Artificial intelligence for detection of microsatellite instability in colorectal cancer-a multicentric analysis of a pre-screening tool for clinical application.

BACKGROUND: Microsatellite instability (MSI)/mismatch repair deficiency (dMMR) is a key genetic feature which should be tested in every patient with colorectal cancer (CRC) according to medical guidelines. Artificial intelligence (AI) methods can detect MSI/dMMR directly in routine pathology slides, but the test performance has not been systematically investigated with predefined test thresholds. METHOD: We trained and validated AI-based MSI/dMMR detectors and evaluated predefined performance metrics using nine patient cohorts of 8343 patients across different countries and ethnicities. RESULTS: Classifiers achieved clinical-grade performance, yielding an area under the receiver operating curve (AUROC) of up to 0.96 without using any manual annotations. Subsequently, we show that the AI system can be applied as a rule-out test: by using cohort-specific thresholds, on average 52.73% of tumors in each surgical cohort [total number of MSI/dMMR = 1020, microsatellite stable (MSS)/ proficient mismatch repair (pMMR) = 7323 patients] could be identified as MSS/pMMR with a fixed sensitivity at 95%. In an additional cohort of N = 1530 (MSI/dMMR = 211, MSS/pMMR = 1319) endoscopy biopsy samples, the system achieved an AUROC of 0.89, and the cohort-specific threshold ruled out 44.12% of tumors with a fixed sensitivity at 95%. As a more robust alternative to cohort-specific thresholds, we showed that with a fixed threshold of 0.25 for all the cohorts, we can rule-out 25.51% in surgical specimens and 6.10% in biopsies. INTERPRETATION: When applied in a clinical setting, this means that the AI system can rule out MSI/dMMR in a quarter (with global thresholds) or half of all CRC patients (with local fine-tuning), thereby reducing cost and turnaround time for molecular profiling.

Epstein-Barr virus and mismatch repair deficiency status differ between oesophageal and gastric cancer: A large multi-centre study.

BACKGROUND: Oesophageal (OeC) and gastric (GC) cancer patients are treated with similar multimodal therapy and have poor survival. There remains an urgent clinical need to identify biomarkers to individualise patient management and improve outcomes. Therapy with immune checkpoint inhibitors has shown promising results in other cancers. Proposed biomarkers to predict potential response to immune checkpoint inhibitors include DNA mismatch repair (MMR) and/or Epstein-Barr virus (EBV) status. The aim of this study was to establish and compare EBV status and MMR status in large multi-centre series of OeC and GC. METHODS: EBV was assessed by EBV-encoded RNA (EBER) in situ hybridisation and MMR protein expression by immunohistochemistry (IHC) in 988 OeC and 1213 GC from multiple centres. In a subset of OeC, microsatellite instability (MSI) was tested in parallel with MMR IHC. RESULTS: Frequency of MMR deficiency (MMRdef) and MSI was low in OeC (0.8% and 0.6%, respectively) compared with GC (10.3%). None of the OeCs were EBER positive in contrast to 4.8% EBER positive GC. EBV positive GC patients were younger (p = 0.01), more often male (p = 0.001) and had a better overall survival (p = 0.012). MMRdef GC patients were older (p = 0.001) and showed more often intestinal-type histology (p = 0.022). CONCLUSIONS: This is the largest study to date indicating that EBV and MMRdef do not play a role in OeC carcinogenesis in contrast to GC. The potential clinical usefulness of determining MMRdef/EBV status to screen patients for eligibility for immune-targeting therapy differs between OeC and GC patients.

Coloenteric fistula in a young patient with recurrent diverticulitis: A case report and review of the literature.

The development of colonic diverticula is common in developed countries and complications of colonic diverticulosis are responsible for a remarkable burden of the disease. The natural history and management of complicated and recurrent diverticulitis in young patients are still a matter of debate. Coloenteric fistula is a rare complication of diverticulitis in young adults. In this report, and utilising a case study, we will review the natural history, outcome and management of acute diverticulitis in the young.

Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer.

Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[(18)F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([(11)C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m(-2)·min(-1)) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM.

