Treatment of stage I seminoma, with one course of adjuvant carboplatin or surveillance, risk-adapted recommendations implementing patient autonomy: a report from the Swedish and Norwegian Testicular Cancer Group (SWENOTECA).

BACKGROUND: The purpose of the protocol was to reduce the treatment burden in clinical stage I (CSI) seminoma by offering risk-adapted treatment. The protocol aimed to prospectively validate the proposed risk factors for relapse, stromal invasion of the rete testis and tumor diameter >4 cm, and to evaluate the efficacy of one course of adjuvant carboplatin. PATIENTS AND METHODS: From 2007 to 2010, 897 patients were included in a prospective, population-based, risk-adapted treatment protocol implementing one course of adjuvant carboplatin AUC7 (n = 469) or surveillance (n = 422). In addition, results from 221 patients receiving carboplatin between 2004 and 2007 are reported. RESULTS: At a median follow-up of 5.6 years, 69 relapses have occurred. Stromal invasion of the rete testis [hazard ratio (HR) 1.9, P = 0.011] and tumor diameter >4 cm (HR 2.7, P < 0.001) were identified as risk factors predicting relapse. In patients without risk factors, the relapse rate (RR) was 4.0% for patients managed by surveillance and 2.2% in patients receiving adjuvant carboplatin. In patients with one or two risk factors, the RR was 15.5% in patients managed by surveillance and 9.3% in patients receiving adjuvant carboplatin. We found no increased RR in patients receiving carboplatin <7 × AUC compared with that in patients receiving ≥7 × AUC. CONCLUSION: Stromal invasion in the rete testis and tumor diameter >4 cm are risk factors for relapse in CSI seminoma. Patients without risk factors have a low RR and adjuvant therapy is not justified in these patients. The efficacy of adjuvant carboplatin is relatively low and there is need to explore more effective adjuvant treatment options in patients with high-risk seminoma. The data do not support the concept of a steep dose response for adjuvant carboplatin.

One course of adjuvant BEP in clinical stage I nonseminoma mature and expanded results from the SWENOTECA group.

BACKGROUND: SWENOTECA has since 1998 offered patients with clinical stage I (CS I) nonseminoma, adjuvant chemotherapy with one course of bleomycin, etoposide and cisplatin (BEP). The aim has been to reduce the risk of relapse, sparing patients the need of toxic salvage treatment. Initial results on 312 patients treated with one course of adjuvant BEP, with a median follow-up of 4.5 years, have been previously published. We now report mature and expanded results. PATIENTS AND METHODS: In a prospective, binational, population-based risk-adapted treatment protocol, 517 Norwegian and Swedish patients with CS I nonseminoma received one course of adjuvant BEP. Patients with lymphovascular invasion (LVI) in the primary testicular tumor were recommended one course of adjuvant BEP. Patients without LVI could choose between surveillance and one course of adjuvant BEP. Data for patients receiving one course of BEP are presented in this study. RESULTS: At a median follow-up of 7.9 years, 12 relapses have occurred, all with IGCCC good prognosis. The latest relapse occurred 3.3 years after adjuvant treatment. The relapse rate at 5 years was 3.2% for patients with LVI and 1.6% for patients without LVI. Five-year cause-specific survival was 100%. CONCLUSIONS: The updated and expanded results confirm a low relapse rate following one course of adjuvant BEP in CS I nonseminoma. One course of adjuvant BEP should be considered a standard treatment in CS I nonseminoma with LVI. For patients with CS I nonseminoma without LVI, one course of adjuvant BEP is also a treatment option.

Alpha emitter radium-223 and survival in metastatic prostate cancer.

BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Local and systemic expressions of MMP-9, TIMP-1 and PAI-1 in patients undergoing surgery for clinically suspected appendicitis.

BACKGROUND/AIMS: To examine, compare and correlate the expressions of matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinase 1 (TIMP-1) and plasminogen activator inhibitor type 1 (PAI-1) in appendiceal tissue and pre- and postoperative blood samples in patients undergoing surgery for clinically suspected appendicitis. METHODS: Fifty-seven patients with complete tissue and blood samples were included and divided into groups of noninflamed appendix/lymphadenitis (n = 7), phlegmonous appendicitis (n = 30), gangrenous appendicitis (n = 11) and perforated appendicitis (n = 9). The protein expressions were assessed with ELISAs. The local expressions of MMP-9, TIMP-1 and PAI-1 were correlated with the systemic expressions at the time of surgery while the systemic individual differences between surgery and recovery were compared. RESULTS: There was a positive correlation between tissue and plasma PAI-1 (p < 0.05). The individual differences for plasma MMP-9 and PAI-1 were statistically nonsignificant, while they were higher for TIMP-1 in patients with perforated appendicitis compared with phlegmonous (p < 0.0001) and gangrenous appendicitis (p < 0.01). CONCLUSIONS: Plasma PAI-1 reflected the levels in appendiceal tissue at the time of surgery. Systemic TIMP-1 could have the potential of distinguishing perforated from nonperforated appendicitis.

