Publication date: Available online 10 January 2018
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Vladimir Makaloski, Konstantinos Spanos, Jürg Schmidli, Tilo Kölbel
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Τετάρτη 10 Ιανουαρίου 2018
Surveillance After Endovascular Treatment for Blunt Thoracic Aortic Injury
Efficacy of adjuvant radiotherapy in the intracranial hemangiopericytoma
Abstract
We retrospectively evaluated an efficacy of adjuvant radiotherapy (RT) in the intracranial hemangiopericytoma (HPC) and analyzed prognostic factors influencing treatment outcomes. Among 49 patients diagnosed as localized intracranial HPC between 1995 and 2016, 31 patients received adjuvant RT after surgery; 26 with fractionated RT and 5 with stereotactic radiosurgery using Gamma Knife. After gross total resection (GTR) (n = 32) and subtotal resection (STR) (n = 17), histopathological grade was confirmed to be grade II (n = 9) or grade III (n = 40). The median follow-up period was 50 months (range 3–216 months). The local recurrence was defined as intracranial relapse within 15 mm and regional recurrence as beyond 15 mm from the margin of surgical bed. The 10-year overall survival (OS) and progression-free survival (PFS) were 69.9 and 34.4%, respectively. The 10-year local, regional, and distant failure-free rates were 56.6, 88.2, and 73.3%, respectively. Local tumor control was better with GTR followed by RT than GTR alone (p = 0.056), while there was no difference in OS. Local tumor control and OS after STR plus RT were equivalent to those after GTR alone. There were no differences in distant metastasis-free survival (DMFS) among GTR plus RT, GTR alone, and STR plus RT. Tumor volume > 40 cm3 was associated with poor PFS (p = 0.024). The local tumor recurrence was reduced by adjuvant RT after surgery. But OS or DMFS was not improved with adjuvant RT. PFS was better in the tumor with small volume at diagnosis.
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Effect of CPAP therapy on liver disease in patients with OSA: a review
Abstract
Obstructive sleep apnea (OSA) may play an important role in the progression of nonalcoholic fatty liver disease (NAFLD).The effect of continuous positive airway pressure (CPAP) treatment, the first-line therapy for OSA, on liver disease in OSA patients is still debated. We provide this review of previous studies to summarize the effects of CPAP treatment on liver disease in OSA patients in aspects of liver function, liver steatosis, fibrosis, and incidence of liver disease. CPAP treatment may be beneficial to liver disease in subjects with OSA independent of metabolic risk factors, but a sufficiently long therapeutic duration (perhaps greater than 3 months) may be needed to achieve these positive effects. Though the mechanism of impact of CPAP treatment on liver in OSA patients is unclear, the influence of CPAP treatment on the factors of the "Two-hit" hypothesis (insulin resistance, fatty acids dysregulation, oxidative stress, and inflammation) may be a reasonable explanation.
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Effect of CPAP therapy on liver disease in patients with OSA: a review
Abstract
Obstructive sleep apnea (OSA) may play an important role in the progression of nonalcoholic fatty liver disease (NAFLD).The effect of continuous positive airway pressure (CPAP) treatment, the first-line therapy for OSA, on liver disease in OSA patients is still debated. We provide this review of previous studies to summarize the effects of CPAP treatment on liver disease in OSA patients in aspects of liver function, liver steatosis, fibrosis, and incidence of liver disease. CPAP treatment may be beneficial to liver disease in subjects with OSA independent of metabolic risk factors, but a sufficiently long therapeutic duration (perhaps greater than 3 months) may be needed to achieve these positive effects. Though the mechanism of impact of CPAP treatment on liver in OSA patients is unclear, the influence of CPAP treatment on the factors of the "Two-hit" hypothesis (insulin resistance, fatty acids dysregulation, oxidative stress, and inflammation) may be a reasonable explanation.
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The journey from genetic predisposition to medication overuse headache to its acquisition as sequela of chronic migraine
Migraine remains one of the biggest clinical case to be solved among the non-communicable diseases, second to low back pain for disability caused as reported by the Global Burden of Disease Study 2016. Despite...
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Sexual Health Issues for the Young Adult with Cancer: An International Symposium Held During the First Global Adolescents and Young Adults Cancer Congress (Edinburgh, United Kingdom)
Journal of Adolescent and Young Adult Oncology , Vol. 0, No. 0.
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Head circumference - a useful single parameter for skull volume development in cranial growth analysis?
The measurement of maximal head circumference is a standard procedure in the examination of childrens' cranial growth and brain development. The objective of the study was to evaluate the validity of maximal h...
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Improvement of the salvage-rate of flap after venous thrombosis with intraparenchymatous venous pressure monitoring
Purpose
Intraparenchymatous venous pressure (IVP) monitoring in flap can measure venous pressure with catheter placement. Among patients with IVP monitoring, this study reviewed postoperative microvascular complications for investigating the transplanted-tissue salvage-rate.
Patients and Methods
Two hundred and seventy-one patients (male, 132; female, 139; mean age, 52.3 years; age range, 9–82 years) underwent free flap transfer and postoperative continuous IVP monitoring, which performed as follows; a venous catheter was connected to a transducer, and venous pressure in the flap was recorded for three consecutive days postoperatively. The threshold of alarm for elevated venous pressure was set at 50 mm Hg. When abnormal measurements or fluctuation were observed, the vascular anastomotic site was exposed immediately. The flap salvage-rate of non-IVP monitoring group (n = 393; male, 305; female, 81; mean age, 61.3 years; age range, 23–83 years), which were confirmed by a portable ultrasonographic device, was compared with that of IVP-monitoring group.
Results
Twenty-one patients developed postoperative microvascular complications at the vascular anastomosis sites. Sensitivity rate of IVP monitoring was 86%; specificity rate, 96%; positive predictive value rates, 64%; negative predictive value rate, 99%; false positive rate, 4%. The flap salvage-rate was 83% in venous thrombosis cases and only 33% in arterial thrombosis cases. In non-IVP monitoring group, flap salvage-rate was 20% with arterial thrombosis and 36% with venous thrombosis, resulting in an increasing the salvage-rate (P = .021).
Conclusions
IVP monitoring could visualize and quantify venous pressure waves in flap and detect early microvascular complications, resulting in a marked improvement in the graft-tissue salvage-rate.
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Disparities in cancer outcomes across age, sex, and race/ethnicity among patients with pancreatic cancer
Abstract
Age, sex, and racial/ethnic disparities exist, but are understudied in pancreatic adenocarcinoma (PDAC). We used the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database to determine whether survival and treatment disparities persist after adjusting for demographic and clinical characteristics. Our study included PDAC patients diagnosed between 1992 and 2011. We used Cox regression to compare survival across age, sex, and race/ethnicity within early-stage and late-stage cancer subgroups, adjusting for marital status, urban location, socioeconomics, SEER region, comorbidities, stage, lymph node status, tumor location, tumor grade, diagnosis year, and treatment received. We used logistic regression to compare differences in treatment received across age, sex, and race/ethnicity. Among 20,896 patients, 84% were White, 9% Black, 5% Asian, and 2% Hispanic. Median age was 75; 56% were female and 53% had late-stage cancer. Among early-stage patients in the adjusted Cox model, older patient subgroups had worse survival compared with ages 66–69 (HR > 1.1, P < 0.01 for groups >69); no survival differences existed between sexes. Black (HR = 1.1, P = 0.01) and Hispanic (HR = 1.2, P < 0.01) patients had worse survival compared with White. Among late-stage cancer patients, patients over age 84 had worse survival than those aged 66–69 (HR = 1.1, P < 0.01), and males (HR = 1.08, P < 0.01) had worse survival than females; there were no racial/ethnic differences. Older age and minority race/ethnicity were associated with lower likelihood of receiving chemotherapy, radiation, and/or surgery. Age and racial/ethnic disparities in survival outcomes and treatment received exist for PDAC patients; these disparities persist after adjusting for differences in demographic and clinical characteristics.
Disparities in pancreatic cancer outcomes exists, but are not fully understood. Our research uses SEER–Medicare data to determine which factors contribute to the differences in treatment receipt and survival outcomes among age, sex, and racial/ethnic subgroups. Our conclusion that disparities continue to persist after adjusting for various covariates highlights the need for additional research in this area.
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Response to ‘Serological diagnostics in the detection of IgG autoantibodies against human collagen VII in epidermolysis bullosa acquisita: a multicentre analysis': reply from authors
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Ticagrelor inhibits platelet–tumor cell interactions and metastasis in human and murine breast cancer
Abstract
Activated platelets promote the proliferation and metastatic potential of cancer cells. Platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets. We examined the potential of the reversible P2Y12 inhibitor ticagrelor, an agent used clinically to prevent cardiovascular and cerebrovascular events, to reduce tumor growth and metastasis. In vitro, MCF-7, MDA-MB-468, and MDA-MB-231 human mammary carcinoma cells exhibited decreased interaction with platelets treated with ticagrelor compared to untreated platelets. Prevention of tumor cell–platelet interactions through pretreatment of platelets with ticagrelor did not improve natural killer cell-mediated tumor cell killing of K562 myelogenous leukemia target cells. Additionally, ticagrelor had no effect on proliferation of 4T1 mouse mammary carcinoma cells co-cultured with platelets, or on primary 4T1 tumor growth. In an orthotopic 4T1 breast cancer model, ticagrelor (10 mg/kg), but not clopidogrel (10 mg/kg) or saline, resulted in reduced metastasis and improved survival. Ticagrelor treatment was associated with a marked reduction in tumor cell–platelet aggregates in the lungs at 10, 30 and 60 min post-intravenous inoculation. These findings suggest a role for P2Y12-mediated platelet activation in promoting metastasis, and provide support for the use of ticagrelor in the prevention of breast cancer spread.
