Fascin is involved in the chemotherapeutic resistance of breast cancer cells predominantly via the PI3K/Akt pathway.

BACKGROUND: A major therapeutic challenge for breast cancer is the ability of cancer cells to evade killing of conventional chemotherapeutic agents. We have recently reported the actin-bundling protein (fascin) as a major regulator of breast cancer metastasis and survival. METHODS: Survival of breast cancer patients that received chemotherapy and xenograft tumour model was used to assess the effect of chemotherapy on fascin-positive and -negative breast cancer cells. Molecular and cellular assays were used to gain in-depth understanding of the relationship between fascin and chemoresistance. RESULTS: We showed a significant correlation between fascin expression and shorter survival in breast cancer patients who received chemotherapy. In xenograft experiments, fascin-positive cancer cells displayed significantly more resistance to chemotherapy-mediated apoptotic cell death than fascin-negative counterparts. This increased chemoresistance was at least partially mediated through PI3K/Akt signalling, and was paralleled by increased FAK phosphorylation, enhanced expression of the inhibitor of apoptosis proteins (XIAP and Livin) and suppression of the proapoptotic markers (caspase 9, caspase 3 and PARP). CONCLUSIONS: This is the first report to demonstrate fascin involvement in breast cancer chemotherapeutic resistance, supporting the development of fascin-targeting drugs for better treatment of chemoresistance breast cancer.

Phase II study of docetaxel, doxorubicin, and cyclophosphamide as first-line chemotherapy for metastatic breast cancer.

PURPOSE: This pilot phase II study investigated the efficacy and toxicity of docetaxel with doxorubicin and cyclophosphamide (TAC) as first-line chemotherapy for anthracycline-naive patients with metastatic breast cancer. PATIENTS AND METHODS: Fifty-four patients received a total of 359 courses consisting of docetaxel 75 mg/m2 given intravenously (IV) over 1 hour, preceded by IV doxorubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 for a maximum of eight 3-week cycles. RESULTS: After an independent panel review, the overall objective response rate was 77% (complete response, 6%). Overall objective response rates in patients with visceral, bone, and liver involvement were 82%, 82%, and 80%, respectively. Median duration of response was 52 weeks, and median time to progression was 42 weeks. With a median follow-up of 32 months, the median survival had not yet been reached, whereas the 2-year survival was 57%. The main toxicities were hematologic (neutropenia grade 3/4 in 100% of patients and 95% of cycles; febrile neutropenia in 34% of patients and 9% of cycles). Documented grade 3 infection was seen in one patient (2%) in one cycle, and no toxic death was reported. Severe acute or chronic nonhematologic adverse events were infrequent, and docetaxel-specific toxicities (such as fluid retention and nail changes) were mild, with only one patient being discontinued for fluid retention. Congestive heart failure was seen in two patients (4%). CONCLUSION: TAC is an active and manageable regimen that has been chosen as the basis of five randomized phase III trials, including two pivotal studies comparing TAC to fluorouracil plus doxorubicin and cyclophosphamide in the metastatic and adjuvant treatment of breast cancer.

Analysis of the relationship between chimerism and the allgeneic humoral response.

