Elimination of virus-like particles reduces protein aggregation and extends replicative lifespan in Saccharomyces cerevisiae.

A major consequence of aging and stress, in yeast to humans, is an increased accumulation of protein aggregates at distinct sites within the cells. Using genetic screens, immunoelectron microscopy, and three-dimensional modeling in our efforts to elucidate the importance of aggregate annexation, we found that most aggregates in yeast accumulate near the surface of mitochondria. Further, we show that virus-like particles (VLPs), which are part of the retrotransposition cycle of Ty elements, are markedly enriched in these sites of protein aggregation. RNA interference-mediated silencing of Ty expression perturbed aggregate sequestration to mitochondria, reduced overall protein aggregation, mitigated toxicity of a Huntington's disease model, and expanded the replicative lifespan of yeast in a partially Hsp104-dependent manner. The results are in line with recent data demonstrating that VLPs might act as aging factors in mammals, including humans, and extend these findings by linking VLPs to a toxic accumulation of protein aggregates and raising the possibility that they might negatively influence neurological disease progression.

Dynamic calcium-mediated stress response and recovery signatures in the fungal pathogen, Candida albicans.

IMPORTANCE: Intracellular calcium signaling plays an important role in the resistance and adaptation to stresses encountered by fungal pathogens within the host. This study reports the optimization of the GCaMP fluorescent calcium reporter for live-cell imaging of dynamic calcium responses in single cells of the pathogen, Candida albicans, for the first time. Exposure to membrane, osmotic or oxidative stress generated both specific changes in single cell intracellular calcium spiking and longer calcium transients across the population. Repeated treatments showed that calcium dynamics become unaffected by some stresses but not others, consistent with known cell adaptation mechanisms. By expressing GCaMP in mutant strains and tracking the viability of individual cells over time, the relative contributions of key signaling pathways to calcium flux, stress adaptation, and cell death were demonstrated. This reporter, therefore, permits the study of calcium dynamics, homeostasis, and signaling in C. albicans at a previously unattainable level of detail.

Seroprevalence of SARS-CoV-2 among potential convalescent plasma donors and analysis of their deferral pattern: Experience from tertiary care hospital in western India.

BACKGROUND AND OBJECTIVES: Seroprevalence estimation of COVID-19 is quite necessary for controlling the transmission of SARS-CoV-2 infection. Seroprevalence rate in recovered COVID-19 patients help us to identify individual with anti-SARS-CoV-2 antibodies and its protective nature. The objective of present study was to evaluate seroprevalence of SARS-CoV-2 among potential convalescent plasma donors and analysis of their deferral reasons. MATERIALS AND METHODS: A total 400 potential convalescent plasma donors were enrolled over five-month period for this prospective study. Inclusion criteria were lab confirmed COVID-19 recovered patients and 14 days of symptoms free period. All prospective plasmapheresis donors were tested for IgG SARS-CoV-2 antibody through chemiluminescent microparticle immunoassay, CBC, serum protein, blood grouping along with other required test for normal blood donation as per Drugs & Cosmetics Act. After pre donation testing and medical examination if donor was found to be ineligible for plasmapheresis was deferred. Seroprevalence rate was calculated by positive IgG antibody test results among the potential plasma donors. RESULTS: Seroprevalence rate was 87% for IgG SARS-CoV-2 antibodies in prospective convalescent plasma donors (recovered COVID-19 patients). There was no significant difference in seroprevalence rate between different sub-groups with respect to gender, age, blood groups, Rh factor, mode of treatment, day of Ab testing and repeat plasma donation. Most common reason for their deferral was absent IgG SARS-CoV-2 antibodies (13%) followed by absenteeism of eligible screen donors (6.7%), low Hb (1.7%) and poor veins for plasmapheresis (1.7%). Till five-month study period none of the plasmapheresis develop symptoms of reinfection with COVID-19. CONCLUSION: In all, 13% recovered patients did not develop IgG antibodies after SARS-CoV-2 infection. SARS-CoV-2 IgG antibodies persist for quite some time and are protective against reinfection. More long-term serology studies are needed to understand better antibody response kinetics and duration of persistence of IgG antibodies.

