Oxalate nephropathy and chronic turmeric supplementation: a case report.

We present a case of a 69-year-old man who presented for routine check-up and was incidentally found to have kidney failure with an initially unrevealing history and bland urinary sediment. He was diagnosed with oxalate nephropathy in the setting of chronic turmeric supplementation and chronic antibiotic therapy with associated diarrhea. Our case provides several key insights into oxalate nephropathy. First, the diagnosis requires a high index of clinical suspicion. It is uncommonly suspected clinically unless there is an obvious clue in the history such as Roux-en-Y gastric bypass or ethylene glycol poisoning. Diagnosis can be confirmed by histopathologic findings and corroborated by serum levels of oxalate and 24-hour urinary excretion. Second, the diagnosis can often be missed by the pathologist because of the characteristics of the crystals unless the renal pathologist has made it a rule to examine routinely all H&E sections under polarized light. This must be done on H&E, as the other stains dissolve the crystals. Third, one oxalate crystal in a routine needle biopsy is considered pathologic and potentially contributing to the AKI or to the CKD in an important way. Fourth, secondary oxalosis can be largely mitigated or prevented in many cases, especially iatrogenic cases. This can come through the surgeon or the gastroenterologist providing proper instructions to patients on an oxalate-restricted diet or other specific dietary measures. Lastly, this case highlights the success that results from cooperation and communication between the pathologist and the treating physician.

Oxalate nephropathy and chronic turmeric supplementation: a case report / Nefropatia por oxalato e suplementação crônica de cúrcuma: relato de caso

ABSTRACT We present a case of a 69-year-old man who presented for routine check-up and was incidentally found to have kidney failure with an initially unrevealing history and bland urinary sediment. He was diagnosed with oxalate nephropathy in the setting of chronic turmeric supplementation and chronic antibiotic therapy with associated diarrhea. Our case provides several key insights into oxalate nephropathy. First, the diagnosis requires a high index of clinical suspicion. It is uncommonly suspected clinically unless there is an obvious clue in the history such as Roux-en-Y gastric bypass or ethylene glycol poisoning. Diagnosis can be confirmed by histopathologic findings and corroborated by serum levels of oxalate and 24-hour urinary excretion. Second, the diagnosis can often be missed by the pathologist because of the characteristics of the crystals unless the renal pathologist has made it a rule to examine routinely all H&E sections under polarized light. This must be done on H&E, as the other stains dissolve the crystals. Third, one oxalate crystal in a routine needle biopsy is considered pathologic and potentially contributing to the AKI or to the CKD in an important way. Fourth, secondary oxalosis can be largely mitigated or prevented in many cases, especially iatrogenic cases. This can come through the surgeon or the gastroenterologist providing proper instructions to patients on an oxalate-restricted diet or other specific dietary measures. Lastly, this case highlights the success that results from cooperation and communication between the pathologist and the treating physician.

RESUMO Relatamos o caso de um homem de 69 anos que se apresentou para exame de rotina e descobriu-se incidentalmente que ele tinha insuficiência renal, com histórico inicialmente não revelador e sedimento urinário brando. Ele foi diagnosticado com nefropatia por oxalato no contexto de suplementação crônica de cúrcuma e antibioticoterapia crônica com diarreia associada. Nosso caso fornece diversas sugestões importantes sobre nefropatia por oxalato. Primeiro, o diagnóstico requer elevado índice de suspeita clínica. A suspeita clínica é incomum, a menos que haja evidência óbvia no histórico, como bypass gástrico em Y de Roux ou envenenamento por etilenoglicol. O diagnóstico pode ser confirmado por achados histopatológicos e corroborado por níveis séricos de oxalato e excreção urinária de 24 horas. Segundo, o diagnóstico pode passar despercebido pelo patologista devido às características dos cristais, a menos que o patologista renal estabeleça como regra examinar rotineiramente todas as seções coradas com H&E sob luz polarizada. Isso deve ser feito com H&E, pois, outras colorações dissolvem os cristais. Em terceiro lugar, um cristal de oxalato em biópsia por agulha de rotina é considerado patológico, contribuindo potencialmente para LRA ou para DRC de maneira significativa. Em quarto lugar, a oxalose secundária pode ser amplamente mitigada ou prevenida em muitos casos, especialmente casos iatrogênicos. Isso pode ser feito pelo cirurgião ou pelo gastroenterologista, fornecendo instruções adequadas aos pacientes sobre uma dieta restrita em oxalato ou outras medidas dietéticas específicas. Por fim, esse caso destaca o sucesso que resulta da cooperação e comunicação entre o patologista e o médico assistente.

Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence.

Complex DNA damage (CDD), containing two or more DNA lesions within one or two DNA helical turns, is a signature of ionising radiation (IR) and contributes significantly to the therapeutic effect through cell killing. The levels and complexity of CDD increases with linear energy transfer (LET), however, the specific cellular response to this type of DNA damage and the critical proteins essential for repair of CDD is currently unclear. We performed an siRNA screen of ~240 DNA damage response proteins to identify those specifically involved in controlling cell survival in response to high-LET protons at the Bragg peak, compared to low-LET entrance dose protons which differ in the amount of CDD produced. From this, we subsequently validated that depletion of 8-oxoguanine DNA glycosylase (OGG1) and poly(ADP-ribose) glycohydrolase (PARG) in HeLa and head and neck cancer cells leads to significantly increased cellular radiosensitivity specifically following high-LET protons, whilst no effect was observed after low-LET protons and X-rays. We subsequently confirmed that OGG1 and PARG are both required for efficient CDD repair post-irradiation with high-LET protons. Importantly, these results were also recapitulated using specific inhibitors for OGG1 (TH5487) and PARG (PDD00017273). Our results suggest OGG1 and PARG play a fundamental role in the cellular response to CDD and indicate that targeting these enzymes could represent a promising therapeutic strategy for the treatment of head and neck cancers following high-LET radiation.

Early effect of the COVID-19 pandemic on the North American cardiothoracic surgery job market.

Background: The present study aims to report the early effect of the coronavirus disease 2019 (COVID-19) pandemic on the cardiothoracic surgery job market in North America. Methods: The Cardiothoracic Surgery Network (CTSNet) job market database was queried, and patterns from January to May for 2019 versus January to May 2020 were compared for trends in job postings and job seekers. Results: Our study is comprised of 395 cardiothoracic surgery job postings, of which 98% were positions located in North America and 63% were academic. The negative impact of the pandemic on the cardiothoracic surgery job market was greatest in the cardiothoracic/cardiovascular combined subspecialty, followed by congenital and adult cardiac surgery, whereas general thoracic surgery experienced an increase in proportion of jobs available. Despite an increase in views per job posted in 2020 vs. 2019 (532 vs. 290), employer views of job seeker curriculum vitae declined over the same time period in 2020 (January, 380 views/month to May, 3 views/month) compared to 2019 (January, 100 views/month to May, 54 views/month). Conclusions: An analysis of job postings from CTSNet suggests a decline in job availability in the North American cardiothoracic surgical job market following declaration of the pandemic with acknowledgement that there is month to month variability and a supply-demand mismatch. The COVID-19 pandemic has had an unprecedented impact on our field, and the ultimate consequences remain unknown.

A comparison of machine learning methods for predicting recurrence and death after curative-intent radiotherapy for non-small cell lung cancer: Development and validation of multivariable clinical prediction models.

BACKGROUND: Surveillance is universally recommended for non-small cell lung cancer (NSCLC) patients treated with curative-intent radiotherapy. High-quality evidence to inform optimal surveillance strategies is lacking. Machine learning demonstrates promise in accurate outcome prediction for a variety of health conditions. The purpose of this study was to utilise readily available patient, tumour, and treatment data to develop, validate and externally test machine learning models for predicting recurrence, recurrence-free survival (RFS) and overall survival (OS) at 2 years from treatment. METHODS: A retrospective, multicentre study of patients receiving curative-intent radiotherapy for NSCLC was undertaken. A total of 657 patients from 5 hospitals were eligible for inclusion. Data pre-processing derived 34 features for predictive modelling. Combinations of 8 feature reduction methods and 10 machine learning classification algorithms were compared, producing risk-stratification models for predicting recurrence, RFS and OS. Models were compared with 10-fold cross validation and an external test set and benchmarked against TNM-stage and performance status. Youden Index was derived from validation set ROC curves to distinguish high and low risk groups and Kaplan-Meier analyses performed. FINDINGS: Median follow-up time was 852 days. Parameters were well matched across training-validation and external test sets: Mean age was 73 and 71 respectively, and recurrence, RFS and OS rates at 2 years were 43% vs 34%, 54% vs 47% and 54% vs 47% respectively. The respective validation and test set AUCs were as follows: 1) RFS: 0·682 (0·575-0·788) and 0·681 (0·597-0·766), 2) Recurrence: 0·687 (0·582-0·793) and 0·722 (0·635-0·81), and 3) OS: 0·759 (0·663-0·855) and 0·717 (0·634-0·8). Our models were superior to TNM stage and performance status in predicting recurrence and OS. INTERPRETATION: This robust and ready to use machine learning method, validated and externally tested, sets the stage for future clinical trials entailing quantitative personalised risk-stratification and surveillance following curative-intent radiotherapy for NSCLC. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Trends in Positive Surgical Margins in cT1-T2 Oral Cavity Squamous Cell Carcinoma.

