Effect of neoadjuvant therapy regimens on lymph nodes yield in rectal cancer.

BACKGROUND AND OBJECTIVES: Pathological nodal staging is relevant to postoperative decision-making and a prognostic marker of cancer survival. This study aimed to assess the effect of different total neoadjuvant therapy (TNT) regimens on lymph node status following total mesorectal excision (TME) for locally advanced rectal cancer (LARC). METHODS: A retrospective cohort study of patients treated for node-positive clinical stage 3 LARC with TNT between January 2015 and August 2022. Patients were stratified into induction therapy and consolidation therapy groups. Variables collated included patient demographics, clinical and radiological characteristics of the tumor, and pathology of the resected specimen. Primary outcome was total harvested lymph nodes. RESULTS: Ninety-seven patients were included (57 [58.8%] males; mean age of 58.5 ± 11.4 years). The induction therapy group included 85 (87.6%) patients while 12 (12.4%) patients received consolidation therapy. A median interquartile range value of 22.00 (5.00-72.00) harvested lymph nodes was recorded for the induction therapy group in comparison to 16.00 (16.00-47.00) in the consolidation therapy arm (p = 0.487). Overall pathological complete response rate was 34%. CONCLUSION: Total harvested nodes from resected specimens were marginally lower in the consolidation therapy group. Induction therapy may be preferrable to optimize postoperative specimen staging.

Genomic Predictors Associated With Exceptional Response to Systemic Therapy in Advanced Pancreatic Cancer.

INTRODUCTION: Exceptional response to therapy is rare in patients with advanced pancreatic cancer. This study explored potential genomic differences between typical and exceptional responses that could confer more favorable biology. METHODS: We included exceptional responders and controls with advanced pancreatic cancer from Cleveland Clinic from April 2013 to August 2017. Exceptional responders were defined as patients with an overall survival of more than 18 months for metastatic disease and more than 24 months for locally advanced disease. Clinical data were obtained, and next-generation sequencing was performed. Statistical analyses comparing the 2 groups were performed using descriptive statistics, the Kaplan-Meier method, and the log-rank test. RESULTS: The study comprised 4 exceptional responders and 6 controls. Both groups were well balanced in age, sex, race, and treatment regimens. Exceptional responders had significantly fewer nonsynonymous mutations than controls (2.25 vs 5.17; P = .014). A mutation count of less than 3 was associated with significantly better progression-free survival (17.2 vs 2.3 months; P = .002) and overall survival (29.4 vs 4.6 months; P = .013). Tumor mutational burden did not differ between exceptional responders and controls (4.88 vs 5.70 mut/Mb; P = .39). CONCLUSION: A lower number of nonsynonymous mutations may correlate with exceptional outcomes in patients with pancreatic cancer. These findings should encourage future studies into genomic signatures of exceptional response.

Immunotherapy in rectal cancer patients-a propensity score matched analysis of the National Cancer Database.

BACKGROUND: Rectal cancer patients with microsatellite instability (MSI-H) are candidates for immunotherapy. However, there is little evidence on its effect on overall survival (OS). METHODS: Retrospective analysis of stage II-IV rectal adenocarcinoma patients in the National Cancer Database (NCDB) between 2010 and 2019. Propensity score matching was adjusted for baseline and treatment confounders. The cohort was divided into patients who received immunotherapy and matched controls. The primary outcome was OS. RESULTS: 5175/206,615 (2.5%) patients with rectal adenocarcinoma underwent immunotherapy. These patients were younger (58 vs 62 years; p < 0.001), more often male (64.4% vs 61.7%; p < 0.001), were more likely to have private insurance (50.8% vs 43.4%; p < 0.001), more metastatic disease at presentation (clinical TNM stage IV-80.8% vs 23.3%; p < 0.001), presented with larger tumors (median: 5 cm vs. 4.2 cm; p < 0.001) and less often underwent surgery (33.7% vs. 69.9%; p < 0.001), radiation therapy (21.5% vs 57.4%; p < 0.001), and standard chemotherapy (38.1% vs 61%; p < 0.001) than controls. After matching, 488 patients were in each group. OS was significantly shorter in the immunotherapy group (mean survival: 56.4 months (95% CI: -53.03-59.86)) compared to controls (mean survival: 70.5 months (95% CI: -66.15-74.92) (p = 0.004)). Cox regression analysis of factors associated with OS demonstrated that immunotherapy was associated with increased mortality (HR 2.16; 95% CI: 2.09-2.24; p < 0.001). After clinical staging stratification, immunotherapy was associated with improved OS in stage IV (HR 0.91, 95% CI: 0.88-0.95; p < 0.001) but lower survival in stage II (HR 2.38; 95% CI: 2.05-2.77; p < 0.001) and stage III (HR 2.43; 95% CI: 2.18-2.7; p < 0.001) patients. CONCLUSION: Immunotherapy showed modest increase in OS in stage IV metastatic rectal cancer. OS was significantly lower in stage II-III disease treated with immunotherapy.

