Effect of dentin matrix components on the mineralization of human mesenchymal stromal cells

In teeth with an injured pulp, dentin matrix orchestrates hard tissue repair through the release of dentin extracellular matrix components (dEMCs). dEMCs regulate the differentiation of resident mesenchymal stromal cells (MSCs), thereby affecting mineral deposition. In this study, we show that low-concentration solubilized dEMCs in osteogenic cultures of human umbilical cord mesenchymal stromal cells (UC-MSCs) and dental pulp stromal cells (DPSCs) enhanced mineral deposition, while adipose stromal cells (ASCs) were barely affected. Interestingly, UC-MSCs displayed significantly greater hydroxyapatite formation compared with DPSCs. UC-MSCs and DPSCs showed a dose-dependent viability and proliferation, whereas proliferation of ASCs remained unaffected. Qualitative analysis of the dEMC-supplemented osteogenic cultures through scanning electron microscopy demonstrated differences in the architecture of the deposited mineralized structures. Large-sized mineral accretions on a poorly organized collagen network were the prominent feature of UC-MSC cultures, while mineral nodules interspersed throughout a collagen mesh were observed in the respective DPSC cultures. The ability of dEMCs to induce mineralization varies between different human MSC types in terms of total mineral formation and architecture. Mineral formation by UC-MSCs exposed to low-concentration dEMCs proved to be the most efficient and therefore could be considered a promising combination for mineralized tissue engineering. Impact Statement This research has been conducted with the aim to contribute to the development of treatment modalities for the reconstruction of lost/damaged mineralized tissues. Currently, determining the most appropriate stromal cell population and signaling cues stands at the core of developing effective treatments. We provide new insights into the effect of innate inductive cues found in human dentin matrix components, on the osteogenic differentiation of various human stromal cell types. The effects of dentin extracellular matrix components on umbilical cord mesenchymal stromal cells have not been investigated before. The findings of this study could underpin translational research based on the development of techniques for mineralized tissue engineering and will be of great interest for the readership of Tissue Engineering Part A

Intraperitoneal chemotherapy for peritoneal metastases of gastric origin:a systematic review and meta-analysis

Background: Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Normothermic catheter-based intraperitoneal chemotherapy and normothermic pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs compared to intravenous administration. We reviewed the effectiveness and safety of different methods of palliative intraperitoneal chemotherapy. Methods: Embase, MEDLINE, Web of Science and Cochrane were searched for articles studying the use of repeated administration of palliative intraperitoneal chemotherapy in patients with gastric cancer and peritoneal metastases, published up to January 2024. The primary outcome was overall survival. Results: Twenty-three studies were included, representing a total of 999 patients. The pooled median overall survival was 14.5 months. The pooled hazard ratio of the two RCTs using intraperitoneal paclitaxel and docetaxel favoured the intraperitoneal chemotherapy arm. The median overall survival of intraperitoneal paclitaxel, intraperitoneal docetaxel and PIPAC with cisplatin and doxorubicin were respectively 18.4 months, 13.2 months and 9.0 months. All treatment methods had a relatively safe toxicity profile. Conversion surgery after completion of intraperitoneal therapy was performed in 16% of the patients.Conclusions: Repeated intraperitoneal chemotherapy, regardless of method of administration, is safe for patients with gastric cancer and peritoneal metastases. Conversion surgery after completion of the intraperitoneal chemotherapy is possible in a subset of patients.</p

Nationwide Association of Surgical Performance of Minimally Invasive Esophagectomy With Patient Outcomes

