"Incidentally discovered medullary thyroid carcinoma in the post-operative Graves' patient - A case report".

OBJECTIVE: To report a very rare case of incidentally discovered Medullary Thyroid Carcinoma after total thyroidectomy in a patient with Graves' disease, review available literature, and present readers with management information. RESULTS: Medullary Thyroid Carcinoma in the setting of Graves' disease is a rare scenario. Only fifteen total cases besides ours has been described in literature, and only six other cases were incidentally discovered. CONCLUSIONS: When Medullary Thyroid Carcinoma is incidentally discovered in the setting of Graves' disease, retroactive workup should begin with postoperative calcitonin, CEA level, testing for RET mutation, and a comprehensive neck ultrasound as soon as the diagnosis is made.

Effectiveness of gabapentin in reducing opioid requirements after radiation in head and neck cancer in a single institution.

BACKGROUND: Gabapentin has been shown to reduce opioid use in head and neck cancer patients. Here, we examine the efficacy of prophylactic gabapentin at reducing opioid use in these patients at our institution. METHODS: A retrospective study of patients receiving radiation was performed, using patients from our previous study as controls. Risk factors for opioid use at 3 and 6 months were determined using univariate and multivariate analyses. RESULTS: In total, 53/185 patients were treated with gabapentin, 39.6% of which took opioids at 3 months vs. 58.3% in the non-gabapentin cohort (p = 0.021). Gabapentin was independently associated with less opioid use on multivariate analysis at 3 months (OR 0.47, 95% CI 0.24-0.9). Gastrostomy tube dependence and pretreatment opioid use were associated with chronic opioid use despite gabapentin. CONCLUSIONS: Gabapentin is effective at expediting opioid tapering in head and neck cancer patients who are not gastrostomy tube dependent or taking opioids pretreatment.

A rare case of a middle ear glomangioma.

Glomus tumors are benign hyperplasia of glomus bodies, and they are rarely found in the head and neck. The middle ear is an exceptionally rare site for a true glomus tumor, and there are only three previously reported cases in this location. Glomus tumors are etiologically different than glomus tympanicum, which are paragangliomas of the middle ear that are often mistakenly referred to as "glomus tumors." This is a common misconception due to the "glomus" misnomer. We report a case of a patient diagnosed with a middle ear glomangioma after initially presenting to our clinic with tinnitus and hearing loss. The mass was surgically removed through a transcanal approach with carbon dioxide laser and sharp dissection. Literature review is also reported and revealed similar presentations in patients with middle ear glomangiomas.

Utility of CT in the workup of adults with sore throat in the emergency department.

OBJECTIVE: The goal of this study was to determine if computed tomography (CT) added any clinical information that was incorporated into the decision regarding treatment for patients who presented to the Emergency Department (ED) with sore throat. METHODS: A retrospective chart review of adult patients who presented to the ED with a chief complaint of sore throat who subsequently underwent CT during that ED visit between 1/1/18 and 12/31/18 at our tertiary academic health center was performed. The association between palatal bulge on Otolaryngology physical exam with successful drainage procedure was examined. The mean Hounsfield units (HU) and maximum dimension of measurable fluid collection on CT were compared between patients who underwent a successful drainage procedure and those who did not undergo a drainage procedure or attempted drainage was unsuccessful. RESULTS: Ninety-four patients met inclusion criteria, with 53% (50/94) men. Of the 22 patients with a palatal bulge on physical examination by Otolaryngology, 86% (19/22) underwent a successful drainage procedure (p < 0.001) when compared to those not undergoing successful drainage. Notably, 56% (53/94) of CT scans were interpreted as normal or tonsillitis. The mean HU was 42.0 in those patients who underwent a successful drainage procedure and 74.1 in those who did not undergo a drainage procedure (p < 0.001). Overall, 21/35 fluid collections had a palatal bulge (p < 0.001). CONCLUSION: Palatal bulge is a reliable finding in identifying patients with a drainable peritonsillar abscess, and CT scans could largely be avoided in patients without physical exam findings suggestive of more extensive deep neck space abscesses. If a CT scan is obtained, HU should be measured and incorporated into the shared decision-making process with the patient.

A case of parapharyngeal space salivary duct cyst with fine needle biopsy suspicious for squamous cell carcinoma.

