I. van der Tweel

Yttrium-90 microsphere radioembolization for the treatment of liver malignancies: a structured meta-analysis

Radioembolization with yttrium-90 microspheres (90Y-RE), either glass- or resin-based, is increasingly applied in patients with unresectable liver malignancies. Clinical results are promising but overall response and survival are not yet known. Therefore a meta-analysis on tumor response and survival in patients who underwent 90Y-RE was conducted. Based on an extensive literature search, six groups were formed. Determinants were cancer type, microsphere type, chemotherapy protocol used, and stage (deployment in first-line or as salvage therapy). For colorectal liver metastases (mCRC), in a salvage setting, response was 79% for 90Y-RE combined with 5-fluorouracil/leucovorin (5-FU/LV), and 79% when combined with 5-FU/LV/oxaliplatin or 5-FU/LV/irinotecan, and in a first-line setting 91% and 91%, respectively. For hepatocellular carcinoma (HCC), response was 89% for resin microspheres and 78% for glass microspheres. No statistical method is available to assess median survival based on data presented in the literature. In mCRC, 90Y-RE delivers high response rates, especially if used neoadjuvant to chemotherapy. In HCC, 90Y-RE with resin microspheres is significantly more effective than 90Y-RE with glass microspheres. The impact on survival will become known only when the results of phase III studies are published.

Acute toxicity of concurrent adjuvant radiotherapy and chemotherapy (CMF or AC) in breast cancer patients: a prospective, comparative, non-randomised study

The concurrent administration of adjuvant chemotherapy and radiotherapy in breast cancer treatment might lead to an increased incidence of side-effects. In this prospective, non-randomised, comparative study, the acute toxicity of radiotherapy alone (RT) and radiotherapy concurrent with doxorubicin-cyclophosphamide (AC/RT) and radiotherapy concurrent with cyclophosphamide-methotrexate-5-fluorouracil (CMF/RT) was compared. We used the common toxicity criteria (CTC) to score the level of acute toxicity before, during and 6 months after the completion of the period of irradiation. The number of hospital admissions, as well as the compliance of chemotherapy, were noted. We observed that patients treated with AC/RT and CMF/RT had significant higher incidences of (high-grade) skin-toxicity, oesophagitis, dyspnoea, malaise, anorexia, nausea and hospital admission compared with those treated with RT only. The target-volume of radiotherapy was the main predictor of (high-grade) acute skin toxicity and oesophagitis. AC/RT was associated with significant more (high-grade) skin toxicity than CMF/RT. The dose of chemotherapy was reduced to less than 85% of the planned dose in 11% of patients, 17% of patients treated with concurrent chemotherapy and radiotherapy needed admission to hospital. From the results of our study, we conclude that the concurrent administration of adjuvant chemotherapy and radiotherapy leads to an unacceptably high level of acute toxicity.

Radiotherapy in T1 laryngeal cancer: Prognostic factors for locoregional control and survival, uni- and multivariate analysis

From 1975 through 1985, 194 patients with T1 glottic, 37 patients with T1 supraglottic, and 3 patients with T1 subglottic cancer were treated with radiotherapy. Local control and ultimate locoregional control (after salvage surgery) was 91% and 97% for T1 glottic, 84% and 81% for T1 supraglottic, and 2/3 and 3/3, respectively for subglottic tumors. In uni- and multivariate analysis local control for glottic tumors was associated with extension of the tumor on the vocal cord (entire length of vocal cord vs others, p = 0.01) and continuation of smoking after therapy (yes/no, p = 0.03). No prognostic factor for local control was found in supraglottic tumors. However, regional control and survival were impaired by N stage (N0 vs N+, p less than 0.0005), local recurrence (yes/no, p less than 0.0005), and extension of the tumor (one supraglottic subsite vs more than one, p less than 0.05). Mild late complications were seen in 13% of patients without salvage therapy. Following univariate analysis, field size, fraction size (greater than 2 Gy), maximum tumor dose (greater than 70 Gy), age, post-treatment biopsy, and tumor site were associated with complication rate. Following multivariate analysis, site, fraction size, maximum tumor dose, and continuation of smoking after therapy were independent prognostic factors for mild late complications (mostly arytenoid edema).

Oral dexamethasone pulse therapy versus daily prednisolone in sub-acute onset myositis, a randomised clinical trial.

