Practical Transfusion Medicine, 5th ed

No abstract available

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Intensive Care Unit Enhanced Recovery Pathway for Patients Undergoing Orthotopic Liver Transplants Recipients: A Prospective, Observational Study

BACKGROUND: Liver transplant recipients continue to have high perioperative resource utilization and prolonged length of stay despite improvements in perioperative care. Enhanced recovery pathways have been shown in other surgical populations to produce reductions in hospital resource utilization. METHODS: A prospective, observational study was performed to examine the effect of an enhanced recovery pathway for postoperative care after liver transplantation. Outcomes from patients undergoing liver transplantation from November 1, 2013, to October 31, 2014, managed by the pathway were compared to transplant recipients from the year before pathway implementation. Multivariable regression analysis was used to assess the association of the clinical pathway on clinical outcomes. RESULTS: The intervention and control groups included 141 and 106 patients, respectively. There were no demographic differences between the control and intervention group including no differences between the length of surgery and cold ischemic time. Median intensive care unit length of stay was reduced from 4.4 to 2.6 days (P

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How to Implement Evidence-Based Healthcare

No abstract available

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Surveying the Literature: Synopsis of Recent Key Publications

No abstract available

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Significance, Errors, Power, and Sample Size: The Blocking and Tackling of Statistics Erratum

No abstract available

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Modern intensity-modulated radiotherapy with image guidance allows low toxicity rates and good local control in chemoradiotherapy for anal cancer patients

Abstract

Purpose

To report outcomes of a population of anal cancer patients treated with modern intensity-modulated radiotherapy and daily image-guided radiotherapy techniques.

Methods

We analyzed data of 155 patients consecutively treated with intensity-modulated radiotherapy +/− chemotherapy in three radiotherapy departments. One hundred twenty-two patients presented a stage II–IIIA disease. Chemotherapy was administered in 138 patients, mainly using mitomycin C and 5-fluorouracil (n = 81). All patients received 36 Gy (1.8 Gy/fraction) on the pelvic and inguinal nodes, on the rectum, on the mesorectum and on the anal canal, and a sequential boost up to a total dose of 59.4 Gy (1.8 Gy/fraction) on the anal canal and on the nodal gross tumor volumes.

Results

Median follow-up was 38 months (interquartile range 12–51). Toxicity data were available for 143 patients: 22% of them presented a G3+ acute toxicity, mainly as moist desquamation (n = 25 patients) or diarrhea (n = 10). Three patients presented a late grade 3 gastrointestinal toxicity (anal incontinence). No grade 4 acute or late toxicity was recorded. Patients treated with fixed-gantry IMRT delivered with a sliding window technique presented a significantly higher risk of acute grade 3 (or more) toxicity compared to those treated with VMAT or helical tomotherapy (38.5 vs 15.3%, p = 0.049). Actuarial 4-year local control rate was 82% (95% CI 76–91%).

Conclusions

Modern intensity-modulated radiotherapy with daily image-guided radiotherapy is effective and safe in treating anal cancer patients and should be considered the standard of care in this clinical setting.

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Clinical significance of visually equivocal amyloid PET findings from the Alzheimer’s Disease Neuroimaging Initiative cohort

To evaluate the clinical and imaging characteristics of patients with visually equivocal amyloid PET images, patients from the Alzheimer's Disease Neuroimaging Initiative cohort who had fluorine-18-florbetapir PET scans both at baseline and 24 months were selected. Five nuclear medicine physicians visually assessed the PET images and classified them as either positive or negative. Images not reaching a majority agreement were classified as equivocal. Among a total of 379 patients, the number of patients in each fluorine-18-florbetapir PET negative/equivocal/positive categories was 218 (57.5%), 32 (8.4%), and 129 (34.0%). Eight to 9% of patients with normal cognition (N=12/141), mild cognitive impairment (N=20/214), and no Alzheimer's disease (N=0/24) showed equivocal PET finding for each. In negative/equivocal/positive groups, positive cerebrospinal fluid Aβ1–42 was observed in 25.7, 81.5, and 98.3%, respectively. Baseline standardized uptake value ratios of fluorine-18-florbetapir PET were 0.75±0.05, 0.86±0.09, and 1.01±0.09, respectively [F(2, 376)=603.547; P

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The Use of Cannabis and Cannabinoids in Treating Symptoms of Multiple Sclerosis: a Systematic Review of Reviews

Abstract

Purpose of Review

Pharmaceutical cannabinoids such as nabiximols, nabilone and dronabinol, and plant-based cannabinoids have been investigated for their therapeutic potential in treating multiple sclerosis (MS) symptoms. This review of reviews aimed to synthesise findings from high quality systematic reviews that examined the safety and effectiveness of cannabinoids in multiple sclerosis. We examined the outcomes of disability and disability progression, pain, spasticity, bladder function, tremor/ataxia, quality of life and adverse effects.

Recent Findings

We identified 11 eligible systematic reviews providing data from 32 studies, including 10 moderate to high quality RCTs. Five reviews concluded that there was sufficient evidence that cannabinoids may be effective for symptoms of pain and/or spasticity in MS. Few reviews reported conclusions for other symptoms.

Summary

Recent high quality reviews find cannabinoids may have modest effects in MS for pain or spasticity. Future research should include studies with non-cannabinoid comparators; this is an important gap in the evidence.

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Congenital Langerhans cell histiocytosis presenting in a 27-week-gestation neonate

Abstract

Langerhans cell histiocytosis is exceedingly rare in premature infants, and the few cases reported suggest a poor prognosis with systemic involvement. We present a case of Langerhans cell histiocytosis limited to a single cutaneous lesion, presenting in a 27-week-gestation infant, which is the youngest gestational age of reported Langerhans cell histiocytosis cases. The lesion showed spontaneous resolution by 41 weeks corrected gestational age, and systemic involvement was absent, demonstrating a mild course of skin-only Langerhans cell histiocytosis in a premature infant.

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Geographic tonguelike presentation in a child with pityriasis rosea: Case report and review of oral manifestations of pityriasis rosea

Abstract

Oral lesions are rarely reported in patients with pityriasis rosea. We report a case of a 3-year-old boy with clinical evidence of generalized pityriasis rosea who developed asymptomatic oral lesions similar in appearance to geographic tongue. The generalized eruption and tongue lesions resolved simultaneously within 4 weeks. We also review the literature on the oral manifestations of Pityriasis rosea.

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Bascule syndrome associated with syncopal episodes

Abstract

Bascule syndrome is a recently described benign vasomotor dermatosis characterized by Bier anemic spots, cyanosis, and urticaria-like eruption. We report a case of a 13-year-old girl with cutaneous lesions consistent with Bascule syndrome who had had three exercise-related syncopal episodes. It would be recommended to exclude orthostatic intolerance or postural orthostatic tachycardia syndrome when evaluating patients with Bascule syndrome.

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Subacute cutaneous lupus erythematosus presenting in twins

Abstract

Subacute cutaneous lupus erythematosus is a clinically distinct form of cutaneous lupus erythematosus, with age of onset typically in the second to fifth decades. Eleven cases have been reported in childhood, and we present the first known case of subacute cutaneous lupus erythematosus in identical twins. Although flares are typically photo-induced, we present an annular eruption typical of subacute cutaneous lupus erythematosus with concurrent pinworm infestation, with recurrence of disease with cutaneous larva migrans. The patient's identical twin had a similar eruption with pinworm infection. This case highlights the possibility of parasitic infestation as a trigger for subacute cutaneous lupus erythematosus in genetically susceptible individuals.

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Parental use of sun protection for their children—does skin color matter?

Abstract

Background/Objectives

Excessive sun exposure during childhood is a risk factor for skin cancer. This study aimed to compare the frequency of ideal sun protection use between parents with lighter- and darker-skinned children and explore their attitudes and beliefs on sun safety and their choice of sun protection.

Methods

Parents of children aged 6 months to 6 years completed self-administered questionnaires about sun protection practices for their children. Parents assessed their child's Fitzpatrick phototype and were divided into lighter- (Fitzpatrick phototype I-III) and darker-skinned (Fitzpatrick phototype IV-VI) groups. Sun safety guidelines from the Canadian Dermatology Association were used to qualify ideal sun protection.

Results

A total of 183 parents were included. Overall, 31 parents (17%) used ideal sun protection for their children. As their children grew older, parents were less likely to use ideal sun protection (odds ratio = 0.69, 95% confidence interval = 0.53-0.90). Parents in the lighter-skinned group were more likely to use ideal sun protection for their children (odds ratio = 7.4, 95% confidence interval = 2.7-20.1), believe that sun exposure was harmful (odds ratio = 17.2, 95% confidence interval = 4.0-74.9), and perceive value in sun protection (odds ratio = 11.4, 95% confidence interval = 3.3-39.0); the darker-skinned group believed that darker skin tones provided more sun protection (odds ratio = 12.4, 95% confidence interval = 6.1-25.4).

Conclusion

Ideal parental sun protection efforts are overall low, particularly in parents of darker-skinned children. The identified attitudes toward and beliefs about sun safety may aid in delivery of future sun protection interventions, especially in multiracial populations.

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Treatment outcomes of vitiligo in Asian children

Abstract

This retrospective study aimed to identify factors that predict treatment response in a cohort of Asian children with vitiligo. Shorter duration of vitiligo was associated with better repigmentation. Patients with focal vitiligo of short duration have a good chance of achieving repigmentation with topical agents alone.

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Single antigen bead assays to define unacceptable antigen mismatches?

No abstract available

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Chemotherapy and immunotherapy for recurrent and metastatic head and neck cancer: a systematic review

Abstract

Head and neck cancer (HNC) is a fatal malignancy with an overall long-term survival of about 50% for all stages. The diagnosis is not rarely delayed, and the majority of patients present with loco-regionally advanced disease. The rate of second primary tumors after a diagnosis of HNC is about 3–7% per year, the highest rate among solid tumors. Currently, a single-modality or a combination of surgery, radiotherapy and chemotherapy (CHT), is the standard treatment for stage III–IV HNC. For the recurrent/metastatic setting, in the last 40 years great efforts have been made in order to develop a more effective CHT regimen, from the use of methotrexate alone, to the combination of cisplatin (CDDP) and 5-fluorouracile (5FU) or paclitaxel. Recently, the introduction of cetuximab, an anti-EGFR monoclonal antibody, to the CDDP–5FU doublet (EXTREME regimen) has improved the overall response rate, the progression-free survival and the overall survival (OS) compared to CHT alone. Nowadays, the EXTREME regimen is the standard of care for the first-line treatment of recurrent/metastatic head and neck carcinoma (RMHNC). In the last years, new promising therapies for RMHNC such as immune checkpoint inhibitors (ICIs), which have demonstrated favorable results in second-line clinical trials, gained special interest. Nivolumab and pembrolizumab are the first two ICIs able to prolong OS in the second-, later-line and platinum-refractory setting, with tolerable toxicities. This review summarizes the current state of the art in RMHNC treatment options.

