Dopamine receptors D1 and D2 show prognostic significance and potential therapeutic applications for endometrial cancer patients.

OBJECTIVE: Catecholaminergic signaling has been a target for therapy in different type of cancers. In this work, we characterized the ADRß2, DRD1 and DRD2 expression in healthy tissue and endometrial tumors to evaluate their prognostic significance in endometrial cancer (EC), unraveling their possible application as an antitumor therapy. METHODS: 109 EC patients were included. The expression of the ADRß2, DRD1 and DRD2 proteins was evaluated by immunohistochemistry and univariate and multivariate analysis to assess their association with clinic-pathological and outcome variables. Finally, HEC1A and AN3CA EC cell lines were exposed to different concentrations of selective dopaminergic agents alone or in combination to study their effects on cellular viability. RESULTS: ADRß2 protein expression was not associated with clinico-pathological parameters or prognosis. DRD1 protein expression was reduced in tumors samples but showed a significant inverse association with tumor size and stage. DRD2 protein expression was significantly associated with non-endometrioid EC, high grade tumors, tumor size, worse disease-free survival (HR = 3.47 (95%CI:1.35-8.88)) and overall survival (HR = 2.98 (95%CI:1.40-6.34)). The DRD1 agonist fenoldopam showed a reduction of cellular viability in HEC1A and AN3CA cells. The exposure to domperidone, a DRD2 antagonist, significantly reduced cell viability compared to the control. Finally, DRD1 agonism and DRD2 antagonism combination induced a significant reduction in cell viability of the AN3CA cells compared to monotherapy, close to being an additive response than a synergistic effect (CI of 1.1 at 0.5% Fa). CONCLUSION: DRD1 and DRD2 expression levels showed a significant association with clinico-pathological parameters. Both the combined activation of DRD1 and blockage of DRD2 may form an innovative strategy to inhibit tumor growth in EC.

EndoTrainer: a novel hybrid training platform for endoscopic surgery.

PURPOSE: Endoscopy implies high demanding procedures, and their practice requires structured formation curricula supported by adequate training platforms. Physical platforms are the most standardised solution for surgical training, but over the last few years, virtual platforms have been progressively introduced. This research work presents a new hybrid, physic-virtual, endoscopic training platform that exploits the benefits of the two kind of platforms combining realistic tools and phantoms together with the capacity of measuring all relevant parameters along the execution of the exercises and of providing an objective assessment performance. METHODS: The developed platform, EndoTrainer, has been designed to train and assess surgical skills in hysteroscopy and cystoscopy following a structured curricula. The initial development and validation is focused on hysteroscopic exercises proposed in the Gynaecological Endoscopic Surgical Education and Assessment (GESEA) Certification Programme from The Academy and European Society for Gynaecological Endoscopy (ESGE) and analyses the obtained results of an extensive study with 80 gynaecologists executing 30 trials of the standard 30 degree endoscope navigation exercise. RESULTS: The experiments demonstrate the benefits of the presented hybrid platform. Multi-variable statistical analysis points out that all subjects have obtained statistically significant improvement in all relevant parameters: shorter and safer trajectories, improved 30-degree endoscope navigation, accurate positioning over the targets and reduction of the execution time. CONCLUSION: This paper presents a new hybrid approach for training, and evaluating whether it provides an objectivable improvement of camera navigation endoscopic basic skills. The obtained results demonstrate the initial hypothesis: all subjects have improved their camera handling and navigation skills.

Surgical treatment in older patients with endometrial cancer: A retrospective study.

