Risk assessment for distant metastasis in differentiated thyroid cancer using molecular profiling: A matched case-control study.

BACKGROUND: Risk stratification for patients with differentiated thyroid cancer (DTC) is based primarily on pathologic tumor characteristics. Accurate preoperative prognostication could allow for more informed initial surgical recommendations, particularly among patients at a higher risk for distant metastasis (DM). The objective of this study was to characterize the genetic profile of DTC with DM and to validate a molecular-based risk stratification. METHODS: A case-control study design was used to analyze patients who had DTC with DM (n = 62) and a propensity matched cohort of patients who had DTC without DM after at least 5 years of follow-up using the ThyroSeq version 3 targeted next-generation sequencing assay. The results were classified into high-risk, intermediate-risk, and low-risk of aggressive disease. RESULTS: Most patients who had DTC with DM (66%) had a late-hit mutation in TERT, TP53, or PIK3CA. After propensity matching by age, tumor size, and sex, the high-risk molecular profile had strong association with DM (high-risk vs intermediate-risk: odds ratio, 25.1; 95% CI, 3.07-204.4; P < .001; high-risk vs low-risk: odds ratio, 122.5; 95% CI, 14.5-1038.4; P < .001). Overall, molecular risk categories were associated with DM risk, with a concordance index of 0.836 (95% CI, 0.759-0.913), which remained consistent after internal validation. Within the range of 5% to 10% of DM observed in DTC, the expected probability of DM would be 0.2% to 0.4% for the low-risk molecular profile, 4.7% to 9.4% for the intermediate-risk molecular profile, and 19.3% to 33.5% for the high-risk molecular profile. CONCLUSIONS: In this matched case-control study, genetic profiling using an available molecular assay provided accurate and robust risk stratification for DM in patients with DTC. The availability of preoperative prognostication may allow tailoring treatment for patients with DTC.

Early squamous cell carcinoma of the oral tongue with histologically benign lymph nodes: A model predicting local control and vetting of the eighth edition of the American Joint Committee on Cancer pathologic T stage.

BACKGROUND: The eighth edition of the American Joint Committee on Cancer staging manual (AJCC8) added depth of invasion to the definition of pathologic T stage (pT). In the current study, the authors assess pT stage migration and the prognostic performance of the updated pT stage and compare it with other clinicopathologic variables in patients with early squamous cell carcinoma of the oral tongue (OTSCC; tumors measuring ≤4 cm) with histologically benign lymph nodes (pN0). METHODS: A multi-institutional cohort of patients with early OTSCC was restaged as per AJCC8. Primary endpoints were local recurrence (LR) and locoregional recurrence (LRR). Influential variables were identified and an LR/LRR prediction model was developed. RESULTS: There were a total of 494 patients, with 49 LR and 73 LRR. AJCC8 pT criteria resulted in upstaging of 37.9% of patients (187 of 494 patients), including 34.5% (64 of 185 patients) from pT2 to pT3, without improving the prognostication for LR or LRR. Both LR and LRR were found to be similar for patients with AJCC8 pT2 and pT3 disease. On multivariate analysis, LR was only found to be associated with distance to the closest margin (hazard ratio, 0.36; 95% CI, 0.20-0.64 [P = .0007]) and perineural invasion (hazard ratio, 1.92; 95% CI, 1.10-0.64 [P = .046]). Based on these 2 predictors, a final proportional hazards regression model (which may be used similar to a nomogram) was developed. The proposed model appeared to be superior to AJCC pT stage for estimating the probability of LR and LRR for individual patients with early OTSCC. CONCLUSIONS: AJCC8 pT criteria resulted in pT upstaging of patients with pN0 disease without improved LR or LRR prognostication. The proposed model based on distance to the closest margin and perineural invasion, status outperformed pT as a predictor of LR and LRR in patients with early OTSCC.

Analytical performance of the ThyroSeq v3 genomic classifier for cancer diagnosis in thyroid nodules.

