Obesity and Inflammatory Factors in the Progression of Early-Onset Colorectal Cancer.

Metabolic dysfunction associated with obesity leads to a chronic pro-inflammatory state with systemic effects, including the alteration of macrophage metabolism. Tumor-associated macrophages have been linked to the formation of cancer through the production of metabolites such as itaconate. Itaconate downregulates peroxisome proliferator-activated receptor gamma as a tumor-suppressing factor and upregulates anti-inflammatory cytokines in M2-like macrophages. Similarly, leptin and adiponectin also influence macrophage cytokine expression and contribute to the progression of colorectal cancer via changes in gene expression within the PI3K/AKT pathway. This pathway influences cell proliferation, differentiation, and tumorigenesis. This work provides a review of obesity-related hormones and inflammatory mechanisms leading to the development and progression of early-onset colorectal cancer (EOCRC). A literature search was performed using the PubMed and Cochrane databases to identify studies related to obesity and EOCRC, with keywords including 'EOCRC', 'obesity', 'obesity-related hormones', 'itaconate', 'adiponectin', 'leptin', 'M2a macrophage', and 'microbiome'. With this concept of pro-inflammatory markers contributing to EOCRC, increased use of chemo-preventative agents such as aspirin may have a protective effect. Elucidating this association between obesity-related, hormone/cytokine-driven inflammatory effects with EOCRC may help lead to new therapeutic targets in preventing and treating EOCRC.

Long-term behavior and functional outcomes of ileal-pouch anal anastomosis in inflammatory bowel disease with changing phenotype.

BACKGROUND: Ileal-pouch-anal anastomosis is the operation of choice after proctocolectomy for ulcerative colitis; some patients will develop Crohn's disease. We aim to determine long-term behavior and outcomes of inflammatory bowel disease-ileal-pouch-anal anastomosis after colectomy, where a specialist gastrointestinal pathologist re-evaluated the initial colectomy specimen. METHODS: Patients with inflammatory bowel disease-ileal-pouch-anal anastomosis were identified from a single-surgeon prospective database containing 1,165 patients accrued from 1991 to 2017 and invited to complete pouch-function and quality-of-life assessments. Medical records were used to obtain clinical outcomes and subjective functional assessments for those unable to be contacted. Data were compared between patients with and without histological assessment disagreement and subsequent inflammatory bowel disease behavior subgroups. RESULTS: For 138 patients included in the analysis, the median follow-up was 22.5 (range: 5-39) years. A total of 39.1% of patients had histologic diagnostic change after gastrointestinal pathologist review, and 19% and 39% developed Crohn's disease-like disease behavior at 10- and 20-year follow-ups. Pouch function and quality-of-life scores were similar across diagnostic change subgroups. Pouch failure was higher in Crohn's-like disease (31.1 vs 13.0%, P < .05). Intestinal continuity was maintained in 68.9% of Crohn's disease-like patients, 57.9% required biologics. Gastrointestinal pathologist review did not alter the time to new diagnosis (P = .419) or time to pouch failure (P = .320), mean: 11.0 and 11.41 years, respectively. CONCLUSION: We describe equivocal patient-reported outcomes in patients with ileal-pouch-anal anastomosis and changing histologic and clinical diagnosis. Although pouch excision and biologic use rates are higher, many Crohn's disease-like patients maintain their pouch. Diagnostic change and pouch failure often occur >10 years after ileal-pouch-anal anastomosis creation. This supports the consideration of ileal-pouch-anal anastomosis after colectomy in carefully selected patients with inflammatory bowel disease, even those with ambiguous histology and the need for close long-term follow-up.

Anti-inflammatory mechanisms in cancer research: Characterization of a distinct M2-like macrophage model derived from the THP-1 cell line.

