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1.
ESMO Open ; 8(4): 101615, 2023 08.
Article in English | MEDLINE | ID: mdl-37562195

ABSTRACT

BACKGROUND: Approximately 80% of all breast cancers (BCs) are currently categorized as human epidermal growth factor receptor 2 (HER2)-negative [immunohistochemistry (IHC) 0, 1+, or 2+/in situ hybridization (ISH) negative]; approximately 60% of BCs traditionally categorized as HER2-negative express low levels of HER2. HER2-low (IHC 1+ or IHC 2+/ISH-) status became clinically actionable with approval of trastuzumab deruxtecan to treat unresectable/metastatic HER2-low BC. Greater understanding of patients with HER2-low disease is urgently needed. PATIENTS AND METHODS: This global, multicenter, retrospective study (NCT04807595) included tissue samples from patients with confirmed HER2-negative unresectable/metastatic BC [any hormone receptor (HR) status] diagnosed from 2014 to 2017. Pathologists rescored HER2 IHC-stained slides as HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 IHC 0 after training on low-end expression scoring using Ventana 4B5 and other assays at local laboratories (13 sites; 10 countries) blinded to historical scores. HER2-low prevalence and concordance between historical scores and rescores were assessed. Demographics, clinicopathological characteristics, treatments, and outcomes were examined. RESULTS: In rescored samples from 789 patients with HER2-negative unresectable/metastatic BC, the overall HER2-low prevalence was 67.2% (HR positive, 71.1%; HR negative, 52.8%). Concordance was moderate between historical and rescored HER2 statuses (81.3%; κ = 0.583); positive agreement was numerically higher for HER2-low (87.5%) than HER2 IHC 0 (69.9%). More than 30% of historical IHC 0 cases were rescored as HER2-low overall (all assays) and using Ventana 4B5. There were no notable differences between HER2-low and HER2 IHC 0 in patient characteristics, treatments received, or clinical outcomes. CONCLUSIONS: Approximately two-thirds of patients with historically HER2-negative unresectable/metastatic BC may benefit from HER2-low-directed treatments. Our data suggest that HER2 reassessment in patients with historical IHC 0 scores may be considered to help optimize selection of patients for treatment. Further, accurate identification of patients with HER2-low BC may be achieved with standardized pathologist training.


Subject(s)
Biomarkers, Tumor , Breast Neoplasms , Humans , Female , Breast Neoplasms/epidemiology , Breast Neoplasms/therapy , Breast Neoplasms/diagnosis , Retrospective Studies , Prevalence , Receptor, ErbB-2/genetics , In Situ Hybridization
2.
Nat Commun ; 13(1): 4129, 2022 07 15.
Article in English | MEDLINE | ID: mdl-35840594

ABSTRACT

A critical challenge during volcanic emergencies is responding to rapid changes in eruptive behaviour. Actionable advice, essential in times of rising uncertainty, demands the rapid synthesis and communication of multiple datasets with prognoses. The 2020-2021 eruption of La Soufrière volcano exemplifies these challenges: a series of explosions from 9-22 April 2021 was preceded by three months of effusive activity, which commenced with a remarkably low level of detected unrest. Here we show how the development of an evolving conceptual model, and the expression of uncertainties via both elicitation and scenarios associated with this model, were key to anticipating this transition. This not only required input from multiple monitoring datasets but contextualisation via state-of-the-art hazard assessments, and evidence-based knowledge of critical decision-making timescales and community needs. In addition, we share strategies employed as a consequence of constraints on recognising and responding to eruptive transitions in a resource-constrained setting, which may guide similarly challenged volcano observatories worldwide.