Morphometry of the lower thoracic and lumbar pedicles and its relevance in pedicle fixation.

PURPOSE: To assess the pedicle morphology in the lower thoracic and lumbar spine in an Indian population and to determine the causes of pedicle wall violation by pedicle screws. METHODS: Computerised tomographic scans of 135 consecutive patients with thoracolumbar and lumbar spine fractures were prospectively analysed to determine the pedicle morphology. The transverse pedicle angle, pedicle diameter and screw path length at 527 uninjured levels were measured. Post-operative CT scans of 117 patients were analysed to determine the accuracy of 468 pedicle screws at 234 vertebrae. RESULTS: The lowest (mean ± SD) transverse pedicle width in the lower thoracic spine was 5.4 ± 0.70 mm, whereas in the lumbar spine it was 7.2 ± 0.87 mm. The shortest (mean ± SD) screw path length in lower thoracic pedicles was 35.8 ± 2.10 and 41.9 ± 2.18 mm in the lumbar spine. The mean transverse pedicle angle in the lower thoracic spine was consistently less than 5°, whereas it gradually increased from L1 through L5 from 8.5° to 30°. Forty-one screws violated the pedicle wall, due to erroneous angle of screw insertion. CONCLUSIONS: In the current study, pedicle dimensions were smaller compared to the Western population. In Indian patients, pedicle screws of 5 mm diameter and 30 mm length, and 6 mm diameter and 35 mm length can safely be used in the lower thoracic and lumbar spine, respectively. However, it is important to assess the pedicle morphology on imaging prior to pedicle fixation.

Dynamic Contrast-Enhanced MRI-Derived Intracellular Water Lifetime (τ i ): A Prognostic Marker for Patients with Head and Neck Squamous Cell Carcinomas.

BACKGROUND AND PURPOSE: Shutter-speed model analysis of dynamic contrast-enhanced MR imaging allows estimation of mean intracellular water molecule lifetime (a measure of cellular energy metabolism) and volume transfer constant (a measure of hemodynamics). The purpose of this study was to investigate the prognostic utility of pretreatment mean intracellular water molecule lifetime and volume transfer constant in predicting overall survival in patients with squamous cell carcinomas of the head and neck and to stratify p16-positive patients based upon survival outcome. MATERIALS AND METHODS: A cohort of 60 patients underwent dynamic contrast-enhanced MR imaging before treatment. Median, mean intracellular water molecule lifetime and volume transfer constant values from metastatic nodes were computed from each patient. Kaplan-Meier analyses were performed to associate mean intracellular water molecule lifetime and volume transfer constant and their combination with overall survival for the first 2 years, 5 years, and beyond (median duration, >7 years). RESULTS: By the last date of observation, 18 patients had died, and median follow-up for surviving patients (n = 42) was 8.32 years. Patients with high mean intracellular water molecule lifetime (4 deaths) had significantly (P = .01) prolonged overall survival by 5 years compared with those with low mean intracellular water molecule lifetime (13 deaths). Similarly, patients with high mean intracellular water molecule lifetime (4 deaths) had significantly (P = .006) longer overall survival at long-term duration than those with low mean intracellular water molecule lifetime (14 deaths). However, volume transfer constant was a significant predictor for only the 5-year follow-up period. There was some evidence (P < .10) to suggest that mean intracellular water molecule lifetime and volume transfer constant were associated with overall survival for the first 2 years. Patients with high mean intracellular water molecule lifetime and high volume transfer constant were associated with significantly (P < .01) longer overall survival compared with other groups for all follow-up periods. In addition, p16-positive patients with high mean intracellular water molecule lifetime and high volume transfer constant demonstrated a trend toward the longest overall survival. CONCLUSIONS: A combined analysis of mean intracellular water molecule lifetime and volume transfer constant provided the best model to predict overall survival in patients with squamous cell carcinomas of the head and neck.

