Selective Gastrectomy with Knowledge of Gastric Anatomy and Blood Supply are Key to Complete Tumour Removal in Advanced Pseudomyxoma: Single-Centre Experience with 120 Gastrectomies Over 20 Years.

BACKGROUND: The role of gastrectomy to achieve complete cytoreduction (CCR) for pseudomyxoma peritonei (PMP) is controversial due to uncertain risk/benefit ratio. The outcomes of patients who gastrectomy over a twenty-year period in a high-volume unit are reported. METHODS: All patients requiring gastrectomy to achieve CCR for appendiceal PMP between 2000 and 2020 were reviewed. Demographics, disease, operative, complication, and survival data were analysed. The first and second decades were compared. RESULTS: A total of 2148 patients underwent CRS and HIPEC, of which 78% had CCR. Gastrectomy was performed in 7.1%. Median age was 55 years, and 52% were female. Among gastrectomy patients, 94.2% had ≥1 elevated tumour marker, and 18% had high-grade disease. Median PCI was 30, and 30% required subtotal colectomy. Clavien-Dindo III-IV complications occurred in 32%, and 90-day mortality was 1.75%. Median survival was 104 months, and 10-year OS was 47%. Comparing the two decades, total CRS cases almost tripled, with a greater proportion achieving CCR (82.2% vs. 67.8%) but fewer requiring gastrectomy (5.3% vs. 13.5%). In those who had gastrectomy, disease was more advanced (higher PCI, more high-grade disease, more colectomies) in the later period. However, on multivariable analysis, there was no difference in survival between decades. High-grade histology was the only predictor of survival. CONCLUSIONS: Gastrectomy can achieve good long-term survival with low mortality and acceptable morbidity and should not deter surgeons from achieving CCR. However, increasing experience shows CCR can be achieved, preserving the stomach in the majority of cases through careful consideration of the anatomy and gastric blood supply.

D3 Lymphadenectomy for Right Colon Cancer: Feasibility, Safety, and Early Outcomes from a District General Hospital in London.

BACKGROUND AND OBJECTIVES: Observational studies suggest a link between D3 lymphadenectomy and improved disease-free survival in some colon cancer patients. However, high-quality randomized controlled trials are needed to confirm its advantage over D2 lymphadenectomy. Concerns about potential complications with D3 have limited its use outside of Japan. This study examines short-term outcomes following D3 lymphadenectomy for right-sided colon cancer compared to the established D2 procedure. Materials and Methods: This retrospective cohort single center study analyzed data on patients with right-sided colon cancer who underwent curative surgery within our healthcare trust between January 2019 and November 2022. Only patients treated by surgeons who routinely perform D3 lymphadenectomy were included for a homogenous study population. The decision to perform D3 was at the discretion of the operating surgeon. Data were collected from both paper charts and electronic medical records. Non-parametric statistical tests were used for data analysis. Results: A total of 214 patients met the criteria, with 170 undergoing D2 lymphadenectomy and 44 undergoing D3 lymphadenectomy. There were no significant differences between the groups in terms of surgery duration, blood loss, postoperative hemoglobin levels, or transfusion needs. Interestingly, the D3 group had a lower complication rate (25%) compared to the D2 group (41.2%). However, the D3 group also had a higher rate of lymph node spread (45.5% vs. 30.6% for D2) and more lymph nodes removed (19 [16, 25] vs. 23 [18, 28]). Importantly, both groups achieved similar complete tumour removal rates. Conclusions: This study suggests D3 lymphadenectomy for right-sided colon cancer might be safe with potential benefits, especially for younger patients with suspected lymph node involvement. However, the limited sample size necessitates larger, randomized trials to confirm these findings and potentially establish D3 lymphadenectomy as standard care.

Changes in neuromuscular structure and functions of human colon during ageing are region-dependent.

