Materials for Smart Soft Actuator Systems.

In contrast to conventional hard actuators, soft actuators offer many vivid advantages, such as improved flexibility, adaptability, and reconfigurability, which are intrinsic to living systems. These properties make them particularly promising for different applications, including soft electronics, surgery, drug delivery, artificial organs, or prosthesis. The additional degree of freedom for soft actuatoric devices can be provided through the use of intelligent materials, which are able to change their structure, macroscopic properties, and shape under the influence of external signals. The use of such intelligent materials allows a substantial reduction of a device's size, which enables a number of applications that cannot be realized by externally powered systems. This review aims to provide an overview of the properties of intelligent synthetic and living/natural materials used for the fabrication of soft robotic devices. We discuss basic physical/chemical properties of the main kinds of materials (elastomers, gels, shape memory polymers and gels, liquid crystalline elastomers, semicrystalline ferroelectric polymers, gels and hydrogels, other swelling polymers, materials with volume change during melting/crystallization, materials with tunable mechanical properties, and living and naturally derived materials), how they are related to actuation and soft robotic application, and effects of micro/macro structures on shape transformation, fabrication methods, and we highlight selected applications.

Survival and chance of reversal after intestinal stoma formation during cytoreductive surgery for advanced ovarian cancer; a population-based cohort study.

OBJECTIVE: Our objective was to examine oncologic outcome in women with advanced epithelial ovarian cancer (aEOC) receiving an intestinal stoma (IS) at the time of cytoreductive surgery (CRS), probability of stoma reversal (SR) and variables affecting odds of SR. METHODS: This population-based cohort study included all women diagnosed with aEOC between 2009 and 2018 in the Stockholm/Gotland Region of Sweden. The association between IS formation at CRS and survival was analyzed with proportional hazards regression yielding hazard ratios (HR) with 95% confidence intervals (CI), adjusted for predefined confounders. Cumulative incidence functions, with death or recurrence as competing risk, were used to estimate chance of SR. The association between clinical factors and SR was analyzed with logistic regression yielding odds ratios (OR) with 95% CI. RESULTS: The final analysis included 888 women undergoing CRS for aEOC. Of these, 129 (14,5%) received an IS of which 74% (n = 95) were defunctioning and 26% (n = 34) permanent. IS was associated with an increased hazard of death (HR 1.30, CI 95%, 1.05-1.61; p = 0.02) in the univariate analysis, however not in the adjusted analysis. The probability of SR of defunctioning IS within 2 years was 48% (95% CI, 38-58). Median time to SR was 10 months. High surgical complexity score (SCS) was associated with increased odds of reversal (OR 3.43, 95% CI, 1.06-11.05; p = 0.04). CONCLUSIONS: IS formation does not seem to affect prognosis in women with aEOC. We could not identify any factor, known at time of CRS, that may predict the odds of SR except a high SCS.

Stratification of lymph node metastases as macrometastases, micrometastases, or isolated tumor cells has no clinical implication in patients with cervical cancer: Subgroup analysis of the SCCAN project.

BACKGROUND: In cervical cancer, presence of lymph-node macrometastases (MAC) is a major prognostic factor and an indication for adjuvant treatment. However, since clinical impact of micrometastases (MIC) and isolated tumor-cells (ITC) remains controversial, we sought to identify a cut-off value for the metastasis size not associated with negative prognosis. METHODS: We analyzed data from 967 cervical cancer patients (T1a1L1-T2b) registered in the SCCAN (Surveillance in Cervical CANcer) database, who underwent primary surgical treatment, including sentinel lymph-node (SLN) biopsy with pathological ultrastaging. The size of SLN metastasis was considered a continuous variable and multiple testing was performed for cut-off values of 0.01-1.0 mm. Disease-free survival (DFS) was compared between N0 and subgroups of N1 patients defined by cut-off ranges. RESULTS: LN metastases were found in 172 (18%) patients, classified as MAC, MIC, and ITC in 79, 54, and 39 patients, respectively. DFS was shorter in patients with MAC (HR 2.20, P = 0.003) and MIC (HR 2.87, P < 0.001), while not differing between MAC/MIC (P = 0.484). DFS in the ITC subgroup was neither different from N0 (P = 0.127) nor from MIC/MAC subgroups (P = 0.449). Cut-off analysis revealed significantly shorter DFS compared to N0 in all subgroups with metastases ≥0.4 mm (HR 2.311, P = 0.04). The significance of metastases <0.4 mm could not be assessed due to limited statistical power (<80%). We did not identify any cut-off for the size of metastasis with significantly better prognosis than the rest of N1 group. CONCLUSIONS: In cervical cancer patients, the presence of LN metastases ≥0.4 mm was associated with a significant negative impact on DFS and no cut-off value for the size of metastasis with better prognosis than N1 was found. Traditional metastasis stratification based on size has no clinical implication.

