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Journal of Cachexia, Sarcopenia and... Feb 2019This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings.
RATIONALE
This initiative is focused on building a global consensus around core diagnostic criteria for malnutrition in adults in clinical settings.
METHODS
In January 2016, the Global Leadership Initiative on Malnutrition (GLIM) was convened by several of the major global clinical nutrition societies. GLIM appointed a core leadership committee and a supporting working group with representatives bringing additional global diversity and expertise. Empirical consensus was reached through a series of face-to-face meetings, telephone conferences, and e-mail communications.
RESULTS
A two-step approach for the malnutrition diagnosis was selected, i.e., first screening to identify "at risk" status by the use of any validated screening tool, and second, assessment for diagnosis and grading the severity of malnutrition. The malnutrition criteria for consideration were retrieved from existing approaches for screening and assessment. Potential criteria were subjected to a ballot among the GLIM core and supporting working group members. The top five ranked criteria included three phenotypic criteria (weight loss, low body mass index, and reduced muscle mass) and two etiologic criteria (reduced food intake or assimilation, and inflammation or disease burden). To diagnose malnutrition at least one phenotypic criterion and one etiologic criterion should be present. Phenotypic metrics for grading severity as Stage 1 (moderate) and Stage 2 (severe) malnutrition are proposed. It is recommended that the etiologic criteria be used to guide intervention and anticipated outcomes. The recommended approach supports classification of malnutrition into four etiology-related diagnosis categories.
CONCLUSION
A consensus scheme for diagnosing malnutrition in adults in clinical settings on a global scale is proposed. Next steps are to secure further collaboration and endorsements from leading nutrition professional societies, to identify overlaps with syndromes like cachexia and sarcopenia, and to promote dissemination, validation studies, and feedback. The diagnostic construct should be re-considered every 3-5 years.
Topics: Adult; Body Mass Index; Consensus; Eating; Global Health; Humans; Malnutrition; Phenotype; Sarcopenia; Weight Loss
PubMed: 30920778
DOI: 10.1002/jcsm.12383 -
International Journal of Molecular... Mar 2019Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed... (Review)
Review
Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of amplified breast cancers has improved meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522.
Topics: Ado-Trastuzumab Emtansine; Antineoplastic Agents, Immunological; Breast Neoplasms; Clinical Trials as Topic; Female; Humans; Maytansine; Protein Kinase Inhibitors; Receptor, ErbB-2; Trastuzumab
PubMed: 30841523
DOI: 10.3390/ijms20051115 -
Investigative Ophthalmology & Visual... Jan 2022Patients diagnosed with diabetes are inclined to have abnormalities on stability of tear film and disorder of meibomian gland (MG). This study aims to explore the...
PURPOSE
Patients diagnosed with diabetes are inclined to have abnormalities on stability of tear film and disorder of meibomian gland (MG). This study aims to explore the pathological change of MG induced by diabetes in a rat model.
METHODS
Sprague-Dawley (SD) rats were intraperitoneally injected with streptozotocin (STZ) to establish a diabetic animal model. Lipid accumulation in MG was detected by Oil Red O staining and LipidTox staining. Cell proliferation status was determined by Ki67 and P63 immunostaining, whereas cell apoptosis was confirmed by TUNEL assay. Gene expression of inflammatory cytokines and adhesion molecules IL-1α, IL-1β, ELAM1, ICAM1, and VCAM1 were detected by RT-PCR. Activation of ERK, NF-κB, and AMPK signaling pathways was determined by Western Blot analysis. Oxidative stress-related factors NOX4, 4HNE, Nrf2, HO-1, and SOD2 were detected by immunostaining or Western Blot analysis. Tom20 and Tim23 immunostaining and transmission electron microscopy were performed to evaluate the mitochondria functional and structure change.
RESULTS
Four months after STZ injection, there was acini dropout in MG of diabetic rats. Evident infiltration of inflammatory cells, increased expression of inflammatory factors, and adhesion molecules, as well as activated ERK and NF-κB signaling pathways were identified. Oxidative stress of MG was evident in 4-month diabetic rats. Phospho-AMPK was downregulated in MG of 2-month diabetic rats and more prominent in 4-month rats. After metformin treatment, phospho-AMPK was upregulated and the morphology of MG was well maintained. Moreover, inflammation and oxidative stress of MG were alleviated after metformin intervention.
CONCLUSIONS
Long-term diabetes may lead to Meibomian gland dysfunction (MGD). AMPK may be a therapeutic target of MGD induced by diabetes.
