Introducing a new section to <Emphasis Type="Italic">Breast Cancer Research</Emphasis>: Endocrinology and hormone therapy

Endocrine therapy is increasingly understood as the conceptual basis for the future treatment and prevention of breast cancer. Endocrine agents have considerably changed the approach to targeted treatment during the past two decades, and select endocrine agents have advanced the goal of preventing breast cancer. Progress has occurred because of a vigorous interaction between laboratory scientists and the clinical trials community. Breast Cancer Research is launching a new section on endocrinology and hormone therapy in order to invigorate this exchange and challenge our readers with novel concepts that might result in enhanced survival in breast cancer.     

Combination of Docetaxel, Epirubicin and Vinorelbine Administered Every 2 Weeks as First-line Therapy in Patients with Metastatic Breast Cancer: A Dose-finding Study

Aims. To assess efficacy and optimum combination dosage of intravenous docetaxel (T), epirubicin (E) and vinorelbine (N) administered every 2 weeks and without colony stimulating factor (CSF) support in patients with metastatic breast cancer (MBC). Patients and method. Patients (n = 51) with MBC were consecutively assigned to four different dose levels (DL) to receive (in mg/m²): Level I = T35 + E30 + N25; Level II = T30 + E30 + N25; Level III = T30 + E25 + N25; and Level IV = T25 + E25 + N25. Consecutive cycles were delayed if absolute neutrophil and/or platelet counts fell below 1.5 × 10⁹ and 100 × 10⁹l^–1, respectively. Treatment at a given dose level was suspended if 33% or more of patients included in a given cohort had unacceptable toxicity. Results. The patients evaluable for toxicity (n = 48) received 448 cycles (median 9; range 1–23). There was neutropenia G 3–4 in 30 patients (63%) with fever in 3 (6%). The G 2–3 non-hematological toxicities were alopecia in 39 patients (81%), mucositis in 11 (23%), and nausea/vomiting in 8 (17%). There were no toxic deaths. Treatment delay or dose reduction after first cycle occurred in 30% of patients treated in all DLs, except the fourth. Objective response was achieved in 29 of the 47 evaluable patients (58%; 95% CI: 50–66). The median duration of response, time-to-progression and overall survival were 13, 11 (range 8–14) and 20 (range 16–24) months, respectively. Conclusion. The combination of docetaxel, epirubicin and vinorelbine without CSF support ought not to exceed 25 mg/m² every 2 weeks. The efficacy is no greater than other existing regimens for first-line treatment of MBC.     

Vasectomy reversal for the post-vasectomy pain syndrome: a clinical and histological evaluation

PURPOSE: The cause of the post-vasectomy pain syndrome is unclear. Some postulated etiologies include epididymal congestion, tender sperm granuloma and/or nerve entrapment at the vasectomy site. To our knowledge nerve proliferation has not been evaluated previously as a cause of pain. Vasectomy reversal is reportedly successful for relieving pain in some patients. We report our experience and correlate histological findings in resected vasal segments with outcome to explain the mechanism of pain in these patients. MATERIALS AND METHODS: We retrospectively reviewed the records of 13 men who underwent vasectomy reversal for the post-vasectomy pain syndrome. We compared blinded histological evaluations of the vasal ends excised at vasectomy reversal in these patients with those of pain-free controls who underwent vasectomy reversal to reestablish fertility. Controls were matched to patients for the interval since vasectomy. Histological features were graded according to the degree of severity of vasitis nodosum, chronic inflammation and nerve proliferation. RESULTS: Mean time to pain onset after vasectomy was 2 years. Presenting symptoms included testicular pain in 9 cases, epididymal pain in 2, pain at ejaculation in 4 and pain during intercourse in 8. Physical examination demonstrated tender epididymides in 6 men, full epididymides in 6, a tender vasectomy site in 4 and a palpable nodule in 4. No patient had testicular tenderness on palpation. Unilateral and bilateral vasovasostomy was performed in 3 and 10 of the 13 patients, respectively. Postoperatively 9 of the 13 men (69%) became completely pain-free. Mean followup was 1.5 years. We observed no differences in vasectomy site histological features in patients with the post-vasectomy pain syndrome and matched controls, and no difference in histological findings in patients with the post-vasectomy pain syndrome who did and did not become pain-free postoperatively. CONCLUSIONS: No histological features aid in identifying a cause of pain or provide prognostic value for subsequent pain relief. Vasectomy reversal appeared to be beneficial for relieving pain in the majority of select patients with the post-vasectomy pain syndrome.     

