RESUMEN
BACKGROUND: The acquisition of oncogenic drivers is a critical feature of cancer progression. For some carcinomas, it is clear that certain genetic drivers occur early in neoplasia and others late. Why these drivers are selected and how these changes alter the neoplasia's fitness is less understood. METHODS: Here we use spatially oriented genomic approaches to identify transcriptomic and genetic changes at the single-duct level within precursor neoplasia associated with invasive breast cancer. We study HER2 amplification in ductal carcinoma in situ (DCIS) as an event that can be both quantified and spatially located via fluorescence in situ hybridization (FISH) and immunohistochemistry on fixed paraffin-embedded tissue. RESULTS: By combining the HER2-FISH with the laser capture microdissection (LCM) Smart-3SEQ method, we found that HER2 amplification in DCIS alters the transcriptomic profiles and increases diversity of copy number variations (CNVs). Particularly, interferon signaling pathway is activated by HER2 amplification in DCIS, which may provide a prolonged interferon signaling activation in HER2-positive breast cancer. Multiple subclones of HER2-amplified DCIS with distinct CNV profiles are observed, suggesting that multiple events occurred for the acquisition of HER2 amplification. Notably, DCIS acquires key transcriptomic changes and CNV events prior to HER2 amplification, suggesting that pre-amplified DCIS may create a cellular state primed to gain HER2 amplification for growth advantage. CONCLUSION: By using genomic methods that are spatially oriented, this study identifies several features that appear to generate insights into neoplastic progression in precancer lesions at a single-duct level.
Asunto(s)
Neoplasias de la Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Genoma Humano/genética , Receptor ErbB-2/genética , Transcriptoma/genética , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Variaciones en el Número de Copia de ADN , Evolución Molecular , Matriz Extracelular/genética , Femenino , Amplificación de Genes , Humanos , Hibridación Fluorescente in Situ , Interferones/metabolismo , Oncogenes/genética , Transducción de Señal/genéticaRESUMEN
BACKGROUND: Rotating shift work is common in high-hazard industries, despite documented associations with sleep disturbance and impairment. In the oil industry, where rotating and extended shift schedules are used to staff safety-sensitive positions, work intensification and increasing overtime rates have been broadly documented over the last few decades. Research on the impacts of these work schedules on sleep and health has been limited for this workforce. METHODS: We examined sleep duration and quality among rotating shift workers in the oil industry and explored associations between schedule characteristics, sleep, and health outcomes. We recruited hourly refinery workers from the West and Gulf Coast oil sector members of the United Steelworkers union. FINDINGS: Impaired sleep quality and short sleep durations were common and associated with health and mental health outcomes common among shift workers. Shortest sleep durations followed shift rotations. Early rise and start times were associated with shorter sleep duration and poorer sleep quality. Drowsiness and fatigue-related incidents were common. CONCLUSION/APPLICATION TO PRACTICE: We observed lower sleep duration and quality and increased overtime in 12-hour rotating shift schedules. These long workdays with early start times may reduce available hours for quality sleep; here they were associated with reduced exercise and leisure activity which correlated with good sleep. This safety-sensitive population appears severely impacted by poor sleep quality, which has broader implications for process safety management. Later start times, slower rotation, and a reconsideration of two-shift schedules are interventions to consider for improving sleep quality among rotating shift workers.
Asunto(s)
Industria del Petróleo y Gas , Seguridad , Horario de Trabajo por Turnos , Calidad del Sueño , Trastornos del Sueño-Vigilia , Tolerancia al Trabajo Programado , Humanos , Ritmo Circadiano/fisiología , Horario de Trabajo por Turnos/efectos adversos , Horario de Trabajo por Turnos/psicología , Sueño/fisiología , Trastornos del Sueño-Vigilia/fisiopatología , Trastornos del Sueño-Vigilia/psicología , Estados Unidos , Tolerancia al Trabajo Programado/fisiología , Tolerancia al Trabajo Programado/psicologíaRESUMEN
The addition of HER2-targeted agents to neoadjuvant chemotherapy has dramatically improved pathological complete response (pCR) rates in early-stage, HER2-positive breast cancer. Nonetheless, up to 50% of patients have residual disease after treatment, while others are likely overtreated. Here, we performed multiplex spatial proteomic characterization of 122 samples from 57 HER2-positive breast tumors from the neoadjuvant TRIO-US B07 clinical trial sampled pre-treatment, after 14-21 d of HER2-targeted therapy and at surgery. We demonstrated that proteomic changes after a single cycle of HER2-targeted therapy aids the identification of tumors that ultimately undergo pCR, outperforming pre-treatment measures or transcriptomic changes. We further developed and validated a classifier that robustly predicted pCR using a single marker, CD45, measured on treatment, and showed that CD45-positive cell counts measured via conventional immunohistochemistry perform comparably. These results demonstrate robust biomarkers that can be used to enable the stratification of sensitive tumors early during neoadjuvant HER2-targeted therapy, with implications for tailoring subsequent therapy.