Subject(s)
Disasters , Volcanic Eruptions
3.
Climacteric ; 24(2): 139-145, 2021 04.
Article in English | MEDLINE | ID: mdl-32880220

ABSTRACT

The Kronos Early Estrogen Prevention Study (KEEPS) was a randomized, double-blind, placebo-controlled trial designed to determine the effects of hormone treatments (menopausal hormone treatments [MHTs]) on the progression of carotid intima-medial thickness (CIMT) in recently menopausal women. Participants less than 3 years from menopause and without a history of overt cardiovascular disease (CVD), defined as no clinical CVD events and coronary artery calcium < 50 Agatston units, received either oral conjugated equine estrogens (0.45 mg/day) or transdermal 17ß-estradiol (50 µg/day), both with progesterone (200 mg/day for 12 days/month), or placebo pills and patches for 4 years. Although MHT did not decrease the age-related increase in CIMT, KEEPS provided other important insights about MHT effects. Both MHTs versus placebo reduced the severity of menopausal symptoms and maintained bone density, but differed in efficacy regarding mood/anxiety, sleep, sexual function, and deposition of ß-amyloid in the brain. Additionally, genetic variants in enzymes for metabolism and uptake of estrogen affected the efficacy of MHT for some aspects of symptom relief. KEEPS provides important information for use of MHT in clinical practice, including type, dose, and mode of delivery of MHT recently after menopause, and how genetic variants in hormone metabolism may affect MHT efficacy on specific outcomes.


Subject(s)
Cardiovascular Diseases/prevention & control , Carotid Intima-Media Thickness , Estrogen Replacement Therapy/methods , Estrogens/administration & dosage , Progesterone/administration & dosage , Administration, Cutaneous , Administration, Oral , Coronary Vessels/drug effects , Double-Blind Method , Estradiol/administration & dosage , Estrogens, Conjugated (USP)/administration & dosage , Female , Humans , Menopause/drug effects , Middle Aged , Treatment Outcome
4.
Ann Oncol ; 30(7): 1096-1103, 2019 07 01.
Article in English | MEDLINE | ID: mdl-31038663

ABSTRACT

BACKGROUND: Microsatellite instability (MSI) is a biomarker for response to immune checkpoint inhibitors (ICPIs). PD-1 inhibitors in metastatic colorectal carcinoma (mCRC) with MSI-high (MSI-H) have demonstrated a high disease control rate and favorable progression-free survival (PFS); however, reported response rates to pembrolizumab and nivolumab are variable and often <50%, suggesting that additional predictive biomarkers are needed. METHODS: Clinicopathologic data were collected from patients with MSI-H mCRC confirmed by hybrid capture-based next-generation sequencing (NGS) treated with PD-1/L1 inhibitors at five institutes. Tumor mutational burden (TMB) was determined on 0.8-1.1 Mb of sequenced DNA and reported as mutations/Mb. Potential biomarkers of response and time to progression were analyzed by univariate and multivariate analyses. Once TMB was confirmed as a predictive biomarker, a larger dataset of 18 140 unique CRC patients was analyzed to define the relevance of the identified TMB cut-point. RESULTS: A total of 22 patients were treated with PD-1/L1 inhibitors including 19 with pembrolizumab monotherapy. Among tested variables, TMB showed the strongest association with objective response (OR; P < 0.001) and PFS, by univariate (P < 0.001) and multivariate analysis (P < 0.01). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37 and 41 mutations/Mb. All 13 TMBhigh cases responded, while 6/9 TMBlow cases had progressive disease. The median PFS for TMBhigh has not been reached (median follow-up >18 months) while the median PFS for TMBlow was 2 months. A TMB of 37.4 mutations/Mb in a large MSI-H mCRC population (821/18, 140 cases; 4.5%) evaluated by NGS corresponded to the 35th percentile cut-point. CONCLUSIONS: TMB appears to be an important independent biomarker within MSI-H mCRC to stratify patients for likelihood of response to ICPIs. If validated in prospective studies, TMB may play an important role in guiding the sequencing and/or combinations of ICPIs in MSI-H mCRC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Mutation , Peritoneal Neoplasms/secondary , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , B7-H1 Antigen/antagonists & inhibitors , Biomarkers, Tumor/genetics , Colorectal Neoplasms/immunology , Colorectal Neoplasms/pathology , Female , Follow-Up Studies , Genetic Testing , High-Throughput Nucleotide Sequencing , Humans , Liver Neoplasms/genetics , Lymphatic Metastasis , Male , Microsatellite Instability , Middle Aged , Nivolumab/administration & dosage , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/genetics , Prognosis , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Retrospective Studies , Survival Rate
5.
Climacteric ; 22(2): 182-189, 2019 04.
Article in English | MEDLINE | ID: mdl-30661405