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Prevalence of pollen-induced allergic rhinitis with high pollen exposure in grasslands of northern China
Abstract
Background
The aim of this study was to investigate the prevalence of epidemiologic and physician-diagnosed pollen-induced AR (PiAR) in the grasslands of northern China, and to study the impact of the intensity and time of pollen exposure on PiAR prevalence.
Methods
A multistage, clustered and proportionately stratified random sampling with a field-interviewer administrated survey study was performed together with skin prick tests (SPT) and measurements of the daily pollen count.
Results
A total of 6043 subjects completed the study; with a proportion of 32.4% epidemiologic AR and 18.5% PiAR. The prevalence was higher in males than females (19.6% vs 17.4%, P=0.024) but no difference between the two major residential and ethnic groups (Han and Mongolian) was observed. Subjects from urban areas showed higher prevalence of PiAR than rural areas (23.1% vs 14.0%, P<0.001). Most PiAR patients were sensitized to two or more pollens (79.4%) with artemisia, chenopodium, and humulus scandens being the most common pollen types; which were similarly found as the top three sensitizing pollen allergens by SPT. There were significant regional differences in the prevalence of epidemiologic AR (from 18.6% to 52.9%) and PiAR (from 10.5% to 31.4%) among the six areas investigated. PiAR symptoms were positively associated with pollen counts, temperature and precipitation (P<0.05), but negatively with wind speed and pressure P<0.05).
Conclusion
PiAR prevalence in the investigated region is extremely high due to high seasonal pollen exposure, which was influenced by local environmental and climate conditions.
This article is protected by copyright. All rights reserved.
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Lolium perenne peptide immunotherapy is well tolerated and elicits a protective B-cell response in seasonal allergic rhinitis patients
Abstract
Background
Systemic allergic reactions are a risk for allergen immunotherapy that utilizes intact allergen preparations. We evaluated the safety, efficacy and immune mechanisms of short-course treatment with adjuvant-free Lolium perenne peptides (LPP) following a 6-week dose-escalation protocol.
Methods
In a prospective, dose-escalation study, 61 grass pollen–allergic patients received 2 subcutaneous injections of LPP once weekly for 6 weeks. Safety was assessed evaluating local reactions, systemic reactions and adverse events. The clinical effect of LPP was determined by reactivity to the conjunctival provocation test (CPT). Specific IgE, IgG4, and blocking antibodies were measured at baseline (V1), during (V6) and after treatment (V8).
Results
No fatality, serious adverse event or epinephrine use was reported. Mean wheal diameters after injections were <0.6 cm and mean redness diameters <2.5 cm, independent of dose. Transient and mostly mild adverse events were reported in 33 patients. Two patients experienced a grade I and 4 patients a grade II reaction (AWMF classification). At V8, 69.8% of patients became non-reactive to CPT. sIgG4 levels were higher at V6 (8.1-fold, P<0.001) and V8 (12.2-fold, P<0.001) than at V1. The sIgE:sIgG4 ratio decreased at V6 (–54.6%, P<0.001) and V8 (–71.6%, P<0.001) compared to V1. The absolute decrease in IgE-facilitated allergen binding was 18% (P<0.001) at V6 and 25% (P<0.001) at V8.
Conclusion
Increasing doses of subcutaneous LPP appeared safe, substantially diminished reactivity to CPT and induced blocking antibodies as early as 4 weeks after treatment initiation. The benefit/risk balance of LPP immunotherapy remains to be further evaluated in large studies.
This article is protected by copyright. All rights reserved.
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Cardiovascular safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients: a prospective evaluation
Future Oncology, Ahead of Print.
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Comparison of three prognostic models for predicting cancer-specific survival among patients with gastrointestinal stromal tumors
Future Oncology, Ahead of Print.
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Thymidylate synthase: a predictive biomarker in resected colorectal liver metastases receiving 5-FU treatment
Future Oncology, Ahead of Print.
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What treatments should be skipped or intensified in localized rectal cancer?
Future Oncology, Ahead of Print.
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Kompetenzbasierte Ausbildung im „geschützten Umfeld“: vom Schonraum zum Realraum
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 12-19
DOI: 10.1055/s-0043-105257
„Lernen im geschützten Umfeld" ist ein häufig gebrauchter, aber unklarer Begriff im Rahmen der anästhesiologischen postgradualen Weiterbildung. Dieser Artikel beleuchtet seine Bedeutung in der Anästhesiologie – einschließlich Lehr- und Lernstrategien, wie kompetenzorientierte und simulationsbasierte Ausbildung. Ein Versuch der Klassifikation von Simulatoren und Unterrichtsmethoden sowie deren Probleme bei der Umsetzung runden den Beitrag ab.
[...]
Georg Thieme Verlag KG Stuttgart · New York
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Behandlung im Voraus planen – Bedeutung für die Intensiv- und Notfallmedizin
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 62-70
DOI: 10.1055/s-0042-118690
Behandlung im Voraus planen (BVP) – im Englischen Advance Care Planning (ACP) – etabliert sich auch in Deutschland als ein neues Konzept zur Realisierung wirksamer Patientenverfügungen. Das Konzept beinhaltet Prozesse zur Ermittlung, Dokumentation und Umsetzung von Behandlungswünschen für den Fall, dass die Betroffenen nicht (mehr) selbst entscheiden können.
[...]
Georg Thieme Verlag KG Stuttgart · New York
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Begünstigt Kaudalanästhesie postoperative Komplikationen nach Hypospadie-OP?
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 6-7
DOI: 10.1055/s-0043-123122
Georg Thieme Verlag KG Stuttgart · New York
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„Lernen im geschützten Umfeld“: Implementierung in die Fort- und Weiterbildung
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 35-46
DOI: 10.1055/s-0043-105259
Aktuelle Aus- und Fortbildungskonzepte in der Akut- oder Notfallmedizin beinhalten Simulations- und Skill-Trainings unter Berücksichtigung von Methoden und Mechanismen der Fehler- und Zwischenfallprävention wie Human Factors, Shared mental Models und Closed-Loop-Communication. Immer noch ungeklärt ist die Frage nach der optimalen Kombination der einzelnen Methoden und Inhalte eines Fortbildungsprogramms in Abhängigkeit von individuellen Abteilungen eines Krankenhauses und dem einzelnen Mitarbeiter bzw. seinem individuellen Ausbildungsstand. Ein von uns angebotenes Konzept ist das „Lernen im geschützten Umfeld": Hier werden Teilnehmer und Patient vor den negativen Auswirkungen einer konventionellen klinisch-praktischen Ausbildungssituation beschützt. Gleichzeitig profitieren die Teilnehmer in unserem Fortbildungsprogramm von standardisierten Kursmodellen. Das Ziel der optimalen Vorbereitung auf die klinische Tätigkeit und einer möglichst praktischen bzw. wirklichkeitsnahen Aus- und Fortbildung wird durch eine ständige Re-Evaluation der Inhalte und Methoden komplettiert. Die Implementierung eines solchen multimodalen Teamtrainings ist für jede Institution individuell anzupassen. Die Methoden zur Implementierung sollten standardisiert angewendet werden. Wir empfehlen eine Curriculumsentwicklung auf Grundlage des „Kern-Zyklus". Auf dieser Basis gelingt die Kombination aus „Lernen im geschützten Umfeld" und Zwischenfalltraining zur optimalen Vorbereitung auf eine akutmedizinische, klinische Tätigkeit mit dem Ziel einer höchstmöglichen Patientensicherheit.
[...]
Georg Thieme Verlag KG Stuttgart · New York
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Hyperchlorämie ist mit akutem Nierenversagen nach SAB verbunden
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 7-8
DOI: 10.1055/s-0043-123121
Georg Thieme Verlag KG Stuttgart · New York
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Lernen im geschützten Umfeld
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 10-11
DOI: 10.1055/s-0043-122170
Georg Thieme Verlag KG Stuttgart · New York
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Etomidat-Analogon mit verringerter Nebennierensuppression
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 8-8
DOI: 10.1055/s-0043-117029
Georg Thieme Verlag KG Stuttgart · New York
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Simulation als Fortbildungsmethode zur Professionalisierung von Teams
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 20-33
DOI: 10.1055/s-0043-105261
Simulation ist eine Methode, virtuelle Lernumgebungen zu erzeugen. Mittels Simulation können Technical Skills, aber auch Soft Skills wie die Funktionsfähigkeit von Teams sehr gut vermittelt werden. Dieser Team-Aspekt wird nachfolgend vor dem Hintergrund spezifischer Trainingsmethoden näher beleuchtet. Der Artikel bezieht sich dabei auf „Zwischenfalltrainings", die in den Zentren der Autoren einen großen Anteil des Kursangebotes einnehmen.
[...]
Georg Thieme Verlag KG Stuttgart · New York
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The Same Procedure As Last Year?
