Polymer-tethered quenched fluorescent probes for enhanced imaging of tumor associated proteases.

Fluorescence-based contrast agents enable real-time detection of solid tumors and their neovasculature, making them ideal for use in image-guided surgery. Several agents have entered late-stage clinical trials or secured FDA approval, suggesting they are likely to become standard of care in cancer surgeries. One of the key parameters to optimize in contrast agent is molecular size, which dictates much of the pharmacokinetic and pharmacodynamic properties of the agent. Here, we describe the development of a class of protease-activated quenched fluorescent probes in which a N-(2-hydroxypropyl)methacrylamide copolymer is used as the primary scaffold. This copolymer core provides a high degree of probe modularity to generate structures that cannot be achieved with small molecules and peptide probes. We used a previously validated cathepsin substrate and evaluated the effects of length and type of linker as well as positioning of the fluorophore/quencher pair on the polymer core. We found that the polymeric probes could be optimized to achieve increased over-all signal and tumor-to-background ratios compared to the reference small molecule probe. Our results also revealed multiple structure-activity relationship trends that can be used to design and optimize future optical imaging probes. Furthermore, they confirm that a hydrophilic polymer is an ideal scaffold for use in optical imaging contrast probes, allowing a highly modular design that enables efficient optimization to maximize probe accumulation and overall biodistribution properties.

Distribution of 35 Polycyclic Aromatic Hydrocarbons in Pine Needle Samples from Selected Locations in the Republic of Korea.

Polycyclic aromatic hydrocarbons (PAHs), dust, and wax were measured in pine needles, and PAHs were also measured in surface soil. Pearson correlation analysis was performed between the analytical values. The main compounds responsible for the increase in total PAHs were non-carcinogenic phenanthrene and fluoranthene. Therefore, the % content of carcinogenic PAHs decreased with a slope = -0.037 (r = 0.47, p < 0.01), as the total PAH concentration in pine needles increased. Correlations between individual PAHs in pine needles and surface soil were very high when only low-number ring PAHs (2R- and 3R-PAHs) were statistically analyzed and significant when only high-number ring PAHs were statistically analyzed. Low-number ring PAH mainly moves in the gas phase and diffuses into the wax layer, so it was found to be statistically significant with the wax content of pine needles. High-number ring PAHs showed a high correlation with the amount of dust in pine needles because they mainly attached to dust particles and accumulated on the surface of pine needles. The ratios of fluoranthene/pyrene and methylphenanthrene/phenanthrene for predicting the origin of atmospheric PAHs have also been proven valid for pine needles.

Risk Factors Associated with Postoperative CSF Leak in Extrasellar Tumors.

Objective While postoperative cerebrospinal fluid (CSF) leak rates of pituitary tumors have been frequently studied, there are fewer studies examining postoperative CSF leak rates for extrasellar tumors. The purpose of this study was to identify risk factors for the development of postoperative CSF leak in patients undergoing endoscopic surgery for extrasellar tumors. Methods A retrospective chart review was done for patients who underwent endoscopic resection for extrasellar tumors between 2008 and 2020. Age, gender, tumor type, tumor location, tumor size, reconstruction technique, medical comorbidities, and other potential risk factors were identified. Data was analyzed to identify significant risk factors for development of postoperative CSF leak. Results There were 100 patients with extrasellar tumors who developed intraoperative CSF leaks. Seventeen patients (17%) developed postoperative CSF leaks. Leaks occurred at a median of 2 days following surgery (range 0-34 days). Clival tumors had a significantly higher incidence of postoperative leak than those in other sites ( p < 0.05). There were no significant differences in other locations, body mass index, tumor size, reconstruction technique, medical comorbidities, or other factors. There were nearly twice as many intraoperative grade III leaks in those who developed postoperative CSF leak, but this was not statistically significant ( p = 0.12). Conclusion Extrasellar tumors, particularly clival tumors, have a higher rate of postoperative CSF leak than pituitary tumors. Prophylactic lumbar drains can be considered for patients at high risk for developing postoperative CSF leak.

International Multicenter Study of Clinical Outcomes of Sinonasal Melanoma Shows Survival Benefit for Patients Treated with Immune Checkpoint Inhibitors and Potential Improvements to the Current TNM Staging System.

