Postoperative serum proteomic profiles may predict metastatic relapse in high-risk primary breast cancer patients receiving adjuvant chemotherapy.

A total of 30-50% of early breast cancer (EBC) patients considered as high risk using standard prognostic factors develop metastatic recurrence despite standard adjuvant systemic treatment. A means to better predict clinical outcome is needed to optimize and individualize therapeutic decisions. To identify a protein signature correlating with metastatic relapse, we performed surface-enhanced laser desorption/ionization-time of flight mass spectrometry profiling of early postoperative serum from 81 high-risk EBC patients. Denatured and fractionated serum samples were incubated with IMAC30 and CM10 ProteinChip arrays. Several protein peaks were differentially expressed according to clinical outcome. By combining partial least squares and logistic regression methods, we built a multiprotein model that correctly predicted outcome in 83% of patients. The 5-year metastasis-free survival in 'good prognosis' and 'poor prognosis' patients as defined using the multiprotein index were strikingly different (83 and 22%, respectively; P<0.0001, log-rank test). In a multivariate Cox regression including conventional pathological factors and multiprotein index, the latter retained the strongest independent prognostic significance for metastatic relapse. Major components of the multiprotein index included haptoglobin, C3a complement fraction, transferrin, apolipoprotein C1 and apolipoprotein A1. Therefore, postoperative serum protein pattern may have an important prognostic value in high-risk EBC.

Impact of plasmacytoid dendritic cells on outcome after reduced-intensity conditioning allogeneic stem cell transplantation.

The reconstitution of the plasmacytoid dendritic cells (PDCs) compartment might influence outcome after allogeneic stem cell transplantation (allo-SCT). Thus, we investigated the impact of blood PDCs measured at the third month after reduced-intensity conditioning (RIC) in 54 patients who received an HLA-identical sibling allo-SCT. The absence of grade II-IV acute graft-versus-host-disease (GVHD) was associated with an improved PDC count at 3 months after RIC-allo-SCT (P=0.003; OR=6.4; 95% CI, 1.9-22). The CD34+ stem cell dose and other lymphoid subsets infused with the allograft did not affect PDC recovery. Although PDC count could not predict death from progression or relapse, patients with a "high" PDC recovery profile had an improved overall survival (OS; P=0.03), in contrast to patients with a "low" PDC recovery profile who had an increased incidence of nonrelapse mortality (GVHD, infections) (P=0.03). The overall incidence of late infections (viral, fungal and bacterial) was significantly higher in the "low" PDC recovery group as compared to the "high" PDC recovery group (59 vs 19%; P=0.002). In a multivariate analysis, only a "high" PDC count was significantly predictive of a decreased risk of death (P=0.04; RR=0.34; 95% CI, 0.12-0.96). Monitoring of PDCs at 3 months after RIC-allo-SCT may be a useful indicator predictor of long-term outcome.

WNT pathway and mammary carcinogenesis: loss of expression of candidate tumor suppressor gene SFRP1 in most invasive carcinomas except of the medullary type.

Secreted Frizzled-related protein 1 (SFRP1) encodes a member of a protein family that contains a cysteine-rich domain similar to the WNT-binding site of Frizzled receptors and regulates the WNT pathway. The WNT pathway is frequently altered in human cancers. We have defined the pattern of SFRP1 mRNA expression in the progression of breast cancer. We show that SFRP1 is expressed in the epithelial component of normal breast, in the in situ component of ductal carcinomas and is lost in more than 80% of invasive breast carcinomas except the medullary type. Loss of SFRP1 expression is correlated with the presence of hormonal receptors. Conversely, the maintenance of SFRP1 in carcinomas is correlated with the presence of lymphoplasmocytic stroma. No significant association was observed between SFRP1 status and the level of apoptosis in tumoral cells.

Intensive sequential chemotherapy with repeated blood stem-cell support for untreated poor-prognosis non-Hodgkin's lymphoma.

