The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate – a randomised controlled trial

Background

Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI.

Methods/Design

We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI.Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included.Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total).An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm).

Discussion

The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women.

Trial registration number

Netherlands Trial register NTR1449

     

Snuff use and smoking among senior high school students: effects of a snuff sales ban

OBJECTIVES: The popularity of snuff especially among adolescents is rising. The association between long-term snuff use and oral cancer discovered in epidemiological studies has prompted a variety of preventive measures to be taken to reduce snuff use and prevent adoption of the habit. In this study, the effect of a recent (I March, 1995) snuff sales ban introduced in Finland was investigated. Further, the rates of smoking, snuff use, alcohol use and drug experimenting were investigated before the introduction of the ban to characterize the study population.
DESIGN AND SUBJECTS: Two questionnaire studies were carried out. The first was carried out 3 months prior to the ban in 1994 and the second 9 months after the ban in 1995 in a senior high school population in southwestern Finland. The participants were 793 students (aged 15–22 years) in the first survey and 545 students (aged 16–23) in the second. Associations between variables were analyzed using cross-tabulation and stepwise logistic regression. The effects of the ban were determined on the basis of direct questions in the second questionnaire relating to the snuff sales ban.
RESULTS: Snuff was used by 9% of the students participating in the first study. The results of the second questionnaire indicate that the implementation of the snuff sales ban reduced the rate of snuff use by 1% in the study population. The majority of the snuff users (76%) reported that they had maintained their snuff habit. Of those reporting that they were snuff users before implementation of the snuff sales ban, 12% had switched to smoking and 5% to drugs.
CONCLUSIONS: The results of the present study suggest that the snuff sales ban in this population with a high rate of snuff use had little effect on snuff use rates and may have some short-term negative consequences as some snuff users switch to other substitutes, such as smoking, with known adverse health effects.     

Primary non-Hodgkin's lymphoma of the CNS treated with CHOD/BVAM or BVAM chemotherapy before radiotherapy: long-term survival and prognostic factors

PURPOSE: To assess the long-term survival and prognostic factors associated with the cyclophosphamide, doxorubicin, vincristine, and dexamethasone (CHOD)/carmustine, vincristine, methotrexate, and cytarabine (BVAM) and BVAM chemotherapy regimens followed by cranial radiotherapy in the treatment of primary central nervous system (CNS) non-Hodgkin lymphoma. METHODS AND MATERIALS: Since 1986, high-dose methotrexate (1.5 g/m(2)), cytarabine, vincristine, and carmustine have been used in the BVAM chemotherapy regimen for primary CNS non-Hodgkin's lymphoma, with one cycle of CHOD given before BVAM in patients or=60 years, performance status >or=2, and multifocal and/or meningeal disease [advanced stage]), a score of 0 (8 patients) was associated with a median survival of 55 months, a score of 1 (29 patients) of 41 months, a score of 2 (28 patients) of 32 months, and a score of 3 (12 patients) a median survival of 1 month (p <0.001). The actuarial overall survival for the 35 patients aged <60 years was 32.4% (95% confidence interval, 14.1-50.8%) at 10 years. CONCLUSION: The Nottingham/Barcelona prediction score, which is similar to the International Prognostic Index, may be useful in comparing survival with different regimens studied in Phase II trials. Patients with primary CNS non-Hodgkin's lymphoma aged <60 years treated with CHOD/BVAM or BVAM followed by radiotherapy have a similar long-term survival to that of patients with large B cell non-Hodgkin's lymphoma at other extranodal sites.     

The membrane mucin MUC4 is elevated in breast tumor lymph node metastases relative to matched primary tumors and confers aggressive properties to breast cancer cells

Introduction

Previous studies indicate that overexpression of the membrane-associated mucin MUC4 is potently anti-adhesive to cultured tumor cells, and suppresses cellular apoptotic response to a variety of insults. Such observations raise the possibility that MUC4 expression could contribute to tumor progression or metastasis, but the potential involvement of MUC4 in breast cancer has not been rigorously assessed. The present study aimed to investigate the expression of the membrane mucin MUC4 in normal breast tissue, primary breast tumors and lymph node metastases, and to evaluate the role of MUC4 in promoting the malignant properties of breast tumor cells.

