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Infektionen sind eine wichtige potenzielle Gefahrenquelle für Schwangere und ihre ungeborenen Kinder. Schwangere und Frauen mit Kinderwunsch sollten sich daher fachkundig darüber beraten lassen, welche Impfungen vor bzw. während einer Schwangerschaft sinnvoll sind. Zur Impfberatung gehören auch Fragestellungen zu Reiseimpfungen, insbesondere wenn das Reiseziel in einem Endemiegebiet für Erkrankungen wie Malaria, Gelbfieber, Tuberkulose, Hepatitis, Human-immunodeficiency-virus-assoziierte Erkrankungen, Leishmaniose, Toxoplasmose und Japanische Enzephalitis liegt. Grundsätzlich können alle Toxoidimpfstoffe, inaktivierten Impfstoffe und Immunglobuline in der Schwangerschaft verabreicht werden, Lebendimpfstoffe sind kontraindiziert. Empfehlenswerte Impfungen in der Schwangerschaft sind Tetanus, Diphtherie, Pertussis im Falle eines fehlenden Impfschutzes, die saisonale Influenzaimpfung und aktuell die Coronavirus-disease-19(COVID-19)-Impfung ab dem zweiten Trimenon. Zu den empfohlenen Reiseschutzimpfungen zählen alle Standardimpfungen, das heißt die Grundimmunisierung gegen Rotaviren, Tetanus, Diphtherie, Pertussis, Haemophilus influenzae Typ B, Poliomyelitis, Hepatitis B, Pneumokokken, Meningokokken, Masern, Mumps, Röteln, Varizellen, humanes Papillomavirus und Influenza. Darüber hinaus hat in der Reisemedizin der Immunschutz gegen Hepatitis A einen hohen Stellenwert. Nach den internationalen Gesundheitsempfehlungen der World Health Organization ist zur Einreise in bzw. Ausreise aus bestimmten Ländern eine zusätzliche spezifische Impfvorschrift für die Gelbfieber- und Poliomyelitisimpfung vorgesehen. Einzelne Länder haben darüber hinaus zusätzliche Impfvorschriften für die Ein- und Ausreise. „Indikationsimpfungen“ setzen ein entsprechendes lokales Risiko voraus.

P1 oncogenerative cell division as a whole cell entity is shown here.

The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiologic stemness of the resulting cell populations. Here, we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy-refractory ovarian tumors, which generate and gestate daughter generation Gn cells intracytoplasmically. Release of Gn cells occurred by ejection through crevices in the P1 cell membrane by body contractions or using a funiculus-like structure. These events characterized a not yet described mechanism of cell segregation. Maternal P1 cells were principally capable of surviving parturition events and continued to breed and nurture Gn progenies. In addition, P1 cells were competent to horizontally transmit offspring Gn cells into other specific proximal cells, injecting them to receptor R1 cells via cell–cell tunneling. This process represents a new mechanism used by tumor cells to invade surrounding tissues and ensure life cycles. In contrast to the pregnant P1 cells with low expression of stem cell markers despite their physiologic stemness, the first offspring generations of daughter G1 cells expressed high levels of ovarian cancer stem cell markers. Furthermore, both P1 and Gn cells overexpressed multiple human endogenous retroviral envelope proteins. Moreover, programmed death-ligand 1 and the immunosuppressive domain of the retroviral envelope proteins were also overexpressed in P1 cells, suggesting effective protection against the host immune system. Together, our data suggest that P1 oncogenerative cancer cells exhibit a not yet described cell biological mechanism of persistence and transmission of malignant cells in patients with advanced cancers.Significance: P1 oncogenerative cell entities express low levels of CSC markers, which are characteristic of their histological origin. Cancer Res; 78(9); 2318–31. ©2018 AACR.

P1 cells seem to undergo divisions in to similar oncogenerative cells by cytoplasm separation. The process is in par orchestrated with the participation of mitochondria which delimitate boundaries of cytoplasms to be separated. After this, it is possible to observe a directional cytokinesis like separation of multinucleated cells.

Expression of CSC markers and morphology of P1 oncogenerative and G1-Gn cells as detected by ICC and IHC.

P1 reconstruction in 3D horizontal projection from TEM sections superposed. The inner structure of G1-containing cells is shown.

Replicative elements found in P1 and G1 cells and the expression of HERV envelope proteins in small G1-G2 cells can be visualised here.

P1 oncogenerative cells undergo long quiescent phases in which they do not appear to generate and eject G1 cells.

Resistance profile and spherogenicity of SKOV3 ovarian carcinoma models.

