HER2 evaluation for clinical decision making in human solid tumours: pearls and pitfalls.

The significant clinical benefits of human epidermal growth factor receptor 2 (HER2)-targeted therapeutic agents have revolutionized the clinical treatment landscape in a variety of human solid tumours. Accordingly, accurate evaluation of HER2 status in these different tumour types is critical for clinical decision making to select appropriate patients who may benefit from life-saving HER2-targeted therapies. HER2 biomarker scoring criteria is different in different organ systems, and close adherence to the corresponding HER2 biomarker testing guidelines and their updates, if available, is essential for accurate evaluation. In addition, knowing the unusual patterns of HER2 expression is also important to avoid inaccurate evaluation. In this review, we discuss the key considerations when evaluating HER2 status in solid tumours for clinical decision making, including tissue handling and preparation for HER2 biomarker testing, as well as pathologist's readout of HER2 testing results in breast carcinomas, gastroesophageal adenocarcinomas, colorectal adenocarcinomas, gynaecologic carcinomas, and non-small cell lung carcinomas.

Validation and interpretation of Pan-TRK immunohistochemistry: a practical approach and challenges with interpretation.

OBJECTIVES: Actionable, solid tumor activating neurotrophic receptor tyrosine kinase (NTRK) fusions are best detected via nucleic acid-based assays, while Pan-TRK immunohistochemistry (IHC) serves as a reasonable screening modality. We describe a practical and cost-effective approach to validate pan-TRK and discuss challenges that may be encountered. METHODS: Pan-TRK Clone EPR17341 was validated in accordance with the 2014 consensus statements set forth by the College of American Pathologists. Confirmation of IHC results were guided by the European Society of Medical Oncology recommendations for standard methods to detect NTRK fusions. RESULTS: Within 36 samples, ETV6-NTRK3 (n = 8) and TPM4-NTRK3 (n = 1) fusions were confirmed. ETV6-NTRK3 fusion positive cases revealed cytoplasmic and nuclear staining. A TPM4-NTRK3 fusion positive high grade malignant peripheral nerve sheath tumor revealed diffuse cytoplasmic staining. A high grade ovarian serous carcinoma revealed focal punctate staining and revealed a non-actionable NTRK1 truncation at intron 2. Diffuse cytoplasmic staining was observed in a case of fusion-negative polymorphous adenocarcinoma. Wild-type expression of TRK in pulmonary meningothelial-like nodules was discovered following a false-positive IHC interpretation. CONCLUSION: Pan-TRK IHC shows some utility as a diagnostic and surrogate marker for NTRK screening however, physiologic or non-specific expression may lead to false-positive results.

Efficient Lung Cancer Molecular Diagnostics by Combining Next Generation Sequencing with Reflex Idylla Genefusion Assay Testing.

Molecular diagnostics for lung cancer is a well-established standard of care, but how to use the available diagnostic tools for optimal and cost-effective patient care remains unresolved. Here, we show that DNA-only, small gene next-generation sequencing (sNGS) panels (<50 genes) combined with ultra-rapid reflex testing for common fusion transcripts using the Idylla Genefusion assay provide a cost-effective and sufficiently comprehensive testing modality for the majority of lung cancer cases. We also demonstrate the need for additional reflex testing capability on larger DNA and fusion panels for a small subset of lung cancers bearing rare single-nucleotide variants, indels and fusion transcripts and secondary, post-treatment resistance mutations. A similar testing workflow could be adopted for other solid tumor types for which extensive gene/fusion variant profiles are available both in the treatment-naïve and post-therapy settings.

Difficult withdrawal of an inferior vena cava filter: Technical considerations and associated variables.

