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Background We compared the relative benefits, harms and cost-effectiveness of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery ± systemic chemotherapy versus cytoreductive surgery ± systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric or ovarian cancers by a systematic review, meta-analysis and model-based cost–utility analysis. Methods We searched MEDLINE, EMBASE, Cochrane Library and the Science Citation Index, ClinicalTrials.gov and WHO ICTRP trial registers until 14 April 2022. We included only randomised controlled trials addressing the research objectives. We used the Cochrane risk of bias tool version 2 to assess the risk of bias in randomised controlled trials. We used the random-effects model for data synthesis when applicable. For the cost-effectiveness analysis, we performed a model-based cost–utility analysis using methods recommended by The National Institute for Health and Care Excellence. Results The systematic review included a total of eight randomised controlled trials (seven randomised controlled trials, 955 participants included in the quantitative analysis). All comparisons other than those for stage III or greater epithelial ovarian cancer contained only one trial, indicating the paucity of randomised controlled trials that provided data. For colorectal cancer, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably results in little to no difference in all-cause mortality (60.6% vs. 60.6%; hazard ratio 1.00, 95% confidence interval 0.63 to 1.58) and may increase the serious adverse event proportions compared to cytoreductive surgery ± systemic chemotherapy (25.6% vs. 15.2%; risk ratio 1.69, 95% confidence interval 1.03 to 2.77). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone (40.8% vs. 60.8%; hazard ratio 0.55, 95% confidence interval 0.32 to 0.95). For gastric cancer, there is high uncertainty about the effects of hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy versus cytoreductive surgery + systemic chemotherapy or systemic chemotherapy alone on all-cause mortality. For stage III or greater epithelial ovarian cancer undergoing interval cytoreductive surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably decreases all-cause mortality compared to cytoreductive surgery + systemic chemotherapy (46.3% vs. 57.4%; hazard ratio 0.73, 95% confidence interval 0.57 to 0.93). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy may not be cost-effective versus cytoreductive surgery + systemic chemotherapy for colorectal cancer but may be cost-effective for the remaining comparisons. Limitations We were unable to obtain individual participant data as planned. The limited number of randomised controlled trials for each comparison and the paucity of data on health-related quality of life mean that the recommendations may change as new evidence (from trials with a low risk of bias) emerges. Conclusions In people with peritoneal metastases from colorectal cancer with limited peritoneal metastases and who are likely to withstand major surgery, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should not be used in routine clinical practice (strong recommendation). There is considerable uncertainty as to whether hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy or cytoreductive surgery + systemic chemotherapy should be offered to patients with gastric cancer and peritoneal metastases (no recommendation). Hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should be offered routinely to women with stage III or greater epithelial ovarian cancer and metastases confined to the abdomen requiring and likely to withstand interval cytoreductive surgery after chemotherapy (strong recommendation). Future work More randomised controlled trials are necessary. Study registration This study is registered as PROSPERO CRD42019130504. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/135/02) and is published in full in Health Technology Assessment; Vol. 28, No. 51. See the NIHR Funding and Awards website for further award information. Plain language summary What was the question? Cancers of the bowel, ovary or stomach can spread to the lining of the abdomen (‘peritoneal metastases’). Chemotherapy (the use of drugs that aim to kill cancer cells) given by injection or tablets (‘systemic chemotherapy’) is one of the main treatment options. There is uncertainty about whether adding cytoreductive surgery (cytoreductive surgery; an operation to remove the cancer) and ‘hyperthermic intraoperative peritoneal chemotherapy’ (warm chemotherapy delivered into the lining of the abdomen during cytoreductive surgery) are beneficial. What did we do? We reviewed all the information from medical literature published until 14 April 2022, to answer the above uncertainty. What did we find? We found the following from eight trials, including about 1000 participants. In people with peritoneal metastases from bowel cancer, hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably does not provide any benefits and increases harm compared to cytoreductive surgery + systemic chemotherapy, while cytoreductive surgery + systemic chemotherapy