Can normalized carcinoembryonic antigen following neoadjuvant chemoradiation predict tumour recurrence after curative resection for locally advanced rectal cancer?

AIM: The aim of this work was to evaluate whether normalized carcinoembryonic antigen (CEA) following neoadjuvant chemoradiation predicts the prognosis following curative resection in locally advanced rectal cancer. METHOD: Patients who underwent neoadjuvant chemoradiation and curative resection for locally advanced rectal cancer between 2010 and 2015 were divided into three groups: Group A (n = 119, normal-to-normal): normal CEA before and after neoadjuvant chemoradiation; Group B (n = 37, high-to-normal): elevated CEA before and normal CEA after neoadjuvant chemoradiation; Group C (n = 36, high-to-high): elevated CEA before and after neoadjuvant chemoradiation. Overall and disease-free survival were compared. Univariate and multivariate analyses identified potential predictors for recurrence. RESULTS: One hundred and ninety two patients [median age 59 years (range 31-87), 65.1% male] were identified: 54.7% had low rectal cancer: 12.5% were clinical stage T4 and 70.3% were clinically node positive; 21.9% achieved complete pathological response; 24.5% had abdominoperineal resection (APR); and 70.3% underwent adjuvant chemotherapy following curative resection. Significantly more patients in Group C underwent APR (p = 0.0209), had advanced pathological T stage (P = 0.0065) and a higher prevalence of perineural invasion (p = 0.0042). Overall and disease-free survival were significantly higher for Group A than for Group C [hazard ratio (HR) = 4.32, 95% CI = 1.66-11.21, p = 0.0026 and HR=2.68, 95% CI = 1.33-5.40, p = 0.0057, respectively]. No significant difference was noted between Groups A and B for overall (p = 0.0591) or disease-free (p = 0.2834) survival. Another risk factor associated with recurrence and death was clinical T4 stage; nodal positivity was a risk factor only for recurrence. CONCLUSION: Elevated CEA after neoadjuvant chemoradiation and clinical stage T4 disease were unfavourable predictors for overall and disease-free survival. Normalized CEA during neoadjuvant chemoradiation may serve as a prognosticator, although pretreatment CEA may significantly affect survival.

Mechanically Tunable Slippery Behavior on Soft Poly(dimethylsiloxane)-Based Anisotropic Wrinkles Infused with Lubricating Fluid.

We demonstrate a novel technique to fabricate mechanically tunable slippery surfaces using one-dimensional (anisotropic) elastic wrinkles. Such wrinkles show tunable topography (amplitude) on the application of mechanical strain. Following Nepenthes pitcher plants, lubricating fluid infused solid surfaces show excellent slippery behavior for test liquid drops. Therefore, combining the above two, that is, infusing suitable lubricating fluid on elastic wrinkles, would enable us to fabricate mechanically tunable slippery surfaces. Completely stretched (flat) wrinkles have uniform coating of lubricating fluid, whereas completely relaxed (full amplitude) wrinkles have most of the lubricating oil in the wrinkle grooves. Therefore, water drops on completely stretched surface show excellent slippery behavior, whereas on completely relaxed surface they show reduced slippery behavior. Therefore, continuous variation of wrinkle stretching provides reversibly tunable slippery behavior on such a system. Because the wrinkles are one-dimensional, they show anisotropic tunability of slippery behavior depending upon whether test liquid drops slip parallel or perpendicular to the wrinkles.

Immunotherapy in Stage III-IV Colon Cancer: A Propensity Score-Matched Analysis of the National Cancer Database.