OBJECTIVE: To analyse the efficacy of the procedure for withdrawing an inferior vena cava (IVC) filter and the clinical and radiological factors associated with difficult withdrawal. MATERIAL AND METHODS: This retrospective observational study included patients who underwent IVC filter withdrawal at a single centre between May 2015 and May 2021. We recorded demographic, clinical, procedural, and radiological variables: type of IVC filter, angle with the IVC > 15°, hook against the wall, and legs embedded in the IVC wall > 3 mm. The efficacy variables were fluoroscopy time, success of IVC filter withdrawal, and number of attempts to withdraw the filter. The safety variables were complications, surgical removal, and mortality. The main variable was difficult withdrawal, defined as more than 5 min fluoroscopy or more than 1 attempt at withdrawal. RESULTS: A total of 109 patients were included; withdrawal was considered difficult in 54 (49.5%). Three radiological variables were more common in the difficult withdrawal group: hook against the wall (33.3% vs. 9.1%; p = 0.027), embedded legs (20.4% vs. 3.6%; p = 0.008), and >45 days since IVC filter placement (51.9% vs. 25.5%; p = 0.006). These variables remained significant in the subgroup of patients with OptEase IVC filters; however, in the group of patients with Celect IVC filters, only the inclination of the IVC filter >15 ° was significantly associated with difficult withdrawal (25% vs 0%; p = 0.029). CONCLUSION: Difficult withdrawal was associated with time from IVC placement, embedded legs, and contact between the hook and the wall. The analysis of the subgroups of patients with different types of IVC filters found that these variables remained significant in those with OptEase filters; however, in those with cone-shaped devices (Celect), the inclination of the IVC filter >15° was significantly associated with difficult withdrawal.

Exploration of HER2 (ERBB2) immunohistochemistry in non-small cell lung cancer: correlation with ERBB2 mutational status: experimental research.

ERBB2 (HER2) is a gene in humans that encodes the ERBB2 protein, a member of the epidermal growth factor receptor family. Non-small cell lung carcinomas do not commonly harbour ERBB2 mutations, with clinical trials conducted to assess for targeted response and progression-free survival. We retrieved cases of lung adenocarcinoma with next-generation sequencing proven ERBB2 point mutations (n=8) or amplifications (n=11) and assessed the concordance of commercially available ERBB2 (HER2) immunohistochemical antibodies with the next-generation sequencing result. At present, no commercially available ERBB2 clone can accurately detect ERBB2 mutations consistently in non-small cell lung carcinoma specimens, but amplifications can be detected with reasonable diagnostic accuracy.

Retirada difícil de filtro de vena cava inferior (FVCI). Consideraciones técnicas y variables asociadas / Difficult withdrawal of an inferior vena cava filter: technical considerations and associated variables

Objetivo: Analizar la eficacia del procedimiento de retirada de los filtros de la vena cava inferior (FVCI), así como los factores clínico-radiológicos asociados a una retirada difícil. Material y método: Estudio retrospectivo, observacional y unicéntrico de pacientes tratados mediante retirada de FVCI entre mayo del 2015 y mayo del 2021. Se recogieron variables clínico-demográficas, del procedimiento y radiológicas: tipo de FVCI, angulación respecto a la vena cava inferior (VCI) >15°, gancho contra la pared y patas del dispositivo incrustadas en la pared de VCI> 3mm. Las variables de eficacia fueron: tiempo de fluoroscopia, éxito en la retirada del FVCI y número de intentos hasta la retirada. Como variables de seguridad: presencia de complicaciones, retirada quirúrgica y mortalidad. La variable principal fue la retirada difícil, definida como más de 5min de fluoroscopia o más de un intento de retirada. Resultados: Se incluyó a 109 pacientes, 54 (49,5%) fueron considerados retirada difícil. Las variables radiológicas gancho contra la pared (33,3% vs. 9,1%; p=0,027), patas incrustadas (20,4% vs. 3,6%; p=0,008) y> 45 días desde la colocación (51,9% vs. 25,5%; p=0,006) fueron significativamente más frecuentes en el grupo de retirada difícil. Estas variables mantienen la asociación al analizar los FVCI Optease®. En los FVCI Celect® solo se asoció con retirada difícil la inclinación del FVCI> 15° (25% vs. 0%; p=0,029).Conclusión: Se ha encontrado asociación entre una retirada difícil y las siguientes variables: tiempo desde colocación del FVCI, patas incrustadas y contacto del gancho con la pared de VCI. Al analizar según el tipo de FVCI, estas variables se mantienen en el tipo Optease®, en cambio, la inclinación de más de 15° dificulta la retirada de los dispositivos de morfología cónica (Celect®).(AU)