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Re: Acrylic stent to aid placement of footplate of palatal distractor during surgically-assisted rapid palatal expansion

Publication date: Available online 10 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): M.Y. Mommaerts




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Transdermal scopolamine for the prevention of a salivary fistula after parotidectomy

Publication date: Available online 3 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): Konstantinos Mantsopoulos, Miguel Goncalves, Heinrich Iro
Our aim was to investigate whether perioperative transdermal application of scopolamine could help to prevent fistulas after parotidectomy, and to this end we retrospectively studied the records of all patients (n=645) who had benign parotid tumours treated by partial parotidectomy between 2011 and 2016. We found that scopolamine led to a significant decrease in the incidence of salivary fistulas from 54/371(15%) in the group not given it to 10/274 (4%) in the group given it (p<0.0001). The "number needed to treat" was 9.17. There was a relatively low incidence of all adverse effects after scopolamine. Our results are encouraging. Thorough consideration of the contraindications and a knowledge of the potential adverse effects are crucial for its successful implementation.



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Monitoring of free flaps and reconstruction for oral cancer

Publication date: Available online 2 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): A. Kanatas, M.W. Ho




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Buccal fat pad and subperiosteal midface lifts in conjunction with open reduction and internal fixation to treat fractures of the zygomaticomaxillary complex

Publication date: Available online 2 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): G.B. Bottini, N. Berridge, A. Messiha




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Genomic analysis to assess disease progression and recurrence in patients with oral squamous cell carcinoma: – a preliminary study

Publication date: Available online 1 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): A. Kanatas, P. Chengot, T.K. Ong, M.W. Ho, N. Sethi, M. Taylor, A. Glover, H.M. Wood
We studied the progression from dysplasia to invasive carcinoma and subsequent second primaries or locoregional recurrences in 11 patients with recurrent squamous cell carcinoma (SCC). Between one and six samples were sequenced/patient. DNA samples were prepared, and libraries multiplexed to between 40 and 80 samples/lane of an Illumina HiSeq 3000 and sequenced with 2×100bp paired end sequencing. Copy number data were generated by CNAnorm (Bioconductor package). Samples of recurrent SCC showed unique patterns of descent when compared with earlier samples from the primary tumour, and three main patterns emerged. In four patients there was convincing evidence that the later lesion was descended directly from cells from the first, and in a further four there were no detectable genomic events between the two lesions. Three patients had some shared events between the early and later lesions, but although there were enough differences to deduce that the two lesions had a shared ancestor, they were not directly descended from each other. We present the patients' characteristics in detail, including the overall survival in each group. There was a distinct genomic pattern after a second episode of SCC in all the groups. A larger study that uses similar methods and a longer duration could provide reliable conclusions with respect to survival. With the use of new techniques, genomic data can be available to clinical teams during the planning of treatment.



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Re: Wrong tooth extraction: an examination of “Never Event” data

Publication date: Available online 10 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): G.J. Knepil




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Evaluation of stress by finite element analysis of the midface and skull base at the time of midpalatal osteotomy in models with or without pterygomaxillary dysjunction

Publication date: Available online 1 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): A. Esen, E. Soganci, E. Dolanmaz, D. Dolanmaz
Surgically-assisted rapid maxillary expansion (SARME) is commonly used to treat skeletally mature patients with transverse discrepancies. Some osteotomies are made in areas that resist expansion, but there is no clear consensus about the sequence in which the osteotomies are made. Some clinicians do the pterygomaxillary osteotomy last, while others do it before the midpalatal osteotomy. We used the finite element method to measure the stresses on the midface, cranial base and pterygoid plates at the time of midpalatal osteotomy in two models, one with and one without pterygomaxillary dysjunction (PMD). In both, SARME consisted of maxillary bilateral osteotomy from the piriform rim to the pterygoid plate. Midpalatal osteotomy was also done in both. In the PMD model, minimum principal stresses increased on the midface, and maximum principal and von Mises stresses increased at the cranial base and on the pterygoid plates. Our results suggest that the stresses on the midface and cranial base can be reduced during midpalatal osteotomy in adults if the pterygomaxillary osteotomy is done last.



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Tuberculosis: the great imitator in the head and neck - our experience of 24 cases in 22 years

Publication date: Available online 1 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): Y.A.M. El-Wajeh, M.G. Watson, D. Igoumenakis, P. Stathopoulos
This retrospective study covered over two decades, during which an individual head and neck surgeon treated 24 patients with cervicofacial lymphadenitis that was related to both Mycobacterium tuberculosis complex (n=17, made up of M tuberculosis (n=16) and M bovis (n=1)), and non-tuberculous mycobacteria. The seven cases of non-tuberculous mycobacteria were caused by M avium complex (n=3), M malmoense (n=3), and M kansaii (n=1). By using a tailored management approach, at times selective combined surgical and antimycobacterial treatment, he achieved a success rate of 23/24 cases, with only one recurrence and no major complications. The results suggest that patients with tuberculosis confined to the head and neck rarely develop constitutional symptoms, so the absence of such symptoms may not exclude tuberculosis. There was also a good correlation between predictive variables (immune state, inflammatory markers on admission, causative mycobacterium, and the antimycobacterial regimen used) and time spent under follow-up at the head and neck outpatient clinic.



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Management of self-inflicted gunshot wounds to the face: retrospective review from a single tertiary care trauma centre

Publication date: Available online 1 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): J.A. Murphy, S.R. McWilliams, M. Lee, G. Warburton
There are limited published data about the surgical management of self-inflicted facial gunshot wounds. The aim of this retrospective study was to review our management of subjects who initially survive such a wound and were admitted to a tertiary care trauma centre between 2002 and 2012. Only subjects with definitive evidence of a self-inflicted facial gunshot wound and who were admitted alive were included. Data collected included personal and clinical details, characteristics of the gunshot wound, and medical and surgical management. Types of operations and their duration were recorded, and primary reconstruction was divided into early (within the first 48hours after presentation) or delayed (longer than 48hours). Determinants of infection were assessed with univariate analysis.Seventy-six subjects (65 male and 11 female, mean (range) age 44 (18–83) years) were included in the study. Twenty-five patients needed an early surgical airway and five needed emergency intervention to control haemorrhage. Forty-five patients had primary reconstructions (28 early and 17 delayed) and 12 who were treated by delayed repair had a submental entry site to the wound. There were no significant differences in infection rates between those who had early, compared with those who had late, reconstructions.Early primary reconstruction can be successful for patients with self-inflicted facial gunshot wounds, particularly when the entry point of the bullet is in the upper and midface area. Delayed primary reconstruction was more common when the bullet entered the lower face.



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Assessment of the anterior loop of the inferior alveolar nerve using reformatted computed tomography: a retrospective study

Publication date: Available online 1 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): V.S. Todorovic, T.C. Postma, A.W. van Zyl
The anterior loop of the inferior alveolar nerve (IAN) is an important landmark in the anterior mandible that must be considered during the placement of dental implants. We measured the length and prevalence of loops of the IAN in 188 consecutive, dentate patients using reformatted computed tomography (CT). A total of 158/188 (84%) had at least one anterior loop; 111/188 (59%) had bilateral loops. The mean (SD) length of the loops in the third quadrant was 1.4 (0.7)mm; 95% CI 1.3 to 1.6; (range 0.3 – 4.0mm). The mean (SD) length of the loops in the fourth quadrant was 1.5 (0.9)mm; 95% CI 1.4 to 1.6; range 0.3 – 5.5mm. In total 42/188 (22%) had loops that were longer than 2mm in quadrants three and four. CT images that have been reformatted with specialised software may be useful to identify loops in the IAN, particularly when recent cone-beam CT images are not freely available. The prevalence of these loops is high while their length varies, which makes meticulous assessment necessary before the placement of implants.



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Structured review of the patient-reported outcome instruments used in clinical trials in head and neck surgery

Publication date: Available online 1 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): H. Boyes, J. Barraclough, R. Ratansi, S.N. Rogers, A. Kanatas
The number of clinical trials that relate to patients with cancer of the head and neck is growing. Patient-reported outcomes, which are rarely the primary outcome, are now an important component, and in this structured review to identify and report the characteristics of the questionnaires that have been used in these trials, we summarise the findings reported. We searched several online databases using the key terms: head and neck oncology, head and neck surgery, reconstruction, clinical trials patient-reported outcomes, questionnaires, quality of life (QoL), validated instruments, and patients' satisfaction. We screened 1342 papers to collect information about the topic of the paper, sample size, selection criteria, main advantages and disadvantages of the patient-reported outcome used, and if it was used in conjunction with another measure. A total of 54 were eligible, and from them we identified 22 questionnaires. The primary reason for using a questionnaire was its relevance to the focus of the paper, such as xerostomia, pain, or swallowing. To allow the experience of patients to be the focus of the primary outcome in a clinical trial, we recommend that the measures used should be appropriate, reliable, valid, responsive, precise, interpretable, acceptable, and feasible. The trials used validated questionnaires, but the patient-reported outcome measures tended not to be the focus. There is merit in such measures being the primary outcomes in future trials and these should be designed around an explicit hypothesis.



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Hard lumps in the neck: diagnostic essentials

Publication date: Available online 1 February 2018
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): A. Sayan, V. Ilankovan




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Pediatric Intracranial Hypertension: a Current Literature Review

Abstract

Purpose of Review

The purpose of this review is to provide an update on pediatric intracranial hypertension.

Recent Findings

The annual pediatric incidence is estimated at 0.63 per 100,000 in the USA and 0.71 per 100,000 in Britain. The Idiopathic Intracranial Hypertension Treatment Trial found improvement in visual fields, optical coherence tomography, Frisen grade, and quality of life with acetazolamide compared to placebo in adult patients, and these findings have been translated to the pediatric population.

Summary

Pediatric intracranial hypertension is a disorder that if left untreated can lead to poor quality of life and morbidity. There are no current treatment studies in pediatrics, but adult data suggests acetazolamide remains an acceptable first-line medication.