SUMMARY: Immunotherapy for the systemic treatment of cancer offers new treatment possibilities for advanced malignancies. Despite promising initial results, evidence on efficacy of immunotherapy for colon cancer is lacking. Thus, we aimed to assess short-term and long-term outcomes of immunotherapy in patients with advanced colon cancer. A US National Cancer Database was searched for patients with stage III-IV colonic adenocarcinoma between 2010 and 2019. Propensity score matching was used to classify the cohort into 2 groups: patients who received immunotherapy and controls. Main outcome measures were primary outcome was overall survival (OS). A total of 23,778 patients with stage III-IV colonic adenocarcinoma were treated with immunotherapy during the study period compared to 114,753 controls. Immunotherapy treated patients were younger (median age 61 vs. 67 y; P <0.001), more often male (57.3% vs. 50.7%, P <0.001), had more private insurance (44.1% vs. 33.7%; P <0.001), had more left-sided tumors (49.5% vs. 39.1%; P <0.001) and liver metastasis (80.2% vs. 61.7%; P <0.001) than controls. Immunotherapy patients received more standard chemotherapy (49.8% vs. 41.6%; P <0.001). After propensity-score matching, mean OS was significantly shorter in the immunotherapy group compared with controls (34.7 vs. 36.2 mo; P =0.008). Cox regression analysis demonstrated that immunotherapy was associated with increased risk for mortality (HR: 1.1; 95% CI: 1.02-1.18; P =0.005). Patients who received immunotherapy had lower 90-day mortality rates compared with controls (2.3% vs. 3.6%; P =0.004), but the groups had equivalent 30-day mortality rates (0.7% vs. 0.8%; P =0.76). Immunotherapy showed no improvement in OS in patients with stage III-IV colon cancer.

Obesity and overweight are associated with worse survival in early-onset colorectal cancer.

BACKGROUND: Obesity and its associated lifestyle are known risk factors for early-onset colorectal cancer and are associated with poor postoperative and survival outcomes in older patients. We aimed to investigate the impact of obesity on the outcomes of early-onset colorectal cancers. METHODS: Retrospective review of all patients undergoing primary resection of colon or rectal adenocarcinoma at our institution between 2015-2022. Patients who had palliative resections, resections performed at another institution, appendiceal tumors, and were underweight were excluded. The primary endpoint was survival according to the patient's body mass index: normal weight (18-24.9 kg/m2), overweight (25-29.9 kg/m2), and obesity (≥30 kg/m2). Patient and tumor characteristics and survival were compared between the three groups. RESULTS: A total of 279 patients aged <50 years with colorectal cancer were treated at our hospital; 120 were excluded from the analysis for the following reasons: main treatment or primary resection performed at another hospital (n = 97), no resection/palliative resection (n = 23), or body mass index <18 kg/m2 (n = 2). Of these, 157 patients were included in the analysis; 61 (38.9%) were overweight and 45 (28.7%) had obesity. Except for a higher frequency of hypertension in the overweight (P = .062) and obese (P = .001) groups, no differences in patient or tumor characteristics were observed. Mean overall survival was 89 months with normal weight, 92 months with overweight, and 65 months with obesity (P = .032). Mean cancer-specific survival was 95 months with normal weight, 94 months with overweight, and 68 months with obesity (P = .018). No statistically significant difference in disease-free survival (75 vs 70 vs 59 months, P = .844) was seen. CONCLUSION: Individuals with early-onset colorectal cancer who are overweight or obese present with similar tumor characteristics and postoperative morbidity to patients with normal weight. However, obesity may have a detrimental impact on their survival. Addressing obesity as a modifiable risk factor might improve early-onset colorectal cancer prognosis.

Biomarker Testing Disparities in Metastatic Colorectal Cancer.