BACKGROUND: Molecular tests have clinical utility for thyroid nodules with indeterminate fine-needle aspiration (FNA) cytology, although their performance requires further improvement. This study evaluated the analytical performance of the newly created ThyroSeq v3 test. METHODS: ThyroSeq v3 is a DNA- and RNA-based next-generation sequencing assay that analyzes 112 genes for a variety of genetic alterations, including point mutations, insertions/deletions, gene fusions, copy number alterations, and abnormal gene expression, and it uses a genomic classifier (GC) to separate malignant lesions from benign lesions. It was validated in 238 tissue samples and 175 FNA samples with known surgical follow-up. Analytical performance studies were conducted. RESULTS: In the training tissue set of samples, ThyroSeq GC detected more than 100 genetic alterations, including BRAF, RAS, TERT, and DICER1 mutations, NTRK1/3, BRAF, and RET fusions, 22q loss, and gene expression alterations. GC cutoffs were established to distinguish cancer from benign nodules with 93.9% sensitivity, 89.4% specificity, and 92.1% accuracy. This correctly classified most papillary, follicular, and Hurthle cell lesions, medullary thyroid carcinomas, and parathyroid lesions. In the FNA validation set, the GC sensitivity was 98.0%, the specificity was 81.8%, and the accuracy was 90.9%. Analytical accuracy studies demonstrated a minimal required nucleic acid input of 2.5 ng, a 12% minimal acceptable tumor content, and reproducible test results under variable stress conditions. CONCLUSIONS: The ThyroSeq v3 GC analyzes 5 different classes of molecular alterations and provides high accuracy for detecting all common types of thyroid cancer and parathyroid lesions. The analytical sensitivity, specificity, and robustness of the test have been successfully validated and indicate its suitability for clinical use. Cancer 2018;124:1682-90. © 2018 American Cancer Society.

Phase 1 study of EGFR-antisense DNA, cetuximab, and radiotherapy in head and neck cancer with preclinical correlatives.

BACKGROUND: Cetuximab combined with radiation therapy (RT) is an evidence-based treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, locoregional failure remains the primary cause of cancer-related death in this disease. Intratumoral injection of epidermal growth factor receptor (EGFR)-antisense plasmid DNA (EGFR-AS) is safe and has been associated with promising lesional responses in patients who have recurrent/metastatic HNSCC. For the current study, the authors investigated the antitumor effects of cetuximab and EGFR-AS in preclinical HNSCC models and reported their phase 1 experience adding intratumoral EGFR-AS to cetuximab RT. METHODS: Antitumor mechanisms were investigated in cell line and xenograft models. Phase 1 trial eligibility required stage IVA through IVC HNSCC and a measurable lesion accessible for repeat injections. Patients received standard cetuximab was for 9 weeks. EGFR-AS was injected weekly until they achieved a lesional complete response. RT was delivered by conventional fractionation for 7 weeks, starting at week 3. Research biopsies were obtained at baseline and week 2. RESULTS: When added to cetuximab, EGFR-AS decreased cell viability and xenograft growth compared with EGFR-sense control, partially mediated by reduced EGFR expression. Six patients were enrolled in the phase 1 cohort. No grade 2 or greater EGFR-AS-related adverse events occurred. The best lesional response was a complete response (4 patients), and 1 patient each had a partial response and disease progression. EGFR expression decreased in 4 patients who had available paired specimens. CONCLUSIONS: In preclinical models, dual EGFR inhibition with cetuximab and EGFR-AS enhanced antitumor effects. In a phase 1 cohort, intratumoral EGFR-AS injections, cetuximab, and RT were well tolerated. A phase 2 trial is needed to conduct an extended evaluation of safety and to establish efficacy.

Multicenter outcomes of robotic reconstruction during the early learning curve for minimally-invasive pancreaticoduodenectomy.