Oncogenerative P1 cells are giant cells with a syncytium-like morphology. This distinctive cell type complete cell life cycles which resemble lysogenic viral cycles. The mode of cellularization of the intracytoplasmically generated G1 cells (generation 1) is unique and takes place in different ways: a) in a lateral form which means that the G1 cells abandon the maternal P1 cells by trans cytoplasmic budding, b) through crevices formed with the participation of mitochondria around G1s until expulsion. After cellularization, the resulted aperture is filled by fusogenic HERV proteins, c) using a kind of funiculus or bridge connected to P1 maternal cells. An interesting process conducted by P1 cells is the horizontal transmission of G1 inoculating these cells into proximal receptor cells.

The lateral separation of G1 from P1 cells is observed in this clip.

The formation of the crevices is observed with the subsequent detachment of G1-Gn cells from mother cytoplasm.

P1 reconstruction in 3D vertical projection from TEM sections superposed. The inner structure of G1-containing cells is shown.

Occurrence and morphology of multinucleated cells in different tumors.

Oncogenerative P1 cells are giant cells with a syncytium-like morphology. This distinctive cell type complete cell life cycles which resemble lysogenic viral cycles. The mode of cellularization of the intracytoplasmically generated G1 cells (generation 1) is unique and takes place in different ways: a) in a lateral form which means that the G1 cells abandon the maternal P1 cells by trans cytoplasmic budding, b) through crevices formed with the participation of mitochondria around G1s until expulsion. After cellularization, the resulted aperture is filled by fusogenic HERV proteins, c) using a kind of funiculus or bridge connected to P1 maternal cells. An interesting process conducted by P1 cells is the horizontal transmission of G1 inoculating these cells into proximal receptor cells.

Expression of CSC markers in multinucleated cells at protein and RNA levels.

Purpose The aim was to develop and update a guideline which would improve the quality of care offered to women with gestational and non-gestational trophoblastic disease, a group of diseases characterized by their rarity and biological heterogeneity. Methods In accordance with the method used to compile S2k-guidelines, the guideline authors carried out a search of the literature (MEDLINE) for the period 1/2020 to 12/2021 and evaluated the recent literature. No key questions were formulated. No structured literature search with methodical evaluation and assessment of the level of evidence was carried out. The text of the precursor version of the guideline from 2019 was updated based on the most recent literature, and new statements and recommendations were drafted. Recommendations The updated guideline contains recommendations for the diagnosis and therapy of women with hydatidiform mole (partial and complete moles), gestational trophoblastic neoplasia after pregnancy or without prior pregnancy, persistent trophoblastic disease after molar pregnancy, invasive moles, choriocarcinoma, placental site nodules, placental site trophoblastic tumor, hyperplasia at the implantation site und epithelioid trophoblastic tumor. Separate chapters cover the determination and assessment of human chorionic gonadotropin (hCG), histopathological evaluation of specimens, and the appropriate molecular pathological and immunohistochemical diagnostic procedures. Separate chapters on immunotherapy, surgical therapy, multiple pregnancies with simultaneous trophoblastic disease, and pregnancy after trophoblastic disease were formulated, and the corresponding recommendations agreed upon.

Cervical dysplasia is a common precancerous lesion affecting 1% to 2% of women worldwide. Significant progress in the diagnosis and treatment of cervical dysplasia have been made in the last decade. We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify controlled clinical trials reporting on the efficacy and safety of diagnostic and therapeutic interventions for cervical dysplasia. Data were analyzed according to PRISMA guidelines. In total, 33 studies reporting on 5935 women were identified. We recommend intravenous or intracervical lidocaine for pain reduction during colposcopically-directed cervical biopsies but not topical lidocaine, music, or video colposcopy. Monsel’s solution might be used to control bleeding after cervical biopsies. The acetic acid test should be scored 1 min after the application of acetic acid and should be followed by Lugol’s iodine test for an optimal yield of LSIL/HSIL. LEEP/LLETZ remains the standard and techniques such as SWETZ, C-LETZ, and TCBEE are not superior. LEEP/LLETZ should be performed under local anesthesia and with direct colposcopic vision. Cryotherapy and thermoablation might be used in women with LSIL, especially in women with HIV infection, but LEEP/LLETZ remains the standard for HSIL. Topical imiquimod remains an experimental procedure. In conclusion, significant progress has been made in the last decade regarding both diagnostic interventions as well as therapeutic interventions for women with cervical dysplasia. Based on >30 controlled clinical trials, we were able to formulate specific and evidence-based recommendations.