Importance: Among patients with metastatic colorectal cancer (mCRC), data are limited on disparate biomarker testing and its association with clinical outcomes on a national scale. Objective: To evaluate the socioeconomic and demographic inequities in microsatellite instability (MSI) and KRAS biomarker testing among patients with mCRC and to explore the association of testing with overall survival (OS). Design, Setting, and Participants: This cohort study, conducted between November 2022 and March 2024, included patients who were diagnosed with mCRC between January 1, 2010, and December 31, 2017. The study obtained data from the National Cancer Database, a hospital-based cancer registry in the US. Patients with mCRC and available information on biomarker testing were included. Patients were classified based on whether they completed or did not complete MSI or KRAS tests. Exposure: Demographic and socioeconomic factors, such as age, race, ethnicity, educational level in area of residence, median household income, insurance type, area of residence, facility type, and facility location were evaluated. Main Outcomes and Measures: The main outcomes were MSI and KRAS testing between the date of diagnosis and the date of first-course therapy. Univariable and multivariable logistic regressions were used to identify the relevant factors in MSI and KRAS testing. The OS outcomes were also evaluated. Results: Among the 41 061 patients included (22 362 males [54.5%]; mean [SD] age, 62.3 [10.1] years; 17.3% identified as Black individuals, 78.0% as White individuals, 4.7% as individuals of other race, with 6.5% Hispanic or 93.5% non-Hispanic ethnicity), 28.8% underwent KRAS testing and 43.7% received MSI testing. A significant proportion of patients had Medicare insurance (43.6%), received treatment at a comprehensive community cancer program (40.5%), and lived in an area with lower educational level (51.3%). Factors associated with a lower likelihood of MSI testing included age of 70 to 79 years (relative risk [RR], 0.70; 95% CI, 0.66-0.74; P < .001), treatment at a community cancer program (RR, 0.74; 95% CI, 0.70-0.79; P < .001), rural residency (RR, 0.80; 95% CI, 0.69-0.92; P < .001), lower educational level in area of residence (RR, 0.84; 95% CI, 0.79-0.89; P < .001), and treatment at East South Central facilities (RR, 0.67; 95% CI, 0.61-0.73; P < .001). Similar patterns were observed for KRAS testing. Survival analysis showed modest OS improvement in patients with MSI testing (hazard ratio, 0.93; 95% CI, 0.91-0.96; P < .001). The median (IQR) follow-up time for the survival analysis was 13.96 (3.71-29.34) months. Conclusions and Relevance: This cohort study of patients with mCRC found that older age, community-setting treatment, lower educational level in area of residence, and treatment at East South Central facilities were associated with a reduced likelihood of MSI and KRAS testing. Highlighting the sociodemographic-based disparities in biomarker testing can inform the development of strategies that promote equity in cancer care and improve outcomes for underserved populations.

Microbe-induced coordination of plant iron-sulfur metabolism enhances high-light-stress tolerance of Arabidopsis.

High-light stress strongly limits agricultural production in subtropical and tropical regions owing to photo-oxidative damage, decreased growth, and decreased yield. Here, we investigated whether beneficial microbes can protect plants under high-light stress. We found that Enterobacter sp. SA187 (SA187) supports the growth of Arabidopsis thaliana under high-light stress by reducing the accumulation of reactive oxygen species and maintaining photosynthesis. Under high-light stress, SA187 triggers dynamic changes in the expression of Arabidopsis genes related to fortified iron metabolism and redox regulation, thereby enhancing the antioxidative glutathione/glutaredoxin redox system of the plant. Genetic analysis showed that the enhancement of iron and sulfur metabolism by SA187 is coordinated by ethylene signaling. In summary, beneficial microbes could be an effective and inexpensive means of enhancing high-light-stress tolerance in plants.

Hemophagocytic lymphohistiocytosis (HLH) in a 25-year-old presenting with multisystem organ failure.

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of extreme inflammation caused by pathologic activation of the immune system. Diagnosis of HLH is challenging as the clinical presentation is similar to common medical entities such as sepsis. When a source of the extreme inflammation is not found, HLH should be considered in the differential diagnosis. In HLH, inflammatory markers such as soluble CD25 and ferritin levels are elevated. Ferritin assay is widely available at most institutions; a level greater than 10,000 is highly suggestive of HLH.2 Delayed diagnosis and failure to initiate cytotoxic chemotherapy will result in a fatal outcome.

Liver Venous Deprivation for Rapid Liver Hypertrophy Before Major Hepatectomy: A Case Report.

