Single large inguinal lymph node metastasis in human papillomavirus-induced early invasive vulvar cancer of the anterior fourchette in two young women.

The incidence of human papillomavirus (HPV)-induced vulvar cancer in young women is increasing and often presents as microinvasive or early invasive tumors in a grade 3 vulvar intraepithelial neoplasia. So far, the risk of lymph node metastases in early invasive vulvar carcinoma (depth of invasion 1.1-2.0 mm) is reported to be less than 8%. We present 2 cases of young women with early invasive vulvar cancers (depth of invasion 1.5 and 2.0 mm) induced by HPV 16 and 42. In both cases, the cancers are located between the clitoris and urethra and are each accompanied by one groin macro-metastatic lymph node. This case report highlights the necessity for complete inguinofemoral lymphadenectomy and/or adequate radiation therapy of the groin in early invasive tumors in young women to prevent cancer recurrence in the groin. Additionally, the indication for a sentinel node procedure in these specific cases requires particular caution.

Invasive breast cancer cells exhibit increased mobility of the actin-binding protein CapG.

The CapG protein, a Gelsolin-related actin-binding protein, is expressed at higher levels in breast cancer, especially in metastasizing breast cancer, than in normal breast epithelium. Furthermore, it is known that an increased expression of the CapG protein triggers an increase in cell motility. According to in vitro experiments, it was supposed that it is the nuclear fraction of the protein, which causes the increase in cell motility. Here, we examined the dynamical distribution of the CapG protein within the living cell, i.e. the import of the CapG protein into the nucleus. The nuclear import kinetics of invasive, metastasizing breast cancer cells were compared to the import kinetics of non-neoplastic cells similar to normal breast epithelium. FRAP kinetics showed a highly significant increase in the recovery of photobleached CapG-eGFP in the cancer cells, so that a differentiation of invasive, metastasizing cells and non-invasive, non-metastasizing cells on the basis of transport processes of the CapG protein between the nucleus and the cytoplasm seems to be possible. Comprehension of the mobility and compartmentalization of the CapG protein in normal and in cancer cells in vivo could constitute a new basis to characterize the invasiveness and metastasizing potential of breast cancer.

An unusual case of advanced bilateral male breast cancer.

BACKGROUND: Breast cancer in men is an uncommon disease. Little is known about its etiology, clinical behavior, treatment, and outcome. Retrospective data indicate that stage- and age-matched male and female breast cancer is similar in presentation. The aim is to find an adequate treatment for male breast cancer, which is not just extrapolated from its female counterpart. CASE REPORT: We present the history of a 41-year-old man who was diagnosed with pT2 (3 cm) breast cancer in 2001. After mastectomy without axillary dissection, 4 cycles of adjuvant epirubicin and cyclophosphamide and radiation therapy were performed followed by hormonal treatment with tamoxifen until 2003. In 2003, 2004, 2005, and 2006, there were relapses with skin metastases, treated with several courses of chemotherapy. In 2006, an inflammatory carcinoma in the contralateral breast was revealed during the course of epirubicin chemotherapy. In May 2007, the patient passed away from extensive tumor progression despite numerous attempts of local and systemic chemotherapeutic treatment. CONCLUSION: Here, an unusual case of male breast cancer is reported. It was first diagnosed at the age of 41 years, which is relatively young for male breast cancer. Although the treatment was started at an early stage, several relapses and contralateral breast cancer occurred within 5 years and could no be controlled.

Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial.

BACKGROUND: Breast cancer with extensive axillary-lymph-node involvement has a poor prognosis after conventional treatment. In trials with historical controls, high-dose chemotherapy produced improved outcomes. We compared an intensive double-cycle high-dose chemotherapy regimen with an accelerated conventionally dosed regimen in high-risk breast cancer in a multicentre trial. METHODS: Patients with at least nine positive nodes were randomly assigned either two courses of accelerated (2-week intervals, with filgrastim support), conventionally dosed epirubicin and cyclophosphamide followed by two courses of high-dose chemotherapy (epirubicin, cyclophosphamide, and thiotepa supported by peripheral-blood progenitors) or four identical cycles of epirubicin and cyclophosphamide followed by three cycles of accelerated cyclophosphamide, methotrexate, and fluorouracil. The primary endpoint was event-free survival. Analyses were done both by intention to treat and per protocol. FINDINGS: 403 patients were enrolled; 201 were assigned high-dose chemotherapy and 202 conventional treatment. The mean number of positive nodes was 17.6, and median follow-up was 48.6 months. 4-year event-free survival (intention-to-treat analysis) was 60% (95% CI 53-67) in the high-dose chemotherapy group and 44% (37-52) in the control group (p=0.00069). The corresponding overall survival was 75% (69-82) versus 70% (64-77; p=0.02). There were no treatment-related deaths. INTERPRETATION: Our finding of significant improvements in both event-free and overall survival for high-dose chemotherapy compared with a dose-dense conventional regimen contrasts with the results of other studies. The discrepancy might be due partly to design differences (tandem, brief induction) between our regimen and those studied in other trials. This approach merits further study.

