RET splice site variants in medullary thyroid carcinoma.

Introduction: Medullary thyroid carcinoma (MTC) is an aggressive cancer that is often caused by driver mutations in RET. Splice site variants (SSV) reflect changes in mRNA processing, which may alter protein function. RET SSVs have been described in thyroid tumors in general but have not been extensively studied in MTC. Methods: The prevalence of RET SSVs was evaluated in 3,624 cases with next generation sequence reports, including 25 MTCs. Fisher exact analysis was performed to compare RET SSV frequency in cancers with/without a diagnosis of MTC. Results: All 25 MTCs had at least one of the two most common RET SSVs versus 0.3% of 3,599 cancers with other diagnoses (p < 0.00001). The 11 cancers with non-MTC diagnoses that had the common RET SSVs were 4 neuroendocrine cancers, 4 non-small cell lung carcinomas, 2 non-MTC thyroid cancers, and 1 melanoma. All 25 MTCs analyzed had at least one of the two most common RET SSVs, including 4 with no identified mutational driver. Discussion: The identification of RET SSVs in all MTCs, but rarely in other cancer types, demonstrates that these RET SSVs distinguish MTCs from other cancer types. Future studies are needed to investigate whether these RET SSVs play a pathogenic role in MTC.

High Pretreatment DHEA Is Associated with Inferior Immunotherapy Response in Metastatic Non-Small Cell Lung Cancer.

Background: Sex difference in the immune response may influence patients' response to immune checkpoint inhibitors (ICIs). We conducted a prospective observation study to determine the correlation between pretreatment sex hormone levels and response to ICIs in metastatic non-small cell lung cancer (NSCLC). Method: Pretreatment plasma samples from 61 patients with newly diagnosed NSCLC prior to ICI therapy were collected. Six sex hormone levels [pyrazole triol, 17 ß-estradiol, 5-androstenediol, 3ß-androstenediol, dehydroepiandrosterone (DHEA), and S-equol] were measured using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS). Overall survival (OS) and progression-free survival (PFS) were compared between the high- and low-level groups in the whole cohort. Result: Among the six sex hormones measured, DHEA levels were significantly higher among patients without clinical benefits in the discovery cohort; the remaining sex hormones did not differ significantly. In the whole cohort, median PFS was 22 months for patients with low DHEA levels vs. 3.8 months for those with high DHEA [hazard ratio, 14.23 (95% CI, 4.7-43); p < 0.001]. A significant association was also observed for OS [hazard ratio, 8.2 (95% CI, 2.89-23.35); p < 0.0001]. Conclusions: High pretreatment plasma DHEA levels were associated with poor clinical outcomes for patients with metastatic NSCLC treated with ICIs.

Age, rehabilitation and surgery characteristics are re-injury risk factors for adolescents following anterior cruciate ligament reconstruction.

OBJECTIVES: To examine the effect of age on post-ACLR rehabilitative outcomes and identify surgical/rehabilitative characteristics as ACL re-injury risk factors in adolescents. DESIGN: Cohort study. SETTING: Children's hospital. PARTICIPANTS: 273 adolescents with first-time ACLR. MAIN OUTCOME MEASURES: Demographics, injury history, surgery, and outcomes documented during post-ACLR physical therapy (PT) sessions were extracted from medical records. Effects of age on outcomes were examined using multivariate regression. ACL re-injury risk factors were identified using survival analysis with Cox regression. RESULTS: Re-injury was recorded in 47 patients (17.2%) with a median follow-up time of 3.1 years and median re-injury time of 13.4 months post-surgery. Younger age (Hazard-Ratio, HR = 1.264 per year decrease; P = 0.005), receiving surgery within 1 month post-injury (HR = 3.378 vs. >3 months; P = 0.012), starting PT within 3 days post-surgery (HR = 3.068; P = 0.022), and decreased number of PT sessions (HR = 1.118 per 3-session decrease; P = 0.010) increased re-injury risk. Although age was associated with re-injury risk, age was not associated with any outcome (P > 0.059). CONCLUSION: Adolescents who are younger, receive surgery and post-surgery PT sooner, or attend fewer PT sessions may be at an increased re-injury risk. Younger patients achieved similar outcomes despite elevated re-injury risk. Current discharge criteria are inadequate in identifying high re-injury risk patients.

Comparison of Postmarketing Findings vs the Initial Clinical Validation Findings of a Thyroid Nodule Gene Expression Classifier: A Systematic Review and Meta-analysis.