OBJECTIVES/HYPOTHESIS: To evaluate trends in contemporary positive surgical margin incidence in cT1-T2 oral cavity squamous cell carcinoma and to evaluate factors associated with surgical margin status. STUDY DESIGN: Retrospective analysis of large dataset. METHODS: Retrospective analysis of the National Cancer Database. RESULTS: Between 2004 and 2016, 39,818 patients with cT1 or cT2 oral cavity squamous cell carcinoma received primary curative-intent surgery. Positive surgical margins were present in 7.95% of patients, and univariable adjusted probability of positive surgical margins over the study period declined by 1% per year (odds ratio [OR], 0.99; 95% confidence interval [CI], 0.98-1.0; P = .049). Multivariable regression revealed the annual rate of positive surgical margins declined significantly (OR, 0.95 per year; 95% CI, 0.92-0.97; P < .001). Factors associated with increased odds of positive surgical margins included cT2 disease, subsite, understaged disease, lymphovascular invasion, tumor grade, and positive lymph nodes. Race and socioeconomic status were not associated with surgical margin status. Treatment at an academic center was associated with increased time to definitive surgery (median 35 days IQR 22-50 vs. median 27 days IQR 14-42; P < .001) and a 20% reduction in positive surgical margin rate (OR, 0.80; 95% CI, 0.71-0.90; P < .001). Treatment at high-volume centers was less likely to be associated with positive surgical margins (OR, 0.85; 95% CI, 0.74-0.98; P = .02). CONCLUSION: Surgical subsite, clinical T and N category, presence of lymphovascular invasion, and histologic grade were independent predictors of positive surgical margins. Patients are increasingly being treated at high-volume and academic centers. Overall, the rate of positive surgical margins in cT1-T2 oral cavity squamous cell carcinoma is decreasing. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1962-1970, 2022.

Circulating Interleukin-6 and CD16 positive monocytes increase following angioplasty of an arteriovenous fistula.

Arteriovenous fistulas are the ideal form of vascular access that allows provision of haemodialysis. Stenotic lesions caused by neointimal hyperplasia commonly occur resulting in patients requiring a fistuloplasty. This is effective but there is a high recurrence rate. We sought to investigate the effects of a fistuloplasty on monocyte populations. Blood samples were taken from patients before and after their fistuloplasty procedure. Samples were analysed using flow cytometry, ELISA and Luminex assays. Univariate cox regression was carried out to investigate associations with post fistuloplasty patency. At 1-2 days post fistuloplasty, the proportion of classical (CD14++CD16-) monocytes decreased (p < 0.001), whilst intermediate (CD14++CD16+) and non-classical (CD14+CD16+) monocytes increased (both p < 0.01) in a cohort of 20 patients. A time course study carried out in 5 patients showed that this was due to an increase in absolute numbers of non-classical and intermediate monocytes. Higher levels of non-classical monocytes pre-fistuloplasty were associated with an increased risk for patency loss (p < 0.05). We measured 41 soluble factors in plasma samples taken before a fistuloplasty in 54 patients, with paired post-fistuloplasty samples (1-2 days) available in 30 patients. After correcting for false discovery, the only factor with a significant change in level was IL-6 (P = 0.0003, q = 0.0124). In a further time-course study in 6 patients, peak level of IL-6 occurred 2-3 h post fistuloplasty. This study demonstrates that there is a systemic inflammatory response to the fistuloplasty procedure and that monocyte subsets and IL-6 may be important in the pathophysiology of restenosis.

