Genomic profiling in low grade serous ovarian cancer: Identification of novel markers for disease diagnosis and therapy.

OBJECTIVES: Low grade serous ovarian cancer (LGSOC) differs from high grade serous in terms of pathogenesis, molecular, genetic, and clinical features. Molecular studies have been hampered by small sample sizes, heterogenous histology, and lack of comprehensive testing. We sought to molecularly profile LGSOC in a homogenously tested, histologically confirmed cohort. METHODS: Using hot-spot and whole exome next generation sequencing (NGS), fusion gene analysis interrogating RNA, fragment analysis, in situ hybridization and/or immunohistochemistry, 179 specimens were evaluated by Caris Life Sciences (Phoenix, AZ). A second independent histologic review confirmed histology in 153 specimens. RESULTS: Most frequently mutated genes (5% or greater) were members of the mitogen-activated protein kinase (MAPK) pathway: KRAS (23.7%, n = 36), NRAS (11.2%, n = 19), NF1 (7.9%, n = 5), and BRAF (6.6%, n = 10). Class III mutations were seen in 3 of 10 BRAF mutations while 7 were Class I V600E. Overall, estrogen and progesterone receptor expression was 80.2% (n = 130) and 27.8% (n = 45), respectively. Of those that were hormone negative, nearly 50% contained KRAS or NF1 mutations. None were NRAS mutated. Markers of response to immunotherapy were low to absent. CONCLUSION: BRAF mutations were seen to be lower than those traditionally reported. With increased MAPK activation resulting in ligand independent activation of ERα, a role of combination therapy with hormonal and targeted therapy should be considered as 49.2% of hormone negative specimens were KRAS or NF1 mutated. Absence of immunotherapy biomarkers suggest limited benefit to immunotherapeutic agents.

Metastatic triple negative breast cancer with NTRK gene fusion on tissue but not on ctDNA molecular profile.

A woman presented to medical oncology with almost 4 years of untreated, slowly progressing, triple negative metastatic breast cancer to the lung. About 15 years prior, she was diagnosed with invasive ductal carcinoma of the right breast with ipsilateral chest wall recurrence 6 years later. Comprehensive molecular profiling of a metastatic lesion detected a hotspot ETV6-NTRK3 fusion, which was not present on circulating tumour DNA or molecular profile performed 4 years prior. A second look pathological examination demonstrated tumour characteristics consistent with secretory breast carcinoma. Identification of ETV6--NKRT3 fusion allowed for treatment with larotrectinib, a tyrosine kinase inhibitor specifically indicated for secretory breast carcinoma. After 3 months, she experienced a partial response.

The Impact of a State-Based Workers' Compensation Insurer's Risk Control Services on Employer Claim Frequency and Cost Rates.

OBJECTIVE: This study evaluated the impact of a state workers' compensation (WC) insurer's onsite risk control (RC) services on insured employers' WC claim frequency and cost. METHODS: We used two methods to model 2004 to 2017 claims data from 4606 employers that received RC visits over time and compare this claims experience to matching employers that did not receive RC services. RESULTS: Relative total WC claim rates increased slightly after RC services, while relative lost-time claims rates either remained similar or decreased and WC cost rates decreased. The impact of RC services on reducing WC costs was cumulative up to the fourth visit but diminished thereafter. CONCLUSIONS: The insurer RC consultation program was effective in reducing WC cost rates for serviced employers. This is consistent with other research conducted on insurer RC services and related regulatory visits.

Workers' compensation claim counts and rates by injury event/exposure among state-insured private employers in Ohio, 2007-2017.