appears to increase survival compared to systemic chemotherapy alone. There is uncertainty about the best treatment for people with peritoneal metastases from stomach cancer. In women with peritoneal metastases from ovarian cancer who require systemic chemotherapy before cytoreductive surgery to shrink the cancer to allow surgery (‘advanced ovarian cancer’), hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy probably increases survival compared to cytoreductive surgery + systemic chemotherapy. What does this mean? In people who can withstand a major operation and in whom cancer can be removed, cytoreductive surgery + systemic chemotherapy should be offered to people with peritoneal metastases from bowel cancer, while hyperthermic intraoperative peritoneal chemotherapy + cytoreductive surgery + systemic chemotherapy should be offered to women with peritoneal metastases from ‘advanced ovarian cancer’. Uncertainty in treatment continues for gastric cancer. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 17/135/02) and is published in full in Health Technology Assessment; Vol. 28, No. 51. See the NIHR Funding and Awards website for further award information. Scientific summary Background There is uncertainty about whether hyperthermic intraoperative peritoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS) improves survival and/or quality of life (QoL) compared to CRS or no treatment in addition to systemic chemotherapy in people with peritoneal metastases who can withstand major surgery. Objectives Primary objectives To compare the relative benefits and harms of HIPEC + CRS ± systemic chemotherapy versus CRS ± systemic chemotherapy or systemic chemotherapy alone in people with peritoneal metastases from colorectal, gastric or stage III or greater epithelial ovarian cancers eligible to undergo HIPEC + CRS by a systematic review and meta-analysis. Secondary objectives To compare the cost-effectiveness of HIPEC + CRS ± systemic chemotherapy versus CRS ± systemic chemotherapy or systemic chemotherapy alone from the NHS and personal social services (PSS) perspective using a model-based cost–utility analysis. Methods We performed a systematic review of literature by searching MEDLINE, EMBASE, Cochrane Library, Science Citation Index, Conference Proceedings Citation Index, as well as trial registers until 14 April 2022. We followed the standard guidance for performing a high-quality systematic review and meta-analysis. We included only randomised controlled trials (RCTs) and assessed the risk of bias using Risk of Bias version 2.0 (ROB 2.0). We were unable to perform an individual participant data (IPD) meta-analysis as planned because of unforeseen circumstances related to coronavirus disease 2019 (COVID-19). This led to trialists who were also clinical researchers being unable to engage for transfer of IPD. We did not foresee that study authors (surgeons) would be sufficiently engaged with providing IPD soon because of the backlog with surgeries and the fatigue induced by COVID-19. Therefore, we performed a meta-analysis based on aggregate data. We calculated the hazard ratio (HR), risk ratio (RR), rate ratio or mean difference (MD) with 95% confidence intervals (CIs) as appropriate. When applicable, we performed meta-analysis using the random-effects model using Review Manager 5.4. We used GRADE guidance to assess the certainty of evidence and determine the strength of recommendations. For the cost-effectiveness analysis, we performed a model-based cost–utility analysis using methods recommended by The National Institute for Health and Care Excellence (NICE). We estimated the costs and quality-adjusted life-years (QALYs) per patient using lifetime horizon. We calculated the incremental net monetary benefit (incremental NMB) for each comparison based on deterministic analysis and probabilistic sensitivity analysis (PSA). We also performed univariate sensitivity analysis and value of information analysis. Results The systematic review included a total of eight RCTs. A total of 955 participants in seven RCTs were included in the quantitative analysis. All comparisons other than those of ovarian cancer contained only one trial. For colorectal cancer, HIPEC + CRS + systemic chemotherapy probably results in little to no difference in all-cause mortality (60.6% in HIPEC + CRS + systemic chemotherapy vs. 60.6% in CRS + systemic chemotherapy; median follow-up 64 months; HR 1.00, 95% CI 0.63 to 1.58; one trial; 265 participants; moderate-certainty evidence) and may increase the number of people who developed serious adverse events compared to CRS +/– systemic chemotherapy (25.6% in HIPEC + CRS + systemic chemotherapy vs. 15.2% in CRS + systemic chemotherapy; RR 1.69, 95% CI 1.03 to 2.77; one trial; 265 participants; low-certainty evidence). HIPEC + CRS + systemic chemotherapy probably decreases all-cause mortality compared to fluorouracil-based systemic chemotherapy alone (40.8% in HIPEC + CRS + systemic chemotherapy vs. 60.8% in systemic chemotherapy alone; median follow-up 22 months; HR 0.55, 95% CI 0.32 to 0.95; one trial; 105 participants; moderate-certainty evidence). For gastric cancer, there is high uncertainty