Resistance to DNA-damaging agents is a significant cause of treatment failure and poor outcomes in oncology. To identify unrecognized regulators of cell survival we performed a whole-genome ...CRISPR-Cas9 screen using treatment with ionizing radiation as a selective pressure, and identified STING (stimulator of interferon genes) as an intrinsic regulator of tumor cell survival. We show that STING regulates a transcriptional program that controls the generation of reactive oxygen species (ROS), and that STING loss alters ROS homeostasis to reduce DNA damage and to cause therapeutic resistance. In agreement with these data, analysis of tumors from head and neck squamous cell carcinoma patient specimens show that low STING expression is associated with worse outcomes. We also demonstrate that pharmacologic activation of STING enhances the effects of ionizing radiation in vivo, providing a rationale for therapeutic combinations of STING agonists and DNA-damaging agents. These results highlight a role for STING that is beyond its canonical function in cyclic dinucleotide and DNA damage sensing, and identify STING as a regulator of cellular ROS homeostasis and tumor cell susceptibility to reactive oxygen dependent, DNA damaging agents.
Extranodal extension (ENE) is a well-established poor prognosticator and an indication for adjuvant treatment escalation in patients with head and neck squamous cell carcinoma (HNSCC). Identification ...of ENE on pretreatment imaging represents a diagnostic challenge that limits its clinical utility. We previously developed a deep learning algorithm that identifies ENE on pretreatment computed tomography (CT) imaging in patients with HNSCC. We sought to validate our algorithm performance for patients from a diverse set of institutions and compare its diagnostic ability to that of expert diagnosticians.
We obtained preoperative, contrast-enhanced CT scans and corresponding pathology results from two external data sets of patients with HNSCC: an external institution and The Cancer Genome Atlas (TCGA) HNSCC imaging data. Lymph nodes were segmented and annotated as ENE-positive or ENE-negative on the basis of pathologic confirmation. Deep learning algorithm performance was evaluated and compared directly to two board-certified neuroradiologists.
A total of 200 lymph nodes were examined in the external validation data sets. For lymph nodes from the external institution, the algorithm achieved an area under the receiver operating characteristic curve (AUC) of 0.84 (83.1% accuracy), outperforming radiologists' AUCs of 0.70 and 0.71 (
= .02 and
= .01). Similarly, for lymph nodes from the TCGA, the algorithm achieved an AUC of 0.90 (88.6% accuracy), outperforming radiologist AUCs of 0.60 and 0.82 (
< .0001 and
= .16). Radiologist diagnostic accuracy improved when receiving deep learning assistance.
Deep learning successfully identified ENE on pretreatment imaging across multiple institutions, exceeding the diagnostic ability of radiologists with specialized head and neck experience. Our findings suggest that deep learning has utility in the identification of ENE in patients with HNSCC and has the potential to be integrated into clinical decision making.
Identification of nodal metastasis and tumor extranodal extension (ENE) is crucial for head and neck cancer management, but currently only can be diagnosed via postoperative pathology. Pretreatment, ...radiographic identification of ENE, in particular, has proven extremely difficult for clinicians, but would be greatly influential in guiding patient management. Here, we show that a deep learning convolutional neural network can be trained to identify nodal metastasis and ENE with excellent performance that surpasses what human clinicians have historically achieved. We trained a 3-dimensional convolutional neural network using a dataset of 2,875 CT-segmented lymph node samples with correlating pathology labels, cross-validated and fine-tuned on 124 samples, and conducted testing on a blinded test set of 131 samples. On the blinded test set, the model predicted ENE and nodal metastasis each with area under the receiver operating characteristic curve (AUC) of 0.91 (95%CI: 0.85-0.97). The model has the potential for use as a clinical decision-making tool to help guide head and neck cancer patient management.
Background
Evidence surrounding the effect of adjuvant treatment in salivary gland cancers is limited. The benefit of adding chemotherapy to adjuvant treatment is also of interest. We investigated ...the association of these treatments with survival and whether this differed by stage or the presence of adverse features.
Methods
A retrospective study of adult salivary gland cancer cases diagnosed from 2004 to 2013 in the National Cancer Data Base (NCDB) was conducted.
Results
Treatment with adjuvant radiotherapy was associated with improved survival for both patients with early‐stage (hazard ratio HR 0.744; P = .004) and late‐stage (HR 0.688; P < .001) disease with adverse features. Further addition of chemotherapy to the adjuvant treatment of patients with late‐stage disease with adverse features was not associated with a survival benefit (HR 1.028; P = .705).
Conclusion
Adjuvant radiotherapy is associated with improved survival for patients with adverse features, regardless of stage. The addition of chemotherapy to the adjuvant treatment of patients with late‐stage disease with adverse features is not associated with improved outcomes.
