The effect of diabetes mellitus on perioperative outcomes after colorectal resection: a national cohort study.

BACKGROUND: Diabetes mellitus is a significant modulator of postoperative outcomes and is an important risk factor in the patient selection process. We aimed to investigate the effect of diabetes mellitus and use of insulin on outcomes after colorectal resection using a national cohort. METHODS: Adults with a recorded colorectal resection in England between 2010 and 2020 were identified from Hospital Episode Statistics data linked to the Clinical Practice Research Database. The primary outcome was 90-day mortality. Secondary outcomes included hospital length of stay (LOS) and readmission within 90 days. RESULTS: Of the 106 139 (52 875, 49.8% male) patients included, diabetes mellitus was prevalent in 10 931 (10.3%), 2145 (19.6%) of whom had a record of use of insulin. Unadjusted 90-day mortality risk was 5.7%, with an increased adjusted hazard ratio (aHR) for people with diabetes mellitus (aHR 1.28, 95% confidence interval [CI] 1.19-1.37, P<0.001). This risk was higher in both people with diabetes using insulin (aHR 1.51, 95% CI 1.31-1.74, P<0.001) and not using insulin (aHR 1.22, 95% CI 1.13-1.33, P<0.001), compared with those without diabetes. Ninety-day readmission occurred in 20 542 (19.4%) patients and this was more likely in those with diabetes mellitus (aHR 1.23, 95% CI 1.18-1.29, P<0.001). Median (inter-quartile range) LOS was 8 (5-15) days and was higher in people with diabetes mellitus (adjusted time ratio 1.10, 95% CI 1.08-1.11, P<0.001). CONCLUSIONS: People with diabetes mellitus undergoing colorectal resection are at a higher risk of 90-day mortality, prolonged LOS, and 90-day readmission, with use of insulin associated with additional risk.

Pancreatic neuroendocrine tumours: a comparison of cytological classification systems.

AIMS: Cytological classification systems provide a standardised interpretation framework for reporting cytological specimens. Three well-known classification systems can be applied when reporting pancreatic cytology. This study aimed to compare the accuracy of these classification systems (C1-C5 system, the Papanicolaou system and the WHO classification) for the assessment of pancreatic neuroendocrine lesions. METHODS: We analysed 73 pancreatic neuroendocrine tumour resections, 49 of which had corroborative cytology available, reported over a 12-year period, at a single UK tertiary referral centre. Each cytology case was classified using the aforementioned systems. The final tumour grade allocated at resection was used to assess and compare the accuracy of each cytological classification system. RESULTS: Cytological assessment accurately reported 77.6% of neuroendocrine lesions as category IVB (neoplastic - other) on Papanicolaou grading, 77.6% as C5 (malignant) lesions and 85.7% as VII (malignant) on WHO grading. 74.3% of resected tumours were grade 1, 17.1% grade 2 and 8.6% grade 3. Complete resection was achieved in 80.8% of cases. CONCLUSIONS: The results demonstrated that the WHO classification appeared to provide reduced ambiguity when compared with both 'C' and Papanicolaou classification systems; with a lower proportion of cases being classified as suspicious of malignancy as opposed to malignant. The Papanicolaou system was able to supersede the other two systems through its ability to distinguish neuroendocrine tumours from more aggressive entities such as pancreatic adenocarcinoma, thus, offering flexibility in management while still retaining a similar level of accuracy to the WHO classification system in distinguishing benign from malignant lesions.

Immunohistochemical inflammation in histologically normal gallbladders containing gallstones.

