Single-centre experience with peptide receptor radionuclide therapy for neuroendocrine tumours (NETs): results using a theranostic molecular imaging-guided approach.

AIM: To summarise our centre's experience managing patients with neuroendocrine tumours (NETs) in the first 5 years after the introduction of peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-octreotate (LUTATE). The report emphasises aspects of the patient management related to functional imaging and use of radionuclide therapy. METHODS: We describe the criteria for treatment with LUTATE at our centre, the methodology for patient selection, and the results of an audit of clinical measures, imaging results and patient-reported outcomes. Subjects are treated initially with four cycles of ~ 8 GBq of LUTATE administered as an outpatient every 8 weeks. RESULTS: In the first 5 years offering LUTATE, we treated 143 individuals with a variety of NETs of which approx. 70% were gastroentero-pancreatic in origin (small bowel: 42%, pancreas: 28%). Males and females were equally represented. Mean age at first treatment with LUTATE was 61 ± 13 years with range 28-87 years. The radiation dose to the organs considered most at risk, the kidneys, averaged 10.6 ± 4.0 Gy in total. Median overall survival (OS) from first receiving LUTATE was 72.5 months with a median progression-free survival (PFS) of 32.3 months. No evidence of renal toxicity was seen. The major long-term complication seen was myelodysplastic syndrome (MDS) with a 5% incidence. CONCLUSIONS: LUTATE treatment for NETs is a safe and effective treatment. Our approach relies heavily on functional and morphological imaging informing the multidisciplinary team of NET specialists to guide appropriate therapy, which we suggest has contributed to the favourable outcomes seen.

Recruitment of activated neutrophils correlates with disease severity in adult Crohn's disease.

Neutrophils are detected in inflamed colon in Crohn's disease (CD). However, whether the frequency and/or activation of circulating or gut tissue neutrophils correlate with endoscopic severity remains to be investigated. A cohort of 73 CD patients was prospectively enrolled according to endoscopic severity and treatment history. Individuals with active disease were stratified using the Montreal classification. Harvey-Bradshaw Index (HBI) and Simple Endoscopic Score for Crohn's Disease (SES-CD) were performed at the time of ileocolonoscopy. Frequency of neutrophils and their expression of CD66b and CD64 were assessed in paired blood and colonic biopsies using flow cytometry. The percentage of neutrophils increased in inflamed colon and correlated with SES-CD in the entire cohort of patients examined, as well as in the subgroup with inflammatory (B1) active disease. SES-CD further correlated with neutrophil CD66b expression in mucosa but not blood and, conversely, with neutrophil CD64 expression in blood but not mucosa. However, the evaluation of neutrophil activation in mucosa when compared to blood reflected disease activity more clearly. Finally, a neutrophil activation power index (CD66b in mucosa X CD64 in blood) that correlated with SES-CD discriminated between patients with mild and severe disease. In conclusion, the frequency and activation of colonic neutrophils correlated with SES-CD, highlighting that mucosal neutrophils are associated with disease severity in CD.

Review article: a clinician's guide for therapeutic drug monitoring of infliximab in inflammatory bowel disease.

BACKGROUND: Tumour necrosis factor (TNF)-antagonists have an established role in the treatment of inflammatory bowel diseases (IBDs), however, subtherapeutic drug levels and the formation of anti-drug antibodies (ADAs) may decrease their efficacy. AIM: The evidence supporting the use of therapeutic drug monitoring (TDM) based clinical algorithms for infliximab (IFX) and their role in clinical practice will be discussed. METHODS: The literature was reviewed to identify relevant articles on the measurement of IFX levels and antibodies-to-infliximab. RESULTS: Treatment algorithms for IBD have evolved from episodic monotherapy used in patients refractory to all other treatments, to long-term combination therapy initiated early in the disease course. Improved remission rates have been observed with this paradigm shift, nevertheless many patients ultimately lose response to therapy. Although empiric dose optimization or switching agents constitute the current standard of care for secondary failure, these interventions have not been applied in an evidence-based manner and are probably not cost-effective. Multiple TDM-based algorithms have been developed to identify patients that may benefit from measurement of IFX and ADA levels to guide adjustments to therapy. CONCLUSIONS: Therapeutic drug monitoring offers a rational approach to the management of secondary failure to IFX. This concept has gained momentum based on evidence from case series, cohort studies and post-hoc analyses of randomised controlled trials.