PURPOSE: To demonstrate the feasibility and efficacy of six ambulatory high-dose sequential chemotherapy courses that include three intensified cycles supported by stem-cell infusion in high-risk and high-intermediate-risk untreated non-Hodgkin's lymphoma (NHL) patients. PATIENTS AND METHODS: A pilot nonrandomized study included 20 untreated patients aged less than 60 years with aggressive histologically identified NHL and two or three adverse-prognosis criteria (International Index). Patients received an ambulatory regimen with high-dose chemotherapy supported by granulocyte colony-stimulating factor (G-CSF) and repeated peripheral-blood stem-cell (PBSC) infusion. The median age was 39 years (range, 20 to 59), with 13 men and seven women. Chemotherapy consisted of one cycle every 21 days for a total of six cycles. The first three cycles (A1, A2, and A3) consisted of cyclophosphamide (Cy) 3,000 mg/m2, doxorubicin (Doxo) 75 mg/m2, and vincristine 2 mg (plus corticosteroids). The last three cycles (B4, B5, and B6) consisted of the same drug combination plus etoposide 300 mg/m2 and cisplatin 100 mg/m2. For an expected duration of 18 weeks, the projected dose-intensity was 25 mg/m2/wk for Doxo and 1,000 mg/m2/wk for Cy. G-CSF 300 micrograms was administered from day 6 following each cycle until neutrophil reconstitution. Two aphereses were performed at approximately day 13 after each A cycle, and PBSCs were injected at day 4 of each B cycle. Radiotherapy on tumor masses > or = 5 cm was scheduled after completion of the last cycle. RESULTS: The median duration of grade 4 neutropenia was 1 day (range, 0 to 7) for each A cycle and 4 days (range, 1 to 10) for each B cycle (P = .02). The median duration of grade 4 thrombopenia was 0 days (range, 0 to 8) for each A cycle and 6 days (range, 1 to 21) for each B cycle (P < .001). Hospitalization for febrile neutropenia was required for 18% and 44% of patients during cycles A and B, respectively (P < .01). Only three patients did not complete the protocol: one due to emergency surgery after cycle B4, one who died after cycle B5 from interstitial pneumonia, and one with delayed hematologic reconstitution after cycle B4. Chemotherapy delivery was optimal (median actual relative dose-intensity, 97%; range, 66 to 100). The median total dose administered over 18 weeks was 18,000 mg Cy (range, 12,000 to 18,000), 450 mg Doxo (range, 300 to 450), 900 mg etoposide (range, 300 to 900), and 300 mg cisplatin (range, 100 to 300). Evaluation of response after six courses showed 13 complete remissions ([CRs] 65%), four partial remissions (PRs), two nonresponses (NRs), and one toxic death. With a median follow-up period of 25 months (range, 16 to 43), 15 patients are alive, with 12 in continuous first CR; five patients relapsed (four of four PRs and one of 13 CRs). Two-year survival and failure-free survival (FFS) rates are 73% and 56%, respectively. The disease-free survival (DFS) rate for the CRs is 86%. CONCLUSION: PBSC support contributes to the feasibility of first-line, very-high-dose, ambulatory chemotherapy delivery in poor-risk NHL and is associated with a high rate of remission and FFS.

Early administration of recombinant erythropoietin improves hemoglobin recovery after reduced intensity conditioned allogeneic stem cell transplantation.

The use of recombinant human erythropoietin (rHuEPO) has been controversial after myeloablative allogeneic Stem cell transplantation (allo-SCT). Reduced intensity conditioning regimens (RIC) offer a novel approach that might translate into a different profile of erythropoietic recovery. We treated 20 consecutive patients with rHuEPO early after matched sibling RIC allo-SCT. Conditioning included fludarabine, busulfan and antithymocyte globulin. EPO treatment was analyzed in terms of toxicity, impact on the frequency of Red blood cell transfusions (RBCT) and kinetics of Hemoglobin recovery within the 60 days post-allo-SCT. Results were compared with 27 matched patients who did not receive rHuEPO. In the first 2 months after allo-SCT all patients receiving rHuEPO (100%) achieved an Hb level > 11 g/dl at a median of 30 (15-35) days post-allo-SCT, as compared to only 63% of the patients not receiving rHuEPO (P = 0.007) at a median of 35 (20-55) days (P = 0.03). A total of 70% (95% CI, 50-90) of rHuEPO patients maintained an Hb over 11 g/dl in the second month as compared to only 19% (95% CI, 4-34) in the other group (P = 0.0004). For patients receiving RBCT, the use of rHuEPO was associated with a trend towards reduced RBCT requirements. This pilot study suggests a potential benefit of early administration of rHuEPO after RIC allo-SCT on early erythropoietic recovery.