Objectives Sinonasal mucosal melanoma (SNMM) is an extremely rare and challenging sinonasal malignancy with a poor prognosis. Standard treatment involves complete surgical resection, but the role of adjuvant therapy remains unclear. Crucially, our understanding of its clinical presentation, course, and optimal treatment remains limited, and few advancements in improving its management have been made in the recent past. Methods We conducted an international multicenter retrospective analysis of 505 SNMM cases from 11 institutions across the United States, United Kingdom, Ireland, and continental Europe. Data on clinical presentation, diagnosis, treatment, and clinical outcomes were assessed. Results One-, three-, and five-year recurrence-free and overall survival were 61.4, 30.6, and 22.0%, and 77.6, 49.2, and 38.3%, respectively. Compared with disease confined to the nasal cavity, sinus involvement confers significantly worse survival; based on this, further stratifying the T3 stage was highly prognostic ( p < 0.001) with implications for a potential modification to the current TNM staging system. There was a statistically significant survival benefit for patients who received adjuvant radiotherapy, compared with those who underwent surgery alone (hazard ratio [HR] = 0.74, 95% confidence interval [CI]: 0.57-0.96, p = 0.021). Immune checkpoint blockade for the management of recurrent or persistent disease, with or without distant metastasis, conferred longer survival (HR = 0.50, 95% CI: 0.25-1.00, p = 0.036). Conclusions We present findings from the largest cohort of SNMM reported to date. We demonstrate the potential utility of further stratifying the T3 stage by sinus involvement and present promising data on the benefit of immune checkpoint inhibitors for recurrent, persistent, or metastatic disease with implications for future clinical trials in this field.

Is lobectomy sufficient for multifocal papillary thyroid microcarcinoma?

IMPORTANCE: Multifocal papillary thyroid microcarcinoma (PTMC) has been associated with a higher incidence of lymph node involvement, bilateral involvement, and extrathyroidal extension compared to unifocal papillary thyroid cancer (PTC). OBJECTIVE: To describe the incidence and determinants of survival for patients with multifocal PTMC using the Surveillance, Epidemiology, and End Result (SEER) database. DESIGN, SETTING, PARTICIPANTS: The SEER registry was utilized to calculate survival trends for patients with PTMC between 2010 and 2015. Patient data was then analyzed with respect to age, sex, race, multifocality, and types of surgery rendered. MAIN OUTCOMES AND MEASURES: Overall Survival (OS) and Disease Specific Survival (DSS). RESULTS: 22,283 cases of papillary thyroid microcarcinoma (T1a N0 M0) were identified. The cohort was composed of 82.6 % females, and about 82 % of patients were of white race. The mean age at diagnosis was 51.9 years. Multifocal PTMC was present in 32.2 % of the tumors (n = 7186). 73.9 % of patients underwent total thyroidectomy and 23.0 % received lobectomy. OS at 2 and 5 years was 98 % and 95 %, respectively. Multivariate analysis revealed that age, sex, and multifocality were determinants of OS. Only age was a determinant of DSS. Kaplan-Meier survival analysis revealed that multifocal PTMC had similar mean OS between lobectomy and total thyroidectomy patients (69.59 months versus 69.82 months). CONCLUSIONS AND RELEVANCE: PTMC has a good prognosis. Our analysis revealed that age was a determinant of OS and DSS; sex and multifocality were also prognosticators for OS. The type of surgery, whether lobectomy or total thyroidectomy, was not a determinant of survival in multifocal PTMC.

Simultaneous determination of PCBs, OCPs and PAHs in mussel by ultrasound-assisted cloudy extraction and gas chromatography-tandem mass spectrometry.

A method for the simultaneous determination in mussel of 8 polychlorinated biphenyls (PCBs), 23 organochlorine pesticides (OCPs), and 35 polycyclic aromatic hydrocarbons (PAHs), including alkyl-PAHs, was optimised using ultrasound-assisted cloudy extraction and gas chromatography-tandem mass spectrometry (GC-MS/MS). Optimal selection of the extraction solvent and the dispersing solvent contributed to a high extraction yield and a clean extract. The ranges of the lower limits of detection of PCBs, OCPs and PAHs were 0.012-0.058, 0.01-0.29 and 0.01-0.5 µg kg-1, respectively. The feasibility of the proposed method was validated by analysing standard reference materials of mussel with satisfactory results. The precision achieved by this method was in the range of 0.677-2.69% (PCBs), 1.14-6.60% (OCPs) and 0.694-7.46% (PAHs), and its accuracy was in the range of 101-104% (PCBs), 99.6-106% (OCPs) and 101-110% (PAHs). The advantages of the method include the simultaneous measurement of 66 analytes and the simplicity, low cost and high sensitivity of the procedure. When the proposed method was used to analyse the target compounds in 11 mussel samples, the analytical results displayed a concentration range of 0.41-0.45 µg kg-1 for PCBs, 0.26-6.49 µg kg-1 for OCPs, and 3.48-30.69 µg kg-1 for PAHs.

