Nicolai Maass

mMaspin: the mouse homolog of a human tumor suppressor gene inhibits mammary tumor invasion and motility.

BackgroundThe human maspin gene encodes a protein in the serine proteinase inhibitor (serpin) family with tumor-suppressing functions in cell culture and in nude mice. In order to examine the role of maspin in an intact mammal, we cloned and sequenced the cDNA of mouse maspin. The recombinant protein was produced and its activity in cell culture was assessed.Materials and MethodsMouse maspin (mMaspin) was cloned by screening a mouse mammary gland cDNA library with the human maspin cDNA probe. Northern blot analysis was used to examine the expression patterns in mouse tissues, mammary epithelial cells, and carcinomas. Recombinant mMaspin protein was produced in E. coli. Invasion and motility assays were used to assess the biological function of mMaspin.ResultsmMaspin is 89% homologous with human maspin at the amino acid level. Like its human homolog, mMaspin is expressed in normal mouse mammary epithelial cells and down-regulated in mouse breast tumor cell lines. The expression is altered at different developmental stages in mammary gland. Addition of the recombinant mMaspin protein to mouse tumor cells was shown to inhibit invasion in a dose-dependent manner. As with the human protein, recombinant mMaspin protein also inhibited mouse mammary tumor motility. Deletion in the putative mMaspin reactive site loop (RSL) region resulted in the loss of its inhibitory functions.ConclusionsmMaspin is the mouse homolog of a human tumor suppressor gene. The expression of mMaspin is down-regulated in tumor cells and is altered at different developmental stages of mammary gland. mMaspin has inhibitory properties similar to those of human maspin in cell culture, suggesting that the homologous proteins play similar physiological roles in vivo.

Everolimus as treatment for breast cancer patients with bone metastases only: results of the phase II RADAR study

AbstractPurposenEverolimus has shown to stop formation and activity of osteoclasts. Breast cancer patients with bone metastases only are candidates for effective but low toxic treatment.Patients and methodsWe evaluated everolimus in a double-blind, placebo-controlled, phase II, randomized discontinuation study in breast cancer patients with HER2 negative breast cancer patients with bone metastases only. After being stable on 8xa0weeks of everolimus 10xa0mg/day, patients were randomized to everolimus-continuation or placebo. Primary outcome was time (from randomization) to progression (TTP). Seventy-six patients would have had to be randomized to show a hazard ration (HR) of 0.5 for everolimus-continuation.ResultsEighty-nine patients were enrolled in 4xa0years. Thirty-nine patients with SD after 8xa0weeks on everolimus were randomized to everolimus-continuation or placebo. TTP in patients with everolimus-continuation was 37.0 (95xa0% CI 16.7–40.3) versus 12.6xa0weeks (95xa0% CI 7.1–17.9) with placebo [HR 0.554 (95xa0% CI 0.282–1.09) pxa0=xa00.0818], adjusted for endocrine therapy [HR 0.464 (95xa0% CI 0.226–0.954) pxa0=xa00.037]. TTP in everolimus responders (nxa0=xa06) was 86xa0weeks.ConclusionThe RADAR study is mainly hypothesis generating. It suggests that everolimus has single-agent activity, and patients with bone metastases only may retrieve long-term benefit from everolimus if they do not progress within 8xa0weeks of treatment.

Phase III study on efficacy of taxanes plus bevacizumab with or without capecitabine as first-line chemotherapy in metastatic breast cancer

