Successful remission of extensive liver metastases in a breast cancer patient with acute liver failure using a combined chemotherapy regimen with mitomycin, folinate, and 5-fluorouracil (Mi/Fo/FU).

BACKGROUND: Liver failure due to disseminated hepatic secondaries represents a therapeutic dilemma in patients with metastatic breast cancer (MBC). Reduced liver function and non-assessable toxicity are limiting factors in the selection of chemotherapeutic agents. Currently, there is no standard treatment after failure of anthracycline-and taxane-based first-line therapies, although there is a variety of well evaluated drugs such as capecitabine. CASE REPORT: We report on a 45-year-old breast cancer patient with disseminated hepatic metastases. She presented in markedly poor condition, showing substantial ascites and extensive jaundice. Blood chemistry analysis showed increased serum levels of liver enzymes (aspartate aminotransferase 271 U/l, alanine transaminase 101 U/l), bilirubin (7.9 mg/dl), and CA 15-3 (1,459 U/l). We induced a palliative chemotherapy with mitomycin, folinate, and 5-fluorouracil (Mi/Fo/FU). The patient improved impressively after the first cycle of systemic therapy. Liver enzymes stabilized continuously, CA 15-3 returned to normal. The patient was discharged 2 weeks after the treatment start. Chemotherapy was well tolerated under dose escalation, no grade 3/4 toxicity was observed. The progression-free interval was 5 months. CONCLUSIONS: A combination therapy with Mi/Fo/FU appears to be a reasonable and tolerable alternative salvage strategy for patients with liver failure due to hepatic breast cancer metastases.

Prognostic impact of hemoglobin levels before and during carboplatin/taxane-based chemotherapy in patients with primary invasive epithelial ovarian cancer.

BACKGROUND: Carboplatin/taxane-based chemotherapy is the standard treatment for advanced primary ovarian cancer. Anemia is a frequent side effect of platinum-containing chemotherapy regimens. Furthermore, ovarian cancer is often associated with tumor anemia. The aim of this study was to evaluate the prognostic relevance of the mean hemoglobin level before and during carboplatin/taxane-based chemotherapy. MATERIAL/METHODS: We studied retrospectively 92 patients with primary invasive epithelial ovarian cancer (EOC) receiving carboplatin/taxane-based chemotherapy. Hemoglobin levels were determined before each cycle of therapy. Study objectives were progression-free survival time (PFS) and overall survival time (OS). Univariate analyses and Cox-regression studies were undertaken to evaluate the prognostic impact of hemoglobin levels before and throughout chemotherapy. In addition, sensitivity/specificity analyses and Kaplan-Meier-studies were performed to determine the cut-off level of prognostically relevant hemoglobin levels. RESULTS: In univariate analysis hemoglobin levels throughout chemotherapy showed prognostic relevance in terms of PFS (p<0.05). Sensitivity/specificity and Kaplan-Meier analyses found a hemoglobin level of 11.2 g/dL to be a prognostically relevant cut-off level in terms of PFS (p<0.05). There was a borderline significance for pretherapeutic hemoglobin levels to influence PFS (p=0.07), with a prognostically relevant cut-off level of 11.6 g/dL (p=0.06). CONCLUSIONS: Hemoglobin levels before and particularly throughout therapy seem to have prognostic relevance for patients with primary EOC undergoing carboplatin/taxane-based chemotherapy. Further trials are required to confirm these data in a prospective attempt and to evaluate the role of correcting anemia as standard supportive therapy in the treatment of patients with primary EOC.

Extensive Osler-Rendu disease in a breast cancer patient: increasing hepatic arteriovenous malformations under endocrine therapy mimicking liver metastases.

