Lack of effect of cyclophosphamide on the immunogenicity of a melanoma antigen vaccine.

Melanoma antigen vaccines are a conceptually attractive approach to prevent or delay disease recurrence in patients with surgically resected malignant melanoma. However, the immunogenicity of current vaccines is relatively low. Cyclophosphamide, when given in low doses prior to antigen exposure, is an immunomodulator which has been shown to enhance both humoral and cellular antitumor responses in animals and humans. We conducted a prospective, randomized, clinical trial to study whether pretreatment with cyclophosphamide augments the immunogenicity of a polyvalent, allogeneic, melanoma antigen vaccine in patients with melanoma and low tumor burden. Forty-five patients with resected stage II melanoma (regional metastases) were randomly allocated to treatment with melanoma vaccine or melanoma vaccine plus cyclophosphamide. All patients received the same dose and schedule of vaccine immunizations; those randomized to cyclophosphamide received 300 mg/m2 i.v. 3 days prior to each vaccine immunization. Cellular immune responses were evaluated by delayed-type hypersensitivity (DTH) skin reactivity to a test dose of vaccine at baseline (prior to treatment) and following the fourth immunization. Humoral immune responses were measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and autoradiographic analysis of indirect immunoprecipitates of patients' sera at the same time points. Twenty-four patients were randomized to cyclophosphamide pretreatment and 21 to vaccine alone; 22 and 18 patients were evaluable in each group, respectively. Differences were statistically nonsignificant with respect to either cellular (DTH) or humoral (antibody) responses between the two groups. DTH responses were induced in 16 of 22 (73%) and 15 of 18 (83%) patients treated with cyclophosphamide plus vaccine and vaccine alone, respectively. The mean posttreatment augmentation in DTH response in the cyclophosphamide group was 9.5 mm, compared with 9.9 mm in the vaccine-only group. Eight of 12 (66%) cyclophosphamide-pretreated patients and 9 of 12 (75%) vaccine-only patients produced increased titers of antimelanoma antibodies following treatment. No differences were observed between the groups in disease-free or overall survival. In summary, low-dose cyclophosphamide pretreatment failed to augment the immunogenicity of a polyvalent, allogeneic, melanoma vaccine in patients with completely resected early-stage melanoma.

Induction of primary cutaneous melanocytic neoplasms in urokinase-type plasminogen activator (uPA)-deficient and wild-type mice: cellular blue nevi invade but do not progress to malignant melanoma in uPA-deficient animals.

Evidence suggests that the plasminogen activators (PAs), in particular urokinase-type PA (uPA), play a pivotal role in tumor invasion and metastasis. We studied the contribution of the PAs to the malignant phenotype through the chemical induction of melanocytic neoplasms in uPA-deficient mice. Primary tumors were induced and promoted concurrently in 35 uPA-/- deficient and 35 uPA+/+ wild-type mice using a single application of 7,12-dimethylbenz(a)anthracene followed by repetitive applications of croton oil. Animals were sacrificed at 60-day intervals for 1 year. At necropsy, the four largest pigmented lesions in each animal were excised, characterized histologically, and evaluated microscopically for evidence of invasion. The regional lymph nodes, lungs, and solid abdominal visceral organs were sectioned and examined microscopically for evidence of metastatic disease. Cellular blue nevi were induced in 100% of uPA-/- and uPA+/+ promoted animals. Although a reduction in the radial and vertical progression of these lesions was noted in the uPA-deficient mice compared with the wild-type group, more than 95% of cellular blue nevi induced in both groups of animals invaded the underlying tissues. These lesions did not metastasize to the regional lymph nodes. Malignant melanoma arose in 5 of 35 (14.3%) of promoted wild-type mice. These tumors were locally aggressive, produced tissue-type PA, but were not metastatic to the regional nodes, lungs, or abdominal viscera. These results indicate that the invasive capability of melanocytic lesions may depend more on tissue-type PA than uPA activity. No melanomas were induced in the uPA-/- mice. The resistance of the uPA -/- strain to melanoma induction suggests that uPA contributes to malignant progression. We propose that the absence of uPA negatively affects tumorigenesis by decreasing the liberation and availability of growth factors such as basic fibroblast growth factor.