Liver venous deprivation (LVD) is an emerging, minimally invasive strategy to induce rapid liver hypertrophy of the future liver remnant (FLR) before a major hepatectomy. LVD (aka "double vein embolization") entails same-session percutaneous embolization of the portal and hepatic veins of the planned liver resection. This report discusses LVD's utilization and technical challenges in managing a 49-year-old male with recurrent multifocal colorectal liver metastases (CRLM). The patient initially underwent neoadjuvant FOLFOX chemotherapy followed by a simultaneous laparoscopic sigmoid colectomy and liver surgery (microwave ablation of segment V and wedge resections of segment one and IVb), followed by completion of chemotherapy. The patient had an R0 resection with clear colon and liver surgical margins. Nine months after the initial surgery, the patient had a rise in tumor markers, and surveillance imaging demonstrated recurrence of liver metastases in segments I and V. LVD was performed by interventional radiology, which led to a 28% increase in FLR (segments II, III, and IV); initially measuring 464 cm3 before LVD and measuring 594 cm3 on post-procedure day 21. The patient underwent right hemi-hepatectomy and caudate resection on post-procedure day 29. The patient did not have any complications and was discharged on postoperative day 6. The patient remains disease-free with no evidence of recurrence at 12 months follow-up.

Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline.

PURPOSE: To develop recommendations involving targeted therapies for patients with advanced gastroesophageal cancer. METHODS: The American Society of Clinical Oncology convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. RESULTS: Eighteen randomized controlled trials met the inclusion criteria for the systematic review. RECOMMENDATIONS: For human epidermal growth factor receptor 2 (HER2)-negative patients with gastric adenocarcinoma (AC) and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 5, first-line therapy with nivolumab and chemotherapy (CT) is recommended. For HER2-negative patients with esophageal or gastroesophageal junction (GEJ) AC and PD-L1 CPS ≥ 5, first-line therapy with nivolumab and CT is recommended. First-line therapy with pembrolizumab and CT is recommended for HER2-negative patients with esophageal or GEJ AC and PD-L1 CPS ≥ 10. For patients with esophageal squamous cell carcinoma and PD-L1 tumor proportion score ≥ 1%, nivolumab plus CT, or nivolumab plus ipilimumab is recommended; for patients with esophageal squamous cell carcinoma and PD-L1 CPS ≥ 10, pembrolizumab plus CT is recommended. For patients with HER2-positive gastric or GEJ previously untreated, unresectable or metastatic AC, trastuzumab plus pembrolizumab is recommended, in combination with CT. For patients with advanced gastroesophageal or GEJ AC whose disease has progressed after first-line therapy, ramucirumab plus paclitaxel is recommended. For HER2-positive patients with gastric or GEJ AC who have progressed after first-line therapy, trastuzumab deruxtecan is recommended. In all cases, participation in a clinical trial is recommended as it is the panel's expectation that targeted treatment options for gastroesophageal cancer will continue to evolve.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Total neoadjuvant therapy: Fact, fantasy, or fallacy?

Colorectal cancer is the second leading cause of cancer death in the United States for men and women, with an estimated 146,000 new cases per year - a staggering 53,000 patients die each year. Rectal cancer comprises a third of these patients, with a 5-year survival rate of 67%. Management of locally advanced rectal cancer in the U.S. had remained stagnant for more than a decade, with most of these patients being treated with long-course chemoradiotherapy, surgery, followed by adjuvant chemotherapy; adjuvant chemotherapy being administered despite lacking a high level of evidence. Over the past few years, with rectal cancer death rates exceeding 30% from metastatic disease, growing interest focused on the attributes of induction chemotherapy to eradicate minimal residual disease and purportedly increase survival. This led to the development of total neoadjuvant therapy (TNT). We now have high-quality data from randomized prospective trials to review the facts, fantasies, and fallacies of TNT.

The Urogenital System's Role in Diseases: A Synopsis.

The human microbiota contains ten times more microbial cells than human cells contained by the human body, constituting a larger genetic material than the human genome itself. Emerging studies have shown that these microorganisms represent a critical determinant in human health and disease, and the use of probiotic products as potential therapeutic interventions to modulate homeostasis and treat disease is being explored. The gut is a niche for the largest proportion of the human microbiota with myriad studies suggesting a strong link between the gut microbiota composition and disease development throughout the body. More specifically, there is mounting evidence on the relevance of gut microbiota dysbiosis in the development of urinary tract disease including urinary tract infections (UTIs), chronic kidney disease, and kidney stones. Fewer emerging reports, however, are suggesting that the urinary tract, which has long been considered 'sterile', also houses its unique microbiota that might have an important role in urologic health and disease. The implications of this new paradigm could potentially change the therapeutic perspective in urological disease.