Taxanes (T) plus bevacizumab (B) and taxanes plus capecitabine (X) showed better progression-free survival (PFS) compared to taxanes alone. Since life-threatening or highly symptomatic situations require polychemotherapy in metastatic breast cancer (MBC), combination of taxanes, capecitabine plus bevacizumab appears reasonable. TABEA (NCT01200212), a prospectively randomized, open-label, phase III trial compares taxanes (paclitaxel 80xa0mg/m2 i.v. d1,8,15 q22 or docetaxel 75xa0mg/m2 i.v. d1 q22) plus bevacizumab (15xa0mg/kg i.v. d1 q22) with (TBX) or without capecitabine (TB, 1800xa0mg/m2 daily d1–14 q22) as first-line therapy in MBC. Histologically confirmed HER2-negative, locally advanced or MBC patients with a chemotherapy indication and measurable or non-measurable target lesions (RECIST criteria) were included. Primary objective was PFS. Secondary objectives were response rate and duration, clinical benefit rate (complete response, partial response, stable disease ≥24xa0weeks), 3-year overall survival, PFS in patients ≥65xa0years, toxicity, and compliance. We assumed 10 and 13.3xa0months PFS for TB and TBX, respectively (HRxa0=xa00.75), requiring 432 patients and 386 events. Preplanned interim futility and safety analyses after 100 events in 202 patients showed no efficacy benefit and higher toxicity for TBX. Recruitment and therapy were stopped following advice from the IDMC. Final analysis revealed a HR 1.13 [95xa0%CI 0.806–1.59], Pxa0=xa00.474, for PFS. Overall grade 3–4 adverse event (77.3 vs. 62.1xa0%, Pxa0=xa00.014) and serious adverse event (40.0 vs. 30.2xa0%, Pxa0=xa00.127) rates were higher for TBX after 26.1xa0months median follow-up, with six deaths for TBX versus 1 for TB. Adding capecitabine to TB cannot be recommended as first-line therapy in MBC.

Nilotinib in Combination with Carboplatin and Paclitaxel Is a Candidate for Ovarian Cancer Treatment

Purpose: Nilotinib is a selective tyrosine kinase inhibitor of c-Kit, Abl and platelet-derived growth factor receptor-α/β. To evaluate nilotinibs potential use as a treatment of human ovarian cancer, we tested nilotinibs preclinical activity in ovarian cancer cell lines with different tyrosine kinase expression patterns. Methods: The effects of nilotinib on ovarian cancer cell growth were studied alone and in combination with carboplatin and paclitaxel. Proapoptotic and antimigratory effects were examined using TUNEL and migration assays. Results: Nilotinib alone and in combination with carboplatin and paclitaxel significantly inhibited cell growth in PDGFR-α-positive ovarian cancer cell lines. The combination of nilotinib with carboplatin and paclitaxel showed synergistic effects on cell proliferation. Nilotinib treatment led to the inhibition of cell migration alone and in combination with carboplatin and paclitaxel. Apoptosis induction occurred in response to nilotinib that increased in combination with carboplatin. Conclusions: Nilotinib may be a feasible targeted therapy option for the treatment of ovarian cancer.

Final safety and efficacy analysis of a phase I/II trial with imatinib and vinorelbine for patients with metastatic breast cancer.

Background: Imatinib is a tyrosine kinase inhibitor of BCR-ABL, ABL, PDGFR-α and -β, KIT, and DDR. In solid tumors, it inhibits proliferation and invasiveness and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in metastatic breast cancer (MBC). This study evaluates the safety and efficacy of imatinib and vinorelbine in combination. Methods: In a prospective, open-label, phase I/II trial, 400 mg imatinib p.o. daily (corrected from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels of 10, 15, 20, and 25 mg/m2 (each n ≥ 5) to treat patients with MBC (expressing PDGFR-α and/or -β, and/or KIT). The last patient of each level was treated for >28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and nonhematological toxicity, and clinical efficacy (data cutoff: November 18, 2011). A total of 33 patients have been enrolled, and all dose levels have been fully recruited. One patient is still on study medication. A translational subprotocol is ongoing. Results: All 33 included patients are evaluable for safety (32 within the ITT population). Eleven patients were excluded early from the study (progressive disease, toxicity, and withdrawal of consent). Twenty-two patients participated in the study for >28 days (‘ITT >28). Within the ITT population, the response rate [complete response (CR) and partial response (PR)] was 9.4% (n = 3), the clinical benefit rate (CBR; CR+PR+stable disease) 50% (n = 16), and the median time to progression (TTP) 155 days. A total of 21.3% of the patients were on study medication for >6 months, and 15.2% for >12 months (mean 140 days, range 15-643). Within ‘ITT >28, the response rate was 13.6%, CBR 72.7%, and median TTP 176 days. The response was independent of the receptor status (PDGFR-α, -β, and KIT). Toxicities were as follows (safety population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% peripheral neuropathy (severe 9.1%), and 36.4% dyspnea (3% severe). Four patients on trial died (nondrug-related). Conclusion: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pretreated patients suggests that this combination may be active. Although toxicities were frequent, they appeared to be manageable.

