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Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown promising results as a synthetically lethal therapeutic approach for BRCA mutant and recurrent OC in clinical use. However, emerging data indicate that BRCA-deficient cancers may be resistant to PARPi, and the mechanisms of this resistance remain elusive. We found that amplification of KRAS likely underlies PARPi resistance in BRCA2-deficient HGSOC. Our data suggest that PLK1 inhibition restores sensitivity to PARPi in HGSOC with KRAS amplification. The sequential combination of PLK1 inhibitor (PLK1i) and PARPi drastically reduces HGSOC cell survival and increases apoptosis. Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist.

Ovarian cancer (OC) accounts for approximately 4% of cancer deaths in women worldwide and is the deadliest gynecologic malignancy. High-grade serous ovarian cancer (HGSOC) is the most predominant ovarian cancer, in which BRCA1/2 gene mutation ranges from 3 to 27%. PARP inhibitors (PARPi) have shown promising results as a synthetically lethal therapeutic approach for BRCA mutant and recurrent OC in clinical use. However, emerging data indicate that BRCA-deficient cancers may be resistant to PARPi, and the mechanisms of this resistance remain elusive. We found that amplification of KRAS likely underlies PARPi resistance in BRCA2-deficient HGSOC. Our data suggest that PLK1 inhibition restores sensitivity to PARPi in HGSOC with KRAS amplification. The sequential combination of PLK1 inhibitor (PLK1i) and PARPi drastically reduces HGSOC cell survival and increases apoptosis. Furthermore, we were able to show that a sequential combination of PLK1i and PARPi enhanced the cellular apoptotic response to carboplatin-based chemotherapy in KRAS-amplified resistant HGSOC cells and 3D spheroids derived from recurrent ovarian cancer patients. Our results shed new light on the critical role of PLK1 in reversing PARPi resistance in KRAS-amplified HGSOC, and offer a new therapeutic strategy for this class of ovarian cancer patients where only limited options currently exist.

The ideal management of early-stage cervical cancer has become the subject of a global controversy following the publication of a prospective study in 2018 that reported a worse oncologic outcome when comparing the minimally invasive approach to the laparotomy approach. The discussion involves both prospective and retrospective data and general and theoretical considerations. We wanted to look at the data available today and review the different opinions, offering an impartial assessment of the ongoing controversy.The available literature was reviewed, focusing on articles arguing for and against minimally invasive surgery in cervical cancer. We tried to avoid any fundamental bias, as is often evident in the available reviews on the subject. Literature both before and after the 2018 publication was taken into consideration.As is usual in discussions of concepts, the literature that is now available provides arguments for both sides of this challenging issue, depending on one's standpoint. Science-related writing is not immune to trends. There is a curious shift in opinion seen before and after 2018. One must question whether there was a prejudice in favor of minimally invasive surgery prior to the publication of the NEJM articles and a bias against it afterward.Whether further minimally invasive surgery for cervical cancer is invariable is tied to the more pressing question of how this surgery will have to be centralized in the future. Unless these questions are linked, no satisfactory solution can be found.

HIFU steht fur „high intensity focussed ultrasound“ und ist eine relativ neue Technologie, die als MRT(Magnetresonanztomographie)- oder als ultraschallgesteuertes HIFU angeboten wird. Wahrend der letzten Jahre sind vermehrt Arbeiten erschienen, die mogliche Optionen klarer definieren und den medizinischen Nutzen dieser neuen Methode objektiv nachweisen wollen. Inhalt der vorliegenden Publikation ist eine Darstellung der dominanten Techniken und der existierenden Literatur zum Stand der verfugbaren evidenzbasierten Medizin. Es soll herausgearbeitet werden, inwieweit Behauptungen zu Therapieerfolgen berechtigt sind und welche Entwicklungen in der Zukunft realistischerweise zu erwarten sind. Durchsicht der relevanten Datenbanken (PubMed, Medline, Embase) und der verfugbaren Industrieinformationen. HIFU ist eine komplexe Technologie, hinter der beachtliche technische Leistungen stehen. Der konkrete klinische Nutzen wird aktuell etabliert. Wie bei vielen neuen Technologien in der Fruhphase ist die Zukunft von HIFU weder garantiert noch komplett abzusehen. Aufgrund der einzigartigen Wirkweise konnte es sich um eine hochrelevante Zukunftstechnologie handeln. Bei der Kritik an aktuellen Insuffizienzen wird ubersehen, welche Schwierigkeiten ahnlich revolutionare Neuerungen, wie der diagnostische Ultraschall oder die Laparoskopie, uberwinden mussten, bevor sie aus der taglichen Routine nicht mehr wegzudenken waren. Die Frauenheilkunde sollte gegenuber dieser Zukunftstechnologie offen sein; es ware ein Fehler, ihr hohes innovatives Potenzial in Deutschland nicht weiter zu verfolgen.