BACKGROUND: The aim of this study was to establish features of inflammation in histologically normal gallbladders with gallstones and compare the expression of inflammatory markers in acutely and chronically inflamed gallbladders. METHODS: Immunohistochemistry was performed on formalin-fixed paraffin-embedded gallbladders for tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-2R, and substance p in three groups: Group I (n = 60) chronic cholecystitis, Group II (n = 57) acute cholecystitis and Group III (n = 45) histologically normal gallbladders with gallstones. Expression was quantified using the H-scoring system. RESULTS: Median, interquartile range expression of mucosal IL-2R in Groups I (2.65, 0.87-7.97) and II (12.30, 6.15-25.55) was significantly increased compared with group III (0.40, 0.10-1.35, p < 0.05). Submucosal IL-2R expression in Groups I (2.0, 1.12-4.95) and II (10.0, 5.95-14.30) was also significantly increased compared with Group III (0.50, 0.15-1.05, p < 0.05). There was no difference in the lymphoid cell IL-6 expression between Groups I (5.95, 1.60-18.15), II (6.10, 1.1-36.15) and III (8.30, 2.60-26.35, p > 0.05). Epithelial IL-6 expression of Group III (8.3, 2.6-26.3) was significantly increased compared with group I (0.5, 0-10.2, p < 0.05) as was epithelial TNF-α expression in Group III (85.0, 70.50-92.0) compared with Groups I (72.50, 45.25.0-85.50, p < 0.05) and II (61.0, 30.0-92.0, p < 0.05). Lymphoid cell Substance P expression in Groups I (1.90, 1.32-2.65) and II (5.62, 2.50-20.8) was significantly increased compared with Group III (1.0,1.0-1.30, p < 0.05). Epithelial cell expression of Substance P in Group III (121.7, 94.6-167.8) was significantly increased compared with Groups I (75.7, 50.6-105.3, p < 0.05) and II (78.9, 43.5-118.5, p < 0.05). CONCLUSION: Histologically normal gallbladders with gallstones exhibited features of inflammation on immunohistochemistry.

A phase 1 trial of human telomerase reverse transcriptase (hTERT) vaccination combined with therapeutic strategies to control immune-suppressor mechanisms.

The presence of inhibitory immune cells and difficulty in generating activated effector T cells remain obstacles to development of effective cancer vaccines. We designed a vaccine regimen combining human telomerase reverse transcriptase (hTERT) peptides with concomitant therapies targeting regulatory T cells (Tregs) and cyclooxygenase-2 (COX2)-mediated immunosuppression. This Phase 1 trial combined an hTERT-derived 7-peptide library, selected to ensure presentation by both HLA class-I and class-II in 90% of patients, with oral low-dose cyclophosphamide (to modulate Tregs) and the COX2 inhibitor celecoxib. Adjuvants were Montanide and topical TLR-7 agonist, to optimise antigen presentation. The primary objective was determination of the safety and tolerability of this combination therapy, with anti-cancer activity, immune response and detection of antigen-specific T cells as additional endpoints. Twenty-nine patients with advanced solid tumours were treated. All were multiply-pretreated, and the majority had either colorectal or prostate cancer. The most common adverse events were injection-site reactions, fatigue and nausea. Median progression-free survival was 9 weeks, with no complete or partial responses, but 24% remained progression-free for ≥6 months. Immunophenotyping showed post-vaccination expansion of CD4+ and CD8+ T cells with effector phenotypes. The in vitro re-challenge of T cells with hTERT peptides, TCR sequencing, and TCR similarity index analysis demonstrated the expansion following vaccination of oligoclonal T cells with specificity for hTERT. However, a population of exhausted PD-1+ cytotoxic T cells was also expanded in vaccinated patients. This vaccine combination regimen was safe and associated with antigen-specific immunological responses. Clinical activity could be improved in future by combination with anti-PD1 checkpoint inhibition to address the emergence of an exhausted T cell population.

Exploring the need for reconsideration of trial design in perioperative outcomes research: a narrative review.