HIV forensics: pitfalls and acceptable standards in the use of phylogenetic analysis as evidence in criminal investigations of HIV transmission.

BACKGROUND: Phylogenetic analysis - the study of the genetic relatedness between HIV strains - has recently been used in criminal prosecutions as evidence of responsibility for HIV transmission. In these trials, the expert opinion of virologists has been of critical importance. PITFALLS: Phylogenetic analysis of HIV gene sequences is complex and its findings do not achieve the levels of certainty obtained with the forensic analysis of human DNA. Although two individuals may carry HIV strains that are closely related, these will not necessarily be unique to the two parties and could extend to other persons within the same transmission network. ACCEPTABLE STANDARDS: For forensic purposes, phylogenetic analysis should be conducted under strictly controlled conditions by laboratories with relevant expertise applying rigorous methods. It is vitally important to include the right controls, which should be epidemiologically and temporally relevant to the parties under investigation. Use of inappropriate controls can exaggerate any relatedness between the virus strains of the complainant and defendant as being strikingly unique. It will be often difficult to obtain the relevant controls. If convenient but less appropriate controls are used, interpretation of the findings should be tempered accordingly. CONCLUSIONS: Phylogenetic analysis cannot prove that HIV transmission occurred directly between two individuals. However, it can exonerate individuals by demonstrating that the defendant carries a virus strain unrelated to that of the complainant. Expert witnesses should acknowledge the limitations of the inferences that might be made and choose the correct language in both written and verbal testimony.

Optimal pinhole techniques for preoperative localization with Tc-99m MIBI for primary hyperparathyroidism.

PURPOSE: Technetium-99m-labeled 2-methoxyisobutylisonitrile (Tc-99m MIBI) has been used extensively to localize parathyroid adenomas before operation. Imaging techniques vary widely, and the aim of this study was to determine the optimal time of delayed imaging and the value of routine correlative pertechnetate thyroid imaging. MATERIALS AND METHODS: In this study, preoperative parathyroid localization was performed using pinhole anterior and oblique images (15 minutes and 2 and 4 hours after injection) with correlative pertechnetate thyroid images. Ninety-seven patients underwent dual- or triple-phase Tc-99m MIBI imaging and correlative pertechnetate thyroid imaging before surgery. Two nuclear medicine physicians blinded to the surgical findings interpreted all available images and various Tc-99m MIBI image combinations at 15 minutes alone; 15 minutes and 2 hours, 15 minutes and 4 hours; and 15 minutes and 2 and 4 hours each with and without correlative pertechnetate thyroid imaging. RESULTS: Ninety parathyroid adenomas were detected in 86 patients. The optimal results were achieved with 15-minute and 2- and 4-hour Tc-99m-MIBI images, with correlative thyroid scans resulting in a sensitivity rate of 88%. Fifteen-minute and 2-hour Tc-99m-MIBI images and correlative thyroid scans and 15-minute and 4-hour Tc-99m MIBI images and correlative thyroid scans produced similar results (sensitivity rate, 86% and 83%, respectively; P = not significant). Compared with all Tc-99m MIBI image combinations alone, the addition of the routine correlative thyroid scan significantly improved sensitivity and also improved reporter confidence in 45% of studies. CONCLUSIONS: Of the pinhole techniques compared, 15-minute and 2-hour Tc-99m MIBI images with correlative thyroid scanning may be the preferred imaging protocol, because this yields results similar to imaging for as long as 4 hours after injection in a shorter, more logistically acceptable imaging time.

