Recurrent Laryngeal Nerve Invasion by Thyroid Cancer: Laryngeal Function and Survival Outcomes.

BACKGROUND: Recurrent laryngeal nerve (RLN) invasion by thyroid carcinoma represents an advanced disease status with potentially significant co-morbidity. METHODS: In a retrospective single-center study, we included patients with invaded RLNs operated on while using nerve monitoring techniques. We studied pre-, intra-, and postoperative parameters associated with postoperative vocal cord paralysis (VCP); 5-year recurrence-free survival (RFS); and 5-year overall survival (OS) in addition to two subgroup analyses of postoperative VCP in patients without preoperative VCP and based on source of RLN invasion. RESULTS: Of 65 patients with 66 nerves-at-risk, 39.3% reported preoperative voice complaints. Preoperative VCP was documented in 43.5%. The RLN was invaded by primary tumor in 59.3% and nodal metastasis in 30.5%. Papillary thyroid carcinoma was the most common pathologic subtype (80%). After 6 months, 81.8% had VCP. Complete tumor resection of the RLN was not associated with 5-year RFS (p = 0.24) or 5-year OS (p = 0.9). Resecting the RLN did not offer statistically significant benefit on 5-year RFS (p = 0.5) or 5-year OS (p = 0.38). Radioactive Iodine (RAI) administration was associated with improvement in 5-year RFS (p = 0.006) and 5-year OS (p = 0.004). Patients without preoperative VCP had higher IONM amplitude compared with patients with VCP. After a mean follow-up of 65.8 months, 35.9% of patients had distant metastases, whereas 36.4% had recurrence. CONCLUSION: Preoperative VCP accompanies less than half of patients with RLN invasion. Invaded RLNs may have existent electrophysiologic stimulability. Complete tumor resection and RLN resection were not associated with better 5-year RFS or OS, but postoperative RAI was. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:2285-2292, 2022.

Association of Estrogen Receptor Alpha Expression With Survival in Oropharyngeal Cancer Following Chemoradiation Therapy.

BACKGROUND: Oropharyngeal squamous carcinoma (OPSC) continues to increase in incidence secondary to human papillomavirus (HPV) infection. Despite the good overall prognosis for these patients, treatment with chemoradiation is associated with morbidity and treatment failure. Better predictors for disease outcome are needed to guide de-intensification regimens. We hypothesized that estrogen receptor α (ERα), a prognostic biomarker in oncology with therapeutic implications, might have similar utility in OPSC. METHODS: To investigate associations among ERα and demographics, HPV status, and survival, we analyzed ERα mRNA expression of head and neck squamous carcinomas (HNSC) from The Cancer Genome Atlas (TCGA) and immunohistochemistry (IHC) of pretreatment biopsy specimens from an independent group of 215 OPSC patients subsequently treated with primary chemoradiation (OPSC-CR). Associations among variables were evaluated with Fisher exact tests and logistic regression; associations with survival were evaluated with log-rank tests and Cox proportional hazards regression. RESULTS: Among 515 patients in TCGA, ERα mRNA expression was highest in HPV-positive OPSC. High ERα mRNA expression was associated with improved survival among those receiving chemoradiation (hazard ratio adjusted for HPV status = 0.44, 95% confidence interval = 0.21 to 0.92). In OPSC-CR, ERα was positive by IHC in 51.6% of tumors and was associated with improved overall, disease-specific, progression-free, and relapse-free survival (log-rank tests: P < .001, P < .001, P = .002, P = .003, respectively); statistically significant associations of ERα positivity with improved survival were maintained after adjusting for clinical risk factors including HPV status. CONCLUSION: In two independent cohorts, ERα is a potential biomarker for improved survival that also may represent a therapeutic target in OPSC.

Improved visualization of peripherally inserted central catheters on chest radiographs of neonates using fractional multiscale image processing.