BACKGROUND: Perceived excess morbidity during the early learning curve of minimally-invasive pancreaticoduodenectomy (MIPD) has limited widespread adoption. It was hypothesized that robot-assisted reconstruction (RA) after MIPD allows anastomotic outcomes equivalent to open pancreaticoduodenectomy (PD). METHODS: Intent to treat analysis of centrally audited data accrued during early adoption of RA-MIPD at five centers. RESULTS: CUSUM analysis of operating times at each center identified 92 RA-MIPD during the early learning curve. Mean age was 65 ± 12 years with body mass index 25.8 ± 5.0. Surgical indications included malignant (60%) and premalignant (38%) lesions. Median operating time was 504 min (interquartile range 133) with 242 ml median estimated blood loss (IQR 398) and twelve (13%) conversions to open PD. Major complication rate (Clavien-Dindo III/IV) was 24% with 2 (2.2%) deaths and ten (10.9%) reoperations. Nine (9.9%) clinically significant pancreatic fistulae were observed (4 grade B; 5 grade C). Margin negative resection rate for malignancy was 90% (75% for PDA) with mean harvest of 16 ± 8 lymph nodes. CONCLUSIONS: These multicenter data during the early learning curve for RA-MIPD do not demonstrate excess anastomotic morbidity compared to open. Further studies are required to determine whether surgeon proficiency and evolving technique improve anastomotic outcomes compared to open.

Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non-small cell lung cancer.

BACKGROUND: Activation of the mesenchymal-epidermal transition factor (MET) tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was evaluated in patients with metastatic, previously treated non-small cell lung cancer. METHODS: In phase 1, a dose de-escalation design was adopted with rilotumumab starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg daily. In phase 2, the disease control rate (DCR) (according to Response Evaluation Criteria in Solid Tumors) of the combination was evaluated using a Simon 2-stage design. The biomarkers examined included 10 plasma-circulating molecules associated with the EGFR and MET pathways. RESULTS: Without indications for de-escalation, the recommended phase 2 dose was dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid progression (hazard ratio, 2.14; 95% CI, 1.48-3.08). CONCLUSIONS: Combined rilotumumab and erlotinib had an acceptable safety profile, and the DCR met the prespecified criteria for success. In the EGFR WT group, the DCR exceeded published reports for erlotinib alone. High circulating levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 2017;123:2936-44. © 2017 American Cancer Society.

Outcomes of patients diagnosed with acute myeloid leukemia after solid organ transplantation.

Organ transplant recipients are at an increased risk for subsequent cancer including acute myeloid leukemia (AML). Treatment of AML following solid transplantation represents a clinical challenge as most patients have significant comorbidities at the time of AML diagnosis. In this study, we evaluated the treatment and outcomes of patients who developed AML following solid organ transplantation at our institution and reviewed the literature on outcomes for these patients. The study cohort consisted of 14 patients (median age 66 years, range 52-77 years) with newly diagnosed AML following solid organ transplantation. The median interval time between solid organ transplantation and AML diagnosis was 72 months (range 15-368 months). Seven patients received standard induction chemotherapy, four patients received intermediate type therapy, and the remaining three patients were deemed not fit for therapy and received palliative and supportive care. Six of the 11 treated patients (55%) achieved complete remission (CR). The median overall survival (OS) for all patients was 6 months. The median OS for the patients who achieved complete remission after therapy was 17 months and 2 months for the remaining patients. Despite initial CR, relapse rates are still high, suggesting that alternative strategies for post-remission therapies are warranted.

Subsets of salivary duct carcinoma defined by morphologic evidence of pleomorphic adenoma, PLAG1 or HMGA2 rearrangements, and common genetic alterations.

BACKGROUND: The authors hypothesized that histogenetic classification of salivary duct carcinoma (SDC) could account for de novo tumors and those with morphologic or molecular evidence (pleomorphic adenoma gene 1 [PLAG1], high-mobility group AT hook 2 [HMGA2] rearrangement, amplification) of pleomorphic adenoma (PA). METHODS: SDCs (n = 66) were reviewed for morphologic evidence of PA. PLAG1 and HMGA2 alterations were detected by fluorescence in situ hybridization (FISH). PLAG1-positive tumors were tested by FISH for fibroblast growth factor receptor 1 (FGFR1) rearrangement. Thirty-nine tumors were analyzed using a commercial panel for mutations and copy number variations in 50 cancer-related genes. RESULTS: On the basis of combined morphologic and molecular evidence of PA, 4 subsets of SDC emerged: 1) carcinomas with morphologic evidence of PA but intact PLAG1 and HMGA2 (n = 22); 2) carcinomas with PLAG1 alteration (n = 18) or 3) HMGA2 alteration (n = 12); and 4) de novo carcinomas, without morphologic or molecular evidence of PA (n = 14). The median disease-free survival was 37 months (95% confidence interval, 28.4-45.6 months). Disease-free survival and other clinicopathologic parameters did not differ for the subsets defined above. Combined Harvey rat sarcoma viral oncogene homolog/phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit α (HRAS/PIK3CA) mutations were observed predominantly in de novo carcinomas (5 of 8 vs 2 of 31 tumors; P = .035). Erb-B2 receptor tyrosine kinase 2 (ERBB2) copy number gain was not observed in de novo carcinomas (0 of 8 vs 12 of 31 tumors; P = .08). Tumor protein 53 (TP53) mutations were more common in SDC ex pleomorphic adenomas than in de novo carcinomas (17 of 31 vs 1 of 8 tumors; P = .033). CONCLUSIONS: The genetic profile of SDC varies with the absence or presence of pre-existing PA and its cytogenetic signature. Most de novo SDCs harbor combined HRAS/PIK3CA mutations and no ERBB2 amplification. Cancer 2016;122:3136-44. © 2016 American Cancer Society.