Topics: Animals; Blood Glucose; Cytokines; Disease Models, Animal; Hyperglycemia; Male; Meibomian Gland Dysfunction; Meibomian Glands; Oxidative Stress; Rats; Rats, Sprague-Dawley; Signal Transduction
PubMed: 35072689
DOI: 10.1167/iovs.63.1.30 -
Investigative Ophthalmology & Visual... Feb 2021To describe the molecular epidemiology of nonsyndromic retinitis pigmentosa (RP) and Usher syndrome (US) in Italian patients.
PURPOSE
To describe the molecular epidemiology of nonsyndromic retinitis pigmentosa (RP) and Usher syndrome (US) in Italian patients.
METHODS
A total of 591 probands (315 with family history and 276 sporadics) were analyzed. For 155 of them, we performed a family segregation study, considering a total of 382 relatives. Probands were analyzed by a customized multigene panel approach. Sanger sequencing was used to validate all genetic variants and to perform family segregation studies. Copy number variants of selected genes were analyzed by multiplex ligation-dependent probe amplification. Four patients who tested negative to targeted next-generation sequencing analysis underwent clinical exome sequencing.
RESULTS
The mean diagnostic yield of molecular testing among patients with a family history of retinal disorders was 55.2% while the diagnostic yield including sporadic cases was 37.4%. We found 468 potentially pathogenic variants, 147 of which were unpublished, in 308 probands and 66 relatives. Mean ages of onset of the different classes of RP were autosomal dominant RP, 19.3 ± 12.6 years; autosomal recessive RP, 23.2 ± 16.6 years; X-linked RP, 13.9 ± 9.9 years; and Usher syndrome, 18.9 ± 9.5 years. We reported potential new genotype-phenotype correlations in three probands, two revealed by TruSight One testing. All three probands showed isolated RP caused by biallelic variants in genes usually associated with syndromes such as PERCHING and Senior-Loken or with retinal dystrophy, iris coloboma, and comedogenic acne syndrome.
CONCLUSIONS
This is the largest molecular study of Italian patients with RP in the literature, thus reflecting the epidemiology of the disease in Italy with reasonable accuracy.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Child; DNA Mutational Analysis; Extracellular Matrix Proteins; Female; Follow-Up Studies; Genetic Association Studies; Genetic Testing; Humans; Incidence; Italy; Male; Middle Aged; Molecular Epidemiology; Mutation; Pedigree; Phenotype; Retinitis Pigmentosa; Retrospective Studies; Usher Syndromes; Exome Sequencing; Young Adult
PubMed: 33576794
DOI: 10.1167/iovs.62.2.13 -
Investigative Ophthalmology & Visual... Feb 2023The purpose of this study was to describe genotype-phenotype associations and novel insights into genetic characteristics in a trio-based cohort of inherited eye...
PURPOSE
The purpose of this study was to describe genotype-phenotype associations and novel insights into genetic characteristics in a trio-based cohort of inherited eye diseases (IEDs).
METHODS
To determine the etiological role of de novo mutations (DNMs) and genetic profile in IEDs, we retrospectively reviewed a large cohort of proband-parent trios of Chinese origin. The patients underwent a detailed examination and was clinically diagnosed by an ophthalmologist. Panel-based targeted exome sequencing was performed on DNA extracted from blood samples, containing coding regions of 792 IED-causative genes and their flanking exons. All participants underwent genetic testing.
RESULTS
All proband-parent trios were divided into 22 subgroups, the overall diagnostic yield was 48.67% (605/1243), ranging from 4% to 94.44% for each of the subgroups. A total of 108 IED-causative genes were identified, with the top 24 genes explaining 67% of the 605 genetically solved trios. The genetic etiology of 6.76% (84/1243) of the trio was attributed to disease-causative DNMs, and the top 3 subgroups with the highest incidence of DNM were aniridia (n = 40%), Marfan syndrome/ectopia lentis (n = 38.78%), and retinoblastoma (n = 37.04%). The top 10 genes have a diagnostic yield of DNM greater than 3.5% in their subgroups, including PAX6 (40.00%), FBN1 (38.78%), RB1 (37.04%), CRX (10.34%), CHM (9.09%), WFS1 (8.00%), RP1L1 (5.88%), RS1 (5.26%), PCDH15 (4.00%), and ABCA4 (3.51%). Additionally, the incidence of DNM in offspring showed a trend of correlation with paternal age at reproduction, but not statistically significant with paternal (P = 0.154) and maternal (P = 0.959) age at reproduction.