Double-blind trial of a polyvalent, shed-antigen, melanoma vaccine.

A polyvalent melanoma vaccine prepared from shed antigens stimulates humoral and cellular immune responses and improves survival compared with historical controls. We conducted a double-blind, prospectively randomized, placebo-controlled trial to assess whether this vaccine could slow the progression of resected melanoma. Thirty-eight patients with resected melanoma metastatic to regional nodes (American Joint Committee on Cancer stage III) who had a particularly poor prognosis on the basis of the nodes being clinically positive or two or more histologically positive nodes were randomly assigned in a 2:1 ratio to treatment with 40 microg of melanoma or placebo (human albumin) vaccine, both of which were bound to alum as an adjuvant. Immunizations were given intradermally into the extremities every 3 weeks x 4, monthly x 3, every 3 months x 2, and then every 6 months for 5 years or until disease progression. Twenty-four patients were treated with the melanoma, and 14 patients were treated with the placebo vaccine. The groups were evenly balanced with respect to prognostic factors. Median length of observation was 2.5 years. There was no local or systemic toxicity. By Kaplan-Meier analysis, median time to disease progression was two and a half times longer in patients treated with melanoma vaccine compared with that in patients treated with placebo vaccine, i.e., 1.6 years (95% confidence interval, 1.0-3.0 years) compared with 0.6 year [95% confidence interval, 0.3-1.9 year(s)]. By Cox proportional hazards analysis, this difference was significant at P = 0.03. Overall survival was 40% longer in the melanoma vaccine-treated group (median overall survival of 3.8 years versus 2.7 years), but this difference was not statistically significant. In a double-blind and placebo-controlled trial, these results suggest that immunization with a melanoma vaccine may be able to slow the progression of melanoma. Although statistically significant, these results must be interpreted with caution because they are based on a small number of patients.

Poly(ADP-ribose) polymerase in human breast cancer: a case-control analysis.

The importance of a genetic polymorphism (A/B allele) of poly(ADP-ribose) polymerase (PARP) pseudogene on chromosome 13q34-qter, and PARP enzyme activities in the development of human breast cancer were evaluated in a cancer case-control study. A total of 309 Caucasian women (> or = 50 years old) were evaluated for the PARP genotype, 70 of whom had histologically confirmed breast cancer, 128 women with benign breast diseases as study controls, and 111 reference controls. Age was significantly associated with case-control status (p < 0.0001), but family history of breast cancer, age at menarche, age at first live birth and parity were not. The frequency of the PARP B allele was similar in breast cancer cases (0.14), study controls (0.13), and reference controls (0.15). In a subset of 14 breast cancer cases and 32 study controls, the mean PARP enzyme activities (induced by H2O2 or oligonucleotide) were observed to be lower in cancer cases; an age-adjusted odds ratio of 3.40 (95% confidence interval = 0.70-19.54) for the below-median oligonucleotide-induced PARP was suggestive of an association. In subjects with the AB or BB genotype, the mean H2O2-induced PARP enzyme activity was significantly higher (p = 0.02, adjusted for case-control status and age) compared with that in subjects with the AA genotype. These findings indicate that: (a) the genetic polymorphism of the PARP pseudogene on chromosome 13 is not associated with the development of breast cancer in our study population; (b) oligonucleotide-induced PARP activity may be useful for identifying postmenopausal women at increased risk for breast cancer; and (c) there is a possible functional link between the genotype of the PARP pseudogene and enzyme activation.

Pathologic predictors of recurrence in stage 1 (TINOMO) breast cancer.

A group of 122 consecutively treated pathologic Stage 1 (TINOMO) patients with cancer of the breast were studied to define histopathologic predictors of recurrence. Lymphatic invasion was the most significant predictor of recurrence; recurrence was present in 32% (8/25) of patients who had lymphatic invasion and in 10.3% (10/97) of patients who did not (P = 0.006). Histologic type was also predictive of recurrent disease. Eighteen per cent (18/101) of patients with invasive ductal or lobular carcinoma developed recurrent disease, while none of the group of 21 patients with medullary carcinoma, tubular carcinoma, colloid carcinoma, Paget's disease, and intraductal carcinoma with minimal invasion suffered a recurrence (P = 0.036). Vascular invasion, grade of malignancy, cellularity, presence or absence of circumscription, cellular infiltrate, fibroblastic response, neural invasion, and necrosis were not significant predictors of recurrence. Multiple logistic regression analysis of patients with invasive ductal or lobular carcinoma confirmed the results for individual factors, that only patients with lymphatic invasion were at higher risk of recurrence.

