Armando E. Giuliano

Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial.

To determine the role of chemotherapy in the multidisciplinary treatment of patients with osteosarcoma, a randomized prospective trial of postoperative adjuvant chemotherapy was begun in 1981. Fifty-nine patients with nonmetastatic classic intramedullary osteosarcoma were randomized; 32 received postoperative adjuvant chemotherapy consisting of high-dose methotrexate, Adriamycin (Adria Laboratories, Columbus, OH), and BCD (bleomycin, cytoxan, actinomycin D), and 27 patients received no adjuvant chemotherapy. At a median follow-up of 2 years, there was a statistically significant improvement in both disease-free and overall survival in those who received adjuvant chemotherapy. In addition, there was no difference in the less than 20% disease-free or overall survival of patients treated in the 1970s who did not receive chemotherapy, as compared with the concurrent nontreatment controls. Therefore, with identical staging procedures, uniform surgical management, and standard pathologic evaluation, postoperative adjuvant chemotherapy definitely improves disease-free and overall survival in patients with osteosarcoma.

Standard for breast conservation therapy in the management of invasive breast carcinoma.

Multidisciplinary guidelines for management of invasive breast carcinoma from the American College of Radiology, the American College of Surgeons, the College of American Pathology, and the Society of Surgical Oncology have been updated to reflect the continuing advances in the diagnosis and treatment of invasive breast cancer. The guidelines provide a framework for clinical decision‐making for patients with invasive breast carcinoma based on review of relevant literature and include information on patient selection and evaluation, technical aspects of surgical treatment, techniques of irradiation, and follow‐up care.

Multiple primary melanoma.

From a series of 712 patients with melanoma, 38 patients (5.3%) had more than one primary melanoma. Twenty‐four patients had two primaries, 11 patients had three, 2 patients had four, and 1 patient had eight. Twelve patients (32%) had one or more synchronous primaries. Forty‐five percent of all multiple primaries were diagnosed within the first year. Microstaging by level and depth was determined prior to treatment and in patients with nonsynchronous primaries, 83% had a subsequent melanoma equal or less advanced than the original. Twenty‐six patients with Stage I primaries were skin‐tested with DNCB prior to therapy. No significant differences in delayed cutaneous hypersensitivity reactions were found between multiple primary and matched controls with only a single melanoma. Four of 10 patients with multiple primaries treated with adjuvant BCG or BCG‐tumor cell vaccine developed subsequent melanomas suggesting that immunotherapy with BCG will not prevent the development of a new primary melanoma. Survival in patients with Stage I and II multiple primary melanomas was improved compared to Stage I and II patients with a single primary. This study suggests that prognosis in multiple primary melanomas is better reflected by the most advanced primary based on microstaging and the presence or absence of regional lymph node metastases than by multiplicity. Cancer 43:939–944, 1979.

LDH and melanoma

The histories of 121 Stage II melanoma patients were reviewed to determine the value of monitoring serum LDH in postoperative follow‐up examinations. Charts of 58 Stage III patients who had autopsies at UCLA also were reviewed to define the relationship between an elevated LDH and liver metastases. The sensitivity and specificity of LDH as an indicator of disease recurrence were 72.1% and 97.0%, respectively. As an indicator of liver metastases, LDH had a sensitivity and specificity of 95.1% and 82.8% in the Stage II patient group and 86.5% and 57.1% in the Stage III autopsied group. An elevated LDH was the first indication of recurrent disease in 11/88 (12.5%) Stage II patients and was almost as frequent an indicator of recurrent disease as pulmonary metastases found on chest x‐ray. Mean survival following elevation of LDH was 5.9 months whether or not liver metastases were present. Monitoring of serum LDH can provide useful information in the postoperative follow‐up of patients with melanoma.

