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.

The clinical significance of hypoalbuminaemia.

Albumin is a relatively small molecule with a radius of 7.5 nm and a molecular weight of 65 kDa. It is the most abundant protein in plasma, accounting for 60-75% of its oncotic pressure. Its concentration in plasma is merely one static measurement reflecting a dynamic and complex system of albumin physiology, and is the net result of several different processes, one or more of which may become deranged by disease or its treatment. It is also unsurprising that hypoalbuminaemia has proved to be an indicator of morbidity and mortality risk since the underlying conditions which cause it, including protein energy malnutrition, crystalloid overload, inflammation, and liver dysfunction are themselves risk factors. In some cases, its underlying cause may require treatment but mostly it is just a parameter to be monitored and used as one measure of clinical progress or deterioration. While malnutrition, associated with a low protein intake, may be a contributory cause of hypoalbuminaemia, in the absence of inflammation and/or dilution with crystalloid its development in response to malnutrition alone is slow compared with the rapid change caused by inflammatory redistribution or dilution with crystalloids. Other significant causes include liver dysfunction and serous losses. These causal factors may occur singly or in combination in any particular case. Treatment is that of the underlying causes and associated conditions such as a low plasma volume, not of hypoalbuminaemia per se.

ESPEN practical guideline on clinical nutrition in acute and chronic pancreatitis.

Both acute and chronic pancreatitis are frequent diseases of the pancreas, which, despite being of benign nature, are related to a significant risk of malnutrition and may require nutritional support. Acute necrotizing pancreatitis is encountered in 20 % of patients with acute pancreatitis, is associated with increased morbidity and mortality, and may require artificial nutrition by enteral or parenteral route, as well as additional endoscopic, radiological or surgical interventions. Chronic pancreatitis represents a chronic inflammation of the pancreatic gland with development of fibrosis. Abdominal pain leading to decreased oral intake, as well as exocrine and endocrine failure are frequent complications of the disease. All of the above represent risk factors related to malnutrition. Therefore, patients with chronic pancreatitis should be considered at risk, screened and supplemented accordingly. Moreover, osteoporosis and increased facture risk should be acknowledged in patients with chronic pancreatitis, and preventive measures should be considered.

Presentation and publication skills: How to review a paper.

We provide comprehensive insights into the peer review process and guide potential reviewers through the steps of reviewing scientific manuscripts. We discuss essential aspects such as the reviewer's responsibility in responding to invitations and maintaining confidentiality throughout the process, the criteria for accepting or rejecting papers, and efficient review of resubmissions. We emphasize the importance of prioritizing the review responsibility within other commitments, communication using professional and courteous language, and adherence to deadlines. We also offer practical tips on evaluating the abstract, introduction, materials and methods, results, and discussion section and summarizing the critiques in the review report.

Perioperative pain management for appendicectomy: A systematic review and Procedure-specific Postoperative Pain Management recommendations.

BACKGROUND: Despite being a commonly performed surgical procedure, pain management for appendicectomy is often neglected because of insufficient evidence on the most effective treatment options. OBJECTIVE: To provide evidence-based recommendations by assessing the available literature for optimal pain management after appendicectomy. DESIGN AND DATA SOURCES: This systematic review-based guideline was conducted according to the PROSPECT methodology. Relevant randomised controlled trials, systematic reviews and meta-analyses in the English language from January 1999 to October 2022 were retrieved from MEDLINE, Embase and Cochrane Databases using PRISMA search protocols. ELIGIBILITY CRITERIA: We included studies on adults and children. If articles reported combined data from different surgeries, they had to include specific information about appendicectomies. Studies needed to measure pain intensity using a visual analogue scale (VAS) or a numerical rating scale (NRS). Studies that did not report the precise appendicectomy technique were excluded. RESULTS: Out of 1388 studies, 94 met the inclusion criteria. Based on evidence and consensus, the PROSPECT members agreed that basic analgesics [paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs)] should be administered perioperatively for open and laparoscopic appendicectomies. A laparoscopic approach is preferred because of lower pain scores. Additional recommendations for laparoscopic appendicectomies include a three-port laparoscopic approach and the instillation of intraperitoneal local anaesthetic. For open appendicectomy, a preoperative unilateral transverse abdominis plane (TAP) block is recommended. If not possible, preincisional infiltration with local anaesthetics is an alternative. Opioids should only be used as rescue analgesia. Limited evidence exists for TAP block in laparoscopic appendicectomy, analgesic adjuvants for TAP block, continuous wound infiltration after open appendicectomy and preoperative ketamine and dexamethasone. Recommendations apply to children and adults. CONCLUSION: This review identified an optimal analgesic regimen for open and laparoscopic appendicectomy. Further randomised controlled trials should evaluate the use of regional analgesia and wound infiltrations with adequate baseline analgesia, especially during the recommended conventional three-port approach. REGISTRATION: The protocol for this study was registered with the PROSPERO database (Registration No. CRD42023387994).

