Summary Background We have previously characterised functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer's disease. To gain further knowledge on the preclinical ...phase of Alzheimer's disease, we sought to characterise structural and functional MRI, CSF, and plasma biomarkers in a cohort of young adults carrying a high-penetrance autosomal dominant mutation that causes early-onset Alzheimer's disease. Methods Between January and August, 2010, 18–26-year-old presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the Colombian Alzheimer's Prevention Initiative Registry in Medellín Antioquia, Colombia, had structural MRI, functional MRI during associative memory encoding and novel viewing and control tasks, and cognitive assessments. Consenting participants also had lumbar punctures and venepunctures. Outcome measures were task-dependent hippocampal or parahippocampal activations and precuneus or posterior cingulate deactivations, regional grey matter reductions, CSF Aβ1–42 , total tau and phospho-tau181 concentrations, and plasma Aβ1–42 concentrations and Aβ1–42 :Aβ1–40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to Alzheimer's disease. Cognitive and fluid biomarkers were compared using Mann-Whitney tests. Findings 44 participants were included: 20 PSEN1 E280A mutation carriers and 24 non-carriers. The carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ε4 carriers. Compared with non-carriers, carriers had greater right hippocampal and parahippocampal activation (p=0·001 and p<0·014, respectively, after correction for multiple comparisons), less precuneus and posterior cingulate deactivation (all p<0·010 after correction), and less grey matter in several parietal regions (all p<0·002 uncorrected and corrected p=0·009 in the right parietal search region). In the 20 participants (ten PSEN1 E280A mutation carriers and ten non-carriers) who had lumbar punctures and venepunctures, mutation carriers had higher CSF Aβ1–42 concentrations (p=0·008) and plasma Aβ1–42 concentrations (p=0·01) than non-carriers. Interpretation Young adults at genetic risk for autosomal dominant Alzheimer's disease have functional and structural MRI findings and CSF and plasma biomarker findings consistent with Aβ1–42 overproduction. Although the extent to which the underlying brain changes are either neurodegenerative or developmental remain to be determined, this study shows the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant Alzheimer's disease. Funding Banner Alzheimer's Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias, National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the State of Arizona.
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Paediatric low-grade glioma is the most common CNS tumour of childhood. Although overall survival is good, disease often recurs. No single universally accepted treatment exists for these patients; ...however, standard cytotoxic chemotherapies are generally used. We aimed to assess the activity of selumetinib, a MEK1/2 inhibitor, in these patients.
The Pediatric Brain Tumor Consortium performed a multicentre, phase 2 study in patients with paediatric low-grade glioma in 11 hospitals in the USA. Patients aged 3–21 years with a Lansky or Karnofsky performance score greater than 60 and the presence of recurrent, refractory, or progressive paediatric low-grade glioma after at least one standard therapy were eligible for inclusion. Patients were assigned to six unique strata according to histology, tumour location, NF1 status, and BRAF aberration status; herein, we report the results of strata 1 and 3. Stratum 1 comprised patients with WHO grade I pilocytic astrocytoma harbouring either one of the two most common BRAF aberrations (KIAA1549–BRAF fusion or the BRAFV600E Val600Glu mutation). Stratum 3 comprised patients with any neurofibromatosis type 1 (NF1)-associated paediatric low-grade glioma (WHO grades I and II). Selumetinib was provided as capsules given orally at the recommended phase 2 dose of 25 mg/m2 twice daily in 28-day courses for up to 26 courses. The primary endpoint was the proportion of patients with a stratum-specific objective response (partial response or complete response), as assessed by the local site and sustained for at least 8 weeks. All responses were reviewed centrally. All eligible patients who initiated treatment were evaluable for the activity and toxicity analyses. Although the trial is ongoing in other strata, enrolment and planned follow-up is complete for strata 1 and 3. This trial is registered with ClinicalTrials.gov, number NCT01089101.
Between July 25, 2013, and June 12, 2015, 25 eligible and evaluable patients were accrued to stratum 1, and between Aug 28, 2013, and June 25, 2015, 25 eligible and evaluable patients were accrued to stratum 3. In stratum 1, nine (36% 95% CI 18–57) of 25 patients achieved a sustained partial response. The median follow-up for the 11 patients who had not had a progression event by Aug 9, 2018, was 36·40 months (IQR 21·72–45·59). In stratum 3, ten (40% 21–61) of 25 patients achieved a sustained partial response; median follow-up was 48·60 months (IQR 39·14–51·31) for the 17 patients without a progression event by Aug 9, 2018. The most frequent grade 3 or worse adverse events were elevated creatine phosphokinase (five 10%) and maculopapular rash (five 10%). No treatment-realted deaths were reported.
