Versatility of dermal regeneration templates in the treatment of burn sequelae

Abstract

Background

The management of burn sequelae is a major challenge for every plastic surgeon. The benefits of Integra® Dermal Regeneration Template in the management of burn injuries have been well documented but there is still a paucity of data regarding its use in reconstructive procedures. The aim of this study is to evaluate its effectiveness in the surgical treatment of post-burn scars.

Methods

We performed a retrospective review of burn patients with major burn sequelae treated with Integra® at our hospital during 2016–2017 period. A modified Vancouver Scar Scale (mVSS) was used to provide a more objective measurement of burn scars. All patients were submitted to a two-stage procedure. The first one consisted in complete excision of the lesions and implantation of Integra and the second one in resurfacing the neodermis with a split thickness skin graft.

Results

The average wound size covered with Integra was 741.6 cm². Follow-up ranged from 9 to 16 months. There were no early complications. In all cases, we achieved satisfactory cosmetic results with significant improvements in functionality and quality of life. mVSS score post-op was significantly lower than pre-op in all patients.

Conclusions

Our results suggest that Integra is a very versatile tool for the treatment of burn sequelae. It yields good cosmetic and functional results in most cases with very little donor site morbidity. We believe that Integra should be viewed as one of the best current options for reconstructive procedures in burn patients.

Level of Evidence: Level IV, therapeutic study.

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Comparative study of the direct black removal by Fe, Cu, and Fe/Cu nanoparticles

Abstract

In this study, direct black dye removal was investigated using iron nanoparticles (Fe NPs), copper (Cu NPs), and Fe/Cu (Fe/Cu NPs). NPs were characterized by transmission electron microscopy (TEM) and X-ray diffraction (XRD). Using a dose of 0.25 g L⁻¹ of Fe, Cu, and Fe/Cu NPs, a degradation efficiency of 13, 26, and 43% respectively was obtained. For the 1.00 g L⁻¹ dose, the efficiency increased to 100, 43, and 100%, respectively. Studies in anoxic and oxic conditions presented degradation rates, respectively, of 100 and 30% for Fe NPs, 90 and 50% for Fe/Cu NPs, and 40% in both reactions for Cu NPs, indicating that the mechanism of dye degradation by NPs is predominantly reducing under the conditions studied. The addition of EDTA decreased the dye removal rate for Fe, Cu, and Fe/Cu NPs at 27, 10, and 35%, respectively. In addition to the degradation, the adsorption phenomena of the by-products formed during the reaction were confirmed by the Fourier transform infrared (FTIR) analysis and verified by the desorption tests. Fe and Fe/Cu NPs showed the highest efficiency in direct black dye reductive degradation and adsorption of by-products, removing 100% of the dye at a dose of 1 g L⁻¹ within 10 min of reaction.

Graphical abstracts

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Interleukin‐2 Can Cure Kidney Cancer

https://ift.tt/2MqnQoO

Durable Response to Nivolumab in a Pediatric Patient with Refractory Glioblastoma and Constitutional Biallelic Mismatch Repair Deficiency

AbstractPrimary brain tumors are a leading cause of cancer‐related morbidity and mortality in children. Glioblastoma (GBM) is a high‐grade astrocytoma that occurs in both children and adults and is associated with a poor prognosis. Despite extensive study in recent years, the clinical management of these tumors has remained largely unchanged, consisting of surgical resection, conventional chemotherapy, and radiotherapy. Although the etiology and genomic drivers in GBM are diverse, constitutional mismatch repair‐deficiency (CMMRD) syndrome is a rare, recessively inherited disease with a predisposition to gliomagenesis. CMMRD results from biallelic mutations in one of the mismatch repair genes including mutL homolog 1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6), and post‐meiotic segregation increased 2 (PMS2). In this report, we present the case of a 5‐year‐old female with GBM and CMMRD due to an MSH6 homozygous c.1883G>A mutation, who continues to experience an exceptional and durable response (9 months) to the immune checkpoint inhibitor (ICPI) nivolumab. Our patient presented with acute neurologic decline and increased intracranial pressure. Neuroimaging studies revealed a large left frontoparietal mass requiring neurosurgical decompression and resection. Histopathologic analyses resulted in a diagnosis of de novo GBM that was BRAF wild type and negative for programmed death‐ligand 1 protein expression. She received standard‐of‐care treatment with surgery, radiation therapy, and temozolomide; however, the tumor recurred 3 months after the initial diagnosis. Molecular analyses of tumor and blood tissues revealed an MSH6 homozygous c.1883G>A mutation consistent with CMMRD. Given her CMMRD status, she was treated with nivolumab (3 mg/kg doses every 2 weeks for 36 weeks) and showed a 60% reduction in tumor size, improved clinical symptoms, and an ongoing durable response lasting 10 months to date. Our study highlights a durable response to the ICPI nivolumab in a pediatric patient with recurrent/refractory CMMRD‐associated GBM. We show that incorporating genomic and/or molecular testing for CMMRD into routine pediatric oncology clinical care can identify a subset of patients likely to benefit from ICPI.Key Points. Constitutional mismatch repair‐deficiency (CMMRD) syndrome, alternatively known as biallelic mismatch repair deficiency syndrome, occurs in subset of pediatric cancer patients, including those with primary brain tumors.Patients from Arab and other developing countries are predicted to have higher incidence of CMMRD due to high prevalence of consanguinity.Integration of molecular and/or genomic testing into routine clinical care for pediatric cancer patients is important to identify patients with CMMRD syndrome.Patient with CMMRD‐associated cancers may show increased responsiveness to immune checkpoint inhibitors.To the authors' knowledge, this is the first report in the Arab world of a durable response to immune checkpoint inhibitors in a pediatric glioblastoma patient.

