Different Sources of Fiber Intake and Risk of 17 Specific Cancers and All Cancers Combined: Prospective Study of 364,856 Participants in the UK Biobank.

Inverse associations between dietary fiber (DF) and colorectal cancer risk are well-established. However, evidence is limited in relation to other cancer sites. This study, of 364,856 participants from the UK Biobank, aimed to evaluate the associations between total and source-specific partial DF and risk of 17 specific cancers and all cancers combined. Partial DF was derived from baseline touchscreen questionnaire data on cereal, bread, fruit, and vegetable intake. The outcomes were incident cancer at 17 sites and all cancers combined. Cox proportional hazards models were applied. Over a median 8.8-year follow-up period, 30,725 people were diagnosed with cancer. After adjusting for sociodemographic and lifestyle factors, those in the highest quintile of partial DF compared with the lowest quintile (<9.6 vs ≥19.1 g/day) had 10% lower risk of cancer overall, with the greatest risk reductions observed for cervical (hazard ratio (HR) = 0.33, 95% confidence interval (CI): 0.14; 0.82), esophageal (HR = 0.66, 95% CI: 0.52; 0.84), lung (HR = 0.67, 95% CI: 0.59; 0.76), bladder (HR = 0.72, 95% CI: 0.56; 0.91), and kidney (HR = 0.75, 95% CI: 0.61; 0.92) cancers. Associations between DF and lung cancer were observed only in current and former smokers. Higher DF intake, in particular cereal fiber and fruit and vegetable fiber, was associated with a lower risk of overall and multiple site-specific cancers.

Self-reported fitness as a measure of perioperative cardiovascular risk: tension between subjective and objective assessments persists.

Despite recent high-quality international studies, the optimal sum and sequence of subjective and objective assessments that build the complex picture of fitness for surgery remains to be defined. Physicians' subjective assessment of patient fitness after a typical unstructured interview has poor prognostic accuracy in predicting the risk of major cardiovascular events after noncardiac surgery. How does self-reported fitness assessed by structured questionnaire compare as an indicator of perioperative cardiovascular risk? Here we discuss the latest evidence in this evolving and fundamental aspect of perioperative care.

Deformation and Durability of Soft Three-Dimensional-Printed Polycarbonate Urethane Porous Membranes for Potential Use in Pelvic Organ Prolapse.

Pelvic organ prolapse (POP) is the herniation of the pelvic organs into the vaginal space, resulting in the feeling of a bulge and organ dysfunction. Treatment of POP often involves repositioning the organs using a polypropylene mesh, which has recently been found to have relatively high rates of complications. Complications have been shown to be related to stiffness mismatches between the vagina and polypropylene, and unstable knit patterns resulting in mesh deformations with mechanical loading. To overcome these limitations, we have three-dimensional (3D)-printed a porous, monofilament membrane composed of relatively soft polycarbonate-urethane (PCU) with a stable geometry. PCU was chosen for its tunable properties as it is comprised of both hard and soft segments. The bulk mechanical properties of PCU were first characterized by testing dogbone samples, demonstrating the dependence of PCU mechanical properties on its measurement environment and the effect of print pathing. The pore dimensions and load-relative elongation response of the 3D-printed PCU membranes under monotonic tensile loading were then characterized. Finally, a fatigue study was performed on the 3D-printed membrane to evaluate durability, showing a similar fatigue resistance with a commercial synthetic mesh and hence its potential as a replacement.

The role of surgery in weaning patients from home parenteral support - A cohort study.

AIM: Some patients with intestinal failure requiring home parenteral support (HPS) may be weaned. This study considered all abdominal surgery in a cohort of HPS patients over a 25-year period. Our aim was to identify how many patients can be weaned from HPS and by what means, and to identify what makes weaning more likely. METHOD: A prospectively collected database of HPS patients to December 2018 was analysed for outcomes of care. RESULTS: At 5 years 56% of 205 patients remained on HPS. Fifty eight patients (28%), who had 68 operations, stopped HPS after surgery. Patients stopping HPS had a longer median final small bowel length (155 cm, range 45-350 cm) and were more likely to have colon in circuit (84%) than patients who had reconstructive surgery but did not stop HPS (median small bowel length 50 cm, range 15-135 cm; 50% colon in circuit). The median period between HPS discharge and reconstructive surgery was 238 days. There were no deaths, but 18 Clavien-Dindo grade 3-4 complications occurred within 30 days. Ninety per cent of patients who stopped HPS survived for 5 years from the start of HPS in comparison with 53% of those who remained on HPS. CONCLUSIONS: No previous study has examined surgery in an entire cohort of HPS patients. More than a quarter of HPS patients can be weaned after reconstructive surgery. The length of bowel available for recruitment at surgery is the main determinant of the ability to stop HPS. The possibility of reconstruction should be considered, since patients who stop HPS appear to have a survival advantage.

