Impact of long-term fertilization practices on the soil aggregation and humic substances under double-cropped rice fields

Abstract

Soil organic matter (SOM) content and soil aggregation are essential components of soil structure, which plays an important role in soil quality and fertility. Also, the SOM content, aggregation, and humus substances in paddy field were affected by application of fertilization practices. However, there is still limited information about the effects of long-term different fertilization practices on soil aggregation and carbon content in the humic acid (C-HAF), fulvic acid (C-FAF), and humin (C-HUM) fractions under double-cropping rice (Oryza sativa L.) system in Southern China paddy fields. Therefore, the effects of long-term fertilizer application on soil aggregation and C-HUM, C-HAF, and C-FAF contents in 0–5-, 5–10-, and 10–20-cm soil depth under double-cropped rice fields in Southern China were investigated. The experiment located at NingXiang County in Hunan Province, China begins in 1986 and the experiment includes five treatments: without fertilizer input (CK), mineral fertilizer alone (MF), rice straw residues and mineral fertilizer (RF), 30% organic matter and 70% mineral fertilizer (LOM), and 60% organic matter and 40% mineral fertilizer (HOM). The results showed that the soil total organic carbon content in paddy soils with RF, LOM, and HOM treatments was significant higher (P < 0.05) than that of the CK treatment at early and late rice maturity stages. The different sizes of soil aggregates with different fertilization treatments were decreased as HOM > LOM > RF > MF > CK. The HOM treatment had the highest percentage of soil aggregates in each size class and the CK treatment had the lowest percentage of soil aggregates in each size class in 0–5-, 5–10-, and 10–20-cm soil depth at early and late rice maturity stages. The soil C-HAF, C-FAF, and C-HUM contents were increased by long-term combined application of manure with mineral fertilizer practices. Meanwhile, the results indicated that the soil C-HAF, C-FAF, and C-HUM contents with RF, LOM, and HOM treatments were significantly higher (P < 0.05) than that of the CK treatment at early and late rice maturity stages. As a result, the soil total organic carbon content, each size class of soil aggregates, and soil C-HAF, C-FAF, and C-HUM contents were increased by long-term combined application of manure with mineral fertilizer in double-cropped rice fields.

Baseline neutrophil to lymphocyte ratio combined with serum LDH level associated with outcome of nivolumab immunotherapy in a Japanese advanced melanoma population

Abstract

Although immune checkpoint inhibitors (ICI) significantly improve the survival of advanced melanoma, more than half of the patients received no benefit. To predict outcomes, efforts to associate baseline peripheral blood biomarkers were started in patients given treatment with ipilimumab. Among the most critical markers is an increased neutrophil-to-lymphocyte ratio (NLR), which negatively correlates with outcome. Although several baseline factors have been reported to correlate with outcome in patients treated with nivolumab/pembrolizumab (eosinophil count, lymphocyte count, lactate dehydrogenase [LDH], and c-reactive protein [CRP]), a positive link between NLR and outcome has yet to be shown.

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Wide skin markings pattern - melanoma descriptor or patient-related factor?

Abstract

We are intrigued by the findings reported in the letter titled "Uncovering the diagnostic dermoscopic features of flat melanomas located on the lower limbs"(1). Bassoli et al investigated the association of the "wider skin marking pattern" with cutaneous melanoma. They state that this feature corresponds to "…linear intercepting furrows, lighter than the lesion's overall pigmentation and wider compared to the surrounding skin. The authors conclude that "recognition of wider skin markings may…prompt the clinician to obtain a biopsy specimen." We respectfully ask the authors to clarify several aspects of their study methodology.

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Application of in vivo reflectance confocal microscopy (RCM) and ex vivo fluorescence confocal microscopy (FCM) in most common subtypes of Basal Cell Carcinoma and correlation with histopathology

Abstract

Basal cell carcinoma (BCC) accounts for 80% of non-melanoma skin cancer. The identification of the histological subtype is crucial for the correct management of the tumor. In vivo reflectance confocal microscopy (RCM) is a novel technique that has demonstrated high sensitivity and specificity in the in vivo diagnosis of BCC. In an effort to determine reliable criteria for preoperative diagnosis of BCC subtypes, Longo et al. and Peppelman et al., described RCM criteria present in different BCC subtypes.

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Hyaluronan metabolism enhanced during epidermal differentiation is suppressed by vitamin C

Abstract

Background

Hyaluronan is a large, linear glycosaminoglycan present throughout the narrow extracellular space of the vital epidermis. Increased hyaluronan metabolism takes place in epidermal hypertrophy, wound healing and cancer. Hyaluronan is produced by hyaluronan synthases (HAS1-3) and catabolized by hyaluronidases (HYAL1 and -2), reactive oxygen species (ROS), and the KIAA1199 protein.

Objectives

To investigate the changes in hyaluronan metabolism during epidermal stratification and maturation, and the impact of vitamin C.

Methods

Hyaluronan synthesis and expression of the hyaluronan-related genes were analyzed during epidermal maturation from a simple epithelium to a fully differentiated epidermis in organotypic cultures of rat epidermal keratinocytes (REK) using qRT-PCR, immunostainings, and western blotting, in the presence and absence of vitamin C.

Results

With epidermal stratification, both the production and the degradation of hyaluronan were enhanced, resulting in an increase of hyaluronan fragments of various sizes. While the mRNA levels of Has3 and KIAA1199 remained stable during the maturation, Has1, Has2, and Hyal2 showed a transient upregulation during stratification, Hyal1 remained permanently increased, and the hyaluronan receptor Cd44 decreased. At maturation, Vitamin C downregulated Has2, Hyal2 and Cd44, while it increased high molecular mass hyaluronan in the epidermis, and reduced small fragments in the medium, suggesting stabilization of epidermal hyaluronan.

Conclusions

Epidermal stratification and maturation is associated with enhanced hyaluronan turnover, and release of large amounts of hyaluronan fragments. The high turnover is suppressed by vitamin C, which is suggested to enhance normal epidermal differentiation in part through its effect on hyaluronan.

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Levocarnitine for vismodegib-associated muscle spasms: a pilot randomized, double-blind, placebo-controlled, investigator initiated trial

Abstract

Smoothened inhibitors (SIs) are a new, targeted therapy for the treatment of advanced basal cell carcinoma (BCC), but their usage is significantly limited by the most common side effect, muscle spasms. Muscle spasms affect up to 80% of users, and are the most common reason for drug discontinuation despite tumor response. Currently, no placebo-controlled trials exist to guide the management of vismodegib-related muscle spasms. The medical literature suggests that the naturally occurring substance, levocarnitine (LC), can improve contractile function of muscle and reduce markers of exercise-induced stress. Hence, we explored the effect of oral LC on vismodegib-related muscle spasms via a double-blind, randomized, placebo-controlled, two-period crossover design.