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Dramatic Response to Concurrent Anti‐PD‐1 Therapy and Radiation in Resistant Tumors with Sarcomatoid Differentiation

AbstractA substantial fraction of patients demonstrate resistance to immune checkpoint inhibitors, which limits their use. Use of radiation concurrently with checkpoint inhibitors has been shown to boost immune responsiveness, resulting in significant tumor regression in patients with metastatic melanoma. However, it is unknown whether radiation could play a role in reversing the inherent resistance to checkpoint inhibition in certain tumor types. Most trials testing this concurrent approach exclude such modestly responsive tumors and pursue checkpoint inhibition using anti‐cytotoxic T‐lymphocyte‐associated protein 4 antibody (anti‐CTLA‐4, ipilimumab). The efficacy of anti‐programmed‐death‐1 (anti‐PD‐1) therapy when used concurrently with radiation is less known but remains an attractive option due to less autoimmune toxicity compared with CTLA‐4 inhibition. In this first reported experience, we have safely and effectively combined anti‐PD‐1 therapy (nivolumab) concurrently with radiation to treat two patients with relapsed sarcomatoid renal carcinoma and heavily pretreated pleomorphic sarcoma. Both patients experienced a dramatic response that was durable.

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Prospective Assessment of Clinical Risk Factors and Biomarkers of Hypercoagulability for the Identification of Patients with Lung Adenocarcinoma at Risk for Cancer‐Associated Thrombosis: The Observational ROADMAP‐CAT Study

AbstractBackground.The aim of this prospective study was to identify the most clinically relevant hypercoagulability biomarkers in lung adenocarcinoma patients for elaboration of an improved risk assessment model (RAM) for venous thromboembolism (VTE).Subjects, Materials, and Methods.One hundred fifty ambulatory patients with lung adenocarcinoma were prospectively enrolled. Thrombin generation, procoagulant phospholipid‐dependent clotting time (Procoag‐PPL), tissue factor activity (TFa), factor VIIa (FVIIa), factor V (FV), antithrombin, D‐Dimers, P‐selectin, and heparanase levels were assessed in platelet‐poor plasma at inclusion (baseline) and at the end of the third chemotherapy cycle (third chemotherapy). Cox regression analysis was used to identify independent VTE predictors.Results.At baseline, patients had significantly attenuated thrombin generation, shorter Procoag‐PPL, higher levels of TFa, D‐Dimers, and heparanase, and lower levels of FVIIa and P‐selectin, compared with controls. A significant increase in Procoag‐PPL, FV, and FVIIa and a decrease of P‐selectin levels were observed between baseline and third chemotherapy. Hospitalization within the last 3 months prior to assessment, time since cancer diagnosis less than 6 months, mean rate index (MRI) of thrombin generation, and Procoag‐PPL were independently associated with symptomatic VTE. Accordingly, a prediction model including Procoag‐PPL and MRI showed significant discriminating capacity (area under the curve: 0.84).Conclusion.Ambulatory patients with lung adenocarcinoma may display pronounced blood hypercoagulability due to decreased Procoag‐PPL, increased endothelial cell activation, and increased degradation of fibrin. Incorporation of Procoag‐PPL and MRI of thrombin generation may improve the accuracy of a VTE‐RAM in the above setting.Implications for Practice.The prospective ROADMAP‐CAT study identified two biomarkers of hypercoagulability, the procoagulant phospholipid‐dependent clotting time (Procoag‐PPL) and the mean rate index (MRI) of the propagation phase of thrombin generation assessed with the Calibrated Automated Thrombinoscope, as being clinically relevant for the classification of ambulatory patients with lung adenocarcinoma receiving a maximum of one cycle of chemotherapy into high and intermediate/low risk for venous thromboembolism. Measurement of Procoag‐PPL and MRI within 1 month after the administration of the first chemotherapy cycle provides significant accuracy of the assessment. Association of the Procoag‐PPL and MRI with the clinical risk assessment model for cancer‐associated thrombosis in ambulatory patients with solid tumors (COMPASS‐CAT RAM) further improved its accuracy.

