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Unfractionated spleen cells taken from tumor-bearing mice contained tumor-primed T cells which produced lymphokines such as IFN-γ and IL-2 through collaboration with antigen-presenting cells (APC) binding tumor antigens when cultured in vitro. Here, we investigated the regulatory mechanisms underlying IFN-γ production by T-APC interactions. Elimination of B cells from a splenic population of tumor-bearing mice resulted in enhanced IFN-γ production. Adding B cells back into cultures down-regulated IFN-γ production to almost the same levels as those induced by unfractionated spleen cells. IL-2 production was not enhanced by B cell depletion, but rather was significantly suppressed. IFN-γ-selective up-regulation was due to an enhancement of IL-12 production because IL-12 was detected in B cell-depleted cultures and enhanced IFN-γ production was prevented by addition of anti-IL-12 mAb or anti-CD40 ligand (CD40L) mAb capable of inhibiting CD401L-induced IL-12 production. These results indicate that B cells interfere with IFN-γ production induced through interactions between anti-tumor T cells and APC, and this suppressive effect is based on the capacity of CD40+ B cells to down-regulate the CD40L-induced IL-12 production by APC. [ABSTRACT FROM PUBLISHER]

Introduction: The aim of the study was to evaluate whether C reactive protein level (CRP) on admission could aid the diagnostic accuracy of Alvarado score in acute appendicitis. Patients and methods : 233 patients (males 115, females 118, median age 28 years, range 15–87 years) who underwent appendicectomy were evaluated. Methods: Patients were categorized in to 3 groups retrospectively based on the Alvarado score. Group I: score 7–10 (n = 154), Group II: score 4–6 (n = 66), Group III: score < 3 (n = 13). Negative (NPV) and positive predictive values (PPV) of CRP which was performed at the time of admission was calculated. Results: Overall, 169 of 233 (72.5%) had histopathological confirmation of acute appendicitis. In Group I it was 134 patients (87%), Group II: 35 patients (53%) and none of patients in Group III. NPV and PPV for Group I was 29.6% and 85.5%, Group II was 65% and 80% respectively. Conclusion: The CRP level improves the predictive value of diagnosing acute appendicitis in the equivocal group of Alvarado 4–6. Patients in this group with a normal CRP should be further investigated before proceeding to appendicectomy. [ABSTRACT FROM AUTHOR]

Background: Limited evidence suggests that positive experiences in childhood may promote cardiovascular health, providing additional opportunities for prevention and early intervention. This study aimed to examine the effects of adverse and positive experiences on cardiovascular health in late childhood., Methods: Data sources: Longitudinal Study of Australian Children (N = 1874)., Exposures: Adverse and positive experiences assessed repeatedly (age 0-11 years)., Outcomes: Cardiovascular health (high versus low or moderate) quantified by four health behaviors (diet, physical activity, cigarette smoking, and sleep) and four health factors (body mass index, non-high-density lipoprotein, blood pressure, and blood glucose) (age 11-12 years) as per the American Heart Association's Life's Essential 8 metrics., Analyses: Separate generalized linear models with log-Poisson links were used to estimate the effects of adverse and positive experiences on cardiovascular health, adjusting for confounders., Results: Children exposed to multiple adverse experiences (≥ 2) were less likely to have high cardiovascular health (RR = 0.82, 95% CI = 0.67 to 1.02) than those not exposed. Children exposed to multiple positive experiences (≥ 2) were more likely to have high cardiovascular health (RR = 1.14, 95% CI = 0.94 to 1.38) than those not exposed. Stratified analyses suggested that exposure to multiple positive experiences might buffer the detrimental effects of multiple adverse experiences on cardiovascular health., Conclusions: Both adverse and positive experiences were found to be modestly associated with cardiovascular health in Australian children. Future research and practice should not only consider addressing childhood adversity but also use a strengths-based approach to promoting positive experiences to improve cardiovascular health., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Australian guidelines recommend that people aged 50-70 years consider taking low-dose aspirin to reduce their risk of colorectal cancer (CRC)., Aim: To determine the effect of a consultation with a researcher before an appointment in general practice using a decision aid presenting the benefits and harms of taking low-dose aspirin compared with a general CRC prevention brochure on patients' informed decision making and low-dose aspirin use., Design and Setting: Individually randomised controlled trial in six general practices in Victoria, Australia, from October 2020 to March 2021., Method: Participants were recruited from a consecutive sample of patients aged 50-70 years attending a GP. The intervention was a consultation using a decision aid to discuss taking aspirin to reduce CRC risk while control consultations discussed reducing CRC risk generally. Self-reported co-primary outcomes were the proportion of individuals making informed choices about taking aspirin at 1 month and on low-dose aspirin uptake at 6 months, respectively. The intervention effect was estimated using a generalised linear model and reported with Bonferroni-adjusted 95% confidence intervals (CIs) and P -values., Results: A total of 261 participants (86% of eligible patients) were randomised into trial arms ( n = 129 intervention; n = 132 control). Of these participants, 17.7% ( n = 20/113) in the intervention group and 7.6% ( n = 9/118) in the control group reported making an informed choice about taking aspirin at 1 month, an estimated 9.1% (95% CI = 0.29 to 18.5) between-arm difference in proportions (odds ratio [OR] 2.47, 97.5% CI = 0.94 to 6.52, P = 0.074). The proportions of individuals who reported taking aspirin at 6 months were 10.2% ( n = 12/118) of the intervention group versus 13.8% ( n = 16/116) of the control group, an estimated between-arm difference of -4.0% (95% CI = -13.5 to 5.5; OR 0.68 [97.5% CI = 0.27 to 1.70, P = 0.692])., Conclusion: The decision aid improved informed decision making but this did not translate into long-term regular use of aspirin to reduce CRC risk. In future research, decision aids should be delivered alongside various implementation strategies., (© The Authors.)

