A Multicentric, Retrospective, Real-world Study on Immune-related Adverse Events in Patients with Advanced Non-small Cell Lung Cancers Treated with Pembrolizumab Monotherapy.

AIMS: We present 7 years of clinical experience with single-agent pembrolizumab immune checkpoint inhibitor immunotherapy in non-small cell lung cancers (NSCLC) from four UK cancer centres. MATERIALS AND METHODS: This multi-institutional retrospective cohort study included 226 metastatic NSCLC patients. Outcomes were number and severity of immune-related adverse events (irAEs), median progression-free survival (mPFS) and median overall survival (mOS). RESULTS: Within our cohort, 119/226 (53%) patients developed irAEs. Of these, 54/119 (45%) experienced irAEs affecting two or more organ systems. The most common irAEs were diarrhoea and rash. The development of an irAE was associated with better mOS (20.7 versus 8.0 months; P < 0.001) and mPFS (12.0 versus 3.9 months; P < 0.001). The development of grade 3/4 toxicities was associated with worse outcomes compared with the development of grade 1/2 toxicities (mOS 6.1 months versus 25.2 months, P < 0.01; mPFS 5.6 months versus 19.3 months, P = 0.01, respectively). Females had a higher proportion of reported grade 3/4 toxicities (13/44 [29.5%] versus 10/74 [13.5%], P = 0.03). Using a multiple Cox regression model, the presence of irAEs was associated with a better overall survival (hazard ratio = 0.42, 95% confidence interval 0.29-0.61; P < 0.01) and better PFS (hazard ratio 0.38, 95% confidence interval 0.27-0.53; P < 0.001). CONCLUSION: In this multicentre retrospective cohort study, the development of at least one irAE was associated with significantly longer mPFS and mOS; however, more severe grade 3 and 4 irAEs were associated with worse outcomes. Delayed-onset irAEs, after the 3-month timepoint, were associated with better clinical outcomes.

A Mathematical Analysis of Clustering-Free Local SAR Compression Algorithms for MRI Safety in Parallel Transmission.

Parallel transmission (pTX) is a versatile solution to enable UHF MRI of the human body, where radiofrequency (RF) field inhomogeneity appears very challenging. Today, state of the art monitoring of the local SAR in pTX consists in evaluating the RF power deposition on specific SAR matrices called Virtual Observation Points (VOPs). It essentially relies on accurate electromagnetic simulations able to return the local SAR distribution inside the body in response to any applied pTX RF waveform. In order to reduce the number of SAR matrices to a value compatible with real time SAR monitoring ( << 103) , a VOP set is obtained by partitioning the SAR model into clusters, and associating a so- called dominant SAR matrix to every cluster. More recently, a clustering-free compression method was proposed, allowing for a significant reduction in the number of SAR matrices. The concept and derivation however assumed static RF shims and their extension to dynamic pTX is not straightforward, thereby casting doubt on the strict validity of the compression approach for these more complicated RF waveforms. In this work, we provide the mathematical framework to tackle this problem and find a rigorous justification of this criterion in the light of convex optimization theory. Our analysis led us to a variant of the clustering-free compression approach exploiting convex optimization. This new compression algorithm offers computational gains for large SAR models and for high-channel count pTX RF coils.

Dentin Discoloration and Pulpal Ion Concentrations Following Silver Diamine Fluoride and Potassium Iodide Treatment.