https://ift.tt/2MJbZ27

The Evolving Treatment Algorithm for Advanced Neuroendocrine Neoplasms: Diversity and Commonalities Across Tumor Types

AbstractNeuroendocrine neoplasms (NEN) most commonly arise in the gastroenteropancreatic system and lungs. The incidence of NEN is increasing globally, with improved diagnostic techniques identifying patients with early‐stage disease. The number of approved therapies for the treatment of advanced disease has grown substantially in the past decade. The treatment algorithm for advanced NEN is evolving from one that is directed by primary site–specific classification to one that is directed by biologic classification, as evidenced by overlapping systemic treatments across the primary tumor sites. Commonalities in biologic characteristics across primary sites include functional status, differentiation status, grade, level of somatostatin receptor expression, and genetic alterations. In this review, we discuss current clinical evidence and available therapies for the treatment of advanced NEN and highlight the need for prospective trials in patients with well‐differentiated, high‐grade NEN.Implications for Practice.This review raises awareness of the evolution of the treatment algorithm for advanced neuroendocrine neoplasms (NEN) from one that is directed by primary tumor site–specific classification to one that is directed by biologic classification. In addition, this review promotes understanding of the new pathologic category of well‐differentiated G3 pancreatic neuroendocrine tumors and highlights the need for prospective trials in this patient population, for whom there is currently no standard of care. This review further provides a conceptual treatment schematic that categorizes the recommendations for systemic treatments for advanced disease by biologic classification, including the new and established categories of NEN.

https://ift.tt/2nCFqYU

Biomarkers of dementia in obstructive sleep apnea

Epidemiologic and mechanistic evidence is increasingly supporting the notion that obstructive sleep apnea is a risk factor for dementia. Hence, the identification of patients at risk of cognitive decline due to obstructive sleep apnea may significantly improve preventive strategies and treatment decision-making. Cerebrospinal fluid and blood biomarkers obtained through genomic, proteomic and metabolomic approaches are improving the ability to predict incident dementia. Therefore, fluid biomarkers have the potential to predict vulnerability to neurodegeneration in individuals with obstructive sleep apnea, as well as deepen our understanding of pathophysiological processes linking obstructive sleep apnea and dementia.

https://ift.tt/2nDtB4K

Fate of febantel in the aquatic environment—the role of abiotic elimination processes

Abstract

Febantel is widely used anthelmintic drug active against a range of gastrointestinal parasites in animals. Despite the fact that it has been detected in the aquatic environment, there is no information on its environmental fate. Therefore, abiotic elimination processes of febantel in the aquatic environment have been studied. The results of direct and indirect photodegradation experiments showed that febantel was persistent against solar radiation. Kinetics of hydrolytic elimination was pH and temperature dependent with half-lives in the range from 210 min to 99 days. Febantel metabolites, fenbendazole and fenbendazole sulfone, were found as major degradation products using high-resolution mass spectrometry. The proposed hydrolytic degradation pathway consisted of the base catalyzed hydrolysis followed by consecutive oxidative cyclization to the five-membered ring of the benzo-imidazole derivative. Aquatic toxicity of febantel and its hydrolytic mixture were evaluated toward the luminescence bacteria Vibrio fischeri. Investigation of febantel sorption onto river sediments showed that the best agreement was obtained with the linear model (R² > 0.99), while the rate of sorption is the best described with the kinetic model of pseudo-second order. The organic carbon-normalized sorption coefficient, K_OC, ranged from 1490 to 3894 L kg⁻¹ for five sediment samples. The results of this research demonstrate that febantel persist in the natural waters and potentially could travel far from the source.

https://ift.tt/2vGEib9

Correction of myopic astigmatism by small incision lenticule extraction: does laterality matter?

