Normal skin test responses in chronic marijuana users.

The cell-mediated immunity of 22 chronic marijuana smokers showed no difference from that of normal controls when evaluated by in vivo skin testing with 2,4-dinitrochlorobenzene. However, a significant difference was seen between these chronic marijuana users, all of whom could be sensitized to 2,4-dinitro-chlorobenzene, and age-matched cancer patients, who showed a decreased capacity to be sensitized.

Outcome after invasive local recurrence in patients with ductal carcinoma in situ of the breast.

PURPOSE: To detail the outcome, in terms of local recurrence, local invasive recurrence, distant recurrence, and breast cancer mortality for patients previously treated for ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: Clinical, pathologic, and outcome data were collected prospectively for 707 patients with DCIS accrued from 1972 through June 1997. RESULTS: There were 74 local recurrences; 39 were noninvasive (DCIS) and 35 were invasive. Fifty-one percent of patients with invasive recurrences presented with stage 1 disease; the remainder presented with more advanced disease. Invasive local recurrence after mastectomy was a rare event that occurred in 0.8% of patients. Invasive recurrence after breast preservation was more common and occurred in 7.4% of patients. The 8-year probability of breast cancer mortality after breast preservation was 2.1%, a number that is likely to increase with longer follow-up. The 8-year breast cancer-specific mortality and distant-disease probability for the subgroup of 74 patients with locally recurrent disease was 8.8% and 20.8%, respectively. If only the 35 invasive recurrences are considered as events, the 8-year breast cancer-specific mortality and distant-disease probability was 14.4% and 27.1%, respectively. CONCLUSION: Invasive local recurrence after breast-preservation treatment for patients with DCIS is a serious event that converts patients with previous stage 0 disease to patients with disease that ranges from stage I to stage IV. These results, however, indicate that most DCIS patients with local recurrence can be salvaged.

The management of ductal carcinoma in situ of the breast.

Ductal carcinoma in situ (DCIS) of the breast is a heterogeneous group of lesions with diverse malignant potential. It is the most rapidly growing subgroup within the breast cancer family with more than 42 000 new cases diagnosed in the United States during 2000. Most new cases are nonpalpable and are discovered mammographically. Treatment is controversial and ranges from excision only, to excision with radiation therapy, to mastectomy. Prospective randomized trials reveal an approximate 50% reduction in local recurrence rate overall with the addition of radiation therapy to excisional surgery, but the published prospective data do not allow the selection of subgroups in whom the benefit from radiation therapy is so small that its risks outweigh its benefits. Nonrandomized single facility series suggest that age, family history, nuclear grade, comedo-type necrosis, tumor size and margin width are all important factors in predicting local recurrence and that one or more of these factors could be used to select subgroups of patients who do not benefit sufficiently from radiation therapy to merit its use. When all patients with ductal carcinoma in situ are considered, the overall mortality from breast cancer is extremely low, only about 1-2%. When conservative treatment fails, approximately 50% of all local recurrences are invasive breast cancer. In spite of this, the mortality rate following invasive local recurrence is relatively low, about 12% with eight years of actuarial follow-up. Genetic changes routinely precede morphological evidence of malignant transformation. Lessons learned from ongoing basic science research will help us to identify those DCIS lesions that are unlikely to progress and to prevent progression in the rest.

Ten-year results comparing mastectomy to excision and radiation therapy for ductal carcinoma in situ of the breast.

The 10-year results of 300 patients with ductal carcinoma in situ (DCIS) without microinvasion are reported; 167 treated with mastectomy and 133 treated with excision and radiation therapy. There was a significant difference in disease-free survival at 10 years, in favour of those treated with mastectomy, 98% versus 81% (P = 0.0004). Multivariate analysis confirmed nuclear grade as the only significant predictor of local recurrence (P = 0.02) or invasive local recurrence (P = 0.03) in patients with DCIS treated with excision and radiation therapy. There was no difference in breast cancer-specific survival or overall survival between the two treatment groups.

Duct carcinoma in situ: 227 cases without microinvasion.

