Anatolio B. Cruz

Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update.

The current findings completely affirm the validity of our original observations indicating the appropriateness of grouping primary breast cancer patients into those with negative, 1 to 3, or ≫4 positive nodes. Results, however, reveal that there is a risk in combining all patients with ≫4 positive nodes into a single group. Since there was a 25% greater disease‐free survival and an 18% greater survival in those with 4 to 6 than in those with ≫13 positive axillary nodes, such a unification may provide misleading information regarding patient prognosis, as well as the worth of a therapeutic regimen when compared with another from a putatively similar patient population. Of particular interest were findings relating the conditional probability, i.e., the hazard rate, of a treatment failure or death each year during the 5‐year period following operation to nodal involvement with tumor. Whereas the hazard rate for those with negative, or 1 to 3 positive nodes, was relatively low and constant, in those with ≫4 positive nodes the risk in the early years was much greater, but by the fifth year it was similar to that occurring when 1‐3 nodes were involved, and not much different from negative node patients. The same pattern existed whether 4 to 6 or ≫13 nodes were positive. When the current findings are considered relative to other factors with predictive import, it is concluded that nodal status still remains the primary prognostic discriminant.

Comparison of radical mastectomy with alternative treatments for primary breast cancer: A first report of results from a prospective randomized clinical trial

In 1971, the National Surgical Adjuvant Breast Project (NSABP) implemented a prospective randomized clinical trial to compare the worth of alternative treatments with radical mastectomy in women with primary operable breast cancer. Information has been obtained from 1,665 patients eligible for follow‐up from 34 NSABP member institutions in Canada and the United States. Results from that trial, at present in its sixth year with patients on study for an average of 36 months, (26 to 62 months), fail to demonstrate an advantage for those who had a radical mastectomy. No significant difference in the treatment failure or survival has as yet been observed in clinically negative node patients who have been randomly managed by conventional radical mastectomy, total mastectomy with postoperative regional radiation or total mastectomy followed by axillary dissection of those patients who subsequently develop positive nodes. Similarly, there presently exists no difference between patients with clinically positive nodes treated by radical mastectomy or by total mastectomy followed by radiation. Of particular interest is the observation that based upon findings from radical mastectomy patients, there may be as many as 40% of patients having a total mastectomy who had histologically positive nodes unremoved, to date only 15% have developed positive nodes requiring an axillary dissection. The persistence of such a difference in incidence would have profound biological significance. The discovery that leaving behind positive axillary nodes has as yet not been influential in enhancing the incidence of distant metastases or the overall proportion of treatment failures and that a disproportionate number of treatment failures in the total mastectomy group occurred in those patients who subsequently required axillary dissection provides reinforcement to the view that positive axillary lymph nodes are not the predecessor of distant tumor spread but are a manifestation of disseminated disease.

Adjuvant chemotherapy with 5-FU, adriamycin, and mitomycin-C (FAM) versus surgery alone for patients with locally advanced gastric adenocarcinoma: A southwest oncology group study

AbstractPurpose: To evaluate FAM [5-FU (5-fluorouracil), doxorubicin, mitomycin C] chemotherapy as adjuvant therapy for patients with resected TNM stage I, II, or III gastric carcinoma. Patients and Methods: One hundred ninety-three eligible patients were accrued from 1978 to 1991 in a phase III trial comparing six cycles (1 year) of postoperative FAM chemotherapy with observation only. Results: The median follow-up on this study was 9.5 years. For all patients, no differences (log-rank analysis) in disease-free survival (p=0.45) and overall survival (p=0.57) between FAM therapy (93 cases) and surgery (100 cases) were observed. Quality of surgical resection affected survival irrespective of FAM use. Cases with curative resection, defined in a retrospective review of pathology and surgical reports as cases having no evidence of residual disease in the abdomen and tumor-free margins >1 cm, had superior survival compared to cases not meeting these requirements (p<0.001). FAM was well tolerated with 6% (five of 90) of cases demonstrating grade IV hematologic toxicity. There were two drug-related fatalities (one cardiomyopathy, one hematolytic uremic syndrome). Conclusion: FAM is not effective adjuvant therapy for TNM stage I, II, and III patients with resected gastric cancer. Future adjuvant studies must emphasize prospective surgical quality control to assure enrollment of appropriately staged and resected cases and wide participation to assure adequate case accrual over a reasonable period.