Why are HIV-infected people not started on antiretroviral therapy? A mixed-methods study from Gujarat, India.

Setting: Five purposively selected antiretroviral therapy (ART) centres in Gujarat, India. Objectives: To assess the proportion of ART-eligible people living with the human immunodeficiency virus (PLHIV) who were not initiated on ART within 2 months of being recorded as eligible, to identify factors associated with non-initiation and to explore reasons from the provider's perspective. Design: We used a mixed-methods design (triangulation) of 1) a quantitative phase involving record reviews and cohort analysis (Poisson regression) of PLHIV registered during April 2014-March 2015, and 2) a qualitative phase involving one-to-one interviews with 25 providers. Results: Of 2079 ART-eligible PLHIV, 339 (16%) were not started on ART within 2 months. PLHIV with CD4 counts of <350 cells/µl and patients who were labourers, hospitalised, bedridden or registered with certain ART centres were more likely not to be initiated on ART. Qualitative results were categorised into two broad themes: government health system- and patient-related challenges, which validated and complemented the quantitative findings. Conclusion: Several patient subgroups at greater risk of ART non-initiation were identified, along with reasons for risk; this has important programme implications for achieving the UNAIDS 90-90-90 goal, and particularly the second 90 component of having 90% of diagnosed PLHIV start ART.

Contexte : Cinq centres du TAR (traitement antirétroviral) sélectionnés dans ce but dans l'état de Gujarat, Inde.Objectifs : Evaluer la proportion de personnes vivant avec le virus de l'immunodéficience humaine (PVVIH) éligibles pour le TAR non mis sous TAR dans les 2 mois de leur éligibilité, identifier les facteurs associés à la non initiation et explorer les raisons vues par les prestataires de soins.Schéma: Nous avons eu recours à un mélange de méthodes (triangulation) : 1) une phase quantitative impliquant une revue des dossiers et une analyse de la cohorte (régression de Poisson) des PVVIH enregistrés entre avril 2014 et mars 2015, et 2) une phase qualitative impliquant des entretiens individuels avec 25 prestataires de soins.Résultats : Sur 2079 PVVIH éligibles au TAR, 339 (16%) n'ont pas été mis sous traitement dans les 2 mois. Les PVVIH ayant un taux de CD4 <350 cellules/µl, les patients qui étaient des travailleurs journaliers, hospitalisés, alités ou suivis par certains centres du TAR ont été plus susceptibles de ne pas être mis sous TAR. Les résultats qualitatifs ont été classés en deux vastes catégories : système de santé du gouvernement et défis liés aux patients ; ceux-ci ont validé et complété les résultats quantitatifs.Conclusion : Plusieurs sous-groupes de patients ayant un risque plus élevé de non mise en route du TAR et les raisons de ce problème ont été identifiés ; ceci pourrait avoir des implications importantes pour le programme dans l'atteinte de l'objectif 90­90­90, surtout en ce qui concerne le deuxième 90, qui consiste à débuter le TAR chez 90% des PVVIH diagnostiqués.

Marco de referencia: Cinco centros de suministro del tratamiento antirretrovírico (TAR) de Gujarat en la India, escogidos por muestreo dirigido.Objetivos: Evaluar la proporción de personas positivas frente al virus de la inmunodeficiencia humana (PPVIH) aptas para recibir el TAR, que no habían iniciado el tratamiento 2 meses después de haberse considerado idóneas; determinar los factores asociados con la falta de iniciación del TAR; y analizar las razones desde la perspectiva de los profesionales de salud.Método: Se utilizó un diseño de métodos mixtos (triangulación), con una fase cuantitativa de análisis de las historias clínicas y de cohortes de PPVIH registradas de abril del 2014 a marzo del 2015 y una fase cualitativa con entrevistas personales a 25 profesionales de salud.Resultados: De las 2079 PPVIH aptas para recibir el TAR, 339 no lo habían iniciado en un lapso de 2 meses (16%). La probabilidad de no iniciar el TAR fue mayor en las PPVIH con cifras de linfocitos CD4 <350 células/µl, los pacientes que eran obreros, estaban hospitalizados, encamados o que acudían a determinados centros de suministro de TAR. Los resultados se clasificaron en dos amplias categorías, a saber: problemas relacionados con el sistema público de salud o atribuibles a los pacientes, con lo cual se validaron y complementaron los resultados cuantitativos.Conclusión: Varios subgrupos de pacientes presentaron un mayor riesgo de no iniciar el TAR y se determinaron las razones del riesgo; los resultados pueden tener repercusiones importantes en el programa y favorecer el progreso hacia el cumplimiento del triple objetivo 90­90­90, sobre todo de su segundo componente, según el cual el 90% de las PPVIH debe iniciar el TAR.

Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

OBJECTIVE: To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns. STUDY DESIGN: The original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment. RESULTS: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window. CONCLUSION: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

Are partners of HIV-infected people being tested for HIV? A mixed-methods research from Gujarat, India.

Setting: Four selected antiretroviral therapy (ART) centres of Gujarat State, India, which accounts for 8% of the human immunodeficiency virus (HIV) burden in India. Objectives: 1) To assess the proportion of people living with HIV (PLHIV) whose partners were not tested for HIV; 2) to assess sociodemographic and clinical characteristics of index cases associated with partner testing; and 3) to understand perceived facilitators and barriers to partner testing and make suggestions on how to improve testing from the perspective of the health-care provider. Design: A mixed-method design with a quantitative phase that involved reviewing the programme records of married PLHIV enrolled during 2011-2015, followed by a qualitative phase of key informant interviews. Results: Of 3884 married PLHIV, 1279 (33%) did not have their partners tested for HIV. Factors including index cases being male, illiterate, aged >25 years, belonging to key populations, substance use and being in advanced clinical stages were more likely to be associated with partner non-testing. Non-disclosure of HIV status (due to fear of marital discord) and lack of awareness and risk perception were the key barriers to testing. Conclusion: One third of PLHIV did not have their partners tested for HIV. Several factors were identified as being associated with the non-testing of partners, and solutions were explored that need to be implemented urgently if we are to achieve the 90-90-90 targets and end HIV.

Contexte : Quatre centres du traitement antirétroviral (TAR) sélectionnés de l'état de Gujarat, qui compte pour 8% du poids du virus de l'immunodéficience humaine (VIH) en Inde.Objective : Nous avons voulu 1) évaluer la proportion de personnes vivant avec le VIH (PVVIH) dont les partenaires n'ont pas été testés pour le VIH ; 2) évaluer les caractéristiques sociodémographiques et cliniques du cas index associées au test du partenaire ; et 3) comprendre les facilitateurs et les contraintes perçus au test du partenaire et faire des suggestions pour améliorer les tests du point de vue des prestataires de soins de santé.Schéma à plusieurs methods: La phase quantitative a impliqué de retrouver dans les archives du programme les PVVIH mariés enrôlés entre 2011 et 2015 ; la phase qualitative a ensuite consisté en entretiens avec des informateurs clés.Résultats: Sur 3884 PVVIH mariés, 1279 (33%) n'ont pas fait tester leurs partenaires pour le VIH. Les facteurs comme le fait que le cas index soit un homme, illettré, d'âge >25 ans, appartenant à des populations clés, utilisant des drogues, étant à un stade avancé de la maladie, ont été plus susceptibles d'être associés à l'absence de test du partenaire. Le non divulgation du statut VIH (due à la peur d'une discorde maritale) et le manque de connaissances et de perception des risques ont été les obstacles majeurs au test.Conclusion : Un tiers des PVVIH n'ont pas fait tester leurs partenaires pour le VIH. Plusieurs facteurs associés à l'absence de test des partenaires ont été identifiés et des solutions ont été recherchées. Elles doivent être mises en œuvre d'urgence si nous voulons atteindre les cibles de 90­90­90 et mettre fin au VIH.

