Stratifying esophago-gastric cancer treatment using a patient-derived organoid-based threshold.

BACKGROUND AND AIMS: This study sought to determine the value of patient-derived organoids (PDOs) from esophago-gastric adenocarcinoma (EGC) for response prediction to neoadjuvant chemotherapy (neoCTx). METHODS: Endoscopic biopsies of patients with locally advanced EGC (n = 120) were taken into culture and PDOs expanded. PDOs' response towards the single substances of the FLOT regimen and the combination treatment were correlated to patients' pathological response using tumor regression grading. A classifier based on FLOT response of PDOs was established in an exploratory cohort (n = 13) and subsequently confirmed in an independent validation cohort (n = 13). RESULTS: EGC PDOs reflected patients' diverse responses to single chemotherapeutics and the combination regimen FLOT. In the exploratory cohort, PDOs response to single 5-FU and FLOT combination treatment correlated with the patients' pathological response (5-FU: Kendall's τ = 0.411, P = 0.001; FLOT: Kendall's τ = 0.694, P = 2.541e-08). For FLOT testing, a high diagnostic precision in receiver operating characteristic (ROC) analysis was reached with an AUCROC of 0.994 (CI 0.980 to 1.000). The discriminative ability of PDO-based FLOT testing allowed the definition of a threshold, which classified in an independent validation cohort FLOT responders from non-responders with high sensitivity (90%), specificity (100%) and accuracy (92%). CONCLUSION: In vitro drug testing of EGC PDOs has a high predictive accuracy in classifying patients' histological response to neoadjuvant FLOT treatment. Taking into account the high rate of successful PDO expansion from biopsies, the definition of a threshold that allows treatment stratification paves the way for an interventional trial exploring PDO-guided treatment of EGC patients.

[Robotic esophageal surgery]. / Robotische Ösophaguschirurgie.

Robot-assisted minimally invasive esophagectomy (RAMIE) is increasingly becoming established as a standard procedure in surgical centers for esophagectomy in cases of cancer. To date, RAMIE has been shown to have fewer postoperative complications and at least equivalent oncological outcomes compared with open resection. Compared with classical minimally invasive resection, there seem to be fewer cases of postoperative pneumonia after RAMIE. In addition, a higher number of harvested lymph nodes could lead to better oncological long-term outcomes. The learning curve for this complex surgical procedure is relatively shallow but can be greatly reduced at high-volume centers through special training and proctoring programs. Robotic surgical approaches have also been described for other esophageal diseases; however, no clear superiority compared to laparoscopic surgery has so far been shown.

Robotic Esophagectomy Compared With Open Esophagectomy Reduces Sarcopenia within the First Postoperative Year: A Propensity Score-Matched Analysis.

INTRODUCTION: Sarcopenia is a known risk factor for adverse outcomes after esophageal cancer (EC) surgery. Robot-assisted minimally invasive esophagectomy (RAMIE) offers numerous advantages, including reduced morbidity and mortality. However, no evidence exists to date comparing the development of sarcopenia after RAMIE and open esophagectomy (OE). The objective was to evaluate whether the development of sarcopenia within the first postoperative year after esophagectomy is associated with the surgical approach: RAMIE versus OE. METHODS: A total of 168 patients with EC were analyzed who either underwent total robotic or fully open Ivor Lewis esophagectomy in a propensity score-matched analysis. Sarcopenia was assessed using the skeletal muscle index (cm2/m2) and psoas muscle thickness per height (mm/m) on axial computed tomography scans during the first postoperative year; in total 540 computed tomography scans were evaluated. RESULTS: After 1-to-1 propensity score matching for confounders, 67 patients were allocated to RAMIE and OE groups, respectively. Skeletal muscle index in the OE group was significantly lower compared with the RAMIE group at the third (43.2 ± 7.6 cm2/m2 versus 49.1 ± 6.9 cm2/m2, p = 0.001), sixth (42.7 ± 7.8 cm2/m2 versus 51.5 ± 8.2 cm2/m2, p < 0.001) and ninth (43.0 ± 7.0 cm2/m2 versus 49.9 ± 6.6 cm2/m2, p = 0.015) postoperative month. Similar results were recorded for psoas muscle thickness per height. CONCLUSIONS: To our knowledge, this study is the first to suggest a substantial benefit of RAMIE compared with open esophagectomy in terms of postoperative sarcopenia. These results add further evidence to support the implementation of the robotic approach in multimodal therapy of EC.

Robotic-assisted minimally invasive Ivor Lewis esophagectomy within the prospective multicenter German da Vinci Xi registry trial.

