Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Predictors of malignancy in melanocytic lesions presenting as new lesions compared to baseline total body photography: A case-control study.

BACKGROUND: Only a small per cent of new melanocytic lesions developing in adults are expected to represent melanomas. Total body photography (TBP) has been widely incorporated in clinical practice, especially for follow-up of high-risk individuals with multiple naevi. However, dynamic changes detected with TBP need to be interpreted with caution to avoid unnecessary excisions. OBJECTIVES: To identify clinical and dermoscopic predictors of malignancy in melanocytic lesions presenting clinically as new lesions on TBP. METHODS: Melanomas and melanocytic naevi excised from a high-risk cohort and presenting as new lesions on TBP were retrospectively included. Naevi were arbitrarily collected up to approximately twice the number of melanomas. Melanomas were categorized as 'unequivocal' or 'borderline' on histopathology review. RESULTS: Sixty melanomas and 110 naevi were included. Median age (range) of cases (55; 27-83) was 9 years older than controls (46; 24-77) (p < 0.0001). Median diameter (IQR) of naevi was 2.6 mm (1.8-3.8) and of melanomas 4.2 mm (2.7-7.0) (p < 0.0001). On histopathology, 40% of the melanomas were 'borderline'. A positive 7-point checklist was reported in 12.5% of 'borderline' melanomas and 33.3% of 'unequivocal' melanomas (p = 0.005), while 18.3% of melanomas were completely featureless. Blue-whitish veil, atypical vascular pattern and shiny white lines were exclusively found in melanomas. The main predictors of malignancy were (OR; 95% CI) regression structures (7.13; 1.88-27.06; p = 0.004); hypo/amelanotic colour (6.00; 1.17-30.73; p = 0.03); irregular pigmentation (3.89; 1.36-11.13; p = 0.01); asymmetrical peripheral dots/globules (3.50; 1.11-11.00; p = 0.03); and asymmetry in pattern and/or colour (2.5; 1.3-4.9; p = 0.007). All invasive melanomas detected in patients younger than 50 years presented at least one dermoscopic predictor of malignancy. CONCLUSIONS: Melanomas presenting as new lesions are frequently featureless or feature poor on dermoscopy and difficult-to-diagnose on histopathology. In high-risk patients, the presence on any of the dermoscopic predictors of malignancy identified should prompt excision; however, the remaining lesions should be closely monitored.

Gathering expert consensus to inform a proposed trial in chronic nonbacterial osteomyelitis (CNO).

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that primarily affects children and adolescents. CNO is associated with pain, bone swelling, deformity, and fractures. Its pathophysiology is characterized by increased inflammasome assembly and imbalanced expression of cytokines. Treatment is currently based on personal experience, case series and resulting expert recommendations. Randomized controlled trials (RCTs) have not been initiated because of the rarity of CNO, expired patent protection of some medications, and the absence of agreed outcome measures. An international group of fourteen CNO experts and two patient/parent representatives was assembled to generate consensus to inform and conduct future RCTs. The exercise delivered consensus inclusion and exclusion criteria, patent protected (excludes TNF inhibitors) treatments of immediate interest (biological DMARDs targeting IL-1 and IL-17), primary (improvement of pain; physician global assessment) and secondary endpoints (improved MRI; improved PedCNO score which includes physician and patient global scores) for future RCTs in CNO.

Quantitation of Total PFAS Including Trifluoroacetic Acid with Fluorine Nuclear Magnetic Resonance Spectroscopy.