Survival associated with extent of radical hysterectomy in early-stage cervical cancer: a subanalysis of the Surveillance in Cervical CANcer (SCCAN) collaborative study.

BACKGROUND: International guidelines recommend tailoring the radicality of hysterectomy according to the known preoperative tumor characteristics in patients with early-stage cervical cancer. OBJECTIVE: This study aimed to assess whether increased radicality had an effect on 5-year disease-free survival in patients with early-stage cervical cancer undergoing radical hysterectomy. The secondary aims were 5-year overall survival and pattern of recurrence. STUDY DESIGN: This was an international, multicenter, retrospective study from the Surveillance in Cervical CANcer (SCCAN) collaborative cohort. Patients with the International Federation of Gynecology and Obstetrics 2009 stage IB1 and IIA1 who underwent open type B/C1/C2 radical hysterectomy according to Querleu-Morrow classification between January 2007 and December 2016, who did not undergo neoadjuvant chemotherapy and who had negative lymph nodes and free surgical margins at final histology, were included. Descriptive statistics and survival analyses were performed. Patients were stratified according to pathologic tumor diameter. Propensity score match analysis was performed to balance baseline characteristics in patients undergoing nerve-sparing and non-nerve-sparing radical hysterectomy. RESULTS: A total of 1257 patients were included. Of note, 883 patients (70.2%) underwent nerve-sparing radical hysterectomy, and 374 patients (29.8%) underwent non-nerve-sparing radical hysterectomy. Baseline differences between the study groups were found for tumor stage and diameter (higher use of non-nerve-sparing radical hysterectomy for tumors >2 cm or with vaginal involvement; P<.0001). The use of adjuvant therapy in patients undergoing nerve-sparing and non-nerve-sparing radical hysterectomy was 27.3% vs 28.6%, respectively (P=.63). Five-year disease-free survival in patients undergoing nerve-sparing vs non-nerve-sparing radical hysterectomy was 90.1% (95% confidence interval, 87.9-92.2) vs 93.8% (95% confidence interval, 91.1-96.5), respectively (P=.047). Non-nerve-sparing radical hysterectomy was independently associated with better disease-free survival at multivariable analysis performed on the entire cohort (hazard ratio, 0.50; 95% confidence interval, 0.31-0.81; P=.004). Furthermore, 5-year overall survival in patients undergoing nerve-sparing vs non-nerve-sparing radical hysterectomy was 95.7% (95% confidence interval, 94.1-97.2) vs non-nerve-sparing 96.5% (95% confidence interval, 94.3-98.7), respectively (P=.78). In patients with a tumor diameter ≤20 mm, 5-year disease-free survival was 94.7% in nerve-sparing radical hysterectomy vs 96.2% in non-nerve-sparing radical hysterectomy (P=.22). In patients with tumors between 21 and 40 mm, 5-year disease-free survival was 90.3% in non-nerve-sparing radical hysterectomy vs 83.1% in nerve-sparing radical hysterectomy (P=.016) (no significant difference in the rate of adjuvant treatment in this subgroup, P=.47). This was confirmed after propensity match score analysis (balancing the 2 study groups). The pattern of recurrence in the propensity-matched population did not demonstrate any difference (P=.70). CONCLUSION: For tumors ≤20 mm, no survival difference was found with more radical hysterectomy. For tumors between 21 and 40 mm, a more radical hysterectomy was associated with improved 5-year disease-free survival. No difference in the pattern of recurrence according to the extent of radicality was observed. Non-nerve-sparing radical hysterectomy was associated with better 5-year disease-free survival than nerve-sparing radical hysterectomy after propensity score match analysis.