"Enhanced recovery after surgery" is a multimodal effort to control perioperative pathophysiology and improve outcome. However, despite advances in perioperative care, postoperative complications and the need for hospitalisation and prolonged recovery continue to be challenging. This is further complicated by procedure-specific and patient-associated risk factors, given the increase in the number of elderly and frail patients with multiple comorbidities undergoing surgery. This paper is a critical assessment of current methodology for trials in perioperative medicine. We make a plea to reconsider the design of future interventional trials to improve surgical outcome, based upon studies of potentially effective interventions, but often without improvements in recovery. The complexity of perioperative pathophysiology necessitates a procedure- and patient-specific approach whenever outcome is assessed or interventions are planned. With improved understanding of perioperative pathophysiology, the way to improve outcomes looks promising, provided that knowledge and established enhanced recovery programmes are integrated in trial design. Funding: None.

The impact of prehabilitation on outcomes in frail and high-risk patients undergoing major abdominal surgery: A systematic review and meta-analysis.

BACKGROUND & AIMS: Prehabilitation comprises multidisciplinary preoperative interventions including exercise, nutritional optimisation and psychological preparation aimed at improving surgical outcomes. The aim of this systematic review and meta-analysis was to determine the impact of prehabilitation on postoperative outcomes in frail and high-risk patients undergoing major abdominal surgery. METHODS: Embase, Medline, CINAHAL and Cochrane databases were searched from January 2010 to January 2023 for randomised clinical trials (RCTs) and observational studies evaluating unimodal (exercise) or multimodal prehabilitation programmes. Meta-analysis was limited to length of stay (primary end point), severe postoperative complications (Clavien-Dindo Classification ≥ Grade 3) and the 6-minute walk test (6MWT). The analysis was performed using RevMan v5.4 software. RESULTS: Sixteen studies (6 RCTs, 10 observational) reporting on 3339 patients (1468 prehabilitation group, 1871 control group) were included. The median (interquartile range) age was 74.0 (71.0-78.4) years. Multimodal prehabilitation was applied in fifteen studies and unimodal in one. Meta-analysis of nine studies showed a reduction in hospital length of stay (weighted mean difference -1.07 days, 95 % CI -1.60 to -0.53 days, P < 0.0001, I2 = 19 %). Ten studies addressed severe complications and a meta-analysis suggested a decline in occurrence by up to 44 % (odds ratio 0.56, 95 % CI 0.37 to 0.82, P < 0.004, I2 = 51 %). Four studies provided data on preoperative 6MWT. The pooled weighted mean difference was 40.1 m (95 % CI 32.7 to 47.6 m, P < 0.00001, I2 = 24 %), favouring prehabilitation. CONCLUSION: Given the significant impact on shortening length of stay and reducing severe complications, prehabilitation should be encouraged in frail, older and high-risk adult patients undergoing major abdominal surgery.

A recurrent retrohepatic abscess secondary to a dropped appendicolith.

Appendicoliths can drop into the peritoneal cavity during the course of an appendicectomy, or more commonly as a result of perforated appendicitis. We report the case of a patient with a history of recurrent retrohepatic abscesses over 7-year period due to a retained appendicolith and review the literature on perihepatic abscesses caused by retained appendicoliths. The abscess had been drained percutaneously 4 times without retrieval of the appendicolith and eventually the patient needed a laparotomy, drainage of the abscess, and extraction of the appendicolith. Treatment of abscesses secondary to dropped appendicoliths may be percutaneous, laparoscopic, or via conventional open surgery, but it is important to retrieve the appendicolith if recurrent abscess formation is to be avoided.

Temporal trends and patterns in initial opioid prescriptions after hospital discharge following colectomy in England over 10 years.

