Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma.

Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR)=1.22; P=5.33×10(-12)), rs3753841 in COL11A1 (per-allele OR=1.20; P=9.22×10(-10)) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR=1.50; P=3.29×10(-9)). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.

[Ultrasonic cyclodialysis in glaucoma surgery in aphakia]. / Ul'trazvukovoi tsiklodializ v khirurgii glaukomy pri afakii.

The authors present the results of a new method for surgical treatment of aphakic eye glaucoma with the use of low-frequency ultrasound. The suggested surgery, ultrasonic cyclodialysis, was carried out in 15 patients with glaucoma on the aphakic eyes. A follow-up of 6 months has demonstrated a stable normalization of intraocular pressure. The mechanism of the hypotensive effect of the operation is explained largely by improvement of fluid discharge and a certain inhibition of the chamber humor production. The authors emphasize the sparing nature of the operation and a serene postoperative course.

Factors affecting recurrence in lumpectomy without irradiation for breast cancer.

Between 1980 and 1988, 122 women with operable invasive breast cancers underwent wide excision and axillary dissection without subsequent irradiation. During the follow-up period of 1 to 8 years (median, 4 years), recurrences were observed in 23 patients (19%), 22 occurring in the breast and one in the axilla. This is a significant rate of recurrence and supports the need for breast irradiation after conservative surgery. The incidence of recurrence in the breast did not appear to be related to the presence or absence of axillary nodal metastasis. No recurrences were noted in 20 patients whose primary tumors were smaller than 1 cm. The incidence of recurrence was directly correlated to the increasing size of the tumor, but it also appeared to decrease with advancing age. In 31 patients over 70 years of age, only one (3%) recurrence was observed. If these early findings are confirmed, it is likely that patients with tumors smaller than 1 cm or patients over 70 years of age may be spared breast irradiation after wide excision.

Treatment options and recurrence potential for cystosarcoma phyllodes.

The surgical treatment and outcome of 31 women with a pathologic diagnosis of cystosarcoma phyllodes at Roswell Park Memorial Institute were reviewed. Surgical excision was performed upon 20 patients with a mean tumor size of 4.5 centimeters (range of 1.0 to 9.0 centimeters). Mastectomy was performed initially upon 11 patients with a mean tumor size of 15 centimeters (range of 3 to 40 centimeters). Local recurrence was seen in five patients treated by excision and one patient treated by mastectomy. All patients retreated by repeat excisions were controlled; one patient retreated with mastectomy died with local recurrence and distant disease. Routine axillary dissections were not performed. Involvement of the axillary lymph nodes occurred in one patient and was associated with advanced systemic disease. Local recurrences did not imply associated systemic spread and were controlled in five of six patients by repeat excision or mastectomy. Although the benign behavior of this tumor is commonly emphasized, four of the patients we studied died of malignant spread of cystosarcoma phyllodes.

Cyclic and sequential therapy with tamoxifen and medroxyprogesterone acetate in metastatic breast cancer.

A clinical trial of sequential tamoxifen and medroxyprogesterone acetate (MPA) was carried out in 36 women with metastatic breast cancer in order to evaluate the therapeutic efficacy of this regimen and to determine if tamoxifen would increase progesterone receptor (PR) levels and thereby increase response to MPA. Fourteen patients (39%) responded to this treatment, with the duration of remission ranging from 2 to 24 + months (the mean and median were 11 months). In 22 patients, PR levels were measured both before and after 7 days of tamoxifen administration. In PR-positive patients, PR changes induced by tamoxifen did not appear to increase the response rate. In PR-negative patients, PR became positive in 3 patients following tamoxifen treatment, with 2 of 3 responding to treatment, whereas in 11 others whose PR levels remained negative, only one response was observed. Our results suggest that potentiation by tamoxifen was not observed, since in our previous study, MPA alone was equally effective. Thus, tamoxifen and MPA should be given independently for palliation of metastatic breast cancer, and MPA should be administered following therapy with tamoxifen.

Therapeutic oophorectomy in metastatic breast cancer.