BACKGROUND: Undefined, increasing hepatic lesions are a common issue in the follow-up care of breast cancer patients and frequently result in invasive diagnostic procedures. CASE REPORT: This case report describes the diagnostic approach in the case of a 58-year-old breast cancer patient with a previously unknown visceral involvement of Osler-Rendu disease. The patient was admitted to our institution because of newly diagnosed, increasing hepatic lesions occurring during endocrine treatment with aromatase inhibitors. On the basis of ultrasound findings, secondary liver metastases were suspected. After a thorough clinical and imaging examination, we reviewed the literature on typical radiological findings of visceral involvement of Osler-Rendu disease, and the impact of endocrine treatment on arteriovenous malformations. Multislice computed tomography scan identified the hepatic lesions as arteriovenous malformations. In the current literature, there are no reports available on the interaction between aromatase inhibitors and arteriovenous malformations. However, some data do show an effect of endocrine therapy with estrogen/progesterone, or tamoxifen on arteriovenous malformations, although some of the results are partially contradictory. CONCLUSION: This case report demonstrates that for undefined hepatic lesions in breast cancer patients, extensive Osler-Rendu disease should be considered as a potential differential diagnosis. Furthermore, we discuss the possible influence of aromatase inhibitors on arteriovenous malformations.

Extensive genital and gluteal epitheliolyses caused by locoregional lichen ruber two years after primary treatment of vulvar cancer.

BACKGROUND: Lichen ruber is a rare inflammatory mucocutaneous dermatosis with unknown etiology. Paraneoplastic manifestations of the disease are rare. Eruptions of lichen ruber subsequent to traumas such as surgery or radiotherapy are described as Köbner's phenomenon. PATIENTS AND METHODS: A 72-year-old woman presented at our institution because of increasing, extensive erosive epitheliolyses of the genital and gluteal area two years after surgery and radiotherapy because of vulvar cancer. RESULTS: Thorough clinical as well as histological examination revealed a localized lichen ruber reaction. All epitheliolyses healed well within weeks under topic treatment with steroids. CONCLUSION: Lichen ruber is a rare dermatologic reaction that can occur several months after surgery and radiotherapy and has to be taken into account on examination of patients with late-onset skin reactions after local cancer treatment.

Serum levels of soluble E-selectin are associated with the clinical course of metastatic disease in patients with liver metastases from breast cancer.

Increasing evidence indicates that the expression of the endothelial adhesion molecule E-selectin is associated with progression and metastasis of breast cancer. Patients with liver metastases also show increased serum levels of the soluble form of E-selectin. It was our aim to compare serum levels of soluble E-selectin (sES) in such patients with the biology of the primary tumor and the course of the metastatic disease under therapy. We examined 69 patients with liver metastases from breast cancer who were selected to receive systemic tumor therapy because of progressive disease (n = 44) or newly detected liver metastases (n = 25). Serum concentrations of sES were measured before each therapy cycle using a specific ELISA. Serum concentrations of sES before the start of therapy were compared to clinical parameters and histopathological findings referring to the primary tumor. Secondly, serum levels of sES were compared to serum concentrations of the corresponding tumor markers. We observed a possible trend for certain unfavorable prognostic parameters (e.g., young women, low-graded tumors, human epidermal growth factor receptor 2 overexpression) to be related to higher serum levels of sES. Serum levels of sES were correlated with tumor marker levels in a logarithmical relation (r = 0.44, P < 0.0005). In some cases it could be demonstrated that serum levels of sES changed similarly to the course of tumor marker levels. We conclude that serum levels of sES are associated with the clinical course of liver metastases from breast cancer. Further investigations are needed to clarify if serum levels of sES may serve as tumor marker in certain clinical situations. E-selectin should be evaluated as a possible target for antimetastatic therapy studies.

Value and feasibility of LLETZ procedures for pregnant women with suspected high-grade squamous intraepithelial lesions and microinvasive cervical cancer.

