The clinical relevance of fractional curettage in the diagnostic management of primary endometrial cancer.

OBJECTIVE: Hysteroscopy and fractional curettage are commonly utilized techniques for the diagnosis of postmenopausal abnormal uterine bleeding (AUB) and histopathological verification of primary endometrial cancer (EC). This study delves into the clinical significance of procuring preoperative endocervical tissue in conjunction with corpus fractions through fractional curettage. DESIGN: This retrospective study encompassed a cohort of 84 patients diagnosed with T1-stage endometrial cancer (EC) and 55 patients diagnosed with T2-stage EC, who underwent primary treatment between the years 2011 and 2021 at the University Hospital Frankfurt or Jung-Stilling Hospital Siegen. MATERIALS, SETTING, METHODS: Among the postoperative T2-stage EC patients, a stratification was performed based on preoperative endocervical curettage (ECC) results obtained through fractional curettage. Categorical and continuous variables were compared utilizing the Pearson-Chi-square test, while for multivariate analyses and regression modeling, the Kaplan-Meier method and Cox regression models were respectively employed. RESULTS: The median age of patients with pT2-stage EC was 64 years (range: 38 to 85). A predominant majority of these patients exhibited the endometrioid subtype of EC (90.9%). Upon conducting comparative analysis between groups, a notably higher frequency of laparotomies was observed (p=0.002) among patients in whom preoperatively detected positive endocervical curettage (ECC) was evident. The detection performance of fractional curettage in identifying positive ECC yielded a sensitivity of 70.9% and a specificity of 73.8%. In multivariate analysis, age at diagnosis (p=0.022), positive ECC observed during fractional curettage (p=0.036), and the FIGO stage (p=0.036) emerged as prognostic determinant for progression-free survival (PFS). Independent prognostic factors for overall survival (OS) were age at diagnosis (p=0.003), positive ECC (p=0.008), histological grading (p=0.016), and the FIGO stage (p=0.022). A significant difference in OS was evident between patients characterized by preoperative negative ECC and those displaying positive ECC (81.8 vs. 59.5 months, p=0.019). LIMITATIONS: The retrospective design of the study, as well as a small number of patients. CONCLUSIONS: Preoperative determination of endocervical involvement of primary T2-stage EC could be a prognostic indicator in decision-making to treat EC. The conduct of prospective trials is necessary to definitively establish the routine application and associated benefits of fractional curettage in the context of primary endometrial cancer.

Postoperative Reproductive Outcomes in Patients with Endometriosis-Associated Infertility: A Single-Center Retrospective Study.

OBJECTIVES: Endometriosis is a chronic inflammatory disease known to contribute to infertility. Laparoscopic excision of endometriotic lesions represents a standard treatment modality for symptomatic women. Our study aims to assess the potential benefits of laparoscopic excision of endometriosis in patients experiencing infertility associated with the condition, as well as to define the clinical factors that may impact the cumulative pregnancy rate. DESIGN: In this retrospective analysis, a total of 102 patients with endometriosis-related infertility were enrolled. MATERIALS, SETTING, METHODS: All participants underwent reproductive surgery and were then categorized into two groups: those who conceived were assigned to group A, while those who did not were assigned to group B. The correlation between clinical factors and pregnancy rate was assessed using the log-rank test, and both univariate and multivariate analyses were conducted utilizing the Cox regression model. RESULTS: The median age of the patients was 33.5 years, with a median follow-up duration of 70 months. Throughout the study period, 71 patients (69.6%) conceived (group A), while the remaining 31 patients (30.4%) did not conceive (group B), irrespective of the use of Assisted-Reproduction Technologies. The Cox regression model revealed that factors such as the duration of infertility, presence of deep infiltrating endometriosis, bowel endometriosis, rASRM stages, pelvic adhesions, and recurrent disease negatively impacted postoperative conception rates. Conversely, complete excision and coagulation of endometriotic lesions, as well as ablation of ovarian endometriomas, emerged as independent positive predictive factors for postoperative clinical pregnancy. LIMITATIONS: Limitations of this study is retrospective design of the study, as well as a small number of patients. CONCLUSIONS: Complete excision of endometriosis during reproductive surgery may yield a positive effect and optimize the likelihood of pregnancy in patients with endometriosis-related infertility.

Sequential Targeting of PLK1 and PARP1 Reverses the Resistance to PARP Inhibitors and Enhances Platin-Based Chemotherapy in BRCA-Deficient High-Grade Serous Ovarian Cancer with KRAS Amplification.

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.