PURPOSE: Robotic-assisted minimally invasive esophagectomy (RAMIE) has become one standard approach for the operative treatment of esophageal tumors at specialized centers. Here, we report the results of a prospective multicenter registry for standardized RAMIE. METHODS: The German da Vinci Xi registry trial included all consecutive patients who underwent RAMIE at five tertiary university centers between Oct 17, 2017, and Jun 5, 2020. RAMIE was performed according to a standard technique using an intrathoracic circular stapled esophagogastrostomy. RESULTS: A total of 220 patients were included. The median age was 64 years. Total minimally invasive RAMIE was accomplished in 85.9%; hybrid resection with robotic-assisted thoracic approach was accomplished in an additional 11.4%. A circular stapler size of ≥28 mm was used in 84%, and the median blood loss and operative time were 200 (IQR: 80-400) ml and 425 (IQR: 335-527) min, respectively. The rate of anastomotic leakage was 13.2% (n=29), whereas the two centers with >70 cases each had rates of 7.0% and 12.0%. Pneumonia occurred in 19.5% of patients, and the 90-day mortality was 3.6%. Cumulative sum analysis of the operative time indicated the end of the learning curve after 22 cases. CONCLUSIONS: High-quality multicenter registry data confirm that RAMIE is a safe procedure and can be reproduced with acceptable leak rates in a multicenter setting. The learning curve is comparably low for experienced robotic surgeons.

Comparative Analysis of Postoperative Complications after Cytoreductive Surgery and HIPEC in Gastric Cancer.

INTRODUCTION: Patients with advanced gastric cancer (AGC) frequently show peritoneal carcinomatosis (PC). PC reduces life expectancy and quality of life. Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to improve overall survival. Nevertheless, it has been reported that CRS and HIPEC are accompanied by an increase in postoperative complications. The purpose of this study was to investigate the complications associated with CRS and HIPEC and overall and disease-free survival. METHODS: Patients with AGC and PC, who received complete CRS and HIPEC, were included in the HIPEC group (n = 15). Patients with AGC but without PC, who received resection of the primary tumor alone, constituted the control group (n = 43). RESULTS: Patients enrolled in the HIPEC group presented with a median PCI of 7. In comparison with the control group, no differences were found in patient characteristics, risk factors, pathological findings, and operative procedures. Twenty-five percentage of the patients in both groups suffered from serious postoperative complications (CDC ≥3a). Surgical and medical complications, rate of reoperation, and mortality did not differ. Also, the recurrence pattern, median survival, and 1- and 2-year survival rates showed no differences. CONCLUSION: CRS and HIPEC do not lead to an increased postoperative morbidity and mortality in AGC with PC. Albeit the poorer prognosis of patients with PC, survival of both groups was comparable.

[Change of strategy to minimally invasive esophagectomy-Results at a certified center]. / Strategiewechsel zur minimal-invasiven Ösophagektomie ­ Ergebnisse an einem zertifizierten Zentrum.

BACKGROUND: There are indications that robot-assisted minimally invasive esophagectomy (RAMIE) can reduce the morbidity compared with the conventional operative technique. OBJECTIVE: A comparative analysis of a single-center change in strategy of the standard from open esophagectomy to RAMIE with perioperative, enteral, selective bowel decontamination (SBD) was carried out. MATERIAL AND METHODS: Patient and morbidity data after elective RAMIE treated according to the novel standard management between July 2018 and September 2020 were compared retrospectively with an historical control cohort after open esophagectomy between January 2014 and June 2018. A 1:1 propensity score matching (PSM) analysis was performed. RESULTS: A total of 75 patients could be analyzed in both groups after PSM. Approximately two thirds of the operations were carried out due to an adenocarcinoma and one third due to a squamous cell carcinoma. The median number of resected lymph nodes was 22 and 21, respectively. In the RAMIE group the intrathoracic esophagogastrostomy was performed using a circular stapler with a diameter of ≥28 mm in 97%, whereas a 25 mm stapler was used in 90% in the control group. The operative time was longer (median 490min vs. 339 min, p < 0.001) but in contrast blood loss (median 300ml vs. 500 ml, p < 0.001), anastomotic leaks (8.0% vs. 25.3%, p = 0.004), surgical site infections (4.0% vs. 17.3%, p = 0.008) and pulmonary complication rates (29.3% vs. 44.0%, p = 0.045) as well as the median hospital stay (14 days vs. 20 days, p < 0.001) and 90-day mortality were significantly reduced compared with the open control group (4.0% vs. 13.3%, p = 0.039). CONCLUSION: A consistent change of the perioperative management including RAMIE and SBD can lead to a stable reduction of morbidity without compromising oncological radicalness.