Intensive sequential chemotherapy (ISC 95) with growth factors and blood stem cell support in high-intermediate and high-risk (IPI 2 and IPI 3) aggressive non-Hodgkin's lymphoma: an oligocentric report on 42 patients.

We previously reported feasibility and efficacy of a monocentric pilot study of intensive sequential chemotherapy (ISC) in poor-risk aggressive non-Hodgkin's lymphoma (NHL) in patients < 60 years. To validate these results on a large cohort of patients, we designed a new and oligocentric study. After a COP (cyclophosphamide (Cy), vincristine (Vcr), prednisone (Pred) debulking, patients received four courses of high-dose CHOP (Cy, doxorubicin (Doxo), Ver, Pred), with the addition of etoposide and cisplatin during the two last courses. G-CSF was delivered after each cycle, and peripheral blood stem cells (PBSC) were used to support the two last cycles. Total duration of chemotherapy was 13 weeks, with a planned dose-intensity (DI) of 1420 mg/m2/week and 23 mg/m2/week for Cy and Doxo, respectively. Radiotherapy (involved fields) was then delivered for patients with node size > or = 5 cm at diagnosis. Forty-two patients were enrolled in this study; 36 completed the treatment and received 75% or more of the planned DI for both Cy and Doxo. Median duration of grade 4 neutropenia was 14 days (range, 2 to 28) for the regimen as a whole, and median duration of rehospitalization for febrile neutropenia was 18 days (range, 4 to 41). Overall response rate was 83%, with 29 patients (69%) in complete response (CR). Six patients failed to respond and one died of toxicity. With a median follow-up of 22.5 months (range, 10 to 42), the 3-year event-free survival (EFS) is 55% (95% CI, 39-71), while disease-free survival (DFS) is 79% (95% CI, 63-95). Ambulatory ISC is accessible and feasible in an oligocentric study. PBSC allow repeated delivery of high-dose chemotherapy cycles, and result in encouraging CR, EFS, and DFS rates for poor-risk aggressive NHL's patients.

Local and distant recurrence after conservative management of "very low-risk" breast cancer are dependent events: a 10-year follow-up.

PURPOSE: To determine the risk factors associated with recurrence after breast-conserving treatments, and the relationship between occurrence of a local recurrence and subsequent distant metastases. METHODS AND MATERIALS: Among the 3697 patients with primary breast cancer treated at Institut Paoli-Calmettes Cancer Center, Marseille, between 1980 and 1995, we retrospectively analyzed 756 patients who had been treated with conservative surgery with uninvolved margins of excision, were node-negative, and had received uniform radiotherapy and no chemotherapy. One third of the patients received hormonal therapy via tamoxifen or surgical castration. The endpoints considered were local failures and distant metastases. All tumors were reviewed by our pathologists. The median follow-up for the 700 survivors was 62 months. RESULTS: In the multivariate analysis, histological multifocality (p = 0.0076), peritumoral vessel invasion (p = 0.0215), and young age (p = 0.0245) were associated with an increased risk of local recurrences, whereas tumor size (p = 0.0013), young age (p = 0.003), and histological multifocality (p = 0.0414) were associated with an increased risk of distant metastases. Local recurrences and distant metastases had similar yearly-event probabilities. Median time to distant metastases was shorter after a local recurrence. Early timing of local recurrences did not mark a higher risk of distant metastases. Hazard of relapsing from distant metastases was 4.4 times higher after a local recurrence. CONCLUSION: our results support the hypothesis that, in this subset of patients, local recurrences favor further dissemination of cancer cells. We are unable to clearly identify a group who would benefit from more aggressive local therapy.

Combined brachytherapy and surgery for early carcinoma of the uterine cervix: analysis of extent of surgery on outcome.