Abstract

To evaluate the outcome after astigmatic correction of small incision lenticule extraction (SMILE) and to compare the refractive results of right eyes with left eyes. Patients who underwent SMILE surgery in our clinic between 2014 and 2016 (Visumax, Carl Zeiss Meditec, Germany) were retrospectively reviewed. Preoperative and postoperative manifest refractions and corrected and uncorrected visual acuities were evaluated and changes in refractive astigmatism were evaluated by vector analysis. One hundred twenty-one eyes from 82 patients with myopic astigmatism were included. The mean preoperative spherical equivalent was − 6 ± 1.7 (range from − 9.50 to − 1.25) D and the mean cylinderical power was − 1.5 ± 0.6 (range from − 3.75 to − 1.00) D. Postoperatively 71.8% of eyes had < 0.50 D cylinder magnitude. Vector analysis results based on laterality revealed that correction index was 0.87 ± 0.3 for left eyes and 0.72 ± 0.3 for right eyes (p 0.02). This study revealed that SMILE has favorable astigmatic correction affect but left eyes have better outcomes than right eyes.

https://ift.tt/2MHtgsm

Adverse effect of tocilizumab treatment on split thickness skin graft—a case report

Abstract

Tocilizumab is a biological immunosuppressive drug used in the treatment of psoriasis arthritis. It works by blocking the interleukin 6 receptor and therefor blocking the immune response caused by IL-6 which plays an important role in arthritis. Tocilizumab is commonly used in RA patients who either have experienced insufficient effect of other treatment options or who have had unacceptable side effects from previous treatment. With this case report, we would like to raise awareness of a potentially previously unheard of adverse effect of tocilizumab treatment on split thickness skin graft (STSG). We present a case of a 61-year-old man, treated with tocilizumab for severe poly-articular, erosive psoriasis arthritis. He was diagnosed with BCC on the scalp and underwent excision followed by STSG with no complications. The patient experienced graft loss after commencing tocilizumab treatment days to weeks post grafting on numerous occasions. We find this possible adverse effect of tocilizumab on skin grafts to be of great importance to report as it is not previously mentioned in any literature. We hope that this case report will increase the awareness of this possible adverse effect on STSG in patients treated with tocilizumab (TCZ). As the patient is dependent on arthritis symptoms to be well controlled, it is of great importance to both medical and surgical teams responsible for treatment to be able to collaborate to plan best treatment, timing, and strategy.Level of Evidence: Level V, risk / prognostic study

Level of Evidence: Level V, risk / prognostic study.

https://ift.tt/2w5ppyu

Photobiomodulation promotes adenoviral gene transduction in auditory cells

Abstract

Gene therapy is the delivery of a therapeutic gene into target cells to treat disorders by replacing disease-causing mutated genes with healthy ones. Gene therapy of the inner ear has been recently described, with applications for sensorineural hearing loss. However, gene delivery to the location of the inner ear, and thus efficacy of therapy, is challenging. Photobiomodulation (PBM) with a low-level laser has been suggested to have a therapeutic effect and has the potential to augment gene therapy. To investigate whether PBM improves the rate of adenovirus (Ad)-mediated viral delivery, we compared low-level laser therapy (LLLT) and non-LLLT HEI-OC1 cells treated with an Ad viral vector carrying green fluorescent protein (GFP). Cultured HEI-OC1 cells were divided into six groups: no treatment control, LLLT only, 1 μL Ad-GFP, 3 μL Ad-GFP, 1 μL Ad-GFP + LLLT, and 3 μL Ad-GFP + LLLT (LLLT: 808 nm at 15 mW for 15 min). Cells were irradiated twice: at 2 h and again at 24 h. A nonparametric Mann-Whitney U test was used to statistically analyze differences between the control and treatment groups. The viral inoculations used in this study did not change the amount of viable HEI-OC1 cells (N = 4–8). The 1 μL Ad-GFP + LLLT and 3 μL Ad-GFP + LLLT groups showed an increased density of GFP-positive cells compared to 1 μL and 3 μL Ad-GFP cells (N = 5–8, 1 μL: p = 0.0159; 3 μL: p = 0.0168,). The quantitative analysis of the epifluorescence of the 1 μL Ad-GFP + LLLT, and 3 μL Ad-GFP + LLLT groups revealed increased GFP expression/cell compared to 1 μL and 3 μL Ad-GFP cells (N = 6–15, 1 μL: p = 0.0082; 3 μL: p = 0.0012). The RT-qPCR results were consistent (N = 4–5, p = 0.0159). These findings suggest that PBM may enhance the gene delivery of Ad-mediated viral transduction, and the combination of the two may be a promising tool for gene therapy for sensorineural hearing loss.

https://ift.tt/2MiCAGr

What is labial hypertrophy and is it normal?

Each person's vagina and vulva are unique, and there is wide variation between people. Labial hypertrophy is when one or both vaginal lips, or labia, are larger than usual. This is normal and not a cause for concern. Some people choose to have surgery for cosmetic reasons. Learn more about vaginal hypertrophy here.

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Safety and efficiency of ultrasound-guided low power microwave ablation in the treatment of cervical metastatic lymph node from papillary thyroid carcinoma: a mean of 32 months follow-up study

Abstract

Purpose

To evaluate the safety and efficiency of microwave ablation (MWA) with low power of 20 w, respectively, in the treatment of cervical metastatic lymph node (CMLN) from papillary thyroid carcinoma (PTC) with a mean of 32-month follow-up.

