Luc G. Morris

The Increasing Incidence of Thyroid Cancer: The Influence of Access to Care

BACKGROUNDnThe rapidly rising incidence of papillary thyroid cancer may be due to overdiagnosis of a reservoir of subclinical disease. To conclude that overdiagnosis is occurring, evidence for an association between access to health care and the incidence of cancer is necessary.nnnMETHODSnWe used Surveillance, Epidemiology, and End Results (SEER) data to examine U.S. papillary thyroid cancer incidence trends in Medicare-age and non-Medicare-age cohorts over three decades. We performed an ecologic analysis across 497 U.S. counties, examining the association of nine county-level socioeconomic markers of health care access and the incidence of papillary thyroid cancer.nnnRESULTSnPapillary thyroid cancer incidence is rising most rapidly in Americans over age 65 years (annual percentage change, 8.8%), who have broad health insurance coverage through Medicare. Among those under 65, in whom health insurance coverage is not universal, the rate of increase has been slower (annual percentage change, 6.4%). Over three decades, the mortality rate from thyroid cancer has not changed. Across U.S. counties, incidence ranged widely, from 0 to 29.7 per 100,000. County papillary thyroid cancer incidence was significantly correlated with all nine sociodemographic markers of health care access: it was positively correlated with rates of college education, white-collar employment, and family income; and negatively correlated with the percentage of residents who were uninsured, in poverty, unemployed, of nonwhite ethnicity, non-English speaking, and lacking high school education.nnnCONCLUSIONnMarkers for higher levels of health care access, both sociodemographic and age-based, are associated with higher papillary thyroid cancer incidence rates. More papillary thyroid cancers are diagnosed among populations with wider access to healthcare. Despite the threefold increase in incidence over three decades, the mortality rate remains unchanged. Together with the large subclinical reservoir of occult papillary thyroid cancers, these data provide supportive evidence for the widespread overdiagnosis of this entity.

Improved detection does not fully explain the rising incidence of well-differentiated thyroid cancer: a population-based analysis

BACKGROUNDnThe increasing incidence of thyroid cancer may be an artifact of increased diagnostic scrutiny, permitting detection of smaller, subclinical thyroid cancers. Our objective was to examine trends in the incidence of well-differentiated thyroid cancers with large size and adverse pathological features.nnnMETHODSnDetailed population-based analysis of incidence trends in well-differentiated thyroid carcinoma (1973-2006) in the Surveillance Epidemiology and End Results (SEER) cancer registry, using weighted least squares and Joinpoint regression models.nnnRESULTSnThe incidence of well-differentiated thyroid cancer (WDTC) in the United States has tripled since 1973 (P < .0001). Incidence trends differ significantly between geographic regions and racial groups. Large WDTCs, including those >4 cm or >6 cm, have more than doubled in incidence (P < .0001). Cancers with extrathyroidal extension and with cervical metastases have also more than doubled in incidence (P < .0001).nnnCONCLUSIONSnWhile the model of improving screening does explain increased diagnoses of small thyroid cancers, significant rises in the incidence of large cancers, and cancers with clinically significant pathological adverse features, are harder to explain. Alternative hypotheses, including a true increase in cancer incidence, would seem to merit exploration.

Genomic Dissection of Hurthle Cell Carcinoma Reveals a Unique Class of Thyroid Malignancy

CONTEXTnHurthle cell cancer (HCC) is an understudied cancer with poor prognosis.nnnOBJECTIVEnOur objective was to elucidate the genomic foundations of HCC.nnnDESIGN AND SETTINGnWe conducted a large-scale integrated analysis of mutations, gene expression profiles, and copy number alterations in HCC at a single tertiary-care cancer institution.nnnMETHODSnMass spectrometry-based genotyping was used to interrogate hot spot point mutations in the most common thyroid oncogenes: BRAF, RET, NRAS, HRAS, KRAS, PIK3CA, MAP2K1, and AKT1. In addition, common oncogenic fusions of RET and NTRK1 as well as PAX8/PPARγ and AKAP9-BRAF were also assessed by RT-PCR. Global copy number changes and gene expression profiles were determined in the same tumor set as the mutational analyses.nnnRESULTSnWe report that the mutational, transcriptional, and copy number profiles of HCC were distinct from those of papillary thyroid cancer and follicular thyroid cancer, indicating HCC to be a unique type of thyroid malignancy. Unsupervised hierarchical clustering of gene expression showed the 3 groups of Hurthle tumors (Hurthle cell adenoma [HA], minimally invasive Hurthle cell carcinoma [HMIN], and widely invasive Hurthle cell carcinoma [HWIDE] clustered separately with a marked difference between HWIDE and HA. Global copy number analysis also indicated distinct subgroups of tumors that may arise as HWIDE and HMIN. Molecular pathways that differentiate HA from HWIDE included the PIK3CA-Akt-mTOR and Wnt/β-catenin pathways, potentially providing a rationale for new targets for this type of malignancy.nnnCONCLUSIONSnOur data provide evidence that HCC may be a unique thyroid cancer distinct from papillary and follicular thyroid cancer.

