Nachsorge und Fertilität nach radikaler vaginaler Trachelektomie

Reproduktive Gesundheit nach überstandener Karzinomtherapie ist für Patientinnen von entscheidender Bedeutung und wesentlicher Bestandteil ihrer Lebensqualität. Vor allem viele junge Frauen erleben die Diagnose Zervixkarzinom mit dem Risiko des Organ- und Fertilitätsverlusts als Bedrohung ihrer weiblichen Identität. Dank chirurgischer Innovationen in den vergangenen drei Jahrzehnten im Bereich des Fertilitätserhalts ist es gelungen, den Patientinnen dabei eine Perspektive zu bieten. Die von Daniel Dargent eingeführte Methode der radikalen vaginalen Trachelektomie kombiniert die Reduktion der operationsbedingten Morbidität mit dem Fertilitätserhalt. Die Gleichwertigkeit der Methode hinsichtlich ihrer onkologischen Sicherheit mit radikaleren operativen Ansätzen ist in mehreren Studien eindeutig belegt worden. Die onkologische Sicherheit ist eine unabdingbare Voraussetzung dafür, eines der Hauptziele der RVT, die Umsetzung des Kinderwunsches, zu verwirklichen. Um diese auch im Follow-up gewährleisten zu können, sind qualifizierte Nachsorgeuntersuchungen essentiell. Das von unserer Arbeitsgruppe entwickelte, auf langjähriger Erfahrung mit der Operationsmethode basierende Nachsorgeprotokoll sichert den Standard der Untersuchungen im Follow-up. Durch Anwendung dieses Protokolls in gynäkologischen Praxen wird für die Patientinnen eine heimatnahe, transsektorale Versorgung möglich. Trotz äquivalenter Überlebensraten im Vergleich zur radikalen Hysterektomie treten nach RVT vereinzelt Rezidive auf. In unseren Arbeiten konnten wir zeigen, dass das Rezidivauftreten weder mit bestimmten histopathologischen Faktoren noch mit der Expression von Zellzyklusregulatoren korreliert. Die Möglichkeit von Schwangerschaften nach RVT ist eindeutig belegt, nicht zuletzt durch unsere Untersuchungen am weltweit größten Kollektiv von Patientinnen nach RVT. Es überrascht allerdings nicht, dass Schwangerschaften nach RVT bei Patientinnen und Kollegen viele Fragen aufwerfen. Vor diesem Hintergrund haben wir Empfehlungen zum Schwangerschaftsmanagement entwickelt, die vor allem das Hauptproblem der Frühgeburtlichkeit thematisieren. Die Anwendung dieser Managementempfehlungen soll die Frühgeburtsrate reduzieren. Die Durchführung eines FTMV kann bei ausgewählten Patientinnen ebenfalls eine Risikoreduktion einer Schwangerschaft nach RVT bedeuten. Eine Untersuchung zur Auswirkung der mütterlichen RVT auf Neugeborene im Vergleich zu in derselben Woche geborenen Kindern von Müttern ohne Voroperation zeigte keine Nachteile für erstere. In mehreren Studien wird aktuell die notwendige Radikalität der Therapie beim Zervixfrühkarzinom einer weiteren Prüfung unterzogen. Sollte sich die RVT in bestimmten Fällen als noch zu radikal erweisen, könnte die Reduktion des notwendigen OP-Ausmaßes eine weitere Verringerung des Frühgeburtsrisikos für künftige Patientinnen bedeuten

Lotne związki organiczne (VOCs) w wydychanym powietrzu pacjentek z rakiem piersi w warunkach klinicznych