Myomas, also known as fibroids, are a specific characteristic of the human species. No other primates develop fibroids. At a cellular level, myomas are benign hyperplastic lesions of uterine smooth muscle cells. There are interesting theoretical concepts that link the development of myomas in humans with the highly specific process of childbirth from an upright position and the resulting need for greatly increased “expulsive” forces during labor. Myomas might be the price our species pays for our bipedal and highly intelligent existence. Myomas affect, with some variability, all ethnic groups and approximately 50% of all women during their lifetime. While some remain asymptomatic, myomas can cause significant and sometimes life-threatening uterine bleeding, pain, infertility, and, in extreme cases, ureteral obstruction and death. Traditionally, over 50% of all hysterectomies were performed for fibroids, leading to a significant healthcare burden. In this article, we review the developments of the past 20 years with regard to multiple new treatment strategies that have evolved during this time.

Dargestellt wird die aktuelle Datenlage bezuglich epidemiologischer Beobachtungen und atiologischer Faktoren fur die unterschiedlichen Vulvamalignome. Das Wissen um die Epidemiologie, die Pathogenese und die atiologischen Faktoren des Vulvakarzinoms ist nicht nur relevant fur Praventionsstrategien, Fruherkennungsmasnahmen, die Implementierung von Screnningprogrammen und fur therapeutische Entscheidungen, sondern auch fur das postoperative Management im Sinne der Risikostratifizierung. Skizziert wird auch das beginnende Verstandnis der molekularbiologischen Pathways. Die weitere Forschung kann kunftig eine dezidiert neue Systematisierung der nosologischen Subentitaten initiieren, ferner moglicherweise auch innovative therapeutische Ansatze und Strategien ermoglichen.

Introduction Acute rejection following kidney transplantation (KTx) is still one of the challenging complications leading to chronic allograft failure. The aim of this study was to investigate the role of microdialysis (MD) in the early detection of acute graft rejection factor following KTx in porcine model. Methods Sixteen pigs were randomized after KTx into case (n = 8, without immunosuppressant) and control groups (n = 8, with immunosuppressant). The rejection diagnosis in our groups was confirmed by histopathological evidences as “acute borderline rejection”. Using MD, we monitored the interstitial concentrations of glucose, lactate, pyruvate, glutamate and glycerol in the transplanted grafts after reperfusion. Results In the early post-reperfusion phase the lactate level in our case group was significantly higher comparing to the control group and remained in higher levels until the end of monitoring. The lactate to pyruvate ratio showed a considerable increase in the case group during the post-reperfusion phase. The other metabolites (glucose, glycerol, glutamate) were nearly at the same levels at the end of our monitoring in both study groups. Conclusion The increase in lactate and lactate to pyruvate ratios seems to be an indicator for early detection of acute rejection after KTx. Therefore, MD as a minimally invasive measurement tool may help to identify the need to immunosuppression adjustment in the early KTx phase before the clinical manifestation of the rejection.

Background: The incidence of diabetes has been steadily increasing. The only curative option for diabetes is pancreas transplantation (PTx). Porcine models are valuable because of their anatomical and physiological similarities to human beings. Our aim is to introduce a simplified technique of PTx in a porcine model. Methods: In Landrace pigs (n = 32), after median laparotomy, the pancreas was mobilized, and the portal and splenic veins were divided. The proper hepatic and splenic arteries and the bile duct were also prepared, and the duodenal bulb was prepared and stapled. The third portion of the duodenum was freed up to the ligament of Treitz and stapled, and the renal arteries were ligated. After systemic heparinization, the pancreas was perfused through the abdominal aorta with histidine-tryptophan-ketoglutarate solution. The portal and splenic veins were cut for evaluating the sufficiency of perfusion. Whole pancreaticoduodenal graft was procured along with an aortic jump graft containing mesenteric and celiac trunks. In recipients, after total pancreatectomy, the suprarenal inferior vena cava and infrarenal aorta were prepared for vascular anastomosis in an end-to-side manner. After pancreas reperfusion, duodenoduodenostomy was performed in an end-to-side manner. Results: Median cold and warm ischemia times were 10 h (range, 9-14 h) and 50 min (range, 35-80 min), respectively. The hemodynamic status was stable throughout the operation. The median follow-up period was 7 days (range, 4-10). There were no major intra- and postoperative complications. Conclusion: By using an aortic jump graft, there was no need to perform additional arterial reconstruction resulting in a short warm ischemic and operation time. End-to-side portocaval and duodenoduodenal anastomoses make this model of PTx a very feasible method for experimental evaluations.