Acceptance for preventive genetic testing and prophylactic surgery in women with a family history of breast and gynaecological cancers.

The fear of family members of patients with breast or gynaecologic cancer of developing a similar disease is often high. We investigated the acceptance for genetic testing of untested women with a positive family history and their attitude for prophylactic surgery. A total of 659 women with a familial history of breast or gynaecologic cancer were asked to answer a questionnaire regarding their interest in genetic testing for breast cancer as well as for gynaecologic carcinoma and their interest in prophylactic surgery. Genetic testing is seen to be accepted by the majority of participants: 85.0 and 77.8% chose a genetic test for breast and gynaecologic cancer, respectively. Prophylactic surgery was much less chosen; prophylactic mastectomy as well as prophylactic hysterectomy or bilateral prophylactic oophorectomy was an option only for a minority of women. Genetic testing for risk assessment of healthy women with a positive family history was observed to be accepted by a majority of participants. Prophylactic surgery was an option only for a minority and was not acceptable for most of the women.

Awareness of general and personal risk factors for uterine cancer among healthy women.

Participation rates in gynaecological cancer screening are influenced by different factors. The knowledge of general and personal risk factors for uterine cancer among women might influence their interest in gynaecological cancer screening. Two thousand nine hundred women in 23 gynaecological outpatient services were invited to answer a structured questionnaire regarding general and personal risk factors for cervical and endometrial carcinoma; 2108 women participated. Women with a history of cancer were excluded from the study. It was found that levels of knowledge about uterine carcinoma were low. Only 47.4% of women knew the difference between the sites of origin of cervical and endometrial cancer. Seventy-seven per cent of participants assessed their knowledge about uterine malignancies as insufficient; 96.3% would appreciate more information about uterine cancer. Younger women were significantly less well informed than postmenopausal women. Known risk factors such as smoking or human papillomavirus (HPV) infection as factors for cervical cancer were underestimated; most women assessed genetic factors as most important for the development of uterine cancer. The level of information about risk factors as well as general facts about gynaecological cancer in women is low. Ameliorating this lack of information might influence the perception of uterine cancer and result in higher participation rates in gynaecological cancer screening.

Age of uptake of early cancer detection facilities by low-risk and high-risk patients with familial breast and ovarian cancer.

INTRODUCTION: Some 5-10% of all cases of breast cancer and ovarian cancer have a hereditary genesis. In the setting of an interdisciplinary cancer genetics clinic, a study of the age at which patients first take advantage of early cancer detection (ECD) facilities was conducted in order to assess the influence of familial risk on health issues. METHODS: The study included 556 women who fulfilled the inclusion criteria (IC) for genetic analysis of the BRCA1 and BRCA2 genes, as well as 205 who did not meet these criteria but attended the primary consultation. RESULTS: Consulters who met the inclusion criteria took advantage of nearly all methods of ECD at an earlier time than women who did not. A comparison of consulters with or without breast cancer showed that those without breast cancer participated in all methods of ECD at an earlier time. CONCLUSION: Methods of improving and increasing participation in ECD facilities, and of encouraging women who are at risk to start on such programs at a younger age, need to be discussed. In this study, familial risk already resulted in a younger age of uptake of ECD facilities.

Radical resection of invasive endometriosis with bowel or bladder involvement--long-term results.

OBJECTIVE: With the present study we wanted to evaluate the effect of a radical resection of bowel and bladder endometriosis with respect to relief of pain symptoms and long-term effects. STUDY DESIGN: Retrospectively we analyzed 23 patients undergoing bowel or bladder resection for infiltrating endometriosis between 1995 and 2004. Chart review was performed and data were analyzed with respect to pain symptoms, fertility, type of surgery, operative morbidity and mortality. At 1, 3 and 5 years of follow-up patients were asked to evaluate their symptoms based on a visual analogue pain scale (0: no pain, 10: most severe pain). Results were compared using the Student's t-test. RESULTS: Leading symptoms were chronic pelvic pain (17/23, 73.9%), dysmenorrhea (11/23, 47.8%), dyspareunia (6/23, 26.1%), infertility (4/23, 17.4%) and dyschezia (4/23, 17.4%). Three patients (13%) had abdominal hysterectomy, 5 (21.7%) LSO (n = 2) or BSO (n = 3), 18 (78.3%) anterior rectal resection, 4 (17.4%) sigmoid resection, 2 (8.6%) segmental bladder resection and one patient (4.3%) cecal resection. Major complications requiring re-operation occurred in three patients (2x postoperative bleeding, 1x anastomosis break-down). During follow-up (mean 40.5 months) 21 of the 23 patients (91.3%) had a persistent improvement of symptoms, 8 of the 23 (34.8%) had recurrent symptoms with a mean symptom-free interval of 40.4 months after surgery (24-60 months). No patient developed dyspareunia or dyschezia during follow-up. Overall cure rate was 73.9%. Four patients became pregnant (23%). Average pain scores increased during follow-up period but still remained significantly below the initial score (p < 0.001). CONCLUSION: Radical surgery for deep endometriosis with bowel or bladder involvement leads to a reliable and persistent relief of pain symptoms. Especially deep dyspareunia and dyschezia might be eliminated by this procedure.

