Pocketed microneedles for rapid delivery of a liquid-state botulinum toxin A formulation into human skin.

Botulinum toxin A (BT) is used therapeutically for the treatment of primary focal hyperhidrosis, a chronic debilitating condition characterised by over-activity of the eccrine sweat glands. Systemic toxicity concerns require BT to be administered by local injection, which in the case of hyperhidrosis means multiple painful intradermal injections by a skilled clinician at 6-monthly intervals. This study investigates the potential of a liquid-loaded pocketed microneedle device to deliver botulinum toxin A into the human dermis with the aim of reducing patient pain, improving therapeutic targeting and simplifying the administration procedure. Initially, ß-galactosidase was employed as a detectable model for BT to (i) visualise liquid loading of the microneedles, (ii) determine residence time of a liquid formulation on the device and (iii) quantify loaded doses. An array of five stainless steel pocketed microneedles was shown to possess sufficient capacity to deliver therapeutic doses of the potent BT protein. Microneedle-mediated intradermal delivery of ß-galactosidase and formaldehyde-inactivated botulinum toxoid revealed effective deposition and subsequent diffusion within the dermis. This study is the first to characterise pocketed microneedle delivery of a liquid formulation into human skin and illustrates the potential of such systems for the cutaneous administration of potent proteins such as BT. A clinically appropriate microneedle delivery system for BT could have a significant impact in both the medical and cosmetic industries.

Duct Excision is Still Necessary to Rule out Breast Cancer in Patients Presenting with Spontaneous Bloodstained Nipple Discharge.

Introduction. Spontaneous nipple discharge is the third most common reason for presentation to a symptomatic breast clinic. Benign and malignant causes of spontaneous nipple discharge continue to be difficult to distinguish. We analyse our experience of duct excisions for spontaneous nipple discharge to try to identify features that raise suspicion of breast cancer and to identify features indicative of benign disease that would be suitable for nonoperative management. Methods. Details of one hundred and ninety-four patients who underwent duct excision for spontaneous nipple discharge between 1995 and 2005 were analysed. Results. Malignant disease was identified in 11 (5.7%) patients, 4 invasive and 7 insitu, which was 10.2% of those presenting with bloodstained discharge. All patients with malignant disease had bloodstained discharge. Discharge due to malignant disease was more likely to be bloodstained than that due to benign causes (Fisher's exact test, 2-tailed P value = 0.00134). Conclusion. Our findings do not support a policy of conservative management of spontaneous bloodstained nipple discharge. Cases of demonstrable spontaneous bloodstained nipple discharge should undergo duct excision to prevent malignant lesions being missed.

Antibiotic prescription for patients referred to a specialist breast clinic.

Hospital referral is indicated as an emergency for breast infections not settling with oral antibiotics. Referrals to a breast clinic over a period of 6 months were assessed for prior antibiotic prescription. A total of 1078 patients were seen during this period. 91 (8%) patients had been prescribed antibiotics, 71% of which had been prescribed for non-infective conditions. Of those patients treated for infection, 42% had the wrong antibiotic prescribed. The final diagnoses for patients inappropriately prescribed antibiotics were chest wall pain in 23% and duct ectasia in 14%. Although the reasons for prescription of antibiotics are mutifactorial, careful examination of the patient will diagnose chest wall pain. Delayed prescribing may be appropriate for some patients.

Kylie Minogue's breast cancer: effects on referrals to a rapid access breast clinic in the UK.

We examine the effect of the announcement of Kylie's breast cancer on referrals to a rapid access breast clinic in the United Kingdom. General practitioner referrals were examined, concentrating on June 2005; the month following Kylie's diagnosis. Time series analysis with autoregressive integrated moving average modeling was used to forecast data. There was a significant increase in referrals and radiographic investigations, with no increase in the number of malignant diagnoses. It is encouraging that media campaigns appear to make women more 'breast aware;' however there may also be a detrimental effect with increased radiation exposure, anxiety and cancer phobia.

Tamoxifen and pregnancy.

Women are conventionally advised to stop tamoxifen before attempting pregnancy. The risks of congenital malformations or late teratogenic manifestations in adulthood are unknown. Following an informed discussion about the uncertainties of tamoxifen exposure on pregnancy women should be offered the choice whether to continue or stop tamoxifen before attempting pregnancy. An unexpected pregnancy in a women taking tamoxifen could continue if the pregnant woman accepts the possibility of a teratogenic effect that tamoxifen could have on the fetus.

Final diagnoses following C3 (atypical, probably benign) breast cytology.