INTRODUCTION: This study analyzed workers' compensation (WC) claims among private employers insured by the Ohio state-based WC carrier to identify high-risk industries by detailed cause of injury. METHODS: A machine learning algorithm was used to code each claim by U.S. Bureau of Labor Statistics (BLS) event/exposure. The codes assigned to lost-time (LT) claims with lower algorithm probabilities of accurate classification or those LT claims with high costs were manually reviewed. WC data were linked with the state's unemployment insurance (UI) data to identify the employer's industry and number of employees. BLS data on hours worked per employee were used to estimate full-time equivalents (FTE) and calculate rates of WC claims per 100 FTE. RESULTS: 140,780 LT claims and 633,373 medical-only claims were analyzed. Although counts and rates of LT WC claims declined from 2007 to 2017, the shares of leading LT injury event/exposures remained largely unchanged. LT claims due to Overexertion and Bodily Reaction (33.0%) were most common, followed by Falls, Slips, and Trips (31.4%), Contact with Objects and Equipment (22.5%), Transportation Incidents (7.0%), Exposure to Harmful Substances or Environments (2.8%), Violence and Other Injuries by Persons or Animals (2.5%), and Fires and Explosions (0.4%). These findings are consistent with other reported data. The proportions of injury event/exposures varied by industry, and high-risk industries were identified. CONCLUSIONS: Injuries have been reduced, but prevention challenges remain in certain industries. Available evidence on intervention effectiveness was summarized and mapped to the analysis results to demonstrate how the results can guide prevention efforts. Practical Applications: Employers, safety/health practitioners, researchers, WC insurers, and bureaus can use these data and machine learning methods to understand industry differences in the level and mix of risks, as well as industry trends, and to tailor safety, health, and disability prevention services and research.

Unusual recurrent metastasizing benign breast papilloma: a case report.

BACKGROUND: Papillary breast lesions may be benign, atypical, and malignant lesions. Pathological and clinical differentiation of breast papillomas can be a challenge. Unlike malignant lesions, benign breast papillomas are not classically associated with lymph node and distant metastasis. We report a unique case of a recurrent, benign breast papilloma presenting as an aggressive malignant tumor. CASE PRESENTATION: Our patient was a 56-year-old postmenopausal African American woman who was followed in the breast clinic with a long history of multiple breast papillomas. She underwent multiple resections over the course of 7-9 years. After being lost to follow-up for 2 years, she once again presented with a slowly enlarging left breast mass. Subsequent imaging revealed a predominantly cystic mass in the left breast, as well as a suspicious hypermetabolic internal mammary node and a hypermetabolic nodule in the pretracheal space. Biopsy of the internal mammary node demonstrated papillary neoplasm with benign morphology and immunostains positive for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2/Neu. Due to the clinical picture concerning for malignancy, the patient was then started on endocrine therapy with palbociclib and letrozole before surgery. She then underwent simple mastectomy and sentinel lymph node dissection with negative nodes and pathology once again revealing benign papillary neoplasm. She underwent adjuvant chest wall radiation for 6 weeks and received letrozole following completion of her radiation therapy. She was without evidence of disease 30 months after surgery. CONCLUSIONS: We present an unusual case of multiple recurrent peripheral papillomas with entirely benign histologic features exhibiting malignant behavior over a protracted period of many years, with an invasion of pectoralis musculature and possibly internal mammary and mediastinal nodes. Her treatment course included multiple surgeries (ultimately mastectomy), radiation therapy, and endocrine therapy.

Workers' compensation claims for traumatic brain injuries among private employers-Ohio, 2001-2011.

BACKGROUND: The purpose of this analysis was to identify and prioritize high-risk industry groups for traumatic brain injury (TBI) prevention efforts. METHODS: Workers with TBI from 2001 to 2011 were identified from the Ohio Bureau of Workers' Compensation data. To prioritize industry groups by claim type (lost-time (≥8 days away from work) and total claims) and injury event categories, we used a prevention index (PI) that averaged TBI counts and rate ranks (PI = (count rank + rate rank)/2). TBI rates per 10 000 estimated full-time equivalent (FTE = 2000 h/y) workers were calculated. RESULTS: From 2001 to 2011, 12 891 TBIs were identified among private employers, resulting in a rate of 5.1 TBIs per 10 000 FTEs. Of these, 40% (n = 5171) were lost-time TBIs, at a rate of 2.0 per 10 000 FTEs. Spectator Sports had the highest lost-time TBI rate (13.5 per 10 000 FTEs), whereas General Freight Trucking had the greatest number of lost-time TBIs (n = 293). Based on PIs, General Freight Trucking ranked first for lost-time TBIs for all injury events combined. Several industry groups within Construction, General and Specialized Freight Trucking, Services to Building and Dwellings, Employment Services, and Restaurants and Other Eating Places ranked high across multiple injury event categories for lost-time TBIs. CONCLUSIONS: The high-ranking industry groups identified from our study can be used to effectively direct occupational TBI prevention efforts.

