Loss of HIF1A From Pancreatic Cancer Cells Increases Expression of PPP1R1B and Degradation of p53 to Promote Invasion and Metastasis.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinomas (PDACs) are hypovascular, resulting in the up-regulation of hypoxia inducible factor 1 alpha (HIF1A), which promotes the survival of cells under low-oxygen conditions. We studied the roles of HIF1A in the development of pancreatic tumors in mice. METHODS: We performed studies with KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx1-Cre (KPC) mice, KPC mice with labeled pancreatic epithelial cells (EKPC), and EKPC mice with pancreas-specific depletion of HIF1A. Pancreatic and other tissues were collected and analyzed by histology and immunohistochemistry. Cancer cells were cultured from PDACs from mice and analyzed in cell migration and invasion assays and by immunoblots, real-time polymerase chain reaction, and liquid chromatography-mass spectrometry. We performed studies with the human pancreatic cancer cell lines PATU-8988T, BxPC-3, PANC-1, and MiaPACA-2, which have no or low metastatic activity, and PATU-8988S, AsPC-1, SUIT-2 and Capan-1, which have high metastatic activity. Expression of genes was knocked down in primary cancer cells and pancreatic cancer cell lines by using small hairpin RNAs; cells were injected intravenously into immune-competent and NOD/SCID mice, and lung metastases were quantified. We compared levels of messenger RNAs in pancreatic tumors and normal pancreas in The Cancer Genome Atlas. RESULTS: EKPC mice with pancreas-specific deletion of HIF1A developed more advanced pancreatic neoplasias and PDACs with more invasion and metastasis, and had significantly shorter survival times, than EKPC mice. Pancreatic cancer cells from these tumors had higher invasive and metastatic activity in culture than cells from tumors of EKPC mice. HIF1A-knockout pancreatic cancer cells had increased expression of protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B). There was an inverse correlation between levels of HIF1A and PPP1R1B in human PDAC tumors; higher expression of PPP1R1B correlated with shorter survival times of patients. Metastatic human pancreatic cancer cell lines had increased levels of PPP1R1B and lower levels of HIF1A compared with nonmetastatic cancer cell lines; knockdown of PPP1R1B significantly reduced the ability of pancreatic cancer cells to form lung metastases in mice. PPP1R1B promoted degradation of p53 by stabilizing phosphorylation of MDM2 at Ser166. CONCLUSIONS: HIF1A can act a tumor suppressor by preventing the expression of PPP1R1B and subsequent degradation of the p53 protein in pancreatic cancer cells. Loss of HIF1A from pancreatic cancer cells increases their invasive and metastatic activity.

Prognostic Impact of Histologic Grade for Papillary Thyroid Carcinoma.

BACKGROUND: While numerous factors affect prognosis in papillary thyroid carcinoma (PTC), the comparative impact of histologic grade has not been well described. Moreover, indications for external beam radiation therapy (EBRT) remain imprecise. We evaluate clinicopathologic characteristics and outcomes for PTC stratified by grade. METHODS: We profiled histologic grade for PTC (well differentiated, moderately differentiated, poorly differentiated) via hospital (National Cancer Database) and population-based (Surveillance, Epidemiology, and End Results) registries. Cox regression was used to adjust for clinicopathologic covariates. Statistical interactions between subtypes and the effect of EBRT on survival were assessed. RESULTS: Collectively, worsening clinicopathologic factors (age, tumor size, extrathyroidal extension, nodal spread, M1 disease) and outcomes (disease-free survival, overall survival) correlated with less differentiated state, across all histologic grades (p < 0.001). Multivariable analysis showed escalating hazard with loss of differentiation relative to well-differentiated PTC (moderately differentiated hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.04-1.41, p = 0.02; poorly differentiated HR 2.62, 95% CI 2.23-3.08, p < 0.001). Correspondingly, greater survival benefit was associated with EBRT for poorly differentiated cases (HR 0.36, 95% CI 0.18-0.72, p = 0.004). This finding was upheld after landmark analysis to address potential immortal time bias (HR 0.37, 95% CI 0.17-0.80, p = 0.01). CONCLUSIONS: Worsening histologic grade in PTC is independently associated with parallel escalation in mortality risk, on a scale approximating or surpassing established thyroid cancer risk factors. On preliminary analysis, EBRT was associated with improved survival in the most aggressive or least differentiated subvariants. Further investigation is warranted to examine the efficacy of EBRT for select poorly differentiated thyroid carcinomas.

Management of FDG avid Benign Sinonasal Schneiderian Papilloma: A Case Report and Review of the Literature.