AIMS: Macrophages play an essential role in cancer development. Tumor-associated macrophages (TAMs) have predominantly M2-like attributes that are associated with tumor progression and poor patient survival. Numerous methods have been reported for differentiating and polarizing macrophages in vitro, but there is no standardized and validated model for creating TAMs. Primary cells show varying cytokine responses depending on their origin and functional studies utilizing these cells may lack generalization and validity. A distinct cell line-derived TAM-like M2 subtype is required to investigate the mechanisms mediated by anti-inflammatory TAMs in vitro. Our previous work demonstrated a standardized protocol for creating an M2 subtype derived from a human THP-1 cell line. The cell expression profile, however, has not been validated. The aim of this study was to characterize and validate the TAM-like M2 subtype macrophage created based on our protocol to introduce them as a standardized model for cancer research. METHODS AND RESULTS: Using qRT-PCR and ELISA, we demonstrated that proinflammatory, anti-inflammatory, and tumor-associated marker expression changed during THP-1-derived marcrophage development in vitro, mimicking a TAM-related profile (e.g., TNFα, IL-1ß). The anti-inflammatory marker IL-8/CXCL8, however, is most highly expressed in young M0 macrophages. Flow cytometry showed increased expression of CD206 in the final TAM-like M2 macrophage. Single-cell RNA-sequencing analysis of primary human monocytes and colon cancer tissue macrophages demonstrated that cell line-derived M2 macrophages resembled a TAM-related gene profile. CONCLUSIONS: The THP-1-derived M2 macrophage based on a standardized cell line model represents a distinct anti-inflammatory TAM-like phenotype with an M2a subtype profile. This model may provide a basis for in vitro investigation of functional mechanisms in a variety of anti-inflammatory settings, particularly colon cancer development.

Unmet Challenges in Patients with Crohn's Disease.

Patients with Crohn's disease can present with a variety of clinical manifestations; treatment strategies should focus on long-term remission and improvement of quality of life. There is no standardized process of diagnosing, predicting prognosis, and treating the disease. This narrative review was based on a literature search using PubMed, Embase, and Science Direct. Data on unmet challenges in patients with Crohn's disease were extracted from identified manuscripts. The aim was to discuss present research on standardized processes in the management of patients with Crohn's disease and to identify the unmet needs in clinical evaluation and treatment approaches. There is no consensus on standardized diagnostic, treatment, and surveillance algorithms, particularly in assessing complications of Crohn's, such as stricturing disease, intestinal cancer risk, and cutaneous manifestations. Complications and treatment failure rates of conventional, interventional, and surgical therapy place emphasis on the need for standardized treatment algorithms, particularly in the case of acute complications of the disease. Research on standardized clinical approaches, reliable biomarkers for disease diagnosis and therapy monitoring, and new treatment agents is necessary to improve therapy and reduce complications in patients with Crohn's disease.

Systemic adiponectin levels in colorectal cancer and adenoma: a systematic review and meta-analysis.

BACKGROUND: Obesity is a well-established risk factor in the development of colorectal cancer; however, the mechanism mediating this relationship is not well understood. The adipokine, adiponectin, has an inverse relationship with obesity. Experimental studies have shown adiponectin to have dichotomous inflammatory and tumorigenic roles. Its role in the development of colorectal cancer, including the potential effect of its increase following bariatric surgery, is not yet clear. There are conflicting results from studies evaluating this relationship. This study sought to provide a systematic review and meta-analysis to examine the association between systemic adiponectin levels in patients with colorectal cancer and adenoma. METHODS: An electronic literature search was performed using PubMed, EMBASE, Web of Science as well as gray literature. Articles were screened for inclusion criteria and assessed for quality using the Newcastle-Ottawa Scale. Pooled mean differences were calculated using a random effects model. Subgroup and meta-regression analyses were performed to identify potential sources of heterogeneity. RESULTS: Thirty-two observational studies comparing systemic adiponectin in colorectal cancer vs healthy controls were included. Colorectal cancer cases had lower systemic adiponectin levels (overall pooled mean difference = -1.05 µg/ml [95% CI: -1.99; -0.12] p = 0.03); however, significant heterogeneity was present (I2 = 95% p < 0.01). Subgroup and meta- regression analyses results could not identify a source of the significant heterogeneity across the studies. CONCLUSIONS: Studies suggest a trend towards lower systemic adiponectin levels in colorectal cancer patients, but the heterogeneity observed showed current evidence is not sufficient to definitively draw any conclusions. These data, however, suggest rising adiponectin is unlikely to account for the reported observation of increased CRC following bariatric surgery. Further studies with prospective age, race, and BMI-matched cohorts, and standardized adiponectin measurements may provide a better understanding of this relationship.

State-of-the-art surgery for Crohn's disease: part III-perianal Crohn's disease.