Fluorine nuclear magnetic resonance (19F-NMR) spectroscopy has been shown to be a powerful tool capable of quantifying the total per- and polyfluoroalkyl substances (PFAS) in a complex sample. The technique relies on the characteristic terminal -CF3 shift (-82.4 ppm) in the alkyl chain for quantification and does not introduce bias due to sample preparation or matrix effects. Traditional quantitative analytical techniques for PFAS, such as liquid chromatography-mass spectrometry (LC-MS) and combustion ion chromatography (CIC), contain inherent limitations that make total fluorine analysis challenging. Here, we report a sensitive 19F-NMR method for the analysis of total PFAS, with a limit of detection of 99.97 nM, or 50 µg/L perfluorosulfonic acid. To demonstrate the capabilities of 19F-NMR, the technique was compared to two commonly used methods for PFAS analysis: total oxidizable precursor (TOP) assay and LC-high resolution MS analysis for targeted quantification and suspect screening. In both cases, the 19F-NMR analyses detected higher total PFAS quantities than either the TOP assay (63%) or LC-MS analyses (65%), suggesting that LC-MS and TOP assays can lead to underreporting of PFAS. Importantly, the 19F-NMR detected trifluoroacetic acid at a concentration more than five times the total PFAS concentration quantified using LC-MS in the wastewater sample. Therefore, the use of 19F-NMR to quantify the total PFAS in highly complex samples can be used to complement classic TOP or LC-MS approaches for more accurate reporting of PFAS contamination in the environment.

Endoprosthetic reconstruction for lower extremity soft tissue sarcomas with bone involvement.

BACKGROUND AND OBJECTIVES: Bone resection and endoprosthetic reconstruction (EPR) in the setting of soft tissue sarcoma (STS) management is rare and incurs unique challenges. We aim to report on the surgical and oncological outcomes of this relatively previously undocumented cohort. METHODS: This is a single-center retrospective review of prospectively collected data for patients who required EPRs following resection of STSs of the lower extremity. Following inclusion criteria, we assessed 29 cases of EPR for primary STS of the lower limb. RESULTS: The mean age was 54 years (range 18-84). Of the 29 patients, there were 6 total femur, 11 proximal femur, 4 intercalary, and 8 distal femur EPRs. Fourteen of 29 patients (48%) underwent re-operations for surgical complications, with 9 relating to infection (31%). When a matched cohort analysis was performed comparing our cohort to STSs that did not necessitate EPR, a reduced rate of overall survival and metastasis-free survival was found in those requiring EPR. CONCLUSION: This series identifies a high rate of complication from EPRs performed for STS. Patients should be cautioned about the high rate of infection, surgical complications, and lower overall survival in this setting.

How Many Chemicals in Commerce Have Been Analyzed in Environmental Media? A 50 Year Bibliometric Analysis.

Over the past 50 years, there has been a tremendous expansion in the measurement of chemical contaminants in environmental media. But how many chemicals have actually been determined, and do they represent a significant fraction of substances in commerce or of chemicals of concern? To address these questions, we conducted a bibliometric survey to identify what individual chemicals have been determined in environmental media and their trends over the past 50 years. The CAplus database of CAS, a Division of the American Chemical Society, was searched for indexing roles "analytical study" and "pollutant" yielding a final list of 19,776 CAS Registry Numbers (CASRNs). That list was then used to link the CASRNs to biological studies, yielding a data set of 9.251 × 106 total counts of the CASRNs over a 55 year period. About 14,150 CASRNs were substances on various priority lists or their close analogs and transformation products. The top 100 most reported CASRNs accounted for 34% of the data set, confirming previous studies showing a significant bias toward repeated measurements of the same substances due to regulatory needs and the challenges of determining new, previously unmeasured, compounds. Substances listed in the industrial chemical inventories of Europe, China, and the United States accounted for only about 5% of measured substances. However, pharmaceuticals and current use pesticides were widely measured accounting for 50-60% of total CASRN counts for the period 2000-2015.

Characterization of Per- and Polyfluorinated Alkyl Substances Present in Commercial Anti-fog Products and Their In Vitro Adipogenic Activity.