Selumetinib is active in recurrent, refractory, or progressive pilocytic astrocytoma harbouring common BRAF aberrations and NF1-associated paediatric low-grade glioma. These results show that selumetinib could be an alternative to standard chemotherapy for these subgroups of patients, and have directly led to the development of two Children's Oncology Group phase 3 studies comparing standard chemotherapy to selumetinib in patients with newly diagnosed paediatric low-grade glioma both with and without NF1.
National Cancer Institute Cancer Therapy Evaluation Program, the American Lebanese Syrian Associated Charities, and AstraZeneca.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Approximately half of ovarian tumors have defects within the homologous recombination repair pathway. Tumors carrying pathogenic variants (PVs) in BRCA1/BRCA2 are more likely to respond to ...poly‐ADP ribose polymerase (PARP) inhibitor treatment. Large rearrangements (LRs) are a challenging class of variants to identify and characterize in tumor specimens and may therefore be underreported. This study describes the prevalence of pathogenic BRCA1/BRCA2 LRs in ovarian tumors and discusses the importance of their identification using a comprehensive testing strategy.
Methods
Sequencing and LR analyses of BRCA1/BRCA2 were conducted in 20 692 ovarian tumors received between March 18, 2016 and February 14, 2023 for MyChoice CDx testing. MyChoice CDx uses NGS dosage analysis to detect LRs in BRCA1/BRCA2 genes using dense tiling throughout the coding regions and limited flanking regions.
Results
Of the 2217 PVs detected, 6.3% (N = 140) were LRs. Overall, 0.67% of tumors analyzed carried a pathogenic LR. The majority of detected LRs were deletions (89.3%), followed by complex LRs (5.7%), duplications (4.3%), and retroelement insertions (0.7%). Notably, 25% of detected LRs encompassed a single or partial single exon. This study identified 84 unique LRs, 2 samples each carried 2 unique LRs in the same gene. We identified 17 LRs that occurred in multiple samples, some of which were specific to certain ancestries. Several cases presented here illustrate the intricacies involved in characterizing LRs, particularly when multiple events occur within the same gene.
Conclusions
Over 6% of PVs detected in the ovarian tumors analyzed were LRs. It is imperative for laboratories to utilize testing methodologies that will accurately detect LRs at a single exon resolution to optimize the identification of patients who may benefit from PARP inhibitor treatment.
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4.
Imaging of pediatric head and neck masses Stern, Jessica S; Ginat, Daniel T; Nicholas, Jennifer L ...
Otolaryngologic clinics of North America,
02/2015, Volume:
48, Issue:
1
Journal Article
Peer reviewed
Medical imaging is an important tool in the evaluation and classification of pediatric head and neck masses. Such lesions may include congenital, inflammatory, infectious, vascular, or neoplastic ...processes. Ultrasound is often the first line modality in the workup of a neck mass in a child, followed by MRI or CT depending on the scenario. This information must be interpreted in the context of the patient's clinical history, physical examination, and demographics. The medical imaging workup of a neck mass in a child must be focused to yield the maximum information possible while minimizing the risks of radiation and sedation.
Using Metabolic Syndrome Traits for Efficient Detection of Impaired Glucose Tolerance
James B. Meigs , MD MPH 1 2 ,
Ken Williams , MS 3 ,
Lisa M. Sullivan , PHD 4 ,
Kelly J. Hunt , PHD 3 ,
Steven M. ...Haffner , MD 3 ,
Michael P. Stern , MD 3 ,
Clicerio González Villalpando , MD 5 ,
Jessica S. Perhanidis , MPH 1 ,
David M. Nathan , MD 2 ,
Ralph B. D’Agostino, Jr , PHD 6 ,
Ralph B. D’Agostino, Sr , PHD 4 and
Peter W.F. Wilson , MD 7
1 General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
2 Diabetes Center, Department of Medicine, Massachusetts Hospital and Harvard Medical School, Boston, Massachusetts
3 Division of Clinical Epidemiology, Department of Medicine, University of Texas Health Science Center, San Antonio, Texas
4 Statistics and Consulting Unit of the Mathematics and Statistics Department at Boston University, Boston, Massachusetts
5 Centro de Estudios en Diabetes, The American British Coudray Hospital and Unidades de Investigación in Médica en Enfermedades
Metabolicas y Epidemiología Clínica, Hospital Gabriel Mancera, Instituto Mexicano del Seguro Social, Mexico City, México
6 Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina
7 Boston University School of Medicine and Framingham Heart Study, Framingham, Massachusetts
Address correspondence and reprint requests to James B. Meigs, MD, MPH, General Internal Medicine Unit Massachusetts General
Hospital, 50 Staniford St., 9th Floor, Boston, MA 02114. E-mail: jmeigs{at}partners.org
Abstract
OBJECTIVE —Efficient detection of impaired glucose tolerance (IGT) is needed to implement type 2 diabetes prevention interventions.