CONCLUSIONS
Trios-based genetic analysis has high accuracy and validity. Our study helps to quantify the burden of the full spectrum IED caused by each gene, offers novel potential for elucidating etiology, and plays a crucial role in genetic counseling and patient management.
Topics: Humans; Virulence; Retrospective Studies; Genetic Testing; Mutation; Eye Diseases; Pedigree; ATP-Binding Cassette Transporters; Eye Proteins
PubMed: 36729443
DOI: 10.1167/iovs.64.2.5 -
Leukemia Mar 2023Epstein-Barr virus (EBV) associated diffuse large B-cell lymphoma (DLBCL) represents a rare aggressive B-cell lymphoma subtype characterized by an adverse clinical...
Epstein-Barr virus (EBV) associated diffuse large B-cell lymphoma (DLBCL) represents a rare aggressive B-cell lymphoma subtype characterized by an adverse clinical outcome. EBV infection of lymphoma cells has been associated with different lymphoma subtypes while the precise role of EBV in lymphomagenesis and specific molecular characteristics of these lymphomas remain elusive. To further unravel the biology of EBV associated DLBCL, we present a comprehensive molecular analysis of overall 60 primary EBV positive (EBV+) DLBCLs using targeted sequencing of cancer candidate genes (CCGs) and genome-wide determination of recurrent somatic copy number alterations (SCNAs) in 46 cases, respectively. Applying the LymphGen classifier 2.0, we found that less than 20% of primary EBV + DLBCLs correspond to one of the established molecular DLBCL subtypes underscoring the unique biology of this entity. We have identified recurrent mutations activating the oncogenic JAK-STAT and NOTCH pathways as well as frequent amplifications of 9p24.1 contributing to immune escape by PD-L1 overexpression. Our findings enable further functional preclinical and clinical studies exploring the therapeutic potential of targeting these aberrations in patients with EBV + DLBCL to improve outcome.
Topics: Humans; Herpesvirus 4, Human; Epstein-Barr Virus Infections; Lymphoma, Large B-Cell, Diffuse; Mutation
PubMed: 36604606
DOI: 10.1038/s41375-022-01804-w -
Investigative Ophthalmology & Visual... Feb 2022To assess the potential of next-generation sequencing (NGS) technologies to characterize cases diagnosed with autosomal recessive (ar) or sporadic (s) macular...
PURPOSE
To assess the potential of next-generation sequencing (NGS) technologies to characterize cases diagnosed with autosomal recessive (ar) or sporadic (s) macular dystrophies (ar/sMD) and describe their mutational spectrum.
METHODS
A cohort of 1036 families was classified according to their suspected clinical diagnosis-Stargardt disease (STGD), cone and cone-rod dystrophy (CCRD) or other maculopathies (otherMD). Molecular studies included genotyping microarrays, Sanger sequencing, NGS, and sequencing of intronic regions of the ABCA4 gene. Clinical reclassification was done after the genetic study.
RESULTS
At the end of the study, 677 patients (65%) had a confirmed genetic diagnosis, representing 78%, 63%, and 38% of STGD, CCRD, and otherMD groups of patients, respectively. ABCA4 is the most mutated gene in all groups, and a second pathogenic variant was found in 76% of STGD patients with one previously identified mutated ABCA4 allele. Autosomal dominant or X-linked mutations were found in 5% of cases together with not-MD genes (CHM, EYS, RHO, RPGR, RLBP1, OPA1, and USH2A among others) leading to their reclassification. Novel variants in the very rare genes PLA2G5 and TTLL5 revealed additional phenotypic associations.
CONCLUSIONS
This study provides for the first time a genetic landscape of 1036 ar/sMD families according to their suspected diagnosis. The analysis of >200 genes associated with retinal dystrophies and the entire locus of ABCA4 increase the rate of characterization, even regardless of available clinical and familiar data. The use of the suspected a priori diagnosis referred by the clinicians, especially in the past, could lead to clinical reclassifications to other inherited retinal dystrophies.
Topics: ATP-Binding Cassette Transporters; Adult; Alleles; Cone-Rod Dystrophies; DNA; DNA Mutational Analysis; Female; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Morbidity; Mutation; Pedigree; Phenotype; Retrospective Studies; Rod Cell Outer Segment; Spain
PubMed: 35119454
DOI: 10.1167/iovs.63.2.11 -
International Journal of Radiation... Jun 2008To develop an atlas of the clinical target volume (CTV) definitions for postoperative radiotherapy of endometrial and cervical cancer to be used for planning pelvic...