PURPOSE: The aim of this retrospective study was to evaluate the survival data and rates and patterns of complications and recurrences for patients who had early uterine cervix carcinoma and underwent brachytherapy and subsequent surgery. METHODS AND MATERIALS: Between January 1990 and December 1997, 192 women with cervical carcinoma (Stages IA2 with vascular invasion [n = 28], IB1 [n = 144], and IIA [n = 20]) underwent brachytherapy, delivering 60 Gy and then hysterectomy with external iliac lymphadenectomy. Piver class I, II, and III hysterectomies were performed on 136, 38, and 18 patients, respectively. Adjuvant chemoradiotherapy was delivered to patients with positive lymph nodes. RESULTS: The median follow-up time was 61 months. After brachytherapy, a pathologically complete response (CR) was observed in 137 (71.3%) of 192 women. The distribution of CRs according to tumor stage was as follows: Stage IA2, 24 (85.7%) of 28; Stage IB1, 105 (72.9%) of 144; and Stage IIA, 8 (40%) of 20. Patients with Stage IB1 cancer had 13 lymph node metastases (9%), as did 6 with Stage IIA disease (30%). Pelvic recurrences occurred in 9 (4.6%) of the 192 patients; in 3, local relapses were associated with relapses at distant sites. Ten patients had systemic relapses (5.2%). Recurrences at distant sites were more frequent (p < 0.02) in partial responders, and other recurrences were more frequent in patients with lymph node metastases (p < 0.04). The overall 5-year disease-free survival rate was 91.2% (96.2% for Stage IA2, 91% for Stage IB1, and 84.4% for Stage IIA cancers). The class of hysterectomy did not influence the outcome. Late complications occurred in 28 patients (Grade 1, 24 [12.5%]; Grade 2, 4 [2%]; and Grade 3, 1 [0.5%] of 192 patients). CONCLUSIONS: Combined treatments resulted in high local control and low morbidity rates in patients with early-stage cervical carcinoma. Limited surgery seemed to be adequate after intracavitary therapy.

High-dose melphalan-based chemotherapy and autologous stem cell transplantation after second look laparotomy in patients with chemosensitive advanced ovarian carcinoma: long-term results.

The importance of dose intensity has been suggested in ovarian carcinoma. We retrospectively evaluated the long-term results of melphalan-based high-dose chemotherapy (HDC) with hematopoietic rescue in a unicentric series of 33 patients with advanced ovarian cancer sensitive to first-line chemotherapy. Before HDC, treatment with debulking surgery and platinum-based chemotherapy was followed by second-look operation (SLO). HDC consisted of melphalan (n = 8), melphalan and cyclophosphamide (n = 9), or melphalan, etoposide and carboplatinum (n = 16). Toxicity was mainly hematological. One death occurred from infection during aplasia. With a median follow-up of 60 months after intensification, the 5-year progression-free survival (PFS) rate was 29% and the 5-year overall survival (OS) rate was 45%. Survival differed significantly according to tumor status at SLO. Women with microscopic or macroscopic disease at SLO, ie with a pathological partial response to first-line therapy (PPR), had survivals of 7% at 5 years, similar to other salvage therapies. Better results were obtained in the 20 women with a complete pathological response (PCR) at SLO with 43% 5-year PFS (median, 51 months) and 75% 5-year OS (median not reached). In conclusion, melphalan-based HDC with hematopoietic rescue had an acceptable toxicity in patients with chemosensitive advanced ovarian cancer. In situations of salvage therapy for patients in PPR, this treatment was not effective in long-term analysis. On the contrary, long-term results were favorable in patients with PCR, suggesting further prospective randomized studies comparing HDC and other consolidation treatments should be undertaken in this particular situation.

Role of high-dose therapy and initial response in survival of poor-risk patients with aggressive non-Hodgkin's lymphoma: a retrospective series on 126 patients from a single center.

It is now established that a subgroup of non-Hodgkin's lymphoma (NHL) patients probably benefit from high-dose therapy (HDT). We therefore retrospectively analyzed survival of 126 consecutive patients with large cell lymphoma (LCL) and high-intermediate (HI) or high-risk (H) age-adjusted international prognostic index (Aa-IPI). They received either standard chemotherapy (CT) (66 patients), or HDT (60 patients). Distribution of the Aa-IPI scores showed no statistical significant difference between the two treatment groups. Complete response (CR) rate was 51% for the whole series, with 41% and 62% for the standard CT group and HDT group, respectively. With a median follow-up of 63 months (range, 16 to 159), the 5-year overall survival (OS) and event-free survival (EFS) for all patients was 52% and 43%, respectively. There was a statistical significant difference in terms of survival towards the HDT group: OS at 76% vs 31%, EFS at 64% vs 24%. Patients who achieved CR with front-line therapy had a 5-year OS at 70%, while it was 34% for patients who were not in CR. These results are comparable to those reported in the literature, and strongly suggest that both initial CR achievement and HDT as front-line treatment are predictive factors for prolonged survival of patients with poor-risk LCL. Bone Marrow Transplantation (2000) 25, 35-40.

