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Mutations in genes encoding DNA double-strand break (DSB) repair components, especially homologous recombination (HR) proteins, were found to predispose to breast and ovarian cancer. Beyond high penetrance risk gene mutations underlying monogenic defects, low risk gene mutations generate polygenic defects, enlarging the fraction of individuals with a predisposing phenotype. DSB repair dysfunction opens new options for targeted therapies; poly (ADP-ribose) polymerase (PARP) inhibitors have been approved for BRCA-mutated and platinum-responsive ovarian cancers. In this work, we performed functional analyses in peripheral blood lymphocytes (PBLs) using a case-control design. We examined 38 women with familial history of breast and/or ovarian cancer, 40 women with primary ovarian cancer and 34 healthy controls. Using a GFP-based test we analyzed error-prone DSB repair mechanisms which are known to compensate for HR defects and to generate chromosomal instabilities. While non-homologous end-joining (NHEJ) did not discriminate between cases and controls, we found increases of single-strand annealing (SSA) in women with familial risk vs. controls (P=0.016) and patients with ovarian cancer vs. controls (P=0.002). Consistent with compromised HR we also detected increased sensitivities to carboplatin in PBLs from high-risk individuals (P

Dysfunction of homologous recombination is a common denominator of changes associated with breast cancer-predisposing mutations. In our previous work, we identified a functional signature in peripheral blood lymphocytes from women who were predisposed that indicated a shift from homologous recombination to alternative, error-prone DNA double-strand break (DSB) repair pathways. To capture both hereditary and nonhereditary factors, we newly established a protocol for isolation and ex vivo analysis of epithelial cells, epithelial-mesenchymal transition cells (EMTs), and fibroblasts from breast cancer specimens (147 patients). By applying a fluorescence-based test system, we analyzed the error-prone DSB repair pathway microhomology-mediated end joining in these tumor-derived cell types and peripheral blood lymphocytes. In parallel, we investigated DNA lesion processing by quantitative immunofluorescence microscopy of histone H2AX phosphorylated on Ser139 focus after radiomimetic treatment. Our study reveals elevated histone H2AX phosphorylated on Ser139 damage removal in epithelial cells, not EMTs, and poly(ADP-ribose)polymerase inhibitor sensitivities, which suggested a DSB repair pathway shift with increasing patient age. Of interest, we found elevated microhomology-mediated end joining in EMTs, not epithelial cells, from patients who received a treatment recommendation of adjuvant chemotherapy, that is, those with high-risk tumors. Our discoveries of altered DSB repair activities in cells may serve as a method to further classify breast cancer to predict responsiveness to adjuvant chemotherapy and/or therapeutics that target DSB repair-dysfunctional tumors.-Deniz, M., Kaufmann, J., Stahl, A., Gundelach, T., Janni, W., Hoffmann, I., Keimling, M., Hampp, S., Ihle, M., Wiesmüller, L. In vitro model for DNA double-strand break repair analysis in breast cancer reveals cell type-specific associations with age and prognosis.

In den letzten Jahrzehnten ist die Pravalenz von Krebserkrankungen in Deutschland deutlich angestiegen, wahrend die Mortalitat bei vielen Entitaten gesunken ist. Dieser Trend fuhrt zu einer wachsenden Anzahl an Patientinnen in der onkologischen Nachsorge. Wahrend die Therapien heutzutage im Allgemeinen auf evidenzbasierten Masnahmen beruhen, stutzen sich die Empfehlungen zur Nachsorge mangels groser randomisierter Studien meist auf Konsensempfehlungen. Wahrend ein Lokalrezidiv haufig kurativ behandelt werden kann, besteht nach Detektion von Fernmetastasen meist nur die Moglichkeit einer palliativen Therapie. Die Herausforderung besteht daher in der Verknupfung sinnvoller medizinischer Masnahmen zur Erkennung eines Rezidivs bzw. symptomatischer Fernmetastasen unter Berucksichtigung der Bedurfnisse und der Lebensqualitat der Patientin. Der Artikel gibt einen Uberblick uber die aktuellen Empfehlungen zur Nachsorge von Patientinnen mit gynakologischen Tumoren, einschlieslich des Mammakarzinoms.