INTRODUCTION: Older patients (OP) diagnosed with endometrial cancer (EC) are less likely to receive an optimal surgical treatment compared with non-older patients (NOP). This undertreatment along with the presence of more aggressive tumours at diagnosis can explain the worse prognosis of EC in OP. There is limited evidence comparing perioperative outcomes between OP and NOP, and the benefit of applying complex procedures to OP is still controversial. The primary objective of the study was to compare intraoperative and postoperative complications between NOP and OP with EC that underwent primary surgery. Secondary objectives were to compare surgical management and survival rates. METHODS: This is a retrospective single-centre observational study including women undergoing surgery for EC between 2010 and 2019. Patients were classified according to age as NOP (younger than 75 years) or OP (75 years or older). Basal characteristics and surgical outcomes of groups were compared using Chi-square, Fisher's exact tests, student T-tests or Mann Whitney tests. Kaplan Meier analysis was used to evaluate survival. RESULTS: In total 281 patients underwent primary surgery for EC between 2010 and 2019 in our centre. At diagnosis, 184 patients were younger than 75 years while 97 were 75 and older. No differences were found in disease characteristics. Most of our patients (83,3%) underwent laparoscopic surgery. Pelvic (58,2% vs. 37,1%, p = 0,001) and para-aortic (46,7% vs. 23,7%, p < 0,001) lymphadenectomies were performed more frequently in NOP compared with OP. Rates of intra-operative (6,5% vs. 12,4%, p = 0,116) and post-operative (13,0% vs. 20,6%, p = 0,120) complications were not statistically different between NOP and OP, and neither was the rate of severe complications according to Clavien-Dindo classification (5,4% vs. 8,2% of complications grade III-V respectively, p = 0,387). The 5-year disease-specific survival (DSS) rate tended to be lower in the OP than in the NOP (74,8% vs. 82,5%, p = 0,071). Considering only patients in whom complete surgical staging was performed, OP presented similar DSS to NOP, with comparable complication rate. CONCLUSIONS: OP do not present a significantly higher rate of perioperative complications compared to NOP. However, they underwent fewer lymphadenectomies and tended to present poorer DSS. Further studies are needed to standardize the surgical management of these patients.

Nano-Based Approved Pharmaceuticals for Cancer Treatment: Present and Future Challenges.

Cancer is one of the main causes of death worldwide. To date, and despite the advances in conventional treatment options, therapy in cancer is still far from optimal due to the non-specific systemic biodistribution of antitumor agents. The inadequate drug concentrations at the tumor site led to an increased incidence of multiple drug resistance and the appearance of many severe undesirable side effects. Nanotechnology, through the development of nanoscale-based pharmaceuticals, has emerged to provide new and innovative drugs to overcome these limitations. In this review, we provide an overview of the approved nanomedicine for cancer treatment and the rationale behind their designs and applications. We also highlight the new approaches that are currently under investigation and the perspectives and challenges for nanopharmaceuticals, focusing on the tumor microenvironment and tumor disseminate cells as the most attractive and effective strategies for cancer treatments.

Neural plasticity of the uterus: New targets for endometrial cancer?

Endometrial carcinoma is the most common gynecological malignancy in Western countries and is expected to increase in the following years because of the high index of obesity in the population. Recently, neural signaling has been recognized as part of the tumor microenvironment, playing an active role in tumor progression and invasion of different solid tumor types. The uterus stands out for the physiological plasticity of its peripheral nerves due to cyclic remodeling brought on by estrogen and progesterone hormones throughout the reproductive cycle. Therefore, a precise understanding of nerve-cancer crosstalk and the contribution of the organ-intrinsic neuroplasticity, mediated by estrogen and progesterone, of the uterine is urgently needed. The development of new and innovative medicines for patients with endometrial cancer would increase their quality of life and health. This review compiles information on the architecture and function of autonomous uterine neural innervations and the influence of hormone-dependent nerves in normal uterus and tumor progression. It also explores new therapeutic possibilities for endometrial cancer using these endocrine and neural advantages.

Closed Piezo Preservation Rhinoplasty.

BACKGROUND: The application of piezoelectric instruments (PEIs), which made the work with the nasal pyramid a predictable and controlled stage of rhinoplasty, is still more often related to the open approach. The intranasal approach is constantly associated with standard methods of osteotomies, including percutaneous techniques, which represent certain limitations in working with the bony vault without managing the surface and thickness of its walls and the risk of uncontrolled fractures. OBJECTIVES: The authors apply PEIs for osteotomies and reshaping of the nasal pyramid through the closed approach with preservation rhinoplasty and complete subperichondrial and subperiosteal dissection. METHODS: The technique of working with the nasal pyramid using PEIs with the closed approach is described. The patients were grouped according to the methods of nasal pyramid surgery-Push Down (PD), Let Down (LD) with Rhinosculpture (Rs), or the combinations. The results of the surgeries with the application of PEIs on 134 patients were retrospectively analyzed before the surgery and 12 months after it according to the "Rhinoplasty Outcome Evaluation" (ROE). RESULTS: The average age of the patients was 28, 125 were female and 9 were male. The patients' satisfaction was excellent in 96% of all the cases included. There were two cases with residual humps and four cases with residual asymmetries in cases of severe deviations. CONCLUSIONS: Via intranasal approach, it is possible to use PEIs for managing the bony vault in primary rhinoplasty. The limitations for this technique are underdevelopment of the nasal dorsum, cleft lip nose situations, post-traumatic and previous rhinoplasty cases. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Convolutional neural networks for PET functional volume fully automatic segmentation: development and validation in a multi-center setting.

