Search

Objectives Studies have demonstrated high rates of mortality in people with proximal femoral fracture and SARS-CoV-2, but there is limited published data on the factors that influence mortality for clinicians to make informed treatment decisions. This study aims to report the 30-day mortality associated with perioperative infection of patients undergoing surgery for proximal femoral fractures and to examine the factors that influence mortality in a multivariate analysis.Setting Prospective, international, multicentre, observational cohort study.Participants Patients undergoing any operation for a proximal femoral fracture from 1 February to 30 April 2020 and with perioperative SARS-CoV-2 infection (either 7 days prior or 30-day postoperative).Primary outcome 30-day mortality. Multivariate modelling was performed to identify factors associated with 30-day mortality.Results This study reports included 1063 patients from 174 hospitals in 19 countries. Overall 30-day mortality was 29.4% (313/1063). In an adjusted model, 30-day mortality was associated with male gender (OR 2.29, 95% CI 1.68 to 3.13, p80 years (OR 1.60, 95% CI 1.1 to 2.31, p=0.013), preoperative diagnosis of dementia (OR 1.57, 95% CI 1.15 to 2.16, p=0.005), kidney disease (OR 1.73, 95% CI 1.18 to 2.55, p=0.005) and congestive heart failure (OR 1.62, 95% CI 1.06 to 2.48, p=0.025). Mortality at 30 days was lower in patients with a preoperative diagnosis of SARS-CoV-2 (OR 0.6, 95% CI 0.6 (0.42 to 0.85), p=0.004). There was no difference in mortality in patients with an increase to delay in surgery (p=0.220) or type of anaesthetic given (p=0.787).Conclusions Patients undergoing surgery for a proximal femoral fracture with a perioperative infection of SARS-CoV-2 have a high rate of mortality. This study would support the need for providing these patients with individualised medical and anaesthetic care, including medical optimisation before theatre. Careful preoperative counselling is needed for those with a proximal femoral fracture and SARS-CoV-2, especially those in the highest risk groups.Trial registration number NCT04323644

Purpose: We compared health outcomes and costs of inguinal lymphadenectomy (IL) versus ilio-inguinal lymphadenectomy (I-IL) for removal of metastatic melanoma to lymph nodes of the groin in adults with stage III melanoma., Methods: A within-trial cost-utility analysis was performed alongside an international randomized trial (EAGLE-FM) with 36 months follow-up from a health system perspective. Healthcare costs were measured by using trial records, and effectiveness measured in quality-adjusted life years (QALYs). Deterministic sensitivity analyses assessed the impact of changes in costs or quality of life on overall results. Statistical bootstrapping was employed to estimate confidence intervals around the cost-utility ratio., Results: Among 98 trial participants (IL n = 50, I-IL n = 48), with no pelvic or distant disease clinically or on PET/CT imaging, the mean life years saved for those randomized to IL showed a small but nonsignificant increase of 0.05 years compared with those in the I-IL group (2.56 vs. 2.51 years, 95% confidence interval [CI] -0.78 to 0.87). The mean difference in QALYs gained showed a small but nonsignificant increase of 0.04 QALYs (1.95 vs. 1.91, 95% CI -0.49 to 0.57). The mean hospital stay among IL patients was 6.16 days, 1.24 days shorter than I-IL patients (7.40 days) at 36 months follow-up. Mean per-patient healthcare costs of IL surgery were AU$6938 lower than for I-IL surgery ($26,555 vs. $33,493, 95% CI -$24,360 to $10,484). Inguinal lymphadenectomy was slightly more effective and slightly less expensive) over I-IL; a finding supported by 81% of bootstrapped estimates and upheld across sensitivity analyses., Conclusions: Our study indicates that less extensive IL surgery might be the preferred surgical strategy for metastatic melanoma to the groin when PET/CT imaging shows no pelvic disease. This surgery is likely to improve quality-adjusted survival and may reduce healthcare costs; however, the differences noted in EAGLE-FM were limited by a small sample size and were not statistically significant., Trial Registration: Clinicaltrials.gov NCT02166788; anzctr.org.au ACTRN12614000721606., Competing Interests: Disclosures: RAM declares no conflicts of interest. CKL declares no conflicts of interest. DAO declares no conflicts of interest. JHWW declares no conflicts of interest. BLVL declares no conflicts of interest. CA declares no conflicts of interest. RPJ declares no conflicts of interest. JH declares no conflicts of interest. AJS declares no conflicts of interest. RLM declares no conflicts of interest. Ethical Approval: The study was approved by the Sydney Local Health District Ethics Review Committee (RPAH Zone) (Ethics approval number: HREC/14/RPAH/229)., (© 2025. The Author(s).)

Cholangiocarcinoma (CCA) remains a devastating malignancy and a significant challenge to treat. The majority of CCA patients are diagnosed at an advanced stage, making the disease incurable in most cases. The advent of high-throughput genetic sequencing has significantly improved our understanding of the molecular biology underpinning cancer. The identification of 'druggable' genetic aberrations and the development of novel targeted therapies against them is opening up new treatment strategies. Currently, 3 targeted therapies are approved for use in CCA; Ivosidenib in patients with IDH1 mutations and Infigratinib/Pemigatinib in those with FGFR2 fusions. As our understanding of the biology underpinning CCA continues to improve it is highly likely that additional targeted therapies will become available in the near future. This is important, as it is thought up to 40 % of CCA patients harbour a potentially actionable mutation. In this review we provide an overview of the molecular pathogenesis of CCA and highlight currently available and potential future targeted treatments., Competing Interests: Declaration of competing interest Palmer has grant funding from BMS, Nucana, Astra Zeneca, Sirtex, honoraria from Boston Scientific and Sirtex, and support for travel from Nucana. Randle reports a relationship with National Centre for the Replacement Refinement and Reduction of Animals in Research (NC3Rs) that includes grant funding and membership of the NC3RS PhD studentship assessment board. Goldring reports financial support by the University of Liverpool. Jones, Young, Diaz-Neito, O’leary, McGreevy, Gilbert, Quinn, Fenwick and Malik declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Vaccines have revolutionised the field of medicine, eradicating and controlling many diseases. Recent pandemic vaccine successes have highlighted the accelerated pace of vaccine development and deployment. Leveraging this momentum, attention has shifted to cancer vaccines and personalised cancer vaccines, aimed at targeting individual tumour-specific abnormalities. The UK, now regarded for its vaccine capabilities, is an ideal nation for pioneering cancer vaccine trials. This article convened experts to share insights and approaches to navigate the challenges of cancer vaccine development with personalised or precision cancer vaccines, as well as fixed vaccines. Emphasising partnership and proactive strategies, this article outlines the ambition to harness national and local system capabilities in the UK; to work in collaboration with potential pharmaceutic partners; and to seize the opportunity to deliver the pace for rapid advances in cancer vaccine technology., Competing Interests: None of the authors have any conflict of interest relevant to this article., (© The Author(s) 2025.)