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Neutrophil-to-lymphocyte ratio as an early marker of outcomes in patients with advanced non-small-cell lung cancer treated with nivolumab

Abstract

Background

There is an unmet need to identify markers that predict the response to nivolumab in patients with non-small-cell lung cancer (NSCLC). The neutrophil-to-lymphocyte ratio (NLR) was recently recognized as an indicator of a poor prognosis in patients with various cancers. In the present study, we quantified the predictive impact of NLR in patients with NSCLC treated with nivolumab.

Methods

We retrospectively analyzed 101 patients with advanced NSCLC treated with nivolumab at Kansai Medical University Hospital from December 2015 to December 2016. Patients were administered nivolumab at a dose of 3 mg/kg every 2 weeks. The predictive value of NLR for disease progression before treatment and 2 and 4 weeks after nivolumab treatment was assessed.

Results

The median progression-free survival (PFS) of patients with an NLR of < 3 before treatment was 3.4 months, whereas that of patients with an NLR of ≥ 3 was 2.9 months (p = 0.484). The median PFS of patients with an NLR of < 3 at 2 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.1 months (p = 0.00528). The median PFS of patients with an NLR of < 3 at 4 weeks after treatment was 5.3 months, whereas that of patients with an NLR of ≥ 3 was 2.0 months (p = 0.00515).

Conclusion

The NLR at 2 and 4 weeks after treatment might be a useful marker for the prediction of the treatment response or disease progression in patients with advanced NSCLC receiving nivolumab.

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Skin lesions serve as clues to relapse of pediatric blastic plasmacytoid dendritic cell neoplasm

Abstract

A 10-year-old girl with a history of blastic plasmacytoid dendritic cell neoplasm, a rare malignancy in children, presented with recurrent skin eruptions beginning while on maintenance chemotherapy, including mildly pruritic skin-colored plaques, tender indurated nodules, and violaceous bound-down plaques. This case highlights an unusual presentation of relapsed blastic plasmacytoid dendritic cell neoplasm on chemotherapy, with skin lesions providing important clues to the progression of systemic disease.

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Advanced imaging technology applications in cytology

Novel techniques have been developed to image cells at cellular and subcellular levels. They allow images to be analyzed with ultra-high resolution, in 2D and/or 3D. Several of these tools have been tested on cytology specimens demonstrating emerging applications that are likely to change the field of cytopathology. This review covers several of these advanced imaging methods. The use of optical coherence tomography to perform optical biopsies during endoscopic ultrasound procedures or visualize cells within effusion samples is discussed. The potential for quantitative phase microscopy to accurately screen Pap test slides or resolve indeterminate diagnoses in urine cytology is reviewed. The article also examines the application of 3D cytology using LuCED for lung cancer detection in sputum samples and the feasibility of imaging flow and mass cytometry to measure multiple biomarkers at the single cell level. Although these novel technologies have great potential, further research is necessary to validate their routine use in cytopathology practice.

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Maternal Thyrotropin Receptor Antibody Concentration and the Risk of Fetal and Neonatal Thyrotoxicosis: A Systematic Review

Thyroid Feb 2018, Vol. 28, No. 2: 257-264.


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Gene Fusions in Thyroid Cancer

Thyroid Feb 2018, Vol. 28, No. 2: 158-167.


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Future Meetings

Thyroid Feb 2018, Vol. 28, No. 2: 279-280.


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Rapid Remission of Graves' Hyperthyroidism Without Thionamides Under Immunosuppressive Treatment for Concomitant Autoimmune Hepatitis

Thyroid Feb 2018, Vol. 28, No. 2: 276-278.


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SIRT1-Regulated Abnormal Acetylation of FOXP3 Induces Regulatory T-Cell Function Defect in Hashimoto's Thyroiditis

Thyroid Feb 2018, Vol. 28, No. 2: 246-256.


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Clinical Impact of Detectable Antithyroglobulin Antibodies Below the Reference Limit (Borderline) in Patients with Papillary Thyroid Carcinoma with Undetectable Serum Thyroglobulin and Normal Neck Ultrasonography After Ablation: A Prospective Study

Thyroid Feb 2018, Vol. 28, No. 2: 229-235.


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The diabetes drug liraglutide reverses cognitive impairment in mice and attenuates insulin receptor and synaptic pathology in a non-human primate model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a devastating neurological disorder that still lacks an effective treatment, and this has stimulated an intense pursuit of disease-modifying therapeutics. Given the increasingly recognized link between AD and defective brain insulin signaling, we investigated the actions of liraglutide, a glucagon-like peptide-1 (GLP-1) analog marketed for treatment of type 2 diabetes, in experimental models of AD. Insulin receptor pathology is an important feature of AD brains that impairs the neuroprotective actions of central insulin signaling. Here, we show that liraglutide prevented the loss of brain insulin receptors and synapses, and reversed memory impairment induced by AD-linked amyloid-β oligomers (AβOs) in mice. Using hippocampal neuronal cultures, we determined that the mechanism of neuroprotection by liraglutide involves activation of the PKA signaling pathway. Infusion of AβOs into the lateral cerebral ventricle of non-human primates (NHPs) led to marked loss of insulin receptors and synapses in brain regions related to memory. Systemic treatment of NHPs with liraglutide provided partial protection, decreasing AD-related insulin receptor, synaptic and tau pathology in specific brain regions. Synapse damage and elimination are amongst the earliest known pathological changes and the best correlates of memory impairment in AD. Results illuminate mechanisms of neuroprotection by liraglutide, and indicate that GLP-1 receptor activation may be harnessed to protect brain insulin receptors and synapses in AD.

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Effect of matrix metalloproteinase 8 inhibitor on resin–dentin bonds

Publication date: Available online 12 February 2018
Source:Dental Materials
Author(s): Qianmin Ou, Ya Hu, Siqi Yao, Yan Wang, Xuefeng Lin
ObjectivesThis study investigated the effect of matrix metalloproteinase 8 (MMP-8) on resin–dentin bonds, assessed the mechanical properties of the interfaces over time, and discussed the potential application of MMP-8 inhibitor I (MMP8-I) as a specific MMP-8 inhibitor to be incorporated into dental adhesives.MethodsThe activation and inhibition of MMP-8 was detected by colorimetric assay. After 1 day, 6 months and 1 year of storage of Control, MMP8-I, and chlorhexidine (CHX) groups, the microtensile bond strengths (μTBS) were used to evaluate the bond strength and failure mode distributions, and nanoleakage analysis was used to evaluate the minor scattered silver particles.ResultsColorimetric assay showed that the activated MMP-8 was enhanced by adhesive procedures, while it was inhibited by the additional treatment of MMP8-I or CHX. Compared with the Control and CHX groups, the MMP8-I group had significantly higher bond strength and the hybrid layer from the MMP8-I-treated dentin exhibited structural integrity of the collagen network and decreased silver nitrate penetration after 1 year of storage.SignificanceMMP-8 inhibition I protects against the degradation of resin–dentin bonds over time, which is better than broad-scale enzyme inhibitor CHX. It shows that MMP8-I may be used in dentistry for preventing collagen degradation within hybrid layers to extend the longevity of resin–dentin bonds.



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Fatigue resistance of all-ceramic fixed partial dentures – Fatigue tests and finite element analysis

Publication date: Available online 12 February 2018
Source:Dental Materials
Author(s): S.D. Heintze, D. Monreal, M. Reinhardt, A. Eser, A. Peschke, J. Reinshagen, V. Rousson
ObjectiveTo estimate the fatigue resistance of a new translucent zirconia material in comparison to lithium disilicate for 3-unit fixed partial dentures (FPDs).MethodsEighteen 3-unit FPDs (replacement of first upper molar) with a connector size of 4mm×4mm were dry milled with a five-axis milling machine (Zenotec Select, Wieland, Germany) using discs made of a new translucent zirconia material (IPS e.max ZirCAD MT, Ivoclar Vivadent). Another 9 FPDs with a reduced connector size (3mm×4mm) were milled. The zirconia FPDs were sintered at 1500°C. For a comparison, 9 FPDs were made of IPS e.max Press, using the same dimensions. These IPS e.max Press FPDs were ground from a wax disc (Wieland), invested and pressed at 920°C. All FPDs were glazed twice. The FPDs were adhesively luted to PMMA dies with Multilink Automix. Dynamic cyclic loading was carried out on the molar pontic using Dyna-Mess testing machines (Stolberg, Germany) with 2×10⁶ cycles at 2Hz in water (37°C). Two specimens per group and load were subjected to decreasing load levels (at least 4) until the two specimens no longer showed any failures. Another third specimen was subjected to this load to confirm the result. All the specimens were evaluated under a stereo microscope (20× magnification). The number of cycles reached before observing a failure, and their dependence on the load and on the material, were modeled, using a Weibull model. This made it possible to estimate the fatigue resistance as the maximum load for which one would observe less than 1% failure after 2×10⁶ cycles. In addition to the experimental study, Finite Element Modeling (FEM) simulations were conducted to predict the force to failure for IPS e.max ZirCAD MT and IPS e.max Press with a reduced cross-section of the connectors.ResultsThe failure mode of the zirconia FPDs was mostly the fracture of the distal connector, whereas the failure mode of the lithium disilicate FPDs observed to be the fracture of the connectors or multiple cracks of the pontic. The fatigue resistance with 1% fracture probability was estimated to be 488N for the IPS e.max ZirCAD MT FPDs (453N for repeated test), 365N for IPS e.max ZirCAD MT FPDs with reduced connector size and 286N for the e.max Press FPDs. All three IPS e.max ZirCAD groups statistically performed significantly better than IPS e.max Press (p<0.001). On the other hand, no significant difference could be established between the two IPS e.max ZirCAD MT3 groups with a 4mm×4mm connector size (p>0.05). The allowable maximum principal stress (σmax) which did not lead to failure during fatigue testing for IPS e.max ZirCAD MT3 was calculated between 208MPa and 223MPa for FPDs with 4mm×4mm connectors for 2×10⁶ cycles. This value could also be verified for the FPDs of the same material with 3mm×4mm connectors. On the other hand fatigue strength in terms of σmax at 2×10⁶ cycles of IPS e.max Press was calculated to be between 78 and 90MPa.SignificanceThe fatigue resistance of the translucent zirconia 3-unit FPDs was about 60–70% higher than that of the lithium disilicate 3-unit FPDs, which may justify their use for molar replacements, provided that a minimal connector size of 4mm×4mm is observed. Even with a limited number of specimens (n=9) per group it was possible to statistically differentiate between the tested groups.