IMPORTANCE: Suboptimal surgical performance is hypothesized to be associated with less favorable patient outcomes in minimally invasive esophagectomy (MIE). Establishing this association may lead to programs that promote better surgical performance of MIE and improve patient outcomes.OBJECTIVE: To investigate associations between surgical performance and postoperative outcomes after MIE.DESIGN, SETTING, AND PARTICIPANTS: In this nationwide cohort study of 15 Dutch hospitals that perform more than 20 MIEs per year, 7 masked expert MIE surgeons assessed surgical performance using videos and a previously developed and validated competency assessment tool (CAT). Each hospital submitted 2 representative videos of MIEs performed between November 4, 2021, and September 13, 2022. Patients registered in the Dutch Upper Gastrointestinal Cancer Audit between January 1, 2020, and December 31, 2021, were included to examine patient outcomes.EXPOSURE: Hospitals were divided into quartiles based on their MIE-CAT performance score. Outcomes were compared between highest (top 25%) and lowest (bottom 25%) performing quartiles. Transthoracic MIE with gastric tube reconstruction.MAIN OUTCOME AND MEASURE: The primary outcome was severe postoperative complications (Clavien-Dindo ≥3) within 30 days after surgery. Multilevel logistic regression, with clustering of patients within hospitals, was used to analyze associations between performance and outcomes.RESULTS:In total, 30 videos and 970 patients (mean [SD] age, 66.6 [9.1] years; 719 men [74.1%]) were included. The mean (SD) MIE-CAT score was 113.6 (5.5) in the highest performance quartile vs 94.1 (5.9) in the lowest. Severe postoperative complications occurred in 18.7% (41 of 219) of patients in the highest performance quartile vs 39.2% (40 of 102) in the lowest (risk ratio [RR], 0.50; 95% CI, 0.24-0.99). The highest vs the lowest performance quartile showed lower rates of conversions (1.8% vs 8.9%; RR, 0.21; 95% CI, 0.21-0.21), intraoperative complications (2.7% vs 7.8%; RR, 0.21; 95% CI, 0.04-0.94), and overall postoperative complications (46.1% vs 65.7%; RR, 0.54; 95% CI, 0.24-0.96). The R0 resection rate (96.8% vs 94.2%; RR, 1.03; 95% CI, 0.97-1.05) and lymph node yield (mean [SD], 38.9 [14.7] vs 26.2 [9.0]; RR, 3.20; 95% CI, 0.27-3.21) increased with oncologic-specific performance (eg, hiatus dissection, lymph node dissection). In addition, a high anastomotic phase score was associated with a lower anastomotic leakage rate (4.6% vs 17.7%; RR, 0.14; 95% CI, 0.06-0.31).CONCLUSIONS AND RELEVANCE: These findings suggest that better surgical performance is associated with fewer perioperative complications for patients with esophageal cancer on a national level. If surgical performance of MIE can be improved with MIE-CAT implementation, substantially better patient outcomes may be achievable.</p

Learning Curve for Robot-Assisted Minimally Invasive Thoracoscopic Esophagectomy : Results From 312 Cases

Background: Thoracic laparoscopic robot-assisted minimally invasive esophagectomy (RAMIE) was developed in 2003. RAMIE was shown to be safe and oncologically effective. The aim of this study was to assess the learning curve and the proctoring program for a newly introduced surgeon (surgeon 2). Methods: The “learning curve” was defined as the number of operations that must be performed by a surgeon to achieve a steady level of performance. Measures of proficiency to describe the learning curve of the proctor and the newly introduced surgeon 2 included operating time, blood loss, and conversion rates and were analyzed using the cumulative sum method. Results of the newly introduced surgeon were compared with the proctor in the same period of time. Results: The proctor performed 232 of 312 procedures (74%) and surgeon 2 performed 80 of 312 procedures (26%). The proctor reached proficiency after 70 procedures in 55 months. The structured proctoring program for surgeon 2 started with 20 procedures as assisting table surgeon, followed by 5 observational and 15 supervised cases. Surgeon 2 performed at the same level as the proctor concerning operating time, blood loss, conversion rates, radicality, and complications. For surgeon 2, the learning phase of thoracic laparoscopic RAMIE was completed within 24 cases (15 supervised and 9 independent cases) in 13 months; a reduction of 66% in the number of operations and a reduction of 76% in time, compared with the proctor. Conclusions: The learning phase of thoracic laparoscopic RAMIE consisted of 70 procedures in 55 months. A structured proctoring for RAMIE substantially reduced the number of procedures and time required to achieve proficiency

Extended thoracic lymph node dissection in robotic-assisted minimal invasive esophagectomy (RAMIE) for patients with superior mediastinal lymph node metastasis

