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2.
Cell Rep ; 42(11): 113355, 2023 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-37922313

RESUMEN

Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains spanning large chromosomal regions, obscuring causal loci. Here, we employed organoid modeling to evaluate candidate oncogenic loci identified via integrative computational analysis of extreme copy gains overlapping with extreme expression dysregulation in The Cancer Genome Atlas. Subsets of "outlier" candidates were contextually screened as tissue-specific cDNA lentiviral libraries within cognate esophagus, oral cavity, colon, stomach, pancreas, and lung organoids bearing initial oncogenic mutations. Iterative analysis nominated the kinase DYRK2 at 12q15 as an amplified head and neck squamous carcinoma oncogene in p53-/- oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, promoted p53-/- esophageal organoid growth reversible by small molecule and soluble receptor antagonism of FGFRs. Our studies establish organoid-based contextual screening of candidate genomic drivers, enabling functional evaluation during early tumorigenesis.


Asunto(s)
Neoplasias , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Oncogenes , Transformación Celular Neoplásica/genética , Neoplasias/genética , Carcinogénesis/genética , Amplificación de Genes
3.
J Natl Compr Canc Netw ; 20(2): 102-104, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35130504

RESUMEN

HER2 mutations have been shown to be targetable in select cases of salivary gland cancers with overexpression or amplification of the HER2 oncogene. Fam-trastuzumab deruxtecan, a novel antibody-drug conjugate that combines trastuzumab with a topoisomerase I inhibitor, has recently demonstrated efficacy as a third-line agent in HER2-overexpressing breast cancer after trastuzumab failure. These promising results in breast cancer suggest a potential paradigm for use in other tumors with known HER2 alterations, including salivary gland cancer. This report describes a 67-year-old man with HER2-positive metastatic parotid gland carcinoma who experienced disease progression after parotidectomy with adjuvant cisplatin-based chemoradiation, neratinib, and ado-trastuzumab emtansine. After disease progression on the latter HER2-directed therapy, his malignancy demonstrated complete response to fam-trastuzumab deruxtecan, which has been sustained for the past 7 months. Fam-trastuzumab deruxtecan appears to be a well-tolerated therapeutic option in patients with HER2-positive salivary gland carcinoma, with activity demonstrated after progression on ado-trastuzumab emtansine and HER2-directed kinase inhibition. Further studies should be conducted to explore the use of this agent in HER2-positive salivary gland cancers.


Asunto(s)
Camptotecina , Carcinoma , Inmunoconjugados , Glándula Parótida , Trastuzumab , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Carcinoma/tratamiento farmacológico , Humanos , Inmunoconjugados/uso terapéutico , Masculino , Glándula Parótida/patología , Receptor ErbB-2/genética , Trastuzumab/uso terapéutico
4.
JNCI Cancer Spectr ; 4(5): pkaa054, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33225206

RESUMEN

BACKGROUND: In light of recent Food and Drug Administration (FDA) approval of immune checkpoint inhibitors for mismatch repair deficient (dMMR) malignancies, identifying patients with dMMR malignancies has become increasingly important. Although screening for dMMR in colorectal cancer (CRC) is recommended, it is less common for extracolonic gastrointestinal (GI) malignancies. At Stanford Comprehensive Cancer Institute (SCCI), all GI malignancies have been screened for dMMR via immunohistochemistry since January 2016. METHODS: In this study, we conducted a retrospective review of all patients with GI malignancies screened for dMMR between January 2016 and December 2017. Tumor sequencing was performed on cases negative for germline pathogenic variants where tumor material was available. RESULTS: A total of 1425 consecutive GI malignancies were screened for dMMR at SCCI during the study period, and 1374 were included for analysis. dMMR was detected in 7.2% of all GI malignancies. We detected the highest prevalence of dMMR in gastric (15 of 150, 10.0%) followed by colorectal (63 of 694, 9.1%), pancreatic (13 of 244, 5.3%), and gastroesophageal malignancy (6 of 132, 4.5%) patients. Lynch syndrome was the most common etiology for dMMR in colorectal cancer (41.5%), double somatic (confirmed or possible) pathogenic variants the most common etiology in pancreatic cancer (44.4%), and somatic MLH1 hypermethylation the most common etiology in gastric (73.3%) and gastroesophageal cancer (83.3%). CONCLUSIONS: Given the relatively high incidence of dMMR in GI malignancies, we recommend screening all GI malignancies. Our results suggest that although a rare occurrence, double somatic pathogenic variants may be a biologically significant pathway causing dMMR in pancreatic cancer.