Surgical outcomes of simultaneous cochlear implantation with subtotal petrosectomy.

OBJECTIVE: To evaluate the surgical outcomes of simultaneous cochlear implantation (CI) with subtotal petrosectomy (SP). METHODS: Medical records of thirty-one patients (31 ears) who underwent simultaneous CI with SP in two tertiary referral centers for management of profound hearing loss secondary to chronic suppurative otitis media, cholesteatoma, previous open cavity, temporal bone fracture, and temporal bone irradiation were retrospectively analyzed. Pre and postoperative speech performances and related complications requiring surgical correction were evaluated. RESULTS: Significant improvement in postoperative speech performance was observed in all 31 patients compared to preoperative result. Of the 31 patients, complications occurred in three patients (9.6%). One patient exhibited the breakdown of blind sac closure of the external auditory canal and two others exhibited the migration of the receiver-stimulator cochlear implant. The migrations occurred despite tie-down fixation of the device to the skull. The migrated devices were repositioned using revision surgery. CONCLUSIONS: Simultaneous CI with SP is an effective and safe surgical method with relatively low complication incidence. However, particular attention should be paid to prevent certain complications. The receiver-stimulator may be predisposed to migrate to abnormal position because it can be placed with lack of tight subperiosteal support at a more superior or posterior location of the skull where the skull curvature changes abruptly than can conventional CI using limited mastoidectomy and posterior tympanotomy approach.

Readmissions after endoscopic skull base surgery: associated risk factors and prevention.

BACKGROUND: Unplanned readmissions within 30 days of discharge is a quality measure introduced by the Centers for Medicare Services. This measure has been used to rate hospital quality and also to penalize hospitals for excess readmissions. It has been hypothesized that shorter hospital stays and fewer readmissions are associated with endoscopic skull base procedures. In this study we analyze endoscopic skull base procedures performed at our institution over a 10-year period to identify rates and factors associated with readmissions after endoscopic skull base surgery. METHODS: A retrospective chart review was performed at a tertiary care academic medical center identifying patients who underwent endoscopic skull base surgery over the past 10 years. Data on patient demographics and tumor variables, as well as patient variables such as body mass index (BMI), revision surgery, history of skull base radiation, medical comorbidities, intraoperative cerebrospinal fluid (CSF) leaks, and postoperative CSF leaks, were recorded. RESULTS: Eight hundred thirty-three patients were included in our study. Sixty-one patients (7.3%) were readmitted a total of 66 times within 30 days. The most common reasons were as follows: hyponatremia (n = 18); CSF leak (n = 17); epistaxis (n = 3); diabetes insipidus (n = 3); rhinorrhea (n = 3); as well as other reasons. Statistical analysis revealed that the presence of intraoperative CSF leak was the only statistically significant variable associated with increased rate of readmissions within 30 days of discharge (p < 0.001). CONCLUSION: Presence of intraoperative CSF leak was the only statistically significant variable associated with an increased risk for readmission after surgery. Other tumor and patient variables were not associated with an increased risk of readmission within 30 days.

The most reliable time point for intact parathyroid hormone measurement to predict hypoparathyroidism after total thyroidectomy with central neck dissection to treat papillary thyroid carcinoma: a prospective cohort study.

PURPOSE: We assessed the optimal time for intact parathyroid hormone (iPTH) measurement for early detection of post-total thyroidectomy (TT) hypocalcemia in patients with papillary thyroid carcinoma (PTC). METHODS: In this single-center prospective cohort study, 143 patients who underwent TT with central neck dissection with or without lateral neck dissection for PTC were included. Biochemical profiles including iPTH, corrected total calcium, and ionized calcium within 24 h after surgery were analyzed. RESULTS: The 4-h postoperative iPTH was the most reliable predictor of post-TT transient or permanent hypoparathyroidism (cutoff for hypocalcemia was 3.75 pg/mL, AUC = 0.885, P < 0.001, sensitivity 81.6%, specificity 86.0%; cutoff for permanent hypocalcemia was 2.48 pg/mL, AUC = 0.819, P < 0.001, sensitivity 100%, specificity 57.8% calculated using ROC curves). CONCLUSIONS: The 4-h postoperative iPTH can most accurately predict hypoparathyroidism after TT with central neck dissection to treat PTC and facilitate the early discharge of low-risk postoperative hypoparathyroidism patients and decrease unnecessary overnight observation and calcium supplementation.