Nach adjuvanter Chemotherapie liegt das Risiko fur eine Ovarialinsuffizienz bei Frauen unter 40 Jahren je nach Art und Anzahl der Chemotherapiezyklen zwischen 10 und 80 %. Daher sollte jede pramenopausale Patientin mit Kinderwunsch uber dieses Risiko und die Moglichkeiten des Fertilitatserhaltes aufgeklart werden. Sowohl die Entnahme und Kryokonservierung von Ovarialgewebe als auch die hormonelle Stimulation mit nachfolgender Kryokonservierung von befruchteten und unbefruchteten Eizellen haben in den letzten Jahren vielversprechende Ergebnisse gezeigt und sollten mit den Patientinnen besprochen werden. Ob GnRH-Agonisten kombiniert oder allein verwendet werden sollten, ist weiterhin kontrovers; fur die einzelne Patientin kann dies in Abhangigkeit vom individuellen Risiko entschieden werden.

Hintergrund Ein Zusammenhang zwischen Endometriose und Infertilitat ist noch nicht zufriedenstellend geklart, auch wenn in letzter Zeit davon ausgegangen wird, dass sowohl die Eizellqualitat als auch die Eizellreserve bei Frauen mit Endometriose verandert ist. Dementsprechend fehlen bisher definierte Behandlungsalgorithmen. Es stehen z. B. individuelle hormonelle Stimulationsprotokolle mit und ohne nachfolgende assistierte Reproduktion zur Verfugung, auserdem stellt sich die Frage, ob eine operative Intervention in Hinblick auf den Kinderwunsch sinnvoll ist, also die Schwangerschaftsrate verbessert.

It is well accepted that innovation in oncology is transported through randomized clinical trials (CT), furthermore there is some evidence that patients profit from participation in CT. However, especially elderly patients aged65 usually do not have access to clinical trials; we therefore used an unselected patient cohort to investigate the following questions: (1) Is there a difference in survival parameters between study participants65 and elderly 65-80 non-participants? (2) Is guideline-adherent adjuvant treatment an equal alternative for elderly patients aged 65-80?This German retrospective multi-center cohort study included 4,142 patients (study participants65 and elderly breast cancer patients 65-80) with primary breast cancer recruited from 1992 to 2008 in 17 participating breast cancer centers.Applying the exclusion criteria, we included 960 (23.2%) study participants (PA)65 and 3,182 (76.8%) elderly65. Elderly non-participants (NPA)65 demonstrate a significantly inferior RFS [RFS: HR = 1.67; p0.001] and OS [OS: HR = 1.98; p0.001] compared to PA65. Within the elderly group, 1,868 (58.7%) patients received guideline-adherent adjuvant treatment. When comparing guideline conform elderly65 versus PA65, we found no significant difference in RFS [RFS: HR = 1.17; p = 0.218] and OS [OS: HR = 1.34; p = 0.054]. In contrast, non-guideline-adherent elderly demonstrated significantly inferior survival parameters [RFS: HR = 2.06; p0.001] [OS: HR = 2.50; p0.001] compared to65 PA.Guideline-adherent adjuvant treatment seems to be an equivalent option for elderly breast cancer patients. There is a strong association between guideline adherence and improved outcome parameters in elderly breast cancer patients.

Objective: Obesity is an important issue among fertile women as it may affect obstetric and neonatal outcomes. Methods: Obstetric and neonatal outcomes of primiparous women were retrospectively analyzed in non-obese (n=11387) and obese (n=943) women. A subgroup analysis was performed in obese women divided into three groups: Grade I obesity (Group A, n=654), Grade II obesity (Group B, n=192), and Grade III obesity (Group C, n=97). Odds ratios (OR) were expressed with the corresponding 95% confidence intervals (CI). Results: The incidence of gestational diabetes (non-obese, 1.9%; obese, 7.6%; Group C, 19.6%) and preeclampsia (non-obese, 3.3%; obese, 13.5%; Group C, 17.5%) increased with rising weight. The risk of non-elective cesarean section was significantly higher in obese women than in non-obese women (21.7% vs. 13.2%). The risk of extreme preterm birth (before 28 weeks of gestation) doubled in the Grade I obesity group (OR, 2.1; 95% CI, 1.4–3.2) and nearly tripled in women with body mass index ≥35 kg/m2 (OR, 2.9; 95% CI, 1.7–4.9). Conclusion: Pre-pregnancy obesity is associated with higher incidences of gestational diabetes and preeclampsia. Our study shows that obese women have a higher risk of non-elective cesarean section and preterm birth.