A simplified technique of pancreas transplantation in a porcine model.

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.

Learning curve for laparoscopic staging of early and locally advanced cervical and endometrial cancer.

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 < 0.0001). The significance of the difference between the two phases and "open" group changed in terms of number of lymph nodes retrieved, intra-operative blood loss and hospital stay. The conversion rate of phase 1 was higher than phase 2 [2 (22.2 %) respectively 1 (9 %)]. CONCLUSIONS: This series confirms previous study findings concerning the feasibility and the safety of laparoscopic staging and provides information for surgeons in single centers considering adopting an endoscopic strategy to monitor the different aspects of outcomes during the implementation process for internal benchmarking. The operative outcome of laparoscopic staging intervention improves with experience. The data reported in this article suggest that after a learning curve of 9 patients, a relevant improvement at least regarding the duration of the operation can be achieved for experienced surgeons who start performing laparoscopic staging of uterine cancers. However, due to the limited number of patients as well as number of para-aortic lymph node sampling procedures, further studies are required for firm conclusions to be drawn.

Pregnancy after laparoscopic surgery for endometriosis: How long should we wait? A retrospective study involving a long-term follow up at a university endometriosis center.

OBJECTIVE: To find the factors that influence the time until pregnancy after laparoscopic intervention and to evaluate the proper time to start assisted reproductive therapy (ART). METHODS: This is a retrospective analysis that includes a prospective evaluation of patients with infertility and with a diagnosis of endometriosis. A subgroup of patients who desired to be pregnant after laparoscopic intervention (102 patients) was followed up for 36-197 months after the surgery. RESULTS: In this study, 71 (69.9%) and 60 (58.8%) of the patients achieved pregnancy and live birth, respectively. In the group of patients who became pregnant, the duration of infertility was significantly lower (2.7 ± 2.1 years vs. 4.7 ± 3.2 years). The median time until pregnancy after laparoscopic intervention was 8 months (the average was 10 months). After 38 months, no pregnancy occurred. CONCLUSION: In the group of patients with endometriosis and infertility, the first 12 months were the optimal time for pregnancy. For women with revised American Society for Reproductive Medicine classification of endometriosis (rASRM) stages I and II, spontaneous pregnancy can probably be delayed for up to 24 months, but in patients with rASRM stages III and IV, ART may be considered after 12 months. The gynecologist must be careful about the timing of further interventions after the operation.

Synergistic Sensitization of High-Grade Serous Ovarian Cancer Cells Lacking Caspase-8 Expression to Chemotherapeutics Using Combinations of Small-Molecule BRD4 and CDK9 Inhibitors.

Ovarian cancer is one of the most lethal gynecological cancers worldwide, with approximately 70% of cases diagnosed in advanced stages. This late diagnosis results from the absence of early warning symptoms and is associated with an unfavorable prognosis. A standard treatment entails a combination of primary chemotherapy with platinum and taxane agents. Tumor recurrence following first-line chemotherapy with Carboplatin and Paclitaxel is detected in 80% of advanced ovarian cancer patients, with disease relapse occurring within 2 years of initial treatment. Platinum-resistant ovarian cancer is one of the biggest challenges in treating patients. Second-line treatments involve PARP or VEGF inhibitors. Identifying novel biomarkers and resistance mechanisms is critical to overcoming resistance, developing newer treatment strategies, and improving patient survival. In this study, we have determined that low Caspase-8 expression in ovarian cancer patients leads to poor prognosis. High-Grade Serous Ovarian Cancer (HGSOC) cells lacking Caspase-8 expression showed an altered composition of the RNA Polymerase II-containing transcriptional elongation complex leading to increased transcriptional activity. Caspase-8 knockout cells display increased BRD4 expression and CDK9 activity and reduced sensitivities to Carboplatin and Paclitaxel. Based on our work, we are proposing three potential therapeutic approaches to treat advanced ovarian cancer patients who exhibit low Caspase-8 expression and resistance to Carboplatin and/or Paclitaxel-combinations of (1) Carboplatin with small-molecule BRD4 inhibitors; (2) Paclitaxel with small-molecule BRD4 inhibitors, and (3) small-molecule BRD4 and CDK9 inhibitors. In addition, we are also proposing two predictive markers of chemoresistance-BRD4 and pCDK9.

Using microdialysis for early detection of vascular thrombosis after kidney transplantation in an experimental porcine model.

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. CONCLUSION: 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.

New Insights on the Minimal-Invasive Therapy of Cervical Cancer.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Modern Myoma Treatment in the Last 20 Years: A Review of the Literature.

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.