Marco de referencia: Cuatro centros de tratamiento antirretrovírico (TAR) en el estado de Guyarat, que representa el 8% de la carga de morbilidad por el virus de la inmunodeficiencia humana (VIH) de la India.Objetivos: 1) Examinar la proporción de personas positivas frente al VIH cuyas parejas no cuentan con la prueba diagnóstica del VIH; 2) analizar las características socioeconómicas y clínicas del caso inicial que se relacionan con la práctica de la prueba diagnóstica en la pareja; y 3) comprender los elementos facilitadores y los obstáculos percibidos a la prueba del VIH en las parejas y las propuestas encaminadas a mejorar su utilización, desde el punto de vista de los profesionales de salud.Métodos: Se aplicó un modelo de métodos mixtos con una etapa inicial cuantitativa, que comportó el examen de los registros del programa de las personas positivas frente al VIH casadas inscritas del 2011 al 2015, seguida por una etapa cualitativa durante la cual se realizaron entrevistas a informantes clave.Resultados: De las 3884 personas positivas frente al VIH casadas, 1279 parejas no contaban con la prueba del VIH (33%). Las características del caso inicial que se asociaron con mayor frecuencia a la falta de prueba diagnóstica de la pareja fueron el sexo masculino, el analfabetismo, la edad más de 25 años, el hecho de pertenecer a una población clave, el consumo de sustancias psicoactivas y un estadio clínico avanzado de la enfermedad. Los principales obstáculos a la práctica de las pruebas fueron la negativa a divulgar su situación frente al VIH (por temor a una discordia conyugal) y la falta de sensibilización y percepción de los riesgos.Conclusión: En un tercio de las personas positivas frente al VIH, no se había practicado a su pareja la prueba diagnóstica de la infección. Se reconocieron diversos factores vinculados con esta situación y se analizaron las soluciones. La aplicación de estas medidas es urgente con el fin de cumplir con las metas 90­90­90 y eliminar la infección por el VIH.

A targeted noise reduction observational study for reducing noise in a neonatal intensive unit.

BACKGROUND: Excessive noise in neonatal intensive care units (NICUs) can interfere with infants' growth, development and healing.Local problem:Sound levels in our NICUs exceeded the recommended levels by the World Health Organization. METHODS: We implemented a noise reduction strategy in an urban, tertiary academic medical center NICU that included baseline noise measurements. We conducted a survey involving staff and visitors regarding their opinions and perceptions of noise levels in the NICU. Ongoing feedback to staff after each measurement cycle was provided to improve awareness, engagement and adherence with noise reduction strategies. After widespread discussion with active clinician involvement, consensus building and iterative testing, changes were implemented including: lowering of equipment alarm sounds, designated 'quiet times' and implementing a customized education program for staff. INTERVENTIONS: A multiphase noise reduction quality improvement (QI) intervention to reduce ambient sound levels in a patient care room in our NICUs by 3 dB (20%) over 18 months. RESULTS: The noise in the NICU was reduced by 3 dB from baseline. Mean (s.d.) baseline, phase 2, 3 and 4 noise levels in the two NICUs were: LAeq: 57.0 (0.84), 56.8 (1.6), 55.3 (1.9) and 54.5 (2.6) dB, respectively (P<0.01). Adherence with the planned process measure of 'quiet times' was >90%. CONCLUSIONS: Implementing a multipronged QI initiative resulted in significant noise level reduction in two multipod NICUs. It is feasible to reduce noise levels if QI interventions are coupled with active engagement of the clinical staff and following continuous process of improvement methods, measurements and protocols.

Denosumab in advanced/unresectable giant-cell tumour of bone (GCTB): For how long?

