Concurrent DNA Copy‐Number Alterations and Mutations in Genes Related to Maintenance of Genome Stability in Uninvolved Mammary Glandular Tissue from Breast Cancer Patients

Somatic mosaicism for DNA copy‐number alterations (SMC‐CNAs) is defined as gain or loss of chromosomal segments in somatic cells within a single organism. As cells harboring SMC‐CNAs can undergo clonal expansion, it has been proposed that SMC‐CNAs may contribute to the predisposition of these cells to genetic disease including cancer. Herein, the gross genomic alterations (>500 kbp) were characterized in uninvolved mammary glandular tissue from 59 breast cancer patients and matched samples of primary tumors and lymph node metastases. Array‐based comparative genomic hybridization showed 10% (6/59) of patients harbored one to 359 large SMC‐CNAs (mean: 1,328 kbp; median: 961 kbp) in a substantial portion of glandular tissue cells, distal from the primary tumor site. SMC‐CNAs were partially recurrent in tumors, albeit with considerable contribution of stochastic SMC‐CNAs indicating genomic destabilization. Targeted resequencing of 301 known predisposition and somatic driver loci revealed mutations and rare variants in genes related to maintenance of genomic integrity: BRCA1 (p.Gln1756Profs*74, p.Arg504Cys), BRCA2 (p.Asn3124Ile), NCOR1 (p.Pro1570Glnfs*45), PALB2 (p.Ser500Pro), and TP53 (p.Arg306*). Co‐occurrence of gross SMC‐CNAs along with point mutations or rare variants in genes responsible for safeguarding genomic integrity highlights the temporal and spatial neoplastic potential of uninvolved glandular tissue in breast cancer patients.     

Functionalization of α-hydroxyphosphonates as a convenient route to N-tosyl-α-aminophosphonates

Direct conversion of the α-hydroxyl group by para-toluenesulfonamide to yield α-(N-tosyl)aminophosphonates is reported. α-Aminophosphonates 23a,b–37a,b were obtained from the corresponding α-hydroxyphosphonates 6a,b–21a,b in the presence of K₂CO₃, via the retro-Abramov reaction of the appropriate aldehydes, 1–5. The subsequent formation of imines with simultaneous addition of diethyl phosphite provided access to the α-sulfonamide phosphonates 23a,b–37a,b with better diastereoselectivity than in the case of the Pudovik reaction. The mechanism for this transformation is proposed herein. When Cbz N-protected aziridine 9a,b and phenylalanine analogue 12a,b were exploited, intramolecular substitution was observed, leading to the corresponding epoxide 38 as the sole product, or oxazolidin-2-one 39 as a minor product. Analogous substitution was not observed in the case of proline 18a,b and serine 21a,b derivatives.

The reaction mechanism and diastereoselectivity of the direct transformation of α-hydroxyphosphonates 6a,b–21a,b by para-toluenesulfonamide, yielding α-(N-tosyl)aminophosphonates 23a,b–37a,b under K₂CO₃ conditions are presented.     

Incidental findings in multislice computed tomography prior to transcatheter aortic valve implantation: frequency,clinical relevance and outcome

Multislice computed tomography (MSCT) has emerged as the mainstay in patients planned for transcatheter aortic valve implantation (TAVI). Incidental findings (IF) in MSCT are common. However, the exact incidence, clinical relevance and further consequences of IF are unclear and it is controversial whether IF adversely affect patients’ outcome. We analyzed MSCT data of 1050 patients screened for TAVI between January 2011 and December 2014. Median follow-up of patients was 20 months. In total, 3194 IF were identified, which were classified into clinically non-relevant IF (2872, 90%) and clinically relevant IF (322, 10%). In 25% of patients (258/1050) at least one clinically relevant IF was present. Age (80?±?7 vs. 80?±?7 years; p?=?0.198) and EuroSCORE II (3.6% [2.1–5.7] vs. 3.6% [2.1–5.9]; p?=?0.874) was similar between patients with and without a clinically relevant IF. TAVI was performed less frequently in patients with a clinically relevant IF (76% vs. 85%; p?<?0.001), with more patients receiving surgical aortic valve replacement in that group (14% vs. 11%; p?=?0.042), possibly due to the high rate of incidental aneurysms of the ascending aorta (n?=?48). If TAVI was performed mortality did not differ (30-days: 4% vs. 3%; p?=?0.339, 1-year: 11% vs. 14%; p?=?0.226) between patients with and without a clinically relevant IF. Our study is the largest study to analyze prevalence, clinical relevance and therapeutic consequences of IF during screening for TAVI. IF in pre-procedural MSCT are common and clinically relevant in one-quarter of patients. However, these findings had no impact on overall mortality.     