ABSTRACT

OBJECTIVE: Women who are currently using menopausal hormone therapy (MHT) have higher cerebrovascular reactivity when compared with postmenopausal women who are not taking MHT; however, the effect of cessation of MHT on cerebrovascular reactivity is not known. Given that MHT can have structural and activational effects on vascular function, this study was performed to characterize cerebrovascular reactivity following cessation of MHT in women at low risk for cerebrovascular disease. METHODS: Cerebrovascular reactivity was measured in a subset of women from the Kronos Early Estrogen Prevention Study (KEEPS) 3 years after cessation of the study drug (oral conjugated equine estrogen, transdermal 17ß-estradiol, or placebo [PLA]). RESULTS: Age, body mass index, and blood pressure were comparable among groups. At rest, the middle cerebral artery velocity (MCAv), cerebrovascular conductance index, mean arterial pressure, and cerebral pulsatility index did not differ among groups. Slope-based summary measures of cerebrovascular reactivity did not differ significantly among groups. However, utilizing repeated-measures modeling, there was a significant upward shift in MCAv responses (p = 0.029) in the combined MHT group compared with the PLA group. CONCLUSION: MHT has a marginal sustained effect on cerebrovascular reactivity when measured 3 years after cessation of hormone treatment.


Subject(s)
Brain/blood supply , Estrogen Replacement Therapy/adverse effects , Menopause , Blood Flow Velocity/drug effects , Blood Pressure , Carbon Dioxide/administration & dosage , Cerebral Arteries/physiology , Cerebrovascular Circulation/drug effects , Cerebrovascular Circulation/physiology , Cerebrovascular Disorders , Estradiol/administration & dosage , Estrogens/administration & dosage , Estrogens, Conjugated (USP)/administration & dosage , Female , Humans , Middle Aged , Placebos , Pulsatile Flow/drug effects
6.
J Urol ; 201(3): 541-548, 2019 03.
Article in English | MEDLINE | ID: mdl-30291913

ABSTRACT

PURPOSE: Metastatic penile squamous cell carcinoma is an aggressive malignancy with limited treatment options. We compared the potential therapy impacting genomic alterations between metastatic penile squamous cell carcinoma and nonpenile metastatic cutaneous squamous cell carcinoma. MATERIALS AND METHODS: DNA was extracted from 40 µ of formalin fixed, paraffin embedded samples from 78 cases of metastatic penile squamous cell carcinoma and 338 of metastatic cutaneous squamous cell carcinoma. Comprehensive genomic profiling was performed using a hybrid capture, adaptor ligation based, next generation sequencing assay to a mean coverage depth of greater than 500×. The tumor mutational burden was determined on 1.1 Mbp of sequenced DNA and microsatellite instability was determined on 114 loci. RESULTS: Potential targeted therapy opportunities in metastatic penile squamous cell carcinoma cases included alterations in the MTOR pathway ( NF1 genomic alterations in 7% and PTEN genomic alterations in 4%) and in the DNA repair pathway ( BRCA2 and ATM genomic alterations in 7% each) and tyrosine kinase ( EGFR genomic alterations in 6%, and FGFR3 and ERBB2 genomic alterations in 4% each). The tumor mutational burden was significantly higher in predominantly ultraviolet light exposed metastatic squamous cell carcinoma than in metastatic penile squamous cell carcinoma, making metastatic squamous cell carcinoma potentially more responsive to immunotherapies than metastatic penile squamous cell carcinoma. Microsatellite high status was extremely rare for metastatic penile and metastatic cutaneous squamous cell carcinoma. CD274 ( PD-L1) amplification was also rare in both tumor types. CONCLUSIONS: Metastatic penile squamous cell carcinoma is a unique subtype of squamous cell carcinoma with distinctive genomic features which contrast with those identified in metastatic cutaneous squamous cell carcinoma of nonpenile ultraviolet light exposed skin. Although not rich in predictors of the response to immunotherapy (the tumor mutational burden and microsatellite instability are low), more than a quarter of metastatic penile squamous cell carcinoma cases may potentially benefit from existing and available therapies targeting MTOR, DNA repair and tyrosine kinase pathways.