The value of oblique pinhole images in pre-operative localisation with 99mTc-MIBI for primary hyperparathyroidism.

Technetium-99m labelled 2-methoxyisobutylisonitrile (MIBI) has been extensively utilised for preoperative localisation of parathyroid adenomas. Imaging techniques have varied widely, with many centres not performing routine oblique images; thus this study aimed to examine the value of routine oblique pinhole imaging. Ninety-two patients underwent pre-operative 99mTc-MIBI imaging including early and delayed anterior oblique pinhole images in addition to standard anterior pinhole images and a thyroid study prior to surgery for primary hyperparathyroidism. These studies were reviewed blindly comparing anterior and oblique images and anterior images only in relation to surgical findings. Of the 92 patients, 83 were found to have 86 parathyroid adenomas or parathyroid adenoma/hyperplasia at surgery. When compared to anterior images only, oblique views improved overall sensitivity from 76% to 88% (P<0.05), correctly localised 11 more adenomas than anterior images alone (13%) and improved the confidence of interpretation in 17 patients (20%). In conclusion, routine oblique pinhole views result in greater sensitivity and reporter confidence in pre-operative parathyroid localisation with 99mTc-MIBI.

Computer-assisted visualization of arteriovenous malformations on the home personal computer.

OBJECTIVE: Arteriovenous malformations (AVMs) are difficult lesions to treat, partly because it is difficult to formulate a three-dimensional mental image of the nidus and its supplying arteries, draining veins, and arteries of passage. Our purpose is to develop personal computer software that allows better visualization of complex, three-dimensional, connected vascular anatomy for surgical planning. METHODS: Vessels are defined from magnetic resonance angiograms and are symbolically linked to form vascular trees. The nidus of the AVM is also defined by magnetic resonance angiography. These representations of the nidus and vasculature can be viewed together in a software program that allows the user to color-code groups of vessels or to selectively turn connected groups of vessels "off" to avoid obscuring the part of the image that the user wants to observe. Structures can be viewed from any angle. The vessels can also be shown intersecting any magnetic resonance angiogram slice or superimposed upon digital subtraction angiograms obtained from the same patient. RESULTS: We report results from two patients with AVMs in which our representations were compared with the findings during surgery. Our three-dimensional vascular trees correctly depicted the relationship of the nidus to feeding vessels in three dimensions. We show findings in an additional, unoperated patient for whom vessel trees were created from three-dimensional digital subtraction angiography data and compared with a volume rendering of the original data set. CONCLUSION: Computer-assisted, three-dimensional visualizations of complex vascular anatomy can be helpful in planning the surgical excision of AVMs. Software programs that produce these images can provide important information that is difficult to obtain by traditional techniques. This imaging method is also applicable to guidance of endovascular procedures and removal of complex tumors.

Role of ischemia and infarction in late right ventricular dysfunction after atrial repair of transposition of the great arteries.