Safety of general anaesthetics on the developing brain: are we there yet?

Thirty years ago, neurotoxicity induced by general anaesthetics in the developing brain of rodents was observed. In both laboratory-based and clinical studies, many conflicting results have been published over the years, with initial data confirming both histopathological and neurodevelopmental deleterious effects after exposure to general anaesthetics. In more recent years, animal studies using non-human primates and new human cohorts have identified some specific deleterious effects on neurocognition. A clearer pattern of neurotoxicity seems connected to exposure to repeated general anaesthesia. The biochemistry involved in this neurotoxicity has been explored, showing differential effects of anaesthetic drugs between the developing and developed brains. In this narrative review, we start with a comprehensive description of the initial concerning results that led to recommend that any non-essential surgery should be postponed after the age of 3 yr and that research into this subject should be stepped up. We then focus on the neurophysiology of the developing brain under general anaesthesia, explore the biochemistry of the observed neurotoxicity, before summarising the main scientific and clinical reports investigating this issue. We finally discuss the GAS trial, the importance of its results, and some potential limitations that should not undermine their clinical relevance. We finally suggest some key points that could be shared with parents, and a potential research path to investigate the biochemical effects of general anaesthesia, opening up perspectives to understand the neurocognitive effects of repetitive exposures, especially in at-risk children.

Development of a Structured Query Language and Natural Language Processing Algorithm to Identify Lung Nodules in a Cancer Centre.

Importance: The stratification of indeterminate lung nodules is a growing problem, but the burden of lung nodules on healthcare services is not well-described. Manual service evaluation and research cohort curation can be time-consuming and potentially improved by automation. Objective: To automate lung nodule identification in a tertiary cancer centre. Methods: This retrospective cohort study used Electronic Healthcare Records to identify CT reports generated between 31st October 2011 and 24th July 2020. A structured query language/natural language processing tool was developed to classify reports according to lung nodule status. Performance was externally validated. Sentences were used to train machine-learning classifiers to predict concerning nodule features in 2,000 patients. Results: 14,586 patients with lung nodules were identified. The cancer types most commonly associated with lung nodules were lung (39%), neuro-endocrine (38%), skin (35%), colorectal (33%) and sarcoma (33%). Lung nodule patients had a greater proportion of metastatic diagnoses (45 vs. 23%, p < 0.001), a higher mean post-baseline scan number (6.56 vs. 1.93, p < 0.001), and a shorter mean scan interval (4.1 vs. 5.9 months, p < 0.001) than those without nodules. Inter-observer agreement for sentence classification was 0.94 internally and 0.98 externally. Sensitivity and specificity for nodule identification were 93 and 99% internally, and 100 and 100% at external validation, respectively. A linear-support vector machine model predicted concerning sentence features with 94% accuracy. Conclusion: We have developed and validated an accurate tool for automated lung nodule identification that is valuable for service evaluation and research data acquisition.

Impact of surgeon rhBMP-2 cost awareness on complication rates and health system costs for spinal arthrodesis.

OBJECTIVE: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used in spinal arthrodesis procedures to enhance bony fusion. Research has suggested that it is the most cost-effective fusion enhancer, but there are significant upfront costs for the healthcare system. The primary objective of this study was to determine whether intraoperative dosing and corresponding costs changed with surgeon cost awareness. The secondary objective was to describe surgical complications before and after surgeon awareness of rhBMP-2 cost. METHODS: A retrospective medical record review was conducted to identify patients who underwent spinal arthrodesis procedures performed by a single surgeon, supplemented with rhBMP-2, from June 2016 to June 2018. Collected data included rhBMP-2 dosage, rhBMP-2 list price, and surgical complications. Expected Medicare reimbursement was calculated. Data were analyzed before and after surgeon awareness of rhBMP-2 cost. RESULTS: Forty-eight procedures were performed using rhBMP-2, 16 before and 32 after surgeon cost awareness. Prior to cost awareness, the most frequent rhBMP-2 dosage level was x-small (38.9%, n = 7), followed by large (27.8%, n = 5) and small (22.2%, n = 4). After cost awareness, the most frequent rhBMP-2 dosage was xx-small (56.8%, n = 21), followed by x-small (21.6%, n = 8) and large (13.5%, n = 5). The rhBMP-2 average cost per surgery was $4116.56 prior to surgeon cost awareness versus $2268.38 after. Two complications were observed in the pre-cost awareness surgical group; 2 complications were observed in the post-cost awareness surgical group. CONCLUSIONS: Surgeon awareness of rhBMP-2 cost resulted in use of smaller rhBMP-2 doses, decreased rhBMP-2 cost per surgery, and decreased overall hospital admission charges, without a detectable increase in surgical complications.

