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1.
J Pediatr ; 272: 114128, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38815745

RESUMEN

OBJECTIVE: To determine associations between presenting symptoms and oropharyngeal dysphagia diagnoses, gastroesophageal reflux disease (GERD) diagnoses, and treatment with acid suppression medication in infants with brief resolved unexplained event (BRUE). STUDY DESIGN: We performed a prospective cohort study of infants with BRUE to review presenting symptoms and their potential impact on testing and treatment. Videofluoroscopic swallow study (VFSS) results and explanatory diagnoses were obtained from medical record review; acid suppression use was determined by parental survey. Binary and multivariable logistic regression models were used to evaluate associations between presenting symptoms and obtaining VFSS, VFSS results, GERD diagnoses, and acid suppression medication. RESULTS: Presenting symptoms were varied in 157 subjects enrolled at 51.0 ± 5.3 days of age, with many symptoms that may be related to GERD or dysphagia. Of these, 28% underwent VFSS with 71% abnormal. Overall, 42% had their BRUE attributed to GERD, and 33% were treated with acid suppression during follow-up. Presenting symptoms were significantly associated with the decision to obtain VFSS but not with abnormal VFSS results. Presenting symptoms were also associated with provision of GERD explanatory diagnoses. Both presenting symptoms and GERD explanatory diagnoses were associated with acid suppression use (aOR 2.3, 95% CI 1.03-5.3, P = .04). CONCLUSIONS: Presenting symptoms may play a role in clinicians' decisions on which BRUE patients undergo VFSS but are unreliable to make a diagnosis of oropharyngeal dysphagia. Presenting symptoms may also influence assignment of GERD explanatory diagnoses that is associated with increased acid suppression medication use.


Asunto(s)
Trastornos de Deglución , Reflujo Gastroesofágico , Humanos , Femenino , Masculino , Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/tratamiento farmacológico , Reflujo Gastroesofágico/complicaciones , Estudios Prospectivos , Lactante , Trastornos de Deglución/diagnóstico , Recién Nacido , Evento Inexplicable, Breve y Resuelto/diagnóstico , Evento Inexplicable, Breve y Resuelto/terapia , Fluoroscopía , Inhibidores de la Bomba de Protones/uso terapéutico
2.
J Pediatr ; 260: 113510, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37244581

RESUMEN

Thickening is efficacious and commonly recommended for oropharyngeal dysphagia and gastroesophageal reflux. Little is known about parental experience with this practice. Results of this cross-sectional questionnaire study suggest attitudes are positive, but parents frequently adjust recipes/nipple sizes, which might increase aspiration risk. Clinical follow-up is essential to ensure safe feeding.


Asunto(s)
Trastornos de Deglución , Reflujo Gastroesofágico , Niño , Humanos , Trastornos de Deglución/etiología , Estudios Prospectivos , Estudios Transversales , Reflujo Gastroesofágico/complicaciones , Padres
3.
J Pediatr Gastroenterol Nutr ; 77(4): 460-467, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37438891

RESUMEN

OBJECTIVES: Aerodigestive disorders encompass various pathological conditions affecting the lungs, upper airway, and gastrointestinal tract in children. While advanced care has primarily occurred in specialty centers, many children first present to general pediatric gastroenterologists with aerodigestive symptoms necessitating awareness of these conditions. At the 2021 Annual North American Society for Pediatric Gastroenterology, Hepatology and Nutrition meeting, the aerodigestive Special Interest Group held a full-day symposium entitled, Pediatric Aerodigestive Medicine: Advancing Collaborative Care of Children with Aerodigestive Disorders. The symposium aimed to underline the significance of a multidisciplinary approach to achieve better outcomes for these complex patients. METHODS: The symposium brought together leading experts to highlight the growing aerodigestive field, promote new scientific and therapeutic strategies, share the structure and benefits of a multidisciplinary approach in diagnosing common and rare aerodigestive disorders, and foster multidisciplinary discussion of complex cases while highlighting the range of therapeutic and diagnostic options. In this article, we showcase the diagnostic and therapeutic approach to oropharyngeal dysphagia (OPD), one of the most common aerodigestive conditions, emphasizing the role of a collaborative model. CONCLUSIONS: The aerodigestive field has made significant progress and continues to grow due to a unique multidisciplinary, collaborative model of care for these conditions. Despite diagnostic and therapeutic challenges, the multidisciplinary approach has enabled and greatly improved efficient, high-quality, and evidence-based care for patients, including those with OPD.