OBJECTIVES: This study was conducted to assess whether myocardial ischemia and/or infarction are involved in the pathogenesis of late right ventricular dysfunction in adult survivors of atrial baffle repair for transposition of the great arteries in infancy. BACKGROUND: The medium-term success of intraatrial baffle repair for transposition of the great arteries is good, with many patients surviving into adult life, but prognosis can be limited by progressive right ventricular dysfunction. We hypothesized that ongoing myocardial ischemia and/or infarction are important factors in the pathogenesis of this complication. Radionuclide techniques offer an opportunity to study both myocardial perfusion and concomitant ventricular wall motion. METHODS: Dipyridamole sestamibi single-photon emission computed tomography followed by rest sestamibi single-photon emission computed tomography was used to assess right ventricular myocardial perfusion, wall motion, wall thickening and ejection fraction in 22 adolescents/young adults who had undergone atrial baffle repair for simple transposition of the great arteries at median 6.7 (range 0.5 to 54) months of age. The patients were aged 10 to 25 (median 15.5) years; 19 in New York Heart Association class I, 2 in class II and 1 in class III. All were in a regular cardiac rhythm during the studies. The right ventricular tomographic images were examined in three parallel and two orthogonal planes, analyzed in 12 segments. RESULTS: Perfusion defects were evident in all patients in at least one segment, in either the rest or stress images. Twelve patients (55%) demonstrated fixed defects only, nine (41%) had fixed and reversible defects and one (4.5%) had reversible defects only. Concomitant wall-thickening abnormalities occurred in 83% of segments with fixed perfusion defects, mirrored by a reduction in wall motion in 91% of segments analyzed. Right ventricular ejection fraction was correlated with age (R = 0.62; p = 0.002), and with wall-thickening abnormalities (R = 0.60; p < 0.005). CONCLUSIONS: Reversible and fixed perfusion defects with concordant regional wall motion abnormalities occur in the right (systemic) ventricle 10 to 20 years after Mustard repair for transposition of the great arteries; this may be important in the pathogenesis of late right ventricular dysfunction in this group.

Right ventricular dysfunction in congenitally corrected transposition of the great arteries.

Although right ventricular (RV) dysfunction is an important complication in subjects with congenitally corrected transposition of the great arteries, its pathogenesis is poorly understood. We assessed the role of RV myocardial perfusion and found perfusion defects at rest in all 20 patients, involving 4.6 +/- 2.3 of a total of 12 segments; the extent of the resting perfusion defects correlated inversely with the RV ejection fraction.

Myocardial infarction complicating neonatal enterovirus myocarditis.

A 10-week-old, 31-week gestation preterm boy re-presented with heart failure after an initial episode of neonatal aseptic meningitis with positive CSF enterovirus polymerase chain reaction. Investigation demonstrated global myocardial dysfunction with left ventricle posterolateral myocardial infarction. The boy's heart failure was controlled with medical treatment but his myocardial dysfunction persisted 9 months after presentation.

Patterns of abnormality on bone scans in acute childhood leukemia.

Bone scintigraphy is not performed routinely in the diagnostic work-up of children with leukemia; however, the initial diagnosis of childhood leukemia is often difficult to make and may be delayed. Patients may present with fever and skeletal symptoms and, in such cases, bone scintigraphy may be requested in the early search for a diagnosis. Recognition of the potential scintigraphic abnormalities that result from leukemic infiltration of bone and bone marrow will often facilitate an early diagnosis of leukemia. Bone scans also play a role in detecting osteomyelitis in the immunosuppressed leukemic child with fever and bone pain. This article presents four patients illustrating the salient features of bone scintigraphy in these clinical settings.

Variability in the interpretation of dimercaptosuccinic acid scintigraphy after urinary tract infection in children.

UNLABELLED: Technetium-99m-dimercaptosuccinic acid (DMSA) scintigraphy is a frequently used diagnostic test in pediatric practice to assess the presence and severity of renal damage. Most commonly it is performed after urinary tract infection. The aim of this study was to investigate the variability in the interpretation of DMSA scans by pediatric nuclear medicine physicians in this clinical setting. METHODS: We selected all 441 scans from children with first-time urinary tract infection who presented between 1993 and 1995 to a pediatric casualty department and who are participants in a prospective cohort study. Two hundred and ninety-four scans were performed at a median time of 7 days after diagnosis, and 147 scans were from children who were free from further infection over a 1-yr follow-up period. Two experienced nuclear medicine physicians independently interpreted the 441 scans according to whether renal damage was present or absent and using the modified 4-level grading system for DMSA abnormality of Goldraich. Apart from being informed that urinary tract infection was the indication for DMSA scintigraphy, no other clinical information was given to the nuclear medicine physicians. The indices of variability used were the percentage of agreement and the kappa statistic. For the grading scale used, both measures were weighted with integers representing the number of categories from perfect agreement. Disagreement was analyzed for children, kidneys and kidney zones. RESULTS: There was agreement in 86% (kappa = 69%) for the normal-abnormal DMSA scan dichotomy, and the weighted agreement was 94% (weighted kappa = 82%) for the grading of abnormality. Disagreement of DMSA scan interpretation of > or =2 grades was present in three cases (0.7%). The same high level of agreement was present for patient, kidney and kidney zone comparisons. Agreement was not influenced by age or timing of scintigraphy after urinary tract infection. CONCLUSION: Two experienced nuclear medicine physicians showed good agreement in the interpretation of DMSA scintigraphy in children after urinary tract infection and using the grading system of Goldraich.