Validation of the PHQ-9 in adults with dissociative seizures.

BACKGROUND: The PHQ-9 is a self-administered depression screening instrument. Little is known about its utility and accuracy in detecting depression in adults with dissociative seizures (DS). OBJECTIVES: Using the Mini - International Neuropsychiatric Interview as a reference, we evaluated the diagnostic accuracy of the PHQ-9 in adults with DS, and examined its convergent and discriminant validity and uniformity. METHODS: Our sample comprised 368 people with DS who completed the pre-randomisation assessment of the CODES trial. The uniformity of the PHQ-9 was determined using factor analysis for categorical data. Optimal cut-offs were determined using the area under the curve (AUC), Youden Index, and diagnostic odds ratio (DOR). Convergent and discriminant validity were assessed against pre-randomisation measures. RESULTS: Internal consistency of the PHQ-9 was high (α = 0.87). While the diagnostic odds ratio suggested that a cut-off of ≥10 had the best predictive performance (DOR = 14.7), specificity at this cut off was only 0.49. AUC (0.74) and Youden Index (0.48) suggested a ≥ 13 cut-off would yield an optimal sensitivity (0.81) and specificity (0.67) balance. However, a cut-off score of ≥20 would be required to match specificity resulting from a cut-off of ≥13 in other medical conditions. We found good convergent and discriminant validity and one main factor for the PHQ-9. CONCLUSIONS: In terms of internal consistency and structure, our findings were consistent with previous validation studies but indicated that a higher cut-off would be required to identify DS patients with depression with similar specificity achieved with PHQ-9 screening in different clinical and non-clinical populations.

FENETRE study: quality-assured follow-up of quiescent neovascular age-related macular degeneration by non-medical practitioners: study protocol and statistical analysis plan for a randomised controlled trial.

OBJECTIVE: Management of age-related macular degeneration (AMD) places a high demand on already constrained hospital-based eye services. This study aims to assess the safety and quality of follow-up within the community led by suitably trained non-medical practitioners for the management of quiescent neovascular AMD (QnAMD). METHODS/DESIGN: This is a prospective, multisite, randomised clinical trial. 742 participants with QnAMD will be recruited and randomised to either continue hospital-based secondary care or to receive follow-up within a community setting. Participants in both groups will be monitored for disease reactivation over the course of 12 months and referred for treatment as necessary. Outcomes measures will assess the non-inferiority of primary care follow-up accounting for accuracy of the identification of disease reactivation, patient loss to follow-up and accrued costs and the budget impact to the National Health Service. ETHICS AND DISSEMINATION: Research ethics approval was obtained from the London Bloomsbury Ethics Committee. The results of this study will be disseminated through academic peer-reviewed publications, conferences and collaborations with eye charities to insure the findings reach the appropriate patient populations. TRIAL REGISTRATION NUMBER: NCT03893474.

INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH.

Marinesco-Sjögren syndrome is a rare human disorder caused by biallelic mutations in SIL1 characterized by cataracts in infancy, myopathy and ataxia, symptoms which are also associated with a novel disorder caused by mutations in INPP5K. While these phenotypic similarities may suggest commonalties at a molecular level, an overlapping pathomechanism has not been established yet. In this study, we present six new INPP5K patients and expand the current mutational and phenotypical spectrum of the disease showing the clinical overlap between Marinesco-Sjögren syndrome and the INPP5K phenotype. We applied unbiased proteomic profiling on cells derived from Marinesco-Sjögren syndrome and INPP5K patients and identified alterations in d-3-PHGDH as a common molecular feature. d-3-PHGDH modulates the production of l-serine and mutations in this enzyme were previously associated with a neurological phenotype, which clinically overlaps with Marinesco-Sjögren syndrome and INPP5K disease. As l-serine administration represents a promising therapeutic strategy for d-3-PHGDH patients, we tested the effect of l-serine in generated sil1, phgdh and inpp5k a+b zebrafish models, which showed an improvement in their neuronal phenotype. Thus, our study defines a core phenotypical feature underpinning a key common molecular mechanism in three rare diseases and reveals a common and novel therapeutic target for these patients.