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.

The 2023 Sir David Cuthbertson Lecture. A fluid journey: Experiments that influenced clinical practice.

This review summarises some of my work on fluid and electrolyte balance over the past 25 years and shows how the studies have influenced clinical practice. Missing pieces in the jigsaw are filled in by summarising the work of others. The main theme is the biochemical, physiological and clinical problems caused by inappropriate use of saline solutions including the hyperchloraemic acidosis caused by 0.9% saline. The importance of accurate and near-zero fluid balance in clinical practice is also emphasised. Perioperative fluid and electrolyte therapy has important effects on clinical outcome in a U-shaped dose response fashion, in which excess or deficit progressively increases complications and worsens outcome. Salt and water overload, with weight gain in excess of 2.5 kg worsens surgical outcome, impairs gastrointestinal function and increases the risk of anastomotic dehiscence. Hyperchloraemic acidosis caused by overenthusiastic infusion of 0.9% saline leads to adverse outcomes and dysfunction of many organ systems, especially the kidney. Salt and water deficit causes similar adverse effects as fluid overload at the cellular level and also leads to worse outcomes. Serum albumin is shown to be affected mainly by dilution and inflammation and is not a good nutritional marker. These findings have been incorporated in the British consensus Guidelines on Intravenous Fluid Therapy for Adult Surgical Patients (GIFTASUP) and National Institute for Health and Care Excellence (NICE) guidelines on intravenous fluid therapy in adults in hospital and are helping change clinical practice and improve outcomes.

Presentation and publication skills: How to get your paper published.

Getting your scientific paper published can be a difficult process. The quality of the paper relates to the quality of the design of the study, the questions asked, and defining an excellent primary endpoint that is easy to understand, and data obtained from a sufficiently large population. Before submitting your paper, go over all requirements like ethical approval, registration in public databases, and conflict of interest declarations. Manuscripts are structured in several sections. The introduction section should mainly focus on why the study was done. The materials and methods section should describe what was used and the results section provides a good representation of all data. Specifically, attention needs to be paid to high quality tables and figures. The discussion section should focus on putting the results in perspective. The abstract should cover all aspects in a condensed and focused manner. The publication process is handled by editors, reviewers, and the publisher. The first impression is the most important factor that decides whether the paper is sent out for review. If revisions are requested, a thoughtful response to the reviewers is needed. Hopefully, it all will lead to acceptance of the paper and publication.

Presentation and publication skills: How to present a paper.

Presenting a paper to a small or large audience should match both the knowledge level of your audience and the title and abstract you submitted to the conference. Your slides should give context to your work. Simpler slides and talks are easier to follow than a highly complex presentation. You must keep to the time scheduled for your talk and remember to Keep It Short and Simple (KISS). Your slides should be readable from the back of the room by keeping them simple but informative. Practice the talk (preferably with an audience of your colleagues) and be prepared to amend as necessary. Know your talk "by heart", so you can relax and enjoy the experience.

Presentation and publication skills: Publication governance and pitfalls to avoid.

There are several pitfalls in the publication process that researchers can fall victim to, and these can occur knowingly or unknowingly. Although some of these errors may have occurred in good faith, disregard of publication governance is a dangerous practice and could bring authors and their co-authors into disrepute. We highlight some of these potential pitfalls, acquaint the reader with some rules that need to be adhered to in research and publishing, and help the reader learn how to avoid tripping-up on the road to publication.

Presentation and publication skills: How to develop a protocol and write a grant.