Integration and Validation of Hysteroscopy Simulation in the Surgical Training Curriculum

OBJECTIVEnThe primary objective of our study was to test the construct validity of the HystSim hysteroscopic simulator to determine whether simulation training can improve the acquisition of hysteroscopic skills regardless of the previous levels of experience of the participants. The secondary objective was to analyze the performance of a selected task, using specially designed scoring charts to help reduce the learning curve for both novices and experienced surgeons.nnnDESIGNnThe teaching of hysteroscopic intervention has received only scant attention, focusing mainly on the development of physical models and box simulators. This encouraged our working group to search for a suitable hysteroscopic simulator module and to test its validation. We decided to use the HystSim hysteroscopic simulator, which is one of the few such simulators that has already completed a validation process, with high ratings for both realism and training capacity. As a testing tool for our study, we selected the myoma resection task. We analyzed the results using the multimetric score system suggested by HystSim, allowing a more precise interpretation of the results.nnnSETTINGnBetween June 2014 and May 2015, our group collected data on 57 participants of minimally invasive surgical training courses at the Kiel School of Gynecological Endoscopy, Department of Gynecology and Obstetrics, University Hospitals Schleswig-Holstein, Campus Kiel.nnnPARTICIPANTSnThe novice group consisted of 42 medical students and residents with no prior experience in hysteroscopy, whereas the expert group consisted of 15 participants with more than 2 years of experience of advanced hysteroscopy operations.nnnRESULTSnThe overall results demonstrated that all participants attained significant improvements between their pretest and posttests, independent of their previous levels of experience (p < 0.002). Those in the expert group demonstrated statistically significant, superior scores in the pretest and posttests (p = 0.001, p = 0.006). Regarding visualization and ergonomics, the novices showed a better pretest value than the experts; however, the experts were able to improve significantly during the posttest. These precise findings demonstrated that the multimetric scoring system achieved several important objectives, including clinical relevance, critical relevance, and training motivation.nnnCONCLUSIONnAll participants demonstrated improvements in their hysteroscopic skills, proving an adequate construct validation of the HystSim. Using the multimetric scoring system enabled a more accurate analysis of the performance of the participants independent of their levels of experience which could be an important key for streamlining the learning curve. Future studies testing the predictive validation of the simulator and frequency of the training intervals are necessary before the introduction of the simulator into the standard surgical training curriculum.

Standard of care and controversies in the adjuvant endocrine treatment of hormone-responsive early breast cancer.

Hormone-responsive early breast cancer is a highly curable disease. In premenopausal women, tamoxifen (TAM) is still the standard treatment. Nowadays, up to 10 years of TAM can be safely administered, especially in women who remain premenopausal. Patients who are considered to be perimenopausal should be initially treated like premenopausal patients. Depending on their serum hormone levels, these patients can be safely switched to an aromatase inhibitor (AI) therapy once the estradiol (E2) and follicle-stimulating hormone (FSH) levels prove the established postmenopausal status. In postmenopausal women, several sequences of endocrine treatment are available. The AI therapy can be induced upfront or sequentially by switching from Tam to AI and vice versa. Extended endocrine therapy, by adding up to 5 years of letrozole after 5 years of TAM, has also been proven to be beneficial in certain patient subgroups. Genotyping of cytochromes such as CYP2D6 did not have any added value in identifying patients who are at higher risk of recurrence. Nevertheless, in all patients the side effects need to be given high consideration. New strategies developed to overcome endocrine resistance are tested in clinical studies. New co-administered drugs such as specific inhibitors of mammalian target of rapamycin (mTOR), Src, or phosphatidylinositol 3-kinase (PI3K) do improve endocrine responsiveness in meta-static disease and will eventually be introduced in the treatment of early breast cancer.