This study investigates the process of planning for future inpatient resources (beds, staff and costs) for maternity (pregnancy and childbirth) services. The process of planning is approached from a patient-centered philosophy; hence, how do we discharge a suitably rested healthy mother who is fully capable of caring for the newborn baby back into the community? This demonstrates some of the difficulties in predicting future births and investigates trends in the average length of stay. While it is relatively easy to document longer-term (past) trends in births and the conditions relating to pregnancy and birth, it is exceedingly difficult to predict the future nature of such trends. The issue of optimum average bed occupancy is addressed via the Erlang B equation which links number of beds, average bed occupancy and turn-away. Turn-away is the proportion of times that there is not an immediately available bed for the next arriving inpatient. Data for maternity units show extreme and unexplained variation in turn-away. Economy of scale implied by queuing theory (and the implied role of population density) explains why many well intended community-based schemes fail to gain traction. The paper also addresses some of the erroneous ideas around the dogma that reducing length of stay 'saves' money. Maternity departments are encouraged to understand how their costs are calculated to avoid the trap where it is suggested by others that in reducing the length of stay, they will reduce costs and increase 'efficiency'. Indeed, up to 60% of calculated maternity 'costs' are apportioned from (shared) hospital overheads from supporting departments such as finance, personnel, buildings and grounds, IT, information, etc., along with depreciation charges on the hospital-wide buildings and equipment. These costs, known as 'the fixed costs dilemma', are totally beyond the control of the maternity department and will vary by hospital depending on how these costs are apportioned to the maternity unit. Premature discharge, one of the unfortunate outcomes of turn-away, is demonstrated to shift maternity costs into the pediatric and neonatal departments as 'boomerang babies', and then require the cost of avoidable inpatient care. Examples are given from the English NHS of how misdirected government policy can create unforeseen problems.

Three models/methods are given to understand the extreme international variation in available and occupied hospital bed numbers. These models/methods all rely on readily available data. In the first, occupied beds (rather than available beds) are used to measure the expressed demand for hospital beds. The expressed occupied bed demand for three countries was in the order Australia > England > USA. Next, the age-standardized mortality rate (ASMR) has dual functions. Less developed countries/regions have low access to healthcare, which results in high ASMR, or a negative slope between ASMR versus available/occupied beds. In the more developed countries, high ASMR can also be used to measure the 'need' for healthcare (including occupied beds), a positive slope among various social (wealth/lifestyle) groups, which will include Indigenous peoples. In England, a 100-unit increase in ASMR (European Standard population) leads to a 15.3-30.7 (feasible range) unit increase in occupied beds per 1000 deaths. Higher ASMR shows why the Australian states of the Northern Territory and Tasmania have an intrinsic higher bed demand. The USA has a high relative ASMR (for a developed/wealthy country) because healthcare is not universal in the widest sense. Lastly, a method for benchmarking the whole hospital's average bed occupancy which enables them to run at optimum efficiency and safety. English hospitals operate at highly disruptive and unsafe levels of bed occupancy, manifesting as high 'turn-away'. Turn-away implies bed unavailability for the next arriving patient. In the case of occupied beds, the slope of the relationship between occupied beds per 1000 deaths and deaths per 1000 population shows a power law function. Scatter around the trend line arising from year-to-year fluctuations in occupied beds per 1000 deaths, ASMR, deaths per 1000 population, changes in the number of persons hidden in the elective, outpatient and diagnostic waiting lists, and local area variation in births affecting maternity, neonatal, and pediatric bed demand. Additional variation will arise from differences in the level of local funding for social care, especially elderly care. The problems associated with crafting effective bed planning are illustrated using the English NHS as an example.

Purpose: This work aimed to investigate the validity of wearable activity monitors (WAMs) as an objective tool to measure the return toward normal functional mobility following abdominal wall surgery. This was achieved by quantifying and comparing pre- and postoperative physical activity (PA)., Methods: A multicenter, prospective, observational cohort study was designed. Patients undergoing abdominal wall surgery were assessed for eligibility and consent for study participation was obtained. Participants were asked to wear a WAM (AX3, Axivity) on the wrist of their dominant hand at least 48 hours pre-operatively, for up to 2 weeks postop, and again after 6 months postop for 48 hours., Results: A cohort of 20 patients were recruited in this validation study with a mean age of 47.3 ± 13.0 years. Postoperation, the percentage median PA (±IQR) dropped to 32.6% (20.1), whereas on day 14, PA had reached 64.6% (22.7) of the preoperative value providing construct validity. Activity levels at >6 months postop increased by 16.4% on an average when compared to baseline preoperative PA (p = 0.046)., Conclusion: This study demonstrates that WAMs are valid markers of postoperative recovery following abdominal wall surgery. This was achieved by quantifying the reduction in PA postoperation, which has not been previously shown. In addition, this study suggests that abdominal wall surgery may improve the patient's quality of life via increased functional mobility at 6 months postop. In the future, this technology could be used to identify the patient and surgical factors that are predictors of outcome following abdominal wall surgery., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

Background: The Evaluation of Groin Lymphadenectomy Extent for Melanoma (EAGLE FM) study sought to address the question of whether to perform inguinal (IL) or ilio-inguinal lymphadenectomy (I-IL) for patients with inguinal nodal metastatic melanoma who have no clinical or imaging evidence of pelvic disease. Primary outcome measure was disease-free survival at 5 years, and secondary endpoints included lymphoedema., Methods: EAGLE FM was designed to recruit 634 patients but closed with 88 patients randomised because of slow recruitment and changes in melanoma management. Lymphoedema assessments occurred preoperatively and at 6, 12, 18, and 24 months postoperatively. Lymphoedema was defined as Inter-Limb Volume Difference (ILVD) > 10%, Lymphoedema Index (L-Dex ® ) > 10 or change of L-Dex ®  > 10 from baseline., Results: Prevalence of leg lymphoedema between the two groups was similar but numerically higher for I-IL at all time points in the first 24 months of follow-up; highest at 6 months (45.9% IL [CI 29.9-62.0%], 54.1% I-IL [CI 38.0-70.1%]) and lowest at 18 months (18.8% IL [CI 5.2-32.3%], 41.4% I-IL [CI 23.5-59.3%]). Median ILVD at 24 months for those affected by lymphoedema was 14.5% (IQR 10.6-18.7%) and L-Dex ® was 12.6 (IQR 9.0-17.2). There was not enough statistical evidence to support associations between lymphoedema and extent of surgery, radiotherapy, or wound infection., Conclusions: Despite a trend for patients who had I-IL to have greater lymphoedema prevalence than IL in the first 24 months after surgery, our study's small sample did not have the statistical evidence to support an overall difference between the surgical groups., (© 2024. Crown.)