OBJECTIVE: To evaluate the efficacy, safety, and feasibility of large loop excision of the transformation zone (LLETZ) procedures during pregnancy. METHODS: A retrospective study included 27 patients who underwent LLETZ during pregnancy for suspected high-grade squamous intraepithelial lesions (HSIL) where microinvasion could not be excluded. The study investigated intraoperative and postoperative complications, and compared preoperative and postoperative results. Questionnaires were used to obtain information about peripartum and postpartum data. RESULTS: Three (11.1%) women had invasive or microinvasive cancer, 22 (81.5%) had cervical intraepithelial neoplasia (CIN) 3, and 1 (3.7%) had CIN 2. Twenty-four were positive for high-risk human papillomavirus. All cervical cancers were classified as HSIL or CIN 3 before LLETZ. There were positive resection margins in 15 (55.6%) cases. No intraoperative complications occurred. One (3.7%) patient had a postoperative missed abortion. Major complications such as premature labor or cervical incompetence without influence on delivery occurred after LLETZ in 4 (14.8%) patients. CONCLUSION: LLETZ during pregnancy can be performed if invasive cancer cannot be excluded by colposcopy, cytology, or biopsy. The procedure has a diagnostic intention but can also be a curative therapy in pregnancy, with low intraoperative, postoperative, and peripartum complication rates.

In vitro blockade of adhesion of breast cancer cells to endothelial cells using anti-inflammatory drugs.

BACKGROUND: Increasing evidence suggests that a pro-inflammatory microenvironment affects distant metastasis of breast cancer cells, in particular by favoring tumor cell adhesion to endothelium. The aim of this study was to investigate the potential of different anti-inflammatory drugs to inhibit this effect in vitro. MATERIALS AND METHODS: Breast cancer cells from the metastatic cell line KM22 were incubated with activated Human umbilical vein endothelial cells (HUVECs). Tumor cell adhesion was quantified by fluorescence microscopy. The anti-inflammatory drugs ibuprofen, aspirin (acetylsalicylic acid), diclofenac, and dexamethasone were used as inhibiting agents. RESULTS: Aspirin and dexamethasone significantly reduced breast cancer cell adhesion to HUVECs (20.3%, p<0.000; and 25%, p<0.05, respectively). Ibuprofen and diclofenac did not significantly reduce tumor cell adhesion. CONCLUSION: Aspirin and dexamethasone seem to be able to partly inhibit adhesion of breast cancer cells to endothelium. Future studies should attempt to optimize this effect in vitro, in preparation for potential in vivo trials.

Breast cancer cell-derived cytokines, macrophages and cell adhesion: implications for metastasis.

BACKGROUND: Liver metastasis is associated with a proinflammatory microenvironment and up-regulation of cell adhesion molecules expressed by endothelial cells. The aim of this study was to characterize the interrelations between breast cancer cell-secreted cytokines, macrophages and E-selectin-mediated cancer cell adhesion and their role in metastasis of breast cancer. MATERIALS AND METHODS: Three metastatic breast cancer cell lines (1590, KM22, ZE) were studied. Cell culture supernatants were screened for cytokines and the potential for cytokines to increase tumor-necrosis factor-α (TNF-α) production by ANA-1-macrophages was analyzed. E-Selectin-mediated tumor cell adhesion of fluorescence labelled tumor cells was evaluated by measurement of fluorescence intensity with and without E-selectin-blocking strategies (monoclonal antibodies, cimetidine). RESULTS: Tumor-specific cytokine secretion patterns were revealed. TNF-α secretion from cultured macrophages increased after incubation with tumor supernatants. Tumor cell adhesion was significantly inhibited by cimetidine and monoclonal antibodies against E-selectin (KM22 with cimetidine, p<0.05). CONCLUSION: Breast cancer cell-secreted cytokines stimulate macrophages to produce TNF-α, a known up-regulator of E-selectin expression, and therefore cell adherence to endothelium. Inhibition of this mechanism could be an attractive therapeutic option for the prevention of breast cnacer metastasis.

Combined Chemotherapy with Mitomycin C, Folinic Acid, and 5-Fluorouracil (MiFoFU) as Salvage Treatment for Patients with Liver Metastases from Breast Cancer - a Retrospective Analysis.