Incidence of and survival after surgical intervention for bowel obstruction in women with advanced ovarian cancer.

INTRODUCTION: Women with advanced ovarian cancer commonly present with peritoneal disease both at primary diagnosis and relapse, with risk of subsequent bowel obstruction. The aims of this study were to assess the cumulative incidence of and survival after intervention for bowel obstruction in women with advanced ovarian cancer, to identify factors predictive of survival and the extent to which the intended outcome of the intervention was achieved. MATERIAL AND METHODS: Women diagnosed with advanced ovarian cancer stages III and IV in 2009-2011 and 2014-2016 in the Stockholm-Gotland Region in Sweden were identified in the Swedish Quality Registry for Gynecologic Cancer. Through hospital records, types of intended and executed interventions for bowel obstruction were assessed, and as well as when in the course of oncologic treatment, the intervention was performed. Time from first intervention to death was analyzed with survival methodology and proportional hazard regression was used. RESULTS: Of 751 identified women, 108 had an intervention for bowel obstruction. Laparotomy was the most prevalent intervention and was used in 87% (94/108) of all women, with a success rate of 87% (82/94). An intervention for bowel obstruction was performed before or during first line treatment in 32% (35/108) with a cumulative incidence in the whole cohort of 14% (108/751, 95% confidence interval [CI] 11-16). Median survival after intervention for bowel obstruction was 4 months (95% CI 3-6). The hazard of death increased when the intervention was performed after completion of primary treatment (HR 4.46, 95% CI 1.61-12.29, P < 0.01), with a median survival of 3 months. In women subjected to radical surgery during primary treatment, the hazard of death after intervention for bowel obstruction decreased (hazard ratio [HR] 0.54, 95% CI 0.32-0.91, P = 0.02). CONCLUSIONS: Women with advanced ovarian cancer undergoing intervention for bowel obstruction have a dismal prognosis, regardless of which line of oncologic treatment the intervention was performed. In the majority of women an intervention for bowel obstruction was performed in a relapse situation with an even worse survival. Our findings emphasize the importance of a holistic approach in the decision-making before an intervention for bowel obstruction in women with advanced ovarian cancer.

Mental health outcomes of hospital staff during the COVID-19 pandemic in Iran.

BACKGROUND: The COVID-19 pandemic, which had recorded 769 million cases and resulted in 6.95 million deaths by August 2023, has put pressure on healthcare systems. Frontline medical professionals face stress, potentially leading to health challenges. This research aimed to examine the mental health of staff during the COVID-19 pandemic. METHODS: This cross-sectional descriptive-analytical study was conducted in several hospitals in Tehran, Kerman, and Golpayegan between 2021 and 2022. The study encompassed a population of 1,231 nurses and physicians. Data collection was done using the General Health Questionnaire-28 (GHQ-28). We applied the K-means clustering algorithm to unveil hidden patterns within the data and extract valuable insights from participants' responses to the GHQ-28. This method was chosen because our dataset lacked explicit labels, making grouping individuals with similar characteristics necessary. The primary aim was to delineate how the COVID-19 pandemic affected the mental health of hospital staff and identify which factors played a more significant role in this process. RESULTS: We have observed that Cluster two exhibits the highest scores in response to the GHQ-28 questions, indicating a more significant degree of mental distress. Within this cluster, 83.0% of individuals identify as female, 71.0% hold bachelor's degrees and 42.8% are nurses who have experienced the most substantial impact. Among these individuals, 90.4% did not have a history of smoking. Additionally, 59.7% are married, suggesting that these mental health issues may also affect their families. CONCLUSION: Given that the most critical subscale is related to anxiety/insomnia within the second cluster, it is necessary to implement management plans aimed at appropriately redistributing night shifts to improve employee health.

Chitosan-coated niosome as an efficient curcumin carrier to cross the blood-brain barrier: an animal study.