Methods

Eleven patients in total with 24 cervical lymph nodes (LNs) diagnosed with CMLN from PTC underwent MWA at a power of 20 w. We recorded images of the LNs under ultrasound first before MWA and 1, 3, 6, 12, months after MWA, and then every 6 months, respectively. The volumes of the LNs were compared before MWA and at each follow-up point after MWA. The thyroglobulin (Tg) test was performed before MWA and 3 months after MWA.

Results

All patients were successfully treated, and they showed no major complications. Before MWA, the mean volume of the LNs was 364.15 ± 306.89 mm³, which decreased to 234.10 ± 230.34 mm³, 107.51 ± 129.47 mm³, 20.88 ± 39.27 mm³, 3.38 ± 12.74 mm³, and completely disappeared at the follow-up point of 1, 3, 6, 12, and 18 months after MWA, respectively. The mean Tg was 11.81 ± 7.50 ng/ml, a data significantly decreased to 0.43 ± 0.11 ng/ml 3 months after MWA (P = 0.000). In the follow-up period, no recurrent lesions were found.

Conclusions

For the treatment of CMLN from PTC, low power MWA showed good safety and efficacy. MWA is likely to be a candidate for patients with high risks or who refuse reoperation.

https://ift.tt/2w57qIu

The impact of Nd: YAG laser posterior capsulotomy by the use of “the circular pattern with vitreous strand cut” technique on anterior chamber parameters

Abstract

Aim

The purpose of this study is to identify the effect of Nd: YAG laser posterior capsulotomy using an anterior chamber morphology.

Methods

This study included 42 eyes of 33 pseudophakic patients with visually significant PCO after uncomplicated cataract surgery. Exclusion criteria were complications related to cataract surgery, corneal pathology, pseudoexfoliation, glaucoma, uveitis, previous ocular surgery or trauma, and posterior segment pathology. All patients underwent routine ophthalmic examinations. The AS-OCT measurements were performed using NIDEK RS-3000 Lite retinal scan with anterior segment module. The anterior chamber depth (ACD) was measured by Monitor A&B Scan biometer. Nd: YAG laser posterior capsulotomy was done in a single session by the circular pattern with rupture of vitreous strands. Anterior chamber depth (ACD), central corneal thickness (CCT), and intraocular pressure (IOP) were measured. Anterior chamber angle (ACA), angle opening distances (AOD) at 500 mm (AOD500), AOD at 750 mm (AOD750), trabecular-iris space area at 500 (TISA 500), and TISA at 750 (TISA 750) were measured both nasally and temporally.

Results

The mean patient age was 55.56 ± 6.33 years. There were non-significant changes in IOP, ACD, and CCT with P values 0.395, 0.153, and 0.541, respectively. ACA, AOD500, AOD750, TISA 500, and TISA 750 highly significantly increased with P value < 0.001 for all.

Conclusion

Nd: YAG laser posterior capsulotomy with the circular pattern with vitreous strand cut technique is a safe technique for laser posterior capsulotomy.

https://ift.tt/2P2thch

Removal of refractory organic pollutants in reverse-osmosis concentrated leachate by Microwave–Fenton process

Abstract

A microwave–Fenton technology was applied to dispose of the reverse-osmosis concentrated leachate. Influential factors on the treatment of concentrated leachate with the pure Fenton and microwave-Fenton method were investigated. For the conventional Fenton process, the removal efficiencies of chemical oxygen demand (COD_Cr), UV₂₅₄, and the color number (CN) reached 84%, 87%, and 96%, respectively, with the biodegradability (BOD₅/COD_Cr) increased from 0.13 to 0.51 at an initial pH of 5.0, Fe²⁺ of 0.04 mol/L, a n(H₂O₂)/n(Fe²⁺) ratio of 8 after a reaction time of 3 h. When incorporating the Fenton process with microwave irradiation, a comparative COD_Cr and UV₂₅₄, and the CN removal rate of 75%, 83%, and 95%, and a high BOD₅/COD_Cr of 0.62 were achieved under a microwave power of 390 W and an extremely shortened reaction time of only 8 min. Meanwhile, sludge quantity showed a reduction of 24.7%, decreased from 8.50 g/L to 6.40 g/L after the participation of microwave. In addition, molecular-weight fraction (MWF), UV-visible spectrum (UV-vis), and 3D-EEM spectrum tests demonstrated that the macromolecular and complex organic compounds in the wastewater were significantly decomposed into small molecular matters. Our results found that microwave–Fenton is a promising technology for concentrated leachate treatment, with much shorter reaction time, lower sludge production, and enhanced biodegradability, as well as comparative organic matter removal performance.

https://ift.tt/2w4UxOn

Safety and efficiency of ultrasound-guided low power microwave ablation in the treatment of cervical metastatic lymph node from papillary thyroid carcinoma: a mean of 32 months follow-up study

Abstract

Purpose

To evaluate the safety and efficiency of microwave ablation (MWA) with low power of 20 w, respectively, in the treatment of cervical metastatic lymph node (CMLN) from papillary thyroid carcinoma (PTC) with a mean of 32-month follow-up.