about the effect of HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy on all-cause mortality (effect estimates not presented because of very low-certainty evidence). HIPEC + CRS + systemic chemotherapy probably decreases all-cause mortality compared to systemic chemotherapy (40.8% in HIPEC + CRS + systemic chemotherapy vs. 100% in systemic chemotherapy alone; minimum follow-up 24 months; HR 0.40, 95% CI 0.30 to 0.52; one trial; 17 participants; moderate-certainty evidence). For stage III or greater epithelial ovarian cancer requiring interval CRS, HIPEC + CRS + systemic chemotherapy probably decreases all-cause mortality compared to CRS + systemic chemotherapy (46.3% in HIPEC + CRS + systemic chemotherapy vs. 57.4% in CRS + systemic chemotherapy; median follow-up 32–70 months; HR 0.73, 95% CI 0.57 to 0.93; three trials; 500 participants; moderate-certainty evidence). It may result in little to no difference in health-related quality of life (HRQoL) (MD 4.85, 95% CI −7.74 to 17.44; one trial; 71 participants; moderate-certainty evidence) or number of people who developed serious adverse events compared to CRS + systemic chemotherapy (26.7% in HIPEC + CRS + systemic chemotherapy vs. 25.2% in CRS + systemic chemotherapy; RR 1.06, 95% CI 0.73 to 1.54; two trials; 316 participants; moderate-certainty evidence), although it probably increases the number of serious adverse events per participant compared to CRS + systemic chemotherapy (41.4 events per 100 participants in HIPEC + CRS + systemic chemotherapy vs. 32.6 events per 100 participants in CRS + systemic chemotherapy; rate ratio 1.27, 95% CI 1.09 to 1.49; one trial; 184 participants; moderate-certainty evidence). The cost-effectiveness analysis included the five comparisons described above: HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy for each of the colorectal, gastric and ovarian cancers and HIPEC + CRS + systemic chemotherapy versus systemic chemotherapy alone for each of the colorectal and gastric cancers. In people with colorectal peritoneal metastases, the incremental NMBs at willingness to pay (WTP) of £20,000 and £30,000 were −£6162.83 and −£6164.19, respectively, indicating that HIPEC + CRS + systemic chemotherapy was not cost-effective compared to CRS + systemic chemotherapy in NHS. The likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to CRS + systemic chemotherapy was 46.5% and 47.6% at WTP of £20,000 and £30,000, respectively. In the same group of people, the incremental NMBs at WTP of £20,000 and £30,000 were £107,909.46 and £167,621.58, respectively, indicating that HIPEC + CRS + systemic chemotherapy may be cost-effective compared to systemic chemotherapy alone in NHS. The likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to systemic chemotherapy alone was 89.3% and 90.3% at WTP of £20,000 and £30,000, respectively. In people with gastric peritoneal metastases, the incremental NMBs at WTP of £20,000 and £30,000 were £14,174.73 and £22,955.89, respectively, for HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy and £81,796.38 and £127,768.23, respectively, for HIPEC + CRS + systemic chemotherapy versus systemic chemotherapy, indicating that HIPEC + CRS + systemic chemotherapy may be cost-effective compared to CRS + systemic chemotherapy or systemic chemotherapy alone in NHS. The likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective ranged between 60% and 70% for the different comparisons and different thresholds. In women with grade III or greater epithelial ovarian cancer requiring interval CRS, the incremental NMBs at WTP of £20,000 and £30,000 were £46,761.81 and £71,938.23, respectively, indicating that HIPEC + CRS + systemic chemotherapy was cost-effective compared to CRS +systemic chemotherapy in NHS. The likelihood of HIPEC + CRS + systemic chemotherapy being cost-effective compared to CRS + systemic chemotherapy was 71.9% and 72.4% at WTP of £20,000 and £30,000, respectively. The value of information analysis indicated that the expected value of perfect information (EVPI) ranged between £3 and £53 million for the different cancer types (when estimation was possible) for WTP of £20,000 and £30,000. Discussion and conclusions Limitations of the review We were unable to obtain IPD as planned. IPD would have allowed us to refine our effect estimates for subgroups of people with peritoneal metastases from colorectal, gastric or stage III or greater epithelial ovarian cancer. It is difficult to estimate whether our conclusions would have changed if we had IPD; however, our systematic review and meta-analysis support similar conclusions as the trial authors, suggesting that the impact of IPD may not be major enough to warrant an IPD once the health services have recovered from the impact of COVID-19. We estimated the HR for survival for gastric cancer trials from Kaplan–Meier curves. This might have introduced bias. However, because of the small number of participants and the estimations that we have performed to calculate the effect estimates, we have concluded that there is uncertainty in the benefit of HIPEC + CRS + systemic chemotherapy in gastric cancers. Because of the paucity of trials under