Biopsy for microcalcification detected by mammography.

Fifty-two patients who were biopsied because of the presence of clustered microcalcifications on mammography, in the absence of any definable mass on x-ray or physical examination, were studied. Localization of the microcalcifications was obtained by measuring the area in relation to the vertical and horizontal axes from the nipple on both lateral and cephalocaudad views. Specimen radiography was obtained to ensure that the area with microcalcifications had been included in the specimen. Carcinoma was found in 17 instances (33%). In four (24%) the detected microcalcifications corresponded to fibrocystic disease, with carcinoma being found only in adjacent tissue with little or no calcifications. Precise localization and removal of only the area containing calcifications without excision of a generous margin of surrounding tissue may result in the exclusion of an adjacent carcinoma.

Lobular carcinoma of the male breast.

BACKGROUND: A case of lobular carcinoma in a male breast is described. Lobular carcinoma is a very uncommon histopathologic form of male breast cancer because of the absence of lobules in the normal male breast. The cytoarchitecture of the normal male breast can be deranged in conditions such as Klinefelter's syndrome or as a result of estrogen exposure. Lobular carcinoma of the male breast has been described in such instances where cytoarchitectural changes are likely to have occurred. METHODS AND RESULTS: After the pathologic diagnosis was made, a fibroblast karyotype was performed to confirm a male genotype. The patient had received no hormonal therapy. The English language literature was reviewed. CONCLUSIONS: This case represents the first report of lobular carcinoma in a proven genotypic male patient receiving no exogenous estrogens.

Use of artificial intelligence to analyze clinical database reduces workload on surgical house staff.

BACKGROUND: The current quantity and diversity of hospital clinical, laboratory, and pharmacy records have resulted in a glut of information, which can be overwhelming to house staff. This study was performed to measure the impact of artificial intelligence analysis of such data on the junior surgical house staff's workload, time for direct patient care, and quality of life. METHODS: A personal computer was interfaced with the hospital computerized patient data system. Artificial intelligence algorithms were applied to retrieve and condense laboratory values, microbiology reports, and medication orders. Unusual laboratory tests were reported without artificial intelligence filtering. RESULTS: A survey of 23 junior house staff showed a requirement for a total of 30.75 man-hours per day, an average of 184.5 minutes per service twice a day for five surgical services each with an average of 40.7 patients, to manually produce a report in contrast to a total of 3.4 man-hours, an average of 20.5 minutes on the same basis (88.9% reduction, p < 0.001), to computer generate and distribute a similarly useful report. Two thirds of the residents reported an increased ability to perform patient care. CONCLUSIONS: Current medical practice has created an explosion of information, which is a burden for surgical house staff. Artificial intelligence preprocessing of the hospital database information focuses attention, eliminates superfluous data, and significantly reduces surgical house staff clerical work, allowing more time for education, research, and patient care.

Regional lymph node dissection for malignant melanoma of the extremities.

Seven hundred thirty-nine patients with malignant melanoma of the extremities were treated with a uniform surgical approach that included wide and deep excision of the primary site and regional node dissection therapeutically and electively for invasive lesions (Clark's levels III, IV, and V). Of the 490 patients who underwent lymph node dissections, follow-up was available for 457 (93%). Life-table comparison of 362 patients with histologically negative nodes to 95 with histologically proved lymph node metastases yielded statistically significant differences in survival (P less than 0.001). Five-year cumulative survival rates were 91% in the group without and 48% in the group with nodal metastases. Among histologically positive patients, differences in life-table survival curves for the 60 clinically negative patients compared to the 35 clinically positive patients were also statistically significant (P = 0.004); 5-year cumulative survival rates were 57% for the former group and 33% for the latter. Although there appears to be an advantage to regional lymph node dissection for micrometastases as opposed to gross nodal involvement, for the majority of patients metastatic melanoma in these nodes is the major indicator of systemic disease.