BACKGROUND: While opioid analgesics are often necessary for the management of acute postoperative pain, appropriate prescribing practices are crucial to avoid harm. The aim was to investigate the changes in the proportion of people receiving initial opioid prescriptions after hospital discharge following colectomy, and describe trends and patterns in prescription characteristics. METHODS: This was a retrospective cohort study. Patients undergoing colectomy in England between 2010 and 2019 were included using electronic health record data from linked primary (Clinical Practice Research Datalink Aurum) and secondary (Hospital Episode Statistics) care. The proportion of patients having an initial opioid prescription issued in primary care within 90 days of hospital discharge was calculated. Prescription characteristics of opioid type and formulation were described. RESULTS: Of 95 155 individuals undergoing colectomy, 15 503 (16.3%) received opioid prescriptions. There was a downward trend in the proportion of patients with no prior opioid exposure (opioid naive) who had a postdischarge opioid prescription (P <0.001), from 11.4% in 2010 to 6.7% in 2019 (-41.3%, P <0.001), whereas the proportions remained stable for those prescribed opioids prior to surgery, from 57.5% in 2010 to 58.3% in 2019 (P = 0.637). Codeine represented 44.5% of all prescriptions and prescribing increased by 14.5% between 2010 and 2019. Prescriptions for morphine and oxycodone rose significantly by 76.6% and 31.0% respectively, while tramadol prescribing dropped by 48.0%. The most commonly prescribed opioid formulations were immediate release (83.9%), followed by modified release (5.8%) and transdermal (3.2%). There was a modest decrease in the prescribing of immediate-release formulations from 86.0% in 2010 to 82.0% in 2019 (P <0.001). CONCLUSION: Over the 10 years studied, there was a changing pattern of opioid prescribing following colectomy, with a decrease in the proportion of opioid-naive patients prescribed postdischarge opioids.

Expression of polymeric immunoglobulin receptor (PIGR) and the effect of PIGR overexpression on breast cancer cells.

Polymeric immunoglobulin receptor (PIGR) has a major role in mucosal immunity as a transporter of polymeric immunoglobulin across the epithelial cells. The aim of this study was to determine the effect of PIGR on cellular behaviours and chemo-sensitivity of MCF7 and MDA-MB468 breast cancer cell lines. Basal levels of PIGR mRNA and protein expression in MCF7 and MDA-MB468 cells were evaluated by real time quantitative polymerase chain reaction and Western blotting, respectively. MCF7/PIGR and MDA-MB468/PIGR stable cell lines, overexpressing the PIGR gene, were generated using a lentiviral vector with tetracycline dependent induction of expression. Cell viability, cell proliferation and chemo-sensitivity of PIGR transfected cells were evaluated and compared with un-transfected cells to determine the effect of PIGR overexpression on cell phenotype. The levels of PIGR mRNA and protein expression were significantly higher in MDA-MB468 cells than in MCF7 cells (380-fold, p < 0.0001). However, the differential expression of PIGR in these two cell lines did not lead to significant differences in chemosensitivity. Viral overexpression of PIGR was also not found to change any of the parameters measured in either cell line. PIGR per se did not affect cellular behaviours and chemosensitivity of these breast cancer cell lines.

Post-Cancer Treatment Reflections by Patients Concerning the Provisions and Support Required for a Prehabilitation Programme.

BACKGROUND: Evidence suggests that physical fitness interventions, mental health support and nutritional advice before surgery (prehabilitation) could reduce hospital stay and improve quality of life of patients with cancer. In this study we captured the opinions of a group of patients with cancer undergoing these interventions after treatment to discover what a prehabilitation programme should encompass. METHODS: Patients from the Cancer and Rehabilitation Exercise (CARE) programme based in Nottingham took part in a 26-point online questionnaire about the design of prehabilitation programmes. RESULTS: The questionnaire was completed over a 2-week period in December 2021 by 54 patients from the CARE programme. Their responses were as follows: 44 (81.5%) participants would have participated in prehabilitation had it been available to them and 28 (51.9%) ranked physical exercise as the most important component. Forty (74.1%) participants believed the counselling aspect of prehabilitation would have contributed to a successful outcome and 35 (64.8%) thought dietary advice would have benefitted them before surgery. Thirty-one (57.4%) participants preferred the programme to take place in a fitness centre, rather than at home or hospital and 43 (79.6%) would have liked to have known about prehabilitation from their doctor at the time of diagnosis. CONCLUSIONS: Patients are interested in prehabilitation to become more physically fit and mentally prepared for surgery. They expressed the need for a focus on physical exercise, counselling to improve mental health and personalised nutritional advice. Tailoring a prehabilitation programme, with input from patients, could contribute to improving patient outcomes following cancer treatments.