To determine if high-dose pulsed dexamethasone is more effective and safer than daily high-dose prednisolone in treatment-naive adult patients with inflammatory myopathies (sporadic inclusion body myositis excluded) we performed a multicenter, double-blind randomised controlled clinical trial with 18 months follow-up. Sixty-two patients were randomised into 28-day cycles of oral high-dose dexamethasone or daily high-dose prednisolone. Primary outcome measures included (1) seven point composite score of six clinically relevant outcomes and (2) (time-to) remission and (time-to) relapse. No difference between both treatment groups on the composite score was found. Side-effects occurred significantly less frequently in the dexamethasone group. Median time to relapse was 60 (2.9) weeks in the prednisolone and 44 (4.7) weeks in the dexamethasone group (log-rank test p=0.03). In conclusion, pulsed high-dose oral dexamethasone is not superior to daily prednisolone as first-line treatment of idiopathic inflammatory myopathies, but is a good alternative by causing substantially fewer side-effects.

Inter- and intra-observer agreement of intrapartum ST analysis of the fetal electrocardiogram in women monitored by STAN.

Objective  The objective of this study was to quantify inter‐ and intra‐observer agreement on classification of the intrapartum cardiotocogram (CTG) and decision to intervene following STAN guidelines.

Feeding frequency and caste differentiation in Bombus terrestris larvae

Summary: The frequency with which bumble bee larvae are fed during their development was studied using video-recordings. The behaviour of the workers while feeding worker, male and queen larvae of Bombus terrestris was recorded. At the beginning of development, female larvae of both castes were fed at a similar frequency. However, during their last phase queen larvae were fed much more often than worker larvae. Despite the differences in frequency, both queen and worker larval feeding followed a similar pattern. Male larvae were fed more often than worker larvae, but less often than queen larvae. They also differed from the female larvae in the way their feeding frequency increased during development. This suggests that the process of feeding male larvae occurs in a different way.¶The time intervals between feedings were very variable for all larvae: from a few seconds up to 3 h. Although there was a general tendency for the intervals to decrease in duration with larval development, the irregularity was always present.¶The differences in feeding frequency found at the individual level for larvae of the same age and the irregularity of the feeding process can be explained by the variation in the amount of food per feeding.¶Finally, our data suggest that larvae play an active role in the regulation of the feeding process. This subject is discussed and compared to the situation in honey bees.

Selenium and the risk of postmenopausal breast cancer in the DOM cohort

SummarySelenium has been claimed to have chemo-preventive properties. However, data showing that in humans selenium levels are already decreased prior to diagnosis of breast cancer were not available. Such information is mandatory before oral selenium supplementation in the primary prevention of (breast) cancer in humans is acceptable. This question of a ‘preventive-potential’ of selenium was evaluated in a case-control study nested in a cohort, because this design allows determination of the time-order of preceding selenium levels and subsequent cancer risk.The cohort consisted of 5577 women aged 55–70 years from the DOM project, a population based breast cancer screening program in the Netherlands. Instrumental Neutron Activation Analysis was used to measure the selenium content of toenail clippings. The 69 cases of breast cancer found during follow-up after screening represent ‘recent’ tumours since all women had a negative screening mammogram 3–5 years previously.No decreased selenium levels, as measured in nail clippings from the big toes, could be detected in cases-to-be, either when compared to 4 age matched controls per case or when compared with a random control group drawn from the entire cohort. On the contrary, a tendency for slightly higher selenium levels among ‘future’ cancer cases was observed.As to the sensitivity of detecting differences in selenium by nail clippings, lower selenium could be detected in nails of current smokers. The smoking-related decrease in nail selenium level was of the same order as the differences between breast cancer cases and controls, but was independent of the breast cancer risk.Results are similar to a comparable study on premenopausal breast cancer and argue against a preventive role for selenium on breast cancer risk.