Asunto(s)
Neoplasias de la Mama , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Proteómica , Receptor ErbB-2/genética , TrastuzumabRESUMEN
INTRODUCTION: Warthin's tumor (WT) is a common benign salivary gland neoplasm with a negligible risk of malignant transformation. However, there is a risk of malignant tumors being misdiagnosed as WT on cytology and inappropriately managed conservatively. METHODS: Patients from nine centers in Italy and the United Kingdom undergoing parotid surgery for cytologically diagnosed WT were included in this multicenter retrospective series. Definitive histology was compared with preoperative cytological diagnoses. Surgical complications were recorded. RESULTS: A total of 496 tumors were identified. In 88.9%, the final histological diagnosis was WT. In 21 cases (4.2%) a malignant neoplasm was diagnosed, which had been incorrectly labeled as WT on cytology. CONCLUSIONS: The risk of undiagnosed malignancy should be balanced against surgical risks when considering the management of WT. Although nonsurgical management remains an appropriate option, there may be a rationale for serial clinical or radiological evaluation if surgical excision is not performed.
Asunto(s)
Adenolinfoma , Neoplasias de la Parótida , Adenolinfoma/cirugía , Humanos , Italia , Glándula Parótida , Neoplasias de la Parótida/diagnóstico , Neoplasias de la Parótida/cirugía , Estudios Retrospectivos , Reino UnidoRESUMEN
Copy number alterations (CNAs) play an important role in molding the genomes of breast cancers and have been shown to be clinically useful for prognostic and therapeutic purposes. However, our knowledge of intra-tumoral genetic heterogeneity of this important class of somatic alterations is limited. Here, using single-cell sequencing, we comprehensively map out the facets of copy number alteration heterogeneity in a cohort of breast cancer tumors. Ou/var/www/html/elife/12-05-2020/backup/r analyses reveal: genetic heterogeneity of non-tumor cells (i.e. stroma) within the tumor mass; the extent to which copy number heterogeneity impacts breast cancer genomes and the importance of both the genomic location and dosage of sub-clonal events; the pervasive nature of genetic heterogeneity of chromosomal amplifications; and the association of copy number heterogeneity with clinical and biological parameters such as polyploidy and estrogen receptor negative status. Our data highlight the power of single-cell genomics in dissecting, in its many forms, intra-tumoral genetic heterogeneity of CNAs, the magnitude with which CNA heterogeneity affects the genomes of breast cancers, and the potential importance of CNA heterogeneity in phenomena such as therapeutic resistance and disease relapse.
Cells in the body remain healthy by tightly preventing and repairing random changes, or mutations, in their genetic material. In cancer cells, however, these mechanisms can break down. When these cells grow and multiply, they can then go on to accumulate many mutations. As a result, cancer cells in the same tumor can each contain a unique combination of genetic changes. This genetic heterogeneity has the potential to affect how cancer responds to treatment, and is increasingly becoming appreciated clinically. For example, if a drug only works against cancer cells carrying a specific mutation, any cells lacking this genetic change will keep growing and cause a relapse. However, it is still difficult to quantify and understand genetic heterogeneity in cancer. Copy number alterations (or CNAs) are a class of mutation where large and small sections of genetic material are gained or lost. This can result in cells that have an abnormal number of copies of the genes in these sections. Here, Baslan et al. set out to explore how CNAs might vary between individual cancer cells within the same tumor. To do so, thousands of individual cancer cells were isolated from human breast tumors, and a technique called single-cell genome sequencing used to screen the genetic information of each of them. These experiments confirmed that CNAs did differ sometimes dramatically between patients and among cells taken from the same tumor. For example, many of the cells carried extra copies of well-known cancer genes important for treatment, but the exact number of copies varied between cells. This heterogeneity existed for individual genes as well as larger stretches of DNA: this was the case, for instance, for an entire section of chromosome 8, a region often affected in breast and other tumors. The work by Baslan et al. captures the sheer extent of genetic heterogeneity in cancer and in doing so, highlights the power of single-cell genome sequencing. In the future, a finer understanding of the genetic changes present at the level of an individual cancer cell may help clinicians to manage the disease more effectively.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Variaciones en el Número de Copia de ADN , Dosificación de Gen , Heterogeneidad Genética , Genómica , Análisis de la Célula Individual , Secuenciación Completa del Genoma , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Ensayos Clínicos Fase II como Asunto , Femenino , Predisposición Genética a la Enfermedad , Humanos , Fenotipo , Pronóstico , RNA-SeqRESUMEN