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 9-9
DOI: 10.1055/s-0043-123165
Georg Thieme Verlag KG Stuttgart · New York
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„Das Kind hat einen Fremdkörper verschluckt“ – was tun?
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 48-60
DOI: 10.1055/s-0042-120991
Sowohl Ingestions- als auch Aspirationsunfälle sind häufige Ereignisse bei Kindern. Sie können unmittelbar lebensbedrohlich sein oder bei fehlender direkter Bedrohung dennoch erhebliche langfristige Beeinträchtigungen für die Kinder verursachen. Der Beitrag zeigt die diagnostischen und therapeutischen Möglichkeiten und Notwendigkeiten auf, durch die eine bestmögliche Sicherheit und möglichst geringe Folgeschäden zu gewährleisten sind.
[...]
Georg Thieme Verlag KG Stuttgart · New York
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Neurologischer Schaden nach Wirbelsäulen-OP
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 71-75
DOI: 10.1055/s-0043-122628
Schlichtungsstellen für Arzthaftpflichtfragen bieten Patienten, Ärzten und Versicherern eine Möglichkeit, Arzthaftungsstreitigkeiten außergerichtlich zu klären. In der Rubrik „Fälle der Schlichtungsstelle" stellen wir abgeschlossene Fälle aus der Schlichtungsstelle für Arzthaftpflichtfragen der norddeutschen Ärztekammern vor.
[...]
Georg Thieme Verlag KG Stuttgart · New York
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Entwicklung neuer Antibiotika: Endpunkte klinischer Studien teils ungeeignet
Anästhesiol Intensivmed Notfallmed Schmerzther 2018; 53: 5-6
DOI: 10.1055/s-0043-117062
Georg Thieme Verlag KG Stuttgart · New York
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Atemübungen schützen ältere Patienten vor gefährlichen Lungenentzündungen
Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 753-753
DOI: 10.1055/s-0043-121213
Georg Thieme Verlag KG Stuttgart · New York
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Interventionen zur präoperativen Unterstützung geriatrischer Patienten mit Frailty
Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 777-783
DOI: 10.1055/s-0043-104684
Der stetig zu beobachtende demografische Wandel geht mit veränderten Anforderungen an die Patientenbetreuung einher. Ältere Patienten weisen häufig einen erhöhten Behandlungsbedarf und eine höhere Komplexität des klinischen Gesamtbildes auf. Dieser Umstand ist – abgesehen von der Routineversorgung – besonders dann zu beachten, wenn eine angedachte Intervention zu schweren und potenziell lebensbedrohlichen Komplikationen führen kann.
[...]
Georg Thieme Verlag KG Stuttgart · New York
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Therapiebegrenzung: DIVI empfiehlt neuen Dokumentationsbogen
Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 752-753
DOI: 10.1055/s-0043-119947
Georg Thieme Verlag KG Stuttgart · New York
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Zervikale Plexusblockaden
Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 806-813
DOI: 10.1055/s-0043-115204
Eine vollständige Blockade des Plexus cervicalis ist weder erwünscht noch ausreichend für eine chirurgische Anästhesie in der vorderen Halsregion. Supplementierungen durch Opioide oder topische Lokalanästhetika sind daher häufig. Die Blockade beteiligter Hirnnerven und des Truncus sympathicus verbessert möglicherweise die Anästhesiequalität, führt aber auch zu typischen Nebenwirkungen. Dieser Beitrag liefert anatomisches Hintergrundwissen und stellt Indikationen vor – auch außerhalb der Karotischirurgie.
[...]
Georg Thieme Verlag KG Stuttgart · New York
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Warum und wie sollte ich Frailty erfassen? – ein Ansatz für die Anästhesieambulanz
Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 765-776
DOI: 10.1055/s-0043-104682
Frailty (Gebrechlichkeit) ist eine Einschränkung der physiologischen Reserve bei älteren Patienten mit schwerwiegenden individuellen und sozioökonomischen Folgen. Multiple Aspekte der Patientenbehandlung sowie das Outcome werden durch Frailty nachhaltig beeinflusst. Obwohl mehr als 60 Messinstrumente existieren, sind die Erfassung und Berücksichtigung funktioneller Assessments in der klinischen Routine unzureichend umgesetzt. Das interdisziplinäre und interprofessionelle Verständnis, warum und wie Frailty beurteilt werden sollte, ist die Grundlage für die dauerhafte Implementierung. Der Artikel zeigt die Auswirkungen von Frailty und Vorteile einer Früherkennung auf und gibt einen Überblick über die wichtigsten Instrumente, die in der Frailty-Erkennung und -Bewertung verwendet werden können. Die frühe präoperative Detektion bietet ein vielfältiges Optimierungspotenzial für die peri- und intraoperative Versorgung. Verschiedene Frailty-Assessment-Tools körperlicher, kognitiver und psychosozialer Domänen werden vorgestellt und diskutiert. Frailty-Assessments variieren immens in Bezug auf die erforderliche Zeit, die Ausrüstung und das Fachwissen zur Durchführung. Wir empfehlen mindestens einen Test für die einzelnen Dimensionen von Frailty, um ein holistisches Bild der geriatrischen Patienten zu erhalten. Die Bewertung von Frailty sollte übergreifend in die interdisziplinären Strukturen der klinischen Routine implementiert werden, um die Patientensicherheit sowie das kurz- und langfristige Outcome zu verbessern.
[...]
Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Abstract | Full text
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Die meisten Todesbescheinigungen weisen Fehler auf
Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 752-752
DOI: 10.1055/s-0043-121621
Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Full text
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Patienten mit Frailty: Anästhesiologie in der Verantwortung
Anästhesiol Intensivmed Notfallmed Schmerzther 2017; 52: 756-757
DOI: 10.1055/s-0043-117836
Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Full text
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Laser treatment of primary axillary hyperhidrosis: a review of the literature
Abstract
Hyperhidrosis o`ccurs when the body produces sweat beyond what is essential to maintain thermal homeostasis. The condition tends to occur in areas marked by high-eccrine density such as the axillae, palms, and soles and less commonly in the craniofacial area. The current standard of care is topical aluminum chloride hexahydrate antiperspirant (10–20%), but other treatments such as anticholinergics, clonidine, propranolol, antiadrenergics, injections with attenuated botulinum toxin, microwave technology, and surgery have been therapeutically implicated as well. Yet, many of these treatments have limited efficacy, systemic side effects, and may be linked with significant surgical morbidity, creating need for the development of new and effective therapies for controlling excessive sweating. In this literature review, we examined the use of lasers, particularly the Neodynium:Yttrium-Aluminum-Garnet (Nd:YAG) and diode lasers, in treating hyperhidrosis. Due to its demonstrated effectiveness and limited side effect profile, our review suggests that Nd:YAG laser may be a promising treatment modality for hyperhidrosis. Nevertheless, additional large, randomized controlled trials are necessary to confirm the safety and efficacy of this treatment option.
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Antitumor effects of blocking protein neddylation in T315I-BCR-ABL leukemia cells and leukemia stem cells
Imatinib (IM) revolutionized the treatment of chronic myeloid leukemia (CML) but drug resistance and disease recurrence remain a challenge. In this study, we suggest a novel strategy based on blocking protein neddylation to address BCR-ABL point mutations and leukemia stem cells (LSCs) that lie at the root of IM-resistant recurrences. Based on the finding that the NEDD8-activating enzyme subunit NAE1 is overexpressed in CML cells, we hypothesized that the function of certain neddylation-dependent protein substrates might be targeted to therapeutic ends in IM-resistant CML cells and LSCs. In support of this hypothesis, we demonstrated that the NAE1 inhibitor MLN4924 induced G2/M-phase arrest and apoptosis in bulk CML cells with wild-type p53, regardless of their T315I mutation status in BCR-ABL. Moreover, MLN4924 inhibited the survival and self-renewal of primary human CML CD34+ cells and LSCs in CML-bearing mice via accumulation of p27kip1 in the nucleus. Notably, p27kip1 silencing attenuated the suppressive effect of MLN4924 on the maintenance of LSCs in CML-bearing mice. Taken together, our findings offer a preclinical proof of concept for targeting protein neddylation as a novel therapeutic strategy to override mutational and LSC-derived IM resistance in CML.
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KRAS oncoprotein expression is regulated by a self-governing eIF5A-PEAK1 feed-forward regulatory loop
There remains intense interest in tractable approaches to target or silence the KRAS oncoprotein as a rational therapeutic strategy to attack pancreatic adenocarcinoma (PDAC) and other cancers which overexpress it. Here we provide evidence that accumulation of the KRAS oncoprotein is controlled by a self-regulating feed-forward regulatory loop that utilizes a unique hypusinated isoform of the translation elongation factor eIF5A and the tyrosine kinase PEAK1. Oncogenic activation of KRAS increased eIF5A-PEAK1 translational signaling, which in turn facilitated increased KRAS protein synthesis. Mechanistic investigations shows that this feed-forward positive regulatory pathway was controlled by oncogenic KRAS-driven metabolic demands, operated independently of canonical mTOR signaling, and did not involve new KRas gene transcription. Perturbing eIF5A-PEAK1 signaling, by genetic or pharmacologic strategies or by blocking glutamine synthesis, was sufficient to inhibit expression of KRAS, eIF5A, and PEAK1, attenuate cancer cell growth and migration, and block tumor formation in established preclinical mouse models of PDAC. Levels of KRAS, eIF5A, and PEAK1 protein increased during cancer progression with the highest levels of expression observed in metastatic cell populations. Combinatorial targeting of eIF5A hypusination and the RAS-ERK signaling pathway cooperated to attenuate KRAS expression and its downstream signaling along with cell growth in vitro and tumor formation in vivo. Collectively, our findings highlight a new mechanistic strategy to attenuate KRAS expression as a therapeutic strategy to target PDAC and other human cancers driven by KRAS activation.
