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Simultaneous presentation of two separate primary breast cancers of differing histology at initial diagnosis is an uncommon phenomenon; it is even rarer to find these pathologically distinct populations within the same biopsy. Here we report the case of a patient diagnosed with clearly demarcated, pathologically heterogenous triple negative breast cancer (TNBC) and HER2+ breast cancer that was treated with a hybrid chemoimmunotherapy regimen combining elements of Keynote-522 and a standard HER2-directed neoadjuvant regimen, yielding apathologic complete response by the time of surgery with no notable adverse events. Molecular analysis of the histologically distinct tumor populations confirmed molecular evidence of differential HER2 expression but also suggested clonal relatedness of the two tumor populations based upon mutational profile, with phenotypic divergence potentially resulting from copy number alterations in NF1. Overall, this case highlights a rare histologic phenomenon that was successfully treated by combining both TNBC and HER2 directed neoadjuvant therapies.
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The majority of human breast cancers are dependent on hormone-stimulated estrogen receptor alpha (ER) and are sensitive to its inhibition. Treatment resistance arises in most advanced cancers due to genetic alterations that promote ligand independent activation of ER itself or ER target genes. Whereas re-targeting of the ER ligand binding domain (LBD) with newer ER antagonists can work in some cases, these drugs are largely ineffective in many genetic backgrounds including ER fusions that lose the LBD or in cancers that hyperactivate ER targets. By identifying the mechanism of ER translation, we herein present an alternative strategy to target ER and difficult to treat ER variants. We find that ER translation is cap-independent and mTOR inhibitor insensitive, but dependent on 5' UTR elements and sensitive to pharmacologic inhibition of the translation initiation factor eIF4A, an mRNA helicase. EIF4A inhibition rapidly reduces expression of ER and short-lived targets of ER such as cyclin D1 and other components of the cyclin D-CDK complex in breast cancer cells. These effects translate into suppression of growth of a variety of ligand-independent breast cancer models including those driven by ER fusion proteins that lack the ligand binding site. The efficacy of eIF4A inhibition is enhanced when it is combined with fulvestrant-an ER degrader. Concomitant inhibition of ER synthesis and induction of its degradation causes synergistic and durable inhibition of ER expression and tumor growth. The clinical importance of these findings is confirmed by results of an early clinical trial (NCT04092673) of the selective eIF4A inhibitor zotatifin in patients with estrogen receptor positive metastatic breast cancer. Multiple clinical responses have been observed on combination therapy including durable regressions. These data suggest that eIF4A inhibition could be a useful new strategy for treating advanced ER+ breast cancer.
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OBJECTIVES: Perioperative stroke is the most dreaded complication of carotid artery interventions and can severely affect patients' quality of life. This study evaluated the impact of this event on mortality for patients undergoing interventional treatment of carotid artery stenosis with three different modalities. METHODS: Patients undergoing carotid revascularization at participating Memorial Hermann Health System facilities were captured from 2003-2022. These patients were treated with either carotid endarterectomy (CEA), transfemoral carotid stenting (TF-CAS), or transcarotid artery revascularization (TCAR). Perioperative outcomes, including stroke and mortality, as well as follow-up survival data at 6-month intervals, were analyzed and stratified per treatment modality. RESULTS: Of the 1681 carotid revascularization patients identified, 992 underwent CEA (59.0%), 524 underwent TCAR (31.2%), and 165 underwent TF-CAS (9.8%). The incidence of stroke was 2.1% (CEA 2.1%, TCAR 1.7%, and TF-CAS 3.6%; P = .326). The perioperative (30-day) death rate was 2.1% (n = 36). The perioperative death rate was higher in patients who suffered from an intraoperative stroke than in those who did not (8.3% vs 1.9%, P = .007). Perioperative death was also different between CEA, TCAR, and TF-CAS for patients who had an intraoperative stroke (.0% vs 33.3% vs .0%, P = .05). TCAR patients were likely to be older (P < .001), have a higher body mass index (P < .001), and have diabetes mellitus (P < .001). Patients who suffered from an intraoperative stroke were more likely to have a symptomatic carotid lesion (58.3% vs 28.8%, P < .001). The TCAR group had a significantly lower survival at 6 months and 12 months when compared to the other two groups (64.9% vs 100% P = .007). CONCLUSION: Perioperative stroke during carotid interventions significantly impacts early patient survival with otherwise no apparent change in mid-term outcomes at 5 years. This difference appears to be even more significant in patients undergoing TCAR, possibly due to their baseline higher-risk profile and lower functional reserve.