Fine needle aspiration cytology is part of the triple assessment of breast lesions. The final diagnoses are reported in patients with breast lesions that produce C3 or atypical, probably benign cytology. C3 cytology was obtained from 61 breast lesions between January 1998 and December 1999. Ten (16%) of these lesions were malignant, only three of which were clinically or radiologically suspicious or malignant. Three were diagnosed by core biopsy, but three required excision biopsy after a benign core, and four diagnosed by excision without core. For benign lesions; in five the core was considered diagnostic, three were excised to confirm benignity, 11 monitored and 32 excised without core. Core biopsy should be performed in preference to cytology in the assessment of breast lesions. Where C3 cytology is obtained, core biopsy should be performed, but excision biopsy may still be required. The definition of C3 cytology should be changed to indeterminate.

Replace fine needle aspiration cytology with automated core biopsy in the triple assessment of breast cancer.

All patients presenting with a symptomatic breast lump are assessed by means of triple assessment (clinical examination, radiology in the form of mammography and cytology by means of a fine needle aspiration) performed by the clinician in the rapid access breast clinic at the Royal Gwent Hospital, Newport, UK. In our initial experience, it was found that a significant number of patients were returning to clinic for the results of the triple assessment to find that the cytology was not conclusive and hence needed a core biopsy, thus delaying diagnosis and definitive treatment. Therefore, a prospective study was carried out over a 6-month period, where all patients presenting with a symptomatic lump with a clinical or radiological suspicion of breast cancer had, in addition to the standard triple assessment, an automated core biopsy, thus giving rise to the quadruple assessment of the breast lump. A total of 52 patients with a clinical or radiological suspicion of breast cancer were included over this 6-month period. Of these 52 patients, 31 had a definitive diagnosis of breast cancer on fine needle aspiration (sensitivity 60%) compared with 50 of the 52 patients on core biopsy (sensitivity 96%). When radiology was diagnostic of breast cancer (R 5), the sensitivity of cytology was 61% compared with 97% with core biopsy. However, when radiology was not diagnostic of cancer (R 1-4), the sensitivity of cytology fell to 53% while the sensitivity of core biopsy remained high at 95%. The overall cellularity rate for cytology was 96%, which exceeds the BASO requirement for fine needle aspiration cytology. From these results, we conclude that automated core biopsy has a superior diagnostic power when compared with fine needle aspiration cytology and hence should replace fine needle aspiration cytology in the assessment of symptomatic breast lumps.

Randomized trial of a specialist genetic assessment service for familial breast cancer.

BACKGROUND: Because of the growing demand for genetic assessment, there is an urgent need for information about what services are appropriate for women with a family history of breast cancer. Our purpose was to compare the psychologic impact and costs of a multidisciplinary genetic and surgical assessment service with those of current service provisions. METHODS: We carried out a prospective randomized trial of surgical consultation with (the trial group) and without (the control group) genetic assessment in 1000 women with a family history of breast cancer. All P: values are from two-sided tests. RESULTS: Although statistically significantly greater improvement in knowledge about breast cancer was found in the trial group (P: =.05), differences between groups in other psychologic outcomes were not statistically significant. Women in both groups experienced statistically significant reductions in anxiety and found attending the clinics to be highly satisfying. An initial specialist genetic assessment cost pound 14.27 (U.S. $22.55) more than a consultation with a breast surgeon. Counseling and genetic testing of affected relatives, plus subsequent testing of family members of affected relatives identified as mutation carriers, raised the total extra direct and indirect costs per woman in the trial group to pound 60.98 (U.S. $96.35) over costs for the control subjects. CONCLUSIONS: There may be little benefit in providing specialist genetics services to all women with a family history of breast cancer. Further investigation of factors that may mediate the impact of genetic assessment is in progress and may reveal subgroups of women who would benefit from specialist genetics services.

The long-term course of mastalgia.

Mastalgia is a common condition in women of reproductive years. We have assessed the long-term course in patients with severe mastalgia by distributing a postal questionnaire to 212 patients previously studied in 1983 who had attended the mastalgia clinic at the University Hospital of Wales, Cardiff. 175 patients (83%) responded, with an original diagnosis of cyclical mastalgia (CM) in 120 and non-cyclical mastalgia (NCM) in 55. The median age of onset of breast pain was 36 years (range 12-63 years). The average duration of pain was long (median 12 years), especially if it started in the second or third decade of life. Pain persisted in 68 (57%) of CM and 35 (64%) of NCM patients. In CM patients resolution was commonly associated with a 'hormonal' event, notably the menopause; in NCM patients it more often seemed to be spontaneous. Severe mastalgia ran a chronic relapsing course often requiring repeated drug treatments.