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Clinical outcomes and prognostic factors in cisplatin versus cetuximab chemoradiation for locally advanced p16 positive oropharyngeal carcinoma

Publication date: April 2018
Source:Oral Oncology, Volume 79
Author(s): Christian L. Barney, Steve Walston, Pedro Zamora, Erin H. Healy, Nicole Nolan, Virginia M. Diavolitsis, Anterpreet Neki, Robert Rupert, Panos Savvides, Amit Agrawal, Matthew Old, Enver Ozer, Ricardo Carrau, Stephen Kang, James Rocco, Theodoros Teknos, John C. Grecula, Jessica Wobb, Darrion Mitchell, Dukagjin Blakaj, Aashish D. Bhatt
ObjectivesRandomized trials evaluating cisplatin versus cetuximab chemoradiation (CRT) for p16+ oropharyngeal cancer (OPC) have yet to report preliminary data. Meanwhile, as a preemptive step toward morbidity reduction, the off-trial use of cetuximab in p16+ patients is increasing, even in those who could potentially tolerate cisplatin. The purpose of this study was to compare the efficacy of cisplatin versus cetuximab CRT in the treatment of p16+ OPC and to identify prognostic factors and predictors of tumor response.Materials and methodsCases of p16+ OPC treated with cisplatin or cetuximab CRT at our institution from 2010 to 2014 were identified. Recursive partitioning analysis (RPA) classification was used to determine low-risk (LR-RPA) and intermediate-risk (IR-RPA) groups. Log-rank/Kaplan-Meier and Cox Regression methods were used to compare groups.ResultsWe identified 205 patients who received cisplatin (n = 137) or cetuximab (n = 68) CRT in the definitive (n = 178) or postoperative (n = 27) setting. Median follow-up was 3 years. Cisplatin improved 3-year locoregional control (LRC) [92.7 vs 65.4%], distant metastasis-free survival (DMFS) [88.3 vs 71.2%], recurrence-free survival (RFS) [86.6 vs 50.6%], and overall survival (OS) [92.6 vs 72.2%] compared to cetuximab [all p < .001]. Concurrent cisplatin improved 3-year OS for LR-RPA (97.1 vs 80.3%, p < .001) and IR-RPA (97.1 vs 80.3%, p < .001) groupings.ConclusionWhen treating p16+ OPC with CRT, the threshold for substitution of cisplatin with cetuximab should be maintained appropriately high in order to prolong survival times and optimize locoregional and distant tumor control. When cetuximab is used in cisplatin-ineligible patients, altered fractionation RT should be considered in an effort to improve LRC.



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Decreased Number of Self-Paced Saccades in Post-Concussion Syndrome Associated with Higher Symptom Burden and Reduced White Matter Integrity

Journal of Neurotrauma , Vol. 0, No. 0.


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Identification and functional analyses of differentially expressed metabolites in early stage endometrial carcinoma

Summary

Diagnosis of endometrial cancer is primarily based on symptoms and imaging, with early-stage disease being difficult to diagnose. Therefore, development of potential diagnostic biomarkers is required. Metabolomics, a quantitative measurement of the dynamic metabolism in living systems, can be applied to determine metabolite profiles in different disease states. Here, serum metabolomics was performed in forty-six early stage endometrial cancer patients and forty-six healthy volunteers. In addition, the effect of identified metabolites on tumour cell behavior (invasion, migration, proliferation, apoptosis, autophagy), was examined in endometrial cancer cell lines. Compared with controls, phenylalanine, indoleacrylic acid (IAA), phosphocholine and lyso-platelet activating factor-16 (lyso-PAF), were differentially detected in patients. Functional analyses demonstrated that IAA, PAF and phenylalanine all dose-dependently inhibited tumour cell invasion and migration, and suppressed cell proliferation. PAF also induced tumour cell apoptosis and autophagy, while phenylalanine had no effect on apoptosis or autophagy. IAA triggered apoptosis and had a biphasic effect on autophagy: inhibiting autophagy with doses less than 1mM but inducing at 1mM. Interestingly, the alterations in proliferation, apoptosis and autophagy caused by 1mM IAA, were all reversed by the concomitant treatment of tryptophan (100μM). Phosphocholine inhibited tumour cell invasion and migration, and promoted cell proliferation and autophagy all in a dose-dependent manner. Phosphocholine also protected cells from TNF-α-induced apoptosis. In conclusion, four serum metabolites were identified by serum metabolomics in endometrial cancer patients and functional analyses suggested that they may play roles in modulation of tumour cell behavior, although their exact mode of action still needs to be determined.

This article is protected by copyright. All rights reserved.

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Glycans Pave the Way for Immunotherapy in Triple-Negative Breast Cancer

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Mariana Salatino, María Romina Girotti, Gabriel A. Rabinovich
The clinical efficacy of therapies targeting the PD-1/PD-L1 pathway is still limited. In this issue of Cancer Cell, Li and colleagues identify a PD-L1 glycosylation-based mechanism in triple-negative breast cancer that fosters immunosuppression by enhancing interactions with PD-1. Targeting glycosylated PD-L1 with a drug-conjugated antibody opens new avenues for treatment.

Teaser

The clinical efficacy of therapies targeting the PD-1/PD-L1 pathway is still limited. In this issue of Cancer Cell, Li and colleagues identify a PD-L1 glycosylation-based mechanism in triple-negative breast cancer that fosters immunosuppression by enhancing interactions with PD-1. Targeting glycosylated PD-L1 with a drug-conjugated antibody opens new avenues for treatment.


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c-Raf in KRas Mutant Cancers: A Moving Target

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Frank McCormick
Therapies for KRas cancers remain a major clinical need. In the current issue of Cancer Cell, Sanclemente and coworkers in Mariano Barbacid's group validate c-Raf as a prime target for these cancers. c-Raf ablation caused regression of advanced KRas^G12V/Trp53 tumors, without obvious systemic toxicity and without affecting MAPK signaling.

Teaser

Therapies for KRas cancers remain a major clinical need. In the current issue of Cancer Cell, Sanclemente and coworkers in Mariano Barbacid's group validate c-Raf as a prime target for these cancers. c-Raf ablation caused regression of advanced KRas^G12V/Trp53 tumors, without obvious systemic toxicity and without affecting MAPK signaling.


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HIPPO Stampede in Nerve Sheath Tumors

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): M. Laura Feltri, Yannick Poitelon
Current therapies for malignant peripheral nerve sheath tumors (MPNSTs) are ineffective. The study by Wu et al. in this issue of Cancer Cell provides evidence that the HIPPO pathway is overactive in human MPNSTs and that combined modulation of LATS1/2-YAP/TAZ and PDGFR signaling in Schwann cells reduces MPNST growth.

Teaser

Current therapies for malignant peripheral nerve sheath tumors (MPNSTs) are ineffective. The study by Wu et al. in this issue of Cancer Cell provides evidence that the HIPPO pathway is overactive in human MPNSTs and that combined modulation of LATS1/2-YAP/TAZ and PDGFR signaling in Schwann cells reduces MPNST growth.


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An Epigenetic Switch: From Senescent Melanocytes to Malignant Melanoma (and Back)

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Verena Wagner, Jesús Gil
Oncogene-induced senescence is an important barrier during melanomagenesis. In this issue of Cancer Cell, Yu et al. show how elevated expression of structurally unrelated H3K9 demethylases disables senescence and constitutes a liability that can be exploited to restore senescence in melanoma by pharmacological inhibition of these epigenetic regulators.

Teaser

Oncogene-induced senescence is an important barrier during melanomagenesis. In this issue of Cancer Cell, Yu et al. show how elevated expression of structurally unrelated H3K9 demethylases disables senescence and constitutes a liability that can be exploited to restore senescence in melanoma by pharmacological inhibition of these epigenetic regulators.


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Cellular Pliancy and the Multistep Process of Tumorigenesis

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Alain Puisieux, Roxane M. Pommier, Anne-Pierre Morel, Fabrice Lavial
Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis.

Teaser

Completion of early stages of tumorigenesis relies on the dynamic interplay between the initiating oncogenic event and the cellular context. Here, we review recent findings indicating that each differentiation stage within a defined cellular lineage is associated with a unique susceptibility to malignant transformation when subjected to a specific oncogenic insult. This emerging notion, named cellular pliancy, provides a rationale for the short delay in the development of pediatric cancers of prenatal origin. It also highlights the critical role of cellular reprogramming in early steps of malignant transformation of adult differentiated cells and its impact on the natural history of tumorigenesis.


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Neomorphic ERα Mutations Drive Progression in Breast Cancer and Present a Challenge for New Drug Discovery

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Donald P. McDonnell, John D. Norris, Ching-yi Chang
In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevant neomorphic activities that likely contribute to tumor pathogenesis.

Teaser

In this issue of Cancer Cell, Jeselsohn et al. dissect the function of several of the most clinically important estrogen receptor alpha mutants associated with endocrine therapy resistance in breast cancer and demonstrate that they manifest disease-relevant neomorphic activities that likely contribute to tumor pathogenesis.


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Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Rinath Jeselsohn, Johann S. Bergholz, Matthew Pun, MacIntosh Cornwell, Weihan Liu, Agostina Nardone, Tengfei Xiao, Wei Li, Xintao Qiu, Gilles Buchwalter, Ariel Feiglin, Kayley Abell-Hart, Teng Fei, Prakash Rao, Henry Long, Nicholas Kwiatkowski, Tinghu Zhang, Nathanael Gray, Diane Melchers, Rene Houtman, X. Shirley Liu, Ofir Cohen, Nikhil Wagle, Eric P. Winer, Jean Zhao, Myles Brown
Estrogen receptor α (ER) ligand-binding domain (LBD) mutations are found in a substantial number of endocrine treatment-resistant metastatic ER-positive (ER⁺) breast cancers. We investigated the chromatin recruitment, transcriptional network, and genetic vulnerabilities in breast cancer models harboring the clinically relevant ER mutations. These mutants exhibit both ligand-independent functions that mimic estradiol-bound wild-type ER as well as allele-specific neomorphic properties that promote a pro-metastatic phenotype. Analysis of the genome-wide ER binding sites identified mutant ER unique recruitment mediating the allele-specific transcriptional program. Genetic screens identified genes that are essential for the ligand-independent growth driven by the mutants. These studies provide insights into the mechanism of endocrine therapy resistance engendered by ER mutations and potential therapeutic targets.