Methods

Eleven patients in total with 24 cervical lymph nodes (LNs) diagnosed with CMLN from PTC underwent MWA at a power of 20 w. We recorded images of the LNs under ultrasound first before MWA and 1, 3, 6, 12, months after MWA, and then every 6 months, respectively. The volumes of the LNs were compared before MWA and at each follow-up point after MWA. The thyroglobulin (Tg) test was performed before MWA and 3 months after MWA.

Results

All patients were successfully treated, and they showed no major complications. Before MWA, the mean volume of the LNs was 364.15 ± 306.89 mm³, which decreased to 234.10 ± 230.34 mm³, 107.51 ± 129.47 mm³, 20.88 ± 39.27 mm³, 3.38 ± 12.74 mm³, and completely disappeared at the follow-up point of 1, 3, 6, 12, and 18 months after MWA, respectively. The mean Tg was 11.81 ± 7.50 ng/ml, a data significantly decreased to 0.43 ± 0.11 ng/ml 3 months after MWA (P = 0.000). In the follow-up period, no recurrent lesions were found.

Conclusions

For the treatment of CMLN from PTC, low power MWA showed good safety and efficacy. MWA is likely to be a candidate for patients with high risks or who refuse reoperation.

https://ift.tt/2w57qIu

Lapatinib with ECF/X in the first-line treatment of metastatic gastric cancer according to HER2neu and EGFR status: a randomized placebo-controlled phase II study (EORTC 40071)

Abstract

Purpose

HER2-targeted therapy with trastuzumab and (CF/X) prolonged overall survival (OS) in metastatic HER2neu+ gastric carcinoma (GC). Lapatinib inhibits both EGFR and HER2neu. We investigated the efficacy and safety of lapatinib with epirubicin (E) + CF/X in GC according to HER2neu and EGFR status.

Methods

Tumors from chemotherapy-naïve patients were screened centrally by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Patients with EGFR and/or HER2neu expression or amplification were allocated to three strata based on EGFR/HER2neu status and were randomized to lapatinib (arm A) or placebo (arm B), with 6 cycles of ECF or ECX (investigator-selected). The primary endpoint was progression-free survival (PFS) in stratum 3.

Results

29 of 72 screened patients were randomized to strata 1 (HER2neu+: by FISH and IHC, n = 6), 2 (HER2neu−: by FISH/+ by IHC, n = 5) and 3 (HER2neu−/EGFR+, n = 18), of which 28 patients were eligible (14 per arm). Enrollment was curtailed after announcement of the negative LOGiC trial results. Median PFS was 8.0 versus 5.9 months (HR = 0.86, 95% CI 0.37–1.99) in the per protocol population, and 8.0 versus 6.3 months (HR = 0.85, 95% CI 0.30–2.46) for stratum 3, in the lapatinib versus placebo arm respectively. Median OS was 13.8 versus 10.1 months, respectively (HR = 0.90, 95% CI 0.35–2.27). There were no safety concerns.

Conclusions

Central EGFR and HER2neu stratification by IHC and FISH can be used for further pan-HER strategies. Lapatinib with ECF/X was well tolerated, but did not show clear activity in patients with metastatic GC.

https://ift.tt/2w7hAIB

In vitro UGT1A1 inhibition by tyrosine kinase inhibitors and association with drug-induced hyperbilirubinemia

Abstract

Purpose

Hyperbilirubinemia has been observed in patients treated with tyrosine kinase inhibitor (TKI) drugs. Therefore, it would be beneficial to understand whether there is a relationship between inhibition of uridine-5′-diphosphate glucuronosyltransferase (UGT) 1A1 activity and observed bilirubin elevations in TKI drug-treated patients. UGT1A1 is responsible for the glucuronidation of bilirubin which leads to its elimination in the bile.

Methods

To examine this question, an in vitro glucuronidation assay was developed to determine the inhibitory effect of TKI drugs employing human liver microsomes (HLM) with varying UGT1A1 activity. Utilizing β-estradiol as the UGT1A1 probe substrate, 20 TKI drugs were evaluated at concentrations that represent clinical plasma levels. Adverse event reports were searched to generate an empirical Bayes geometric mean (EGBM) score for clinical hyperbilirubinemia with the TKI drugs.