Anti-fog sprays and solutions are used on eyeglasses to minimize the condensation of water vapor, particularly while wearing a mask. Given their water-repellent properties, we sought to characterize per- and polyfluorinated alkyl substance (PFAS) compounds in four anti-fog spray products, five anti-fog cloth products, and two commercial fluorosurfactant formulations suspected to be used in preparing anti-fog products. Fluorotelomer alcohols (FTOHs) and fluorotelomer ethoxylates (FTEOs) were detected in all products and formulations. While 6:2 FTOH and the 6:2 FTEO polymeric series were predominant, one anti-fog cloth and one formulation contained 8:2, 10:2, 12:2, 14:2, and 16:2 FTOH and FTEO polymeric series. PFAS concentrations varied in samples and were detected at levels up to 25,000 µg/mL in anti-fog sprays and 185,000 µg (g cloth)-1 in anti-fog cloth products. The total organic fluorine (TOF) measurements of anti-fog products ranged from 190 to 20,700 µg/mL in sprays and 44,200 to 131,500 µg (g cloth)-1 in cloths. Quantified FTOHs and FTEOs accounted for 1-99% of TOF mass. In addition, all four anti-fog sprays and both commercial formulations exhibited significant cytotoxicity and adipogenic activity (either triglyceride accumulation and/or pre-adipocyte proliferation) in murine 3T3-L1 cells. Results suggest that FTEOs are a significant contributor to the adipogenic activity exhibited by the anti-fog sprays. Altogether, these results suggest that FTEOs are present in commercial products at toxicologically relevant levels, and more research is needed to fully understand the health risks from using these PFAS-containing products.

Structure Database and In Silico Spectral Library for Comprehensive Suspect Screening of Per- and Polyfluoroalkyl Substances (PFASs) in Environmental Media by High-resolution Mass Spectrometry.

Per and polyfluoroalkyl substances (PFASs) are an important class of organic pollutants. Many diverse PFASs are used in commerce and most are not amenable to conventional targeted chemical analysis due to lack of reference standards. Therefore, methods for elucidating the chemical structure of previously unreported or unexpected PFASs in the environment rely extensively on high-resolution mass spectrometry (HRMS). High-throughput structure identification by HRMS is hindered by a lack of PFAS molecular databases and tandem mass spectral libraries. Here, we report a new approach for generating an environmentally relevant PFAS molecular database constructed from curated structure lists and biotic/abiotic in silico predicted transformation products. Further, we have generated a predicted tandem mass spectral library using computational mass spectrometry tools. Results demonstrate the utility of the generated database and approach for identifying PFASs in HRMS-enabled suspect- and nontarget screening studies.

Management of meningeal solitary fibrous tumors/hemangiopericytoma; surgery alone or surgery plus postoperative radiotherapy?

INTRODUCTION: A meningeal solitary fibrous tumor (SFT), also called hemangiopericytoma, is a rare mesenchymal malignancy. Due to anatomic constrains, even after macroscopic complete surgery with curative intent, the local relapse risk is still relatively high, thus increasing the risk of dedifferentiation and metastatic spread. This study aims to better define the role of postoperative radiotherapy (RT) in meningeal SFTs. PATIENTS AND METHODS: A retrospective study was performed across seven sarcoma centers. Clinical information was retrieved from all adult patients with meningeal primary localized SFT treated between 1990 and 2018 with surgery alone (S) compared to those that also received postoperative RT (S + RT). Differences in treatment characteristics between subgroups were tested using independent samples t-test for continuous variables and chi-square tests for proportions. Local control (LC) and overall survival (OS) rates were calculated as time from start of treatment until progression or death from any cause. LC and OS in groups receiving S or S + RT were compared using Kaplan-Meier survival curves. RESULTS: Among a total of 48 patients, 7 (15%) underwent S and 41 (85%) underwent S + RT. Median FU was 65 months. LC was significantly associated with treatment. LC after S at 60 months was 60% versus 90% after S + RT (p = 0.052). Furthermore, R1 resection status was significantly associated with worse LC (HR 4.08, p = 0.038). OS was predominantly associated with the mitotic count (HR 3.10, p = 0.011). CONCLUSION: This retrospective study, investigating postoperative RT in primary localized meningeal SFT patients, suggests that combining RT to surgery in the management of this patient population may reduce the risk for local failures.

Analysis of Single-Walled Carbon Nanotubes in Estuarine Sediments by Density Gradient Ultracentrifugation Coupled to Near-Infrared Fluorescence Spectroscopy Reveals Disassociation of Residual Metal Catalyst Nanoparticles.