A soft elastomer alternative to polypropylene for pelvic organ prolapse repair: a preliminary study.

INTRODUCTION AND HYPOTHESIS: We compared the impact of a mesh manufactured from the soft elastomer polydimethylsiloxane (PDMS) to that of a widely used lightweight polypropylene (PP) mesh. To achieve a similar overall device stiffness between meshes, the PDMS mesh was made with more material and therefore was heavier and less porous. We hypothesized that the soft polymer PDMS mesh, despite having more material, would have a similar impact on the vagina as the PP mesh. METHODS: PDMS and PP meshes were implanted onto the vaginas of 20 rabbits via colpopexy. Ten rabbits served as sham. At 12 weeks, mesh-vagina complexes were explanted and assessed for contractile function, histomorphology, total collagen, and glycosaminoglycan content. Outcome measures were compared using one-way ANOVA and Kruskal-Wallis testing with appropriate post-hoc testing. RESULTS: Relative to sham, vaginal contractility was reduced following the implantation of PP (p = 0.035) but not the softer PDMS (p = 0.495). PP had an overall greater negative impact on total collagen and glycosaminoglycan content, decreasing by 53% (p < 0.001) and 54% (p < 0.001) compared to reductions of 35% (p = 0.004 and p < 0.001) with PDMS. However, there were no significant differences in the contractility, collagen fiber thickness, total collagen, and glycosaminoglycan content between the two meshes. CONCLUSIONS: Despite having a substantially higher weight, PDMS had a similar impact on the vagina compared to a low-weight PP mesh, implicating soft polymers as potential alternatives to PP. The notion that heavyweight meshes are associated with a worse host response is not applicable when comparing across materials.

Disease recurrence after right hemicolectomy in Scotland: Is there rationale to adopt complete mesocolic excision (CME)?

AIMS: Complete mesocolic excision (CME) has been proposed as a way to improve the oncological outcomes in patients with colon cancer. To investigate whether there is rationale for adopting the technique in Scotland, our aim was to define the incidence of disease recurrence following standard right hemicolectomy and to compare this with published CME outcomes. METHODS: Data was collected on consecutive patients undergoing right or extended right hemicolectomy for colonic adenocarcinoma (2012-2017) at three hospitals in Scotland (Raigmore Hospital, Aberdeen Royal Infirmary and Glasgow Royal Infirmary). Emergency or palliative surgery was excluded. Patients were followed up with CT scans and colonoscopy for a minimum of 3 years. RESULTS: 689 patients (M 340, F 349) were included. 30-day mortality was 1.6%. Final pathological stage was Stage I (14%), Stage II (49.8%) and Stage III (36.1%). During follow-up, 10.5% developed loco-regional recurrence and 12.2% developed distant metastases. The 1, 3 and 5-year disease-free survival (DFS) was 94%, 84% and 82% respectively. Primary determinants of recurrence were T stage (p < 0.001), N stage (p < 0.001), apical node involvement (p < 0.001) and EMVI (p < 0.001). When compared to the literature, 30-day mortality was lower than many published series and DFS rates were similar to the largest CME study to date (4 year DFS 85.8% versus 83%). CONCLUSION: The outcomes of patients undergoing right hemicolectomy in Scotland compare favourably with many published CME studies. The technique demands further evaluation before it can be recommended for adoption into routine surgical practice.

Comparison of 2 single incision slings on the vagina in an ovine model.