Myocardial perfusion defects and associated systemic ventricular dysfunction in congenitally corrected transposition of the great arteries.

BACKGROUND: Patients with systemic ventricles of right ventricular morphology are at high risk of contractile dysfunction, the cause of which has not been fully elucidated. OBJECTIVE: To assess whether ischaemia or infarction contributes to ventricular impairment in unoperated patients with uncomplicated congenitally corrected transposition of the great arteries (TGA) by studying myocardial perfusion and function. SETTING: Paediatric and adult congenital cardiac clinics of a tertiary referral centre. PATIENTS: Five patients with congenitally corrected TGA but without associated structural cardiac defects (aged 3.5 to 34 years). INTERVENTIONS: Maximal exercise stress testing using standard or modified Bruce protocols. Sestamibi (technetium-99m methoxy isobutyl isonitrile) scanning after isotope injection at maximal exercise and rest. MAIN OUTCOME MEASURES: Maximum exercise capacity; right ventricular myocardial perfusion, regional wall motion, and thickening; right ventricular ejection fraction. RESULTS: The two youngest patients (3.5 and 11 years) had normal exercise capacity for age, while the others had reduced exercise performance. Sestamibi scanning showed reversible myocardial ischaemia in four patients and fixed defects indicating infarction in five. Irreversible defects were mostly associated with impaired wall motion and thickening. The ejection fraction was normal (65%) in the youngest patient but < 55% in the others (mean (SD) 47(11)%). CONCLUSIONS: Patients with unoperated congenitally corrected TGA have a high prevalence of myocardial perfusion defects, with consequent abnormalities of regional wall motion and thickening, and impaired ventricular contractility. These data suggest that ischaemia and infarction are important in the pathogenesis of ventricular failure in this condition.

Tl-201 positive, Ga-67 negative hepatoblastoma: a case report of a 12-year-old boy.

Hepatoblastoma is a primary liver neoplasm in which prompt diagnosis and resection are critical to long-term survival. Nuclear scintigraphy plays an important role in the characterization of hepatic masses. The authors present an unusual case of hepatoblastoma in a 12-year-old boy in whom Ga-67 scintigraphy and serum alpha-fetoprotein were negative. Positive Tl-201 scintigraphy pointed toward the true malignant nature of the mass and should be considered in the investigation of hepatic masses in childhood.

Percutaneous stent placement for treatment of stenosis of a portacaval H-graft shunt.

Surgical treatment of an occluded or stenotic portacaval shunt carries a high risk of mortality, but the rate of restenosis after transluminal angioplasty is also high. The authors report high-grade stricture of a portacaval H-graft shunt in a 51-year-old man, who presented with hematemesis and melena. The patient was treated with concomitant balloon angioplasty and placement of a metallic stent through a percutaneous venous approach. The procedure was tolerated well by the patient, and stenosis had not recurred at follow-up 1 year later.

Cochlear implantation in a patient after removal of an acoustic neuroma. The implications of magnetic resonance imaging with gadolinium on patient management.

