Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

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Anatomical endoscopic enucleation of the prostate: The next gold standard? Yes!

Anatomical endoscopic enucleation of the prostate (AEEP) differs from other surgical techniques for benign prostatic obstruction (BPO) in that it removes the entire benign prostatic hyperplasia (BPH) component of the prostate. We summarise the main advantages of AEEP compared to other surgical techniques for BPO. These include better urodynamic relief of bladder outlet obstruction, superior outcomes for urinary retention even in the presence of impaired detrusor contractility, safe and effective for any size prostate, and superior durability compared to vaporisation and resection techniques. We summarise evidence that suggests AEEP offers outcomes that are independent of patient age and prostate volume. We conclude that AEEP is the gold standard surgical treatment for men with either lower urinary tract symptoms (LUTS) or urinary retention, regardless of prostate volume, detrusor contractility and age. It offers the ability to safely and effectively treat a wider range of patients than any other BPO procedure. More widespread use of mentorship programmes, that take advantage of the growing number of experienced mentors, is recommended to train more urologists in AEEP.     

Diagnostic evaluation of magnetization transfer and diffusion kurtosis imaging for prostate cancer detection in a re-biopsy population

Objective

To evaluate diffusion kurtosis imaging (DKI) and magnetisation transfer imaging (MTI) compared to standard MRI for prostate cancer assessment in a re-biopsy population.

Methods

Thirty-patients were imaged at 3 T including DKI (K_app and D_app) with b-values 150/450/800/1150/1500 s/mm² and MTI performed with and without MT saturation. Patients underwent transperineal biopsy based on prospectively defined MRI targets. Receiver-operating characteristic (ROC) analyses assessed the parameters and Wilcoxon-signed ranked test assessed relationships between metrics.

Results

Twenty patients had ≥ 1 core positive for cancer in a total of 26 MRI targets (Gleason 3+3 in 8, 3+4 in 12, ≥ 4+3 in 6): 13 peripheral (PZ) and 13 transition zone (TZ). The apparent diffusion coefficient (ADC) and D_app were significantly lower and the K_app and MT ratio (MTR) significantly higher in tumour versus benign tissue (all p ≤ 0.005); ROC values 0.767-1.000. Normal TZ had: lower ADC and D_app and higher K_app and MTR compared to normal PZ. MTR showed a moderate correlation to K_app (r = 0.570) and D_app (r = -0.537) in normal tissue but a poor correlation in tumours. No parameter separated low-grade (Gleason 3+3) from high-grade (≥ 3+4) disease for either PZ (p = 0.414-0.825) or TZ (p = 0.148-0.825).

Conclusion

ADC, D_app, K_app and MTR all distinguished benign tissue from tumour, but none reliably differentiated low- from high-grade disease.

Key Points

? MTR was significantly higher in PZ and TZ tumours versus normal tissue ? K _app was significantly lower and D _app higher for PZ and TZ tumours ? There was no incremental value for DKI/MTI over mono-exponential ADC parameters ? No parameter could consistently differentiate low-grade (Gleason 3+3) from high-grade (≥ 3+4) disease ? Divergent MTR/DKI values in TZ tumours suggests they offer different functional information

     

A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome

OBJECTIVE: Familial cold autoinflammatory syndrome (FCAS) is caused by mutations in the CIAS1 gene, leading to excessive secretion of interleukin-1beta (IL-1beta), which is associated with cold-induced fevers, joint pain, and systemic inflammation. This pilot study was conducted to assess the safety and efficacy of rilonacept (IL-1 Trap), a long-acting IL-1 receptor fusion protein, in patients with FCAS. METHODS: Five patients with FCAS were studied in an open-label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical efficacy, and remained off treatment until a clinical flare occurred. At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week. Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intrapatient dosage-escalation phase. Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fevers), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation (erythrocyte sedimentation rate [ESR], high-sensitivity C-reactive protein [hsCRP], serum amyloid A [SAA], and IL-6) were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values. RESULTS: In all patients, clinical symptoms typically induced by cold (rash, fever, and joint pain/swelling) improved within days of rilonacept administration. Markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (P < 0.01, P < 0.001, and P < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute-phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug. The drug was well-tolerated. Weight gain in 2 patients was noted. No study drug-related serious adverse events were seen. CONCLUSION: In this study, we present 2-year safety and efficacy data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggest that this drug may be a promising therapeutic option in patients with FCAS, and the data led to the design of a phase III study in this patient population.     