Graphical abstract

Teaser

Jeselsohn et al. show that estrogen receptor α (ER) mutations found in endocrine treatment-resistant metastatic breast cancers confer not only ligand-independent ER functions, but also allele-specific neomorphic properties. Importantly, the authors identify potential approaches for treating these breast cancers.


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Eradication of Triple-Negative Breast Cancer Cells by Targeting Glycosylated PD-L1

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Chia-Wei Li, Seung-Oe Lim, Ezra M. Chung, Yong-Soo Kim, Andrew H. Park, Jun Yao, Jong-Ho Cha, Weiya Xia, Li-Chuan Chan, Taewan Kim, Shih-Shin Chang, Heng-Huan Lee, Chao-Kai Chou, Yen-Liang Liu, Hsin-Chih Yeh, Evan P. Perillo, Andrew K. Dunn, Chu-Wei Kuo, Kay-Hooi Khoo, Jennifer L. Hsu, Yun Wu, Jung-Mao Hsu, Hirohito Yamaguchi, Tzu-Hsuan Huang, Aysegul A. Sahin, Gabriel N. Hortobagyi, Stephen S. Yoo, Mien-Chie Hung
Protein glycosylation provides proteomic diversity in regulating protein localization, stability, and activity; it remains largely unknown whether the sugar moiety contributes to immunosuppression. In the study of immune receptor glycosylation, we showed that EGF induces programmed death ligand 1 (PD-L1) and receptor programmed cell death protein 1 (PD-1) interaction, requiring β-1,3-N-acetylglucosaminyl transferase (B3GNT3) expression in triple-negative breast cancer. Downregulation of B3GNT3 enhances cytotoxic T cell-mediated anti-tumor immunity. A monoclonal antibody targeting glycosylated PD-L1 (gPD-L1) blocks PD-L1/PD-1 interaction and promotes PD-L1 internalization and degradation. In addition to immune reactivation, drug-conjugated gPD-L1 antibody induces a potent cell-killing effect as well as a bystander-killing effect on adjacent cancer cells lacking PD-L1 expression without any detectable toxicity. Our work suggests targeting protein glycosylation as a potential strategy to enhance immune checkpoint therapy.

Teaser

Li et al. show that glycosylation of PD-L1 is essential for PD-L1/PD-1 interaction and immunosuppression in triple-negative breast cancer (TNBC). They generate a glycosylation-specific antibody that induces PD-L1 internalization and an antibody-drug conjugate with potent anti-tumor activities in TNBC models.


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The Integrated Genomic Landscape of Thymic Epithelial Tumors

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Milan Radovich, Curtis R. Pickering, Ina Felau, Gavin Ha, Hailei Zhang, Heejoon Jo, Katherine A. Hoadley, Pavana Anur, Jiexin Zhang, Mike McLellan, Reanne Bowlby, Thomas Matthew, Ludmila Danilova, Apurva M. Hegde, Jaegil Kim, Mark D.M. Leiserson, Geetika Sethi, Charles Lu, Michael Ryan, Xiaoping Su, Andrew D. Cherniack, Gordon Robertson, Rehan Akbani, Paul Spellman, John N. Weinstein, D. Neil Hayes, Ben Raphael, Tara Lichtenberg, Kristen Leraas, Jean Claude Zenklusen, Junya Fujimoto, Cristovam Scapulatempo-Neto, Andre L. Moreira, David Hwang, James Huang, Mirella Marino, Robert Korst, Giuseppe Giaccone, Yesim Gokmen-Polar, Sunil Badve, Arun Rajan, Philipp Ströbel, Nicolas Girard, Ming S. Tsao, Alexander Marx, Anne S. Tsao, Patrick J. Loehrer
Thymic epithelial tumors (TETs) are one of the rarest adult malignancies. Among TETs, thymoma is the most predominant, characterized by a unique association with autoimmune diseases, followed by thymic carcinoma, which is less common but more clinically aggressive. Using multi-platform omics analyses on 117 TETs, we define four subtypes of these tumors defined by genomic hallmarks and an association with survival and World Health Organization histological subtype. We further demonstrate a marked prevalence of a thymoma-specific mutated oncogene, GTF2I, and explore its biological effects on multi-platform analysis. We further observe enrichment of mutations in HRAS, NRAS, and TP53. Last, we identify a molecular link between thymoma and the autoimmune disease myasthenia gravis, characterized by tumoral overexpression of muscle autoantigens, and increased aneuploidy.

Graphical abstract

Teaser

Radovich et al. perform multi-platform analyses of thymic epithelial tumors. They identify high prevalence of GTF2I mutations and enrichment of mutations in HRAS, NRAS, and TP53 and link overexpression of muscle autoantigens and increased aneuploidy in thymoma and patients' risk of having myasthenia gravis.


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Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Christopher A.G. Booth, Nikolaos Barkas, Wen Hao Neo, Hanane Boukarabila, Elizabeth J. Soilleux, George Giotopoulos, Noushin Farnoud, Alice Giustacchini, Neil Ashley, Joana Carrelha, Lauren Jamieson, Deborah Atkinson, Tiphaine Bouriez-Jones, Rab K. Prinjha, Thomas A. Milne, David T. Teachey, Elli Papaemmanuil, Brian J.P. Huntly, Sten Eirik W. Jacobsen, Adam J. Mead
Lympho-myeloid restricted early thymic progenitors (ETPs) are postulated to be the cell of origin for ETP leukemias, a therapy-resistant leukemia associated with frequent co-occurrence of EZH2 and RUNX1 inactivating mutations, and constitutively activating signaling pathway mutations. In a mouse model, we demonstrate that Ezh2 and Runx1 inactivation targeted to early lymphoid progenitors causes a marked expansion of pre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS-signaling pathway mutation (Flt3-ITD) results in an aggressive leukemia co-expressing myeloid and lymphoid genes, which can be established and propagated in vivo by the expanded ETPs. Both mouse and human ETP leukemias show sensitivity to BET inhibition in vitro and in vivo, which reverses aberrant gene expression induced by Ezh2 inactivation.

Graphical abstract

Teaser

Booth et al. show that inactivation of Ezh2 and Runx1 in early thymic progenitors (ETPs) causes cell expansion and gene expression changes similar to those seen in human ETP leukemia. Addition of Flt3-ITD to the Ezh2^−/−;Runx1^−/− ETP cells leads to aggressive leukemia, which is sensitive to BET inhibition.


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Programming of Schwann Cells by Lats1/2-TAZ/YAP Signaling Drives Malignant Peripheral Nerve Sheath Tumorigenesis

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Lai Man Natalie Wu, Yaqi Deng, Jincheng Wang, Chuntao Zhao, Jiajia Wang, Rohit Rao, Lingli Xu, Wenhao Zhou, Kwangmin Choi, Tilat A. Rizvi, Marc Remke, Joshua B. Rubin, Randy L. Johnson, Thomas J. Carroll, Anat O. Stemmer-Rachamimov, Jianqiang Wu, Yi Zheng, Mei Xin, Nancy Ratner, Q. Richard Lu
Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive Schwann cell (SC)-lineage-derived sarcomas. Molecular events driving SC-to-MPNST transformation are incompletely understood. Here, we show that human MPNSTs exhibit elevated HIPPO-TAZ/YAP expression, and that TAZ/YAP hyperactivity in SCs caused by Lats1/2 loss potently induces high-grade nerve-associated tumors with full penetrance. Lats1/2 deficiency reprograms SCs to a cancerous, progenitor-like phenotype and promotes hyperproliferation. Conversely, disruption of TAZ/YAP activity alleviates tumor burden in Lats1/2-deficient mice and inhibits human MPNST cell proliferation. Moreover, genome-wide profiling reveals that TAZ/YAP-TEAD1 directly activates oncogenic programs, including platelet-derived growth factor receptor (PDGFR) signaling. Co-targeting TAZ/YAP and PDGFR pathways inhibits tumor growth. Thus, our findings establish a previously unrecognized convergence between Lats1/2-TAZ/YAP signaling and MPNST pathogenesis, revealing potential therapeutic targets in these untreatable tumors.

Graphical abstract

Teaser

Wu et al. find that HIPPO-TAZ/YAP expression is elevated in malignant peripheral nerve sheath tumors (MPNST). Lats1/2 deficiency in Schwann cells induces hyperactivation of TAZ/YAP and increased PDGFR signaling, leading to the development of MPNST in mice. Inhibition of TAZ/YAP and PDGFR reduces MPNST growth.


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DNA Methylation Patterns Separate Senescence from Transformation Potential and Indicate Cancer Risk

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Wenbing Xie, Ioannis Kagiampakis, Lixia Pan, Yang W. Zhang, Lauren Murphy, Yong Tao, Xiangqian Kong, Byunghak Kang, Limin Xia, Filipe L.F. Carvalho, Subhojit Sen, Ray-Whay Chiu Yen, Cynthia A. Zahnow, Nita Ahuja, Stephen B. Baylin, Hariharan Easwaran
Overall shared DNA methylation patterns between senescence (Sen) and cancers have led to the model that tumor-promoting epigenetic patterns arise through senescence. We show that transformation-associated methylation changes arise stochastically and independently of programmatic changes during senescence. Promoter hypermethylation events in transformation involve primarily pro-survival and developmental genes, similarly modified in primary tumors. Senescence-associated hypermethylation mainly involves metabolic regulators and appears early in proliferating "near-senescent" cells, which can be immortalized but are refractory to transformation. Importantly, a subset of transformation-associated hypermethylated developmental genes exhibits highest methylation gains at all age-associated cancer risk states across tissue types. These epigenetic changes favoring cell self-renewal and survival, arising during tissue aging, are fundamentally important for stratifying cancer risk and concepts for cancer prevention.

Graphical abstract

Teaser

Xie et al. show that transformation-associated methylation changes arise stochastically and evolve independently of senescence. A subset of transformation-associated hypermethylated genes favoring cell self-renewal and survival exhibits highest methylation gains during aging and early tumorigenesis.