Total Neoadjuvant Therapy Is a Predictor for Complete Pathological Response in Patients Undergoing Surgery for Rectal Cancer.

INTRODUCTION: Total neoadjuvant therapy (TNT) is a new therapeutic strategy in patients with rectal cancer. We examined the role of TNT, in addition to other pre-operative factors, as a predictor for pathologic complete response (pCR). METHODS: A retrospective analysis of all rectal cancer patients who underwent surgery between 2016 and 2021 was conducted. Patients were classified into two groups-pCR group and residual tumor group. Patient data were reviewed and entered into univariate and multivariate analyses to determine predictors of pCR. RESULTS: A total of 172 patients were treated with neoadjuvant therapy and underwent surgery during the study period. Sixty patients (34.9%) were treated with TNT while 112 (65.1%) were treated with traditional neoadjuvant chemoradiation. The overall pCR rate was 25.6% (44 patients), with 31.6% (19 patients) in patients who received TNT compared to 22.3% (25 patients) in patients who received neoadjuvant chemoradiation (NCRT). Univariate analysis of clinical and radiological factors correlated with pCR demonstrated no significant differences between the two groups in cT stage (p = 0.46), cN stage (p = 0.52), positive circumferential resection margin (CRM) (p = 0.72), tumor location (p = 0.35), symptomatic presentation (p = 0.09), and anal sphincter involvement (p = 0.68). Multivariate logistic analysis demonstrated that only pre-operative TNT (OR:2.35; 95% CI 1.06-5.25; p = 0.03) was predictive of pCR, while extramural vascular invasion (EMVI) was a predictor for lower rates of pCR (OR: 0.28; 95% CI 0.09-0.9; p = 0.03). CONCLUSION: Rectal cancer patients undergoing TNT prior to surgery have a higher chance of developing a complete pathologic response. Evaluation of this therapy should be continued and extended to larger numbers of patients to see if the differences we observed are real.

Medullary carcinoma of the colon: A comprehensive analysis of the National Cancer Database.

PURPOSE: Medullary carcinomas (MC) of the colon are uncommon tumors. In this study, we analyzed demographic and disease characteristics as well as survival outcomes of MC versus undifferentiated (UDA) and poorly differentiated (PDA) adenocarcinomas (AC) of the colon. MATERIALS AND METHODS: The National Cancer Database (2004-2018) was utilized to identify patients with colon cancer. Patient demographics (including age, gender, race), disease characteristics (including grade, TNM stage, carcinoembryonic levels, perineural and lymphovascular invasion, lymph node status, microsatellite stability, KRAS mutation, and primary tumor site), and facility type and location were evaluated. Chi-square tests were used to compare descriptive data. Cox Regression and Kaplan Meier analyses were used to analyze survival characteristics. RESULTS: 1,041,753 patients with colon cancer were identified of whom 2709 patients had MC and 897,902 had AC (136,597 PDA and 18,042 UDA). MC was seen in older patients (mean age 74 ± 13 years) and women (72.5% vs. 27.5% males). Most MCs were poorly differentiated (63.3%), and 82.4% of patients with MC had microsatellite instability. Fewer patients with MC had perineural invasion (15.6% vs. 22.0% in PDA and 22.4% in UDA, p < 0.001) and positive lymph nodes (38.4% versus 59.9% with PDA and 59.7% with UDA, p < 0.0001). MC diagnosis increased by year (Cochran-Armitage trend test, p < 0.0001). Kaplan Meir analysis revealed a better prognosis for patients with MC when compared to PDA or UDA (p < 0.001). CONCLUSION: Given the rarity, pathologists should maintain a high suspicion for MC when encountering poorly differentiated or undifferentiated right-sided colon cancer with associated MSI-H.

The Gut Microbiome and Alzheimer's Disease: A Growing Relationship.