This study aims to improve the curcumin bio-stability and brain permeability by loading in bare niosome (BN) and chitosan-coated niosome (ChN). Span 60, tween 60, and cholesterol were optimized as niosome shell components to attain the highest encapsulation efficiency (EE), besides the lowest particle size, using the mixture design method. The resulting optimized BN had a mean diameter of 80 ± 0.2 nm and surface charge of -31 ± 0.1 mv, which changed to 85 ± 0.15 nm and 35 ± 0.12 mv, respectively, after applying the chitosan layer. The EE% in bare niosome were about 80 ± 0.2, which changed to 82 ± 0.21 in ChN. The optimized formulation displayed sustained release, following the Hixson-Crowell model.Wistar rats were subjected to intraperitoneal injection (i.p.) of BN and ChN to evaluate the blood-brain barrier permeability of the curcumin. In this regard, ChN significantly increased curcumin concentration in different parts of the liver, plasma, and central nervous system (cerebral cortex, cerebellum, and stratum), compared with BN. Altogether, our results showed that ChN could be used as a promising delivery system for the treatment of some neurological diseases such as Alzheimer's.

Co-encapsulation of curcumin and boswellic acids in chitosan-coated niosome: an in-vitro digestion study.

In this study, chitosan-coated niosome (ChN) was utilised for bioavailability enhancement of curcumin (Cn) and boswellic acids (BAs). The bare niosome (BN) was prepared by the heating method and optimised by using the mixture design procedure. Physicochemical stability, as well as the in vitro release, and bioavailability of Cn and BAs in BN and ChN were studied. The optimised BN had a mean diameter of 70.00 ± 0.21 nm and surface charge of -31.00 ± 0.25 mv, which changed to 60.01 ± 0.20 nm and +40.00 ± 0, respectively, in ChN. In-vitro digestion study revealed chitosan layer augmented the bioavailability of Cn and BAs to 79.02 ± 0.13 and 81 ± 0.10, respectively. The chitosan layer obviously improved the physical stability of Cn and BA in the niosome vehicle, by means of vesicle size, zeta potential, and encapsulation efficiency. The ChN was considered to be promising delivery system for increasing the bioavailability of Cn and BAs.

Perioperative fluid balance and major postoperative complications in surgery for advanced epithelial ovarian cancer.

OBJECTIVE: Appropriate fluid balance in the perioperative period is important as both hypo- and hypervolemia are associated with increased risk of complications. Women undergoing cytoreductive surgery (CRS) for advanced epithelial ovarian cancer (EOC) may have major fluid shifts. The optimal perioperative fluid balance in these women is yet to be determined. Our objective was to investigate the association between perioperative fluid balance and major postoperative complications. METHODS: Women with advanced stage EOC who underwent surgery at Karolinska University Hospital, Stockholm, Sweden were identified from the institutional database. Women subjected to surgery with curative intent were included in the analysis. Additional data were retrieved from medical records. The association between perioperative fluid balance and major postoperative complications was investigated by multivariable regression and adjusted for predefined confounders. RESULTS: Of the 270 women identified in the institutional database during 2014-2017, 184 women were included in the analyses. Of these women, 22% (n = 40) experienced a major postoperative complication. The fully adjusted odds of major postoperative complications increased when perioperative fluid balance exceeded >3000 mL, (Odds Ratio (OR) 4.85, 95% Confidence Interval (CI) 1.23-19.2, p = 0.02) and > 5000 mL (OR 33.7, 95% CI 4.13-275, p < 0.01). There was no association between negative fluid balance and major postoperative complications (OR 3.33, 95% CI 0.25-44.1, p = 0.36). CONCLUSIONS: Fluid balance >3000 mL perioperatively during surgery for advanced EOC increased the odds of major postoperative complications. Management of perioperative fluid balance in advanced EOC surgery remains a challenge.

Surgery performed later in the week is associated with inferior survival in advanced ovarian cancer.