BACKGROUND: Giant-cell tumours of bone (GCTB) are RANK/RANK-ligand (RANKL) positive, aggressive and progressive osteolytic tumours. Denosumab, a RANKL inhibitor, was FDA-approved for adults and skeletally mature adolescents with unresectable GCTB or when surgical resection is likely to result in severe morbidity. Data on long-term toxicity and activity of denosumab monthly 'GCTB-schedule' (120 mg per 12/year, 1440 mg total dose/year) are lacking. METHODS: Patients with GCTB receiving denosumab, 120 mg on days 1, 8, 15, 29 and every 4 weeks thereafter, from 2006 to 2015 treated in two centres were included. Long-term toxicity was evaluated. RESULTS: Ninety-seven patients were identified. 43 patients underwent resection of the tumour with a median time on denosumab treatment of 12 months (range 6-45 months). Fifty-four patients had unresectable GCTB's (male/female 23/31, median age 35 years [range: 13-76 years], 26% presented with lung metastases, 31% had primary tumor located to the spine, 63% were relapsed after previous surgery) with a median time on denosumab of 54 months (9-115 months). In the unresectable GCTB group, tumour control and clinical benefits were observed in all patients undergoing denosumab, whereas 40% of patients discontinuing denosumab had tumour progression after a median of 8 months (range 7-15 months). ADVERSE EVENTS: Overall, six (6%) patients developed osteonecrosis of jaw (ONJ): 1/43 (2%) in the resectable group, 5/54 (9%) in the unresectable group, with a 5-year ONJ-free survival of 92% (95% CI 84-100). Only patients with prolonged treatment experienced mild peripheral neuropathy (6/54, 11%), skin rash (5/54, 9%), hypophosphataemia (2/54, 4%) and atypical femoral fracture (2/54, 4%). CONCLUSIONS: Prolonged treatment with denosumab has sustained activity in GCTB, with a mild toxicity profile. The dose-dependent toxicity observed recommends a careful and strict monitoring of patients who need prolonged treatment. Decreased dose-intensity schedules should be further explored in unresectable GCTB.

Role of targeted magnetic resonance imaging sequences in the surgical management of anterior skull base pathology.

BACKGROUND: The skull base is a highly complex anatomical region that provides passage for important nerves and vessels as they course into and out of the cranial cavity. Key to the management of pathology in this region is a thorough understanding of the anatomy, with its variations, and the relationship of various neurovascular structures to the pathology in question. Targeted high-resolution magnetic resonance imaging on high field strength magnets can enable the skull base surgeon to understand this intricate relationship and deal with the pathology from a position of relative advantage. OBJECTIVE: With the help of case studies, this paper illustrates the application of specialised magnetic resonance techniques to study pathology of the orbital apex in particular. CONCLUSION: The fine anatomical detail provided gives surgeons the ability to design an endonasal endoscopic procedure appropriate to the anatomy of the pathology.

Cord blood lead level in an urban inner-city hospital.

Lead levels were measured by inductively coupled plasma mass spectrometry (ICP-MS) in umbilical cord blood samples of 150 neonates in an urban inner-city hospital. The mean (SD) gestation and birth weight of our cohort were 38.8 (1.7) weeks and 3,217 (519) grams. There were 89% African-Americans, 53% males and 79% were born via vaginal delivery. Mean (SD) maternal age was 24.5 (5.8) years. History of drug abuse and smoking was reported in 8.7% and 10.7% respectively, with only 1 mother reporting a history of high lead level in childhood. Prenatal vitamin intake was reported in 99.3%. Cord blood lead level was available in 144 patients, with lead level of <1µg/dL seen in 141 (97.9%) and>1 in 3 (2.1%) patients. No patient had cord blood lead level of >2µg/dL. High lead levels during childhood in high-risk urban population, however, suggest the need for intensive efforts for prevention of environmental exposure to lead in early childhood.

Iron and Non-Iron-Related Characteristics of Multiple Sclerosis and Neuromyelitis Optica Lesions at 7T MRI.