each comparison, evidence from new RCTs of low risk of bias may change our recommendations. There are concerns regarding the clinical recommendations for people with colorectal peritoneal metastases based on the PRODIGE-7 trial. We have discussed in detail the different concerns raised and why these concerns should not be used as a justification for not basing clinical practice on PRODIGE-7 trial (in the full article). In summary, we based our clinical practice recommendations for colorectal peritoneal metastases on PRODIGE-7 trial because the trial was a low risk of bias trial for the comparison of HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy. An appropriate analysis was used to analyse trial data, and there was no other trial of low of bias comparing HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy. While the CRS + systemic chemotherapy was not directly compared with systemic chemotherapy alone, we recommended CRS + systemic chemotherapy in people with colorectal peritoneal metastases because of the lack of any ‘systemic chemotherapy alone’ treatments that provide equivalent median survival as that observed in the control arm (CRS + systemic chemotherapy) in the PRODIGE-7 trial. Because of the difficulties in estimating the Peritoneal Cancer Index (PCI) during surgery, we have not recommended HIPEC + CRS + systemic chemotherapy even for the subset of patients with PCI 11–15, but this exploratory subgroup analysis can guide future research. We have not based our recommendations on non-randomised studies, as we did not find any non-randomised study in which similar participants with colorectal peritoneal metastases underwent HIPEC + CRS + systemic chemotherapy versus CRS + systemic chemotherapy or systemic chemotherapy alone. CRS + systemic chemotherapy provides equivalent median survival of 41 months as HIPEC + CRS + systemic chemotherapy. When there is an existing, less invasive treatment that provides equivalent survival, it can hardly be considered life-threatening to warrant recommendations based on low-or very low-certainty evidence. Recommendations for clinical practice In people with peritoneal metastases from colorectal cancer, based on the results of PRODIGE-7 trial, HIPEC + CRS + systemic chemotherapy probably results in little to no difference in all-cause mortality or progression-free survival and results in increased complications compared to CRS + systemic chemotherapy. Therefore, HIPEC based on oxaliplatin regimen used in PRODIGE-7 trial + CRS + systemic chemotherapy should not be used in routine clinical practice (strong recommendation). Because of the lack of reliability of preoperative or perioperative PCI, the lack of pre-PRODIGE-7 trial standard classification of PCI into PCI 15 and pre-defined subgroup analysis based on the PCI classification, HIPEC based on oxaliplatin regimen used in PRODIGE-7 trial + CRS + systemic chemotherapy cannot be recommended for any subgroups. Because of the median survival observed in the CRS + systemic chemotherapy arm of PRODIGE-7 trial (41 months) and the poor survival observed in people with disseminated colorectal peritoneal metastases (

Background Antipsychotic-induced weight gain (AIWG) is a substantial contributor to high obesity rates in psychiatry. Limited management guidance exists to inform clinical practice, and individuals with experience of managing AIWG have had no or minimal input into its development. A lack of empirical research outlining patient values and preferences for management also exists. Recommendations addressing weight management in psychiatry may be distinctly susceptible to ideology and sociocultural values regarding intervention appropriateness and expectations of self-management, reinforcing the need for co-produced management guidance. This study is the first to ask: how do individuals conceptualise preferred AIWG management and how can this be realised in practice? Aims 1. Explore the management experiences of individuals with unwanted AIWG. 2. Elicit their values and preferences regarding preferred management. Method Qualitative descriptive methodology informed study design. A total of 17 participants took part in semi-structured interviews. Data analysis was undertaken using reflexive thematic analysis. Results Participants reported that clinicians largely overestimated AIWG manageability using dietary and lifestyle changes. They also reported difficulties accessing alternative management interventions, including a change in antipsychotic and/or pharmacological adjuncts. Participants reported current management guidance is oversimplified, lacks the specificity and scope required, and endorses a ‘one-size-fits-all’ management approach to an extensively heterogenous side-effect. Participants expressed a preference for collaborative AIWG management and guidance that prioritises early intervention using the range of evidence-based management interventions, tailored according to AIWG risk, participant ability and participant preference. Conclusion Integration of this research into guideline development will help ensure recommendations are relevant and applicable, and that individual preferences are represented.

