Prostaglandin E2 labour induction with intravaginal (Minprostin) versus intracervical (Prepidil) administration at term: randomized study of maternal and neonatal outcome and patient's perception using the osgood semantic differential scales.

AIM: To compare the efficacy, safety, and patient's perception of two prostaglandin E2 application methods for induction of labour. METHOD: Above 36th weeks of gestation, all women, who were admitted to hospital for induction of labour, were prospectively randomised to intravaginal 1 mg or intracervical 0.5 mg irrespective of cervical Bishop score. The main outcome variables were induction-to-delivery interval, number of foetal blood samples, PDA rate, rate of oxytocin augmentation, rate of vaginal delivery, and patient's perception using semantic differential questionnaire. RESULTS: Thirty-nine patients were enrolled in this study. There was no statistical significant difference between the two groups in regard to perceptions of induction. The median induction delivery time using intravaginal versus intracervical administration was 29.9 versus 12.8 hours, respectively (P = 0.04). No statistically difference between the groups was detected in regard to parity, gestation age, cervical Bishop score, number of foetal blood samples, PDA rate, rate of oxytocin augmentation, and mode of birth. SUMMARY: Irrespective of the cervical Bishop Score, intracervical gel had a shorter induction delivery time without impingement on the women's perception of induction.

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.

Acceptance of oral chemotherapy in breast cancer patients - a survey study.

BACKGROUND: Oral (p.o.) chemotherapy treatments gained increasing importance in the palliative treatment of metastatic breast cancer (MBC). Aim of this survey was to evaluate the acceptance of p.o. treatment and patients' individual attitudes towards it. METHODS: A specific 14 item-questionnaire was designed. Patients suffering from breast cancer receiving a newly launched p.o. or i.v. chemotherapy treatment were prospectively evaluated during 4 months of time. 224 questionnaires using descriptive statistics, chi-square test, Spearman correlation were evaluated. RESULTS: Patients' median age was 54 years, 164 received i.v., 60 p.o therapy. 89% with p.o. and 67% with i.v. regimens would choose p.o. over i.v. therapy, if equal efficacy is guaranteed. Significant differences were especially found in terms of personal benefit (55% i.v., 92% p.o.), reduced feeling of being ill due to p.o. treatment (26% i.v., 65% p.o.), better coping with disease due to p.o. therapy (36% i.v., 68% p.o.). Side effects were significantly less often reported under p.o. treatment (19% p.o. vs. 53% i.v.) CONCLUSION: P.o. chemotherapy shows a high acceptance in MBC patients under palliative therapy. Compliance can be achieved in particular through a differentiated indication, patient education and competent support along a p.o. treatment.

Phase II study evaluating consolidation whole abdominal intensity-modulated radiotherapy (IMRT) in patients with advanced ovarian cancer stage FIGO III--the OVAR-IMRT-02 Study.

BACKGROUND: The prognosis for patients with advanced FIGO stage III epithelial ovarian cancer remains poor despite the aggressive standard treatment, consisting of maximal cytoreductive surgery and platinum-based chemotherapy. The median time to recurrence is less than 2 years, with a 5-years survival rate of -20-25%. Recurrences of the disease occur mostly intraperitoneally.Ovarian cancer is a radiosensitive tumor, so that the use of whole abdominal radiotherapy (WAR) as a consolidation therapy would appear to be a logical strategy. WAR used to be the standard treatment after surgery before the chemotherapy era; however, it has been almost totally excluded from the treatment of ovarian cancer during the past decade because of its high toxicity. Modern intensity-modulated radiation therapy (IMRT) has the potential of sparing organs at risk like kidneys, liver, and bone marrow while still adequately covering the peritoneal cavity with a homogenous dose.Our previous phase I study showed for the first time the clinical feasibility of intensity-modulated WAR and pointed out promising results concerning treatment tolerance. The current phase-II study succeeds to the phase-I study to further evaluate the toxicity of this new treatment. METHODS/DESIGN: The OVAR-IMRT-02 study is a single-center one arm phase-II trial. Thirty seven patients with optimally debulked ovarian cancer stage FIGO III having a complete remission after chemotherapy will be treated with intensity-modulated WAR as a consolidation therapy.A total dose of 30 Gy in 20 fractions of 1.5 Gy will be applied to the entire peritoneal cavity including the liver surface and the pelvic and para-aortic node regions. Organ at risk are kidneys, liver (except the 1 cm-outer border), heart, vertebral bodies and pelvic bones.Primary endpoint is tolerability; secondary objectives are toxicity, quality of life, progression-free and overall survival. DISCUSSION: Intensity-modulated WAR provides a new promising option in the consolidation treatment of ovarian carcinoma in patients with a complete pathologic remission after adjuvant chemotherapy. Further consequent studies will be needed to enable firm conclusions regarding the value of consolidation radiotherapy within the multimodal treatment of advanced ovarian cancer. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01180504.

