSA doubling time <24 mo. Induction included 7-mo treatment. Off-treatment period started when PSA was ≤4 ng/ml and lasted up to 24 mo based on PSA and testosterone levels. Treatment was reinitiated when PSA was >4 ng/ml.

Intervention

Each induction period included a starting dose of degarelix 240 mg, and thereafter 80 mg once a month for 6 mo, followed by off-treatment periods.

Outcome measurements and statistical analysis

The primary end point was time to PSA >4 ng/ml. Secondary end points were subgroup analysis of the primary end point, time to testosterone >0.5 and >2.2 ng/ml, quality of life (QoL), and sexual function during the first off-treatment period.

Results and limitations

Of 213 patients in the first induction period, 191 entered the first off-treatment period, 35 patients entered the second induction, and 30 entered the second off-treatment period. Only two patients entered the third cycle. Median time to PSA >4 ng/ml and duration of first off-treatment period was 392 d each. Significant differences in time to PSA >4 ng/ml were observed between subgroups stratified by prognostic factors (previous curative treatment, cancer stage, PSA levels, and Gleason scores). Time to testosterone >0.5 and >2.2 ng/ml was 112 and 168 d, respectively. Change in QoL remained nonsignificant, and sexual function gradually improved during the off-treatment period. Adverse events were fewer during the off-treatment period and subsequent treatment cycles.

Conclusions

IAD with degarelix resulted in an improvement in sexual function commensurate with increased testosterone levels while PSA remained suppressed. The treatment for one treatment cycle or more was well tolerated.

Patient summary

Guidelines for prostate cancer treatment suggest that intermittent androgen deprivation (IAD) can be considered for certain patients. IAD with degarelix resulted in improved sexual function commensurate with increased testosterone levels while prostate-specific antigen remained suppressed. The treatment for one treatment cycle or more was well tolerated.

Trial registration

Clinicaltrials.gov identifier NCT00801242.     

Applanation resonance tonometry for intraocular pressure in humans

Glaucoma is a group of diseases associated with optic nerve damage and loss of visual field. The aetiology is not completely understood, but one of the major risk factors is elevated intraocular pressure (IOP). Reliable methods for measuring the IOP are therefore important. The aim of the study was to investigate the ability of the applanation resonance tonometry (ART) system, based on continuous force and area recording, to measure IOP in humans. Both the phase of initial indentation (IOPIndentation) and the phase when the sensor was removed (IOPRemoval) from the cornea were analysed. The Goldmann applanation tonometry (GAT) was used as reference method. The study included 24 healthy volunteers with normal IOP and 24 patients with elevated IOP. The correlation and standard deviation (SD) between IOPIndentation and IOPGAT was R = 0.92 (p < 0.001), SD = 3.6 mmHg, n = 104, and between IOPRemoval and IOPGAT R = 0.94 (p < 0.001), SD = 3.1 mmHg, n = 104. In conclusion, resonance sensor technology has made it possible to introduce a new multi-point method for measuring IOP, and the method is relevant for measuring IOP in humans. The study indicates that with further development towards elimination of position dependence, the ART has the potential to become a useful clinical instrument for IOP measurement.     

Preoperative MRI of the Breast (POMB) Influences Primary Treatment in Breast Cancer: A Prospective,Randomized, Multicenter Study

Background

Breast magnetic resonance imaging (MRI) has shown high sensitivity in determining tumor extent, multifocality, and occult contralateral breast cancer. Low specificity, unnecessary mastectomies, and costs are arguments against MRI. The purpose of this study was to determine whether preoperative breast MRI would affect primary surgical management, reduce reexcision/reoperation procedures, and influence the choice of neoadjuvant treatment in patients with newly diagnosed breast cancer.

Methods

This prospective, randomized, multicenter study included 440 breast cancer patients younger than aged 56 years from three, Swedish, large-volume breast units. Patients were randomly allocated on a 1:1 basis to either preoperative staging with breast MRI (n = 220) or no breast MRI (n = 220) (control group). Treatment planning of all patients was discussed at multidisciplinary team conferences.

