The availability of drug by liposomal drug delivery

Summary

Lately, the usefulness of liposomal drug delivery systems has been debated. To better understand the underlying pharmacokinetics of the targeted drug delivery by liposomes, individual encapsulated and non-encapsulated drug concentrations in blood, tumor, liver, spleen and kidneys were quantified after i.v. administration of liposomal prednisolone phosphate in mice. Kinetic analysis shows that the tumor influx of encapsulated drug is not dominant compared to the uptake by the other tissues. Further, from a quantitative point of view, the availability of non-encapsulated drug in the tumor tissue after liposomal delivery is not pronounced as compared to the other tissues studied. However, drug release in the tumor seems more extended than in the other tissues and the non-encapsulated drug concentration decreases more slowly in the tumor than in the liver and spleen. The spleen shows a high affinity for the uptake of encapsulated drug as well as the release of drug from the liposomes. Subsequently, released drug in the spleen, and possibly also in other tissues, is probably quickly redistributed towards the blood and other tissues. This also impairs the drug delivery effect of the liposomes. In contrast to the released drug in the central circulation, liver and spleen, the released drug concentration in the tumor remains at a fairly constant level likely due to the extended release kinetics from the liposomes. These extended release characteristics in the tumor most probably contribute to the beneficial effect. Nevertheless, it should be noted that larger released drug concentrations are formed in healthy tissues.

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In Vivo Analysis of Urinary Stones With Dual-Energy Computed Tomography

Objective Formation mechanisms and treatment of the urinary stones are different, depending on their chemical structure. Therefore, determining the stone type plays a key role in planning treatment and preventive measures. Computed tomography (CT), with the use of dual-energy technology in recent years, has made it possible to do in vivo analysis of urinary stones. In this study, we aimed to evaluate the diagnostic efficacy of dual-energy CT (DECT) and compare its results with in vitro analysis, which is accepted as a gold standard for analysis of urinary stones. Materials and Methods The DECT examinations were performed on 373 patients using 128-slice dual-source CT scanner. Analysis of attenuation ratios in the high and low kilovoltage peak values of the stone was performed at workstation, and stones were classified as hydroxyapatite, calcium oxalate, cystine, and uric acid. On follow-up, the stone was obtained in 35 patients as a result of surgery or passed spontaneously. The DECT analysis and in vitro analysis results were compared and statistically evaluated. Results In all patients, 136 hydroxyapatite, 160 calcium oxalate, 57 uric acid, and 20 cystine stones were detected with DECT. In vitro analyses of the stones were performed in 35 patients, and 8 hydroxyapatite, 18 calcium oxalate, 6 uric acid, and 3 cystine stones were revealed. When DECT analysis results were compared with in vitro analysis results, stone types were detected correctly in 32 (91.4%) patients and incorrectly in 3 (8.6%) patients. Especially all uric acid and cystine stones were correctly detected with DECT. Conclusions With advanced postprocess analysis methods, DECT is able to analyze urinary stones. The DECT is found superior especially in detecting uric acid and cystine stones. Its success in detecting hydroxyapatite and calcium oxalate stones is also high. When in vivo analyses of the stones are performed with DECT, it will be possible to make a contribution to the personalization and optimization of the treatment. Received for publication June 20, 2018; accepted August 7, 2018. Correspondence to: Hasan Erdogan, MD, Department of Radiology, University of Health Sciences, Konya Training and Research Hospital, 42090 Konya, Turkey (e-mail: dr.hasanerdogan@gmail.com). The authors have received no funding for this study. The authors declare no conflict of interest. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Extracochlear Stimulation of Electrically Evoked Auditory Brainstem Responses (eABRs) Remains the Preferred Pre-implant Auditory Nerve Function Test in an Assessor-blinded Comparison

Objective: Electrically evoked auditory brainstem responses (eABRs) can be recorded before cochlear implant (CI) surgery to verify auditory nerve function, and is particularly helpful in to assess the function of the auditory nerve in cases of auditory nerve hypoplasia. This is the first study to compare three preimplant eABRs recording techniques: 1) standard extracochlear, 2) novel intracochlear, and 3) conventional intracochlear with the CI. Study Design: A within-participants design was used where eABRs were sequentially measured during CI surgery using three methods with stimulation from: 1) an extracochlear electrode placed at the round window niche, 2) two different electrodes on a recently developed Intracochlear Test Array (ITA), and 3) two different electrodes on a CI electrode array. Setting: New adults implantees (n = 16) were recruited through the Manchester Auditory Implant Centre and eABR measurements were made in theater at the time of CI surgery. Patients: All participants met the clinical criteria for cochlear implantation. Only participants with radiologically normal auditory nerves were recruited to the study. All participants were surgically listed for either a MED-EL Synchrony implant or a Cochlear Nucleus Profile implant, per standard practice in the implant centre. Outcome Measures: Primary outcome measures were: 1) charge (μC) required to elicit a threshold response, and 2) latencies (ms) in the threshold waveforms. Secondary outcome measures were: 1) morphologies of responses at suprathreshold stimulation levels and 2) wave V growth patterns. Results: eABRs were successfully measured from 15 participants. In terms of primary outcome measures, the charge required to elicit a response using the extracochlear electrode (median = 0.075 μC) was approximately six times larger than all other electrodes and the latency of wave V was approximately 0.5 ms longer when using the extracochlear electrode (mean = 5.1 ms). In terms of secondary outcomes, there were some minor quantitative differences in responses between extracochlear and intracochlear stimulation; in particular, ITA responses were highly variable in quality. The ITA responses were rated poor quality in 33% of recordings and in two instances did not allow for data collection. When not disrupted by open circuits, the median ITA response contained one more waveform than the median extracochlear response. Conclusions: In this first study comparing intracochlear and extracochlear stimulation, the results show that both can be used to produce an eABR that is representative of the one elicited by the CI. In the majority of cases, extracochlear stimulation was the preferred approach for preimplant auditory nerve function testing because of consistency, recordings that could be analyzed, and because extracochlear placement of the electrode does not require a cochleostomy to insert an electrode.

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Vestibular Traumatic Neuroma Following Temporal Bone Fracture

No abstract available

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Delayed Effect and Gain Restoration After Intratympanic Gentamicin for Menière's Disease

Objective: This study aimed to evaluate the changes in the VOR gain after intratympanic gentamicin therapy and to correlate them with the mid-term effects on the control of vertigo, in a population of Menière's disease patients. Study Design: The study design was a prospective "Outcomes research." Setting: Tertiary referral center. Patients: This study included 20 patients with unilateral Menière's disease refractory to medical therapy for at least 1 year, and treated with an on demand intratympanic gentamicin protocol. Intervention: Therapeutic. Main Outcome Measure: Audiometry, caloric testing, and a vHIT before beginning the protocol were performed. Patients underwent weekly vHIT assessments until a significant gain reduction was observed. Subsequently we performed vHIT tests 1 month after the therapy completion, and then every 3 months for at least 1 year. Results: Complete vertigo control (class A) was achieved in 14 patients at the 12-month follow-up assessment. We observed a significant reduction in VOR gain values at the 3-week follow-up assessment. We found a significant correlation between the 1-month posttreatment ipsilateral hVOR gain and the rate of vertigo recurrence after the first IT gentamicin treatment (p = 0.012; r2 = 0.400). At the mid-term assessment, 10 patients exhibited a significant partial recovery of the hVOR gain. Conclusions: The delayed effect of intratympanic gentamicin and the subsequent gain restoration are factors that may influence the patients' outcome. The feasibility of the vHIT system makes it a useful tool to monitorize the VOR changes.

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Naunton's Masking Dilemma Revisited

Background: Pure-tone audiometry is essential in diagnosing clinical hearing loss. Masking of the nontest ear is mandatory for determining accurate hearing thresholds in the presence of asymmetrical levels between the two ears and for ascertaining the presence of a conductive hearing loss. Paradoxically, over masking occurs when the intensity of the required masking noise to the contralateral ear is such that it exceeds interaural cranial attenuation by an amount sufficient to mask the test ear. Ralph F Naunton was the first to describe this phenomenon, which has since been known as "Naunton's masking dilemma." Methods: A formula was derived mathematically to predict when Naunton's masking dilemma might occur in air and bone conduction. Review of Ralph F Naunton's primary works and related publications was performed. Results: Our derived mathematical formulae predict when "Naunton's masking dilemma" may occur. During air conduction testing, a masking dilemma may occur when the sum of the air/bone gaps is greater than or equal to twice the interaural attenuation minus 15 dB (Σ ABGNTE+TE ≥ 2 × IA – 15 dB). During bone conduction testing, a masking dilemma may occur when the air-bone gap of the nontest ear is greater than or equal to the interaural attenuation minus 15 dB (ABGNTE ≥ IAAIR − 15 dB). Conclusion: Naunton's masking dilemma imposes a significant limitation to conventional audiometric testing. To the best of our knowledge, we think this is the first time that Naunton's masking dilemma has been represented in a simplified mathematical equation.