Objectives Safe implementation and thorough evaluation of new treatments require prospective data monitoring and standardization of treatments. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a promising alternative for the treatment of patients with peritoneal disease with an increasing number of suggested drug regimens. The aim was to reach expert consensus on current PIPAC treatment protocols and to define the most important research topics. Methods The expert panel included the most active PIPAC centers, organizers of PIPAC courses and principal investigators of prospective studies on PIPAC. A comprehensive literature review served as base for a two-day hybrid consensus meeting which was accompanied by a modified three-round Delphi process. Consensus bar was set at 70% for combined (strong and weak) positive or negative votes according to GRADE. Research questions were prioritized from 0 to 10 (highest importance). Results Twenty-two out of 26 invited experts completed the entire consensus process. Consensus was reached for 10/10 final questions. The combination of doxorubicin (2.1 mg/m2) and cisplatin (10.5 mg/m2) was endorsed by 20/22 experts (90.9%). 16/22 (72.7%) supported oxaliplatin at 120 with potential reduction to 90 mg/m2 (frail patients), and 77.2% suggested PIPAC-Ox in combination with 5-FU. Mitomycin-C and Nab-paclitaxel were favoured as alternative regimens. The most important research questions concerned PIPAC conditions (n=3), standard (n=4) and alternative regimens (n=5) and efficacy of PIPAC treatment (n=2); 8/14 were given a priority of ≥8/10. Conclusions The current consensus should help to limit heterogeneity of treatment protocols but underlines the utmost importance of further research.

BackgroundThe efficacy of the humoral and cellular immunity determines the outcome of viral infections. An appropriate immune response mediates protection, whereas an overwhelming immune response has been associated with immune-mediated pathogenesis in viral infections. The current study explored the general and SARS-CoV-2 specific cellular and humoral immune status in patients with different COVID-19 severities.MethodsIn this prospective study, we included 53 patients with moderate, severe, and critical COVID-19 manifestations comparing their quantitative, phenotypic, and functional characteristics of circulating immune cells, SARS-CoV-2 antigen specific T-cells, and humoral immunity.ResultsSignificantly diminished frequencies of CD8+T-cells, CD4+ and CD8+T-cell subsets with activated differentiated memory/effector phenotype and migratory capacity were found in circulation in patients with severe and/or critical COVID-19 as compared to patients with moderate disease. Importantly, the improvement of the clinical courses from severe to moderate was accompanied by an improvement in the T-cell subset alterations. Furthermore, we surprisingly observed a detectable SARS-CoV-2-reactive T-cell response in all three groups after stimulation with SARS-CoV-2 S-protein overlapping peptide pool already at the first visit. Of note, patients with a critical COVID-19 demonstrated a stronger response of SARS-CoV-2-reactive T-cells producing Th1 associated inflammatory cytokines. Furthermore, clear correlation between antibody titers and SARS-CoV-2-reactive CD4+ frequencies underscore the role of specific immunity in disease progression.ConclusionOur data demonstrate that depletion of activated memory phenotype circulating T-cells and a strong SARS-CoV-2-specific cellular and humoral immunity are associated with COVID-19 disease severity. This counter-intuitive finding may have important implications for diagnostic, therapeutic and prophylactic COVID-19 management.

Patients with peritoneal metastasis (PM) of gastrointestinal and gynecological origin present with a nutritional deficit characterized by increased resting energy expenditure (REE), loss of muscle mass, and protein catabolism. Progression of peritoneal metastasis, as with other advanced malignancies, is associated with cancer cachexia anorexia syndrome (CAS), involving poor appetite (anorexia), involuntary weight loss, and chronic inflammation. Eventual causes of mortality include dysfunctional metabolism and energy store exhaustion. Etiology of CAS in PM patients is multifactorial including tumor growth, host response, cytokine release, systemic inflammation, proteolysis, lipolysis, malignant small bowel obstruction, ascites, and gastrointestinal side effects of drug therapy (chemotherapy, opioids). Metabolic changes of CAS in PM relate more to a systemic inflammatory response than an adaptation to starvation. Metabolic reprogramming is required for cancer cells shed into the peritoneal cavity to resist anoikis (i.e., programmed cell death). Profound changes in hexokinase metabolism are needed to compensate ineffective oxidative phosphorylation in mitochondria. During the development of PM, hypoxia inducible factor-1α (HIF-1α) plays a key role in activating both aerobic and anaerobic glycolysis, increasing the uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α upregulates hexokinase II, phosphoglycerate kinase 1 (PGK1), pyruvate dehydrogenase kinase (PDK), pyruvate kinase muscle isoenzyme 2 (PKM2), lactate dehydrogenase (LDH) and glucose transporters (GLUT) and promotes cytoplasmic glycolysis. HIF-1α also stimulates the utilization of glutamine and fatty acids as alternative energy substrates. Cancer cells in the peritoneal cavity interact with cancer-associated fibroblasts and adipocytes to meet metabolic demands and incorporate autophagy products for growth. Therapy of CAS in PM is challenging. Optimal nutritional intake alone including total parenteral nutrition is unable to reverse CAS. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) stabilized nutritional status in a significant proportion of PM patients. Agents targeting the mechanisms of CAS are under development.