Globalization of The Journal of Craniofacial Surgery Over The Last Decade: A Continent, Country, and State Level Analysis.

ABSTRACT: Craniofacial surgery continues to be a rapidly evolving field, due in part to interdisciplinary collaboration that has allowed for sharing of knowledge and methodologies, which has expanded greatly due to online journals and publications. The Journal of Craniofacial Surgery (JCS) is a highly regarded journal that has attracted attention for its mission to increase diversity and global representation in manuscript submissions and research publications. The purpose of this study is to provide an objective measurement of global participation in craniofacial research specifically as it pertains to the JCS. Through a bibliometric analysis, the country of origin of all articles published in the JCS from 2010 to 2019 was analyzed. In line with its mission, the JCS increased its overall production 1.9 times during the past decade and increased its global representation 1.6 times, as represented by the number of countries contributing (78). The journal produced 8147 articles with Turkey (1424), USA (1397), China (1178), South Korea (1023), and Italy (644) being the top producers. The highest represented states were Florida (156), New York (130), California (117), Massachusetts (112), and Pennsylvania (106). The Journal of Craniofacial Surgery has the greatest diversity of country representation of the major plastic and reconstructive journals compared. Overall the JCS has stayed true to its mission to foster craniofacial research and is a valuable resource for craniofacial surgeons across the world. This study provides an analysis of trends in global contributions to craniofacial research and highlights areas for further increasing global contributors to the field of craniofacial surgery.

Benign Breast Intraductal Papillomas Without Atypia at Core Needle Biopsies: Is Surgical Excision Necessary?

PURPOSE: The aim of this study was to determine the upgrade rate of image-guided core needle biopsy (CNB)-proven benign breast intraductal papillomas (IDPs) without atypia to high-risk benign lesions or malignancy after surgical excision. METHODS: A retrospective database search at a single institution identified 102 adult female patients with benign breast IDPs without atypia diagnosed on imaging-guided CNBs who subsequently had surgical excisions between 2011 and 2016. Patient characteristics, imaging features, biopsy techniques, and the pathology reports from imaging-guided CNBs and subsequent surgical excisions were reviewed. The upgrade rate to malignancies or high-risk benign lesions was determined at the patient level. RESULTS: The upgrade rate to malignancy was 2.9% (3/102), including two cases of ductal carcinoma in situ (DCIS) and one case of microinvasive (< 1 mm) ductal carcinoma arising from DCIS. The upgrade rate to high-risk benign lesions was 7.8% (8/102), with seven cases of atypical ductal hyperplasia and one case of atypical lobular hyperplasia. A personal history of breast cancer and a larger mean lesion size were significantly associated with an upgrade to malignancy (p < 0.05). CONCLUSIONS: The management of benign breast IDPs without atypia detected on imaging-guided CNBs is controversial. Our results suggest risk stratification is important in approaching these patients. Although surgical excision should be considered for all benign breast IDPs without atypia, observation with serial imaging may be appropriate in selected low-risk patients. This approach will save many women from surgeries and decrease the cost of medical care.

Results from a prospective longitudinal survey of employment and work outcomes in newly diagnosed cancer patients during and after curative-intent chemotherapy: A Wisconsin Oncology Network study.

BACKGROUND: Postcancer work limitations may affect a substantial proportion of patients and contribute to the "financial toxicity" of cancer treatment. The degree and nature of work limitations and employment outcomes are poorly understood for cancer patients, particularly in the immediate period of transition after active treatment. We prospectively examined employment, work ability, and work limitations during and after treatment. METHODS: A total of 120 patients receiving curative therapy who were employed prior to their cancer diagnosis and who intended to work during or after end of treatment (EOT) completed surveys at baseline (pretreatment), EOT, and 3, 6, and 12 months after EOT. Surveys included measures of employment, work ability, and work limitations. Descriptive statistics (frequencies, percentages, means with standard deviations) were calculated. RESULTS: A total of 111 participants completed the baseline survey. On average, participants were 48 years of age and were mostly white (95%) and female (82%) with a diagnosis of breast cancer (69%). Full-time employment decreased during therapy (from 88% to 50%) and returned to near prediagnosis levels by 12-month follow-up (78%). Work-related productivity loss due to health was high during treatment. CONCLUSIONS: This study is the first to report the effects of curative intent cancer therapy on employment, work ability, and work limitations both during and after treatment. Perceived work ability was generally high overall 12 months after EOT, although a minority reported persistent difficulty. A prospective analysis of factors (eg, job type, education, symptoms) most associated with work limitations is underway to assist in identifying at-risk patients.

