Long-term survival and toxicity in patients with neuroendocrine tumors treated with 177 Lu-octreotate peptide radionuclide therapy.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) has shown favorable results in neuroendocrine tumors (NETs). Long-term safety and efficacy data for 177 Lu-octreotate PRRT, particularly in combination with chemotherapy, is lacking. METHODS: The authors conducted a retrospective review of the long-term toxicity and survival outcomes of 104 patients with advanced NETs treated on 4 phase 2 clinical trials with Lutetium-177-octreotate (177 Lu-octreotate) PRRT, mostly in combination with chemotherapy. Median follow-up was 68 months, which represents the longest follow-up study of 177 Lu-octreotate PRRT for NETs to date. RESULTS: Median progression-free survival (PFS) was 37 months, and median overall survival (OS) was 71 months. Five- and 10-year OS were 62% and 29%, and 5- and 10-year PFS were 36% and 21%, respectively, demonstrating 177 Lu-octreotate can provide durable responses. PRRT was well tolerated with 1.9% of patients developing chronic renal impairment and 1% of patients developing long-term thrombocytopenia. Interestingly, there was a relatively high rate of myelodysplasia (MDS)/leukemia (6.7%), possibly attributable to the longer follow-up (with all except 1 case occurring more than 4 years after PRRT treatment) or to the addition of concurrent chemotherapy. CONCLUSIONS: Lutetium-177-Octreotate PRRT remains an efficacious and well tolerated treatment in long-term follow-up. For clinicians deciding on the timing of PRRT for individual patients, the 6.7% long-term risk of MDS/leukemia needs to be balanced against the 21% PFS at 10 years.

Pituitary function following peptide receptor radionuclide therapy for neuroendocrine tumours.

Peptide receptor radionuclide therapy (PRRT) is an increasingly used treatment for unresectable neuroendocrine tumours (NETs) that express somatostatin receptors. Normal pituitary tissue expresses somatostatin receptors so patients receiving PRRT may be at risk of developing hypopituitarism. The aim was to assess the prevalence of clinically significant hypopituitarism a minimum of 2 years following radioisotope therapy for metastatic NET. This was a multicentre study (Australia and New Zealand). Sixty-six patients with unresectable NETs were included-34 had received PRRT and 32 comparison patients. Median follow-up after PRRT was 68 months. Male hypogonadism was the most common hormonal abnormality (16 of 38 men [42%]) from the total cohort. Of these, seven men had primary hypogonadism (five from PRRT group) and nine had secondary hypogonadism (six in PRRT group). There was no difference in either male hypogonadism or other hormonal dysfunction between patients who had received PRRT and those that had not. Patients who have received PRRT out to 68 months following treatment do not show concerning hypopituitarism although there may be the suggestion of growth hormone deficiency developing. However, hypogonadism is common in men with NETs so the gonadal axis should be assessed in men with suggestive symptoms as the treatment of testosterone deficiency may improve the quality of life.

Disorders of sex development (DSD) web-based information: quality survey of DSD team websites.

OBJECTIVES: Consumers rely on online health information, particularly for unusual conditions. Disorders of Sex Development (DSD) are complex with some aspects of care controversial. Accurate web-based DSD information is essential for decision-making, but the quality has not been rigorously evaluated. The purpose of the present study was to assess the quality of online health information related to DSD presented by 12 pediatric institutions comprising the NIH-sponsored DSD-Translational Research Network (DSD-TRN). METHODS: DSD-TRN sites identified team webpages, then we identified linked webpages. We also used each institution search engine to search common DSD terms. We assessed webpages using validated tools: the Simple Measure of Gobbledygook (SMOG) determined reading level, the Patient Education Materials Assessment Tool (PEMAT) evaluated content for understandability and actionability, and the DISCERN tool assessed treatment decision-making information (for hormone replacement and surgery). We developed a "Completeness" measure which assessed the presence of information on 25 DSD topics. RESULTS: The SMOG reading level of webpages was at or above high-school grade level. Mean (SD) PEMAT understandability score for Team Pages and Team Links was 68% (6%); on average these pages met less than 70% of the understandability criteria. Mean (SD) PEMAT actionability score was 23% (20%); few patient actions were identified. The DISCERN tool determined that the quality of information related to hormone treatment and to surgery was poor. Sites' webpages covered 12-56% of the items on our Completeness measure. CONCLUSIONS: Quality of DSD online content was poor, and would be improved by using a variety of strategies, such as simplifying word choice, using visual aids, highlighting actions patients can take and acknowledging areas of uncertainty. For complex conditions such as DSD, high-quality web-based information is essential to empower patients (and caregiver proxies), particularly when aspects of care are controversial.

Cross-Platform Comparison of Computer-assisted Image Analysis Quantification of In Situ mRNA Hybridization in Investigative Pathology.