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The Epidemiology of Otosclerosis in a British Cohort

Objective: To analyse the epidemiology of otosclerosis in a British cohort collected between 2011 and 2017. Design: Retrospective cohort study. Setting: Five UK ENT Departments. Patients: Patients with surgically confirmed otosclerosis. Main Outcome Measures: Questionnaire data documented family history of otosclerosis, age of onset, medical history, and information on associated risk factors for 657 patients. Pre and post-surgical pure-tone audiometry was collected for 154 of these patients. Results: The age of onset, incidence of bilateral disease, tinnitus and vertigo, a higher prevalence of women (65%) than men (35%) are similar to those reported previously for otosclerosis cohorts. No association with measles infection was detected. Patients with a family history (40%) have an earlier age of onset and a higher incidence of bilateral disease and vertigo than non-familial subjects. Pedigree analysis is consistent with an autosomal dominant inheritance with reduced penetrance being apparent in 44/91 pedigrees studied. Women who associate their hearing loss with pregnancy have an earlier age of onset than those that do not (p = 6 × 10−6). Conclusions: This study confirms that otosclerosis is an early adult onset disease that is more prevalent in women than men with a large minority of patients having a family history of otosclerosis. We report new evidence to support a relationship between pregnancy and otosclerosis progression in a proportion of women. In addition, this is the first study to identify differences in severity between familial and non-familial cases of otosclerosis, highlighting the possibility that more than one etiology may be involved.

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Cochlear Implantation in Refsum Disease with Facial Nerve Enlargement

No abstract available

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Tripolar Stimulation Improves Polyphonic Pitch Detection in Cochlear Implant Users

Objective: Cochlear implant (CI) users struggle with pitch perception, particularly for polyphonic stimuli. Tripolar (TP) stimulation has been proposed as a way to mitigate the broad spread of neural excitation observed in traditional monopolar (MP) stimulation, thereby potentially improving perception of polyphony. Study Design: Prospective cohort study. Setting: Tertiary academic center. Patients: Eleven postlingually deafened adults with Advanced Bionics HiRes 90K CIs. Intervention(s): We performed pitch ranking and polyphonic pitch detection testing under MP and TP configurations. To assess pitch ranking, users were asked to identify the higher pitch between two notes. In polyphonic pitch detection, users were asked to distinguish between single-pitch tones and two-pitch tones. Two-pitch stimuli consisted of one pitch of three base frequencies (392, 523, 740 Hz) and a second pitch between 1 and 12 semitones above the base frequency. Main Outcome Measure: Pitch performance was analyzed as a function of current delivery mode (tripolar vs. monopolar), with smaller semitone interval pitch resolution indicating better performance. Results: In pitch ranking tasks, TP configuration did not confer an advantage over MP stimulation. In polyphonic perception, however, tripolar stimulation improved performance in lower frequencies and resulted in statistically significant (p 

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A Systematic Review of the Reported Proportions of Diagnoses for Dizziness and Vertigo

Objectives: To determine the typical proportions of diagnoses for patients presenting with dizziness or vertigo based on clinical speciality and to assess the change in proportions of diagnoses over time. Data Sources: Following PRISMA guidelines, systematic searches of PubMed and CINAHL databases and follow-up reference searches were performed for articles published in English up to October 2016. Study Selection: Analysis of searches yielded 42 studies meeting the criteria of case series of adult patients with dizziness and/or vertigo presenting to general practice, emergency departments or specialist outpatient clinics. Data Extraction: Data comprising demographics, diagnostic cases, and the total number of cases were recorded and independently tested, followed by a risk of bias analysis. Data Synthesis: Sample size weighted proportions expressed as percentages with confidence intervals were calculated and compared using χ2 analysis and a reference proportion formed by the combination of Ear Nose and Throat and Neurotology case series published between 2010 and 2016. Analysis of diagnostic trends over time used Poisson regression with consideration for overdispersion. Conclusions: This systematic review of case series demonstrated significant differences in the proportions of diagnoses for patients presenting with dizziness or vertigo, depending on the specialty making the diagnosis. ENT proportions were dominated by BPPV, Psychogenic and Menière's disease diagnostic categories, whereas emergency proportions were dominated by Other, Cardiac, and Neurological categories. Analysis of case series proportions over time revealed increases in diagnoses such as Benign Paroxysmal Positional Vertigo and Vestibular Migraine, and a corresponding decrease in the diagnoses of Menière's disease.

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Application of Ultrasonic Bone Aspirator for Decompression of the Internal Auditory Canal via the Middle Cranial Fossa Approach

Objective: Evaluate the safety and efficacy of the ultrasonic bone aspirator (UBA) during middle cranial fossa (MCF) approach to vestibular schwannoma (VS). Study Design: Retrospective case series. Setting: Tertiary referral center. Patients: Charts of 192 consecutive VS patients over 18 years of age were reviewed to identify 65 patients who underwent MCF approach to VS resection between 2006 and 2017. A combination of UBA and high-speed drill (HSD) was used to decompress the internal auditory canal (IAC) in 25 patients and HSD alone was used in the other 40 patients. Intervention(s): Use of UBA during vestibular schwannoma surgery via MCF approach for decompression of the IAC. Main Outcome Measure(s): Postoperative facial nerve outcomes assessed by the House–Brackmann (HB) facial nerve grading scale. Rates of gross total resection (GTR) and cerebrospinal fluid (CSF) leak. Results: There were no significant differences in postoperative facial nerve function, in rate of GTR of tumor, or in rate of CSF leak. In the UBA group 24/25 (96%) had postoperative HB grade I–II compared with 36/40 (90%) in the HSD group (p-value = 0.66). GTR was achieved in 25/25 (100%) in the UBA group compared with 38/40 (95%) in the HSD group (p-value = 1). In the UBA group, there were 0/25 (0%) cases of CSF leak compared with 1/40 (2.5%) in the HSD group (p-value = 1). Conclusions: UBA use is a safe and effective alternative or adjunct to HSD during MCF approach to expose the IAC contents. This surgical tool allows for bone removal with low risk of injury to adjacent structures.

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Relationship Between Tinnitus Loudness Measure by Visual Analogue Scale and Psychoacoustic Matching of Tinnitus Loudness

Objective: The aim of the study was to assess the relationship between psychoacoustic matches of tinnitus loudness and tinnitus loudness measured with a visual analogue scale (VAS) in patients with normal hearing and patients with hearing loss. Study Design: Cross-sectional study. Patients: A clinical group of 140 adult patients (46.4% women, 53.6% men) aged from 19 to 81 years old who had had tinnitus for at least 6 months were included in the study. The most frequent reported localization of their tinnitus sensation was bilateral (48.6%); 40% experienced unilateral tinnitus; and 11.4% heard tinnitus in the head. Methods: All participants were first asked to complete a VAS to indicate their tinnitus loudness. Hearing thresholds were then determined for each patient at frequencies from 0.125 to 8 kHz; loudness and frequency of the tinnitus were also matched psychoacoustically. Results: Tinnitus loudness measured in dB SL was significantly lower in patients with bilateral hearing loss than in patients with unilateral hearing loss or in patients with normal hearing. Tinnitus loudness measured with VAS was significantly higher in patients with bilateral hearing loss than in patients with normal hearing. In patients with normal hearing there was a relationship between psychoacoustic matches of tinnitus loudness and tinnitus loudness measured with VAS, but this relationship did not hold for the hearing loss patients. Conclusions: The VAS scale for tinnitus loudness does not generally correspond to psychoacoustic measures of tinnitus loudness. It is only indicative for tinnitus patients who have normal hearing.

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Peripheral Vestibular Disorders: An Epidemiologic Survey in 70 Million Individuals

Background: Dizziness is a common complaint in medicine. Nevertheless, there is a lack of valid data concerning the age and gender distribution of dizziness disorders within a larger population. Therefore, the aim of the present study is to undertake a representative epidemiological survey that examines all age groups of an entire population and describes the age and gender distribution of the most common peripheral vestibular disorders. Methods: A population-based epidemiological survey based on confirmed ICD-10 codes, of an entire national population was performed. The population-based data of 70,315,919 patients were leveraged, as provided by 123 statutory health insurance companies in Germany. Patients of all age groups were analyzed. Outcome measures were age and gender distribution and the prevalence of unspecific vertigo, Meniere's disease, benign paroxysmal positional vertigo, vestibular neuritis, and other peripheral vestibular disorders. Results: The prevalence among the recorded diagnoses was 6.5% (6,461/100,000 individuals), with women (N = 2,973,323; 65.4%) being significantly more frequently affected by vertigo than men (N = 1,570,240; 34.6%; p 

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An In-Vitro Insertion-Force Study of Magnetically Guided Lateral-Wall Cochlear-Implant Electrode Arrays: Erratum

No abstract available

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Phenotypic Characterization of DFNB16-associated Hearing Loss

Hypothesis: We hypothesized that patients with DFNB16 caused hearing loss show characteristical audiological findings depending on genetic results. Background: Hearing loss belongs to the most frequent congenital diseases. In 50–70% of individuals, hearing loss is caused by genetic defects. DFNB1 (deafness, neurosensory, autosomal-recessive) is the most frequently affected locus. Despite its great genetic heterogeneity, comprehensive analysis of genes like STRC, encoding stereocilin (DFNB16) is possible. The genetic architecture of the DFNB16 locus is challenging and requires a unique molecular genetic testing assay. The aim of the study is a systematic characterization of the audiological phenotype in DFNB16-positive patients. Methods: Since 2011, 290 patients with suspicion of inherited hearing loss received a human genetic exploration. Eighty two DFNB1-negative patients advanced to further testing in the DFNB16 locus. STRC-positive patients obtained complete audiological diagnostic workup. Additionally, epidemiological data was collected. Results: Nine of 82 (11%) of the examined patients (mean age 5 yr) showed mutations in the STRC (3 homozygous, 6 compound heterozygous). Aside from a moderate hearing loss in the pure tone audiogram, auditory brainstem response thresholds were 40–50 dB nHL. Otoacoustic emissions were detectable in only one patient. Conclusions: Examination of the DFNB16-locus should be a standard diagnostic test after negative DFNB1-gene screening result. Notably, DFNB16-associated hearing loss can be audiologically characterized as moderate sensorineural hearing loss in the main speech field with absent otoacoustic emissions. Our study is the first to correlate audiological findings with genetic results in patients with hearing loss due to STRC.

