Clinical results of radionuclide therapy of neuroendocrine tumours with <Superscript>90</Superscript>Y-DOTATATE and tandem <Superscript>90</Superscript>Y/<Superscript>177</Superscript>Lu-DOTATATE: which is a better therapy option?

Purpose  

Peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues is a treatment option for patients with disseminated neuroendocrine tumours (NET). A combination treatment using the high-energy ⁹⁰Y beta emitter for larger lesions and the lower energy ¹⁷⁷Lu for smaller lesions has been postulated in the literature.The aim of the study was to evaluate combined ⁹⁰Y/¹⁷⁷Lu-DOTATATE therapy in comparison to ⁹⁰Y-DOTATATE alone.     

Long-term results and tolerability of tandem peptide receptor radionuclide therapy with <Superscript>90</Superscript>Y/<Superscript>177</Superscript>Lu-DOTATATE in neuroendocrine tumors with respect to the primary location: a 10-year study

Introduction

The peptide receptor radionuclide therapy (PRRT) with ⁹⁰Y and ¹⁷⁷Lu is a form of molecular targeted therapy for inoperable or disseminated neuroendocrine tumors (NET).

Aim

The aim of the study was to evaluate clinical results and long-term side effects of tandem ⁹⁰Y /¹⁷⁷Lu-DOTATATE therapy in patients with NET. Additionally, we evaluated clinical results with reference to the primary site.

Materials and methods

59 patients with disseminated NET were included in the study prospectively. 3–5 cycles of combined 1:1 ⁹⁰Y/¹⁷⁷Lu-DOTATATE (total injected activity 11.1–16.65 GBq) with mixed amino acids for kidney protection were performed.

Results

During a median follow-up of 75.8 months, the PFS was 32.2 months, and the OS was 82 months; 25 patients died. Depending on primary tumor’s site, the PFS and the OS for pancreatic NET vs. small bowel, NET vs. large bowel, NET were 30.4 vs. 29.5 vs. 40.3 and 78.9 vs. 58.1 vs. 82.5, respectively. The observed 5-year overall survival was 63%, and a 2-year risk of progression was 39.4%. The following imaging response was observed: CR in 2%, PR in 22%, SD in 65%, and PD in 6% patients. The disease control rate was 89%. The objective response rate was 24%. The PRRT was well tolerated by all patients. One patient (2%) revealed MDS, and one patient (2%) grade 3 nephrotoxicity. No other grade 3 and 4 hematological or renal toxicity was observed.

Conclusions

These results indicated the tandem ⁹⁰Y/¹⁷⁷Lu-DOTATATE therapy for patients with disseminated/inoperable NET as highly effective and safe, considering long-term side effects. In the majority of patients, clinical improvement was observed.

     

Outcome in cervical recurrences of papillary or follicular thyroid cancer]

The aim of this study was to evaluate the treatment and outcome of patients with local recurrence (LR) of differentiated thyroid carcinoma. This retrospective study concerned patients treated between 1974 and 1990 for papillary or follicular thyroid cancer. Our patients had at least one LR. LR diagnosed within 6 months after thyroidectomy and patients with increased serum thyroglobulin levels were excluded. Thirty one patients (80% female) aged 15 to 84 years had at least one LR. LR was diagnosed 7 to 200 months after thyroidectomy (mean 63.7). There were 25 papillary and 6 follicular cancers. There were 1.5 LR per patient (range 1-6). LR were treated by radioiodine in 21 cases and by surgery in 22 cases. Among the 22 surgically treated patients, 7 had nodal recurrences, 7 had nodes and tumor, 3 had only tumor, 1 had recurrence in the remnant thyroid. After a mean follow-up of 75.8 months, 11 patients had distant metastases, 11 had died from their thyroid carcinoma (7 after metastases). Three of the 7 patients with nodal recurrence died. In one third of cases, LR announced distant metastases. Node recurrence had a poor prognosis.     

Direct imaging of the disruption of hepatitis C virus replication complexes by inhibitors of lipid metabolism

Here we have simultaneously characterized the influence of inhibitors of peroxisome proliferator-activated receptor α (PPARα) and the mevalonate pathway on hepatocyte lipid metabolism and the subcellular localization of hepatitis C virus (HCV) RNA using two-photon fluorescence (TPF) and coherent anti-Stokes Raman scattering (CARS) microscopy. Using this approach, we demonstrate that modulators of PPARα signaling rapidly cause the dispersion of HCV RNA from replication sites and simultaneously induce lipid storage and increases in lipid droplet size. We demonstrate that reductions in the levels of cholesterol resulting from inhibition of the mevalonate pathway upregulates triglyceride levels. We also show that the rate of dispersion of HCV RNA is very rapid when using a PPARα antagonist. This occurs with a faster rate to that of direct inhibition of 3-hydroxy-3-methyglutaryl CoA reductase (HMG-CoA reductase) using lovastatin in living cells, demonstrating the potential therapeutic value of modulating host cell pathways as part of a strategy to eliminate chronic HCV infection.     