Gene variations in sex hormone pathways and the risk of testicular germ cell tumour: a case-parent triad study in a Norwegian-Swedish population.

BACKGROUND: Testicular germ cell tumour (TGCT) is the most common cancer in young men, and an imbalance between the estrogen and androgen levels in utero is hypothesized to influence TGCT risk. Thus, polymorphisms in genes involved in the action of sex hormones may contribute to variability in an individual's susceptibility to TGCT. METHODS: We conducted a Norwegian-Swedish case-parent study. A total of 105 single-nucleotide polymorphisms (SNPs) in 20 sex hormone pathway genes were genotyped using Sequenom MassArray iPLEX Gold, in 831 complete triads and 474 dyads. To increase the statistical power, the analysis was expanded to include 712 case singletons and 3922 Swedish controls, thus including triads, dyads and the case-control samples in a single test for association. Analysis for allelic associations was performed with the UNPHASED program, using a likelihood-based association test for nuclear families with missing data, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. False discovery rate (FDR) was used to adjust for multiple testing. RESULTS: Five genetic variants across the ESR2 gene [encoding estrogen receptor beta (ERß)] were statistically significantly associated with the risk of TGCT. In the case-parent analysis, the markers rs12434245 and rs10137185 were associated with a reduced risk of TGCT (OR = 0.66 and 0.72, respectively; both FDRs <5%), whereas rs2978381 and rs12435857 were associated with an increased risk of TGCT (OR = 1.21 and 1.19, respectively; both FDRs <5%). In the combined case-parent/case-control analysis, rs12435857 and rs10146204 were associated with an increased risk of TGCT (OR = 1.15 and 1.13, respectively; both FDRs <5%), whereas rs10137185 was associated with a reduced risk of TGCT (OR = 0.79, FDR <5%). In addition, we found that three genetic variants in CYP19A1 (encoding aromatase) were statistically significantly associated with the risk of TGCT in the case-parent analysis. The T alleles of the rs2414099, rs8025374 and rs3751592 SNPs were associated with an increased risk of TGCT (OR = 1.30, 1.30 and 1.21, respectively; all FDRs <5%). We found no statistically significant differences in allelic effect estimates between parental inherited genetic variation in the sex hormone pathways and TGCT risk in the offspring, and no evidence of heterogeneity between seminomas and non-seminomas, or between the Norwegian and the Swedish population, in any of the SNPs examined. CONCLUSIONS: Our findings provide support for ERß and aromatase being implicated in the aetiology of TGCT. Exploring the functional role of the TGCT risk-associated SNPs will further elucidate the biological mechanisms involved.

Regional trends in prostate cancer incidence, treatment with curative intent and mortality in Norway 1980-2007.

OBJECTIVES: To compare the trends in prostate cancer incidence, treatment with curative intent and mortality across regions and counties in Norway, and to consider changes in incidence (an indicator for early diagnosis) and treatment with curative intent as explanatory factors for the decreasing prostate cancer mortality rates. PATIENTS AND METHODS: Prostate cancer incidence and mortality data (1980-2007) alongside treatment data (1987-2005) were obtained from the national, population-based Cancer Registry of Norway. Joinpoint regression models were fitted to age-adjusted incidence, treatment and mortality rates to identify linear changes in the trends. RESULTS: Both age-adjusted incidence rates and rates of curative treatment of prostate cancer increased significantly in all five regions of Norway since the early 1990s. There was a strong positive correlation between increasing incidence and increasing use of curative treatment. The frequency of curative treatment in Western Norway was almost threefold that in the Northern and Central regions around year 2000. Subsequently, the regional trends converged and only minor differences in prostate cancer incidence and use of curative treatment were observed by 2005. The declines in mortality were observed earliest in the regions with the highest incidence and the most frequent use of curative treatment, while the largest decreases in mortality were found in counties where the largest increases in curative treatment were observed. CONCLUSIONS: The elucidation of the prostate cancer mortality trends is hindered by an inability to tease out the potential effects of early treatment from the more general impact of improved and more active treatment. However, it is likely that both sets of intervention have contributed to the decline in prostate cancer mortality in Norway since 1996.

Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients.

BACKGROUND: A trial in selected men suggested that antibiotic therapy could be an alternative to appendicectomy in appendicitis. This study aimed to evaluate antibiotic therapy in unselected men and women with acute appendicitis. METHODS: Consecutive patients were allocated to study (antibiotics) or control (surgery) groups according to date of birth. Study patients received intravenous antibiotics for 24 h and continued at home with oral antibiotics for 10 days. Control patients had a standard appendicectomy. Follow-up at 1 and 12 months was carried out according to intention and per protocol. RESULTS: Study and control patients were comparable at inclusion; 106 (52.5 per cent) of 202 patients allocated to antibiotics completed the treatment and 154 (92.2 per cent) of 167 patients allocated to appendicectomy had surgery. Treatment efficacy was 90.8 per cent for antibiotic therapy and 89.2 per cent for surgery. Recurrent appendicitis occurred in 15 patients (13.9 per cent) after a median of 1 year. A third of recurrences appeared within 10 days and two-thirds between 3 and 16 months after hospital discharge. Minor complications were similar between the groups. Major complications were threefold higher in patients who had an appendicectomy (P < 0.050). CONCLUSION: Antibiotic treatment appears to be a safe first-line therapy in unselected patients with acute appendicitis. REGISTRATION NUMBER: NCT00469430 (http://www.clinicaltrials.gov).

