Background The role of molecular markers in predicting the response to treatment of breast cancer is poorly defined. The Cancer and Leukemia Group B (CALGB) conducted a randomized adjuvant-chemotherapy trial (CALGB 8541) comparing three doses (high, moderate, and low) of cyclophosphamide, doxorubicin, and fluorouracil in 1572 women with node-positive breast cancer. This study (CALGB 8869) was designed to determine whether the DNA index, the S-phase fraction, c-erbB-2 expression, or p53 accumulation could be used as a marker to identify a subgroup of patients more likely than others to benefit from high doses of chemotherapy. Methods Tissue blocks were obtained from 442 patients randomly selected from the larger CALGB trial. Paraffin sections from the primary lesions were analyzed for DNA content, S-phase fraction, c-erbB-2 expression, and p53 accumulation. Results Patients randomly assigned to the high-dose regimen of adjuvant chemotherapy had significantly longer disease-free and overall survival if thei...

c-erbB-2 Expression and Response to Adjuvant Therapy in Women with Node-Positive Early Breast Cancer

Mathematical models for the analysis of pulse-cytophotometric (PCP) data are described. With computer programs based on these models the fractions of cells in G1-, S- and(G2 + M)-phases are obtained. The methods are applied to PCP measurements of Ehrlich ascites tumor cells, human bone marrow cells and L-929-cells in culture. The results of the L-cell experiment are compared with autoradiographic results; for both methods the duration of the various phases has been calculated. Two different mathematical models for PCP-data evaluation and the autoradiographic method yielded results agreeing within statistical error. The application of the two models on different types of DNA-histograms is discussed: One model is suitable for asynchronous cell populations with a low fraction of S-phase cells, the other can be applied for partially synchronized cells and high S-phase fractions as well.

Analysis of PCP-data to determine the fraction of cells in the various phases of cell cycle.

OBJECTIVE: Tumor invasion of the superior mesenteric-portal vein (SMPV) confluence is often considered a contraindication to pancreaticoduodenectomy for patients with malignant tumors of the pancreas or periampullary region. The authors sought to determine whether pancreaticoduodenectomy with en bloc resection of the SMPV confluence could be safely performed and whether tumors involving the SMPV confluence were associated with pathologic parameters suggesting poor prognosis. SUMMARY BACKGROUND DATA: Several centers have reported high rates of retroperitoneal margin positivity after pancreaticoduodenectomy for tumors of the pancreatic head and periampullary region. Positive-margin or incomplete resection is associated with early tumor recurrence and no survival benefit compared with palliative therapy. Tumor adherence to the lateral of posterior wall of the SMPV confluence often represents the only barrier to complete tumor resection at the time of pancreaticoduodenectomy. METHODS: Data on all patients undergoing pancreaticoduodenectomy for adenocarcinoma of the pancreas or periampullary region over a 3.5-year period were entered prospectively in a pancreatic tumor database. To be considered for surgery, patients were required to fulfill the following computed tomography criteria for resectability: 1) the absence of extrapancreatic disease, 2) no tumor encasement of the superior mesenteric artery or celiac axis, and 3) a patent SMPV confluence. Tumor adherence to the superior mesenteric vein or SMPV confluence was assessed intraoperatively, and en bloc venous resection was performed when necessary to achieve complete tumor extirpation. Data on operative characteristics, morbidity, mortality, tumor size, nodal metastases, margin positivity, perineural invasion, and tumor DNA content were compared for patients who did and did not receive venous resection. RESULTS: Fifty-nine patients underwent pancreaticoduodenectomy, 36 without venous resection and 23 with en bloc resection of the SMPV confluence. No differences in median hospital stay, morbidity, mortality, tumor size, margin positivity, nodal positivity, or tumor DNA content were observed between groups. CONCLUSIONS: When necessary, segmental resection of the SMPV confluence may be performed safely during pancreaticoduodenectomy for periampullary malignant tumors. Tumors invading the SMPV confluence are not associated with histologic parameters suggesting a poor prognosis. Our data suggest that venous involvement is a function of tumor location rather than an indicator of aggressive tumor biology.