Objective: To analyze the efficacy of the procedure for withdrawing an inferior vena cava (IVC) filter and the clinical and radiological factors associated with difficult withdrawal. Material and methods: This retrospective observational study included patients who underwent IVC filter withdrawal at a single center between May 2015 and May 2021. We recorded demographic, clinical, procedural, and radiological variables: type of IVC filter, angle with the IVC> 15°, hook against the wall, and legs embedded in the IVC wall> 3mm. The efficacy variables were fluoroscopy time, success of IVC filter withdrawal, and number of attempts to withdraw the filter. The safety variables were complications, surgical removal, and mortality. The main variable was difficult withdrawal, defined as more than 5minutes fluoroscopy or more than 1 attempt at withdrawal. Results: A total of 109 patients were included; withdrawal was considered difficult in 54 (49.5%). Three radiological variables were more common in the difficult withdrawal group: hook against the wall (33.3% vs. 9.1%; p=0.027), embedded legs (20.4% vs. 3.6%; p=0.008), and>45 days since IVC filter placement (51.9% vs. 25.5%; p=0.006). These variables remained significant in the subgroup of patients with OptEase IVC filters; however, in the group of patients with Celect IVC filters, only the inclination of the IVC filter>15° was significantly associated with difficult withdrawal (25% vs 0%; p=0.029). Conclusion: Difficult withdrawal was associated with time from IVC placement, embedded legs, and contact between the hook and the wall. The analysis of the subgroups of patients with different types of IVC filters found that these variables remained significant in those with OptEase filters; however, in those with cone-shaped devices (Celect), the inclination of the IVC filter>15° was significantly associated with difficult withdrawal.(AU)

Determination of trajectories using IKZ/CF inertial navigation: Methodological proposal.

Nowadays, there are different methods used in the autonomous navigation task; current solutions include inertial navigation systems (INS). However, these systems present drift errors that are attenuated by the integration of absolute reference systems such as GPS, and antennas, among others. Consequently, few works concentrate efforts on developing a methodology to reduce drift errors in INS due to the widespread practice of incorporating absolute references into their systems. However, absolute references must be placed beforehand, which is not always possible. This work presents an improvement on our methodological proposal IKZ for tracking and localization of moving objects by integrating a complementary filter (CF). The main contribution of this paper is the methodological proposal in the integration between IKZ and CF, maintaining the restrictive properties to the drift error and significantly improving the handling characteristics of the system in real applications. Furthermore, the IKZ/CF was tested with raw data from an MPU-9255 in order to analyze the results between tests.

Diffuse pulmonary meningotheliomatosis with pan-TRK expression by immunohistochemistry: a novel finding and potential pitfall.

BACKGROUND: Pulmonary meningothelial-like nodules (PMNs) are benign proliferations of unclear clinical significance. They are mainly asymptomatic lesions that are usually discovered during the pathologic evaluation of resected pulmonary specimens or following post-mortem examination. Diffuse pulmonary meningotheliomatosis (DPM), which presents as bilateral multiple PMNs throughout the lungs, has been described less frequently. DPMs are benign lesions associated with both neoplastic and non-neoplastic pulmonary conditions. CASE PRESENTATION: We report the case of a 59-year-old female patient who presented with a history of cough. Computerized tomography (CT) imaging revealed multiple subcentimeter bilateral pulmonary nodules. transbronchial biopsies were obtained which revealed foci of nodular interstitial proliferations composed of epithelioid to spindled cells in a vague whorled pattern. Immunohistochemical stains were diffusely positive for EMA and progesterone receptor. Furthermore, pan-TRK exhibited strong and diffuse membranous expression in the lesional cells. INSM1 was negative for expression. RNA-based next-generation sequencing for the detection of NTRK fusions was performed and was negative for gene rearrangements involving NTRK1, NTRK2, and NTRK3. CONCLUSION: Here, we report a rare case of DPM and report pan-TRK expression in PMNs which has not been described. We provide a brief review of the literature and provide insight into the potential physiologic nature of PMNs. Lastly, we emphasize the recognition of pan-TRK immunoexpression in PMNs to avoid potential diagnostic errors.