5.
Clin Lung Cancer ; 19(5): 377-386, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29653819

RESUMEN

Cancer cooperative groups have historically played a critical role in the advancement of non-small-cell lung cancer therapy. Representatives from cooperative groups worldwide convene at the International Lung Cancer Congress annually. The International Lung Cancer Congress had its 17th anniversary in the summer of 2016. The present review highlights the thoracic malignancy studies discussed by presenters. The included studies are merely a sample of the trials of thoracic malignancies ongoing globally.


Asunto(s)
Ensayos Clínicos como Asunto , Inmunoterapia , Cooperación Internacional , Neoplasias Torácicas/terapia , Humanos , Pronóstico , Neoplasias Torácicas/inmunología
6.
Neuropsychiatr Dis Treat ; 13: 2469-2475, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29026310

RESUMEN

Medically intractable epilepsy is associated with increased morbidity and mortality. For those with focal epilepsy and correlated electrophysiological or radiographic features, open surgical resection can achieve high rates of seizure control, but can be associated with neurologic deficits and cognitive effects. Recent innovations have allowed for more minimally invasive methods of surgical seizure control such as magnetic resonance-guided laser interstitial therapy (MRgLITT). MRgLITT achieves the goal of ablating seizure foci while preserving neuropsycho-logical function and offering real-time feedback and monitoring of tissue ablation. This review summarizes the utilization of MRgLITT for mesial temporal lobe epilepsy and other seizure disorders. Overall, the efficacy of MRgLITT is comparable to that of open surgery and offers a less invasive approach in patients with significantly less morbidity.

7.
Mol Vis ; 18: 2711-6, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23213272

RESUMEN

PURPOSE: Primary and recurrent infections of the cornea by herpes simplex virus 1 (HSV-1) are important causes of eye disease. Three unrelated classes of glycoprotein D receptors for HSV-1 entry into cells have been identified. This study was undertaken to uncover the relative significance of nectin-1 as an entry receptor in corneal infection and HSV-1 spread to the trigeminal ganglia (TG), a site important for HSV-1 latency and recurrent corneal infection. METHODS: To assess the significance of nectin-1, a member of the immunoglobulin superfamily, in primary HSV-1 infection and spread to the TG, we used a murine model of corneal infection and a HSV-1 mutant, KOS(Rid1), which can only use nectin-1 for entry. Immunohistochemistry, real-time PCR, and plaque assays using HSV-1 infected tissues were performed. RESULTS: We demonstrated that receptor usage by HSV-1 limited to nectin-1 does not significantly change the spread of HSV-1 in the corneal epithelium during primary infection. We also found that nectin-1-specific entry does not affect the capacity of the virus to spread to the TG from the cornea. CONCLUSIONS: Our findings suggest that nectin-1 alone is sufficient for HSV-1 entry into the cornea and spread to the TG.


Asunto(s)
Moléculas de Adhesión Celular/metabolismo , Epitelio Corneal/metabolismo , Herpes Simple/metabolismo , Herpesvirus Humano 1/metabolismo , Receptores Virales/metabolismo , Ganglio del Trigémino/metabolismo , Internalización del Virus , Animales , Moléculas de Adhesión Celular/genética , Modelos Animales de Enfermedad , Epitelio Corneal/patología , Epitelio Corneal/virología , Expresión Génica , Herpes Simple/patología , Herpes Simple/virología , Herpesvirus Humano 1/genética , Humanos , Inmunohistoquímica , Queratitis Herpética , Ratones , Ratones Endogámicos BALB C , Mutación , Nectinas , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Virales/genética , Ganglio del Trigémino/patología , Ganglio del Trigémino/virología , Ensayo de Placa Viral , Latencia del Virus , Replicación Viral
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