Pathologic review of atypical hyperplasia identified by image-guided breast needle core biopsy: Correlation with excision specimen

CONTEXT Management of breast needle core biopsies diagnosed as atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ is controversial. Current recommendations involve excisional biopsy to rule out ductal carcinoma in situ and/or invasive carcinoma, which have been reported in more than 50% of cases in some series. OBJECTIVE To determine how frequently these diagnoses made on needle core biopsy are ultimately found to represent in situ or invasive carcinoma based on excisional biopsy specimens, in order to identify predictive factors. DESIGN One thousand eight hundred thirty-six image-guided needle core biopsies were performed between January 1, 1995 and May 1, 2001. Fifty-four (2.9%) patients diagnosed with atypical ductal hyperplasia (n = 36), atypical lobular hyperplasia (n = 12), atypical ductal hyperplasia + atypical lobular hyperplasia (n = 3), or lobular carcinoma in situ (n = 3) subsequently underwent breast excisions. Pathologic features were reviewed in each of the needle core biopsies using Pages criteria and were then correlated with excision specimens. SETTING University medical center. RESULTS Review of the needle core biopsy cases with either ductal carcinoma in situ or invasive carcinoma + ductal carcinoma in situ on final excision showed that nucleoli were evident in most of the needle core cases, with foci of nuclear pleomorphism and individual cell necrosis or apoptosis. CONCLUSION A more precise diagnosis can be made by using strict criteria for atypical ductal hyperplasia versus ductal carcinoma in situ on needle core biopsy. Cytologic atypia, even if in a small area, particularly when there is apoptosis/individual cell necrosis, correlates with the finding of a more serious lesion on excision.

Direct cloning of human breast cancer in soft agar culture

A human tumor cloning system has been utilized to grow human breast carcinoma. A total of 225 specimens have been placed in culture. One hundred thirty‐two were from primary chest cancer specimens and 93 were from metastatic lesions. Of these, 71% of the primary breast carcinomas and 75% of metastases formed ⩾5 colonies per 500,000 cells plated. Forty‐five percent of the primary breast carcinomas and 52% of the metastases formed enough colonies (⩾30 colonies per 500,000 cells plated) to perform meaningful in vitro drug testing. Estrogen Receptor status did not influence the percentage of tumors which formed colonies in vitro. Histologic and nude mouse studies provided confirmatory evidence the colonies were composed of breast cancer cells. In 176 in vitro chemotherapeutic drug tests, the anticancer agents commonly used clinically for treatment of breast cancer, i.e., Adriamycin, 5‐fluorouracil, etc., showed some in vitro activity. This activity was not as dramatic as is seen in the clinic with these conventional agents. Future work should concentrate on improving the number of colonies which form from breast cancer specimens and on prospective use of the system for screening for new agents for the treatment of human breast cancer.

HER-2/neu expression as a predictor of response to neoadjuvant docetaxel in patients with operable breast carcinoma

The use of biologic markers to predict response to neoadjuvant chemotherapy may permit tailoring regimens to achieve maximal tumor response. Taxanes have demonstrated excellent activity in breast carcinoma; however, tumor‐specific factors that predict clinical response have not been characterized thoroughly.