Characterization of a human follicular thyroid carcinoma cell line (UCLA RO 82 W-1)

SummaryA thyroid tumor cell line has been established from the metastases of a follicular carcinoma in a female patient. Although the primary tumor released thyroglobulin (Tg) into the circulation (> 10000 ng/ml), the uptake of I131 was less than 2%. After 37 replications the doubling time was 4 days and confluency was reached after 7 days from inoculation of 3 × 107 cells. This human thyroid tumor cell line has now been growing in culture for several years. An aneuploid chromosomal pattern was observed (62–82 chromosomes). A pair of X chromosomes was present but no Y chromosome was found which is compatible with the female origin of the cell line. EM studies revealed the presence of microvilli. Immunoperoxidase staining using specific anti-human Tg antisera indicated the presence of Tg within the cells. Nude mice developed solid-cystic tumors within 6 months after injection of the cells. The basal release of immunodetectable Tg, as measured in a perifusion system, increased in response to thyroid stimulating hormone (TSH) (p< 0.025) or TSH combined with theophylline (p< 0.001). Unusual isoenzyme patterns for galactose-1-phosphate-uridyltransferase (GALT) and phosphoglucomutase1 (PGM1) were detected in the tumor, compared with normal human fibroblasts and blood cells and isoenzyme patterns from the patient’s lymphocytes. Because this malignant human thyroid follicular cell line has retained the ability to synthesize Tg it represents a valuable model for the study of human follicular carcinomas.

Nodal Stage Classification for Breast Carcinoma: Improving Interobserver Reproducibility Through Standardized Histologic Criteria and Image-Based Training

PURPOSEnReliable pathologic stage classification of axillary lymph nodes is an important determinant of prognosis and therapeutic decision making for patients with invasive breast cancer. Pathologists distinction between micrometastasis (pN1mi) and isolated tumor cells [ITC; pN0(i+)] is variable using the American Joint Committee on Cancer (AJCC) Staging Manual (Sixth Edition). We sought to determine whether a set of clearly defined histologic criteria could lead to reproducible nodal classification by pathologists.nnnPATIENTS AND METHODSnDigital images of sentinel lymph node biopsies from 56 patients with small-volume nodal metastases were examined by six experienced breast pathologists (MDs), first as a pre-test, and again as a post-test after studying a training program that outlined and illustrated the classification criteria.nnnRESULTSnPost-test results, after study of the training program, were significantly improved. Compared with the reference MD, agreement improved from 76.2% (pre-test kappa = 0.575; standard deviation [SD], 0.25) to 97.3% (post-test kappa = 0.947; SD, 0.049). Multirater analysis of agreement among the six MDs improved from 71.5% (pre-test kappa = 0.487; ASE, 0.039) to 95.7% (post-test kappa = 0.915; ASE, 0.037). Agreement on lobular carcinoma metastasis classification improved from 55% (23 of 42; pre-test) to 100% (42 of 42; post-test) (P < .001), and agreement on ITC classification in nodal parenchyma improved from 67.6% (69 of 102; pre-test) to 98.0% (100 of 102; post-test; P < .001).nnnCONCLUSIONnApplication of current definitions for classification of small-volume nodal metastases are inconsistent, leading to variable classification of ITC and micrometastases. Reproducibility of pathologic nodal stage classification is achievable through study of a training set to clarify the AJCC criteria.

Use of aspiration cytology and frozen section examination for management of benign and malignant thyroid nodules

Between January 1980 and December 1988, 161 patients underwent thyroidectomy with intraoperative frozen section consultation after fine‐needle aspiration (FNA) of a thyroid nodule. The FNA were insufficient in 15 instances (9%) and in error in 39 (24%). In 15 cases, the incorrect aspiration diagnosis could have led to excessive surgery and in ten cases to delayed therapy if it had been the only guide for therapy. The diagnosis was deferred to permanent section analysis in 30 (19%) frozen sections. Twenty‐two errors (14% of cases) were made in the interpretation of frozen section material, and in an additional 15 patients (9%), the diagnosis suggested (but deferred at frozen section) was in error. In one patient, this error could have led to more extensive surgery than necessary; in 21 patients, the frozen section error could have led to undertreatment. When frozen section results were combined with those of FNA, no therapeutically important false‐positive diagnoses were made. In five patients, the combination of both FNA and frozen section results would not have identified a carcinoma which, in three cases, was a small occult papillary carcinoma not found in the index nodule.