Systemic neutrophil-to-lymphocyte ratio in colorectal cancer: the relationship to patient survival, tumour biology and local lymphocytic response to tumour.

BACKGROUND: Colorectal cancer (CRC) is a major cause of mortality and morbidity. The impact of inflammatory biomarkers (C-reactive protein etc.) on CRC is increasingly studied including systemic neutrophil-to-lymphocyte ratio (NLR) as they seem to predict outcome. METHODS: All patients who underwent curative resection for CRC from 2000 to 2004 at Leeds Teaching Hospitals NHS Trust had pre-operative NLR calculated. Demographic, histopathological and survival data were collected. Tissue microarrays were created and stained to determine the mismatch repair (MMR) protein status of each tumour. Local lymphocytic response to the tumour was assessed and graded. RESULTS: About 358 patients were eligible. Of these 88 had an NLR ⩾5, which predicted lower overall survival and greater disease recurrence. A high NLR is associated with higher pT- and pN-stage and a greater incidence of extramural venous invasion. MMR protein status was not associated with NLR. A pronounced lymphocytic reaction at the invasive margin (IM) indicated a better prognosis and was associated with a lower NLR. CONCLUSION: Neutrophil-to-lymphocyte ratio predicts disease-free and overall survival and is associated with a more aggressive tumour phenotype. The lymphocytic response to tumour at the IM is associated with NLR however dMMR is not. Neutrophil-to-lymphocyte ratio is a cheap, easy-to-access test that predicts outcome in CRC.

What can the molecular pathologist offer for optimal decision making?

As a consequence of new innovative therapies and therapeutic combinations, the treatment of advanced colorectal cancer is becoming increasingly complex. Validated molecular biomarkers could contribute to patient management, but until recently, none has been routinely used. With the recognition that activating mutations of the KRAS oncogene can predict resistance to anti-epidermal growth factor receptor agents, the clinical value of biomarkers in advanced colorectal cancer has been brought to the fore. Prognostic and predictive biomarkers that reflect the molecular and therapeutic complexities of advanced colorectal cancer may provide valuable information regarding likely clinical outcome and therapeutic response and thus may improve patient management and therapeutic agent selection. Such biomarkers are discussed herein.

The proportion of tumour cells is an independent predictor for survival in colorectal cancer patients.

BACKGROUND: The proportion of epithelial and stromal cells in tumours is thought to have an important role in the progression of epithelial malignancy. We aimed to determine whether the relative proportion of tumour (PoT) was related to survival in colorectal cancer. METHODS: The PoT at the luminal surface was measured by point counting using virtual tissue sections in a series of 145 colorectal cancer cases. The relationship of PoT to clinicopathological parameters including cancer-specific survival was analysed. Modified receiver operating characteristic curves were used to determine the optimum cut off points to dichotomise the data for survival analyses. RESULTS: Tumours with PoT-low (

Molecular pathology--the future?

The diagnosis and management of complex disease requires multidisciplinary clinical collaboration. Histopathological assessment of tissues is an important part of this approach and relies on the morphological appraisal of stained tissues by light microscopy. Although considered the 'gold standard', morphology alone is becoming increasingly insufficient in disease where molecular characterisation has altered clinical practice. As the ability to define the molecular alterations associated with disease expands, the requirement to analyse such alterations for diagnostic and therapeutic purposes follows suit. Despite the widespread use of small scale molecular approaches such as immunohistochemistry and fluorescent in situ hybridisation, the demand for detailed molecular classification of disease states increases unabated. In this review, we summarise the clinical applications of various molecular techniques already used within the modern histopathology department. Thereafter, we consider novel high throughput, array based technologies and their possible impact on future histopathological practice.

Precision of 3.0 Tesla quantitative magnetic resonance imaging of cartilage morphology in a multicentre clinical trial.