Asunto(s)
Trastornos de Deglución , Gastroenterología , Medicina , Humanos , Niño , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Trastornos de Deglución/terapia , Pulmón
4.
Oncologist ; 26(5): 375-382, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33687775

RESUMEN

INTRODUCTION: Pembrolizumab was approved with an accompanying companion diagnostic (CDx) assay (PD-L1 DAKO 22C3) for urothelial carcinoma (UC). In this study, we further characterize the clinicopathologic and genomic features of UC that are programmed death-ligand 1 (PD-L1) positive. MATERIALS AND METHODS: The cohort of this study consisted of a total of 528 consecutive UC patients with PD-L1 immunohistochemistry (IHC) and comprehensive genomic profiling (CGP). All PD-L1 IHC testing was performed using the DAKO 22C3 CDx assay for UC. PD-L1 positivity was determined at a combined positive score ≥ 10. RESULTS: A total of 44.5% (235/528) patients with UC were PD-L1positive . A lower PD-L1 positivity rate was detected in primary (42.3%, 148/350) versus metastatic sites (48.9%, 87/178). PD-L1 positivity was dependent on the location of the metastatic sites. CGP revealed PD-L1positive patients had more frequent genomic alterations (GAs) in TP53 (p = .006) and RB1 (p = .003) and less frequent GAs in FGFR3 (p = .001) and MTAP (p = .028). The APOBEC mutational signature and tumor mutational burden (TMB)-high were more common in PD-L1positive patients. By testing patients with UC with CGP, in addition to PD-L1 IHC, an additional 97 patients (18.4%) in the total cohort were eligible for immunotherapy based on TMB status. CONCLUSION: PD-L1positive and PD-L1negative urothelial carcinomas are genomically different. Also, our study provides the framework for future clinical investigation with regard to specimen site selection for PD-L1 testing as well as candidate biomarker genomic alterations that may predict for better response or lack of response to immune checkpoint inhibitors. IMPLICATIONS FOR PRACTICE: In this study, a higher prevalence of TP53 and RB1 alterations and APOBEC mutational signatures in the PD-L1positive urothelial carcinoma disease subset and enrichment of FGFR3 alterations in the PD-L1negative disease subset were found. These data provide the basis for future investigation into the role of these genomic changes as positive and negative predictors of immunotherapy response. Also, differences wer seen in PD-L1 positivity based on the collection site of the sample, which can provide a framework for future clinical trial design and could influence sample selection for PD-L1 testing in patients with urothelial carcinoma when multiple samples are available.


Asunto(s)
Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Antígeno B7-H1/genética , Biomarcadores de Tumor/genética , Genómica , Humanos , Inmunohistoquímica
5.
Oncologist ; 26(7): e1263-e1272, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33904632

RESUMEN

BACKGROUND: Histiocytic and dendritic cell neoplasms are a diverse group of tumors arising from monocytic or dendritic cell lineage. Whereas the genomic features for Langerhans cell histiocytosis and Erdheim-Chester disease have been well described, other less common and often aggressive tumors in this broad category remain poorly characterized, and comparison studies across the World Health Organization diagnostic categories are lacking. METHODS: Tumor samples from a total of 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs), underwent hybridization capture with analysis of up to 406 cancer-related genes. RESULTS: Among the entire cohort of 102 patients, CDKN2A mutations were most frequent across subtypes and made up 32% of cases, followed by TP53 mutations (22%). Mitogen-activated protein kinase (MAPK) pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCS (72% vs. 0%; p < .0001). In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytoses (61% vs. 12%; p < .0001). Tumor mutational burden was significantly higher in M group histiocytoses as compared with FDCSs (median 4.0/Mb vs. 2.4/Mb; p = .012). We also describe a pediatric patient with recurrent secondary histiocytic sarcoma treated with targeted therapy and interrogated by molecular analysis to identify mechanisms of therapeutic resistance. CONCLUSION: A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies. Our findings highlight the potential value of molecular testing to enable precise tumor classification, identify candidate oncogenic drivers, and define personalized therapeutic options for patients with these aggressive tumors. IMPLICATIONS FOR PRACTICE: This study presents comprehensive genomic profiling results on 102 patient cases within four major subtypes of malignant histiocytic and dendritic cell neoplasms, including 44 follicular dendritic cell sarcomas (FDCSs), 41 histiocytic sarcomas (HSs), 7 interdigitating dendritic cell sarcomas (IDCSs), and 10 Langerhans cell sarcomas (LCSs). MAPK pathway mutations were present and enriched among the malignant histiocytosis (M) group (HS, IDCS, and LCS) but absent in FDCSs. In contrast, NF-κB pathway mutations were frequent in FDCSs but rare in M group histiocytosis. A total of 42 patient tumors (41%) harbored pathogenic mutations that were potentially targetable by approved and/or investigative therapies.