Background Laparoscopic staging is rapidly evolving as an important surgical approach in the field of gynecology oncology. However, the specific learning curve associated with this approach remains poorly investigated. This study aimed to evaluate the learning curve for laparoscopic staging of uterine cancers. Methods A series of 28 consecutive laparoscopic hysterectomies with or without pelvic and/or para-aortic lymph node sampling for the treatment of early and locally advanced endometrial or cervical cancer were performed between July 2008 and January 2011. The analyses of the learning curves of the institution were performed for 20 patients who had undergone pelvic lymphadenectomy and/or para-aortal lymph node sampling. The learning curve period has also been compared with the last 26 patients who received laparotomy staging (“open” group) due to the same diagnosis and by the same surgical team. To assess the short- and long-term outcomes, we used validated questionnaires to record the clinical and follow-up results, any complaints or subjective reports from the patients, and details of their quality of life. All data were collected prospectively in a database and reviewed retrospectively. The learning was evaluated using the cumulative sum (CUSUM) method. Results The CUSUM learning curve consisted of two distinct phases: phase 1 (the initial 9 cases) and phase 2 (the subsequent cases) which presented the mastery phase, with the operative time of 397.7 ± 63.5 versus 300.6 ± 19.4 min (p

Background Advances in surgical techniques and immunosuppressive therapy have improved graft survival in transplant recipients. However, intense long-term immunosuppression increases the incidence of cancer in these patients compared with the general population, not least because of viral infections. Cervical cancer is the third most common malignancy worldwide. In early invasive cervical cancer, surgery is the treatment of choice. Case In 2010, we performed a laparoscopically assisted vaginal hysterectomy (LAVH) in a 42-year-old patient with micro-invasive cervical adenocarcinoma (FIGO stage IA1) who had undergone two liver transplantations in 2006 and 2008. The patient was followed up for 18 months after surgery. Despite upper abdominal adhesions and minor difficulties in inserting the Veress needle, the pneumoperitoneum was created safely. The procedure was completed within 157 minutes without any intraoperative complications. Blood loss was less than 100 mL. Postoperative course was uncomplicated with minimal fluctuations in liver function markers. Immunosuppressive therapy was continued without modification. The patient was discharged on postoperative day 9. No complications or recurrence were reported during the 18-month follow-up. Conclusions The laparoscopic approach is a justifiable form of surgical management in the treatment of a liver transplant recipient with early-stage cervical cancer.

Background: Microdialysis (MD) can detect organ-related metabolic changes before they become measurable in plasma through the biochemical parameters. This study aims to evaluate the early detection of metabolic changes during experimental kidney transplantation (KTx). Material and methods: During preparation of 8 donor kidneys, one MD catheter was inserted in the renal cortex and samples were collected. After a 6-hour cold ischemia time (CIT), kidneys were implanted in the 8 recipient pigs. Throughout the warm ischemia time (WIT) and after reperfusion, kidneys were monitored. The interstitial glucose, lactate, pyruvate, glutamate, and glycerol concentrations were evaluated. Results: A significant decline in glucose level was observed at the end of CIT. The lactate level was reduced to the minimum point of 0.35 ± 0.08 mmol/L in CIT. After reperfusion, lactate values raised significantly. During the WIT, the pyruvate level increased, continued until the end of the WIT. For glutamate, a steady increase was noted during explantation, CIT, WIT, and early reperfusion phases. The increase of glycerol value continued in the early postreperfusion, which was then followed by a sharp decline. Conclusion: MD is a fast and simple minimally invasive method for measurement of metabolic substrates in renal parenchyma during KTx. MD offers the option of detecting minor changes of interstitial glucose, lactate, pyruvate, glutamate, and glycerol in every stage of KTx. Through the use of MD, metabolic changes can be continuously monitored during the entire procedure of KTx.