Targeted inhibition of ATR or CHEK1 reverses radioresistance in oral squamous cell carcinoma cells with distal chromosome arm 11q loss.

Oral squamous cell carcinoma (OSCC), a subset of head and neck squamous cell carcinoma (HNSCC), is the eighth most common cancer in the U.S.. Amplification of chromosomal band 11q13 and its association with poor prognosis has been well established in OSCC. The first step in the breakage-fusion-bridge (BFB) cycle leading to 11q13 amplification involves breakage and loss of distal 11q. Distal 11q loss marked by copy number loss of the ATM gene is observed in 25% of all Cancer Genome Atlas (TCGA) tumors, including 48% of HNSCC. We showed previously that copy number loss of distal 11q is associated with decreased sensitivity (increased resistance) to ionizing radiation (IR) in OSCC cell lines. We hypothesized that this radioresistance phenotype associated with ATM copy number loss results from upregulation of the compensatory ATR-CHEK1 pathway, and that knocking down the ATR-CHEK1 pathway increases the sensitivity to IR of OSCC cells with distal 11q loss. Clonogenic survival assays confirmed the association between reduced sensitivity to IR in OSCC cell lines and distal 11q loss. Gene and protein expression studies revealed upregulation of the ATR-CHEK1 pathway and flow cytometry showed G2 M checkpoint arrest after IR treatment of cell lines with distal 11q loss. Targeted knockdown of the ATR-CHEK1 pathway using CHEK1 or ATR siRNA or a CHEK1 small molecule inhibitor (SMI, PF-00477736) resulted in increased sensitivity of the tumor cells to IR. Our results suggest that distal 11q loss is a useful biomarker in OSCC for radioresistance that can be reversed by ATR-CHEK1 pathway inhibition.

Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay.

BACKGROUND: Fine-needle aspiration (FNA) cytology is a common approach to evaluating thyroid nodules, although 20% to 30% of FNAs have indeterminate cytology, which hampers the appropriate management of these patients. Follicular (or oncocytic) neoplasm/suspicious for a follicular (or oncocytic) neoplasm (FN/SFN) is a common indeterminate diagnosis with a cancer risk of approximately 15% to 30%. In this study, the authors tested whether the most complete next-generation sequencing (NGS) panel of genetic markers could significantly improve cancer diagnosis in these nodules. METHODS: The evaluation of 143 consecutive FNA samples with a cytologic diagnosis of FN/SFN from patients with known surgical outcomes included 91 retrospective samples and 52 prospective samples. Analyses were performed on a proprietary sequencer using the targeted ThyroSeq v2 NGS panel, which simultaneously tests for point mutations in 13 genes and for 42 types of gene fusions that occur in thyroid cancer. The expression of 8 genes was used to assess the cellular composition of FNA samples. RESULTS: In the entire cohort, histologic analysis revealed 104 benign nodules and 39 malignant nodules. The most common point mutations involved the neuroblastoma RAS viral oncogene homolog (NRAS), followed by the Kirsten rat sarcoma viral oncogene homolog (KRAS), the telomerase reverse transcriptase (TERT) gene, and the thyroid-stimulating hormone receptor (TSHR) gene. The identified fusions involved the thyroid adenoma associated (THADA) gene; the peroxisome proliferator-activated receptor γ (PPARG) gene; and the neurotrophic tyrosine kinase, receptor, type 3 (NTRK3) gene. Performance characteristics were similar in the retrospective and prospective groups. Among all FN/SFN nodules, preoperative ThyroSeq v2 performed with 90% sensitivity (95% confidence interval [CI], 80%-99%), 93% specificity (95% CI, 88%-98%), a positive predictive value of 83% (95% CI, 72%-95%), a negative predictive value of 96% (95% CI, 92%-100%), and 92% accuracy (95% CI, 88%-97%). CONCLUSIONS: The current results indicate that comprehensive genotyping of thyroid nodules using a broad NGS panel provides a highly accurate diagnosis for nodules with FN/SFN cytology and should facilitate the optimal management of these patients.