Asunto(s)
Sarcoma de Células Dendríticas Foliculares , Trasplante de Células Madre Hematopoyéticas , Sarcoma , Niño , Sarcoma de Células Dendríticas Foliculares/genética , Células Dendríticas , Genómica , Humanos , Mutación , Recurrencia Local de Neoplasia , Sarcoma/genética
6.
Mod Pathol ; 34(7): 1425-1433, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33637877

RESUMEN

Positive program death-ligand 1 (PD-L1) immunohistochemistry (IHC) is an approved companion diagnostic guiding the use of immune checkpoint inhibitors in uterine cervical carcinoma (CXC). The clinical and genomic features of PD-L1-positive (PD-L1positive) CXC have not been previously described. We reviewed the clinicopathologic and molecular features of 647 CXC cases that were tested using DAKO 22C3 PD-L1 IHC and comprehensive genomic profiling during the course of clinical care. PD-L1positive cases were defined via a combined positive score of ≥ 1. No differences were found in age, genetic ancestry, and HPV status of the PD-L1positive (n = 548) and PD-L1negative disease subset. The PD-L1 positivity rate varied by histologic subtype of CXC with squamous cell carcinoma (SCC) having a PD-L1 positivity rate of 91% (397/437) and usual-type adenocarcinoma's PD-L1 positivity rate being 60% (35/58). In addition, the PD-L1 positivity rate varied depending on site of the specimen with 89.1% (261/293) positivity rate observed in cervix specimens compared to 25% (2/8) in brain metastases specimens. No significant difference in tumor mutational burden (TMB), microsatellite instability, and CD274 (encoding PD-L1) amplification was observed between PD-L1positive and PD-L1negative CXC subsets. By combining TMB with PD-L1, an additional 17 patients are eligible for pembrolizumab when compared to PD-L1 testing alone. TERT promoter alterations and APOBEC mutational signature were enriched in the PD-L1positive CXC SCC (p = 0.011, and p = 0.004, respectively). Our study reveals important prevalence data on PD-L1 positivity in CXC non-SCC and suggests that further studies in these histologic subtypes are warranted. In addition, we also provide a key framework to guide both specimen selection and future investigations of predictors of immunotherapy response in cervical cancer patients. Lastly, TERT promoter alterations and APOBEC mutational signature may be a biologically unique subset of PD-L1positive CXC SCC.


Asunto(s)
Antígeno B7-H1 , Carcinoma , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias del Cuello Uterino
7.
Mod Pathol ; 34(2): 252-263, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32884129

RESUMEN

PD-L1 immunohistochemistry (IHC) currently has the most Food and Drug Administration (FDA) approvals as a companion diagnostic (CDx) for immunotherapies in specific tumor types; however, multiple other immunotherapy biomarkers exist. We performed this study to examine and report the prevalence of PD-L1 expression in a wide variety of tumor types and examine its relationship to microsatellite instability (MSI), tumor mutational burden (TMB), and CD274 (PD-L1) gene amplification. We performed a retrospective analysis of all cases in which both PD-L1 IHC (using the DAKO 22C3 IHC assay with either tumor proportion score (TPS) or combined positive score (CPS); or the VENTANA SP142 assay with infiltrating immune cell score (IC)) and comprehensive genomic profiling (CGP) were tested at Foundation Medicine between January 2016 and November 2019. Of note, PD-L1 positivity is defined per the CDx indication and tumor proportion score (TPS ≥ 1) for indications without a CDx claim; and TMB positivity is defined as ≥10 mutations/Mb. A total of 48,782 cases were tested for PD-L1 IHC and CGP. Immune cell expression of PD-L1 was more frequently identified than tumor cell expression of PD-L1. We saw a high correlation between PD-L1 expression and CD274 gene amplification (p < 0.0001), MSI and TMB (p < 0.0001), and PD-L1 and TMB (p < 0.0001). In addition, the combination of PD-L1 and TMB identified four unique disease subsets PD-L1-/TMB-, PD-L1+/TMB-, PD-L1-/TMB+, and PD-L1+/TMB+ with varying prevalence dependent on tumor type. Lastly, 50.3% (24527/48782) of the overall cohort was positive for at least one of the CDx or exploratory biomarkers described above. This is the largest pan-cancer analysis of relevant biomarkers associated with response to checkpoint inhibitors to date, including more than 48,000 cases. Additional clinical trials with treatment outcome data in individual tumor types are needed to determine whether the double positive PD-L1+/TMB+ disease subset would respond best to immunotherapy.


