Notes: Abstract: Tumor response to preoperative chemotherapy varies from complete to partial to none. To evaluate pathologic predictors of tumor response to preoperative chemotherapy, we reviewed 287 cases of locally advanced breast carcinoma treated with chemotherapy prior to definitive surgery. The patients ranged in age from 18 to 79 years (mean, 48 years). There were 77 (26.8%) patients with stage II disease, 194 (67.6%) with stage III disease, and 16 (5.6%) with stage IV disease. Following the initial diagnosis of invasive carcinoma (by fine-needle aspirate or cutting needle biopsy), the patients received three to four cycles of both doxorubicin-based and cyclophosphamide-based regimens followed by mastectomy or lumpectomy with axillary dissection. The pathologic parameters that were evaluated included stage, clinical tumor size, and tumor nuclear grade (NG). The latter was performed on fine-needle aspirates using Black's nuclear grading system wherein NG1 was considered well differentiated; NG2, moderately differentiated; and NG3, poorly differentiated. Based on pathologic examination of the resected specimens, tumor responses were categorized into complete response, partial response, no response, or progressive disease. The overall response rate was 71% (12% complete and 59% partial responses). In univariate analyses, tumor size and nuclear grade were significantly related to pathologic tumor response to chemotherapy (p = 0.04 and p = 0.0003, respectively), while disease stage was not (p = 0.17). In multivariate analyses, size remained significant even when NG was present in the equation (p = 0.013). Similarly, when size was included, NG remained significant (p = 0.002). NG3 tumors showed better response than NG2 or NG1 tumors did. While 19.3% of NG3 tumors showed complete response, none of the NG1 tumors completely responded to chemotherapy. Initial tumor size was inversely proportional to degree of tumor response. Our findings indicate that tumor clinical size and nuclear grade are important independent predictors of response to preoperative chemotherapy and that poorly differentiated tumors and small tumors showed the most response.

Notes: Summary PANC02 is a ductal adenocarcinoma of the pancreas that is resistant to every known class of clinically active antitumor agent. To study the mechanism(s) underlying the intrinsic drug resistance of this tumor, a mammary adenocarcinoma (CA-755) that also grows in C57/BL mice and is known to be drugsensitive was used for comparison. PANC02 resistance and CA-755 sensitivity to several antitumor agents and to X-ray therapy was confirmed in mice, and PANC02 also demonstrated relative resistance in tissue culture. Relative to Chinese hamster ovary (CHO) and CA-755 cells, PANC02 did not appear to show a higher rate of mutation to drug resistance in culture as based on the 6-thioguanine resistance marker. Although P-glycoprotein characteristic of the multidrug resistance (MDR) phenomenon could be demonstrated at the mRNA level using a sensitive RNAse protection assay, the level of expression found was several orders of magnitude lower than that observed in phenotypic MDR cell lines. Furthermore, quinidine failed to increase the sensitivity of PANC02 cells to Adriamycin under conditions that clearly potentiated the toxicity of the drug to a CHO cell line exhibiting classic MDR traits. The heterogeneity in the distribution of drugs was inferred as being significantly greater in PANC02 versus CA-755 cells in vivo as based on measurements of within-animal, within-tumor variance in the distribution of the marker compounds inulin and antipyrine. Although it may not be the only mechanism involved, this greater intratumor heterogeneity in drug distribution could theoretically play a major role in the intrinsic drug resistance of PANC02 in vivo.

Notes: Summary Cultured human tumor cells of various histologic origins were infected with PR8/A/34 influenza virus. Nonviable crude membrane extracts were derived from the infected and uninfected cells. The extracts were coded and tested for their ability to produce delayed hypersensitivity skin reactions (DHSR) in allogeneic patients with squamous uterine cervical carcinoma, epithelial ovarian carcinoma, and malignant melanoma. Augmented antigen sensitivity to the virus-modified extracts compared with virus alone or to the unmodified extracts was observed in all patient groups. There was insufficient specificity to delineate a response by individual tumor type and related tumor extract, but some of the observed responses suggested tumor or organ site associations. Cervical carcinoma patients reacted more frequently to the virus-modified cervix extract, which also produced a high frequency of response in patients with ovarian carcinoma and melanoma. Ovarian carcinoma patients demonstrated increased sensitivity to both virus-modified ovarian carcinoma extracts, although 14 of 21 patients also showed responsiveness to one of the unmodified ovarian extracts. Malignant melanoma patients showed increased sensitivity to all virus-modified extracts except one of two derived from the ovarian carcinoma, and demonstrated a significantly augmented response to the virus-modified melanoma extract when the response to this extract was compared with that in ovarian carcinoma patients. The augmented reactions appear to be due to an association of the PR8 virus and as yet undetermined cellular components rather than to the virus alone. The possible involvement of tumor-associated determinants and the clinical significance of this phenomenon require further investigation.