Enhanced Recovery After Surgery (ERAS®) Society Consensus Guidelines for Emergency Laparotomy Part 3: Organizational Aspects and General Considerations for Management of the Emergency Laparotomy Patient.

BACKGROUND: This is Part 3 of the first consensus guidelines for optimal care of patients undergoing emergency laparotomy using an enhanced recovery after surgery (ERAS) approach. This paper addresses organizational aspects of care. METHODS: Experts in management of the high-risk and emergency general surgical patient were invited to contribute by the International ERAS® Society. PubMed, Cochrane, Embase, and MEDLINE database searches were performed for ERAS elements and relevant specific topics. Studies were selected with particular attention to randomized clinical trials, systematic reviews, meta-analyses and large cohort studies, and reviewed and graded using the Grading of Recommendations, Assessment, Development and Evaluation system. Recommendations were made on the best level of evidence, or extrapolation from studies on elective patients when appropriate. A modified Delphi method was used to validate final recommendations. RESULTS: Components of organizational aspects of care were considered. Consensus was reached after three rounds of a modified Delphi process. CONCLUSIONS: These guidelines are based on best current available evidence for organizational aspects of an ERAS® approach to patients undergoing emergency laparotomy and include discussion of less common aspects of care for the surgical patient, including end-of-life issues. These guidelines are not exhaustive but pull together evidence on important components of care for this high-risk patient population. As much of the evidence is extrapolated from elective surgery or emergency general surgery (not specifically laparotomy), many of the components need further evaluation in future studies.

Consensus Guidelines for Perioperative Care for Emergency Laparotomy Enhanced Recovery After Surgery (ERAS®) Society Recommendations Part 2-Emergency Laparotomy: Intra- and Postoperative Care.

BACKGROUND: This is Part 2 of the first consensus guidelines for optimal care of patients undergoing emergency laparotomy (EL) using an Enhanced Recovery After Surgery (ERAS) approach. This paper addresses intra- and postoperative aspects of care. METHODS: Experts in aspects of management of high-risk and emergency general surgical patients were invited to contribute by the International ERAS® Society. PubMed, Cochrane, Embase, and Medline database searches were performed for ERAS elements and relevant specific topics. Studies on each item were selected with particular attention to randomized clinical trials, systematic reviews, meta-analyses, and large cohort studies and reviewed and graded using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. Recommendations were made on the best level of evidence, or extrapolation from studies on elective patients when appropriate. A modified Delphi method was used to validate final recommendations. Some ERAS® components covered in other guideline papers are outlined only briefly, with the bulk of the text focusing on key areas pertaining specifically to EL. RESULTS: Twenty-three components of intraoperative and postoperative care were defined. Consensus was reached after three rounds of a modified Delphi Process. CONCLUSIONS: These guidelines are based on best available evidence for an ERAS® approach to patients undergoing EL. These guidelines are not exhaustive but pull together evidence on important components of care for this high-risk patient population. As much of the evidence is extrapolated from elective surgery or emergency general surgery (not specifically laparotomy), many of the components need further evaluation in future studies.

The effect of post-discharge oral nutritional supplements on outcomes after gastrointestinal surgery: A systematic review and meta-analysis.