Asunto(s)
Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Neoplasias/genética , Neoplasias/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Amplificación de Genes , Humanos , Inmunohistoquímica , Inestabilidad de Microsatélites , Mutación , Estudios Retrospectivos
8.
Clin Chem ; 67(11): 1554-1566, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34626187

RESUMEN

BACKGROUND: The amounts of circulating cell-free DNA (cfDNA) and circulating-tumor DNA (ctDNA) present in peripheral blood liquid biopsies can vary due to preanalytic/analytic variables. In this study, we examined the impact of patient age, sex, stage, and tumor type on cfDNA yield, ctDNA fraction, and estimated ctDNA quantity from a large cohort of clinical liquid biopsy samples. METHODS: We performed a retrospective analysis of 12 139 consecutive samples received for liquid biopsy (FoundationOne® Liquid) clinical testing. RESULTS: Significant differences in both cfDNA yield and estimated ctDNA quantity were observed based on the underlying tumor type that initiated the liquid biopsy analysis and the stage of the patient (P < 0.001). In addition, significant differences in ctDNA quantity were present based in both the patient age and sex (P < 0.001). Importantly, we saw a significantly higher success rate of issuing a clinically useful report in patients with higher levels of cfDNA yield and ctDNA quantity (P < 0.001). CONCLUSIONS: In this study, we show that ctDNA quantity varied significantly based on patient age, sex, stage, and tumor type, which could offer an explanation as to why certain liquid biopsy specimens are more likely to fail sequencing or provide clinically meaningful results. In addition, this could affect future clinical decisions on the blood sample volumes required to allow successful liquid biopsy testing.


Asunto(s)
Ácidos Nucleicos Libres de Células , ADN Tumoral Circulante , Neoplasias , Biomarcadores de Tumor/genética , Humanos , Biopsia Líquida/métodos , Mutación , Neoplasias/diagnóstico , Neoplasias/genética , Estudios Retrospectivos
9.
J Pediatr ; 238: 42-49.e2, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34186104

RESUMEN

OBJECTIVE: To determine whether the use of acid suppression and thickened feeds impact laryngomalacia outcomes in infants, including supraglottoplasty risk, time to supraglottoplasty, and hospitalization risk. STUDY DESIGN: We performed a retrospective cohort study to compare risk and time with supraglottoplasty and frequency and duration of hospitalizations for infants diagnosed with laryngomalacia at Boston Children's Hospital between January 1 and December 31, 2017. The primary outcomes were supraglottoplasty requirement, time to supraglottoplasty, and hospitalization risk. Multivariate analyses were performed to determine predictors of supraglottoplasty and hospitalization risk after adjusting for laryngomalacia severity and comorbidities in addition to propensity score adjustment. Kaplan-Meier curves were created to determine the impact of acid suppression use on time to supraglottoplasty. RESULTS: In total, 236 subjects with mean age 62.6 ± 4 days were included in the analysis; 55% were treated with acid suppression. Subjects treated with acid suppression had a greater risk of supraglottoplasty (hazard ratio 3.36, 95% CI 1.36-8.29, P = .009), shorter time to supraglottoplasty (5.64 ± 0.92 vs 7.98 ± 1.92 months, P = .006), and increased respiratory hospitalization risk (relative risk 1.97, 95% CI 1.01-3.85, 0.047), even after adjustment for covariates. Subjects receiving thickening had fewer respiratory hospitalization nights and longer time to supraglottoplasty (9.3 ± 1.7 vs 4.56 ± 0.73 months, P = .004), even after adjustment. CONCLUSIONS: Acid suppression use does not reduce the frequency of supraglottoplasty and related hospitalizations compared with untreated subjects. However, patients treated with thickening have decreased hospitalization and longer time to supraglottoplasty, suggesting that thickening of feeds may be a preferred intervention over acid suppression.


Asunto(s)
Antiulcerosos/administración & dosificación , Trastornos de Deglución/terapia , Reflujo Gastroesofágico/prevención & control , Laringomalacia/complicaciones , Antiulcerosos/efectos adversos , Trastornos de Deglución/etiología , Femenino , Reflujo Gastroesofágico/etiología , Glotis/cirugía , Hospitalización , Humanos , Lactante , Laringomalacia/cirugía , Laringomalacia/terapia , Masculino , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
10.
J Pediatr Gastroenterol Nutr ; 72(3): 372-377, 2021 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-33264182