Pancreatic ductal adenocarcinoma is a highly metastatic disease and macrophages support liver metastases. Efferocytosis, or engulfment of apoptotic cells by macrophages, is an essential process in tissue homeostasis and wound healing, but its role in metastasis is less well understood. Here, we found that the colonization of the hepatic metastatic site is accompanied by low-grade tissue injury and that efferocytosis-mediated clearance of parenchymal dead cells promotes macrophage reprogramming and liver metastasis. Mechanistically, progranulin expression in macrophages is necessary for efficient efferocytosis by controlling lysosomal acidification via cystic fibrosis transmembrane conductance regulator and the degradation of lysosomal cargo, resulting in LXRα/RXRα-mediated macrophage conversion and upregulation of arginase 1. Pharmacological blockade of efferocytosis or macrophage-specific genetic depletion of progranulin impairs macrophage conversion, improves CD8 + T cell functions, and reduces liver metastasis. Our findings reveal how hard-wired functions of macrophages in tissue repair contribute to liver metastasis and identify potential targets for prevention of pancreatic ductal adenocarcinoma liver metastasis., (© 2024. The Author(s).)

Genomics is a crucial part of managing surgical disease. This review focuses on some of the genomic advances that are available now and looks to the future of their application in surgical practice. Whole-genome sequencing enables unbiased coverage across the entire human genome of approximately three billion base pairs. Newer technologies, such as those that permit long-read sequence analysis, provide additional information in longer phased fragment and base pair epigenomic (methylomic) data. Whole-genome sequencing is currently available in England for cancers in children, teenagers and young adults, central nervous system tumours, sarcoma and haematological malignancies. Circulating tumour DNA (ctDNA), immunotherapy and pharmacogenomics have emerged as groundbreaking approaches in the field of cancer treatment. These are now revolutionising the way oncologists and surgeons approach curative cancer surgery. Cancer vaccines offer an innovative approach to reducing recurrence after surgery by priming the immune system to trigger an immune response. The Cancer Vaccine Launch Pad project facilitates cancer vaccine studies in England. The BNT122-01 trial is recruiting patients with ctDNA-positive high-risk colorectal cancer after surgery to assess the impact of cancer vaccines. The evolving landscape of cancer treatment demands a dynamic and integrated approach from the surgical multidisciplinary team. Immunotherapy, ctDNA, pharmacogenomics, vaccines, mainstreaming and whole-genome sequencing are just some of the innovations that have the potential to redefine the standards of care. The continued exploration of these innovative diagnostics and therapies, the genomic pathway evolution and their application in diverse cancer types highlights the transformative impact of precision medicine in surgery.

Based upon 30-years of research by the author, a new approach to hospital bed planning and international benchmarking is proposed. The number of hospital beds per 1000 people is commonly used to compare international bed numbers. This method is flawed because it does not consider population age structure or the effect of nearness-to-death on hospital utilization. Deaths are also serving as a proxy for wider bed demand arising from undetected outbreaks of 3000 species of human pathogens. To remedy this problem, a new approach to bed modeling has been developed that plots beds per 1000 deaths against deaths per 1000 population. Lines of equivalence can be drawn on the plot to delineate countries with a higher or lower bed supply. This method is extended to attempt to define the optimum region for bed supply in an effective health care system. England is used as an example of a health system descending into operational chaos due to too few beds and manpower. The former Soviet bloc countries represent a health system overly dependent on hospital beds. Several countries also show evidence of overutilization of hospital beds. The new method is used to define a potential range for bed supply and manpower where the most effective health systems currently reside. The method is applied to total curative beds, medical beds, psychiatric beds, critical care, geriatric care, etc., and can also be used to compare different types of healthcare staff, i.e., nurses, physicians, and surgeons. Issues surrounding the optimum hospital size and the optimum average occupancy will also be discussed. The role of poor policy in the English NHS is used to show how the NHS has been led into a bed crisis. The method is also extended beyond international benchmarking to illustrate how it can be applied at a local or regional level in the process of long-term bed planning. Issues regarding the volatility in hospital admissions are also addressed to explain the need for surge capacity and why an adequate average bed occupancy margin is required for an optimally functioning hospital.

Introduction: Recurrence post hepatectomy for colorectal liver metastases (CRLM) occurs in 70 % of patients within two years. No established guidance on the method or intensity of follow-up currently exists. The aim of this systematic review was to summarise literature and determine whether it is possible to identify an optimal follow up regime. To this date there are no randomised prospective studies investigating this., Methods: A systematic review was performed according to PRISMA guidelines. Outcomes included general demographics, method, frequency and duration of follow up, survival and recurrence data. Quality assessment of the papers was performed., Results: Twenty-five articles published between 1994 and 2022 were included, including 9945 patients. CT was the most common imaging modality (n = 14) and CEA most common blood test (n = 11). Intensity of follow up was higher in the first two years post resection and only two papers continued follow up post 5 years resection. There was wide variation in outcome measures - Overall survival (OS) was most commonly reported. Nine papers reported OS ranging between 39 and 78.1 %., Conclusions: There is wide variation in follow up methods and outcome reporting. There is no strong evidence to support intensive follow up, and the benefits of long term follow up are also unknown due to the lack of patient centred data. High quality, prospective studies should be the focus of future research as further retrospective data is unlikely to resolve uncertainties around optimal follow up., Competing Interests: Declaration of competing interest Nil., (© 2023 Published by Elsevier Ltd.)