OBJECTIVE: The objective of this in vitro study was to evaluate the effects of potassium iodide on dentin discoloration and ion penetration into the pulp chamber after application of silver diamine fluoride (SDF). METHODS: Proximal surfaces of extracted one-rooted sound human teeth were polished to obtain flat dentin and treated with 17% EDTA for two minutes. Each tooth was then fixed to a test tube. The specimens were distributed into five groups according to the treatment: SDF (Advantage Arrest, Elevate Oral Care); SDF-KI (SSKI, Upsher-Smith); RV-SDF (Riva Star, SDI); and RV-SDFKI. The CIE L*a*b* color value for each proximal dentin was assessed using a colorimeter (CR200, Konica-Minolta) at baseline, after two minutes, 10 minutes, and 24 hours, and ΔE compared to baseline was calculated. Subsequently, the water-filled tube was inverted to collect the ions that had penetrated from the tooth surface into the pulp chamber. Silver, iodide, and fluoride in the pulp were measured using trace element analysis (ISMat) and fluoride ion-selective electrode (Orion, Thermo Scientific) at days 1, 2, 7, and 14. RESULTS: Dentin in both SDF-KI groups showed no visual change in color whereas the groups using only SDF exhibited gradual staining. The time, the treatment and their interaction had a significant effect on ΔE (p<0.001). The fluoride concentrations at day 1 and day 14 for group SDF and KI were significantly lower compared to SDF (p=0.044). There was a difference between control groups and other groups in silver and iodine (p<0.05), whereas there was no significant difference among groups with treatment after 14 days (p>0.05). CONCLUSION: The application of KI after SDF treatment could significantly reduce the dentin staining. The pulpal fluoride concentration in the groups using SDF-KI was lower compared to the ones using SDF only, whereas there was no difference observed in iodide and silver among the groups with treatment.

The gut microbiome: what the oncologist ought to know.

The gut microbiome (GM) has been implicated in a vast number of human pathologies and has become a focus of oncology research over the past 5 years. The normal gut microbiota imparts specific function in host nutrient metabolism, xenobiotic and drug metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation and protection against pathogens. Strong evidence is emerging to support the effects of the GM on the development of some malignancies but also on responses to cancer therapies, most notably, immune checkpoint inhibition. Tools for manipulating the GM including dietary modification, probiotics and faecal microbiota transfer (FMT) are in development. Current understandings of the many complex interrelationships between the GM, cancer, the immune system, nutrition and medication are ultimately based on a combination of short-term clinical trials and observational studies, paired with an ever-evolving understanding of cancer biology. The next generation of personalised cancer therapies focusses on molecular and phenotypic heterogeneity, tumour evolution and immune status; it is distinctly possible that the GM will become an increasingly central focus amongst them. The aim of this review is to provide clinicians with an overview of microbiome science and our current understanding of the role the GM plays in cancer.

The management of perineal hernia following abdomino-perineal excision for cancer.

PURPOSE: Perineal hernia (PH) is a tardive complication following abdomino-perineal resection (APR). Many repair methods are described and evidences are lacking. The aim of this study was to report PH management, analyze surgery outcomes and review the available literature. METHODS: We retrospectively included all consecutive PH repair after APR performed between 2001 and 2017. We recorded data on APR surgery, PH symptoms and repair, and follow-up (recurrence and morbidity). Literature review included published articles on PubMed between 1960 and 2017. RESULTS: 24 PH repairs were included. The approach was perineal N = 16, abdominal N = 5 and combined N = 3. A biological mesh was used for 17, a synthetic for 5 and a flap for 2 patients. The median follow-up was 25 months. Overall morbidity was 37.5% (N = 9): 37.5% for the perineal, 20% for the abdominal, and 66.7% for the combined approach. Complications occurred in 35.3% of biological and 20% of synthetic mesh repairs. Recurrence rate was 41.7%, similar for biological (n = 8, 47.1%) and synthetic meshs (n = 2; 40%). No recurrence occurred in the flap group. Depending of the approach, we found 50% for perineal (n = 8) and 40% of the abdominal cohort (N = 2). Among twelve studies, recurrence rates ranged from 0 to 66.7%. Abdominal or laparoscopic approach with synthetic mesh was associated with less recurrences (0 and 12.5% respectively) and complications (37.5% and 9.5%). CONCLUSIONS: Recurrences following PH repair are high irrespective of the repair technique. More studies are necessary to identify PH risk factors and decide the appropriate perineal reconstruction.

Monolithic Axial and Radial Metal-Semiconductor Nanowire Heterostructures.