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Factors associated with delayed referral for infantile hemangioma necessitating propranolol

Abstract

Background

Oral propranolol is the gold-standard to treat infantile hemangiomas. There is better efficacy and a lower risk of sequelae if therapy is started before the end of the growth phase, but most children are referred too late. Herein, we report the first study to investigate the delay and its associated factors when referring infants with infantile hemangiomas that need propranolol therapy.

Objectives

The primary objective was to determine the delay in referral (time between age at referral [first phone contact] and the optimal age for referral (fixed at 75 days). The second objective was to determine the impact of weighted factors associated with delayed referral assessed by logistic regression performed on two subgroups (referral <75 vs. >75 days).

Methods

Monocentric, retrospective, observational study included infants with infantile hemangiomas treated with oral propranolol between August 2014 and May 2017.

Results

82 children (83% females) were included. Before referral, 81 (99%) children had seen another physician (a pediatrician in 67% of cases). Median age at referral was 99 [2-478] days and 63% phoned after 75 days. Median age at the first visit was 111 days [2-515] and median age when propranolol was started was 128 days [32-541]. After adjustment, in multivariate analyses, location on the lips (OR (CI_95%): 4.21[1.19–14.89]) and superficial hemangioma (OR (CI_95%): 4.19 [1.55–11.34]) emerged as the most significant factors to influence referral before 75 days.

Conclusions

This study adds to our understanding regarding delayed referral and has identified targets for future information campaigns.

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Comparison of fungal fluorescent staining and ITS rDNA PCR-based sequencing with conventional methods for the diagnosis of onychomycosis

Abstract

Background

The current gold standard for diagnosing onychomycosis is direct microscopic examination and culturing. Fungal culture is a time-consuming procedure, while direct microscopy of potassium hydroxide (KOH) mounts suffers from low sensitivity. More rapid and sensitive methods for the diagnosis of onychomycosis are in high demand.

Objective

To establish an effective method for the diagnosis of onchomycosis by assessing the efficacies of fungal fluorescent staining and internal transcribed spacer (ITS) ribosomal DNA (rDNA) polymerase chain reaction (PCR)-based sequencing.

Methods

A total of 204 clinical specimens from patients with suspected onychomycosis were analysed. The gold standard for a true positive sample was positive by KOH, culturing, or both methods. All specimens were also tested by fungal fluorescent staining and its rDNA PCR-based sequencing. We compared the detection, sensitivity, and specificity for these two methods with conventional methods.

Results

In total, 126 (62%) and 102 (50%) were detected by fluorescent staining and PCR-based sequencing, respectively. According to the conventional diagnostic standard, the sensitivity of fluorescent staining and PCR-based sequencing was 97% and 78%, respectively, and specificities of 89% and 90%, respectively. Use of fluorescence enhanced the sensitivity of direct examination by 12% compared with KOH. PCR-based sequencing increased the sensitivity by 6% compared with culturing.

Conclusions

Fluorescence microscopy has a higher sensitivity for the detection of fungi in nail specimens compared with KOH and can be used as a rapid screening tool. PCR-based sequencing was faster and more sensitive compared with culture and when used in conjunction with fluorescence microscopy resulted in higher efficiency.

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Molecular genetic analyses of human endogenous retroviral elements belonging to the HERV-P and -R family in Primary Cutaneous T-Cell Lymphomas

Abstract

Mycosis fungoides (MF) is characterized by longstanding, scaly patch lesions preferentially involving the buttocks and body areas infrequently exposed to sunlight and by a slow evolution over years from patches to plaques and eventually tumors or erythroderma. Lymph node and visceral involvement, as well as large cell transformation, frequently occur in the late stages of the disease [1]. Sézary syndrome (SS) is an erythrodermic cutaneous T-cell lymphoma (CTCL) with leukemic involvement, an aggressive clinical behavior and poor prognosis [2].

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Studying the effect of systemic and biological drugs on intima-media thickness in patients suffering from moderate and severe psoriasis

Abstract

Background

Psoriasis has been related to a large number of cardiovascular risk factors such as hypertension, diabetes mellitus and arteriosclerosis. The increased carotid intima-media thickness (IMT) could be considered to be a marker of generalized arteriosclerosis.

Objective

To assess the effect of systemic and biological drugs on psoriatic patients′ carotid IMT.

Methods

A prospective study was performed. We studied 53 patients with moderate and severe psoriasis from our psoriasis dermatological unit, analyzing lipid and glucose metabolism and performing a carotid IMT sonography before introduction of systemic and biological drugs. After that, we performed an 8-month closely analytic and sonographic follow-up.

Results

The IMT of the psoriatic patients treated with biological drugs tended to decrease, although this occurrence was not statistically significant (p=0.086). The subgroup analysis revealed that patients treated with Methotrexate (p=0,045) and Anti Il-12/23 (p=0,010) presented a decrease of their IMT levels. This analysis also showed a decrease in glycaemia and insulin levels in patients treated with TNF-alpha Inhibitors and Ustekinumab.

Conclusions

Our study suggest that the carotid-IMT may benefits from treatment with biological drugs, particularly Anti IL-12/23, and methotrexate in patients suffering from moderate and severe psoriasis. However, larger longitudinal studies should be performed in order to fully confirm these results.

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Use of Medical Photography Among Dermatologists: A Nationwide Online Survey Study

Abstract

Background

Medical photography enhances patient care, medical education, and research. Despite medical photography's widespread use, little is known about how dermatologists choose to implement photography in routine clinical practice, and how they approach issues of image storage, image security, and patient consent.

Objective

To characterize dermatologists' medical photography habits and opinions.

Methods

A 32-item anonymous, multiple-choice SurveyMonkey questionnaire about medical photography practices was emailed to program directors of the 117 United States (US) dermatology residency programs between May and August 2015, with a request to forward to faculty and affiliated dermatologists. Only board-certified dermatologists practicing in the US were eligible. The Institutional Review Board exempted our study from full review.

Results

Our survey included 153 board-certified dermatologists, primarily representing the northeast (43.1%) and identifying as academic dermatologists (75.5%). Medical photography is prevalent: 61.8% report everyday use and 21.7% photograph every patient. Those reporting rare use (3.3%) were, on average, 20 years older. Dermatologists most commonly use photography to mark biopsy sites (87.5%), track disease (82.9%), and for education/teaching (72.4%). Nearly half (46%) use smartphone cameras. Emailing and texting photographs with patients or colleagues are common (69.1%). Most dermatologists (75.7%) always request patient consent for photographs. Only 23.7% adhere to a photography protocol and 73.9% desire more training opportunities.

Conclusion

Dermatologists value medical photography. While patterns of image acquisition, storage, and consent are noted, a variety of methods and preferences exist. Clearer photography guidelines and increased educational resources are likely to improve image quality, exchangeability, and confidentiality.