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Narrow band imaging versus laryngovideostroboscopy in precancerous and malignant vocal fold lesions
Abstract
Background
This is a comparative analysis of the diagnostic accuracy of narrow band imaging (NBI) and laryngovideostroboscopy (LVS) in the assessment of premalignant and malignant vocal fold lesions.
Methods
A prospective analysis was performed on 105 consecutive patients with vocal fold lesions. The NBI and LVS were obtained before the microsurgery.
Results
The NBI and LVS showed no significant differences in identifying premalignant and malignant pathologies. However, in analysis restricted to identification of only malignant lesions, the specificity (88.9% vs 20.6%), accuracy (90.5% vs 51.4%), and positive predictive value (PPV; 84.8% vs 45.1%) were significantly higher for NBI (P value < .001; .015; and .045, respectively). A comparison of LVS scored results relative to each NBI type revealed statistically significant differences (P < .001). A moderate positive correlation between NBI and LVS was demonstrated (P = .54).
Conclusion
The NBI and LVS are useful, complementary tools in evaluating early potential vocal fold malignancies. The NBI was superior to LVS on several statistical analyses.
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Re: Characteristics of a Mild Traumatic Brain Injury Sample Recruited Using Amazon’s Mechanical Turk
As Mr Bernstein and Dr Calamia note in their recent article, "Characteristics of a Mild Traumatic Brain Injury Sample Recruited Using Amazon's Mechanical Turk," Amazon's Mechanical Turk (MTurk) is an increasingly popular platform for recruiting research participants in the behavioral and health sciences [1]. We agree that MTurk provides efficient and low-cost access to high-quality data. However, researchers must also navigate important drawbacks to effectively use this platform. We use Bernstein and Calamia's study to highlight some of these drawbacks and offer strategies to address them.
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Response to Shapiro and Chandler Letter to the Editor
We thank Drs Shapiro and Chandler for their helpful comments [1] on our manuscript [2] and their larger discussion of the potential pitfalls when using MTurk to assess clinical populations. In the space below, as a response to some of the concerns noted, we provide additional details not included in our manuscript on a few aspects of our study.
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Necrotizing fasciitis. Possible profiles of professional liability with reference to two cases.
| Related Articles |
Necrotizing fasciitis. Possible profiles of professional liability with reference to two cases.
Ann Ital Chir. 2017 Dec 18;6:
Authors: Marella GL, De Dominicis E, Paliani GB, Santeusanio G, Marsella LT, Potenza S
Abstract
Necrotizing fasciitis is one of the most dangerous complication of an abscess and it is still a disease with a high mortality. In this work, we decided to consider two cases: the first one concerns a male subject, aged 66, deceased because of a fatal necrotizing fasciitis associated to a cervical descending mediastinitis, which evolved from a primary peritonsillar abscess; the second is about a 50-year-old woman with a perineal abscess, then evolved into necrotizing fasciitis associated to a fatal septis shock. After a systematic consideration of necrotizing fasciitis as pathology and an analysis of the possible related risks to a diagnostic or therapeutic delay, we analyzed the particular history of both cases to underline the possible critical issues in professional behavior of the medical staff intervened.
KEY WORDS: Abscess, Medical malpractice, Mortality, Necrotizing fasciitis, Professional liability.
PMID: 29311423 [PubMed - as supplied by publisher]
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Serum Copper Homeostasis in Hypertensive Intracerebral Hemorrhage and its Clinical Significance
Abstract
This study was to investigate the alterations of serum copper homeostasis after hypertensive intracerebral hemorrhage (ICH), which is not yet clear. We recruited 85 hypertensive ICH patients and determined their serum levels of total copper (TCu), small molecule copper (SMC), and ceruloplasmin (Cp). Sera from 32 healthy persons and 12 primary hypertension patients were collected and analyzed as well. Serum TCu levels in ICH patients were tested at three time points (on admission, day 3, and day 7) and found to be higher than that in hypertension patients (p < 0.05). The serum SMC levels in hypertension patients and ICH patients at three time points were higher than that in healthy controls (p < 0.05). Higher serum SMC levels on days 3 and 7 were associated with death in the hospital. Additionally, higher serum SMC levels on the seventh day were associated with poor outcome at discharge. High serum Cp levels on admission, as well as low serum Cp levels on the seventh day, were associated with death in the hospital (p = 0.002 and p = 0.034, respectively). Our findings indicated that declines in serum Cp and increases in serum SMC are correlated with lethal or poor outcome in hypertensive ICH patients, possibly as a result of contributions to secondary injury of brain after hemorrhage due to impairment of iron transport and enhanced oxidative stress.
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Unilaterale Halsschwellung – eine überraschende Differentialdiagnose
Laryngo-Rhino-Otol
DOI: 10.1055/s-0043-123651
Georg Thieme Verlag KG Stuttgart · New York
Article in Thieme eJournals:
Table of contents | Full text
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Cytotoxic and inflammatory effects of alendronate and zolendronate on human osteoblasts, gingival fibroblasts and osteosarcoma cells
The aim of this paper was to assess the effects of zoledronate (ZOL) andalendronate (FOS) on apoptotic behaviour and gene expression of pro- and inflammatory cytokines of three cell types (human osteoblasts, human gingival fibroblasts and human osteogenic sarcoma cell lines) during a period of 4 weeks.
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Clinical Forum: Treatment of Stuttering in Children
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Reply to “Movement-related neural processing in people with congenital mirror movements beyond the (cortical) surface”
Thank you for the invitation to respond, and for bringing to our attention the interesting research of Manara and colleagues on Kallmann syndrome (KS). We would first like to point out that our published research involving people with mirror movements has focused only on those with isolated congenital mirror movements, that is non-syndromic (referred to as 'CMM' in our papers and in this response). CMM involves mirroring of the hands/fingers in the homologous motor system(s) of intended unimanual movements, although a minority of cases also show evidence of mirroring in the upper arms or feet (Franz, 2003; Franz et al., 2015; Franz and Fu, 2017).
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Thirty-day readmissions following parathyroidectomy: Evidence from the National Readmissions Database, 2013–2014
Parathyroidectomy is one of the most common procedures performed in the United States, and are increasingly being performed safely in the outpatient setting. However, complications from surgery can be life-threatening, and thus an understanding of who may be at risk is essential. We analyzed and compared the risk factors for patients readmitted within 30 days following inpatient parathyroidectomy for primary or secondary hyperparathyroidism.
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Are prognostic indices for brain metastases of melanoma still valid in the stereotactic era?
Malignant melanoma brain metastases (MBM) are the third most common cause for brain metastases (BM). Historically Whole-brain radiotherapy (WBRT) was considered the goldstandard of treatment even though melano...
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Mild Complications or Unusual Persistence of Porcine Collagen and Hyaluronic Acid Gel Following Periocular Filler Injections
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Orbital Extranodal Marginal Zone Lymphoma Following Radiotherapy: A Report of 2 Cases
Purpose: To present 2 patients in whom orbital radiation preceded the development of periorbital extranodal marginal zone lymphoma by more than a decade and to investigate the likelihood of this representing irradiation-induced malignancy. Methods: Retrospective chart review and histopathologic study with immunohistochemistry of 2 cases. Results: The first patient was a 58-year-old woman who developed an orbital mass within the vicinity of the lateral rectus muscle 17 years after external beam proton radiation therapy for an inferotemporal choroidal melanoma. The second patient was a 32-year-old woman who developed a mass in the right lacrimal gland 12 years after external beam photon radiation therapy for chronic inflammatory dacryoadenitis. Histopathologic and immunohistochemical studies confirmed orbital extranodal marginal zone lymphoma in both cases. Retrospective review of older histopathologic slides from the second patient revealed underlying immunoglobulin G4–related disease. Discussion: The unusual sequence of events in these 2 cases raises the question of whether orbital radiation may in rare instances promote the development of orbital extranodal marginal zone lymphoma. The literature pertaining to irradiation-induced secondary malignancy in the orbit is reviewed. Conclusions: Clinicians should consider the possibility of a secondary malignancy when evaluating a patient with an orbital mass and a history of prior local radiation exposure. Accepted for publication November 5, 2017. Natalie Wolkow is supported by a Heed Ophthalmic Fellowship. The remaining authors have no conflicts of interest to disclose. Address correspondence and reprint requests to Frederick A. Jakobiec, M.D., D.Sc., Department of Ophthalmology, David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Suite 328, Boston, Massachusetts 02114. E-mail: Fred_Jakobiec@meei.harvard.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.