RESEARCH DESIGN AND METHODS —We assessed the capacity of the metabolic syndrome (MetS) to identify IGT in a cross-sectional analysis of 3,326 Caucasian
Framingham Offspring Study (FOS), 1,168 Caucasian and 1,812 Mexican-American San Antonio Heart Study (SAHS), 1,983 Mexico
City Diabetes Study (MCDS), and 452 Caucasian, 407 Mexican-American, and 290 African-American Insulin Resistance Atherosclerosis
Study (IRAS) men and women aged 30–79 years who had a clinical examination and an oral glucose tolerance test (OGTT) during
1987–1996. Those with diabetes treatment or fasting plasma glucose ≥7.0 mmol/l were excluded (MetS was defined by Third Report
of the National Cholesterol Education Program’s Adult Treatment Panel criteria and IGT as 2-h postchallenge glucose 2hPG
≥7.8 mmol/l). We calculated positive (PPV) and negative predictive values (NPV), population attributable risk percentages
(PAR%), age- and sex-adjusted odds ratios (ORs), and areas under the receiver operating characteristic curve (AROCs) associated
with MetS traits.
RESULTS —Among FOS, SAHS, and MCDS subjects, 24–43% had MetS and 15–23% had IGT (including 2–5% with 2hPG ≥11.1 mmol/l). Among those
with MetS, OR for IGT were 3–4, PPV were 0.24–0.41, NPV were 0.84–0.91, and PAR% were 30–40%. Among subjects with MetS defined
by impaired fasting glucose (IFG) and any two other traits, OR for IGT were 9–24, PPV were 0.62–0.89, NPV were 0.78–0.87,
and PAR% were 3–12%. Among IRAS subjects, 24–34% had MetS and 37–41% had IGT. Among those with MetS, ORs for IGT were 3–6,
PPVs were 0.57–0.73, and NPVs were 0.67–0.72. In logistic regression models, IFG, large waist, and high triglycerides were
independently associated with IGT (AROC 0.71–0.83) in all study populations.
CONCLUSIONS —The MetS, especially defined by IFG, large waist, and high triglycerides, efficiently identifies subjects likely to have
IGT on OGTT and thus be eligible for diabetes prevention interventions.
AR%, attributable risk percentage
AROC, area under the receiver operating characteristic curve
FOS, Framingham Offspring Study
FPG, fasting plasma glucose
IFG, impaired fasting glucose
IGT, impaired glucose tolerance
IRAS, Insulin Resistance Atherosclerosis Study
MCDS, Mexico City Diabetes Study
MetS, metabolic syndrome
NCEP ATP III, Third Report of the National Cholesterol Education Program’s Adult Treatment Panel III
NPV, negative predictive value
PAR%, population AR%
PPV, positive predictive value
OGTT, oral glucose tolerance test
SAHS, San Antonio Heart Study
2hPG, 2-h postchallenge glucose
Footnotes
P.W.F.W. has received grant support from GlaxoSmithKline.
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.
Accepted March 1, 2004.
Received November 10, 2003.