BACKGROUND: Peripherally inserted central catheters (PICCs) provide secure intravenous access for the delivery of life-sustaining medications and nutrition. They are commonly used in pediatrics. Confirmation of correct central catheter tip position is crucial. Verification is usually done by a radiograph. The aim of this study is to evaluate the ability of Fractional Multiscale image Processing (FMP) to detect PICC tips on the digital chest radiographs of neonates. METHODS: A total of 94 radiographs of 47 patients were included in the study. 29 patients were male, 18 were female. The mean age of all examined children was 9.2 days (range 0-99 days). In total, six readers (two radiologists, two residents in radiology, one last year medical student, one neonatologist) evaluated 94 unprocessed and catheter-enhanced radiographs using a 5-point Likert scale (1 = poor catheter tip visualization, 5 = excellent catheter tip visualization). Additionally, the two radiologists evaluated the diagnostic confidence for chest pathologies using a 5-point Likert scale (1 = poor diagnostic confidence, 5 = excellent diagnostic confidence). Radiographs were evaluated on a dedicated workstation. RESULTS: In all cases, the catheter-enhanced radiograph rated higher than (n = 471), or equal (n = 93) to, the unprocessed radiograph when visualizing catheter tips. 87% of the catheter-enhanced radiographs obtained a rating of 4 or higher, while only 42% of unprocessed radiographs received 4 or more points. Regarding diagnostic confidence for chest pathologies one radiologist rated two catheter-enhanced radiographs higher than the unprocessed radiographs, while all other 186 evaluations rated the catheter-enhanced radiographs equal to (n = 78) or lower than (n = 108) the unprocessed radiographs. Only 60% of the catheter-enhanced radiographs yielded a diagnostic confidence of 4 or higher, while 90% of the unprocessed images received 4 or more points. CONCLUSION: Catheter-enhanced digital chest radiographs demonstrate improved visualization of low contrast PICC tips in neonates compared to unprocessed radiographs. Furthermore, they enable detection of accompanying chest pathologies. However, definitive diagnosis of chest pathologies should be made on unprocessed radiographs.

3 Tesla 23Na Magnetic Resonance Imaging During Acute Kidney Injury.

RATIONALE AND OBJECTIVES: Sodium and proton magnetic resonance imaging (23Na/1H-MRI) have shown that muscle and skin can store Na+ without water. In chronic renal failure and in heart failure, Na+ mobilization occurs, but is variable depending on age, dialysis vintage, and other features. Na+ storage depots have not been studied in patients with acute kidney injury (AKI). MATERIALS AND METHODS: We studied 7 patients with AKI (mean age: 51.7 years; range: 25-84) and 14 age-matched and gender-matched healthy controls. All underwent 23Na/1H-MRI at the calf. Patients were studied before and after acute hemodialysis therapy within 5-6 days. The 23Na-MRI produced grayscale images containing Na+ phantoms, which served to quantify Na+ contents. A fat-suppressed inversion recovery sequence was used to quantify H2O content. RESULTS: Plasma Na+ levels did not change. Mean Na+ contents in muscle and skin did not significantly change following four to five cycles of hemodialysis treatment (before therapy: 32.7 ± 6.9 and 44.2 ± 13.5 mmol/L, respectively; after dialysis: 31.7 ± 10.2 and 42.8 ± 11.8 mmol/L, respectively; P > .05). Water content measurements did not differ significantly before and after hemodialysis in muscle and skin (P > .05). Na+ contents in calf muscle and skin of patients before hemodialysis were significantly higher than in healthy subjects (16.6 ± 2.1 and 17.9 ± 3.2) and remained significantly elevated after hemodialysis. CONCLUSIONS: Na+ in muscle and skin accumulates in patients with AKI and, in contrast to patients receiving chronic hemodialysis and those with acute heart failure, is not mobilized with hemodialysis within 5-6 days.

Staged Surgery for Advanced Thyroid Cancers: Safety and Oncologic Outcomes of Neural Monitored Surgery.

Objective Thyroidectomy with extensive multicompartment bilateral neck dissections for advanced-stage thyroid cancer may lead to increased risk of complications, including bilateral recurrent laryngeal nerve (RLN) paralysis and hypoparathyroidism. A planned staged approach derived from a detailed preoperative radiographic map is associated with a low complication profile. This study evaluates oncologic results and safety of neural monitored, staged thyroid cancer surgery for management of advanced thyroid cancer. Study Design Case series with chart review. Setting Tertiary care center. Subjects and Methods With institutional review board approval, 35 consecutive patients with advanced thyroid malignancy and extensive nodal disease managed with staged surgery between January 2004 and May 2013 by the senior author (G.W.R.) were identified, and the oncologic and surgical outcomes were reviewed. Results In total, 37.2% of patients had stage III or IV disease, with extrathyroidal extension in 71.4%, vascular invasion in 51.4%, and RLN invasion in 17% of patients. A total of 34% patients had positive lymph nodes in more than 5 nodal compartments; the average positive lymph node yield was 17, and extranodal extension was present in 51%. Three patients had RLN sacrifice, and there were no other cases of temporary or permanent RLN paralysis; permanent hypoparathyroidism and chyle leak occurred in one patient each. Locoregional recurrence occurred in 5.7% of patients after a 147-week mean follow-up. In patients with papillary thyroid carcinoma, median postoperative nonstimulated and stimulated thyroglobulin levels were 0.2 and 0.75 ng/mL, respectively. Conclusion A neural monitored, staged surgical approach was conducted without significant adverse events in this small sample and represents and effective alternative strategy option to simultaneous bilateral surgery in the management of thyroid cancer with extensive neck metastases.

