Allen S. Ho

The mutational landscape of adenoid cystic carcinoma

Adenoid cystic carcinomas (ACCs) are among the most enigmatic of human malignancies. These aggressive salivary gland cancers frequently recur and metastasize despite definitive treatment, with no known effective chemotherapy regimen. Here we determined the ACC mutational landscape and report the exome or whole-genome sequences of 60 ACC tumor-normal pairs. These analyses identified a low exonic somatic mutation rate (0.31 non-silent events per megabase) and wide mutational diversity. Notably, we found mutations in genes encoding chromatin-state regulators, such as SMARCA2, CREBBP and KDM6A, suggesting that there is aberrant epigenetic regulation in ACC oncogenesis. Mutations in genes central to the DNA damage response and protein kinase A signaling also implicate these processes. We observed MYB-NFIB translocations and somatic mutations in MYB-associated genes, solidifying the role of these aberrations as critical events in ACC. Lastly, we identified recurrent mutations in the FGF-IGF-PI3K pathway (30% of tumors) that might represent new avenues for therapy. Collectively, our observations establish a molecular foundation for understanding and exploring new treatments for ACC.

Exomic Sequencing of Medullary Thyroid Cancer Reveals Dominant and Mutually Exclusive Oncogenic Mutations in RET and RAS

CONTEXT Medullary thyroid cancer (MTC) is a rare thyroid cancer that can occur sporadically or as part of a hereditary syndrome. OBJECTIVE To explore the genetic origin of MTC, we sequenced the protein coding exons of approximately 21,000 genes in 17 sporadic MTCs. PATIENTS AND DESIGN We sequenced the exomes of 17 sporadic MTCs and validated the frequency of all recurrently mutated genes and other genes of interest in an independent cohort of 40 MTCs comprised of both sporadic and hereditary MTC. RESULTS We discovered 305 high-confidence mutations in the 17 sporadic MTCs in the discovery phase, or approximately 17.9 somatic mutations per tumor. Mutations in RET, HRAS, and KRAS genes were identified as the principal driver mutations in MTC. All of the other additional somatic mutations, including mutations in spliceosome and DNA repair pathways, were not recurrent in additional tumors. Tumors without RET, HRAS, or KRAS mutations appeared to have significantly fewer mutations overall in protein coding exons. CONCLUSIONS Approximately 90% of MTCs had mutually exclusive mutations in RET, HRAS, and KRAS, suggesting that RET and RAS are the predominant driver pathways in MTC. Relatively few mutations overall and no commonly recurrent driver mutations other than RET, HRAS, and KRAS were seen in the MTC exome.

Decision making in the management of recurrent head and neck cancer.

Despite substantial improvements in head and neck squamous cell carcinoma (HNSCC) treatment, the major obstacle to long‐term survival remains disease recurrence. Salvage options are often limited due to prior therapy and the escalated morbidity of retreatment. The costs of treatment must be measured against the anticipated quality and quantity of life recovered, even with resectable disease. This review surveys the recurrent HNSCC literature to better guide decision making. Across multiple studies, negative prognostic factors include impaired performance status, advanced recurrent stage, brief disease‐free interval, previous chemotherapy, and nonlaryngeal sites of recurrence. When possible, surgical salvage remains the principal option for durable disease control, quality of life preservation, and cure. Nonsurgical therapies have also demonstrated measurable improvements in locoregional control. Interpretation of salvage literature must be tempered by recognition of significant selection bias. The decision for salvage therapy must be individualized, with management that involves well‐informed patients resulting in the best outcomes.

Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence

In head and neck cancer (HNC), 3‐month post‐treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post‐treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months.

Epigenetic therapy: use of agents targeting deacetylation and methylation in cancer management

The emergence of epigenetic mechanisms as key regulators of gene expression has led to dramatic advances in understanding cancer biology. Driven by complex layers that include aberrant DNA methylation and histone modification, epigenetic aberrations have emerged as critical processes that disrupt cellular machinery and homeostasis. Recent discoveries have already translated into successful clinical trials and improved patient care, with several agents approved for hematologic disease and others undergoing study. As the field matures, substantial challenges persist that will require resolution. These include the need to decipher more fully the interplay between the epigenetic and genetic machinery, patient selection and improving treatment efficacy in solid tumors, and optimizing combination therapies to counteract chemoresistance and minimize adverse effects. Here, we review recent progress in epigenetic treatments and consider their implications for future cancer therapy.

Pediatric Tracheal Stenosis

Tracheal stenosis is a rare, potentially life-threatening condition described as innate narrowing of the tracheal lumen. The causes of tracheal stenosis vary widely. The most common forms result from prolonged intubation, although congenital causes usually involve complete tracheal rings or compression from cardiovascular malformations. The condition historically has harbored a poor prognosis, but significant advances in radiologic diagnosis, cardiac bypass, and endoscopic and surgical treatments have led to a range of options, better overall survival, and reduced morbidity. The complex, long-term manifestations of tracheal stenosis point to the need for individualized treatment as well as multidisciplinary care.