BACKGROUND: Stress urinary incontinence carries a significant healthcare burden for women worldwide. Single incision slings are minimally invasive mesh devices designed to treat stress urinary incontinence. For prolapse repair, meshes with higher porosity and lower structural stiffness have been associated with improved outcomes. OBJECTIVE: In this study, we compared the higher stiffness, lower porosity Altis sling with the lower stiffness, higher porosity Solyx sling in an ovine model. We hypothesized that SIS-B would have a negative impact on the host response. STUDY DESIGN: A total of Altis and Solyx single incision slings were implanted suburethrally into sheep according to the manufacturer's instructions on minimal tension. The mesh-urethral-vaginal complex and adjacent ungrafted vagina (no mesh control) were harvested en bloc at 3 months. Masson's trichrome and picrosirius red staining of 6 µm thin sections was performed to measure interfiber distance and tissue integration. Smooth muscle contractility to a 120 mM KCl stimulus was performed in an organ bath to measure myofiber-driven contractions. Standard biochemical assays were used to quantify glycosaminoglycan, total collagen, and elastin content, and collagen subtypes. Bending stiffness was performed in response to a uniaxial force to define susceptibility to folding/buckling. Statistical analysis was performed using Mann-Whitney, Gabriel's pairwise post hoc, Wilcoxon matched-pairs, and chi-square tests. RESULTS: The animals had similar ages (3-5 years), parity (multiparous), and weights (45-72 kg). Trichrome cross sections showed that the Altis sling buckled in a "C" or "S" shape in most samples (8 of 11), whereas buckling after Solyx sling implantation was observed in only a single sample (1 of 13; P=.004). Tissue integration, as measured by the presence of collagen or smooth muscle between the mesh fibers on trichrome 4× imaging, was increased in samples implanted with the Solyx sling compared with the Altis sling (P<.05). Total collagen content decreased significantly with both products when compared with the ungrafted vagina consistent with stress shielding. There was no difference in the 2 groups with regard to glycosaminoglycan or elastin content. The Altis sling mesh tissue complex demonstrated significantly higher amounts of both collagen types I and III than the Solyx sling-implanted tissue and the ungrafted control. Smooth muscle contractility in response to 120 mM KCl was decreased after implantation of both slings compared with the sham (P=.011 and P<.01), with no difference between mesh types (P=.099). Bending stiffness in the Altis sling was more than 4 times lower than in the Solyx, indicating an increased propensity to buckle (0.0186 vs 0.0883). CONCLUSION: The structurally stiffer Altis sling had decreased tissue integration and increased propensity to buckle after implantation. Increased collagen types I and III after the implantation of this device suggests that these changes may be associated with a fibrotic response. In contrast, the Solyx sling largely maintained a flat configuration and had improved tissue integration. The deformation of the Altis sling is not an intended effect and is likely caused by its lower bending stiffness. Both meshes induced a decrease in collagen content and smooth muscle contractility similar to previous findings for prolapse meshes and consistent with stress shielding. The long-term impact of buckling warrants further investigation.

Aortic calcification is associated with non-infective rather than infective postoperative complications following colorectal cancer resection: an observational cohort study.

OBJECTIVES: Complications following colorectal cancer resection are common. The degree of aortic calcification (AC) on CT has been proposed as a predictor of complications, particularly anastomotic leak. This study assessed the relationship between AC and complications in patients undergoing colorectal cancer resection. METHODS: Patients from 2008 to 2016 were retrospectively identified from a prospectively maintained database. Complications were classified using the Clavien-Dindo (CD) scale. Calcification was quantified on preoperative CT by visual assessment of the number of calcified quadrants in the proximal and distal aorta. Scores were grouped into categories: none, minor (< median AC score) and major (> median AC score). The relationship between clinicopathological characteristics and complications was assessed using logistic regression. RESULTS: Of 657 patients, 52% had proximal AC (> median score (1)) and 75% had distal AC (> median score (4)). AC was more common in older patients and smokers. Higher burden of AC was associated with non-infective complications (proximal AC 28% vs 16%, p = 0.004, distal AC 26% vs 14% p = 0.001) but not infective complications (proximal AC 28% vs 29%, p = 0.821, distal AC 29% vs 23%, p = 0.240) or anastomotic leak (proximal AC 6% vs 4%, p = 0.334, distal AC 7% vs 3%, p = 0.077). Independent predictors of complications included open surgery (OR 1.99, 95%CI 1.43-2.79, p = 0.001), rectal resection (OR 1.51, 95%CI 1.07-2.12, p = 0.018) and smoking (OR 2.56, 95%CI 1.42-4.64, p = 0.002). CONCLUSIONS: These data suggest that high levels of AC are associated with non-infective complications after colorectal cancer surgery and not anastomotic leak. KEY POINTS: • Aortic calcification measured by visual quantification of the number of calcified quadrants at two aortic levels on preoperative CT is associated with clinical outcome following colorectal cancer surgery. • An increased burden of aortic calcification was associated with non-infective complications but not anastomotic leak. • Assessment of the degree of aortic calcification may help identify patients at risk of cardiorespiratory complications, improve preoperative risk stratification and assign preoperative strategies to improve fitness for surgery.