Evaluation of electromagnetic navigational bronchoscopic biopsy of lung lesions performed by a thoracic surgical service.

BACKGROUND: With the increasing use of computed tomography scans for lung cancer screening and surveillance of other cancers, thoracic surgeons are being referred patients with lung lesions for biopsies. Electromagnetic navigational bronchoscopy-guided lung biopsy is a relatively new technique for bronchoscopic biopsy. Our objective was to evaluate the diagnostic yields and safety of electromagnetic navigational bronchoscopy-guided lung biopsy. METHODS: We conducted a retrospective review of patients who underwent an electromagnetic navigational bronchoscopy biopsy, performed by a thoracic surgical service, and evaluated its safety and diagnostic accuracy. RESULTS: In total, 110 patients (men 46, women 64) underwent electromagnetic navigational bronchoscopy sampling of pulmonary lesions (n = 121; median size 27 mm; interquartile range 17-37 mm). There was no procedure-related mortality. Pneumothorax requiring pigtail drainage occurred in 4 patients (3.5%). Ninety-three (76.9%) of the lesions were malignant. Eighty-seven (71.9%) of the 121 lesions had an accurate diagnosis. Accuracy increased with increased lesion size (P = .0578) with a yield of 50% for lesions <2 cm, increasing to 81% for lesions ≥2 cm. The lesions that demonstrated a positive "bronchus sign" had a yield of 87% (45/52) compared with 61% (42/69) in lesions with a negative "bronchus sign" (P = .0359). CONCLUSION: Thoracic surgeons can perform electromagnetic navigational bronchoscopy safely, with minimal morbidity and with good diagnostic yields. Accuracy increases with the presence of a bronchus sign and increasing lesion size. Patients with larger tumors and the bronchus sign may be candidates for this approach to biopsy. Further work is required to define the role of electromagnetic navigational bronchoscopy in the diagnosis of pulmonary lesions.

Bile exposure inhibits expression of squamous differentiation genes in human esophageal epithelial cells.

OBJECTIVE: This study aimed to identify pathways and cellular processes that are modulated by exposure of normal esophageal cells to bile and acid. BACKGROUND: Barrett's esophagus most likely develops as a response of esophageal stem cells to the abnormal reflux environment. Although insights into the underlying molecular mechanisms are slowly emerging, much of the metaplastic process remains unknown. METHODS: We performed a global analysis of gene expression in normal squamous esophageal cells in response to bile or acid exposure. Differentially expressed genes were classified into major biological functions using pathway analysis and interaction network software. Array data were verified by quantitative PCR and western blot both in vitro and in human esophageal biopsies. RESULTS: Bile modulated expression of 202 genes, and acid modulated expression of 103 genes. Genes involved in squamous differentiation formed the largest functional group (n = 45) all of which were downregulated by bile exposure. This included genes such as involucrin (IVL), keratinocyte differentiation-associated protein (KRTDAP), grainyhead-like 1 (GRHL1), and desmoglein1 (DSG1) the downregulation of which was confirmed by quantitative PCR and western blot. Bile also caused expression changes in genes involved in cell adhesion, DNA repair, oxidative stress, cell cycle, Wnt signaling, and lipid metabolism. Analysis of human esophageal biopsies demonstrated greatly reduced expression of IVL, KRTDAP, DSG1, and GRHL1 in metaplastic compared to squamous epithelia. CONCLUSIONS: We report for the first time that bile inhibits the squamous differentiation program of esophageal epithelial cells. This, coordinated with induction of genes driving intestinal differentiation, may be required for the development of Barrett's esophagus.