PURPOSE
To develop an atlas of the clinical target volume (CTV) definitions for postoperative radiotherapy of endometrial and cervical cancer to be used for planning pelvic intensity-modulated radiotherapy.
METHODS AND MATERIALS
The Radiation Therapy Oncology Group led an international collaboration of cooperative groups in the development of the atlas. The groups included the Radiation Therapy Oncology Group, Gynecologic Oncology Group, National Cancer Institute of Canada, European Society of Therapeutic Radiology and Oncology, and American College of Radiology Imaging Network. The members of the group were asked by questionnaire to define the areas that were to be included in the CTV and to outline theses areas on individual computed tomography images. The initial formulation of the group began in late 2004 and culminated with a formal consensus conference in June 2005.
RESULTS
The committee achieved a consensus CTV definition for postoperative therapy for endometrial and cervical cancer. The CTV should include the common, external, and internal iliac lymph node regions. The upper 3.0 cm of the vagina and paravaginal soft tissue lateral to the vagina should also be included. For patients with cervical cancer, or endometrial cancer with cervical stromal invasion, it is also recommended that the CTV include the presacral lymph node region.
CONCLUSION
This report serves as an international template for the definition of the CTV for postoperative intensity-modulated radiotherapy for endometrial and cervical cancer.
Topics: Endometrial Neoplasms; Female; Humans; International Cooperation; Medical Illustration; Radiation Oncology; Radiotherapy Dosage; Radiotherapy, Intensity-Modulated; Tomography, X-Ray Computed; Tumor Burden; Uterine Cervical Neoplasms
PubMed: 18037584
DOI: 10.1016/j.ijrobp.2007.09.042 -
JAMA May 2011Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies.
CONTEXT
Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies.
OBJECTIVE
To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer.
DESIGN, SETTING, AND PATIENTS
Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens (then endocrine therapy if estrogen receptor [ER]-positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response.
MAIN OUTCOME MEASURES
Distant relapse-free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years).
RESULTS
Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy.
CONCLUSION
A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.
Topics: Adult; Algorithms; Anthracyclines; Antineoplastic Agents, Hormonal; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Breast Neoplasms; Bridged-Ring Compounds; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Forecasting; Gene Expression Profiling; Genes, Neoplasm; Genes, erbB-2; Genomics; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Oligonucleotide Array Sequence Analysis; Predictive Value of Tests; Prognosis; Prospective Studies; Receptors, Estrogen; Risk; Taxoids
PubMed: 21558518
DOI: 10.1001/jama.2011.593 -
International Journal of Molecular... Feb 2021The study of the human microbiome in oncology is a growing and rapidly evolving field. In the past few years, there has been an exponential increase in the number of... (Review)
Review
The study of the human microbiome in oncology is a growing and rapidly evolving field. In the past few years, there has been an exponential increase in the number of studies investigating associations of microbiome and cancer, from oncogenesis and cancer progression to resistance or sensitivity to specific anticancer therapies. The gut microbiome is now known to play a significant role in antitumor immune responses and in predicting the efficacy of immune-checkpoint inhibitors in cancer patients. Beyond the gut, the tumor-associated microbiome-microbe communities located either in the tumor or within its body compartment-seems to interact with the local microenvironment and the tumor immune contexture, ultimately impacting cancer progression and treatment outcome. However, pre-clinical research focusing on causality and mechanistic pathways as well as proof-of-concept studies are still needed to fully understand the potential clinical utility of microbiome in cancer patients. Moreover, there is a need for the standardization of methodology and the implementation of quality control across microbiome studies to allow for a better interpretation and greater comparability of the results reported between them. This review summarizes the accumulating evidence in the field and discusses the current and upcoming challenges of microbiome studies.
Topics: Animals; Antineoplastic Agents; Carcinogenesis; Cell Transformation, Neoplastic; Computational Biology; Cytoplasm; Disease Progression; Dysbiosis; Gastrointestinal Microbiome; Gene Expression Regulation, Bacterial; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Humans; Immunity; Metagenome; Metagenomics; Mice; Microbiota; Neoplasms; RNA, Ribosomal, 16S; Tumor Microenvironment
PubMed: 33535583
DOI: 10.3390/ijms22031446