Tall-cell variant of papillary thyroid carcinoma: a matched-pair analysis of survival.

BACKGROUNDnThe tall-cell variant (TCV) of papillary thyroid carcinoma (PTC) is considered a more aggressive variant of PTC, with a poor prognosis. This is largely due to the tendency for TCV to present at an older age and with extrathyroidal extension (ETE). When these two variables are controlled for, it is unclear whether tall-cell histology alone portends a poor prognosis. Because previous studies have been underpowered to adequately answer this question, we hypothesized that TCV may have poorer prognosis than PTC. Our objective was to utilize a large cancer registry to obtain sufficient power to differentiate between outcomes in cases of TCV and PTC.nnnMETHODSnUsing the National Cancer Institutes Surveillance, Epidemiology, and End Results database, we identified 278 TCV patients and 2522 classical PTC patients with sufficient information for a detailed matched-pair analysis. Each TCV patient was matched with a PTC patient for age, sex, extent of ETE, regional and distant metastases, surgical and adjuvant therapy, and year of diagnosis. The TCV cohort was then compared against all PTC cases and matched PTC cases.nnnRESULTSnCompared with classical PTC, TCV patients presented at an older age (54.3 years vs. 46.3 years, p < 0.0001) had a higher rate of ETE (53.6% vs. 30.2%, p < 0.0001) and poorer 5-year disease-specific survival (81.9% vs. 97.8%, p < 0.0001). In the matched-pair analysis comparing TCV patients to the matched PTC cohort, 5-year disease-specific survival was poorer in the TCV cohort (81.9% vs. 91.3%, p = 0.049). The number of deaths in the TCV cohort was higher than in the matched PTC cohort (p = 0.043).nnnCONCLUSIONSnTCV exhibits poorer survival than classical PTC. When the major prognostic factors for thyroid cancer are controlled for, including age and ETE, tall-cell histology alone remains a significant prognostic factor for disease-specific death.

SCCRO (DCUN1D1) Is an Essential Component of the E3 Complex for Neddylation

Covalent modification of cullins by the ubiquitin-like protein NEDD8 (neddylation) regulates protein ubiquitination by promoting the assembly of cullin-RING ligase E3 complexes. Like ubiquitination, neddylation results from an enzymatic cascade involving the sequential activity of a dedicated E1 (APPBP1/Uba3), E2 (Ubc12), and an ill-defined E3. We show that SCCRO (also known as DCUN1D1) binds to the components of the neddylation pathway (Cullin-ROC1, Ubc12, and CAND1) and augments but is not required for cullin neddylation in reactions using purified recombinant proteins. We also show that SCCRO recruits Ubc12∼NEDD8 to the CAND1-Cul1-ROC1 complex but that this is not sufficient to dissociate or overcome the inhibitory effects of CAND1 on cullin neddylation in purified protein assays. In contrast to findings in cellular systems where no binding is seen, we show that SCCRO and CAND1 can bind to the neddylated Cul1-ROC1 complex in assays using purified recombinant proteins. Although neddylated (not unneddylated) Cul1-ROC1 is released from CAND1 upon incubation with testis lysate from SCCRO+/+ mice, the addition of recombinant SCCRO is required to achieve the same results in lysate from SCCRO–/– mice. Combined, these results suggest that SCCRO is an important component of the neddylation E3 complex that functions to recruit charged E2 and is involved in the release of inhibitory effects of CAND1 on cullin-RING ligase E3 complex assembly and activity.

