Abstract only
e17574
Background: There is active debate concerning the ethics and risks of non-clinically indicated biopsies (bxs) in patients (pts) with cancer. In this analysis we examined our ...single institution experience regarding acceptance, safety, and success rate with research biopsies in pts with breast cancer (BC). Methods: An IRB-approved ongoing prospective study at the Dana-Farber Cancer Institute collects research bxs from pts with BC. Research bxs are performed as additional passes at the time of a clinical bx (cohort 1) or as a separate procedure for banking purposes only (cohort 2) on known tumor or suspicious lesions. Bxs are not linked to a specific therapeutic or correlative trial. Bx-site related risks are pre-specified in consent forms. Grade 2-5 adverse events (AEs) associated with the procedure are prospectively collected. Chart review for bxs between 2005-2013 was performed in this analysis. Results: As of January 2013, 158 pts had consented to the study; 3 pts withdrew consent and 4 pts did not have bxs. 151 pts are in the analytic cohort (total bxs performed= 161); 82% in cohort 1, 18% in cohort 2. Most pts were white (89%) with a performance status of 0-1 (98%). A majority of pts (96%) underwent a bx in the setting of known or suspected metastatic disease. 39% of bxs were performed at time of diagnosis or first recurrence. The most common sites for bx were liver (38%, n=61), skin (24%, n=39) and breast (18%, n=29). Lung was uncommon (3%, n=4). Research biopsies were successfully performed in 114 (92%) pts in cohort 1 and 27 (100%) pts in cohort 2. In cohort 1, research biopsies were not successful in 10 pts. In 9 pts the clinical samples had insufficient material, leading to the forfeit of the banked research sample for clinical purposes; in 1 pt the bx was suspended for severe pain. Only 3 (1.9%) pts had AEs ≥ grade 2: 1 with grade 2 pain; 1 with grade 2 pneumothorax; and 1 with grade 3 pain. Conclusions: Our experience in an academic medical center suggests that pts with BC are willing to undergo research bxs outside the context of a therapeutic or translational trial. These procedures can be performed safely with a high rate of successful tissue collection. Additional data are needed to fully quantify the risks and to demonstrate the value of these procedures.
To compare proteins related to Alzheimer disease (AD) in the frontal cortex and cerebellum of subjects with early-onset AD (EOAD) with or without presenilin 1 (PS1) mutations with sporadic late-onset ...AD (LOAD) and nondemented control subjects.
Immunohistochemistry, immunoblot analysis, and ELISA were used to detect and assess protein levels in brain.
In EOAD and to a lesser extent in LOAD, there was increased amyloid beta (Abeta) deposition (by immunohistochemistry), increased soluble Abeta (by immunoblot analysis), and specific increases in Abeta40 and Abeta42 (by ELISA) in the frontal cortex and, in some cases, in the cerebellum. Surprisingly, immunoblot analysis revealed reduced levels of PS1 in many of the subjects with EOAD with or without PS1 mutations. In those PS1 mutation-bearing subjects with the highest Abeta, PS1 was barely, if at all, detectable. This decrease in PS1 was specific and not attributable solely to neuronal loss because amyloid precursor protein (APP) and the PS1-interacting protein beta-catenin levels were unchanged.
This study shows that in the frontal cortex and cerebellum from Alzheimer disease patients harboring certain presenilin 1 mutations, high levels of amyloid beta are associated with low levels of presenilin 1. The study provides the premise for further investigation of mechanisms underlying the downregulation of presenilin 1, which may have considerable pathogenic and therapeutic relevance.
The aim of this study was to verify whether botulinum toxin (BTX)-induced clinical improvement of cranial dystonia is associated with changes in the cortical silent period (SP), a measure of cortical ...excitability. By transcranial magnetic stimulation (TMS), high-intensity stimuli were delivered with a round coil centered at the vertex during a maximal muscle contraction of the orbicularis oculi. Motor evoked potentials (MEPs) and SPs were obtained from surface electrodes placed over the orbicularis oculi muscle before and 2 to 3 weeks after BTX-A injection into the affected muscles in 10 patients with cranial dystonia and 8 age-matched control subjects. BTX injection improved blepharospasm in all patients. Facial muscle SPs were significantly shorter in patients than in control subjects and did not significantly change after treatment, at the time of maximal clinical improvement. We conclude that the clinical improvement induced by BTX in patients with cranial dystonia is largely symptomatic. It does not appear to result from modulation of abnormal aspects of intracortical excitability, although these may play a role in craniofacial dystonia.