BACKGROUND: Malnutrition is a risk-factor for adverse postoperative outcomes. This systematic review and meta-analysis evaluated the impact of post-discharge oral nutritional supplements (ONS) on outcomes in patients undergoing gastrointestinal surgery. METHODS: The Medline and Embase databases were searched for randomised clinical trials in patients undergoing gastrointestinal surgery who had received ONS for at least two weeks after discharge from hospital. The primary endpoint was weight change. Secondary endpoints included quality of life, total lymphocyte count, total serum protein and serum albumin. Analysis was performed using RevMan5.4 software. RESULTS: Fourteen studies with 2480 participants (1249 ONS/1231 controls) were included. Pooling of results revealed that a reduction in postoperative weight loss in patients taking ONS, when compared with control: overall weighted mean difference (WMD) -1.69 kg, 95% CI -2.98 to -0.41, P = 0.01. Serum albumin concentration was increased in the ONS group: WMD = 1.06 g/L, 95% CI 0.04 to 2.07, P = 0.04. Haemoglobin was also increased: WMD = 2.91 g/L, 95% CI 0.58 to 5.25, P = 0.01. Total serum protein, total lymphocyte count, total cholesterol and quality of life did not differ between the groups. Patient compliance was relatively poor across the studies and there was variability in the composition of ONS, volume consumed and surgical procedures performed. CONCLUSIONS: There was a reduction in postoperative weight loss and an improvement in some biochemical parameters in patients receiving ONS after gastrointestinal surgery. Future RCTs with more consistent methodologies are needed to investigate the efficacy of ONS after discharge from hospital following gastrointestinal surgery.

Digital Informed Consent: Modernising Information Sharing in Surgery to Empower Patients.

BACKGROUND: Despite the 2015 Montgomery Ruling highlighting key requisites for informed consent, little has changed to modernise data-sharing and documentation of the consent process. It can be difficult to gauge patient understanding and address all patient concerns in time-limited appointments. We aimed to assess the feasibility of a digital information-sharing platform to support a move towards a digital informed consent process. METHODS: All adult patients referred to a single centre with symptomatic gallstones were invited to use a digital information-sharing platform to support the informed consent process prior to their first surgical clinic appointment. The platform provided patients with multimedia information on gallstones and available treatment options. It recorded the time spent accessing information, asked patients multiple choice questions (MCQs) to allow a self-test of understanding, documented a summary medical history, and allowed free text for patient questions. This information was summarised into a clinical report to support outpatient clinic consultations. RESULTS: Of the 349 patients registered to use the digital platform, 203 (58.2%) [165 (81.3%) female, mean age 47.6 years (range 19-84 years)] completed all modules necessary to generate a clinical report. Some 130 patients (64.0%) answered all 10 MCQs correctly and spent a mean of 18.7 min (range 3-88 min) reading the consent information. Most patient-reported medical histories were deemed to be accurate. CONCLUSION: Despite difficulties with access, resulting in drop-outs, patients welcomed the opportunity to receive information digitally, prior to their consultation. Patients described feeling empowered and better informed to be involved in decision-making.

Nascent to novel methods to evaluate malnutrition and frailty in the surgical patient.

Preoperative nutrition status is an important determinant of surgical outcomes, yet malnutrition assessment is not integrated into all surgical pathways. Given its importance and the high prevalence of malnutrition in patients undergoing surgical procedures, preoperative nutrition screening, assessment, and intervention are needed to improve postoperative outcomes. This narrative review discusses novel methods to assess malnutrition and frailty in the surgical patient. The Global Leadership Initiative for Malnutrition (GLIM) criteria are increasingly used in surgical settings although further spread and implementation are strongly encouraged to help standardize the diagnosis of malnutrition. The use of body composition (ie, reduced muscle mass) as a phenotypic criterion in GLIM may lead to a greater number of patients identified as having malnutrition, which may otherwise be undetected if screened by other diagnostic tools. Skeletal muscle loss is a defining criterion of malnutrition and frailty. Novel direct and indirect approaches to assess muscle mass in clinical settings may facilitate the identification of patients with or at risk for malnutrition. Selected imaging techniques have the additional advantage of identifying myosteatosis (an independent predictor of morbidity and mortality for surgical patients). Feasible pathways for screening and assessing frailty exist and may determine the cost/benefit of surgery, long-term independence and productivity, and the value of undertaking targeted interventions. Finally, the evaluation of nutrition risk and status is essential to predict and mitigate surgical outcomes. Nascent to novel approaches are the future of objectively identifying patients at perioperative nutrition risk and guiding therapy toward optimal perioperative standards of care.

Three Centuries of Appendicectomy.