Results

Erlotinib, nilotinib, regorafenib, pazopanib, sorafenib and vemurafenib had IC₅₀ values that were lower than their clinical steady-state C_max concentrations. These TKI drugs had high incidences of hyperbilirubinemia and higher EBGM scores. The IC₅₀ values and C_max/IC₅₀ ratios correlated well with EBGM scores for hyperbilirubinemia (P < 0.005). For the TKI drugs with higher incidence of hyperbilirubinemia in Gilbert syndrome patients, who have reduced UGT1A1 activity, six of eight had smaller ratios in the low UGT1A1 activity microsomes than the wild-type microsomes for drugs, indicating greater sensitivity to the drugs in this phenotype.

Conclusions

These results suggest that in vitro UGT1A1 inhibition assays have the potential to predict clinical hyperbilirubinemia.

https://ift.tt/2nztzdS

Prehabilitation of Patients With oEsophageal Malignancy Undergoing Peri-operative Treatment

Conditions:   Oesophageal Adenocarcinoma;   Chemotherapy Effect;   Surgery
Intervention:   Behavioral: Exercise prehabilitation during chemotherapy before surgery
Sponsor:   Guy's and St Thomas' NHS Foundation Trust
Recruiting

https://ift.tt/2P5Ho07

Compensatory hypertrophy of the liver after external beam radiotherapy for primary liver cancer

Abstract

Purpose

We investigated whether external beam radiotherapy (EBRT) could induce compensatory liver hypertrophy in liver cancers and assessed related clinical factors.

Methods

A total of 82 consecutive patients receiving EBRT for hepatocellular carcinoma (n = 77) or cholangiocarcinoma (n = 5) from April 2012 to June 2014 were recruited and divided into two subgroups according to tumor location in the right or left lobe. The left lateral and right lobes were considered as unirradiated volumes accordingly. Total liver volume (TLV), nontumor liver volume (NLV), left and right lobe whole volume (LLWV and RLWV, respectively), volume of liver irradiated < 30 Gy (V_< 30 Gy), Child–Pugh (CPS) score, future liver remnant (FLR) ratio, and percentage of FLR hypertrophy from baseline (%FLR) were assessed.

Results

In the right lobe group, %FLR hypertrophy and LLWV increased significantly at all follow-ups (p < 0.001). %FLR hypertrophy steadily increased until the fourth follow-up. Multivariate analysis showed that the factor associated with maximum %FLR hypertrophy was tumor extent (upper or lower lobe vs. both lobes; p = 0.022). Post-RT treatments including transarterial chemoembolization or hepatic arterial infusion chemotherapy were associated with a CPS increase ≥ 2 (p = 0.002). Analysis of the RT only subgroup also showed a significant increase of %FLR until the fourth follow-up (p < 0.001). In the left lobe group, %FLR hypertrophy and RLWV showed no significant changes during follow-up.

Conclusion

Significant compensatory hypertrophy of the liver was observed, with a steady increase of %FLR hypertrophy until the fourth follow-up (median: 396 days). Locally advanced tumors extending across the upper and lower right lobe were a significant factor for compensating hypertrophy after EBRT.

https://ift.tt/2OzwpuZ

Absorption, translocation, and detoxification of Cd in two different castor bean ( Ricinus communis L.) cultivars

Abstract

Cadmium (Cd) is considered to be the most phytotoxic heavy metal pollutant. The selection of castor bean cultivars with Cd tolerance and the exploration of the physiological mechanisms involved in Cd tolerance are critical steps for improving phytoremediation performance. In this study, a hydroponic experiment was used to investigate variations in Cd transportation, chelation, and subcellular distribution in two different castor bean cultivars, namely JX-22 and ZB-9. Both cultivars had high tolerance index scores, indicating that both cultivars were tolerant to Cd. The findings of the present study indicate that Cd is significantly more mobile in JX-22 than in ZB-9 during xylem and phloem transportation, resulting in the accumulation of Cd in the shoots of JX-22 was 7.67 times that in ZB-9. Subcellular distribution assessment verified that more Cd was bound to the biologically detoxified metal fractions than the metal sensitive fractions in JX-22. The contents of the non-protein thiol pool and glutathione in the leaves were higher in JX-22 than ZB-9 when exposed to Cd. These results indicate that JX-22 has a greater ability to accumulate Cd, and well-coordinated physiological changes in JX-22 afford greater Cd tolerance in comparison to ZB-9 under Cd exposure, indicating that JX-22 is suitable for use in the remediation of Cd-contaminated soils.

https://ift.tt/2MLcqZC

Comparative study of the effects of venlafaxine and duloxetine on chemotherapy-induced peripheral neuropathy

Abstract

Objective

One of the complications of chemotherapy is peripheral neuropathy. Various studies have shown that potent norepinephrine and serotonin reuptake inhibitors such as gabapentin, venlafaxine and duloxetine have therapeutic effects on neuropathy. The aim of this study was to compare the effects of venlafaxine vs. duloxetine on chemotherapy-induced peripheral neuropathy.