Semi-automated De-identification of German Content Sensitive Reports for Big Data Analytics.

Purpose Projects involving collaborations between different institutions require data security via selective de-identification of words or phrases. A semi-automated de-identification tool was developed and evaluated on different types of medical reports natively and after adapting the algorithm to the text structure. Materials and Methods A semi-automated de-identification tool was developed and evaluated for its sensitivity and specificity in detecting sensitive content in written reports. Data from 4671 pathology reports (4105 + 566 in two different formats), 2804 medical reports, 1008 operation reports, and 6223 radiology reports of 1167 patients suffering from breast cancer were de-identified. The content was itemized into four categories: direct identifiers (name, address), indirect identifiers (date of birth/operation, medical ID, etc.), medical terms, and filler words. The software was tested natively (without training) in order to establish a baseline. The reports were manually edited and the model re-trained for the next test set. After manually editing 25, 50, 100, 250, 500 and if applicable 1000 reports of each type re-training was applied. Results In the native test, 61.3 % of direct and 80.8 % of the indirect identifiers were detected. The performance (P) increased to 91.4 % (P25), 96.7 % (P50), 99.5 % (P100), 99.6 % (P250), 99.7 % (P500) and 100 % (P1000) for direct identifiers and to 93.2 % (P25), 97.9 % (P50), 97.2 % (P100), 98.9 % (P250), 99.0 % (P500) and 99.3 % (P1000) for indirect identifiers. Without training, 5.3 % of medical terms were falsely flagged as critical data. The performance increased, after training, to 4.0 % (P25), 3.6 % (P50), 4.0 % (P100), 3.7 % (P250), 4.3 % (P500), and 3.1 % (P1000). Roughly 0.1 % of filler words were falsely flagged. Conclusion Training of the developed de-identification tool continuously improved its performance. Training with roughly 100 edited reports enables reliable detection and labeling of sensitive data in different types of medical reports. Key Points: · Collaborations between different institutions require de-identification of patients' data. · Software-based de-identification of content-sensitive reports grows in importance as a result of 'Big data'. · A de-identification software was developed and tested natively and after training. · The proposed de-identification software worked quite reliably, following training with roughly 100 edited reports. · A final check of the texts by an authorized person remains necessary. Citation Format · Seuss H, Dankerl P, Ihle M et al. Semi-automated De-identification of German Content Sensitive Reports for Big Data Analytics. Fortschr Röntgenstr 2017; 189: 661 - 671.

Development and Evaluation of a Semi-automated Segmentation Tool and a Modified Ellipsoid Formula for Volumetric Analysis of the Kidney in Non-contrast T2-Weighted MR Images.

Volumetric analysis of the kidney parenchyma provides additional information for the detection and monitoring of various renal diseases. Therefore the purposes of the study were to develop and evaluate a semi-automated segmentation tool and a modified ellipsoid formula for volumetric analysis of the kidney in non-contrast T2-weighted magnetic resonance (MR)-images. Three readers performed semi-automated segmentation of the total kidney volume (TKV) in axial, non-contrast-enhanced T2-weighted MR-images of 24 healthy volunteers (48 kidneys) twice. A semi-automated threshold-based segmentation tool was developed to segment the kidney parenchyma. Furthermore, the three readers measured renal dimensions (length, width, depth) and applied different formulas to calculate the TKV. Manual segmentation served as a reference volume. Volumes of the different methods were compared and time required was recorded. There was no significant difference between the semi-automatically and manually segmented TKV (p = 0.31). The difference in mean volumes was 0.3 ml (95% confidence interval (CI), -10.1 to 10.7 ml). Semi-automated segmentation was significantly faster than manual segmentation, with a mean difference = 188 s (220 vs. 408 s); p < 0.05. Volumes did not differ significantly comparing the results of different readers. Calculation of TKV with a modified ellipsoid formula (ellipsoid volume × 0.85) did not differ significantly from the reference volume; however, the mean error was three times higher (difference of mean volumes -0.1 ml; CI -31.1 to 30.9 ml; p = 0.95). Applying the modified ellipsoid formula was the fastest way to get an estimation of the renal volume (41 s). Semi-automated segmentation and volumetric analysis of the kidney in native T2-weighted MR data delivers accurate and reproducible results and was significantly faster than manual segmentation. Applying a modified ellipsoid formula quickly provides an accurate kidney volume.