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Identification and Validation of Appropriate Reference Genes for qRT-PCR Analysis in Corynebacterium glutamicum

Abstract

Real-time quantitative PCR (qRT-PCR) is a fast and efficient technology for detecting gene expression levels in the study of the Corynebacterium glutamicum protein expression system, but it requires normalization to ensure the reliability of the results obtained. We selected 13 genes from the commonly used housekeeping genes and from transcriptome data as candidate reference genes. The Ct values of the 13 genes were obtained by qRT-PCR at different fermentation stages and under three stress conditions (temperature, acid, and salt). The expression stability of the reference genes was evaluated by geNorm and NormFinder software. For the study of different growth stages, the most appropriate reference genes are Ncgl2772 and leua, which encode acetyl-CoA carboxylase beta subunit and 2-isopropylmalate synthase, separately. For the study of different stress factors, the optimal minimum number of reference genes is 3, with Ncgl2772, gyrb encoding DNA gyrase B and siga encoding RNA polymerase sigma factor A as the most suitable combination. Additionally, clpx and clpc, encoding ClpX and ClpC protease subunits, were used to validate the candidate reference genes. The identification of new reference genes makes qRT-PCR more convenient, and using these genes for normalization can improve the accuracy and reliability of the measurements of target gene expression levels obtained by qRT-PCR for C. glutamicum.

Age-related differences in the functional properties of lips compared with skin

Abstract

Background/aims

Lips can easily become dry and rough and their biggest problems are drying and chapping. The cause of those problems is considered to be that the stratum corneum (SC) moisture is small and its barrier function is low. However, those problems decrease in subjects as they approach 40 years of age, after which problems due to their shape and color increase. The purpose of this study was to investigate relationships between SC properties of the lips during aging and to clarify the cause(s) of lip problems.

Methods

One hundred and 38 Japanese female subjects with normal skin ranging in age from 16 to 78 years were enrolled in the study. The capacitance and transepidermal water loss (TEWL) values, viscoelasticity, and color of their lips were measured and compared with their cheeks.

Results

The capacitance values for the lip and the cheek increased and TEWL values for both areas decreased with age. TEWL values for the lip decreased until ~30 years of age and this is considered to be related to the problem of drying. Although the maximum amplitude U_f of the lip increased with age, the U_r/U_f had no correlation with age. As for color, the L* and a* values decreased with age.

Conclusion

Age-related changes with regard to SC functions, viscoelasticity and color of the lips have been clarified for the first time, and it is clear that these changes are related to problems of the lips. Compared with the cheeks, differences with the lips are more apparent.

Non-invasive evaluation of human mucosal structures by multiphoton laser scanning tomography in vitro

Abstract

Background

Mucous membranes may be affected by various diseases and the diagnostic accessibility is limited. Multiphoton laser tomography (MPT) is a useful tool for in vivo evaluation of superficial skin structures and might also be useful for the imaging of mucosa.

Objectives

In order to investigate the suitability of MPT for the evaluation of mucous membranes, tissue samples of different donors and anatomical localizations have been imaged.

Methods

Human mucosa samples from the urinary bladder, palatine tonsil and ocular conjunctiva were investigated by MPT and subsequently compared with conventional histology.

Results

Horizontal images of the epithelium and the underlying connective tissue were obtained using the autofluorescence and second harmonics generation signals by MPT. The stratification of multilayered epithelium was consistently reproduced. Also inflammatory changes like lymphocytic infiltrates and widened intercellular spaces were imaged in some cases.

Conclusion

Mucous tissue samples were obtained and MPT imaging was successfully performed. In the direct comparison with histology of the same tissue samples, the characteristic morphology of the epithelia was found. Further studies are necessary in order to compare images of healthy and diseased mucosal epithelium and the use of MPT for its evaluation in vivo.

Plasma exeresis for active acne vulgaris: Clinical and in vivo microscopic documentation of treatment efficacy by means of reflectance confocal microscopy

Herpes zoster at the vaccination site in immunized healthy children

Abstract

In this case series, we report seven immunized healthy children without underlying immunodeficiency who presented with herpes zoster that correlated with varicella-zoster vaccination site. The morphology of the lesions included erythematous papules, pseudovesicles, and plaques, with associated pain in two and pruritus in three patients; systemic symptoms ranged from none to low-grade fevers, upper respiratory symptoms, and joint pain. These cases highlight the clinical, diagnostic, and therapeutic implications of herpes zoster in vaccinated children.

Metastatic melanoma with dedifferentiation and extensive rhabdomyosarcomatous heterologous component

Melanoma may undergo dedifferentiation and sarcomatous transformation with loss of melanocytic markers. Dedifferentiated melanoma rarely forms true rhabdomyoblasts with skeletal muscle immunophenotype (rhabdomyosarcomatous heterologous component). A 52 year-old woman was diagnosed with invasive melanoma (Breslow depth 0.83 mm) of the upper back in 2012, treated by wide local excision only. In 2013, an axillary mass was excised to show metastatic melanoma with two morphologies: an epithelioid morphology expressing S100 and MART-1 and a spindled morphology with loss of melanocytic markers but strong expression of desmin. This metastasis was found to have BRAF V600E mutation. In 2015, a thoracic epidural mass biopsy showed atypical spindle cells with focal HMB-45 but essentially no S100 expression. Numerous rhabdomyoblasts, some with striations that were strongly positive for desmin and myogenin, were present. In 2016, a right nephrectomy was performed for metastasis to the kidney, and showed sheets of spindle cells and rhabdomyoblasts expressing desmin and myogenin but not S100. Only focal areas demonstrated expression of HMB-45 and SOX-10, supporting the melanocytic origin of the tumor. The numerous rhabdomyoblasts and the loss of S100 expression in the metastatic lesions in this case could have easily led to misdiagnosis if the clinical history was not known.

Tools, techniques, and technologies for pollution prevention, control, and resource recovery

Long-term study of the efficacy and safety of OnabotulinumtoxinA for the prevention of chronic migraine: COMPEL study

OnabotulinumtoxinA is approved for the prevention of headache in those with chronic migraine (CM); however, more clinical data on the risk-benefit profile for treatment beyond one year is desirable.

