Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database

BACKGROUND: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. METHODS: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. FINDINGS: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. INTERPRETATION: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. FUNDING: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017

Anterior cruciate ligament reconstruction is associated with greater tibial tunnel widening when using a bioabsorbable screw compared to an all-inside technique with suspensory fixation

Purpose: To compare clinical outcomes and tunnel widening following anterior cruciate ligament reconstruction (ACLR) performed with an all-inside technique (Group A) or with a bioabsorbable tibial screw and suspensory femoral fixation (Group B). Methods: Tunnel widening was assessed using computed tomography (CT) and a previously validated analytical best fit cylinder technique at approximately 1-year following ACLR. Clinical follow-up comprised evaluation with IKDC, KSS, Tegner, Lysholm scores, and knee laxity assessment. Results: The study population comprised 22 patients in each group with a median clinical follow-up of 24 months (range 21–27 months). The median duration between ACLR and CT was 13 months (range 12–14 months). There were no significant differences in clinical outcome measures between groups. There were no differences between groups with respect to femoral tunnel widening. However, there was a significantly larger increase in tibial tunnel widening, at the middle portion, in Group B (2.4 ± 1.5 mm) compared to Group A (0.8 ± 0.4 mm) (p = 0.027), and also at the articular portion in Group B (1.5 ± 0.8 mm) compared to Group A (0.8 ± 0.8 mm) (p = 0.027). Conclusion: Tibial tunnel widening after ACLR using hamstring tendon autograft is significantly greater with suspensory femoral fixation and a bioabsorbable tibial interference screw when compared to an all-inside technique at a median follow-up of 2 years. The clinical relevance of this work lies in the rebuttal of concerns arising from biomechanical studies regarding the possibility of increased tunnel widening with an all-inside technique. Level of evidence: III

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so

Reproducing the biomechanical environment of the chondrocyte for cartilage tissue engineering

It is well known that the biomechanical and tribological performance of articular cartilage is inextricably linked to its extracellular matrix structure and zonal heterogeneity. Furthermore, it is understood that the presence of native extracellular matrix components such as collagen II and aggrecan promote healthy homeostasis in the resident chondrocytes. What is less frequently discussed is how chondrocyte metabolism is related to the extracellular mechanical environment, at both the macro and micro scale. The chondrocyte is in immediate contact with the pericellular matrix of the chondron, which acts as a mechanocoupler, transmitting external applied loads from the ECM to the chondrocyte. Therefore, components of the pericellular matrix also play essential roles in chondrocyte mechanotransduction and metabolism. Recreating the biomechanical environment through tuning material properties of a scaffold and/or the use of external cyclic loading can induce biosynthetic responses in chondrocytes. Decellularised scaffolds which retain the native tissue macro and micro-structure also represent an effective means of recapitulating such an environment. The use of such techniques in tissue engineering applications can ensure the regeneration of skeletally mature articular cartilage with appropriate biomechanical and tribological properties to restore joint function. Despite the pivotal role in graft maturation and performance, biomechanical and tribological properties of such interventions is often underrepresented. This review outlines the role of biomechanics in relation to native cartilage performance and chondrocyte metabolism, and how application of this theory can enhance the future development and successful translation of biomechanically relevant tissue engineering interventions

Two strategies of morphine administration on the control of post-surgical pain after anesthesia with remifentanil

AIM The post-operative pain (POP) is accompanied by autonomic, psychological and behavioural responses which can result in a significant increase in morbidity and mortality. The purpose of this study was to compare the efficacy and safety of intravenous bolus administration of morphine versus subcutaneous administration. MATERIAL OF STUDY: Fifty subjects scheduled for elective abdominal surgery were randomized into a group S (n = 26) and group E (n = 24). The first group was administered morphine (0.35 mg/kg) subcutaneously immediately after induction of anesthesia, while the second group the same drug at a dose of 0.25 mg/kg was administered intravenously 45' before the end of the intervention. All patients received intraoperative remifentanil (0,25-0,50 mu g/kg/min), and at the end of surgery paracetameolo 1g and ondansetron 4mg. Upon awakening, the DPO has been reviewed by the NRS (numerical scale of pain) at time zero (T0), after 30' (t1), 1h (T2) and 24h (T3). Furthermore, it was annotated request for rescue doses of morphine and the collateral effects. RESULTS: The two study groups did not show significant differences related to the anthropometric characteristics, duration of surgery, type of surgery, ASA class. No difference between the two groups was highlighted during the evaluation of POR through NRS scale and quantity of "rescue" doses requested. In group E there was a single case of respiratory depression. CONCLUSIONS: Our study suggests that whether intravenous or subcutaneous administration of morphine, both simple and economical analgesic techniques, they are able to guarantee the same quality control of POP in patients undergoing abdominal surgery

Colonic explosion during treatment of radiotherapy complications in prostatic cancer

The use of lasers has been of great importance in the field of endoscopy and surgery for their applications in coagulation and the ability to vaporize tissue. In the 1990s, new machines were introduced based on a different technology, the argon-plasma-coagulation (APC) system. This technology causes different biological effects without direct contact. An example is the hemostasis of bleeding. In the literature, several cases of complications have been reported during endoscopic treatment with APC. In this study, we report our experience of a case with colon explosion during an APC procedure for bleeding due to radiotherapy and also review the literature on the complications of APC treatment