From 1979 to 1990, 227 patients with intraductal carcinomas (DCIS) without microinvasion were selectively treated; the least favourable (large lesions with involved biopsy margins) with mastectomy, the most favourable (small lesions with clear margins) with breast preservation. The preservation group was further subdivided into those who received radiation therapy (excision and radiation) and those who did not (excision alone). In the mastectomy group, there were 98 patients (43%) with an average lesional size of 3.3 cm; 41% had multifocal lesions, 15% had multicentric lesions. There has been one local invasive recurrence and no deaths. The 7-year actuarial disease-free survival is 98% with mastectomy. In the excision and radiation group, there were 103 patients (45%) with an average lesional size of 1.4 cm. 10 patients have had local recurrences (5 invasive and 5 noninvasive) one of whom has died. The 7-year actuarial disease-free survival is 84%, a statistically significant difference when excision and radiation is compared with mastectomy (P = 0.038). In the excision alone group, there were 26 patients (11%) with an average lesional size of 1.0 cm. There have been two local recurrences (8%), one of which was invasive and no deaths. The 7-year actuarial disease-free survival is 67%, but only 3 patients have been followed for more than 4 years. A total of 163 axillary node dissections were done; all were negative. Since DCIS without microinvasion rarely metastasizes to axillary lymph nodes, routine dissection should not be performed. Patients in this series with intraductal carcinoma treated with excision and radiation recurred locally at a statistically higher rate than those treated with mastectomy, in spite of the fact that those chosen for excision and radiation had clinically more favourable lesions. 6 of 12 (50%) local recurrences in conservatively treated patients were invasive. There was, however, no significant difference in overall survival in any subgroup regardless of treatment.

Breast cancer diagnosis and prognosis in women following augmentation with silicone gel-filled prostheses.

62 healthy women were studied mammographically before and after augmentation mammoplasty. Postaugmentation mammograms were done using both the implant compression and implant displacement technique. The amount of visualisable tissue was measured in all films before and after augmentation. We concluded: State-of-the-art film-screen mammography is extremely difficult to obtain in most patients augmented with silicone-gel-filled prostheses. On average, there is a decrease in measurable visualised breast tissue after augmentation mammoplasty with silicone-gel-filled prostheses. The area of mammographically measurable tissue is no different whether smooth or textured implants are used. Textured implants are less likely to form an early capsular contracture and are therefore preferred. However, the cancer-causing potential of polyurethane in humans is currently unknown. Anterior breast tissue is generally seen better with displacement mammography; posterior breast tissue with compression mammography. Better films are generally obtained when the implant is in the subpectoral position rather than subglandular. The more severe the capsular contracture, the poorer the mammogram. In addition 42 previously augmented patients developed breast carcinomas an average of 8.4 years after augmentation with silicone-gel-filled implants; 95% had palpable lesions (only 60% of which could be seen on mammography), 90% had infiltrating carcinomas, 45% had metastases to axillary nodes, and 7 patients have recurred, 5 of whom have died. We concluded: Augmented women who develop breast cancer are similar, in terms of tumour size and nodal positivity, to non-augmented breast cancer patients who present with palpable masses. When compared with non-augmented women whose breast cancers are found with screening mammography, augmented patients with breast cancer present with a higher percentage of invasive lesions and involved axillary lymph nodes, resulting in a poorer prognosis. The 40% false negative rate for mammography in this series is unduly high and alarming. Augmentation mammoplasty with silicone-gel-filled implants should be discouraged in women with a high risk of developing breast cancer.

Metastatic potential of metastases.

Nine cases of known metastases originating from other metastatic foci were documented at operation. The primary tumors included four melanomas, two osteosarcomas, a synovial sarcoma, an anaplastic lung carcinoma, and a rhadbomyosarcoma. Secondary metastatic sites to the regional lymph nodes were noted in the pulmonary hilum (one), mediastinum (one), pulmonary hilum and mediastinum (three), small bowel mesentary (two), retroperitoneum (one), and axilla (one). All patients were immunocompetent as evidenced by their ability to be sensitized to 2,4-dinitrochlorobenzene (DNCB) and/or their positive response to common skin test antigens. The metastatic potential of cells from metastases does not appear to differ from cells of the primary.

Bilateral adrenalectomy for advanced breast cancer: a 21 year experience.

Of 680 patients who had bilateral adrenalectomies for metastatic breast cancer, 583 were evaluable. Two hundred and nine patients (36 percent) responded (180 objective, 29 subjective responders) for at least 6 months. Age, menstrual status, prior response to oophorectomy, disease-free interval, involved organ systems, and incidental splenectomy were correlated with adrenalectomy response. Patients aged 21 to 35 years did poorly (23 percent response rate), whereas 41 percent of patients aged 51 to 65 responded. Menstrual status appeared to have no effect upon whether or not a patient responded to adrenalectomy. Oophorectomy responders benefited from adrenalectomy 40 percent of the time and oophorectomy failures responded in 27 percent of the cases. Patients with a disease-free interval of zero to 2.5 years responded to adrenalectomy at a rate of 31 percent whereas patients with a free interval greater than 2.5 years responded at a rate of 50 percent. When a single visceral organ or any combination of bone and soft tissue was involved, the average response rate was 39 percent. However, when multiple visceral organs or a single visceral organ with any combination of bone or soft tissue was involved, the response rate dropped to 26 percent. Sixty-six patients had splenectomies at the time of adrenalectomy with a 44 percent response rate, whereas nonsplenectomized patients had a 35 percent response rate. The median survival rate of 209 adrenalectomy responders was 26 months; it was 10 months for 374 nonresponders. The 5 and 10 year survival rates for adrenalectomy responders were 18 and 7 percent, respectively, and zero percent for adrenalectomy nonresponders. The patients who received greatest benefit from adrenalectomy in this series were aged 51 to 65 years, had a disease-free interval greater than 2.5 years and had metastases limited to a single visceral organ or any combination of bone and soft tissues.