RESUMEN

OBJECTIVES: Infants frequently present with feeding difficulties and respiratory symptoms, which are often attributed to gastroesophageal reflux but may be because of oropharyngeal dysphagia with aspiration. The Infant Gastroesophageal Reflux Questionnaire Revised (I-GERQ-R) is a clinical measure of gastroesophageal reflux disease but now there is greater understanding of dysphagia as a reflux mimic. We aimed to determine the degree of overlap between I-GERQ-R and evidence of dysphagia, measured by Pediatric Eating Assessment Tool-10 (Pedi-EAT-10) and videofluoroscopic swallow study (VFSS). METHODS: We performed a prospective study of subjects <18 months old with feeding difficulties. All parents completed Pedi-EAT-10 and I-GERQ-R as a quality initiative to address parental feeding concerns. I-GERQ-R results were compared with Pedi-EAT-10 and, whenever available, results of prior VFSS. Pearson correlation coefficients were calculated to determine the relationship between scores. Groups were compared with 1-way ANOVA and Fisher exact test. ROC analysis was completed to compare scores with VFSS results. RESULTS: One hundred eight subjects with mean age 7.1 ±â€Š0.5 months were included. Pedi-EAT-10 and I-GERQ-R were correlated (r = 0.218, P = 0.023) in all subjects and highly correlated in the 77 subjects who had prior VFSS (r = 0.369, P = 0.001). The blue spell questions on I-GERQ-R had relative risk 1.148 (95% confidence interval [CI] 1.043-1.264, P = 0.142) for predicting aspiration/penetration on VFSS, with 100% specificity. Scores on the question regarding crying during/after feedings were also higher in subjects with abnormal VFSS (1.1 ±â€Š0.15 vs 0.53 ±â€Š0.22, P = 0.04). CONCLUSIONS: I-GERQ-R and the Pedi-EAT-10 are highly correlated. I-GERQ-R results may actually reflect oropharyngeal dysphagia and not just gastroesophageal reflux disease in infants.


Asunto(s)
Trastornos de Deglución , Esofagitis Péptica , Reflujo Gastroesofágico , Niño , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/etiología , Reflujo Gastroesofágico/diagnóstico , Humanos , Lactante , Estudios Prospectivos , Encuestas y Cuestionarios
11.
Oncologist ; 25(2): e198-e202, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32043779

RESUMEN

For pediatric patients with high-grade gliomas, standard-of-care treatment includes surgery, chemotherapy, and radiation therapy; however, most patients ultimately succumb to their disease. With advances in genomic characterization of pediatric high-grade gliomas, the use of targeted therapies in combination with current treatment modalities offer the potential to improve survival in this patient population. In this report, we present the case of a 3-year-old girl with glioblastoma who continues to experience an exceptional and durable response (>2 years) to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib. Our patient presented with persistent and progressive seizure activity that upon workup was the result of a large heterogeneously enhancing, mixed cystic and solid mass in the left frontal-parietal-temporal region. Histopathologic analysis of resected tumor tissue confirmed the diagnosis of glioblastoma, and comprehensive genomic profiling demonstrated absence of any BRAF or H3F3A mutations. Genomic profiling, however, did reveal a probable germline heterozygous BRCA2 Lys3326Ter (K3226*) nonsense variant. After debulking surgery, the patient received standard-of-care treatment with radiation and temozolomide. Nine months later the PARP inhibitor olaparib was administered in combination with temozolomide for 16 cycles. This regimen was well tolerated by the patient and serial imaging showed reduction in tumor size. Since completion of the regimen, the patient remains neurologically intact with no evidence of tumor recurrence. To our knowledge, this represents the first case of a pediatric glioblastoma that maintains a durable response to a therapeutic strategy that included the PARP inhibitor olaparib and more generally highlights the potential clinical utility of incorporating these agents into the treatment of pediatric high-grade gliomas. KEY POINTS: Germline mutations detected in pediatric gliomas may represent a cancer predisposition syndrome. Integrating molecular testing into routine clinical care for pediatric patients with glioma is critical to identify therapeutic targets and patients with a cancer predisposition syndrome. Patients with glioma with defects in DNA repair pathway components (e.g., BRCA1/2) may show increased responsiveness to poly (ADP-ribose) polymerase (PARP) inhibitors. Combining PARP inhibitors with temozolomide (standard-of-care treatment) revealed no adverse events or toxicities over the course of 18 months.


Asunto(s)
Antineoplásicos , Glioblastoma , Neoplasias Ováricas , Antineoplásicos/uso terapéutico , Niño , Preescolar , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Humanos , Recurrencia Local de Neoplasia , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/uso terapéutico , Piperazinas , Temozolomida/uso terapéutico
12.
Oncologist ; 25(11): 943-953, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32869930