Superb Micro-vascular Imaging (SMI): a Doppler ultrasound technique with potential to identify,classify, and follow up endoleaks in patients after Endovascular Aneurysm Repair (EVAR)

Purpose

The aim of the study was to assess the effectiveness of Superb Micro-vascular Imaging (SMI) as an alternative to Contrast-Enhanced Ultrasound (CEUS) and Computed Tomography Angiography (CTA) for endoleak detection and classification in patients followed up after endovascular abdominal aortic aneurysm repair (EVAR).

Materials and methods

From May 2015 to January 2017, 30 patients underwent post-EVAR follow-up with Color Doppler Ultrasound (CDUS), CEUS, SMI, and CTA examinations. Aneurysmal sac diameter and graft patency were evaluated; endoleaks were identified and classified. Sensitivity, specificity, and accuracy values were calculated for each of the four diagnostic methods of endoleak detection. A percentage of agreement and Cohen’s Kappa coefficient were calculated for comparison of methods in terms of endoleak identification.

Results

CTA revealed fifteen endoleaks (50%): three type Ia, nine type II, and three type III. The sensitivity of CDUS, CEUS, and SMI relative to CTA was 27%, 100%, and 100%, respectively. Specificity was 93%, 93%, and 93%, respectively. Accuracy was 60%, 97%, and 97%, respectively. There were no differences between SMI and CEUS in terms of sensitivity, specificity, or accuracy (100%, 93%, and 97%). We do not observe statistically significant differences between CTA, CEUS, and SMI concerning endoleak identification ability. The weakest method in endoleak identification was CDUS.

Conclusions

The analysis showed that SMI is effective, repeatable, and comparable with the CEUS modality in identification endoleaks after EVAR; it may be considered as a potential tool to monitor patients after EVAR implantation, especially those with renal insufficiency or with an allergy to any contrast media.

     

The Effect of Lactobacillus plantarum 299v on the Incidence of Clostridium difficile Infection in High Risk Patients Treated with Antibiotics

Background: Lactobacillus plantarum 299v (LP299v) has been used in order to reduce gastrointestinal symptoms during antibiotic exposure. However, it remains controversial whether or not probiotics are effective in the prevention of Clostridium difficile infections (CDI) among patients receiving antibiotics. The aim of this study was to analyze the CDI among patients receiving antibiotics and hospitalized in the period before and after starting routine use of LP299v as a prevention of this infection. Methods: Among 3533 patients hospitalized in the nephrology and transplantation ward during a two-year period, 23 patients with CDI were diagnosed and enrolled in this retrospective study. Since November 2013, prevention of CDI with oral use of LP299v was performed in all patients treated with antibiotics and who were at a high risk of developing CDI. The observation period was divided into two twelve-month intervals before and after initiation of the use of LP299v as a prophylactic against CDI. Results: A significant (p = 0.0001) reduction of the number of cases of CDI was found after routinely using LP299v (n = 2; 0.11% of all hospitalized patients) compared with the previous twelve-month period of observation (n = 21; 1.21% of all hospitalized patients). Conclusions: Routine use of LP299v during treatment with antibiotics may prevent C. difficile infection in the nephrology and transplantation ward.     

Toxic optic neuropathies: an updated review

Toxic optic neuropathy (TON) is caused by the damage to the optic nerve through different toxins, including drugs, metals, organic solvents, methanol and carbon dioxide. A similar clinical picture may also be caused by nutritional deficits, including B vitamins, folic acid and proteins with sulphur‐containing amino acids. This review summarizes the present knowledge on disease‐causing factors, clinical presentation, diagnostics and treatment in TON. It discusses in detail known and hypothesized relations between drugs, including tuberculostatic drugs, antimicrobial agents, antiepileptic drugs, antiarrhythmic drugs, disulfiram, halogenated hydroquinolones, antimetabolites, tamoxifen and phosphodiesterase type 5 inhibitors and optic neuropathy.