Since 2020, COVID-19 has caused serious mortality around the world. Given the ambiguity in establishing COVID-19 as the direct cause of death, we first investigate the effects of age and sex on all-cause mortality during 2020 and 2021 in England and Wales. Since infectious agents have their own unique age profile for death, we use a 9-year time series and several different methods to adjust single-year-of-age deaths in England and Wales during 2019 (the pre-COVID-19 base year) to a pathogen-neutral single-year-of-age baseline. This adjusted base year is then used to confirm the widely reported higher deaths in males for most ages above 43 in both 2020 and 2021. During 2020 (+COVID-19 but no vaccination), both male and female population-adjusted deaths significantly increased above age 35. A significant reduction in all-cause mortality among both males and females aged 75+ could be demonstrated in 2021 during the widespread COVID-19 vaccination period; however, deaths below age 75 progressively increased. This finding arises from a mix of vaccination coverage and year-of-age profiles of deaths for the different SARS-CoV-2 variants. In addition, specific effects of age around puberty were demonstrated, where females had higher deaths than males. There is evidence that year-of-birth cohorts may also be involved, indicating that immune priming to specific pathogen outbreaks in the past may have led to lower deaths for some birth cohorts. To specifically identify the age profile for the COVID-19 variants from 2020 to 2023, we employ the proportion of total deaths at each age that are potentially due to or 'with' COVID-19. The original Wuhan strain and the Alpha variant show somewhat limited divergence in the age profile, with the Alpha variant shifting to a moderately higher proportion of deaths below age 84. The Delta variant specifically targeted individuals below age 65. The Omicron variants showed a significantly lower proportion of overall mortality, with a markedly higher relative proportion of deaths above age 65, steeply increasing with age to a maximum around 100 years of age. A similar age profile for the variants can be seen in the age-banded deaths in US states, although they are slightly obscured by using age bands rather than single years of age. However, the US data shows that higher male deaths are greatly dependent on age and the COVID variant. Deaths assessed to be 'due to' COVID-19 (as opposed to 'involving' COVID-19) in England and Wales were especially overestimated in 2021 relative to the change in all-cause mortality. This arose as a by-product of an increase in COVID-19 testing capacity in late 2020. Potential structure-function mechanisms for the age-specificity of SARS-CoV-2 variants are discussed, along with potential roles for small noncoding RNAs (miRNAs). Using data from England, it is possible to show that the unvaccinated do indeed have a unique age profile for death from each variant and that vaccination alters the shape of the age profile in a manner dependent on age, sex, and the variant. The question is posed as to whether vaccines based on different variants carry a specific age profile.

Introduction: The COVID-19 pandemic has caused severe disruption of healthcare services worldwide and interrupted patients' access to essential services. During the first lockdown, many healthcare services were shut to all but emergencies. In this study, we aimed to determine the immediate and long-term indirect impact of COVID-19 health services utilisation on hepatocellular cancer (HCC) outcomes., Methods: A prospective cohort study was conducted from 1 March 2020 until 30 June 2020, correlating to the first wave of the COVID-19 pandemic. Patients were enrolled from tertiary hospitals in the UK and Germany with dedicated HCC management services. All patients with current or past HCC who were discussed at a multidisciplinary meeting (MDM) were identified. Any delay to treatment (DTT) and the effect on survival at one year were reported., Results: The median time to receipt of therapy following MDM discussion was 49 days. Patients with Barcelona Clinic Liver Cancer (BCLC) stages-A/B disease were more likely to experience DTT. Significant delays across all treatments for HCC were observed, but delay was most marked for those undergoing curative therapies. Even though severe delays were observed in curative HCC treatments, this did not translate into reduced survival in patients., Conclusion: Interruption of routine healthcare services because of the COVID-19 pandemic caused severe delays in HCC treatment. However, DTT did not translate to reduced survival. Longer follow is important given the delay in therapy in those receiving curative therapy.

Electrochemotherapy has been proven to be an efficient treatment for cutaneous metastases of various cancers. Data on breast cancer (BC) patients with cutaneous metastases were retrieved from the INSPECT database. Patients were divided by their receptor status: HER2+, HR+ (ER/PgR+), and TN (triple negative). Groups were similar for histological subtype and location of the nodules. Most patients were previously treated with surgery/systemic therapy/radiotherapy. We found no differences in the three groups in terms of response ratio (OR per patient 86% HER2+, 80% HR+, 76% TN, p = 0.8664). The only factor positively affecting the complete response rate in all groups was small tumor size (<3 cm, p = 0.0105, p = 0.0001, p = 0.0266, respectively). Local progression-free survival was positively impacted by the achievement of complete response in HER2+ ( p = 0.0297) and HR+ ( p = 0.0094), while overall survival was affected by time to local progression in all groups ( p = 0.0065 in HER2+, p < 0.0001 in HR+, p = 0.0363 in TN). ECT treatment is equally effective among groups, despite different receptor status. Response and local tumor control seem to be better in multiple small lesions than in big armor-like lesions, suggesting that treating smaller, even multiple, lesions at the time of occurrence is more effective than treating bigger long-lasting armor-like cutaneous lesions.

Introduction: Liver resection is the only curative treatment for colorectal liver metastases (CLM). Resectability decision-making is therefore a key determinant of outcomes. Wide variation has been demonstrated in resectability decision-making, despite the existence of criteria. This paper summarises a study protocol to evaluate the potential added value of two novel assessment tools in assessing CLM technical resectability: the Hepatica preoperative MR scan (MR-based volumetry, Couinaud segmentation, liver tissue characteristics and operative planning tool) and the LiMAx test (hepatic functional capacity)., Methods and Analysis: This study uses a systematic multistep approach, whereby three preparatory workstreams aid the design of the final international case-based scenario survey:Workstream 1: systematic literature review of published resectability criteria.Workstream 2: international hepatopancreatobiliary (HPB) interviews.Workstream 3: international HPB questionnaire.Workstream 4: international HPB case-based scenario survey.The primary outcome measures are change in resectability decision-making and change in planned operative strategy, resulting from the novel test results. Secondary outcome measures are variability in CLM resectability decision-making and opinions on the role for novel tools., Ethics and Dissemination: The study protocol has been approved by a National Health Service Research Ethics Committee and registered with the Health Research Authority. Dissemination will be via international and national conferences. Manuscripts will be published., Registration Details: The CoNoR Study is registered with ClinicalTrials.gov (registration number NCT04270851). The systematic review is registered on the PROSPERO database (registration number CRD42019136748)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Flucloxacillin is a β-lactam antibiotic associated with a high incidence of drug-induced liver injury. Although expression of HLA-B*57:01 is associated with increased susceptibility, little is known of the pathological mechanisms involved in the induction of the clinical phenotype. Irreversible protein modification is suspected to drive the reaction through the provision of flucloxacillin-modified peptides that are presented to T-cells by the protein encoded by the risk allele. In this study, we have shown that flucloxacillin binds to multiple proteins within human primary hepatocytes, including major hepatocellular proteins (hemoglobin and albumin) and mitochondrial proteins. Inhibition of membrane transporters multidrug resistance-associated protein 2 (MRP2) and P-glycoprotein (P-gp) appeared to reduce the levels of covalent binding. A diverse range of proteins with different functions was found to be targeted by flucloxacillin, including adaptor proteins (14-3-3), proteins with catalytic activities (liver carboxylesterase 1, tRNA-splicing endonuclease subunit Sen2, All-trans-retinol dehydrogenase ADH1B, Glutamate dehydrogenase 1 mitochondrial, Carbamoyl-phosphate synthase [ammonia] mitochondrial), and transporters (hemoglobin, albumin, and UTP-glucose-1-phosphate uridylyltransferase). These flucloxacillin-modified intracellular proteins could provide a potential source of neoantigens for HLA-B*57:01 presentation by hepatocytes. More importantly, covalent binding to critical cellular proteins could be the molecular initiating events that lead to flucloxacillin-induced cholestasis Data are available via ProteomeXchange with identifier PXD038581., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Surgery for perihilar cholangiocarcinoma (pCCA) offers the only possibility of long-term survival, but remains a formidable undertaking. Traditionally, 90-day post-operative complications and death are used to define operative risk. However, there is concern that this metric may not accurately capture long-term morbidity after such complex surgery., Methods: A retrospective review of a prospective database of patients undergoing surgery for pCCA at a Western centre between January 2009-2020., Results: Eighty-five patients underwent surgical resection for pCCA with a median overall survival of 36.3 months. Post-op (<90day) morbidity rates were high with 46% of patients developing a major complication (Clavien-Dindo grade 3-4). Post-op mortality rate was 13%. In total 38% (28/74) of patients experienced at least 1 episode of delayed morbidity (>90-days of surgery) resulting in 53 separate admissions with a median LOS of 7 days (IQR 2-15). These episodes were predominately secondary to biliary obstruction with the majority requiring radiological intervention (Clavien-Dindo grade 3). The development of long-term morbidity was associated with increased recurrence rates and correlated with poorer OS (27.6 months vs. 65.7 months HR 2.2 CI 1.63-2.77)., Conclusions: Routinely cited 90-day morbidity and mortality does not accurately capture the patient morbidity experienced following surgery for pCCA. Surgery clearly offers a survival benefit and should be pursued in selected patients, but they must be fully counselled on the potential for long-term morbidity before embarking on this strategy., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Pathogen interference is the ability of one pathogen to alter the course and clinical outcomes of infection by another. With up to 3000 species of human pathogens the potential combinations are vast. These combinations operate within further immune complexity induced by infection with multiple persistent pathogens, and by the role which the human microbiome plays in maintaining health, immune function, and resistance to infection. All the above are further complicated by malnutrition in children and the elderly. Influenza vaccination offers a measure of protection for elderly individuals subsequently infected with influenza. However, all vaccines induce both specific and non-specific effects. The specific effects involve stimulation of humoral and cellular immunity, while the nonspecific effects are far more nuanced including changes in gene expression patterns and production of small RNAs which contribute to pathogen interference. Little is known about the outcomes of vaccinated elderly not subsequently infected with influenza but infected with multiple other non-influenza winter pathogens. In this review we propose that in certain years the specific antigen mix in the seasonal influenza vaccine inadvertently increases the risk of infection from other non-influenza pathogens. The possibility that vaccination could upset the pathogen balance, and that the timing of vaccination relative to the pathogen balance was critical to success, was proposed in 2010 but was seemingly ignored. Persons vaccinated early in the winter are more likely to experience higher pathogen interference. Implications to the estimation of vaccine effectiveness and influenza deaths are discussed., Competing Interests: The authors declare no conflict of interest.