Cost-effectiveness and value of information analyses of neuraminidase inhibitors for the treatment of influenza

OBJECTIVES: To assess the cost-effectiveness of alternative strategies for the treatment of suspected influenza in otherwise healthy adults and to identify future research priorities using value of information analysis. METHODS: A decision model was used to estimate the costs and effects, in terms of quality-adjusted life-years (QALYs) of amantadine, zanamivir, and oseltamivir for the treatment of influenza in otherwise healthy adults using data predominantly from meta-analysis of randomized controlled trials. Probabilistic sensitivity analysis using Monte Carlo simulation was conducted. The expected value of perfect information for the entire model and for individual parameters was calculated. RESULTS: Based on mean costs and effects, zanamivir is dominated by oseltamivir. The incremental cost-effectiveness ratio for amantadine (compared with no treatment) is pound 11,000 and pound 44,000 for oseltamivir (compared with amantadine). The probability that amantadine is cost-effective at a willingness to pay of pound 30,000 per QALY is 0.74, falling to 0.49 at pound 20,000 per QALY. Global expected value of perfect information (EVPI) is pound 2 m over 15 years if a willingness to pay threshold of pound 30,000 per QALY is assumed rising to pound 9.6 m at pound 45,000 per QALY. EVPI for only one parameter exceeds pound 500,0000 at pound 30,000 per QALY: the quality of life for untreated influenza. CONCLUSIONS: At traditionally accepted values of willingness to pay for health benefits, it is unlikely that additional research would be an efficient use of scarce resources. The only exception to this would be to examine the health-related quality of life impact of influenza in an untreated patient group. If a higher threshold value were acceptable, there are a small group of parameters that may warrant further investigation. These would, however, require comparative, potentially expensive, research studies.     

Axillary lymph node nanometastases are prognostic factors for disease-free survival and metastatic relapse in breast cancer patients.

PURPOSE: Early breast cancer presents with a remarkable heterogeneity of outcomes. Undetected, microscopic lymph node tumor deposits may account for a significant fraction of this prognostic diversity. Thus, we systematically evaluated the presence of lymph node tumor cell deposits相似文献   

Recurrent hepatocellular carcinoma after liver transplantation mimicking post‐transplantation lymphoproliferative disorder

Approximately 5% of patients with end‐stage cirrhosis undergoing orthotopic liver transplantation have occult hepatocellular carcinoma. Careful follow up is required to detect recurrent tumour, and knowledge of the patterns of recurrence may avoid diagnostic confusion with other malignancies, such as post‐transplantation lymphoproliferative disorder. This case report illustrates an unusual presentation of recurrent hepatocellular carcinoma in a 56‐year‐old man presenting with a para‐aortic soft tissue mass, thought clinically and radiologically to represent lymphoma or post‐transplantation lymphoproliferative disorder. This case demonstrates that recurrent hepatocellular carcinoma can present late after transplantation as retroperitoneal lymphadenopathy, and should alert physicians and radiologists to be aware of the radiological appearances of recurrence and of the need for early biopsy to avoid diagnostic confusion with other malignancies.     