Background: Carcinogenic products in the exhaled breath of cancer patients are of growing medical interest as they can serve as noninvasive disease markers. Breath analysis can be used as an alternative or complementary diagnostic tool in breast cancer patients who have a different pattern of chemical composition in their breath. This study aims to verify the existence of specific volatile organic compounds (VOCs) in the breath of breast cancer patients. Methods: This prospective study included ten patients suffering from breast cancer and ten healthy pair-matched women. Breath samples of each member of the two respective groups were taken and scanned by gas chromatography/mass spectometry for the presence of volatile organic compounds such as alkanes, ketones, halogenated hydrocarbon, aldehydes, and esters. Results: The spectrum of VOCs differed significantly within the two groups. Five specific VOCs could be identified as typical discriminatory markers in the breath samples. Four VOCs were elevated in the healthy controls, one specific VOC was found to be elevated in women affected by breast cancer. Conclusions: This pilot study revealed a specific VOC pattern using gas chromatography in the breath of breast cancer patients. Five specific breast cancer-VOCs were identified. At relatively low cost the identification of VOCs may be used to detect breast cancer.Streszczenie Cel: Coraz bardziej rośnie zainteresowanie medycyny produktami karcinogenezy w wydychanym powietrzu pacjentów chorych na raka jako możliwych nieinwazyjnych markerów choroby. Analiza powietrza wydychanego może być wykorzystana jako alternatywne lub pomocnicze narzędzie w raku piersi u pacjentek, które mają odmienny skład chemiczny oddechu. Celem tego badania była weryfikacja obecności lotnych związków organicznych (VOCs) w wydychanym powietrzu pacjentek z rakiem piersi. Metoda: Przeprowadzono prospektywne badanie, do którego włączono 10 pacjentek cierpiących na raka piersi i 10 zdrowych dobranych do pary kobiet. Pobrano próbki wydychanego powietrza od każdego uczestnika badania i poddano gazowej chromatografii/spektrometrii masowej na obecność następujących lotnych związków organicznych: alkanów, ketonów, halogenowanych wodorowęglanów, aldehydów i estrów. Wyniki: Spektrum VOCs różniło się istotnie w obu grupach. Pięć specyficznych VOCs zdefiniowano jako typowe markery w wydychanych próbkach. Cztery VOCs były podwyższone w grupie kontrolnej, natomiast jeden specyficzny VOC był podwyższony w grupie kobiet z rakiem piersi. Wnioski: To badanie pilotażowe, przy pomocy gazowej chromatografii, wykazało specyficzny wzór VOC w wydychanym powietrzu u pacjentek chorych na raka piersi. Zidentyfikowano pięć specyficznych dla raka piersi VOCs. Przy relatywnie niskich kosztach identyfikacja VOCs może być wykorzystana do wykrywania raka piersi

Interdisciplinary risk counseling for hereditary breast and ovarian cancer: real-world data from a specialized center

Purpose Hereditary breast and ovarian cancer has long been established to affect a considerable number of patients and their families. By identifying those at risk ideally before they have been diagnosed with breast and/or ovarian cancer, access to preventive measures, intensified screening and special therapeutic options can be obtained, and thus, prognosis can be altered beneficially. Therefore, a standardized screening and counseling process has been established in Germany under the aegis of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). As one of these specialized clinics, the HBOC-Center at Charite offers genetic counseling as well as genetic analysis based on the GC-HBOC standards. This analysis aims first at depicting this process from screening through counseling to genetic analysis as well as the patient collective and second at correlating the results of genetic analysis performed. Thus, real-world data from an HBOC-Center with a substantial patient collective and a high frequency of pathogenic variants in various genes shall be presented. Methods The data of 2531 people having been counseled at the HBOC-Center at Charite in 2016 and 2017 were analyzed in terms of patient and family history as well as pathogenic variants detected during genetic analysis with the TruRisk (R) gene panel when genetic analysis was conducted. This standardized analysis is compiled and regularly adjusted by the GCHBOC. The following genes were included at time of research: BRCA1, BRCA2, ATM, CDH1, CHEK2, PALB2, RAD51C, RAD51D, NBN, and TP53. Results Genetic analysis was conducted in 59.8% of all cases meeting the criteria for genetic analysis and 286 pathogenic variants were detected among 278 (30.3%) counselees tested using the TruRisk (R) gene panel. These were primarily found in the genes BRCA1 (44.8%) and BRCA2 (28.3%) but also in CHEK2 (12.2%), ATM (5.6%) and PALB2 (3.5%). The highest prevalence of pathogenic variants was seen among the families with both ovarian and breast cancer (50.5%), followed by families with ovarian cancer only (43.2%) and families with breast cancer only (35.6%)-these differences are statistically significant (p < 0.001). Considering breast cancer subtypes, the highest rate of pathogenic variants was detected among patients with triple-negative breast cancer (40.7%) and among patients who had had been diagnosed with triple-negative breast cancer before the age of 40 (53.4%)-both observations proved to be statistically significant (p = 0.003 and p = 0.001). Conclusion Genetic counseling and analysis provide the foundation in the prevention and therapy of hereditary breast and ovarian cancer. The rate of pathogenic variants detected is associated with family history as well as breast cancer subtype and age at diagnosis, and can reach considerable dimensions. Therefore, a standardized process of identification, genetic counseling and genetic analysis deems mandatory

iKNOWgynetics – A web‐based learning concept to empower primary care gynecologists to participate in the care of patients with a family history of breast and ovarian cancer