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Estenosis Carotídea , Endarterectomía Carotidea , Procedimientos Endovasculares , Accidente Cerebrovascular , Humanos , Procedimientos Endovasculares/efectos adversos , Calidad de Vida , Factores de Riesgo , Medición de Riesgo , Resultado del Tratamiento , Accidente Cerebrovascular/complicaciones , Estenosis Carotídea/complicaciones , Estenosis Carotídea/diagnóstico por imagen , Estenosis Carotídea/cirugía , Endarterectomía Carotidea/efectos adversos , Arterias Carótidas , Stents/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a minimally invasive alternative to resuscitative thoracotomy (RT) for patients with hemorrhagic shock. However, the potential benefits of this approach remain subject of debate. The aim of this study was to compare the outcomes of REBOA and RT for traumatic cardiac arrest. METHODS: A planned secondary analysis of the United States Department of Defense-funded Emergent Truncal Hemorrhage Control study was performed. Between 2017 and 2018, a prospective observational study of noncompressible torso hemorrhage was conducted at six Level I trauma centers. Patients were dichotomized by REBOA or RT, and baseline characteristics and outcomes were compared between groups. RESULTS: A total of 454 patients were enrolled in the primary study, of which 72 patients were included in the secondary analysis (26 underwent REBOA and 46 underwent resuscitative thoracotomy). Resuscitative endovascular balloon occlusion of the aorta patients were older, had a greater body mass index, and were less likely to be the victims of penetrating trauma. Resuscitative endovascular balloon occlusion of the aorta patients also had less severe abdominal injuries and more severe extremity injuries, although the overall injury severity scores were similar. There was no difference in mortality between groups (88% vs. 93%, p = 0.767). However, time to aortic occlusion was longer in REBOA patients (7 vs. 4 minutes, p = 0.001) and they required more transfusions of red blood cells (4.5 vs. 2.5 units, p = 0.007) and plasma (3 vs. 1 unit, p = 0.032) in the emergency department. After adjusted analysis, mortality remained similar between groups (RR, 0.89; 95% confidence interval, 0.71-1.12, p = 0.304). CONCLUSION: Resuscitative endovascular balloon occlusion of the aorta and RT were associated with similar survival after traumatic cardiac arrest, although time to successful aortic occlusion was longer in the REBOA group. Further research is needed to better define the role of REBOA in trauma. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level III.
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Oclusión con Balón , Toracotomía , Humanos , Aorta , Hemorragia , Resucitación , Estados Unidos , Estudios ProspectivosRESUMEN
The association between loss of BRCA1/2 and a homologous recombination deficiency phenotype is lineage dependent. In BRCA-associated cancers such as breast, ovarian, pancreas and prostate, this phenotype confers sensitivity to PARP inhibitors and platinum-therapies. Somatic reversion mutations restoring BRCA1/2 function mediate resistance, and have exclusively been reported in BRCA-associated tumors. In this study, we analyze matched tumor and normal sequencing from 31,927 patients and identify 846 (2.7%) patients with germline BRCA1/2 variants across 43 different cancer types, including 11 with somatic reversion mutations. While nine are in BRCA-associated tumors, we find two reversion mutations in non-BRCA-associated histologies, namely lung and esophagogastric adenocarcinomas. Both were detected following platinum therapy. Whole exome sequencing confirms the homologous recombination deficiency phenotype of these tumors. While reversion mutations arise in all BRCA-associated cancer types, here we show that reversion mutations arising post-platinum in non-BRCA associated histologies, while rare, may indicate BRCA1/2 mediated tumorigenesis.