The risk of carcinoma in wire localization biopsies for mammographically detected clustered microcalcifications.

A total of 183 consecutive patients undergoing biopsies for unilateral microcalcifications concentrated in one or more segments of the breast in the absence of any palpable findings were analyzed to characterize their risk of cancer. Biopsy findings were benign in 86 patients (47%) and malignant in 97 (53%). Of the clinical and mammographic characteristics evaluated, an increasing number of linear microcalcifications, either without a dominant density (p = 0.014) or with a dominant density (p = 0.019) and the presence of heterogeneous microcalcifications (p = 0.055), were associated with a significantly increased risk of malignancy. Conversely a fibronodular parenchymal pattern (p = 0.008) was associated with a significantly decreased risk of malignancy. A high-risk group was identified, 95% (40/42) of whom had malignant biopsy findings, whose mammograms had more than 10 linear microcalcifications not associated with a dominant density (16/17) or at least one linear microcalcification associated with a dominant density (24/25). Conversely a low-risk group for cancer was identified, 88% (28/32) of whom had benign biopsy findings, whose mammograms had exclusively punctate microcalcifications within a fibronodular parenchymal milieu (26/30) or demonstrated some change in the configuration of the microcalcifications on the various mammographic views (10/10). For the remaining 109 patients there was an almost equal division between malignant and benign diagnoses (49% vs 51%).

Thoracotomy for metastatic malignant melanoma of the lung.

The outcome of 29 patients who underwent lung resection for treatment of metastatic malignant melanoma from January 1976 to November 1988 was studied. Twenty-two patients underwent total resection for cure of all apparent metastatic disease, whereas seven patients did not undergo total resection. Of the 22 patients who underwent curative resection, the median survival was 11 months, with a 2-year survival of 13.6% and a 5-year survival of 4.5%. Four patients who underwent curative resection are currently alive and free of disease, with one patient surviving more than 10 years. The patients who underwent palliative resection had a median survival of 5 months, only one patient living longer than 10 months. The difference in survival of the patients who underwent curative resection compared with palliative resection was statistically significant. The thickness of the primary cutaneous malignant melanoma, the presence of regional lymph node metastases, the disease-free interval from primary diagnosis to metastatic pulmonary disease, and whether one or two metastatic nodules were removed during curative lung resection were not statistically significant in altering survival. These results demonstrate that although prolonged survival for metastatic melanoma is rare, lung resection in selected patients may be associated with long-term survival.

A prognostic model for clinical stage I melanoma of the lower extremity. Location on foot as independent risk factor for recurrent disease.

Thirteen variables were studied to determine their usefulness in predicting recurrent disease in 158 patients with stage I melanoma of the lower extremity. A Cox proportional hazards analysis demonstrated that three variables were independent risk factors for recurrent disease in these patients: (1) thickness, in millimeters, of the primary tumor (P = 0.000009), (2) primary tumor location on the foot (P = 0.0003), and (3) the number of mitoses/mm2 (P = 0.0244). Life-table analyses of patient subgroups defined by different combinations of these three variables demonstrated that thick (greater than or equal to 3.0 mm) melanomas of the foot were associated with recurrent disease much more frequently than tumors of similar thickness located on the thigh or calf. These data provide guidelines that can be used to evaluate results of surgical and/or adjuvant therapy studies for patients with melanoma of the lower extremity.

Surgical management for malignant melanoma of the trunk.

A group of 525 patients with primary cutaneous malignant melanoma of the trunk was treated by a uniform surgical approach that included regional lymph node dissection for selected patients; 266 (50.6%) had regional lymph node dissections in addition to wide and deep excision, all with primary lesions extending below the superficial papillary dermis. Of 171 patients treated over five years ago, 130 had histologically negative nodes; 94 (72%) are alive with no evidence of disease (NED). Of 41 with histologically positive nodes, 12 (29%) are alive with NED. A comparison of the 21 patients with clinically occult micrometastases shows eight (38%) alive with NED, whereas four of 20 (20%) with clinically demonstrable as well as histologically proven nodal metastases are alive with NED. Though there may be a modest benefit to lymph node dissection for microscopic rather than gross nodal metastases for invasive melanoma of the trunk, for most such patients melanoma in regional nodes indicates the presence of systemic metastatic disease.