BACKGROUND: Persistence of antigens has been suggested to play a role in two opposing immunological phenomena: tolerance and memory. Therefore, we studied the impact of chimerism on alloreactive antibody (allo-Ab) production in kidney transplant patients. METHODS: Thirty-five female renal transplant recipients of male donor organs were classified into the following groups: group 1, 13 sensitized uremic patients on dialysis; group 2, 5 nonsensitized uremic patients on dialysis; group 3, six sensitized patients experiencing graft rejection (3 acute vascular, 1 acute cellular, and 2 chronic); and group 4, 11 nonsensitized with functioning allografts (9 with good function, 1 with acute cellular rejection, and 1 with chronic rejection). Mean duration of dialysis after graft failure was similar in groups 1 (56+/-29.7 months) and 2 (41.8+/-42.4 months), as was dialysis efficiency. Chimerism was measured indirectly in the peripheral blood lymphocytes by polymerase chain reaction amplification of a specific Y chromosome DNA gene sequence with a detection sensitivity limit of 1 male cell per 1 million female cells. Allo-Ab production was measured by the PRA-STAT enzyme-linked immunosorbent assay (Sangstat) method. RESULTS: Chimerism was observed in 60% of groups 1 and 2, 83% of group 3, and 82% of group 4. Among all groups, graft existence, irrespective of its function, positively predicted chimerism in 92% with a sensitivity of 88% and a specificity of 78%. In group 3, all three patients with acute vascular rejection had chimerism and donor-specific allo-Abs. In group 4, eight of the nine patients with no rejection had chimerism. CONCLUSION: Chimerism relates to persistence of allogeneic stimulus irrespective of its function. Chimerism did not confer protection against allo-Ab production or vascular rejection, and its existence was not crucial for sustenance of allo-Ab production.

Soft tissue malignant lymphoma at sites of previous surgery.

Three diffuse centroblastic lymphomas developed at the site of previous surgery. Two were preceded by atypical lymphoid infiltrates. Clinical data, microscopic features, and immunophenotypic studies were reviewed. All three patients presented with soft tissue masses at the site of previous surgery and metallic implants, with no evidence of lymphadenopathy, hepatosplenomegaly, or bone marrow involvement. There was no history of immunosuppression or risk factors. In two cases the initial diagnosis was of atypical lymphoid infiltrate progressing to lymphoma. Pathological examination showed a diffuse centroblastic lymphoma with an angiocentric pattern in one case. Phenotypic studies confirmed B cell origin. Soft tissue malignant lymphoma, though uncommon, can occur at the site of previous orthopaedic surgery, in particular joint replacement. Atypical lymphoid infiltrate may signal such an event.

Docetaxel/doxorubicin/cyclophosphamide in the treatment of metastatic breast cancer.

Preliminary results from phase I trials suggest that the use of docetaxel (Taxotere) and doxorubicin (Adriamycin) is a well tolerated and highly active combination regimen for patients with metastatic breast cancer. The maximum tolerated dose of this combination was 50 mg/m2 of doxorubicin given as an intravenous bolus followed 1 hour later with 75 mg/m2 of docetaxel given as a 1-hour intravenous infusion. Because cardiotoxicity was not observed with this combination, we added cyclophosphamide (Cytoxan, Neosar) in a phase II trial to determine the antitumor activity and tolerability of this 3-drug combination as first-line therapy in patients with metastatic breast cancer. Preliminary results from this study indicate that the Taxotere/ Adriamycin/Cyclophosphamide (TAC) combination produces response rates of up to 80%. However, frequent grade 4 neutropenia was seen in 68% of cycles, febrile neutropenia in 5.5% of cycles, and grade 3 to 4 infection in .8% of cycles. Cardiac toxicity was rare, with 1 case of reversible congestive heart failure (2%), which occurred 2 months after completion of chemotherapy. These preliminary data show that TAC is highly active and that docetaxel did not significantly increase the cardiotoxicity of doxorubicin. Phase III studies in both the first-line and adjuvant settings are warranted.

Prophylactic mastectomy and genetic testing: an update.

PURPOSE/OBJECTIVES: To examine and discuss the possible benefits and difficulties with recommending prophylactic mastectomy to BRCA1- and BRCA2-positive women. DATA SOURCES: Published research articles, professional review articles, textbooks. DATA SYNTHESIS: Women with BRCA1 and BRCA2 mutations face a much higher risk of developing breast cancer than the general population, with limited options available for prevention. Prophylactic mastectomy has been shown to have a survival advantage in young women who carry BRCA1 and BRCA2 mutations. Challenges exist, however, in the use of prophylactic mastectomy and genetic testing. CONCLUSIONS: Methods of preventing breast cancer in BRCA1- and BRCA2-positive women currently are limited to watch-and-wait surveillance, prophylactic mastectomy, and, perhaps, chemoprevention. Genetic testing and prophylactic mastectomy each present unique challenges while offering certain benefits as well. Recent studies have shown survival advantages to BRCA1- and BRCA2-positive women who undergo prophylactic mastectomy. IMPLICATIONS FOR NURSING PRACTICE: Nurses need to be aware of the complex issues surrounding testing for BRCA1 and BRCA2 mutations and prophylactic mastectomy to be able to provide current information to patients and assist in decision making.