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Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma

Publication date: 12 February 2018
Source:Cancer Cell, Volume 33, Issue 2
Author(s): Yong Yu, Kolja Schleich, Bin Yue, Sujuan Ji, Philipp Lohneis, Kristel Kemper, Mark S. Silvis, Nouar Qutob, Ellen van Rooijen, Melanie Werner-Klein, Lianjie Li, Dhriti Dhawan, Svenja Meierjohann, Maurice Reimann, Abdel Elkahloun, Steffi Treitschke, Bernd Dörken, Christian Speck, Frédérick A. Mallette, Leonard I. Zon, Sheri L. Holmen, Daniel S. Peeper, Yardena Samuels, Clemens A. Schmitt, Soyoung Lee
Oncogene-induced senescence, e.g., in melanocytic nevi, terminates the expansion of pre-malignant cells via transcriptional silencing of proliferation-related genes due to decoration of their promoters with repressive trimethylated histone H3 lysine 9 (H3K9) marks. We show here that structurally distinct H3K9-active demethylases—the lysine-specific demethylase-1 (LSD1) and several Jumonji C domain-containing moieties (such as JMJD2C)—disable senescence and permit Ras/Braf-evoked transformation. In mouse and zebrafish models, enforced LSD1 or JMJD2C expression promoted Braf-V600E-driven melanomagenesis. A large subset of established melanoma cell lines and primary human melanoma samples presented with a collective upregulation of related and unrelated H3K9 demethylase activities, whose targeted inhibition restored senescence, even in Braf inhibitor-resistant melanomas, evoked secondary immune effects and controlled tumor growth in vivo.

Graphical abstract

Teaser

Yu et al. show that two different types of histone H3 lysine 9 (H3K9) demethylases, LSD1 and JMJD2C, disable oncogenic Ras- or Braf-induced senescence by enabling the expression of E2F target genes, which permits transformation. Inhibition of the H3K9 demethylases restores senescence and controls tumor growth.


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Comparison of Dysplastic Fundic Gland Polyps in Patients with and without Familial Adenomatous Polyposis

Abstract

Aim

Dysplastic FGPs (d-FGPs) typically arise in patients with familial adenomatous polyposis (FAP) but may occur in nonsyndromic patients. They rarely develop malignancy, but their significance is unclear, especially in nonsyndromic patients. APC/β-catenin alterations have been implicated in their pathogenesis, and β-catenin immunohistochemistry (IHC) may show nuclear positivity.

Methods and results

We identified 124 FGPs with low-grade dysplasia (LGD) or high-grade dysplasia (HGD) or indefinite for dysplasia (IFD) from 66 patients (27 with FAP, 39 nonsyndromic). We recorded patient sex, age at first d-FGP, time until subsequent d-FGP (if any), history of non-gastric cancer (no patients had gastric cancer), proton-pump inhibitor (PPI) use, and presence of Helicobacter pylori. β-catenin IHC was performed on cases with available blocks. Mean age at d-FGP diagnosis was 31 years for FAP patients and 61 years for nonsyndromic patients (P<0.0001). Sixteen FAP patients (59%) developed at least one subsequent d-FGP, compared to 10 (27%) nonsyndromic patients (P=0.0099). Median time between d-FGP detection was 11.5 months in FAP patients and 7 months in nonsyndromic patients (P=0.82). Six FAP patients (22%) and 17 nonsyndromic patients (44%) had non-gastric malignancies (P=0.11). β-catenin IHC showed nuclear positivity in 14/112 (13%) d-FGPs: 12/94 with LGD, 2/3 with HGD, 0/15 IFD.

Conclusion

FAP patients develop d-FGPs earlier and more often develop additional ones than nonsyndromic patients. Dysplastic FGPs in FAP and nonsyndromic patients have similar low rates of β-catenin nuclear IHC positivity. FAP and nonsyndromic patients developed non-gastric cancers at similar rates, suggesting that d-FGPs may portend a general increased risk of carcinogenesis in nonsyndromic patients.

This article is protected by copyright. All rights reserved.

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Homeobox transcriptional factor engrailed homeobox 1 is specifically expressed in normal and neoplastic sweat gland cells

Abstract

Aim

A number of homeobox transcriptional factors are utilized as organ-specific markers in the histopathological diagnosis of neoplasms. We have screened a homeobox gene that is specifically expressed in normal sweat gland cells and is useful for the histopathological diagnosis of sweat gland neoplasms.

Methods and results

By screening an open database resource of The Human Protein Atlas, 37 genes among the 235 homeobox transcriptional factors were found to be specifically expressed in the skin. Among those 37 genes, the engrailed homeobox 1 (En1) was expressed in normal eccrine glands but not in the epidermal keratinocytes. Expression of En1 was found throughout the eccrine glands, but not in the apocrine secretory coils, sebaceous glands, or hair follicles. Expression of En1 was immunohistochemically examined in 111 cases of cutaneous epithelial neoplasms. All the 9 cases of poroma, 7 cases of spiradenoma, and 6 cases of syringoma, which are considered to differentiate toward eccrine glands, showed positive nuclear staining in most of the tumour cells. Sebaceous gland and hair follicle tumours were immuno-negative. En1 was focally expressed in the epidermal neoplasms of seborrheic keratosis and squamous cell carcinoma.

Conclusion

En1 was specifically expressed in normal eccrine glands and was expressed in most of the tumour cells of sweat gland neoplasms with eccrine gland differentiation. En1 was focally expressed in epidermal neoplasms, however, it was absent in sebaceous or hair follicle neoplasms. These findings will help in the histopathological diagnosis as well as to understand the histogenesis of sweat gland neoplasms.

This article is protected by copyright. All rights reserved.

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Alum-adjuvanted allergoids induce functional IgE-blocking antibodies

Abstract

The only therapy that is able to modulate the cause of IgE-mediated allergy and to attain a long-term effect is allergen-specific immunotherapy (AIT). In conventional subcutaneous AIT, the vaccine consists of an extract from an allergen source that contains major and minor allergens as well as non-allergenic proteins. To reduce IgE-mediated side effects caused by the injection of intact allergens, chemically modified extracts with less IgE-binding activity, named allergoids, have been used for AIT since the 1980′s.

This article is protected by copyright. All rights reserved.

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Reconstruction of Tragus and External Auditory Meatus using Remnant Auricle during Microtia Reconstruction

Facial plast Surg
DOI: 10.1055/s-0037-1617436

This article investigates an effective method with which to reconstruct the tragus and external auditory meatus for microtia reconstruction. The external ear was reconstructed using a delayed postauricular skin flap in patients with congenital microtia. After the first stage of delaying the postauricular skin flap and the second stage of otoplasty with ear framework fabricated from autogenous rib cartilage draping with the delayed skin flap, the third stage involved tragus and external auditory meatus canaloplasty. After designing the remnant auricle flap, the lower part was trimmed and the tragus was reconstructed. The upper part was trimmed into a thin skin flap, which was rotated and used to cover the hollowed wound posterosuperior to the tragus so as to mimic the external auditory meatus. If remnant wounds were present, skin grafting was conducted. In total, 121 patients with congenital microtia were treated from March 2010 to March 2016. The reconstructed tragus and external auditory meatus were well formed, and all wounds healed well. No severe complications such as flap necrosis occurred. Six months postoperatively, the morphology of the reconstructed tragus and external auditory meatus was good. Overall, the patients and their families were satisfied. The use of remnant auricle to reconstruct the tragus and external auditory meatus is an effective auricular reconstruction technique.
[...]

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text

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Treatment of glioblastoma with herbal medicines

Abstract

Background

In the latest years, a lot of research studies regarding the usage of active agents from plants in the treatment of tumors have been published, but there is no data about successful usage of herbal remedies in the treatment of glioblastoma in humans.

Methods

The phytotherapy involved five types of herbal medicine which the subjects took in the form of tea, each type once a day at regular intervals. Three patients took herbal medicine along with standard oncological treatment, while two patients applied for phytotherapy after completing medical treatment. The composition of herbal medicine was modified when necessary, which depended on the results of the control scans using the nuclear magnetic resonance technique and/or computed tomography.

Results

Forty-eight months after the introduction of phytotherapy, there were no clinical or radiological signs of the disease, in three patients; in one patient, the tumor was reduced and his condition was stable, and one patient lived for 48 months in spite of a large primary tumor and a massive recurrence, which developed after the treatment had been completed.

Conclusions

The results achieved in patients in whom tumor regression occurred exclusively through the use of phytotherapy deserve special attention.

In order to treat glioblastoma more effectively, it is necessary to develop innovative therapeutic strategies and medicines that should not be limited only to the field of conventional medicine. The results presented in this research paper are encouraging and serve as a good basis for further research on the possibilities of phytotherapy in the treatment of glioblastoma.

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Impact of the anti-cancer drug NT157 on tyrosine kinase signalling networks

The small molecule drug NT157 has demonstrated promising efficacy in pre-clinical models of a number of different cancer types, reflecting activity against both cancer cells and the tumour microenvironment. Two known mechanisms of action are degradation of insulin-receptor substrates (IRS)-1/2, and reduced Stat3 activation, although it is possible that others exist. In order to interrogate the effects of this drug on cell signalling pathways in an unbiased manner, we have undertaken mass spectrometry-based global tyrosine phosphorylation profiling of NT157-treated A375 melanoma cells. Bioinformatic analysis of the resulting dataset resolved 5 different clusters of tyrosine-phosphorylated peptides that differed in the directionality and timing of response to drug treatment over time. The receptor tyrosine kinase AXL exhibited a rapid decrease in phosphorylation in response to drug treatment, followed by proteasome-dependent degradation, identifying an additional potential target for NT157 action. However, NT157 treatment also resulted in increased activation of p38 MAPKα and , as well as the JNKs and specific Src family kinases. Importantly, co-treatment with the p38 MAPK inhibitor SB203580 attenuated the anti-proliferative effect of NT157, while synergistic inhibition of cell proliferation was observed when NT157 was combined with a Src inhibitor. These findings provide novel insights into NT157 action on cancer cells, and highlight how globally profiling the impact of a specific drug on cellular signalling networks can identify effective combination treatments.

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A distinct oncogenerative multinucleated cancer cell serves as a source of stemness and tumor heterogeneity

The effects of anticancer treatments on cell heterogeneity and their proliferative potential play an important role in tumor persistence and metastasis. However, little is known about de-polyploidization, cell fate, and physiological stemness of the resulting cell populations. Here we describe a distinctive cell type termed "pregnant" P1 cells found within chemotherapy refractory ovarian tumors, which generate and gestate daughter generation Gn-cells intracytoplasmically. Release of Gn-cells occurred by ejection through crevices in P1 cell membrane by body contractions or using a funiculus-like structure. These events characterized a not yet described mechanism of cell segregation. Maternal P1-cells were principally capable of surviving parturition events and continued to breed and nurture Gn progenies. In addition, P1-cells were competent to horizontally transmit offspring Gn-cells into other specific proximal cells, injecting them to receptor R1-cells via cell-cell tunneling. This process represents a new mechanism used by tumor cells to invade surrounding tissues and ensure life cycles. In contrast to the pregnant P1-cells with low expression of stem cell markers despite their physiological stemness, the first offspring generations of daughter G1-cells expressed high levels of ovarian cancer stem cell markers. Furthermore, both P1- and Gn-cells overexpressed multiple human endogenous retroviral envelope proteins. Moreover, programmed death-ligand 1 and the immunosuppressive domain of the retroviral envelope proteins were also overexpressed in P1-cells, suggesting effective protection against the host immune system. Together, our data suggest that P1 oncogenerative cancer cells exhibit a not yet described cell-biological mechanism of persistence and transmission of malignant cells in patients with advanced cancers.