Chemical transformation of mouse liver cells results in altered cyclin D-CDK protein complexes

Dysregulated cell proliferation is one phenotypic change associated with neoplasia. Key protein complexes involved in regulating cell division are composed of cyclins, cyclin-dependent kinases (CDK) and CDK inhibitors (CDI). Many virally transformed cells in culture exhibit disrupted cyclin-CDK-CDI complexes, suggesting that such changes may play a mechanistic role in viral transformation. To determine whether similar alterations may be involved in chemical carcinogenesis we characterized cyclin D1-CDK-CDI protein complexes in a non-tumorigenic mouse liver cell line and investigated whether complexes were altered after transformation with the genotoxic carcinogens N-methyl-N'-nitro-N- nitrosoguanidine (MNNG) or 3-methylcholanthrene (MC). In non- tumorigenic mouse liver cells cyclin D1 associated with CDK6, CDK4 or CDK2 to form binary (cyclin D1-CDK), tertiary (cyclin D1-CDK-p27KIP1) or quaternary (cyclin D1-CDK-p21WAF1-PCNA) complexes. After chemical transformation of mouse liver cells with either MC or MNNG, select cyclin D1-CDK-CDI protein complexes were altered. In MC-transformed cells formation of various binary, tertiary and quaternary cyclin D1- CDK-(CDI) protein complexes was reduced, resulting in decreased CDK4 kinase activity. Interestingly, CDK6 kinase activity was dramatically elevated due to high levels of cyclin D3 in association with CDK6. In MNNG-transformed cells select cyclin D1-CDK6-CDI and cyclin D1-CDK2-CDI protein complexes were altered but CDK6 and CDK4 kinase activity remained unaffected. Distinct changes in cyclin D1-CDK-CDI complexes found between the two chemically transformed mouse liver cell lines suggest that each cell line harbored unique mutations or alterations that differentially contributed to stabilization of cyclin D1-CDK-CDI holoenzymes. p53 gene mutations were not detected in the MC- or MNNG- transformed mouse liver cell lines and thus were not involved in disrupting cyclin D1-CDK-CDI protein complexes. In summary, this study presents evidence that D-type CDK protein complexes can be altered physically and functionally after chemical transformation with genotoxic carcinogens, suggesting that components of the cell cycle machinery can be targeted during chemical carcinogenesis.      

ECG and echocardiographic diagnosis of pulmonary thromboembolism associated with central venous lines

The aim was to establish the prevalence of pulmonary embolism in 21 children (median age 12 months; range 5-132 months) with central venous lines in situ > 3 months (median 10 months; range 3-47). Twelve-lead electrocardiograms (ECGs) and echocardiograms were analysed in a retrospective study using ECG and echocardiographic criteria for pulmonary embolism-previously established and validated in adult patients- and standard paediatric ECG values as control data. Patients were scored as having definite (n = 7), probable (n = 5), or no pulmonary embolism (n = 9). Overall 57% of ECGs showed abnormalities compatible with pulmonary embolism. In two patients, serial ECGs obtained during an acute cardiorespiratory illness showed cumulative changes diagnostic of pulmonary embolism. Eight of 12 patients with abnormal ECGs had echocardiography; in seven of these (88%) the right ventricular end diastolic diameter was > 2SD above the mean value for age. Twelve of the patients included in this study have died; two died following an acute respiratory illness. There was postmortem evidence of pulmonary thromboembolism in both of the two children for whom necropsy information was available. The data suggest that pulmonary embolism is common in children who have central venous lines in situ for > 3 months. Serial studies are of value in some patients. Pulmonary embolism may compromise the long term survival of children with small bowel failure and preclude consideration for liver and small bowel transplantation.     

Analysis of adenomatous polyposis coli gene in thyroid tumours.

Familial adenomatous polyposis (FAP) is known to be associated with neoplasia of various tissues, including thyroid carcinoma. Germline mutations of the tumour-suppressor gene APC, responsible for the predisposition to FAP, may therefore be involved in the pathogenesis of these tumours. In this report the structure of the APC gene has been investigated in 26 thyroid tumours, at different stages of dedifferentiation, that were surgically excised from patients with a negative history of FAP. Approximately 35% of the APC gene coding region, where most of the mutations are clustered, has been analysed by a combination of single-strand conformation polymorphism and direct sequencing. No significant alterations could be demonstrated in any sample examined. It is concluded that, at least in patients not affected by FAP, APC gene abnormalities do not seem to play a relevant role in the pathogenesis of thyroid carcinoma.