Evaluation for High-risk HPV in Squamous Cell Carcinomas and Precursor Lesions Arising in the Conjunctiva and Lacrimal Sac.

High-risk human papilloma virus (HR-HPV) is a well-established causative agent of oropharyngeal squamous cell carcinoma (SCC). In addition, HR-HPV has occasionally been reported to be present in dysplastic and malignant lesions of the conjunctiva and lacrimal sac, although its overall incidence and etiological role in periocular SCC are controversial. Sequential surgical samples of 52 combined cases of invasive SCC (I-SCC) and SCC in situ (SCCIS) from 2 periocular sites (conjunctiva and lacrimal sac) diagnosed over a 14-year period (2000 to 2014) were selected for evaluation, and relevant patient characteristics were documented. p16 immunohistochemistry was performed as a screening test. All p16-positive cases were further evaluated for HR-HPV using DNA in situ hybridization (DNA ISH), and a subset was also analyzed by polymerase chain reaction (PCR). Of 43 ocular surface squamous neoplasias (OSSNs), 30% (n=13; 8 SCCIS and 5 I-SCC cases) were positive for HR-HPV. HPV-positive OSSNs occurred in 8 men and 5 women with a mean age of 60 years (range, 39 to 94 y). HPV type-16 was detected in all conjunctival cases evaluated by PCR. All 5 conjunctival I-SCCs were nonkeratinizing (n=4) or partially keratinizing (n=1) and managed by simple excision. In contrast, HPV-negative conjunctival I-SCCs were predominantly keratinizing (11 keratinizing and 2 nonkeratinizing). Of 9 lacrimal sac I-SCCs (LSSCCs), 66.7% (n=6) were positive for HR-HPV by p16 and DNA ISH; HPV subtypes were HPV-16 (n=5) and HPV-58 (n=1). In addition, 2 p16-positive cases with negative DNA ISH results were HR-HPV positive (HPV-16 and HPV-33) when evaluated by PCR, suggesting that the rate of HR-HPV positivity among the LSSCCs may be as high as 89% (n=8). The combined group of HR-HPV-positive LSSCCs was seen in 4 men and 4 women with a mean age of 60 years (range, 34 to 71 y). Seven of the 8 HPV-positive LSSCCs (87.5%) had a nonkeratinizing or partially keratinizing histomorphology, whereas 1 case (12.5%) was predominantly keratinizing. The presence of HR-HPV in 30% of OSSNs and at least 66.7% of LSSCCs suggests the possibility of an etiologic role for HR-HPV at these sites.

Intra-tumor genetic heterogeneity and mortality in head and neck cancer: analysis of data from the Cancer Genome Atlas.