PURPOSE: In this work, we addressed fully automatic determination of tumor functional uptake from positron emission tomography (PET) images without relying on other image modalities or additional prior constraints, in the context of multicenter images with heterogeneous characteristics. METHODS: In cervical cancer, an additional challenge is the location of the tumor uptake near or even stuck to the bladder. PET datasets of 232 patients from five institutions were exploited. To avoid unreliable manual delineations, the ground truth was generated with a semi-automated approach: a volume containing the tumor and excluding the bladder was first manually determined, then a well-validated, semi-automated approach relying on the Fuzzy locally Adaptive Bayesian (FLAB) algorithm was applied to generate the ground truth. Our model built on the U-Net architecture incorporates residual blocks with concurrent spatial squeeze and excitation modules, as well as learnable non-linear downsampling and upsampling blocks. Experiments relied on cross-validation (four institutions for training and validation, and the fifth for testing). RESULTS: The model achieved good Dice similarity coefficient (DSC) with little variability across institutions (0.80 ± 0.03), with higher recall (0.90 ± 0.05) than precision (0.75 ± 0.05) and improved results over the standard U-Net (DSC 0.77 ± 0.05, recall 0.87 ± 0.02, precision 0.74 ± 0.08). Both vastly outperformed a fixed threshold at 40% of SUVmax (DSC 0.33 ± 0.15, recall 0.52 ± 0.17, precision 0.30 ± 0.16). In all cases, the model could determine the tumor uptake without including the bladder. Neither shape priors nor anatomical information was required to achieve efficient training. CONCLUSION: The proposed method could facilitate the deployment of a fully automated radiomics pipeline in such a challenging multicenter context.

Utility of Intraoperative Fluorescence Imaging in Gynecologic Surgery: Systematic Review and Consensus Statement.

BACKGROUND: This study aimed to review the current knowledge on the utility of intraoperative fluorescence imaging in gynecologic surgery and to give evidence-based recommendations to improve the quality of care for women who undergo gynecologic surgery. METHODS: A computer-based systematic review of the MEDLINE, CENTRAL, Pubmed, EMBASE, and SciSearch databases as well as institutional guidelines was performed. The time limit was set at 2000-2019. For the literature search, PRISMA guidelines were followed. A modified-Delphi method was performed in three rounds by a panel of experts to reach a consensus of conclusions and recommendations. RESULTS: Indocyanine green (ICG) is used primarily in gynecology for sentinel node-mapping. In endometrial and cervical cancer, ICG is a feasible, safe, time-efficient, and reliable method for lymphatic mapping, with better bilateral detection rates. Experience in vulvar cancer is more limited, with ICG used together with Tc-99 m as a dual tracer and alone in video endoscopic inguinal lymphadenectomy. In early ovarian cancer, results are still preliminary but promising. Indocyanine green fluorescence imaging also is used for ureteral assessment, allowing intraoperative ureteral visualization, to reduce the risk of ureteral injury during gynecologic surgery. CONCLUSIONS: For most gynecologic cancers, ICG fluorescence imaging is considered the tracer of choice for lymphatic mapping. The use of this new technology expands to a better ureteral assessment.

Tumor total lesion glycolysis and number of positive pelvic lymph nodes on pretreatment positron emission tomography/computed tomography (PET/CT) predict survival in patients with locally advanced cervical cancer.