Although availability of automated platforms has proliferated, there is no standard practice for computer-assisted generation of scores for mRNA in situ hybridization (ISH) visualized by brightfield microscopic imaging on tissue sections. To address this systematically, an ISH for peptidylprolyl isomerase B (PPIB) (cyclophilin B) mRNA was optimized and applied to a tissue microarray of archival non-small cell lung carcinoma cases, and then automated image analysis for PPIB was refined across 4 commercially available software platforms. Operator experience and scoring results from ImageScope, HALO, CellMap, and Developer XD were systematically compared with each other and to manual pathologist scoring. Markup images were compared and contrasted for accuracy, the ability of the platform to identify cells, and the ease of visual assessment to determine appropriate interpretation. Comparing weighted scoring approaches using H-scores (Developer XD, ImageScope, and manual scoring) a correlation was observed (R value=0.7955), and association between the remaining 2 approaches (HALO and CellMap) was of similar value. ImageScope showed the highest R value in comparison with manual scoring (0.7377). Mean-difference plots showed that HALO produced the highest relative normalized values, suggesting higher relative sensitivity. ImageScope overestimated PPIB ISH signal at the high end of the range scores; however, this tendency was not observed in other platforms. HALO emerged with the highest number of favorable observations, no apparent systematic bias in score generation compared with the other methods, and potentially higher sensitivity to detect ISH. HALO may serve as a tool to empower teams of investigative pathology laboratory scientists to assist pathologists readily with quantitative scoring of ISH.

Application of Rapid Visco Analyser (RVA) viscograms and chemometrics for maize hardness characterisation.

It has been established in this study that the Rapid Visco Analyser (RVA) can describe maize hardness, irrespective of the RVA profile, when used in association with appropriate multivariate data analysis techniques. Therefore, the RVA can complement or replace current and/or conventional methods as a hardness descriptor. Hardness modelling based on RVA viscograms was carried out using seven conventional hardness methods (hectoliter mass (HLM), hundred kernel mass (HKM), particle size index (PSI), percentage vitreous endosperm (%VE), protein content, percentage chop (%chop) and near infrared (NIR) spectroscopy) as references and three different RVA profiles (hard, soft and standard) as predictors. An approach using locally weighted partial least squares (LW-PLS) was followed to build the regression models. The resulted prediction errors (root mean square error of cross-validation (RMSECV) and root mean square error of prediction (RMSEP)) for the quantification of hardness values were always lower or in the same order of the laboratory error of the reference method.

Comparison of potential preventive therapeutic agents green tea, thymoquinone, and dilinoleoylphosphatidylcholine on human neuroblastoma cells.

Alzheimer’s disease (AD) is the only cause of death among the top 10 diseases that cannot be prevented, cured, or slowed with the current treatments available. Amyloid beta is thought to be the main initiator of AD cognitive decline, activating internal pathways which lead to inflammation, oxidation, and cell death. The objective of this study was to determine if pretreatment of human SH-SY5Y neuroblastoma cells, a model for AD, with antioxidants thymoquinone (TQ), epigallocatechin-3-gallate (EGCG), or dilinoleoylphosphatidylcholine (DLPC) 30 minutes prior to a challenge with tumor necrosis factor a (TNFa), an inflammatory mediator, can prevent oxidation of amyloid beta (Aß). Following treatment, cells were incubated and groups evaluated at 24, 48, and 72 hours. Human amyloid precursor protein (APP) enzyme-linked immune-sorbent assay (ELISA) and nitric oxide assays were performed from supernatant whereas protein and glutathione assays were performed from cells. When TNFa was added to cells, Aß significantly increased 3-fold compared to untreated cells. The addition of antioxidants EGCG, TQ, and DLPC reduced Aß back toward control value at the initial time point. TNFa also caused a significant increase in nitric oxide without changes in glutathione. TQ administered to the cells prior to a challenge with TNFa resulted in a decrease in nitric oxide and an increase in glutathione which may be a possible mechanism to reduce inflammation and reduce oxidation. Additional studies are needed to determine the signaling pathways implemented in the SH-SY5Y cells following TNFa.

An investigation of the ability of orally primed and tolerised T cells to help B cells upon mucosal challenge.

The oral delivery of soluble antigens induces unresponsiveness to systemic challenge that can be demonstrated as a reduced ability of tolerised T cells to support B-cell expansion and antibody production. However, it remains controversial whether previously induced oral tolerance results in suppression or priming, or has no effect on B-cell responses upon oral challenge. Using a double adoptive transfer system, we primed or tolerised T cells (independently of B cells) with a high dose of fed antigen, and examined the ability of these primed or tolerised T cells to support B-cell clonal expansion in response to orally delivered conjugated antigen. We demonstrated directly in vivo that, in contrast to orally primed T cells, transgenic T cells tolerised by feeding a high dose of antigen are incapable of providing cognate help to support B-cell clonal expansion and antibody production in response to oral challenge. This defect appears to be a result of a reduced ability of orally tolerised transgenic T cells to clonally expand and migrate to B-cell follicles after oral challenge.

An investigation of the distribution of antigen fed in tolerogenic or immunogenic forms.

It remains unclear which cells present fed antigen and whether their phenotype and/or activation state differs between oral tolerance and priming. Furthermore, it is also controversial whether the presentation occurs locally in the gut and/or systemically. Clarifying these issues will be important for the design and use of oral vaccines, the therapeutic use of oral tolerance and understanding of IBD. Previous studies using activation of T cell receptor transgenic T cells to compare local and systemic distribution of fed antigen have yielded conflicting results. We have therefore employed the C4H3 antibody, specific for HEL peptide (46-61) in the context of I-Ak, to examine antigen distribution in oral tolerance and priming. Our studies indicate that immunologically relevant antigen can be detected in both local and systemic lymphoid tissue soon after feeding antigen in tolerogenic or immunogenic forms. Furthermore, targeting fed antigen to BcR tg B cells via their specific B cell receptor also results in local and systemic presentation and leads to up-regulation of costimulatory molecules on these cells that suggests their role in presentation of the fed antigen.