Portal infusion of tumor necrosis factor increases mortality in rats

Tumor necrosis factor (TNF) is a protein found in the serum of mice presensitized with BCG following injection of endotoxin. Although TNF has been shown to cause hemorrhagic necrosis of certain tumors, the marked toxicity of recombinant human TNF has limited the clinical usefulness of this compound. This experiment was designed to determine whether hepatic metabolism would reduce the systemic toxicity of TNF delivered by the portal circulation. Twenty male Fischer rats received a continuous infusion of recombinant human TNF (100 micrograms/kg/day), 10 through a portal venous branch, and 10 through a branch of the inferior vena cava. Control animals received an infusion of carrier solution by the same route. After 7 days the animals were sacrificed and their organs weighed and sectioned. Mortality in the portal TNF group was 100%. The animals followed the clinical pattern seen with lethal TNF injection. Histologic sections revealed significant gastric and small intestinal mucosal injury, pulmonary edema, and acute tubular necrosis. Animals receiving TNF systemically lost more weight per day of infusion than controls, but followed a relatively benign course. Systemically infused animals had evidence of mild pulmonary edema, and a periportal mononuclear infiltrate in the liver, but no obvious renal or gastrointestinal injury. In a second experiment the effect of escalating doses of portal TNF infusion on liver enzymes was assessed. TNF was infused intraportally at 10, 50, or 100 micrograms/kg/day for 3 days. Control animals received a carrier solution. Mortality was dose-related with 100% mortality in animals receiving 100 micrograms/kg/day, and 40% mortality in the 50 micrograms/kg/day group.(ABSTRACT TRUNCATED AT 250 WORDS)

Systemic chemotherapy of advanced head and neck malignancies

Several Phase II chemotherapy protocols were evaluated in patients with advanced malignancies; 158 were evaluable head and neck cases. The protocols were as follows: five‐drug combination (COMFP), four‐drug (COMF), (CCNU, Adriamycin, DTIC, and cytosine arabinoside. Insufficient numbers and data were received to adequately evaluate Yoshi 864, 5 Azacytidine, porfiromycin, BCNU, and Azaserine. Significant responses to therapy were noted in the four and five‐drug combinations in which 30–44% of the patients had 50% or greater regression, with an average duration of 2.2 months. Adriamycin and CCNU demonstrated lesser antitumor effects, while DTIC and cytosine arabinoside did not demonstrate significant antitumor activity in the head and neck areas. Usual toxicity consisted largely of nausea and vomiting, leukopenia, and thrombocytopenia. Alopecia was not pronounced in Adriamycin‐treated patients. It appears that combination chemotherapy had a higher response rate compared to single agents used in the different cooperative protocols.

Morphologic and immunophenotypic markers as surrogate endpoints of tamoxifen effect for prevention of breast cancer.

SummaryPrevention trials using incidence or mortality as endpoints require a large number of participants and long follow-up. Trials using biomarkers as endpoints would potentially require fewer participants, less time, and significantly less resources to test promising new agents for breast cancer prevention. To test this idea, a randomized trial of tamoxifen for 1 year versus observation for 1 year was conducted to determine whether tamoxifen can cause regression of hyperplastic breast tissue, whether it changes the biomarker phenotype of premalignant disease or normal breast epithelium, and if biomarkers can be used as early surrogate indicators of response to tamoxifen. Women were identified by having an abnormal mammogram and ductal hyperplasia diagnosed by core needle biopsy. Image-directed needle biopsy was repeated in the same site of the breast after 1 year. Approximately 3000 women were screened, and 265 were eligible. Sixty-three women were randomized and paired biopsies from 45 subjects were available for analysis. There was no evidence of substantial regression of hyperplasia – fewer samples showed hyperplasia at 1 year follow-up, but this was seen in both untreated and tamoxifen-treated women. There were trends for reductions in ER and PgR and trends for increases in bcl-2 in normal and hyperplastic tissue in the tamoxifen-treated arm, though these changes did not reach statistical significance. Proliferation, determined by Ki67 staining, was not significantly changed. Clinical trials of this type are difficult to carry out and modifications in trial design are needed to make this process more efficient.

Upper gastrointestinal bleeding following renal transplantation

Upper gastrointestinal bleeding has been shown to be a common complication of renal transplantation and one which carries a significant risk of mortality. In a retrospective review of 200 consecutive renal transplants in 194 patients, we found an incidence of only 6 per cent and a mortality rate of 8.3 per cent. Allograft survival in this group of patients was 58 per cent. These results are the product of careful preoperative evaluation, close attention to the patients for early signs of bleeding, and aggressive diagnostic and therapeutic intervention at the first evidence of bleeding. We also report an association of hypercalcemia with post-transplant upper gastrointestinal bleeding, with cessation of bleeding after parathyroidectomy.