Objectives
Approximately 3% to 9% of head and neck cancer presents with a metastatic node and no identifiable primary tumor. These cases of head and neck carcinoma of unknown primary (HNCUP) present ...a therapeutic challenge. Therapy of this disease varies based on factors such as institutional, surgeon, and patient preference. Evidence demonstrating the outcomes associated with these therapies for HNCUP is limited, and among the available series, the tumor human papillomavirus (HPV) status is often ignored. Treatment deintensification has been proposed for a subset of these patients. We aim to evaluate the treatment‐related outcomes for HPV‐associated and HPV‐negative HNCUP.
Methods
A retrospective study of 978 adult HNCUP diagnosed from 2010 to 2013 in the NCDB was conducted. Multivariate Cox survival regressions as well as univariate Kaplan‐Meier analyses were conducted.
Results
Patients with HPV‐associated disease had superior survival, with a 3‐year survival of 94.8% (standard error SE: 1.0), compared with 80.3% (SE: 2.9) among those with HPV‐negative disease. Among HPV‐negative patients with clinical nodal classification (cN)2/cN3 disease, treatment with definitive radiotherapy alone compared to definitive chemoradiotherapy was associated with diminished survival (hazard ratio 5.507, P = 0.005). Among patients with HPV‐associated cancer and cN2/cN3 disease, all treatments (surgery alone, surgery with adjuvant radiotherapy, surgery with adjuvant chemoradiotherapy, definitive chemoradiotherapy, definitive radiotherapy) resulted in statistically equivalent survival.
Conclusion
Tumor HPV status has a significant prognostic value for HNCUP and should be considered in future studies of treatment deintensification in this group. Treatment deintensification to radiotherapy alone in cN2/cN3 cases may result in poorer patient survival for HPV‐negative patients, whereas it may be a promising option for further investigation in HPV‐positive patients.
Level of Evidence
4 Laryngoscope, 129:684–691, 2019
Human papillomavirus-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) is the most common HPV-associated cancer in the United States, with a rapid increase in incidence over the last ...two decades. The burden of HPV+ HNSCC is likely to continue to rise, and given the long latency between infection and the development of HPV+ HNSCC, it is estimated that the effect of the HPV vaccine will not be reflected in HNSCC prevalence until 2060. Efforts have begun to decrease morbidity of standard therapies for this disease, and its improved characterization is being leveraged to identify and target molecular vulnerabilities. Companion biomarkers for new therapies will identify responsive tumors. A more basic understanding of two mechanisms of HPV carcinogenesis in the head and neck has identified subtypes of HPV+ HNSCC that correlate with different carcinogenic programs and that identify tumors with good or poor prognosis. Current development of biomarkers that reliably identify these two subtypes, as well as biomarkers that can detect recurrent disease at an earlier time, will have immediate clinical application.
Squamous cell carcinomas of the head and neck (SCCHN) affect anatomical sites including the oral cavity, nasal cavity, pharynx, and larynx. Laryngeal cancers are characterized by high recurrence and ...poor overall survival, and currently lack robust molecular prognostic biomarkers for treatment stratification. Using an algorithm for integrative clustering that simultaneously assesses gene expression, somatic mutation, copy number variation, and methylation, we for the first time identify laryngeal cancer subtypes with distinct prognostic outcomes, and differing from the non-prognostic laryngeal subclasses reported by The Cancer Genome Atlas (TCGA). Although most common laryngeal gene mutations are found in both subclasses, better prognosis is strongly associated with damaging mutations of the methyltransferases NSD1 and NSD2, with findings confirmed in an independent validation cohort consisting of 63 laryngeal cancer patients. Intriguingly, NSD1/2 mutations are not prognostic for nonlaryngeal SCCHN. These results provide an immediately useful clinical metric for patient stratification and prognostication.
High Dose Cisplatin: Still the One? Husain, Zain A; Burtness, Barbara A
International journal of radiation oncology, biology, physics,
07/2020, Letnik:
107, Številka:
4
Journal Article
Oropharyngeal squamous cell carcinoma (OPSCC) accounts for more than half of all head and neck cancers. Since the 1970s, OPSCC has shifted from an environmentally triggered to virally mediated ...disease due to a sharp rise in human papillomavirus (HPV)-related squamous cell carcinoma. Although a highly effective prophylactic vaccine is available, its current implementation is far below national targets, and OPSCC incidence is predicted to further increase by 2045. However, we believe that with prompt action now, we can not only defy these predictions but also effectively eradicate HPV-related OPSCC in these next 20 years. We herein provide an overview of the necessary elements to eliminate this disease: improved primary vaccine uptake, a 1-time universal vaccination effort, and implementation of novel therapeutics that have potential to cure existing disease.
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