Mesenchymal Stromal/Stem Cell Therapy Improves Salivary Flow Rate in Radiation-Induced Salivary Gland Hypofunction in Preclinical in vivo Models: A Systematic Review and Meta-Analysis.

BACKGROUND: Mesenchymal stromal/stem cells (MSCs) have been suggested for salivary gland (SG) restoration following radio-induced salivary gland damage. This study aimed to determine the safety and effectiveness of MSC therapy on radio-induced SG damage and hypofunction in preclinical in vivo studies. METHODS: PubMed and EMBASE were systematically searched for preclinical in vivo interventional studies evaluating efficacy and safety of MSC treatment following radio-induced salivary gland damage published before 10th of January 2022. The primary endpoint was salivary flow rate (SFR) evaluated in a meta-analysis. The study protocol was published and registered on PROSPERO ( www.crd.ac.uk/prospero ), registration number CRD42021227336. RESULTS: A total of 16 preclinical in vivo studies were included for qualitative analysis (858 experimental animals) and 13 in the meta-analysis (404 experimental animals). MSCs originated from bone marrow (four studies), adipose tissue (10 studies) and salivary gland tissue (two studies) and were administered intravenously (three studies), intra-glandularly (11 studies) or subcutaneously (one study). No serious adverse events were reported. The overall effect on SFR was significantly increased with a standardized mean difference (SMD) of 6.99 (95% CI: 2.55-11.42). Studies reported improvements in acinar tissue, vascular areas and paracrine factors. CONCLUSION: In conclusion, this systematic review and meta-analysis showed a significant effect of MSC therapy for restoring SG functioning and regenerating SG tissue following radiotherapy in preclinical in vivo studies without serious adverse events. MSC therapy holds significant therapeutic potential in the treatment of radio-induced xerostomia, but comprehensive, randomized, clinical trials in humans are required to ascertain their efficacy in a clinical setting.

The incidence of venous thromboembolism after curative colon cancer surgery within an enhanced recovery after surgery programme.

AIM: Based on three randomised controlled trials performed more than a decade ago, several national guidelines recommend prolonged venous thromboprophylaxis for 28 days following elective surgery for colon cancer. None of these studies were conducted within enhanced recovery after surgery setting. Newer studies indicate that prolonged prophylaxis might not be necessary with enhanced recovery after surgery. We aimed to provide further evidence to this unresolved discussion. METHOD: Retrospective study of patients undergoing elective surgery for colon cancer stage I-III with enhanced recovery after surgery in the Capital Region of Denmark from 2014 to 2017. Patients were excluded if discharged on postoperative day 28 or later, dying before discharge, undergoing concomitant rectum resection, or discharged with vitamin K antagonists, direct-oral anticoagulants, or low molecular weight heparin treatment. All patients received only low-dose low molecular weight heparin as prophylaxis during their admission. The primary endpoint was symptomatic lower limb deep venous thrombosis or pulmonary embolism diagnosed within 60 days postoperatively. RESULTS: Out of the included population of 1806 patients, only three experienced a symptomatic venous thromboembolic event; none was fatal. Two had pulmonary embolism associated with pneumonia, while one patient was diagnosed with lower limb deep venous thrombosis at postoperative day 15 after an uncomplicated course with first discharge at postoperative day 2. CONCLUSION: The risk of symptomatic venous thromboembolism after elective surgery for colon cancer with enhanced recovery after surgery seems negligible even without prolonged prophylaxis. The current guidelines need to be reconsidered.

Validation of the German classification system for quality assessment of right-sided colon cancer specimens.

AIM: The German classification system of the completeness of mesocolic excision aims to assess the quality of right-sided colonic cancer surgery by review of photographs. We aimed to validate the reliability of the classification in a clinical context. METHOD: The study was based on a cohort of patients undergoing resection for right-sided colon cancer in two university hospitals served by the same group of pathologists. Prospectively collected photographs of the specimens were assessed twice by six colorectal surgeons to determine the intra-rater and inter-rater accuracy of the German classification and a modification assessing extended right-sided resections. RESULTS: Specimens from 613 resections for right-sided colon cancer were reviewed. Twenty-one specimens were found to be non-assessable, leaving 436 right hemicolectomies, 139 extended right hemicolectomies and 17 right-sided subtotal colectomies. Intra-rater reliability was 0.57-0.74 and weighted kappa coefficients 0.58-0.74, without differences between subgroups. The percentage of agreement between all six participants was 20.3% for all specimens, 21.1% for right hemicolectomy specimens and 18.1% for extended hemicolectomy and right-sided subtotal colectomy specimens. For the right hemicolectomy specimens, the model-based kappa coefficient for agreement was 0.27 (95% CI 0.24-0.30) and for association 0.45 (95% CI 0.41-0.49). CONCLUSION: The German classification of right hemicolectomy specimens showed low intra-rater reliability and inter-rater agreement and association. The use of this classification for scientific purposes appeared not to be reliable.

Association between plane of mesocolic dissection and recurrence after complete mesocolic excision for right-sided colon cancer: a cohort study.