Evidence that the gut microbiota plays a key role in the pathogenesis of Alzheimer's disease is already un-ravelling. The microbiota-gut-brain axis is a bidirectional communication system that is not fully understood but includes neural, immune, endocrine, and metabolic pathways. The progression of Alzheimer's disease is supported by mechanisms related to the imbalance in the gut microbiota and the development of amyloid plaques in the brain, which are at the origin of Alzheimer's disease. Alterations in the composition of the gut microbiome led to dysregulation in the pathways governing this system. This leads to neurodegeneration through neuroinflammation and neurotransmitter dysregulation. Neurodegeneration and disruption of the blood-brain barrier are frontiers at the origin of Alzheimer's disease. Furthermore, bacteria populating the gut microbiota can secrete large amounts of amyloid proteins and lipopolysaccharides, which modulate signaling pathways and alter the production of proinflammatory cytokines associated with the pathogenesis of Alz-heimer's disease. Importantly, through molecular mimicry, bacterial amyloids may elicit cross-seeding of misfolding and induce microglial priming at different levels of the brain-gut-microbiota axis. The potential mechanisms of amyloid spreading include neuron-to-neuron or distal neuron spreading, direct blood-brain barrier crossing, or via other cells such as astrocytes, fibroblasts, microglia, and immune system cells. Gut microbiota metabolites, including short-chain fatty acids, pro-inflammatory factors, and neurotransmitters may also affect AD pathogenesis and associated cognitive decline. The purpose of this review is to summarize and discuss the current findings that may elucidate the role of gut microbiota in the development of Alzheimer's disease. Understanding the underlying mechanisms may provide new insights into novel therapeutic strategies for Alzheimer's disease, such as probiotics and targeted oligosaccharides.

Assessment of mesorectal fascia status in MRI compared with circumferential resection margin after total mesorectal excision and predictors of involved margins.

BACKGROUND: Circumferential resection margin is an important prognosticator for total mesorectal excision outcome. We investigated the status of mesorectal fascia on magnetic resonance imaging compared with circumferential resection margin on pathology and factors associated with status change. METHODS: This was a retrospective analysis of a prospective database of rectal cancer patients who underwent surgery. Mesorectal fascia status on magnetic resonance imaging done before neoadjuvant therapy and circumferential resection margin status on pathology were compared. The study outcomes were factors associated with a margin status conversion between magnetic resonance imaging and pathology, and predictors of involved circumferential resection margin. RESULTS: In total, 244 patients (average follow-up of 25.4 months) were included. Eighty-one (33.2%) patients had potentially involved mesorectal fascia in magnetic resonance imaging and 12 (4.9%) had involved circumferential resection margin in pathology. A total of 2.8% of patients had a conversion of clear mesorectal fascia in magnetic resonance imaging to involved circumferential resection margin. Abdominoperineal resection was significantly associated with this status change (odds ratio: 25, 95% confidence interval: 2.4-255.8, P = .007). In total, 7.4% of patients with potentially involved mesorectal fascia had persistently involved circumferential resection margin. Lack of total neoadjuvant therapy was associated with higher, yet statistically insignificant, odds of persistently involved circumferential resection margin (odds ratio: 12, 95% confidence interval: 0.65-220.8, P = .09). The significant independent predictors of involved circumferential resection margin were body mass index (odds ratio: 1.2, P = .016) and abdominoperineal resection (odds ratio: 4.22, P = .04). CONCLUSION: Change of clear mesorectal fascia in magnetic resonance imaging to an involved circumferential resection margin in pathology was recorded in 2.8% of patients; abdominoperineal resection might be associated with this change. Approximately 7% of patients had persistent involvement of circumferential resection margin as determined by pathology. Omission of total neoadjuvant therapy might be associated with persistent margin involvement.

Further structural characterization of ovine forestomach matrix and multi-layered extracellular matrix composites for soft tissue repair.

Decellularized extracellular matrix (dECM)-based biomaterials are of great clinical utility in soft tissue repair applications due to their regenerative properties. Multi-layered dECM devices have been developed for clinical indications where additional thickness and biomechanical performance are required. However, traditional approaches to the fabrication of multi-layered dECM devices introduce additional laminating materials or chemical modifications of the dECM that may impair the biological functionality of the material. Using an established dECM biomaterial, ovine forestomach matrix, a novel method for the fabrication of multi-layered dECM constructs has been developed, where layers are bonded via a physical interlocking process without the need for additional bonding materials or detrimental chemical modification of the dECM. The versatility of the interlocking process has been demonstrated by incorporating a layer of hyaluronic acid to create a composite material with additional biological functionality. Interlocked composite devices including hyaluronic acid showed improved in vitro bioactivity and moisture retention properties.