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Significance of Early Postoperative Eyelid Position on Late Postoperative Result in Mueller’s Muscle Conjunctival Resection and External Levator Advancement Surgery
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Anomalous Sphenoid Diploe Vein: Case Report Highlighting the Value of Careful CT Evaluation Prior to Decompression Surgery
Lateral bony decompression may offer several biomechanical advantages and has become a commonly used surgical approach. Preoperative imaging plays a key role in surgical planning by providing information about the locoregional anatomy. The marrow space of the greater wing of the sphenoid is a focal point of the decompression surgery based on the volume that it occupies. Several vessels pass through the sphenoid bone, but most are small caliber vessels. The authors describe a case of an uncommon anatomical variant of the cranial diploic venous system in which the anterior transverse diploic vessel traverses the marrow space of the sphenoid. The vessel was identified on preoperative CT evaluation. Despite anticipation of potential bleeding, lateral decompression was abandoned due to difficulties in maintaining hemostasis which compromised the view for safe surgical progress. Accepted for publication November 5, 2017. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Hamzah Mustak, M.D., Stein Eye Institute, University of California Los Angeles, 300 Stein Plaza, Los Angeles, CA 90095. E-mail: shmustak@hotmail.com © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.
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Clinical Characteristics and Short-term Outcomes of Acute Low Frequency Sensorineural Hearing Loss With Vertigo.
 | Related Articles |
Clinical Characteristics and Short-term Outcomes of Acute Low Frequency Sensorineural Hearing Loss With Vertigo.
Clin Exp Otorhinolaryngol. 2018 Jan 10;:
Authors: Park MJ, Kim SH, Kim SS, Yeo SG
Abstract
Objectives: This study analyzed short-term prognosis in patients with acute low frequency hearing loss (ALHL), and also investigate hearing recovery rates in patients with ALHL accompanied vertigo.
Methods: Retrospective medical record review of the patients who received treatment for ALHL between June 2005 and June 2015 were analyzed. Of the 84 patients, 53 were without vertigo, and 31 were with vertigo. Of the 31 patients, eight were treated with steroids, seven with diuretics alone, and 16 with both. Clinical and auditory characteristics before and after treatment were compared in these three groups.
Results: Pure tone audiometry after 8 weeks of treatment showed that patients with vertigo had significantly higher than patients without vertigo (P=0.020). Patients with vertigo who recovered from ALHL had a greater tendency to receive early treatment than patients who did not recover. Patients who received the two steroid therapy groups (steroids alone and steroids plus diuretics) had a higher recovery rate than patients who received diuretics alone (P=0.043 and P=0.037, respectively).
Conclusion: The prognosis of patients with ALHL is worse in those with vertigo compared to without vertigo. The hearing recovery rate in patients with vertigo tends to be higher in those treated with steroids than with diuretics alone.
PMID: 29310430 [PubMed - as supplied by publisher]
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Effect of Auditory-Perceptual Training With Natural Voice Anchors on Vocal Quality Evaluation
To analyze the effects of auditory-perceptual training with anchor stimuli of natural voices on inter-rater agreement during the assessment of vocal quality.
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Probabilistic versus “Pure” Volitional Orienting: a Monocular Difference
Abstract
Human volitional orienting is typically assessed using Posner's endogenous cuing task. As a volitional process, the literature has long emphasized the role of neocortical structures in this higher cognitive function. Based on recent data, we explored the possibility that subcortical channels may have a functional role in volitional orienting as measured by a Posner cuing task in which a nonspatial feature of a centrally presented cue is predictively related to the location of the target. In addition, we have compared this typical cuing task to a "purer" version, which does not involve the probability manipulation. A sensitive behavioral method was used to probe the contribution of monocular channels (mostly subcortical) in the two types of endogenous orienting tasks. In both tasks, a spatially informative cue and its ensuing target were presented to the same or different eyes at varying cue-target intervals. In the typically used endogenous task, the onset of facilitation was apparent earlier when the cue and target were presented to the same eye. In contrast, in the "pure" task no difference was found between the two eye-of-origin conditions. These data support the notion that endogenous facilitation, as measured in the typical Posner cuing task, involves lower monocular regions. Hence, in the typical endogenous task, which was developed to explore "volitional" orienting, a simple associative learning mechanism might elicit monocular, rapid orienting responses. Notably, the typical volitional orienting paradigm might be contaminated by simple contingency benefits and thus may not provide a pure measure of volitional processes.
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Intentional binding of visual effects
Abstract
When an action produces an effect, the effect is perceived earlier in time compared to a stimulus without preceding action. This temporal bias is called intentional binding (IB) and serves as an implicit measure of sense of agency. Typically, IB is investigated by presenting a rotating clock hand while participants execute an action and perceive a resulting tone. Participants are asked to estimate the time point of tone onset by referring to the clock hand position. This time point estimate is compared to a time point estimate of a tone in a condition in which the tone occurs without preceding action. Studies employing this classic clock paradigm employed auditory action effects. We modified this paradigm to investigate potential IB of visual action effects, and, additionally, to investigate how IB differs for visual action effects (Experiment 1) in comparison to auditory action effects (Experiment 2). Our results show that, like the IB of an auditory effect, the time point of a visual action effect is shifted toward the causing action, and that the size of the IB depends on the delay duration of the effect. Comparable to auditory action effects, earlier action effects showed stronger IB compared to later action effects. Yet overall IB of the visual effects was weaker than IB of the auditory effects. As IB is seen as an indicator of sense of agency, this may have important implications for the design of human-machine interfaces.
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‘Hidden’ occupational allergens such as additives
Purpose of review With the development of innovative technologies, new agents are continually introduced to the workplace. Some of these agents can act as hidden allergens whenever they are not declared in the product labels or whenever their health hazards are unknown. This review article focuses on the identification and description of unusual and/or hidden allergens recently incriminated in occupational diseases. Recent findings Occupational exposure is an important global health issue that can induce respiratory and cutaneous disorders, as well as life-threatening anaphylaxis. Apart from the classic forms of occupational exposure, reports have emerged from nonconventional or newly identified allergens or additives. These compounds are substances added to another in order to alter or improve the general quality or to counteract undesirable properties, and some of them may behave as potent and frequently hidden allergens. These highly uncommon and/or hidden allergens belong to several categories: foods, spices, cosmetics, insects, enzymes, chemicals, drugs, preservatives, and coloring agents, among others. Summary A high level of suspicion and awareness about the potential hidden allergens is necessary to ascertain the allergens implicated. It is of utmost importance to identify the specific eliciting agents of the occupational diseases in order to avoid strictly further exposure to them. Correspondence to Santiago Quirce, MD, PhD, Department of Allergy, Hospital La Paz Institute for Health Research (IdiPAZ), 28046 Madrid, Spain. E-mail: squirce@gmail.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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High intraoperative inspiratory oxygen fraction and risk of major respiratory complications
British Journal of Anaesthesia, 2017; 119(1): 140–9, DOI 10.1093/bja/aex128
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Tutorial: Assessment and Analysis of Polysyllables in Young Children
Purpose
Polysyllables, words of 3 or more syllables, represent almost 30% of words used in American English. The purpose of this tutorial is to support speech-language pathologists' (SLPs') assessment and analysis of polysyllables, extending the focus of published assessment tools that focus on sampling and analyzing children's segmental accuracy and/or the presence of phonological error patterns. Method
This tutorial will guide SLPs through a review of 53 research papers that have explored the use of polysyllables in assessment, including the sampling and analysis procedures used in different research studies. The tutorial will also introduce two new tools to analyze and interpret polysyllable speech samples: the Word-Level Analysis of Polysyllables (WAP; Masso, 2016b) and the Framework of Polysyllable Maturity (Framework; Masso, 2016a). Results
Connected speech and single-word sampling tasks were used across the 53 studies to elicit polysyllables, and a number of analysis methods were reported, including measures of segmental accuracy and measures of structural and suprasegmental accuracy. The WAP and the Framework extend SLPs' depth of analysis of polysyllables. Conclusion
SLPs need a range of clinical tools to support the assessment and analysis of polysyllables. A case study comparing different speech analysis methods demonstrates the clinical value in utilizing the WAP and the Framework to interpret children's polysyllable productions in addition to traditional methods of speech sampling and analysis.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2liNzA7
Percent Grammatical Responses as a General Outcome Measure: Initial Validity
Purpose
This report investigated the validity of using percent grammatical responses (PGR) as a measure for assessing grammaticality. To establish construct validity, we computed the correlation of PGR with another measure of grammar skills and with an unrelated skill area. To establish concurrent validity for PGR, we computed the correlation of PGR with a previously validated measure of grammaticality, percent grammatical utterances (PGU), and examined the extent to which PGR and PGU agreed upon pass/fail decisions for children. Method