Background: This Clinical Practice Guideline (CPG) for the management of obesity in adults in Ireland, adapted from the Canadian CPG, defines obesity as a complex chronic disease characterised by excess or dysfunctional adiposity that impairs health. The guideline reflects substantial advances in the understanding of the determinants, pathophysiology, assessment, and treatment of obesity. Summary: It shifts the focus of obesity management toward improving patient-centred health outcomes, functional outcomes, and social and economic participation, rather than weight loss alone. It gives recommendations for care that are underpinned by evidence-based principles of chronic disease management; validate patients’ lived experiences; move beyond simplistic approaches of “eat less, move more” and address the root drivers of obesity. Key Messages: People living with obesity face substantial bias and stigma, which contribute to increased morbidity and mortality independent of body weight. Education is needed for all healthcare professionals in Ireland to address the gap in skills, increase knowledge of evidence-based practice, and eliminate bias and stigma in healthcare settings. We call for people living with obesity in Ireland to have access to evidence-informed care, including medical, medical nutrition therapy, physical activity and physical rehabilitation interventions, psychological interventions, pharmacotherapy, and bariatric surgery. This can be best achieved by resourcing and fully implementing the Model of Care for the Management of Adult Overweight and Obesity. To address health inequalities, we also call for the inclusion of obesity in the Structured Chronic Disease Management Programme and for pharmacotherapy reimbursement, to ensure equal access to treatment based on health-need rather than ability to pay.

Abstract Background Whether non-genetic prognostic factors significantly influence the variable prognosis of antipsychotic-induced weight gain (AIWG) has not yet been systematically explored. Methods Searches for both randomized and non-randomized studies were undertaken using four electronic databases, two trial registers, and via supplemental searching methods. Unadjusted and adjusted estimates were extracted. Meta-analyses were undertaken using a random-effects generic inverse model. Risk of bias and quality assessments were undertaken using Quality in Prognosis Studies (QUIPS) and Grading of Recommendations Assessment, Development and Evaluation (GRADE), respectively. Results Seventy-two prognostic factors were assessed across 27 studies involving 4426 participants. Only age, baseline body mass index (BMI), and sex were suitable for meta-analysis. Age (b=−0.044, 95%CI −0.157–0.069), sex (b=0.236, 95%CI −0.086–0.558), and baseline BMI (b=−0.013 95%CI −0.225–0.200) were associated with nonsignificant effects on AIWG prognosis. The highest quality GRADE rating was moderate in support of age, trend of early BMI increase, antipsychotic treatment response, unemployment, and antipsychotic plasma concentration. Trend of early BMI increase was identified as the most clinically significant prognostic factor influencing long-term AIWG prognosis. Conclusions The strong prognostic information provided by BMI trend change within 12 weeks of antipsychotic initiation should be included within AIWG management guidance to highlight those at highest risk of worse long-term prognosis. Antipsychotic switching and resource-intensive lifestyle interventions should be targeted toward this cohort. Our results challenge previous research that several clinical variables significantly influence AIWG prognosis. We provide the first mapping and statistical synthesis of studies examining non-genetic prognostic factors of AIWG and highlight practice, policy, and research implications.