Familial cancer burden and genetics play an increasingly important role in the early detection and prevention of gynecological cancers. However, people with hereditary cancer risks are often identified late when they already have cancer. We aimed at developing and evaluating a training concept for primary care gynecologists—iKNOWgynetics—to improve their knowledge and awareness of genetic cancer syndromes and their ability to identify patients with increased familial cancer risks based on up-to-date evidence and current guidelines (in Germany, primary care includes all doctors treating patients on an outpatient basis without a clear separation of the expertise of the doctor or of their specialty). Starting off with a needs assessment among primary care gynecologists, we developed and evaluated an online training concept—using a web-based learning platform in combination with a live virtual seminar—to convey practice-relevant knowledge about familial cancer. After registration, participants get access to the web-based learning platform (www.iknowgynetics.de) to prepare for the virtual seminars and to use it as online reference to re-access the contents after the training. Evaluation included multiple-choice (MC) questions on knowledge and participants' self-efficacy to implement the acquired knowledge, which were administered in a pre-post design. Of 109 participants, 103 (94.5%) filled out pre- and post-questionnaires. Eighty-five participants were gynecologists in primary care from Berlin (81.2%) and Brandenburg (18.8%) and had an average of 24.1 years (SD = 8.5 years) of professional experience. After the training, participants answered significantly more knowledge questions correctly (M = 15.2 of 17, SD = 1.3) than before (M = 13.8 of 17, SD = 1.7) (p < 0.01) and felt more confident to be able to apply referral criteria for specialized counseling in practice (p < 0.001). The online-based training iKNOWgynetics considers the busy schedule of primary care gynecologists and supports them in acquiring practice-relevant information on familial cancer risks and on how to identify healthy persons at risk, which may ultimately help to improve the prevention of gynecological cancers. In future studies, the reported concept could be transferred to other entities

Web-based patient-reported outcomes using the International Consortium for Health Outcome Measurement dataset in a major German university hospital: observational study

Background: Collecting patient-reported outcome (PRO) data systematically enables objective evaluation of treatment and its related outcomes. Using disease-specific questionnaires developed by the International Consortium for Health Outcome Measurement (ICHOM) allows for comparison between physicians, hospitals, and even different countries. Objective: This pilot project aimed to establish a digital system to measure PROs for new patients with breast cancer who attended the Charité Breast Center. This approach should serve as a blueprint to further expand the PRO measurement to other disease entities and departments. Methods: In November 2016, we implemented a Web-based system to collect PRO data at Charité Breast Center using the ICHOM dataset. All new patients at the Breast Center were enrolled and answered a predefined set of questions using a tablet computer. Once they started their treatment at Charité, automated emails were sent to the patients at predefined treatment points. Those emails contained a Web-based link through which they could access and answer questionnaires. Results: By now, 541 patients have been enrolled and 2470 questionnaires initiated. Overall, 9.4% (51/541) of the patients were under the age of 40 years, 49.7% (269/541) between 40 and 60 years, 39.6% (214/541) between 60 and 80 years, and 1.3% (7/541) over the age of 80 years. The average return rate of questionnaires was 67.0%. When asked about the preference regarding paper versus Web-based questionnaires, 6.0% (8/134) of the patients between 50 and 60 years, 6.0% (9/150) between 60 and 70 years, and 12.7% (9/71) over the age of 70 years preferred paper versions. Conclusions: Measuring PRO in patients with breast cancer in an automated electronic version is possible across all age ranges while simultaneously achieving a high return rate