The continued growth of the nanotechnology industry and the incorporation of nanomaterials into consumer applications will inevitably lead to their release into environmental systems. Single-walled carbon nanotubes (SWCNTs) in particular have exhibited many attractive optical, mechanical, and electrical properties that lend themselves to new and exciting applications. Assessing their environmental impact upon release into the environment is contingent upon quantifying and characterizing SWCNTs in environmental matrixes. In this study, SWCNTs were isolated from estuarine sediments using density gradient ultracentrifugation (DGU), followed by online flow-through analysis of the density fractions via near-infrared spectroscopy. This approach yielded significant improvements in the quantitative detection limit, from 62 to 1.5 µg g-1. In addition, fractions of the density gradient were also obtained for further analysis by bulk inductively coupled plasma mass spectrometry (ICP-MS) and single-particle ICP-MS. Using fluorescent, semiconductive SWCNTs, the primary fluorescent nanotube fraction was found to be separated from the sediment matrix during DGU; however, the residual metal catalyst particles that had been assumed to be physically bound to the SWCNTs were found to form a separate band in the density gradient apart from the fluorescent SWCNTs. This result was repeated for a number of SWCNT types regardless of the metal catalyst and synthesis method, with a 0.1 g cm-3 density difference between most fractions. The apparent disconnect between the fluorescent fraction of SWCNTs and their metal-containing constituents potentially complicates CNT risk assessment as analysis techniques focusing solely on either CNT fluorescence or metal fingerprints may misrepresent exposure concentrations and their toxicological implications.

Development of a sensitive direct injection LC-MS/MS method for the detection of glyphosate and aminomethylphosphonic acid (AMPA) in hard waters.

Glyphosate is currently the most widely used herbicide in the world; however, the zwitterionic and highly polar properties of glyphosate make current pesticide analysis methods unsuitable for its trace analysis in natural waters. Additionally, current glyphosate analysis methods do not account for waters of varying hardness, which is vital as glyphosate can complex with cationic species such as Ca2+ and Mg2+ in the environment. We detail here a robust LC-MS/MS method for the quantitation of glyphosate and its primary transformation product aminomethylphosphonic acid (AMPA) in environmental waters of varying water hardness. Chromatographic separation was achieved with a reversed-phase and weak anion-exchange mixed-mode column. We found that the addition of EDTA into hard water samples increases the response of both glyphosate and AMPA in the mass spectrometer. Limits of detection of 0.23 and 0.30 µg L-1 for glyphosate and AMPA in EDTA-amended hard water were achieved, respectively. We have demonstrated that the accuracy of the method was consistent over a wide range of water hardness levels up to a maximum of ~340 mg mL-1 CaCO3 hardness. We validated the method using matrix fortification of uncontaminated environmental samples from US river water. We then demonstrated that the method was successful at quantifying glyphosate and AMPA across surface and drinking water samples of varying water hardness from North Carolina and Sri Lanka. Measured concentrations of glyphosate and AMPA ranged from 1.6 to 13 µg L-1 and 0.50 to 2.5 µg L-1, respectively. This study represents a significant increase in sensitivity for LC-MS/MS analysis of glyphosate in hard water systems. Graphical abstract.

Estimating the potential impact of interventions to reduce over-calling and under-calling of melanoma.

BACKGROUND: Pathologists sometimes disagree over the histopathologic diagnosis of melanoma. 'Over-calling' and 'under-calling' of melanoma may harm individuals and healthcare systems. OBJECTIVES: To estimate the extent of 'over-calling' and 'under-calling' of melanoma for a population undergoing one excision per person and to model the impact of potential solutions. METHODS: In this epidemiological modelling study, we undertook simulations using published data on the prevalence and diagnostic accuracy of melanocytic histopathology in the U.S. POPULATION: We simulated results for 10 000 patients each undergoing excision of one melanocytic lesion, interpreted by one community pathologist. We repeated the simulation using a hypothetical intervention that improves diagnostic agreement between community pathologist and a specialist dermatopathologist. We then evaluated four scenarios for how melanocytic lesions judged to be neither clearly benign (post-test probability of melanoma < 5%), nor clearly malignant (post-test probability of melanoma > 90%) might be handled, before sending for expert dermatopathologist review to decide the final diagnosis. These were (1) no intervention before expert review, (2) formal second community pathologist review, (3) intervention to increase diagnostic agreement and (4) both the intervention and formal second community pathologist review. The main outcomes were the probability of 'over-calling' and 'under-calling' melanoma, and number of lesions requiring expert referral for each scenario. RESULTS: For 10 000 individuals undergoing excision of one melanocytic lesion, interpreted by a community pathologist, a hypothetical intervention to improve histopathology agreement reduced the number of benign lesions 'over-called' as melanoma from 308 to 164 and the number of melanomas 'under-called' from 289 to 240. If all uncertain diagnoses were sent for expert review, the number of referrals would decrease from 1500 to 737 cases if formal second community pathologist review was used, and to 701 cases if the hypothetical intervention was additionally used. CONCLUSIONS: Interventions to improve histopathology agreement may reduce melanoma 'over-calling' and 'under-calling'.