Female fertility preservation before chemotherapy has become a common issue among postpubertal and premenopausal women who desire children. Von Wolff et al. [1] recently published a practical guideline for different fertility preservation techniques, based on data from the FertiPROTEKT network database. The published practical guideline particularly addresses women with breast cancer, Hodgkin disease, or borderline ovarian tumour. The following are the different fertility preservation techniques covered: (1) hormonal stimulation and cryopreservation of unfertilised and fertilised oocytes, (2) cryopreservation of ovarian tissue, and (3) administration of gonadotropin-releasing hormone agonists (GnRHa). There is one or more than 1 option available for cancer patients, depending on cancer type, partnership, and individual desire. The classical Hodgkin’s lymphoma presents with an enlargement of lymph nodes and unspecific symptoms like night sweats, unexplained weight loss, fatigue and others. It is classified histopathologically by the typical Sternberg-Reed-Cells and may be cured with modern polychemotherapy in more than 80 % [2]. Women with Morbus Hodgkin receiving COPP/ABVD (cyclophosphamide, vincristine [O], procarbazine, prednisolone/adriamycin, bleomycin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine [O], procarbazine, and prednisolone) have a high risk of amenorrhoea after chemotherapy [1, 3, 4]. The incidence of Hodgkin disease in pregnancy is low, with an estimated prevalence of 1 per 6,000 pregnancies [5]. If the diagnosis is made during the first trimester, the pregnancy usually needs to be interrupted [5]; however, with low-risk lymphoma, the pregnancy might be prolonged until labour. Even if a woman has given birth to a healthy child, she may still have the desire for more children. Therefore, fertility preservation techniques should be considered, especially for young mothers. To the best of our knowledge, no report has been published on fertility preservation in pregnant women or women who had given birth just a few days before an anti-cancer treatment.

The Synchrotron Radiation Center (SRC) operates the Aladdin electron storage ring at energies of 800 MeV or 1 GeV in support of a broad range of national and international research programs. A low emittance configuration is in routine operation during 800‐MeV shifts and offers improved photon flux density with about the same beam lifetime. An improved undulator compensation algorithm and new optical beam position monitors have been implemented improving beam stability and maintaining vertical beam size variations to < 2% peak‐to‐peak during undulator scanning. Instrumentation initiatives include construction of a modified Wadsworth beamline (7.8 – 50 eV) and a variable‐line‐spacing plane‐grating monochromator (VLS‐PGM, 75 – 2000 eV) to utilize radiation from a permanent magnet undulator. The Wadsworth beamline is being commissioned for photoelectron spectroscopy (PES) experiments using high‐resolution Scienta analyzers. The VLS‐PGM is being constructed for experiments that require higher photon energies a...

We discuss the first bench tests of a sample manipulator which was recently designed at SRC for the Scienta 2002 User system. The manipulator concept utilizes the 10° angular window of the Scienta in the horizontal plane (angle dispersion) by rotating the sample normal around the vertical axis while angular scans along the vertical axis (energy dispersion) are continuous within ±30° relative to the electron lens by rotating the sample around the horizontal axis. With this concept it is possible to precisely map the entire two‐dimensional k‐space of a crystal by means of stitching together 10° wide stripes centered +15° to −50° relative to the sample normal. Three degrees of translational freedom allow positioning the sample surface at the focal point of the analyzer. Two degrees of rotational freedom are available at this position for manipulating the sample. Samples are mounted to a standard holder and transferred to the manipulator via a load‐lock system attached to a prep chamber. The manipulator is configured with a cryogenic cold head, an electrical heater, and a temperature sensor permitting continuous closed‐loop operation for 20–380 K.

1063 Background: It is well accepted that innovation in oncology is transported through randomized clinical trials (CT). However, elderly patients (>65) are usually excluded from CT. Therefore this...