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Adenocarcinoma , Platino (Metal) , Humanos , Masculino , Proteína BRCA1/genética , Células Germinativas , Mutación , Fenotipo , Proteína BRCA2/genéticaRESUMEN
An infected femoral artery pseudoaneurysm after aortic reconstruction is a devastating surgical complication associated with the morbidity of limb loss and pelvic ischemia with a reinfection rate of ≤10%. In the present case report, we have described a unique approach for an infected femoral pseudoaneurysm after thoraco-bifemoral bypass using an innovative configuration, in addition to an obturator bypass technique, in a patient with a complex vascular history. This unique approach made use of an existing limb of a thoraco-bifemoral bypass graft to provide inflow to two outflow conduits, the external iliac artery and superficial femoral artery, allowing for preservation of both pelvic and lower extremity perfusion.
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OBJECTIVE: Transcarotid artery revascularization (TCAR) is a new surgical option for carotid artery stenosis. While this procedure is optimally performed in hybrid operating rooms (OR), it is currently unclear whether it could be safely performed using portable, C-arm fluoroscopy with equivalent results. The aim of this study is to determine whether there are differences in intraoperative and perioperative outcomes stratified by imaging modality. METHODS: A retrospective review of all TCAR procedures attempted within our health system was performed, capturing all cases between September 2017 and May 2022. Procedures were divided into 2 cohorts, based on whether they were performed in a hybrid OR or with portable, C-arm in a standard OR. Patient demographics, intraoperative results, and postoperative outcomes were compared using univariate strategies. RESULTS: A total of 503 patients were included for review, of which 422 were performed in a hybrid OR (84%) and 81 were performed using a portable C-arm (16%). Intraoperatively, an increased estimated blood loss (47.7 ± 54.7 vs 26.1 ± 26.9 mLs, p < 0.01) and operative time was found in the cases performed in a hybrid OR. However, the fluoroscopy time was lower (4.0 ± 2.6 vs 5.2 ± 5.8 min, p = 0.01) in the setting of advanced intraoperative imaging. Postoperatively, we found no differences with respect to myocardial infarction (0.2% vs. 0%, p > 0.99), stroke (2.4% vs. 2.5%, p = 0.96), or death (0.7% vs. 2.5%, p = 0.15) between groups. CONCLUSIONS: While there are some intraoperative variabilities between TCAR performed in hybrid versus standard ORs, postoperative outcomes are comparable. Therefore, the lack of a hybrid room should not be a deterrent to the adoption of TCAR.
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We have reported the case of a duodenal-caval fistula in a 46-year-old man with peptic ulcer disease. He had previously undergone an open Graham patch repair for a perforated anterior duodenal ulcer and had presented 1 month after surgery with an upper gastrointestinal bleeding episode. A duodenal-caval fistula was diagnosed after computed tomography and was confirmed by upper endoscopy. The patient underwent staged repair of his duodenal-caval fistula with inferior vena cava thrombectomy, pyloric exclusion, and gastrojejunostomy creation.
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The efficacy of the highly selective RET inhibitor selpercatinib is now established in RET-driven cancers, and we sought to characterize the molecular determinants of response and resistance. We find that the pre-treatment genomic landscape does not shape the variability of treatment response except for rare instances of RAS-mediated primary resistance. By contrast, acquired selpercatinib resistance is driven by MAPK pathway reactivation by one of two distinct routes. In some patients, on- and off-target pathway reactivation via secondary RET solvent front mutations or MET amplifications are evident. In other patients, rare RET-wildtype tumor cell populations driven by an alternative mitogenic driver are selected for by treatment. Multiple distinct mechanisms are often observed in the same patient, suggesting polyclonal resistance may be common. Consequently, sequential RET-directed therapy may require combination treatment with inhibitors targeting alternative MAPK effectors, emphasizing the need for prospective characterization of selpercatinib-treated tumors at the time of monotherapy progression.