DIABETES CARE
Background Approximately half of ovarian tumors have defects within the homologous recombination repair pathway. Tumors carrying pathogenic variants (PVs) in BRCA1/BRCA2 are more likely to respond to ...poly‐ADP ribose polymerase (PARP) inhibitor treatment. Large rearrangements (LRs) are a challenging class of variants to identify and characterize in tumor specimens and may therefore be underreported. This study describes the prevalence of pathogenic BRCA1/BRCA2 LRs in ovarian tumors and discusses the importance of their identification using a comprehensive testing strategy. Methods Sequencing and LR analyses of BRCA1/BRCA2 were conducted in 20 692 ovarian tumors received between March 18, 2016 and February 14, 2023 for MyChoice CDx testing. MyChoice CDx uses NGS dosage analysis to detect LRs in BRCA1/BRCA2 genes using dense tiling throughout the coding regions and limited flanking regions. Results Of the 2217 PVs detected, 6.3% (N = 140) were LRs. Overall, 0.67% of tumors analyzed carried a pathogenic LR. The majority of detected LRs were deletions (89.3%), followed by complex LRs (5.7%), duplications (4.3%), and retroelement insertions (0.7%). Notably, 25% of detected LRs encompassed a single or partial single exon. This study identified 84 unique LRs, 2 samples each carried 2 unique LRs in the same gene. We identified 17 LRs that occurred in multiple samples, some of which were specific to certain ancestries. Several cases presented here illustrate the intricacies involved in characterizing LRs, particularly when multiple events occur within the same gene. Conclusions Over 6% of PVs detected in the ovarian tumors analyzed were LRs. It is imperative for laboratories to utilize testing methodologies that will accurately detect LRs at a single exon resolution to optimize the identification of patients who may benefit from PARP inhibitor treatment.
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The assessment of mood states in individuals with dementia is a challenging yet clinically useful task. The purpose of the present study was to examine the validity of the Visual Analog Mood Scales ...(VAMS) in individuals with dementia.
Thirty-one patients who met diagnostic criteria for dementia completed the VAMS and a modified Profile of Mood States.
Authors found good convergent validity between all monotrait-heteromethod mood states. Excellent discriminant validity was found for VAMS Happy, Confused, Angry, and Energetic scales.
These results provide evidence for the validity of the VAMS in patients with dementia.
Abstract
BACKGROUND: Pediatric low-grade glioma (pLGG) is the most common CNS tumor of childhood. Progression-free survival (PFS) is much lower than overall survival emphasizing the need for ...alternative treatments. In addition, many children suffer functional morbidities such as visual and motor disturbances. Recently, there has been an appropriate prioritization of functional outcomes in children with pLGG. METHODS: We present the results of a PBTC phase II trial evaluating selumetinib, (AZD6244, ARRY-142886) a MEK-1/2 inhibitor, in children with recurrent/progressive pLGG on 2 strata, including visual outcomes. RESULTS: Stratum 3 enrolled Neurofibromatosis type 1 (NF1)-associated pLGG. Ten of 25 (40%) eligible patients had partial response (PR), 14/25 (56%) had stable disease (SD) and 1/25 (4%) had progressive disease (PD); 2-year PFS was 96+4%. Ten patients with optic pathway glioma (OPG) were evaluable for visual acuity (VA) at baseline and 1 year. VA improved in 2/10 patients (20%) and was stable in 8/10 (80%). One patient (10%) had improvement in visual fields (VF) and 9 patients (90%) had stable VF. Stratum 4 included patients with non-NF1-associated recurrent/progressive hypothalamic and OPG. Five of 25 (20%) eligible patients had PR, 16/25 (64%) had SD and 4 (16%) had PD; 2-year PFS was 78+8.5%. Nineteen of 25 patients were evaluable for VA. VA improved in 4/19 patients (21%), was stable in 13/19 (68%) and worsened in 2/19 (11%). Five patients (26%) had improved VF and 14 (74%) had stable VF. The most common toxicities included grade 1/2 CPK elevation, diarrhea, hypoalbuminemia and rash. Rare grade 3 toxicities included elevated CPK, rash and paronychia. CONCLUSIONS: Selumetinib was tolerable and effective in treating children with NF1-associated and sporadic recurrent/progressive hypothalamic and OPG based upon radiographic response and PFS. Twenty-seven of 29 (93%) evaluable patients had stable or improved vision based on VA and VF testing.
The Europan Molecular Indicators of Life Investigation (EMILI) is an instrument concept being developed for the Europa Lander mission currently under study. EMILI will meet and exceed the scientific ...and technical/resource requirements of the organic composition analyzer identified as a core instrument on the Lander. EMILI tightly couples two complementary analytical techniques, based on 1) liquid extraction and processing with capillary electrophoresis and 2) thermal and chemical extraction with gas chromatography, to robustly detect, structurally characterize, and quantify the broadest range of organics and other Europan chemicals over widely-varying concentrations. Dual processing and analysis paths enable EMILI to perform a thorough characterization of potential molecular biosignatures and contextual compounds in collected surface samples. Here we present a summary of the requirements, design, and development status of EMILI with projected scientific opportunities on the Europa Lander as well as on other potential life detection missions seeking potential molecular biosignatures in situ.
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