BACKGROUND: Complete macroscopic resection without any residual tumour after completion of surgery is a strong prognostic factor in advanced epithelial ovarian cancer (EOC). It has previously been reported that surgery performed later in the week is associated with failure to achieve complete macroscopic resection. Our objective was to examine if weekday of surgery influences oncologic outcome. MATERIALS AND METHODS: This population-based observational study included 100% of all women diagnosed with advanced-stage invasive epithelial ovarian cancer between 2009-2011 and 2014-2016 in the Stockholm/Gotland County of Sweden. The association between weekday of surgery and survival was analysed with proportional hazards regression yielding hazard ratios (HR) with 95% confidence intervals (CI), adjusted for predefined confounders. RESULTS: Out of 1066 identified women, 524 with advanced stage EOC treated with surgery were included in the final analysis. Surgery performed Wednesday to Thursday was associated with an increased hazard of death (HR 1.28, 95% CI 1.04-1.58, p-value 0.02). The trend of the hazard of surgery performed throughout the week from Monday through Thursday was also significant (p = 0.01). CONCLUSION: The increased mortality associated with surgery that is performed later in the week suggests that surgery for advanced ovarian cancer is best conducted early in the week.

Ultra-radical upfront surgery does not improve survival in women with advanced epithelial ovarian cancer; a natural experiment in a complete population.

OBJECTIVE: Ultra-radical surgery to achieve complete resection in advanced epithelial ovarian cancer (EOC) has been widely accepted without strong supporting data. Our objective was to assess overall survival after a structured shift to an ultra-radical upfront surgical treatment algorithm and to investigate changes in the distribution of primary treatments after this shift. PATIENTS AND METHODS: In this population-based cohort study, all women with suspected EOC in the Stockholm-Gotland region of Sweden reported to the Swedish Quality Registry for Gynecologic Cancer (SQRGC) and National Cancer Registry (NCR) were selected in two 3-year cohorts, based on year of diagnosis (before (cohort1) or after (cohort 2) change in surgical treatment algorithm) and followed for at least three years. 5-year overall survival (OS) in non-surgically and surgically treated women was analyzed. Moreover, proportional distribution of primary treatment was evaluated. RESULTS: 752 women were included in the final analysis (n = 364 and 388 in cohort 1 and 2 respectively) with a median follow-up of 29 and 27 months. The complete resection rate increased from 37 to 67% (p ≤ 0.001) as well as proportion non-surgically treated women, 24 to 33%. No improvement in OS was observed in non-surgically (HR 0.76 (95% CI, 0.58-1.01); p = 0.06) or surgically treated (HR 0.94 (95% CI, 0.75-1.18); p = 0.59) women, even when complete resection was achieved (HR 1.31 (95% CI, 0.89-1.92); p = 0.17). CONCLUSION: A shift to ultra-radical upfront surgery in EOC did not improve survival despite a significant increase in complete resection rate. Identifying the limitations of surgical treatment remains a challenge.

Surgery performed later in the week is associated with failure to achieve complete radical surgical resection in advanced ovarian cancer.

Background: The surgical treatment of advanced ovarian cancer aims to resect all visible tumor to no gross residual, these procedures are often extensive with need of prolonged attention to detail. Our objective was to investigate the association between week-day of surgery, time of year (season) when surgery was performed and non-radical surgery (surgical failure) in advanced ovarian cancer.Material and methods: Women diagnosed with primary invasive epithelial ovarian cancer in the Stockholm/Gotland Region, Sweden were identified in the regional Swedish Quality Registry of Gynecologic Cancer (SQRGC). Data of all women with International Federation of Gynecology and Obstetrics (FIGO) stages III and IV were validated against the National Cancer Registry. Women subjected to surgery with curative intent were selected and included in the analysis. Uni- and multivariable regression analyses were performed.Results: Out of 538 women identified in the SQRGC-string ovary between 2014 and 2016, 240 were eligible for analysis. In 29% of women, complete radical resection was not achieved. There was a significant trend of increased non-radical resection when surgery was performed from Monday through Thursday (p = .03). The adjusted odds of non-radical surgery increased if surgery was performed on Thursday rather than Monday (Odds Ratio (OR) 3.04, 95% Confidence Interval (CI) 1.05-8.79, p = .04). Surgery performed during summer compared to the rest of the year, did not significantly increase the adjusted odds of non-radical surgery (OR 1.92, 95% CI 0.91-4.07, p = .09).Conclusion: Complete surgical resection of tumor is one of the strongest prognostic factors for survival in advanced epithelial ovarian cancer. For this reason, advanced ovarian cancer surgery should be scheduled early in the week.

