Antibody inhibition of oxidative activation and inactivation of the carcinogen 2-acetylaminofluorene by purified hepatic cytochrome P-450 from 3-methylcholanthrene pretreated rats.

Immunochemical studies on metabolic N- and ring hydroxylation of 2-acetylaminofluorene (AAF) were performed with total cytochrome P-450 isozymes and with highly purified P-450 D isozyme isolated from liver microsomes from 3-methylcholanthrene (MC)-pretreated rats. In a reconstituted system with rat P-450 D, addition of antibodies against beta-naphthoflavone (BNF) induced rat P-450 B at 15 mg IgG/nmol P-450 inhibited both oxidations completely. With total P-450 isozymes in a reconstituted system, antibody against BNF-rat-P-450 B at 20 mg IgG/nmol P-450 inhibited both oxidations up to 70-80% only. At these concentrations, preimmune antibody or phenobarbital (PB) induced antibody against rat-P-450 B showed no inhibition of AAF oxidations. These results suggest that P-450 D is the predominant cytochrome P-450 isozyme responsible for AAF N- and ring-oxidations in liver microsomes from MC-pretreated rats. Other P-450 isozymes are also suggested to be involved in AAF oxidations.

Prognostic significance of eosinophils and mast cells in rectal cancer: findings from the National Surgical Adjuvant Breast and Bowel Project (protocol R-01).

The numbers of eosinophils and mast cells observed at the tumor border of 331 rectal cancers from patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP), protocol R-01, were correlated according to overall survival rate, as well as Dukes' stage, tumor differentiation, nodal status, degree of lymphoid and stromal reactions, sex, and age. Life table plots disclosed a significantly better overall survival rate when ten or more eosinophils per 30 oil immersion fields were found. However, the numbers of eosinophils were strongly associated with Dukes' stage and, when life table plots were adjusted for Dukes' stage, this relationship to survival rate was not evident. On the other hand, overall survival rate was significantly higher in patients in whom 0 to three mast cells per 30 oil immersion fields were found than in those patients in whom four or more mast cells were found. This relationship persisted even when life table plots were adjusted for treatment, Dukes' stage, or nodal status, and indicated that the number of mast cells further defined survival rate among patients exhibiting Dukes' A, B, and C stages. It is concluded that numbers of eosinophils and mast cells may play a role in the natural history of rectal cancer but only the latter represents a prognostic parameter independent of Dukes' stage or nodal status. The mechanism whereby mast cells may exert this effect is at present unknown.

Oxidative activation and inactivation of the carcinogen 2-acetylaminofluorene by various purified cytochromes P-450 from 3-methylcholanthrene pretreated rats.

Ring- and N-hydroxylations of 2-acetylaminofluorene (AAF) have been examined in a reconstituted system with 4 purified hepatic microsomal cytochromes P-450 isolated from 3-methylcholanthrene (MC)-pretreated rats. Among these 4 isozymes, P-450D showed the most activity whereas P-450C was devoid of any activity; two other P-450s exhibited moderate activity. These and Ouchterlony's double diffusion analyses suggest involvement of multiple cytochromes P-450 in AAF oxidations.

Pathologic findings from the National Surgical Adjuvant Breast Project (protocol 6). I. Intraductal carcinoma (DCIS).

Seventy-eight examples of intraductal carcinoma (DCIS) were identified after pathologic review of 2072 specimens obtained from National Surgical Adjuvant Breast Project protocol 6. This randomized clinical trial compares the therapeutic merit of total mastectomy (TM) with lumpectomy (L), with (LX) and without (LO) postoperative irradiation. All patients were subjected to axillary lymph node dissection. Seven (14%) of the 51 patients with DCIS treated by L exhibited breast recurrence within or close to the site of the initial lesion 4 to 53 months (average, 16 months) after L. Only 2 (7%) of these events occurred in the 29 women treated by LX, as opposed to 23% in the LO group. No pathologic features were noticed that might have been considered predictive of local breast recurrence. The three DCIS recurrences and the four invasive forms noted are considered to represent overlooked or incompletely excised foci of cancer because of the multifocality (not multicentricity) of some breast cancers. The possibility that DCIS may represent a marker of risk for the development of cancer rather than a precursor lesion per se is suggested. Despite apparent difficulties in the pathologic diagnosis of DCIS as well as uncertainty concerning its natural history, no evidence was found to indicate that it represents a more ominous disease than invasive cancer. Indeed, treatment failure occurred in only one patient treated by LX and a similar number subjected to TM (4% versus 2%). Although these observations are short term (average follow-up, 39 months), estimates of the probability of local recurrence or survival suggest that they will not be significantly altered after longer periods of surveillance. Thus, there are no compelling reasons why DCIS may not be treated in a cosmetically acceptable manner by LX. A randomized clinical trial addressing this issue is now in progress.

Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Five-year observations concerning lobular carcinoma in situ.

BACKGROUND: Extant information reveals inconsistencies concerning the natural history, pathologic features, and treatment of lobular carcinoma in situ (LCIS) of the breast. It is uncertain whether these are related to the methods of study, diagnostic criteria employed, relative paucity of cases, or varying lengths of follow-up. METHODS: The cohort was comprised of 182 women with LCIS who were enrolled in National Surgical Adjuvant Breast Project (NSABP) Protocol B-17 but received no treatment other than lumpectomy. Nineteen pathologic features were assessed and related to ipsilateral breast tumor recurrence (IBTR) and contralateral breast tumor recurrence (CBTR) at a mean time on study of 5 years. RESULTS: Thirteen IBTR and 4 CBTR, including 1 instance of bilateral recurrence, were observed. All IBTR occurred in the same quadrant as the index LCIS. All 4 (2.2%) IBTR that were invasive cancers were of the lobular type, as was 1 of the 2 (1.1%) CBTR that were invasive. The other was a mucinous carcinoma. Three (1.6%) IBTR were pure ductal carcinoma in situ (DCIS) and another was accompanied by LCIS. One instance of CBTR was also comprised of DCIS and LCIS. The remaining five IBTR and one CBTR were LCIS only. The only pathologic parameter found to be significantly predictive for invasive IBTR and DCIS was type 3 and, to a lesser extent, type 2 LCIS. Some heretofore unrecognized or little appreciated pathologic features of LCIS are noted. Ancillary histochemical findings strongly implicate the derivation of LCIS from ductal or secretory cells rather than "new cells" or myoepithelial elements. All examples tested were found to be c-erb B-2 negative, universally diploid with normoproliferative DNA content, and estrogen receptor and progesterone receptor positive. No other events related to the breast were encountered. CONCLUSIONS: The number of events observed in this large cohort of patients with LCIS is markedly less than that noted by others after a comparable period of follow-up. Possible reasons for this dichotomy, including differences in patient characteristics, diagnostic criteria, and status of resection margins, are discussed. Considerations are also offered to support the view that LCIS may exhibit precursor activity as well as represent a risk factor (the term marker is literally inaccurate). In this light, the designation LCIS rather than lobular neoplasia is preferred. These preliminary findings and historical information presented in this study fail to provide any reason to perform mastectomy on patients with LCIS.