Anticoagulation strategies and risk of bleeding events in critically ill COVID-19 patients / Estrategias de anticoagulación y riesgo de sangrado en pacientes ingresados en una Unidad de Cuidados Intensivos por COVID-19

Objective To evaluate the rate of thrombosis, bleeding and mortality comparing anticoagulant doses in critically ill COVID-19 patients. Design Retrospective observational and analytical cohort study. Setting COVID-19 patients admitted to the intensive care unit of a tertiary hospital between March and April 2020. Patients 201 critically ill COVID-19 patients were included. Patients were categorized into three groups according to the highest anticoagulant dose received during hospitalization: prophylactic, intermediate and therapeutic. Interventions The incidence of venous thromboembolism (VTE), bleeding and mortality was compared between groups. We performed two logistic multivariable regressions to test the association between VTE and bleeding and the anticoagulant regimen. Main variables of interest VTE, bleeding and mortality. Results 78 patients received prophylactic, 94 intermediate and 29 therapeutic doses. No differences in VTE and mortality were found, while bleeding events were more frequent in the therapeutic (31%) and intermediate (15%) dose group than in the prophylactic group (5%) (p<0.001 and p<0.05 respectively). The anticoagulant dose was the strongest determinant for bleeding (odds ratio 2.4, 95% confidence interval 1.26–4.58, p=0.008) but had no impact on VTE. Conclusion Intermediate and therapeutic doses appear to have a higher risk of bleeding without a decrease of VTE events and mortality in critically ill COVID-19 patients (AU)

Objetivo Evaluar la incidencia de eventos trombóticos, sangrado y mortalidad comparando diferentes regímenes de anticoagulación en pacientes ingresados en unidades de Cuidados Intensivos (UCI) por COVID-19. Diseño Estudio de cohortes retrospectivo observacional y analítico. Ámbito Pacientes con COVID-19 ingresados en una UCI de un hospital terciario entre marzo y abril del 2020. Pacientes Se incluyó a un total de 201 pacientes de UCI ingresados por COVID-19. Los pacientes se categorizaron en 3 grupos en función de la dosis de anticoagulación más alta recibida durante el ingreso: profiláctica, intermedia y terapéutica. Intervenciones Se comparó la incidencia de eventos trombóticos, hemorragia y mortalidad entre los grupos. Se realizaron 2 regresiones logísticas multivariables para comprobar la asociación entre los eventos trombóticos y el sangrado con el régimen anticoagulante. Principales variables de interés Eventos trombóticos, sangrado y mortalidad. Resultados De los pacientes incluidos, 78 recibieron dosis profilácticas, 94 intermedias y 29 terapéuticas. No se encontraron diferencias en los eventos trombóticos y la mortalidad entre grupos, mientras que los sangrados fueron más frecuentes en el grupo de dosis terapéutica (31%) e intermedia (15%) que en el grupo de dosis profiláctica (5%) (p <0,001 y p <0,05, respectivamente). El régimen anticoagulante fue el mayor determinante de sangrado (odds ratio 2,4;, intervalo de confianza del 95%, 1,26-4,58; p=0,008) pero no tuvo ningún impacto en los eventos trombóticos. Conclusiones Las dosis intermedias y terapéuticas parecen tener un mayor riesgo de sangrado sin una disminución de los eventos trombóticos ni la mortalidad en pacientes de UCI con COVID-19 (AU)

A Rare Case of a Large Ameloblastoma and Cervical Lynphoepitelial Cyst Treated Simultaneously by an Intraoral Approach and Immediate Reconstruction.