Radiation therapy for intraductal carcinoma. Is it an equal alternative?

Of 213 consecutive patients with intraductal carcinoma, 109 were selectively treated with mastectomy and 104 with radiation therapy. There were eight local recurrences, seven in patients treated with radiation therapy and one in a patient treated with mastectomy. Histologically, there were 110 comedocarcinomas and 103 noncomedocarcinomas. Seven local recurrences occurred in patients with comedocarcinomas and one in a patient with a noncomedo tumor. Three (38%) of eight local recurrences (all comedo) were invasive. The 5-year actuarial survival for all subgroups was 100%. The median follow-up was 51 months. Intraductal carcinoma is unlikely to metastasize to axillary lymph nodes, and routine dissection is unnecessary. Ductal carcinoma in situ of the comedo variety is more aggressive and more likely to recur than its noncomedo counterpart. We currently view conservative therapy for patients with intraductal comedocarcinoma with caution.

Breast conservation management of breast tumors 4 cm or larger.

Randomized studies of stage I and II breast cancer have shown that breast conservation treatment is equivalent to modified radical mastectomy in regard to local-regional control and survival. Little has been published on breast conservation for patients with large tumors. We analyzed 68 patients with tumors measuring 4 cm or larger (range, 4 to 12 cm) treated with breast-conserving surgery and radiation therapy. The median follow-up was 46 months; the mean tumor size was 5 cm. The 5-year actuarial local-regional recurrence rate was 8.5%, and the overall survival and disease-free survival rates were 76% and 68%, respectively. We conclude that breast conservation treatment may be a reasonable alternative to mastectomy in patients with tumors 4 cm or larger without compromise in local-regional control or survival, while achieving acceptable cosmesis.

Breast cancer in women after augmentation mammoplasty.

More than 1 million American women have undergone augmentation mammoplasty; 100,000 (10%) will develop or already have developed breast cancer. Between March 1981 and August 1986, 20 patients with previous augmentation mammoplasty were treated for breast carcinoma. All patients had unilateral infiltrating carcinomas and presented with a palpable mass. None of the cancers were occult (discovered mammographically). Thirteen patients (65%) had metastases to axillary lymph nodes. During the same period, 733 nonaugmented patients with breast cancer were treated: 207 (28%) had involved axillary nodes, 194 (26%) had in situ lesions, and 154 cancers (21%) were occult. Augmentation mammoplasty with sillicone-gel-filled implants reduces the ability of mammography, our best diagnostic tool, to visualize breast parenchyma. When compared with our own nonaugmented breast cancer population, augmented patients with breast cancer presented with more advanced disease; they had a higher percentage of invasive lesions and positive axillary nodes, resulting in a worsened prognosis.

Predicting axillary node positivity in patients with invasive carcinoma of the breast by using a combination of T category and palpability.

BACKGROUND: In spite of the development of numerous new tumor markers, axillary lymph node status continues to be the single most important prognostic variable regarding survival of patients with carcinoma of the breast. This study was undertaken to determine whether or not the combination of T category (TNM staging system) and palpability would be a better predictor of nodal positivity than T category alone. STUDY DESIGN: Clinical and pathologic data were analyzed for 1,554 patients who underwent axillary lymph node dissection as part of their treatment for invasive carcinoma of the breast. Data were analyzed by the primary lesion's T category and whether or not the lesion was palpable. RESULTS: Five hundred fifty-one (35 percent) of 1,554 axillary node dissections contained metastases. The probability of nodal involvement was significantly higher and the average tumor diameter was slightly, but significantly, larger for palpable T1b, T1c, and T2 lesions when compared with nonpalpable lesions within the same T category (all p values less than or equal to 0.003). The probability of lymphatic tumor emboli or vascular invasion was generally higher for palpable lesions compared with nonpalpable lesions and increased as lesions got larger. The percentage of patients with low nuclear grade and favorable histology was generally lower for patients with palpable lesions compared with those having nonpalpable lesions and decreased as lesions got larger. CONCLUSIONS: Nodal positivity was significantly higher for palpable T1b, T1c, and T2 carcinoma of the breast when compared with nonpalpable carcinoma of the breast within the same T category. The combination of T category and palpability was a more accurate predictor of nodal positivity than T category alone.