Methods

In this clinical trial, cancer patients who were suffering from chemotherapy-induced peripheral neuropathy comprised the study population. They were randomly assigned to three pharmacotherapy groups including venlafaxine, duloxetine and placebo. Cranial, sensory, motor neuropathies as well as neuropathic pain were evaluated on day 1, week 2, and week 4 after enrollment.

Results

Grade of cranial, motor, sensory and neuropathic pain decreased significantly in venlafaxine and duloxetine groups. This reduction was more considerable in duloxetine group compared to venlafaxine group (P < 0.05).

Conclusion

Duloxetine seems to be more effective than venlafaxine in decreasing the symptoms of chemotherapy-induced peripheral neuropathy. Duloxetine was more effective than venlafaxine in decreasing motor neuropathy and neuropathic pain grade.

https://ift.tt/2BhbJq3

A new non-dilution rapid desensitization protocol successfully applied to all-grade platinum hypersensitivity

Abstract

Purpose

Desensitization is a safe alternative for patients with hypersensitivity reactions (HSRs) to platinum-based chemotherapeutic agents and widely used in real practice by employing stepwise administration of multiple serial dilutions of the culprit drugs. However, its labor-intensive nature has required a simpler protocol that is easier to prepare and perform.

Methods

We performed an observational study of patients with platinum HSR who underwent a new non-dilution one-bag desensitization protocol. Premedication consisted of Montelukast as well as H1 and H2 blockers. The outcomes and safety profiles of a new protocol were assessed.

Results

A total of 36 patients were recruited (oxaliplatin 23, carboplatin 9, and cisplatin 4) and the most common grade of HSR presented was grade 2 (61.1%), followed by grade 3 (25%), and grade 1 (13.9%). Of 175 desensitization procedures, all cases were successfully completed in re-administration of culprit chemotherapeutic platinum agents; 146 (83.4%) had no breakthrough reactions (BTRs) while 29 (16.6%) did. Most BTRs were mild reactions (grade 1, 51.7%) or moderate reactions (grade 2, 44.8%) of Brown's Scale. Although there was one case of asymptomatic mild hypotension (grade 3, 3.5%), categorized as severe reaction, dyspnea, desaturation, and anaphylaxis did not occur. The proportion of severe HSRs was significantly lower than that of initial HSRs (3.5% vs. 25%, P = 0.0167).

Conclusions

The new non-dilution desensitization protocol was safe and effective for re-administration of culprit platinum agents in patients with a history of HSRs. Therefore, this new protocol can be used as an alternative to existing protocols using multiple serial dilutions.

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Hotspots and main drivers of fecal pollution in Neusiedler See, a large shallow lake in Central Europe

Abstract

To minimize the risk of negative consequences for public health from fecal pollution in lakes, the continuous surveillance of microbiological water quality parameters, alongside other environmental variables, is necessary at defined bathing sites. Such routine surveillance may prove insufficient to elucidate the main drivers of fecal pollution in a complex lake/watershed ecosystem, and it may be that more comprehensive monitoring activities are required. In this study, the aims were to identify the hotspots and main driving factors of fecal pollution in a large shallow Central European lake, the Neusiedler See, and to determine to what degree its current monitoring network can be considered representative spatially. A stochastic and geostatistical analysis of a huge data set of water quality data (~ 164,000 data points, representing a 22-year time-series) of standard fecal indicator bacteria (SFIB), water quality and meteorological variables sampled at 26 sampling sites was conducted. It revealed that the hotspots of fecal pollution are exclusively related to sites with elevated anthropogenic activity. Background pollution from wildlife or diffuse agricultural run-off at more remote sites was comparatively low. The analysis also showed that variability in the incidence of SFIB was driven mainly by meteorological phenomena, above all, temperature, number of sunny hours, and wind (direction and speed). Due to antagonistic effects and temporal undersampling, the influence of precipitation on SFIB variance could not be clearly determined. Geostatistical analysis did reveal that the current spatial sampling density is insufficient to cover SFIB variance over the whole lake, and that the sites are therefore in the most part representative of local phenomena. Suggestions for the future monitoring and managing of fecal pollution are offered. The applied statistical approach may also serve as a model for the study of other such areas, and in general indicate a method for dealing with similarly large and spatiotemporally heterogeneous datasets.

https://ift.tt/2OtIDFw