OBJECTIVE: To determine if human colonic neuromuscular functions decline with increasing age. DESIGN: Looking for non-specific changes in neuromuscular function, a standard burst of electrical field stimulation (EFS) was used to evoke neuronally mediated (cholinergic/nitrergic) contractions/relaxations in ex vivomuscle strips of human ascending and descending colon, aged 35-91 years (macroscopically normal tissue; 239 patients undergoing cancer resection). Then, to understand mechanisms of change, numbers and phenotype of myenteric neurons (30 306 neurons stained with different markers), densities of intramuscular nerve fibres (51 patients in total) and pathways involved in functional changes were systematically investigated (by immunohistochemistry and use of pharmacological tools) in elderly (≥70 years) and adult (35-60 years) groups. RESULTS: With increasing age, EFS was more likely to evoke muscle relaxation in ascending colon instead of contraction (linear regression: n=109, slope 0.49%±0.21%/year, 95% CI), generally uninfluenced by comorbidity or use of medications. Similar changes were absent in descending colon. In the elderly, overall numbers of myenteric and neuronal nitric oxide synthase-immunoreactive neurons and intramuscular nerve densities were unchanged in ascending and descending colon, compared with adults. In elderly ascending, not descending, colon numbers of cell bodies exhibiting choline acetyltransferase immunoreactivity increased compared with adults (5.0±0.6 vs 2.4±0.3 neurons/mm myenteric plexus, p=0.04). Cholinergically mediated contractions were smaller in elderly ascending colon compared with adults (2.1±0.4 and 4.1±1.1 g-tension/g-tissue during EFS; n=25/14; p=0.04); there were no changes in nitrergic function or in ability of the muscle to contract/relax. Similar changes were absent in descending colon. CONCLUSION: In ascending not descending colon, ageing impairs cholinergic function.

Ex vivo study of human visceral nociceptors.

OBJECTIVE: The development of effective visceral analgesics free of deleterious gut-specific side effects is a priority. We aimed to develop a reproducible methodology to study visceral nociception in human tissue that could aid future target identification and drug evaluation. DESIGN: Electrophysiological (single unit) responses of visceral afferents to mechanical (von Frey hair (VFH) and stretch) and chemical (bradykinin and ATP) stimuli were examined. Thus, serosal afferents (putative nociceptors) were used to investigate the effect of tegaserod, and transient receptor potential channel, vanilloid 4 (TRPV4) modulation on mechanical responses. RESULTS: Two distinct afferent fibre populations, serosal (n=23) and muscular (n=21), were distinguished based on their differences in sensitivity to VFH probing and tissue stretch. Serosal units displayed sensitivity to key algesic mediators, bradykinin (6/14 units tested) and ATP (4/10), consistent with a role as polymodal nociceptors, while muscular afferents are largely insensitive to bradykinin (0/11) and ATP (1/10). Serosal nociceptor mechanosensitivity was attenuated by tegaserod (-20.8±6.9%, n=6, p<0.05), a treatment for IBS, or application of HC067047 (-34.9±10.0%, n=7, p<0.05), a TRPV4 antagonist, highlighting the utility of the preparation to examine the mechanistic action of existing drugs or novel analgesics. Repeated application of bradykinin or ATP produced consistent afferent responses following desensitisation to the first application, demonstrating their utility as test stimuli to evaluate analgesic activity. CONCLUSIONS: Functionally distinct subpopulations of human visceral afferents can be demonstrated and could provide a platform technology to further study nociception in human tissue.

The impact of long-course chemoradiotherapy on the myenteric plexus, neuromuscular functions and responses to prokinetic drugs in the human rectum.

BACKGROUND & AIMS: The long-term effects of chemoradiotherapy on human rectum are poorly understood. The aims were to investigate changes in inflammatory status, myenteric neuron numbers/phenotype, neuromuscular functions and prokinetic drug efficacy. METHODS: Macroscopically normal proximal-to-mid rectum was obtained from 21 patients undergoing surgery for bowel cancer, 98 days (range: 63-350) after concurrent capecitabine and pelvic radiotherapy, and 19 patients without chemoradiotherapy. Inflammatory status was measured by H&E, CD45 staining and qPCR. Myenteric neurons were examined by immunohistochemistry. Neuromuscular functions and drug efficacy were studied using exogenous agents and electrical field stimulation (EFS) to activate intrinsic nerves. RESULTS: Inflammation was not detected. Numbers of myenteric ganglia/neurons were unchanged (11.7 ± 2.4 vs. 10.3 ± 2.2 neurons/mm myenteric plexus with/without chemoradiotherapy) as were the numbers of cholinergic/nitrergic neurons. EFS stimulated cholinergic and nitrergic neurons so the contractile response of the muscle was the sum of both but dominated by cholinergic (causing contraction) or less often, nitrergic activity (relaxation), followed, after termination of EFS, by neuronally mediated contraction. Inhibition of nitric oxide synthase (by L-NAME 300 µM) more clearly defined EFS-evoked contractions. The 5-HT4 agonist prucalopride 10 µM and the cholinesterase inhibitor donepezil 1 µM, respectively increased and greatly increased the composite contractile response to EFS (measured as 'area-under-the curve') and the contractions isolated by L-NAME (respectively, by 22 ± 14% and 334 ± 87%; n = 11/8). After chemoradiotherapy, nitrergic-mediated muscle relaxations occurred more often during EFS (in 29.8 ± 6.1% preparations vs. 12.6 ± 5.1% without chemoradiotherapy, n = 21/18). With L-NAME, the ability of prucalopride to facilitate EFS-evoked contraction was lost and that of donepezil approximately halved (contractions increased by 132 ± 36%; n = 8). CONCLUSIONS: Several months after chemoradiotherapy, the rectum was not inflamed and myenteric neuron numbers/phenotype unchanged. However, nitrergic activity was increased relative to cholinergic activity, and prokinetic-like drug activity was lost or greatly reduced. Thus, chemoradiotherapy causes long-term changes in neuromuscular functions and markedly reduces the efficacy of drugs for treating constipation.