Rationale for En Bloc Vein Resection in the Treatment of Pancreatic Adenocarcinoma Adherent to the Superior Mesenteric-Portal Vein Confluence

Tumour biological features of BRCA1-induced breast and ovarian cancer.

Measures of the proliferative activity of tumor cells have prognostic value in patients with node-negative breast cancer. We studied 367 women in southern Sweden who had undergone surgical resection for such cancer. Tumor specimens were analyzed with DNA flow cytometry in order to estimate both the DNA content (ploidy) and the fraction of cells in the synthetic phase of the cell cycle (S phase). The median duration of follow-up was four years; 28 percent of the patients received adjuvant therapy, usually with tamoxifen (n = 83). A multivariate analysis based on complete data on 250 patients included the following covariates: age (greater than or equal to 75, 50 to 74, and less than or equal to 49 years), tumor size (less than or equal to 20 vs. greater than 20 mm), concentration of estrogen and progesterone receptors (less than 10 vs. greater than or equal to 10 fmol per milligram of protein), ploidy (diploid vs. nondiploid), and S-phase category (fraction of cells in S phase: less than 7.0 percent, 7.0 to 11.9 percent, and greater than or equal to 12 percent). The S-phase fraction yielded the most prognostic information, followed by progesterone-receptor status and tumor size. A prognostic model based on these three variables identified 37 percent of the patients as constituting a high-risk group with a fourfold increased risk of distant recurrence. In the remaining 63 percent of the patients, the five-year overall survival rate (92 +/- 4 [+/- SE] percent) did not differ from the expected age-adjusted rate for Swedish women. We conclude that a prognostic index that includes indicators of the proliferative activity of tumor cells may be able to identify women with node-negative breast cancer in whom the risk of recurrence is sufficiently low that adjuvant chemotherapy can be avoided.

https://www.nejm.org/doi/pdf/10.1056/NEJM199004123221505

Indicators of prognosis in node-negative breast cancer

Die mittlere Dauer der Phasen des Zellzyklus von L-929-Zellen in Kultur wurde autoradiographisch und impulscytophotometrisch bestimmt. Die Mittelwerte von funf Untersuchungen wichen biei beden Verfahren nur im Rahmen des statistischen Fehlers voneinander ab. Die Reproduzierbarkeit der ICP-Messungen war besser. Auf Konsequenzen fur eine klinische Anwendung wird hingewiesen.

Die dauer der phasen im zellzyklus von l-929-zellen

Impulsecytophotometric studies on the effects of daunomycin on synchronised L-cells

[Duration of the phases of the cell cycle in L-929 cells (author's transl)].

Mouse fibroblasts, subline L-929 F were synchronized by mitotic detachment. The synchronized cell cultures were irradiated with 200 kVp X-rays at different time after mitosis, and age reponse functions and dose effect curves were determined using the colony test. The cell age in the mitotic cycle was obtained from a computer analysis of flow cytometric DNA histograms. Both intrinsic radiosensitivity 1/D
0 and extrapolation numbern were found to vary during the cell cycle. TheD
0 has a maximum value of 176 ± 1 rad in the middle ofG
1 phase and a minimum of 71 ± 1 rad at theS/G
2 transition, while the extrapolation number is rather constant from the beginning ofG
1 phase (1.9 ± 0.1) to the middle ofS phase (2.3 ± 0.1) and reaches a steep maximum of 9.3 ± 1.1 atS/G
2 transition. The values ofn in the various phases of cell cycle are compared with the respective values of the recovery factorγ determined after fractionated irradiation. - Cell survival after a single dose of 616 rad has minima for irradiation atG
1/S transition and in earlyG
2 phase; the survival in earlyG
2 being about 40 times smaller than in earlyG
1 phase. Implications for a cell cycle specific therapy are discussed.

W. A. Linden

Papers

Analysis of PCP-data to determine the fraction of cells in the various phases of cell cycle.

Die dauer der phasen im zellzyklus von l-929-zellen

Impulsecytophotometric studies on the effects of daunomycin on synchronised L-cells

[Duration of the phases of the cell cycle in L-929 cells (author's transl)].

Radiosensitivity and recovery of mouse L cells during the cell cycle