Identification of a single peridinin sensing Chl-a excitation in reconstituted PCP by crystallography and spectroscopy

The peridinin-chlorophyll a-protein (PCP) of dinoflagellates is unique among the large variety of natural photosynthetic light-harvesting systems. In contrast to other chlorophyll protein complexes, the soluble PCP is located in the thylakoid lumen, and the carotenoid pigments outnumber the chlorophylls. The structure of the PCP complex consists of two symmetric domains, each with a central chlorophyll a (Chl-a) surrounded by four peridinin molecules. The protein provides distinctive surroundings for the pigment molecules, and in PCP, the specific environment around each peridinin results in overlapping spectral line shapes, suggestive of different functions within the protein. One particular Per, Per-614, is hypothesized to show the strongest electronic interaction with the central Chl-a. We have performed an in vitro reconstitution of pigments into recombinant PCP apo-protein (RFPCP) and into a mutated protein with an altered environment near Per-614. Steady-state and transient optical spectroscopic experiments comparing the RFPCP complex with the reconstituted mutant protein identify specific amino acid-induced spectral shifts. The spectroscopic assignments are reinforced by a determination of the structures of both RFPCP and the mutant by x-ray crystallography to a resolution better than 1.5 Å. RFPCP and mutated RFPCP are unique in representing crystal structures of in vitro reconstituted light-harvesting pigment-protein complexes.     

Redox properties of Met(35) in neurotoxic beta-amyloid peptide. A molecular modeling study

The beta-amyloid peptide (betaAP) is the principal component of plaque associated with the pathology of Alzheimer's disease. Part of its neurotoxicity appears to correlate with the ability of the peptide to reduce Cu(II) and form free radicals. Both processes are dependent on the presence and oxidizability of Met(35) in the C-terminus of the peptide but no mechanistic details on the reactions leading to Met oxidation are known. On the basis of previous studies with model peptides, we hypothesize that a one-electron oxidation of Met(35) in betaAP is facilitated through a neighboring group effect. Complexed to Cu(II) and/or in a lipid-mimicking environment, the solution structure of betaAP includes a large alpha-helical part. The solution NMR structure of betaAP1-40 in aqueous SDS micelles reveals an alpha-helix between residues 27 and 36, containing Met(35). In this helical C-terminus of betaAP, the peptide bond C=O group C-terminal of Ile(31) is located very close to the Met(35) sulfur and could stabilize a Met(35) sulfide radical cation through formation of an (S-O) three-electron bond. In the present paper, we have computationally validated this hypothesis using Langevin dynamics methods to determine the collision frequency of the Met(35) thioether sulfur and the oxygen atoms of several peptide bonds in the betaAP sequence. Nanosecond time scale computations were carried out for four distinct betaAP congeners, betaAP26-40, betaAP26-36, betaAP26-40(Ile(31)Pro), betaAP40-26, and their respective Met(35)-sulfur-centered cation radicals. Here, betaAP26-40, betaAP26-40(Ile(31)Pro) and betaAP40-26 are representative fragments of the full length betaAP1-42 or betaAP42-1 sequence, respectively, whereas betaAP26-36 represents a unique betaAP sequence for which biological data are available. Initial structures of betaAP26-40, betaAP26-40(Ile(31)Pro), and betaAP26-36 were selected to be identical to that of the betaAP26-40 or betaAP26-36 sequence in full-length betaAP1-40. As the structures of betaAP40-26 and betaAP42-1 are not known, various initial conformations such as alpha-helix and antiparallel beta-sheet were selected for betaAP40-26. Our computational results show that betaAP26-40, representative for the same sequence in full-length betaAP1-42, has the highest tendency to form (S-O) bonds between Ile(31)C=O and Met(35)S. We conclude that native betaAP1-42 has a higher tendency to support Met(35) oxidation through (S-O) bond formation, consistent with the experimental observation that betaAP1-42 is more neurotoxic compared to the other investigated sequences.     

Training and practice of neurosurgery in USA-personal experience after two-year fellowship in University of Arizona

Author describes his observations from two-year neurosurgical fellowship in University of Arizona, USA. During the fellowship he underwent rotations to Pediatric Neurosurgery Department at Phoenix Children's Hospital for one year, Neurosurgery Department at University Medical Center for six months, Neurosurgery Department at Veterans Affairs Hospital for three months and private neurosurgery group based on three separate hospitals for three months. Work in the particular departments is described as well as process of fellowship position obtainment and statistical data regarding fellowships and residences in neurosurgery in USA.