The electrical and optical properties of low-dimensional nanostructures depend critically on size and geometry and may differ distinctly from those of their bulk counterparts. In particular, ultrathin semiconducting layers as well as nanowires have already proven the feasibility to realize and study quantum size effects enabling novel ultrascaled devices. Further, plasmonic metal nanostructures attracted recently a lot of attention because of appealing near-field-mediated enhancement effects. Thus, combining metal and semiconducting constituents in quasi one-dimensional heterostructures will pave the way for ultrascaled systems and high-performance devices with exceptional electrical, optical, and plasmonic functionality. This Letter reports on the sophisticated fabrication and structural properties of axial and radial Al-Ge and Al-Si nanowire heterostructures, synthesized by a thermally induced exchange reaction of single-crystalline Ge-Si core-shell nanowires and Al pads. This enables a self-aligned metallic contact formation to Ge segments beyond lithographic limitations as well as ultrathin semiconducting layers wrapped around monocrystalline Al core nanowires. High-resolution transmission electron microscopy, energy dispersive X-ray spectroscopy, and µ-Raman measurements proved the composition and perfect crystallinity of these metal-semiconductor nanowire heterostructures. This exemplary selective replacement of Ge by Al represents a general approach for the elaboration of radial and axial metal-semiconductor heterostructures in various Ge-semiconductor heterostructures.

Signal-domain optimization metrics for MPRAGE RF pulse design in parallel transmission at 7 tesla.

PURPOSE: Standard radiofrequency pulse design strategies focus on minimizing the deviation of the flip angle from a target value, which is sufficient but not necessary for signal homogeneity. An alternative approach, based directly on the signal, here is proposed for the MPRAGE sequence, and is developed in the parallel transmission framework with the use of the kT -points parametrization. METHODS: The flip angle-homogenizing and the proposed methods were investigated numerically under explicit power and specific absorption rate constraints and tested experimentally in vivo on a 7 T parallel transmission system enabling real time local specific absorption rate monitoring. Radiofrequency pulse performance was assessed by a careful analysis of the signal and contrast between white and gray matter. RESULTS: Despite a slight reduction of the flip angle uniformity, an improved signal and contrast homogeneity with a significant reduction of the specific absorption rate was achieved with the proposed metric in comparison with standard pulse designs. CONCLUSION: The proposed joint optimization of the inversion and excitation pulses enables significant reduction of the specific absorption rate in the MPRAGE sequence while preserving image quality. The work reported thus unveils a possible direction to increase the potential of ultra-high field MRI and parallel transmission. Magn Reson Med 76:1431-1442, 2016. © 2015 International Society for Magnetic Resonance in Medicine.

Rate of cyp51A mutation in Aspergillus fumigatus among lung transplant recipients with targeted prophylaxis.

OBJECTIVES: The most common mechanism of azole (itraconazole and voriconazole) resistance in Aspergillus fumigatus is a mutation at the cyp51A locus. The aim of our study was to determine the rate of cyp51A mutations in lung transplant recipients (LTR) undergoing targeted antifungal prophylaxis with 12 weeks of voriconazole. METHODS: We conducted a prospective study that included 22 LTR with A. fumigatus between October 2008 and November 2011. Of those, 10 LTR were colonized with A. fumigatus and 12 had invasive pulmonary aspergillosis. RESULTS: Four patients were found to have A. fumigatus isolates with a cyp51A mutation, two had colonization and two had invasive pulmonary aspergillosis. The remaining 18 LTR had WT cyp51A A. fumigatus isolates. All A. fumigatus isolates (except one due to mixed growth) were tested for antifungal susceptibility. A total of nine LTR were exposed to azoles prior to A. fumigatus isolation for a median duration of 249 (IQR 99-524) days. Azole exposure preceded the isolation of two mutant isolates and seven WT isolates. None of the cyp51A mutant isolates conferred phenotypic resistance to azoles. CONCLUSIONS: Targeted antifungal prophylaxis in LTR did not lead to cyp51A resistance mutations in this cohort. Data on larger cohorts who receive universal antifungal prophylaxis are needed.

Parallel-transmission-enabled magnetization-prepared rapid gradient-echo T1-weighted imaging of the human brain at 7 T.

