The risk of breast cancer in BRCA1 and BRCA2 mutation carriers without a first-degree relative with breast cancer.

The objective of this study was to estimate the lifetime risk of breast cancer in women with a BRCA1 or BRCA2 mutation with and without at least 1 first-degree relative with breast cancer. A total of 2835 women with a BRCA1 or BRCA2 mutation were followed. Age- and gene-specific breast cancer rates were calculated. The relative risks of breast cancer for subjects with a family history of breast cancer, compared to no family history were calculated. The mean age at baseline was 41.1 years, and they were followed for a mean of 6.0 years. The estimated penetrance of breast cancer to age 80 years was 60.8% for BRCA1 and 63.1% for BRCA2. For all BRCA carriers, the penetrance of breast cancer to age 80 for those with no first-degree relative with breast cancer was 60.4% and 63.3% for those with at least 1 first-degree relative with breast cancer. The risk of breast cancer for BRCA carriers with no first-degree relative with breast cancer is substantial, and as a result, clinical management for these women should be the same as those for women with an affected relative.

Delineating the phenotypic spectrum of Bainbridge-Ropers syndrome: 12 new patients with de novo, heterozygous, loss-of-function mutations in ASXL3 and review of published literature.

BACKGROUND: Bainbridge-Ropers syndrome (BRPS) is a recently described developmental disorder caused by de novo truncating mutations in the additional sex combs like 3 (ASXL3) gene. To date, there have been fewer than 10 reported patients. OBJECTIVES: Here, we delineate the BRPS phenotype further by describing a series of 12 previously unreported patients identified by the Deciphering Developmental Disorders study. METHODS: Trio-based exome sequencing was performed on all 12 patients included in this study, which found a de novo truncating mutation in ASXL3. Detailed phenotypic information and patient images were collected and summarised as part of this study. RESULTS: By obtaining genotype:phenotype data, we have been able to demonstrate a second mutation cluster region within ASXL3. This report expands the phenotype of older patients with BRPS; common emerging features include severe intellectual disability (11/12), poor/ absent speech (12/12), autistic traits (9/12), distinct face (arched eyebrows, prominent forehead, high-arched palate, hypertelorism and downslanting palpebral fissures), (9/12), hypotonia (11/12) and significant feeding difficulties (9/12) when young. DISCUSSION: Similarities in the patients reported previously in comparison with this cohort included their distinctive craniofacial features, feeding problems, absent/limited speech and intellectual disability. Shared behavioural phenotypes include autistic traits, hand-flapping, rocking, aggressive behaviour and sleep disturbance. CONCLUSIONS: This series expands the phenotypic spectrum of this severe disorder and highlights its surprisingly high frequency. With the advent of advanced genomic screening, we are likely to identify more variants in this gene presenting with a variable phenotype, which this study will explore.

Health care provider recommendations for reducing cancer risks among women with a BRCA1 or BRCA2 mutation.

There is a significant variation in the uptake of cancer risk reducing options by women with a BRCA1 or BRCA2 mutation. It is currently unclear why these differences exist and it is possible that recommendations vary between providers and these influence patient decisions. Eligible health care providers who provide genetic counseling for hereditary breast and ovarian cancer families in Canada were identified. Each provider was asked to complete a study specific questionnaire that included their opinion of various cancer risk reduction options and their recommendations for specific cases. Respondents recommended prophylactic oophorectomy more often than prophylactic mastectomy or tamoxifen for women with a BRCA1 or BRCA2 mutation (p < 0.0001). Fewer than half of the respondents agreed with the recommendation for prophylactic mastectomy, and a minority of the respondents supported the recommendation for tamoxifen for chemoprevention. The majority of Canadian genetics health care providers adhere to the National Comprehensive Cancer Network (NCCN) Guideline of recommending prophylactic oophorectomy to mutation carriers, however, the minority of genetics health care providers recommend either prophylactic mastectomy or tamoxifen.

A comparison of the detection of BRCA mutation carriers through the provision of Jewish population-based genetic testing compared with clinic-based genetic testing.