New Zealand white rabbit: a novel model for prolapse mesh implantation via a lumbar colpopexy.

INTRODUCTION AND HYPOTHESIS: New Zealand white rabbits are an inexpensive large-animal model. This study explored the rabbit as a model for mesh-augmented colpopexy using the intra-abdominal vagina. We hypothesized that polypropylene mesh would negatively impact rabbit vaginal smooth muscle (VSM) morphology and contractile function, similar to the nonhuman primate (NHP)-the established model for prolapse mesh evaluation. METHODS: Restorelle was implanted onto the vagina of ten rabbits via lumbar colpopexy after a hysterectomy. Ten rabbits served as sham. Twelve weeks post-implantation, the vagina was excised and VSM morphology and vaginal contractility were assessed. Outcome measures were compared using independent samples t and Mann-Whitney U tests with a Bonferroni correction, where appropriate. Results from the rabbits were compared with published NHP data. RESULTS: Animals had similar age, parity and BMI. VSM was 18% thinner after Restorelle implantation, P = 0.027. Vaginal contractility was 43% decreased in response to 120 mM KCl (P = 0.003), similar to the 46% reduction observed in the NHP vagina implanted with Restorelle (P = 0.027). Three meshes wrinkled in vivo, resulting in dramatic thinning of the underlying vagina in the area of the mesh causing a mesh exposure. CONCLUSIONS: Polypropylene mesh negatively impacts VSM morphology and vaginal contractility in the rabbit, similar to the NHP, suggesting that the rabbit may serve as an alternative large-animal model. The vaginal thinning and appearance of a mesh exposure in the area of a mesh wrinkle suggest the rabbit may also serve as a model for understanding the pathophysiology of mesh exposure.

Impact of polypropylene prolapse mesh on vaginal smooth muscle in rhesus macaque.

BACKGROUND: The use of polypropylene prolapse mesh to treat pelvic organ prolapse has been limited by mesh-related complications. Gynemesh PS mesh, implanted via sacrocolpopexy in rhesus macaques, had a negative impact on the vagina with thinning of vaginal muscularis and decreased vaginal smooth muscle contractility. The negative effect was attenuated when a bioscaffold derived from urinary bladder extracellular matrix was used as a composite with Gynemesh PS. OBJECTIVE: The objective of the study was to further elucidate the impact of Gynemesh PS polypropylene mesh and MatriStem extracellular matrix bioscaffolds on the vaginal smooth muscle in terms of micromorphology of vaginal smooth muscle (muscle bundles and individual myocytes), innervation, and nerve-mediated contractile function following their implantations in a rhesus macaque model via sacrocolpopexy. STUDY DESIGN: Thirty-two middle-aged rhesus macaques were randomized to undergo either a sham surgery (sham, n = 8), or the implantation of Gynemesh PS alone (n = 8) vs composite mesh comprised of Gynemesh PS plus 2-ply MatriStem (n = 8) vs 6-ply MatriStem alone (n = 8) via sacrocolpopexy. The graft-vagina complexes were harvested 3 months later. Histomorphometrics of smooth muscle bundles and myocytes were performed by immunofluorescent labeling of alpha smooth muscle actin, caveolin-3 (membrane protein), and cell nuclei followed by confocal imaging. The cross-sectional diameters of smooth muscle bundles and individual myocytes were quantified using images randomly taken in at least 5 areas of each section of sample. Contractile proteins alpha smooth muscle actin and smoothelin were quantified by Western immunoblotting. Nerve density was measured by immunohistochemical labeling of a pan-neuron marker, PGP9.5. Nerve-mediated smooth muscle contractility was quantified using electrical field stimulation. One-way analysis of variance and appropriate post hoc tests were used for statistical comparisons. RESULTS: Compared with sham, the implantation of Gynemesh PS alone resulted in a disorganized smooth muscle morphology with the number of small muscle bundles (cross-sectional diameter less than 20 µm) increased 67% (P = .004) and the myocyte diameter decreased 22% (P < .001). Levels of contractile proteins were all decreased vs sham with alpha smooth muscle actin decreased by 68% (P = .009), low-molecular-weight smoothelin by 51% (P = .014), and high-molecular-weight smoothelin by 40% (P = .015). Nerve density was decreased by 48% (P = .03 vs sham) paralleled by a 63% decrease of nerve-mediated contractility (P = .02). Following the implantation of composite mesh, the results of measurements were similar to sham (all P > .05), with a 39% increase in the myocyte diameter (P < .001) and a 2-fold increase in the level of alpha smooth muscle actin relative to Gynemesh (P = .045). Following the implantation of MatriStem alone, the number of small muscle bundles were increased 54% vs sham (P = .002), while the other parameters were not significantly different from sham (all P > .05). CONCLUSION: The implantation of Gynemesh PS had a negative impact on the structural and functional integrity of vaginal smooth muscle evidenced by atrophic macro- and microscopic muscle morphology, decreased innervation, and impaired contractile property, consistent with a maladaptive remodeling response. The extracellular matrix bioscaffold (MatriStem), when used with Gynemesh PS as a composite (2 ply), attenuated the negative impact of Gynemesh PS; when used alone (6 ply), it induced adaptive remodeling as evidenced by an increased fraction of small smooth muscle bundles with normal contractility.