Participants included 79 3-year-olds from mostly middle socioeconomic status homes. Language samples were elicited by asking children to describe 15 pictures in response to 4 questions per picture. To calculate PGU, children's responses to all 4 questions were segmented into communication units, and each communication unit was evaluated for grammatical errors. To calculate PGR, the entire response to just the first question was evaluated for grammatical errors. Results
PGR scores significantly correlated with a standardized test of grammar (r = .70), but not with a measure of vocabulary (i.e., type–token ratio; r = .11). In addition, PGR scores were significantly correlated with PGU scores (r = .88). Agreement between PGR and PGU was 92% for pass decisions and 94% for fail decisions. Conclusions
The current study establishes the construct validity of PGR as a measure of grammar and supports the use of PGR as a measure to assess grammaticality.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2yPDWk8
Diagnostic Accuracy of Traditional Measures of Phonological Ability for Bilingual Preschoolers and Kindergarteners
Purpose
Bilingual children whose phonological skills are evaluated using measures designed for monolingual English speakers are at risk for misdiagnosis of speech sound disorders (De Lamo White & Jin, 2011). Method
Forty-four children participated in this study: 15 typically developing monolingual English speakers, 7 monolingual English speakers with phonological disorders, 14 typically developing bilingual Spanish–English speakers, and 8 bilingual children with phonological disorders. Children's single-word speech productions were examined on Percentage Consonants Correct–Revised (Shriberg, Austin, Lewis, McSweeny, & Wilson, 1997a) and accuracy of early-, middle-, and late-developing sounds (Shriberg, 1993) in English. Consonant accuracy in English was compared between monolinguals and bilinguals with and without speech sound disorders. Logistic regression and receiver operating characteristic curves were used to observe diagnostic accuracy of the measures examined. Results
Percentage Consonants Correct–Revised was found to be a good indicator of phonological ability in both monolingual and bilingual English-speaking children at the age of 5;0. No significant differences were found between language groups on any of the measures examined. Conclusions
Our results suggest that traditional measures of phonological ability for monolinguals could provide good diagnostic accuracy for bilingual children at the age of 5;0 years. These findings are preliminary, and children younger than 5;0 years should be examined for risk of misdiagnosis.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2qR20Bp
Selecting Treatments and Monitoring Outcomes: The Circle of Evidence-Based Practice and Client-Centered Care in Treating a Preschool Child Who Stutters
Purpose
The purpose of the present clinical forum is to compare how 2 clinicians might select among therapy options for a preschool-aged child who presents with stuttering close to onset. Method
I discuss approaches to full evaluation of the child's profile, advisement of evidence-based practice options open to the family, the need for monitoring of the child's response, and selection of other approaches, if the child appears nonresponsive to the 1st-line approach. Results
Although some researchers and clinicians appear to favor endorsement of a single recommended treatment for early stuttering, I do not find this approach helpful or consistent with newer mandates for patient-centered care. I am also most comfortable recommending RESTART demands and capacities model as the 1st treatment approach, with parent consent, because its mechanism of action appears transparent and well-documented. Conclusions
There are numerous well-supported intervention options for treating preschool children who stutter. No single therapy can possibly work for all clients. I discuss available options that I feel have sufficient evidence-based support for use with young children who stutter. I emphasize the need to consider more, not fewer, acceptable therapy options for children who do not respond positively to a selected treatment approach within a reasonable time frame.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2qU5Aus
Best Practice for Developmental Stuttering: Balancing Evidence and Expertise
Purpose
Best practice for developmental stuttering remains a topic of debate. In the clinical forum following this introduction, four fluency experts balance the evidence and expertise to describe their approach to assessment and treatment.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2moX5Dd
Evidence, Goals, and Outcomes in Stuttering Treatment: Applications With an Adolescent Who Stutters
Purpose
The purpose of this clinical focus article is to summarize 1 possible process that a clinician might follow in designing and conducting a treatment program with John, a 14-year-old male individual who stutters. Method
The available research evidence, practitioner experience, and consideration of individual preferences are combined to address goals, treatment procedures, and outcomes for John. Conclusions
The stuttering treatment research literature includes multiple well-designed reviews and individual studies that have shown the effectiveness of prolonged speech (and smooth speech and related variations) for improving stuttered speech and for improving social, emotional, cognitive, and related variables in adolescents who stutter. Based on that evidence, and incorporating the additional elements of practitioner experience and client preferences, this clinical focus article suggests that John would be likely to benefit from a treatment program based on prolonged speech. The basic structure of 1 possible such program is also described, with an emphasis on the goals and outcomes that John could be expected to achieve.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2qV94NA
Which Preschool Children With Specific Language Impairment Receive Language Intervention?
Purpose
Potential biases in service provision for preschool children with specific language impairment (SLI) were explored. Method
In Study 1, children with SLI receiving treatment (SLI-T) and those with SLI not receiving treatment (SLI-NT) were compared on demographic characteristics and developmental abilities. Study 2 recruited children with articulation disorders receiving treatment (ARTIC-T) to determine if knowing service provision status influenced the results of Study 1. Results
In Study 1, the SLI-T group was rated by teachers as having poorer executive functioning than children in the SLIT-NT group, and the SLI-T group also came from families whose mothers had more education. These 2 variables alone predicted SLI-T and SLI-NT group membership with 84% accuracy. In Study 2, the ARTIC-T group were perceived as having comparable executive functioning to the SLI-NT group and better than the SLI-T group, indicating that teachers' knowledge of service provision did not influence their ratings of children's executive functioning. Discussion
Preschool children with SLI, whose mothers have higher education levels and whose teachers perceive them as having poorer executive functioning, are more likely to receive intervention. Recognizing service delivery biases is critical for improving early provision of intervention for this population.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mqmjkx
Comprehensive Stuttering Treatment for Adolescents: A Case Study
Purpose
This article will focus on a hypothetical case study to highlight comprehensive assessment and treatment for adolescent children who stutter. Method
Assessment and treatment are laid out with a literature review utilizing the components of the International Classification of Functioning, Disability and Health model. Specific assessment and treatment strategies and approaches are discussed. Results
Using the International Classification of Functioning, Disability and Health model can help guide clinicians through the assessment and treatment process to ensure that all areas of stuttering are considered. Conclusion
Comprehensive assessment and treatment helps clinicians address all relevant elements of a stuttering disorder, rather than focusing exclusively on reducing speech disruptions.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2qV8X4C
Conceptual Scoring and Classification Accuracy of Vocabulary Testing in Bilingual Children
Purpose
This study examined the effects of single-language and conceptual scoring on the vocabulary performance of bilingual children with and without specific language impairment. We assessed classification accuracy across 3 scoring methods. Method
Participants included Spanish–English bilingual children (N = 247) aged 5;1 (years;months) to 11;1 with and without specific language impairment. Children completed the English and bilingual versions of the Expressive One-Word Picture Vocabulary Test–Third Edition (Brownell, 2000a, 2001). Six scores, 2 representing monolingual scores in English and Spanish and 4 conceptual scores, were derived. The conceptual scores included within-test conceptual scores, which credited language responses in the other language during test administration, and across-test conceptual scores, which we compiled by examining responses across independent administrations of the test in each language. Results
Across-test conceptual scoring resulted in the highest scores and better overall classification, sensitivity, and specificity than within-test conceptual scoring. Both were superior to monolingual scoring; however, none of the methods achieved minimum standards of 80% accuracy in sensitivity and specificity. Conclusions
Results suggest that bilingual children are not always able to readily access their other language in confrontation naming tasks. Priming or inhibition may play a role in test performance. Across-test conceptual scoring yielded the highest classification accuracy but did not meet minimum standards.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2y8Tyff
Stuttering in Preschool Children: Direct Versus Indirect Treatment
Purpose
The purpose of this article is to discuss the controversial topic of stuttering in preschool children and how to evaluate the options for treatment, emphasizing the role of external research evidence. Method
A hypothetical but realistic case study of a 3-year-old boy who stutters is described. Two contrasting approaches to treatment are presented, the Lidcombe Program (LP) and the demands and capacities model (DCM). Studies published in peer-reviewed research journals that have examined the effectiveness of each approach are summarized and critiqued. Results
The review indicates that the LP is the preferred treatment approach for stuttering in preschool children and that it offers the best opportunity for rapid success. Conclusion
The LP should be carried out by knowledgeable, experienced, and flexible speech-language pathologists who are able to accommodate the individual needs and differences of every child and family.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2qU5zGU
Revealing Alzheimer’s disease genes spectrum in the whole-genome by machine learning
Alzheimer's disease (AD) is an important, progressive neurodegenerative disease, with a complex genetic architecture. A key goal of biomedical research is to seek out disease risk genes, and to elucidate the f...