Tropical Dermatology, 2nd ed

The effect of dietary selenium addition on the concentrations of heavy metals in the tissues of fallow deer ( Dama dama L.) in Croatia

Abstract

The aim of this research was to determine the concentrations of cadmium, lead, mercury, and arsenic and the essential elements iron and selenium in the tissues (muscle, kidney, liver, spleen, and fat) of fallow deer (Dama dama L.) without and with supplemental selenium addition. Another aim was to determine the effect of selenium addition on the indicators of oxidative stress, namely, the levels of superoxide dismutase, glutathione peroxidase, glutathione, and vitamin E. The research was carried out with 40 fallow deer during two research periods. Supplemental feed without selenium addition was provided during the first research period, and supplemental feed with added selenium (3 mg/kg) was provided for 60 days during the second research period. The concentration of selenium in tissues was higher in the second research period than in the first research period (in kidney tissue, 0.957 vs. 0.688 mg/kg, P < 0.05). The dietary addition of selenium decreased (P < 0.05) the concentrations of some heavy metals (lead in the spleen = 0.06 vs. 0.27 mg/kg and in the fatty tissue = 0.17 vs. 0.69 mg/kg; arsenic in the muscle tissue = 0.005 vs. 0.014 mg/kg, liver = 0.003 vs. 0.009 mg/kg, spleen = 0.004 vs. 0.013 mg/kg, and fat = 0.008 vs. 0.016 mg/kg). The activity of glutathione peroxidase was significantly higher (P < 0.05) in the second research period than in the first research period (1375.36 vs. 933.23 U/L).

In situ investigation of heavy metals at trace concentrations in greenhouse soils via portable X-ray fluorescence spectroscopy

Abstract

Soil pollution by heavy metals (HMs) has rapidly become a major threat to vegetable security. Nearly all cultivated soils are at risk of metal accumulation, and greenhouse soils are among the most heavily impacted soils. In this study, a rapid assessment of HMs at trace concentrations was conducted via portable X-ray fluorescence (PXRF) spectroscopy in Shouguang, China. Measurements were made via PXRF under in situ, ex situ and sieved conditions and by inductively coupled plasma mass spectrometry (ICP-MS) after acid digestion. The performance of each PXRF measure relative to the ICP-MS method was assessed by linear regression. Redundancy analysis was performed to quantify the proportion of explained variability between the PXRF and ICP-MS data. Evaluation of the possible sources of HMs and their potential risks was then conducted by multivariate analysis. The results showed that the PXRF data were closely correlated with ICP-MS quantification for Cu, Mn and Zn, whereas no significant correlations were found for As, Ni and Pb. The uncertainties of PXRF measurement derived from soil heterogeneity accounted for 20.02% of total variability and those from moisture and particle size accounted for 20.15%. The geo-accumulation index (I_geo) indicated that the greenhouse soils were potentially contaminated by Cu and Zn (I_geo > 0), which can be attributed to anthropogenic activities. Overall, PXRF spectroscopy is promising as a rapid and nondestructive in situ technique for assessing the potential risks of HMs at trace concentrations in greenhouse soils.

Geochemistry of rare earth elements within waste rocks from the Montviel carbonatite deposit, Québec, Canada

Abstract

Several rare earth element (REE) mine projects around the world are currently at the feasibility stage. Unfortunately, few studies have evaluated the contamination potential of REE and their effects on the environment. In this project, the waste rocks from the carbonatites within the Montviel proterozoic alkaline intrusion (near Lebel-sur-Quévillon, Quebec, Canada) are assessed in this research. The mineralization is mainly constituted by light REE (LREE) fluorocarbonates (qaqarssukite-Ce, kukharenkoite-Ce), LREE carbonates (burbankite, Sr-Ba-Ca-REE, barytocalcite, strontianite, Ba-REE-carbonates), and phosphates (apatite, monazite). The gangue minerals are biotites, chlorite, albite, ankerite, siderite, and calcite. The SEM-EDS analyses show that (i) the majority of REE are associated with the fine fraction (< 106 μm), (ii) REE are mainly associated with carbonates, (iii) all analyzed minerals preferably contain LREE (La, Ce, Pr, Nd, Sm, Eu), (iv) the sum of LREE in each analyzed mineral varies between ~ 3 and 10 wt%, (v) the heavy REE (HREE) identified are Gd and Yb at < 0.4 wt%, and (vi) three groups of carbonate minerals were observed containing variable concentrations of Ca, Na, and F. Furthermore, the mineralogical composition of REE-bearing minerals, REE mobility, and REE speciation was investigated. The leachability and geochemical behavior of these REE-bearing mine wastes were tested using normalized kinetic testing (humidity cells). Leachate results displayed higher LREE concentrations, with decreasing shale-normalized patterns. Thermodynamical equilibrium calculations suggest that the precipitation of secondary REE minerals may control the REE mobility.

Cutaneous meningeal heterotopia on the thigh

Abstract

Cutaneous aggregates of meningeal cells have been variously designated as cutaneous meningioma, meningeal heterotopia, and ectopic meningeal rest, with most cases occurring on the head and neck.^1,2 We present an unusual dermal collection of meningeal, adipose, and smooth muscle tissue arising on the thigh of an adult.

Melanoma Mimicking Rosai-Dorfman Disease

Abstract

Despite advances in treatment and increased public awareness, the incidence of melanoma has dramatically increased over the last 50 years ^1,2. Primary and secondary prevention is critical for decreasing the incidence and improving outcomes in melanoma³. A proper clinical and histopathological diagnosis is necessary for definitive management.

Effect of dewatering and composting on helminth eggs removal from lagooning sludge under semi-arid climate

Abstract

In this work, we assessed the drying and composting effectiveness of helminth eggs removal from sewage sludge of a lagoon wastewater treatment plant located in Chichaoua city. The composting was run after mixing sludge with green waste in different proportions: M1 (½ sludge + ½ green waste), M2 ( \( \raisebox{1ex}{\(2\)}\!\left/ \!\raisebox{-1ex}{\(3\)}\right. \) sludge + \( \raisebox{1ex}{\(1\)}\!\left/ \!\raisebox{-1ex}{\(3\)}\right. \) green waste), and M3 ( \( \raisebox{1ex}{\(1\)}\!\left/ \!\raisebox{-1ex}{\(3\)}\right. \) sludge + \( \raisebox{1ex}{\(2\)}\!\left/ \!\raisebox{-1ex}{\(3\)}\right. \) green waste) for 105 days. The analysis of the dewatered sewage sludge showed a load of 8–24 helminth eggs/g of fresh matter identified as Ascaris spp. eggs (5–19 eggs/g) followed by Toxocara spp. (0.2 to 2.4 eggs/g); Hookworm spp. and Capillaria spp. (0.4–1 egg/g); Trichuris spp., Taenia spp., and Shistosoma spp. (< 1 egg/g) in the untreated sludge. After 105 days of treatment by composting, we noted a total reduction of helminth eggs in the order of 97.5, 97.83, and 98.37% for mixtures M1, M2, and M3, respectively. The Ascaris spp. eggs were reduced by 98% for M1 and M3 treatments and by 97% for M₂ Treatment. Toxocara spp., Hookworm spp., Trichuris spp., Capillaria spp., and Shistosoma spp. eggs were totally eliminated (100% decrease) and the Taenia spp. was absent from the first stage of composting. These results confirm the effectiveness of both dehydrating and composting processes on the removal of helminth eggs.

Agminated Spitz naevi or metastatic spitzoid melanoma?