Subject(s)
Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/secondary , Penile Neoplasms/genetics , Penile Neoplasms/pathology , Skin Neoplasms/genetics , Skin Neoplasms/secondary , Aged , Carcinoma, Squamous Cell/therapy , DNA Mutational Analysis , DNA, Neoplasm/analysis , Genetic Profile , Genomics , Humans , Male , Middle Aged , Mutation , Skin Neoplasms/therapy
8.
Ann Oncol ; 29(6): 1394-1401, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29538669

ABSTRACT

Background: Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods: In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results: RET fusions were more frequent in older patients (median age of 66 versus 60 years, P = 0.052), with ECOG PS 1-2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P = 0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions: Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.


Subject(s)
Biomarkers, Tumor/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Gene Rearrangement , Oncogene Proteins, Fusion/genetics , Proto-Oncogene Proteins c-ret/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Male , Middle Aged , Neoplasm Metastasis , Prognosis , Survival Rate , Young Adult
10.
Climacteric ; 21(1): 53-59, 2018 02.
Article in English | MEDLINE | ID: mdl-29189095

ABSTRACT

OBJECTIVE: This study examined relationships, by pregnancy histories, between bone mineral density (BMD) and coronary artery calcification (CAC) in postmenopausal women. METHODS: Forty women identified from their medical record as having pre-eclampsia (PE) were age/parity-matched with 40 women having a normotensive pregnancy (NP). Vertebral (T4-9) BMD and CAC were assessed by quantitative computed tomography in 73 (37 with PE and 36 with NP) of the 80 women. Analyses included linear regression using generalized estimating equations. RESULTS: Women averaged 59 years of age and 35 years from the index pregnancy. There were no significant differences in cortical, trabecular or central BMD between groups. CAC was significantly greater in the PE group (p = 0.026). In multivariable analysis, CAC was positively associated with cortical BMD (p = 0.001) and negatively associated with central BMD (p = 0.036). There was a borderline difference in the association between CAC and central BMD by pregnancy history (interaction, p = 0.057). CONCLUSIONS: Although CAC was greater in women with a history of PE, vertebral BMD did not differ between groups. However, both cortical and central BMD were associated with CAC. The central BMD association was marginally different by pregnancy history, suggesting perhaps differences in underlying mechanisms of soft tissue calcification.


Subject(s)
Coronary Artery Disease/complications , Osteoporosis/complications , Pre-Eclampsia , Reproductive History , Vascular Calcification/diagnostic imaging , Absorptiometry, Photon , Bone Density , Coronary Artery Disease/epidemiology , Female , Humans , Linear Models , Menopause , Middle Aged , Minnesota/epidemiology , Multivariate Analysis , Osteoporosis/epidemiology , Pregnancy , Risk Factors , Tomography, X-Ray Computed
11.
Ann Oncol ; 28(10): 2539-2546, 2017 Oct 01.
Article in English | MEDLINE | ID: mdl-28961851