BACKGROUND AND PURPOSE: Characterization of iron deposition associated with demyelinating lesions of multiple sclerosis and neuromyelitis optica has not been well studied. Our aim was to investigate the potential of ultra-high-field MR imaging to distinguish MS from neuromyelitis optica and to characterize tissue injury associated with iron pathology within lesions. MATERIALS AND METHODS: Twenty-one patients with MS and 21 patients with neuromyelitis optica underwent 7T high-resolution 2D-gradient-echo-T2* and 3D-susceptibility-weighted imaging. An in-house-developed algorithm was used to reconstruct quantitative susceptibility mapping from SWI. Lesions were classified as "iron-laden" if they demonstrated hypointensity on gradient-echo-T2*-weighted images and/or SWI and hyperintensity on quantitative susceptibility mapping. Lesions were considered "non-iron-laden" if they were hyperintense on gradient-echo-T2* and isointense or hyperintense on quantitative susceptibility mapping. RESULTS: Of 21 patients with MS, 19 (90.5%) demonstrated at least 1 quantitative susceptibility mapping-hyperintense lesion, and 11/21 (52.4%) had iron-laden lesions. No quantitative susceptibility mapping-hyperintense or iron-laden lesions were observed in any patients with neuromyelitis optica. Iron-laden and non-iron-laden lesions could each be further characterized into 2 distinct patterns based on lesion signal and morphology on gradient-echo-T2*/SWI and quantitative susceptibility mapping. In MS, most lesions (n = 262, 75.9% of all lesions) were hyperintense on gradient-echo T2* and isointense on quantitative susceptibility mapping (pattern A), while a small minority (n = 26, 7.5% of all lesions) were hyperintense on both gradient-echo-T2* and quantitative susceptibility mapping (pattern B). Iron-laden lesions (n = 57, 16.5% of all lesions) were further classified as nodular (n = 22, 6.4%, pattern C) or ringlike (n = 35, 10.1%, pattern D). CONCLUSIONS: Ultra-high-field MR imaging may be useful in distinguishing MS from neuromyelitis optica. Different patterns related to iron and noniron pathology may provide in vivo insight into the pathophysiology of lesions in MS.

Outcome of uterine sarcoma patients treated with pazopanib: A retrospective analysis based on two European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) clinical trials 62043 and 62072.

BACKGROUND: Uterine sarcomas are a group of mesenchymal tumours comprising several histologies. They have a high recurrence rate following surgery, modest outcome to systemic therapy, and poor overall survival. Pazopanib is a multi-targeted tyrosine kinase inhibitor approved for non-adipocytic advanced soft tissue sarcomas (STS). Here we investigated whether response to pazopanib in patients with uterine sarcomas differs from that of patients with non-uterine sarcomas. PATIENTS AND METHODS: Uterine sarcoma patients were retrieved from all soft tissue sarcoma patients treated with pazopanib in EORTC Phase II (n=10) and Phase III (PALETTE) (n=34) studies. Patient and tumour characteristics, response, progression free and overall survival data were compared. RESULTS: Forty-four patients with uterine sarcoma were treated with pazopanib. The majority of patients had uterine leiomyosarcoma (LMS) (n=39, 88.6%) with high grade tumours (n=37, 84.1%) compared to 54.8% (n=164) in the non-uterine population. The median age was 55years (range 33-79) and median follow up was 2.3years. Uterine patients were heavily pre-treated, 61.3% having ≥2 lines of chemotherapy prior to pazopanib compared to 40.8% in the non-uterine population. Five patients (11%), all LMS, had a partial response (95% CI 3.8-24.6). Median progression free survival (PFS) 3.0months (95% CI 2.5-4.7) in uterine versus 4.5 (95% CI 3.7-5.1) in non-uterine STS. Median overall survival (OS) was 17.5months (95% CI 11.1-19.6), longer than the non-uterine population, 11.1months (95% CI 10.2-12.0) (p=0.352). CONCLUSIONS: Despite heavy pre-treatment, pazopanib shows signs of activity in patients with uterine sarcoma with the similar outcomes to patients with non-uterine STS.

Differentiating Tumor Progression from Pseudoprogression in Patients with Glioblastomas Using Diffusion Tensor Imaging and Dynamic Susceptibility Contrast MRI.