Oral retinoids and depression: reply from the authors

We strongly agree with both teams that our review has limitations including the paucity of the information of some reported cases and the limitations inherent to the Naranjo score. Nevertheless, the Naranjo score was developed to achieve consensus in estimating the probability that a drug has caused an adverse event. It is the only tool that can be used to homogenize the reading of very heterogeneous notifications.

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Pre-treatment magnetic resonance-based texture features as potential imaging biomarkers for predicting event free survival in anal cancer treated by chemoradiotherapy

Abstract

Aim

To assess regular MRI findings and tumour texture features on pre-CRT imaging as potential predictive factors of event-free survival (disease progression or death) after chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC) without metastasis.

Materials and methods

We retrospectively included 28 patients treated by CRT for pathologically proven ASCC with a pre-CRT MRI. Texture analysis was carried out with axial T2W images by delineating a 3D region of interest around the entire tumour volume. First-order analysis by quantification of the histogram was carried out. Second-order statistical texture features were derived from the calculation of the grey-level co-occurrence matrix using a distance of 1 (d1), 2 (d2) and 5 (d5) pixels. Prognostic factors were assessed by Cox regression and performance of the model by the Harrell C-index.

Results

Eight tumour progressions led to six tumour-specific deaths. After adjusting for age, gender and tumour grade, skewness (HR = 0.131, 95% CI = 0-0.447, p = 0.005) and cluster shade_d1 (HR = 0.601, 95% CI = 0-0.861, p = 0.027) were associated with event occurrence. The corresponding Harrell C-indices were 0.846, 95% CI = 0.697-0.993, and 0.851, 95% CI = 0.708-0.994.

Conclusion

ASCC MR texture analysis provides prognostic factors of event occurrence and requires additional studies to assess its potential in an "individual dose" strategy for ASCC chemoradiation therapy.

Key Points

• MR texture features help to identify tumours with high progression risk.

• Texture feature maps help to identify intra-tumoral heterogeneity.

• Texture features are a better prognostic factor than regular MR findings.

Genotype prediction of ATRX mutation in lower-grade gliomas using an MRI radiomics signature

Abstract

Objectives

To predict ATRX mutation status in patients with lower-grade gliomas using radiomic analysis.

Methods

Cancer Genome Atlas (TCGA) patients with lower-grade gliomas were randomly allocated into training (n = 63) and validation (n = 32) sets. An independent external-validation set (n = 91) was built based on the Chinese Genome Atlas (CGGA) database. After feature extraction, an ATRX-related signature was constructed. Subsequently, the radiomic signature was combined with a support vector machine to predict ATRX mutation status in training, validation and external-validation sets. Predictive performance was assessed by receiver operating characteristic curve analysis. Correlations between the selected features were also evaluated.

Results

Nine radiomic features were screened as an ATRX-associated radiomic signature of lower-grade gliomas based on the LASSO regression model. All nine radiomic features were texture-associated (e.g. sum average and variance). The predictive efficiencies measured by the area under the curve were 94.0 %, 92.5 % and 72.5 % in the training, validation and external-validation sets, respectively. The overall correlations between the nine radiomic features were low in both TCGA and CGGA databases.

Conclusions

Using radiomic analysis, we achieved efficient prediction of ATRX genotype in lower-grade gliomas, and our model was effective in two independent databases.

Key Points

• ATRX in lower-grade gliomas could be predicted using radiomic analysis.

• The LASSO regression algorithm and SVM performed well in radiomic analysis.

• Nine radiomic features were screened as an ATRX-predictive radiomic signature.

• The machine-learning model for ATRX-prediction was validated by an independent database.

Shear-wave elastography can evaluate annulus fibrosus alteration in adolescent scoliosis

Abstract

Objectives

In vitro studies showed that annulus fibrosus lose its integrity in idiopathic scoliosis. Shear-wave ultrasound elastography can be used for non-invasive measurement of shear-wave speed (SWS) in vivo in the annulus fibrosus, a parameter related to its mechanical properties. The main aim was to assess SWS in lumbar annulus fibrosus of scoliotic adolescents and compare it to healthy subjects.

Methods

SWS was measured in 180 lumbar IVDs (L3L4, L4L5, L5S1) of 30 healthy adolescents (13 ± 1.9 years old) and 30 adolescent idiopathic scoliosis patients (13 ± 2 years old, Cobb angle: 28.8° ± 10.4°). SWS was compared between the scoliosis and healthy control groups.

Results

In healthy subjects, average SWS (all disc levels pooled) was 3.0 ± 0.3 m/s, whereas in scoliotic patients it was significantly higher at 3.5 ± 0.3 m/s (p = 0.0004; Mann-Whitney test). Differences were also significant at all disc levels. No difference was observed between males and females. No correlation was found with age, weight and height.

Conclusion

Non-invasive shear-wave ultrasound is a novel method of assessment to quantitative alteration of annulus fibrosus. These preliminary results are promising for considering shear-wave elastography as a biomechanical marker for assessment of idiopathic scoliosis.

Key Points

• Adolescent idiopathic scoliosis may have an altered lumbar annulus fibrosus.

• Shear-wave elastography can quantify lumbar annulus fibrosus mechanical properties.

• Shear-wave speed was higher in scoliotic annulus than in healthy subjects.

• Elastography showed potential as a biomechanical marker for characterizing disc alteration.

High-pitch low-voltage CT coronary artery calcium scoring with tin filtration: accuracy and radiation dose reduction

Abstract

Objectives

To investigate diagnostic accuracy and radiation dose of high-pitch CT coronary artery calcium scoring (CACS) with tin filtration (Sn100kVp) versus standard 120kVp high-pitch acquisition.

Methods

78 patients (58% male, 61.5±9.1 years) were prospectively enrolled. Subjects underwent clinical 120kVp high-pitch CACS using third-generation dual-source CT followed by additional high-pitch Sn100kVp acquisition. Agatston scores, calcium volume scores, Agatston score categories, percentile-based risk categorization and radiation metrics were compared.

Results

61/78 patients showed coronary calcifications. Median Agatston scores were 34.9 [0.7–197.1] and 41.7 [0.7–207.2] and calcium volume scores were 34.1 [0.7–218.0] for Sn100kVp and 35.7 [1.1–221.0] for 120kVp acquisitions, respectively (both p<0.0001). Bland-Altman analysis revealed underestimated Agatston scores and calcium volume scores with Sn100kVp versus 120kVp acquisitions (mean difference: 16.4 and 11.5). However, Agatston score categories and percentile-based risk categories showed excellent agreement (ĸ=0.98 and ĸ=0.99). Image noise was 25.8±4.4HU and 16.6±2.9HU in Sn100kVp and 120kVp scans, respectively (p<0.0001). Dose-length-product was 9.9±4.8mGy*cm and 40.9±14.4mGy*cm with Sn100kVp and 120kVp scans, respectively (p<0.0001). This resulted in significant effective radiation dose reduction (0.13±0.07mSv vs. 0.57±0.2mSv, p<0.0001) for Sn100kVp acquisitions.