IMPORTANCE: In the United States, the most used molecular test for the evaluation of cytologically indeterminate thyroid nodules is the Afirma gene expression classifier (GEC). OBJECTIVE: To evaluate the GEC's diagnostic performance through a novel approach to assess whether the findings of the initial validation study are consistent with the results of postmarketing studies. DATA SOURCES: PubMed was systematically searched from inception through October 26, 2017, using the terms gene expression classifier or Afirma or GEC and thyroid. STUDY SELECTION: Studies included were those in which the GEC diagnostic performance could be calculated on consecutively resected cytologically indeterminate thyroid nodules. DATA EXTRACTION AND SYNTHESIS: Two observers independently assessed study eligibility and risk of bias using the quality assessment tool for observational cohort and cross-sectional studies of the National Heart, Lung, and Blood Institute. Summary data were extracted by a reviewer and reviewed independently by another. Study authors were contacted if missing data were needed. Data were pooled using a random-effects model. PRISMA and MOOSE guidelines were followed. MAIN OUTCOMES AND MEASURES: Evaluation of the linear correlation between the benign call rate (BCR) and the positive predictive value (PPV). RESULTS: Of the 137 retrieved titles, 19 (13.9%) were included, comprising a total of 2568 thyroid nodules. Based on a simulation using the sensitivity and specificity reported in the initial validation study, the observed BCR and PPV values in postmarketing studies would have to be explained by different underlying prevalence rates of cancer (15% vs 30%), which is an impossible event. Furthermore, the overall correlation between BCR and PPV for independent studies fell outside the PPV 95% CI of the initial validation study (95% CI, 0.17-0.32) at the BCR of pooled independent studies (0.45) and was just at the limit of the BCR 95% CI of the initial validation study (95% CI, 0.32-0.45) at the PPV of pooled independent studies (0.45). The diagnostic performance was statistically significantly better for atypia or follicular lesions of undetermined significance (diagnostic odds ratio [DOR], 5.67; 95% CI, 4.23-7.60) compared with follicular neoplasms (DOR, 2.24; 95% CI, 1.45-3.47). CONCLUSIONS AND RELEVANCE: The findings suggest that the initial validation study cohort was not representative of the populations in whom the GEC has been used, calling into question its reported diagnostic performance, including its negative predictive value.

Association of Tumor Size With Histologic and Clinical Outcomes Among Patients With Cytologically Indeterminate Thyroid Nodules.

Importance: Tens of thousands of unnecessary operations are performed each year for diagnostic purposes among patients with cytologically indeterminate thyroid nodules. Whereas a diagnostic lobectomy is recommended for most patients with solitary indeterminate thyroid nodules, a total thyroidectomy is preferred for nodules larger than 4 cm. Objective: To determine whether histologic or clinical outcomes of indeterminate thyroid nodules 4 cm or larger are worse than those for nodules smaller than 4 cm, thus justifying a more aggressive initial surgical approach. Design, Setting, and Participants: In this retrospective cohort study, 652 indeterminate thyroid nodules (546 nodules <4 cm and 106 nodules ≥4 cm) with surgical follow-up were consecutively evaluated at an academic cancer center from October 1, 2008, through April 30, 2016. Exposure: Tumor size. Main Outcomes and Measures: Differences in cancer rates, rates of invasive features, cancer aggressiveness, and response to therapy between indeterminate thyroid nodules smaller than 4 cm and 4 cm or larger. Results: A total of 652 indeterminate thyroid nodules (546 nodules <4 cm and 106 nodules ≥4 cm) from 589 patients (mean [SD] age, 53.1 [13.8] years; 453 [76.9%] female) were studied. No differences were found in the baseline characteristics of patients or nodules between the 2 size groups. Tumor size was not associated with the cancer rate as a categorical (140 of 546 [25.6%] for nodules <4 cm and 33 of 106 [31.1%] for nodules ≥4 cm; effect size, 0.05; 95% CI, 0.002-0.12) or continuous (odds ratio [OR], 1.03; 95% CI, 0.92-1.15) variable. No association was found between nodule size and prevalence of extrathyroidal extension, positive margins, lymphovascular invasion, lymph node metastasis, or distant metastasis. Most malignant tumors were low risk in both size groups (70% in the nodules <4 cm and 72% in the nodules ≥4 cm), and tumor size was not associated with tumor aggressiveness as a categorical (effect size, 0.10; 95% CI, 0.03-0.31) or continuous variable (OR for intermediate-risk cancer, 0.91; 95% CI, 0.72-1.14; OR for high-risk cancer, 1.43; 95% CI, 0.96-2.15). At the last follow-up visit, 88 of 105 patients (83.8%) with malignant tumors in the smaller than 4 cm group and 21 of 25 (84.0%) in the 4 cm or greater group had no evidence of disease, and tumor size was not associated with response to therapy (effect size, 0.13; 95% CI, 0.07-0.33). Conclusions and Relevance: Most indeterminate thyroid nodules are benign or low-risk malignant tumors regardless of tumor size. In the absence of other indications for total thyroidectomy, this study suggests that a thyroid lobectomy is sufficient initial treatment for most solitary cytologically indeterminate thyroid nodules independent of the tumor size.