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Superficial Siderosis of the Central Nervous System: Neurotological Findings Related to Magnetic Resonance Imaging

Objective: To compare the neurotological results of five patients suffering from progressive hearing loss and ataxia due to superficial siderosis (SS) with the magnetic resonance imaging (MRI) findings. Study Design: Retrospective case review. Setting: Primary and hospital care center. Participants: Five adult patients with neurotological symptoms of SS underwent MRI with acquisition of our temporal bone protocol including 3D-constructive interference in steady state (3D-CISS) and susceptibility-weighted imaging (SWI). All patients underwent a complete neurotological examination, the results of which were compared with the imaging findings. Main Outcome Measures: Cochleovestibular deficits were present in all five patients as determined by uni- or bilateral bithermal caloric testing and/or video head impulse tests. Sacculocollic reflex was present with increased P1 and N1 latencies on both sides in all patients. MRI revealed an extensive hypointense SWI signal outlining the surface of the brain and the VIIIth cranial nerve in all five patients. Desynchronization of the brainstem auditory evoked potentials (BAEP) and partial or complete absence of the visual suppression of vestibulo-ocular reflex during the pendular rotatory test was particularly consistent with the lesions of the cochleovestibular nerves as well as the cerebellar atrophy seen on MRI. Conclusion: The MRI results with SWI were related to neurotological findings in patients suffering from sensorineural deafness with ataxia due to SS. Our findings support the integration of the SWI and 3D-CISS sequences into the MRI protocol for all patients referred for evaluation of the extent of SS.

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Salvage Radiosurgery After Subtotal Resection for Catecholamine-secreting Jugular Paragangliomas: Report of Two Cases and Review of the Literature

Objectives: Catecholamine-secreting jugular paragangliomas (JPs) represent a rare subset of head and neck paragangliomas that may present with hypertension, arrhythmia, or syncopal episodes. Subtotal resection to protect critical neurovascular structures may result in persistent catecholamine excess from residual tumor. Herein, we report our experience with stereotactic radiosurgery (SRS) for salvage treatment of catecholamine-secreting JP following subtotal microsurgical resection. Patients: Adult patients treated with SRS after subtotal microsurgical resection of catecholamine-secreting JP. Interventions: SRS. Main Outcome Measures: Post-treatment catecholamine and metanephrine levels, clinical outcomes, and tumor control. Results: Of 85 patients with JPs treated with primary or salvage radiosurgery between 1990 and 2017, 2 (2%) harbored nonmalignant secreting tumors. Patient 1 developed catecholamine excess with elevated norepinephrine (NE) at 475 mcg/24 hours (normal 

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Utility of Postoperative Magnetic Resonance Imaging in Patients Who Fail Superior Canal Dehiscence Surgery

Objective: The etiology of symptoms following primary repair of superior canal dehiscence (SCD) may be due to a persistent third window. However, the extent of surgery cannot be seen on postoperative computed tomography (CT) since most repair materials are not radiopaque. We hypothesize that the extent of superior semicircular canal (SSC) occlusion following primary repair can be quantified based on postoperative magnetic resonance imaging (MRI) data. Study design: Retrospective series. Setting: Tertiary care center. Patients: Adult patients with a history of SCD syndrome who 1) report persistent symptoms following primary SCD repair and 2) underwent heavily T2-weighted MRI postoperatively. Interventions: Analysis of SSC using 3D-reconstruction of CT co-registered with MRI data. Main outcome measures: Arc length of fluid void on MRI and quantification of persistent SCD based on CT/MRI co-registration. Results: We identified 9 revision cases from a cohort of 145 SCD repairs at our institution (2002–2017) with CT/MRI data. A fluid void on postoperative MRI (indicating occlusion of the SSC) was observed in all cases (anterior limb: 50.1 degrees [±21.8 SD] and posterior limb 48.1 degrees [±28.5 SD]). Co-registration of CT/MRI revealed a residual defect that was most commonly found along the posterior limb in most patients with persistent symptoms. Conclusions: The extent of SCD repair can be determined using reformatted or direct T2-weighted MRI sequences in the plane of Pöschl. Co-registration of CT/MRI may be useful to determine the location of a residual superior canal defect and when present was found most commonly along the posterior limb.

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Otopathology of Unilateral Cochlear Implantation in Patients With Bilateral Temporal Bone Fracture

Objective: Audiometric outcomes following cochlear implantation (CI) in patients with temporal bone fracture (TBF) are variable and the pathophysiology is not well understood. Herein, we describe otopathologic findings in two such cases to provide insight into pathophysiology and outcomes. Patients: Two patients had a history of head trauma resulting in bilateral TBF and sudden, profound, sensorineural hearing loss. Intervention: Both cases underwent unilateral CI following head trauma. Main Outcome Measures: Both TBs from each patient were harvested postmortem and histologically analyzed to determine fracture lines, intralabyrinthine fibroosseous changes, and spiral ganglion neuron (SGN) counts. Clinical histories and audiometric outcomes were also reviewed. Results: In both cases, the implanted TB showed extensive intracochlear ossification, which was greater when fracture involved the cochlea. In contrast, the nonimplanted cochleae were patent with small osseous deposits at the round window membrane. Interaural SGN counts were lower on the implanted side and hearing results were moderate to poor. Conclusions: Otopathologic analyses of patients with a CI after bilateral TBF are rare. Based on otopathology of two patients with bilateral TBF and subsequent CI, implanted TBs show extensive intracochlear fibroosseous changes greater than the nonimplanted side. Findings have implications for auditory rehabilitation after TBF.

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Spinal Surgery With Electrically Evoked Potential Monitoring and Monopolar Electrocautery: Is Prior Removal of a Cochlear Implant Necessary?

Transcranial electric stimulation to generate motor evoked potentials in lower limb muscles is the standard technique used to monitor spinal cord efferent pathways during surgical correction for spinal deformities. Monopolar electrical cauterization is also used by default in the thoracic and lumbar area of the spine during this kind of surgery to prevent major blood loss. Owing to the high levels of current used, both techniques are considered contraindicative if the patient has a cochlear implant (CI). Here, we present a CI patient who underwent corrective spinal fusion surgery for a severe kyphoscoliotic spinal deformity on whom both techniques were used without any negative effects on the CI function. A major improvement in sagittal body balance was achieved with no loss in implant-aided hearing levels. These results add to reports that CI manufactures should review their evidence underlying recommendations that transcranial electric stimulation and upper thoracic monopolar electrical cauterization are high risk for CI users, possibly initiating verification studies.

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Strengthening Our Societies With Diversity and Inclusion

No abstract available

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Perioperative Recording of Cochlear Implant Evoked Brain Stem Responses After Removal of the Intralabyrinthine Portion of a Vestibular Schwannoma in a Patient with NF2

Objective: To predict and optimize hearing outcomes with a cochlear implant (CI) in patients with intracochlear schwannoma and neurofibromatosis type 2 (NF2). Patient: A patient with NF2 and bilateral deafness. Interventions: The intracochlear portion of a vestibular schwannoma was removed with a partial cochleoectomy. During the procedure, a CI was implanted. Main Outcome Measures: Perioperatively, electrically evoked auditory brainstem responses (eABRs) were recorded with a novel intracochlear, CI-evoked, broad band stimulus to support the decision to implant a CI. Results: We found positive eABR responses, with thresholds at around the 200 current level. The eV wave was discernible at all stimulated electrodes, with a prolonged latency of about 6.5 ms. The eIII wave was detected at electrodes 9 and 13, with a latency of 4.5 ms. The acoustic reflex was detectable at all stimulated electrodes. Subjective auditory perception could be achieved by stimulating 3 days after surgery. In open-set word recognition, the patient achieved 60% recognition of monosyllables after the first audio processor fitting and 100% 1 month later. Conclusions: After a partial cochleoectomy, this method may serve as a peri-operative, objective assessment of cochlear nerve integrity that could potentially impact the prediction of CI performance. Potential future applications might be assessments of cochlear nerve integrity in patients with inner ear malformations, radiologically suspected cochlear nerve deficiencies, and resected or irradiated spontaneous vestibular schwannomas or NF2.