Comparing international or regional hospital bed numbers is not an easy matter, and a pragmatic method has been proposed that plots the number of beds per 1000 deaths versus the log of deaths per 1000 population. This method relies on the fact that 55% of a person's lifetime hospital bed utilization occurs in the last year of life-irrespective of the age at death. This is called the nearness to death effect. The slope and intercept of the logarithmic relationship between the two are highly correlated. This study demonstrates how lines of equivalent bed provision can be constructed based on the value of the intercept. Sweden looks to be the most bed-efficient country due to long-term investment in integrated care. The potential limitations of the method are illustrated using data from English Clinical Commissioning Groups. The main limitation is that maternity, paediatric, and mental health care do not conform to the nearness to death effect, and hence, the method mainly applies to adult acute care, especially medical and critical care bed numbers. It is also suggested that sensible comparison can only be made by comparing levels of occupied beds rather than available beds. Occupied beds measure the expressed bed demand (although often constrained by access to care issues), while available beds measure supply. The issue of bed supply is made complex by the role of hospital size on the average occupancy margin. Smaller hospitals are forced to operate at a lower average occupancy; hence, countries with many smaller hospitals such as Germany and the USA appear to have very high numbers of available beds. The so-called 85% occupancy rule is an "urban myth" and has no fundamental basis whatsoever. The very high number of "hospital" beds in Japan is simply an artefact arising from "nursing home" beds being counted as a "hospital" bed in this country. Finally, the new method is applied to the expressed demand for occupied acute beds in Australian states. Using data specific to acute care, i.e., excluding mental health and maternity, a long-standing deficit of beds was identified in Tasmania, while an unusually high level of occupied beds in the Northern Territory (NT) was revealed. The high level of demand for beds in the NT appears due to an exceptionally large population of indigenous people in this state, who are recognized to have elevated health care needs relative to non-indigenous Australians. In this respect, indigenous Australians use 3.5 times more occupied bed days per 1000 deaths (1509 versus 429 beds per 1000 deaths) and 6 times more occupied bed days per 1000 population (90 versus 15 beds per 1000 population) than their non-indigenous counterparts. The figure of 1509 beds per 1000 deaths (or 4.13 occupied beds per 1000 deaths) for indigenous Australians is indicative of a high level of "acute" nursing care in the last months of life, probably because nursing home care is not readily available due to remoteness. A lack of acute beds in the NT then results in an extremely high average bed occupancy rate with contingent efficiency and delayed access implications., Competing Interests: The author declares no conflict of interest.

Background: The current method for assessing critical care (CCU) bed numbers between countries is unreliable., Methods: A pragmatic method is presented using a logarithmic relationship between CCU beds per 1000 deaths and deaths per 1000 population, both of which are readily available. The method relies on the importance of the nearness to death effect, and on the effect of population size., Results: The method was tested using CCU bed numbers from 65 countries. A series of logarithmic relationships can be seen. High versus low countries can be distinguished by adjusting all countries to a common crude mortality rate. Hence at 9.5 deaths per 1000 population 'high' CCU bed countries average of around 30 CCU beds per 1000 deaths, while 'very low' countries only average 3 CCU beds per 1000 deaths. The United Kingdom falls among countries with low critical care provision with an average of 8 CCU beds per 1000 deaths, and during the COVID-19 epidemic UK industry intervened to rapidly manufacture various types of ventilators to avoid a catastrophe. CCU bed numbers in India are around 8.1 per 1000 deaths, which places it in the low category. However, such beds are inequitably distributed with the poorest states all in the 'very low' category. In India only around 50% of CCU beds have a ventilator., Conclusion: A feasible region is defined for the optimum number of CCU beds., (© 2022 John Wiley & Sons Ltd.)