Mutations in the gene encoding presenilin 1 (PS-1) account for 50% of early-onset familial Alzheimer’s disease (EOFAD) cases. In this study, we identified two missense mutations in the coding ...sequence of the presenilin (PS-1) gene in two EOFAD pedigrees. AD was confirmed in one pedigree by autopsy. Mutation analysis of PCR products amplified from genomic DNA templates showed two novel PS-1 mutations resulting in Gln222His and Tyr256Ser. The two novel mutations are located within predicted transmembrane domains five (TM-5) and six (TM-6), respectively, and are associated with very early ages of onset. The Tyr256Ser is associated with one of the youngest age of AD onset, 25 years, which is consistent with a drastic change in function of the altered PS-1 protein. A morphometric analysis of the cortical degenerative changes of the Tyr256Ser case, showed severe involvement of the primary motor cortex, which correlated well with the pyramidal changes, including tetraspasticity. Immunoblot analysis showed the Tyr256Ser case had the greatest expression of Aβ
1–40 and Aβ
1–42, which was confirmed by ELISA, compared to other PS-1 mutant FAD cases and age-matched controls and, thus, contributes to the severity of the disease pathology.
RET mutations play an important role in the development of human neuroendocrine tumors. The prevalence of the RET polymorphism G691S of exon 11 is higher in patients with medullary thyroid carcinoma ...(MTC) as compared to the general population. A weak association between RET polymorphisms and sporadic papillary thyroid carcinoma (PTC) has also been described. We hereby describe the association of MTC, bronchial carcinoid tumor, and PTC in a familial setting. A 75-yr-old woman developed MTC 7 yr after successful treatment of a bronchial carcinoid. Serum calcitonin was 12.9 pg/ml with a peak response to pentagastrin (151.0 pg/ml). The patient underwent total thyroidectomy and a genetic mutational analysis of the RET gene. Histological evaluation confirmed MTC with no evidence of lymph nodes involvement. After thyroidectomy serum calcitonin was <2.0 pg/ml. A germline missense mutation at codon 691 in exon 11 of the RET gene was found. The mutational analysis was extended to the patient’s offspring, and her daughter was found to bear the G691S polymorphism of RET. Wild type RET gene was found in the son. The daughter, who showed a nodular goiter, autoimmune thyroiditis and normal serum calcitonin, also underwent thyroidectomy. Histologic examination of the thyroid revealed an incidental PTC. This is the first description of a bronchial carcinoid tumor occurring in association with MTC. The occurrence of apparently unrelated NET in the same subject, or within a family, should be regarded as a challenge for deeper investigations into the possible oncogenic role of this genetic alteration.
Some studies have shown that the mother's nutritional condition may influence offspring's endocrine function through metabolic imprinting. Recently, we showed that the kind of maternal malnutrition ...during lactation affects adult body weight of the offspring and it is related to milk composition. We studied lactating rats fed an 8 % protein-restricted diet (PR), a control 23 % protein diet (C), and an energy-restricted diet group (ER). After weaning, all animals received a normal diet until they were 180 days of age. At this time, the animals received a single i. p. injection of (131)I and were sacrificed 2 h after the injection. Total triiodothyronine (TT3) and total thyroxin (TT4) serum concentrations were measured by enzyme immunoassay. The PR group had significantly a higher thyroid (131)I uptake, TT3 serum concentration and in TT4 serum concentration, compared to the controls. The ER group had only significantly higher TT3 serum concentration. These results showed that thyroid function regulation in adulthood may depend on maternal nutritional condition during lactation. Probably, PR group had a high thyroid function, whereas the ER group only had an increase in the deiodination of T4. The hyperthyroidism in the PR group could explain the low body weight observed in those animals.
Thermal ablation of renal tumors is achieved by the delivery of extreme heat or extreme cold directly to the lesion in order to obtain in situ destruction of the malignant cells without having to ...remove the entire organ. Cryotherapy and radiofrequency ablation are becoming more and more attractive for the treatment of small lesions in select cases. Other types of energy such as microwave, laser and high intensity ultrasound have also been used to destroy kidney lesions but must still be considered in the experimental stage. Cryotherapy and radiofrequency ablation are minimally invasive and have been shown to be safe and effective in treating tumors up to 3 -4 cm in diameter. However, the number of case series is rather limited and follow-up, especially for radiofrequency ablation, is short. Only now are workers beginning to present outcomes after 5 years for cryoablation. Therefore, the long-term oncological efficacy of these ablation techniques remains to be seen. As longer follow-up and greater patient numbers are reported we will get a clearer picture of the true potential of these modalities. Randomized prospective trials would be auspicable. For now, CA and RFA should be limited to few select patients - i.e. patients with comorbidities which render them at high risk for a surgical procedure and possibly patients with genetic conditions such as Von Hippel Lindau disease who will probably develop multiple tumors.
PDF
