A new large animal model of CLN5 neuronal ceroid lipofuscinosis in Borderdale sheep is caused by a nucleotide substitution at a consensus splice site (c.571+1G>A) leading to excision of exon 3

Batten disease (neuronal ceroid lipofuscinoses, NCLs) are a group of inherited childhood diseases that result in severe brain atrophy, blindness and seizures, leading to premature death. To date, eight different genes have been identified, each associated with a different form. Linkage analysis indicated a CLN5 form in a colony of affected New Zealand Borderdale sheep. Sequencing studies established the disease-causing mutation to be a substitution at a consensus splice site (c.571+1G>A), leading to the excision of exon 3 and a truncated putative protein. A molecular diagnostic test has been developed based on the excision of exon 3. Sequence alignments support the gene product being a soluble lysosomal protein. Western blotting of isolated storage bodies indicates the specific storage of subunit c of mitochondrial ATP synthase. This flock is being expanded as a large animal model for mechanistic studies and trial therapies.     

Evaluation of prostate cancer detection with ultrasound real-time elastography: a comparison with step section pathological analysis after radical prostatectomy

BACKGROUND: Conventional gray scale ultrasound has a low sensitivity and specificity for prostate cancer detection. Better imaging modalities are needed. OBJECTIVE: To determine sensitivity and specificity for prostate cancer detection with ultrasound-based real-time elastography (elastography) in patients scheduled for radical prostatectomy (RP). DESIGN, SETTING, AND PARTICIPANTS: Between July and October 2007, 109 patients with biopsy-proven localized prostate cancer (PCa) underwent elastography before RP. The investigator was blinded to clinical data. MEASUREMENTS: A EUB-6500HV ultrasound system with a V53W 7.5MHz end-fire transrectal probe was used preoperatively. Areas found to be suspicious for PCa were recorded for left and right side of the apex, mid-gland, and base. These findings were correlated with the obtained whole-mount sections after RP. RESULTS AND LIMITATIONS: Sensitivity and specificity for detecting PCa were 75.4% and 76.6%, respectively. A total of 439 suspicious areas in elastography were recorded, and 451 cancerous areas were found in the RP specimens. Positive predictive value, negative predictive value, and accuracy for elastography were 87.8%, 59%, and 76%, respectively. Nevertheless, there are limitations to our studies because we investigated specific patients scheduled for RP with apparent PCa. Whether elastography is practical as a diagnostic tool or can be used to target a biopsy and be at least as sensitive in tumor detection as extended biopsy schemes has yet to be determined. CONCLUSION: Elastography can detect prostate cancer foci within the prostate with good accuracy and has potential to increase ultrasound-based PCa detection. Further studies need to be done to approve these data and to evaluate whether tumor detection can be increased by elastography-guided biopsies.     

Placental growth factor-1 attenuates vascular endothelial growth factor-A-dependent tumor angiogenesis during beta cell carcinogenesis

Members of the vascular endothelial growth factor (VEGF) family are critical players in angiogenesis and lymphangiogenesis. Although VEGF-A has been shown to exert fundamental functions in physiologic and pathologic angiogenesis, the exact role of the VEGF family member placental growth factor (PlGF) in tumor angiogenesis has remained controversial. To gain insight into PlGF function during tumor angiogenesis, we have generated transgenic mouse lines expressing human PlGF-1 in the beta cells of the pancreatic islets of Langerhans (Rip1PlGF-1). In single-transgenic Rip1PlGF-1 mice, intra-insular blood vessels are found highly dilated, whereas islet physiology is unaffected. Upon crossing of these mice with the Rip1Tag2 transgenic mouse model of pancreatic beta cell carcinogenesis, tumors of double-transgenic Rip1Tag2;Rip1PlGF-1 mice display reduced growth due to attenuated tumor angiogenesis. The coexpression of transgenic PlGF-1 and endogenous VEGF-A in the beta tumor cells of double-transgenic animals causes the formation of low-angiogenic hPlGF-1/mVEGF-A heterodimers at the expense of highly angiogenic mVEGF-A homodimers resulting in diminished tumor angiogenesis and reduced tumor infiltration by neutrophils, known to contribute to the angiogenic switch in Rip1Tag2 mice. The results indicate that the ratio between the expression levels of two members of the VEGF family of angiogenic factors, PlGF-1 and VEGF-A, determines the overall angiogenic activity and, thus, the extent of tumor angiogenesis and tumor growth.     