Incidence of Oropharyngeal Cancer Among Elderly Patients in the United States.

Importance An escalating incidence of human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has been reported predominantly among middle-aged adults. However, HPV infection is believed to occur many years before cancer develops, and tissue studies suggest that HPV DNA is found in the majority of OPSCC diagnosed in patients 65 years or older. Objective To update the trends in OPSCC incidence using US cancer registry data, with an emphasis on age-specific trends. Design, Setting, and Participants Data from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2012) were queried to compare changes in incidence and survival trends in OPSCC with selected tobacco-related cancers (larynx, oral cavity, hypopharynx, lung) and an HPV-related cancer (anus). A total of 40 264 patients who received a diagnosis of OPSCC from 2000 to 2012 were included. Elderly patients were defined as those 65 years or older. Main Outcomes and Measures The annual percentage change in OPSCC incidence from 2000 to 2012, stratified according to age group. Results Among the 40 264 patients who received a diagnosis of OPSCC from 2000 to 2012, 13 313 (33.1%) were aged 65 years or older and 80.3% were male. Significant increases in the age-adjusted incidence of OPSCC were observed during the study period for both younger adults aged 45 to 64 years (annual percentage change [APC], 2.31; 95% CI, 1.76-2.86; P < .001) and patients 65 years or older (APC, 2.92; 95% CI, 2.32-3.51; P < .001). These changes were driven predominantly by base-of-tongue and tonsil cancers in men. Concomitantly, the incidence of tobacco-associated head and neck cancers decreased for elderly patients (larynx: APC, -1.54; 95% CI, -2.00 to -1.08; P < .001; oral cavity: APC, -1.23; 95% CI, -1.84 to -0.62; P = .001; hypopharynx: APC, -2.44; 95% CI, -3.01 to -1.86; P < .001), whereas the incidence of anal cancer significantly increased (APC, 4.42; 95% CI, 3.28 to 5.57; P < .001). Furthermore, improved overall and cause-specific survival over time were observed for both younger and elderly patients with OPSCC. Nevertheless, absolute cause-specific survival remained worse for elderly patients (3-year CSS, 60.8%; 95% CI, 59.6%-61.9%) in comparison with those aged 45 to 64 years (75.7%; 95% CI, 75.1%-76.4%; P < .001). Conclusions and Relevance The incidence of OPSCC is increasing among elderly patients in the United States, likely driven by HPV-associated cancers. Given the unique challenges related to treating elderly patients with OPSCC, their limited enrollment in clinical trials, and the aging US population, clinical studies investigating improved therapeutic strategies for elderly patients with HPV-positive OPSCC should be performed.

Increasing diagnosis of subclinical thyroid cancers leads to spurious improvements in survival rates.

Survival rates are commonly used to measure success in treating cancer, but can be misleading. Modern diagnostic practices can lead to the appearance of improving cancer survival, as tumors are diagnosed earlier (lead‐time bias) or as an increasing proportion are slow‐growing (length bias), whereas the actual burden of cancer deaths is unchanged. Increasingly, more subclinical thyroid cancers are being diagnosed. The objective of the current study was to determine whether thyroid cancer survival rates have been affected by this phenomenon.

Carbon Dioxide Laser-Assisted Endoscopic Cricopharyngeal Myotomy With Primary Mucosal Closure

Objectives: Carbon dioxide laser–assisted endoscopic cricopharyngeal myotomy (ECPM) has emerged as a viable therapy for dysphagia. The risks of the procedure include pharyngoesophageal perforation and mediastinitis, which may discourage adoption of this technique. To address these complications, we examined outcomes of ECPM with primary mucosal closure. Methods: A case series of 7 patients who underwent ECPM between 2006 and 2008 were reviewed for length of operation, length of hospitalization, postoperative complications, and outcomes by use of the M. D. Anderson Dysphagia Index (MDADI) and the Functional Outcome Swallowing Scale (FOSS). The results were compared to those of a control group of 7 patients treated during the same period via open cricopharyngeal myotomy. Results: All patients who had ECPM were treated successfully without complications. The operative times averaged 128 minutes. The hospitalization averaged 2.1 days. Statistically significant improvements in swallowing were seen (MDADI score from 51.3 to 77.7, p < 0.0006; FOSS score from 3.7 to 1.3, p < 0.0005), and were similar to those in the patients who had the open procedure (FOSS score from 3.0 to 1.0, p < 0.006). Trends toward decreased blood loss, a shorter hospital stay, and a lower complication rate were observed in the patients who had ECPM. Conclusions: ECPM is beneficial as a primary treatment for cricopharyngeal dysfunction. Closure of the mucosal defect may help reduce the incidence of postoperative cervical emphysema and mediastinitis, and does not appear to compromise functional outcome.

Treatment at high‐volume facilities and academic centers is independently associated with improved survival in patients with locally advanced head and neck cancer

The treatment of head and neck cancers is complex and associated with significant morbidity, requiring multidisciplinary care and physician expertise. Thus, facility characteristics, such as clinical volume and academic status, may influence outcomes.