Modulations of dose intensity of doxorubicin and cyclophosphamide in association with G-CSF and peripheral blood stem cells in adjuvant chemotherapy for breast cancer: comparative evaluation of completion and safety of three intensive regimens.

The aim of this study was to evaluate and to compare in terms of toxicity the modulations of dose intensity of cyclophosphamide and doxorubicin in adjuvant chemotherapy for high-risk breast cancer. Four cycles of sequential high-dose chemotherapy with doxorubicin and cyclophosphamide (AC), supported with G-CSF and peripheral blood stem cells (PBSC) were administered to 81 women. Three successive cohorts were studied: doxorubicin (75 mg/m(2)) + cyclophosphamide (3000 mg/m(2)) every 21 days (group 1), doxorubicin (75 mg/m(2)) + cyclophosphamide (3000 mg/m(2)) every 15 days (group 2), and doxorubicin (75 mg/m(2)) + cyclophosphamide (6000 mg/m(2)) every 21 days (group 3). Seventy-five patients received four cycles of treatment with a total of 310 cycles administered. The received dose intensity of doxorubicin was higher in group 2 and that of cyclophosphamide was lower in group 1 than in the other two groups. Hematological and extra-hematological toxicities, as well as the number and duration of hospitalizations for toxicity, were significantly higher in group 3. We conclude that the group 3 regimen is associated with toxicities comparable to autologous transplantation. Increasing dose intensity of doxorubicin and cyclophosphamide is feasible in an outpatient setting and safe in groups 1 and 2 with the support of hematopoietic factor and PBSC.

Overexpression of erb B2 remains a major risk factor in non-metastatic breast cancers treated with high-dose alkylating agents and autologous stem cell transplantation.

The importance of dose intensity has been strongly emphasized in high-risk breast cancer. Overexpression of erb B2 is clearly correlated with an overall poor prognosis which could be limited in patients receiving intensive chemotherapy with alkylating agents and autologous stem cell transplants (SST). Thirty-five patients with high-risk non-metastatic breast cancer (>4 involved lymph nodes), treated with high-dose chemotherapy (HDC) followed by SST were analyzed. All were previously treated by four cycles of standard-dose anthracycline or anthracene dione. Nine had erb B2 overexpression. Minimum follow-up duration was 41 months (median 68 months). At 5 years, the actuarial relapse-free survival is 57.4% and actuarial overall survival 67.4%. Patients with overexpression of erb B2 had significantly lower disease-free survivals (P: 0.021) and overall survivals (P: 0.001). On multivariate analysis, erb B2 overexpression appeared to be the single independent poor prognosis factor for relapse (RR 3.25, range 1.12 to 9.45) and overall (RR 5.28, range 1.74 to 16.03) survival. These results suggest that poor prognosis of erb B2 overexpression is unchanged after HDC with alkylating agents but a possible benefit may exist in these patients with the additional monoclonal antibody, herceptin.

Occult tumor cell contamination in patients with stage II/III breast cancer receiving sequential high-dose chemotherapy.

The purpose of this study was to evaluate the presence of micrometastatic cells in the apheresis products from patients with breast cancer, and also to determine if repeated infusion of contaminated products had any clinical impact. A total of 94 patients with high-risk breast cancer were enrolled in a prospective single center study to evaluate the use of dose-intensified chemotherapy (doxorubicine 75 mg/m(2) and cyclophosphamide 3000 or 6000 mg/m(2) for four cycles) with repeated (x 2) stem cell reinfusion. All women were monitored for the presence of metastatic cells in aphereses, collected after first course of intensive chemotherapy, and following additional mobilization with rhG-CSF. Epithelial cells were screened with monoclonal antibodies directed to cytokeratin. Eight of the 94 patients had detectable tumor cells in one or several aphereses collected after intensive chemotherapy; this was unrelated to other tumor characteristics, including size, histology, Scarff Bloom and Richardson (SBR) grading (presence or absence of hormone receptors). Hemato-poietic reconstitution was similar in the cells from these eight patients, and in the total patient population. Three of these eight patients relapsed. This study has confirmed that contamination of apheresis products remains a rare event, which does not seem to affect clinical evolution, even when reinfused into the patient.

