Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent Pheochromocytoma or Paraganglioma

Context: No therapies are approved for the treatment of metastatic and/or recurrent pheochromocytoma or paraganglioma (PPGL) in the United States. Objective: To determine the maximum tolerated dose (MTD) of high-specific-activity I-131 meta-iodobenzylguanidine (MIBG) for the treatment of metastatic and/or recurrent PPGL. Design: Phase 1, dose-escalating study to determine the MTD via a standard 3 + 3 design, escalating by 37 MBq/kg starting at 222 MBq/kg. Setting: Three centers. Patients: Twenty-one patients were eligible, received study drug, and were evaluable for MTD, response, and toxicity. Intervention: Open-label use of high-specific-activity I-131 MIBG therapy. Main Outcome Measures: Dose-limiting toxicities, adverse events, radiation absorbed dose estimates, radiographic tumor response, biochemical response, and survival. Results: The MTD was determined to be 296 MBq/kg on the basis of two observed dose-limiting toxicities at the next dose level. The highest mean radiation absorbed dose estimates were in the thyroid and lower large intestinal wall (each 1.2 mGy/MBq). Response was evaluated by total administered activity: four patients (19%), all of whom received \u3e18.5 GBq of study drug, had radiographic tumor responses of partial response by Response Evaluation Criteria in Solid Tumors. Best biochemical responses (complete or partial response) for serum chromogranin A and total metanephrines were observed in 80% and 64% of patients, respectively. Overall survival was 85.7% at 1 year and 61.9% at 2 years after treatment. The majority (84%) of adverse events were considered mild or moderate in severity. Conclusions: These findings support further development of high-specific-activity I-131 MIBG for the treatment of metastatic and/or recurrent PPGL at an MTD of 296 MBq/kg

SNM Practice Guideline for Breast Scintigraphy with Breast-Specific gamma-Cameras 1.0

The intention of this guideline is to assist breast imaging practitioners in selecting patients for, performing, interpreting, and reporting 99mTc-sestamibi breast-specific γ-imaging

Isolated Splenic Metastasis from Rectal Carcinoma: A Rare Occurrence

The presence of isolated splenic metastasis in rectal carcinoma is uncommon and usually presents as an asymptomatic mass, noted incidentally on imaging. Splenectomy is usually performed with the goal of curing metastatic disease. It is unclear if adjuvant chemotherapy affords any benefit, and the prognosis is unknown. The case of a young woman is reported, in whom an isolated metastatic lesion in the spleen was discovered 9 months after adjuvant chemotherapy for stage III rectal adenocarcinoma. The patient has remained disease-free for nearly 5 years following splenectomy and chemotherapy. To our knowledge, this is the fourth reported case in the English literature of an isolated splenic metastatic lesion from rectal cancer. We discuss the unique presentation, the importance of post-treatment surveillance, and the implementation of multi-modality treatment strategies in this young patient

Cycles of Police Reform in Latin America.

yesOver the last quarter century post-conflict and post-authoritarian transitions in Latin America have been accompanied by a surge in social violence, acquisitive crime, and insecurity. These phenomena have been driven by an expanding international narcotics trade, by the long-term effects of civil war and counter-insurgency (resulting in, inter alia, an increased availability of small arms and a pervasive grammar of violence), and by structural stresses on society (unemployment, hyper-inflation, widening income inequality). Local police forces proved to be generally ineffective in preventing, resolving, or detecting such crime and forms of “new violence”3 due to corruption, frequent complicity in criminal networks, poor training and low pay, and the routine use of excessive force without due sanction. Why, then, have governments been slow to prioritize police reform and why have reform efforts borne largely “limited or nonexistent” long-term results? This chapter highlights a number of lessons suggested by various efforts to reform the police in Latin America over the period 1995-2010 . It focuses on two clusters of countries in Latin America. One is Brazil and the Southern Cone countries (Chile, Argentina, and Uruguay), which made the transition to democracy from prolonged military authoritarian rule in the mid- to late 1980s. The other is Central America and the Andean region (principally El Salvador, Guatemala, Honduras, Peru, and Colombia), which emerged/have been emerging from armed conflict since the mid- 1990s. The chapter examines first the long history of international involvement in police and security sector reform in order to identify long-run tropes and path dependencies. It then focuses on a number of recurring themes: cycles of de- and re-militarization of the policing function; the “security gap” and “democratization dilemmas” involved in structural reforms; the opportunities offered by decentralization for more community-oriented police; and police capacity to resist reform and undermine accountability mechanisms

90Y-clivatuzumab tetraxetan with or without low-dose gemcitabine: A phase Ib study in patients with metastatic pancreatic cancer after two or more prior therapies