One hundred five patients undergoing therapeutic oophorectomy for metastatic breast cancer (n = 105) from 1975 to 1985 were reviewed. There were 54 responders (51%) to oophorectomy, with a median duration of response of 16 months (range, 3 to 129 months). Thirty of 42 (71%) estrogen receptor (ER)-positive patients responded to oophorectomy versus five of 24 (21%) ER-negative patients (P less than 0.001). Of the 39 patients with unknown ER status, 19 (49%) responded to oophorectomy. Osseous, soft tissue, and pulmonary metastases responded at similar rates. Of the 16 patients who had received adjuvant chemotherapy, there were five responders (31%) to oophorectomy. Second-line endocrine therapy was effective in 29 of 53 (55%) patients. Fifteen of 28 (54%) ER-positive patients responded to second-line endocrine therapy while two of six (33%) ER-negative patients responded. Twenty-three of 37 (62%) oophorectomy responders responded to second-line endocrine therapy versus six of 16 (38) nonresponders. Oophorectomy appears to be a valuable palliative treatment for metastatic breast cancer. ER-positive patients have the best chance of responding to this therapy. However, ER-negative patients have a reduced but definite chance of responding with a good duration of response. Response to further endocrine treatments is predicted by response to oophorectomy and to a lesser degree by ER status.

Aminoglutethimide in patients with metastatic breast cancer.

Aminoglutethimide (AG) was administered as palliative therapy in 112 patients with metastatic breast cancer. In 36 patients, the dose level was 1000 mg/day; 76 patients received a dose level of 500 mg/day. Patients with brain or liver metastasis were excluded, as were patients with tumors determined to be negative for estrogen receptors. Objective regression was observed in 35 (31%) patients, with the duration of response ranging from 4 to 36 + months (mean, 12 months; median, 10 months). Response was observed in 11 of 31 (35%) patients with soft tissue metastasis; 16/59 (27%) patients with osseous metastasis; and 8 of 22 (36%) having visceral metastasis. In 93 patients with positive estrogen receptor (ER), 33 responded (35%), whereas in 19 patients with unknown ER status, two responded (11%). Response to previous treatment with tamoxifen (TAM) had occurred in 31 patients; of these, response to AG was noted in 11 (35%). Of 24 patients failing to respond to prior treatment with tamoxifen, four (17%) responded to subsequent therapy with AG. Thirteen patients had previously received combination chemotherapy, and response to AG was noted in two (15%). The side effects observed in this study included skin rash in ten patients, fever in eight, somnolence in three, weakness and dizziness in one, headache in one, insomnia in one, dyspnea in one, and ataxia in one. Treatment had to be discontinued in eight patients, due to the severity of the side effects. As expected, patients receiving AG at the lower dose level of 500 mg/day experienced fewer and less severe side effects than those treated with the higher dose. The response rate in the 1000 mg/day group was 10/36 (28%) and in the 500 mg/day group, it was 25/76 (33%). The lower dosage was better tolerated without apparent compromise in therapeutic efficacy.

Changing strategies in the treatment of hormone-dependent breast cancer.

Hormone Receptor concept provides better prediction of hormone dependency of breast cancer and therefore proper selection of therapy. The fate of receptors following hormonal manipulation is not clearly understood. It is suggested that in a hormone-dependent breast cancer, the cessation of response to one form of hormonal therapy is not an indication of emergence of hormone independence of the cancer. Contrary to the present belief, the author suggests that the hormone-dependent tumors retain their biological and biochemical characteristics in the recurrent tumor and therefore will respond to other forms of endocrine therapy. The presence of extraglandular synthesis of estrogen is considered as a major reason for the relapse of a regressing breast cancer following endocrine manipulation. A hypothesis is advanced for test in a clinical trial.

Prevention of mammary carcinogenesis in rats by pregnancy: effect of full-term and interrupted pregnancy.

In this study, the role of parity in conferring protection of the mammary gland against chemical carcinogenesis induced by 7,12-dimethylbenz(a)anthracene (DMBA) was investigated. Experiments were also carried out to determine if an 'interrupted' pregnancy was capable of reducing the incidence of mammary tumour induction. Since it has been suggested that morphological development or the proliferative pattern of the mammary gland at the time of carcinogen administration may be involved in reducing the susceptibility of the mammary gland to chemical carcinogenesis, experiments were designed to elucidate the possible influence of these two factors. Sprague-Dawley female rats were mated and were either allowed to complete pregnancy and parturition or were subjected to Caesarian section on day 5, 10 or 15 of the pregnancy. When DMBA was administered i.v. to animals which had been allowed to complete a full-term pregnancy, only 14% developed tumours, compared to 70% in age-matched nulliparous controls. Termination of the pregnancy on days 5, 10 or 15 was as effective in reducing tumour incidence as full-term gestation and parturition, but still resulted in partial and statistically significant inhibition, compared to age-matched nulliparous controls. There was no significant difference in 3H-thymidine labelling index (LI) at the time of DMBA treatment in the parous rats compared to age-matched nulliparous controls. We also observed no significant differences in the morphological development of the mammary gland in parous and nulliparous rats of the same age. These results indicate that the protective mechanism may not lie in the mammary gland per se, but may indeed be a host factor, such as hormonal or immunological changes occurring in the host as a result of the pregnancy.