Conservation therapy for invasive lobular carcinoma of the breast

Earlier literature suggests a high incidence of multicentricity and bilaterality, with an overall poor prognosis, in patients with invasive lobular carcinoma of the breast. Consequently, there is considerable disagreement regarding appropriate local management of this disease. To determine the influence of invasive lobular histologic findings on local tumor control, disease‐free survival, and overall survival, the authors reviewed 60 patients with Stage I and II invasive lobular breast carcinoma treated with local tumor excision and radiation therapy between 1981 and 1987 (mean follow‐up, 5.5 years; range, 2.5 to 10 years). The 5‐year actuarial risk of locoregional recurrence was 5%, with two of three failures occurring in the regional lymphatics. The mean time to locoregional failure was 28 months. The 5‐year actuarial disease‐free survival (84%) and overall survival (91%) were comparable to those seen in several large series of similarly treated patients with invasive ductal carcinoma. Contralateral breast cancer occurred at a rate of approximately 0.6% per year. This study and a review of the literature suggest that breast conservation, with local resection and radiation therapy, is appropriate therapy for invasive lobular breast cancer.

Assessment of DNA methylation status in early stages of breast cancer development.

Background:Molecular pathways determining the malignant potential of premalignant breast lesions remain unknown. In this study, alterations in DNA methylation levels were monitored during benign, premalignant and malignant stages of ductal breast cancer development.Methods:To study epigenetic events during breast cancer development, four genomic biomarkers (Methylated-IN-Tumour (MINT)17, MINT31, RARβ2 and RASSF1A) shown to represent DNA hypermethylation in tumours were selected. Laser capture microdissection was employed to isolate DNA from breast lesions, including normal breast epithelia (n=52), ductal hyperplasia (n=23), atypical ductal hyperplasia (n=31), ductal carcinoma in situ (DCIS, n=95) and AJCC stage I invasive ductal carcinoma (IDC, n=34). Methylation Index (MI) for each biomarker was calculated based on methylated and unmethylated copy numbers measured by Absolute Quantitative Assessment Of Methylated Alleles (AQAMA). Trends in MI by developmental stage were analysed.Results:Methylation levels increased significantly during the progressive stages of breast cancer development; P-values are 0.0012, 0.0003, 0.012, <0.0001 and <0.0001 for MINT17, MINT31, RARβ2, RASSF1A and combined biomarkers, respectively. In both DCIS and IDC, hypermethylation was associated with unfavourable characteristics.Conclusion:DNA hypermethylation of selected biomarkers occurs early in breast cancer development, and may present a predictor of malignant potential.

Underuse of Axillary Dissection for the Management of Sentinel Node Micrometastases in Breast Cancer

BACKGROUNDnCurrent American Society of Clinical Oncology guidelines for management of sentinel node micrometastases (SNMM) in breast cancer recommend axillary lymph node dissection (ALND) for all patients.nnnOBJECTIVEnTo assess nationwide use of ALND for SNMM.nnnDESIGNnPopulation-based retrospective observational study.nnnSETTINGnThe National Cancer Institutes Surveillance, Epidemiology, and End Results database (1998-2005).nnnPATIENTSnFive thousand three hundred fifty-three patients with SNMM.nnnMAIN OUTCOME MEASUREnUse of ALND after identification of SNMM.nnnRESULTSnThe prevalence of SNMM increased from 2.5% in 1998 to 17.7% in 2005. Of 5353 patients with SNMM, 2160 (40.4%) had no further nodal surgery and 3193 (59.6%) underwent ALND. In the latter group, histopathologic examination of nonsentinel nodes upstaged 18.6% of cases to N1, 2.2% to N2, and 0.1% to N3 disease. Multivariate analysis using logistic regression showed that age younger than 66 years (odds ratio [OR], 1.79; 95% confidence interval [CI], 1.56-2.04), high tumor grade (OR, 1.22; 95% CI, 1.07- 1.40), and tumor size larger than 2 cm (OR, 1.16; 95% CI, 1.01-1.32) were predictive of ALND. Predictors of upstaging were infiltrating lobular histology (OR, 1.23; 95% CI, 1.00-1.51), T2 stage (OR, 1.38; 95% CI, 1.14-1.67), T3 stage (OR, 3.66; 95% CI, 1.70-7.90), and number of nodes examined (OR, 1.04; 95% CI, 1.03-1.05).nnnCONCLUSIONSnOnly 60% of patients with SNMM from breast cancer are treated according to American Society of Clinical Oncology guidelines. Nodal staging based only on sentinel node biopsy may underestimate the extent of nodal disease in 20.9% of cases. Surgical management of SNMM should be standardized.