Laparoscopic Fertility-Sparing Surgery for Early Ovarian Malignancies

The demand for fertility-sparing surgery (FSS) has increased in the last decade due to increased maternal age, increased incidence of ovarian malignancies in younger patients, and technical advances in surgery. Data on oncological safety and fertility outcomes of patients with ovarian cancer after laparoscopic FSS are sparse, but some retrospective studies have shown that open FSS may be offered to selected patients. We assessed the role of minimally invasive FSS in comparison with radical surgery (RS) in terms of oncological safety and reproductive outcomes after FSS in this multicenter study. Eighty patients with FIGO stage I/II ovarian cancer treated with laparoscopic FSS or RS between 01/2000 and 10/2018 at the participating centers (comprehensive gynecological cancer centers with minimally invasive surgical expertise) were included in this retrospective analysis of prospectively kept data. Case–control (n = 40 each) matching according to the FIGO stage was performed. Progression-free survival [150 (3–150) and 150 (5–150) months; p = 0.61] and overall survival [36 (3–150) and 50 (1–275) months; p = 0.65] did not differ between the FSS and RS groups. Eight (25.8%) women became pregnant after FSS, resulting in seven (22.5%) deliveries; three (37.5%) patients conceived after in vitro fertilization, and five (62.5%) conceived spontaneously. Laparoscopic FSS seems to be applicable and oncologically safe for patients with early-stage ovarian cancer, with adequate fertility outcomes

Discovery and development of Seliciclib. How systems biology approaches can lead to better drug performance

Seliciclib (R-Roscovitine) was identified as an inhibitor of CDKs and has undergone drug development and clinical testing as an anticancer agent. In this review, the authors describe the discovery of Seliciclib and give a brief summary of the biology of the CDKs Seliciclib inhibits. An overview of the published in vitro and in vivo work supporting the development as an anti-cancer agent, from in vitro experiments to animal model studies ending with a summary of the clinical trial results and trials underway is presented. In addition some potential non-oncology applications are explored and the potential mode of action of Seliciclib in these areas is described. Finally the authors argue that optimisation of the therapeutic effects of kinase inhibitors such as Seliciclib could be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division

Neoadjuvant Chemoradiotherapy versus Chemotherapy for Gastroesophageal Junction Adenocarcinoma; Which Is the Optimal Treatment Option?

Background: Locally advanced gastroesophageal junction adenocarcinoma (GEJ) is treated with either perioperative chemotherapy (CT) or preoperative radiochemotherapy (RCT) followed by surgery. The aim of this study was to compare pathologic response and long-term outcomes in junction adenocarcinoma treated with neoadjuvant RCT versus CT. Methods: All patients with locally advanced GEJ adenocarcinoma treated with neoadjuvant treatment (NAT) followed by surgery between 2009 and 2018 were retrospectively analyzed. Results: A total of 94 patients were included, 67 (71.2%) RCT and 27 (28.8%) CT. Complete pathologic response was more frequent in RCT patients (13.4% vs. 7.4%, p = 0.009) with a trend to better lymph node control (ypN0) (55.2% vs. 33.3%; p = 0.057). RCT offered no benefit in R0 resection (66.7% vs. 72.1% CT, p = 0.628) and was related to higher postoperative cardiovascular complications (35.8% vs. 11.1%; p = 0.017). Long-term overall and disease-free survival were similar (5-year OS 61.1% RCT vs. 75.7% CT, p = 0.259; 5-year DFS 33.5% RCT vs. 22.8% CT; p = 0.763). NAT type was neither independently associated with pathologic response nor long-term survival. Discussion: Patients with locally advanced GEJ adenocarcinoma treated with RCT had more postoperative cardiovascular complications but higher rates of complete pathologic response and a trend to superior locoregional lymph node control. This did not translate in a survival or recurrence benefit

Untersuchungen zur Beteiligung von Proteasen an der kälteinduzierten Apoptose von Rattenleberendothelzellen