Retrospective Cohort Study of Venous Thromboembolism Rates in Ambulatory Cancer Patients: Association With Khorana Score and Other Risk Factors.

BACKGROUND: Guidelines do not recommend that cancer outpatients receive thromboprophylaxis unless at high venous thromboembolism (VTE) risk, with the Khorana score suggested for risk stratification. This study investigated VTE incidence in outpatients with pancreatic, endometrial, colorectal, ovarian and cervical cancer, the role of Khorana score in risk assessment and potential risk factors. METHODS: Data were retrospectively collected 1 year after cancer diagnosis. VTE associated with inpatient admissions was excluded. RESULTS: Seven hundred forty-six patients were included. VTE rates varied: 26.8% pancreatic; 5.7% endometrial; 9.8% colorectal; 10.2% ovarian; and 0.0% cervical cancer. Excluding VTE at diagnosis, potentially preventable VTE rates were 16.5% in pancreatic, 3.8% in endometrial, 9.8% in colorectal and 8.7% in ovarian cancer. Khorana score was associated with VTE in endometrial cancer only (high-risk: 16.7% vs. low-risk: 1.5%; P < 0.001). VTE rates for patients with central venous catheters (CVCs) were 22.6-34.8% in pancreatic, endometrial, colorectal and ovarian cancers. VTE was associated with CVCs in endometrial, colorectal and ovarian; chemotherapy and Hb < 100 g/L in pancreatic; surgery in endometrial and ovarian; and body mass index > 35 in ovarian cancers following adjusted analysis (P < 0.05). CONCLUSIONS: VTE is a significant burden in pancreatic, endometrial, colorectal and ovarian cancers. Khorana score was not predictive in most cancers. The major VTE-associated variable was CVC. Our data suggest a role for clinical trials of thromboprophylaxis in targeted cancer outpatients.

A Strategy for the Convergent and Stereoselective Assembly of Polycyclic Molecules.

The stereoselective oxidative coupling of cyclic ketones via silyl bis-enol ethers followed by ring-closing metathesis is shown to be a general and powerful reaction sequence for the preparation of diverse polycyclic scaffolds from simple precursors. The modular strategy successfully constructs substructures prevalent in numerous bioactive natural product families, varying in substitution and carbocyclic composition. Several of the prepared compounds were shown to possess potent cytotoxic activity against a panel of tumor cell lines. The utility of this strategy was further demonstrated by a concise and highly convergent 17-step formal synthesis of the complex antimalarial marine diterpene, (+)-7,20-diisocyanoadociane.

Boosting Intracellular Delivery of Lipid Nanoparticle-Encapsulated mRNA.

Intracellular delivery of mRNA holds great potential for vaccine1-3 and therapeutic4 discovery and development. Despite increasing recognition of the utility of lipid-based nanoparticles (LNPs) for intracellular delivery of mRNA, particle engineering is hindered by insufficient understanding of endosomal escape, which is believed to be a main limiter of cytosolic availability and activity of the nucleic acid inside the cell. Using a series of CRISPR-based genetic perturbations of the lysosomal pathway, we have identified that late endosome/lysosome (LE/Ly) formation is essential for functional delivery of exogenously presented mRNA. Lysosomes provide a spatiotemporal hub to orchestrate mTOR signaling and are known to control cell proliferation, nutrient sensing, ribosomal biogenesis, and mRNA translation. Through modulation of the mTOR pathway we were able to enhance or inhibit LNP-mediated mRNA delivery. To further boost intracellular delivery of mRNA, we screened 212 bioactive lipid-like molecules that are either enriched in vesicular compartments or modulate cell signaling. Surprisingly, we have discovered that leukotriene-antagonists, clinically approved for treatment of asthma and other lung diseases, enhance intracellular mRNA delivery in vitro (over 3-fold, p < 0.005) and in vivo (over 2-fold, p < 0.005). Understanding LNP-mediated intracellular delivery will inspire the next generation of RNA therapeutics that have high potency and limited toxicity.