Two-protein signature of novel serological markers apolipoprotein-A2 and serum amyloid alpha predicts prognosis in patients with metastatic renal cell cancer and improves the currently used prognostic survival models

BACKGROUND In metastatic renal cell cancer (mRCC), the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model is widely used for clinical trial design and patient management. To improve prognostication, we applied proteomics to identify novel serological proteins associated with overall survival (OS). PATIENTS AND METHODS Sera from 114 mRCC patients were screened by surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS). Identified proteins were related to OS. Three proteins were subsequently validated with enzyme-linked immunosorbent assays and immunoturbidimetry. Prognostic models were statistically bootstrapped to correct for overestimation. RESULTS SELDI-TOF MS detected 10 proteins associated with OS. Of these, apolipoprotein A2 (ApoA2), serum amyloid alpha (SAA) and transthyretin were validated for their association with OS (P = 5.5 x 10(-9), P = 1.1 x 10(-7) and P = 0.0004, respectively). Combining ApoA2 and SAA yielded a prognostic two-protein signature [Akaikes Information Criteria (AIC) = 732, P = 5.2 x 10(-7)]. Including previously identified prognostic factors, multivariable Cox regression analysis revealed ApoA2, SAA, lactate dehydrogenase, performance status and number of metastasis sites as independent factors for survival. Using these five factors, categorization of patients into three risk groups generated a novel protein-based model predicting patient prognosis (AIC = 713, P = 4.3 x 10(-11)) more robustly than the MSKCC model (AIC = 729, P = 1.3 x 10(-7)). Applying this protein-based model instead of the MSKCC model would have changed the risk group in 38% of the patients. CONCLUSIONS Proteomics and subsequent validation yielded two novel prognostic markers and survival models which improved prediction of OS in mRCC patients over commonly used risk models. Implementation of these models has the potential to improve current risk stratification, although prospective validation will still be necessary.

A prospective quality of life study in patients with locally advanced prostate cancer, treated with radiotherapy with or without regional or interstitial hyperthermia

Introduction : The aim of this prospective study was to describe quality of life (QoL) in patients with locally advanced prostate carcinoma treated with conventional radiotherapy and to evaluate the influence of adding regional or interstitial hyperthermia. Materials and methods : All patients were irradiated using a CT-planned conventional three field technique, administering 70 Gy to prostate and vesicles. In two different phase I studies, hyperthermia was added to the radiotherapy. Twelve patients were treated with one interstitial hyperthermia treatment, lasting 60 min. Fourteen patients have been treated with five regional hyperthermia treatments, lasting 75 min each. In both hyperthermia studies, the body, bladder and rectum temperatures remained below safety limits. Patients treated with radiotherapy alone ( n = 58) or combined with regional ( n = 8) or interstitial hyperthermia ( n = 12) completed the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (C30 + 3), the EORTC prostate cancer module (PR25) and the Rand 36 health survey before treatment and 1 and 6 months after completion of treatment. Analysis of Variance (ANOVA) for repeated measurements has been performed to describe the data. Results : All patient groups were comparable concerning patient characteristics. No significant interaction or difference in QoL has been noticed between the two hyperthermia patient groups and the patient group without hyperthermia. Therefore, all groups were analysed together ( n = 78) to detect QoL changes in time. A deterioration of QoL has been measured from baseline to 1 month after treatment. Fatigue, pain, urinary symptoms, bowel symptoms and financial difficulties increased significantly. Social, physical and role functioning worsened significantly. No differences in QoL were measured 6 months after treatment compared to the baseline measurement, except for a decrease in sexual activity. Conclusions : After radiotherapy with or without hyperthermia only a temporary deterioration of QoL occurs, concerning social, psychological and disease related symptoms. Additional hyperthermia does not seem to decrease QoL.

Turnover time of Leydig cells and other interstitial cells in testes of adult rats.

The aim of this study was to investigate the turnover of Leydig cells and other interstitial cells in the adult rat testis. Normal adult rats received injections of [3H]thymidine at 9:00 and 21:00 for 2, 5, or 8 days. The percentage of labeled Leydig cells, which was initially low (0.8% +/- 0.2%), gradually increased during treatment to 1.4% +/- 0.3%. The percentage of labeled peritubular cells was considerably higher and increased from 1.4% +/- 0.1% to 3.5% +/- 0.4% during [3H]thymidine treatment. The remaining interstitial cells were the most actively proliferating cells: the percentage of labeled cells increased from 2.4% +/- 0.2% to 7.5% +/- 0.8% during [3H]thymidine treatment. Leydig cells, peritubular cells, and the remaining interstitial cells in the adult rat testis undergo proliferation. By means of a linear regression analysis and an arcsin transformation, an estimation of the time interval needed to replace various types of interstitial cells was obtained. Taking into account the 95% confidence interval, the turnover time of Leydig cells ranged from 142 to 2823 days. The calculated turnover time for the peritubular cells was 85 to 257 days.