OBJECTIVES: To report a unique case of salivary duct cyst presenting as parapharyngeal space mass and review relevant literature regarding salivary duct cyst and fine needle aspiration biopsy of salivary gland lesions. METHODS: After a case description, a review of the literature regarding salivary duct cyst etiology, pathophysiology, presentation, histologic features, and the accuracy of FNA in the context of salivary gland lesions was conducted. RESULTS: Salivary duct cysts are rare, often acquired, cystic dilatations of salivary ducts thought to arise secondary to ductal obstruction, commonly occurring in the major salivary glands. Fine needle aspiration is the biopsy method of choice for most head and neck lesions. There is controversy surrounding this method in salivary lesions, but recent data indicates it can be just as reliable as in other locations. CONCLUSIONS: Here, we highlight a patient with a salivary duct cyst presenting as a parapharyngeal mass, which has not been described in the literature. Overall, FNA in salivary lesions is highly pathologist dependent, which likely contributes to varying accuracy in the literature.

Implications of Treatment Modality on Chronic Opioid Use Following Treatment for Head and Neck Cancer.

OBJECTIVE: To investigate the relationship between treatment modality and chronic opioid use in a large cohort of patients with head and neck cancer. STUDY DESIGN: Retrospective cohort study. SETTING: Single academic center. METHODS: There were 388 patients with head and neck cancer treated between January 2011 and December 2017 who met inclusion criteria. Clinical risk factors for opioid use at 3 and 6 months were determined with univariate and multivariate analyses. RESULTS: The prevalence of opioid use was 43.0% at 3 months and 33.2% at 6 months. On multivariate analysis, primary chemoradiation (odds ratio [OR], 4.04; 95% CI, 1.91-8.55) and surgery with adjuvant chemoradiation (OR, 2.39; 95% CI, 1.09-5.26) were associated with opioid use at 3 months. Additional risk factors at that time point included pretreatment opioid use (OR, 7.63; 95% CI, 4.09-14.21) and decreasing age (OR, 1.03; 95% CI, 1.01-1.06). At 6 months, primary chemoradiation (OR, 2.40; 95% CI, 1.34-4.28), pretreatment opioid use (OR, 5.86; 95% CI, 3.30-10.38), current tobacco use (OR, 2.00; 95% CI, 1.18-3.40), and psychiatric disorder (OR, 1.79; 95% CI, 1.02-3.14) were associated with opioid use. CONCLUSION: Of the patients who receive different treatment modalities, those receiving primary chemoradiation are independently at highest risk for chronic opioid use. Other risk factors include pretreatment opioid use, tobacco use, and a psychiatric disorder. In an effort to reduce their risk of chronic opioid use, preventative strategies should be especially directed to these patients.

Prophylactic arterial ligation following transoral robotic surgery: A systematic review and meta-analysis.

Prophylactic arterial ligation has been proposed to reduce the severity of postoperative hemorrhage following transoral robotic surgery (TORS). Previous studies have shown a trend toward a reduction in major and severe bleeding. Search strategies were implemented in multiple databases and completed in August 2018. Inclusion and exclusion criteria were designed to capture studies examining adults undergoing TORS for oropharyngeal cancer. Four retrospective studies were selected appropriate for analysis by two reviewers who independently extracted data. PRISMA guidelines were followed. A random-effects model was used for meta-analysis. Meta-analysis of 619 patients in four retrospective reviews showed that the pooled RR of major and severe bleeding events was significantly lower in prophylactically ligated patients (RR, 0.28; 95% CI, 0.08-0.92; I2 = 0). Prophylactic arterial ligation of external carotid artery branches is associated with a decreased risk of major and severe bleeding events, although confounding factors remain incompletely analyzed.

Onset of Telomere Dysfunction and Fusions in Human Ovarian Carcinoma.

Telomere dysfunction has been strongly implicated in the initiation of genomic instability and is suspected to be an early event in the carcinogenesis of human solid tumors. Recent findings have established the presence of telomere fusions in human breast and prostate malignancies; however, the onset of this genomic instability mechanism during progression of other solid cancers is not well understood. Herein, we explored telomere dynamics in patient-derived epithelial ovarian cancers (OC), a malignancy characterized by multiple distinct subtypes, extensive molecular heterogeneity, and widespread genomic instability. We discovered a high frequency of telomere fusions in ovarian tumor tissues; however, limited telomere fusions were detected in normal adjacent tissues or benign ovarian samples. In addition, we found relatively high levels of both telomerase activity and hTERT expression, along with anaphase bridges in tumor tissues, which were notably absent in adjacent normal ovarian tissues and benign lesions. These results suggest that telomere dysfunction may occur early in ovarian carcinogenesis and, importantly, that it may play a critical role in the initiation and progression of the disease. Recognizing telomere dysfunction as a pervasive feature of this heterogeneous malignancy may facilitate the future development of novel diagnostic tools and improved methods of disease monitoring and treatment.

Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies.

Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes. Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span. Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity. Results: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10(-3) unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10(-3), -1.01 × 10(-3)) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10(-3) unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10(-3), -1.25 × 10(-3)). The associations were predominantly for the white pooled population. No sex differences were observed. Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.

Economic Impact of Frozen Section for Thyroid Nodules with "Suspicious for Malignancy" Cytology.

Objective To perform a cost analysis of the routine use of intraoperative frozen section (iFS) among patients undergoing a thyroid lobectomy with "suspicious for malignancy" (SUSP) cytology in the context of the 2015 American Thyroid Association guidelines. Study Design Case series with chart review; cost minimization analysis. Setting Academic. Subjects and Methods Records were reviewed for patients with SUSP cytology who underwent thyroid surgery between 2010 and 2015 in which iFS was utilized. The diagnostic test performance of iFS and the frequency of indicated completion/total thyroidectomies based on the 2015 guidelines were calculated. A cost minimization analysis was performed comparing lobectomy, with and without iFS, and the need for completion thyroidectomy according to costs estimated from 2014 data from Medicare, the Bureau of Labor Statistics, and the Nationwide Inpatient Sample. Results Sixty-five patients met inclusion criteria. The malignancy rate was 61.5%, 45% of which was identified intraoperatively. The specificity and positive predictive value were 100%. The negative predictive value and sensitivity were 83% and 95%, respectively. Completion/total thyroidectomy was indicated for 9% of patients; 83% of these individuals had findings on iFS that would have changed management intraoperatively. Application of the new guidelines would have resulted in a significant reduction in the frequency of conversion to a total thyroidectomy when compared with the actual management (26.1% vs 7.7%, P = .005). Performing routine iFS was the less costly scenario, resulting in a savings of $474 per case. Conclusion For patients with SUSP cytology undergoing lobectomy, routine use of iFS would result in decreased health care utilization.

The futility of intraoperative frozen section in the evaluation of follicular thyroid lesions.

OBJECTIVE: Investigate the utility of intraoperative frozen section (iFS) in patients with follicular thyroid lesions following publication of the 2015 American Thyroid Association (ATA) guidelines. STUDY DESIGN: Retrospective chart review. METHODS: Patient demographics, preoperative cytology, frozen pathology, and final pathology were reviewed on patients undergoing thyroid surgery at a tertiary care hospital in which iFS was utilized over a 5-year period. The test performance of iFS and the frequency of indicated completion/total thyroidectomies pre- and postpublication of the 2015 ATA guidelines were calculated. RESULTS: One hundred and one patients met inclusion criteria: 54 patients with follicular lesions of undetermined significance (FLUS) and 47 patients with a cytologic diagnosis of suspicious for follicular neoplasm/follicular neoplasm. The malignancy rate was 36%, but only 14% of malignancies were identified on iFS. A definitive benign or malignant diagnosis was given on iFS in only 21% of cases, and operative management was altered in two cases as a result of iFS. There was a statistically significant reduction in the frequency of indicated total/completion thyroidectomies based on high-risk features as a result of the 2015 ATA guidelines compared to prior recommendations (20.8% vs. 5.0%, P = < 0.001). None of these patients had findings on iFS that would have altered management intraoperatively. CONCLUSION: Intraoperative frozen section offers minimal diagnostic utility in the evaluation of follicular thyroid lesions. Updates in the 2015 ATA guidelines further diminish its potential to impact management intraoperatively. Significant improvements in its ability to identify malignancies would be needed to justify its use. LEVEL OF EVIDENCE: 4. Laryngoscope, 128:1501-1505, 2018.

DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo.