OBJECTIVE: Quantitative MRI (qMRI) of cartilage morphology is a promising tool for disease-modifying osteoarthritis drug (DMOAD) development. Recent studies at single sites have indicated that measurements at 3.0 Tesla (T) are more reproducible (precise) than those at 1.5 T. Precision errors and stability in multicentre studies with imaging equipment from various vendors have, however, not yet been evaluated. METHODS: A total of 158 female participants (97 Kellgren and Lawrence grade (KLG) 0, 31 KLG 2 and 30 KLG 3) were imaged at 7 clinical centres using Siemens Magnetom Trio and GE Signa Excite magnets. Double oblique coronal acquisitions were obtained at baseline and at 3 months, using water excitation spoiled gradient echo sequences (1.0x0.31x0.31 mm3 resolution). Segmentation of femorotibial cartilage morphology was performed using proprietary software (Chondrometrics GmbH, Ainring, Germany). RESULTS: The precision error (root mean square coefficient of variation (RMS CV)%) for cartilage thickness/volume measurements ranged from 2.1%/2.4% (medial tibia) to 2.9%/3.3% (lateral weight-bearing femoral condyle) across all participants. No significant differences in precision errors were observed between KLGs, imaging sites, or scanner manufacturers/types. Mean differences between baseline and 3 months ranged from <0.1% (non-significant) in the medial to 0.94% (p<0.01) in the lateral femorotibial compartment, and were 0.33% (p<0.02) for the total femorotibial subchondral bone area. CONCLUSIONS: qMRI performed at 3.0 T provides highly reproducible measurements of cartilage morphology in multicentre clinical trials with equipment from different vendors. The technology thus appears sufficiently robust to be recommended for large-scale multicentre trials.

A case-control study of the pathology of oesophageal disease in systemic sclerosis (scleroderma).

BACKGROUND: Atrophy of the smooth muscle layers of the muscularis propria characterises oesophageal involvement in systemic sclerosis (scleroderma). The aetiology of this atrophy and of the resultant oesophageal dysfunction is unknown. OBJECTIVES: To examine oesophageal tissue for evidence of fibrosis, vascular disease, inflammatory reactions and neural abnormalities to determine the possible causes of this disease process. METHODS: A case-control survey was conducted using oesophageal tissue from 74 scleroderma cases and 74 age, race and sex-matched controls from our autopsy files. Histological evidence of oesophageal muscle atrophy was correlated with the degree of vascular changes, inflammatory infiltration, fibrosis, abnormalities of the myenteric plexus and reduction of interstitial cells of Cajal (ICC) using a predesigned semiquantitative descriptive method. RESULTS: Smooth-muscle atrophy was found in 94% of scleroderma cases, and in 5% of controls (p<0.001). Atrophy was evident in the circular smooth muscle in 93% of cases, and in the longitudinal smooth muscle in 66% of cases. Intimal proliferation of arterioles was found in 38% of cases and in 5% of controls (p<0.001), but was not associated with smooth-muscle atrophy (p = 0.29). Despite these vascular changes, there was no evidence of compromised perfusion, such as findings suggestive of acute ischaemic necroses. Minimal cellular infiltrates were seen in the myenteric plexus in 82% of cases and in 92% of controls (p = 0.091). ICC were found in fewer numbers in areas of atrophic smooth muscle compared with adjacent normal smooth muscle in selected scleroderma cases. CONCLUSION: The pathological findings of oesophageal lesions in scleroderma seem inconsistent with either an ischaemic or an inflammatory process. The loss of circular and longitudinal smooth muscle in the distal scleroderma oesophagus may represent loss of normal neural function followed by secondary tissue atrophy, or may be a primary smooth muscle lesion.

Filamin A mutations cause periventricular heterotopia with Ehlers-Danlos syndrome.