Conclusion

CACS using high-pitch low-voltage tin-filtered acquisitions demonstrates excellent agreement in Agatston score and percentile-based cardiac risk categorization with standard 120kVp high-pitch acquisitions. Furthermore, radiation dose was significantly reduced by 78% while maintaining accurate risk prediction.

Key points

• Coronary artery calcium scoring with tin filtration reduces radiation dose by 78%.

• There is excellent correlation between high-pitch Sn100kVp and standard 120kVp acquisitions.

• Excellent agreement regarding Agatston score categories and percentile-based risk categorization was achieved.

• No cardiac risk reclassifications were observed using Sn100kVp coronary artery calcium scoring.

Liver fibrosis: stretched exponential model outperforms mono-exponential and bi-exponential models of diffusion-weighted MRI

Abstract

Objectives

To compare the ability of diffusion-weighted imaging (DWI) parameters acquired from three different models for the diagnosis of hepatic fibrosis (HF).

Methods

Ninety-five patients underwent DWI using nine b values at 3 T magnetic resonance. The hepatic apparent diffusion coefficient (ADC) from a mono-exponential model, the true diffusion coefficient (D_t ), pseudo-diffusion coefficient (D_p ) and perfusion fraction (f) from a biexponential model, and the distributed diffusion coefficient (DDC) and intravoxel heterogeneity index (α) from a stretched exponential model were compared with the pathological HF stage. For the stretched exponential model, parameters were also obtained using a dataset of six b values (DDC^#, α^#). The diagnostic performances of the parameters for HF staging were evaluated with Obuchowski measures and receiver operating characteristics (ROC) analysis. The measurement variability of DWI parameters was evaluated using the coefficient of variation (CoV).

Results

Diagnostic accuracy for HF staging was highest for DDC^# (Obuchowski measures, 0.770 ± 0.03), and it was significantly higher than that of ADC (0.597 ± 0.05, p < 0.001), D_t (0.575 ± 0.05, p < 0.001) and f (0.669 ± 0.04, p = 0.035). The parameters from stretched exponential DWI and D_p showed higher areas under the ROC curve (AUCs) for determining significant fibrosis (≥F2) and cirrhosis (F = 4) than other parameters. However, D_p showed significantly higher measurement variability (CoV, 74.6%) than DDC^# (16.1%, p < 0.001) and α^# (15.1%, p < 0.001).

Conclusions

Stretched exponential DWI is a promising method for HF staging with good diagnostic performance and fewer b-value acquisitions, allowing shorter acquisition time.

Key Points

• Stretched exponential DWI provides a precise and accurate model for HF staging.

• Stretched exponential DWI parameters are more reliable than D _p from bi-exponential DWI model

• Acquisition of six b values is sufficient to obtain accurate DDC and α

Are pancreatic IPMN volumes measured on MRI images more reproducible than diameters? An assessment in a large single-institution cohort

Abstract

Objectives

To assess reproducibility of volume and diameter measurement of intraductal papillary mucinous neoplasms (IPMNs) on MRI images.

Methods

Three readers measured the diameters and volumes of 164 IPMNs on axial T2-weighted images and coronal thin-slice navigator heavily T2-weighted images using manual and semiautomatic techniques. Interobserver reproducibility and variability were assessed.

Results

Interobserver intraclass correlation coefficients (ICCs) for the largest diameter measured using manual and semiautomatic techniques were 0.979 and 0.909 in the axial plane, and 0.969 and 0.961 in the coronal plane, respectively. Interobserver ICCs for the volume measurements were 0.973 and 0.970 in axial and coronal planes, respectively. The highest intraobserver reproducibility was noted for coronal manual measurements (ICC 0.981) followed by axial manual measurements (ICC 0.969). For the diameter measurements, Bland-Altman analysis revealed the lowest interobserver variability for manual axial measurements with an average range of 95% limits of agreement (LOA) of 0.68 cm. Axial and coronal volume measurements showed similar 95% LOA ranges (8.9 cm³ and 9.4 cm³, respectively).

Conclusions

Volume and diameter measurements on axial and coronal images show good interobserver and intraobserver reproducibility. The single largest diameter measured manually on axial images showed the highest reproducibility and lowest variability. The 95% LOA may help define reproducible size changes in these lesions using measurements from different readers.

Key Points

• MRI measurements by different radiologists can be used for IPMN follow-up.

• Both diameter and volume measurements demonstrate excellent interobserver and intraobserver reproducibility.

• Manual axial measurements show the highest interobserver reproducibility in determining size.

• Axial and coronal volume measurements show similar limits of agreement.

• Manual axial measurements show the lowest variability in agreement range.

Dual-energy CT: a phantom comparison of different platforms for abdominal imaging

Abstract

Objectives

Evaluation of imaging performance across dual-energy CT (DECT) platforms, including dual-layer CT (DLCT), rapid-kVp-switching CT (KVSCT) and dual-source CT (DSCT).

Methods

A semi-anthropomorphic abdomen phantom was imaged on these DECT systems. Scans were repeated three times for CTDIvol levels of 10 mGy, 20 mGy, 30 mGy and different fat-simulating extension rings. Over the available range of virtual-monoenergetic images (VMI), noise as well as quantitative accuracy of hounsfield units (HU) and iodine concentrations were evaluated.

Results

For all VMI levels, HU values could be determined with high accuracy compared to theoretical values. For KVSCT and DSCT, a noise increase was observed towards lower VMI levels. A patient-size dependent increase in the uncertainty of quantitative iodine concentrations is observed for all platforms. For a medium patient size the iodine concentration root-mean-square deviation at 20 mGy is 0.17 mg/ml (DLCT), 0.30 mg/ml (KVSCT) and 0.77mg/ml (DSCT).

Conclusion

Noticeable performance differences are observed between investigated DECT systems. Iodine concentrations and VMI HUs are accurately determined across all DECT systems. KVSCT and DLCT deliver slightly more accurate iodine concentration values than DSCT for investigated scenarios. In DLCT, low-noise and high-image contrast at low VMI levels may help to increase diagnostic information in abdominal CT.

Key Points

• Current dual-energy CT platforms provide accurate, reliable quantitative information.

• Dual-energy CT cross-platform evaluation revealed noticeable performance differences between different systems.

• Dual-layer CT offers constant noise levels over the complete energy range.

Imaging prediction of nonalcoholic steatohepatitis using computed tomography texture analysis

Abstract

Objectives

To determine if texture analysis of non-contrast-enhanced CT (NECT) images is able to predict nonalcoholic steatohepatitis (NASH).