ABSTRACT

BACKGROUND: Relapsed/metastatic salivary gland carcinomas (SGCs) have a wide diversity of histologic subtypes associated with variable clinical aggressiveness and response to local and systemic therapies. We queried whether comprehensive genomic profiling could define the tumor subtypes and uncover clinically relevant genomic alterations, revealing new routes to targeted therapies for patients with relapsed and metastatic disease. PATIENTS AND METHODS: From a series of 85 686 clinical cases, DNA was extracted from 40 µm of formalin-fixed paraffin embedded (FFPE) sections for 623 consecutive SGC. CGP was carried out on hybridization-captured, adaptor ligation-based libraries (mean coverage depth, >500×) for up to 315 cancer-related genes. Tumor mutational burden was determined on 1.1 Mb of sequenced DNA. All classes of alterations, base substitutions, short insertions/deletions, copy number changes, and rearrangements/fusions were determined simultaneously. RESULTS: The clinically more indolent SGC including adenoid cystic carcinoma, acinic cell carcinoma, polymorphous low-grade adenocarcinoma, mammary analog secretory carcinoma, and epithelial-myoepithelial carcinomas have significantly fewer genomic alterations, TP53 mutations, and lower tumor mutational burden than the typically more aggressive SGCs including mucoepidermoid carcinoma, salivary duct carcinoma, adenocarcinoma, not otherwise specified, carcinoma NOS, and carcinoma ex pleomorphic adenoma. The more aggressive SGCs are commonly driven by ERBB2 PI3K pathway genomic alterations. Additional targetable GAs are frequently seen. CONCLUSIONS: Genomic profiling of SGCs demonstrates important differences between traditionally indolent and aggressive cancers. These differences may provide therapeutic options in the future.


Subject(s)
Carcinoma/genetics , Neoplasm Recurrence, Local/genetics , Salivary Gland Neoplasms/genetics , Aged , Carcinoma/pathology , DNA, Neoplasm/genetics , Female , Formaldehyde , Gene Expression Profiling , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/pathology , Paraffin Embedding , Salivary Gland Neoplasms/pathology , Tissue Fixation
12.
Ann Oncol ; 28(11): 2866-2873, 2017 Nov 01.
Article in English | MEDLINE | ID: mdl-28945887

ABSTRACT

BACKGROUND: Genomic changes that occur in breast cancer during the course of disease have been informed by sequencing of primary and metastatic tumor tissue. For patients with relapsed and metastatic disease, evolution of the breast cancer genome highlights the importance of using a recent sample for genomic profiling to guide clinical decision-making. Obtaining a metastatic tissue biopsy can be challenging, and analysis of circulating tumor DNA (ctDNA) from blood may provide a minimally invasive alternative. PATIENTS AND METHODS: Hybrid capture-based genomic profiling was carried out on ctDNA from 254 female patients with estrogen receptor-positive breast cancer. Peripheral blood samples were submitted by clinicians in the course of routine clinical care between May 2016 and March 2017. Sequencing of 62 genes was carried out to a median unique coverage depth of 7503×. Genomic alterations (GAs) in ctDNA were evaluated and compared with matched tissue samples and genomic datasets of tissue from breast cancer. RESULTS: At least 1 GA was reported in 78% of samples. Frequently altered genes were TP53 (38%), ESR1 (31%) and PIK3CA (31%). Temporally matched ctDNA and tissue samples were available for 14 patients; 89% of mutations detected in tissue were also detected in ctDNA. Diverse ESR1 GAs including mutation, rearrangement and amplification, were observed. Multiple concurrent ESR1 GAs were observed in 40% of ESR1-altered cases, suggesting polyclonal origin; ESR1 compound mutations were also observed in two cases. ESR1-altered cases harbored co-occurring GAs in PIK3CA (35%), FGFR1 (16%), ERBB2 (8%), BRCA1/2 (5%), and AKT1 (4%). CONCLUSIONS: GAs relevant to relapsed/metastatic breast cancer management were identified, including diverse ESR1 GAs. Genomic profiling of ctDNA demonstrated sensitive detection of mutations found in tissue. Detection of amplifications was associated with ctDNA fraction. Genomic profiling of ctDNA may provide a complementary and possibly alternative approach to tissue-based genomic testing for patients with estrogen receptor-positive metastatic breast cancer.