Transoral endoscopic repair of Zenker diverticulum by a thoracic surgical service.

OBJECTIVE: Zenker diverticulum (ZD), a pulsion diverticulum of the esophagus, has been traditionally managed with an open surgical approach, but endoscopic transoral stapling has been reported with increasing frequency. The objective of this study was to evaluate the results of endoscopic repair of ZD by a thoracic surgery service. METHODS: We conducted a retrospective review of patients who underwent transoral stapling repair of ZD at our institution by the thoracic surgery service. We evaluated perioperative outcomes including dysphagia (1, no dysphagia to 5, unable to swallow saliva) and failure of repair requiring surgical intervention. RESULTS: A total of 151 patients (median age, 78 years; 75 men, 76 women) underwent evaluation for endoscopic repair of ZD. Endoscopic stapled repair of the ZD was completed in 135. Sixteen patients underwent conversion to open repair. The perioperative mortality was 0.6% (1 patient). The median hospital stay was 2 days (range, 0-18 days). Complications occurred in 5 patients who underwent endoscopic repair. The mean preoperative dysphagia score was 2.8 and improved to 1.2 during follow-up (median, 16 months; P < .001). During further follow-up (median, 52 months), 8 patients (5.3%) had failure of the endoscopic repair requiring open surgery (n = 5) or redo transoral stapling (n = 3). CONCLUSIONS: Endoscopic stapling repair of ZD can be performed safely with good results in experienced centers by thoracic surgeons with significant esophageal experience. Long-term follow-up is required to evaluate the durability of endoscopic repair of ZD.

Phase I Trial of Cetuximab, Radiotherapy, and Ipilimumab in Locally Advanced Head and Neck Cancer.

PURPOSE: Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4-positive (CTLA-4+) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti-CTLA-4 mAb, to cetuximab-radiotherapy. PATIENTS AND METHODS: A (3 + 3) design was used to establish the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, every-3-week doses to fixed, standard cetuximab-radiotherapy. Eligible subjects had stage III to IVb, high-risk [human papillomavirus-negative (HPV-)] or intermediate-risk HPV-positive (HPV+)] HNSCC. Dose-limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or immune-related (ir) AE requiring ≥2 weeks of systemic steroids. Baseline tumor and serial blood specimens were collected for immune correlatives. RESULTS: From July 2013 to May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering deescalation of ipilimumab to 1 mg/kg. Dose level -1 was expanded to N = 12 without DLT. irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1), and grade 1 hyperthyroidism (1). Three-year disease-free survival (DFS) and overall survival were 72% [90% confidence interval (CI), 57-92] and 72% (90% CI, 56-92). High expression of coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg was associated with worse DFS (HR = 5.6; 95% CI, 0.83-37.8; P = 0.08). CONCLUSIONS: The RP2D for ipilimumab plus standard cetuximab-radiotherapy is 1 mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy.

PET/CT Poorly Predicts AJCC 8th Edition Pathologic Staging in HPV-Related Oropharyngeal Cancer.

OBJECTIVE: The American Joint Committee on Cancer (AJCC) 8th edition introduced distinct clinical and pathological staging paradigms for human papilloma virus positive (HPV+) oropharyngeal squamous cell carcinoma (OPSCC). Treatment planning for OPSCC often utilizes positron emission tomography/computed tomography (PET/CT) to assess clinical stage. We hypothesize that PET/CT will accurately predict final pathologic AJCC 8th edition staging in patients with HPV+ OPSCC. METHODS: All patients with primary HPV+ OPSCC with preoperative PET/CT who underwent transoral robotic surgery and neck dissection between 2011 and 2017 were identified. Data were collected via chart review. Two neuroradiologists performed blinded re-evaluation of all scans. Primary tumor size and cervical nodal disease characteristics were recorded and TNM staging was extrapolated. Cohen's kappa statistic was used to assess interrater reliability. Test for symmetry was performed to analyze discordance between radiologic and pathologic staging. RESULTS: Forty-nine patients met inclusion criteria. Interrater reliability was substantial between radiologists for nodal (N) and overall staging (OS) (κ = 0.715 and 0.715). Radiologist A review resulted in identical OS for 67% of patients, overstaging for 31%, and understaging for 2%. Radiologist B review resulted in 61% identical OS, 39% overstaging, and 0% understaging. In misclassified cases, the test of symmetry shows strong bias toward overstaging N stage and OS (P < .001). Radiologic interpretation of extracapsular extension showed poor interrater reliability (κ = 0.403) and poor accuracy. CONCLUSION: PET/CT predicts a higher nodal and overall stage than pathologic staging. PET/CT should not be relied upon for initial tumor staging, as increased FDG uptake is not specific for nodal metastases. PET/CT is shown to be a poor predictor of ECE. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:1535-1541, 2021.