Background: Infant feeding guidelines in Australia changed in 2016 to recommend introducing common allergy-causing foods by age 1 year to prevent food allergy. Although most Australian infants now eat peanut and egg by age 6 months, some still develop food allergy despite the early introduction of allergens., Objectives: To describe the prevalence of food allergy in a cohort recruited after introducing the nationwide allergy prevention recommendations; identify characteristics of infants who developed allergy despite early introduction of allergens; and estimate the causal effect of modifiable exposures on food allergy prevalence and whether this differed between infants who were introduced to allergens before or after age 6 months., Methods: We recruited a population-based sample of 12-month-old infants in Melbourne, Australia. Infants had skin prick tests to four foods and parents completed questionnaires. Infants with evidence of sensitization were offered oral food challenges. Prevalence estimates were adjusted using inverse probability weighting., Results: In a cohort of infants (n = 1,420) in which nearly all infants had been introduced to common allergens such as egg, milk, and peanut by age 1 year, the prevalence of food allergy remained high at 11.3% (95% CI, 9.6-13.4). Infants who developed food allergy despite introduction of the allergen by age 6 months were more likely to have Asian-born parents. Early-onset moderate or severe eczema was associated with an increased odds of food allergy irrespective of whether allergens were introduced before or after age 6 months. Among infants who were introduced to peanut at age 6 months or earlier, antibiotic use by age 6 months was associated with an increased odds of peanut allergy (adjusted odds ratio = 6.03; 95% CI, 1.15-31.60)., Conclusions: In a cohort in which early allergen introduction was common, the prevalence of food allergy remained high. Infants who developed food allergy despite introduction of the respective allergen by age 6 months were more likely to have had Asian parents and early-onset eczema. New interventions are needed for infants with a phenotype of food allergy that is not amenable to early allergen introduction., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Gallbladder polyps are increasingly being identified due to the widespread use of abdominal ultrasound imaging. They are concerning lesions due to their potential malignant risk. It is hoped that managing them correctly will play a role in improving poor survival rates of gallbladder cancer. Awareness of these lesions is lacking. Management continues to be guided by expert opinion and observational studies and a number of consensus statements exist., Objective: This paper reviews and summarises the current literature and provides an approach for general practitioners based on the available guidance., Discussion: Although minor variation exists between consensus statements, the risk of malignancy for gallbladder polyps is still largely dictated by size, with those ≤5 mm generally considered to pose little risk and not requiring follow-up, whereas those ≥10 mm considered at greater risk and requiring referral for cholecystectomy.

Background: There are limited longitudinal data on the population prevalence of allergic conditions during childhood, and few studies have incorporated the reference standard oral food challenge to confirm food allergy., Objective: To describe the population prevalence of IgE-mediated food allergy, eczema, asthma, and rhinitis at ages 6 and 10 years in Melbourne, Australia., Methods: The HealthNuts study recruited 5,276 1-year-old infants in Melbourne, Australia, with repeat assessments at ages 6 and 10 years. At ages 6 and 10 years, carers completed a questionnaire on symptoms and doctor diagnosis of allergic conditions (International Study of Asthma and Allergies in Children). Children were invited to attend a clinic assessment including skin prick test, lung function tests, and oral food challenges when indicated. To minimize the impact of attrition bias, prevalence estimates among participants at ages 6 and 10 years were weighted to reflect characteristics of the whole cohort at recruitment., Results: In total, 4,455 and 4,065 families participated at ages 6 and 10 years, respectively (84% and 77% of the original cohort). Of those, 73% and 55% of participants ages 6 and 10 years, respectively, completed clinical assessments. Overall, 36.5% (95% CI, 34.8-38.2) and 38.2% (95% CI, 36.5-40.1%) of 6- and 10-year-olds had at least one current allergic disease, and around one third of those had two or more allergic diseases. Food allergy occurred in 6.4% (95% CI, 5.6-7.2) of 6-year olds and 6.3% (95% CI, 5.5-7.2) of 10-year-olds. Among infants with challenge-confirmed food allergy in infancy, 45% had persistent disease at age 10 years. The prevalence of current diagnosed asthma at ages 6 and 10 years were 12.1% (95% CI, 10.9-13.3) and 13.1% (95% CI, 11.9-14.4), respectively, current eczema decreased slightly from 15.3% (95% CI, 14.1-19.7) at age 6 years to 12.9% (95% CI, 11.7-14.2) at age 10 years, and current rhinitis increased from 15.1% (95% CI, 13.9-16.5) at age 6 years to 25.0% (95% CI, 23.4-26.7) at age 10 years., Conclusions: Allergic diseases affect 40% of primary school-age children; one third have multiple allergic diagnoses. Challenge-confirmed food allergy prevalence remains high, and 45% of infants with food allergy have persistent disease to age 10 years., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: There are no studies of longitudinal immunoglobulin measurements in a population-based cohort alongside challenge-confirmed peanut allergy outcomes. Little is known about biomarkers for identifying naturally resolving peanut allergy during childhood., Objectives: To measure longitudinal trends in whole peanut and component Ara h 2 sIgE and sIgG 4 in the first 10 years of life, in a population cohort of children with challenge-confirmed peanut allergy, and to determine whether peanut-specific immunoglobulin levels or trends are associated with peanut allergy persistence or resolution by 10 years of age., Methods: One-year-old infants with challenge-confirmed peanut allergy (n = 156) from the HealthNuts study (n = 5276) were prospectively followed at ages 4, 6, and 10 years with questionnaires, skin prick tests, oral food challenges, and plasma total-IgE, sIgE and sIgG 4 to peanut and Ara h 2., Results: Peanut allergy resolved in 33.9% (95% CI = 25.3%, 43.3%) of children by 10 years old with most resolving (97.4%, 95% CI = 86.5%, 99.9%) by 6 years old. Decreasing Ara h 2 sIgE (p = .01) and increasing peanut sIgG 4 (p < .001), Ara h 2 sIgG 4 (p = .01), peanut sIgG 4 /sIgE (p < .001) and Ara h 2 sIgG 4 /sIgE (p < .001) from 1 to 10 years of age were associated with peanut allergy resolution. Peanut sIgE measured at 1 year old had the greatest prognostic value (AUC = 0.75 [95% CI = 0.66, 0.82]); however, no single threshold produced both high sensitivity and specificity., Conclusion: One third of infant peanut allergy resolved by 10 years of age. Decreasing sIgE and sIgG 4 to peanut and Ara h 2 over time were associated with natural resolution of peanut allergy. However, biomarker levels at diagnosis were not strongly associated with the natural history of peanut allergy., (© 2024 European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Background Up to 15% of patients with cholelithiasis have choledocholithiasis, with almost 10% not detected pre-operatively. Our study aims to quantify the prevalence of incidental choledocholithiasis during routine intra-operative cholangiogram (IOC), identify the best management pathway, and identify reliable pre-operative factors to predict choledocholithiasis. Methods We conducted a single-centre, retrospective cohort study at St John of God Midland Hospital in Western Australia, Perth, on 880 consecutive patients who underwent cholecystectomies performed by 15 surgeons between January 2, 2020, and December 30, 2021.  Results The overall choledocholithiasis rates were 10.6% (93), with 4.0% (35) diagnosed pre-operatively and 6.6% (58) diagnosed during IOC. In all, 50% of incidental choledocholithiasis during IOC were managed with hyoscine butylbromide, with a 55.2% success rate; 22.4% of patients received octreotide, with a 61.5% success rate; and 8.6% of patients underwent trans-cystic bile duct exploration (TCBE) and 8.6% underwent postoperative endoscopic retrograde cholangiopancreatography (ERCP), both with 100% success rates. Choledocholithiasis most commonly presents with gallstone pancreatitis, with a median aspartate aminotransferase (AST) level 7.2 times and alanine transaminase (ALT) level 7.8 times higher than those of patients without choledocholithiasis. Magnetic resonance cholangiopancreatography (MRCP) was the most sensitive in identifying choledocholithiasis with a 66.7% pickup rate. The median common bile duct (CBD) diameter on ultrasound was 8 mm, computerised tomography scans were 11 mm, and MRCP was 9 mm. Conclusion One in 10 cholecystectomies will be complicated with choledocholithiasis, and over half will be incidentally diagnosed during routine IOC. We propose IOC in all cases and hyoscine butylbromide, octreotide, and saline flushes as first-line treatment; if unsuccessful, TCBE is performed. Gallstone pancreatitis, markedly elevated AST/ALT, and imaging showing CBD ≥8 mm may serve as early predictors of choledocholithiasis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Tan et al.)