BACKGROUND: The aim of this study was to analyze the activity and tolerability of a combined chemotherapy with mitomycin C, folinic acid, and 5-fluorouracil (MiFoFU) in patients with hepatic metastases from breast cancer, and in particular in patients with impaired liver function. PATIENTS AND METHODS: We retrospectively studied the charts of 44 patients who were treated with a MiFoFU combination therapy because of progressive metastatic breast cancer. Predominant site of metastases was the liver. Primary endpoints were response and time to progression (TTP); secondary endpoints were overall survival (OS) and tolerability. RESULTS: Median age prior to treatment was 59 years. A median of 6 treatment cycles were administered per patient. Clinical benefit rate amounted to 64%. A mean TTP of 9 months and a mean OS of 14 months were found. Main clinical signs of nonhematological toxicity were stomatitis, nausea, and diarrhea. Grade III/IV hematotoxicity was seen in only 9 patients. 16 patients showed clinical signs of liver dysfunction. A clinical benefit could be achieved in 8 of these patients. CONCLUSION: MiFoFU combination chemotherapy is a well-tolerated treatment alternative in the palliative therapy of patients with liver metastases from breast cancer. Particularly in patients with hepatic dysfunction, this regimen seems to represent a helpful treatment option.

Weekly administration of bendamustine as salvage therapy in metastatic breast cancer: final results of a phase II study.

Single-agent bendamustine has shown promise in the treatment of metastatic breast cancer. As toxicity was low after weekly administration of this drug in other solid tumors, the present double-center phase II trial was conducted to evaluate the efficacy and toxicity of weekly bendamustine as salvage treatment in metastatic breast cancer. A total of 34 patients with anthracycline (88%) and/or taxane (71%) pretreated for metastatic breast cancer received 60 mg/m bendamustine on day 1, 8 and 15 every 28 days for six cycles. In addition, 10 patients with HER2/neu-overexpressing tumors either continued (five patients) or started treatment with 2 mg/kg trastuzumab weekly (loading dose 4 mg/kg) at study entry. Patients had predominantly visceral disease and had received one (88%) or two chemotherapy regimens for metastatic breast cancer. All patients were eligible for toxicity and 27 for response evaluation. No grade 3 or 4 hematologic toxicity occurred. Only three patients experienced grade 3 nonhematologic toxicity. Five patients (19%) reached a partial response. Stable disease for at least 6 months was achieved in eight patients, for a clinical benefit rate of 48%. The median progression-free survival and median overall survival were 6 months (range, 1-16) and 15 months (range, 2-28), respectively. We conclude that weekly bendamustine is a valid treatment option in patients with anthracycline-pretreated and/or taxanepretreated metastatic breast cancer; in particular, due to its low toxicity profile. Future trials should evaluate higher single doses of bendamustine in a weekly schedule.

Serum levels of hepatocyte growth factor/scatter factor in patients with liver metastases from breast cancer.

OBJECTIVE: Recent studies have shown that the pleiotropic cytokine hepatocyte growth factor/scatter factor (HGF/SF) and its receptor c-Met play major roles in the malignant progression of numerous tumors. For patients with breast cancer liver metastases, increased serum levels of HGF/SF have been reported. We studied the relationship between the clinical course of the disease and the serum levels of HGF/SF in such patients. METHODS: We examined 51 patients treated for breast cancer liver metastases. Serum concentrations of HGF/SF were measured before each therapy cycle and compared to the corresponding tumor marker levels. RESULTS: Mean serum levels of HGF/SF in patients with liver metastases were increased above the reported reference levels of primary breast cancer patients. Serum levels of HGF/SF were correlated with tumor marker levels in a logarithmic relation (r = 0.47, p < 0.001). In some cases serum concentrations of HGF/SF changed similarly to the course of the corresponding tumor markers. CONCLUSIONS: Serum levels of HGF/SF are associated with the clinical course of metastatic breast cancer patients with liver metastases. Further studies are required to clarify the potential value of the HGF/SF serum concentration as a tumor marker. HGF/SF and its receptor c-Met should be further evaluated as therapeutic targets.

Activity and tolerability of a combined palliative chemotherapy with mitomycin C, folinate, and 5-Fluorouracil in patients with advanced breast cancer after intensive pretreatment: a retrospective analysis.