Surgical factors associated with patient-reported quality of life outcomes after free flap reconstruction of the oral cavity.

OBJECTIVES: To determine which surgical factors are associated with quality-of-life (QOL) outcomes in oral cavity cancer survivors after free flap reconstruction of the oral cavity. PATIENTS AND METHODS: A cross-sectional study was conducted from a multidisciplinary head and neck cancer (HNC) survivorship clinic. Oral cavity cancer survivors with at least 6-months of postoperative follow-up from ablation and free flap reconstruction were included. Primary outcome measures were validated patient-reported outcome measures (PROMs) including the Eating Assessment Tool-10 (EAT-10) measure of swallowing-specific QOL, University of Washington Quality of Life (UW-QOL) physical and social-emotional subscale scores and feeding tube dependence. RESULTS: Extent of tongue resection was associated with EAT-10 and the UW-QOL Physical subscale scores. Patients with oral tongue defects reported worse scores than with composite defects in the EAT-10 and UW-QOL physical domain (p = 0.0004, 0.0025, respectively). This association no longer applies when controlling for differences in extent of tongue resection. Patients with anterior composite resections reported worse EAT-10 scores than lateral resections (p = 0.024). This association no longer applies when controlling for extent of tongue resection (p = 0.46). Gastric tube dependence demonstrates similar trends to PROMs. CONCLUSION: Extent of tongue resection was strongly associated with poor QOL outcomes after free tissue reconstruction of the oral cavity and mediates the associations between other defect characteristics and QOL. These findings demonstrate the need for emphasis on expected oral tongue defects when counseling patients and highlight the need to address QOL in a multidisciplinary fashion post-operatively.

Do Ultrasound Patterns and Clinical Parameters Inform the Probability of Thyroid Cancer Predicted by Molecular Testing in Nodules with Indeterminate Cytology?

Background: Molecular testing (MT) is commonly used to refine cancer probability in thyroid nodules with indeterminate cytology. Whether or not ultrasound (US) patterns and clinical parameters can further inform the risk of thyroid cancer in nodules predicted to be positive or negative by MT remains unknown. The aim of this study was to test if clinical parameters, including patient age, sex, nodule size (by US), Bethesda category (III, IV, V), US pattern (American Thyroid Association [ATA] vs. American College of Radiology Thyroid Image Reporting and Data System [TI-RADS] systems), radiation exposure, or family history of thyroid cancer can modify the probability of thyroid cancer or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) predicted by MT. Methods: We studied 257 thyroid nodules in 232 patients from 10 study centers with indeterminate fine needle aspiration cytology and informative MT results using the ThyroSeq v3 genomic classifier (TSv3). Univariate and multivariate logistic regression was used for data analysis. Results: The presence of cancer/NIFTP was associated with positive TSv3 results (odds ratio 61.39, p < 0.0001). On univariate regression, patient sex, age, and Bethesda category were associated with cancer/NIFTP probability (p < 0.05 for each). Although ATA (p = 0.1211) and TI-RADS (p = 0.1359) US categories demonstrated positive trends, neither was significantly associated with cancer/NIFTP probability. A multivariate regression model incorporating the four most informative non-MT covariates (sex, age, Bethesda category, and ATA US pattern; Model No. 1) yielded a C index of 0.653; R2 = 0.108. When TSv3 was added to Model number 1, the C index increased to 0.888; R2 = 0.572. However, age (p = 0.341), Bethesda category (p = 0.272), and ATA US pattern (p = 0.264) were nonsignificant, and other than TSv3 (p < 0.0001), male sex was the only non-MT parameter that potentially contributed to cancer/NIFTP risk (p = 0.095). The simplest and most efficient clinical model (No. 3) incorporated TSv3 and sex (C index = 0.889; R2 = 0.588). Conclusions: In this multicenter study of thyroid nodules with indeterminate cytology and MT, neither the ATA nor TI-RADS US scoring systems further informed the risk of cancer/NIFTP beyond that predicted by TSv3. Although age and Bethesda category were associated with cancer/NIFTP probability on univariate analysis, in sequential nomograms they provided limited incremental value above the high predictive ability of TSv3. Patient sex may contribute to cancer/NIFTP risk in thyroid nodules with indeterminate cytology.