Health related quality of life is excellent and sustained at two decades after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in survivors of pseudomyxoma peritonei of appendiceal origin.

INTRODUCTION: Optimal management of pseudomyxoma peritonei (PMP) is by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), which can achieve 20-year disease-free, and overall survival. There is limited information on the health-related quality of life (HRQOL) of PMP survivors beyond five years. We report longitudinal HRQOL in patients with PMP of appendiceal origin up to 17-years after their CRS and HIPEC in 2003-2004. METHODS: Patients had HRQOL assessed with EORTC QLQ-C30 questionnaires pre-operatively, and at 1-, 10- and 17-years post-operatively. Comparisons in global health-related QOL (global-HRQOL) measures were made with (1) an age- and sex-matched normal European population, (2) between patients who underwent complete cytoreduction (CRS CC0/1) versus maximal tumor debulking (MTD), and (3) between those with and without peritoneal recurrence. RESULTS: Forty-six patients underwent CRS & HIPEC for appendiceal PMP. One patient withdrew from the study. Of the 45 patients, 23 patients were alive at ten and 15 patients at 17-years post-operatively. 21/23 (91%) and 14/15 patients (93%) completed questionnaires respectively. Pre-operatively, patients had significantly lower global-HRQOL compared with the reference population. Over follow-up, patients experienced improvements in their global-HRQOL. By post-operative year-10 and -17, there was no difference between the global-HRQOL of patients and reference population. As expected, patients with CC0/1 and without peritoneal tumor recurrence had better global-HRQOL at ten- and 17-years post-operatively compared with those with MTD or recurrence. CONCLUSIONS: Optimal CRS and HIPEC is an effective treatment for appendiceal PMP that can achieve long-term survival. HRQOL is excellent and maintained, in those who have CC0/1 without recurrence.

Bowel ischaemia in COVID-19 infection: a scoping review protocol.

INTRODUCTION: COVID-19 disease was declared as a pandemic by WHO since March 2020 and can have a myriad of clinical presentations affecting various organ systems. Patients with COVID-19 are known to have an increased risk of thromboembolism, including cardiovascular, pulmonary and cerebral ischaemic events. However, an increasing number of case studies have reported that COVID-19 infection is also associated with gastrointestinal ischaemia. This scoping review aims to collate the current evidence of COVID-19-related gastrointestinal ischaemia and raise awareness among healthcare professionals of this lesser known, but serious, non-pulmonary complication of COVID-19 infection. METHODS: The proposed scoping review will be conducted as per the Arksey and O'Malley methodological framework (2005) the Joanna Briggs Institute methodology for scoping reviews. A systematic search will be undertaken on different databases including EMBASE, PubMed and MEDLINE. Two independent reviewers will screen titles, abstracts and full-text articles according to the inclusion criteria and extract relevant data from the included articles. Results will be presented in a tabular form with a narrative discussion. ETHICS AND DISSEMINATION: Ethical approval will not be required for this scoping review. This scoping review will provide an extensive overview of the association between COVID-19 infection and bowel ischaemia. Further ethical and methodological challenges will also be discussed in our findings to define a new research agenda. Findings will be disseminated through peer-reviewed publications and presentations at both national and international conferences.

Functional and anatomical deficits in visceral nociception with age: a mechanism of silent appendicitis in the elderly?

The ability to sense visceral pain during appendicitis is diminished with age leading to delay in seeking health care and poorer clinical outcomes. To understand the mechanistic basis of this phenomenon, we examined visceral nociception in aged mouse and human tissue. Inflamed and noninflamed appendixes were collected from consenting patients undergoing surgery for the treatment of appendicitis or bowel cancer. Supernatants were generated by incubating samples in buffer and used to stimulate multiunit activity in intestinal preparations, or single-unit activity from teased fibres in colonic preparations, of young and old mice. Changes in afferent innervation with age were determined by measuring the density of calcitonin gene-related peptide-positive afferent fibres and by counting dorsal root ganglia back-labelled by injection of tracer dye into the wall of the colon. Finally, the effect of age on nociceptor function was studied in mouse and human colon. Afferent responses to appendicitis supernatants were greatly impaired in old mice. Further investigation revealed this was due to a marked reduction in the afferent innervation of the bowel and a substantial impairment in the ability of the remaining afferent fibres to transduce noxious stimuli. Translational studies in human tissue demonstrated a significant reduction in the multiunit but not the single-unit colonic mesenteric nerve response to capsaicin with age, indicative of a loss of nociceptor innervation. Our data demonstrate that anatomical and functional deficits in nociception occur with age, underpinning the atypical or silent presentation of appendicitis in the elderly.