Deformation of Transvaginal Mesh in Response to Multiaxial Loading.

Synthetic mesh for pelvic organ prolapse (POP) repair is associated with high complication rates. While current devices incorporate large pores (>1 mm), recent studies have shown that uniaxial loading of mesh reduces pore size, raising the risk for complications. However, it is difficult to translate uniaxial results to transvaginal meshes, as in vivo loading is multidirectional. Thus, the aim of this study was to (1) experimentally characterize deformation of pore diameters in a transvaginal mesh in response to clinically relevant multidirectional loading and (2) develop a computational model to simulate mesh behavior in response to in vivo loading conditions. Tension (2.5 N) was applied to each of mesh arm to simulate surgical implantation. Two loading conditions were assessed where the angle of the applied tension was altered and image analysis was used to quantify changes in pore dimensions. A computational model was developed and used to simulate pore behavior in response to these same loading conditions and the results were compared to experimental findings. For both conditions, between 26.4% and 56.6% of all pores were found to have diameters <1 mm. Significant reductions in pore diameter were noted in the inferior arms and between the two superior arms. The computational model identified the same regions, though the model generally underestimated pore deformation. This study demonstrates that multiaxial loading applied clinically has the potential to locally reduce porosity in transvaginal mesh, increasing the risk for complications. Computational simulations show potential of predicting this behavior for more complex loading conditions.

Preventing Mesh Pore Collapse by Designing Mesh Pores With Auxetic Geometries: A Comprehensive Evaluation Via Computational Modeling.

Pelvic organ prolapse (POP) meshes are exposed to predominately tensile loading conditions in vivo that can lead to pore collapse by 70-90%, decreasing overall porosity and providing a plausible mechanism for the contraction/shrinkage of mesh observed following implantation. To prevent pore collapse, we proposed to design synthetic meshes with a macrostructure that results in auxetic behavior, the pores expand laterally, instead of contracting when loaded. Such behavior can be achieved with a range of auxetic structures/geometries. This study utilized finite element analysis (FEA) to assess the behavior of mesh models with eight auxetic pore geometries subjected to uniaxial loading to evaluate their potential to allow for pore expansion while simultaneously providing resistance to tensile loading. Overall, substituting auxetic geometries for standard pore geometries yielded more pore expansion, but often at the expense of increased model elongation, with two of the eight auxetics not able to maintain pore expansion at higher levels of tension. Meshes with stable pore geometries that remain open with loading will afford the ingrowth of host tissue into the pores and improved integration of the mesh. Given the demonstrated ability of auxetic geometries to allow for pore size maintenance (and pore expansion), auxetically designed meshes have the potential to significantly impact surgical outcomes and decrease the likelihood of major mesh-related complications.

Extracellular matrix regenerative graft attenuates the negative impact of polypropylene prolapse mesh on vagina in rhesus macaque.