Impact of oncogene panel results on surgical management of cytologically indeterminate thyroid nodules.

BACKGROUND: The impact of oncogene panel results on the surgical management of indeterminate thyroid nodules (ITNs) is currently unknown. METHODS: Surgical management of 649 patients consecutively evaluated from October 2008 to April 2016 with a single nodule biopsied and indeterminate cytology (193 evaluated with and 456 without oncogene panels) was assessed and compared. Histological features of 629 consecutively resected ITNs (164 evaluated with and 465 without oncogene panels) were also characterized and compared. RESULTS: Oncogene panel evaluation was associated with higher rates of total thyroidectomy (45% vs 28%; P = .006), and central lymph node dissection (19% vs 12%; P = .03) without increasing the yield of malignancy or decreasing the rate of completion thyroidectomy. Most malignancies (64%), including 83% of those with driver mutation identified, were low-risk cancers for which a lobectomy could have been sufficient initial treatment. CONCLUSION: Current oncogene panel results seem insufficient to guide the surgical extent of solitary ITNs.

Cancer Risk Associated with Nuclear Atypia in Cytologically Indeterminate Thyroid Nodules: A Systematic Review and Meta-Analysis.

BACKGROUND: Indeterminate categories of thyroid cytopathology (categories B-III and B-IV of the Bethesda system) are integrated by a heterogeneous spectrum of cytological scenarios that are generally clustered for analysis and management recommendations. It has been suggested that aspirates exhibiting nuclear atypia have a higher risk of malignancy. This study aimed to assess whether cytologically indeterminate thyroid nodules with nuclear atypia have a significantly higher cancer risk than those without nuclear atypia. METHODS: On June 30, 2016, PubMed and EMBASE were searched for articles in English or Spanish using a search strategy developed by an endocrinologist and a librarian. Case reports were excluded, and no date limits were used. The references of all included studies were also screened for relevant missing studies. Studies were included if the prevalences of malignancy of cytologically indeterminate thyroid nodules with histological confirmation with and without nuclear atypia were reported. Studies were excluded if they had: (i) nodules suspicious for malignancy; (ii) nodules with non-indeterminate (B-III or B-IV) cytology on repeated biopsy, if performed; (iii) nodules not consecutively evaluated; or (iv) cohorts overlapping with another larger series. Two investigators independently assessed the eligibility and risk of bias of the studies. PRISMA and MOOSE guidelines were followed. Summary data were extracted from published reports by one investigator and independently reviewed by another. Data were pooled using a random-effects model. Heterogeneity was explored using subgroup analysis and mixed-effect model meta-regression. The odds ratio for malignancy of cytologically indeterminate thyroid nodules with nuclear atypia over cytologically indeterminate thyroid nodules without nuclear atypia was calculated. RESULTS: Of 2571 retrieved studies, 20 were eligible. The meta-analysis was conducted on summary data of 3532 cytologically indeterminate thyroid nodules: 1162 with and 2370 without nuclear atypia. The odds ratio for malignancy in cytologically indeterminate thyroid nodules with nuclear atypia was 3.63 [confidence interval 3.06-4.35]. There was no evidence of publication bias, and heterogeneity was insignificant (I2 < 0.01%, p = 0.40). CONCLUSIONS: Nuclear atypia is a significant indicator of malignancy in cytologically indeterminate thyroid nodules and needs to be standardized and implemented into clinical practice.

Cancer Risk Stratification of Indeterminate Thyroid Nodules: A Cytological Approach.