Intraperitoneal ropivacaine reduces time interval to initiation of chemotherapy after surgery for advanced ovarian cancer: randomised controlled double-blind pilot study.

BACKGROUND: Advanced-stage ovarian cancer has a poor prognosis; surgical resection with the intent to leave no residual tumour followed by adjuvant chemotherapy is the standard treatment. Local anaesthetics (LA) have anti-inflammatory and analgesic effects. We hypothesised that intraperitoneal LA (IPLA) would lead to improved postoperative recovery, better pain relief, and earlier start of chemotherapy. METHODS: This was a prospective, randomised, double-blind, placebo-controlled pilot study in 40 women undergoing open abdominal cytoreductive surgery. Patients were randomised to receive either intraperitoneal ropivacaine (Group IPLA) or saline (Group Placebo) perioperatively. Except for study drug, patients were treated similarly. Intraoperatively, ropivacaine 2 mg ml-1 or 0.9% saline was injected thrice intraperitoneally, and after operation via a catheter and analgesic pump into the peritoneal cavity for 72 h. Postoperative pain, time to recovery, home discharge, time to start of chemotherapy, and postoperative complications were recorded. RESULTS: No complications from LA administration were recorded. Pain intensity and rescue analgesic consumption were similar between groups. Time to initiation of chemotherapy was significantly shorter in Group IPLA (median 21 [inter-quartile range 21-29] vs 29 [inter-quartile range 21-40] days; P=0.021). Other parameters including time to home readiness, home discharge and incidence, and complexity of postoperative complications were similar between the groups. CONCLUSIONS: Intraperitoneal ropivacaine during and for 72 h after operation after cytoreductive surgery for ovarian cancer is safe and reduces the time interval to initiation of chemotherapy. Larger studies are warranted to confirm these initial findings. CLINICAL TRIAL REGISTRATION: NCT02256228.

Pelvic sentinel lymph node biopsy in endometrial cancer-a simplified algorithm based on histology and lymphatic anatomy.

OBJECTIVE: To achieve the full potential of sentinel lymph node (SLN) detection in endometrial cancer, both presumed low- and high-risk groups should be included. Perioperative resource use and complications should be minimized. Knowledge on distribution and common anatomical sites for metastatic SLNs may contribute to optimizing the concept while maintaining sensitivity. Proceeding from previous studies, simplified algorithms based on histology and lymphatic anatomy are proposed. METHODS: Data on mapping rates and locations of pelvic SLNs (metastatic and non-metastatic) from two previous prospective SLN studies in women with endometrial cancer were retrieved. Cervically injected indocyanine green was used as a tracer and an ipsilateral re-injection was performed in case of non-display of the upper and/or lower paracervical pathways. A systematic surgical algorithm was followed with clearly defined SLNs depicted on an anatomical chart. In high-risk endometrial cancer patients, removal of SLNs was followed by a pelvic and para-aortic lymphadenectomy. RESULTS: 423 study records were analyzed. The bilateral mapping rates of the upper and lower paracervical pathways were 88.9% and 39.7%, respectively. 72% of all SLNs were typically positioned along the upper paracervical pathway (interiliac and/or proximal obturator fossa) and 71 of 75 (94.6%) of pelvic node positive women had at least one metastatic SLN at either of these positions. Women with grade 1-2 endometroid cancers (n=275) had no isolated metastases along the lower paracervical pathway compared with two women with high-risk histologies (n=148). CONCLUSION: SLNs along the upper paracervical pathway should be identified in all endometrial cancer histological subtypes; removal of nodes at defined typical positions along the upper paracervical pathway may replace a site-specific lymphadenectomy in case of non-mapping despite tracer re-injection. Detection of SLNs along the lower paracervical pathway can be restricted to high-risk histologies and a full pre-sacral lymphadenectomy should be performed in case of non-display.

Spider Silk for Tissue Engineering Applications.