Normative values for region-specific colonic and gastrointestinal transit times in 111 healthy volunteers using the 3D-Transit electromagnet tracking system: Influence of age, gender, and body mass index.

BACKGROUND: The 3D-Transit electromagnet tracking system (Motilis Medica, SA, Lausanne, Switzerland) is an emerging tool for the ambulatory assessment of gastrointestinal (GI) transit and motility. Using this tool, we aimed to derive normative values for region-specific colonic and GI transit times and to assess the influence of age, gender, and body mass index (BMI). METHODS: Regional and total colonic transit times (CTT), gastric emptying (GET), small intestinal (SITT), and whole gut (WGTT) transit times were extracted from 111 healthy volunteers from the United Kingdom and Denmark (58 female; median age: 40 years [range: 21-88]). The effects of age, gender, and BMI were assessed using standard statistical methods. KEY RESULTS: The ascending, transverse, descending, and rectosigmoid colon transit times accounted for 32%, 34%, 17%, and 17% of total CTT in females, and 33%, 25%, 14%, and 28% of total CTT in males. CTT and WGTT were seen to cluster at intervals separated by approximately 24 hours, providing further evidence of the non-continuous nature of these measurements. Increasing age was associated with longer CTT (P = .021), WGTT (P < .001) ascending (P = .004), transverse (P < .001), and total right (P < .001) colon transit times, but shorter rectosigmoid (P = .004) transit time. Female gender was significantly associated with longer transverse (P = .049) and descending (P < .001) colon transit times, but shorter rectosigmoid (P < .001) transit time. Increasing BMI was significantly associated with shorter WGTT (P = .012). CONCLUSIONS AND INFERENCES: For the first time, normative reference values for region-specific colonic transit have been presented. Age, gender, and BMI were seen to have an effect on transit times.

The Aurora kinase inhibitor VX-680 induces endoreduplication and apoptosis preferentially in cells with compromised p53-dependent postmitotic checkpoint function.

VX-680 is a potent inhibitor of Aurora kinases that induces the accumulation of cells with > or =4N DNA content, followed by cell death. Here, we define the role of p53 and p21(Waf1/Cip1) in cell cycle perturbations following exposure to VX-680. Endoreduplication and apoptosis in response to VX-680 are limited in A549 and MCF-7 cells expressing wild-type p53, and markedly enhanced in cells lacking p53, including those engineered to express the HPV16-E6 oncoprotein or short interfering RNA pools targeting p53. In contrast, endoreduplication and apoptosis occur in the p53 wild-type cell lines, RKO and U2OS. The difference in response to VX-680 among these cell lines correlates with the timing of induction of p21(Waf1/Cip1) and its ability to inhibit cyclin E-cdk2 activity. In A549 cells, VX-680 induces the expression of p53 and p21(Waf1/Cip1) within 24 hours, with consequent inhibition of cyclin E-cdk2, and reduction of retinoblastoma protein phosphorylation, limiting endoreduplication. In RKO and U2OS cells, the induction of p21(Waf1/Cip1) is delayed and associated with higher residual cyclin E-cdk2 kinase activity and retinoblastoma protein phosphorylation, followed by progressive endoreduplication and apoptosis. Abrogation of p21(Waf1/Cip1) expression by short interfering RNA targeting in A549 cells results in a substantial increase in the degree of endoreduplication, whereas inducible expression of p21(Waf1/Cip1) in p53-negative NCI-H1299 cells inhibits VX-680-induced endoreduplication and cell death. These data suggest that the integrity of the p53-p21(Waf1/Cip1)-dependent postmitotic checkpoint governs the response to Aurora kinase inhibition. Although cells with intact checkpoint function arrest with 4N DNA content, those with compromised checkpoint function are more likely to undergo endoreduplication followed by eventual apoptosis.

Human native kappa opioid receptor functions not predicted by recombinant receptors: Implications for drug design.