Histopathological features of complete pathological response predict recurrence-free survival following neoadjuvant targeted therapy for metastatic melanoma.

BACKGROUND: Recent clinical trials demonstrated the safety and efficacy of neoadjuvant dabrafenib and trametinib (DT) among patients with surgically resectable clinical stage III BRAFV600E/K mutant melanoma. Although patients achieving a complete pathological response (pCR) exhibited superior recurrence-free survival (RFS) versus those who did not, 30% of pCR patients relapsed. We sought to identify whether histopathological features of the pathological response further delineated risk of relapse. METHODS: Surgical resection specimens from DT-treated patients in two phase 2 clinical trials were reviewed. Histopathological features, including relative amounts of viable tumour, necrosis, melanosis, and fibrosis (hyalinized or immature/proliferative) were assessed for associations with patient outcomes. RESULTS: Fifty-nine patients underwent surgical resection following neoadjuvant DT. Patients achieving pCR (49%) had longer RFS compared with patients who did not (P = 0.005). Patients whose treated tumour showed any hyalinized fibrosis had longer RFS versus those without (P = 0.014), whereas necrosis (P = 0.012) and/or immature/proliferative fibrosis (P = 0.026) correlated with shorter RFS. Multivariable analyses showed absence of pCR or presence of immature fibrosis independently predicted shorter RFS. Among pCR patients, mature/hyalinized-type fibrosis correlated with improved RFS (P = 0.035). CONCLUSIONS: The extent and composition of the pathological response following neoadjuvant DT in BRAFV600E/K mutant melanoma correlates with RFS, including pCR patients. These findings support the need for detailed histological analysis of specimens collected after neoadjuvant therapy.

In Vitro Metabolism of Isopropylated and tert-Butylated Triarylphosphate Esters Using Human Liver Subcellular Fractions.

Isopropylated and tert-butylated triarylphosphate esters (ITPs and TBPPs, respectively) are plasticizers and flame retardants that are ubiquitous in indoor environments; however, no studies to date have characterized their metabolism. Using human liver subcellular S9 fractions, phase I and II in vitro metabolism of triphenyl phosphate (TPHP), 4-tert-butylphenyl diphenyl phosphate (4tBPDPP), 2-isopropylphenyl diphenyl phosphate (2IPPDPP), and 4-isopropylphenyl diphenyl phosphate (4IPPDPP) was investigated at 1 and 10 µM doses. Parent depletion and the formation of known or suspected metabolites (e.g., likely hydrolysis or hydroxylated products), including diphenyl phosphate (DPHP), hydroxyl-triphenyl phosphate (OH-TPHP), isopropylphenyl phenyl phosphate (ip-PPP), and tert-butylphenyl phenyl phosphate (tb-PPP), were monitored and quantified via GC/MS or LC-MS/MS. tb-PPP and its conjugates were identified as the major in vitro metabolites of 4tBPDPP and accounted for 71% and 49%, respectively, of the parent molecule that was metabolized during the incubation. While the mass balance between parents and metabolites was conserved for TPHP and 4tBPDPP, approximately 20% of the initial parent mass was unaccounted for after quantifying suspected metabolites of 2IPPDPP and 4IPPDPP that had authentic standards available. Two novel ITP metabolites, mono-isopropenylphenyl diphenyl phosphate and hydroxy-isopropylphenyl diphenyl phosphate, were tentatively identified by high-resolution mass spectrometry and screened for in recently collected human urine where mono-isopropenylphenyl diphenyl phosphate was detected in one of nine samples analyzed. This study provides insight into the biological fate of ITP and TBPP isomers in human tissues and is useful in identifying appropriate biomarkers of exposure to monitor, particularly in support of epidemiological studies.