Ameloblastoma is a benign locally aggressive odontogenic tumor of epithelial origin with unlimited growth capacity. Cervical lymphoepithelial cyst is a developmental cyst located in the superior-lateral region of the neck with treatment consisting of surgical excision, which presents low recurrence rates. This article reports the case of patient J.G.S.L., 24 years old, female, who reported to the service with a histopathological evaluation compatible with intraosseous mandibular ameloblastoma. On physical examination, a nontender swelling was palpable along the body of left mandible where the ameloblastoma was located, with a fluctuant region detected just below it. Imaging exams confirmed the suspicion of two independent lesions. The treatment plan consisted of two stages: first, mandibular resection of the area affected by the ameloblastoma, followed by reconstruction with a titanium plate simultaneous to excisional biopsy of the as yet undiagnosed lesion, both through intraoral access; second, mandibular reconstruction with iliac crest graft. Histopathological examination of the second lesion indicated a diagnosis of cervical lymphoepithelial cyst, being the first case in the literature with these concomitant lesions. Currently, the patient is in her third postoperative year with no signs of recurrence.

Imaging and Clinical Findings in a Series of Six Cases of Rare Primary Mediastinal Liposarcoma.

Primary mediastinal liposarcoma is a rare, fat-containing malignant lesion that can manifest incidentally with varied imaging appearances. The size and location within the mediastinum can vary among patients. Here, the authors describe the clinical presentation, radiographic characteristics, management, and prognosis in a series of six patients with primary mediastinal liposarcoma. The following case series suggests that even simple-appearing fatty intrathoracic lesions may lead to the development of malignant imaging features. Keywords: Conventional Radiography, CT, MR Imaging, PET/CT, Soft Tissues/Skin, Thorax, Mediastinum ©RSNA, 2022.

Heterogeneity of neuroendocrine transcriptional states in metastatic small cell lung cancers and patient-derived models.

Molecular subtypes of small cell lung cancer (SCLC) defined by the expression of key transcription regulators have recently been proposed in cell lines and limited number of primary tumors. The clinical and biological implications of neuroendocrine (NE) subtypes in metastatic SCLC, and the extent to which they vary within and between patient tumors and in patient-derived models is not known. We integrate histology, transcriptome, exome, and treatment outcomes of SCLC from a range of metastatic sites, revealing complex intra- and intertumoral heterogeneity of NE differentiation. Transcriptomic analysis confirms previously described subtypes based on ASCL1, NEUROD1, POU2F3, YAP1, and ATOH1 expression, and reveal a clinical subtype with hybrid NE and non-NE phenotypes, marked by chemotherapy-resistance and exceedingly poor outcomes. NE tumors are more likely to have RB1, NOTCH, and chromatin modifier gene mutations, upregulation of DNA damage response genes, and are more likely to respond to replication stress targeted therapies. In contrast, patients preferentially benefited from immunotherapy if their tumors were non-NE. Transcriptional phenotypes strongly skew towards the NE state in patient-derived model systems, an observation that was confirmed in paired patient-matched tumors and xenografts. We provide a framework that unifies transcriptomic and genomic dimensions of metastatic SCLC. The marked differences in transcriptional diversity between patient tumors and model systems are likely to have implications in development of novel therapeutic agents.

Kawasaki disease shock syndrome in the COVID-19 pandemic.

Multisystem inflammatory syndrome in children is a new entity in association with SARS-CoV2. Clinical features of Kawasaki disease were noted from the first reported cases of MIS-C. Before the COVID-19 pandemic, Kawasaki disease shock syndrome was considered to be a distinct and unique form of KD. We present a representative case that prove the current difficulty in clearly distinguishing MIS-C from pre-COVID-19-KDSS and emphasie the overlap of the diagnostic criteria.

Development and Characterization of pH-Dependent Cellulose Acetate Phthalate Nanofibers by Electrospinning Technique.