BACKGROUND: The use of wide pore lightweight polypropylene mesh to improve anatomical outcomes in the surgical repair of prolapse has been hampered by mesh complications. One of the prototype prolapse meshes has been found to negatively impact the vagina by inducing a decrease in smooth muscle volume and contractility and the degradation of key structural proteins (collagen and elastin), resulting in vaginal degeneration. Recently, bioscaffolds derived from extracellular matrix have been used to mediate tissue regeneration and have been widely adopted in tissue engineering applications. OBJECTIVE: Here we aimed to: (1) define whether augmentation of a polypropylene prolapse mesh with an extracellular matrix regenerative graft in a primate sacrocolpopexy model could mitigate the degenerative changes; and (2) determine the impact of the extracellular matrix graft on vagina when implanted alone. STUDY DESIGN: A polypropylene-extracellular matrix composite graft (n = 9) and a 6-layered extracellular matrix graft alone (n = 8) were implanted in 17 middle-aged parous rhesus macaques via sacrocolpopexy and compared to historical data obtained from sham (n = 12) and the polypropylene mesh (n = 12) implanted by the same method. Vaginal function was measured in passive (ball-burst test) and active (smooth muscle contractility) mechanical tests. Vaginal histomorphologic/biochemical assessments included hematoxylin-eosin and trichrome staining, immunofluorescent labeling of α-smooth muscle actin and apoptotic cells, measurement of total collagen, collagen subtypes (ratio III/I), mature elastin, and sulfated glycosaminoglycans. Statistical analyses included 1-way analysis of variance, Kruskal-Wallis, and appropriate post-hoc tests. RESULTS: The host inflammatory response in the composite mesh-implanted vagina was reduced compared to that following implantation with the polypropylene mesh alone. The increase in apoptotic cells observed with the polypropylene mesh was blunted in the composite (overall P < .001). Passive mechanical testing showed inferior parameters for both polypropylene mesh alone and the composite compared to sham whereas the contractility and thickness of smooth muscle layer in the composite were improved with a value similar to sham, which was distinct from the decreases observed with polypropylene mesh alone. Biochemically, the composite had similar mature elastin content, sulfated glycosaminoglycan content, and collagen subtype III/I ratio but lower total collagen content when compared to sham (P = .011). Multilayered extracellular matrix graft alone showed overall comparable values to sham in aspects of the biomechanical, histomorphologic, or biochemical endpoints of the vagina. The increased collagen subtype ratio III/I with the extracellular matrix graft alone (P = .033 compared to sham) is consistent with an ongoing active remodeling response. CONCLUSION: Mesh augmentation with a regenerative extracellular matrix graft attenuated the negative impact of polypropylene mesh on the vagina. Application of the extracellular matrix graft alone had no measurable negative effects suggesting that the benefits of this extracellular matrix graft occur when used without a permanent material. Future studies will focus on understanding mechanisms.

Colorectal cancer in the elderly and the influence of lead time bias: better survival does not equate with improved life expectancy.

AIMS: Poorer outcomes in those aged ≥80 years who undergo colorectal cancer surgery have been previously reported. Little is known about the natural history of those managed non-operatively. We explored outcomes in all patients with colorectal cancer aged ≥80 years at time of diagnosis based on treatment received. METHODS: Patients ≥80 years diagnosed with colorectal cancer in one hospital trust between 1998 and 2011 were identified from a prospectively maintained database. Primary endpoints were age at diagnosis, age at death/censor and mortality at 30, 90 and 365 days. RESULTS: Six hundred sixty-eight patients were identified. Four hundred twelve (61.7%) underwent surgery, 44 (6.6%) received endoscopic therapy and 212 (31.7%) had no active treatment. Of those who underwent surgery, 359 (87.1%) had resectional surgery, 34 (8.3%) defunctioning only, 13 (3.2%) received bypass surgery and 6 (1.5%) had an open and close laparotomy. The mean age at diagnosis was younger in those who underwent surgical resection (83.7 years) compared to those having defunctioning surgery (84.9 years, P = 0.043), endoscopic therapy (85.1 years, P = 0.008) or no surgical intervention (85.6 years, P < 0.001). There was no significant difference in the mean age of death or censor between groups. CONCLUSIONS: There was no significant difference in age at death or censor between treatment groups among patients aged ≥80 years presenting with colorectal cancer, suggesting that differences in the observed survival time are heavily influenced by lead time bias. Age at death or censor should be reported in addition to survival times in this age group to enable fair comparison of outcomes.

Exploring the basic science of prolapse meshes.