Due to its properties, such as biodegradability, low density, excellent biocompatibility and unique mechanics, spider silk has been used as a natural biomaterial for a myriad of applications. First clinical applications of spider silk as suture material go back to the 18th century. Nowadays, since natural production using spiders is limited due to problems with farming spiders, recombinant production of spider silk proteins seems to be the best way to produce material in sufficient quantities. The availability of recombinantly produced spider silk proteins, as well as their good processability has opened the path towards modern biomedical applications. Here, we highlight the research on spider silk-based materials in the field of tissue engineering and summarize various two-dimensional (2D) and three-dimensional (3D) scaffolds made of spider silk. Finally, different applications of spider silk-based materials are reviewed in the field of tissue engineering in vitro and in vivo.

Stimuli-responsive hydrogels for manipulation of cell microenvironment: From chemistry to biofabrication technology.

Native tissues orchestrate their functions by complex interdependent cascades of biochemical and biophysical cues that vary spatially and temporally during cellular processes. Scaffolds with well-tuned structural, mechanical, and biochemical properties have been developed to guide cell behavior and provide insight on cell-matrix interaction. However, static scaffolds very often fail to mimic the dynamicity of native extracellular matrices. Stimuli-responsive scaffolds have emerged as powerful platforms that capture vital features of native tissues owing to their ability to change chemical and physical properties in response to cytocompatible stimuli, thus enabling on-demand manipulation of cell microenvironment. The vast expansion in biorthogonal chemistries and stimuli-responsive functionalities has fuelled further the development of new smart scaffolds that can permit multiple irreversible or reversible spatiotemporal modulation of cell-directing cues, thereby prompting in-depth studies to interpret the decisive elements that regulate cell behavior. Integration of stimuli-responsive hydrogels with current biofabrication technologies has allowed the development of dynamic scaffolds with organizational features and hierarchical architectures similar to native tissues. This review highlights the progress achieved using stimuli-responsive hydrogels in fundamental cell biology studies, with particular emphasis on the interplay between chemistry, biomaterials design, and biofabrication technologies for manipulation of cell microenvironment.

3D Bioprinting in Skeletal Muscle Tissue Engineering.

Skeletal muscle tissue engineering (SMTE) aims at repairing defective skeletal muscles. Until now, numerous developments are made in SMTE; however, it is still challenging to recapitulate the complexity of muscles with current methods of fabrication. Here, after a brief description of the anatomy of skeletal muscle and a short state-of-the-art on developments made in SMTE with "conventional methods," the use of 3D bioprinting as a new tool for SMTE is in focus. The current bioprinting methods are discussed, and an overview of the bioink formulations and properties used in 3D bioprinting is provided. Finally, different advances made in SMTE by 3D bioprinting are highlighted, and future needs and a short perspective are provided.

Lymphedema, serious adverse events, and imaging 1 year after comprehensive staging for endometrial cancer: results from the RASHEC trial.

BACKGROUND AND OBJECTIVES: In the Robot Assisted Surgery for High Risk Endometrial Cancer (RASHEC) trial, patients with high-risk endometrial cancer were randomly assigned to robot-assisted laparoscopic surgery (RALS) or laparotomy for pelvic and infrarenal para-aortic lymph node dissection. We here report on self-reported lower limb lymphedema (LLL), lymphocyst formation, ascites, and long-term serious adverse events 12 months after surgery. PATIENTS AND METHODS: Patients were enrolled between 2013 and 2016, and 96 patients were included in the per protocol analysis, evenly distributed between RALS and laparotomy. Self-reported LLL was recorded using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for endometrial cancer-EN24, assessed before and 12 months after surgery. Computed tomography was assessed at baseline, 3, and 12 months. Medical charts were reviewed for serious adverse events and hospital admissions 31 to 365 days after surgery. RESULTS: At 12 months after laparotomy and RALS, 61% and 50% patients, respectively, reported LLL (p = 0.31). In univariate analysis, the mean score of LLL at 12 months was significantly higher for laparotomy than for RALS (p < 0.05) and for those without abdominal drainage (p = 0.02), but was not independently associated with LLL in the multivariate analysis. Imaging showed no significant difference in lymphocyst formation or ascites between surgical modalities. No difference was found in serious adverse events and admissions to hospital for any reason. There was no agreement between lymphocyst formation or ascites and self-reported LLL. CONCLUSION: Follow-up 1 year after comprehensive surgical staging for high-risk endometrial cancer showed no differences in self-reported LLL, findings on imaging, or SAE between laparotomy and robot-assisted surgery.