The head and neck cancer immune landscape and its immunotherapeutic implications

Recent clinical trials have demonstrated a clear survival advantage in advanced head and neck squamous cell carcinoma (HNSCC) patients treated with immune checkpoint blockade. These emerging results reveal that HNSCC is one of the most promising frontiers for immunotherapy research. However, further progress in head and neck immuno-oncology will require a detailed understanding of the immune infiltrative landscape found in these tumors. We leveraged transcriptome data from 280 tumors profiled by The Cancer Genome Atlas (TCGA) to comprehensively characterize the immune landscape of HNSCC in order to develop a rationale for immunotherapeutic strategies in HNSCC and guide clinical investigation. We find that both HPV+ and HPV- HNSCC tumors are among the most highly immune-infiltrated cancer types. Strikingly, HNSCC had the highest median Treg/CD8+ T cell ratio and the highest levels of CD56dim NK cell infiltration, in our pan-cancer analysis of the most immune-infiltrated tumors. CD8+ T cell infiltration and CD56dim NK cell infiltration each correlated with superior survival in HNSCC. Tumors harboring genetic smoking signatures had lower immune infiltration and were associated with poorer survival, suggesting these patients may benefit from immune agonist therapy. These findings illuminate the immune landscape of HPV+ and HPV- HNSCC. Additionally, this landscape provides a potentially novel rationale for investigation of agents targeting modulators of Tregs (e.g., CTLA-4, GITR, ICOS, IDO, and VEGFA) and NK cells (e.g., KIR, TIGIT, and 4-1BB) as adjuncts to anti-PD-1 in the treatment of advanced HNSCC.

Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival

As tumors accumulate genetic alterations, an evolutionary process occurs in which genetically distinct subclonal populations of cells co-exist, resulting in intratumor genetic heterogeneity (ITH). The clinical implications of ITH remain poorly defined. Data are limited with respect to whether ITH is an independent determinant of patient survival outcomes, across different cancer types. Here, we report the results of a pan-cancer analysis of over 3300 tumors, showing a varied landscape of ITH across 9 cancer types. While some gene mutations are subclonal, the majority of driver gene mutations are clonal events, present in nearly all cancer cells. Strikingly, high levels of ITH are associated with poorer survival across diverse types of cancer. The adverse impact of high ITH is independent of other clinical, pathologic and molecular factors. High ITH tends to be associated with lower levels of tumor-infiltrating immune cells, but this association is not able to explain the observed survival differences. Together, these data show that ITH is a prognostic marker in multiple cancers. These results illuminate the natural history of cancer evolution, indicating that tumor heterogeneity represents a significant obstacle to cancer control.

Malpractice Litigation After Surgical Injury of the Spinal Accessory Nerve: An Evidence-Based Analysis

OBJECTIVEnTo review the background, case characteristics, and outcomes of malpractice litigation resulting from surgical injury of the spinal accessory nerve.nnnDESIGNnRetrospective review of indemnity insurance cases (part 1) and court trials (part 2) between January 1, 1985, and January 1, 2007. In part 1, records of the Medical Liability Mutual Insurance Company identified 41 lawsuits in New York State; part 2 was a review of a national legal database (WestLaw) that identified 81 court trials. Case details were analyzed, and awards were adjusted for inflation.nnnRESULTSnFor part 1, of 41 indemnity insurance cases, 39 (95%) involved a posterior triangle lymph node biopsy. Defendants were mainly general surgeons and otolaryngologists. Most lawsuits against surgeons (22 of 34 [65%]) were settled before trial, and only 4 of 34 (12%) were discontinued. Of these 34 cases, 28 (82%) ultimately compensated the plaintiff. The mean inflation-adjusted pretrial settlement was

Acoustic rhinometry predicts tolerance of nasal continuous positive airway pressure : A pilot study

264 395, and the mean settlement at trial was

Nasal obstruction and sleep-disordered breathing: a study using acoustic rhinometry.

443 538. Cases reaching trial received significantly higher settlements (P = .01). For part 2, 81 cases of alleged surgical injury to the spinal accessory nerve were identified. Defendant physicians were mainly general surgeons and otolaryngologists. Most operations were cervical lymph node biopsies (55 [68%]), followed by sebaceous cyst excisions (6 [7%]), neck dissections (4 [5%]), and other procedures (12 [15%]). Morbidity included weakness (81 patients [100%]), pain (30 patients [37%]), inability to work (20 patients [25%]), need for a nerve repair procedure (16 patients [20%]), deformity (9 patients [11%]), and numbness (4 patients [5%]). Types of malpractice alleged included negligent surgical technique (79 cases [98%]), lack of informed consent (17 cases [21%]), and failure to diagnose the injury (16 cases [20%]). Thirty-seven cases (46%) were decided for the defendant, 32 (40%) were decided for the plaintiff, and 12 (15%) were settled (percentages do not total 100 because of rounding). The mean inflation-adjusted settlement was