Unexpected outcomes are usually associated with interventions in complex systems. Excess winter mortality (EWM) is a measure of the net effect of all competing forces operating each winter, including influenza(s) and non-influenza pathogens. In this study over 2400 data points from 97 countries are used to look at the net effect of influenza vaccination rates in the elderly aged 65+ against excess winter mortality (EWM) each year from the winter of 1980/81 through to 2019/20. The observed international net effect of influenza vaccination ranges from a 7.8% reduction in EWM estimated at 100% elderly vaccination for the winter of 1989/90 down to a 9.3% increase in EWM for the winter of 2018/19. The average was only a 0.3% reduction in EWM for a 100% vaccinated elderly population. Such outcomes do not contradict the known protective effect of influenza vaccination against influenza mortality per se-they merely indicate that multiple complex interactions lie behind the observed net effect against all-causes (including all pathogen causes) of winter mortality. This range from net benefit to net disbenefit is proposed to arise from system complexity which includes environmental conditions (weather, solar cycles), the antigenic distance between constantly emerging circulating influenza clades and the influenza vaccine makeup, vaccination timing, pathogen interference, and human immune diversity (including individual history of host-virus, host-antigen interactions and immunosenescence) all interacting to give the observed outcomes each year. We propose that a narrow focus on influenza vaccine effectiveness misses the far wider complexity of winter mortality. Influenza vaccines may need to be formulated in different ways, and perhaps administered over a shorter timeframe to avoid the unanticipated adverse net outcomes seen in around 40% of years.

Trends in excess winter mortality (EWM) were investigated from the winter of 1900/01 to 2019/20. During the 1918-1919 Spanish flu epidemic a maximum EWM of 100% was observed in both Denmark and the USA, and 131% in Sweden. During the Spanish flu epidemic in the USA 70% of excess winter deaths were coded to influenza. EWM steadily declined from the Spanish flu peak to a minimum around the 1960s to 1980s. This decline was accompanied by a shift in deaths away from the winter and spring, and the EWM calculation shifted from a maximum around April to June in the early 1900s to around March since the late 1960s. EWM has a good correlation with the number of estimated influenza deaths, but in this context influenza pandemics after the Spanish flu only had an EWM equivalent to that for seasonal influenza. This was confirmed for a large sample of world countries for the three pandemics occurring after 1960. Using data from 1980 onward the effect of influenza vaccination on EWM were examined using a large international dataset. No effect of increasing influenza vaccination could be discerned; however, there are multiple competing forces influencing EWM which will obscure any underlying trend, e.g., increasing age at death, multimorbidity, dementia, polypharmacy, diabetes, and obesity-all of which either interfere with vaccine effectiveness or are risk factors for influenza death. After adjusting the trend in EWM in the USA influenza vaccination can be seen to be masking higher winter deaths among a high morbidity US population. Adjusting for the effect of increasing obesity counteracted some of the observed increase in EWM seen in the USA. Winter deaths are clearly the outcome of a complex system of competing long-term trends.

Background: Preoperative diagnosis for suspected gallbladder cancers is challenging, with a risk of overtreating benign disease, for example, xanthogranulomatous cholecystitis, with radical cholecystectomies. We retrospectively evaluated the surgeon's intraoperative assessment alone, and with the addition of intraoperative frozen sections, for suspected gallbladder cancers from a tertiary hepatobiliary multidisciplinary team (MDT)., Methods: MDT patients with complex gallbladder disease were included. Collated data included demographics, MDT discussion, operative details, and patient outcomes., Results: A total of 454 patients with complex gallbladder disease were reviewed, 48 (10.6%) were offered radical surgery for suspected cancer. Twenty-five underwent frozen section that led to radical surgery in 6 (25%). All frozen sections were congruent with final histopathology but doubled the operating time (p < 0.0001). Both the surgeon's subjective and additional frozen section's objective assessment, allowed for de-escalation of unnecessary radical surgery, comparing favourably to a 13.0% cancer diagnosis among radical surgery historically., Conclusions: The MDT process was highly sensitive in identifying gallbladder cancers but lacked specificity. The surgeon's intraoperative assessment is paramount in suspected cancers, and deescalated unnecessary radical surgery. Intraoperative frozen section was a safe and viable adjunct at a cost of resources and operative time., (© 2021 The Authors. Journal of Surgical Oncology published by Wiley Periodicals LLC.)

Electrochemotherapy (ECT) is an effective locoregional therapy for cutaneous melanoma metastases and has been safely combined with immune checkpoint inhibitors in preliminary experiences. Since ECT is known to induce immunogenic cell death, its combination with immune checkpoint inhibitors might be beneficial. In this study, we aimed to investigate the effectiveness of ECT on cutaneous melanoma metastases in combination with pembrolizumab. We undertook a retrospective matched cohort analysis of stage IIIC-IV melanoma patients, included in the International Network for sharing practices of ECT (InspECT) and the Slovenian Cancer Registry. We compared the outcome of patients who received the following treatments: (a) pembrolizumab alone, (b) pembrolizumab plus ECT, and (c) ECT. The groups were matched for age, sex, performance status, and size of skin metastases. The local objective response rate (ORR) was higher in the pembrolizumab-ECT group than in the pembrolizumab group (78% and 39%, p < 0.001). The 1 year local progression-free survival (LPFS) rates were 86% and 51% ( p < 0.001), and the 1 year systemic PFS rates were 64% and 39%, respectively ( p = 0.034). The 1 year overall survival (OS) rates were 88% and 64%, respectively ( p = 0.006). Our results suggest that skin-directed therapy with ECT improves superficial tumor control in melanoma patients treated with pembrolizumab. Interestingly, we observed longer PFS and OS in the pembrolizumab-ECT group than in the pembrolizumab group. These findings warrant prospective confirmation.

TLRs, including TLR4, play a crucial role in inflammatory-based diseases, and TLR4 has been identified as a therapeutic target for pharmacological intervention. In previous studies, we investigated the potential of FP7, a novel synthetic glycolipid active as a TLR4 antagonist, to inhibit haematopoietic and non-haematopoietic MyD88-dependent TLR4 pro-inflammatory signalling. The main aim of this study was to investigate the action of FP7 and its derivative FP12 on MyD88-independent TLR4 signalling in THP-1 derived macrophages. Western blotting, Ab array and ELISA approaches were used to explore the effect of FP7 and FP12 on TRIF-dependent TLR4 functional activity in response to LPS and other endogenous TLR4 ligands in THP-1 macrophages. A different kinetic in the inhibition of endotoxin-driven TBK1, IRF3 and STAT1 phosphorylation was observed using different LPS chemotypes. Following activation of TLR4 by LPS, data revealed that FP7 and FP12 inhibited TBK1, IRF3 and STAT1 phosphorylation which was associated with down-regulation IFN-β and IP-10. Specific blockage of the IFN type one receptor showed that these novel molecules inhibited TRIF-dependent TLR4 signalling via IFN-β pathways. These results add novel information on the mechanism of action of monosaccharide FP derivatives. The inhibition of the TRIF-dependent pathway in human macrophages suggests potential therapeutic uses for these novel TLR4 antagonists in pharmacological interventions on inflammatory diseases.