AbstractBackgroundFor patients with metastatic pancreatic adenocarcinoma, there are no approved or established treatments beyond the 2nd line. A Phase Ib study of fractionated radioimmunotherapy was undertaken in this setting, administering 90Y-clivatuzumab tetraxetan (yttrium-90-radiolabelled humanised antibody targeting pancreatic adenocarcinoma mucin) with or without low radiosensitising doses of gemcitabine.MethodsFifty-eight patients with three (2–7) median prior treatments were treated on Arm A (N=29, 90Y-clivatuzumab tetraxetan, weekly 6.5mCi/m2doses×3, plus gemcitabine, weekly 200mg/m2 doses×4 starting 1week earlier) or Arm B (N=29, 90Y-clivatuzumab tetraxetan alone, weekly 6.5mCi/m2doses×3), repeating cycles after 4-week delays. Safety was the primary endpoint; efficacy was also evaluated.ResultsCytopaenias (predominantly transient thrombocytopenia) were the only significant toxicities. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ⩾1 full treatment cycles, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including seven (6 Arm A, 1 Arm B; 12%) given 3–9 cycles. Two patients in Arm A had partial responses by RECIST criteria. Kaplan–Meier overall survival (OS) appeared improved in Arm A versus B (hazard ratio [HR] 0.55, 95% CI: 0.29–0.86; P=0.017, log-rank) and the median OS for Arm A versus Arm B increased to 7.9 versus 3.4months with multiple cycles (HR 0.32, P=0.004), including three patients in Arm A surviving >1year.ConclusionsClinical studies of 90Y-clivatuzumab tetraxetan combined with low-dose gemcitabine appear feasible in metastatic pancreatic cancer patients beyond 2nd line and a Phase III trial of this combination is now underway in this setting

Phase II Study of Lutetium-177-Labeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Metastatic Castration-Resistant Prostate Cancer

To assess the efficacy of a single infusion of radiolabeled anti-prostate specific membrane antigen monoclonal antibody J591 (177Lu-J591) by PSA decline, measurable disease response, and survival

Fractionated radioimmunotherapy with 90Y-clivatuzumab tetraxetan and low-dose gemcitabine is active in advanced pancreatic cancer: A phase 1 trial

It has been demonstrated that the humanized clivatuzumab tetraxetan (hPAM4) antibody targets pancreatic ductal carcinoma selectively. After a trial of radioimmunotherapy that determined the maximum tolerated dose of single-dose yttrium-90-labeled hPAM4 (90Y-hPAM4) and produced objective responses in patients with advanced pancreatic ductal carcinoma, the authors studied fractionated radioimmunotherapy combined with low-dose gemcitabine in this disease

Gene Expression Changes in the Prefrontal Cortex, Anterior Cingulate Cortex and Nucleus Accumbens of Mood Disorders Subjects That Committed Suicide

Suicidal behaviors are frequent in mood disorders patients but only a subset of them ever complete suicide. Understanding predisposing factors for suicidal behaviors in high risk populations is of major importance for the prevention and treatment of suicidal behaviors. The objective of this project was to investigate gene expression changes associated with suicide in brains of mood disorder patients by microarrays (Affymetrix HG-U133 Plus2.0) in the dorsolateral prefrontal cortex (DLPFC: 6 Non-suicides, 15 suicides), the anterior cingulate cortex (ACC: 6NS, 9S) and the nucleus accumbens (NAcc: 8NS, 13S). ANCOVA was used to control for age, gender, pH and RNA degradation, with P≤0.01 and fold change±1.25 as criteria for significance. Pathway analysis revealed serotonergic signaling alterations in the DLPFC and glucocorticoid signaling alterations in the ACC and NAcc. The gene with the lowest p-value in the DLPFC was the 5-HT2A gene, previously associated both with suicide and mood disorders. In the ACC 6 metallothionein genes were down-regulated in suicide (MT1E, MT1F, MT1G, MT1H, MT1X, MT2A) and three were down-regulated in the NAcc (MT1F, MT1G, MT1H). Differential expression of selected genes was confirmed by qPCR, we confirmed the 5-HT2A alterations and the global down-regulation of members of the metallothionein subfamilies MT 1 and 2 in suicide completers. MTs 1 and 2 are neuro-protective following stress and glucocorticoid stimulations, suggesting that in suicide victims neuroprotective response to stress and cortisol may be diminished. Our results thus suggest that suicide-specific expression changes in mood disorders involve both glucocorticoids regulated metallothioneins and serotonergic signaling in different regions of the brain

Using functional data analysis to understand daily activity levels and patterns in primary school-aged children: Cross-sectional analysis of a UK-wide study

Temporal characterisation of physical activity in children is required for effective strategies to increase physical activity (PA). Evidence regarding determinants of physical activity in childhood and their time-dependent patterns remain inconclusive. We used functional data analysis (FDA) to model temporal profiles of daily activity, measured objectively using accelerometers, to identify diurnal and seasonal PA patterns in a nationally representative sample of primary school-aged UK children. We hypothesised that PA levels would be lower in girls than boys at play times and after school, higher in children participating in social forms of exercise (such as sport or play), and lower among those not walking to school.Children participating in the UK-wide Millennium Cohort Study wore an Actigraph GT1M accelerometer for seven consecutive days during waking hours. We modelled 6,497 daily PA profiles from singleton children (3,176 boys; mean age: 7.5 years) by means of splines, and used functional analysis of variance to examine the cross-sectional relation of time and place of measurement, demographic and behavioural characteristics to smoothed PA profiles.Diurnal and time-specific patterns of activity showed significant variation by sex, ethnicity, UK country and season of measurement; girls were markedly less active than boys during school break times than boys, and children of Indian ethnicity were significantly less active during school hours (9:30-12:00). Social activities such as sport clubs, playing with friends were associated with higher level of PA in afternoon (15:00-17:30) and early evenings (17:30-19:30). Lower PA levels between 8:30-9:30 and 17:30-19:30 were associated with mode of travel to and from school, and number of cars in regular use in the household.Diminished PA in primary school aged children is temporally patterned and related to modifiable behavioural factors. FDA can be used to inform and evaluate public health policies to promote childhood PA