OBJECTIVE: To define the clinical, radiologic, and genetic features of periventricular heterotopia (PH) with Ehlers-Danlos syndrome (EDS). METHODS: Exonic sequencing and single stranded conformational polymorphism (SSCP) analysis was performed on affected individuals. Linkage analysis using microsatellite markers on the X-chromosome was performed on a single pedigree. Western blotting evaluated for loss of filamin A (FLNA) protein and Southern blotting assessed for any potential chromosome rearrangement in this region. RESULTS: The authors report two familial cases and nine additional sporadic cases of the EDS-variant form of PH, which is characterized by nodular brain heterotopia, joint hypermobility, and development of aortic dilatation in early adulthood. MRI typically demonstrated bilateral nodular PH, indistinguishable from PH due to FLNA mutations. Exonic sequencing or SSCP analyses of FLNA revealed a 2762 delG single base pair deletion in one affected female. Another affected female harbored a C116 single point mutation, resulting in an A39G change. A third affected female had a 4147 delG single base pair deletion. One pedigree with no detectable exonic mutation demonstrated positive linkage to the FLNA locus Xq28, an affected individual in this family also had no detectable FLNA protein, but no chromosomal rearrangement was detected. CONCLUSION: These results suggest that the Ehlers-Danlos variant of periventricular heterotopia (PH), in part, represents an overlapping syndrome with X-linked dominant PH due to filamin A mutations.

Melanoma patients evaluated by four different positron emission tomography reconstruction techniques.

One hundred and nineteen patients with malignant melanoma were studied using 2-[ F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET). The images were reconstructed using ordered subset expectation maximization with and without attenuation correction and filtered backprojection with and without attenuation correction. The most probable draining lymph node chains were surgically explored and the tumour volume was quantified at histology. The four different reconstructions of the PET images were retrospectively graded on a five-point scale by two blind readers and compared with the tumour volume. The readers agreed within +/-1 grade 93% (529/568) of the time. Comparing the areas under the receiver operating characteristic (ROC) curves gave 0.698, 0.668, 0.694 and 0.684 for the four reconstruction techniques. The lowest value comparing any pair of the four reconstruction techniques was P=0.371. Thus, none of the reconstruction techniques gave significantly better results than any of the others. The sensitivity of detection was 85% for tumour volumes of 113 m or more (about 6 mm in diameter), but only 4% for tumours less than this size. It can be concluded that the use of attenuation correction gives aesthetically more pleasing images, but the sensitivity and specificity are not significantly improved.

A study of persistent post-concussion symptoms in mild head trauma using positron emission tomography.

BACKGROUND: Complaints of persistent cognitive deficits following mild head trauma are often uncorroborated by structural brain imaging and neuropsychological examination. OBJECTIVE: To investigate, using positron emission tomography (PET), the in vivo changes in regional cerebral uptake of 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG) and regional cerebral blood flow (rCBF) in patients with persistent symptoms following mild head trauma. METHODS: Five patients with mild head trauma and five age and education matched healthy controls were imaged using FDG-PET to measure differences in resting regional cerebral glucose metabolism. Oxygen-15 labelled water (H(2)(15)O)-PET was also used to measure group differences in rCBF changes during a spatial working memory task. In addition, neuropsychological testing and self report of dysexecutive function and post-concussion symptoms were acquired to characterise the sample. RESULTS: There was no difference between patients and controls in normalised regional cerebral FDG uptake in the resting state in frontal and temporal regions selected a priori. However, during the spatial working memory task, patients had a smaller increase in rCBF than controls in the right prefrontal cortex. CONCLUSIONS: Persistent post-concussive symptoms may not be associated with resting state hypometabolism. A cognitive challenge may be necessary to detect cerebral changes associated with mild head trauma.

Controversies in female urethral anatomy and their significance for understanding urinary continence: observations and literature review.

To re-examine the anatomy of the female urethra and related structures, three female pelves serially sectioned in sagittal, coronal or transverse planes, and four sets of transverse histological slides of female urethras, were studied. The observations were assembled, rendered as illustrations, and correlated with published works to present an overall explanation of the gross and histological anatomy of the female pelvis and perineum as related to continence. The figures accompanying the text present the anatomy in a series of views in the three anatomical planes. The anatomical relationships of the paraurethral and paravaginal tissues are examined in relation to the conflicting nomenclature applied to these structures. The figures show the spatial relationships within the pelves and perineum that explain their effective function in urinary continence.

Pathogenesis of acardiac twinning: clues from an almost acardiac twin.