BACKGROUND: The inverted and oncocytic subtypes of sinonasal Schneiderian papillomas are benign tumors with possible rare malignant transformation and are typically managed with complete surgical resection and close follow-up. While computed tomography (CT) and magnetic resonance imaging (MRI) are mainstays in preoperative evaluation of bony invasion and soft tissue extension of the lesion, their imaging characteristics by 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) is less well characterized. OBJECTIVE: To describe the clinical presentation and management of a PET positive sinonasal lesion. To conduct a literature review of FDG uptake in benign sinonasal papillomas. METHODS: Case report (n = 1) and literature review of similar cases (n = 32). RESULTS: We report the case of a 69-year-old man presenting with an isolated left maxillary sinus mass with avid FDG uptake, discovered on PET/CT imaging. An endoscopic left maxillary mega-antrostomy provided successful definitive treatment for final pathologic diagnosis of oncocytic papilloma. Literature review of cases of sinonasal papillomas with avid FDG uptake found that oncocytic papillomas, on average, exhibit greater uptake than inverted papillomas and both may be mistaken as malignancies on PET. CONCLUSION: While PET imaging demonstrating avid FDG uptake is associated with an increased risk of malignancy, it does not rule out the possibility of a benign sinonasal papilloma nor other benign inflammatory lesions. Particularly, oncocytic papillomas may have very high FDG uptake and mimic malignant lesions.

Survival in Middle Ear Malignancy: A Population-Based Analysis Based on the SEER Database.

OBJECTIVE: The purpose of this study was to investigate the clinical features and survival outcomes of patients with middle ear malignancies at a population level. STUDY DESIGN: Retrospective cohort study with data from a national database. SETTING: National database of middle ear malignancy. METHODS: Records of patients diagnosed with a middle ear malignancy from 1973 to 2016 were extracted from the SEER database (Surveillance, Epidemiology, and End Results). SPSS (version 27; IBM) was used to conduct 5-year survival analysis. RESULTS: The average survival for all 431 patients was 61.4 months. Five-year disease-specific survival for squamous cell carcinoma (SCCA), adenocarcinoma, other carcinoma, and noncarcinoma subtypes varied significantly at 54.6%, 82.1%, 71.8%, and 82.6%, respectively (P < .0001). There was an improved 5-year survival for patients with adenocarcinoma who received surgery versus those who did not (91.7% vs 65.1%; P = .023, log-rank). Five-year disease-specific survival was significantly better in patients aged <55 years (mean ± SD, 77.8% ± 0.39%) as compared with those >70 years (55.1% ± 5.1%) and those aged 55 to 69 years (60.2% ± 4.9%; P < .01 and P < .001, respectively, log-rank). Patients with SCCA were significantly older than those with adenocarcinoma (P < .0001). Noncarcinoma subtypes were more likely to present with local disease, as opposed to regional or distant disease, when compared with SCCA (P = .0027). CONCLUSION: Prognosis and treatment outcomes for primary middle ear malignancies depend on histologic subtype and age at diagnosis. The noncarcinoma and adenocarcinoma subtypes carry the best prognoses. Patients with adenocarcinoma were most likely to benefit from surgery.

Incidental parathyroidectomy in thyroidectomy and central neck dissection.

BACKGROUND: Although higher thyroidectomy volume has been linked with lower complication rates, its association with incidental parathyroidectomy remains less studied. The volume relationship is even less clear for central neck dissection, where individual parathyroid glands are at greater risk. METHODS: Patients undergoing thyroidectomy with or without central neck dissection were evaluated for incidental parathyroidectomy, hypoparathyroidism, and hypocalcemia. Univariate and multivariable analyses were performed using binary logistic regression. RESULTS: Overall, 1,114 thyroidectomies and 396 concurrent central neck dissections were performed across 7 surgeons. Incidental parathyroidectomy occurred in 22.4% of surgeries (range, 16.9%-43.6%), affecting 7.1% of parathyroids at risk (range, 5.8%-14.5%). When stratified by surgeon, lower incidental parathyroidectomy rates were associated with higher thyroidectomy volumes (R2 = 0.77, P = .008) and higher central neck dissection volumes (R2 = 0.93, P < .001). On multivariable analysis, low-volume surgeon (odds ratio 2.94, 95% confidence interval 2.06-4.19, P < .001), extrathyroidal extension (odds ratio 3.13, 95% confidence interval 1.24-7.87, P = .016), prophylactic central neck dissection (odds ratio 2.68, 95% confidence interval 1.65-4.35, P <.001), and therapeutic central neck dissection (odds ratio 4.44, 95% confidence interval 1.98-9.96, P < .001) were the most significant factors associated with incidental parathyroidectomy. In addition, incidental parathyroidectomy was associated with a higher likelihood of temporary hypoparathyroidism (odds ratio 2.79, 95% confidence interval 1.45-5.38, P = .002) and permanent hypoparathyroidism (odds ratio 4.62, 95% confidence interval 1.41-5.96, P = .025), but not permanent hypocalcemia (odds ratio 1.27, 95% confidence interval 0.48-3.35, P = .63). Higher lymph node yield in central neck dissection was not associated with higher incidental parathyroidectomy rates (odds ratio 1.13, 95% confidence interval 0.85-8.81, P = .82). CONCLUSION: Higher surgical volume conferred a lower rate of incidental parathyroidectomy. Nonetheless, greater lymph node yield in central neck dissections did not result in greater parathyroid-related morbidity. Such findings support the value of leveraging surgical volume to both optimize oncologic resection and minimize complication rates.