BACKGROUND: Guidelines for genetic testing for BRCA1 or BRCA2 stipulate that a personal or family history of cancer is necessary to be eligible for testing. Approximately 2% of Ashkenazi Jewish women carry a mutation, but to date population-based testing has not been advocated. Little is known about the relative yield of a conventional genetic testing programme versus a programme of widespread testing in a population with common founder mutations. METHODS: We provided both referral-based and Jewish population-based testing between 2008 and 2012. We compared the numbers of BRCA mutation carriers identified through the two streams and estimated the number of genetic counselling hours devoted to each programme. RESULTS: From 2008 to 2012, 38 female carriers were identified through 487 referrals to our genetics centre (29 unaffected with cancer). During the same time, 6179 Jewish women were tested through our population-based programme and 93 mutation carriers were identified (92 unaffected with cancer). Fewer counsellor hours were devoted to the population-based than to the clinical referral-based testing programme. CONCLUSION: Genetic testing of all Jewish women above the age of 25 years will greatly expand the number of BRCA mutation carriers identified without a commensurate increase in the number of hours required for counselling.

The impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual function in women who carry a BRCA mutation.

OBJECTIVE: Prophylactic salpingo-oophorectomy is recommended to women who carry a BRCA1 or BRCA2 mutation to reduce the risks of breast, ovarian and fallopian tube cancer. We measured the impact of prophylactic salpingo-oophorectomy on menopausal symptoms and sexual functioning in women with a BRCA mutation. METHODS: Women who underwent prophylactic salpingo-oophorectomy between October 1, 2002 and June 26, 2008 for a known BRCA1 or BRCA2 mutation were invited to participate. Participants completed questionnaires before prophylactic surgery and again one year after surgery. Measures of sexual functioning and menopausal symptoms before and after surgery were compared. Satisfaction with the decision to undergo prophylactic salpingo-oophorectomy was evaluated. RESULTS: 114 women who underwent prophylactic surgery completed questionnaires before and one year after surgery. Subjects who were premenopausal at the time of surgery (n=75) experienced a significant worsening of vasomotor symptoms (hot flashes, night sweats and sweating) and a decline in sexual functioning (desire, pleasure, discomfort and habit). The increase in vasomotor symptoms and the decline in sexual functioning were mitigated by HRT, but symptoms did not return to pre-surgical levels. HRT decreased vaginal dryness and dyspareunia; however, the decrease in sexual pleasure was not alleviated by HRT. Satisfaction with the decision to undergo prophylactic salpingo-oophorectomy remained high regardless of increased vasomotor symptoms and decreased sexual function. CONCLUSIONS: Women who undergo prophylactic salpingo-oophorectomy prior to menopause experience an increase in vasomotor symptoms and a decrease in sexual functioning. These symptoms are improved by HRT, but not to pre-surgical levels.

Patient satisfaction and cancer-related distress among unselected Jewish women undergoing genetic testing for BRCA1 and BRCA2.

It is not known to what extent participation in a genetic testing program for BRCA1 and BRCA2, which does not include an extensive pre-test counselling session, influences cancer-related distress, cancer risk perception and patient satisfaction. Unselected Jewish women in Ontario were offered genetic testing for three common Jewish BRCA mutations. Before testing and 1-year post-testing, the women completed questionnaires which assessed cancer-related distress, cancer risk perception, and satisfaction. A total of 2080 women enrolled in the study; of these, 1516 (73%) completed a 1-year follow-up questionnaire. In women with a BRCA mutation, the mean breast cancer risk perception increased from 41.1% to 59.6% after receiving a positive genetic test result (p = 0.002). Among non-carriers, breast cancer risk perception decreased slightly, from 35.8% to 33.5% (p = 0.08). The mean level of cancer-related distress increased significantly for women with a BRCA mutation, but did not change in women without a mutation; 92.8% expressed satisfaction with the testing process. The results of this study suggest that the majority of Jewish women who took part in population genetic screening for BRCA1 and BRCA2 were satisfied with the delivery of genetic testing and would recommend testing to other Jewish women. However, women with a BRCA mutation experienced increased levels of cancer-related distress.

Breast cancer risks in women with a family history of breast or ovarian cancer who have tested negative for a BRCA1 or BRCA2 mutation.