One of the promises of Ultra High Field (UHF) MRI scanners is to bring finer spatial resolution in the human brain images due to an increased signal to noise ratio. However, at such field strengths, the spatial non-uniformity of the Radio Frequency (RF) transmit profiles challenges the applicability of most MRI sequences, where the signal and contrast levels strongly depend on the flip angle (FA) homogeneity. In particular, the MP-RAGE sequence, one of the most commonly employed 3D sequences to obtain T1-weighted anatomical images of the brain, is highly sensitive to these spatial variations. These cause deterioration in image quality and complicate subsequent image post-processing such as automated tissue segmentation at UHF. In this work, we evaluate the potential of parallel-transmission (pTx) to obtain high-quality MP-RAGE images of the human brain at 7 T. To this end, non-selective transmit-SENSE pulses were individually tailored for each of 8 subjects under study, and applied to an 8-channel transmit-array. Such RF pulses were designed both for the low-FA excitation train and the 180° inversion preparation involved in the sequence, both utilizing the recently introduced k(T)-point trajectory. The resulting images were compared with those obtained from the conventional method and from subject-specific RF-shimmed excitations. In addition, four of the volunteers were scanned at 3 T for benchmarking purposes (clinical setup without pTx). Subsequently, automated tissue classification was performed to provide a more quantitative measure of the final image quality. Results indicated that pTx could already significantly improve image quality at 7 T by adopting a suitable RF-Shim. Exploiting the full potential of the pTx-setup, the proposed k(T)-point method provided excellent inversion fidelity, comparable to what is commonly only achievable at 3 T with energy intensive adiabatic pulses. Furthermore, the cumulative energy deposition was simultaneously reduced by over 40% compared to the conventional adiabatic inversions. Regarding the low-FA k(T)-point based excitations, the FA uniformity achieved at 7 T surpassed what is typically obtained at 3 T. Subsequently, automated white and gray matter segmentation not only confirmed the expected improvements in image quality, but also suggests that care should be taken to properly account for the strong local susceptibility effects near cranial cavities. Overall, these findings indicate that the k(T)-point-based pTx solution is an excellent candidate for UHF 3D imaging, where patient safety is a major concern due to the increase of specific absorption rates.

Risk factors for voriconazole hepatotoxicity at 12 weeks in lung transplant recipients.

Voriconazole is commonly used for prophylaxis and treatment of invasive aspergillosis in lung transplant recipients. However, the use of voriconazole may at times be limited by the development of hepatotoxicity. Our goal is to determine predictors of voriconazole-associated hepatotoxicity in lung transplant recipients. We conducted a single center retrospective cohort study of lung transplant recipients from 2006 to 2010 who received voriconazole therapy. We compared characteristics of patients who developed hepatotoxicity and those who did not. One hundred five lung transplant recipients received voriconazole. Hepatotoxicity occurred in 51% (54/105) of patients and lead to discontinuation in 34% (36/105). In univariate analysis, age less than 40 years, cystic fibrosis, use of azathioprine, history of liver disease and early initiation of voriconazole were associated with hepatotoxicity. In multivariable logistic regression analysis, perioperative initiation of voriconazole (within 30 days of transplantation) was independently associated with hepatotoxicity (OR 4.37, 95% CI: 1.53-12.43, p = 0.006). The five risk factors identified in the univariate analysis were used to build a K-nearest neighbor algorithm predictive model for hepatotoxicity. This model predicted hepatotoxicity with an accuracy of 70%. Voriconazole therapy initiated within the first 30 days of transplantation is associated with a greater risk of developing hepatotoxicity.

kT -points: short three-dimensional tailored RF pulses for flip-angle homogenization over an extended volume.

With Transmit SENSE, we demonstrate the feasibility of uniformly exciting a volume such as the human brain at 7T through the use of an original minimalist transmit k-space coverage, referred to as "k(T) -points." Radio-frequency energy is deposited only at a limited number of k-space locations in the vicinity of the center to counteract transmit sensitivity inhomogeneities. The resulting nonselective pulses are short and need little energy compared to adiabatic or other B 1+-robust pulses available in the literature, making them good candidates for short-repetition time 3D sequences at high field. Experimental verification was performed on three human volunteers at 7T by means of an 8-channel transmit array system. On average, whereas the standard circularly polarized excitation resulted in a 33%-flip angle spread (standard deviation over mean) throughout the brain, and a static radio-frequency shim showed flip angle variations of 17% and up, application of k(T) -point-based excitations demonstrated excellent flip angle uniformity (8%) for a small target flip angle and with sub-millisecond durations.

[Cutaneous necrosis at apomorphine injection points]. / Nécroses cutanées localisées aux points d'injection d'apomorphine.