Workers' compensation injury claims among workers in the private ambulance services industry-Ohio, 2001-2011.

BACKGROUND: Ambulance service workers frequently transfer and transport patients. These tasks involve occupational injury risks such as heavy lifting, awkward postures, and frequent motor vehicle travel. METHODS: We examined Ohio workers' compensation injury claims among state-insured ambulance service workers working for private employers from 2001 to 2011. Injury claim counts and rates are presented by claim types, diagnoses, and injury events; only counts are available by worker characteristics. RESULTS: We analyzed a total of 5882 claims. The majority were medical-only (<8 days away from work). The overall injury claim rate for medical-only and lost-time cases was 12.1 per 100 full-time equivalents. Sprains and strains accounted for 60% of all injury claims. Overexertion from patient handling was the leading injury event, followed by motor vehicle roadway incidents. CONCLUSIONS: Study results can guide the development or improvement of injury prevention strategies. Focused efforts related to patient handling and vehicle incidents are needed.

Applying Machine Learning to Workers' Compensation Data to Identify Industry-Specific Ergonomic and Safety Prevention Priorities: Ohio, 2001 to 2011.

OBJECTIVE: This study leveraged a state workers' compensation claims database and machine learning techniques to target prevention efforts by injury causation and industry. METHODS: Injury causation auto-coding methods were developed to code more than 1.2 million Ohio Bureau of Workers' Compensation claims for this study. Industry groups were ranked for soft-tissue musculoskeletal claims that may have been preventable with biomechanical ergonomic (ERGO) or slip/trip/fall (STF) interventions. RESULTS: On the basis of the average of claim count and rate ranks for more than 200 industry groups, Skilled Nursing Facilities (ERGO) and General Freight Trucking (STF) were the highest risk for lost-time claims (>7 days). CONCLUSION: This study created a third, major causation-specific U.S. occupational injury surveillance system. These findings are being used to focus prevention resources on specific occupational injury types in specific industry groups, especially in Ohio. Other state bureaus or insurers may use similar methods.

Development of methods for using workers' compensation data for surveillance and prevention of occupational injuries among State-insured private employers in Ohio.

BACKGROUND: Workers' compensation (WC) claims data may be useful for identifying high-risk industries and developing prevention strategies. METHODS: WC claims data from private-industry employers insured by the Ohio state-based workers' compensation carrier from 2001 to 2011 were linked with the state's unemployment insurance (UI) data on the employer's industry and number of employees. National Labor Productivity and Costs survey data were used to adjust UI data and estimate full-time equivalents (FTE). Rates of WC claims per 100 FTE were computed and Poisson regression was used to evaluate differences in rates. RESULTS: Most industries showed substantial claim count and rate reductions from 2001 to 2008, followed by a leveling or slight increase in claim count and rate from 2009 to 2011. Despite reductions, there were industry groups that had consistently higher rates. CONCLUSION: WC claims data linked to employment data could be used to prioritize industries for injury research and prevention activities among State-insured private employers. Am. J. Ind. Med. 59:1087-1104, 2016. © 2016 Wiley Periodicals, Inc.

The effectiveness of insurer-supported safety and health engineering controls in reducing workers' compensation claims and costs.

BACKGROUND: This study evaluated the effectiveness of a program in which a workers' compensation (WC) insurer provided matching funds to insured employers to implement safety/health engineering controls. METHODS: Pre- and post-intervention WC metrics were compiled for the employees designated as affected by the interventions within 468 employers for interventions occurring from 2003 to 2009. Poisson, two-part, and linear regression models with repeated measures were used to evaluate differences in pre- and post-data, controlling for time trends independent of the interventions. RESULTS: For affected employees, total WC claim frequency rates (both medical-only and lost-time claims) decreased 66%, lost-time WC claim frequency rates decreased 78%, WC paid cost per employee decreased 81%, and WC geometric mean paid claim cost decreased 30% post-intervention. Reductions varied by employer size, specific industry, and intervention type. CONCLUSIONS: The insurer-supported safety/health engineering control program was effective in reducing WC claims and costs for affected employees.