Efficacy of three proton-pump inhibitor therapeutic strategies on laryngopharyngeal reflux disease; a prospective randomized double-blind study.

OBJECTIVES: Proton-pump inhibitor (PPI) prescribing practices in laryngopharyngeal reflux disease (LPR) differ among physicians. We assessed the improvement in reflux symptom index (RSI) and reflux finding score (RFS) after treating LPR with three different regimens. DESIGN: A prospective, double-blind, randomized clinical trial. SETTING: Chungnam national university hospital in Korea. PARTICIPANTS: From July 2015 to July 2017, 100 patients with LPR included in the study. The patients were prescribed one of the following regimens for 3 months: group A, ilaprazole 10 mg, once a day (QD), n = 29; group B, ilaprazole 10 mg, twice a day (BID), n = 27; and group C, ilaprazole 10 mg BID plus mosapride citrate 5 mg three times a day (TID), n = 44. MAIN OUTCOME MEASURES: The total RSI and RFS scores and each subitems in RSI and FRS of the patients were evaluated. RESULTS: Total RFS and RSI scores improved significantly at the 3-month follow-up in all groups, and the improvements were of similar magnitudes. Regarding the RFS, the degrees of improvement in vocal cord oedema (P = 0.002) and diffuse laryngeal oedema (P = 0.003) scores differed significantly among the three groups. Moreover, overweight or obese patients in group C showed the greatest improvement in RFS. However, age had no effect on treatment efficacy. CONCLUSION: Three PPI therapeutic strategies showed similar efficacies against LPR according to total RFS and RSI scores. The addition of a prokinetic resulted in improvements in specific endoscopic findings, such as vocal cord oedema and diffuse laryngeal oedema. Furthermore, the addition of a prokinetic to PPI therapy was particularly beneficial for overweight or obese patients.

Clinical Characteristics of Temporal Bone Metastases.

OBJECTIVES: The purpose of this study were to evaluate the clinical characteristics of temporal bone metastasis (TBM) and to determine whether the characteristics differed according to primary malignancy. METHODS: We retrospectively analyzed data on 20 patients diagnosed with TBM between January 2000 and January 2017. Demographics, the period from diagnosis of primary malignancy to TBM diagnosis, the period from TBM diagnosis to death, the type and staging of primary malignancy, otologic manifestations, and TBM sites were assessed. After the primary malignancies were divided into solid cancers and hematologic malignancies, each parameter was compared between the two groups. RESULTS: The most common primary malignancy with TBM was lung cancer (45%). The most common otologic symptoms and signs were facial palsy (30.5%) and hearing loss (30.5%). The temporal squama (23%) and the facial nerve (20%) were the most commonly involved. Most TBMs occurred late in the disease process after the primary malignancy first metastasized to other organs. Hematologic malignancies metastasized significantly more frequently to the external auditory canal and the middle ear/mastoid compared to solid cancers (P=0.001 and P=0.004, respectively). CONCLUSION: If otologic manifestations such as facial palsy and hearing loss are presented in patients at advanced stages of malignancy, TBM of primary malignancy should be suspected. In addition, hematologic malignancies tend to metastasize to the external auditory canal and the middle ear cleft more commonly than solid cancers do.

Financial implications of telemedicine visits in an academic endocrine surgery program.