RESUMEN

BACKGROUND: We examined the current biomarker landscape in breast cancer when programmed death-ligand 1 (PD-L1) testing is integrated with comprehensive genomic profiling (CGP). MATERIAL AND METHODS: We analyzed data from samples of 312 consecutive patients with breast carcinoma tested with both CGP and PD-L1 (SP142) immunohistochemistry (IHC) during routine clinical care. These samples were stratified into hormone receptor positive (HR+)/human epidermal growth factor receptor negative (HER2-; n = 159), HER2-positive (n = 32), and triple-negative breast cancer (TNBC) cohorts (n = 121). RESULTS: We found that in the TNBC cohort, 43% (52/121) were immunocyte PD-L1-positive, and in the HR+/HER2- cohort, 30% (48/159) had PIK3CA companion diagnostics mutations, and hence were potentially eligible for atezolizumab plus nab-paclitaxel or alpelisib plus fulvestrant, respectively. Of the remaining 212 patients, 10.4% (22/212) had a BRCA1/2 mutation, which, if confirmed by germline testing, would allow olaparib plus talazoparib therapy. Of the remaining 190 patients, 169 (88.9%) were positive for another therapy-associated marker or a marker that would potentially qualify the patient for a clinical trial. In addition, we examined the relationship between immunocyte PD-L1 positivity and different tumor mutation burden (TMB) cutoffs and found that when a TMB cutoff of ≥9 mutations per Mb was applied (cutoff determined based on prior publication), 11.6% (14/121) patients were TMB ≥9 mutations/Mb and of these, TMB ≥9 mutations per Mb, 71.4% (10/14) were also positive for PD-L1 IHC. CONCLUSION: Our integrated PD-L1 and CGP methodology identified 32% of the tested patients as potentially eligible for at least one of the two new Food and Drug Administration approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker-guided potential therapeutic options. IMPLICATIONS FOR PRACTICE: This integrated programmed death-ligand 1 immunohistochemistry and comprehensive genomic profiling methodology identified 32% of the tested patients as eligible for at least one of the two new Food and Drug Administration-approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker-guided potential therapeutic options. These findings suggest new research opportunities to evaluate the predictive utility of other commonly seen PIK3CA mutations in hormone receptor-positive breast cancers and to standardize tumor mutation burden cutoffs to evaluate its potentially predictive role in triple-negative breast cancer.


Asunto(s)
Antígeno B7-H1 , Neoplasias de la Mama Triple Negativas , Antígeno B7-H1/genética , Biomarcadores de Tumor/genética , Genómica , Humanos , Inmunohistoquímica
13.
Gynecol Oncol ; 157(2): 357-366, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32156473

RESUMEN

OBJECTIVE: Genomic alterations of BCOR via ZC3H7B-BCOR fusion or BCOR internal tandem duplication (ITD) define a subset of endometrial stromal sarcoma (ESS). The goals of this study were to: 1) determine the molecular landscape of BCOR-rearranged ESS, 2) to identify novel BCOR fusion gene partners in ESS and their associated clinicopathological characteristics, and 3) to potentially unravel targetable genomic alterations in BCOR-mutated ESS. METHODS: A retrospective database search of a CLIA-certified molecular laboratory was performed for uterine sarcomas that contained BCOR rearrangements or BCOR ITD. The cases were previously assayed by comprehensive genomic profiling via both DNA- and RNA-based targeted next generation sequencing during the course of clinical care. Clinicopathological and genomic data was centrally re-reviewed. RESULTS: We identify largest cohort of BCOR-rearranged ESS to date (n = 40), which included 31 cases with canonical ZC3H7B-BCOR fusion as well as 8 cases with novel BCOR gene rearrangement partners, such as BCOR-L3MBTL2, EP300-BCOR, BCOR-NUTM2G, BCOR-RALGPS1, BCOR-MAP7D2, RGAG1-BCOR, ING3-BCOR, BCOR-NUGGC, KMT2D-BCOR, CREBBP-BCOR and 1 case with BCOR internal rearrangement. Re-review of cases with novel rearrangements demonstrated sarcomas with spindle, epithelioid or small round cell components and frequent myxoid stromal change. Comprehensive genomic profiling revealed high frequency of CDK4 and MDM2 amplification in 38% and 45% of BCOR-rearranged cases, respectively, and homozygous deletion of CDKN2A, which encodes an inhibitor of CDK4 in 28% of cases. Notably, CDK4 and MDM2 amplification was absent in all cases from 15 different ESS cases harboring BCOR ITD. CONCLUSIONS: Alterations of CDK4 pathway members, for which targeted therapy is clinically available (i.e. palbociclib), via CDK4 amplification or CDKN2A loss, contributes to the pathogenesis of BCOR-rearranged uterine sarcomas, which may have therapeutic implications.


Asunto(s)
Quinasa 4 Dependiente de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Sarcoma/genética , Neoplasias Uterinas/genética , Adulto , Estudios de Cohortes , Bases de Datos Genéticas , Femenino , Amplificación de Genes , Reordenamiento Génico , Genómica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Leiomiosarcoma/genética , Leiomiosarcoma/patología , Inestabilidad de Microsatélites , Persona de Mediana Edad , Estudios Retrospectivos , Sarcoma/patología , Sarcoma Estromático Endometrial/genética , Sarcoma Estromático Endometrial/patología , Neoplasias Uterinas/patología
14.
J Pediatr ; 211: 112-119.e4, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31103259