Bioaccumulation of Novel Per- and Polyfluoroalkyl Substances in Mice Dosed with an Aqueous Film-Forming Foam.

Per- and polyfluoroalkyl substances (PFASs) are widespread in the blood of the general human population, and their bioaccumulation is of considerable scientific and regulatory interest. PFAS exposure resulting from aqueous film-forming foam (AFFF) ingestion is poorly understood due to the complexity of AFFF mixtures and the presence of polyfluorinated substances that may undergo metabolic transformation. C57BL/6 mice were dosed with an AFFF primarily containing electrochemically fluorinated PFASs for 10 days, followed by a 6 day depuration. Urine was collected throughout the study and serum was collected post-depuration. Samples were analyzed via high-resolution mass spectrometry. Relative to the dosing solution, C6 and C7 perfluoroalkyl sulfonates (PFSAs) were enriched in dosed mouse serum, suggesting in vivo transformation of sulfonamide precursors. Some substituted C8 PFSAs [keto-perfluorooctane sulfonate (PFOS), hydrogen-PFOS, and unsaturated PFOS] appeared to be more bioaccumulative than linear PFOS, or were formed in vivo from unidentified precursors. A series of seven peaks in dosed mouse serum was tentatively identified as sulfonimide dimers that were either a minor component of the AFFF or were formed via metabolism of other AFFF components. This work highlights the importance of sulfonamide precursors in contributing to bioaccumulation of AFFF-associated PFSAs and identifies several classes of potentially bioaccumulative novel PFASs that warrant further investigation.

Molecular characterization of nonionic surfactant components of the Corexit® 9500 oil spill dispersant by high-resolution mass spectrometry.

RATIONALE: Approximately 7 million liters of Corexit® dispersants were applied during the 2010 Deepwater Horizon oil spill to facilitate the dispersion of crude oil. At the time of application, the exact chemical composition of Corexit® was relatively unknown. Characterization of Corexit® 9500 was performed using high-resolution mass spectrometry to further understand the complexity of the nonionic surfactant components of this mixture. METHODS: Corexit®9500 was analyzed by ultra-high-performance liquid chromatography (UHPLC) coupled to a high resolution Orbitrap Fusion Lumos mass spectrometer operated in positive electrospray ionization mode and a charged aerosol detector. Chromatographic conditions were optimized to efficiently separate isobaric and isomeric compounds. Polyethoxylated nonionic surfactants in Corexit® 9500 were identified using the following criteria: accurate mass (<3 ppm), retention time, and homologue series; in addition, interpretation of high-resolution tandem mass spectra was used to annotate tentative component structures. RESULTS: More than 2000 polysorbate nonionic surfactants in 87 homologue series were detected. Polysorbate surfactants were characterized by the type of molecular basis group (sorbitan, isosorbide, or fatty acid), degree of esterification (n = 0-4), ester chain length (C6-C24), and ester saturation, in addition to polydispersion by ethoxylation. Isomeric compounds were differentiated by LC/HRMS/MS analysis with product ion assignment. Results from the charged aerosol detector showed that the diesters (23.9 ± 0.78%) were the most abundant component in Corexit® 9500 followed by dioctyl sodium sulfosuccinate (DOSS) (19.2 ± 1.5%), triesters (17.3 ± 1.5%), and monoesters (15.7 ± 2.3%). CONCLUSIONS: Our analytical approach facilitated the characterization of polysorbate surfactants within Corexit® 9500 and allowed a systematic study to differentiate isomeric and isobaric compounds, when standards were not available. The characterized composition of Corexit® 9500 will facilitate future studies to determine the chemical and biological transformation kinetics and byproducts of Corexit® 9500 under environmental conditions.

Author Correction: Chemotherapy with radiotherapy influences time-to-development of radiation-induced sarcomas: a multicenter study.

Since the publication of this paper, the authors noticed an error in Fig. 1. The X-axis on all the figure panels should read 'Time (years)', not 'Time (months)'. The corrected Fig. 1 is shown below.

Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma.