PURPOSE: Diagnosis and treatment of perianal Crohn's disease is challenging and requires its own domain of therapy. Different types of perianal disease require a spectrum of treatment strategies. Treatment options range from conservative therapy, including immunosuppressives, biologics, or stem cell therapy, to surgical treatment with specific indications depending on the underlying lesion. This is part III of the series "state-of-the-art surgery for Crohn's disease," focusing on the management of perianal disease. We discuss the definition and diagnosis of perianal Crohn's disease, the treatment of perianal lesions, and specific surgical indications and techniques. RESULTS AND CONCLUSION: Pitfalls and complications play a substantial role in the treatment of perianal Crohn's disease, and surgical therapy may fail. Realistic treatment goals and an individual patient-oriented treatment approach are crucial in the treatment of perianal Crohn's disease.

State-of-the-art surgery for Crohn's disease: Part II-colonic Crohn's disease and associated neoplasms.

Despite advances in medical therapy, surgery continues to play a vital role in the management of Crohn's disease and its complications. Continuing from Part I of this series (small intestine/ileal disease), we focus next on colonic Crohn's disease and associated neoplasms. We will first review the surgical management of medical-refractory Crohn's colitis and its complications and then examine cancer risk, surveillance, and surgical management of Crohn's-associated colorectal dysplasia and malignancy. We conclude with a discussion of restoration of gastrointestinal continuity following colonic surgery for Crohn's disease.

A predictive Bayesian network that risk stratifies patients undergoing Barrett's surveillance for personalized risk of developing malignancy.

BACKGROUND: Barrett's esophagus is strongly associated with esophageal adenocarcinoma. Considering costs and risks associated with invasive surveillance endoscopies better methods of risk stratification are required to assist decision-making and move toward more personalised tailoring of Barrett's surveillance. METHODS: A Bayesian network was created by synthesizing data from published studies analysing risk factors for developing adenocarcinoma in Barrett's oesophagus through a two-stage weighting process. RESULTS: Data was synthesized from 114 studies (n = 394,827) to create the Bayesian network, which was validated against a prospectively maintained institutional database (n = 571). Version 1 contained 10 variables (dysplasia, gender, age, Barrett's segment length, statin use, proton pump inhibitor use, BMI, smoking, aspirin and NSAID use) and achieved AUC of 0.61. Version 2 contained 4 variables with the strongest evidence of association with the development of adenocarcinoma in Barrett's (dysplasia, gender, age, Barrett's segment length) and achieved an AUC 0.90. CONCLUSION: This Bayesian network is unique in the way it utilizes published data to translate the existing empirical evidence surrounding the risk of developing adenocarcinoma in Barrett's esophagus to make personalized risk predictions. Further work is required but this tool marks a vital step towards delivering a more personalized approach to Barrett's surveillance.

Decision analysis of minimally invasive management options for cholecysto-choledocholithiasis.

BACKGROUND: The management of cholecysto-choledocholithiasis is controversial with the risks and benefits of one versus two-stage approaches debated. This study aims to perform decision analysis of minimally invasive laparo-endoscopic approaches. METHODS: An advanced decision tree was constructed to compare pre, intra and post-operative ERCP and laparoscopic common bile duct exploration in terms of primary ductal clearance and significant complications for patients intended to undergo laparoscopic cholecystectomy. Transition probabilities were calculated from randomised controlled trials following a comprehensive literature search. Model uncertainties were extensively tested through deterministic and probabilistic Monte Carlo sensitivity analysis. Utility outcomes were 1 and 0.5 for successful primary clearance without and with complications, respectively, and 0 for failure of primary clearance of the duct. RESULTS: Twenty-one studies (n = 2697) were included in the analysis. At base case analysis, a laparo-endoscopic rendezvous approach had the highest utility output (0.90; no complication probability: 0.87/complication probability 0.06). Laparoscopic common bile duct exploration was ranked second with a utility output 0.87 (no complication probability: 0.82/complication probability 0.10). Pre-operative ERCP utility score was 0.84 (no complication probability: 0.78/ complication probability 0.11) and post-operative ERCP utility score was 0.78 (no complication probability: 0.71/complication probability 0.13). Monte Carlo analysis showed that laparo-endoscopic rendezvous and laparoscopic common bile duct exploration had an equal mean utility output of 0.57 (standard deviation 0.36; variance 0.13; 95% confidence interval 0.00-0.99 versus standard deviation 0.34; variance 0.12; 95% confidence interval 0.01-0.98). Laparo-endoscopic rendezvous had a superior treatment selection frequency of 39.93% followed by laparoscopic bile duct exploration (36.11%), pre-operative ERCP (20.67%) and post-operative ERCP (2.99%). CONCLUSION: One-stage approach to the management of cholecysto-choledocholithiasis is superior to two-stage, in terms of primary clearance of the duct and risk of operative morbidity. Laparo-endoscopic rendezvous approach could offer marginal additional benefit but more high-quality randomised controlled trials are needed.