In this education paper, we want to give some advice to aid in successful scientific grant writing. Besides defining an important research hypothesis and how to support this hypothesis, there are also technical aspects in grant writing that need to be fulfilled. Therefore, read carefully the requirements before starting to write the proposal. You must also determine what skilled people, equipment and consumables are needed in order to reach your research goal. It is advised to develop a timeline with the key milestones (background, partnership, budget, writing, peer-evaluation, submission). Spend enough time on the summary, title and acronyms, in order to make them attractive to the reader. The research objectives must be SMART (Specific, Measurable, Achievable, Realistic, Time-Sensitive), not DUMB (Diverse, Unmeasurable, Mediocre and Basically-Unachievable). In the end, understand that also non-experts will review your grant and therefore they should be able to understand what your goals are, but also at the same time add sufficient details of your proposed methodology to convince the experts.

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.

Changes in serum albumin concentrations over 7 days in medical inpatients with and without nutritional support. A secondary post-hoc analysis of a randomized clinical trial.

BACKGROUND: Serum albumin concentrations are frequently used to monitor nutritional therapy in the hospital setting but supporting studies are largely lacking. Within this secondary analysis of a randomized nutritional trial (EFFORT), we assessed whether nutritional support affects short-term changes in serum albumin concentrations and whether an increase in albumin concentration has prognostic implications regarding clinical outcome and response to treatment. METHODS: We analyzed patients with available serum albumin concentrations at baseline and day 7 included in EFFORT, a Swiss-wide multicenter randomized clinical trial that compared individualized nutritional therapy with usual hospital food (control group). RESULTS: Albumin concentrations increased in 320 of 763 (41.9%) included patients (mean age 73.3 years (SD ± 12.9), 53.6% males) with no difference between patients receiving nutritional support and controls. Compared with patients that showed a decrease in albumin concentrations over 7 days, those with an increase had a lower 180-day mortality [74/320 (23.1%) vs. 158/443 (35.7%); adjusted odds ratio 0.63, 95% CI 0.44 to 0.90; p = 0.012] and a shorter length of hospital stay [11.2 ± 7.3 vs. 8.8 ± 5.6 days, adjusted difference -2.2 days (95%CI -3.1 to -1.2)]. Patients with and without a decrease over 7 days had a similar response to nutritional support. CONCLUSION: Results from this secondary analysis indicate that nutritional support did not increase short-term concentrations of albumin over 7 days, and changes in albumin did not correlate with response to nutritional interventions. However, an increase in albumin concentrations possibly mirroring resolution of inflammation was associated with better clinical outcomes. Repeated in-hospital albumin measurements in the short-term is, thus, not indicated for monitoring of patients receiving nutritional support but provides prognostic information. TRAIL REGISTRATION: ClinicalTrials.gov Identifier: NCT02517476.

Risk of osteopaenia, osteoporosis and osteoporotic fractures in patients with chronic pancreatitis: A systematic review and meta-analysis.

BACKGROUND & AIMS: Chronic pancreatitis results in irreversible pancreatic dysfunction and malnutrition which, alongside excess alcohol intake, can increase the risk of low bone density. Osteoporosis increases the risk of fractures and chronic bone pain, reduces quality of life, and poses considerable costs to healthcare. Despite this, there remains a paucity of literature evaluating bone health in this patient population. This systematic review and meta-analysis evaluated the prevalences of osteopaenia, osteoporosis and fractures in patients with chronic pancreatitis. METHODS: A comprehensive search of Medline, Embase, ClinicalTrials.gov, and CENTRAL databases was undertaken to identify eligible studies from January 2000 to May 2022. The prevalences of osteopenia, osteoporosis and fragility fractures were extracted from the included studies. Where available, a subgroup analysis was performed to compare the likelihood of developing osteoporosis in patients with chronic pancreatitis compared with control. RESULTS: Nineteen studies reporting on 2,027,764 participants (20,460 with chronic pancreatitis and 2,007,304 controls) were included. The pooled prevalence of osteoporosis was 19% (95% CI 13 to 26%; I2 = 94%). Patients with chronic pancreatitis were more likely to have osteoporosis when compared with those in the control group (OR 2.80, 95% CI 1.86 to 4.21; I2 = 21%). The prevalences of osteopaenia and fractures in patients with chronic pancreatitis were 37% (95% CI 31 to 44%; I2 = 81%) and 14% (95% CI 7 to 22%; I2 = 99%) respectively. CONCLUSION: The prevalences of osteopenia and osteoporosis are significant in patients with chronic pancreatitis and can increase the risk of developing fractures. Further population-based studies are required to evaluate the disease burden of osteoporotic fractures and associated morbidity and mortality in chronic pancreatitis.

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.