Die moderne Lebertransplantation wäre ohne die Verwendung von Hypothermie (4°C) und Konservierungslösungen nicht möglich. Trotz der Fortschritte der Lebertrans-plantation in den letzten Jahren kommt es auch heute noch zur Konservierungsschädigung der Leber; von dieser sind vor allem die Leberendothelzellen betroffen. Der Schädigungsfaktor Kälte/Wiedererwärmung führt in kultivierten sinusoidalen Leberendothelzellen über einen Anstieg des chelatisierbaren Eisenpools mit konsekutiver Freisetzung reaktiver Sauerstoffspezies zur kälteinduzierten Apoptose. Ob und, falls ja, welche Proteasen an diesem Prozess beteiligt sind, war Gegenstand der vorliegenden Arbeit. In kultivierten konfluenten Rattenleberendothelzellen wurden zunächst verschiedene Proteaseinhibitoren eingesetzt und ihr Effekt auf die Vitalität und Morphologie der Zellen nach Kaltinkubation beurteilt. Hierbei wurde ein sehr guter Schutzeffekt durch den Serin- (und Cystein-) Proteaseinhibitor 3,4-Dichloroisocumarin (DCI) beobachtet. In der Folge wurden die einzelnen Proteaseaktivitäten, insbesondere Serin- und Cysteinproteaseaktivitäten, fluorimetrisch bestimmt. Es ließ sich jedoch keine erhöhte Aktivität von Calpainen, Caspasen, Cathepsin B oder auch Aspartatproteasen nachweisen. Stattdessen konnte eine erhöhte Suc-Leu-Leu-Val-Tyr-AMC und eine Suc-Ala-Ala-Ala-AMC spaltende Aktivität nachgewiesen werden. Weitere Untersuchungen zeigten, dass es sich bei diesen beiden (erhöhten) Aktivitäten um zwei unterschiedliche Proteasen handelt. Die Suc-Leu-Leu-Val-Tyr-AMC spaltende Aktivität, wahrscheinlich für den Zelltod bedeutsamer, ließ sich durch DCI und die Proteasominhibitoren Lactacystin und MG-132 signifikant inhibieren. Sie wies einen Km-Wert von ca. 25 µM für Suc-Leu-Leu-Val-Tyr-AMC und einen Ki-Wert von ca. 25 nM für MG-132 auf und konnte über Immunopräzipitation mit einem Antiproteasomantikörper als Chymotrypsin-ähnliche Aktivität des Proteasoms identifiziert werden. Bei der anderen Protease handelt es sich um eine Serinprotease von bisher unbekannter Art und Bedeutung. Die Aktivierung beider Proteasen (nicht jedoch ihre Aktivität) erwies sich als eisenabhängig. Die Hemmung des Proteasoms (und seiner eisenabhängigen Aktivierung) kann die Schädigung der Leberendothelzellen deutlich reduzieren. Der Einsatz von Eisenchelatoren und/oder Proteasominhibitoren in den Konservierungslösungen während der Kaltlagerung der Leber könnte also über eine Verminderung von Endothelzellschädigung und Mikrozirkulationsstörungen zur Verbesserung der Konservierung führen und das unmittelbare Transplantatversagen reduzieren

Der Einfluss von Thrombopoetin auf den postischämischen Leberschaden

In der vorliegenden Dissertation wurde am experimentellen Mausmodell die therapeutische Wirksamkeit von Thrombopoetin auf den Ischämie-/Reperfusionsschaden der Leber untersucht. Intravitalmikroskopisch wurden die sinusoidale Perfusion, die Leukozyten-Endothelzell-Interaktion und die Apoptoserate im Leberparenchym erfasst. Zudem wurden laborchemische Parameter zur Quantifizierung der hepatozellulären Integrität und der Inflammation erhoben. Ein signifikanter Einfluss von Thrombopoetin auf den Ischämie-/Reperfusionsschaden der Leber konnte anhand dieser Studie nicht nachgewiesen werden

Long-term effects in bone mineral density after different bariatric procedures in patients with type 2 diabetes: outcomes of a randomized clinical trial

There is scant evidence of the long-term effects of bariatric surgery on bone mineral density (BMD). We compared BMD changes in patients with severe obesity and type 2 diabetes (T2D) 5 years after randomization to metabolic gastric bypass (mRYGB), sleeve gastrectomy (SG) and greater curvature plication (GCP). We studied the influence of first year gastrointestinal hormone changes on final bone outcomes. Forty-five patients, averaging 49.4 (7.8) years old and body mass index (BMI) 39.4 (1.9) kg/m(2), were included. BMD at lumbar spine (LS) was lower after mRYGB compared to SG and GCP: 0.89 [0.82;0.94] vs. 1.04 [0.91;1.16] vs. 0.99 [0.89;1.12],p= 0.020. A higher percentage of LS osteopenia was present after mRYGB 78.6% vs. 33.3% vs. 50.0%, respectively. BMD reduction was greater in T2D remitters vs. non-remitters. Weight at fifth year predicted BMD changes at the femoral neck (FN) (adjustedR(2): 0.3218;p= 0.002), and type of surgery (mRYGB) and menopause predicted BMD changes at LS (adjustedR(2): 0.2507;p< 0.015). In conclusion, mRYGB produces higher deleterious effects on bone at LS compared to SG and GCP in the long-term. Women in menopause undergoing mRYGB are at highest risk of bone deterioration. Gastrointestinal hormone changes after surgery do not play a major role in BMD outcomes

Growing Strong and Healthy with Mister Bone: An Educational Program to Have Strong Bones Later in Life.