Paradigmatic Approach to Support Personalized Counseling With Digital Health (iKNOW)

iKNOW is the first evidence-based digital tool to support personalized counseling for women in Germany with a hereditary cancer risk. The counseling tool is designed for carriers of pathogenic gBRCA (germline breast cancer gene) variants that increase the lifetime risk of breast and ovarian cancer. Carriers of pathogenic variants are confronted with complex, individualized risk information, and physicians must be able to convey this information in a comprehensible way to enable preference-sensitive health decisions. In this paper, we elaborate on the clinical, regulatory, and practical premises of personalized counseling in Germany. By operationalizing these premises, we formulate 5 design principles that, we suggest, are specific enough to develop a digital tool (eg, iKNOW), yet wide-ranging enough to inform the development of counseling tools for personalized medicine more generally: (1) digital counseling tools should implement the current standard of care (eg, based on guidelines); (2) digital counseling tools should help to both standardize and personalize the counseling process (eg, by enabling the preference-sensitive selection of counseling contents from a common information base); (3) digital counseling tools should make complex information easy to access both cognitively (eg, by using evidenced-based risk communication formats) and technically (eg, by means of responsive design for various devices); (4) digital counseling tools should respect the counselee's data privacy rights (eg, through strict pseudonymization and opt-in consent); and (5) digital counseling tools should be systematically and iteratively evaluated with the users in mind (eg, using formative prototype testing to ensure a user-centric design and a summative multicenter, randomized controlled trial). On the basis of these paradigmatic design principles, we hope that iKNOW can serve as a blueprint for the development of more digital innovations to support personalized counseling approaches in cancer medicine

Prevalence of pathogenic BRCA1/2 germline mutations among 802 women with unilateral triple-negative breast cancer without family cancer history

Background: There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group. Methods: The study comprised 802 women (median age 40 years, range 19–76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation. Results: A total of 127 women with TNBC (15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1.1%). The mutation prevalence was 32.9% in the age group 20–29 years compared to 6.9% in the age group 60–69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95%CI 1.50–2.32, p &lt; 0.001). gBRCA mutation risk was predicted to be &gt; 10% for women diagnosed below approximately 50 years. Conclusions: Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Making Sense of a Health Threat: Illness Representations, Coping, and Psychological Distress among BRCA1/2 Mutation Carriers

Little is known about how women with a BRCA1/2 mutation develop an individual understanding of their breast and ovarian cancer risk and how this affects their psychological distress. In this study, we investigated associations between illness representations, coping strategies and psychological distress. N = 101 BRCA1/2 mutation carriers answered self-report questionnaires on illness representations, coping strategies, cancer worry and depressive symptoms. Women without cancer were compared to women with a previous cancer diagnosis. Illness representations explained 50% and 45% of the variability in cancer worry and depressive symptoms, respectively. Woman perceiving severe consequences (β = 0.29, p < 0.01) and having more concerns (β = 0.37, p < 0.01) were found to report more cancer worry. Perceiving information about the mutation as less coherent (β = -0.17, p < 0.05) and experiencing negative emotional responses (β = 0.60, p < 0.01) were both associated with more depressive symptoms. Women with a previous cancer diagnosis show patterns of illness representations that are potentially more distressing than women without a cancer diagnosis. Findings suggest that physicians involved in counseling should pay attention to illness representations of distressed women. Thereby, it would be possible to detect maladaptive thoughts associated with the mutation, address negative emotions and encourage adaptive coping strategies

What Causes Cancer in Women with a gBRCA Pathogenic Variant? Counselees&rsquo; Causal Attributions and Associations with Perceived Control

Laypersons have a strong need to explain critical life events, such as the development of an illness. Expert explanations do not always match the beliefs of patients. We therefore assessed causal attributions made by women with a pathogenic germline variant in BRCA1/2 (gBRCA1/2-PV), both with and without a cancer diagnosis. We assumed that attributions would be associated with the control experience. We conducted a cross-sectional study of N = 101 women with a gBRCA1/2-PV (mean age 43.3 &plusmn; 10.9). Women answered self-report questionnaires on perceived causes and control. Most women (97%) named genes as a causal factor for the development of cancer. Surprisingly, the majority of women also named stress and health behavior (both 81%), environment (80%), and personality (61%). Women with a cancer diagnosis tended to endorse more causes. The attributions to personality (&rho; = 0.39, p &lt; 0.01) health behavior (&rho; = 0.44, p &lt; 0.01), and environment (&rho; = 0.22, p &lt; 0.05) were significantly associated with personal control, whereas attribution to genes showed a small, albeit significant association with treatment control (&rho; = 0.20, p &lt; 0.05). Discussing causal beliefs in clinical counseling may provide a &ldquo;window of opportunity&rdquo; in which risk factors and health behaviors could be better addressed and individually targeted