BACKGROUND: Apomorphine is a specific dopaminergic agonist used in the treatment of severe fluctuations of Parkinson's disease, particularly in patients on L-dopa. The drug is usually given subcutaneously, either as several daily injections or via a continuous subcutaneous delivery system. We describe two cases of localized cutaneous necrosis at the points of subcutaneous apomorphine injection. OBSERVATIONS: Two male patients presenting Parkinson's disease were treated by subcutaneous injection of apomorphine. One month later, asymptomatic necrotic lesions measuring from 2 to 5 mm appeared at the injection sites. Complete blood count, standard and advanced coagulation studies and screening tests were normal. One patient had taken acetylsalicylic acid. A skin biopsy showed normal epidermis, oedema of the papillary dermis with perivascular lymphocytic infiltrates, reticular dermal infiltrate with neutrophils, and necrosis of the reticular dermis and hypodermis in one patient, and in the other, necrosis in the epidermis, dermis, hypodermis and skin appendages, with dermal leucocytoclastic vasculitis and cytosteatonecrosis. Due to the severity of necrosis, apomorphine was stopped, resulting in improvement of skin lesions in one patient. In the second, due to the localized nature of the lesions and the improvement in the patient's quality of life since the introduction of apomorphine, the drug was continued, resulting in the appearance of new lesions, which continued to be limited to the injection sites. COMMENTS: To our knowledge, this is the first description of biopsy-proven apomorphine-induced localized skin necrosis. Reported cutaneous side effects of the drug include pruritic subcutaneous nodules corresponding to panniculitis with large numbers of eosinophils, allergic contact dermatitis, pigmented nodules resulting from oxidation of apomorphine, and nonspecific rashes. Cutaneous necrosis at injection sites could arise through various mechanisms: localized vasoconstriction ("dopamine necrosis"), direct toxicity of the injected drug, local manifestations of pre-existent coagulation disorders, immunological mechanisms or poor administration technique involving intravascular injection. The specific pharmacodynamic properties of apomorphine rule out vasomotor phenomena in the aetiology of such necrosis. Screening tests for thrombophilia were negative in the first patient. Although the underlying mechanism of this form of necrosis remains unknown, an immunological mechanism of the immune complex type could be considered aetiologically relevant on histological grounds due to the presence of vasculitis in one of the two patients.

Lactobacillus probiotic use in cardiothoracic transplant recipients: a link to invasive Lactobacillus infection?

Organisms contained in probiotics are generally regarded as non-pathogenic and safe to administer. However, increasing reports of probiotic-associated infection raise concern over the safety of these products. We report a case of Lactobacillus empyema in a human immunodeficiency virus-infected lung transplant recipient receiving a probiotic containing Lactobacillus rhamnosus GG. We compare the epidemiology of Lactobacillus infections in heart and lung transplant recipients at our institution before and after the introduction of this probiotic, and discuss the potential mechanism for Lactobacillus within the probiotic to cause infections and disseminate.

Verapamil but not calpain or creatine alters arsenate-induced cardiac cell death.

The objective of this study was to examine the potential of arsenate to induce cardiomyocyte cell death and to explore the cellular mechanisms of arsenate toxicity. Isolated cardiomyocytes in culture from embryonic chick hearts were treated with a pentavalent arsenic species (H3AsO4) or arsenate. Arsenate produced a significant (P < 0.01) concentration-dependent increase in cell death with an EC50 about 1 mM. Cardiomyocytes manifested a loss of actin structure, reduced size, and damaged nuclei. Creatine 0.1-100 uM did not significantly modify arsenate-induced cell death. In contrast, verapamil, 0.01-1 uM, produced a significant concentration-dependent accentuation of arsenate-induced cell death. The effect of verapamil was evident at low concentrations of arsenate, which produced only a small increase in cell death, and at high concentrations of arsenate, which induced a large amount of cell death. Verapamil alone did not alter cardiomyocyte cell death. By comparison, calpain inhibitor II did not modify arsenate-induced cardiomyocyte cell death. These data suggest that cardiomyocytes are vulnerable to the effects of verapamil to increase the cellular toxicity of arsenate. Two potential cellular mechanisms of arsenate toxicity, however, are likely not involved in arsenate toxicity namely calpain activation and reduction of creatine phosphate production.