OBJECTIVES: The aim of this retrospective study was to evaluate the activity and toxicity of a combined chemotherapy containing mitomycin, folinate, and 5-fluorouracil (MiFoFU) in patients with advanced metastatic breast cancer and reduced performance status, ie, elderly patients or heavily pretreated patients. METHODS: We studied the charts of 76 patients with progressive metastatic breast cancer who received MiFoFU chemotherapy at our institution between 1997 and 2003. Primary end points were response and time-to-progression (TTP); secondary end points were overall survival (OAS) and tolerability. RESULTS: Median age was 57 years. Seventeen patients had > or =2 palliative cytostatic treatments before; 19 patients were older 65 years. Patients received a median of 6 cycles. Clinical benefit rate was 58%. After MiFoFU, median TTP and OAS were 8 months and 14 months, respectively. Main nonhematologic toxicity was stomatitis (grade I/II, 21%) and diarrhea (grade I/II, 37%). Grade III/IV hematotoxicity was seen in 18 patients (24%). CONCLUSIONS: A combined MiFoFU chemotherapy is a well-tolerated treatment option in the palliative therapy for patients with metastatic breast cancer. In particular, the favorable efficacy/toxicity ratio in intensively pretreated or elderly patients makes this combination a reasonable alternative within these settings.

Prognostic factors for patients with liver metastases from breast cancer.

BACKGROUND: The prognosis of patients with liver metastases from breast cancer is commonly poor. After initial diagnosis of hepatic metastases, a median survival time of 1-20 months can be expected. The definition of prognostic factors for such patients may influence therapeutic decisions. In particular, the characterization of patients who can expect long-term survival could assist in optimizing treatment. METHODS: We retrospectively studied n = 350 patients with liver metastases from breast cancer. All patients were stratified following their survival after occurrence of liver metastases. Kaplan-Meier studies were performed, as well as univariate and multivariate analyses of several clinical, histopathological and therapeutic factors. RESULTS: Median survival time was 14 months. N = 66 (18.9%) patients survived longer than 36 months after the primary diagnosis. Multivariate analysis showed prognostic relevance for the time interval between the primary diagnosis of breast cancer and the initial diagnosis of hepatic metastases (p < 0.05). Furthermore, prognostic relevance was found for the pattern of metastasization (p < 0.05) and for signs of hepatic dysfunction (ascites, jaundice, p < 0.005). Univariate analysis showed a prognostic benefit for patients with an expression of Ki-67 < 20%, p53 < 50% and a positive hormonal receptor status. Patients who received a regional therapy survived on average longer than patients who were only treated systemically (33 versus 11 months, p < 0.001). CONCLUSIONS: Consideration of prognostic implications of the described parameters may help to find the most appropriate treatment for patients with liver metastases from breast cancer. The possibility of local therapeutic interventions should be considered in a defined subgroup.

Long-term remission of excessive liver metastases in a breast cancer patient with chronic alcohol abuse using a monotherapy with trastuzumab.

We report on the successful treatment of a 43-year-old breast cancer patient with excessive liver metastases and chronic alcohol abuse. After first occurrence of hepatic metastases, systemic and interventional therapies were performed, and resulted in short-term partial remission. Finally, an excessive progression of the hepatic metastases was diagnosed. A systemic therapy with weekly trastuzumab (Herceptin) infusions was induced and a complete remission was achieved that is ongoing now for over 45 months.

Endoscopic stenting of the common bile duct allows successful treatment of a breast cancer patient with excessive liver metastases.

The treatment of a jaundiced patient with hyperbilirubinaemia due to breast cancer liver metastases is still a challenging problem. The associated hepatic dysfunction often represents a limiting factor for delivering standard dose chemotherapy. We report on the successful treatment of a jaundiced patient with excessive, recurrent liver metastases from breast cancer, using a combined chemotherapy of mitomycin and 5-fluorouracil after endoscopic stenting of the common bile duct.