Genetic testing for mutations in BRCA1 and BRCA2 is available in Canada for women with a significant family history of breast cancer. For the majority of tested women, a BRCA1 or BRCA2 mutation is not found, and counselling regarding breast cancer risk is based on the review of the pedigree. In this prospective study, we estimate breast cancer risks in women with a family history of breast cancer and for whom the proband tested negative for a mutation in BRCA1 or BRCA2. Families with two or more breast cancers under the age of 50 years, or with three cases of breast cancer at any age, and who tested negative for a BRCA1 or BRCA2 mutation were identified. Follow-up information on cancer status was collected on all first-degree relatives of breast cancer cases. The standardised incidence ratios (SIRs) for breast cancer were calculated by dividing the observed numbers of breast cancer by the expected numbers of breast cancers, based on the rates in the provincial cancer registries. A total of 1492 women from 365 families were included in the analyses. The 1492 first-degree relatives of breast cancer cases contributed 9109 person-years of follow-up. Sixty-five women developed breast cancer, compared to 15.2 expected number (SIR=4.3). The SIR was highest for women under the age of 40 (SIR=14.9) years and decreased with increasing age. However, the absolute risk was higher for women between the age of 50 and 70 (1% per year) years than for women between 30 and 50 (0.4% per year) years of age. There was no elevated risk for ovarian, colon or any other form of cancer. Women with a significant family history of breast cancer (ie, two or more breast cancers under the age of 50 years, or three or more breast cancers at any age), but who test negative for BRCA mutations have approximately a four-fold risk of breast cancer. Women in these families may be candidates for tamoxifen chemoprevention and/or intensified breast screening with an MRI.

Clinical use of cabergoline as primary and adjunctive treatment for acromegaly.

BACKGROUND: Cabergoline is a dopamine agonist that may be used as primary or adjunctive therapy for acromegaly. Although one study suggested biochemical control may be achieved in a substantial proportion of patients, it is still commonly perceived to be a relatively ineffective treatment. DESIGN AND METHOD: A prospective audit was performed of 15 consecutive acromegalic patients (eight males, seven females, median age 55, range 31-92 at presentation) treated with cabergoline to determine the effective dose and tolerability. All had normal anterior pituitary function; two patients had hyperprolactinaemia. Magnetic resonance imaging revealed nine adenomata, two partially empty sellae and four structurally normal pituitary glands. Nine patients had undergone transsphenoidal surgery 1-12 months, and one patient had received pituitary radiotherapy 18 years, prior to commencement of cabergoline. All patients had biochemical GH excess; median serum IGF1 471 ng/ml, range 239-746 ng/ml. The calculated mean of a series of GH measurements ranged from 2.7-45.8 mIU/l, median 9.7 mIU/l. RESULTS: On a median weekly dose of cabergoline of 1.75 mg (range 0.5-7 mg) normalisation of both IGF1 and GH occurred in 4 out of the 15 patients (27%). Out of the 15 patients (33%), 5 achieved a serum IGF1 within the reference range with notable reductions seen in a further five patients. Nine patients (60%) achieved a mean serum GH level of less than 5 mIU/l. Duration of treatment was 2-52 months and was well tolerated in 14 patients. CONCLUSION: Cabergoline can be an effective and well tolerated primary or adjunctive therapy for acromegaly and useful clinical responses are noted even with modest doses.

Family history as a predictor of uptake of cancer preventive procedures by women with a BRCA1 or BRCA2 mutation.

Women with a BRCA1 or BRCA2 mutation are at an elevated risk of developing breast and ovarian cancer; however, it is unclear to what extent family history influences the uptake of cancer prevention options. Women with a BRCA1/2 mutation completed a follow-up questionnaire that assessed uptake of cancer preventive options. The pedigree of each woman was reviewed, and information was recorded on cancers diagnosed in relatives. Five hundred and seventeen women were included in the study. Women with a sister with breast cancer were more likely to have a prophylactic mastectomy than those without a sister with breast cancer [odds ratios (OR) = 2.4, p = 0.003]. Uptake of prophylactic mastectomy was significantly lower in women with a mother with ovarian cancer compared with those whose mother did not have ovarian cancer (OR = 0.4, p = 0.01). Having a mother or sister with ovarian cancer significantly predicted the uptake of prophylactic oophorectomy (OR = 1.6, p = 0.04). Women with a BRCA2 mutation were less likely to have a prophylactic oophorectomy than those with a BRCA1 mutation (OR = 0.49, p = 0.0004). Among women with a BRCA1 or BRCA2 mutation, family history predicts the uptake of prophylactic mastectomy and prophylactic oophorectomy.