If activation of recombinant G protein-coupled receptors in host cells (by drugs or other ligands) has predictive value, similar data must be obtained with native receptors naturally expressed in tissues. Using mouse and human recombinant κ opioid receptors transfected into a host cell, two selectively-acting compounds (ICI204448, asimadoline) equi-effectively activated both receptors, assessed by measuring two different cell signalling pathways which were equally affected without evidence of bias. In mouse intestine, naturally expressing κ receptors within its nervous system, both compounds also equi-effectively activated the receptor, inhibiting nerve-mediated muscle contraction. However, whereas ICI204448 acted similarly in human intestine, where κ receptors are again expressed within its nervous system, asimadoline was inhibitory only at very high concentrations; instead, low concentrations of asimadoline reduced the activity of ICI204448. This demonstration of species-dependence in activation of native, not recombinant κ receptors may be explained by different mouse/human receptor structures affecting receptor expression and/or interactions with intracellular signalling pathways in native environments, to reveal differences in intrinsic efficacy between receptor agonists. These results have profound implications in drug design for κ and perhaps other receptors, in terms of recombinant-to-native receptor translation, species-dependency and possibly, a need to use human, therapeutically-relevant, not surrogate tissues.

What is the role of screening in the management of abdominal aortic aneurysms?

A best-evidence topic in vascular surgery was written according to a structured protocol. The question addressed was whether screening asymptomatic individuals for an abdominal aortic aneurysm (AAA) is feasible and improves disease-free survival. Seven studies presented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and limitations of the studies are tabulated. In total, four randomized population-based studies have evaluated ultrasound screening for AAA: two British studies, Multicentre Aneurysm Screening Study (MASS) and the Chichester trial, and one each in Viborg County, Denmark and Western Australia. Participants were randomized to receive an invitation to screen or not. The MASS trial randomized 67 770 men, followed participants over 10 years and concluded that screening would almost half AAA-related deaths in men aged 65-74 years. The smaller Chichester trial included only 6040 men but demonstrated a 42% reduction in AAA-related mortality at 5 years, with ongoing benefit at 15 years (11% reduction). The Viborg County trial recruited 12 639 men aged 64-73 years, showed a 66% reduction in AAA-related mortality over 14 years. Finally, the Western Australia trial evaluated 41 000 men but included an older population of 65-83 years old. No benefit was seen in this age group but subgroup analysis of men aged 65-74 showed a significant mortality benefit. Only a small or insignificant benefit in all-cause mortality was seen in any of these studies. A recent meta-analysis of these trials has shown a significant benefit in AAA-related mortality in the long term and concluded that AAA screening is superior to other established screening programmes. The cost-effectiveness of screening was assessed in the MASS and Viborg County trials and was found to be substantially below the cost threshold set by the National Institute of Clinical Excellence for acceptance of interventions. Quality of life was assessed in the MASS and in a case-control study and showed no adverse effects that outweigh the benefits. We concluded that ultrasound screening for AAAs has met all the criteria to become a screening programme and would substantially reduce disease-related death with no adverse effect on quality of life.

Is it safe to perform coronary angiography during acute endocarditis?

A best evidence topic was written according to a structured protocol. The question addressed was 'Is it safe to perform coronary angiography (CA) in acute endocarditis?' Three hundred and ninety-seven papers were found using the reported search, of which six represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes, key results and limitations of these papers are tabulated. One of the papers is a case report, which reported a fatal vegetation embolism from an infected aortic valve into the left main coronary artery 14 h after angiography. The remaining five papers are cohort studies. Four of these studies were performed between 1970 and 1980 before the era of echocardiography and were aimed at quantifying the severity of valvular regurgitation. No embolic complications or dislodgement of vegetations occurred in any of the five studies (186 patients). Guidelines published by the European Society of Cardiology (ESC) in 2009 recommended CA in the context of infective endocarditis (IE) for men >40 years old, postmenopausal women, and patients with at least one cardiovascular risk factor or a history of coronary artery disease. Exceptions include patients with large aortic vegetations which may be dislodged during catheterisation, and when emergency surgery is necessary - 1) native aortic or mitral IE with severe acute regurgitation or valve obstruction, or prosthetic valve IE with severe prosthetic dysfunction (dehiscence or obstruction) causing refractory pulmonary oedema or cardiogenic shock; 2) native aortic, mitral, or prosthetic valve IE with fistula into a cardiac chamber or pericardium causing refractory pulmonary oedema or shock. This is reiterated by the guidelines on the management of valvular heart disease published by the ESC in 2007. From the findings of the six papers, it can be concluded that coronary angiography can be performed safely in IE and should be performed if deemed necessary, unless the patients are haemodynamically unstable requiring emergency surgery, or have large vegetations of the aortic valve. This is consistent with the ESC guidelines.