This study examines the recommendations of international guidelines on the use of antepartum and intrapartum cardiotocography.The guidelines of Germany, Canada, UK, USA, Sri Lanka, Australia as well as FIGO have been compared. The recommendations on the use of cardiotocography were separately evaluated for antepartum and intrapartum use.Antepartum: In risk-free pregnancies the use of cardiotocography is not recommended in all countries. On the other hand the use of cardiotocography is indicated in the presence of a defined maternal and fetal risk factors. While the NICE guidelines recommend cardiotocography in the case of maternal hypertension, as well as preeclampsia, the German guidelines as well as SOGC list considerably more risk factors. Intrapartually, the recommendations vary greatly from country to country. While German guidelines suggest the use of cardiotocography from late 1st stage of labor, the other countries strongly recommend the auscultation of the fetal heart rate of non-risk pregnancies. This is due to the current study situation, which does not show any advantage of cardiotocography as opposed to intermittent auscultation. Furthermore studies have indicated that the use of cardiotocography caused an increase in iatrogenic induced cesarean sections. In high risk pregnancies the use of cardiotocography is strongly recommended in the compared countries, however there are major differences in the definition of high risk pregnancy and therefore the indication for cardiotocographic monitoring.Intermittent auscultation is a more cost-effective alternative compared to cardiotocography. However, in the case of legal litigation intermittent auscultation is harder to reconstruct the well-being of the newborn during birth. On the other hand cardiotocography might result in a higher cesarean section rate, but can be more helpful to prove fetal well-being during birth for a legal litigation process. Despite the lack of evidence only German guidelines recommend cardiotocographic monitoring from the late 1st stage of labor for risk-free pregnancies.Untersucht werden soll der leitliniengerechte Einsatz des Cardiotokogramms (CTG), sowohl ante partum als auch sub partu, im internationalen Vergleich.Verglichen wurden die Leitlinien verschiedener Länder (Deutschland, Kanada, Großbritannien, USA, Sri Lanka und Australien) sowie die Empfehlungen der Fédération Internationale de Gynécologie et d̛Obstétrique (FIGO). Gegenübergestellt wurden die Empfehlungen zum Einsatz des CTG sowohl ante partum als auch sub partu.CTG ante partum: Es lässt sich feststellen, dass bei risikofreier Schwangerschaft der Einsatz des CTG in allen untersuchten Ländern nicht empfohlen wird. Bei Vorhandensein definierter Risikofaktoren für das fetale oder maternale Wohl wird der Einsatz des CTG hingegen empfohlen. Während die englische National Institute for Health and Care Excellence (NICE)-Guideline den Einsatz nur bei maternaler Hypertonie und Präeklampsie vorsieht, listet die Leitlinie der Deutschen Gesellschaft für Gynäkologie und Geburtshilfe (DGGG) in Anlehnung an die Empfehlungen der Society of Obstetricians and Gynaecologists of Canada (SOGC) deutlich mehr Risikofaktoren auf. Sub partu: Subpartual unterscheiden sich die Empfehlungen von Land zu Land deutlich. In Deutschland wird der Einsatz des CTG ab der späten Eröffnungsperiode empfohlen. Die Leitlinien der anderen untersuchten Länder empfehlen während einer Nichtrisikoschwangerschaft vorrangig die Auskultation der fetalen Herzfrequenz unter der Geburt. Begründet wird dies mit der bisherigen Studienlage, die keinen Vorteil des CTG gegenüber der intermittierenden Auskultation erkennen lässt. Viel mehr ließ sich in den ausgewerteten Studien erkennen, dass es unter dem Einsatz des CTG zu einem Anstieg der Kaiserschnitterate kam. Anders sehen die Empfehlungen zur Anwendung des CTG unter der Geburt bei Risikoschwangerschaften aus. Hier wird in den Leitlinien der verglichenen Länder der Einsatz des CTG durchaus empfohlen, obwohl Unterschiede bezüglich der Indikation für den Einsatz des CTG festzustellen sind.Die intermittierende Auskultation ist im Vergleich zum CTG zwar eine kostengünstigere Alternative, sie ist jedoch nicht kontinuierlich anwendbar und im Falle von Regressen schlechter nachvollziehbar als das CTG. Das CTG führt zu einer höheren Rate an Kaiserschnitten, bietet jedoch bei korrekter Anwendung Sicherheit für Fetus und Mutter sowie Rechtssicherheit für das geburtshilfliche Personal. Im internationalen Vergleich empfehlen die deutschen Leitlinien als einzige, trotz fehlender Evidenz, die CTG-Diagnostik ab der späten Eröffnungsperiode bei Nichtrisikoschwangerschaften.