Ocular toxicity and cancer chemotherapy. A review.

BACKGROUND: Systemic anticancer therapies can produce acute and chronic organ damage, but the eye is usually considered a protected site. Nonetheless, the oculo-visual system has a potentially high degree of sensitivity to toxic substances. Ocular toxicity induced by cancer chemotherapy includes a broad spectrum of disorders, reflecting the unique anatomic, physiologic, and biochemical features of this essential organ. METHODS: A review of the literature regarding the ocular toxicity of chemotherapeutic agents, hormonal agents, biologic agents, and high dose chemotherapy with allogeneic and autologous bone marrow transplantation was conducted. RESULTS: Ocular toxicity induced by anticancer chemotherapy is not uncommon. The development of more aggressive regimens as well as new agents and combination chemotherapies have resulted in a significant increase of reported cases of chemotherapy-induced ocular side effects. In most instances, the mechanisms of ocular toxicity continue to be poorly understood. CONCLUSIONS: Ocular toxicities induced by chemotherapeutic agents are generally not preventable; therefore, clinicians must be aware of potential vision-threatening complications. Prompt consultation with an ophthalmologist can lead to early detection, proper diagnosis, and appropriate therapeutic measures. Dose reduction or discontinuation of incriminated drugs may help in reducing the severity and the duration of side effects.

Cortical blindness as a manifestation of hypomagnesemia secondary to cisplatin therapy: case report and review of literature.

Cisplatin is widely used in the treatment of solid tumors and is known to have a number of side effects including hypomagnesemia. We present a case report of a patient with a Stage IIA carcinoma of the cervix who initially was treated with radiotherapy and cisplatin and subsequently presented with sudden onset of blindness. The diagnosis was uncertain but the possibility of functional blindness was considered. Serum magnesium was low. Correction of this electrolyte abnormality resolved this profound visual symptom. This case emphasizes the importance of serially observing cisplatin-treated patients for the possible development of the clinical syndrome of magnesium deficiency.

Autologous bone marrow support and bone disease in metastatic breast cancer.

High-dose chemotherapy (HDCT) and autotransplantation of hematopoietic cells is being investigated as a therapy for either metastatic or localized high-risk breast cancer. Breast cancer has a tendency to metastasize to the bones and the bone marrow (BM) and therefore the probability of harvesting malignant cells when collecting stem cells for autotransplantation appears high. Thus, the elimination or decrease of this contamination in the transplanted product appears mandatory. Autologous peripheral blood stem cell transplantation (PBSCT) has shown significant advantages over autologous bone marrow transplantation (ABMT) in improving the feasibility of HDCT, while possible limiting the BM contamination. The transplantation of only CD34+ products may even be a further advance. The role of ex vivo purging of cancer cells has not been established in ABMT or PBSCT. The question remains if the positive selection of CD34+ products is sufficient for controlling cancer cell contamination or if this product should be purged as well. The review of the literature suggests that contamination of the bone marrow could have an impact in terms of risk or relapse and could thus play a role as a pejorative prognostic factor. These data, although not totally adequate for the autotransplantation setting, are raising concerns over the probability of reinfusing malignant cells at time of autotransplantation following HDCT. There is a tremendous need to address these concerns in the laboratory along with prospective clinical trials. Until further data is available, this risk must be taken into consideration when patients with breast cancer are treated with curative intent.