Background: Resection margin status is a known prognosticator in patients who undergo resection for hilar cholangiocarcinoma. However, the influence of an isolated positive circumferential margin on clinical outcome is unclear., Methods: Patients with resected de novo hilar cholangiocarcinoma from two European hepatobiliary centres (Medical University of Vienna and Aintree University Hospital, 2006-2016) were classified according to resection margin status (negative, surgically positive, isolated circumferentially positive) and investigated with respect to overall survival (OS), recurrence-free survival (RFS) and recurrence pattern., Results: Eighty-three (48 male/35 female) patients were enrolled. The median age was 64 years (range 33-80). The median follow-up was 21.7 months (range 0.3-92.4). Forty (48%) patients had negative resection margins, 25 (30%) had an isolated positive circumferential margin and 18 (22%) had a positive surgical margin. The 5-year OS rates in patients with negative, isolated positive circumferential and positive surgical resection margins were 47%, 33% and 0%, respectively. Median OS was 45.6, 32.7 and 14.5 months, respectively (log rank, P = 0.011). Upon multivariable Cox regression analysis, resection margin status and lymph node status remained statistically significant (P < 0.05). No difference with respect to RFS and recurrence pattern was found between the groups (P > 0.05)., Conclusion: Our data show that these three resection margin types were associated with different clinical outcomes. Circumferential margin status may therefore serve as a novel prognostic biomarker.

A new model for hospital bed numbers which adjusts for end-of-life care and age structure is used to demonstrate that England has 20% fewer occupied beds than the other countries in the United Kingdom. It also shows that occupied beds in English Clinical Commissioning Groups (CCGs) lie parallel to a line of equivalence with New Zealand and Singapore. This is despite New Zealand and Singapore having invested many years into developing integrated care, while England has not. In addition, England has around half the number of nursing home beds per death available in these two countries. Large bed reductions proposed in the sustainability and transformation plans were likely to have been manipulated to meet financial cost-saving targets rather than a result of genuine modelling of demand. The ways in which bed demand models can be manipulated to give whatever answer is required are discussed. Trends in occupied acute medical beds in England over the past 20 years show no real reduction, despite a large reduction in available beds. This has resulted in daytime occupancy for adult beds being close to 100% and with resulting queues to admission. The ways to improve the small-area application of the model including the use of deprivation or social groups are discussed., (© 2020 John Wiley & Sons Ltd.)

To investigate the dynamic issues behind intra- and international variation in EWM (Excess Winter Mortality) using a rolling monthly EWM calculation. This is used to reveal seasonal changes in the EWM calculation and is especially relevant nearer to the equator where EWM does not reach a peak at the same time each year. In addition to latitude country specific factors determine EWM. Females generally show higher EWM. Differences between the genders are highly significant and seem to vary according to the mix of variables active each winter. The EWM for respiratory conditions in England and Wales ranges from 44% to 83%, which is about double the all-cause mortality equivalent. A similar magnitude of respiratory EWM is observed in other temperate countries. Even higher EWM can be seen for specific respiratory conditions. Age has a profound effect on EWM with a peak at puberty and then increases EWM at older ages. The gap between male and female EWM seems to act as a diagnostic tool reflecting the infectious/metrological mix in each winter. Difference due to ethnicity are also observed. An EWM equivalent calculation for sickness absence demonstrates how other health-related variables can be linked to EWM. Midway between the equator and the poles show the highest EWM since such areas tend to neglect the importance of keeping dwellings warm in the winter. Pandemic influenza does not elevate EWM, although seasonal influenza plays a part each winter. Pandemic influenza and changes in influenza strain/variant mix do, however, create structural breaks in the time series and this implies that comparing EWM between studies conducted over different times can be problematic. Cancer is an excellent example of the usefulness of rolling method since cancer EWM drifts each year, in some years increasing winter EWM and in other years diminishing it. In addition, analysis of sub-national EWM in the UK reveals high spatiotemporal granularity indicating roles for infectious outbreaks. The rolling method gives greater insight into the dynamic nature of EWM, which otherwise lies concealed in the current static method.

Background: For patients with metastatic colorectal cancer, stratification for treatment (surgery or chemotherapy) is often based on crude clinicopathological characteristics like tumour size and number of lesions. Circulating tumour DNA (ctDNA) acts as a potential biomarker of disease trajectory and biology, allowing better stratification. This study aims to systematically review ctDNA in stage IV colorectal cancer to assess its potential role as a prospective biomarker to guide management decisions., Methods: A literature search was performed to identify studies where the measurement of ctDNA in stage IV colorectal cancer was correlated with a clinical outcome (radiological response, secondary resection rate, PFS, DFS or OS)., Results: Twenty-eight studies were included, reporting on 2823 patients. Circulating tumour DNA was detectable in between 80% and 90% of patients prior to treatment. Meta-analysis identified a strong correlation between detectable ctDNA after treatment (surgery or chemotherapy) and overall survival (HR 2.2, 95% CI 1.79-2.69, p < 0.00001), as well as progression-free survival (HR 3.15, 95% CI 2.10-4.73, p < 0.00001). ctDNA consistently offered an early marker of long-term prognosis in irresectable disease, with changes after one cycle of systemic therapy demonstrating prognostic value. In resectable disease treated with curative intent, detection of ctDNA offered a lead time over radiological recurrence of 10 months., Conclusion: Circulating tumour DNA is detectable in the majority of resectable and irresectable patients. The presence of ctDNA is clearly associated with shorter overall survival, with changes in ctDNA an early biomarker of adverse disease behaviour. Prospective trials are essential to test its clinical efficacy., Competing Interests: Conflict of interest statement The authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

(1) Background: To evaluate the level of hospital bed numbers in U.S. states relative to other countries using a new method for evaluating bed numbers, and to determine if this is sufficient for universal health care during a major Covid-19 epidemic in all states (2) Methods: Hospital bed numbers in each state were compared using a new international comparison methodology. Covid-19 deaths per 100 hospital beds were used as a proxy for bed capacity pressures. (3) Results: Hospital bed numbers show large variation between U.S. states and half of the states have equivalent beds to those in developing countries. Relatively low population density in over half of US states appeared to have limited the spread of Covid-19 thus averting a potential major hospital capacity crisis. (4) Conclusions: Many U.S. states had too few beds to cope with a major Covid-19 epidemic, but this was averted by low population density in many states, which seemed to limit the spread of the virus.