The advent of magnetic resonance imaging has allowed otologists to focus on the early removal of acoustic neuromas with the goal of hearing preservation. Clearly, there are some unpredictable factors, such as placement of the tumor in the medial vs the lateral segment of the internal auditory canal and the capricious nature of the blood supply to these benign neoplasms, that make prediction of hearing preservation difficult. Nonetheless, the present goal of surgery for removal of acoustic tumors has changed its focus from preservation of the facial nerve alone to preservation of the facial nerve and preservation of hearing. In a patient with an only-hearing ear and a small acoustic neuroma, there is some controversy concerning whether the tumor should be removed early, with the goal of hearing preservation, or if the patient should be allowed to progress to a considerable hearing loss in an effort to preserve natural hearing as long as possible. We report a case in which an acoustic tumor was removed from an only-hearing ear in a patient with neurofibromatosis after hearing loss had progressed in that ear but before the development of total deafness. Postoperatively, the patient successfully underwent cochlear implantation. We also discuss decisions that we made during the surgical procedure, as well as the feasibility of cochlear implantation in patients with profound deafness after the excision of acoustic neuromas.

Cardiovascular autonomic insufficiency in a patient with metastatic malignancy.

A case of cardiovascular autonomic insufficiency is described in a cachectic 70-year-old man with widely metastatic small-cell tumor. The patient experienced disabling syncopal episodes in association with severe postural hypotension. Tests of cardiovascular autonomic insufficiency were abnormal. The introduction of fludrocortisone and the use of elastic stockings produced palliation of the symptomatology, but his condition deteriorated and he died. Autopsy demonstrated unexpectedly extensive tumor invasion of autonomic nervous tissue. Although cardiovascular autonomic insufficiency (CAI) has been described in association with malignancy and malnutrition, local tumor invasion of autonomic nervous tissue and radiation injury may have been other possible, albeit unusual, etiologic factors. This case illustrates the differential diagnosis of hypotension and CAI in patients with advanced metastatic malignancy and also emphasizes the need for autopsy studies when speculating as to the cause of CAI in this group of patients.

Incidence of pulmonary embolism in single segmental mismatch on lung scanning.

UNLABELLED: Controversy exists as to whether patients with single segmental mismatch (SSM) on a ventilation/perfusion (VQ) lung scan should be given a low or an intermediate probability of pulmonary embolism (PE). METHODS: Pulmonary angiography was used to evaluate the incidence of PE in SSM at the authors' institution. From January 1991 to January 1993, 1449 VQ scans were performed. RESULTS: With modified Biello criteria, 283 were high probability; 628, low probability; 273, normal; and 273, intermediate probability. Of the intermediate probability scans, 61 had SSM. Forty of these patients underwent pulmonary angiography. Twelve patients had PE in the area of the SSM, giving an incidence of PE of 30%. The risk of PE in SSM in the different lung regions was also analyzed. Twenty-three SSM were in the bases of the lung with a 22% incidence of PE; 17 SSM were either in the midzone or apex with a 41% incidence of PE (p = not significant). CONCLUSION: SSM carries a 30% risk of PE. Accordingly, SSM should be given an intermediate probability of PE and not a low probability of PE.

Malignant biliary obstruction: preliminary results of palliative treatment with hepaticogastrostomy under fluoroscopic, endoscopic, and laparoscopic guidance.

PURPOSE: To report a technique of peripheral biliary decompression by means of anastomosis of a bile duct in segment II of the liver to the lesser curvature of the stomach. MATERIALS AND METHODS: Seven patients with unresectable biliary neoplasm were treated. After transhepatic catheterization of a segment II bile duct, the left lobe of the liver and the lesser curvature of the stomach were perforated under fluoroscopic and laparoscopic guidance. Anastomosis between the biliary tree and the stomach was maintained with a gastrostomy tube placed across the tract. After 2 weeks, the tube was removed and patency of the tract was preserved with a metallic stent. RESULTS: Three patients died, at 3, 6, and 9 months, respectively, without reocclusion; the other four were alive at 5 months without jaundice. One patient had an episode of cholangitis, which was resolved with antibiotic therapy. CONCLUSION: This method yields a good patency rate with few problems. Further investigation is required to evaluate long-term patency and the necessity of laparoscopic guidance.