Development and testing of a decision aid for breast cancer prevention for women with a BRCA1 or BRCA2 mutation.

For women who carry a mutation in BRCA1 or BRCA2, the risk of breast cancer is up to 87% by the age of 70. There are options available to reduce the risk of breast cancer; however, each option has both risks and benefits, which makes decision making difficult. The objective is to develop and pilot test a decision aid for breast cancer prevention for women with a BRCA1 or BRCA2 mutation. The decision aid was developed and evaluated in three stages. In the first stage, the decision aid was developed and reviewed by cancer genetics experts. The second stage was a review of the decision aid by women with a BRCA1 or BRCA2 mutation for acceptability and feasibility. The final stage was a pre-test--post-test evaluation of the decision aid. Twenty-one women completed the pre-test questionnaire and 20 completed the post-test questionnaire. After using the decision aid, there was a significant decline in mean decisional conflict scores (p = 0.001), a significant improvement in knowledge scores (p = 0.004), and fewer women uncertain about prophylactic mastectomy (p = 0.003) and prophylactic oophorectomy (p = 0.009). Use of the decision aid decreased decisional conflict to levels suggestive of implementation of a decision. In addition, knowledge levels increased and choice predisposition changed with fewer women being uncertain about each option. This has significant clinical implications as it implies that with greater uptake of cancer prevention options by women with a BRCA1 or BRCA2 mutation, fewer women will develop and/or die of hereditary breast cancer.

Obstructive sleep apnea presenting as pseudopheochromocytoma: a case report.

Sudden arousal from sleep causes a transient surge in sympathetic nervous activity. Repeated arousals, as occur in obstructive sleep apnea (OSA), are well documented to cause a more prolonged sympathetic overactivity and consequent elevations in 24-h urinary catecholamine levels. We describe here a series of five patients, each presenting with a clinical and biochemical picture indistinguishable from that of pheochromocytoma. Thorough investigations have failed to find catecholamine-secreting tumor in any of these subjects, but all have been diagnosed with OSA. Primary treatment of OSA with nasal continuous positive airways pressure has led to normalization of systemic blood pressure and urinary catecholamines. Pseudopheochromocytoma is therefore a rare, but treatable, presentation of obstructive sleep apnea.

Attitudes toward preventive oophorectomy among BRCA1 mutation carriers in Poland.

Currently genetic testing for BRCA1 and BRCA2 susceptibility genes is performed throughout Europe and North America. In Poland three founder mutations in BRCA1 account for 14% of all invasive ovarian cancers and oophorectomy is frequently recommended to mutation carriers as a preventive measure. The purpose of the present study was to evaluate patient acceptance of the recommendation for prophylactic oophorectomy in a hereditary cancer clinic. Seventy-two women over the age of 40 and who carried a BRCA1 mutation were advised to undergo prophylactic oophorectomy. After a mean follow-up period of 19 months, 43 of the women (60%) had undergone the procedure. Of the 29 women who had not had an oophorectomy, five indicated that they did not intend to do so, 19 indicated that they intended to have the operation in the near future and five were undecided. In conclusion, preventive oophorectomy is acceptable to most Polish women at high risk of hereditary ovarian cancer and should be among the range of services offered in cancer genetics clinics.

The effect of cessation of growth hormone (GH) therapy on bone mineral accretion in GH-deficient adolescents at the completion of linear growth.