Whilst obesity and visceral adipose tissue (VAT) have been reported to be associated with an increased risk of severe AP, the established predictive scoring systems have not yet encompassed the impact of obesity or visceral adiposity. In the acute setting, computed tomography (CT) is often performed to assess AP severity and associated complications. With the added benefit of quantifying body fat distribution, it can be opportunistically used to quantify visceral adiposity and assess its relationship with the course of AP. This systematic review identified fifteen studies evaluating the relationship between visceral adiposity measured on CT and the severity of presentations of acute pancreatitis from January 2000 to November 2022. The primary outcome was to assess the relationship between CT quantified VAT and AP severity. The secondary outcomes were to assess the impact of VAT on patients developing local and systemic complications associated with AP. Whilst ten studies showed there was a significant correlation between an increased VAT and AP severity, five studies found otherwise. The majority of current literature demonstrate a positive correlation between increased VAT and AP severity. CT quantification VAT is a promising prognostic indicator with the potential to guide initial management, prompt more aggressive treatment measures or earlier re-evaluation and to aid disease prognostication in patients with acute pancreatitis., (© 2023. The Author(s) under exclusive licence to Japan Radiological Society.)

Background: Food allergy is considered a precursor to asthma in the context of the atopic march, but the relationship between infant food allergy phenotypes and lung function and asthma in childhood is unclear. We aimed to examine the association between food sensitisation and challenge-confirmed food allergy in infancy, as well as persistent and resolved food allergy up to age 6 years, and the risk of lung function deficits and asthma at age 6 years., Methods: The longitudinal, population-based HealthNuts cohort study in Melbourne, VIC, Australia, recruited 5276 infants children aged 1 year who attended council-run immunisation sessions between Sept 28, 2007, and Aug 5, 2011. At age 1 year, all children completed skin prick testing to four food allergens (egg, peanut, sesame, and either shrimp or cow's milk) and an oral food challenge (egg, peanut, and sesame) at the Royal Children's Hospital in Melbourne. Parents completed questionnaires about their infant's allergy history, demographic characteristics, and environmental exposures. At age 6 years, children were invited for a health assessment that included skin prick testing for ten foods (milk, egg, peanut, wheat, sesame, soy, shrimp, cashew, almond, and hazelnut) and eight aeroallergens (alternaria, cladasporum, house dust mite, cat hair, dog hair, bermuda grass, rye grass, and birch mix), oral food challenges, and lung function testing by spirometry. Questionnaires completed by parents (different to those completed at age 1 year) captured the child's allergy and respiratory history and demographics. We investigated associations between food allergy phenotypes (food-sensitised tolerance or food allergy; and ever, transient, persistent, or late-onset food allergy), lung function spirometry measures (forced expiratory volume in 1 sec [FEV 1 ] and forced vital capacity [FVC] z-scores, FEV 1 /FVC ratio, forced expiratory flow at 25% and 75% of the pulmonary volume [FEF 25-75% ], and bronchodilator responsiveness), and asthma using regression methods. Only children with complete data on the exposure, outcome, and confounders were included in models. Infants without food sensitisation or food allergy at age 1 year and 6 years served as the reference group., Findings: Of 5276 participants, 3233 completed the health assessment at age 6 years and were included in this analysis. Food allergy, but not food-sensitised tolerance, at age 1 year was associated with reduced FEV 1 and FVC (aβ -0·19 [95% CI -0·32 to -0·06] and -0·17 [-0·31 to -0·04], respectively) at age 6 years. Transient egg allergy was associated with reduced FEV 1 and FVC compared with never having egg allergy (-0·18 [95% CI -0·33 to -0·03] and -0·15 [-0·31 to 0·00], respectively), whereas persistent egg allergy was not (FEV 1 -0·09 [-0·48 to 0·31]; FVC -0·20 [-0·62 to 0·21]). Transient peanut allergy was associated with reduced FEV 1 and FVC (FEV 1 aβ -0·37 [-0·79 to 0·04] and FVC aβ -0·55 [-0·98 to -0·12]), in addition to persistent peanut allergy (FEV 1 aβ -0·30 [-0·54 to -0·06] and FVC aβ-0·30 [-0·55 to -0·05]), and late-onset peanut allergy (FEV 1 aβ -0·62 [-1·06 to -0·18] and FVC aβ-0·49 [-0·96 to -0·03]). Estimates suggested that food-sensitised tolerance and food allergy were associated with reduced FEF 25-75% , although some estimates were imprecise. Food allergy phenotypes were not associated with an FEV 1 /FVC ratio. Late-onset peanut allergy was the only allergy phenotype that was possibly associated with increased risk of bronchodilator responsiveness (2·95 [95% CI 0·77 to 11·38]). 430 (13·7%) of 3135 children were diagnosed with asthma before age 6 years (95% CI 12·5-15·0). Both food-sensitised tolerance and food allergy at age 1 year were associated with increased asthma risk at age 6 years (adjusted odds ratio 1·97 [95% CI 1·23 to 3·15] and 3·69 [2·81 to 4·85], respectively). Persistent and late-onset peanut allergy were associated with higher asthma risk (3·87 [2·39 to 6·26] and 5·06 [2·15 to 11·90], respectively)., Interpretation: Food allergy in infancy, whether it resolves or not, is associated with lung function deficits and asthma at age 6 years. Follow-up studies of interventions to prevent food allergy present an opportunity to examine whether preventing these food allergies improves respiratory health., Funding: National Health & Medical Research Council of Australia, Ilhan Food Allergy Foundation, AnaphylaxiStop, the Charles and Sylvia Viertel Medical Research Foundation, the Victorian Government's Operational Infrastructure Support Program., Competing Interests: Declaration of interests MLKT has received research funding from Prota Therapeutics, is an employee of Prota Therapeutics, has received consultancy fees from Pfizer, and is an inventor on patents owned by MCRI “A method for of inducing tolerance to an allergen” and “Allergy Treatment”. KPP is Chair of the scientific advisory board for AllergyPal; has received research grants from DBV Technologies, Novartis, Aravax, and Siolta; and consultant fees from Aravax, outside of the submitted work, paid to their institution. SCD, CJL, and AJL received investigator-initiated grants from GSK for unrelated work. AJL, SCD, and JJK have received grant funding from Sanofi Regeneron for unrelated research. AJL has received in kind contributions of study intervention (EpiCeram) from Primus Pharmaceuticals for unrelated research. RLP receives honoraria for editorial involvement with the journal Paediatric Allergy and Immunology. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Majority of adhesive small bowel obstruction (SBO) cases can be managed non-operatively. However, a proportion of patients failed non-operative management., Aim: To evaluate the predictors of successful non-operative management in adhesive SBO., Methods: A retrospective study was performed for all consecutive cases of adhesive SBO from November 2015 to May 2018. Data collated included basic demographics, clinical presentation, biochemistry and imaging results and management outcomes. The imaging studies were independently analyzed by a radiologist who was blinded to the clinical outcomes. The patients were divided into group A operative (including those that failed initial non-operative management) and group B non-operative for analysis., Results: Of 252 patients were included in the final analysis; group A ( n = 90) (35.7%) and group B ( n = 162) (64.3%). There were no differences in the clinical features between both groups. Laboratory tests of inflammatory markers and lactate levels were similar in both groups. From the imaging findings, the presence of a definitive transition point [odds ratio (OR) = 2.67, 95% confidence interval (CI): 0.98-7.32, P = 0.048], presence of free fluid (OR = 2.11, 95%CI: 1.15-3.89, P = 0.015) and absence of small bowel faecal signs (OR = 1.70, 95%CI: 1.01-2.88, P = 0.047) were predictive of the need of surgical intervention. In patients that received water soluble contrast medium, the evidence of contrast in colon was 3.83 times predictive of successful non-operative management (95%CI: 1.79-8.21, P = 0.001)., Conclusion: The computed tomography findings can assist clinicians in deciding early surgical intervention in adhesive SBO cases that are unlikely to be successful with non-operative management to prevent associated morbidity and mortality., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article. Dr Zi Qin Ng received the General Surgeons Australia Junior Doctor Research Grant in 2018 for this study., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: There are limited longitudinal studies on the effects of the COVID-19 pandemic on mental health and well-being, including the effects of imposed restrictions and lockdowns., Aims: This study investigates how living in a pandemic, and related lockdowns and restrictions, affected the mental health of people living in Australia during the first year of the COVID-19 pandemic., Method: A total of 875 people living in Australia participated in a longitudinal survey from 27 May to 14 December 2020. This time period includes dates that span pre-, during and post-wave 2 lockdowns in Australia, with strict and sustained public health measures. Linear mixed models were fitted to investigate the effect of lockdown on depression and anxiety symptoms., Results: Symptoms of depression and anxiety improved over time, during and after lockdowns. More adverse mental health symptoms were observed for people with a history of medical or mental health problems, caring responsibilities, more neurotic personality traits or less conscientiousness, and for people who were younger. People who reported being more conscientious reported better mental health., Conclusions: Despite notoriously strict lockdowns, participants did not experience a deterioration of mental health over time. Results suggest a lack of significant adverse effects of lockdown restrictions on mental health and well-being. Findings highlight cohorts that could benefit from targeted mental health support and interventions, so that public policy can be better equipped to support them, particularly if future strict public health measures such as lockdowns are being considered or implemented for the COVID-19 pandemic and other disasters.

Background Unplanned readmission to the hospital after discharge is a costly issue for healthcare systems and patients. It is a delicate balance between the resolution of the surgical problem and the length of hospital stay. Most studies have focused on readmissions within 28 or 30 days after discharge, despite data showing that many occur early in this period. This study examined the reasons for unplanned readmission within the first day after discharge.  Methods A retrospective cohort analysis of readmissions between 1st May 2016 and 1st May 2021 was undertaken by chart review. Readmissions on the "day of" and the "day after" discharge and their respective index admissions were identified via the hospital's patient administration database, webPAS (DXC Technology, USA). Results There were 126 readmissions (0.5%) across 25,119 admissions. Common reasons for readmission were pain (28%, n=35), readmission for the same diagnosis (21%, n=26), surgical site infection (SSI) (11%, n=14), bleeding (11%, n=14) and ileus (6%, n=7). Analysis of index admissions showed that 18/35 readmissions for pain had inadequate pain management based on pain scores, analgesic use and discharge medications and 7/14 readmissions for SSI did not have appropriate treatment of a recognised SSI or did not have antibiotic prophylaxis guidelines adhered to. Fourteen of 26 readmissions for the same diagnosis received just continuation of treatment initiated at index admission.  Conclusion Pain is the most common reason for readmission within the first day after discharge in surgical patients. Better pain management, following antibiotic prophylaxis guidelines, and involving patients in discharge planning could prevent many readmissions., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Chidambaram et al.)

Three-level data structures arising from repeated measures on individuals clustered within larger units are common in health research studies. Missing data are prominent in such studies and are often handled via multiple imputation (MI). Although several MI approaches can be used to account for the three-level structure, including adaptations to single- and two-level approaches, when the substantive analysis model includes interactions or quadratic effects, these too need to be accommodated in the imputation model. In such analyses, substantive model compatible (SMC) MI has shown great promise in the context of single-level data. Although there have been recent developments in multilevel SMC MI, to date only one approach that explicitly handles incomplete three-level data is available. Alternatively, researchers can use pragmatic adaptations to single- and two-level MI approaches, or two-level SMC-MI approaches. We describe the available approaches and evaluate them via simulations in the context of three three-level random effects analysis models involving an interaction between the incomplete time-varying exposure and time, an interaction between the time-varying exposure and an incomplete time-fixed confounder, or a quadratic effect of the exposure. Results showed that all approaches considered performed well in terms of bias and precision when the target analysis involved an interaction with time, but the three-level SMC MI approach performed best when the target analysis involved an interaction between the time-varying exposure and an incomplete time-fixed confounder, or a quadratic effect of the exposure. We illustrate the methods using data from the Childhood to Adolescence Transition Study., (© 2021 The Authors. Biometrical Journal published by Wiley-VCH GmbH.)