Results

In patients randomized to the MRI group, who had an observed higher percentage of planned breast-conserving surgery (BCS) compared with the control group, a change from suggested breast conservation to mastectomy occurred in 23 of 153 (15 %) patients. Breast MRI provided additional information in 83 of 220 (38 %) patients, which caused a change in treatment plan in 40 (18 %). The breast reoperation rate was significantly lower in the MRI group: 11 of 220 (5 %) versus 33 of 220 (15 %) in the control group (p < 0.001). The number of mastectomies, axillary reoperations, and the number of patients receiving neoadjuvant chemotherapy after definitive treatment did not differ significantly between the groups.

Conclusions

Preoperative staging with breast MRI in women younger than age 56 years altered the treatment plan in 18 % of the patients. Although a higher MRI-related conversion rate from breast conservation to mastectomy was found, the final numbers of mastectomies did not differ between the two groups. The breast reoperation rate in the MRI group was significantly reduced.     

Initiation factors for translation of proteins in the rectus abdominis muscle from patients on overnight standard parenteral nutrition before surgery

Previous studies have provided conflicting conclusions concerning the efficacy of improving protein balance in patients by standard intravenous nutrition [TPN (total parenteral nutrition)], which is either explained by suboptimal nutritional regimens or insensitive clinical methods. The aim of the present study was therefore to evaluate the effects on the initiation of translation of skeletal muscle proteins by standard overnight TPN. A total of 12 patients who underwent standard surgery were included. TPN was provided as an all-in-one treatment by constant infusion [0.16 gN.kg(-1) of body weight.day(-1) (30 kcal.kg(-1) of body weight.day(-1))]. Saline-infused patients served as controls. Rectus abdominis muscle biopsies were taken at the time of the operation. The phosphorylation state of the proteins for initiation of translation was quantified. Plasma glucose, and serum insulin, glycerol, triacylglycerols (triglycerides) and NEFAs (non-esterified fatty acids; 'free fatty acids') were not significantly altered during TPN infusion, whereas total plasma amino acids increased, as shown by increases in methionine, phenylalanine, threonine, alanine, arginine, aspartic acid, glycine and histidine (P<0.05). Overnight TPN increased the formation of active eIF4G-eIF4E (where eIF is eukaryotic-initiation factor) complexes (P<0.05), whereas the inhibitory complex 4E-BP1 (eIF4E-binding protein)-eIF4E was moderately decreased (P<0.06). TPN increased the amount of the most phosphorylated form of 4E-BP1 (P<0.05), and increased the amount (P<0.04) and phosphorylation (P<0.01) of p70(S6K) (70 kDa ribosomal protein S6 kinase). In conclusion, an overnight pre-operative constant infusion of standard TPN altered initiation factor complexes, indicating activation of the initiation of protein translation in rectus abdominis muscle in the presence of increased plasma amino acid levels, but without a concomitant increase in energy substrates and insulin. In contrast with our results from previous studies, the methodology used in the present study appears to be more sensitive in reflecting directional changes in human muscle protein synthesis compared with traditional methods, particularly based on measurements of amino acid flux.     

The impact of early cytomegalovirus infection after kidney transplantation on long‐term graft and patient survival

This prospective observational cohort study is an extension of a previous study reporting effects of cytomegalovirus (CMV) on graft and patient survival in 471 patients who underwent kidney transplantation between 1994 and 1997. CMV pp65 antigen was measured every 7–14 d during the first three months after transplantation, given as number of CMV pp65‐positive cells per 10⁵ leukocytes. A positive test was defined as CMV infection. None of the patients received CMV prophylaxis or preemptive treatment. During a median of 13.7 (7.1–14.9) yr, the number of death‐censored graft losses was 118 (25%) and of patient deaths 224 (48%). CMV infection was an independent significant risk factor for mortality in multivariate analysis (HR = 1.453, 95% CI 1.033–2.045, p = 0.032), adjusting for patient and donor age, preemptive transplantation, HLA‐DR and ‐AB mismatches, living donor, acute rejection during the first three months, donor–recipient CMV IgG antibody status and diabetic nephropathy. In univariate analysis, CMV infection was significantly associated with death‐censored graft loss but the association was not significant in multivariate model. CMV infection early after kidney transplantation is a predictor of overall mortality but not of death‐censored graft loss after a median observation period of 13.7 yr.