In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer (N = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N = 34), lapatinib (L; N = 36), or both (TL; N = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30-65%) and TL (52%, 95% CI 38-65%), and a lower pCR rate with L (25%, 95% CI 13-43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment (N = 110), after one cycle of HER2-targeted therapy alone (N = 89), and at time of surgery (N = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Microambiente Tumoral/efectos de los fármacos , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/cirugía , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lapatinib/administración & dosificación , Lapatinib/uso terapéutico , Persona de Mediana Edad , Terapia Molecular Dirigida/métodos , Terapia Neoadyuvante , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Trastuzumab/administración & dosificación , Trastuzumab/uso terapéutico , Resultado del Tratamiento , Microambiente Tumoral/genéticaRESUMEN
The original version of this Article omitted from the Author Contributions statement that 'R.S. and J.G.R contributed equally to this work.' This has been corrected in both the PDF and HTML versions of the Article.
RESUMEN
Genomic changes observed across treatment may result from either clonal evolution or geographically disparate sampling of heterogeneous tumors. Here we use computational modeling based on analysis of fifteen primary breast tumors and find that apparent clonal change between two tumor samples can frequently be explained by pre-treatment heterogeneity, such that at least two regions are necessary to detect treatment-induced clonal shifts. To assess for clonal replacement, we devise a summary statistic based on whole-exome sequencing of a pre-treatment biopsy and multi-region sampling of the post-treatment surgical specimen and apply this measure to five breast tumors treated with neoadjuvant HER2-targeted therapy. Two tumors underwent clonal replacement with treatment, and mathematical modeling indicates these two tumors had resistant subclones prior to treatment and rates of resistance-related genomic changes that were substantially larger than previous estimates. Our results provide a needed framework to incorporate primary tumor heterogeneity in investigating the evolution of resistance.
Asunto(s)
Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Terapia Neoadyuvante/métodos , Receptor ErbB-2/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Modelos Teóricos , Secuenciación del Exoma/métodosRESUMEN
Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2-4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.
Asunto(s)
Carcinoma Basocelular/tratamiento farmacológico , Linfocitos Infiltrantes de Tumor/inmunología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T/inmunología , Carcinoma Basocelular/inmunología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/inmunología , Humanos , Inmunoterapia , Receptores de Antígenos de Linfocitos T/fisiología , Análisis de Secuencia de ARN , Factor 1 de Transcripción de Linfocitos T/fisiologíaAsunto(s)
Embolización Terapéutica , Síntomas del Sistema Urinario Inferior , Hiperplasia Prostática , Masculino , Humanos , Hiperplasia Prostática/complicaciones , Hiperplasia Prostática/diagnóstico por imagen , Hiperplasia Prostática/terapia , Próstata/diagnóstico por imagen , Próstata/irrigación sanguínea , Síntomas del Sistema Urinario Inferior/terapia , Síntomas del Sistema Urinario Inferior/complicaciones , ArteriasRESUMEN
BACKGROUND: Anaplastic thyroid carcinoma (ATC) is an uncommon thyroid malignancy with a poor prognosis. American Thyroid Association (ATA) guidelines acknowledge the complexity of airway management in these patients. We studied our local experience with the aim of providing guidance in airway management in ATC. METHODS: Patients with histologically confirmed ATC from January 2004 to December 2011 were identified from our institutional database. The data were retrospectively analyzed using hospital case notes. RESULTS: Twenty-six patients were identified with ATC, 25 of who died from the disease. Five of 26 patients (19%) had stridor at presentation. A further 6 of 26 patients (23%) developed stridor during or soon after radiotherapy. Nine patients (36%) died of airway obstruction. CONCLUSION: Tracheotomy can facilitate completion of palliative treatment in those patients with ATC and stridor. Given the short life expectancy of these patients, a balanced decision must be made regarding the role and timing of tracheotomy.