BACKGROUND AND PURPOSE: Early assessment of treatment response is critical in patients with glioblastomas. A combination of DTI and DSC perfusion imaging parameters was evaluated to distinguish glioblastomas with true progression from mixed response and pseudoprogression. MATERIALS AND METHODS: Forty-one patients with glioblastomas exhibiting enhancing lesions within 6 months after completion of chemoradiation therapy were retrospectively studied. All patients underwent surgery after MR imaging and were histologically classified as having true progression (>75% tumor), mixed response (25%-75% tumor), or pseudoprogression (<25% tumor). Mean diffusivity, fractional anisotropy, linear anisotropy coefficient, planar anisotropy coefficient, spheric anisotropy coefficient, and maximum relative cerebral blood volume values were measured from the enhancing tissue. A multivariate logistic regression analysis was used to determine the best model for classification of true progression from mixed response or pseudoprogression. RESULTS: Significantly elevated maximum relative cerebral blood volume, fractional anisotropy, linear anisotropy coefficient, and planar anisotropy coefficient and decreased spheric anisotropy coefficient were observed in true progression compared with pseudoprogression (P < .05). There were also significant differences in maximum relative cerebral blood volume, fractional anisotropy, planar anisotropy coefficient, and spheric anisotropy coefficient measurements between mixed response and true progression groups. The best model to distinguish true progression from non-true progression (pseudoprogression and mixed) consisted of fractional anisotropy, linear anisotropy coefficient, and maximum relative cerebral blood volume, resulting in an area under the curve of 0.905. This model also differentiated true progression from mixed response with an area under the curve of 0.901. A combination of fractional anisotropy and maximum relative cerebral blood volume differentiated pseudoprogression from nonpseudoprogression (true progression and mixed) with an area under the curve of 0.807. CONCLUSIONS: DTI and DSC perfusion imaging can improve accuracy in assessing treatment response and may aid in individualized treatment of patients with glioblastomas.

Hypertension (HTN) as a potential biomarker of efficacy in pazopanib-treated patients with advanced non-adipocytic soft tissue sarcoma. A retrospective study based on European Organisation for Research and Treatment of Cancer (EORTC) 62043 and 62072 trials.

BACKGROUND: Reliable biomarkers of pazopanib's efficacy in soft tissue sarcoma (STS) are lacking. Hypertension (HTN) is an on-target effect of vascular endothelial growth factor (VEGF)-receptor inhibitors such as pazopanib. We evaluated the association of pazopanib-induced HTN with antitumour efficacy in patients with metastatic non-adipocytic STS. METHODS: Associations between pazopanib-induced-HTN and antitumour efficacy were retrospectively assessed across 2 prospective studies (European Organisation for Research and Treatment of Cancer (EORTC) study 62043 and 62072) in metastatic STS patients who received pazopanib 800 mg daily. Only patients with baseline blood pressure (BP)<150/90 mmHg, were included. BP was measured monthly. HTN was reported according to National Cancer Institute-Common Toxicity Criteria Adverse Events (NCI-CTC AE) grading (v3.0), and as absolute differences compared to baseline. The effect of HTN developing in patients without baseline anti-hypertensive medication was assessed on progression-free (PFS) and overall survival (OS) using a landmark analysis stratified by study; univariately using the Kaplan-Meier method and a log-rank test, and in a multivariate Cox regression model after adjustment for important prognostic factors. RESULTS: Of the 337 patients eligible for this analysis, 21.7% received anti-hypertensive medication at baseline and had a similar PFS and OS compared to those who did not. In patients without baseline anti-hypertensive medication, 38.6% developed HTN. As the majority of patients developing HTN did so within 5 weeks after initiation of pazopanib (68.6%), this time point was used as landmark. Univariately, there was no effect on PFS or OS from occurrence of HTN within 5 weeks of treatment expressed either in NCI-CTC AE criteria or as maximal differences from baseline in systolic and diastolic BP. Also in multivariate analysis, after adjusting for important prognostic factors, the occurrence of HTN expressed in the different parameters was not associated with PFS and OS. CONCLUSIONS: In this retrospective analysis, pazopanib-induced HTN did not correlate with outcome in pazopanib-treated STS patients. The occurrence of HTN cannot serve as biomarker in this setting.