Subject(s)
Biomarkers, Tumor/genetics , Breast Neoplasms/genetics , Circulating Tumor DNA/genetics , Clinical Decision-Making , High-Throughput Nucleotide Sequencing/methods , Mutation , Receptors, Estrogen/metabolism , Adult , Aged , Aged, 80 and over , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Female , Follow-Up Studies , Genomics/methods , Humans , Middle Aged , Neoplasm Metastasis , Prognosis , Receptor, ErbB-2/metabolism , Receptors, Estrogen/genetics
13.
Lung Cancer ; 111: 84-87, 2017 09.
Article in English | MEDLINE | ID: mdl-28838405

ABSTRACT

Mutations in the epidermal growth factor receptor (EGFR) are drivers for a subset of lung cancers. Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) recently approved for the treatment of T790M-positive non-small cell lung cancer (NSCLC); however, acquired resistance to osimertinib is evident and resistance mechanisms remain incompletely defined. The EGFR G724S mutation was detected using hybrid-capture based comprehensive genomic profiling (CGP) and a hybrid-capture based circulating tumor DNA (ctDNA) assays in two cases of EGFR-driven lung adenocarcinoma in patients who had progressed on osimertinib treatment. This study demonstrates the importance of both tissue and blood based hybrid-capture based genomic profiling at disease progression to identifying novel resistance mechanisms in the clinic.


Subject(s)
Adenocarcinoma/genetics , Adenocarcinoma/pathology , Alleles , Amino Acid Substitution , ErbB Receptors/genetics , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Acrylamides , Adenocarcinoma/drug therapy , Adenocarcinoma of Lung , Aged , Aniline Compounds , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Disease Progression , Drug Resistance, Neoplasm/genetics , Exons , Fatal Outcome , Female , Humans , Lung Neoplasms/drug therapy , Male , Middle Aged , Neoplasm Staging , Piperazines/pharmacology , Piperazines/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Tomography, X-Ray Computed , Treatment Outcome
14.
J Gerontol Soc Work ; 60(6-7): 504-518, 2017.
Article in English | MEDLINE | ID: mdl-28463059

ABSTRACT

Growing numbers of seniors across the United States require skilled nursing facility care after an inpatient hospital stay. Previous studies indicate that roughly 20 percent of all hospitalized Medicare beneficiaries are admitted to a skilled nursing facility following a qualifying hospital stay. Social workers address psychosocial problems, social support, networks, and healthcare needs during transitions in care, particularly discharge planning. Ecosystems perspective and the eco-map as a discharge planning tool is presented. Social workers can use these tools to examine the patient with respect to their transactional relationships with systems. This will further will facilitate provision of wrap-around services upon discharge.


Subject(s)
Community Participation/methods , Ecosystem , Patient Discharge/standards , Skilled Nursing Facilities/standards , Social Behavior , Community Participation/psychology , Humans , Patient Discharge/trends , Skilled Nursing Facilities/trends , United States
16.
J Neonatal Perinatal Med ; 10(1): 113-118, 2017.
Article in English | MEDLINE | ID: mdl-28282819

ABSTRACT

Congenital mesoblastic nephroma (CMN) is the most common renal tumor of infancy; however, it occurs infrequently with an incidence of 1 : 125,000. The cellular and classical variants are the most common subtypes of tumors, with a mixed variant occurring infrequently. We describe two cases of mixed variant CMN, which presented within days of each other differing in their clinical behavior. The first case followed a typical course, previously described in the literature, while the other deviated significantly. Traditionally, CMN presents as large abdominal mass in the neonatal period associated with a paraneoplastic syndrome, which can result in hypertension or hypercalcemia. Surgical resection is curative in most cases and long-term prognosis is excellent. Hypertension rarely persists after removal of the tumor, but remained in one of our two patients.