Malignant melanoma. Delayed hypersensitivity skin testing.

One hundred eighty-two patients undergoing initial surgical therapy for primary malignant melanoma were evaluated for delayed hypersensitivity using a battery of recall antigens prior to surgery. Fifty-six patients were also sensitized with 2, 4-dinitrochlorobenzene. All tumors were classified by Clark-Mihm levels and the patients were clinically staged. They were followed up for an average period of 55 months. There was no significant difference in the ability of patients with varied Clark-Mihm level lesions to mount a delayed hypersensitivity response to the recall battery or to 2, 4-dinitrochlorobenzene. Thirteen stage I melanoma patients in whom recurrence developed at a distant site exhibited no difference in immune responsiveness when compared to 148 patients in whom recurrence did not develop when both groups were tested with recall antigens. No difference was noted in patients with stage II disease in whom recurrence developed, as measured by reaction to these same antigens. Twelve patients demonstrated anergy to recall antigens, in none of whom has recurrence developed to date. Fifty-six patients who were tested with 2, 4-dinitrochlorobenzene showed no difference in reactivity with tumors classified at any of the Clark-Mihm levels. Anergy demonstrated by delayed hypersensitivity skin testing appears to reflect increasing tumor burden, rather than a preexisting deficiency that can be used to predict patients at high risk for the development of recurrent disease.

Primary melanoma thickness correlated with regional lymph node metastases.

We studied 119 patients with stage I primary cutaneous malignant melanoma, who were undergoing regional lymph node dissection, to determine the relationship of lymph node metastases to thickness of the primary lesion. The lymph nodes in the dissection specimen were each evaluated by serial sections. None of the patients with lesions less than 1.0 mm thick had nodal micrometastases. When lesions exceeded 1.0 mm in thickness, there was no appreciable increase in the incidence of nodal metastases until a thickness greater than 4.0 mm was reached, in which cases the incidence of metastases was 50%. Predictive variables were determined by multiple logistic regression analysis. Only lesions that were at least 4.0 mm thick and were not located on the upper extremities were significant predictors of lymph node metastases; within this category there was a 64% incidence of lymph node metastases.

Stereotaxic localization for fine-needle aspiration breast biopsy. Initial experience with 300 patients.

The efficacy of stereotaxic aspiration biopsy was evaluated in 300 consecutive patients with nonpalpable mammographic lesions. Sixty-eight patients (23%) had suspicious or malignant aspirates; all cases were proved malignant by subsequent examination of operative specimens. Two hundred sixteen patients (72%) had benign aspirates. Of these, 65 were confirmed by operation and 151 had subsequent mammography at 6- and 12-month intervals with no demonstrable mammographic change. In 10 instances (3%), the aspirates were atypical, and in six (2%), nondiagnostic. Biopsy specimens were obtained in all 16 instances, and eight were malignant. The sensitivity of stereotaxic breast aspiration for the diagnosis of cancer was 96%, and the specificity was 100%. Our experience confirms the efficacy of stereotaxic aspiration for the initial evaluation of mammographically detected, nonpalpable lesions.

Primary hyperparathyroidism associated with two enlarged parathyroid glands.

An increasingly recognized although small percentage of patients with primary hyperparathyroidism have enlargement of two parathyroid glands. We have treated nine patients with primary hyperparathyroidism associated with such double parathyroid gland enlargement. In four of these patients, marked asymmetry of the two enlarged glands was noted and the failure to recognize and excise a second enlarged parathyroid gland resulted in persistent or recurrent hyperparathyroidism. In one of these patients, the second enlargement was present in a super-numerary mediastinal gland. The subsequent excision of the second enlarged parathyroid gland resulted in normocalcemia in each instance. This contrasts with five patients in whom initial excision of two enlarged glands resulted in normocalcemia with no recurrence of hypercalcemia. Only three patients fulfilled the histologic criteria of true double adenomas. The remainder showed multiglandular hypercellularity. This experience supports identifying all parathyroid glands and recognizing that even minimal enlargement of a gland may be important pathophysiologically, regardless of its histopathologic classification. Excision of both enlarged glands, even if asymmetric, is appropriate.