Constitutive activation of the pro-survival transcription factor NF-κB has been associated with resistance to both chemotherapy and radiation therapy in many human cancers, including prostate cancer. Our lab and others have demonstrated that the natural product parthenolide can inhibit NF-κB activity and sensitize PC-3 prostate cancers cells to X-rays in vitro; however, parthenolide has poor bioavailability in vivo and therefore has little clinical utility in this regard. We show here that treatment of PC-3 and DU145 human prostate cancer cells with dimethylaminoparthenolide (DMAPT), a parthenolide derivative with increased bioavailability, inhibits constitutive and radiation-induced NF-κB binding activity and slows prostate cancer cell growth. We also show that DMAPT increases single and fractionated X-ray-induced killing of prostate cancer cells through inhibition of DNA double strand break repair and also that DMAPT-induced radiosensitization is, at least partially, dependent upon the alteration of intracellular thiol reduction-oxidation chemistry. Finally, we demonstrate that the treatment of PC-3 prostate tumor xenografts with oral DMAPT in addition to radiation therapy significantly decreases tumor growth and results in significantly smaller tumor volumes compared to xenografts treated with either DMAPT or radiation therapy alone, suggesting that DMAPT might have a potential clinical role as a radiosensitizing agent in the treatment of prostate cancer.

Optogenetic regulation of site-specific subtelomeric DNA methylation.

Telomere length homeostasis, critical for chromosomal integrity and genome stability, is controlled by intricate molecular regulatory machinery that includes epigenetic modifications. Here, we examine site-specific and spatiotemporal alteration of the subtelomeric methylation of CpG islands using optogenetic tools to understand the epigenetic regulatory mechanisms of telomere length maintenance. Human DNA methyltransferase3A (DNMT3A) were assembled selectively at chromosome ends by fusion to cryptochrome 2 protein (CRY2) and its interacting complement, the basic helix loop helix protein-1 (CIB1). CIB1 was fused to the telomere-associated protein telomere repeat binding factor-1 (TRF1), which localized the protein complex DNMT3A-CRY2 at telomeric regions upon excitation by blue-light monitored by single-molecule fluorescence analyses. Increased methylation was achieved selectively at subtelomeric CpG sites on the six examined chromosome ends specifically after blue-light activation, which resulted in progressive increase in telomere length over three generations of HeLa cell replications. The modular design of the fusion constructs presented here allows for the selective substitution of other chromatin modifying enzymes and for loci-specific targeting to regulate the epigenetic pathways at telomeres and other selected genomic regions of interest.

Widespread telomere instability in prostatic lesions.

A critical function of the telomere is to disguise chromosome ends from cellular recognition as double strand breaks, thereby preventing aberrant chromosome fusion events. Such chromosome end-to-end fusions are known to initiate genomic instability via breakage-fusion-bridge cycles. Telomere dysfunction and other forms of genomic assault likely result in misregulation of genes involved in growth control, cell death, and senescence pathways, lowering the threshold to malignancy and likely drive disease progression. Shortened telomeres and anaphase bridges have been reported in a wide variety of early precursor and malignant cancer lesions including those of the prostate. These findings are being extended using methods for the analysis of telomere fusions (decisive genetic markers for telomere dysfunction) specifically within human tissue DNA. Here we report that benign prostatic hyperplasia (BPH), high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer (PCa) prostate lesions all contain similarly high frequencies of telomere fusions and anaphase bridges. Tumor-adjacent, histologically normal prostate tissue generally did not contain telomere fusions or anaphase bridges as compared to matched PCa tissues. However, we found relatively high levels of telomerase activity in this histologically normal tumor-adjacent tissue that was reduced but closely correlated with telomerase levels in corresponding PCa samples. Thus, we present evidence of high levels of telomere dysfunction in BPH, an established early precursor (PIN) and prostate cancer lesions but not generally in tumor adjacent normal tissue. Our results suggest that telomere dysfunction may be a common gateway event leading to genomic instability in prostate tumorigenesis. .

Hydrocarbons emitted by waggle-dancing honey bees increase forager recruitment by stimulating dancing.