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.

Intensity-modulated whole abdominal radiotherapy after surgery and carboplatin/taxane chemotherapy for advanced ovarian cancer: phase I study.

PURPOSE: To assess the feasibility and toxicity of consolidative intensity-modulated whole abdominal radiotherapy (WAR) after surgery and chemotherapy in high-risk patients with advanced ovarian cancer. METHODS AND MATERIALS: Ten patients with optimally debulked ovarian cancer International Federation of Gynecology and Obstetrics Stage IIIc were treated in a Phase I study with intensity-modulated WAR up to a total dose of 30 Gy in 1.5-Gy fractions as consolidation therapy after adjuvant carboplatin/taxane chemotherapy. Treatment was delivered using intensity-modulated radiotherapy in a step-and-shoot technique (n = 3) or a helical tomotherapy technique (n = 7). The planning target volume included the entire peritoneal cavity and the pelvic and para-aortal node regions. Organs at risk were kidneys, liver, heart, vertebral bodies, and pelvic bones. RESULTS: Intensity-modulated WAR resulted in an excellent coverage of the planning target volume and an effective sparing of the organs at risk. The treatment was well tolerated, and no severe Grade 4 acute side effects occurred. Common Toxicity Criteria Grade III toxicities were as follows: diarrhea (n = 1), thrombocytopenia (n = 1), and leukopenia (n = 3). Radiotherapy could be completed by all the patients without any toxicity-related interruption. Median follow-up was 23 months, and 4 patients had tumor recurrence (intraperitoneal progression, n = 3; hepatic metastasis, n = 1). Small bowel obstruction caused by adhesions occurred in 3 patients. CONCLUSIONS: The results of this Phase I study showed for the first time, to our knowledge, the clinical feasibility of intensity-modulated whole abdominal radiotherapy, which could offer a new therapeutic option for consolidation treatment of advanced ovarian carcinoma after adjuvant chemotherapy in selected subgroups of patients. We initiated a Phase II study to further evaluate the toxicity of this intensive multimodal treatment.

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.

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.

Adjuvant whole abdominal intensity modulated radiotherapy (IMRT) for high risk stage FIGO III patients with ovarian cancer (OVAR-IMRT-01) - Pilot trial of a phase I/II study: study protocol.

BACKGROUND: The prognosis for patients with advanced epithelial ovarian cancer remains poor despite aggressive surgical resection and platinum-based chemotherapy. More than 60% of patients will develop recurrent disease, principally intraperitoneal, and die within 5 years. The use of whole abdominal irradiation (WAI) as consolidation therapy would appear to be a logical strategy given its ability to sterilize small tumour volumes. Despite the clinically proven efficacy of whole abdominal irradiation, the use of radiotherapy in ovarian cancer has profoundly decreased mainly due to high treatment-related toxicity. Modern intensity-modulated radiation therapy (IMRT) could allow to spare kidneys, liver, and bone marrow while still adequately covering the peritoneal cavity with a homogenous dose. METHODS/DESIGN: The OVAR-IMRT-01 study is a single center pilot trial of a phase I/II study. Patients with advanced ovarian cancer stage FIGO III (R1 or R2< 1 cm) after surgical resection and platinum-based chemotherapy will be treated with whole abdomen irradiation as consolidation therapy using intensity modulated radiation therapy (IMRT) to a total dose of 30 Gy in 1.5 Gy fractions. A total of 8 patients will be included in this trial. For treatment planning bone marrow, kidneys, liver, spinal cord, vertebral bodies and pelvic bones are defined as organs at risk. The planning target volume includes the entire peritoneal cavity plus pelvic and para-aortic node regions. DISCUSSION: The primary endpoint of the study is the evaluation of the feasibility of intensity-modulated WAI and the evaluation of the study protocol. Secondary endpoint is evaluation of the toxicity of intensity modulated WAI before continuing with the phase I/II study. The aim is to explore the potential of IMRT as a new method for WAI to decrease the dose to kidneys, liver, bone marrow while covering the peritoneal cavity with a homogenous dose, and to implement whole abdominal intensity-modulated radiotherapy into the adjuvant multimodal treatment concept of advanced ovarian cancer FIGO stage III.

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.