Multivariate analysis of survival in inflammatory breast cancer: impact of intensity of chemotherapy in multimodality treatment.

The prognosis of inflammatory breast cancer (IBC) is poor. We evaluated clinical and biopathological characteristics that could affect survival in 74 women with nonmetastatic IBC consecutively treated in our institution between 1976 and 2000. Patients received primary anthracycline-based chemotherapy at conventional doses (n=20) or high-dose chemotherapy (HDC) with haematopoietic stem cell support (HSCS) (n=54). After chemotherapy, 84% of patients underwent mastectomy, 95% were given radiotherapy and 55% tamoxifen. Immunohistochemistry data (ER, PR, ERBB2, P53) on pre-chemotherapy specimens suggested strong differences between IBC and non-IBC. The rate of pathological complete response to chemotherapy was 26% (27% with HDC and 17% with conventional doses, not significant). No single factor was found predictive of response. With a median follow-up of 48 months after diagnosis, the 5-year projected disease-free survival (DFS) was 24% and overall survival (OS) 41%. In multivariate analysis, the strongest independent prognostic factor was the delivery of HDC. The 5-year DFS and OS of patients were respectively 28 and 50% with HDC and 15 and 18% with conventional chemotherapy. These results and comparisons with other series of patients suggest a role for HDC with HSCS as part of the therapeutic approach in IBC. Further prospective studies are required to confirm it.

Differential MUC 1 expression in normal and neoplastic human pancreatic tissue. An immunohistochemical study of 60 samples.

Neoplastic transformation of epithelial cell sis commonly associated with altered synthesis of mucin glycoproteins. Few studies have been performed on the correlation between MUC 1 expression and pancreatic carcinoma using immunohistochemical methods. We compared the patterns of MUC 1 expression in normal pancreatic tissue, in pancreatic carcinoma, and in chronic pancreatitis. Immunohistochemical studies were performed using 3 monoclonal anti-MUC 1 antibodies (12C10, 1G5, and H23) on surgical specimens and on fine-needle aspiration biopsy specimens. In the neoplastic cells from adenocarcinomas, high levels of cytoplasmic MUC 1 expression were observed, with some membrane staining. No such cytoplasmic expression was observed in normal tissue, tissue from chronic pancreatitis, or benign neoplastic tissue. These data show conspicuous quantitative and qualitative differences between the patterns of MUC 1 expression observed in nonmalignant vs malignant pancreatic tissue and may be useful in the histologic diagnosis of adenocarcinoma in biopsy samples.

Second neoplasms following high-dose chemotherapy and autologous stem cell transplantation for malignant lymphomas: a report of six cases in a cohort of 171 patients from a single institution.

High dose chemotherapy with autologous stem cell transplantation (ASCT) is increasingly used in the treatment of patients with lymphoma. As previously shown with conventional treatments, second neoplasms are emerging as a long term complication of the procedure. In this study, we investigate the incidence of second neoplasm in a cohort of 171 patients treated with BEAM or BEAC regimens for Hodgkin's disease (n = 62) and non-Hodgkin's lymphomas (n = 109) followed up for a median of 52 months post ASCT. Six patients developed six second malignancies 12 to 105 months after ASCT: fibrolamellar carcinoma of the liver, malignant fibrous histiocytoma, pancreatic carcinoma, squamous cell carcinoma of the lung, invasive carcinoma of the vulva and acute myelogenous leukemia. The cumulative actuarial risk for developing second malignancy is 16.7% (95% confidence interval: 5.9-39.3%) 13 years after transplant. The age-adjusted incidence of cancer in the study group is 4.1 times higher than that of primary cancer in the general population. These data confirm that ASCT recipients are at increased risk of later malignancies. This complication adds significant morbidity and mortality to the transplant process and therefore, needs to be taken into account in long term evaluation of new strategies which involve early intensification in the treatment of lymphomas.

Prognostic value of simultaneous expression of p21 and mdm2 in breast carcinomas treated by adjuvant chemotherapy with antracyclin.

One hundred and sixty-two breast carcinomas treated by adjuvant chemotherapy were investigated in immunohistochemistry for expression of p53 and two wild-type p53-regulated induced proteins, mdm2 and p21/waf1. p21 and mdm2 were expression stongly correlated with Ki67 but not with survival. The p53+/p21+, p53+/p21- and p53+/mdm2- phenotypes were associated with the worst prognosis. The p53+/p21+/ mdm2+ tumors were associated with a better outcome than the other phenotypes, they may be tumors expressing wild-type p53 and p21, and a form of mdm2 that might lead to the stabilization of p53. It is suggested that p21/mdm2 expression should be investigated in all cases of p53 positive breast cancer.