Hydrocarbons emitted by waggle-dancing honey bees are known to reactivate experienced foragers to visit known food sources. This study investigates whether these hydrocarbons also increase waggle-dance recruitment by observing recruitment and dancing behavior when the dance compounds are introduced into the hive. If the hydrocarbons emitted by waggle-dancing bees affect the recruitment of foragers to a food source, then the number of recruits arriving at a food source should be greater after introduction of dance compounds versus a pure-solvent control. This prediction was supported by the results of experiments in which recruits were captured at a feeder following introduction of dance-compounds into a hive. This study also tested two nonexclusive behavioral mechanism(s) by which the compounds might stimulate recruitment; 1) increased recruitment could occur by means of increasing the recruitment effectiveness of each dance and/or 2) increased recruitment could occur by increasing the intensity of waggle-dancing. These hypotheses were tested by examining video records of the dancing and recruitment behavior of individually marked bees following dance-compound introduction. Comparisons of numbers of dance followers and numbers of recruits per dance and waggle run showed no significant differences between dance-compound and solvent-control introduction, thus providing no support for the first hypothesis. Comparison of the number of waggle-dance bouts and the number of waggle runs revealed significantly more dancing during morning dance-compound introduction than morning solvent-control introduction, supporting the second hypothesis. These results suggest that the waggle-dance hydrocarbons play an important role in honey bee foraging recruitment by stimulating foragers to perform waggle dances following periods of inactivity.

mPEG-PAMAM-G4 nucleic acid nanocomplexes: enhanced stability, RNase protection, and activity of splice switching oligomer and poly I:C RNA.

Dendrimer chemistries have virtually exploded in recent years with increasing interest in this class of polymers as gene delivery vehicles. An effective nucleic acid delivery vehicle must efficiently bind its cargo and form physically stable complexes. Most importantly, the nucleic acid must be protected in biological fluids and tissues, as RNA is extremely susceptible to nuclease degradation. Here, we characterized the association of nucleic acids with generation 4 PEGylated poly(amidoamine) dendrimer (mPEG-PAMAM-G4). We investigated the formation, size, and stability over time of the nanoplexes at various N/P ratios by gel shift and dynamic light scatter spectroscopy (DLS). Further characterization of the mPEG-PAMAM-G4/nucleic acid association was provided by atomic force microscopy (AFM) and by circular dichroism (CD). Importantly, mPEG-PAMAM-G4 complexation protected RNA from treatment with RNase A, degradation in serum, and various tissue homogenates. mPEG-PAMAM-G4 complexation also significantly enhanced the functional delivery of RNA in a novel engineered human melanoma cell line with splice-switching oligonucleotides (SSOs) targeting a recombinant luciferase transcript. mPEG-PAMAM-G4 triconjugates formed between gold nanoparticle (GNP) and particularly manganese oxide (MnO) nanorods, poly IC, an anticancer RNA, showed enhanced cancer-killing activity by an MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) cell viability assay.

The luminal progenitor compartment of the normal human mammary gland constitutes a unique site of telomere dysfunction.

Telomeres are essential for genomic integrity, but little is known about their regulation in the normal human mammary gland. We now demonstrate that a phenotypically defined cell population enriched in luminal progenitors (LPs) is characterized by unusually short telomeres independently of donor age. Furthermore, we find that multiple DNA damage response proteins colocalize with telomeres in >95% of LPs but in <5% of basal cells. Paradoxically, 25% of LPs are still capable of exhibiting robust clonogenic activity in vitro. This may be partially explained by the elevated telomerase activity that was also seen only in LPs. Interestingly, this potential telomere salvage mechanism declines with age. Our findings thus reveal marked differences in the telomere biology of different subsets of primitive normal human mammary cells. The chronically dysfunctional telomeres unique to LPs have potentially important implications for normal mammary tissue homeostasis as well as the development of certain breast cancers.

Telomere fusions in early human breast carcinoma.

Several lines of evidence suggest that defects in telomere maintenance play a significant role in the initiation of genomic instability during carcinogenesis. Although the general concept of defective telomere maintenance initiating genomic instability has been acknowledged, there remains a critical gap in the direct evidence of telomere dysfunction in human solid tumors. To address this topic, we devised a multiplex PCR-based assay, termed TAR (telomere-associated repeat) fusion PCR, to detect and analyze chromosome end-to-end associations (telomere fusions) within human breast tumor tissue. Using TAR fusion PCR, we found that human breast lesions, but not normal breast tissues from healthy volunteers, contained telomere fusions. Telomere fusions were detected at similar frequencies during early ductal carcinoma in situ and in the later invasive ductal carcinoma stage. Our results provide direct evidence that telomere fusions are present in human breast tumor tissue and suggest that telomere dysfunction may be an important component of the genomic instability observed in this cancer. Development of this robust method that allows identification of these genetic aberrations (telomere fusions) is anticipated to be a valuable tool for dissecting mechanisms of telomere dysfunction.