OBJECTIVE: The aim of this study was to investigate the prognostic value of metabolic parameters obtained at pretreatment [18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ([18F]FDG PET/CT) in patients with locally advanced cervical cancer. We hypothesize that these metabolic parameters could optimize the treatment decision and thus favor the outcome of patients suffering locally advanced cervical cancer. METHODS: Patients with locally advanced cervical cancer underwent pretreatment PET/CT. Standard uptake values (maximum, mean, peak), metabolic tumor volume, and total lesion glycolysis were measured in the tumor and in the hypermetabolic pelvic lymph nodes. The relationship between clinical, pathological, and PET/CT metabolic parameters with recurrence-free survival and overall survival was assessed by Cox regression analysis. RESULTS: 115 patients with a median age of 52 years (range 23-77) presented with locally advanced cervical cancer. After a mean follow-up of 33.0 months after initiation of therapy, 26 patients (22.6%) recurred of which 17 patients had distant metastasis; 18 (15.7%) patients died. Recurrence-free survival at 2 and 5 years was 79.2% and 72.2%, respectively. The total lesion glycolysis of the tumor and the delay between diagnosis and treatment were significantly associated with recurrence-free survival in the multivariate analysis (HR 1.00, p=0.004, and HR 2.04, p=0.02, respectively). Only the total lesion glycolysis of the tumor ≥373.54 (HR 2.49, 95% CI 1.15 to 5.38; p=0.02) remained significant after log rank testing. Overall survival at 2 and 5 years was 91.7% and 68.8%, respectively. The number of PET-positive pelvic lymph nodes was the only independent prognostic factor for overall survival in the multivariate analysis (HR 1.43, 95% CI 1.13 to 1.81; p=0.003). CONCLUSION: Tumor total lesion glycolysis and the number of positive pelvic lymph nodes on pretreatment PET/CT appear to be independent prognostic factors for recurrence and survival in patients with locally advanced cervical cancer. This may help to select patients who may benefit from therapeutic optimization and closer surveillance.

Implications of extraperitoneal paraaortic lymphadenectomy to the left renal vein in locally advanced cervical cancer. A Spanish multicenter study.

OBJECTIVE: Paraaortic lymph node involvement is an important prognostic factor in locally advanced cervical cancer (LACC), but the anatomic limit of aortic lymphadenectomy is controversial. We assessed the impact of extraperitoneal paraaortic lymphadenectomy up to the left renal vein in patients with LACC undergoing pretherapeutic staging. METHODS: A retrospective, multicenter study of patients with LACC stages FIGO 2009 IB2 and IIA2-IVA treated in 10 Spanish reference hospitals in gynecological oncology between 2000 and 2016. Sites of metastatic paraaortic lymph nodes above or below the inferior mesenteric artery were evaluated. Procedural-related intraoperative and early and late complications were assessed. RESULTS: We included 634 patients undergoing paraaortic lymphadenectomy, in 616 (97.2%) of which the left renal vein was the upper limit of dissection (laparoscopy 592, robotic-assisted 24). The median surgical time was 150 min (interquartile range (IQR) 120-180), blood loss was 50 mL (range 20-80), and the length of stay was 2 days (range 2-3). Metastatic paraaortic involvement was found in 114 patients (18.5%), with infrarenal metastases in 73 (64%) of them. There were 11 patients (9.6%) with infrarenal metastases only, whereas in the remaining 62 (54.4%) patients concomitant infrarenal and inframesenteric metastases were observed. Intraoperative, early, and late postoperative complications occurred in 3.6%, 7.0%, and 4.5% of patients, respectively. CONCLUSIONS: In this study of patients with LACC undergoing surgical staging, paraaortic lymphadenectomy up to the left renal vein detected skip or isolated infrarenal metastasis in 9.6% of patients, with an acceptable surgical morbidity.

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Added value of para-aortic surgical staging compared to 18F-FDG PET/CT on the external beam radiation field for patients with locally advanced cervical cancer: An ONCO-GF study.