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2FlytTv
Comment on “Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee”
I read with interest and trepidation "Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee" 1 —interest because at St Jude we invest significant time and expertise in researching and optimizing pediatric neuro-oncologic imaging; trepidation because I was a member of this committee but felt compelled to withdraw because I felt that 2 recommendations were counter to existing evidence and potentially detrimental to patient care.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mfvof7
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mfvof7
A change at the helm of Neuro-Oncology
I would like to begin by congratulating our past Editor-in-Chief, Dr. Patrick Wen, for his outstanding work in evolving Neuro-Oncology to increasing heights in quality and impact. Over the past 4 years, under the tutelage and expert leadership of Patrick, Neuro-Oncology has not only thrived, it has exceeded all of our expectations. Patrick has led our journal to an increase in impact factor and has introduced both new features and a sense of enthusiasm and excitement about the journal. The Journal's loss of Patrick is mitigated by the fact that SNO is fortunate to have him as president, and we wish him well in this endeavor, as he continues to participate in helping with the journal.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CV7sIp
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CV7sIp
Reviewer Lists for Neuro-Oncology
The following lists refer to the number of times reviewed within the 12-month period ending October 31, 2017. The names of Editorial Board members and Editorial Team members are excluded from the lists.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mfQzxs
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mfQzxs
Highlights from the Literature
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CVyKhE
Forthcoming Meetings
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2md0WlX
Response to Harreld re: “Response assessment in medulloblastoma and leptomeningeal seeding tumors: recommendations from the Response Assessment in Pediatric Neuro-Oncology Committee”
What is lost in the letter by Harreld is the mandate of the RAPNO committee and the purpose of the proposed recommendations. Our goal, as a committee, was to develop consensus recommendations on the response assessment for use in clinical trials of patients with medulloblastoma and other seeding tumors, which could then be tested prospectively. Committee recommendations were based on scientific justification where this exists in peer-reviewed literature, or based upon the extensive experience of leaders in the field who are members of this group. Rather than recommend advanced imaging sequences utilized in limited institutions, we proposed recommendations that can be utilized at most institutions and that will allow uniformity and quality data collection. This approach is also in line with the Brain Tumor Drug Development Coalition Imaging Standardization Steering Committee and their recommendations. 1 As such, it required compromise from the committee members in order to be applicable and feasible for the majority of institutions.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CV7srT
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CV7srT
Extent of surgery in low-grade gliomas: an old question in a new context
See the article by Wijnenga et al on pages 103–112
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mh4XG2
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mh4XG2
Control versus cognition: the changing paradigm of adjuvant therapy for resected brain metastasis
Twenty years ago, Patchell and colleagues1 demonstrated that whole-brain radiotherapy (WBRT) mitigates relapse both in the surgical bed and elsewhere in the brain and prevents death from neurologic causes in patients with resected brain metastasis. Therefore, postoperative WBRT became the standard of care.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CZs1U2
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CZs1U2
Synergy of vaccination and agonist OX40 treatment—toward a mechanism-driven combination of glioma immunotherapy
See the article by Jahan et al on pages44–54.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CYVn4U
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CYVn4U
The impact of surgery in molecularly defined low-grade glioma: an integrated clinical, radiological, and molecular analysis
Abstract
Background
Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes. Methods
We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model. Results
Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1–5.0 cm3) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002–1.02; P = 0.016) per cm3 increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1–5.0 cm) already negatively affected OS. Conclusion
Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CUXmXU
Longitudinal assessment of late-onset neurologic conditions in survivors of childhood central nervous system tumors: a Childhood Cancer Survivor Study report
Abstract
Background
Survivors of childhood central nervous system (CNS) tumors experience high rates of treatment-related neurologic sequelae. Whether survivors continue to be at increased risk for new events as they age is unknown. Methods
Adverse neurologic health conditions in 5-year survivors of CNS tumors from the Childhood Cancer Survivor Study (n = 1876) were evaluated longitudinally at a median 23.0 years from diagnosis (range, 5.1–38.9), median age at last evaluation 30.3 years (range, 6.1–56.4). Multivariable regression estimated hazard ratios (HRs) and 95% CIs. Results
From 5 to 30 years post diagnosis, cumulative incidence increased for seizures from 27% to 41%, motor impairment 21% to 35%, and hearing loss 9% to 23%. Risks were elevated compared with siblings (eg, seizures HR: 12.7; 95% CI: 9.6–16.7; motor impairment HR: 7.6; 95% CI: 5.8–9.9; hearing loss HR: 18.4; 95% CI: 13.1–25.9). Regional brain doses of radiation therapy were associated with development of new deficits (eg, frontal ≥50 Gy and motor impairment HR: 2.0; 95% CI: 1.2–3.4). Increased risk for motor impairment was also associated with tumor recurrence (HR: 2.6; 95% CI: 1.8–3.8), development of a meningioma (HR: 2.3; 95% CI: 0.9–5.4), and stroke (HR: 14.9; 95% CI: 10.4–21.4). Seizure risk was doubled by recurrence (HR: 2.3; 95% CI: 1.6–3.2), meningioma (HR: 2.6; 95% CI: 1.1–6.5), and stroke (HR: 2.0; 95% CI: 1.1–3.4). Conclusions
CNS tumor survivors remain at risk for new-onset adverse neurologic events across their lifespans at a rate greater than siblings. Cranial radiation, stroke, tumor recurrence, and development of meningioma were independently associated with late-onset adverse neurologic sequelae.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mdpvPB
Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location
Abstract
Background
The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis. Methods
Here, we characterized 85 centrally reviewed diffuse gliomas on midline locations enrolled in the nationwide pediatric German HIT-HGG registry regarding tumor site, histone 3 mutational status, WHO grade, age, sex, and extent of tumor resection. Results
We found 56 H3.3 K27M-mutant tumors (66%), 6 H3.1 K27M-mutant tumors (7%), and 23 H3-wildtype tumors (27%). H3 K27M-mutant gliomas shared an aggressive clinical course independent of their anatomic location. Multivariate regression analysis confirmed the significant impact of the H3 K27M mutation as the only independent parameter predictive of overall survival (P = 0.009). In H3 K27M-mutant tumors, neither anatomic midline location nor histopathological grading nor extent of tumor resection had an influence on survival. Conclusion
These results substantiate the clinical significance of considering diffuse midline glioma, H3 K27M-mutant, as a distinct entity corresponding to WHO grade IV, carrying a universally fatal prognosis.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CTXrLv
Inability of positive phase II clinical trials of investigational treatments to subsequently predict positive phase III clinical trials in glioblastoma
Abstract
Background
Glioblastoma is the most common primary malignant brain tumor in adults, but effective therapies are lacking. With the scarcity of positive phase III trials, which are increasing in cost, we examined the ability of positive phase II trials to predict statistically significant improvement in clinical outcomes of phase III trials. Methods
A PubMed search was conducted to identify phase III clinical trials performed in the past 25 years for patients with newly diagnosed or recurrent glioblastoma. Trials were excluded if they did not examine an investigational chemotherapy or agent, if they were stopped early owing to toxicity, if they lacked prior phase II studies, or if a prior phase II study was negative. Results
Seven phase III clinical trials in newly diagnosed glioblastoma and 4 phase III clinical trials in recurrent glioblastoma met the inclusion criteria. Only 1 (9%) phase III study documented an improvement in overall survival and changed the standard of care. Conclusion
The high failure rate of phase III trials demonstrates the urgent need to increase the reliability of phase II trials of treatments for glioblastoma. Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging, and mathematical modeling warrant testing. Additionally, it is critical to increase our expectations of phase II trials so that positive findings increase the probability that a phase III trial will be successful.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mfrvqy
Prognostic relevance of genetic alterations in diffuse lower-grade gliomas
Abstract
Background
Diffuse lower-grade gliomas (LGGs) are genetically classified into 3 distinct subtypes based on isocitrate dehydrogenase (IDH) mutation status and codeletion of chromosome 1p and 19q (1p/19q). However, the subtype-specific effects of additional genetic lesions on survival are largely unknown. Methods
Using Cox proportional hazards regression modeling, we investigated the subtype-specific effects of genetic alterations and clinicopathological factors on survival in each LGG subtype, in a Japanese cohort of LGG cases fully genotyped for driver mutations and copy number variations associated with LGGs (n = 308). The results were validated using a dataset from 414 LGG cases available from The Cancer Genome Atlas (TCGA). Results
In Oligodendroglioma, IDH-mutant and 1p/19q codeleted, NOTCH1 mutations (P = 0.0041) and incomplete resection (P = 0.0019) were significantly associated with shorter survival. In Astrocytoma, IDH-mutant, PIK3R1 mutations (P = 0.0014) and altered retinoblastoma pathway genes (RB1, CDKN2A, and CDK4) (P = 0.013) were independent predictors of poor survival. In IDH-wildtype LGGs, co-occurrence of 7p gain, 10q loss, mutation in the TERT promoter (P = 0.024), and grade III histology (P < 0.0001) independently predicted poor survival. IDH-wildtype LGGs without any of these factors were diagnosed at a younger age (P = 0.042), and were less likely to have genetic lesions characteristic of glioblastoma, in comparison with other IDH-wildtype LGGs, suggesting that they likely represented biologically different subtypes. These results were largely confirmed in the cohort of TCGA. Conclusions
Subtype-specific genetic lesions can be used to stratify patients within each LGG subtype. enabling better prognostication and management.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CTXozj
Agonist OX40 immunotherapy improves survival in glioma-bearing mice and is complementary with vaccination with irradiated GM-CSF–expressing tumor cells
Abstract
Background