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Oncogenic kinase-induced PKM2 tyrosine 105 phosphorylation converts non-oncogenic PKM2 to a tumor promoter and induces cancer stem-like cells

The role of pyruvate kinase M2 isoform (PKM2) in tumor progression has been controversial. Previous studies showed that PKM2 promoted tumor growth in xenograft models; however, depletion of PKM2 in the Brca1-loss-driven mammary tumor mouse model accelerates tumor formation. Since oncogenic kinases are frequently activated in tumors and PKM2 phosphorylation promotes tumor growth, we hypothesized that phosphorylation of PKM2 by activated kinases in tumor cells confers PKM2 oncogenic function, whereas non-phosphorylated PKM2 is non-oncogenic. Indeed, PKM2 was phosphorylated at tyrosine 105 (Y105) and formed oncogenic dimers in MDA-MB-231 breast cancer cells, whereas PKM2 was largely unphosphorylated and formed non-tumorigenic tetramers in non-transformed MCF10A cells. PKM2 knockdown did not affect MCF10A cell growth but significantly decreased proliferation of MDA-MB-231 breast cancer cells with tyrosine kinase activation. Multiple kinases that are frequently activated in different cancer types were identified to phosphorylate PKM2-Y105 in our tyrosine kinase screening. Introduction of the PKM2-Y105D phospho-mimetic mutant into MCF10A cells induced colony formation and the CD44hi/CD24neg cancer stem-like cell population by increasing YAP protein nuclear localization. ErbB2, a strong inducer of PKM2-Y105 phosphorylation, boosted nuclear localization of YAP and enhanced the cancer stem-like cell population. Treatment with the ErbB2 kinase inhibitor lapatinib decreased PKM2-Y105 phosphorylation and cancer stem-like cells, impeding PKM2 tumor-promoting function. Taken together, phosphorylation of PKM2-Y105 by activated kinases exerts oncogenic functions in part via activation of YAP downstream signaling to increase cancer stem-like cell properties.

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Crosstalk signaling between HER3 and HPV16 E6 and E7 mediates resistance to PI3K inhibitors in head and neck cancer

Human papillomavirus (HPV) type 16 is implicated in approximately 75% of head and neck squamous cell carcinomas (HNSCC) that arise in the oropharynx, where viral expression of the E6 and E7 oncoproteins promote cellular transformation, tumor growth, and maintenance. An important oncogenic signaling pathway activated by E6 and E7 is the phosphatidylinositol 3-kinase (PI3K) pathway, a key driver of carcinogenesis. The PI3K pathway is also activated by mutation or amplification of PIK3CA in over half of HPV(+) HNSCC. In this study, we investigated the efficacy of PI3K-targeted therapies in HPV(+) HNSCC preclinical models and report that HPV(+) cell line- and patient-derived xenografts are resistant to PI3K inhibitors due to feedback signaling emanating from E6 and E7. Receptor tyrosine kinase (RTK) profiling indicated that PI3K inhibition led to elevated expression of the HER3 receptor, which in turn increased the abundance of E6 and E7 to promote PI3K inhibitor resistance. Targeting HER3 with siRNA or the monoclonal antibody CDX-3379 reduced E6 and E7 abundance and enhanced the efficacy of PI3K-targeted therapies. Together, these findings suggest that crosstalk between HER3 and HPV oncoproteins promotes resistance to PI3K inhibitors and that co-targeting HER3 and PI3K may be an effective therapeutic strategy in HPV(+) tumors

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RSK Regulates PFK-2 Activity to Promote Metabolic Rewiring in Melanoma

Metabolic reprogramming is a hallmark of cancer that includes increased glucose uptake and accelerated aerobic glycolysis. This phenotype is required to fulfill anabolic demands associated with aberrant cell proliferation and is often mediated by oncogenic drivers such as activated BRAF. In this study, we show that the MAPK-activated p90 ribosomal S6 kinase (RSK) is necessary to maintain glycolytic metabolism in BRAF-mutated melanoma cells. RSK directly phosphorylated the regulatory domain of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), an enzyme that catalyzes the synthesis of fructose-2,6-bisphosphate during glycolysis. Inhibition of RSK reduced PFKFB2 activity and glycolytic flux in melanoma cells, suggesting an important role for RSK in BRAF-mediated metabolic rewiring. Consistent with this, expression of a phosphorylation-deficient mutant of PFKFB2 decreased aerobic glycolysis and reduced the growth of melanoma in mice. Together these results indicate that RSK-mediated phosphorylation of PFKFB2 plays a key role in the metabolism and growth of BRAF-mutated melanomas.

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FOXO transcription factors both suppress and support breast cancer progression.

FOXO transcription factors are regulators of cellular homeostasis and putative tumor suppressors, yet the role of FOXO in cancer progression remains to be determined. The data on FOXO function, particularly for epithelial cancers, are fragmentary and come from studies that focused on isolated aspects of cancer. To clarify the role of FOXO in epithelial cancer progression, we characterized the effects of inducible FOXO activation and loss in a mouse model of metastatic invasive lobular carcinoma. Strikingly, either activation or loss of FOXO function suppressed tumor growth and metastasis. We show that the multitude of cellular processes critically affected by FOXO function include proliferation, survival, redox homeostasis, and PI3K-signaling, all of which must be carefully balanced for tumor cells to thrive.

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Surrogate and Intermediate Endpoints in Randomized Trials: What's the Goal?

Establishing trial-level surrogacy of an intermediate endpoint for predicting survival benefit in future trials is extremely challenging because of the extrapolations required, but there are other useful drug development and patient management applications of intermediate endpoints.

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A Model Linking Sickle Cell Hemoglobinopathies and SMARCB1 Loss in Renal Medullary Carcinoma

Renal medullary carcinoma (RMC) is a highly aggressive malignancy that predominantly afflicts young adults and adolescents with sickle hemoglobinopathies. It is characterized by complete loss of expression of the chromatin remodeler and tumor suppressor SMARCB1. Despite therapy, the outcomes of patients with RMC remain very poor, highlighting the need to understand the etiology of this cancer, and develop new diagnostic, preventive, and therapeutic strategies. A key knowledge gap in RMC biology is why sickle hemoglobinopathies predispose to the development of this cancer. We propose a model wherein the extreme conditions of hypoxia and hypertonicity of the renal medulla, combined with regional ischemia induced by red blood cell sickling, activate DNA repair mechanisms to drive deletions and translocations in SMARCB1, which is localized in a fragile region of chromosome 22.  This mechanism would explain the linkage between RMC and sickle hemoglobinopathies, as well as the age-dependence and predilection of RMC towards the right kidney.

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The U.K. approach to putting patient safety first when receiving non-surgical cosmetic therapies: The cosmetic practice standards authority

The 2013 Keogh Review of Cosmetic Regulation stated: In fact, a person having a non-surgical cosmetic intervention has no more protection and redress than someone buying a ballpoint pen or a toothbrush. This Department of Health Review of the regulation of Cosmetic Interventions presented the stark reality that non-surgical treatments are not regulated, patients are not protected and there needs to be significant change.1

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Temperature effects on multiphase reactions of organic molecular markers: A modeling study

Publication date: April 2018
Source:Atmospheric Environment, Volume 179
Author(s): Vikram Pratap, Ying Chen, Guangming Yao, Shunsuke Nakao
Various molecular markers are used in source apportionment studies. In early studies, molecular markers were assumed to be inert. However, recent studies suggest that molecular markers can decay rapidly through multiphase reactions, which makes interpretation of marker measurements challenging. This study presents a simplified model to account for the effects of temperature and relative humidity on the lifetime of molecular markers through a shift in gas-particle partitioning as well as a change in viscosity of the condensed phase. As a model case, this study examines the stability of levoglucosan, a key marker species of biomass burning, over a wide temperature range relevant to summertime and wintertime. Despite the importance of wood combustion for space heating in winter, the lifetime of levoglucosan in wintertime is not well understood. The model predicts that in low-temperature conditions, levoglucosan predominantly remains in the particle phase, and therefore its loss due to gas-phase oxidation reactions is significantly reduced. Furthermore, the movement of the levoglucosan from the bulk of the particle to the particle surface is reduced due to low diffusivity in the semi-solid state. The simplified model developed in this study reasonably reproduces upper and lower bounds of the lifetime of levoglucosan investigated in previous studies. The model results show that the levoglucosan depletion after seven days reduces significantly from ∼98% at 25 °C to <1% at 0 °C under dry conditions. The depletion of levoglucosan increases at higher relative humidities. However, at temperatures below 0 °C, levoglucosan appears to be a useful marker (lifetime > 1 week) even at 60% relative humidity irrespective of the assumed fragility parameter D that controls estimated diffusivity. The model shows that lifetime of an organic molecular marker strongly depends on assumed D especially when a semi-volatile marker is in semi-solid organic aerosol.

Graphical abstract

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Anatomists’ perceptions of the skills and attributes required of newly-recruited medical students

Publication date: Available online 11 February 2018
Source:Annals of Anatomy - Anatomischer Anzeiger
Author(s): Bernard J. Moxham, Odile Plaisant, Baptiste Lignier, Feisal Brahim
Background and purposeAdmission procedures for recruiting students to medical school vary considerably across the world. Notwithstanding such variability, it is important to know what skills and attributes are required of the students by their teachers on entering medical school.ProceduresAnatomists are often the teachers who first meet the students as they enter medical school and this report analyses, by means of a questionnaire, the putative skills required of their medical students by anatomists from the U.S.A. and Europe.FindingsThe findings from a questionnaire suggest that there are few differences between anatomists in the U.S.A. and Europe, even though medical students are postgraduates in the U.S.A. but undergraduates in Europe. Furthermore, the skill requirements expected of the students differed only slightly according to the gender and age of the anatomists and to whether or not they had clinical qualifications. The most important skills and attributes required of the students were found to be: good study skills and abilities to study independently, understanding of biology (but not chemistry, physics, mathematics, statistics, or understanding of the scientific method), memory/factual retention, communication and teamwork skills, problem-solving abilities, and attributes related to life-long learning, readiness to be challenged, and emotional stability and conscientiousness.ConclusionsAnatomists within the U.S.A. and Europe essentially agree on the skills and attributes initially required of their medical students, as well as those not deemed initially important. These findings are presented with the view of enhancing admission policies and procedures for admitting students into medical schools.