Photodynamic therapy for palliation of locally recurrent breast carcinoma.

Fourteen women with locally recurrent breast carcinoma on the chest wall following mastectomy were given 30 courses of photodynamic therapy (PDT). All patients had been heavily pretreated with conventional modes of therapy (radiation therapy, chemotherapy, hormonal therapy, surgical resection). Twenty-two courses yielded a partial response; two courses yielded a complete response; four courses showed no response; one patient was treated as an adjunct to surgery; and one patient was lost to follow-up. Duration to response was variable, ranging from 6 weeks to 8 months. Several women had chest wall disease controlled for prolonged periods of time using repeated courses of PDT. Two women had re-epithelialization of ulcerated lesions. Complications were minimal and included pain (two patients), sunburn (two), and infection (one). These results suggest that treatment with PDT can aid in local control of chest wall recurrence following mastectomy in selected patients.

Intraductal carcinoma. Analysis of presentation, pathologic findings, and outcome of disease.

A retrospective analysis of 52 patients with intraductal carcinoma or ductal carcinoma in situ (DCIS) and 30 patients with microinvasive DCIS was performed. All patients but one were treated by mastectomy. The average follow-up was 5 1/2 years. The clinical presentation of the patients having DCIS only included the presence of a mass in 33% (17/52), nipple discharge in 34% (18/52), or suspicious mammographic finding in 33% (17/52), whereas in those patients having DCIS with microinvasion, the initial presenting symptom was a mass in 63% (19/30) of the patients, nipple discharge in 13% (4/30), and mammographic finding in 23% (7/30). The presence of axillary lymph node metastasis was identified in one of the 52 patients with DCIS and six (20%) of the 30 patients with DCIS and microinvasion. Associated carcinomas in the mastectomy specimens of patients with DCIS were as follows: DCIS, 18% (9/51); lobular carcinoma in situ, 13% (7/51); Paget's disease, 8% (4/51); and invasive carcinoma, 2% (1/51). In the 30 patients with microinvasion, DCIS was found in other quadrants in 23% (7/51) of the patients; lobular carcinoma in situ, 7% (2/51); Paget's disease, 13% (4/51); and invasive carcinoma, 7% (2/51). There was one death due to cancer in the patients with DCIS only. Of the patients diagnosed as having DCIS with microinvasion, seven patients have developed metastasis and four have died of the disease.

Oral medroxyprogesterone in the treatment of metastatic breast cancer.

In 47 postmenopausal women with evaluable breast cancer, oral medroxyprogesterone acetate (MPA) was given at a daily dose level of 400 mg. Patients with negative estrogen receptors, poor performance status, or nonresponse to previous endocrine therapy were excluded from this study. There were 25 (53%) responders to this agent. Periods of remission ranged from 5-26 months with a median of 10 and a mean of 12+ months. Higher rates of response were noted in women over 50 years of age, in patients with osseous metastasis, and in patients with a longer disease-free interval. Adverse effects included weight gain, Cushingoid appearance, skin rash, and vaginal discharge. In this selected group of patients, oral medroxyprogesterone at a dose level of 400 mg/day appeared to provide a significant frequency of tumor response.

Does more intense palliative treatment improve overall survival in metastatic breast cancer patients?

A retrospective review of 483 women who had metastatic breast cancer and were treated between 1942 and 1975 was carried out to examine the effects of improving and aggressive palliative modalities on patient survival. There was a steady increase in the proportion of patients treated by chemotherapy and/or hormonal ablative therapy. Additive hormonal therapy, irradiation, and surgery for palliation decreased in frequency during the same period. Survival time from the first recurrence did not appear to increase in these patients over the period of this study. In spite of increasingly sophisticated palliative therapies, the survival time of patients with metastasis did not appear to be significantly prolonged.

Some biochemical properties of human breast tumor sialyltransferase.

Sialyltransferase activity in normal human breast tissue and tumors was investigated with lactose, desialylated fetuin, and bovine submaxillary mucin as the acceptors. While microsomal preparations from the normal tissue showed little or no sialyltransferase activity toward these acceptors, tumors showed elevated enzymic activities. Tween-20 at 0.5% concentrations stimulated sialic acid transfer to all three acceptors. Another nonionic detergent, Triton X-100, stimulated asialo fetuin sialyltransferase activity while inhibiting activity toward asialo BSM and lactose. Interestingly, lysolecithin, a normal cellular constituent which possesses detergent properties also had an effect similar to that of Triton X-100. Thermal denaturation curves of enzymic activity toward asialo BSM, however, resembled those seen with asialo fetuin as the acceptor. Kinetic studies showed that at acceptor concentrations of 500 micrograms each, sialyl transfers to asialo fetuin, asialo BSM, and lactose showed apparent Km values of 50, 60, and 300 microM, respectively. At CMP-sialic acid concentrations of 300 microM, the Km values for the above acceptors were 25, 15, and 5000 microM.