Safety and economical innovations regarding surgical treatment of fibroids

Abstract Uterine leiomyomas are the most frequent benign tumors of the female genital tract. Fibroids are associated with a variety of clinical problems, e.g. bleeding disorders, bulk-related symptoms or infertility. For women wishing to preserve their uterus, fibroids can be surgically removed by hysteroscopy, laparoscopy or laparotomy. The purpose of our review is to show that hysterectomy offers the only definitive solution. The indication for treatment has to be taken carefully after weighing up alternative treatment methods, such as expectant management, medical treatment or interventional radiologic methods, and after obtaining informed consent. The optimal method of treatment takes into account the patient’s interests and wishes and the practical feasibility in the clinical setup. Surgical skills and experience play an important role as surgical procedures on the uterus are not without risk and can lead to severe complications. The decision to operate anticipates an improvement of the initial situation; therefore, the ideal surgical approach is of utmost importance.

Fetal gender and gestational age differentially affect PCSK9 levels in intrauterine growth restriction

BackgroundMaternal and fetal Low Density Lipoprotein-Cholesterol (LDL-C) concentrations are compromised in intrauterine growth restriction (IUGR). Generally, LDL-C catabolism is under control of PCSK9 by binding to the LDL-receptor leading to its degradation. Hence, we hypothesized a role for PCSK9 in the modulation of lipid metabolism and placental transport in IUGR.Methods172 women, 70 IUGR and 102 controls were included in the study. Maternal and fetal serum PCSK9 levels and lipid profiles including LDL-C were measured. Placental LDL-receptor and PCSK9 expressions were estimated by tissue microarray immunohistochemistry, and analyzed by two blinded observers using an immunoreactivity score. Non-parametric tests and multivariate regression analyses were used for statistical estimations.ResultsPCSK9 levels in the maternal and fetal compartment independently predicted LDL-C levels (maternal compartment: adjusted R2u2009=u20090.2526; coefficient biu2009=u20090.0938, standard error sbi =0.0217, rpartialu2009=u20090.4420, t-valueu2009=u20094.323, pu2009<u20090.0001; fetal compartment: adjusted R2u2009=u20090.2929; biu2009=u20090.1156, sbi =0.020, rpartialu2009=u20090.5494, t-valueu2009=u20095.81, pu2009<u20090.0001). We did not find significant differences in maternal PCSK9 concentrations between IUGR and controls. However, we found lower fetal serum PCSK9 concentrations in IUGR than in controls (IUGR median 137.1xa0ng/mL (95% CI 94.8-160.0) vs. controls 176.8 (154.6-202.5), pu2009=u20090.0005). When subgrouping according to early onset, late onset IUGR, and fetal gender differences remained consistent only for male neonates born before 34xa0weeks of gestation. In the placenta we found no correlation between PCSK9 and LDL-receptor expression patterns. However, the LDL-receptor was significantly upregulated in IUGR when compared to controls (pu2009=u20090.0063).ConclusionsOur results suggest that PCSK9 play a role in impaired fetal growth by controlling fetal LDL-C metabolism, which seems to be dependent on gestational age and fetal gender. This underlines the need to identify subgroups of IUGR that may benefit from individualized and gender-specific pharmacotherapy in future studies.

Abdominal anatomy in the context of port placement and trocars

Although the anatomy of the human being has not changed, technical developments in operating materials and methods demand a simultaneous development in operative management. Developments in electronic and optical technologies permit many gynecological operations to be performed laparoscopically. One fundamental distinction between any other operating method and laparoscopy is the hurdle that the initial entry, whether with a needle, cannula, or trocar, is mostly performed blind. However, there is a risk that blind entry may result in vascular or organ damage. One of the difficulties associated with entry complications is that any damage may not be immediately recognized, leading to major abdominal reparative surgery, and at worst, a temporary colostomy. Therefore, the technical and operative quality of laparoscopic surgery begins with port placement and trocars. Visual access systems are available but are not yet widely used. The aim of this review was to introduce the different port placement and trocar systems as well as their correct and professional usage in correlation with the abdominal functional anatomy.