BACKGROUND: Save for the contribution of Charles McBurney, who described his eponymous point and the appendicectomy incision, the history of appendicectomy is largely unknown among the medical profession. This review traces the history from the first anatomical depiction of the appendix to the development of open appendicectomy and the recent minimally invasive and non-operative methods. METHODS: Historical articles, monographs and books containing anatomical descriptions of the vermiform appendix and reports of appendicitis and its surgical treatment were retrieved after searching the PubMed, Google Scholar and Embase databases from their inception to 31 March 2022. RESULTS: The first inadvertent appendicectomy was performed during an operation for a groin hernia by Cookesley in 1731, and Mestivier was the first to drain a right iliac fossa abscess, due to appendicitis, in 1757. Krönlein performed the first appendicectomy for acute appendicitis in 1884 but his patient died. The first successful appendicectomy for acute appendicitis leading to patient survival was by Morton in 1887. In 1976, Wirschafter and Kaufman performed an inadvertent colonoscopic appendicectomy and, in 1980, Semm carried out the first laparoscopic appendicectomy. The first appendicectomy via a natural orifice (transgastric) appendicectomy was by Rao and Reddy in 2004. CONCLUSION: This historical review charts the development of surgical knowledge concerning the management of appendicitis, from the first anatomical drawings of the appendix and descriptions of appendicitis to the development of surgical and conservative treatments up to the present day. It also corrects some inaccuracies of attribution in previous historical reviews.

Prehabilitation: high-quality evidence is still required.

Prehabilitation comprises multidisciplinary healthcare interventions, including exercise, nutritional optimisation, and psychological preparation, which aim to dampen the metabolic response to surgery, shorten the period of recovery, reduce complications, and improve the quality of recovery and quality of life. This editorial evaluates the potential benefits and limitations of and barriers to prehabilitation in surgical patients. The results of several randomised clinical trials and meta-analyses on prehabilitation show differing results, and the strength of the evidence is relatively weak. Heterogeneity in patient populations, interventions, and outcome measures, with a wide range for compliance, contribute to this variation. Evidence could be strengthened by the conduct of large-scale, appropriately powered multicentre trials that have unequivocal clinically relevant and patient-centric endpoints. Studies on prehabilitation should concentrate on recruiting patients who are frail and at high risk. Interventions should be multimodal and exercise regimens should be tailored to each patient's ability with longitudinal measurements of impact.

M1 macrophages evoke an increase in polymeric immunoglobulin receptor (PIGR) expression in MDA-MB468 breast cancer cells through secretion of interleukin-1ß.

High expression of polymeric immunoglobulin receptor (PIGR) in breast cancer is associated with increased 5-year survival rate. However, the factors influencing PIGR expression in breast cancer have not been elucidated. The aim of this study was to determine the role of macrophages and cytokines affecting expression of PIGR in two breast cancer cell lines. M1, M2 macrophage conditioned media (CM) and recombinant human cytokines were used to determine factors which increased PIGR expression in MCF7 (HTB-22) and MDA-MB468 (HTB-132) breast cancer cell lines. The level of PIGR expression in the cells and PIGR secretory component were evaluated by real-time quantitative polymerase chain reaction and Western blotting. M1 macrophage CM induced a dose-dependent increase in PIGR mRNA expression in MDA-MB468 cells, up to 20-fold. The level of PIGR expression in MCF7 cells was very low and not affected by M1 and M2 CM. Interferon gamma (IFN-γ) and interleukin (IL)-1ß also increased PIGR expression in MDA-MB468 and MCF7 cells. However, IL-1ß was demonstrated to increase in M1 macrophages, while IFN-γ was not. The role of IL-1ß secreted from M1 macrophages in increasing expression of PIGR was confirmed by IL-1 receptor blockade, indicating that IL-1ß was the major M1 macrophage-derived cytokine that enhanced PIGR expression. Elevated PIGR expression in breast cancer in vivo may reflect the polarization state of tumor-associated immune cells.