Sudden and unexplained increases in hospital medical admissions and population total deaths have been characterized in the United Kingdom. These sudden increases appear to endure for around 1 to 3 years before they abate. This study demonstrates that the sudden increases in deaths also occur in 125 countries and occur at subnational geographies. The magnitude of the sudden increase diminishes as a power law function up to around 10 000 deaths. Above 10 000 deaths, there is only a small decline with increasing size (deaths). At around 10 000 deaths, a 10% maximum sudden increase applies across many countries or subnational regions. The nearness to death effect, where around half of a person's lifetime hospital admissions occurs in the last 6 months of life, results in higher associated increases in medical admissions. This paper confirms that the use of calendar year data can be misleading. Periods of unexplained higher deaths appear to occur in bursts across multiple countries and appear to show spatial spread within the neighbourhoods which constitute the whole country., (© 2019 John Wiley & Sons, Ltd.)

A simple method is presented to evaluate bed numbers between countries using a logarithmic relationship between beds per 1000 deaths and deaths per 1000 population, both of which are readily available. The method relies on the importance of the nearness to death effect. This method was tested using data from Australian States. Beds per 1000 deaths varied considerably between States. This variation reduced after adjusting for the ratio of deaths per 1000 population which is a measure of population age structure. After this adjustment, most Australian States roughly approximate to the international average for developed countries while Tasmania was shown to have a chronic bed shortage, as has been recognized for many years. The Northern Territory and the Australian Capital Territory, both of which have the youngest populations, have more beds relative to the other States. The nearness to death effect must be incorporated into capacity planning models in order to give robust estimates of future bed demand and to evaluate differences between countries and health care systems., (© 2019 John Wiley & Sons, Ltd.)

Colorectal cancer is the third most commonly diagnosed cancer among both men and women. Personalised treatment options remain complex, although there is broad agreement over which patients with colorectal liver metastases (CRLM) should and should not be offered resection. Decisions on an optimal management strategy involves careful assessment of both technical and oncological factors. In this review we aim to summarise current prognostic biomarkers for metastatic colorectal cancers, specifically patients considered for resection. A number of clinico-pathological factors have been identified as prognostically important with good internal validity, but limited external validity. Furthermore, these prognostic scoring systems do not take factor in modern chemotherapeutic agents and the disease modification these agents produce. Histopathological response to chemotherapy is of significant prognostic importance. Molecular markers can help predict the efficacy of a biological agent. An important prognostic factor of liver metastasis is the recognition that location of the primary colorectal cancer impacts on metastatic phenotype and represents difference in genotype, i.e. proximal tumours are more aggressive than distal tumours with an increased likelihood of disease progression. Several mutational molecular markers identified include microsatellite instability, BRAF, and KRAS/NRAS and combination mutations, which confer poorer outcomes. Accurate prognostication in patients with liver limited colorectal metastases remains crucial, as this allows tailoring treatment options to each disease and improving outcomes. Access to tissue before treatment remains a limitation although advances in ability to assess tumour biology by non-invasive methods are promising., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)

Importance: The patterns of disease recurrence after resection of pancreatic ductal adenocarcinoma with adjuvant chemotherapy remain unclear., Objective: To define patterns of recurrence after adjuvant chemotherapy and the association with survival., Design, Setting, and Participants: Prospectively collected data from the phase 3 European Study Group for Pancreatic Cancer 4 adjuvant clinical trial, an international multicenter study. The study included 730 patients who had resection and adjuvant chemotherapy for pancreatic cancer. Data were analyzed between July 2017 and May 2019., Interventions: Randomization to adjuvant gemcitabine or gemcitabine plus capecitabine., Main Outcomes and Measures: Overall survival, recurrence, and sites of recurrence., Results: Of the 730 patients, median age was 65 years (range 37-81 years), 414 were men (57%), and 316 were women (43%). The median follow-up time from randomization was 43.2 months (95% CI, 39.7-45.5 months), with overall survival from time of surgery of 27.9 months (95% CI, 24.8-29.9 months) with gemcitabine and 30.2 months (95% CI, 25.8-33.5 months) with the combination (HR, 0.81; 95% CI, 0.68-0.98; P = .03). The 5-year survival estimates were 17.1% (95% CI, 11.6%-23.5%) and 28.0% (22.0%-34.3%), respectively. Recurrence occurred in 479 patients (65.6%); another 78 patients (10.7%) died without recurrence. Local recurrence occurred at a median of 11.63 months (95% CI, 10.05-12.19 months), significantly different from those with distant recurrence with a median of 9.49 months (95% CI, 8.44-10.71 months) (HR, 1.21; 95% CI, 1.01-1.45; P = .04). Following recurrence, the median survival was 9.36 months (95% CI, 8.08-10.48 months) for local recurrence and 8.94 months (95% CI, 7.82-11.17 months) with distant recurrence (HR, 0.89; 95% CI, 0.73-1.09; P = .27). The median overall survival of patients with distant-only recurrence (23.03 months; 95% CI, 19.55-25.85 months) or local with distant recurrence (23.82 months; 95% CI, 17.48-28.32 months) was not significantly different from those with only local recurrence (24.83 months; 95% CI, 22.96-27.63 months) (P = .85 and P = .35, respectively). Gemcitabine plus capecitabine had a 21% reduction of death following recurrence compared with monotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .03)., Conclusions and Relevance: There were no significant differences between the time to recurrence and subsequent and overall survival between local and distant recurrence. Pancreatic cancer behaves as a systemic disease requiring effective systemic therapy after resection., Trial Registration: ClinicalTrials.gov identifier: NCT00058201, EudraCT 2007-004299-38, and ISRCTN 96397434.

Background: Successful use of ablation for small hepatocellular carcinomas (HCC) has led to interest in the role of ablation for colorectal liver metastases (CRLM). However, there remains a lack of clarity about the use of ablation for colorectal liver metastases (CRLM), specifically its efficacy compared with hepatic resection. Methods: A systematic review of the literature on ablation or resection of colorectal liver metastases was performed using MEDLINE, Cochrane Library, and Embase until December 2018. The aim of this study was to summarize the evidence for ablation vs. resection in the treatment of CRLM. Results: This review identified 1,773 studies of which 18 were eligible for inclusion. In the majority of the studies, overall survival (OS) and disease-free survival (DFS) were significantly higher and local recurrence (LR) rates were significantly lower in the resection groups. On subgroup analysis of solitary CRLM, resection was associated with improved OS, DFS, and reduced LR. Three series assessed the outcome of resection vs. ablation for technically resectable CRLM, and showed improved outcome in the resection group. In fact, there were no studies showing a survival advantage of ablation compared to resection in the treatment of CRLM. Conclusions: Resection remains the "gold standard" in the treatment of CRLM and should not be replaced by ablation at present. This review supports the use of ablation only as an adjunct to resection and as a single treatment option when resection is not safely possible., (Copyright © 2019 Kron, Linecker, Jones, Toogood, Clavien and Lodge.)