Background. In kidney transplantation (KTx), vascular thrombosis has a major impact on morbidity and graft survival. The ischaemia, caused by thrombosis, can lead to interstitial metabolite changes. The aim of this experimental study was to create conditions in which the graft would be prone to vascular thrombosis following KTx and then to evaluate the role of microdialysis (MD) for its early detection. Methods. Sixteen randomized pigs in the control group received heparin and immunosuppressive drugs, while the case group received none. Based on histopathological evidence of vascular thrombosis, the case group was subdivided into mildly and severely congested subgroups. Using MD, we evaluated the interstitial concentrations of glucose, lactate to pyruvate ratio, glutamate and glycerol in the transplanted grafts during different phases of KTx. Results. Following reperfusion, we noted considerable changes. The severely congested subgroup showed a low and decreasing level of glucose. Only in this group did the lactate to pyruvate ratio continue to increase until the end of monitoring. The glycerol level increased continuously in the entire case group and this increase was most significant in the severely congested subgroup. In all of the study groups, glutamate concentration remained in a low steady state until the end of monitoring. Conclusions. MD can be an appropriate method for early detection of vascular complications after KTx. Decreasing glucose levels, increased lactate to pyruvate ratio and increased glycerol levels are appropriate indicators for early detection of vascular thromboses following KTx. Particularly, the glycerol level could predict the necessity and urgency of intervention needed to ultimately save the transplanted kidney.

Without adequate prophylaxis, liver transplantation (LTx) is frequently followed by hepatitis B virus (HBV) reinfection, which results in rapidly progressing liver disease and significantly decreased overall survival. In the last two decades, significant progress has been made in the prophylaxis and treatment of HBV.We present an overview of different protocols and regimens used for prophylaxis of HBV reinfection after LTx and describe the protocol implemented at our center. Following LTx, HBV reinfection can be effectively prevented by administration of anti-hepatitis B immunoglobulin (HBIg) alone or more recently in combination with antiviral nucleoside/nucleotide analogs (NUCs). Several studies reported good results with the use of HBIg alone, but combination treatment with HBIg and NUCs has proven to be a superior prophylactic regimen for HBV recurrence. At present, combination therapy (HBIg and a nucleoside or nucleotide analog) is the gold standard used in many transplantation centers. This preventive regimen reduces the risk of a recurrence of HBV infection and thereby the need for re-transplantation. Future and ongoing studies will show how long HBIg must be given after transplantation, especially when used in combination with potent antivirals, such as entecavir or tenofovir.

Although the use of non-heart-beating donors (NHBD) is the oldest type of organ transplantation, the results were and still are disappointing. To consider using a liver from NHBD, it is of importance to assess the graft viability. Our aim was to assess the role of reduced liver glutathione (rGSHL) as a potential predictive marker of liver function before transplantation. Autotransplanted livers were subjected to 0, 60, and 90 minutes of ischemia in 20 pigs. We analyzed systemic cardiocirculatory parameters, bowel ischemia by endotoxin, endotoxin-neutralizing capacity, oxidative stress, hepatic perfusion parameters, liver enzymes, local bowel ischemia, and liver oxidative stress (rGSHL and oxidized glutathione in the liver). Autotransplantation was comparable to donor explantation/recipient transplantation with respect to systemic and hepatic parameters. Liver ischemia for 0, 60, and 90 minutes resulted in survival in 100% (NHBD-0), 71% (NHBD-60), and 57% (NHBD-90) of animals. Of all parameters, only hepatic microperfusion, pHi of the sigmoid colon, and bowel ischemia by endotoxin in the NHBD-90 group showed significant changes compared to NHBD-60 and control animals. Although systemic endotoxin-neutralizing capacity and total glutathione in erythrocytes levels were mainly influenced by cold perfusion, hepatic oxidative stress increased with ischemia time. The cut-off value of 11.5 ng/mmol of rGSHL could distinguish survivors from nonsurvivors, independent of the ischemia time. In conclusion, rGSHL has the potential of becoming an important viability marker, as it could predict survival in autotransplantation NHBD model regardless of the ischemia time. Further investigation to declare reasons for differing rGSHL levels within the liver is required.