Endometrioid adenocarcinoma in an extrauterine adenomyoma.

BACKGROUND: Focal involvement by endometrioid adenocarcinoma in an extrauterine adenomyoma in a patient with stage 1 endometrioid adenocarcinoma presented a unique problem in staging and management of extrauterine endometrial cancer. CASE: A 49-year-old white woman, gravida 0, referred for endometrioid adenocarcinoma was found to have an extrauterine adenomyoma involved with endometrioid adenocarcinoma in the inguinal canal after surgical staging. The endometrioid adenocarcinoma involving the extrauterine adenomyoma was low-grade and noninvasive, representing an embryological anomaly transformed into endometrioid adenocarcinoma by unopposed estrogen. Stage 1A, grade 2 endometrioid adenocarcinoma was diagnosed and observed. CONCLUSION: Stage 1 endometrioid adenocarcinoma with concurrent, noninvasive, focal involvement in an extrauterine adenomyoma represents a secondary site and does not alter disease stage.

Live full-term ovarian ectopic pregnancy: a case report.

BACKGROUND: Ovarian ectopic pregnancy is rare, with an incidence of 1/7,000 to 1/40,000. Only a few of them progress to full term and survive. Most of them rupture in the first trimester and require emergency surgical intervention. CASE: An African American woman at 38 4/7 weeks' gestation presented to labor thd delivery with decreased smaal movement. Fetal presentation was vertex by ultrasound, which failed to detect ectopic pregnancy. The patient underwent cesarean section for nonreassuring fetal status. Dense pelvic adhesions and an unexpected, live, left ovarian ectopic pregnancy were encountered during laparotomy. CONCLUSION: This case stresses the importance of starting prenatal care early and having a routine first trimester transvaginal ultrasound, which could enhance

Lung scedosporiosis in human immunodeficiency virus/acquired immunodeficiency syndrome.

A 31-year-old African American woman with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) (recent CD4 count of 66/mm) presented to the emergency room with a tension pneumothorax that required an emergent chest tube placement. Computed tomography scan showed fungus balls in multiple lung cavities and surrounding infiltrates. The patient showed remarkable improvement with voriconazole suggesting aspergillosis. However, the patient was serologically negative for Aspergillus and other common fungal infections. Because of a persistent air leak, surgical intervention was needed. The histological finding was consistent with invasive mycosis, and cultures were positive for Scedosporium apiospermum. Literature review showed that, among patients with HIV/AIDS, Scedosporium can present from focal localized to systemic disease, is resistant to traditional antifungal agents, and may respond to prompt management with voriconazole.

Synthesis of novel benzamidine- and guanidine-derived polyazamacrocycles: Selective anti-protozoal activity for human African trypanosomiasis.

Efficient synthetic routes have been developed for the preparation of two new polyazamacrocycles tagged with structural motifs recognised by the Trypanosoma brucei P2 aminopurine transporter. Biological testing of these compounds showed highly selective anti-protozoal activity against trypanosomes.

Synthesis and anti-protozoal activity of C2-substituted polyazamacrocycles.

A focused library of C2-substituted-1,4,7,10-tetraazacyclododecanes was synthesised and the compounds were tested for their ability to kill trypanosome and malaria parasites. Several compounds showed significant in vitro activity and were selectively active against the parasites over human embryonic kidney cells used as a counter screen.

Synthesis, characterisation and anti-protozoal activity of carbamate-derived polyazamacrocycles.