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Standardized Cost Estimates for Home Visiting: Pilot Study of the Home Visiting Budget Assistance Tool (HV-BAT)

Abstract

Purpose Using a standardized approach and metrics to estimate home visiting costs across multiple evidence-based models and regions could improve the consistency and accuracy of cost estimates, allow stakeholders to observe trends in cost allocation, analyze how home visiting costs vary, and develop future program budgets. Between October 2015 and December 2018, we developed and pilot-tested the Home Visiting Budget Assistance Tool (HV-BAT) to standardize the collection of home visiting program costs and analyze costs for local implementing agencies (LIAs). Methods We recruited LIAs that implemented at least one of nine evidence-based home visiting models in 15 states implementing the Maternal, Infant, and Early Childhood Home Visiting (MIECHV) Program. LIAs reported their costs to implement a home visiting model using the HV-BAT and provided feedback on the tool. We estimated annual total cost and cost per family served for each LIA, examined cost summary statistics for the sample, and analyzed whether and how LIA characteristics affected home visiting costs using regression analyses. Results Of the 168 LIAs invited to participate in the HV-BAT pilot study, 75 agreed to participate, and 45 across 14 states completed the HV-BAT. We estimated home visiting costs of approximately $8500 per family per year, but costs varied across LIAs (range $1970–$39,770; standard deviation = $5794). The marginal cost of adding a family declined as the number of families served by an LIA increased. Feedback from LIAs indicated that users had difficulty providing some details on costs (e.g., mileage for specific services), needed more detailed instructions, and desired a summary of subtotals and total costs reported in the HV-BAT. Conclusions The HV-BAT provides an approach to standardize cost data collection for home visiting programs. Pilot study results indicate that there may be significant economies of scale for home visiting services. This study provides preliminary estimates of costs that can help in program planning and budgeting.

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Gray-zone Lymphoma Between cHL and Large B-Cell Lymphoma: A Histopathologic Series From the LYSA

Gray-zone lymphoma (GZL) with features intermediate between classic Hodgkin lymphoma (cHL) and large B-cell lymphoma (LBCL) was introduced as a provisional entity into the World Health Organization classification in 2008. However, as diagnostic criteria are imprecise, reliable identification of GZL cases remains challenging. Here, we describe the histopathologic features of 139 GZL cases from a retrospective Lymphoma Study Association (LYSA) study with the goal to improve classification accuracy. Inclusion criteria were based on literature review and an expert consensus opinion of the LYSA hematopathologist panel. We observed 86 cases with a morphology more closely related to cHL, but with an LBCL immunophenotype based on strong and homogenous B-cell marker expression (CD20 and/or CD79a, OCT2, BOB1, PAX5) on all tumor cells (cHL-like GZL). Fifty-three cases were morphologically more closely related to LBCL but harbored a cHL immunophenotype (LBCL-like GZL). Importantly, we observed a continuous morphologic and immunophenotypic spectrum within these 2 GZL categories. The majority of cases presented genetic immune escape features with CD274/PDCD1LG2 and/or CIITA structural variants by fluorescence in situ hybridization. Patients without mediastinal involvement at diagnosis (17%) were older than those with mediastinal tumors (median: 56 vs. 39 y). Cases associated with Epstein-Barr virus (24%) presented with similar patient characteristics and outcome as Epstein-Barr virus negative cases. In summary, we provide refined diagnostic criteria that contribute to a more precise pathologic and clinical characterization of GZL within a broad spectrum from cHL-like to LBCL-like disease. A.M. and A.T.-G. contributed equally to this work. Conflicts of Interest and Source of Funding: C.S. received a research grant from ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la vie et de la santé, National Alliance for Life Sciences and Health) within the framework of the Cancer Plan; Nuovo Soldati Fundation; Servier Fundation. A.T.G. and C.S. received research fundings from Takeda. The remaining authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Clémentine Sarkozy, MD, Centre Hospitalier Lyon Sud, Pierre Bénite, France (e-mail: clementine.sarkozy@chu-lyon.fr). Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

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Optimizing the removal of nitrate from aqueous solutions via reduced graphite oxide – supported nZVI: synthesis, characterization, kinetics, and reduction mechanism

Abstract

Graphene has been considered an ideal absorbent and excellent carrier for nanoparticles. Reduced graphite oxide (rGO)–supported nanoscale zero-valent iron (nZVI@rGO) is an effective material for removing nitrate from water. nZVI@rGO nanocomposites were prepared by a liquid-phase reduction method and then applied for nitrate-nitrogen (NO₃⁻-N) removal in aqueous solution under anaerobic conditions. The experimental results showed that the stability and activity of the nZVI@rGO nanocomposites were enhanced compared with those of nZVI. The influence of the reaction conditions, including the initial concentration of NO₃⁻-N, coexisting anions, initial pH of the solution, and water temperature, on NO₃⁻-N removal was also investigated by batch experiments. In a neutral or slightly alkaline environment, 90% of NO₃⁻-N at a concentration less than 50 mg/L could be removed within 1 h, and nitrogen production was approximately 15%. The process of NO₃⁻-N removal by nZVI@rGO fits well with different reaction kinetics. In addition, magnetite was the main oxidation product. RGO-supported nZVI might become a promising filler in the permeable reactive barrier process for groundwater remediation.

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Spermatocytic Seminoma: A Report of 85 Cases Emphasizing Its Morphologic Spectrum Including Some Aspects Not Widely Known

Spermatocytic seminoma (or, alternatively, spermatocytic tumor) of the testis is rare and errors in pathologic diagnosis are still made. As it has a good prognosis, except when it, rarely, undergoes sarcomatous transformation, accurate diagnosis and differentiating it from usual seminoma and other malignant neoplasms such as lymphoma are crucial. To potentially contribute information of diagnostic aid we reviewed the largest series of cases reported to date to characterize in detail their histologic spectrum. The patients ranged from 30 to 81 years (average, 52 y); 30% were in the fourth decade. The neoplasms ranged from 1.4 to 15 cm (average, 5.7 cm). Most were fleshy, soft, and often lobulated and 11 were edematous or mucoid. Low-power microscopic examination either showed a predominant multinodular (43/85) or diffuse (42/85) pattern. All tumors had the classic "tripartite" cellular population. Five tumors showed a relatively monomorphic population of the intermediate cell type with vesicular chromatin and very prominent nucleoli, at least focally. Two tumors underwent sarcomatous transformation, with 1 having a focus of atypical cartilage. Additional findings, some not previously reported or emphasized, included: (1) frequent edema fluid (87%) often causing spaces, both follicle-like (24%) and irregular (39%), a finding seen in some usual seminomas (but less frequently) and rarely seen in lymphomas; (2) tumor nodules showing partial rims of fibrin (20%); (3) a distinctive arrangement of connecting tumor islands (19%); (4) prominent lymphocytic infiltrates (8%); (5) granulomatous inflammation (1%); (6) striking mitotic activity and apoptosis; (7) intratubular spread (64%); and (8) vessel invasion (11%) and necrosis (8%). Awareness of these aspects may be of importance either at the time of intraoperative evaluation or on final pathologic analysis and help avoid significant errors in diagnosis.

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Acquisition of WNT Pathway Gene Alterations Coincides With the Transition From Precursor Polyps to Traditional Serrated Adenomas

Colorectal traditional serrated adenomas (TSAs) are often associated with precursor polyps, including hyperplastic polyps and sessile serrated adenoma/polyps. To elucidate the molecular mechanisms involved in the progression from precursor polyps to TSAs, the present study analyzed 15 precursor polyp-associated TSAs harboring WNT pathway gene mutations. Laser microdissection-based sequencing analysis showed that BRAF or KRAS mutations were shared between TSA and precursor polyps in all lesions. In contrast, the statuses of WNT pathway gene mutations were different between the 2 components. In 8 lesions, RNF43, APC, or CTNNB1 mutations, were exclusively present in TSA. RNF43 mutations were shared between the TSA and precursor components in 3 lesions; however, they were heterozygous in the precursor polyps whereas homozygous in the TSA. In 4 lesions with PTPRK-RSPO3 fusions, RNA in situ hybridization demonstrated that overexpression of RSPO3, reflecting PTPRK-RSPO3 fusion transcripts, was restricted to TSA components. Consistent with the results of the genetic and in situ hybridization analyses, nuclear β-catenin accumulation and MYC overexpression were restricted to the TSA component in 13 and 12 lesions, respectively. These findings indicate that the WNT pathway gene alterations are acquired during the progression from the precursor polyps to TSAs and that the activation of the WNT pathway plays a critical role in the development of TSA rather than their progression to high-grade lesions.