Osteocytes. / Osteozyten.

For a long time, osteocytes were regarded as passive bystanders of bone metabolism. Bone remodeling was considered to be an interplay between bone forming osteoblasts and bone degrading osteoclasts. However, the dogma of osteocytes as bystanders within the bone has changed fundamentally since the turn of the millenium. Rather than being silent bystanders, osteocytes are the master cells of bone metabolism. To illustrate the central role of osteocytes, we performed a selective literature research in PubMed and Google Scholar using the search terms "osteocyte", "fracture healing", "bone healing", "bone remodeling", "bone metabolism", "sclerostin", "RANKL/OPG", "Wnt signaling pathway" and "FGF23". We included German and English clinical and preclinical studies as well as literature reviews. Osteocytes develop out of osteoblasts and are the key player in bone metabolism. They build a network within bone and make up 90 - 95% of all bone cells. In contrast to osteoblasts and osteoclasts, osteocytes can reach the age of the organism itself. Their morphology - with its dendritic connection through nexus - forms the perfect basis of osteocyte function. Besides the role as mechanosensor in bone, osteocytes control osteoblasts via sclerostin and osteoclasts via the RANK/RANKL/OPG pathway. Bone mineralisation is controlled by directing local phosphate concentrations. The systemic phosphate levels are regulated in interaction with the kidneys by the hormone FGF23. Understanding the role of osteocytes promises better therapies in clinical practice. Sclerostin antibodies and denusomab, an OPG agonist, are already established for clinical application in osteoporosis therapy. Antibodies against FGF23 or its receptors are used in preclinical and clinical trials. Bortezomib, an antibody which improves vitality of osteocytes, is already used for multiple myeloma therapy. For orthopaedic surgery, understanding the role of osteocytes promises new therapeutic approaches in future. Improvement in osseous integration of metallic implants and medical treatment of disturbed fracture healing are future fields in which therapies may be established by manipulating osteocytes.

An Optimized Approach to Perform Bone Histomorphometry.

Bone histomorphometry allows quantitative evaluation of bone micro-architecture, bone formation, and bone remodeling by providing an insight to cellular changes. Histomorphometry plays an important role in monitoring changes in bone properties because of systemic skeletal diseases like osteoporosis and osteomalacia. Besides, quantitative evaluation plays an important role in fracture healing studies to explore the effect of biomaterial or drug treatment. However, until today, to our knowledge, bone histomorphometry remain time-consuming and expensive. This incited us to set up an open-source freely available semi-automated solution to measure parameters like trabecular area, osteoid area, trabecular thickness, and osteoclast activity. Here in this study, the authors present the adaptation of Trainable Weka Segmentation plugin of ImageJ to allow fast evaluation of bone parameters (trabecular area, osteoid area) to diagnose bone related diseases. Also, ImageJ toolbox and plugins (BoneJ) were adapted to measure osteoclast activity, trabecular thickness, and trabecular separation. The optimized two different scripts are based on ImageJ, by providing simple user-interface and easy accessibility for biologists and clinicians. The scripts developed for bone histomorphometry can be optimized globally for other histological samples. The showed scripts will benefit the scientific community in histological evaluation.

Osteocyte Regulation of Receptor Activator of NF-κB Ligand/Osteoprotegerin in a Sheep Model of Osteoporosis.

Osteoporosis induction in a sheep model by steroid administration combined with ovariectomy recapitulates decreased bone formation and substandard matrix mineralization in patients. Recently, the role of osteocytes has been frequently addressed, with focus on their role in osteoclastogenesis. However, the quantification of receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) signaling in osteocytes was not studied in sheep. The current study reproduced the sheep model of osteoporosis to study the RANKL/OPG ratio correlation to the method of osteoporosis induction. We investigated the induction of osteoporosis after 8 months using 31 female merino land sheep divided into four groups: control, ovariectomy, ovariectomy with dietary limitation, and ovariectomy with dietary limitation and steroid injection. In accordance to previous reports, the present study showed trabecular thinning, higher numbers of apoptotic osteocytes, and imbalanced metabolism, leading to defective mineralization. The global RANKL/OPG ratio in the spine after 8 months of steroid and dietary treatment was not different from that of the control. Interestingly, assessment of the osteocyte-specific RANKL/OPG ratio showed that the steroid-induced osteoporosis in its late progressive phase stimulates RANKL expression in osteocytes. Sclerostin is suggested to induce RANKL expression in osteocytes. The findings of this study can contribute to further explain the success of sclerostin antibodies in treating osteoporotic patients despite increased osteocyte-expressed RANKL.