Methods

MUC4 expression levels in patient-matched normal and tumor breast tissue was initially examined by immunoblotting lysates of fresh frozen tissue samples with a highly specific preparation of anti-MUC4 monoclonal antibody 1G8. Immunohistochemical analysis was then carried out using tissue microarrays encompassing patient-matched normal breast tissue and primary tumors, and patient-matched lymph node metastases and primary tumors. Finally, shRNA-mediated knockdown was employed to assess the contribution of MUC4 to the cellular growth and malignancy properties of JIMT-1 breast cancer cells.

Results

Immunoblotting and immunohistochemistry revealed that MUC4 levels are suppressed in the majority (58%, p < 0.001) of primary tumors relative to patient-matched normal tissue. On the other hand, lymph node metastatic lesions from 37% (p < 0.05) of patients expressed higher MUC4 protein levels than patient-matched primary tumors. MUC4-positive tumor emboli were often found in lymphovascular spaces of lymph node metastatic lesions. shRNA-mediated MUC4 knockdown compromised the migration, proliferation and anoikis resistance of JIMT-1 cells, strongly suggesting that MUC4 expression actively contributes to cellular properties associated with breast tumor metastasis.

Conclusions

Our observations suggest that after an initial loss of MUC4 levels during the transition of normal breast tissue to primary tumor, the re-establishment of elevated MUC4 levels confers an advantage to metastasizing breast tumor cells by promoting the acquisition of cellular properties associated with malignancy.     

Prospective study of a noninvasive treatment for two common congenital toe abnormalities (curly/varus/underlapping toes and overlapping toes)

OBJECTIVE

To assess, in the newborn, the efficacy of a standard taping treatment used in children for two selected congenital toe abnormalities (curly/varus/underlapping toes and overlapping toes), and compare the outcome with the available world literature.

METHODS

All children referred by their family physician between January 2004 and January 2006 were included. The newborns were reviewed by one author (WGS) within 10 days of birth, assessed for severity, and the toes were taped in a standard manner if the abnormalities met the study criteria. After one and two months, the same author reviewed the children, and retaped the toes. The children’s toes were photographed before the taping and then after three months when the tape was removed permanently. After six months, the children, with their pictures, were sent to a second author (JTS), and were scored for the grade of severity and improvement using standard criteria.

RESULTS

The world literature and standard textbooks indicate a 25% spontaneous improvement of these abnormalities. The recommendation is for surgical correction at a later date because intervention with taping has not shown success after the newborn period. No prior studies have been undertaken in the newborn. In the present study of 84 toes, the abnormality occurred in 2.8% of newborns, and 94% of the toes were improved or cured with no complications related to the technique.

CONCLUSION

A simple, office-friendly technique of taping underlapping and overlapping toes in the newborn proved successful in 94% of the toes.     

Undergraduate ophthalmology education survey of New Zealand ophthalmologists, general practitioners and optometrists

Aim : To determine what New Zealand ophthalmologists, general practitioners and optometrists consider important ophthalmic topic areas requiring emphasis in the medical undergraduate curriculum. Method : A total of 793 questionnaires related to the content and teaching of undergraduate ophthalmology were sent to ophthalmologists, general practitioners and optometrists. Results were analysed separately for the three respondent groups and as a whole. Results : Four hundred and fourteen questionnaires were returned (52% return rate). Overall responses of the three participant groups were similar and agreed favourably with the current curriculum. The ability to measure visual acuity (97%) and pupillary reflexes (93%), perform ophthalmoscopy (92%), and assess visual fields (68%) were regarded as ‘important or essential’ by the majority of respondents. Only 53% of respondents consider the ability to diagnose chronic open angle glaucoma as important. The respondents stressed the importance of the diagnosis of predominantly anterior segment disease contrasting with the traditional bias towards the teaching of ophthalmoscopy and posterior segment disease. The majority of respondents stressed the importance of graduating medical students being able to treat bacterial and allergic conjunctivitis, styes, blepharitis, corneal abrasion, and corneal and conjunctival foreign bodies, areas present but not normally emphasized in current curricula. Conclusion : The findings of this study provided additional data to facilitate curriculum design and illustrated the value of an integrated problem‐based learning approach in ophthalmology undergraduate teaching.     

Duodenal hematoma: the ring sign in MR imaging

Proper management of duodenal hematoma requires that an accurate diagnosis be made using noninvasive radiological methods. Conventional imaging may be nonspecific if there is no history of trauma or coagulopathy. Two cases of duodenal hematoma that were imaged by magnetic resonance (MR) and computed tomography (CT) are described. In both cases the hematoma had a well-defined concentric ring configuration on MR images, a finding which helped establish the diagnosis. MR imaging may provide tissue-specific characterization of duodenal hematomas.