OBJECTIVE: Extended field chemoradiation is recommended for patients with locally advanced cervical cancer (LACC) and para-aortic lymph node (PALN) metastases. The radiation planning may be based on PET/CT while others recommend to rely on surgical staging. We report the rate of patients for whom the radiation field defined on PET/CT was modified by the histological PALN status. METHODS: Between March 2010 and December 2016, 168 consecutive patients with LACC underwent a pre-therapeutic PET/CT and PALN dissection. The data were reviewed retrospectively. The diagnostic performance of the PET/CT for definition of PALN status was calculated. We determined the percentage of patients for whom PALN dissection altered the external beam radiotherapy (EBRT) field defined on the PET/CT basis. RESULTS: Of 151 patients with negative PALNs on PET/CT, 26 had histological PALN metastases. Of 17 patients with positive PALNs on PET/CT, 9 were negative on histology of which 7 were located in the common iliac region. Sensitivity, specificity, positive and negative predictive value of PET/CT were 23.5, 93.3, 47.1 and 82.8% respectively. In total, 35 out of 168 patients underwent EBRT - field adaptation (pelvic vs extended field). The rate of radiation field modification (27,7%) was particularly high in the subgroup of patients with metastatic pelvic lymph nodes (PLNs) on PET/CT. CONCLUSION: Para-aortic surgical staging contributes significantly to individualize the radiation treatment of patients with LACC, particularly for those with positive PLNs at PET/CT. Indication of surgical staging deserves particular attention when the PET/CT suggests positive LNs in the common iliac region.

Endometrioid endometrial carcinomas with microcystic, elongated, and fragmented (MELF) type of myoinvasion: role of immunohistochemistry in the detection of occult lymph node metastases and their clinical significance.

In endometrioid endometrial carcinomas (EECs), microcystic, elongated, and fragmented (MELF) myoinvasion is associated with easily overlooked lymph node metastases; however, the role of immunohistochemistry in their detection and their clinical significance have not been addressed. We identified MELF in 43 of 101 (43%) myoinvasive EECs. Nodes were removed in 49 (49%), 25 with MELF and 24 without MELF. Metastases were initially reported in 3 of the former (12%) and 2 of the latter (8%). All negative nodes were reviewed, and cytokeratin immunohistochemistry was performed. Three metastases were identified in the MELF group but none in the EECs without MELF. By immunohistochemistry, metastatic nodal isolated tumor cells (ITCs) were found in 6 of the remaining 19 MELF-positive cases. In contrast, lymph node metastases were detected in only 2 of the 22 EECs without MELF. MELF-positive cases had more lymph node metastases (P=.03) than myoinvasive EECs without MELF. At follow-up, all 6 patients with grade 1-2 EECs and nodal ITCs/micrometastases were alive (5 no evidence of disease and 1 with perineal disease). In contrast, 3 of 4 patients with grade 3 EECs and nodal ITCs/micrometastases died of disease, and the other patient was alive with tumor. In MELF, the frequency of ITCs/micrometastases in apparently negative lymph nodes is high. In patients with grade 1-2 EEC who had not received chemotherapy, the presence of nodal ITCs/micrometastases did not affect survival. In contrast, in high-grade tumors, ITCs/micrometastases were associated with unfavorable prognosis. Immunohistochemistry should be done in MELF-positive cases to detect occult lymph node metastases, especially in high-grade tumors.

CD8 down-regulation on cytotoxic T lymphocytes of patients with endometrioid endometrial carcinomas.

Carcinogenesis is a multistep process in which cancer cells and tumor stroma cells play important roles. T lymphocytes are immune constituents of tumor stroma and play a crucial function in anti-tumor response. By immunohistochemistry and flow cytometry, we studied T cytotoxic (CTLs) and T helper lymphocyte distribution and percentage in the tumor microenvironment and peripheral blood from 35 patients with endometrioid endometrial carcinomas (EEC). We also studied 23 healthy donors' blood samples as a control group. Tumor and non-tumoral endometrium samples were obtained. Immunohistochemistry revealed a high number of CTLs and T helper lymphocytes in the tumor stroma of myoinvasive EECs. T lymphocytes were mostly located in the invasive front. By flow cytometry, the percentages of CTLs and T helper lymphocytes were significantly higher in the tumor compared with the non-neoplastic endometrium (P = .0492 and P = .002). The mean fluorescence intensity of CD8 staining was lower in the tumor compared to the non-neoplastic endometrium (P = .001). There was also reduction of the mean fluorescence intensity of CD8 staining on peripheral blood from patients with grade 3 EECs compare to the peripheral blood from healthy donors (P = .0093). No alterations in the expression of granzymes A and B were found in the CTLs from the EEC cases. Finally, in a proteome profiler cytokine array we found that the growth differentiation factor 15 (GDF15) increased in blood in parallel to the tumor grade. EECs are capable of down-regulating CD8 expression of CTLs. Most likely, this effect is mediated by a soluble molecule present in plasma and is not a result of anergy or exhaustion state.