AIM: Dissection in the mesocolic plane is considered by some medical professionals to be crucial in complete mesocolic excision. We aimed to assess whether intramesocolic plane dissection is associated with a risk of recurrence after complete mesocolic excision for right-sided colon cancer. METHOD: This is a single-centre study based on prospectively registered data on patients undergoing resection for Union for International Cancer Control Stage I-III right-sided colon adenocarcinoma during the period 2010-2017. Patients were stratified in an intramesocolic plane group or a mesocolic plane group based on a prospective assessment of fresh specimens by a pathologist. Primary outcome was the 4.2 year risk of recurrence after inverse probability treatment weighting and competing risk analyses. RESULTS: Of 383 patients, 4 (1%) were excluded as the specimen was assessed as muscularis propria plane, 347 (91.6%) specimens were deemed as mesocolic and 32 (8.4%) as intramesocolic. The 4.2 year cumulative incidence of recurrence after inverse probability treatment weighting was 9.1% (95% CI 6.0%-12.1%) in the mesocolic group compared with 14.0% (3.6%-24.5%) in the intramesocolic group with an absolute risk difference in favour of mesocolic plane dissection of 4.9% (-5.7 to 15.6, p = 0.37). No difference was observed in the risk of local recurrence, death before recurrence or overall survival after 4.2 years between the two groups. CONCLUSION: Mesocolic plane dissection can be achieved in more than 90% of patients. The classification seems to be a guide for good surgical practice and not to be used for research purposes.

Plane of mesocolic dissection as predictor of recurrence after complete mesocolic excision for sigmoid colon cancer: A cohort study.

AIM: To investigate whether intramesocolic plane dissection assessed on fresh specimens by the pathologist is a risk factor for recurrence after complete mesocolic excision for sigmoid cancer when compared with mesocolic plane dissection. METHOD: Single-centre study based on prospectively registered data on patients undergoing resection for UICC stage I-III sigmoid colon adenocarcinoma during the period 2010-2017. The patients were stratified into either an intramesocolic plane group or a mesocolic plane group. Primary outcome was risk of recurrence after 4.2 years using inverse probability treatment weighting and competing risk analyses. RESULTS: Of a total of 332 patients, two were excluded as the specimen was assessed as muscularis propria plane, 237 (72%) specimens were deemed as mesocolic and 93 (28%) as intramesocolic. The 4.2-year cumulative incidence of recurrence after inverse probability treatment weighting was 14.9% (10.4-19.3) in the mesocolic group compared with 9.4% (3.7-15.0) in the intramesocolic group, thus the absolute risk difference between the mesocolic plane and intramesocolic plane was 5.5% (-12.5-1.6; p = 0.13) in favour of the intramesocolic group. CONCLUSION: Intramesocolic plane dissection was not a risk factor for recurrence after complete mesocolic excision for sigmoid cancer when compared with mesocolic plane dissection. No difference in risk of local recurrence, death before recurrence, and in overall survival after 4.2 years was observed between the two groups. With less than 1% of the specimens deemed as muscularis propria plane dissection, the classification appears unusable for the risk prediction of sigmoid colon cancer.

Accuracy of preoperative staging with multidetector computed tomography in colon cancer.

AIM: Multidetector computed tomography (MDCT) is the main preoperative decision-making tool in colon cancer treatment, thus the validation of daily clinical practice is warranted. The only published study validating the accuracy of MDCT in a national cohort was performed more than a decade ago. With neoadjuvant chemotherapy for patients with preoperatively assessed locally advanced cancer and the emergence of other personalized treatments we aimed to validate the accuracy of MDCT in a national cohort. METHOD: The study is based on the Danish Colorectal Cancer Group (DCCG) database and included all Danish patients diagnosed with primary colon adenocarcinoma between January 2015 and December 2018. The primary study outcome was the accuracy of MDCT in identifying patients with locally advanced disease. The secondary outcomes were the accuracy of predicting UICC Stage I based on predicting the tumour category (pT3-T4 versus pT1-T2) and lymph node metastasis. RESULTS: A total 3465 patients were included in the analyses regarding locally advanced colon cancer. The sensitivity and specificity were 0.61 (0.58-0.64) and 0.85 (0.83-0.86), respectively, for CT to predict locally advanced disease. The sensitivity and specificity were 0.63 (0.59-0.66) and 0.80 (0.78-0.81), respectively, for predicting UICC Stage I in 4496 patients. Thirty six per cent of the patients assessed as having locally advanced disease and 58% assessed as Stage I were misclassified by MDCT. CONCLUSION: The present standard in Denmark questions whether the implementation of personalized medicine such as neoadjuvant adjuvant chemotherapy and tailor-made resections based on MDCT is justified.

Mesenchymal Stem Cell Therapy for Osteoradionecrosis of the Mandible: a Systematic Review of Preclinical and Human Studies.

BACKGROUND: Osteoradionecrosis (ORN) of the mandible is a severe complication of radiotherapy for head and neck cancer and is arduously difficult to manage. Current treatment options carry risks with some patients remaining incurable. Mesenchymal stromal/stem cell (MSC) therapy has shown promising results supporting osteogenesis and regeneration of radiotherapy-damaged tissues. The aim of this study was to systematically review the literature on the safety and efficacy of MSCs in treating ORN. METHODS: A systematic search was performed on MEDLINE, Embase, Cochranes Library online databases, and clinicaltrials.gov to identify preclinical and clinical studies examining the effect of MSCs on osseous healing of ORN. The preclinical studies were assessed according to the SYRCLEs guidelines and risk of bias tool. RESULTS: Six studies (n = 142) from 5 countries were eligible for analysis. Of these four were preclinical studies and two clinical case studies. Preclinical studies found MSC treatment to be safe, demonstrating bone restorative effects and improved soft tissue regeneration. In the clinical cases, healing of bone and soft tissue was reported with no serious adverse events. CONCLUSION: The evidence from the included studies suggests that MSCs may have beneficial regenerative effects on the healing of ORN. None of the studies reported adverse events with the use of MSCs. More carefully controlled studies with well-identified cells are however needed to demonstrate the efficacy of MSCs in a clinical setting. Graphical abstract.