OBJECTIVE: To search for clues to the pathogenesis of acardiac twinning. METHODS: We examined a case of monoamniotic twins in which twin A's only sonographic abnormality was a dilated, tortuous ductus venosus. Twin B also had this abnormality as well as multiple other anomalies that included enormous hydrops and a severely hypoplastic heart. Following termination of pregnancy, autopsy was performed. RESULTS: Postmortem examination of the placenta confirmed monochorionic, monoamniotic placentation with two adjacent trivascular cords. Autopsy confirmed the sonographic findings of enormous hydrops in twin B with a severely malformed, almost nonexistent heart. In addition, the liver was small and was represented by a cyst-like structure with thin rims of congested parenchyma surrounding large vascular spaces. CONCLUSION: We believe the sequence of events in this case was early twin-to-twin transfusion resulting in a dysfunctional heart in twin B. This enabled a twin reversal arterial perfusion sequence with further deterioration of twin B's heart and extreme congestion of deoxygenated blood exiting the heart into the inferior vena cava and ductus venosus. This case supports the concept that circulatory reversal in the face of an initially functioning heart may lead to congestion, tissue hypoxia and secondary organ atrophy.

Aortic and mitral fenfluramine-phentermine valvulopathy in 64 patients treated with anorectic agents.

CONTEXT: Few published studies of the pathology of fenfluramine-phentermine (fen-phen) valvulopathy, described by Connolly and colleagues in 1997, have appeared. OBJECTIVES: To define temporal changes in the morphology of the stuck-on plaques and to determine whether the plaques progress or regress after cessation of fen-phen. METHODS: The available clinical information and pathology material from 35 aortic valves (AVs) and 43 mitral valves (MVs) from 64 patients were reviewed. RESULTS: The valves fell into 3 groups: 17 AVs and 28 MVs had fen-phen lesions only, 2 AVs and 7 MVs had fen-phen changes associated with other valve diseases, and 16 AVs and 8 MVs had no fen-phen changes. Fenfluramine-phentermine-attributable dysfunction was regurgitation in all instances. Typical plaques showed proliferation of myofibroblastic cells with myxoid stroma. Small vascular channels and slight lymphocytic accumulations were often present. Deeper parts of some plaques had dense fibroelastic tissue underlying typical plaque. CONCLUSIONS: Considerable individual variation in the time course of anorectic agent use and the severity of fen-phen valvulopathy was observed. Possible plaque regression could not be assessed from this study. The observations suggest that in some patients fen-phen-induced plaques may continue to have surface proliferation despite drug withdrawal.

Lack of evidence for an association between neurofibromatosis type I and intracranial aneurysms: autopsy study and review of the literature.

BACKGROUND AND PURPOSE: Neurofibromatosis type I (NF1) is an autosomal dominant, hereditary, neurocutaneous syndrome purported to be associated with intracranial aneurysms. To study the relationship between NF1 and intracranial aneurysms, we have analyzed all intracranial autopsies of NF1 patients performed at our institution from 1889 to 1999 and analyzed all intracranial aneurysm cases at our institution from 1990 to 1999 in an attempt to identify patients with NF1. In addition, we have reviewed published clinical series of NF1 patients. METHODS: The autopsy database at our institution, which contains 50 000 cases from 1889 to 1999, was searched to identify NF1 patients, and the results of these autopsies were reviewed. The prevalence of intracranial aneurysms in these NF1 patients was compared with the prevalence of intracranial aneurysms in our hospital's autopsy population and with the published prevalence of intracranial aneurysms in the general population. To identify patients with intracranial aneurysms and NF1, our institution's intracranial aneurysm database was searched for patients with clinical manifestations of NF1. Published clinical series of NF1 patients were identified through searches of the literature. RESULTS: None of the 25 autopsy patients with NF1 had an intracranial aneurysm. None of the 925 patients treated for intracranial aneurysms were affected by NF1. A review of the literature identified 8 comprehensive clinical studies, all of which failed to document any relationship between NF1 and intracranial aneurysms. CONCLUSIONS: The autopsy prevalence of no NF1 patients with intracranial aneurysms out of 25 is not different from the prevalence of intracranial aneurysms in the general autopsy population. In addition, no patients treated for intracranial aneurysms at this institution had NF1. These findings are supported by the observation that an association between NF1 and intracranial aneurysms has never been identified in 8 large clinical studies of NF1 patients. We conclude that there is a lack of evidence for any association between NF1 and intracranial aneurysms.