Metastatic spinal cord compression: diagnostic delay, treatment, and outcome.

BACKGROUND: Metastatic spinal cord compression (MSCC) is a disabling complication of malignant disease. The aim of this study was to estimate diagnostic delay, treatment outcome, and prognostic factors in patients with MSCC. MATERIAL AND METHODS: In 86 patients treated for MSCC at our institution, the median age was 65 years and there was a preponderance of males (73%). The median observation period was 39 months. Carcinoma of the prostate, lung, breast, and kidney constituted 66% of the primary malignancies. Prior to treatment, 34% had grade 1, 53% grade 2, and 13% grade 3 paresis. 33% underwent surgical laminectomy with postoperative radiotherapy (combined therapy), while 67% were irradiated only. RESULTS: Median time from the start of symptoms to the first doctor contact was 1 day, and to hospital admission or treatment start 6 days and 8 days. The pre-treatment grade of paresis, preservation of gait function, and primary tumour histology were strong predictors for treatment response. Pain relief, reported by 82% of assessable patients, correlated to treatment response grade. Median survival from treatment start was 4.1 months. Survival corresponded positively to preserved gait function at admission, to treatment response grade, and to the employment of combined therapy. Primary tumour histology was an important predictor as breast cancer and prostate cancer had 3 to 6-fold longer survival compared to lung cancer patients. CONCLUSION: Prolonged survival in a minority of the patients signified the importance of optimal treatment. To settle whether radiotherapy alone is the optimal treatment in all MSCC patients, a randomised trial is warranted.

Antibiotic resistance in Escherichia coli of the normal intestinal flora of swine.

Twelve hundred enterobacterial Escherichia coli isolates of porcine origin were screened phenotypically for antibiotic resistance. The bacteria were isolated from 10 herds of swine with different histories of exposure to antimicrobial agents for therapeutic purposes. The bacterial isolates were part of the normal bacterial flora of the intestines of the animals because they were isolated from healthy individuals. The strains were tested for phenotypic antibiotic resistance against sulfonamides, trimethoprim, streptomycin, ampicillin, neomycin, chloramphenicol, and tetracycline. Resistance against streptomycin was found to be most common, followed by resistance against sulfonamides and tetracycline. The highest number of resistant bacteria was found in herds where the use of antimicrobial agents was considered to be high. A selection of multiresistant bacterial isolates were further genetically characterized by hybridization with probes specific for the antibiotic resistance genes; sulI, sulII, dfrI, dfrIIb, dfrIX, and the class A, B, C, and D tetracycline resistance determinants. A PCR was developed and used for detection of the strA-strB gene pair encoding streptomycin resistance in gram-negative bacteria. The strA-strB gene pair was the most frequent resistance determinant in the isolates examined. This study indicates that nonpathogenic E. coli from swine may represent a considerable reservoir of antibiotic resistance genes that might be transferable to pathogens.

Induced abortion: Chlamydia trachomatis and postabortal complications. A cost benefit analysis.

The overall prevalence of Chlamydia trachomatis among 873 abortion-seeking women was 9.3% during 1985. Significantly higher age-specific prevalences of C. trachomatis occurred among younger women (p less than 0.001). None of 17 women treated for C. trachomatis before the abortion was carried out, was readmitted to the hospital. Of 64 Chlamydia-positive women, who commenced treatment within the first 2 weeks after the abortion was carried out, 14.1% were readmitted to the hospital, compared with 5.7% of Chlamydia-negative women (p less than 0.02). Postabortal salpingitis was verified at readmission among 10.9% of Chlamydia-positive women and 3.2% of Chlamydia-negative women (p less than 0.01). An analysis of screening of all abortion-seeking women is estimated to be worthwhile when the prevalence of C. trachomatis exceeds 4.3%. We recommend screening for Chlamydia trachomatis of all abortion-seeking women, 30 years or younger, at the pre-abortion visit, provided that treatment can be completed before the abortion is carried out.

The effects of vocational services provided to the mentally disabled.

The purpose of this study was to evaluate the effects of vocational services provided to mentally disabled clients of the Fresno County Department of Health by the California State Department of Vocational Rehabilitation located in Fresno, California. The findings were (a) 46% were discharged as employed; (b) cost per client was $1,590: (c) cost per success was $3,448; (d) the employed persons entered a variety of competitive jobs; (e) average annual income for persons employed at discharge was $5,539; (f) persons who were employed were less psychiatrically disabled and had a better work history; (g) only 26% of the severely disabled were employed, compared to 50% of the persons who were mildly or moderately disabled; (h) the main benefit of the program appeared to be that of returning less disabled clients with better work histories to work at normative levels shown prior to vocational services; and (i) cost-benefit analysis showed that annual earned income exceeded program cost.