Background: Clinical trials have recently evaluated safety and efficacy of neoadjuvant therapy among patients with surgically resectable regional melanoma metastases. To capture informative prognostic data connected to pathological response in such trials, it is critical to standardize pathologic assessment and reporting of tumor response after this treatment. Methods: The International Neoadjuvant Melanoma Consortium meetings in 2016 and 2017 assembled pathologists from academic centers to develop consensus guidelines for pathologic examination and reporting of surgical specimens from AJCC (8th edition) stage IIIB/C/D or oligometastatic stage IV melanoma patients treated with neoadjuvant-targeted or immune therapy. Patterns of pathologic response are provided context to inform these guidelines. Results: Based on our collective experience and guided by efforts in well-established neoadjuvant settings like breast cancer, procedures directing handling of pre- and post-neoadjuvant therapy-treated melanoma specimens are provided to facilitate comparison of findings across different trials and centers. Definitions of pathologic response are provided together with guidelines for reporting and quantifying the extent of pathologic response. Finally, the spectrum of histopathologic responses observed following neoadjuvant-targeted and immune-checkpoint therapy is described and illustrated. Conclusions: Standardizing pathologic evaluation of resected melanoma metastases following neoadjuvant-targeted or immune-checkpoint therapy allows more robust stratification of patient outcomes. This includes recognizing the spectrum of histopathologic response patterns to neoadjuvant therapy and a standard approach to grading pathologic responses. Such an approach will facilitate comparison of results across clinical trials and inform ongoing correlative studies into the mechanisms of response and resistance to agents applied in the neoadjuvant setting.

Impact of genomics on the surgical management of melanoma.

BACKGROUND: Although surgery for early-stage melanoma offers the best chance of cure, recent advances in molecular medicine have revolutionized the management of late-stage melanoma, leading to significant improvements in clinical outcomes. Research into the genomic drivers of disease and cancer immunology has not only ushered in a new era of targeted and immune-based therapies for patients with metastatic melanoma, but has also provided new tools for monitoring disease recurrence and selecting therapeutic strategies. These advances present new opportunities and challenges to the surgeon treating patients with melanoma. METHODS: The literature was reviewed to evaluate diagnostic and therapeutic advances in the management of cutaneous melanoma, and to highlight the impact of these advances on surgical decision-making. RESULTS: Genomic testing is not required in the surgical management of primary melanoma, although it can provide useful information in some situations. Circulating nucleic acids from melanoma cells can be detected in peripheral blood to predict disease recurrence before it manifests clinically, but validation is required before routine clinical application. BRAF mutation testing is the standard of care for all patients with advanced disease to guide therapy, including the planning of surgery in adjuvant and neoadjuvant settings. CONCLUSION: Surgery remains central for managing primary melanoma, and is an important element of integrated multidisciplinary care in advanced disease, particularly for patients with resectable metastases. The field will undergo further change as clinical trials address the relationships between surgery, radiotherapy and systemic therapy for patients with high-risk, early-stage and advanced melanoma.

Chemical Mixtures Isolated from House Dust Disrupt Thyroid Receptor ß Signaling.

House dust is a source of exposure to chemicals that can impact hormone regulation. This study was designed to evaluate the potential of house dust mixtures ( n = 137) to disrupt thyroid hormone nuclear receptor signaling in a cell-based reporter assay and to examine associations with thyroid hormones (TH) measured in residents of the homes. Approximately 41% of the extracts (ranging from 10.5 to 4.097 µg of dust/mL) significantly antagonized thyroid receptor ß (TRß) signaling by 20-67% relative to the hormone control. The concentrations of 12 flame retardants (FRs) quantified in the mixtures were significantly correlated with TRß antagonism; however, they were inactive when tested individually. We hypothesize that the observed antagonism is due to mixture effects or unidentified compounds that co-occur with FRs. Dust extract potency was significantly associated with free thyroxine (FT4, rs = -0.64, p < 0.001), suggesting that more potent dust samples are associated with higher FT4 levels in residents. Overall, these results suggest that house dust is a significant source of exposure to TH-disrupting chemicals, and TRß may have a role in mediating effects of exposure on TH levels. Additional studies are needed to identify the chemical(s) driving the observed effects on TRß and to determine if these changes lead to any adverse outcomes.