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Neoplasias Pulmonares , Neoplasias de la Tiroides , Humanos , Pulmón , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Estudios Prospectivos , Proteínas Proto-Oncogénicas c-ret/genética , Neoplasias de la Tiroides/tratamiento farmacológico , Neoplasias de la Tiroides/genéticaRESUMEN
PURPOSE: The RET proto-oncogene encodes a receptor tyrosine kinase that is activated by gene fusion in 1%-2% of non-small cell lung cancers (NSCLC) and rarely in other cancer types. Selpercatinib is a highly selective RET kinase inhibitor that has recently been approved by the FDA in lung and thyroid cancers with activating RET gene fusions and mutations. Molecular mechanisms of acquired resistance to selpercatinib are poorly understood. PATIENTS AND METHODS: We studied patients treated on the first-in-human clinical trial of selpercatinib (NCT03157129) who were found to have MET amplification associated with resistance to selpercatinib. We validated MET activation as a targetable mediator of resistance to RET-directed therapy, and combined selpercatinib with the MET/ALK/ROS1 inhibitor crizotinib in a series of single patient protocols (SPP). RESULTS: MET amplification was identified in posttreatment biopsies in 4 patients with RET fusion-positive NSCLC treated with selpercatinib. In at least one case, MET amplification was clearly evident prior to therapy with selpercatinib. We demonstrate that increased MET expression in RET fusion-positive tumor cells causes resistance to selpercatinib, and this can be overcome by combining selpercatinib with crizotinib. Using SPPs, selpercatinib with crizotinib were given together generating anecdotal evidence of clinical activity and tolerability, with one response lasting 10 months. CONCLUSIONS: Through the use of SPPs, we were able to offer combination therapy targeting MET-amplified resistance identified on the first-in-human study of selpercatinib. These data suggest that MET dependence is a recurring and potentially targetable mechanism of resistance to selective RET inhibition in advanced NSCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas , Ensayos Clínicos Fase I como Asunto , Crizotinib/farmacología , Crizotinib/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Amplificación de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Proyectos Piloto , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-ret/genética , Pirazoles/farmacología , Pirazoles/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Resultado del TratamientoRESUMEN
PURPOSE: Selpercatinib and pralsetinib induce deep and durable responses in patients with advanced RET fusion-positive lung and thyroid cancer. RET fusion testing strategies with rapid and reliable results are critical given recent FDA approval. Here, we assess various clinical assays in a large pan-cancer cohort. EXPERIMENTAL DESIGN: Tumors underwent DNA-based next-generation sequencing (NGS) with reflex to RNA-based NGS if no mitogenic driver or if a RET structural variant of unknown significance (SVUS) were present. Canonical DNA-level RET fusions and RNA-confirmed RET fusions were considered true fusions. Break-apart FISH and IHC performance were assessed in subgroups. RESULTS: A total of 171 of 41,869 patients with DNA NGS harbored RET structural variants, including 139 canonical fusions and 32 SVUS. Twelve of 32 (37.5%) SVUS were transcribed into RNA-level fusions, resulting in 151 oncogenic RET fusions. The most common RET fusion-positive tumor types were lung (65.6%) and thyroid (23.2%). The most common partners were KIF5B (45%), CCDC6 (29.1%), and NCOA4 (13.3%). DNA NGS showed 100% (46/46) sensitivity and 99.6% (4,459/4,479) specificity. FISH showed 91.7% (44/48) sensitivity, with lower sensitivity for NCOA4-RET (66.7%, 8/12). A total of 87.5% (7/8) of RET SVUS negative for RNA-level fusions demonstrated rearrangement by FISH. The sensitivity of IHC varied by fusion partner: KIF5B sensitivity was highest (100%, 31/31), followed by CCDC6 (88.9%, 16/18) and NCOA4 (50%, 6/12). Specificity of RET IHC was 82% (73/89). CONCLUSIONS: Although DNA sequencing has high sensitivity and specificity, RNA sequencing of RET SVUS is necessary. Both FISH and IHC demonstrated lower sensitivity for NCOA4-RET fusions.