RESUMEN

OBJECTIVES: To determine if hospitalization, testing, diagnosis, and management of suspected gastroesophageal reflux, and follow-up visits decreased since introduction of American Academy of Pediatrics guidelines for brief resolved unexplained events (BRUEs). STUDY DESIGN: We performed a retrospective cohort study of infants with BRUE evaluated at Boston Children's Hospital in the year before and after guideline implementation to determine if practice patterns have changed. Outcomes included hospitalization rates, frequency of swallow assessments, other diagnostic testing, and reflux diagnoses, cost of care, and number of repeat visits. Groups were compared based on whether they presented before or after guideline implementation. RESULTS: In total, 359 subjects (186 pre-, 173 post-guidelines) were identified. There were no significant differences in practice patterns or outcomes before or after guideline implementation. Subjects had mean age 2.53 ± 0.15 months, and 80% were hospitalized for 2.49 ± 0.26 days. Each subject had 2.47 diagnostic tests performed, and 89% were noncontributory. Despite only 13% having videofluoroscopic swallow study performed, 72% showed aspiration/penetration. No subject had gastroesophageal reflux testing, yet reflux was implicated as the cause for admission in 40% of subjects, resulting in increased odds of discharge on acid suppressing medications (OR 2.88, 95% CI 1.68-4.92, P = .0001). In follow-up, 28% of subjects had repeat hospitalizations or emergency department visits for persistent symptoms. CONCLUSIONS: Infants with BRUE continue to undergo low-yield diagnostic testing and after admission remain symptomatic and frequently re-present to medical care. Swallow testing remains infrequent despite its high-yield, reflux continues to be implicated and children are still being discharged on acid suppression despite lack of efficacy.


Asunto(s)
Reflujo Gastroesofágico/diagnóstico , Reflujo Gastroesofágico/tratamiento farmacológico , Síntomas sin Explicación Médica , Pediatría/organización & administración , Pediatría/normas , Guías de Práctica Clínica como Asunto , Algoritmos , Boston , Femenino , Hospitalización , Hospitales Pediátricos , Humanos , Lactante , Masculino , Alta del Paciente , Readmisión del Paciente , Pautas de la Práctica en Medicina , Prescripciones , Estudios Retrospectivos , Factores de Riesgo , Sociedades Médicas , Estados Unidos
15.
J Pediatr Gastroenterol Nutr ; 68(2): 218-224, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30320668

RESUMEN

OBJECTIVES: To determine if children with laryngeal penetration on videofluoroscopic swallow study (VFSS) who received feeding interventions (thickened liquids, change in liquid flow rate, and/or method of liquid delivery) had improved symptoms and decreased hospitalizations compared with those without intervention. METHODS: We performed a retrospective cohort study of children under 2 years with laryngeal penetration on VFSS at our institution in 2015 to determine initial and follow-up VFSS findings, symptom improvement at follow-up, and hospitalization risk before and after VFSS. Proportions were compared with Fisher exact test and hospitalizations with paired t tests. RESULTS: We evaluated 137 subjects with age 8.93 ±â€Š0.59 months who had laryngeal penetration without aspiration on VFSS. Fifty-five percent had change in management, with 40% receiving thickening and 15% a change in flow rate. There was significant improvement in symptoms for children that had feeding intervention and this improvement was the greatest with thickening (OR 41.8, 95% CI 12.34-141.69, P < 0.001). On repeat VFSS, 26% had evidence of aspiration that was not captured on initial VFSS. Subjects had decreased total and pulmonary hospitalizations with feeding intervention and decreased pulmonary nights with thickening (P < 0.05). CONCLUSIONS: Laryngeal penetration appears to be clinically significant in children with oropharyngeal dysphagia and interventions to decrease its occurrence are associated with improved outcomes including decreased symptoms of concern and hospitalization nights. Thickening or other feeding intervention should be considered for all symptomatic children with laryngeal penetration on swallow study.


Asunto(s)
Trastornos de Deglución/terapia , Enfermedades de la Laringe/terapia , Apoyo Nutricional/métodos , Deglución , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/fisiopatología , Femenino , Fluoroscopía , Estudios de Seguimiento , Humanos , Lactante , Enfermedades de la Laringe/diagnóstico , Enfermedades de la Laringe/fisiopatología , Masculino , Estudios Retrospectivos , Resultado del Tratamiento
16.
Curr Gastroenterol Rep ; 21(7): 30, 2019 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-31098722

RESUMEN

PURPOSE OF REVIEW: The purpose of this review is to discuss current knowledge and recent findings regarding clinical aspects of thickeners for pediatric gastroesophageal reflux and oropharyngeal dysphagia. We review evidence for thickener efficacy, discuss types of thickeners, practical considerations when using various thickeners, and risks and benefits of thickener use in pediatrics. RECENT FINDINGS: Thickeners are effective in decreasing regurgitation and improving swallowing mechanics and can often be used empirically for the treatment of infants and young children. Adverse effects have been reported, but with careful consideration of appropriate thickener types, desired thickening consistency, and follow-up in collaboration with feeding specialists, most patients have symptomatic improvements. Thickeners are typically well tolerated and with few side effects, but close follow-up is needed to make sure patients tolerate thickeners and have adequate symptom improvement.