Autologous bone marrow support and bone disease in metastatic breast cancer.

High-dose chemotherapy (HDCT) and autotransplantation of hematopoietic cell is being investigated as a therapy for either metastatic or localized high-risk breast cancer. Breast cancer has a tendency to metastasize to the bones and the bone marrow (BM) and therefore the probability of harvesting malignant cells when collecting stem cells for autotransplantation appears high. Thus, the elimination or decrease of this contamination in the transplanted product appears mandatory. Autologous peripheral blood stem cell transplantation (PBSCT) has shown significant advantages over autologous bone marrow transplantation (ABMT) in improving the feasibility of HDCT, while possibly limiting the BM contamination. The transplantation of only CD34+ products may even be a further advance. The role of ex vivo purging of cancer cells has not been established in ABMT or PBSCT. The question remains if the positive selection of CD34+ products is sufficient for controlling cancer cell contamination or if this product should be purged as well. The review of the literature suggests that contamination of the bone marrow could have an impact in terms or risk of relapse and could thus play a role as a pejorative prognostic factor. These data, although not totally adequate for the autotransplantation setting, are raising concerns over the probability of reinfusing malignant cells at time of autotransplantation following HDCT. There is a tremendous need to address these concerns in the laboratory along with prospective clinical trials. Until further data is available, this risk must be taken into consideration when patients with breast cancer are treated with curative intent.

Glioblastoma multiforme presenting with recurrent neurological deficits: Transient ischemic attacks or tumor attacks.

Transient ischemic attacks result from the temporary focal interruption of blood flow to the brain. We present three patients with glioblastoma multiforme and recurrent speech arrests or right-sided numbness. The clinical diagnosis of "transient ischemic attack" was made in each patient. This diagnosis remained unchanged for months to 2 years after initial presentation and investigations. The correct diagnosis was made with a brain biopsy in two patients and as a result of additional investigations in the third patient. It is important to remember brain tumor in the differential diagnosis of patients presenting with recurrent brief neurological symptoms.

Ovarian cancer gene therapy: repeated treatment with thymidine kinase in an adenovirus vector and ganciclovir improves survival in a novel immunocompetent murine model.

OBJECTIVE: Our purpose was to assess the effect of multiple injections of the system of herpes simplex virus thymidine kinase in an adenovirus vector and ganciclovir on survival in a murine model of human epithelial ovarian cancer. STUDY DESIGN: In this work we tested the ability of the system of thymidine kinase delivered by an adenovirus vector and ganciclovir to treat ovarian cancer in a novel murine model for epithelial ovarian cancer, SaskMouse. SaskMouse was developed by injecting LM-1 cells, a murine epithelial ovarian cancer cell line, intraperitoneally into a syngeneic C57BL/6N x C3H/He mouse strain. The cells developed into multiple cancer implants on different abdominal organs, leading to ascites and rapid death. The model has an intact immune system, as evidenced by the inability of different human cancer cells to develop into cancers when injected into the mice intraperitoneally. RESULTS: The system of thymidine kinase delivered by an adenovirus vector and ganciclovir was applied to SaskMouse. Mice were either untreated (group 1), treated with one intraperitoneal injection of adenovirus- thymidine kinase at 250 plaque-forming units/cell (group 2), or treated with two intraperitoneal injections of adenovirus-thymidine kinase at 250 plaque-forming units/cell on days 0 and 23 (group 3). Survivals were 23 +/- 2, 27 +/- 2, and 35 +/- 4 days, respectively (P <.05). Antiadenoviral antibodies were assayed both in the serum and in the peritoneal fluid of treated mice. Despite high antibody titers in serum, there were no detectable antibodies in the peritoneal fluid. CONCLUSION: Our data suggest that multiple intraperitoneal injections of the combination of thymidine kinase delivered by an adenovirus vector and ganciclovir are effective in prolonging survival in the presence of ovarian cancer. There are potential implications for other abdominal malignancies.