NOTES-assisted transvaginal splenectomy: the next step in the minimally invasive approach to the spleen.

HYPOTHESIS: Natural orifice transluminal endoscopic surgery (NOTES) has marked yet another step forward in less-invasive surgical procedures. Access to solid organs located deep in the left hypochondrium can be difficult using this technique but the transvaginal approach with the patient positioned in full lateral decubitus may be an option. MATERIAL AND METHODS: We present the case of a 60-year-old woman with a symptomatic splenic polycystic tumor. The procedure was carried out by a multidisciplinary team using a standard flexible videogastroscope and endoscopic instruments. Transvaginal visualization of the spleen and standard dissection of attachments were feasible, and splenectomy was completed using transvaginal stapling of the splenic hilum. The organ was extracted transvaginally. RESULTS: The postoperative course was uneventful. The patient had minimal postoperative pain and minimal scars, and was discharged on the second postoperative day. CONCLUSIONS: Transvaginal access can be safely used for operative visualization, hilum transection, and spleen removal with conventional instrumentation, reducing parietal wall trauma to a minimum. The clinical, esthetic, and functional advantages require further analysis.

Lipoabdominoplasty.

This article describes extensive liposuction with minimal abdominoplasty, a technique developed by the author and colleagues at the Institut Vila-Rovira. The technique represents another step in the evolution of liposuction procedures. Especially for patients with a body mass index of 30 to 35, the procedure is a surgical alternative that preserves the safety of the traditional lipoabdominoplasties.

Rotura traqueal yatrogénica por intubación orotraqueal / Iatrogenic tracheal rupture after endotracheal intubation

Las laceraciones traqueobronquiales traumáticas postintubación son una complicación clínica poco frecuente en la práctica diaria. Se han relacionado con intentos repetitivos de intubación e hiperinsuflación del balón, así como con alteraciones anatómicas y factores individuales que puedan predisponerla. El diagnóstico se obtiene, actualmente, mediante la endoscopia respiratoria, ya que informa sobre su localización y la extensión lesional. Presentamos el caso de una paciente con laceración de la cara posterior traqueal secundaria a intubación endotraqueal que comenzó con enfisema mediastínico subcutáneo y neumotórax bilateral en el postoperatorio inmediato. El diagnóstico se realizó mediante fibrobroncoscopia y tomografía computarizada y requirió cirugía traqueal de urgencia (AU)

Tracheobronchial rupture after tracheal intubation is rare in clinical practice. Possible contributory factors are multiple vigorous attempts at intubation, overinflation of the cuff, anatomic alterations, and predisposing individual factors. These lesions can be detected by bronchoscopy, which is the most effec-tive method to confirm the diagnosis and determine the exact location and extent of the tear. We report the case of a woman with membranous tracheal rupture after endotracheal intubation. Subcutaneous emphysema, pneumomediastinum and bilateral pneumothorax were noted after extubation. The diagnosis was confirmed by fiberoptic bronchoscopy and computed tomography scan, and the patient required emergency surgical repair (AU)

[Iatrogenic tracheal rupture after endotracheal intubation]. / Rotura traqueal yatrogénica por intubación orotraqueal.

Tracheobronchial rupture after tracheal intubation is rare in clinical practice. Possible contributory factors are multiple vigorous attempts at intubation, overinflation of the cuff, anatomic alterations, and predisposing individual factors. These lesions can be detected by bronchoscopy, which is the most effective method to confirm the diagnosis and determine the exact location and extent of the tear. We report the case of a woman with membranous tracheal rupture after endotracheal intubation. Subcutaneous emphysema, pneumomediastinum and bilateral pneumothorax were noted after extubation. The diagnosis was confirmed by fiberoptic bronchoscopy and computed tomography scan, and the patient required emergency surgical repair.