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Molecular and Ultrastructural Features of Diffuse Intrapulmonary Malignant Mesothelioma

No abstract available

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Congenital Cystic Lung Lesions: Redefining the Natural Distribution of Subtypes and Assessing the Risk of Malignancy

Asymptomatic cystic lung lesions—congenital pulmonary airway malformations (CPAMs), sequestrations, and bronchogenic cysts—are commonly diagnosed prenatally. Indications to resect are to eliminate risk of malignancy or infection. CPAMs consist of a spectrum of malformations, with type 1 historically considered the most common. Mucinous cell clusters, seen almost exclusively in type 1, are premalignant lesions at risk for progression to mucinous adenocarcinoma. We reviewed and classified 2.5 years of consecutive, prenatally diagnosed lesions as extralobar sequestration, intralobar sequestration, type 1 CPAM, type 2 CPAM/bronchial atresia, or "other" to determine the distribution of lesion types and risk of malignancy. One hundred eighty-four lesions in 174 patients showed type 1 CPAM to be least common subtype. Type 1 CPAMs had more severe presentation, infrequently had features of obstruction, and usually had cysts ≥2 cm. Fifteen of eighteen type 1 CPAMs had mucinous cell clusters (total risk, 8%), with mucous cells outside main cyst in 12/15. No pleuropulmonary blastomas were identified. Additional historic cases were reviewed to further evaluate risk of malignancy. Over 14 years, 28 infants with fetal/type 1 lesions were identified, with clusters of mucinous cells in 75% of cases. A total of 9 pleuropulmonary blastomas were diagnosed in 6 patients over 16 years. Contrary to historical studies, type 1 CPAMs are much less common than type 2, likely related to detection of asymptomatic lesions prenatally. A majority of type 1 CPAMs contain mucinous cell clusters. This data is useful in management of patients in centers that do not resect asymptomatic lesions.

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Somatic Mutations of TSC2 or MTOR Characterize a Morphologically Distinct Subset of Sporadic Renal Cell Carcinoma With Eosinophilic and Vacuolated Cytoplasm

The differential diagnosis of renal cell neoplasms with solid or nested architecture and eosinophilic cytoplasm has become increasingly complex. Despite recent advances in classifying a number of entities exhibiting this morphology, some tumors remain in the unclassified category. Here we describe a morphologically distinct group of sporadic renal cell carcinoma (RCC) with predominantly nested architecture, eosinophilic, and remarkably vacuolated cytoplasm retrospectively identified from a cohort of previously unclassified tumors. We examined the clinicopathologic and immunohistochemical features of these tumors and investigated their mutational and copy number alterations using a targeted next-generation sequencing platform. The study included 7 patients with a mean age of 54 years (range: 40 to 68 y) and a male to female ratio of 3:4. All patients presented with a solitary renal mass and had no prior medical or family history raising concern for syndromic conditions. Tumors were well-circumscribed, unencapsulated, and comprised of nests of eosinophilic cells in a hypocellular and often edematous stroma. Tumor cells had round nuclei with prominent nucleoli and granular cytoplasm with striking vacuolization. Thick-walled vessels and calcifications were also frequently present, whereas increased mitotic activity, necrosis, foamy histiocytes or lymphocytic infiltrates were not identified. All cases were positive for PAX8, had retained expression of SDHB and FH, and exhibited a CK7−/CK20− phenotype. While cathepsin-K was positive in 5 cases, none exhibited immunoreactivity to HMB45 or Melan A, or TFE3 immunostaining. Next-generation sequencing identified somatic inactivating mutations of TSC2 (3/5 tumors tested) or activating mutations of MTOR (2/5) as the primary molecular alterations, consistent with hyperactive mTOR complex 1 signaling which was further demonstrated by phospho-S6 and phospho-4E-BP1 immunostaining. Copy number analysis revealed a loss of chromosome 1 in both cases with MTOR mutation. These tumors represent a novel subset of sporadic RCC characterized by alterations in TSC1-TSC2 complex or the mTOR complex 1 pathway. Recognition of their characteristic morphologic and immunophenotypic features will allow them to be readily identified and separated from the unclassified RCC category.

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An Immune Suppression-associated EBV-positive Anaplastic Large Cell Lymphoma With a BRAF V600E Mutation

Iatrogenic lymphoproliferative disorders have been described in patients receiving immunosuppressive/immunomodulatory agents outside the transplantation setting. Novel biological agents such as TNF-α blockers and JAK-inhibitors have also proven to be effective in many disorders including rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis and Crohn disease), psoriasis, and others. A significant dilemma exists in those lymphoproliferative disorders associated with immunosuppressants and rheumatologic conditions, that relies on whether the association of the process is with the medication or the underlying autoimmune condition. In the current case report, we describe an extraordinary case of Epstein-Barr virus–positive anaplastic large cell lymphoma, in association with rheumatoid arthritis and the use of JAK-inhibitors. Comprehensive molecular testing (fluorescence in situ hybridization, OncoScan microarray, pyrosequencing) was done comparing sequential biopsies in this patient from skin and lung, which revealed a driving mutation in the BRAF V600E gene, a crucial finding, given the potential use of targeted therapy in this pathway.

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Utility of Combined EZH2, p-ERK1/2, p-STAT, and MYC Expression in the Differential Diagnosis of EZH2-positive Hodgkin Lymphomas and Related Large B-Cell Lymphomas

EZH2 is a methyltransferase that plays an important tumorigenic role in various neoplasms. We previously found that EZH2 is expressed in a range of aggressive B-cell lymphomas (ABCLs), T-cell lymphomas, and histiocytic neoplasms, with differential expression of intracellular signaling molecules p-ERK, MYC, and p-STAT3, potential regulators of EZH2 expression. We studied EZH2 expression in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), classic Hodgkin lymphoma (cHL), T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), and B-cell Lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphomas and classic Hodgkin lymphoma (BCLu-DLBCL/cHL), as well as the coexpression of p-ERK, MYC, and p-STAT3 in these neoplasms. The neoplastic LP cells of NLPHL and Hodgkin/Reed-Sternberg cells of cHL were strongly positive for EZH2, as were the neoplastic cells in THRLBCL and BCLu-DLBCL/cHL. EZH2 expression correlated with proliferation rate, as assessed by Ki-67 staining. LP cells in NLPHL and Hodgkin/Reed-Sternberg cells in cHL were strongly positive for p-ERK, p-STAT3, and MYC, as were the neoplastic cells in THRLBCL and BCLu-DLBCL/cHL, in contrast to the differential expression of these molecules seen in ABCLs. These findings suggest that combined expression of p-ERK, MYC, and p-STAT3 is a useful immunohistochemical pattern for the diagnosis of EZH2-positive Hodgkin lymphomas and related lymphomas, in contrast to ABCLs. Furthermore, the overexpression of EZH2, in association with coexpression of tumorigenic signaling molecules, suggests an oncogenic role for this molecule in the development of Hodgkin lymphomas and related lymphomas. THRLBCL and BCLu-DLBCL/cHL appear to have a mechanism for the regulation of EZH2 expression that is similar to NLPHL and cHL and different from that of ABCLs. In addition, EZH2 and associated signaling cascades may serve as therapeutic targets for the treatment of Hodgkin lymphomas and related lymphomas.

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Clinicopathologic and Molecular Characteristics of Mesonephric Adenocarcinoma Arising From the Uterine Body

Mesonephric adenocarcinoma (MNAC) is a rare tumor of the female genital tract mainly occurring in the uterine cervix. To date, only a few cases of MNAC arising from of the uterine body (UB-MNAC) have been reported. The clinicopathologic and molecular characteristics of UB-MNAC remain unknown. In this study, we investigated the clinical, histopathologic, immunohistochemical, and genetic features of UB-MNAC. In total, 11 cases were included. Six patients developed metastatic disease, most commonly in lungs (5/6). Histopathologically, UB-MNAC was characterized by an admixture of tubular, glandular, papillary, retiform, glomeruloid, sex cord-like, and comedonecrosis-like architectural patterns. Three adverse pathologic characteristics, including advanced International Federation of Gynecology and Obstetrics stage, high mitotic activity, and presence of lymphovascular the invasion, were independent factors predicting the development of metastasis. All cases were positive for GATA-binding protein 3 and paired box 2 expression and showed wild-type p53, patchy p16, and preserved PTEN expression, as indicated by immunohistochemistry. Next-generation sequencing using 12 samples (11 primary tumors and 1 metastatic tumor) revealed 42 single nucleotide variations in 16 genes, mostly in KRAS (10/12) and ARID1A (9/12). Copy number variation was found in 16 genomic regions, and consisted of 57 gains and 10 losses, with 1q gain (11/12) being the most prevalent. In conclusion, UB-MNAC displays an aggressive biological behavior, with a tendency to metastasize to the lungs. Adverse pathologic characteristics reflect the aggressive nature of UB-MNAC. Distinct molecular features of UB-MNAC include frequent somatic mutations of KRAS and ARID1A and gain of 1q.