The aim of this work was to obtain pH-dependent nanofibers with an electrospinning technique as a novel controlled release system for the treatment of periodontal disease (PD). Cellulose acetate phthalate (CAP) was selected as a pH-sensitive and antimicrobial polymer. The NF was optimized according to polymeric dispersion variables, polymer, and drug concentration, and characterized considering morphology, diameter, entrapment efficiency (EE), process efficiency (PE), thermal properties, and release profiles. Two solvent mixtures were tested, and CHX-CAP-NF prepared with acetone/ethanol at 12% w/v of the polymer showed a diameter size of 934 nm, a uniform morphology with 42% of EE, and 55% of PE. Meanwhile, CHX-CAP-NF prepared with acetone/methanol at 11% w/v of polymer had a diameter of 257 nm, discontinuous nanofiber morphology with 32% of EE, and 40% of PE. EE and PE were dependent on the polymer concentration and the drug used in the formulation. Studies of differential scanning calorimetry (DSC) showed that the drug was dispersed in the NF matrix. The release profiles of CHX from CHX-CAP-NF followed Fickian diffusion dependent on time (t0.43-0.45), suggesting a diffusion-erosion process and a matrix behavior. The NF developed could be employed as a novel drug delivery system in PD.

Linfoma de Hodgkin anal primario y tumor neuroendocrino intestinal sincrónicos: a propósito de un caso y revisión de la literatura / Primary rectal Hodgkin's lymphoma and synchronous small bowel neuroendocrine tumor: Case report and literature review

Resumen La localización extranodal gastrointestinal del linfoma de Hodgkin comprende el 5% de todos los linfomas. Dentro de este grupo, el linfoma anal primario representa menos del 0,05%, siendo por tanto una entidad extremadamente rara. Por otro lado, los tumores neuroendocrinos son un grupo heterogéneo de neoplasias relativamente poco frecuentes, pero de localización fundamentalmente digestiva. La asociación entre un linfoma de Hodgkin de localización anal y un tumor neuroendocrino intestinal no ha sido descrita previamente en la literatura, pero no es en absoluto raro que los tumores neuroendocrinos puedan coexistir con otro tipo de neoplasias. Los autores presentan el caso infrecuente de presentación de linfoma Hodgkin de localización anal asociado a un tumor neuroendocrino intestinal en una paciente mujer de 74 años, describiéndose la clínica, resultados de pruebas complementarias y tratamiento recibido.

Abstract Extranodal gastrointestinal Hodgkin's lymphoma comprises 5% of all lymphomas. In this group, primary rectal lymphoma represents less than 0.05%; thus, it is an extremely rare entity. On the other hand, neuroendocrine tumors are a heterogeneous group of infrequent neoplasms, mainly of digestive location. The association between a rectal Hodgkin's lymphoma and an intestinal neuroendocrine tumor has not been previously described in the literature, but it is not at all uncommon for neuroendocrine tumors to coexist with other types of neoplasms. The authors present a rare case of rectal Hodgkin's lymphoma associated with an intestinal neuroendocrine tumor in a 74-year-old female patient, describing the symptoms, complementary test results, and treatment.

Anticoagulation strategies and risk of bleeding events in critically ill COVID-19 patients.

OBJECTIVE: To evaluate the rate of thrombosis, bleeding and mortality comparing anticoagulant doses in critically ill COVID-19 patients. DESIGN: Retrospective observational and analytical cohort study. SETTING: COVID-19 patients admitted to the intensive care unit of a tertiary hospital between March and April 2020. PATIENTS: 201 critically ill COVID-19 patients were included. Patients were categorized into three groups according to the highest anticoagulant dose received during hospitalization: prophylactic, intermediate and therapeutic. INTERVENTIONS: The incidence of venous thromboembolism (VTE), bleeding and mortality was compared between groups. We performed two logistic multivariable regressions to test the association between VTE and bleeding and the anticoagulant regimen. MAIN VARIABLES OF INTEREST: VTE, bleeding and mortality. RESULTS: 78 patients received prophylactic, 94 intermediate and 29 therapeutic doses. No differences in VTE and mortality were found, while bleeding events were more frequent in the therapeutic (31%) and intermediate (15%) dose group than in the prophylactic group (5%) (p<0.001 and p<0.05 respectively). The anticoagulant dose was the strongest determinant for bleeding (odds ratio 2.4, 95% confidence interval 1.26-4.58, p=0.008) but had no impact on VTE. CONCLUSIONS: Intermediate and therapeutic doses appear to have a higher risk of bleeding without a decrease of VTE events and mortality in critically ill COVID-19 patients.