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Biomarcadores de Tumor/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Hibridación Fluorescente in Situ/métodos , Neoplasias/patología , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-ret/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Neoplasias/genética , Pronóstico , Estudios Retrospectivos , Adulto JovenRESUMEN
PURPOSE: Calcimimetics are currently indicated for severe secondary hyperparathyroidism (SHPT). However, the role of parathyroidectomy (PTX) for these patients is still under debate, and its impact on subsequent kidney transplantation (KTX) is unclear. In this study, we compare the outcomes of kidney transplantation after PTX or medical treatment. METHODS: Patients who underwent KTX and had SHPT were analyzed retrospectively. Two groups were selected (patients who had either PTX or calcimimetics prior to KTX) using a propensity score for sex, age, donor type, and parathyroid hormone levels (PTH) during dialysis. The primary outcome was graft failure, and secondary outcomes were surgical KTX complications, survival, serum PTH, serum calcium, and serum phosphate levels post-KTX. RESULTS: Matching succeeded for 92 patients. After PTX, PTH was significantly lower on the day of KTX as well as at 1 and 3 years post-KTX (14.00 pmol/L (3.80-34.00) vs. 71.30 pmol/L (30.70-108.30), p < 0.01, 10.10 pmol/L (2.00-21.00) vs. 32.35 pmol/L (21.58-51.76), p < 0.01 and 13.00 pmol/L (6.00-16.60) vs. 19.25 pmol/L (13.03-31.88), p = 0.027, respectively). No significant differences in post-KTX calcium and phosphate levels were noted between groups. Severe KTX complications were more common in the calcimimetics group (56.5% vs. 30.4%, p = 0.047). There were no differences in 10-year graft failure and overall survival. CONCLUSION: PTX resulted in lower PTH after KTX in comparison to patients who received calcimimetics. Severe complications were more common after calcimimetics, but graft failure and overall survival were similar.
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Calcimiméticos/uso terapéutico , Hiperparatiroidismo Secundario/tratamiento farmacológico , Hiperparatiroidismo Secundario/cirugía , Trasplante de Riñón , Paratiroidectomía , Adulto , Biomarcadores/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Países Bajos , Hormona Paratiroidea/sangre , Puntaje de Propensión , Estudios RetrospectivosRESUMEN
It is widely accepted that a signal bandlimited by σ cannot oscillate at higher frequencies. The phenomenon of superoscillation provides a refutation of that quite general belief. Temporal superoscillations have been rarely demonstrated and are mostly treated as a mathematical curiosity. In the present article we demonstrate experimentally for the first time to our best knowledge, the transmission of superoscillating signals through commercial low pass filters. The experimental system used for the demonstration is described, providing the insight into the transmission of superoscillations, or super-narrow pulses. Thus, while the phenomenon may seem rather esoteric, a very simple system is used for our demonstration.