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Differences in gene expression profile between vocal cord Leukoplakia and normal larynx mucosa by gene chip

Long non-coding RNAs (lncRNAs) play an important role in tumorigenesis. Vocal cord leukoplakia is a precancerous lesion in otolaryngological practice. Till now, the expression patterns and functions of lncRNAs...

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SMURF1 facilitates estrogen receptor ɑ signaling in breast cancer cells

Estrogen receptor alpha (ER alpha) is expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression. ER alpha positive breast cancer can be well controlled by ER alpha modulato...

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Utility and Versatility of the Supraclavicular Artery Island Flap in Head and Neck Reconstruction

Publication date: January–February 2018
Source:Acta Otorrinolaringologica (English Edition), Volume 69, Issue 1
Author(s): José A. González-García, Carlos M. Chiesa-Estomba, Jon A. Sistiaga, Ekhiñe Larruscain, Leire Álvarez, Xabier Altuna
IntroductionThe supraclavicular island flap is a rotational pedicled flap and may have some advantages in head and neck reconstruction compared with free-tissue transfer when this kind of reconstruction is not affordable or recommended.Material and methodsWe present our experience during the year 2016 in the application of the supraclavicular island flap in five cases as an alternative to microvascular reconstruction in several defects after resection of head and neck tumours. In two patients, the flap was used to close the surgical pharyngostoma after total laryngectomy with partial pharyngectomy. In one patient, it was used in lateral facial reconstruction after partial resection of the temporal bone. In one case, it was used to close a skin defect after total laryngectomy with prelaryngeal tissue extension. And in the last case to close a neck skin defect after primary closure of a pharyngo-cutaneous fistula. There were no flap complications, and the result was satisfactory in all cases.ResultsThe supraclavicular artery island flap is useful and versatile in head and neck reconstruction. Operating room time in aged patients or those with comorbidities will be reduced compared to free flaps. The surgical technique is relatively easy and can be used for skin and mucosal coverage.ConclusionThe supraclavicular island flap could be a recommended option in head and neck reconstruction, its use seems to be increasing and provides a safe and time-saving option to free flaps in selected patients.



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Application of Flexible Endoscopy-Based Biopsy in the Diagnosis of Tumour Pathologies in Otorhinolaryngology

Publication date: January–February 2018
Source:Acta Otorrinolaringologica (English Edition), Volume 69, Issue 1
Author(s): Carlos Saga, Manuel Olalde, Ekhiñe Larruskain, Leire Álvarez, Xabier Altuna
Introduction and objectivesInterventional endoscopy allows us to act on the pathology of the patient with minimal discomfort, low costs and high efficiency. We assessed the validity of flexible endoscopic biopsies in our hospital, in lesions suspected of malignancy in the rhino-pharyngo-laryngeal space.Subjects and methodsRetrospective study of patients with a pathology suspected of malignancy assessed between 2006 and 2016 in our centre. We evaluated the effectiveness, the tolerance and the number of complications. We calculated the cost reduction in comparison with direct laryngoscopy in the operating room. We compared our sample with others of similar characteristics described in the literature.ResultsThirty patients were studied with a flexible endoscopic biopsy during that period. Nineteen patients obtained positive results which allowed them to start treatment for their pathology. Seven cases had no evidence of malignancy and required another biopsy under general anaesthesia, which confirmed the carcinoma diagnosis. Two samples ruled out malignancy which was confirmed by laryngeal microsurgery. One case showed inflammation and the lesion was cured after antibiotherapy. It was impossible to collect the sample in one case. Thus, we obtained sensitivity levels of 73% with a specificity of 100%. There were no complications. The cost reduction in our sample was above 80%.ConclusionsFlexible endoscopic biopsy has advantages over direct laryngoscopy that are relevant in the diagnosis of oncological pathology in otorhinolaryngology.



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Accuracy of FNAC and CT in the Differentiation of Benign and Malignant Parotid Tumours in a Case Series

Publication date: January–February 2018
Source:Acta Otorrinolaringologica (English Edition), Volume 69, Issue 1
Author(s): Marina A. Gavín-Clavero, Tomás Usón-Bouthelier, Úrsula M. Jariod-Ferrer, Arancha Fernández-Larrañaga, Bianca Pantilie, Fernando Lobera-Molina, M. Victoria Simón-Sanz, Bartolomé Nadal Cristóbal
IntroductionParotid tumours, in addition to the wide variety of types, are histologically complex. Differentiating between benign and malignant tumours in preoperative diagnosis is important in deciding the type of surgery required. Fine needle aspiration cytology (FNAC) is a simple, quick, low-cost, low-invasive and well-tolerated tool used in the preoperative diagnosis of these tumours.Material and methodswe calculated the sensitivity, specificity, predictive positive value (PPV) and negative predictive value (NPV) of FNAC and computed tomography (CT) in the differentiation of benign and malignant parotid tumours operated between 2010 and 2014 in the oral and maxillofacial surgery department of the University Hospital Miguel Servet.ResultsThe sensitivity of FNAC is 50%, while the specificity is high, at 98.7%. FNAC offers high reliability in the diagnosis of malignant tumours, despite its low sensitivity. However, when the diagnosis is indeterminate or benign, other than pleomorphic adenoma or Whartin tumour, the reliability to exclude malignancy decreases.ConclusionThe low sensitivity of FNAC to differentiate malignant from benign parotid tumours, means that we cannot rule out other diagnostic tests, clinical symptoms and especially the intraoperative vision of each surgeon. Especially when the diagnosis is indeterminate. Nevertheless, it is a technique used in a systematised way and helps in pre-surgical decision-making.



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Inlay Butterfly Miringoplasty. Our Experience

Publication date: January–February 2018
Source:Acta Otorrinolaringologica (English Edition), Volume 69, Issue 1
Author(s): Paula Cruz Toro, Ángela Callejo Castillo, Rafael Moya Martínez, Iván Domenech Juan
IntroductionMultiple surgical techniques have been proposed to close tympanic perforations. Eavey, two decades ago, described a technique aimed at closing central perforations in children. For this, he designed a butterfly-shaped cartilage graft that was placed between the tympanic membrane in an inlay manner. This technique showed great effectiveness for the closure of perforations as well as low morbidity, rapidity and great economic difference.MethodsWe performed a descriptive study of a series of cases analysing 32 interventions in children and adults with the modified Eavey technique, during the period from January 2012 to November 2016. We evaluated the surgical and audiometric functional results.ResultsSurgical success was achieved in 93% of cases, including complete closures in 27 patients (84%) and 3 cases in which minimal asymptomatic dehiscences occurred. There was rejection of the graft and persistence of the perforation in only one case. No major surgical or postoperative complications associated with the procedure were described. The mean improvement in the audiometric gap was from 17dB preoperatively to 7dB after the intervention.ConclusionsThe modified Eavey technique is a low morbidity, cost-effective procedure with a technical facility that proves effective for the closure of tympanic perforations in adults and children.



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On ciprofloxacin concentration in chronic rhinosinusitis

Publication date: January–February 2018
Source:Acta Otorrinolaringologica (English Edition), Volume 69, Issue 1
Author(s): José Gameiro dos Santos, Rosário Figueirinhas, José P. Liberal, João C. Almeida, Joana Sousa, Amílcar Falcão, Corália Vicente, João Paço, Cecília A. Sousa
ObjectiveConsidering that all the evidence indicates that chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are distinct entities, the aim of this study was to compare the concentrations obtained in plasma and in sinonasal mucosa with oral and nasal topical ciprofloxacin, in patients with and without nasal polyps, without evaluating the effectiveness of the use of an antibiotic.MethodsProspective clinical study with single-blind randomization. The population consisted of patients with chronic rhinosinusitis with eligible for endonasal surgery, over 18 years old. It took place between January 2010 and December 2014. A single preoperative dose of ciprofloxacin (oral or nasal topic- spray, gel or drops) was given and samples of plasma and nasal mucosa (inferior turbinate, middle turbinate, ethmoid and maxillary sinus) were collected prior to surgery. The plasma and mucosal ciprofloxacin concentrations were assayed with high performance liquid chromatography (HPLC) with fluorescence detection (FD).ResultsThe oral ciprofloxacin achieved better mucosal concentrations but had a significant plasmatic expression in all patients. None of the topical formulations achieved measurable ciprofloxacin plasmatic levels. Among the topical formulations, the gel had the best mucosal results, despite the existence of polyposis.



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Transoral laser microsurgery as standard approach to hypopharyngeal cancer survival analysis in a hospital based population

Publication date: January–February 2018
Source:Acta Otorrinolaringologica (English Edition), Volume 69, Issue 1
Author(s): Eduardo Breda, Raquel Catarino, Eurico Monteiro
ObjectiveCancer of the hypopharynx remains one of the most challenging chapters in head and neck oncology. The objective of this study is to ascertain the relevance of a transoral laser approach as a valid functional option for treatment of cancer of the hypopharynx in Portugal, and additionally, to confirm the reproducibility of survival and functional outcomes described in other reference centers.Subjects and methodsThe outcomes of 37 out of 60 patients presenting hypopharyngeal carcinoma primarily treated by TLM (transoral laser microsurgery) and neck dissection and or adjuvant treatment when needed, with curative intention in tertiary referral center, were retrospectively evaluated and compared with published results.ResultsThere were no patients in stage I. Three-year and five-year overall survival (Kaplan–Meier) were 83.5% and 63.5% for stage II (n=12), 57.1% (only 3-year overall survival evaluable for this stage) for stage III (n=7), and 53.1% and 39.8% for stage IVa (n=18), respectively. Five-year local control rates were 90% for stage II and 87.5% for stage IVa, respectively; only three-year local control rates were possible to evaluate for stage III, with a 100% control rate. Five-year total larynx preservation rate was 97.3%.ConclusionsTLM, alone or with neck dissection and adjuvant therapy, is a valid procedure for treatment of hypopharyngeal cancer in different stages. Furthermore, this kind of approach can be replicated in different oncologic centers with similar oncologic and functional results.



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