A phase II single institutional experience with preoperative radiochemotherapy in pancreatic adenocarcinoma.

BACKGROUND: Resection of pancreatic adenocarcinoma has a limited impact on survival. We hypothesized that delivering preoperative radiochemotherapy (RTCT) might enhance local control of the cancer and improve survival. METHODS: Nineteen patients with localized pancreatic cancer (14 head and 5 body) were treated during the past 4 years with an intramural protocol consisting of continuous infusion of fluorouracile (5-FU: 650 mg/m(2)/D1-D5 and D21-D25 and Cisplatin 80 mg/m(2)/bolus D2 and D22 with preoperative external beam radiotherapy (RT) (30Gy split course RT or 45 Gy standard fractionation RT). RESULTS: Four patients did not have surgical resection: Three patients were noted to have liver metastases and 1 patient developed peritoneal carcinomatosis. The remaining 15 patients had potentially curative resection (12 Whipple procedure and 3 distal subtotal pancreatectomy). There was no postoperative death. Pathologic findings showed five major responses including 2 patients with complete pathologic response. The overall median survival for the 19 study patients was 20 months. The median disease free and 2-year overall survival for the group with resection were 30 months and 52.3%. CONCLUSIONS: Preoperative RTCT followed by resection is well-tolerated and safe for patients with localized pancreatic cancer. Major histological response occurred for 25% of patients. This approach could offer improvement in patient survival.

High-dose chemotherapy with hematopoietic stem cell support in patients with advanced epithelial ovarian cancer: analysis of 67 patients treated in a single institution.

BACKGROUND: Advanced ovarian carcinoma is a chemosensitive tumor, but its prognosis is poor with 20 to 30% 5-year survival using conventional therapy. Increasing doses of chemotherapy might improve the prognosis because of the dose-effect. MATERIALS AND METHODS: Between 1980 and 1994 at Institut Paoli-Calmettes, 67 patients with advanced ovarian cancer were treated with different alkylating agents-based regimens of high dose chemotherapy (HDC) and hematopoietic stem cell support (HSCS). The population was divided in 2 groups: a salvage group (n = 30) including initial conventional chemotherapy-refractory patients, and a consolidation group (n = 37) including patients whose disease was sensitive to classical first-line chemotherapy after debulking surgery. RESULTS: Toxicity was essentially hematological (severe aplasia) and digestive (mucositis). Four toxic deaths occurred related to infection during immunosuppression. In the salvage group, 9 out of 22 evaluable patients responded (41%), but the duration of responses was short (median range of 6 months) and the 2-year overall survival rate was 13%. In the consolidation group, 17 patients are still alive, 12 with progression with a median follow-up of 63 months. The 5-year disease-free survival rate was 32% while the 5-year overall survival rate was 46%. CONCLUSIONS: Toxicity of HDC with HSCS is acceptable for poor-prognosis patients. In the long term, this therapy is not beneficial for chemotherapy refractory patients, despite objective response rates better than the conventional treatment, confirming the dose-effect for alkylating agents in ovarian cancer. On the other hand, the results seem better than classical therapy in case of chemosensitive disease and should be confirmed prospectively in a larger cohort of patients.

Peritumoral vascular invasion in women with node-negative breast cancer, receiving no adjuvant therapy.

BACKGROUND: The prognostic value of peritumoral vascular invasion (PVI) in node negative breast cancer (N-) is a controversial issue. Considerable debate has focused on how PVI should be defined, and the techniques used to detect them have differed considerably from one study to another. MATERIAL AND METHODS: In our study, 167 cases of N- breast cancers were reviewed, with a view to determining whether or not PVI, as defined in the recently published European recommendations, were present. RESULTS: Based on the results of the subsequent statistical study, the presence of PVI was not found to constitute a reliable prognostic index to the outcome of N- breast cancer. CONCLUSION: Referring each case to the data available in the literature, the difficulties encountered when searching for PVI of this kind are described, the results of various studies on the topic are reviewed and whether it is worth pursuing studies along these lines is discussed.