Subject(s)
Kidney Neoplasms/diagnostic imaging , Nephroma, Mesoblastic/diagnostic imaging , Adult , Female , Humans , Hypertension/etiology , Infant, Newborn , Infant, Premature , Kidney Neoplasms/complications , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Lymph Node Excision , Magnetic Resonance Imaging , Male , Nephrectomy , Nephroma, Mesoblastic/complications , Nephroma, Mesoblastic/pathology , Nephroma, Mesoblastic/surgery , Paraneoplastic Syndromes/etiology , Pregnancy , Radiography
17.
Blood Cancer J ; 7(2): e535, 2017 02 24.
Article in English | MEDLINE | ID: mdl-28234347

ABSTRACT

The purpose of this study is to identify prognostic markers and treatment targets using a clinically certified sequencing panel in multiple myeloma. We performed targeted sequencing of 578 individuals with plasma cell neoplasms using the FoundationOne Heme panel and identified clinically relevant abnormalities and novel prognostic markers. Mutational burden was associated with maf and proliferation gene expression groups, and a high-mutational burden was associated with a poor prognosis. We identified homozygous deletions that were present in multiple myeloma within key genes, including CDKN2C, RB1, TRAF3, BIRC3 and TP53, and that bi-allelic inactivation was significantly enriched at relapse. Alterations in CDKN2C, TP53, RB1 and the t(4;14) were associated with poor prognosis. Alterations in RB1 were predominantly homozygous deletions and were associated with relapse and a poor prognosis which was independent of other genetic markers, including t(4;14), after multivariate analysis. Bi-allelic inactivation of key tumor suppressor genes in myeloma was enriched at relapse, especially in RB1, CDKN2C and TP53 where they have prognostic significance.


Subject(s)
Multiple Myeloma/genetics , Retinoblastoma Binding Proteins/genetics , Ubiquitin-Protein Ligases/genetics , Humans , Multiple Myeloma/pathology , Neoplasm Recurrence, Local , Prognosis , Retinoblastoma Protein/genetics
18.
Leukemia ; 31(1): 151-158, 2017 01.
Article in English | MEDLINE | ID: mdl-27363283

ABSTRACT

Genomic studies have identified recurrent somatic mutations in acute leukemias. However, current murine models do not sufficiently encompass the genomic complexity of human leukemias. To develop preclinical models, we transplanted 160 samples from patients with acute leukemia (acute myeloid leukemia, mixed lineage leukemia, B-cell acute lymphoblastic leukemia, T-cell ALL) into immunodeficient mice. Of these, 119 engrafted with expected immunophenotype. Targeted sequencing of 374 genes and 265 frequently rearranged RNAs detected recurrent and novel genetic lesions in 48 paired primary tumor (PT) and patient-derived xenotransplant (PDX) samples. Overall, the frequencies of 274 somatic variant alleles correlated between PT and PDX samples, although the data were highly variable for variant alleles present at 0-10%. Seventeen percent of variant alleles were detected in either PT or PDX samples only. Based on variant allele frequency changes, 24 PT-PDX pairs were classified as concordant while the other 24 pairs showed various degree of clonal discordance. There was no correlation of clonal concordance with clinical parameters of diseases. Significantly more bone marrow samples than peripheral blood samples engrafted discordantly. These data demonstrate the utility of developing PDX banks for modeling human leukemia, and emphasize the importance of genomic profiling of PDX and patient samples to ensure concordance before performing mechanistic or therapeutic studies.


Subject(s)
Heterografts/pathology , Leukemia/genetics , Acute Disease , Adolescent , Adult , Animals , Blood Cells/transplantation , Bone Marrow Transplantation , Cattle , Child , Gene Expression Profiling , Humans , Immunophenotyping , Leukemia/pathology , Mice , Middle Aged , Young Adult
19.
Ann Oncol ; 27(7): 1336-41, 2016 07.
Article in English | MEDLINE | ID: mdl-27052656