Novel cGMP liposomal vectors mediate efficient gene transfer.

Viral vector systems are the most commonly used gene transfer tools for clinical gene therapy. However, lipofection systems are potential alternatives because of lower immunogenicity and easier cGMP production, but in vivo stability and transduction efficacy need to be improved. Therefore, we investigated gene transduction efficiency of our novel cGMP cationic lipids, CCQ22 and CCQ32, by FACS analysis. Toxicity analysis was performed to determine the cytotoxic side effects of the novel lipids. To evaluate the stability of the compounds in the context of local delivery to patients with intraperitoneally metastatic ovarian cancer, gene transfer was also tested in the presence of malignant ascites. Our novel cGMP standard lipids mediated gene transfer rates of more than 50%. However, for most cell lines cytotoxic side effects were similar to our reference lipofection system. In general, ascites had no major influence on gene transduction rates with the novel lipids. Our results suggest that CCQs may compare favorably with commercially available lipofection systems. These promising results facilitate further analysis of the compounds.

Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma.

PURPOSE: Alternative and complementary therapeutic strategies need to be developed for metastatic breast cancer. Virotherapy is a novel therapeutic approach for the treatment of cancer in which the replicating virus itself is the anticancer agent. However, the success of virotherapy has been limited due to inefficient virus delivery to the tumor site. The present study addresses the utility of human mesenchymal stem cells (hMSCs) as intermediate carriers for conditionally replicating adenoviruses (CRAds) to target metastatic breast cancer in vivo. EXPERIMENTAL DESIGN: HMSC were transduced with CRAds. We used a SCID mouse xenograft model to examine the effects of systemically injected CRAd loaded hMSC or CRAd alone on the growth of MDA-MB-231 derived pulmonary metastases (experimental metastases model) in vivo and on overall survival. RESULTS: Intravenous injection of CRAd loaded hMSCs into mice with established MDA-MB-231 pulmonary metastatic disease homed to the tumor site and led to extended mouse survival compared to mice treated with CRAd alone. CONCLUSION: Injected hMSCs transduced with CRAds suppressed the growth of pulmonary metastases, presumably through viral amplification in the hMSCs. Thus, hMSCs may be an effective platform for the targeted delivery of CRAds to distant cancer sites such as metastatic breast cancer.

Maternal IVS1-401 T allele of the estrogen receptor alpha is an independent predictor of late fetal loss.

OBJECTIVE: To investigate whether sequence variants in the gene encoding for estrogen receptor alpha (ER-alpha) are risk determinants for fetal loss. DESIGN: Case-control study. SETTING: University medical center. PATIENT(S): One hundred four women with a history of fetal loss and 277 healthy women with at least one previous pregnancy and no previous fetal loss. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The IVS1-401C/T polymorphism of the human ER-alpha, the G1691A mutation of the factor V gene (factor V Leiden), the G20210A mutation of the prothrombin gene, and the C677T polymorphism of the methylenetetrahydrofolate-reductase (MTHFR) gene were determined by polymerase chain reaction. RESULT(S): In the subgroup analysis of women with at least one late miscarriage (n = 70), the prevalences of the ER-alpha IVS1-401 T allele (T/T vs. C/C, odds ratio [OR]: 2.85, P=.018; T/T + C/T vs. C/C, OR: 2.28, P=.043) and of heterozygous factor V Leiden (OR, 3.2; P=.002) were significantly higher among women with late fetal loss than among healthy women. Carriers of both risk determinants have an at-least additive increase in risk for late abortions (OR, 7.0; P=.0004). The population of all late abortions that would be attributable to the genetic variants (population attributable risk) was 13.9% for factor V Leiden and 49.2% for the ER-alpha IVS1-401 T allele. CONCLUSION(S): Women with the IVS1-401 T allele of the ER-alpha and/or factor V Leiden are at increased risk for late fetal loss.

Twin-to-twin transfusion syndrome complicated by spontaneous mid-trimester uterine rupture.

Twin-to-twin-transfusion syndrome (TTS) is a serious complication in about 15% of monochorionic twin pregnancies. In severe TTS, the anemic pump twin (donor) develops anhydramnios and the hypervolemic recipient tense polyhydramnios, which often first calls attention to the condition. The most common problems of TTS are fetal complications such as single or double intrauterine demise, spontaneous abortion, prematurity due to uterine distension leading to contractions, preterm rupture of membranes and ultimately neurological impairment. We report a pregnancy with TTS in which rapid development of polyhydramnios led to rupture of a scarred uterus at 19 weeks' gestation. To the best of our knowledge, this is the first report of a potentially lethal maternal complication of TTS.