The effect of danazol on discrete benign breast lumps.

Surgical biopsy of benign breast lumps produces a significant surgical workload, morbidity and cost. A double-blind placebo-controlled trial of danazol 200 mg daily was carried out with the aim of reducing the size of solid discrete breast lumps, thereby avoiding surgical biopsy in benign cases. Twenty-two women with lumps diagnosed as benign by clinical examination, mammography and cytology were randomized to take danazol and 26 placebo. The patients were assessed monthly by two clinicians until surgical biopsy. Twenty patients in each treatment group were evaluated and five patients discontinued treatment (two on danazol, three on placebo) and three (all on placebo) were found to be malignant. There was no difference in the number of lumps which responded to treatment with danazol or placebo. There was a reduction in the number of lumps which subsequently developed in the breasts treated with danazol during the 12-month follow-up period, but this failed to achieve statistical significance. Danazol does not promote resolution of solid discrete benign breast lumps. Careful selection of women over 25 years for surgery with solid discrete breast lumps is required, utilizing a dedicated breast cytologist with a multidisciplinary approach, to avoid missing breast cancers.

Drug therapy of mastalgia. What are the options?

Severe breast pain or mastalgia is a common symptom, affecting up to 70% of the female population at some time in their lives. It accounts for approximately 50% of referrals to a specialised breast clinic, two-thirds of patients having cyclical and one-third experiencing noncyclical mastalgia, or pain arising from the chest wall deep to the breast. After exclusion of breast cancer and proper reassurance, 85% of patients can be discharged from the clinic without specific treatment. In only 15% of patients is the pain severe enough to affect their lifestyle and warrant drug therapy. Using EF-12 (gammalinolenic acid; gamolenic acid) as first-line therapy, with danazol and bromocriptine usually as second-line agents, a clinically useful improvement in pain can be anticipated in 92% of patients with cyclical and 64% with noncyclical mastalgia. Patients with severe recurrent or refractory mastalgia may require treatment with tamoxifen, goserelin or testosterone, but the short and long term adverse effects of these drugs preclude their use as first-line agents. Chest wall pain is usually self-limiting, but symptomatic relief can often be obtained using steroidal and local anaesthetic injections or nonsteroidal anti-inflammatory drugs.

Massive lower gastrointestinal haemorrhage secondary to metastatic squamous cell carcinoma of the lung.

Clinically significant symptoms due to gastrointestinal metastases from primary lung cancers is rare. A case of life-threatening lower gastrointestinal haemorrhage secondary to metastatic squamous cell carcinoma of the lung is reported. Previous reports of such metastases are reviewed, with reference to management and prognosis. After resection of colonic metastases from squamous cell lung cancer, survival is similar to that for primary disease. It is suggested that patients with known or suspected squamous cell lung cancer presenting with lower gastrointestinal symptoms be managed as aggressively as those with no previous history of disease.

Plasma fatty acid profiles in benign breast disorders.

Breast pain (mastalgia) and macroscopic breast cysts present commonly. Mastalgia may be improved by dietary manipulation to reduce saturated fat or supplement essential fatty acid intake. Fatty acid profiles were measured in women with mastalgia and breast cysts, before and during treatment with evening primrose oil, a rich source of essential fatty acids. The fatty acid profiles of both groups of patients were abnormal, with increased proportions of saturated fatty acids and reduced proportions of essential fatty acids. Treatment with evening primrose oil improved the fatty acid profiles towards normal, but this was not necessarily associated with a clinical response.

A case control study of factors associated with macroscopic breast cysts.

Women who have a breast cyst aspirated are at increased risk of developing breast cancer. We present an age-matched case control study comparing the reproductive characteristics of 352 women who had a breast cyst aspirated with a control group of 352 contemporaneous clinically normal women. Women with breast cysts were more likely to be nulliparous [odds ratio (OR) = 2.28, 95% confidence interval (CI) = 1.34-3.88] or have a late age at first live birth (chi 2 trend = 5.6, P less than 0.025), and a late menopause (chi 2 trend = 4.3, P less than 0.05). They were less likely to have ever used the oral contraceptive pill (OR = 0.38, 95% CI = 0.26-0.55) or to have used the pill for a short duration (chi 2 trend = 16.8, P less than 0.001), and were less likely to have had a hysterectomy (OR = 0.58, 95% CI = 0.36-0.93). They were more likely to wear a small bra (chi 2 trend = 18.6, P less than 0.001) and bra cup (chi 2 trend = 5.6, P less than 0.025). Nulliparity, late age at first live birth and late menopause are factors common to breast cancer risk.