Asunto(s)
Trastornos de Deglución/terapia , Aditivos Alimentarios , Reflujo Gastroesofágico/terapia , Preescolar , Humanos , Lactante , Resultado del Tratamiento , Viscosidad
17.
J Pediatr ; 201: 141-146, 2018 10.
Artículo en Inglés | MEDLINE | ID: mdl-29960768

RESUMEN

OBJECTIVES: To determine if any presenting symptoms are associated with aspiration risk, and to evaluate the reliability of clinical feeding evaluation (CFE) in diagnosing aspiration compared with videofluoroscopic swallow study (VFSS). STUDY DESIGN: We retrospectively reviewed records of children under 2 years of age who had evaluation for oropharyngeal dysphagia by CFE and VFSS at Boston Children's Hospital and compared presenting symptoms, symptom timing, and CFE and VFSS results. We investigated the relationship between symptom presence and aspiration using the Fisher exact test and stepwise logistic regression with adjustment for comorbidities. CFE and VFSS results were compared using the McNemar test. Intervals from CFE to VFSS were compared using the Student t test. RESULTS: A total of 412 subjects with mean (±SD) age 8.9 ± 6.9 months were evaluated. No symptom, including timing relative to meals, predicted aspiration on VFSS. This lack of association between symptoms and VFSS results persisted even in the adjusted multivariate model. The sensitivity of CFE for predicting aspiration by VFSS was 44%. Patients with a reassuring CFE waited 28.2 ± 8.5 days longer for confirmatory VFSS compared with those with a concerning CFE (P < .05). CONCLUSIONS: Presenting symptoms are varied in patients with aspiration and cannot be relied upon to determine which patients have aspiration on VFSS. The CFE does not have the sensitivity to consistently diagnose aspiration so a VFSS should be performed in persistently symptomatic patients.


Asunto(s)
Trastornos de Deglución/complicaciones , Deglución/fisiología , Aspiración Respiratoria/epidemiología , Boston/epidemiología , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/fisiopatología , Femenino , Fluoroscopía/métodos , Estudios de Seguimiento , Humanos , Incidencia , Lactante , Masculino , Reproducibilidad de los Resultados , Aspiración Respiratoria/etiología , Aspiración Respiratoria/fisiopatología , Estudios Retrospectivos , Factores de Riesgo
18.
19.
J Pediatr Gastroenterol Nutr ; 65(2): 168-172, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-27741062

RESUMEN

OBJECTIVES: The aim of the present study was to investigate the prevalence of oropharyngeal dysfunction with resultant aspiration in patients admitted after apparent life-threatening events (ALTE) and to determine whether historical characteristics could predict this oropharyngeal dysphagia and aspiration risk. METHODS: We retrospectively reviewed the records of all patients admitted to Boston Children's Hospital between 2012 and 2015 with a diagnosis of ALTE to determine the frequency of evaluation for oropharyngeal dysphagia using video fluoroscopic swallow studies (VFSS) and clinical feeding evaluations, to determine the prevalence of swallowing dysfunction in subjects admitted after ALTE and to compare presenting historical characteristics to swallow study results. RESULTS: A total of 188 children were admitted with a diagnosis of ALTE of which 29% (n = 55) had an assessment of swallowing by VFSS. Of those who had a VFSS, 73% (n = 40) had evidence of aspiration or penetration on VFSS. Of all of the diagnostic tests ordered on patients with ALTEs, the VFSS had the highest rate of abnormalities of any test ordered. None of the historical characteristics of ALTE predicted which patients were at risk for aspiration. In patients who had both clinical feeding evaluations and VFSS, observed clinical feedings incorrectly identified 26% of patients as having no oropharyngeal dysphagia when in fact aspiration was present on VFSS. CONCLUSIONS: Oropharyngeal dysphagia with aspiration is the most common diagnosis identified in infants presenting with ALTEs. The algorithm for ALTE should be revised to include an assessment of VFSS as clinical feeding evaluations are inadequate to assess for aspiration.


Asunto(s)
Evento Inexplicable, Breve y Resuelto/etiología , Trastornos de Deglución/complicaciones , Aspiración Respiratoria/complicaciones , Trastornos de Deglución/diagnóstico , Trastornos de Deglución/epidemiología , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Prevalencia , Aspiración Respiratoria/diagnóstico , Aspiración Respiratoria/epidemiología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo
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