Nonphosphorylatable PEA15 mutant inhibits epithelial-mesenchymal transition in triple-negative breast cancer partly through the regulation of IL-8 expression.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks targeted therapies. Patients with TNBC have a very poor prognosis because the disease often metastasizes. New treatment approaches addressing drivers of metastasis and tumor growth are crucial to improving patient outcomes. Developing targeted gene therapy is thus a high priority for TNBC patients. PEA15 (phosphoprotein enriched in astrocytes, 15 kDa) is known to bind to ERK, preventing ERK from being translocated to the nucleus and hence blocking its activity. The biological function of PEA15 is tightly regulated by its phosphorylation at Ser104 and Ser116. However, the function and impact of phosphorylation status of PEA15 in the regulation of TNBC metastasis and in epithelial-to-mesenchymal transition (EMT) are not well understood. METHODS: We established stable cell lines overexpressing nonphosphorylatable (PEA15-AA) and phospho-mimetic (PEA15-DD) mutants. To dissect specific cellular mechanisms regulated by PEA15 phosphorylation status, we performed RT-PCR immune and metastasis arrays. In vivo mouse models were used to determine the effects of PEA15 phosphorylation on tumor growth and metastasis. RESULTS: We found that the nonphosphorylatable mutant PEA15-AA prevented formation of mammospheres and expression of EMT markers in vitro and decreased tumor growth and lung metastasis in in vivo experiments when compared to control, PEA15-WT and phosphomimetic PEA15-DD. However, phosphomimetic mutant PEA15-DD promoted migration, mesenchymal marker expression, tumorigenesis, and lung metastasis in the mouse model. PEA15-AA-mediated inhibition of breast cancer cell migratory capacity and tumorigenesis was the partial result of decreased expression of interleukin-8 (IL-8). Further, we identified that expression of IL-8 was possibly mediated through one of the ERK downstream molecules, Ets-1. CONCLUSIONS: Our results show that PEA15 phosphorylation status serves as an important regulator for PEA15's dual role as an oncogene or tumor suppressor and support the potential of PEA15-AA as a therapeutic strategy for treatment of TNBC.

Notch signaling and efficacy of PD-1/PD-L1 blockade in relapsed small cell lung cancer.

Immune checkpoint blockade (ICB) benefits only a small subset of patients with small cell lung cancer (SCLC), yet the mechanisms driving benefit are poorly understood. To identify predictors of clinical benefit to ICB, we performed immunogenomic profiling of tumor samples from patients with relapsed SCLC. Tumors of patients who derive clinical benefit from ICB exhibit cytotoxic T-cell infiltration, high expression of antigen processing and presentation machinery (APM) genes, and low neuroendocrine (NE) differentiation. However, elevated Notch signaling, which positively correlates with low NE differentiation, most significantly predicts clinical benefit to ICB. Activation of Notch signaling in a NE human SCLC cell line induces a low NE phenotype, marked by increased expression of APM genes, demonstrating a mechanistic link between Notch activation, low NE differentiation and increased intrinsic tumor immunity. Our findings suggest Notch signaling as a determinant of response to ICB in SCLC.

Erratum: Anterior mediastinal large cell neuroendocrine carcinoma with elevated AFP: A case report and review.

[This corrects the article DOI: 10.3892/mco.2020.2196.].