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Kidney Biopsy Adequacy: A Metric-based Study

There are differences in renal biopsy yield related to on-site evaluation, tissue division, and operator, among others. To understand these variations, we collected adequacy-associated data (%cortex, glomeruli, arteries, length) from consecutive native and allograft kidney biopsies over a 22-month period. In total, 1332 biopsies (native: 873, allograft: 459) were included, 617 obtained by nephrologists, 663 by radiologists, and 559 with access to on-site division. Proceduralists with access to on-site evaluation had significantly lower inadequacy rates and better division of tissue for light microscopy (LM), immunofluorescence, and electron microscopy than those without access to on-site evaluation. Radiologists in our region were significantly less likely to have access to on-site evaluation than nephrologists. On multivariate analysis for native kidney biopsies, the effect of having a radiologist perform the biopsy and having access to on-site division were both significant predictors of obtaining greater calculated amount of cortex for LM. Despite the trend for radiologists to obtain more tissue in general, biopsies from nephrologists contained a greater percentage of cortex and were more likely to be considered adequate for LM (native kidney inadequacy rate for LM: 1.11% vs. 5.41%, P=0.0086). Biopsies in which inadequate or marginal cortical tissue was submitted for LM had only minor decreases in the amount of cortex submitted for immunofluorescence and electron microscopy, revealing an opportunity for improved specimen triaging when limited tissue is obtained. In conclusion, both on-site evaluation/division and proceduralist significantly affect quantitative kidney biopsy metrics, which in turn affects the pathologist's ability to render an accurate diagnosis with appropriate prognostic information for the patient and treating nephrologist.

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Multiple Eruptive Epithelioid Hemangiomas: A Subset of Cutaneous Cellular Epithelioid Hemangioma With Expression of FOS-B

There is a wide clinicopathologic spectrum of vascular proliferations characterized by the presence of epithelioid endothelial cells, comprising epithelioid hemangioma (EH)—pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma (PM-HAE), epithelioid hemangioendothelioma, and epithelioid angiosarcoma. Immunohistochemical FOS-B expression as well as FOS-B rearrangement (fluorescent in situ hybridization [FISH]) have recently been described as diagnostically relevant underpinnings of EH (restricted to osseous lesions) and PM-HAE. The aim of this study was to clinicopathologically characterize and to elucidate FOS-B expression in patients with eruptive lesions of the cellular variant of cutaneous EH. All cases of cutaneous cellular EH (n=16) showed strong diffuse immunohistochemical expression of FOS-B, in conjunction with positivity for ERG and nestin. Expression of MYC, CAMTA-1, AE1/3, and MNF116 was negative in all cases. FISH investigations did not show any sign of rearrangements for CAMTA-1 or MYC amplification. Negative-control cases included 15 lobular hemangiomas, 5 epithelioid angiosarcomas, and 5 nodular Kaposi sarcomas, all of which were negative for FOS-B. Positive-control cases included 15 angiolymphoid hyperplasia with eosinophilia cases, all of them being positive. In contrast with what has been published so far, cutaneous variants of cellular EH exhibit positive immunostaining for FOS-B. Remarkably, FOS-B expression is not restricted to the intraosseous subset of EH. For differential diagnosis of epithelioid vascular tumors, we therefore suggest a helpful panel of antibodies including CAMTA-1, TFE-3, FOS-B, and AE1/AE3. We point out the telltale immunophenotypes: angiolymphoid hyperplasia with eosinophilia and EH (FOS-B+/others negative), PM-HAE (FOS-B+/AE1/AE3+/others negative), epithelioid hemangioendothelioma (CAMTA-1+ or TFE-3+/others negative). Remarkably, MYC is not expressed in these tumors, neither is there an MYC amplification by FISH. We suggest the term multiple eruptive EHs for this subset of cutaneous vascular tumors.

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Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) Parathyroid Tumors Demonstrate Distinctive Morphologic Features

The gene CDC73 (previously known as HRPT2) encodes the protein parafibromin. Biallelic mutation of CDC73 is strongly associated with malignancy in parathyroid tumors. Heterozygous germline mutations cause hyperparathyroidism jaw tumor syndrome,which is associated with a high life-time risk of parathyroid carcinoma. Therefore loss of parafibromin expression by immunohistochemistry may triage genetic testing for hyperparathyroidism jaw tumor syndrome and be associated with malignant behavior in atypical parathyroid tumors. We share our experience that parafibromin-negative parathyroid tumors show distinctive morphology. We searched our institutional database for parathyroid tumors demonstrating complete loss of nuclear expression of parafibromin with internal positive controls. Forty-three parafibromin-negative tumors from 40 (5.1%) of 789 patients undergoing immunohistochemistry were identified. Thirty-three (77%) were external consultation cases; the estimated incidence in unselected tumors was 0.19%. Sixteen (37.2%) fulfilled World Health Organization 2017 criteria for parathyroid carcinoma and 63% had serum calcium greater than 3mmol/L. One of 27 (3.7%) noninvasive but parafibromin-negative tumors subsequently metastasized. Parafibromin-negative patients were younger (mean, 36 vs. 63 y; P

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ALK Expression in Angiomatoid Fibrous Histiocytoma: A Potential Diagnostic Pitfall

We recently encountered a case of primary pulmonary angiomatoid fibrous histiocytoma (AFH), which was initially misdiagnosed as inflammatory myofibroblastic tumor (IMT) based in part on anaplastic lymphoma kinase (ALK) expression by immunohistochemistry (IHC). Prompted by this experience, we evaluated ALK expression in 11 AFH, 15 IMT, and 11 follicular dendritic cell sarcomas using 3 different antibody clones: D5F3, 5A4, and ALK1. ALK IHC positive cases were analyzed with fluorescence in situ hybridization (FISH) using dual color ALK break-apart probe kit. The majority of AFH cases studied were positive for ALK IHC with at least 1 antibody (9/11 D5F3, 6/9 5A4, 1/9 ALK1), most demonstrating moderate to strong cytoplasmic staining. AFH with positive ALK IHC showed no ALK gene rearrangement by FISH (0/8) with ALK copy number ranging from 1.6 to 2.1. Sixty-seven percent of IMT were ALK positive by IHC (10/15 D5F3, 8/15 5A4, 7/15 ALK1), and 9 of the 10 cases were positive for ALK gene rearrangement by FISH. All follicular dendritic cell sarcomas were negative for ALK by IHC (D5F3 and 5A4). Our results indicate that ALK expression in AFH is common, particularly with the highly sensitive D5F3 and 5A4 antibodies and enhanced detection systems, and may be a potential source of diagnostic confusion with IMT. The underlying mechanism of ALK expression in AFH is unclear, although it does not appear to be from ALK rearrangement or amplification.

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Role of Immunohistochemistry in the Identification of Supratentorial C11ORF95-RELA Fused Ependymoma in Routine Neuropathology

Ependymomas (EPs) are tumors of the brain and spinal cord constituting ∼10% of the childhood central nervous system neoplasms and about 30% in children aged

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Cyclin D1-positive Mediastinal Large B-Cell Lymphoma With Copy Number Gains of CCND1 Gene: A Study of 3 Cases With Nonmediastinal Disease

Primary mediastinal large B-cell lymphoma (PMBL) is a mature large B-cell lymphoma of putative thymic B-cell origin involving the mediastinum with younger age distribution and better prognosis than diffuse large B-cell lymphoma (DLBCL), not otherwise specified. Recently, based on gene expression profile analysis and morphologic findings, cases of PMBL without mediastinal involvement have been reported. In this study, we analyzed 3 cases of nodal DLBCL with morphologic features of PMBL presenting in submandibular or supraclavicular lymph nodes, in middle-aged to elderly patients, 2 of them without clinical or radiologic evidence of mediastinal involvement. The 3 patients presented with stage I/II disease and had excellent response to R-CHOP/R-EPOCH therapy. The 3 cases showed MAL expression and were positive for CD23 and/or CD30. All 3 cases expressed cyclin D1 with copy number gains of CCND1 gene but without rearrangement. There was no rearrangement of CIITA or PDL1/PDL2. Reverse transcriptase-multiplex ligation-dependent probe amplification, a mRNA-based gene expression profile analysis revealed high probability of PMBL (87.6%, 98.7%, and 99%) in these 3 cases. Targeted next-generation sequencing analysis showed SOCS1 mutations in the 3 cases, and TNFAIP3 and XPO1 mutations in one, further supporting the diagnosis of PMBL. In conclusion, we report 3 cases of nodal PMBL, 2 of them without mediastinal mass, and expression of cyclin D1 due to copy number gains of CCND1 gene, a diagnostic pitfall with mantle cell lymphoma and DLBCL, not otherwise specified.