Hypothesis and practice: are there several types of treatment for ductal carcinoma in situ of the breast?

Currently, we approach DCIS based on its morphology rather than its etiology. However, morphologically normal-appearing tissue surrounding areas of DCIS may reveal losses of heterozygosity similar to the primary tumor (Lakhani et al. 1995; Stratton et al. 1995; Radford et al. 1995; Fujii et al. 1996). In all likelihood, genetic changes precede morphologic evidence of malignant transformation. We in medicine must learn how to recognize these genetic changes, exploit them, and, in the future, prevent them. DCIS is a lesion in which the complete malignant phenotype of unlimited growth, angiogenesis, genomic elasticity, invasion, and metastasis has not been fully expressed. With sufficient time, most noninvasive lesions will learn how to invade and metastasize. We must learn how to prevent this.

Not everyone with ductal carcinoma in situ of the breast treated with breast preservation needs post-excisional radiation therapy.

While the results of NSABP protocol B-17 and EORTC protocol 10853 prove that radiation therapy decreases the overall rate of local recurrence in patients with DCIS, there are clearly subgroups of patients who do not benefit from radiation therapy or whose benefit is so small that the addition of radiation therapy to their treatment regimen is simply not worthwhile. Identifying these subgroups is of paramount importance. Factors like tumour size, margin width, nuclear grade, and the presence or absence of comedonecrosis can be used to define favorable subgroups that do not require post-excisional radiation therapy. The most recent results of NSABP protocol B-17 and EORTC protocol 10853 confirm that, regardless of treatment, there is no difference in the single most important end-point: survival. If there is no difference in breast cancer mortality, it is clearly worthwhile to try to define the subgroups of patients who can be spared the time, costs, and side-effects of a treatment that they do not need.

Use of predictors of recurrence to plan therapy for DCIS of the breast.

Despite the results of the National Surgical Adjuvant Breast and Bowel Project B-17, there continues to be debate regarding the most appropriate treatment for patients with ductal carcinoma in situ (DCIS) of the breast. Numerous clinical, pathologic, and laboratory factors can aid clinicians and patients wrestling with the difficult treatment decision-making process. Our research has shown that nuclear grade, the presence of comedo-type necrosis (coagulative necrosis), tumor size, and margin width are all important predictors of local recurrence in patients with DCIS. We used these factors to devise the Van Nuys Prognostic Index (VNPI), which assigns lesions a score from 1 to 3 for each of three factors: tumor size, margin width, and pathologic classification (determined by nuclear grade and necrosis). By scoring DCIS lesions according to this index, it may be possible to identify subgroups of patients who do not require irradiation, if breast conservation is elected, as well as patients whose recurrence rate is potentially so high, even with breast irradiation, that mastectomy is preferable.

The Van Nuys Breast Center: the first free-standing multidisciplinary breast center.

This article describes the author's 30-year experience with the design and development of breast centers. It describes the author's initial attempt at developing a breast center at UCLA, the history of the Van Nuys Breast Center (its patient population, philosophy, problems, finances, and demise), and the development of the Harold E. and Henrietta C. Lee Breast Center. Breast centers are defined as focused multidisciplinary facilities of excellence, dealing with the complete range of breast problems. The main focus of this article is the Van Nuys Breast Center, which was the prototype model for most breast centers developed in the United States.

Ductal carcinoma in situ. The success of breast conservation therapy: a shared experience of two single institutional nonrandomized prospective studies.