BACKGROUND: Telemedicine is an emerging medium for the delivery of ambulatory care, but the reimbursement profile of telemedicine visits in the surgical setting has not been well studied. METHODS: A retrospective assessment of telemedicine encounters for thyroid and parathyroid conditions occurring from April 2015 to April 2017 was performed. Financial reimbursement from commercial payers for new and established patient visits were compared between telemedicine visits and in-person visits. Patient "savings" in terms of travel distance and drive time were calculated. RESULTS: A total of 290 telemedicine encounters were conducted; 7% were initial consultations, 47% were postoperative visits, and 45% were follow-up visits. The median patient age was 57 years. The median round-trip travel distance saved was 123.6 miles with estimated drive time of 2.4 hours per encounter. In 2% of cases, a second in-person visit within the 90-day global period occurred after a postoperative telemedicine encounter. Charges were filed for 67 encounters. The initial unpaid claims rate was 6%, which was consistent with the unpaid claims rate for in-person visits. The charge-to-collection ratio was comparable to that of in-person visits. There was a higher ratio of level 2 visits in the telemedicine encounters. Over the study period, 70 clinic hours were liberated via the use of telemedicine. CONCLUSION: Endocrine surgery telemedicine visits have the same level for level reimbursement profile as in-person visits. Down-coding and elimination of components of in-office physical examinations may lead to modest decreases in overall reimbursement. Other advantages include reallocation of clinic resources and decreased travel burden for patients.

Relationship Between 18F-fluorodeoxyglucose Accumulation and the BRAF V600E Mutation in Papillary Thyroid Cancer.

BACKGROUND: To determine whether 18F-fluoro-2-deoxyglucose (18F-FDG)-PET/CT is useful for predicting the BRAF V600E mutation status of a primary papillary thyroid carcinoma (PTC). METHODS: A retrospective analysis was performed in 108 patients who underwent 18F-FDG positron emission tomography-computed tomography (PET/CT) for staging before thyroidectomy and BRAF analysis in biopsy-confirmed PTC. The maximum standardized uptake value (SUVmax) of the primary tumor was calculated according to FDG accumulation. Univariate and multivariate analyses were performed to assess the association between the SUVmax and clinicopathological variables. RESULTS: The BRAF V600E mutation was detected in 71 of 108 (65.7%) patients. In all subjects, the tumor size and BRAF V600E mutation were independently related to the SUVmax according to multivariate analyses (P = 0.002 and 0.007, respectively). The SUVmax was significantly higher in tumors with the BRAF V600E mutation than in tumors with wild-type BRAF (10.24 ± 11.89 versus 4.02 ± 3.86; P = 0.007). In the tumor size >1 cm subgroup, the BRAF V600E mutation was the only factor significantly associated with the SUVmax (P = 0.016). A SUVmax cutoff level of 4.9 was determined to be significant for predicting the BRAF V600E mutation status (sensitivity 77.4%, specificity 100.0%, area under the curve 0.929; P < 0.0001) according to ROC curve analysis. CONCLUSIONS: The BRAF V600E mutation is independently associated with high 18F-FDG uptake in PTC, especially in those with a tumor size >1 cm.

Decreasing Use of Radioactive Iodine for Low-Risk Thyroid Cancer in California, 1999 to 2015.

Context: Routine radioactive iodine (RAI) ablation for low-risk differentiated thyroid cancer (DTC) is not supported by current practice guidelines. Objective: To assess recent stage-specific trends in use of RAI ablation. Design, Setting, and Patients: Retrospective study of patients with DTC (1999 to 2015) identified from the California Cancer Registry. Statistical analysis included standardized differences, P values, and multivariable analyses using RAI as the predictor variable. Main Outcome Measures: Trends and drivers of RAI ablation for low-risk DTC. Results: Of 46,906 patients with DTC who underwent near-total or total thyroidectomy [mean age 48.2 ± 15.5 (standard deviation) years, 77% female), 25,457 (54%) received RAI. The proportion of patients with regional/distant disease who received RAI remained stable at 68%. Use of RAI for patients with localized disease (no extrathyroidal extension, lymph node, or distant metastases) decreased from 55% (1999) to 30% (2015), with the most substantial change occurring in tumors <1 cm (39% to 11%). The rate also decreased for localized tumors between 1 and 2 cm (62% to 34%) and 2 and 4 cm (67% to 49%) and remained stable at 59% for tumors >4 cm. In multivariable analyses, patients with localized disease were less likely to receive RAI if they were >65 years old [odds ratio (OR) 0.77, 95% confidence interval (CI): 0.71 to 0.83], had tumors <1 cm (OR 0.33, 95% CI: 0.31 to 0.35), or were treated in an academic hospital (OR 0.71, 95% CI: 0.67 to 0.75). Conclusions: The rate of RAI ablation decreased over time, mainly attributable to decreased use for localized DTCs <2 cm. Many patients with low-risk DTC still receive RAI unnecessarily.