myHip&Knee: Improving Patient Engagement and Self-Management Through Mobile Technology.

Given the increasing volume of hip and knee replacement surgery with reduced hospital stays and resources, we explored technology to address gaps in patient care and enhance self-management. The team at the Holland Orthopaedic and Arthritic Centre of Sunnybrook Health Sciences Centre, which performs a high volume of joint replacement surgery, partnered with patients and a health technology company to create a mobile app: myHip&Knee. The results to date demonstrate that the app improves patient experience and reduces follow-up calls to surgeons' offices, ultimately reducing demand on healthcare resources. Early engagement of privacy and legal services, close patient and family collaboration and a well-developed evaluation strategy represent critical steps to successful development.

Evaluation of an advanced-practice physical therapist in a specialty shoulder clinic: diagnostic agreement and effect on wait times.

PURPOSE: To examine the role of an advanced-practice physiotherapist (APP) with respect to (1) agreement with an orthopaedic surgeon on diagnosis and management of patients with shoulder problems; (2) wait times; and (3) satisfaction with care. METHODS: This prospective study involved patients with shoulder complaints who were referred to a shoulder specialist in a tertiary care centre. Agreement was examined on seven major diagnostic categories, need for further examination and surgery, and type of surgical procedure. Wait times were compared between the APP- and surgeon-led clinics from referral date to date of initial consultation, date of final diagnostic test, and date of confirmed diagnosis and planned treatment. A modified and validated version of the Visit-Specific Satisfaction Instrument assessed satisfaction in seven domains. Kappa (κ) coefficients and bias- and prevalence-adjusted kappa (PABAK) values were calculated, and strength of agreement was categorized. Wait time and satisfaction data were examined using non-parametric statistics. RESULTS: Agreement on major diagnostic categories varied from 0.68 (good) to 0.96 (excellent). Agreement with respect to indication for surgery was κ=0.75, p<0.001; 95% CI, 0.62-0.88 (good). Wait time for APP assessment was significantly shorter than wait time for surgeon consultation at all time points (p<0.001); the surgeon's wait time was significantly reduced over 3 years. High satisfaction was reported in all components of care received from both health care providers. CONCLUSIONS: Using experienced physiotherapists in an extended role reduces wait times without compromising patient clinical management and overall satisfaction.

Objectif : Examiner le rôle du physiothérapeute en pratique avancée en ce qui a trait (1) aux accords avec un chirurgien orthopédique sur le diagnostic et la gestion de patients aux prises avec des problèmes à l'épaule; (2) au temps d'attente; (3) à la satisfaction par rapport aux soins. Méthode : Cette étude prospective a fait appel à des patients avec des douleurs à l'épaule qui ont été dirigés vers des spécialistes de l'épaule dans un centre de soins tertiaires. Les accords ont été examinés pour sept catégories de diagnostics, en fonction de la nécessité d'examens plus poussés ou de chirurgie et du type d'intervention chirurgicale projeté. On a comparé les temps d'attente pour le physiothérapeute en pratique avancée et les cliniques dirigées par un chirurgien à partir de la date où le patient a été redirigé à la consultation initiale, jusqu'à la date de diagnostic définitif, jusqu'à la date de diagnostic confirmé et jusqu'au traitement planifié. Une version modifiée et validée de l'instrument d'évaluation de la satisfaction à la suite d'une consultation (Visit-Specific Satisfaction Instrument) a permis de mesurer la satisfaction dans sept domaines. Les coefficients kappa (κ) et les valeurs kappa ajustées pour la prévalence et le biais (PABAK) ont été calculés et les accords ont été catégorisés selon leur force. Les données sur les temps d'attente et la satisfaction ont été examinées à l'aide de statistiques non paramétriques. Résultats : Le degré d'accord sur les diagnostics importants variait de 0,68 (bon) à 0,96 (excellent). Les accords en ce qui concerne le recours à la chirurgie étaient de κ=0,75, p<0,001, I.C. 95%, 0,62­0,88 (bon). Les temps d'attente pour une évaluation par un physiothérapeute en pratique avancée étaient considérablement plus courts que ceux pour une consultation auprès d'un chirurgien à toutes les étapes (p<0,001); les temps d'attente pour un chirurgien étaient considérablement réduits sur 3 ans. Un degré élevé de satisfaction a été observé dans toutes les composantes des soins prodigués par des fournisseurs de soins. Conclusions : Le recours à un physiothérapeute expérimenté dont la pratique s'étend hors des rôles traditionnels réduit les temps d'attente sans nuire à la gestion clinique du patient ni influer sur sa satisfaction globale.