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ALK-rearranged Tumors Are Highly Enriched in the STUMP Subcategory of Uterine Tumors

Smooth muscle tumor of uncertain malignant potential (STUMP) is a rare diagnosis rendered when there is uncertainty concerning the biological potential of a smooth muscle tumor. The initial differential diagnosis is often broad, as tumors in this subgroup are morphologically heterogenous. Recent data suggest uterine inflammatory myofibroblastic tumors (IMTs) with anaplastic lymphoma kinase (ALK) rearrangement may be misclassified as STUMPs, but the extent to which this occurs has not been examined. We identified 60 female patients with tumors previously diagnosed as STUMP (48 cases) or prospectively considered for the diagnosis of STUMP (12 cases). Each case underwent histologic review, ALK immunohistochemistry (IHC) and confirmatory break-apart fluorescence in situ hybridization (FISH) for ALK if immunoreactive. Six of the 43 (14%) uterine and cervical tumors were ALK IHC positive, whereas tumors at all other sites were ALK IHC negative. Myxoid features, although limited in some cases, were present in all 6 ALK IHC positive tumors, representing 35% (6/17) of tumors displaying myxoid features at uterine and cervical sites. All ALK immunoreactive tumors were confirmed to have ALK rearrangements by FISH with 1 tumor showing numerous (3 to 8) 3' ALK signals, an unusual FISH pattern not previously described in uterine IMTs. Two patients developed recurrent disease and were treated with ALK-targeted therapy with initial response. Our data demonstrate that a significant proportion of uterine and cervical tumors considered to be STUMPs are ALK—positive by IHC and FISH. Future screening of all uterine and cervical mesenchymal tumors under consideration for the diagnosis of STUMP, particularly those with myxoid features, is recommended to identify ALK-rearranged IMTs that could potentially be treated with targeted therapy using tyrosine kinase inhibitors.

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International Endocervical Adenocarcinoma Criteria and Classification: Validation and Interobserver Reproducibility

The current World Health Organization (WHO) classification for endocervical adenocarcinoma (EA) is based on descriptive morphologic characteristics; however, it does not fully reflect our current knowledge of the diverse pathogenesis of cervical glandular neoplasia. A novel classification system, the International Endocervical Adenocarcinoma Criteria and Classification (IECC), which incorporates etiology and biological behavior into the morphologic scheme, has been recently proposed. We aimed to validate the IECC by assessing its interobserver reproducibility in comparison to the WHO system. A cohort of 75 EAs was reviewed independently by 7 gynecologic pathologists and categorized following IECC and WHO criteria based on hematoxylin and eosin material alone and after immunohistochemistry results for p16, PR, p53, Napsin-A, vimentin, CDX2, and GATA3 were provided. Human papillomavirus (HPV) in situ hybridization and polymerase chain reaction results were compared with consensus diagnoses. IECC was superior to WHO in terms of interobserver agreement with κ=0.46 versus 0.3, respectively, on hematoxylin and eosin review and κ=0.51 versus 0.33, respectively, with immunohistochemistry. Under the IECC, 73 (97%) of EAs had majority agreement (≥4 reviewers in agreement) whereas 42 (56%) had perfect agreement (7/7 reviewers in agreement). Conversely, WHO showed majority agreement in 56 (75%) and perfect agreement in only 7 (10%) EAs. Reproducibility was poor in HPV-related WHO types (usual κ=0.36, mucinous not otherwise specified κ=0.13, intestinal κ=0.31, villoglandular κ=0.21) and good in major HPV-unrelated categories (gastric type κ=0.63, clear cell κ=0.81, mesonephric κ=0.5). Classification as per the IECC had excellent correlation with HPV status (by RNA in situ hybridization or polymerase chain reaction). We have shown that the IECC has superior interobserver agreement compared with the WHO classification system, and that distinction between HPV-related and HPV-unrelated EA can be made with good reproducibility and excellent prediction of HPV status. WHO morphologic variants of HPV-related EA are poorly reproducible. Conversely, agreement is high among important high-risk HPV-unrelated subtypes. Thus, our results further support replacing the current WHO classification with the IECC.

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South Korean scientists protest treatment of university president accused of misusing funds

South Korean scientists protest treatment of university president accused of misusing funds

South Korean scientists protest treatment of university president accused of misusing funds, Published online: 13 December 2018; doi:10.1038/d41586-018-07742-x

The science ministry alleges that KAIST leader Shin Sung-Chul made illegal payments to a California lab, but many scientists see a political purge.

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Subgingival Microbial Changes During the First 3 Months of Fixed Appliance Treatment in Female Adult Patients

Abstract

Although periodontal diseases during fixed appliance treatment are a common issue, few studies have focused on the clinical and microbial factors associated with orthodontic appliances. Hence, we investigated changes in the subgingival microbial community and their association with periodontal changes at the early stage of fixed appliance treatment. Subgingival plaques from ten female patients with fixed appliances were obtained at three time points: before, 1 month and 3 months after the placement of the brackets (T0, T1 and T2). The 16S rRNA gene sequencing was used to analyze the microbial community of the subgingival plaque. The Plaque Index (PI) and Gingival Bleeding Index (GBI) were also recorded. The GBI significantly increased at T2, and the PI showed a temporary increase without a significant difference. The alpha diversity indices were stable. However, the beta diversity was significantly higher at T2 compared to T0 and T1. The relative abundance of core microbiomes at the genus level was relatively stable. Four periodontal pathogens at the species level, including Prevotella intermedia (Pi), Campylobacer rectus (Cr), Fusobacterium nucleatum (Fn), and Treponema denticola (Td), increased without significant differences. The subgingival microbial community affected by fixed appliance treatment might cause transient mild gingival inflammation.

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Continuum multiscale model of root water and nutrient uptake from soil with explicit consideration of the 3D root architecture and the rhizosphere gradients

Abstract

Background and aims

Although modelling of water and nutrient uptake by root systems has advanced considerably in recent years, steep local gradients of nutrient concentration near the root-soil interface in the rhizosphere are still a central challenge for accurate simulation of water and nutrient uptake at the root system scale. Conventionally, mesh refinement is used to resolve these gradients. However, it results in excessive computational costs. The object of the study is to present a multiscale approach which resolves the steep gradient of nutrient concentrations at rhizosphere scale and simulates nutrient and water fluxes within the entire root zone at macroscale scale in a computationally efficient way.

Methods

We developed a 3D water and nutrient transport model of the root-soil system with explicit consideration of the 3D root architecture. To capture the nutrient gradients at root surfaces, 1D axisymmetric soil models at rhizosphere scale were constructed and coupled to the coarse 3D root-system-scale simulations using a mass conservative approach. The multiscale model was investigated under different scenarios for water and potassium (K⁺) uptake of a single root, multiple roots, and whole 3D architecture of a Zea mays L. root system in conditions of dynamic soil water and different soil buffer capacity of K⁺.

Results

The steep gradients of K⁺ concentrations were efficiently resolved in the multiscale simulations thanks to the 1D model at the rhizosphere scale. In comparison with the refinement method, the multiscale model achieved a significant accuracy of K⁺ uptake prediction with a relative error below 5%. Meanwhile, the simulation at macroscale with coarse mesh could overestimate the K⁺ uptake in one order of magnitude. Moreover, the computational cost of multiscale simulations was decreased considerably by using coarse soil mesh.

Conclusions

The newly developed model can describe the effect of the drying and nutrient transport in the root zone on nutrient uptake. It also allows to simulate processes in larger and complex root systems because of the considerable reduction in computational cost.

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South Korean scientists protest treatment of university president accused of misusing funds

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Modulator of the PI3K/Akt oncogenic pathway affects mTOR complex 2 in human adenocarcinoma cells

Summary

Chaetoglobosin K (ChK) is a natural product that has been shown to promote F-actin capping, inhibit growth, arrest cell cycle G2 phase, and induce apoptosis. ChK also has been shown to downregulate two important kinases involved in oncogenic pathways, Akt and JNK. This report investigates how ChK is involved in the receptor tyrosine kinase pathway (RTK/PI3K/mTORC2/Akt) to the centrally located protein kinase, Akt. Studies have reported that ChK does not inhibit PI3K comparable to wortmannin and does not affect PDK1 activation. PDK1 is responsible for phosphorylation on Akt T308, while mTORC2 phosphorylates Akt S473. Yet, Akt's two activation sites, T308 and S473, are known to be affected by ChK treatment. It was our hypothesis that ChK acts on the mTORC2 complex to inhibit the phosphorylation seen at Akt S473. This inhibition at mTORC2 should decrease phosphorylation at both these proteins, Akt and mTORC2 complex, compared to a known mTOR specific inhibitor, Torin1. Human lung adenocarcinoma H1299 and H2009 cells were treated with IGF-1 or calyculin A to increase phosphorylation at complex mTORC2 and Akt. Pretreatment with ChK was able to significantly decrease phosphorylation at Akt S473 similarly to Torin1 with either IGF-1 or calyculin A treatment. Moreover, the autophosphorylation site on complex mTORC2, S2481, was also significantly reduced with ChK pretreatment, similar to Torin1. This is the first report to illustrate that ChK has a significant effect at mTORC2 S2481 and Akt S473 comparable to Torin1, indicating that it may be a mTOR inhibitor.