In many countries, treatment of childhood-onset GH deficiency (GHD) with GH ceases when linear growth is complete. Peak bone mass occurs several years after the completion of linear growth. Given that GH has important anabolic actions on bone, discontinuation of GH therapy at the completion of linear growth may have adverse consequences for the attainment of peak bone mass in adolescent GHD patients. In this United Kingdom multicenter study, 24 adolescents (13 males, mean age 17.0 +/- 1.4 yr, SD) with severe GHD were randomized to discontinue or continue GH (0.35 IU/kg x wk) at the completion of linear growth. Whole body bone mineral content (BMC) and lumbar spine bone mineral density were assessed by dual-energy x-ray absorptiometry at baseline and then at 6-month intervals for 1 yr. Markers of bone remodeling (serum bone-specific alkaline phosphatase and urinary deoxypyridinoline) were measured at the same time points. In patients who continued GH (GH+), median BMC increased by 3.8% (interquartile range, 2.6, 5.9, P < 0.001) at 6 months; and by 6.0% (3.7-9.1, P < 0.001) at 12 months. In patients who discontinued GH (GH-) median BMC was unchanged at 6 and 12 months (+1.9%, -0.4-4.2, P = 0.9; and +2.4%, 0.4-4.9, P = 0.5, respectively, median, interquartile range). The differences in median change in BMC between the two groups at 6 and 12 months was marginally significant (P = 0.085 and 0.074, respectively). Mean lumbar spine bone mineral density increased by 4.7 (95% confidence interval, 1.0, 8.2) at 12 months in patients continuing GH (P = 0.01), but the mean change was not statistically significant change in patients who discontinued GH [+2.7% (95% confidence interval, -0.8, +6.2)]. These preliminary data suggest that, in adolescent patients with severe GHD, discontinuation of GH at completion of growth may limit the attainment of peak bone mass in this patient group. This may predispose to clinically significant osteopenia in later adult life.

Evaluation of the needs of spouses of female carriers of mutations in BRCA1 and BRCA2.

The process of genetic testing involves the entire family, including spouses. The objective of this study was to measure the specific needs and to describe the experiences of spouses of women who received genetic counseling for a positive BRCA1/2 result. We surveyed 59 spouses of female mutation carriers. The mean length of relationships was 26 years (range: 2.5-50 years). All were supportive of their spouses' decision to undergo genetic testing and counselling. Four respondents stated that they wished that they had received additional support at the time of test disclosure and 20% felt that their wives had received inadequate support. One-quarter of the spouses believed that their relationship had changed because of genetic testing; most felt that they had become closer to their wives. Husbands were most concerned about the risk of their wife dying of cancer (43%), followed by the risk of their spouse developing cancer (19%) and the risk that their children would test positive for the BRCA mutation (14%). Distress levels, measured by the Impact of Event scale, suggest that few spouses were experiencing clinical levels of distress.

A survey of TWIST for mutations in craniosynostosis reveals a variable length polyglycine tract in asymptomatic individuals.

The human TWIST gene encodes a 202 amino acid transcription factor characterized by a highly conserved basic-helix-loop-helix motif in the C-terminal half, and a less conserved N-terminal half that has binding activity toward the histone acetyltransferase p300. Between these domains is a repeat region of unknown function that encodes the glycine-rich sequence (Gly)5Ala(Gly)5. Heterozygous mutations of TWIST were previously described in Saethre-Chotzen craniosynostosis syndrome [El Ghouzzi et al., 1997; Howard et al., 1997]. During a search for TWIST mutations in patients with craniosynostosis, we identified, in addition to 11 novel and one previously described bona fide mutations, several individuals with rearrangements of the glycine-rich region, involving either deletion of 18 nucleotides or insertion of three, 15, or 21 nucleotides. None of these rearrangements was consistently associated with clinical disease and we conclude that they are at most weakly pathogenic. The glycine stretch may serve as a flexible linker between the functional domains of the TWIST protein, and as such may be subject to reduced evolutionary constraint.

Concordance for type 1 diabetes in identical twins is affected by insulin genotype.

OBJECTIVE: Monozygotic twins are usually discordant (only one twin affected) for type 1 diabetes. Discordance for disease between such twins implies a role for nongenetically determined factors but could also be influenced by a decreased load of diabetes susceptibility genes. The aim of this study was to determine whether two susceptibility genes were less prevalent in discordant twins compared with concordant twins. RESEARCH DESIGN AND METHODS: We studied 77 monozygotic twin pairs (INS), 40 concordant and 37 discordant, for type 1 diabetes at polymorphism of the insulin gene region on chromosome 11 p and HLA-DQBI. RESULTS: The disease-associated INS genotype (Hph I) was identified in 87.5% of the concordant twins but only in 59.5% (P = 0.005) of the discordant twins. Neither DQB1*0201 nor DQB1*0302 was seen in 2 of 40 (5%) concordant twins compared with 8 of 37 (22%) discordant twins (P = 0.04). No statistical differences were seen between concordant and discordant twins at individual alleles of DQB1. Combining insulin and DQ data, 5% of concordant twins compared with 32.4% of discordant twins had neither DQB1*0201/DQB1*0302 nor the high-risk Hph I INS "++" genotype (P = 0.002). CONCLUSIONS: We conclude that the possession of the high-risk Hph I insulin genotype increases the likelihood of identical twins being concordant for type 1 diabetes and that the "load" of both major histocompatibility complex (MHC) and non-MHC susceptibility genes has an impact on the disease penetrance of type 1 diabetes.