Protein Signatures and Tissue Diagnosis of Pancreatic Cancer.

BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration fails to diagnose up to 25% of patients with pancreatic ductal adenocarcinoma (PDAC). Proteomics can help to overcome this clinical dilemma. We hypothesized that soluble protein signatures can differentiate PDAC from benign tissues. STUDY DESIGN: Tissues were obtained from resected surgical specimens, lysed, and homogenates collected for analysis with a 41-protein multiplex assay. Analyte concentrations were normalized to total protein. Statistical analysis was performed to evaluate for differences in PDAC vs benign tissue. RESULTS: Tissues were obtained from 159 patients, 82 patients with PDAC naïve to therapy and 77 with benign pancreatic pathology. Fourteen analytes had a receiver operating characteristic curve area of >0.75 for predicting PDAC vs benign tissue. A recursive partitioning model using only 2 analytes, interleukin 1 receptor antagonist and transforming growth factor-α, provided an accuracy, sensitivity, and specificity of 91.2%, 90.2%, and 92.2%, respectively. A penalized logistic regression model found 12 analytes that provide diagnostic value to a protein signature. The mean area under the receiver operating characteristic after 50 tenfold cross-validations was 0.951. Accuracy, sensitivity, and specificity of this model were 91.2%, 87.8%, and 94.8%, respectively. Applying the scenario of 80% disease prevalence in patients undergoing endoscopic ultrasound with fine-needle aspiration for a pancreatic head mass, positive predictive value is 98.5% (95% CI 93.0% to 99.7%) and negative predictive value is 66.0% (95% CI 54.9% to 75.6%). CONCLUSIONS: Protein signatures from pancreatic specimens can differentiate PDAC from benign tissue. Additional work to validate these findings in a unique sample set is warranted.

Phase I Study of Ficlatuzumab and Cetuximab in Cetuximab-Resistant, Recurrent/Metastatic Head and Neck Cancer.

Cetuximab, an anti-EGFR monoclonal antibody (mAb), is approved for advanced head and neck squamous cell carcinoma (HNSCC) but benefits a minority. An established tumor-intrinsic resistance mechanism is cross-talk between the EGFR and hepatocyte growth factor (HGF)/cMet pathways. Dual pathway inhibition may overcome cetuximab resistance. This Phase I study evaluated the combination of cetuximab and ficlatuzumab, an anti-HGF mAb, in patients with recurrent/metastatic HNSCC. The primary objective was to establish the recommended Phase II dose (RP2D). Secondary objectives included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Mechanistic tumor-intrinsic and immune biomarkers were explored. Thirteen patients enrolled with no dose-limiting toxicities observed at any dose tier. Three evaluable patients were treated at Tier 1 and nine at Tier 2, which was determined to be the RP2D (cetuximab 500 mg/m2 and ficlatuzumab 20 mg/kg every 2 weeks). Median PFS and OS were 5.4 (90% CI = 1.9-11.4) and 8.9 (90% CI = 2.7-15.2) months, respectively, with a confirmed ORR of 2 of 12 (17%; 90% CI = 6-40%). High circulating soluble cMet levels correlated with poor survival. An increase in peripheral T cells, particularly the CD8+ subset, was associated with treatment response whereas progression was associated with expansion of a distinct myeloid population. This well-tolerated combination demonstrated promising activity in cetuximab-resistant, advanced HNSCC.