Background: Robot-assisted surgery may have a role in improving oncological outcomes in esophagectomy. Especially in the anatomical areas in the chest that are more difficult to reach in open surgery (including the superior mediastinum). The dexterity of the robotic instruments aid in performing a more extensive nodal dissection and the precision and detailed vision of the robotic system potentially improves staging, oncological outcomes and reduces complications (i.e., recurrent nerve palsy). In this article, we describe our experience and clinical outcomes in patients treated by robot assisted minimal invasive esophagectomy (RAMIE) in cN+ esophageal cancer patients with positive nodes localized in the superior mediastinum. Methods: From May 2007-2018, all patients who had involved nodes by either fluor-18-deoxyglucose positron-emission-tomography-computed tomography (FDG-PET-CT) or endoscopic ultrasound (EUS) + fine needle aspiration (FNA) localized in the superior mediastinum (above level Th4/sternal angle) were identified. Patient characteristics, perioperative data, postoperative clinical outcomes/complications and overall survival were prospectively recorded and retrospectively evaluated. Results: Forty patients (48% adenocarcinoma) met our inclusion criteria. All patients underwent a three-stage procedure with cervical anastomosis and 90% of the patients underwent neoadjuvant chemoradiotherapy. Mortality occurred in three patients (7.5%), of which two were caused by severe acute respiratory distress syndrome (ARDS). The most frequent complications were pneumonia (25%), chylothorax (20%), anastomotic leakage (17.5%) and vocal cord paralysis (17.5%) which was grade 1 in 72% of the patients. Radicality rate (R0 resection) was 98% and the average lymph node yield was 24 (range, 9-57). Median overall and disease-free survival was 26 and 17 months, respectively. Conclusions: RAMIE for esophageal cancer patients with node positive disease in the superior mediastinum is associated with increased mortality/morbidity. Oncological outcome showed excellent lymph node yield, R0 rate and survival was equal compared to patients with lower mediastinal node positive disease

The FA/BRCA pathway is involved in melphalan-induced DNA interstrand cross-link repair and accounts for melphalan resistance in multiple myeloma cells

Melphalan, a DNA cross-linker, is one of the most widely used and effective drugs in the treatment of multiple myeloma (MM). In this report, we demonstrate that enhanced interstrand cross-link (ICL) repair via the Fanconi anemia (FA)/BRCA pathway contributes to acquired drug resistance in melphalan-resistant myeloma cell lines, and disruption of this pathway reverses drug resistance. Using the alkaline comet assay (single-cell gel electrophoresis), we observed that melphalan-resistant cells have reduced ICL formation and enhanced ICL repair compared with melphalan-sensitive cells. Cell-cycle studies demonstrated that enhanced ICL repair released cells from melphalan-induced cell-cycle delay. Using siRNA to knock down FANCF in 8226/LR5 and U266/LR6 drug-resistant cells demonstrated a direct relationship between ICL repair capacity and drug sensitivity. Overexpression of FANCF in 8226/S and U266/S drug-sensitive cells partially reproduced the drug-resistant phenotype. These data show that enhanced DNA repair via the Fanconi anemia/BRCA pathway is involved in acquired melphalan resistance. Our findings provide for a new target to enhance response to DNA cross-linking agents in cancer treatment. (Blood. 2005;106:698-705

Robot-assisted minimally invasive esophagectomy (RAMIE) improves perioperative outcomes : a review

Robotic assisted minimal invasive esophagectomy (RAMIE) is increasingly applied as a clinically and oncologically safe technique in the surgical treatment of esophageal cancer. This review focuses on the advantages and potential opportunities of RAMIE to improve the perioperative and oncological outcomes based on the evidence from current literature. In addition, critical notes on aspects such as procedure duration and costs are addressed in this paper

Sample size of surgical randomized controlled trials : a lack of improvement over time

Background: Interpretation of randomized controlled trials (RCTs) without a significant difference regarding the primary outcome (negative RCTs) is frequently challenging, due to concerns about sample size and thus sufficient statistical power. We aimed to assess the adequacy of sample size and corresponding power of surgical RCTs. Methods: We previously identified all surgical RCTs available in PubMed in two distinct years a decade apart (1999 and 2009). For all “negative” trials, we estimated whether the sample size of the trial was appropriate to detect a difference in the primary outcome measure. The main outcome measure was a sufficient sample size to detect large, medium, and small treatment effects. We also performed a post hoc power analysis based on the actual observed effect difference. Results: A total of 228 negative RCTs (74 in 1999 and 121 in 2009) were included. The median sample size was 76 (± 222) and 80 (± 163) in 1999 and 2009, respectively. Sample size calculation was increasingly reported from 40% in 1999 to 54% in 2009 (P = 0.02). The proportion of studies adequately powered to detect large (57% versus 68%), medium (26% versus 25%), or small (8% versus 7%) differences did not differ significantly between 1999 and 2009, respectively. To reach sufficient power, the required increases in sample size were 130%, 240%, and 1032% for large, medium, and small differences, respectively. Reporting a sample size calculation was the only independent predictor for adequate power. Conclusions: Despite slight improvement in the reporting of a sample size calculation, about a third of surgical trials remains underpowered to demonstrate differences that are likely to be clinically significant. Increased attention of researchers, medical ethical boards, and journal editors is required to reduce potentially wasted resources on underpowered trials