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Higher Serum Uric Acid is a Risk Factor of Reduced Muscle Mass in Men with Type 2 Diabetes Mellitus

Exp Clin Endocrinol Diabetes
DOI: 10.1055/a-0805-2197

Objective Sarcopenia has been recognized as a diabetic complication, and hyperuricemia is often accompanied by type 2 diabetes mellitus (T2DM). However, it is unknown whether serum uric acid (UA) levels are associated with reduced muscle mass in T2DM. Methods We conducted a cross-sectional study to investigate the association of serum UA with muscle mass in 401 subjects with T2DM (209 men and 192 postmenopausal women). The relative skeletal muscle mass index (RSMI) was evaluated using whole-body dual-energy x-ray absorptiometry. Results Multiple regression analyses adjusted for body weight, age, serum creatinine, hemoglobin A1c (HbA1c), and duration of T2DM showed that serum UA was negatively associated with RSMI in all subjects and men with T2DM (β=−0.13, p=0.001 and β=−0.17, p=0.003, respectively). Moreover, logistic regression analyses adjusted for these confounding factors showed that a higher serum UA level was significantly associated with low RSMI in men with T2DM [odds ratio (OR)=1.94, 95% confidence interval (CI)=1.10–3.45 per SD increase, p=0.023]. In addition, higher serum UA levels were significantly associated with low RSMI after additional adjustment for age, duration of T2DM, HbA1c level, serum creatinine level, and sex in all subjects with T2DM [OR=1.80, 95% CI=1.20–2.72 per SD increase, p=0.005]. Conclusions The present study showed for the first time that higher serum UA is an independent risk factor of reduced muscle mass in men with T2DM.
[...]

© Georg Thieme Verlag KG Stuttgart · New York

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

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[ASAP] Extraordinary Redox Activities in Ladder-Type Conjugated Molecules Enabled by B ? N Coordination-Promoted Delocalization and Hyperconjugation

Journal of the American Chemical Society

DOI: 10.1021/jacs.8b11337

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[ASAP] Na3MnZr(PO4)3: A High-Voltage Cathode for Sodium Batteries

Journal of the American Chemical Society

DOI: 10.1021/jacs.8b11388

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How Indian biotech is driving innovation

How Indian biotech is driving innovation

How Indian biotech is driving innovation, Published online: 12 December 2018; doi:10.1038/d41586-018-07671-9

Bolstered by government support, a wealth of investment and an eager graduate workforce, the country's biotechnology industry is booming.

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Reptile urine used as paint in ancient Peru

Reptile urine used as paint in ancient Peru

Reptile urine used as paint in ancient Peru, Published online: 12 December 2018; doi:10.1038/d41586-018-07712-3

Snake waste the probable source of white colour on pottery from first millennium BC.

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Gene therapy

Gene therapy

Gene therapy, Published online: 12 December 2018; doi:10.1038/d41586-018-07639-9

Gene tinkering opens the door to treatments for an array of diseases

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The Wright brothers’ real story, cosmic chronology, and what happened to the megafauna: Books in brief

The Wright brothers' real story, cosmic chronology, and what happened to the megafauna: Books in brief

The Wright brothers' real story, cosmic chronology, and what happened to the megafauna: Books in brief, Published online: 12 December 2018; doi:10.1038/d41586-018-07677-3

Barbara Kiser reviews five of the week's best science picks.

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Pest categorisation of Septoria malagutii

Abstract

The Panel on Plant Health performed a pest categorisation of Septoria malagutii, the causal agent of annular leaf spot of potato, for the EU. The pest is a well‐defined fungal species and reliable methods exist for its detection and identification. S. malagutii is present in Bolivia, Ecuador, Peru and Venezuela. The pest is not known to occur in the EU and is listed as Septoria lycopersici var. malagutii in Annex IAI of Directive 2000/29/EC, meaning its introduction into the EU is prohibited. The major cultivated host is Solanum tuberosum (potato), but other Solanum species including wild solanaceous plants are also affected. All hosts and pathways of entry of the pest into the EU are currently regulated. Host availability and climate matching suggest that S. malagutii could establish in parts of the EU and further spread mainly by human‐assisted means. The pest affects leaves, stems and petioles of potato plants (but not the underground parts, including tubers) causing lesions, leaf necrosis and premature defoliation. In some infested areas, the disease has been reported to cause almost complete crop loss with favourable weather conditions and susceptible potato cultivars. The introduction of the pest into the EU would potentially cause impacts to potato production. The main uncertainties concern the host range, the maximum period the pest survives on host debris in soil, the maximum distance over which conidia of the pest could be dispersed by wind‐driven rain and the magnitude of potential impacts to the EU. S. malagutii meets all the criteria assessed by EFSA for consideration as potential Union quarantine pest. The criteria for considering S. malagutii as a potential Union regulated non‐quarantine pest are not met, since the pest is not known to occur in the EU.

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The European Union summary report on trends and sources of zoonoses, zoonotic agents and food‐borne outbreaks in 2017

Abstract

This report of the European Food Safety Authority and the European Centre for Disease Prevention and Control presents the results of zoonoses monitoring activities carried out in 2017 in 37 European countries (28 Member States (MS) and nine non‐MS). Campylobacteriosis was the commonest reported zoonosis and its EU trend for confirmed human cases increasing since 2008 stabilised during 2013–2017. The decreasing EU trend for confirmed human salmonellosis cases since 2008 ended during 2013–2017, and the proportion of human Salmonella Enteritidis cases increased, mostly due to one MS starting to report serotype data. Sixteen MS met all Salmonella reduction targets for poultry, whereas 12 MS failed meeting at least one. The EU flock prevalence of target Salmonella serovars in breeding hens, laying hens, broilers and fattening turkeys decreased or remained stable compared to 2016, and slightly increased in breeding turkeys. Salmonella results on pig carcases and target Salmonella serovar results for poultry from competent authorities tended to be generally higher compared to those from food business operators. The notification rate of human listeriosis further increased in 2017, despite Listeria seldom exceeding the EU food safety limit in ready‐to‐eat food. The decreasing EU trend for confirmed yersiniosis cases since 2008 stabilised during 2013–2017. The number of confirmed shiga toxin‐producing Escherichia coli (STEC) infections in humans was stable. A total of 5,079 food‐borne (including waterborne) outbreaks were reported. Salmonella was the commonest detected agent with S. Enteritidis causing one out of seven outbreaks, followed by other bacteria, bacterial toxins and viruses. The agent was unknown in 37.6% of all outbreaks. Salmonella in eggs and Salmonella in meat and meat products were the highest risk agent/food pairs. The report further summarises trends and sources for bovine tuberculosis, Brucella, Trichinella, Echinococcus, Toxoplasma, rabies, Coxiella burnetii (Q fever), West Nile virus and tularaemia.

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Evaluation of the safety and efficacy of the organic acids lactic and acetic acids to reduce microbiological surface contamination on pork carcasses and pork cuts

Abstract

Studies evaluating the safety and efficacy of lactic and acetic acids to reduce microbiological surface contamination on pork carcasses pre‐chill and pork meat cuts post‐chill were assessed. Lactic acid treatments consisted of 2–5% solutions at temperatures of up to 80°C applied to carcasses by spraying or up to 55°C applied on cuts by spraying or dipping. Acetic acid treatments consisted of 2–4% solutions at temperatures of up to 40°C applied on carcasses by spraying or on cuts by spraying or dipping. The maximum treatment duration was 30 s. The Panel concluded that: [1] the treatments are of no safety concern, provided that the substances comply with the European Union specifications for food additives; [2] spraying of pork carcasses pre‐chill with lactic acid was efficacious compared to untreated control, but based on the available data, the Panel could not conclude whether lactic acid was more efficacious than water treatment when spraying of pork carcasses pre‐chill or pork meat cuts post‐chill. The Panel concluded that dipping of pork meat cuts post‐chill in lactic acid was more efficacious than water treatment. However, it could not conclude on the efficacy of acetic acid treatment of pork carcasses pre‐chill and/or pork meat cuts post‐chill; [3] the potential selection and emergence of bacteria with reduced susceptibility to biocides and/or resistance to therapeutic antimicrobials linked to the use of the substances is unlikely as long as Good Hygienic Practices are implemented; and [4] the release of both organic acids is not of concern for the environment, assuming that wastewaters released by the slaughterhouses are treated, if necessary, to counter the potentially low pH caused by lactic or acetic acid, in compliance with local rules.

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Baby gene edits could affect a range of traits

Baby gene edits could affect a range of traits

Baby gene edits could affect a range of traits, Published online: 12 December 2018; doi:10.1038/d41586-018-07713-2

Gene targeted for its role in HIV is linked to increased severity of other infectious diseases — and has implications for learning in mice.

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Satellite spies methane bubbling up from Arctic permafrost

Satellite spies methane bubbling up from Arctic permafrost

Satellite spies methane bubbling up from Arctic permafrost, Published online: 12 December 2018; doi:10.1038/d41586-018-07751-w

Radar instrument aboard a Japanese probe can spot signs of gas seeping from lakes that form as the ground thaws.

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Gene therapy targets sickle-cell disease

Gene therapy targets sickle-cell disease

Gene therapy targets sickle-cell disease, Published online: 12 December 2018; doi:10.1038/d41586-018-07646-w

The research is promising, but a true cure for this painful condition could be years away.

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