BACKGROUND: Management recommendations for thyroid nodules rely primarily on the cytological diagnosis. However, 25% of biopsies render an indeterminate cytology for which management decision is more challenging due to heterogeneity of the specimens. This study aimed to stratify the cancer risk through subcategorization of indeterminate cytology. METHODS: The indeterminate cytological specimens (Bethesda-III or IV) of 518 thyroid nodules consecutively evaluated at our academic cancer center between October 2008 and September 2015, blinded to the histological outcome, were retrospectively reviewed. Cytological specimens were subclassified into four groups: aspirates exhibiting nuclear atypia (n = 158; 31%); architectural atypia (n = 222; 43%); oncocytic features (n = 120; 23%); or other types of atypia (n = 18; 3%). The prevalence of malignancy and odds ratio for malignancy were calculated in 323 nodules with histological confirmation. RESULTS: The prevalence of malignancy was 26% overall (20% in Bethesda-III and 29% in Bethesda-IV; p = 0.07), and 47%, 12%, 24%, and 25% for aspirates with nuclear atypia, architectural atypia, oncocytic features, or other types of atypia, respectively. The OR of nuclear atypia over architectural atypia was 6.4 (3.4-12.2; p < 0.001), and 2.7 over oncocytic features (1.4-5.1; p = 0.01), whereas the OR of architectural atypia over oncocytic features was 0.4 (0.2-0.9; p = 0.03). Results were similar for Bethesda-III and IV aspirates when analyzed independently. Furthermore, cytological subcategories improved cytology-histology correlation, as they were associated with distinct profiles of histological diagnoses (p < 0.001). CONCLUSIONS: Cytological subcategories can effectively stratify the risk of malignancy of thyroid nodules with indeterminate cytology and improve cytology-histology correlation.

Evaluation of ThyroSeq v2 performance in thyroid nodules with indeterminate cytology.

ThyroSeq v2 claims high positive (PPV) and negative (NPV) predictive values in a wide range of pretest risks of malignancy in indeterminate thyroid nodules (ITNs) (categories B-III and B-IV of the Bethesda system). We evaluated ThyroSeq v2 performance in a cohort of patients with ITNs seen at our Academic Cancer Center from September 2014 to April 2016, in light of the new diagnostic criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Our study included 182 patients (76% female) with 190 ITNs consecutively tested with ThyroSeq v2. Patient treatment followed our institutional thyroid nodule clinical pathway. Histologies of nodules with follicular variant papillary thyroid carcinoma or NIFTP diagnoses were reviewed, with reviewers blinded to molecular results. ThyroSeq v2 performance was calculated in nodules with histological confirmation. We identified a mutation in 24% (n = 45) of the nodules. Mutations in RAS were the most prevalent (n = 21), but the positive predictive value of this mutation was much lower (31%) than that in prior reports. In 102 resected ITNs, ThyroSeq v2 performance was as follows: sensitivity 70% (46-88), specificity 77% (66-85), PPV 42% (25-61) and NPV 91% (82-97). The performance in B-IV nodules was significantly better than that in B-III nodules (area under the curve 0.84 vs 0.57, respectively; P = 0.03), where it was uninformative. Further studies evaluating ThyroSeq v2 performance are needed, particularly in B-III.

A disciplined approach to implementation of evidence-based practices decreases ICU and hospital length of stay in traumatically injured patients.

BACKGROUND: Evidence-based medicine has gained wide acceptance in practice of medicine since the 1990s. The objective of our study was to demonstrate the effect of evidence-based critical care practices on ICU and hospital length of stay in mechanically ventilated trauma patients. MATERIALS AND METHODS: Retrospective cohort using historic controls. During 2004, several different evidence-based practices were implemented, including low tidal volume ventilation, protocol driven trauma resuscitation, and a sepsis bundle. Outcomes in critically ill, mechanically ventilated patients who were ≥ 18 y old were compared between a historic control group (2000-2003) and the study group after implementation (2005-2008). Patients were identified using the institutional trauma registry (NATIONAL TRACS). Gender, age, ISS, mechanism of injury, and mortality were also examined to identify trends in epidemiology. RESULTS: From 2000 to 2003. there were 6920 trauma admissions and during 2005-2008 there were 8911 (increase of 28.8%). These included 217 and 337 (increase of 55.3%) admissions to the ICU of mechanically ventilated patients, respectively. The mean age was 43.9 y versus 45.9 y (P = 0.258). Males were 66.4% versus 71.8% (P = 0.610). The mean ISS was 29 versus 27 (P = 0.25). Blunt mechanism was 87% versus 89% (P = 0.913). Mortality rate was 36.4% versus 36.5% (P = 0.944). The mean number of ICU days and hospital days decreased from 7.6 versus 5.5 (P = 0.02) and 13.2 versus 9.7 (P = 0.03), respectively. CONCLUSION: The application of evidence-based critical care practices decreases length of ICU and hospital stay, but not mortality, in critically ill, mechanically ventilated trauma patients. Our trauma volume, including critically ill patients, increased during the study periods.

Informal social support networks and the maintenance of voluntary driving cessation by older rural women.