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OBJECTIVES: To examine the outcomes of planned induction of labour versus spontaneous onset of labour among women using prophylactic-dose low-molecular weight heparin (LMWH) therapy. DESIGN: Retrospective cohort study. SETTING: University hospital. POPULATION: Women receiving antepartum prophylactic LMWH therapy undergoing a trial of vaginal delivery. METHODS: Charts from 2018-2019 were reviewed. MAIN OUTCOME MEASURES: Duration of anticoagulation interruption and eligibility to receive neuraxial anaesthesia. RESULTS: Data from 199 women were analysed; 78 (39.2%) were admitted following spontaneous onset of labour and 121 (60.8%) underwent planned induction of labour. Compared to women who underwent planned induction of labour, women who presented with spontaneous onset of labour had a shorter median admission-to-delivery interval (4.7 versus 29.3 hours, P < 0.001). Similarly, intervals from the last LMWH injection to delivery (25.8 versus 48.2 hours, P < 0.001) and to the first postpartum LMWH injection (41.2 versus 63.7 hours, P < 0.001) were shorter. Among those with spontaneous onset of labour, 69 (88.5%) were eligible to receive neuraxial anaesthesia. Rates of postpartum haemorrhage and blood transfusion were similar between the groups. No thrombotic events were encountered in those with spontaneous onset of labour, but four (3.3%) women who delivered following induction of labour developed a postpartum thrombotic event. CONCLUSION: Planned induction of labour was associated with a higher risk of postpartum thrombotic events than was spontaneous onset of labour (4 of 121 [3.3%] versus 0 of 78 [0%]), presumably due to prolonged duration of anticoagulation interruption, although the difference was not statistically significant. Allowing spontaneous onset of labour was associated with comparable rates of bleeding complications, and only a low proportion (9 of 78, 11.5%) were not eligible to receive neuraxial anaesthesia. TWEETABLE ABSTRACT: Planned induction among women using prophylactic LMWH therapy might increase the risk of thromboembolic complications.
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Anticoagulantes/administración & dosificación , Heparina de Bajo-Peso-Molecular/administración & dosificación , Trabajo de Parto Inducido/métodos , Adulto , Anticoagulantes/efectos adversos , Parto Obstétrico/estadística & datos numéricos , Femenino , Heparina de Bajo-Peso-Molecular/efectos adversos , Humanos , Trabajo de Parto Inducido/efectos adversos , Tiempo de Internación , Embarazo , Estudios Retrospectivos , Factores de Tiempo , Tromboembolia Venosa/prevención & controlRESUMEN
With the FDA approval of larotrectinib, NTRK fusion assessment has recently become a standard part of management for patients with locally advanced or metastatic cancers. Unlike somatic mutation assessment, the detection of NTRK fusions is not straightforward, and various assays exist at the DNA, RNA, and protein level. Here, we investigate the performance of immunohistochemistry and DNA-based next-generation sequencing to indirectly or directly detect NTRK fusions relative to an RNA-based next-generation sequencing approach in the largest cohort of NTRK fusion positive solid tumors to date. A retrospective analysis of 38,095 samples from 33,997 patients sequenced by a targeted DNA-based next-generation sequencing panel (MSK-IMPACT), 2189 of which were also examined by an RNA-based sequencing assay (MSK-Fusion), identified 87 patients with oncogenic NTRK1-3 fusions. All available institutional NTRK fusion positive cases were assessed by pan-Trk immunohistochemistry along with a cohort of control cases negative for NTRK fusions by next-generation sequencing. DNA-based sequencing showed an overall sensitivity and specificity of 81.1% and 99.9%, respectively, for the detection of NTRK fusions when compared to RNA-based sequencing. False negatives occurred when fusions involved breakpoints not covered by the assay. Immunohistochemistry showed overall sensitivity of 87.9% and specificity of 81.1%, with high sensitivity for NTRK1 (96%) and NTRK2 (100%) fusions and lower sensitivity for NTRK3 fusions (79%). Specificity was 100% for carcinomas of the colon, lung, thyroid, pancreas, and biliary tract. Decreased specificity was seen in breast and salivary gland carcinomas (82% and 52%, respectively), and positive staining was often seen in tumors with neural differentiation. Both sensitivity and specificity were poor in sarcomas. Selection of the appropriate assay for NTRK fusion detection therefore depends on tumor type and genes involved, as well as consideration of other factors such as available material, accessibility of various clinical assays, and whether comprehensive genomic testing is needed concurrently.
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Biomarcadores de Tumor/análisis , Proteínas de Fusión Oncogénica/análisis , Receptor trkA/análisis , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica/métodos , Proteínas de Fusión Oncogénica/genética , Receptor trkA/genéticaRESUMEN
An Amendment to this paper has been published and can be accessed via a link at the top of the paper.