Summary Background/Objective Currently, due to lack of optimal donors, more marginal organs are transplanted. Therefore, there is a high interest to ameliorate preischemic organ preservation, especially for critical donor organs. In this regard, a new histidine-tryptophane ketoglutarate (HTK-N) solution has been designed and its protective efficacy was compared with the standard preservation solutions—University of Wisconsin solution and standard HTK or Custodiol (Bretschneider's solution). Methods Seventy-two landrace pigs were included into the study, as donors and recipients. The donor kidneys were perfused during explantation with cold University of Wisconsin solution ( n = 12), standard HTK ( n = 12), or HTK-N solutions ( n = 12), kept in the respective preservation solution at 4°C for 30 hours, implanted in the recipient pigs, and reperfused. The pigs survived in daily control for 7 days. The serum creatinine and blood urea nitrogen were assessed in pre- and postreperfusion phase on the 3 rd day and 7 th day posttransplantation. Additionally, tissue samples were taken to analyze the histopathological degree of tubular injury and regeneration before and after reperfusion. Results The three preservation groups were comparable in age, body weight, and hemodynamic parameters. According to statistical proof, they differed in none of the control parameters. Conclusion Although the new preservation HTK solution is in several points a well-thought-out modification of the standard HTK solution, its preservation efficacy, at least for kidney preservation in a pig model for 30 hours, seems to be comparable to the current used solutions. A real advantage, however, could be confirmed in clinical settings, where marginal organs may influence the clinical outcome.

Introduction: Polycystic ovary syndrome (PCOs) is the most common endocrinopathy affecting premenopausal women. It has been associated with 75% of cases with anovulatory infertility. Methods: A prospective study was performed in 87 PCOs women from Dr. Maleknia Endocrinology Laboratory and Research Center (Tehran, Iran) (patients were referred from all over Iran). These PCOs patients had anovulatory infertility. For all the patients, the values of glucose and insulin levels in different hours of OGTT, and BMI were recorded. For all the patients with fasting glucose-to-insulin ratio less than 4.5, metformin was started. We compared the patients who had got pregnant after 12 months (group 1) with the patients who did not get pregnant (group 2). Results: A total of 47 (54%) patients got pregnant (group 1). Age in group 1 was 28.02±5.63 years and in group 2 was 28.8±5.51 years old. Fasting glucose-to-insulin ratio in group 1 was 3.87±0.35 and in group 2 was 3.96±0.37. There was no significant difference between these two groups in Age and fasting G/I ratio. BMI in group 1 was 26.42±3.34, and in group 2 was 28.54±2.98 kg/m2. There was a statistically significant difference between these two groups in BMI (p

Summary Introduction One of the great challenges in pancreas transplantation is the ischemia reperfusion injury. It is mentioned that free oxygen and/or nitrogen radicals play a prominent role in this phase. To minimize this problem, a modified histidine–tryptophan–ketoglutarate (HTK) solution that contains modified antioxidants has been developed. Our aim was to evaluate this solution in improving the viability of the pancreas in comparison with standard HTK and University of Wisconsin (UW) solutions in a porcine model of pancreas transplantation. Materials and methods Twenty-three Landrace pigs were divided into three identical groups. After a 10-hour preservation time at 4°C, the pancreas was implanted in the organs of the recipients in a standardized manner. Serum parameters were assessed prior to and after implantation on the 1 st postoperative day, 3 rd postoperative day, and 7 th postoperative day. Furthermore, three biopsies were taken: prior to and after reperfusion, and on Day 7 to assess the grafts. Results An analysis of serum glucose among the three groups showed no significant differences. Evaluation of the insulin levels showed no significant difference between the modified and standard HTK groups; however, differences between HTK and UW were significant ( p = 0.004 in favor of UW solutions). The histopathological results showed a trend of a higher grade of rejection of pancreas tissue in the UW group compared to both HTK groups. Conclusion The modified HTK solution could preserve the pancreas for the preservation of the graft with similar results to those observed for standard solutions without any significant difference. The trend showed that the pathological finding in the UW group was not as good as that in the modified HTK and standard HTK groups.

Aims. Different surgical transection methods have been used for distal pancreatectomy (DP), but none of them has yet achieved perfect results. This study compares 2 standard transection techniques with the alternative LigaSure technique. Methods. Forty-eight pigs underwent a DP. Sixteen animals were operated on with a scalpel followed by hand suturing. Sixteen pigs received a DP using an Endo GIA, and the pancreas of 16 pigs was transected with LigaSure. The transection surface of remnant pancreas was observed for liquid collection and abscess on postoperative day 7. Results. Operating time on the day of DP was significantly different, with a shorter operating time in the stapler and LigaSure groups. The morbidity on postoperative day 7 was similar in all groups. Conclusion. In the present experimental animal study, LigaSure seems to be fast and safe as well as comparable with the standard transection and closure techniques in DP.