Tamoxifen (Nolvadex) versus adrenalectomy in metastatic breast cancer.

The relative efficacy of adrenalectomy and tamoxifen (Nolvadex) was evaluated in a randomized study of 51 patients with metastatic breast cancer. In 25 patients undergoing adrenalectomy, there were 13 responders. There were 9 responders of 26 patients receiving tamoxifen. There was no statistically significant difference. In the crossover phase, 15 patients received tamoxifen following adrenalectomy and 3 responded, one of the 6 previous adrenalectomy responders and 2 of the 9 adrenalectomy nonresponders. Nine patients underwent adrenalectomy following tamoxifen, and there were five responders, one of two tamoxifen responders and four of seven tamoxifen nonresponders. Both tamoxifen and adrenalectomy were effective modalities, and appear to retain effectiveness in crossover trials. The frequency of remission was similar in both groups treated by both modalities in different sequences. Response rates to adrenalectomy, considered as both primary and secondary therapy, were significantly higher, since 18 of 34 patients (53%) responded to this therapy, whereas 12 of 41 (29%) responded to tamoxifen as either primary or secondary therapy.

Metastatic breast cancer in males. Assessment of endocrine therapy.

From June 1958 to June 1982, 22 men with metastatic breast cancer were treated with endocrine therapy. All 22 patients were initially treated by bilateral orchiectomy, and objective response was seen in 11 (50%) patients for 15 months. Bilateral adrenalectomy was performed subsequently in 10 patients, and 8 (80%) patients had a mean duration of objective response of 15 months. Five of seven orchiectomy responders and 3 of 3 orchiectomy nonresponders subsequently responded to bilateral adrenalectomy. Tamoxifen was tried in three patients after relapse following adrenalectomy; all three patients responded with a mean duration of 9 months. One patient was successfully treated with aminoglutethimide for 7 months following orchiectomy failure. In this patient bilateral adrenalectomy was performed on disease relapse and again resulted in objective remission. In this review, a sequential endocrine therapy program provided palliation in men. Further study is required to determine the timing of the various endocrine modalities.

Is medullary carcinoma of the breast hormone dependent?

From 1951 to 1981, 22 patients with metastatic medullary carcinoma of the breast were treated with hormonal therapies at Roswell Park Memorial Institute. Bilateral oophorectomy was performed in 6 premenopausal patients, and none had objective response, although one patient did have stable disease for 7 months. Three of these patients subsequently underwent bilateral adrenalectomy and none responded. Thirteen of 16 postmenopausal patients underwent bilateral adrenalectomy and only one had an objective response of 4 months. Eight of 22 patients received additive hormones, and one patient was treated with Tamoxifen. There was no objective response to these therapies. From this study, it appears that medullary carcinoma of the breast is less often responsive to endocrine therapy, and this finding correlates well with the recent data showing lower frequency of estrogen receptor-positive tumors in these patients.

Effect of duration of high fat intake on enhancement of mammary carcinogenesis in rats.

The relationship between dietary fat and mammary carcinogenesis was studied in weanling female inbred Fischer rats fed a purified, high-fat, low-carbohydrate (HF) or a purified, low-fat, high-carbohydrate (LF) diet and given N-nitroso-N-methylurea (NMU) at 50, 90, or 133 days of age. By a change in the diet at different times after NMU treatment (50 mg/kg body wt), it was found that mammary tumor incidence was positively correlated with the time period that the rats were fed an HF diet. A dose-response effect of NMU at 10, 20, 30, 40, and 50 mg/kg body weight was also studied in groups of rats fed an HF or an LF diet. The results show an optimal carcinogenic dose of 50 mg NMU/kg body weight and a threshold dose of 27 mg NMU/kg body weight. The data conclusively demonstrated that the HF diet enhanced mammary carcinogenesis at every dose level of NMU, except 10 mg/kg. Further, the experiments also showed that an HF diet failed to promote mammary carcinogenesis in rats receiving a subthreshold dose (20 mg/kg body wt) of NMU. Altogether, the data demonstrate that an HF diet is not just a promoter but is in fact co-carcinogenic in mammary tumor induction by a chemical carcinogen.