Toward a joint health and disease management program. Toronto hospitals partner to provide system leadership.

The Joint Health and Disease Management Program in the Toronto Central Local Health Integration Network (TC LHIN) is envisioned as a comprehensive model of care for patients with hip and knee arthritis. It includes access to assessment services, education, self-management programs and other treatment programs, including specialist care as needed. As the first phase of this program, the hospitals in TC LHIN implemented a Hip and Knee Replacement Program to focus on improving access and quality of care, coordinating services and measuring wait times for patients waiting for hip or knee replacement surgery. The program involves healthcare providers, consumers and constituent hospitals within TC LHIN. The approach used for this program involved a definition of governance structure, broad stakeholder engagement to design program elements and plans for implementation and communication to ensure sustainability. The program and approach were designed to provide a model that is transferrable in its elements or its entirety to other patient populations and programs. Success has been achieved in creating a single wait list, developing technology to support referral management and wait time reporting, contributing to significant reductions in waits for timely assessment and treatment, building human resource capacity and improving patient and referring physician satisfaction with coordination of care.

A framework for the development and implementation of an advanced practice role for physiotherapists that improves access and quality of care for patients.

A new model of care has been implemented at the Sunnybrook Holland Orthopaedic and Arthritic Centre that expands the role of physiotherapists to improve access and quality of care for patients requiring hip and knee replacement surgery. An advanced practice physiotherapist (APP) role was created to support both referral management and post-operative care to reduce surgeon workload and better streamline services. This article describes our nine-step framework for implementing an APP role and can be used as a template for other organizations evolving similar roles. The framework was adapted from the participatory, evidence-based, patient-focused process for the development of an advanced practice nurse role. Key steps include (1) obtaining stakeholder consensus, (2) identifying barriers and facilitators and (3) developing the necessary administrative and training supports as well as clinical protocols and an evaluation framework. Approaching change in a series of small steps (plan-do-study-act [PDSA] methodology) alongside existing processes has facilitated buy-in and role acceptance. The early and continued involvement of decision-makers within the organization has been paramount to successful implementation. In addition, patient input has been central to the evolution of the role, with patient satisfaction a key indicator. The new role and model of care reconfigures traditional roles and introduces a team approach that results in timely access to care for patients. Benefits include an improved assessment process, enhanced education across the care continuum and improved coordination and delivery of services.

Achieving team consensus on best practice rehabilitation guidelines following primary total hip replacement (THR) surgery.

The demand for hip replacements is on the rise; however, despite commonly employed post-operative positional and activity restrictions, limited evidence exists to substantiate such practices. Guidelines provide a means of assisting the healthcare team in decision-making; however, when a clinical decision has to be made in the absence of scientific evidence, guideline developers rely on consensus processes. A formal consensus process based on a nominal group technique was used to incorporate the scientific evidence and practitioner experience for the development of primary total hip replacement guidelines at a specialized orthopaedic tertiary care facility. Agreement was reached regarding a number of practice issues, which historically had varied among the surgeons. Given the lack of available guidance on how to synthesize research findings in conjunction with expert opinion, the process we employed has been described so that others may use, modify and refine it. Further scientific inquiry into safe activity resumption post-total hip replacement is warranted.