Optimal peak bone mass and bone health later in life are favored by a sufficient calcium intake in infancy, childhood and adolescence. The purpose of this study was to test a new educational program created to monitor and to improve calcium and vitamin D intake in children. Nutritional habits in children were evaluated through a food frequency questionnaire (FFQ) to assess the intake of calcium, vitamin D, dairy products, and total caloric energy at baseline and after seven months of exposure to a unique educational program applied between November 2013 and May 2014 in 176 schoolchildren (48% male, 52% female) attending the fourth and fifth grades of two selected primary schools in Florence, Italy. A significant increase of calcium (from 870 ± 190 to 1100 ± 200 mg/day, p &lt; 0.05), and vitamin D (from 3.6 ± 1.53 to 4.1 ± 2 µg/day) intake in children was documented after the educational program. The amount of specific foods important for bone health consumed, such as milk and vegetables, increased significantly, both in male and female children (p &lt; 0.05). The proposed educational program appears to be effective in modifying calcium intake in children, with a significant increase in the consumption of dairy products and vegetables, but without a significant change in the total caloric intake

Methane Admixture Protects Liver Mitochondria and Improves Graft Function after Static Cold Storage and Reperfusion

Mitochondria are targets of cold ischemia-reperfusion (IR), the major cause of cell damage during static cold preservation of liver allografts. The bioactivity of methane (CH4) has recently been recognized in various hypoxic and IR conditions as having influence on many aspects of mitochondrial biology. We therefore hypothesized that cold storage of liver grafts in CH4-enriched preservation solution can provide an increased defence against organ dysfunction in a preclinical rat model of liver transplantation. Livers were preserved for 24 h in cold histidine–tryptophan–ketoglutarate (HTK) or CH4-enriched HTK solution (HTK-CH4) (n = 24 each); then, viability parameters were monitored for 60 min during normothermic isolated reperfusion and perfusate and liver tissue were collected. The oxidative phosphorylation capacity and extramitochondrial Ca2+ movement were measured by high resolution respirometry. Oxygen and glucose consumption increased significantly while hepatocellular damage was decreased in the HTK-CH4 grafts compared to the HTK group. Mitochondrial oxidative phosphorylation capacity was more preserved (128.8 ± 31.5 pmol/s/mL vs 201.3 ± 54.8 pmol/s/mL) and a significantly higher Ca2+ flux was detected in HTK-CH4 storage (2.9 ± 0.1 mV/s) compared to HTK (2.3 ± 0.09 mV/s). These results demonstrate the direct effect of CH4 on hepatic mitochondrial function and extramitochondrial Ca2+ fluxes, which may have contributed to improved graft functions and a preserved histomorphology after cold IR

Recent Advances in Minimally Invasive Surgery

Minimally invasive surgery has become a common term in visceral as well as gynecologic surgery. It has almost evolved into its own surgical speciality over the past 20 years. Today, being firmly established in every subspeciality of visceral surgery, it is now no longer a distinct skillset, but a fixed part of the armamentarium of surgical options available. In every indication, the advantages of a minimally invasive approach include reduced intraoperative blood loss, less postoperative pain, and shorter rehabilitation times, as well as a marked reduction of overall and surgical postoperative morbidity. In the advent of modern oncologic treatment algorithms, these effects not only lower the immediate impact that an operation has on the patient, but also become important key steps in reducing the side-effects of surgery. Thus, they enable surgery to become a module in modern multi-disciplinary cancer treatment, which blends into multimodular treatment options at different times and prolongs and widens the possibilities available to cancer patients. In this quickly changing environment, the requirement to learn and refine not only open surgical but also different minimally invasive techniques on high levels deeply impact modern surgical training pathways. The use of modern elearning tools and new and praxis-based surgical training possibilities have been readily integrated into modern surgical education,which persists throughout the whole surgical career of modern gynecologic and visceral surgery specialists