Robot-assisted approach to cervical cancer (RACC): an international multi-center, open-label randomized controlled trial.

BACKGROUND: Radical hysterectomy with pelvic lymphadenectomy represents the standard treatment for early-stage cervical cancer. Results from a recent randomized controlled trial demonstrate that minimally invasive surgery is inferior to laparotomy with regards to disease-free and overall survival. PRIMARY OBJECTIVE: To investigate the oncologic safety of robot-assisted surgery for early-stage cervical cancer as compared with standard laparotomy. STUDY HYPOTHESIS: Robot-assisted laparoscopic radical hysterectomy is non-inferior to laparotomy in regards to recurrence-free survival with the advantage of fewer post-operative complications and superior patient-reported outcomes. TRIAL DESIGN: Prospective, multi-institutional, international, open-label randomized clinical trial. Consecutive women with early-stage cervical cancer will be assessed for eligibility and subsequently randomized 1:1 to either robot-assisted laparoscopic surgery or laparotomy. Institutional review board approval will be required from all participating institutions. The trial is coordinated from Karolinska University Hospital, Sweden. MAJOR INCLUSION/EXCLUSION CRITERIA: Women over 18 with cervical cancer FIGO (2018) stages IB1, IB2, and IIA1 squamous, adenocarcinoma, or adenosquamous will be included. Women are not eligible if they have evidence of metastatic disease, serious co-morbidity, or a secondary invasive neoplasm in the past 5 years. PRIMARY ENDPOINT: Recurrence-free survival at 5 years between women who underwent robot-assisted laparoscopic surgery versus laparotomy for early-stage cervical cancer. SAMPLE SIZE: The clinical non-inferiority margin in this study is defined as a 5-year recurrence-free survival not worsened by >7.5%. With an expected recurrence-free survival of 85%, the study needs to observe 127 events with a one-sided level of significance (α) of 5% and a power (1-ß) of 80%. With 5 years of recruitment and 3 years of follow-up, the necessary number of events will be reached if the study can recruit a total of 768 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Trial launch is estimated to be May 2019 and the trial is estimated to close in May 2027 with presentation of data shortly thereafter. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov (NCT03719547).

Outside-in HLA class I signaling regulates ICAM-1 clustering and endothelial cell-monocyte interactions via mTOR in transplant antibody-mediated rejection.

Antibody-mediated rejection (AMR) resulting in transplant allograft vasculopathy (TAV) is the major obstacle for long-term survival of solid organ transplants. AMR is caused by donor-specific antibodies to HLA, which contribute to TAV by initiating outside-in signaling transduction pathways that elicit monocyte recruitment to activated endothelium. Mechanistic target of rapamycin (mTOR) inhibitors can attenuate TAV; therefore, we sought to understand the mechanistic underpinnings of mTOR signaling in HLA class I Ab-mediated endothelial cell activation and monocyte recruitment. We used an in vitro model to assess monocyte binding to HLA I Ab-activated endothelial cells and found mTOR inhibition reduced ezrin/radixin/moesin (ERM) phosphorylation, intercellular adhesion molecule 1 (ICAM-1) clustering, and monocyte firm adhesion to HLA I Ab-activated endothelium. Further, in a mouse model of AMR, in which C57BL/6. RAG1-/- recipients of BALB/c cardiac allografts were passively transferred with donor-specific MHC I antibodies, mTOR inhibition significantly reduced vascular injury, ERM phosphorylation, and macrophage infiltration of the allograft. Taken together, these studies indicate mTOR inhibition suppresses ERM phosphorylation in endothelial cells, which impedes ICAM-1 clustering in response to HLA class I Ab and prevents macrophage infiltration into cardiac allografts. These findings indicate a novel therapeutic application for mTOR inhibitors to disrupt endothelial cell-monocyte interactions during AMR.