Three-level data arising from repeated measures on individuals clustered within higher-level units are common in medical research. A complexity arises when individuals change clusters over time, resulting in a cross-classified data structure. Missing values in these studies are commonly handled via multiple imputation (MI). If the three-level, cross-classified structure is modeled in the analysis, it also needs to be accommodated in the imputation model to ensure valid results. While incomplete three-level data can be handled using various approaches within MI, the performance of these in the cross-classified data setting remains unclear. We conducted simulations under a range of scenarios to compare these approaches in the context of an acute-effects cross-classified random effects substantive model, which models the time-varying cluster membership via simple additive random effects. The simulation study was based on a case study in a longitudinal cohort of students clustered within schools. We evaluated methods that ignore the time-varying cluster memberships by taking the first or most common cluster for each individual; pragmatic extensions of single- and two-level MI approaches within the joint modeling (JM) and the fully conditional specification (FCS) frameworks, using dummy indicators (DI) and/or imputing repeated measures in wide format to account for the cross-classified structure; and a three-level FCS MI approach developed specifically for cross-classified data. Results indicated that the FCS implementations performed well in terms of bias and precision while JM approaches performed poorly. Under both frameworks approaches using the DI extension should be used with caution in the presence of sparse data., (© 2022 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Introduction and Importance: Endoscopic foreign body retrieval in the upper gastrointestinal tract is well established, however indications for endoscopy for retained foreign bodies in the lower gastrointestinal tract and specifically the right colon is still being navigated [3]. A PubMed and Google Scholar search discovered a variety of case reports detailing various methods and indications for endoscopic retrieval of right sided colonic foreign bodies. This case report endeavors to supplement the literature so that guidelines can one day be established for colonoscopic retrieval of right-sided foreign bodies., Case Presentation: 36-year-old male prisoner swallowed 6.5 cm nail clippers with a long-standing history of intentional foreign body ingestion (FBI) including multiple laparotomies for foreign body retrievals. Computerized tomography (CT) was used initially to confirm the position of the nail clippers. After almost two weeks of failure of the foreign body (FB) to move beyond the caecum as demonstrated on plain abdominal X-rays, the patient had a colonoscopy with successful retrieval of the FB., Clinical Discussion: This case report hopes to encourage the consideration of colonoscopy for retrieval of right sided colonic foreign bodies that have failed to pass on their own and where an operation may come with increased risk (multiple laparotomies, multiple comorbidities, and higher anaesthetic risk for a general anaesthetic). Colonoscopy/endoscopy still has inherent risk and this patient did have an episode of temporary laryngospasm that required intubation and monitoring in the intensive care unit post operatively. Despite this the patient recovered and was discharged day one post procedure without further complication. The case report has been reported in line with the SCARE 2020 criteria (Agha et al., 2020 [2])., Conclusion: Indications for consideration of endoscopic retrieval of foreign bodies in the right colon have not been entirely detailed as endoscopy is for upper gastrointestinal foreign bodies. This case report documents the indications for endoscopy in the clinical context of a recurrent FBI and a history of multiple laparotomies with failure of the FB to move beyond the caecum., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

The aim of this study was to systematically review the feasibility and safety of non-operative management of small bowel obstruction (SBO) in virgin abdomen. A systematic review was performed through December 2019. The primary outcome was the resolution of non-operative management of SBO in virgin abdomen. Secondary outcomes were the etiology of SBO and findings of exploratory laparotomy. Six studies were included in the analysis. Of the 442 patients, 2 with metastatic cancer received palliative care, and the management in 26 was not reported, so these patients were excluded. A total of 414 patients were ultimately analyzed, including 203 patients (49%) who were managed non-operatively and 211 (51%) who underwent surgical management. Of the 203 managed non-operatively, the condition of 194 (96%) was resolved without further intervention. The remaining 9 (5%) patients failed non-operative management and ultimately required surgery. Of the 211 patients who underwent surgical exploration, only 137 had their intraoperative findings reported. Adhesions (n = 67; 49%) were the main cause, followed by malignancy (n = 14; 10%) and others (n = 33; 24%). No cause was found in 23 patients (17%). In highly select cases of SBO with virgin abdomen, non-operative management can be attempted if patients are clinically stable and computed tomography does not demonstrate concerning features or obvious pathology. Further well-designed prospective studies will be required prior to the introduction of this concept in clinical practice, as current evidence remains heterogeneous., (© 2021. Springer Nature Singapore Pte Ltd.)

Background: Diverticular disease has been linked to obesity. Recent studies have assessed the role of visceral adiposity with diverticulitis and its complications. The aim of this study was to evaluate the association of quantitative radiological measures of visceral adiposity in patients with diverticulitis with vital signs, biochemistry results, uncomplicated versus complicated diverticulitis and its interventions., Methods: A retrospective analysis of all patients with diverticulitis admitted from November 2015 to April 2018 at a single institution was performed. Data collected included demographics, vital signs, biochemistry results, CT scan findings and management outcomes. The patients were divided into uncomplicated (U) and complicated diverticulitis (C) groups. Visceral fat area (VFA), subcutaneous fat area (SFA) and VFA/SFA ratio (V/S) were measured at L4/L5 level by the radiologist. Statistical analysis was performed to evaluate the association of VFA, SFA, V/S with the parameters in both U and C groups., Results: 352 patients were included in this study (U:C = 265:87). There was no significant difference in vital signs and biochemistry results in both groups. There was no significant difference in VFA, SFA, V/S ratios in both groups. In patients with V/S ratio > 0.4, they were 5.06 times more likely to undergo emergency intervention (95% CI 1.10-23.45) (p = 0.03). On multivariate analysis, a heart rate > 100 (OR 2.9, 95% CI 1.2-6.7), CRP > 50 (OR 3.4, 95% CI 1.9-6.0), WCC < 4 or > 12 (OR 2.1, 95% CI 1.2-3.6) and V/S ratio > 0.4 (OR 2.8, 95% CI 1.5-5.4) were predictive of complicated diverticulitis., Conclusion: The quantitative radiological measurement of visceral adiposity is useful in prognostication in patients presenting with diverticulitis.