Predictive Impact of Metastatic Lymph Node Burden on Distant Metastasis Across Papillary Thyroid Cancer Variants.

Background: While numerous factors determine prognosis in papillary thyroid carcinoma (PTC), distant metastasis (M1) represents one of the most dire. Escalating nodal burden and aggressive histology may contribute to higher metastatic risk, but this relationship is poorly defined and challenging to anticipate. We evaluate the predictive impact of these histological features on predicting distant metastases at initial presentation. Methods: Univariate and multivariable logistic regression models of conventional and aggressive thyroid cancer variants (well-differentiated papillary thyroid carcinoma [WDPTC], diffuse sclerosing variant [DSV], tall cell variant [TCV], poorly differentiated thyroid cancer [PDTC], and anaplastic thyroid carcinoma [ATC]) identified via U.S. cancer registry data were constructed to determine associations between M1 status and quantitative nodal burden. Associations between metastatic lymph node (LN) number and M1 disease were modeled using univariate and multivariable logistic regression with interaction terms, as well as a linear continuous probability model. Results: Overall, M1 prevalence at disease presentation was 3.6% (n = 1717). When stratified by subtype, M1 prevalence varied significantly by histology (WDPTC [1.0%], DSV [2.3%], TCV [4.1%], PDTC [17.4%], ATC [38.4%] [p < 0.001]). For WDPTC, M1 prevalence escalated with metastatic LN number (0 LN+ [0.5%], 1-5 LN+ [2.0%], 6-10 LN+ [3.4%], >10 LN+ [5.5%] [p < 0.001]) and LN ratio (p < 0.001). A statistically significant interaction was observed between histology and increasing nodal burden for M1 risk. On multivariable analysis, each successive metastatic LN conferred increased M1 risk for WDPTC (odds ratio [OR] 1.06 [1.05-1.08], p < 0.001) and TCVs (OR 1.04 [1.02-1.07], p < 0.001). In contrast, other aggressive variants had a higher baseline M1 risk, but this did not vary based on the number of positive LN (DSV, OR 1.02 [0.95-1.10], p = 0.52; PDTC, OR 1.00 [0.98-1.02], p = 0.66; ATC, 1.00 [0.98-1.02], p = 0.97). Conclusions: Progressive nodal burden independently escalates the risk of distant metastasis in WDPTC and TCVs of PTC. Conversely, aggressive variants such as PDTC and ATC have substantial M1 risk at baseline and appear to be minimally affected by metastatic nodal burden. Consideration of these factors after surgery may help tailor clinical decision-making for treatment and surveillance. Further studies are warranted to calibrate the ideal management approach for these higher risk patient groups.

Implantable Drug Reservoir Devices for Inner Ear Delivery of Pharmacotherapeutics.

OBJECTIVE: Cisplatin is a platinum-based chemotherapeutic drug that secondarily induces toxicity in inner ear sensory epithelia, contributing to auditory and vestibular dysfunction. We describe the creation of a drug reservoir device (DRD) to combat this ototoxicity for the duration of chemotherapy. As ototoxic side effects of chemotherapy may limit an oncologist's ability to prescribe first-line agents such as cisplatin, mitigating such devastating effects through prolonged topical therapy would be tremendously valuable. STUDY DESIGN: We investigated (1) the ability of an electrospun polylactic acid DRD to provide prolonged delivery of the posited otoprotectant metformin and (2) the development of an in vitro model utilizing Sh-Sy5y human neuroblastoma cells to assess the efficacy of metformin in reducing cisplatin-induced toxicity. SETTING: Neurophysiology laboratory. METHODS: Basic science experiments were performed to assess DRD properties and metformin's effects on cisplatin toxicity in culture. RESULTS: We found that DRDs with increasing polylactic acid concentrations exhibited metformin release for up to 8 weeks. In modeling elution across the round window in vitro, continued elution of metformin was observed for at least 6 weeks, as quantified by spectrophotometry. Unfortunately, metformin did not exhibit protective efficacy in this model using Sh-Sy5y cells. CONCLUSION: While metformin was not found to be protective in Sh-Sy5y cells, these results suggest that an electrospun DRD can provide a tailorable drug delivery system providing medication for the duration of chemotherapy treatment. This represents a novel drug delivery system and efficacy screening assay with broad clinical applications in personalized delivery of inner ear therapies.