A combined database of 342 patients with DCIS treated by lumpectomy alone versus lumpectomy and radiation therapy with a median 82-month follow-up is summarized in this joint study. Reproducible subtype classification and common methods of mammographic-pathologic correlation and complete tissue processing are unique features of this database, and they permit outcome to be analyzed by pathologic subtype, size, and margine status. Striking differences are noted in local control rates analyzed by subtype, which were largely independent of irradiation (see Table 1). Analysis of local recurrence-free survival restricted to those cases with a 10 mm or larger free margin width revealed no significant differences between the irradiated and nonirradiated groups. The local recurrence rates were 5% in those treated by lumpectomy alone and 4.5% in those treated by lumpectomy and irradiation (Table 4). Although differences in local recurrence rates for DCIS with a 10 mm plus free margin, with or without irradiation, were noted, they were not large. For DCIS patients with adequate (10 mm or more) or intermediate (1-9 mm) margin width, there was a reduction in local recurrence limited to the high-grade subtype (group III) with radiation therapy; an absolute 8% reduction for those with adequate margins and 11% for those with intermediate margins, but the difference was significant only for the latter group (Table 5). However, no significant differences were noted for the lower grade DCIS subtypes (groups I and II). For DCIS patients with inadequate margins (i.e., less than 1 mm), irradiation provided no benefit for local control. We conclude that an adequate surgical excision for DCIS, defined as a free margin of 10 mm or more, largely makes moot the question of local control related to pathologic subtype and treatment modality. Specifically, adequately excised high-grade (group III) DCIS received a benefit for local control from radiation therapy of only 8% within the median follow-up period. This difference is not significant. The impact of DCIS size or extent on local recurrence is much smaller than margin width (see Table 3). Significant differences achieved by radiation therapy were demonstrable only for the smallest size group (15 mm or less) in the highgrade subtype (group III). Differences in local recurrence rates for low and intermediate subtypes (group I and II) based on radiation therapy could not be demonstrated within the three size categories used in the study. We conclude that although adequate margins are more difficult to achieve for larger or more extensive DCIS, size alone is not a prohibition to breast conservation.

Results from a multidisciplinary breast center. Analysis of disease discovered.

This study was undertaken to report the clinical, pathologic, and outcome data of our nonrandomized series of patients with nonpalpable breast cancer and to understand better the differences between patients with palpable and nonpalpable lesions, particularly those patients aged 49 and younger. The clinical, pathologic, recurrence, and survival data from 560 patients with nonpalpable breast carcinomas found by mammography and wire-directed breast biopsy were compared with similar data from 1640 patients who presented with palpable breast cancer (see Table 3). All node dissections in patients with noninvasive disease were negative. In patients with invasive breast cancer, the chances of axillary node involvement increased as lesions increased in size. When patients were grouped by tumor size, nodal involvement was more likely for palpable than nonpalpable lesions. The 10-year disease-free survival rate probability for patients with nonpalpable invasive cancer was 81% compared with 65% for patients with palpable invasive cancer. The 10-year breast cancer-specific survival rate (including deaths only from carcinoma of the breast) was 91% versus 73%, whereas the 10-year overall survival (rate including deaths from any cause) was 79% for nonpalpable invasive cancer versus 68% for patients with palpable invasive cancer (all P values < 0.001) (see Table 6). Patients under age 50 with nonpalpable invasive cancer fared just as well as older patients with nonpalpable invasive cancer; both had 10-year breast cancer-specific survival rates of 94% (see Table 8). However, biopsy of nonpalpable lesions in patients aged 49 and younger was only half as likely to reveal cancer than biopsy of nonpalpable lesions in patients aged 50 and older (17% versus 32%, P < 0.0001) (see Table 7). When cancer was found in younger women, it was more likely to be noninvasive. Wire-directed breast biopsy of nonpalpable mammographically suspicious areas yields a subgroup of breast cancer patients with a lower probability of recurrence and a higher probability of survival at 10 years when compared with patients who present with palpable breast cancer.

Noninvasive breast cancer. The dilemma of the 1990s.

The most profound impact in the field of breast cancer during the last 15 years has been the development and acceptance of screening mammography: a test capable of finding nonpalpable cancer years before it would have become clinically evident. Many of these nonpalpable lesions are noninvasive; many of them are not even real cancers. The spectrum of treatment for noninvasive breast cancer runs from nothing more than excisional biopsy to bilateral mastectomy. No wonder noninvasive breast cancer is one of the most confusing problems in oncology today, for both patients and physicians.

Conservation therapy for breast cancer following augmentation mammaplasty.

Breast conservation therapy (wide local excision, axillary lymph node dissection, and whole-breast irradiation) is an increasingly popular alternative to mastectomy for breast cancer patients. A sizable (and growing) number of breast cancers occur in women with prior augmentation mammaplasty. Augmented breast cancer patients are currently being treated with conservation therapy, but no study has investigated complications and cosmetic results of radiation therapy specifically in this group of women. Between 1981 and 1988, we used conservation therapy in 17 augmented breast cancer patients. Fifteen patients were available for follow-up. In 10 (67 percent), significant capsular contracture occurred in the irradiated breast an average of 12 weeks following completion of treatment. Four patients have undergone revisionary surgery to correct symptoms arising from contracture. This poor outcome contradicts the results reported in previously published studies. We conclude that irradiation of the breast for cancer in augmented women results in a high incidence of scar-tissue contracture and poor cosmetic results.