An evaluation of needs of female BRCA1 and BRCA2 carriers undergoing genetic counselling.

BACKGROUND: The discovery of the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 has improved our ability to counsel women at increased risk of developing breast and ovarian cancer. The objective of our study was to identify the needs of women who have undergone genetic counselling and testing for BRCA1/2 and to determine the impact of receiving a positive BRCA1/2 result. This is the first study to report on a large group of women who have received positive BRCA1/2 mutation results. METHODS: Questionnaires were distributed to 105 women who had received pre- and post-test genetic counselling for a positive BRCA1/2 result at the University of Toronto or at McGill University in Montreal, Canada between the years of 1994 and 1998. The questionnaire items included patient motivation for seeking genetic services, information needs, screening and prophylactic surgery practices, satisfaction with access to services and support, the desire for a support group, and overall client satisfaction. RESULTS: Seventy nine female carriers were surveyed. The majority of the respondents (77%) were satisfied with the information they received during the genetic counselling process. Women with a previous diagnosis of cancer indicated that they needed more information relating to cancer treatment compared to women without cancer (p=0.05). Nineteen percent of the women felt they needed more support than was received. Fifty eight percent of the women reported that their screening practices had changed since they received their result. Young women (below the age of 50) and women with no previous diagnosis of cancer were most likely to have changed their screening practices. Nearly two thirds of the respondents said they had considered prophylactic surgery of the breasts or ovaries. Twenty eight percent of the women had prophylactic mastectomy and 54% had undergone prophylactic oophorectomy. Women with an educational level of high school or more were more likely to have undergone prophylactic bilateral mastectomy than those with less education (p=0.07) but were less likely to undergo prophylactic oophorectomy (p=0.0007). CONCLUSION: These findings have a direct impact on the counselling and risk management of female BRCA mutation carriers. Age, education, and a previous diagnosis of cancer are important determinants in a woman's decision making after receiving positive genetic test results.

Meeting the needs of women living with HIV.

HIV research, treatment, and support programs in North America have been based on the premise that HIV is a gay man's disease. HIV also affects women. The purposes of this study were to: (1) examine the feelings, concerns, and needs of HIV infected women in a mid-sized Canadian city; and (2) determine whether a community agency for HIV positive persons was adequately supporting women. With informed consent, HIV positive women attending the community agency or a regional medical care facility were interviewed using qualitative research methods to elicit their lived experience. Eight women were interviewed (20% of the women who are HIV positive in this center). Four areas of concern were identified: (1) the impact of diagnosis on women and their children; (2) need for supports specific to HIV positive women; (3) differences in needs and supports available to men and women; and (4) lack of comfort with, or knowledge about, currently available facilities. These results are consistent with previously reported research. HIV positive women who are neither drug-users nor promiscuous feel stigmatized and less supported than HIV positive males. Recommendations for practice included: formulation of self-help groups for women, a more female friendly atmosphere, presence of female staff and other HIV positive women to support these women, and improved inter-agency cooperation. Many recommendations have been implemented and exceeded. The community agency now includes a child's play area, the hiring of a female social worker, and the establishment of an off-site support group for HIV positive women.

Intraventricular craniopharyngioma: a long-term follow-up of six cases.

Intraventricular craniopharyngiomas are rare tumours. They are wholly within the third ventricle and can be distinguished from suprasellar lesions which extend into the third ventricle by the presence of an intact floor of the third ventricle. They are attached to the wall of the third ventricle to a variable extent, most commonly in the region of the tuber cinereum. The long-term follow-up on six cases treated by one of the authors is presented. Headache and visual disturbance were the most common presenting features but, unlike the more common suprasellar lesions, symptomatic endocrine disturbances were not a common presenting feature. Total surgical removal can cause hypothalamic damage and the resulting morbidity can be serious and sometimes life-threatening. Subtotal removal followed by radiotherapy is probably the treatment of choice for these lesions.