Detection of tumor-specific DNA in blood and bone marrow plasma from patients with prostate cancer

Tumor tissues, blood plasma and bone marrow (BM) aspirates of 57 prostate cancer patients (PCa) without clinical signs of overt metastases were assessed for LOH (loss of heterozygosity) by a PCR-based fluorescence microsatellite analysis, using a panel of 15 markers. Additionally, micrometastatic tumor cells in BM were monitored by an immunocytological cytokeratin assay. In total, 25 (44%), 32 (56%) and 41 (72%) of the patients had at least 1 LOH in their blood, BM and tumor samples, respectively. Among the informative cases, the frequency of LOH was highest in blood plasma for the markers D8S360 (18%) and D10S1765 (15%), and in BM plasma for THRB (24%) and D8S137 (22%). Comparison of blood plasma and BM with tumors showed discrepant results in 35% and 45% of patients, respectively. Whereas all LOHs at THRB in BM plasma were also detected in the autologous tumor tissues, LOHs at D6S474 and D11S898 in BM were not retrieved in the tumors. The comparison with established risk factors showed a correlation of borderline significance for LOH at D9S1748 in the BM aspirates (p=0.055) and a significant correlation in the tumor samples (p=0.004) with increasing pathologic Gleason scores. Interestingly, 22% of the PCa patients harbored tumor cells in their BM and tended (p=0.065) to have more frequent LOH (16%) in BM plasma compared to patients without tumor cells (9%). These data demonstrate, for the first time, the presence of free tumor-specific DNA in blood and BM of PCa patients and suggest a possible relationship to BM micrometastasis.     

The Role of Non‐Suicidal Self‐Injury and Binge‐Eating/Purging Behaviours in Family Functioning in Eating Disorders

This study aimed to investigate family functioning of restrictive and binge‐eating/purging eating disordered adolescents with or without non‐suicidal self‐injury (NSSI), as perceived by the patients and their parents (mothers and fathers). In total, 123 patients (between 14 and 24 years), 98 mothers and 79 fathers completed the Family Assessment Device. Patients completed the Self‐Injury Questionnaire‐Treatment Related and the Symptom Checklist 90‐Revised. No main effects were found of restrictive versus binge‐eating/purging behaviour nor of presence/absence of NSSI. For the parents, a significant interaction between binge‐eating/purging behaviour and NSSI emerged: Mothers and fathers reported worse family functioning in the binge‐eating/purging group in presence of NSSI, whereas mothers reported worse family functioning in the restrictive group without NSSI. Parental perception of family functioning is affected by the combined presence of binge‐eating/purging behaviour and NSSI. This finding should be taken into account when treating families living with eating disorders. Copyright © 2015 John Wiley & Sons, Ltd and Eating Disorders Association.     

Pre-therapy Somatostatin Receptor-Based Heterogeneity Predicts Overall Survival in Pancreatic Neuroendocrine Tumor Patients Undergoing Peptide Receptor Radionuclide Therapy

Purpose

Early identification of aggressive disease could improve decision support in pancreatic neuroendocrine tumor (pNET) patients prior to peptide receptor radionuclide therapy (PRRT). The prognostic value of intratumoral textural features (TF) determined by baseline somatostatin receptor (SSTR)-positron emission tomography (PET) before PRRT was analyzed.

Procedures

Thirty-one patients with G1/G2 pNET were enrolled (G2, n?=?23/31). Prior to PRRT with [¹⁷⁷Lu]DOTATATE (mean, 3.6 cycles), baseline SSTR-PET computed tomography was performed. By segmentation of 162 (median per patient, 5) metastases, intratumoral TF were computed. The impact of conventional PET parameters (SUV_mean/max), imaging-based TF, and clinical parameters (Ki67, CgA) for prediction of both progression-free survival (PFS) and overall survival (OS) after PRRT were evaluated.

Results

Within a median follow-up of 3.7 years, tumor progression was detected in 21 patients (median, 1.5 years) and 13/31 deceased (median, 1.9 years). In ROC analysis, the TF entropy, reflecting derangement on a voxel-by-voxel level, demonstrated predictive capability for OS (cutoff?=?6.7, AUC?=?0.71, p?=?0.02). Of note, increasing entropy could predict a longer survival (>?6.7, OS?=?2.5 years, 17/31), whereas less voxel-based derangement portended inferior outcome (<?6.7, OS?=?1.9 years, 14/31). These findings were supported in a G2 subanalysis (>?6.9, OS?=?2.8 years, 9/23 vs. <?6.9, OS?=?1.9 years, 14/23). Kaplan–Meier analysis revealed a significant distinction between high- and low-risk groups using entropy (n?=?31, p?<?0.05). For those patients below the ROC-derived threshold, the relative risk of death after PRRT was 2.73 (n?=?31, p?=?0.04). Ki67 was negatively associated with PFS (p?=?0.002); however, SUV_mean/max failed in prognostication (n.s.).

Conclusions

In contrast to conventional PET parameters, assessment of intratumoral heterogeneity demonstrated superior prognostic performance in pNET patients undergoing PRRT. This novel PET-based strategy of outcome prediction prior to PRRT might be useful for patient risk stratification.