PURPOSE OF REVIEW: Polypropylene mesh has been widely used in the surgical repair of pelvic organ prolapse. However, low but persistent rates of complications related to mesh, most commonly mesh exposure and pain, have hampered its use. Complications are higher following transvaginal implantation prompting the Food and Drug Administration to release two public health notifications warning of complications associated with transvaginal mesh use (PHN 2008 and 2011) and to upclassify transvaginal prolapse meshes from Class II to Class III devices. Although there have been numerous studies to determine the incidence and management of mesh complications as well as impact on quality of life, few studies have focused on mechanisms. RECENT FINDINGS: In this review, we summarize the current understanding of how mesh textile properties and mechanical behavior impact vaginal structure and function, as well as the local immune response. We also discuss how mesh properties change in response to loading. SUMMARY: We highlight a few areas of current and future research to emphasize collaborative strategies that incorporate basic science research to improve patient outcomes.

Impact of parity on ewe vaginal mechanical properties relative to the nonhuman primate and rodent.

INTRODUCTION AND HYPOTHESIS: Parity is the leading risk factor for the development of pelvic organ prolapse. To assess the impact of pregnancy and delivery on vaginal tissue, researchers commonly use nonhuman primate (NHP) and rodent models. The purpose of this study was to evaluate the ewe as an alternative model by investigating the impact of parity on the ewe vaginal mechanical properties and collagen structure. METHODS: Mechanical properties of 15 nulliparous and parous ewe vaginas were determined via uniaxial tensile tests. Collagen content was determined by hydroxyproline assay and collagen fiber thickness was analyzed using picrosirius red staining. Outcome measures were compared using Independent samples t or Mann-Whitney U tests. ANOVA (Gabriel's pairwise post-hoc test) or the Welch Alternative for the F-ratio (Games Howell post-hoc test) was used to compare data with previously published NHP and rodent data. RESULTS: Vaginal tissue from the nulliparous ewe had a higher tangent modulus and tensile strength compared with the parous ewe (p < 0.025). The parous ewe vagina elongated 42 % more than the nulliparous ewe vagina (p = 0.015). No significant differences were observed in collagen structure among ewe vaginas. The tangent modulus of the nulliparous ewe vagina was not different from that of the NHP or rodent (p = 0.290). Additionally, the tangent moduli of the parous ewe and NHP vaginas did not differ (p = 0.773). CONCLUSIONS: Parity has a negative impact on the mechanical properties of the ewe vagina, as also observed in the NHP. The ewe may serve as an alternative model for studying parity and ultimately prolapse development.

The Glasgow Microenvironment Score: an exemplar of contemporary biomarker evolution in colorectal cancer.

Colorectal cancer remains a leading cause of mortality worldwide. Significant variation in response to treatment and survival is evident among patients with similar stage disease. Molecular profiling has highlighted the heterogeneity of colorectal cancer but has had limited impact in daily clinical practice. Biomarkers with robust prognostic and therapeutic relevance are urgently required. Ideally, biomarkers would be derived from H&E sections used for routine pathological staging, have reliable sensitivity and specificity, and require minimal additional training. The biomarker targets would capture key pathological features with proven additive prognostic and clinical utility, such as the local inflammatory response and tumour microenvironment. The Glasgow Microenvironment Score (GMS), first described in 2014, combines assessment of peritumoural inflammation at the invasive margin with quantification of tumour stromal content. Using H&E sections, the Klintrup-Mäkinen (KM) grade is determined by qualitative morphological assessment of the peritumoural lymphocytic infiltrate at the invasive margin and tumour stroma percentage (TSP) calculated in a semi-quantitative manner as a percentage of stroma within the visible field. The resulting three prognostic categories have direct clinical relevance: GMS 0 denotes a tumour with a dense inflammatory infiltrate/high KM grade at the invasive margin and improved survival; GMS 1 represents weak inflammatory response and low TSP associated with intermediate survival; and GMS 2 tumours are typified by a weak inflammatory response, high TSP, and inferior survival. The prognostic capacity of the GMS has been widely validated while its potential to guide chemotherapy has been demonstrated in a large phase 3 trial cohort. Here, we detail its journey from conception through validation to clinical translation and outline the future for this promising and practical biomarker.

Sarcopenia is independently associated with poor preoperative physical fitness in patients undergoing colorectal cancer surgery.