Surface area analysis of dental implants using micro-computed tomography

Objectives: In this study, we present and evaluate a micro‐computed tomography (micro‐CT)‐based method for the calculation of the potential bone/implant contact area (p‐BICA) on the surface of dental implants. Material and methods: For seven commercially available implants (Ankylos? implant, Brånemark System^®, Frialit CELLplus?, Replace^® Select Tapered, Straumann Solid screw?, XiVE S CELLplus?, 3i Osseotite XP? Threaded Miniplant^®), the p‐BICA surface is determined by means of three‐dimensional X‐ray computed‐tomography and computer‐based data processing. Measurements were repeated two times, and the stability and repeatability of the measurement method were evaluated. Results: Our analysis revealed a p‐BICA of 118 mm² for the XiVE S CELLplus? implant, 134 mm² for the Ankylos?, 136 mm² for the Frialit CELLplus?, 138 mm² for the Brånemark System^®, 139 mm² for the Replace^®, 159 mm² for the 3i Osseotite XP? and 199 mm² for the Straumann Solid screw? implant. The measurement method proved to be stable and led to reproducible results. Conclusions: The micro‐ and macrostructure of dental implants define the surface and the p‐BICA. Precise determination of this parameter can be achieved by means of the micro‐CT‐based method as presented in this study. The value of p‐BICA lies in the predictability of industrial design before preclinical and clinical testing. Based on this method, dental implant properties become comparable even if geometrical details are not disclosed by the manufacturer.     

Biochemical and clinical studies in Libyan Jewish cystinuria patients and their relatives

Cystinuria is a hereditary disorder manifested by the development of kidney stones. Three subtypes of the disease have been described, based on urinary excretion of cystine and the dibasic amino acids in heterozygotes, and oral loading tests in homozygotes. Cystinuria is very common among Libyan Jews living in Israel. Recently, we mapped the disease-causing gene in Libyan Jews to 19q, and have shown a very strong founder effect. In this report we present the results of biochemical and clinical studies performed on Libyan Jewish cystinuria patients and members of their families. High levels of cystine and the dibasic amino acids in heterozygotes support previous data that cystinuria in Libyan Jews is a non–type I disease. Oral loading tests performed with lysine showed some degree of intestinal absorption, but less than in normal controls. Previous criteria for determining the disease type, based solely on urinary amino acid levels, proved useless due to a very wide range of cystine and the dibasic amino acids excreted by the heterozygotes. Urinary cystine levels were useful in distinguishing between unaffected relatives and heterozygotes, but were unhelpful in differentiating between heterozygotes and homozygotes. Urinary levels of ornithine or arginine, and the sum of urinary cystine and the dibasic amino acids, could distinguish between the last two groups. Among stone formers, 90% were homozygotes and 10% were heterozygotes; 15% of the homozygotes were asymptomatic. Am. J. Med. Genet. 80:173–176, 1998. © 1998 Wiley-Liss, Inc.     

Clinical differences between North African and Iraqi Jews with familial Mediterranean fever

Familial Mediterranean fever (FMF) is an autosomal recessive disease causing attacks of fever and serositis. The gene causing this disease, designated MEFV, was mapped to the short arm of chromosome 16, but has not yet been cloned. North African and Iraqi Jews constitute the two largest population groups suffering from the disease in Israel. In this report we compared the severity of the disease between these two populations. North African Jews were found to have a more severe disease manifested by an earlier age of onset, an increase in frequency and severity of joint involvement, a higher incidence of erysipelas-like erythema, and a higher dose of colchicine required to control symptoms. The involvement of additional genes, environmental factors, and different mutations in MEFV, may explain the clinical variation in disease severity between these two population groups. Am. J. Med. Genet. 75:216–219, 1998. © 1998 Wiley-Liss, Inc.