Methods

NECT images from 88 patients who underwent a liver biopsy for the diagnosis of suspected NASH were assessed and texture feature parameters were obtained without and with filtration. The patient population was divided into a predictive learning dataset and a validation dataset, and further divided into groups according to the prediction of liver fibrosis as assessed by hyaluronic acid levels. The reference standard was the histological result of a liver biopsy. A predictive model for NASH was developed using parameters derived from the learning dataset that demonstrated areas under the receiver operating characteristic curve (AUC) of >0.65. The resulting model was then applied to the validation dataset.

Results

In patients without suspected fibrosis, the texture parameter mean without filter and skewness with a 2-mm filter were selected for the NASH prediction model. The AUC of the predictive model for the validation dataset was 0.94 and the accuracy was 94%. In patients with suspicion of fibrosis, the mean without filtration and kurtosis with a 4-mm filter were selected for the NASH prediction model. The AUC for the validation dataset was 0.60 and the accuracy was 42%.

Conclusions

In patients without suspicion of fibrosis, NECT texture analysis effectively predicted NASH.

Key Points

• In patients without suspicion of fibrosis, NECT texture analysis effectively predicted NASH.

• The mean without filtration and skewness with a 2-mm filter were modest predictors of NASH in patients without suspicion of liver fibrosis.

• Hepatic fibrosis masks the characteristic texture features of NASH.

Endovascular interventional modalities for haemorrhage control in abnormal placental implantation deliveries: a systematic review and meta-analysis

Abstract

Objectives

To examine the evidence regarding the effectiveness and safety of endovascular interventional modalities for haemorrhage control in abnormal placentation deliveries.

Methods

MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from inception to July 2017. Blood loss volume was regarded as the primary endpoint. Other important results are described. Random and fixed effects models were used for the meta-analysis.

Results

Of 385 studies identified, 69 (1,811 patients, mean age 32.9 years, range 23–39 years) were included. Mean gestational age at delivery was 35.1 weeks (range 27–38 weeks). Of 1,395 patients who underwent endovascular intervention, 587 (42%) had placenta accreta, 254 (18%) placenta increta and 313 (22%) placenta percreta. Prophylactic balloon occlusion of the internal iliac arteries (PBOIIA) was performed in 470 patients (33.6%), of the abdominal aorta (PBOAA) in 460 patients (33%), of the uterine artery (PBOUA) in 181 patients (13%), and of the common iliac arteries (PBOCIA) in 21 patients (1.5%). Primary embolization of the UA was performed in 246 patients (18%), of the pelvic collateral arteries in 12 patients (0.9%), and of the anterior division of the IIA in 5 patients (0.3%). Follow-up ranged from 0.5 to 42 months. Endovascular intervention was associated with less blood loss than no endovascular intervention (p < 0.001) with the lowest blood loss volume in patients who underwent PBOAA (p < 0.001). PBOAA was associated with a lower rate of hysterectomy (p = 0.030). Endovascular intervention did not result in increases in operative time or hospital stay.

Conclusions

Endovascular intervention is effective in controlling haemorrhage in abnormal placentation deliveries. PBOAA was associated with a lower rate of hysterectomy and less blood loss than other modalities.

Key points

• Endovascular intervention in abnormal placentation deliveries is effective in reducing blood loss.

• Endovascular intervention did not result in longer operative time or hospital stay.

• Prophylactic balloon occlusion of the abdominal aorta is superior to other modalities.

Intravoxel incoherent motion magnetic resonance imaging for differentiating metastatic and non-metastatic lymph nodes in pancreatic ductal adenocarcinoma

Abstract

Objectives

To evaluate the diagnostic potential of intravoxel incoherent motion (IVIM) DWI for differentiating metastatic and non-metastatic lymph node stations (LNS) in pancreatic ductal adenocarcinoma (PDAC).

Methods

59 LNS histologically diagnosed following surgical resection from 15 patients were included. IVIM DWI with 12 b values was added to the standard MRI protocol. Evaluation of parameters was performed pre-operatively and included the apparent diffusion coefficient (ADC), pure diffusion coefficient (D), pseudo-diffusion coefficient (D*) and perfusion fraction (f). Diagnostic performance of ADC, D, D* and f for differentiating between metastatic and non-metastatic LNS was evaluated using ROC analysis.

Results

Metastatic LNS had significantly lower D, D*, f and ADC values than the non-metastatic LNS (p< 0.01). The best diagnostic performance was found in D, with an area under the ROC curve of 0.979, while the area under the ROC curve values of D*, f and ADC were 0.867, 0.855 and 0.940, respectively. The optimal cut-off values for distinguishing metastatic and non-metastatic lymph nodes were D = 1.180 × 10⁻³ mm²/s; D* = 14.750 × 10⁻³ mm²/s, f = 20.65 %, and ADC = 1.390 × 10⁻³ mm²/s.

Conclusion

IVIM DWI is useful for differentiating between metastatic and non-metastatic LNS in PDAC.

Key Points

• IVIM DWI is feasible for diagnosing LN metastasis in PDAC.

• Metastatic LNS has lower D, D*, f, ADC values than non-metastatic LNS.

• D-value from IVIM model has best diagnostic performance, followed by ADC value.

• D* has the lowest AUC value.

Monilethrix: A case report imaged by trichoscopy, reflectance confocal microscopy and histopathology

Statistical Controversies in Clinical Research: Limitations of open-label studies assessing antiangiogenic therapies with regard to evaluation of vascular adverse drug events. A meta-analysis

Abstract

Background

Previous meta-analyses have shown paradoxical increased risk of bleeding and thrombotic events in patients receiving antiangiogenics (AA) that may be simply explained by the studies design included. By a meta-epidemiological approach, we aim to investigate the impact of double-blind (DB) and open-label study designs on the risks of bleeding, venous thrombotic events (VTE) and arterial thrombotic events (ATE) in cancer patients treated with AA.

Materials and Methods

We searched Medline, Cochrane, ClinicalTrials.gov databases, and proceedings of major oncology congresses for clinical trials published from January 2003 to January 2016. Randomized clinical trials that assigned patients with solid cancers to AA or control groups were eligible for inclusion. Combined odds ratios (OR) for the risks of bleeding events, VTE and ATE were calculated for open and DB trials. Estimation bias of the treatment effect was determined by the ratio of odds ratio (ROR), by dividing the OR values obtained in open-label trials by those obtained in DB trials.

Results

The literature-based meta-analysis included 166 trials (72,024 patients). For bleeding events, comparison of AA versus control yielded an overall OR of 2.41 (95% CI 2.12-2.73; P <0.001), but this risk was overestimated by 1.68 (95% CI 1.33-2.13) in open-label studies. Concerning VTE, the OR was 1.19 (95% CI 1.04-1.35; P =0.012) overall with AA, but this effect disappears when considering only DB trials (OR 0.99, 95% CI, 0.83-1.17). The corresponding ROR showed a significant overestimation of 1.53 (95% CI 1.19-1.96) in open-label trials. For ATE, an OR of 1.59 (95% CI 1.30-1.94; P <0.001) was observed, associated with a significant overestimation of 1.65 (95% CI 1.13-2.43) in open-label trials.