Seventy-five rural women over the age of 77 participated in this study to describe the impact of informal social support on the maintenance of voluntary driving cessation. After being screened for mental status, they completed a demographic questionnaire and the Lubben Social Network Scale (2006). They also participated in a semistructured interview designed to probe factors leading to driving cessation and the ability to maintain it. Findings suggest that most participants stopped driving due to a decline in physical function and/or involvement in a nonfatal accident. Adequate support from family and friends was critical to the maintenance of driving cessation. Those with a limited informal social network resumed driving due to the lack of transportation, feelings of insecurity and fear for their survival, and the desire to assist friends who were less fortunate. Implications for community health nurses working in rural areas are discussed.

Fluoride-related bone disease associated with habitual tea consumption.

Acquired osteosclerosis is a rare disorder of bone formation but an important consideration in adults with sclerotic bones or elevated bone density results. In such patients, malignancy, hepatitis C, and fluorosis should all be considered when making a diagnosis. We describe 4 patients evaluated at our Metabolic Bone Disease Clinic from May 1, 1997, to July 1, 2006, whose bone disorders resulted from chronic fluoride exposure due to excessive tea intake. Three of these patients had toxic serum fluoride levels (> 15 micromol/L). Although the clinical presentation of the patients varied, all 4 had an unexpectedly elevated spine bone mineral density that was proportionately higher than the bone mineral density at the hip. Other clinical features included gastrointestinal symptoms such as nausea, vomiting, and weight loss; lower extremity pain sometimes associated with stress fractures of the lower extremities; renal insufficiency; and elevated alkaline phosphatase levels. Readily available, tea often contains high levels of fluoride. Obsessive-compulsive drinking behaviors and renal insufficiency may predispose to excessive fluoride consumption and accumulation. The current cases show that fluoride-related bone disease is an important clinical consideration in patients with dense bones or gastrointestinal symptoms and a history of excessive tea consumption. Furthermore, fluoride excess should be considered in all patients with a history of excessive tea consumption, especially due to its insidious nature and nonspecific clinical presentation.

Ambiguous chronic illness in women: community health nursing concern.

The purpose of this study was to explore how women with ambiguous chronic illness, such as celiac disease and interstitial cystitis, cope with the difficulty of being diagnosed and the subsequent realities of daily life. A convenience sample of 15 women with chronic ambiguous illness in 4 geographic areas was interviewed via qualitative methods. Data were analyzed using conceptual coding and constant comparative methods. These categories were identified: persistence in obtaining a correct diagnosis, trivialization and stigmatization, embarrassment, being an inconvenience, and ways of coping. Women were misdiagnosed for years (R = 2 to 11) and felt dismissed as being depressed or hysterical. Yet, they emphasized that persistence in obtaining a correct diagnosis is essential even though it may mean suffering embarrassment and inconvenience. Suggestions for community health nurses to improve the lives of women with ambiguous chronic illness are offered.

A rural state's response to the nursing shortage. Nevada's story.

This article describes how the nursing leadership in Nevada is responding to the nursing shortage crisis. The Nevada Hospital Association and Nevada legislature have supported statewide educational initiatives. Outcomes of a task force include recommendations to improve articulation agreements between schools of nursing and community colleges, external funding for summer salaries for faculty, efforts to recruit and retain minority and other nontraditional students, reallocation of financial resources among all universities and colleges in the state, reexamination of state-mandated faculty-to-student ratios, and changes in the work environment to encourage nurses to remain in the profession. A plan was developed to double enrollments in nursing schools through federal and state funding strategies, creative scheduling, and academic resource support.

The use of music to promote sleep in older women.

Fifty-two women over the age of 70 participated in a study to investigate the use of an individualized music protocol to promote sleep onset and maintenance. They were recruited from the practices of physicians and nurse practitioners, and met the inclusion and exclusion criteria of the International Classification of Sleep Disorders (1990), and the Diagnostic and Statistical Manual of Mental Disorders (1994). Results indicated that the use of music decreased time to sleep onset and the number of nighttime awakenings. Consequently, it increased satisfaction with sleep. Nurses may wish to recommend the use of music at bedtime to older women with insomnia.

Why rural elders drive against advice.

The purpose of this study was to describe the reasons rural elders continue to drive against the advice of health professionals, family, or friends. Interviews were conducted with a convenience sample of 45 older adults living in isolated communities with populations ranging from 225 to 8,700 residents. Findings suggest that declining health was the primary reason the participants were advised to stop driving. They refused to do so because they did not believe they were unsafe, valued their independence, and feared isolation if they could not drive. Significant reassurance that they would not be forgotten would be required for them to stop driving.