BACKGROUND: Although the involvement of intra-tumor genetic heterogeneity in tumor progression, treatment resistance, and metastasis is established, genetic heterogeneity is seldom examined in clinical trials or practice. Many studies of heterogeneity have had prespecified markers for tumor subpopulations, limiting their generalizability, or have involved massive efforts such as separate analysis of hundreds of individual cells, limiting their clinical use. We recently developed a general measure of intra-tumor genetic heterogeneity based on whole-exome sequencing (WES) of bulk tumor DNA, called mutant-allele tumor heterogeneity (MATH). Here, we examine data collected as part of a large, multi-institutional study to validate this measure and determine whether intra-tumor heterogeneity is itself related to mortality. METHODS AND FINDINGS: Clinical and WES data were obtained from The Cancer Genome Atlas in October 2013 for 305 patients with head and neck squamous cell carcinoma (HNSCC), from 14 institutions. Initial pathologic diagnoses were between 1992 and 2011 (median, 2008). Median time to death for 131 deceased patients was 14 mo; median follow-up of living patients was 22 mo. Tumor MATH values were calculated from WES results. Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3). This relation of intra-tumor heterogeneity to survival was not due to intra-tumor heterogeneity's associations with other clinical or molecular characteristics, including age, human papillomavirus status, tumor grade and TP53 mutation, and N classification. MATH improved prognostication over that provided by traditional clinical and molecular characteristics, maintained a significant relation to survival in multivariate analyses, and distinguished outcomes among patients having oral-cavity or laryngeal cancers even when standard disease staging was taken into account. Prospective studies, however, will be required before MATH can be used prognostically in clinical trials or practice. Such studies will need to examine homogeneously treated HNSCC at specific head and neck subsites, and determine the influence of cancer therapy on MATH values. Analysis of MATH and outcome in human-papillomavirus-positive oropharyngeal squamous cell carcinoma is particularly needed. CONCLUSIONS: To our knowledge this study is the first to combine data from hundreds of patients, treated at multiple institutions, to document a relation between intra-tumor heterogeneity and overall survival in any type of cancer. We suggest applying the simply calculated MATH metric of heterogeneity to prospective studies of HNSCC and other tumor types.

Impact of human papillomavirus on oropharyngeal cancer biology and response to therapy: implications for treatment.

Oropharyngeal squamous cell carcinoma (OPSCC) originating from human papillomavirus infection has emerged as a new entity in head and neck cancer, defining a subset of patients with distinct carcinogenesis, risk factor profiles, and clinical presentation that show markedly improved survival than patients with classic OPSCC. De-escalation of therapy and identification of relevant biomarkers to aid in patient selection are actively being investigated. This review addresses the implications of these findings in clinical care.

Fatal neonatal myocarditis caused by a recombinant human enterovirus-B variant.

We report a case of fatal myocarditis in a newborn infant who was infected with a human enterovirus detected by throat culture and RT-PCR for viral RNA in plasma. Whole genome sequence analysis revealed the virus to be a genomic chimera that likely arose from recombination between coxsackievirus B3 and two recently identified enteroviruses, EV 86 and EV97.

Shedding and reversion of oral polio vaccine type 3 in Mexican vaccinees: comparison of mutant analysis by PCR and enzyme cleavage to a real-time PCR assay.

A uracil-to-cytosine mutation at nucleotide position 472 of oral poliovirus vaccine type 3 (OPV3) contributes to the development of vaccine-associated paralytic poliomyelitis (VAPP). To analyze OPV3 shedding patterns, we previously used the multistep method of mutant analysis by PCR and enzyme cleavage (MAPREC). This involves conventional reverse transcription-PCR to detect OPV3, followed by a restriction digest to quantify position 472 reversion. Real-time PCR detects and quantifies nucleic acid as PCR occurs and avoids postreaction processing. The goal of this study was to compare a real-time PCR method to MAPREC. Seventy-three stool samples from Mexican OPV recipients underwent the reverse transcription-PCR step of MAPREC and real-time PCR. Real-time PCR identified 23% more OPV3-positive samples than conventional reverse transcription-PCR. When reversion was compared, the revertant proportion (RP), defined as the percentage of revertants in a sample, differed by < or =10% in 21/25 (84%) samples. The four samples differing by >10% were obtained within 5 days of OPV administration. The real-time PCR assay identified samples with an RP of > or =85% with 94% sensitivity and 86% specificity compared to MAPREC. The mean difference in RP between the two methods was 3.6% (95% confidence interval, -0.3 to 7.5%). Real-time PCR methods reliably detect OPV3, and reversion estimates correlate more consistently with MAPREC when OPV3 reversion rates are high. Detecting VAPP-related mutations by real-time PCR is rapid and efficient and can be useful in monitoring ongoing global polio eradication efforts.

Quantitative analysis of the effect of cell type and cellular differentiation on protective antigen binding to human target cells.

We quantitatively measured protective antigen (PA) binding to human cells targeted by anthrax lethal toxin (LT). Affinities were less than 50 nM for all cells, but differentiated cells (macrophages and neutrophils) had significantly increased PA binding and endothelial cells demonstrated the most binding. Combined with the function of such cells, this suggests that PA receptors interact with the extracellular matrix and that differentiation increases the number of PA-specific receptors, which supports previously observed differentiation-induced LT susceptibility. Our results quantifiably confirm that the generality of PA binding will complicate its use as a tumor targeting agent.