Assessment of dietary therapies in a canine model of Batten disease.

The neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases that occur in a number of animal species, including dogs. A study was conducted to determine whether the resupply of nutrients lost in NCL English Setter dogs would modify the course of the disease. Carnitine and polyunsaturated fatty acids have been reported to be reduced in NCL English Setters. Therefore, the normal laboratory diets of NCL dogs were supplemented with carnitine, fish oil and corn oil and the disease progression was compared with that of an untreated litter mate. The following specific prognostic indicators of NCL were monitored: cognitive function, brain atrophy, brain glucose metabolism and lifespan. Carnitine, with or without lipid supplements, dramatically delayed the progression of cognitive decline in NCL dogs. When fish oil and corn oil only were supplied, brain atrophy was reduced. A combination of all three supplements preserved cognitive function and increased lifespan by 10%. However, brain glucose hypometabolism and cerebral atrophy were not reduced. The results in this study indicated that the effectiveness of therapeutic interventions can be assessed by non-invasive methods at a relatively early stage of the disease process. Our study suggests that dietary supplementation with carnitine is a promising new approach for delaying or preventing the cognitive decline in dogs, and perhaps, with human NCL patients.

Advantages of short-lived positron-emitting radioisotopes for intracoronary radiation therapy with liquid-filled balloons to prevent restenosis.

UNLABELLED: Balloon catheters filled with liquid radioisotopes provide excellent dose homogeneity for intracoronary radiation therapy but are associated with risk for rupture or leakage. We hypothesized that the safety of liquid-filled balloons may be improved once positron emitters with half-lives below 2 h are used instead of the high-energy beta-emitters 166Ho, 186Re, or 188Re, all of which have a longer half-life of at least 17 h. METHODS: To support this concept, the suitability of 18F (half-life, 109.8 min), 68Ga (half-life, 67.6 min), 11C (half-life, 20.4 min), 13N (half-life, 9.97 min), and 15O (half-life, 2.04 min) for intracoronary radiation therapy was evaluated. Potential tissue penetration of positron radiation was assessed in a series of phantom experiments using Gafchromic film. Antiproliferative efficacy of positrons emitted by 68Ga was investigated in vitro using cultured bovine aortic smooth muscle cells (BASMCs), and was compared with gamma-radiation emitted by 137Cs. To characterize the remaining risk, we estimated radiotoxicity after accidental intravascular balloon rupture on the basis of tabulated isotope-specific doses (ICRP 53) and compared these values with 188Re. RESULTS: Half-dose depth of tissue penetration measured in phantom experiments was 0.29 mm for 18F, 0.42 mm for 11C, 0.54 mm for 13N, 0.79 mm for 15O, and 0.9 mm for 68Ga. Irradiation of cultured BASMCs with positron radiation (68Ga) induced dose-dependent inhibition of proliferation with complete proliferative arrest at doses exceeding 6 Gy. ED(50) and ED(80) were 2.5 +/- 0.4 Gy (mean +/- SD) and 4.4 +/- 0.8 Gy, respectively. Antiproliferative efficacy was equal to that of the 662-keV gamma-radiation emitted by 137Cs (ED(50), 3.8 +/- 0.2 Gy; ED(80), 8.0 +/- 0.3 Gy). Estimates made for patient whole-body and organ doses were generally below 50 mSv/1.85 GBq for all investigated positron emitters. The same dose estimates for 188Re were 6-20 fold higher. CONCLUSION: Among the studied radioisotopes, 68Ga is the most attractive source for liquid-filled balloons because of its convenient half-life, sufficient positron energy (2.92 MeV), documented antiproliferative efficacy, and uncomplicated availability from a radioisotope generator. The safety profile for 68Ga is significantly better than that of 188Re, which suggests this radioisotope should be evaluated further in preclinical studies.