There is considerable evidence to suggest that individuals with mental illness as well as their carers and families are discriminated against across a number of domains. It is also well recognized that people with mental illness are likely to die younger than their counterparts who do not have mental illness. We propose that a Magna Carta is urgently needed to protect the rights of people with mental illness and help reduce discrimination. In this paper a background and rationale for this is offered alongside suggestions for reducing discrimination. The simple message is this; progress in health, economic, environmental and global development will not be made without improvements in mental health. The reasons are equally straightforward as mental illnesses cause more disability than any other health condition and bring enormous pain and suffering to individuals, their families and communities. These impacts lead to early death, damage to the economy and restrain individual progress. Every country needs to take urgent responsibility for defending the rights of individuals with mental illness.

Background and Aim: Appendicitis after colonoscopy is an exceedingly rare complication. It remains to be explored if this entity is truly a complication of colonoscopy or a coincidental occurrence of appendicitis post-colonoscopy. The aim of this study was to systematically review all the available evidence since it was first described in 1988., Methods: The literature on post-colonoscopy appendicitis was searched using PubMed, EMBASE, and Cochrane databases. Additional manual search was performed and cross-checked for additional references. The search was performed up to November 2019. Data collected included demographics, reason for colonoscopy, time to diagnosis, imaging performed, management, and outcome., Results: Fifty-three cases were found in the systematic review with a median age of 55 years (24-84 years). The time to diagnosis post-colonoscopy was mostly within 24-48 h. Clinical features mimicked those of common acute appendicitis. In the past decade, computed tomography scan has been the imaging choice to investigate abdominal pain after colonoscopy, mainly to rule out perforation. The mainstay of management was appendectomy (open or laparoscopy). Four of the 12 cases (33.3%) were treated successfully with antibiotics alone. There has been a twofold increase in cases reported in the past decade (2009-2019, n = 31 vs 1999-2008, n = 15)., Conclusion: There is a considerable variation in the definition of post-colonoscopy appendicitis in the current literature. Regardless of whether post-colonoscopy appendicitis is a true entity, it should be considered as a differential diagnosis in any patient presenting with acute abdomen following colonoscopy., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Recent evidence suggested that radiological measures of visceral adiposity are a better tool for risk assessment of colorectal adenomas. The aim of this study was to investigate the association of visceral adiposity with the development of colorectal adenomas., Methods: A retrospective review of all cases of computed tomography-confirmed acute diverticulitis from November 2015 to April 2018 was performed. Data collated included basic demographics, computed tomography scan results (uncomplicated versus complicated diverticulitis), treatment modality (conservative versus intervention), outcomes and follow-up colonoscopy results within 12 months of presentation. The patients were divided into no adenoma (A) and adenoma (B) groups. Visceral fat area (VFA), subcutaneous fat area (SFA) and VFA/SFA ratio (V/S) were measured at L4/L5 level. Statistical analysis was performed to evaluation the association of VFA, SFA, V/S and different thresholds with the risk of adenoma formation., Results: A total of 169 patients were included in this study (A:B = 123:46). The mean ± standard deviation for VFA was higher in group B (201 ± 87 cm 2 versus 176 ± 79 cm 2 ) with a trend towards statistical significance (P = 0.08). There was no difference in SFA and V/S in both groups. When the VFA >200 cm 2 was analysed, it was associated with a threefold risk of adenoma formation (odds ratio 2.7, 95% confidence interval 1.35-5.50, P = 0.006). Subgroup analysis of gender with VFA, SFA and V/S found that males have a significantly higher VFA in group B (220.0 ± 95.2 cm 2 versus 187.3 ± 69.2 cm 2 ; P = 0.05)., Conclusions: The radiological measurement of visceral adiposity is a useful tool for opportunistic assessment of risk of colorectal adenoma., (© 2020 Royal Australasian College of Surgeons.)

Background: Carcinoid tumours of the appendix are the most common primary malignant lesion of the appendix. However, the overall incidence remains low; found in as few as 0.3-0.9% appendicectomy specimens. Almost all appendiceal carcinoids are found incidentally during surgery for suspected appendicitis., Methods: A retrospective review of all appendiceal carcinoids was performed in six hospitals from January 1990 until December 2013. Demographic data, operative technique, histopathological characteristics, clinic reviews and need for further treatment were recorded and compared with literature., Results: Appendiceal carcinoids were identified in 175 specimens. The mean age is 32 years (range 8-87 years), with 69 (39.4%) males and 106 (60.6%) females (P < 0.0001). Of these, 106 underwent open surgery with standard McBurney incision, nine underwent full laparotomy and 60 underwent laparoscopic surgery. Six of the laparoscopic surgeries were converted to open procedures. We recorded 159 (90.75%) classical carcinoids and 16 (9.25%) goblet cell carcinoids. Overall, 131 (75.7%) had concurrent appendicitis; classical carcinoid 72.6% versus goblet cell carcinoid 93.8%. The median size of the goblet cell carcinoids was significantly larger than classical carcinoids. Classical carcinoids were mostly distal to the base, while goblet cell carcinoids had equal distribution. It appears that the involvement of resection margins was not influenced by the surgical technique. Thirty patients required further right hemicolectomy as treatment for high-risk features; open 19 (15.9%) versus laparoscopic 11 (20.4%)., Conclusions: Laparoscopic appendicectomy did not seem to adversely influence the margin clearance in appendiceal carcinoid, though we recommend that all appendicectomies should include the mesoappendix., (© 2020 Royal Australasian College of Surgeons.)