ABSTRACT

BACKGROUND: Squamous cell cancers of the anal canal (ASCC) are increasing in frequency and lack effective therapies for advanced disease. Although an association with human papillomavirus (HPV) has been established, little is known about the molecular characterization of ASCC. A comprehensive genomic analysis of ASCC was undertaken to identify novel genomic alterations (GAs) that will inform therapeutic choices for patients with advanced disease. PATIENTS AND METHODS: Hybrid-capture-based next-generation sequencing of exons from 236 cancer-related genes and intronic regions from 19 genes commonly rearranged in cancer was performed on 70 patients with ASCC. HPV status was assessed by aligning tumor sequencing reads to HPV viral genomes. GAs were identified using an established algorithm and correlated with HPV status. RESULTS: Sixty-one samples (87%) were HPV-positive. A mean of 3.5 GAs per sample was identified. Recurrent alterations in phosphoinositol-3-kinase pathway (PI3K/AKT/mTOR) genes including amplifications and homozygous deletions were present in 63% of cases. Clinically relevant GAs in genes involved in DNA repair, chromatin remodeling, or receptor tyrosine kinase signaling were observed in 30% of cases. Loss-of-function mutations in TP53 and CDKN2A were significantly enhanced in HPV-negative cases (P < 0.0001). CONCLUSIONS: This is the first comprehensive genomic analysis of ASCC, and the results suggest new therapeutic approaches. Differing genomic profiles between HPV-associated and HPV-negative ASCC warrants further investigation and may require novel therapeutic and preventive strategies.


Subject(s)
Anus Neoplasms/genetics , Carcinoma, Squamous Cell/genetics , Cyclin-Dependent Kinase Inhibitor p18/genetics , Genomics , Tumor Suppressor Protein p53/genetics , Adult , Aged , Aged, 80 and over , Anus Neoplasms/pathology , Anus Neoplasms/virology , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/virology , Cyclin-Dependent Kinase Inhibitor p16 , Exons/genetics , Female , High-Throughput Nucleotide Sequencing , Humans , Male , Middle Aged , Mutation , Neoplasm Proteins/genetics , Nuclear Proteins/genetics , Papillomaviridae/genetics , Papillomaviridae/isolation & purification , Papillomaviridae/pathogenicity , Transcription Factors/genetics
20.
Climacteric ; 19(1): 49-59, 2016.
Article in English | MEDLINE | ID: mdl-26652904

ABSTRACT

BACKGROUND: Serotonin (5-hydroxytryptamine, 5-HT) is modulated by sex steroid hormones and affects vascular function and mood. In the Kronos Early Estrogen Prevention Cognitive and Affective Ancillary Study (KEEPS-Cog), women randomized to oral conjugated equine estrogens (oCEE) showed greater benefit on affective mood states than women randomized to transdermal 17ß-estradiol (tE2) or placebo (PL). This study examined the effect of these treatments on the platelet content of 5-HT as a surrogate measure of 5-HT synthesis and uptake in the brain. METHODS: The following were measured in a subset (n = 79) of women enrolled in KEEPS-Cog: 5-HT by ELISA, carotid intima-medial thickness (CIMT) by ultrasound, endothelial function by reactive hyperemic index (RHI), and self-reported symptoms of affective mood states by the Profile of Mood States (POMS) questionnaire. RESULTS: Mean platelet content of 5-HT increased by 107.0%, 84.5% and 39.8%, in tE2, oCEE and PL groups, respectively. Platelet 5-HT positively correlated with estrone in the oCEE group and with 17ß- estradiol in the tE2 group. Platelet 5-HT showed a positive association with RHI, but not CIMT, in the PL and oCEE groups. Reduction in mood scores for depression-dejection and anger-hostility was associated with elevations in platelet 5-HT only in the oCEE group (r = -0.5, p = 0.02). CONCLUSIONS: Effects of oCEE compared to tE2 on RHI and mood may be related to mechanisms involving platelet, and perhaps neuronal, uptake and release of 5-HT and reflect conversion of estrone to bioavailable 17ß-estradiol in platelets and the brain.


Subject(s)
Affect/drug effects , Endothelium, Vascular/drug effects , Estradiol/administration & dosage , Estrogen Replacement Therapy , Estrogens, Conjugated (USP)/administration & dosage , Serotonin/blood , Administration, Cutaneous , Female , Humans , Middle Aged , Postmenopause
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