Glioma immunotherapy is an active area of clinical investigation. Glioma-associated immunosuppression remains an obstacle to efficacious immunotherapy, and combination approaches are likely necessary for durable success. OX40 is a member of the tumor necrosis factor receptor superfamily that is upregulated on activated lymphocytes, ligation of which results in enhanced activity and may be active against cancer. We sought to confirm the efficacy of agonist anti-OX40 immunotherapy against glioma and hypothesized that it is complementary with irradiated whole tumor cell vaccination. Methods
GL261 tumor cells were implanted into the right frontal lobes of syngeneic mice, which were then treated with controls, agonist anti-OX40 monoclonal antibody, vaccination with subcutaneous injection of irradiated granulocyte macrophage colony stimulating factor (GM-CSF)–expressing GL261 cells (GVAX), or vaccination + agonist anti-OX40 therapy. Animals were followed for survival. On day 18, splenocytes were harvested for enzyme-linked immunosorbent spot analyses and brains were harvested for immunohistochemistry and flow cytometry analyses of infiltrating lymphocytes. Results
Combination immunotherapy with GVAX and systemic agonist anti-OX40 monoclonal antibody improved survival by 14 days over controls (median survival 36 vs 22 days, P < 0.00005). Systemically, T helper cell type 1 (Th1) antitumor immunity was enhanced significantly by combination therapy. In the brain, combination immunotherapy increased the percentage of Th1 CD4+ T lymphocytes and reduced the fraction that were Th2. In the brain, vaccination improved the ratio of CD8+ to FoxP3+ T lymphocytes, while combination immunotherapy reversed intracranial T-lymphocyte exhaustion, reducing their coexpression of programmed cell death protein 1 (PD-1) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) as well as PD-1 and lymphocyte-activation gene 3 (LAG-3). Conclusions
Anti-OX40 immunotherapy is active against intracranial glioma and synergizes with GVAX. Vaccination and anti-OX40 immunotherapy are mechanistically complementary, particularly in the glioma microenvironment.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2me2s76
Dissecting human gliomas by single-cell RNA sequencing
Abstract
Diffuse gliomas are the most common human primary brain tumors and remain incurable. They are complex entities in which diverse genetic and nongenetic effects determine tumor biology and clinical course. Our current understanding of gliomas in patients is primarily based on genomic and transcriptomic methods that have profiled them as bulk, providing critical information yet masking the diversity of cells within each tumor. Recent advances in single-cell DNA and RNA profiling have paved the way to studying tumors at cellular resolution. Here, we review initial studies deploying single-cell analysis in clinical glioma samples, with a focus on RNA expression profiling. We highlight how these studies provide new insights into glioma biology, tumor heterogeneity, cancer cell lineages, cancer stem cell programs, the tumor microenvironment, and glioma classification.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CXEdVa
Activation of WEE1 confers resistance to PI3K inhibition in glioblastoma
Abstract
Background
Oncogenic activation of phosphatidylinositol-3 kinase (PI3K) signaling plays a pivotal role in the development of glioblastoma (GBM). However, pharmacological inhibition of PI3K has so far not been therapeutically successful due to adaptive resistance through a rapid rewiring of cancer cell signaling. Here we identified that WEE1 is activated after transient exposure to PI3K inhibition and confers resistance to PI3K inhibition in GBM. Methods
Patient-derived glioma-initiating cells and established GBM cells were treated with PI3K inhibitor or WEE1 inhibitor alone or in combination, and cell proliferation was evaluated by CellTiter-Blue assay. Cell apoptosis was analyzed by TUNEL, annexin V staining, and blotting of cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase. Both subcutaneous xenograft and orthotropic xenograft studies were conducted to evaluate the effects of the combination on tumorigenesis; the tumor growth was monitored by bioluminescence imaging, and tumor tissue was analyzed by immunohistochemistry to validate signaling changes. Results
PI3K inhibition activates WEE1 kinase, which in turn phosphorylates cell division control protein 2 homolog (Cdc2) at Tyr15 and inhibits Cdc2 activity, leading to G2/M arrest in a p53-independent manner. WEE1 inhibition abrogated the G2/M arrest and propelled cells to prematurely enter into mitosis and consequent cell death through mitotic catastrophe and apoptosis. Additionally, combination treatment significantly suppressed tumor growth in a subcutaneous model but not in an intracranial model due to limited blood–brain barrier penetration. Conclusions
Our findings highlight WEE1 as an adaptive resistant gene activated after PI3K inhibition, and inhibition of WEE1 potentiated the effectiveness of PI3K targeted inhibition, suggesting that a combinational inhibition of WEE1 and PI3K might allow successful targeted therapy in GBM.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mdCosI
CD70, a novel target of CAR T-cell therapy for gliomas
Abstract
Background
Cancer immunotherapy represents a promising treatment approach for malignant gliomas but is hampered by the limited number of ubiquitously expressed tumor antigens and the profoundly immunosuppressive tumor microenvironment. We identified cluster of differentiation (CD)70 as a novel immunosuppressive ligand and glioma target. Methods
Normal tissues derived from 52 different organs and primary and recurrent low-grade gliomas (LGGs) and glioblastomas (GBMs) were thoroughly evaluated for CD70 gene and protein expression. The association between CD70 and patients' overall survival and its impact on T-cell death was also evaluated. Human and mouse CD70-specific chimeric antigen receptors (CARs) were tested respectively against human primary GBMs and murine glioma lines. The antitumor efficacies of these CARs were also examined in orthotopic xenograft and syngeneic models. Results
CD70 was not detected in peripheral and brain normal tissues but was constitutively overexpressed by isocitrate dehydrogenase (IDH) wild-type primary LGGs and GBMs in the mesenchymal subgroup and recurrent tumors. CD70 was also associated with poor survival in these subgroups, which may link to its direct involvement in glioma chemokine productions and selective induction of CD8+ T-cell death. To explore the potential for therapeutic targeting of this newly identified immunosuppressive axis in GBM tumors, we demonstrate that both human and mouse CD70-specific CAR T cells recognize primary CD70+ GBM tumors in vitro and mediate the regression of established GBM in xenograft and syngeneic models without illicit effect. Conclusion
These studies identify a previously uncharacterized and ubiquitously expressed immunosuppressive ligand CD70 in GBMs that also holds potential for serving as a novel CAR target for cancer immunotherapy in gliomas.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CWeZ9D
Neurological complications of new chemotherapy agents
Abstract
This last decade has yielded more robust development of cancer treatments and first-in-class agents than ever before. Since 2006, nearly one hundred new drugs have received regulatory approval for the treatment of hematological and solid organ neoplasms. Moreover, older conventional therapies have received approval for new clinical indications and are being used in combination with these newer small-molecule targeted treatments. The nervous system is vulnerable to many of the traditional cancer therapies, manifesting both already well-described acute and chronic toxicities. However, newer agents may produce toxicities that may seem indistinguishable from the underlying cancer. Early recognition of neurotoxicities from new therapeutics is vital to avoid irreversible neurological injury. This review focuses on cancer therapies in use in the last 10 years and approved by the FDA from January 2006 through January 1, 2017.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2mh4VOq
MerTK as a therapeutic target in glioblastoma
Abstract
Background
Glioma-associated macrophages and microglia (GAMs) are components of the glioblastoma (GBM) microenvironment that express MerTK, a receptor tyrosine kinase that triggers efferocytosis and can suppress innate immune responses. The aim of the study was to define MerTK as a therapeutic target using an orally bioavailable inhibitor, UNC2025. Methods
We examined MerTK expression in tumor cells and macrophages in matched patient GBM samples by double-label immunohistochemistry. UNC2025-induced MerTK inhibition was studied in vitro and in vivo. Results
MerTK/CD68+ macrophages increased in recurrent tumors while MerTK/glial fibrillary acidic protein–positive tumor cells did not. Pharmacokinetic studies showed high tumor exposures of UNC2025 in a syngeneic orthotopic allograft mouse GBM model. The same model mice were randomized to receive vehicle, daily UNC2025, fractionated external beam radiotherapy (XRT), or UNC2025/XRT. Although median survival (21, 22, 35, and 35 days, respectively) was equivalent with or without UNC2025, bioluminescence imaging (BLI) showed significant growth delay with XRT/UNC2025 treatment and complete responses in 19%. The responders remained alive for 60 days and showed regression to 1%–10% of pretreatment BLI tumor burden; 5 of 6 were tumor free by histology. In contrast, only 2% of 98 GBM mice of the same model treated with XRT survived 50 days and none survived 60 days. UNC2025 also reduced CD206+ macrophages in mouse tumor samples. Conclusions
These results suggest that MerTK inhibition combined with XRT has a therapeutic effect in a subset of GBM. Further mechanistic studies are warranted.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2CVyIX4
B Lymphoblastic Leukemia/Lymphoma With Burkitt-like Morphology and IGH/MYC Rearrangement: Report of 3 Cases in Adult Patients
Isolated MYC rearrangement without other recurrent genetic abnormalities is rare in B lymphoblastic leukemia/lymphoma (B-ALL/LBL), with most cases reported in pediatric patients. We report 3 adult cases with lymphoblasts showing a precursor B cell immunophenotype, and isolated MYC/IGH translocation. All 3 cases occurred in male patients with initial presentation of diffuse lymphadenopathy. Cases 1 and 2 had B-ALL with significantly increased lymphoblasts in peripheral blood and bone marrow. Case 3, a patient with human immunodeficiency virus infection, had the diagnosis of B-LBL made on a retroperitoneal lymph node biopsy and had no peripheral blood or bone marrow involvement. The leukemic and lymphoma cells in all 3 cases demonstrated Burkitt lymphoma-like morphology with deeply basophilic cytoplasm and numerous cytoplasmic vacuoles. However, all 3 had immature immunophenotypes including expression of terminal deoxynucleotidyl transferase (TdT), absence of BCL6, and dim-to-negative CD45. CD20 was largely negative in 2 of 3 cases. All 3 had confirmed MYC/IGH translocation, but lacked rearrangements of BCL2 or BCL6. EBV was negative by Epstein-Barr virus encoded small RNA in situ hybridization. Treatment protocols varied, including both high-risk ALL-type (protocol 8707) and high-grade lymphoma regimens (hyper-CVAD [cyclophosphamide, vincristine, adriamycin, and dexamethasone]), but no patient achieved continuous complete remission. These cases seem to represent a distinct biological phenomenon, in which a MYC translocation may be acquired at an immature stage of differentiation, thus manifesting features of both B-ALL/LBL and Burkitt lymphoma.from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2EwRLV0
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