Introduction There is uncertainty about whether cytoreductive surgery (CRS)+hyperthermic intraoperative peritoneal chemotherapy (HIPEC) improves survival and/or quality of life compared with standard of care (SoC) in people with peritoneal metastases who can withstand major surgery.Primary objectives To compare the relative benefits and harms of CRS+HIPEC versus SoC in people with peritoneal metastases from colorectal, ovarian or gastric cancers eligible to undergo CRS+HIPEC by a systematic review and individual participant data (IPD) meta-analysis.Secondary objectives To compare the cost-effectiveness of CRS+HIPEC versus SoC from a National Health Service (NHS) and personal social services perspective using a model-based cost–utility analysis.Methods and analysis We will perform a systematic review of literature by updating the searches from MEDLINE, Embase, Cochrane library, Science Citation Index as well as trial registers. Two members of our team will independently screen the search results and identify randomised controlled trials comparing CRS+HIPEC versus SoC for inclusion based on full texts for articles shortlisted during screening. We will assess the risk of bias in the trials and obtain data related to baseline prognostic characteristics, details of intervention and control, and outcome data related to overall survival, disease progression, health-related quality of life, treatment related complications and resource utilisation data. Using IPD, we will perform a two-step IPD, that is, calculate the adjusted effect estimate from each included study and then perform a random-effects model meta-analysis. We will perform various subgroup analyses, meta-regression and sensitivity analyses. We will also perform a model-based cost–utility analysis to assess whether CRS+HIPEC is cost-effective in the NHS setting.Ethics and dissemination This project was approved by the UCL Research Ethics Committee (Ethics number: 16023/001). We aim to present the findings at appropriate international meetings and publish the review, irrespective of the findings, in a peer-reviewed journal.PROSPERO registration number CRD42019130504.

BACKGROUND:This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have disease-modifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. METHODS AND FINDINGS:NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of ≥12 and

There is strong published and unpublished evidence that our CD105 Mab E9, which is highly reactive with angiogenic endothelial cells, could be a useful reagent to target the vasculature of solid tumors in man. Since Mab E9 does not cross-react with animal tissues, we undertook here to evaluate its localization using human kidney as an ex vivo model. Perfusion was performed through the renal artery of 99Tcm-labeled purified CD105 Mab in freshly excised kidneys from 7 patients with renal carcinoma. In all 7 cases, immunoscintigraphs showed the presence of well-defined radioactive hot spots, which matched the positions of the tumors as identified by presurgery MRI scans and subsequent histopathologic examination. Importantly, in one instance, where a presurgery MRI scan had identified only one tumor, immunoscintigraphs showed 2 distinct hot spots of radioactivity. The pathology report confirmed that the additional hot spot corresponded to a small secondary well-vascularized tumor. The implication of this finding is that the radiolabeled Mab, E9, may be of use in the detection of metastatic disease. That the labeling of tumors was specific was confirmed when prior perfusion of unlabeled mab E9 in 2 kidneys completely blocked the localization of 99Tcm-conjugated Mab E9. Radioactivity in samples of tumor and normal tissue taken from 7 kidneys was counted in a gamma counter. In all cases, there was a greater uptake of radioactivity in tumors compared with the corresponding normal kidneys. The median values, adjusted per gram wet weight, for 99Tcm were 14.8 times (range, 4.8–113.0) greater in kidney tumors than in normal kidney tissue (p < 0.007). Immunofluorescent staining of cryostat sections of tumor tissues in each of the 7 cases showed strong and uniform localization of Mab E9 in tumor microvessels. Interestingly, chimeric staining of endothelial cells (ECs) was seen in an occasional microvessel segment. That is, while most of the ECs lining a microvessel were strongly stained, an occasional EC was negative. This was not an artifact of staining. Unstained ECs may be nonangiogenic or apoptotic since CD105 is a proliferation/activation-associated antigen. Further investigations are warranted to establish the pharmacokinetics of 99Tcm-labeled CD105 antibody in vivo. This would enable us to determine whether an apparently highly successful ex vivo study has the potential for tumor imaging/therapeutic vascular targeting in patients with cancer. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]