A short, highly efficient approach for the synthesis of a novel class of polyazamacrocycles containing N-functionalised carbamate side-chains has been developed. The key steps involved a phase-transfer mediated macrocyclisation to form the ring system as well as a tin-catalysed reaction with isocyanates to introduce the carbamate side-chains. X-Ray crystallography confirmed successful formation of the 1,4,7,10-tetraazacyclododecane ring and N-functionalisation of all the amine centres. Preliminary testing of the biological activity of the compounds revealed significant anti-parasitic activity against bloodstream form African trypanosomes.

Synthesis of 5-deazaflavin derivatives and their activation of p53 in cells.

A family of 5-deazaflavin derivatives has been synthesised using a two-step convergent strategy. The biological activity of these compounds was evaluated in cells, by assessing their ability to stabilize and activate p53. These compounds may act as low molecular weight inhibitors of the E3 activity of HMD2 in tumours that retain wild-type p53. Importantly, we have demonstrated that the nitro group present in all three of the original lead compounds [1-3 (HL198C-E)] is not essential for observation of this biological activity.

Synthesis and antimelanoma activity of reversed amide analogues of N-acetyl-4-S-cysteaminylphenol.

The melanin biosynthetic pathway from tyrosine is a potential target for combating malignant melanoma. N-Acetyl-4-S-cysteaminylphenol 1 is a previously synthesized analogue of tyrosine that probably acts by this pathway. It interferes with cell growth and proliferation via selective oxidation in melanocytes to an oquinone that can alkylate cellular nucleophiles. We previously synthesized a range of analogues of the original lead compound 1 most of which displayed greater cytotoxicity than 1. Eighteen new analogues with the amide group reversed have now been synthesized and tested for antimelanoma activity. Most of these reverse amides showed greater cytotoxicity than N-acetyl-4-S-cysteaminylphenol towards five representative melanoma cell lines. The highest cytotoxicity was observed for the piperidine and hexamethyleneimine derivatives 7, 8, 12, 13, and 17 and the catechol 18. The most active compound, 7, had cytotoxicity comparable to cisplatin against the five melanoma cell lines. The moderate activity of 7 and 18 against SK-Mel-24 (non-tyrosinase containing) and an ovarian cell line suggests that interference with the melanin pathway may not be the only mode of action of these compounds. Assays of some of the compounds as substrates for tyrosinase showed that the catechol 18 was the best substrate and that the piperidine derivative 7 was the best substrate of the phenolic compounds synthesized.

Synthesis and antimelanoma activity of sterically congested tertiary amide analogues of N-acetyl-4-S-cysteaminylphenol.

Interference with the biosynthetic pathway to melanin may be a useful means for developing new chemotherapeutic drugs to combat malignant melanoma. N-Acetyl-4-S-cysteaminylphenol (1) is an analogue of tyrosine that is involved in the pathway to melanin. It is probably oxidized selectively in melanocytes to an o-quinone that can alkylate thiol groups on important cellular enzymes, resulting in interference with cell growth and proliferation. We previously synthesized a range of more lipophilic analogues of 1 by independently varying the acyl portion and introducing substitution alpha to the nitrogen. Most of the new compounds displayed greater cytotoxicity than the original lead compound 1. We also made a series of tertiary amides that again showed higher cytotoxicity than 1. In this work three new acetamides and two new cyclohexanecarboxamides containing 4-S-cysteaminylphenol were prepared incorporating both substitution alpha to the nitrogen and different substituents on the nitrogen of the amide in each compound to increase lipophilicity and to reduce further the possibility of hydrolysis of the amides. Most of the new tertiary amides showed greater cytotoxicity towards five representative melanoma cell lines than the parent secondary amide. The highest cytotoxicity against these five cell lines with IC50 values of 1-15 nicroM, comparable to cisplatin, was observed for N-[2[(4-hydroxyphenyl)thio]-1,1-dimethylethyl]-N-methylcyclohexanecarboxamide (8c). The IC50 values of 14.5 and 5.4 microM for this compound against SK-Mel-24 (not containing tyrosinase) and an ovarian cell line, respectively, suggest that interference with the melanin pathway may not be the only mode of action of this new compound. The cyclohexanecarboxamides were better substrates for mushroom tyrosinase (EC 1.14.18.1) than the acetamides.