Background: Three-level data arising from repeated measures on individuals who are clustered within larger units are common in health research studies. Missing data are prominent in such longitudinal studies and multiple imputation (MI) is a popular approach for handling missing data. Extensions of joint modelling and fully conditional specification MI approaches based on multilevel models have been developed for imputing three-level data. Alternatively, it is possible to extend single- and two-level MI methods to impute three-level data using dummy indicators and/or by analysing repeated measures in wide format. However, most implementations, evaluations and applications of these approaches focus on the context of incomplete two-level data. It is currently unclear which approach is preferable for imputing three-level data., Methods: In this study, we investigated the performance of various MI methods for imputing three-level incomplete data when the target analysis model is a three-level random effects model with a random intercept for each level. The MI methods were evaluated via simulations and illustrated using empirical data, based on a case study from the Childhood to Adolescence Transition Study, a longitudinal cohort collecting repeated measures on students who were clustered within schools. In our simulations we considered a number of different scenarios covering a range of different missing data mechanisms, missing data proportions and strengths of level-2 and level-3 intra-cluster correlations., Results: We found that all of the approaches considered produced valid inferences about both the regression coefficient corresponding to the exposure of interest and the variance components under the various scenarios within the simulation study. In the case study, all approaches led to similar results., Conclusion: Researchers may use extensions to the single- and two-level approaches, or the three-level approaches, to adequately handle incomplete three-level data. The two-level MI approaches with dummy indicator extension or the MI approaches based on three-level models will be required in certain circumstances such as when there are longitudinal data measured at irregular time intervals. However, the single- and two-level approaches with the DI extension should be used with caution as the DI approach has been shown to produce biased parameter estimates in certain scenarios.

Purpose: Recent evidence suggests routine colonoscopy after acute diverticulitis is not necessary but remains debatable. The aim of this study was to investigate the incidence of follow-up colonoscopic finding of adenoma, advanced neoplastic lesion, and adenocarcinoma after diverticulitis., Materials and Methods: A retrospective review of all cases of acute diverticulitis admitted from November 2015 to April 2018 was performed. Data collected included demographics, computed tomography (CT) findings, and findings of the follow-up colonoscopy within 12 months., Results: A total of 368 patients were admitted for acute diverticulitis. A total of 366 patients underwent CT scan for diagnosis. Of whom, 185 patients (50.5%) had a follow-up colonoscopy; 115 (31.4%) did not have a follow-up colonoscopy, and the remaining have had a recent colonoscopy. The overall incidence of adenomas was 25.9% (n=48) and advanced colonic neoplasia 1.62% (n=3) in patients who underwent follow-up colonoscopy., Conclusions: The finding of advanced colonic neoplasia in follow-up colonoscopy after an acute episode of CT-proven diverticulitis is equivalent to, or less than, that of the population colorectal cancer screening program. Routine colonoscopy is not necessary unless there are other concerning symptoms/CT findings.

Background: Jejunal diverticulitis is rare and usually an incidental diagnosis found on imaging. Its symptoms are non-specific. Hence, the diagnosis often is delayed, and a high mortality rate has been reported. The aim of this study was to review our experience in the management of jejunal diverticulitis and to propose a management algorithm. Methods: A retrospective review of all cases of jejunal diverticulitis seen from November 2015 to November 2018 was performed. Data collected included demographics, history of diverticulitis, risk factors, clinical presentation, biochemistry and imaging results, and management outcome. Results: Eight patients were identified during the study period, five females and three males with a median age of 71 years (range 61-85 years). One patient was on steroid treatment, and one patient had a history of jejunal diverticulitis. Abdominal pain was present in all patients, but other symptoms were variable. Two patients were initially believed to have constipation and were discharged home. All patients underwent a computed tomography (CT) scan for the diagnosis, showing that three had uncomplicated jejunal diverticulitis and five had localized perforation. Five patients were managed conservatively initially; two failed this treatment because of small bowel obstruction and persistent abdominal pain with rising inflammatory markers. Three underwent emergency laparotomy (two because of sepsis; one was thought to have a foreign body). There were no deaths. A proposed management algorithm is discussed. Conclusions: A CT scan is the mainstay for the accurate diagnosis of jejunal diverticulitis. The proposed algorithm can aid in selection of patients suitable for conservative management.

Giant abdominal cyst can lead to various non-specific symptoms such as abdominal bloating, nausea/vomiting, constipation due to its mass effect. In rarer circumstances, it can lead to bowel obstruction, hydronephrosis and even abdominal compartment syndrome. Hereby, we present a case of giant abdominal cyst in a young woman where its origin was a diagnostic dilemma despite exhausting all imaging techniques. A laparotomy was performed and the giant cyst was found to be originating from the left ovary. The final histopathology confirmed it as an ovarian benign serous cystadenoma. The patient made a fully recovery without any complications., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Haemorrhagic cholecystitis is a rare entity of acute cholecystitis that carries a high morbidity and mortality rate if management is delayed. Its clinical course can mirror that of acute cholecystitis. Characteristic findings on ultrasound or CT scan are useful clues to early diagnosis. Urgent cholecystectomy is required prior to progressing to perforation of gallbladder. Most of the literature are case reports with causes associated with anticoagulation. Herein, we described a morbidly obese patient with poorly controlled diabetes presenting with non-specific right upper quadrant pain and was subsequently diagnosed with haemorrhagic cholecystitis. A review of the literature was also performed to summarise the potential clinical presentations, distinctive imaging findings and management options available for this rare condition., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2018. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Cystic ovarian teratomas comprise 20% of all ovarian neoplasms, and are commonly encountered in patients between 20 and 40 years of age. Although these cysts are usually asymptomatic, we present the case of a patient whose cyst resulted in pruritus and abdominal pain. Based on a MEDLINE search of the literature, we believe this is the first case report of a twisted ovarian cyst presenting with generalized pruritus., Case Presentation: A 35-year-old Sri Lankan woman presented with lower abdominal pain of one day's duration with vomiting and generalized pruritus. She had no history of allergies and was not on medication. Upon a physical examination, our patient was found to have an acute abdomen, localized peritonism in her lower abdomen and tachycardia of 100 beats per minute. Computed tomography showed that the cyst, which contained calcified structures, originated from her left ovary. After laparoscopy-assisted removal of the twisted ovarian cyst, her symptoms resolved completely. Histological examination confirmed a benign ovarian teratoma., Conclusions: An unusual case of torsion of an ovarian teratoma presenting with abdominal pain and generalized pruritus, believed to be due to an antibody-mediated response, was resolved after surgical removal of the cyst.

Background: Liver parenchymal transection can be associated with significant blood loss and morbidity. We present our initial experience with the Gyrus PlasmaKinetic coagulation device in liver parenchymal resection in both cirrhotic and non-cirrhotic patients., Methods: Liver resections were performed in 51 consecutive patients, from 20 July 2005 to 31 August 2007, using the Gyrus PlasmaKinetic coagulator. Requirement for blood transfusions, operating time, duration of hospital stay and major complications were evaluated initially for the group as a whole. Subsequently, the 11 patients with histologically confirmed cirrhosis (nine men, two women, median age 54 years, range 24-74 years) were compared with 40 patients without cirrhosis (25 men, 15 women, median age 57 years, range 24-87 years)., Results: There were 34 men and 17 women. The median age was 56 (range 24-87 years). There were 48 open procedures and 3 laparoscopic procedures. There were 30 major resections (>2 segments) and 21 minor resections (one to two segments). The overall median operating time was 260 min (range 90-690). Length of stay had a median of 9 days, range 4-50 days. Twenty-one patients (41%) required a blood transfusion. Two biliary leaks were observed in non-cirrhotic patients initially before the settings of the Gyrus device were optimized., Conclusions: The Gyrus PlasmaKinetic coagulation device is a novel instrument for hepatic parenchymal transection in liver resection, which can be safely used in cirrhotic and non-cirrhotic patients.