Conclusions

Open-label studies overestimated the risk of vascular adverse events with AA by at least 50%. Meta-analyses assessing adverse drug events should therefore be restricted to DB randomized trials.

EXPRESSION III: Patient´s Expectations and Preferences regarding Physician–Patient Relationship and Clinical Management. Results of the International NOGGO/ENGOT-ov4-GCIG study in 1,830 Ovarian Cancer Patients from European countries.

Abstract

Backround

The primary aim of this study was to investigate information needs and treatment preferences of patients with ovarian cancer, focusing especially on physician-patient relationship and treatment

Patients and methods

A questionnaire was developed based on the experiences of the national German survey Expression II, and was provided to patients with ovarian cancer either at initial diagnosis or with recurrent disease via Internet (online-version) or as print-out-version.

Results

From December 2009 to October 2012, a total of 1,830 patients with ovarian cancer from eight European countries (Austria, Belgium, France, Germany, Italy, Poland, Romania, Spain) participated, 902 (49.3%) after initial diagnosis and 731 (39.9%) with recurrent ovarian cancer. The median age was 58 years (range 17–89). Nearly all patients (96.2%) had experienced upfront surgery followed by first-line chemotherapy (91.8%). The majority of patients were satisfied with the completeness and comprehensibility of the explanation about the diagnosis and treatment options. The 3 most important aspects, identified by patients to improve the treatment for ovarian cancer included: "the therapy should not induce alopecia" (42%), "there must be more done to counter fatigue" (34.5%), and "the therapy should be more effective" (29.7%). Out of 659 (36%) patients, who were offered participation in a clinical trial, 476 (26%) were included.

Conclusion

This study underlines the high need of patients with ovarian cancer for all details concerning treatment options irrespective of their cultural background, the stage of disease and the patient's age. Increased information requirements regarding potential side effects and treatment alternatives were recorded. Besides the need for more effective therapy, alopecia and fatigue are the most important side effects of concern to patients.

Developing Androgen Receptor Targeting for Salivary Gland Cancers

Phase 1-2 trial designs: how early should efficacy guide the dose recommendation process?

Nivolumab versus docetaxel in previously treated advanced non-small cell lung cancer (CheckMate 017 and CheckMate 057): 3-year update and outcomes in patients with liver metastases

Abstract

Background

Long-term data with immune checkpoint inhibitors in non-small cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti–programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and non-squamous (CheckMate 057) NSCLC. We report results from ≥3 years' follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC.

Patients and methods

Patients were randomized 1:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m² every 3 weeks) until progression or discontinuation. The primary endpoint of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses.

Results

After 40.3 months' minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% (95% confidence interval [CI], 14–21%) versus 8% (95% CI, 6–11%) in the pooled population with squamous or non-squamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50–0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61–0.81). Rates of treatment-related hepatic adverse events (primarily grade 1–2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%).

Conclusions

After 3 years' minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated.

Clinical trial registration

CheckMate 017: NCT01642004; CheckMate 057: NCT01673867

CHK1 Inhibition in Soft-Tissue Sarcomas: Biological and Clinical Implications

Abstract

Background

Inhibition of ChK1 appears as a promising strategy for selectively potentiate the efficacy of chemotherapeutic agents in G1 checkpoint-defective tumor cells such as those that lack functional p53 protein. The p53 pathway is commonly dysregulated in soft-tissue sarcomas (STS) through mutations affecting TP53 or MDM2 amplification. GDC-0575 is a selective ATP-competitive inhibitor of CHK1.

Methods

We have performed a systematic screening of a panel of 10 STS cell lines by combining the treatment of GDC-0575 with chemotherapy. Cell proliferation, cell death and cell cycle analysis were evaluated with high throughput assay. In vivo experiments were performed by using TP53-mutated and TP53 wild-type patient-derived xenograft models of STS. Clinical activity of GDC-0575 combined with chemotherapy in patients with TP53-mutated and TP53 wild-type STS was also assessed.

Results

We found that GDC-0575 abrogated DNA damage-induced S and G2–M checkpoints, exacerbated DNA double-strand breaks and induced apoptosis in STS cells. Moreover, we observed a synergistic or additive effect of GDC-0575 together with gemcitabine in vitro and in vivo in TP53-proficient but not TP53-deficient sarcoma models. In a phase 1 study of GDC-0575 in combination with gemcitabine, two patients with metastatic TP53-mutated STS had an exceptional, long-lasting response despite administration of a very low dose of gemcitabine whereas one patient with wild-type TP53 STS had no clinical benefit. Genetic profiling of samples from a patient displaying secondary resistance after 1 year showed loss of one preexisting loss-of-function mutation in the helical domain of DNA2.

Conclusion

We provide the first pre-clinical and clinical evidence that potentiation of chemotherapy activity with a CHK1 inhibitor is a promising strategy in TP53-deficient STS and deserves further investigation in the phase 2 setting.

Molecular detection and genotypic characterization of enteric adenoviruses in a hospital wastewater

Abstract

Hospital wastewater (HWW) represents a major source of the diffusion of many antibiotics and some toxic pathogenic microorganisms in the aquatic environment. Sanitation services play a critical role in controlling transmission of numerous waterborne pathogens, especially enteric human adenoviruses (HAdVs) that can cause acute gastroenteritis. This study intended to evaluate the human adenoviruses (HAdVs) detection rates, to determine the genotype of these viruses and to assess the efficiency of HAdVs removal in hospital pilot wastewater treatment plant (PWWTP) in Tunis City, Tunisia. Therefore, hospital wastewater samples (n = 102) were collected during the study year from the two biological wastewater treatment techniques: natural oxidizing ponds and the rotating biological disks or biodisks. Nested polymerase chain reaction (Nested PCR) was used to evaluate the HAdVs detection rates. The genotype of HAdVs positive samples was achieved by the sequencing of the PCR products. HAdVs were detected in 64% (65/102) of positive wastewater samples. A substantial increase in the frequencies of HAdVs was observed at the exit of the two wastewater treatment techniques studied. The typing of HAdVs species F showed the occurrence of only HAdVs type 41. This data acquired for the first time in Tunisia showed high persistence and survival of HAdVs in the two biological wastewater treatment techniques experienced, and mainly highlighted the poor virological quality of the treated wastewater intended for recycling, agriculture reuse, and discharges into the natural receiving environments. Consequently, tertiary wastewater treatment appeared necessary in this case to decrease the load of enteric viruses flowing in the water environment.

Lichen sclerosus on the face