BACKGROUND: Accurate preoperative risk assessment for major colorectal cancer (CRC) surgery remains challenging. Body composition (BC) and cardiopulmonary exercise testing (CPET) can be used to evaluate risk. The relationship between BC and CPET in patients undergoing curative CRC surgery is unclear. METHODS: Consecutive patients undergoing CPET prior to CRC surgery between 2010 and 2020 were identified between two different UK hospitals. Body composition phenotypes such as sarcopenia, myosteatosis, and visceral obesity were defined using widely accepted thresholds using preoperative single axial slice CT image at L3 vertebrae. Relationships between clinicopathological, BC, and CPET variables were investigated using linear regression analysis. RESULTS: Two hundred eighteen patients with stage I-III CRC were included. The prevalence of sarcopenia, myosteatosis, and visceral obesity was 62%, 33%, and 64%, respectively. The median oxygen uptake at anaerobic threshold (VO2 at AT) was 12.2 mL/kg/min (IQR 10.6-14.2), and oxygen uptake at peak exercise (VO2 peak) was 18.8 mL/kg/min (IQR 15.4-23). On univariate linear regression analysis, male sex (P < 0.001) was positively associated with VO2 at AT. While ASA grade (P < 0.001) and BMI (P = 0.007) were negatively associated with VO2 at AT, on multivariate linear regression analysis, these variables remained significant (P < 0.05). On univariate linear regression analysis, male sex (P < 0.001) was positively associated with VO2 peak, whereas age (P < 0.001), ASA grade (P < 0.001), BMI (P = 0.003), sarcopenia (P = 0.015), and myosteatosis (P < 0.001) were negatively associated with VO2 peak. On multivariate linear regression analysis age (P < 0.001), ASA grade (P < 0.001), BMI (P < 0.001), and sarcopenia (P = 0.006) were independently and negatively associated with VO2 peak. CONCLUSIONS: The novel finding that sarcopenia is independently associated with reduced VO2 peak performance in CPET supports the supposition that reduced muscle mass relates to poor physical function in CRC patients. Further work should be undertaken to assess whether sarcopenia diagnosed on CT can act as suitable surrogate for CPET to further enhance personalized risk stratification.

Mesh deformation: A mechanism underlying polypropylene prolapse mesh complications in vivo.

Polypropylene meshes used in pelvic organ prolapse (POP) repair are hampered by complications. Most POP meshes are highly unstable after tensioning ex vivo, as evidenced by marked deformations (pore collapse and wrinkling) that result in altered structural properties and material burden. By intentionally introducing collapsed pores and wrinkles into a mesh that normally has open pores and remains relatively flat after implantation, we reproduce mesh complications in vivo. To do this, meshes were implanted onto the vagina of rhesus macaques in nondeformed (flat) vs deformed (pore collapse +/- wrinkles) configurations and placed on tension. Twelve weeks later, animals with deformed meshes had two complications, (1) mesh exposure through the vaginal epithelium, and (2) myofibroblast proliferation with fibrosis - a mechanism of pain. The overarching response to deformed mesh was vaginal thinning associated with accelerated apoptosis, reduced collagen content, increased proteolysis, deterioration of mechanical integrity, and loss of contractile function consistent with stress shielding - a precursor to mesh exposure. Regional differences were observed, however, with some areas demonstrating myofibroblast proliferation and matrix deposition. Variable mechanical cues imposed by deformed meshes likely induce these two disparate responses. Utilizing meshes associated with uniform stresses on the vagina by remaining flat with open pores after tensioning is critical to improving outcomes. STATEMENT OF SIGNIFICANCE: Pain and exposure are the two most reported complications associated with the use of polypropylene mesh in urogynecologic procedures. Most meshes have unstable geometries as evidenced by pore collapse and wrinkling after tensioning ex vivo, recapitulating what is observed in meshes excised from women with complications in vivo. We demonstrate that collapsed pores and wrinkling result in two distinct responses (1) mesh exposure associated with tissue degradation and atrophy and (2) myofibroblast proliferation and matrix deposition consistent with fibrosis, a tissue response associated with pain. In conclusion, mesh deformation leads to areas of tissue degradation and myofibroblast proliferation, the likely mechanisms of mesh exposure and pain, respectively. These data corroborate that mesh implantation in a flat configuration with open pores is a critical factor for reducing complications in mesh-augmented surgeries.