Stereotactic aspiration biopsy of nonpalpable nodules of the breast.

To evaluate the reliability of stereotactic aspiration biopsy (SAB) in assessing which nonpalpable nodules of the breast should be excised, SAB was performed upon 373 nodules. The nodules were classified as well-circumscribed or irregular and evaluated for the presence of microcalcifications. The cytologic diagnoses were classified as malignant, atypical or benign. Cytologically malignant and atypical nodules were excised. Benign nodules were excised if there was a family or past history of carcinoma of the breast or if they changed mammographically. Twenty-five nodules proved to be malignant. Of these, the diagnoses by stereotactic aspiration biopsy were adenocarcinoma in 20 patients, atypical in three, malignant hemangiopericytoma in one patient and benign in one. The borders of the malignant nodules were well-defined in eight patients and irregular in 17. Three malignant nodules with irregular borders had clustered microcalcifications. One false-positive instance was a sclerosing papilloma with atypical hyperplasia. Twenty-four nodules with benign cytologic diagnoses, which were excised, proved to be benign. An additional 132 nodules with benign cytologic diagnoses had six month interval mammograms for two years; 131 were without interval change and one increased in size and proved to be a carcinoma. SAB is reliable for diagnosing nonpalpable nodules. Nodules with malignant and atypical results must be excised. It is reasonable to have follow-up evaluation of well-defined nodules mammographically when the aspirate is benign.

Malpractice litigation involving patients with carcinoma of the breast.

BACKGROUND: We sought to evaluate recent trends in the United States of America regarding malpractice awards for patients with carcinoma of the breast. STUDY DESIGN: A retrospective review was performed of 118 cases of purported malpractice in the diagnosis and management of patients with carcinoma of the breast and related problems. The information was tabulated from Westlaw Transmission, a computerized database. RESULTS: Gynecologists were the specialists most often sued and accounted for 47 percent of the physicians involved in lawsuits. Radiologists were cited in only 13 percent of the cases. Health maintenance organizations (HMOs) were cited in 5 percent of the cases. The most common complaint was delay in diagnosis, made by a plaintiff who detected her own breast mass (52 percent). In 15 percent of the cases, the plaintiffs complained that a mammogram was not obtained, and 9 percent complained that other diagnostic tests, such as ultrasound or fine-needle aspiration biopsy, were not performed. The average delay in diagnosis was 14 months. The average award to plaintiffs with carcinoma of the breast was $691,449. The average plaintiff's age was 44 years. CONCLUSIONS: Most malpractice complaints related to carcinoma of the breast are instituted by women under the age of 50 years who identified the breast mass by themselves and were assumed by their physicians to have fibrocystic disease of the breast. Complaints can be expected to increase regarding failure to order further diagnostic tests, such as ultrasound or fine-needle aspiration biopsy, despite a negative mammogram. Complaints against HMOs are now also being made, citing failure to properly diagnose or treat patients with carcinoma of the breast.

Favorable prognosis for malignant melanomas associated with acquired melanocytic nevi.

In a clinicohistopathologic study of 557 patients with primary cutaneous malignant melanoma, there were fewer metastases and/or deaths from melanoma when histologic evidence of a coexisting acquired melanocytic nevus was found. A total of 130 patients with melanocytic nevus and 427 cases of melanoma without histologic evidence of a nevus (denovo) were studied. Clinical follow-up evaluation for evidence of metastases and/or death was obtained. Only ten of the patients (7.7%) with nevus-associated melanoma had metastases and/or death v 78 (18.3%) with de novo melanoma. When stratified by lesion thickness, the logrank test for survival revealed a statistically significant difference between the two groups. An overall favorable outcome seen in patients with malignant melanomas associated with acquired melanocytic nevi was found, therefore, to be independent of lesion thickness as well as six other variables reported to be related to the biologic behavior of malignant melanoma. Thus, the presence of nevus cells in a specimen of malignant melanoma portends a better prognosis and may have important implications in the biology of this neoplasm.