Administration of recombinant interleukin 12 (IL-12) induces tumor regression that is associated with T-cell infiltration in the OV-HM ovarian carcinoma and CSA1M fibrosarcoma models. After confirming the blocking of regression by injection of anti-IFN-gamma monoclonal antibody (mAb), we investigated the mechanisms underlying the requirement of IFN-gamma in T-cell migration and tumor regression. T-cell migration was inhibited by injection of anti-IFN-gamma mAb to OV-HM tumor-bearing mice prior to IL-12 treatment. We examined, using the lymphoid cell migration assay, whether IFN-gamma is required for enhancing the migratory capacity of T cells or the T cell-accepting potential of tumor masses during IL-12 treatment. Spleen cells from IL-12-treated or untreated OV-HM-bearing mice were stained in vitro with a fluorescein chemical and transferred i.v. into OV-HM-bearing mice that were not treated with IL-12. Migration of donor cells was quantitated by counting the number of fluorescent cells on cryostat sections of tumor masses from recipient mice. Compared to spleen cells from OV-HM-bearing mice that were not treated with IL-12, enhanced migration was observed for cells from IL-12-treated OV-HM-bearing mice. Anti-IFN-gamma pretreatment of donor mice before IL-12 treatment did not reduce the migratory capacity of T cells, whereas migration was markedly inhibited in recipient mice injected with anti-IFN-gamma. Anti-IFN-gamma pretreatment decreased vascular cell adhesion molecule-1 (VCAM-1)-/intercellular adhesion molecule-1 (ICAM-1)-positive blood vessels at tumor sites. Consistent with this, migration was also inhibited by treatment of recipient mice with either anti-VCAM-1 or anti-ICAM-1 mAb. In contrast to the OV-HM model, T-cell migration was not affected in the CSA1M model following preinjection of anti-IFN-gamma mAb. In this model, VCAM-1-/ICAM-1-positive blood vessels existed even after anti-IFN-gamma treatment, although tumor regression was completely inhibited. These results indicate that IFN-gamma plays two distinct roles in expressing the antitumor efficacy of IL-12: one is to support the T-cell acceptability of tumor masses, and the other is to mediate the antitumor effects of migrated T cells.

Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), a second counterreceptor for the B7 family of costimulatory molecules, functions as a negative regulator of T-cell activation. Here, we investigated whether the blockade of the CTLA-4 function leads to enhancement of antitumor T-cell responses at various stages of tumor growth. Unfractionated spleen cells taken from CSAIM fibrosarcoma-bearing mice 1-2 weeks after CSA1M cell implantation (early tumor-bearing mice) contained tumor-primed T cells that produced interleukin 2 and IFN-gamma through collaboration with antigen-presenting cell-binding tumor antigens when cultured in vitro. However, this initial lymphokine-producing capacity decreased at later stages of tumor growth (7-10 weeks after tumor cell implantation). Anti-CTLA-4 monoclonal antibody (mAb) was added to whole-spleen cell cultures from early or late tumor-bearing mice. Spleen cells from early tumor-bearing mice exhibited enhanced production of interleukin 2 and IFN-gamma upon in vitro culture in the presence of anti-CTLA-4 mAb. However, addition of anti-CTLA-4 mAb to whole-spleen cell cultures from late tumor-bearing mice failed to display such an enhancement. Consistent with these in vitro results, the in vivo antitumor effect of anti-CTLA-4 administration was observed in a tumor-bearing stage-restricted manner; in vivo administration of anti-CTLA-4 (1 mg/mouse, three times at 1-week intervals) into early tumor-bearing mice resulted in regression of growing tumors, whereas the same treatment did not affect tumor growth when performed for late tumor-bearing mice. Similar anti-CTLA-4 effect was observed in another tumor (OV-HM ovarian carcinoma) model. These in vitro and in vivo results indicate that CTLA-4 blockade in tumor-bearing individuals enhances the capacity to generate antitumor T-cell responses, but the expression of such an enhancing effect is restricted to early stages of tumor growth.

Administration of interleukin 12 (IL-12) into mice bearing CSA1M, OV-HM, Meth A, or MCH-1-A1 tumor induced complete regression of CSA1M and OV-HM tumors but induced only a slight growth inhibition of Meth A and MCH-1-A1 tumors. These effects of IL-12 were associated with high and only marginal levels of T-cell infiltration into CSA1M/OV-HM and Meth A/MCH-1-A1 tumor masses, respectively. Here, we investigated the role of IL-12 in the induction of T-cell migration. Spleen cells from untreated or IL-12-treated CSA1M-bearing mice were stained in vitro with a fluorescein chemical and transferred i.v. into IL-12-untreated CSA1M-bearing mice. Migration of donor cells was quantitated by counting the number of fluorescent cells on cryostat sections of tumor masses. Although only a slight migration was detected for spleen cells from IL-12-untreated CSA1M-bearing as well as IL-12-treated or untreated normal mice, enhanced migration was observed for cells from IL-12-treated CSA1M-bearing mice. A similar enhanced migration was observed for the OV-HM model. In contrast, such an enhancement was only marginal in the Meth A and MCH-1-A1 models. Immunohistochemical studies of tumors from IL-12-treated mice revealed that the predominant T-cell subset was CD4+ in CSA1M and CD8+ in OV-HM tumor masses. Consistent with this observation, the dominant subset of migrating T cells was found to be CD4+ in the CSA1M and CD8+ in the OV-HM models. T-cell migration was inhibited by pretreatment of recipients with either combination of anti-very late antigen 4 + anti-vascular cell adhesion molecule 1 or anti-lymphocyte function-associated antigen 1 + anti-intercellular adhesion molecule 1 monoclonal antibody. These results indicate that IL-12 can confer T cells with a capacity to migrate to tumor sites through very late antigen 4/lymphocyte function-associated antigen 1 adhesion pathways and that the in vivo acquisition of such a capacity following IL-12 treatment correlates with the induction of tumor regression.