Early detection and intervention are likely to be the most effective means for reducing morbidity and mortality of human cancer. However, development of methods for noninvasive detection of ...early-stage tumors has remained a challenge. We have developed an approach called targeted error correction sequencing (TEC-Seq) that allows ultrasensitive direct evaluation of sequence changes in circulating cell-free DNA using massively parallel sequencing. We have used this approach to examine 58 cancer-related genes encompassing 81 kb. Analysis of plasma from 44 healthy individuals identified genomic changes related to clonal hematopoiesis in 16% of asymptomatic individuals but no alterations in driver genes related to solid cancers. Evaluation of 200 patients with colorectal, breast, lung, or ovarian cancer detected somatic mutations in the plasma of 71, 59, 59, and 68%, respectively, of patients with stage I or II disease. Analyses of mutations in the circulation revealed high concordance with alterations in the tumors of these patients. In patients with resectable colorectal cancers, higher amounts of preoperative circulating tumor DNA were associated with disease recurrence and decreased overall survival. These analyses provide a broadly applicable approach for noninvasive detection of early-stage tumors that may be useful for screening and management of patients with cancer.
Objectives This study sought to determine if the risk of mortality associated with inappropriate implantable cardioverter-defibrillator (ICD) shocks is due to the underlying arrhythmia or the shock ...itself. Background Shocks delivered from ICDs are associated with an increased risk of mortality. It is unknown if all patients who experience inappropriate ICD shocks have an increased risk of death. Methods We evaluated survival outcomes in patients with an ICD and a cardiac resynchronization therapy defibrillator enrolled in the LATITUDE remote monitoring system (Boston Scientific Corp., Natick, Massachusetts) through January 1, 2010. First shock episode rhythms from 3,809 patients who acutely survived the initial shock were adjudicated by 7 electrophysiologists. Patients with a shock were matched to patients without a shock (n = 3,630) by age at implant, implant year, sex, and device type. Results The mean age of the study group was 64 ± 13 years, and 78% were male. Compared with no shock, there was an increased rate of mortality in those who received their first shock for monomorphic ventricular tachycardia (hazard ratio HR: 1.65, p < 0.0001), ventricular fibrillation/polymorphic ventricular tachycardia (HR: 2.10, p < 0.0001), and atrial fibrillation/flutter (HR: 1.61, p = 0.003). In contrast, mortality after first shocks due to sinus tachycardia and supraventricular tachycardia (HR: 0.97, p = 0.86) and noise/artifact/oversensing (HR: 0.91, p = 0.76) was comparable to that in patients without a shock. Conclusions Compared with no shock, those who received their first shock for ventricular rhythms and atrial fibrillation had an increased risk of death. There was no significant difference in survival after inappropriate shocks for sinus tachycardia or noise/artifact/oversensing. In this study, the adverse prognosis after first shock appears to be more related to the underlying arrhythmia than to an adverse effect from the shock itself.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A web-based survey was conducted of ergonomics practitioners holding certifications in the U.S., Canada, Great Britain, Australia, and New Zealand. The survey follows 12 years after an earlier ...initial survey reported by Dempsey et al. (2005). Approximately 1221 eligible participants were invited by e-mail to participate, and 405 surveys were included in the final analysis. The survey queried use of basic instruments relevant to ergonomic practice as well as more specific analytical tools such as observational techniques for assessing postural demands of work and instrumentation for direct measurement of such demands. Some ergonomic assessment methods appear to have increased in their overall use by U.S. ergonomists compared to 2005 data. This was observed for: RULA, REBA, Psychophysical Upper Extremity Data, Strain Index, and ACGIH TLV for Hand Activity Level. There is minimal evidence of increased overall use of direct measurement approaches in the U.S. There appear to be geographic differences between countries/continents in terms of use of various methods. The use of mobile device/smart phone “apps” by ergonomists was queried and these technologies presently appear to be in early adoption phase with 24–28% of practitioners reporting use of an app in their ergonomics practice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose In early-stage non-small cell lung cancer (NSCLC), post-treatment mortality may influence the comparative effectiveness of surgery and stereotactic body radiotherapy (SBRT), with implications ...for shared decision making among high-risk surgical candidates. We analyzed early mortality after these interventions using the National Cancer Database. Patients and Methods We abstracted patients with cT1-T2a, N0, M0 NSCLC diagnosed between 2004 and 2013 undergoing either surgery or SBRT. Thirty-day and 90-day post-treatment mortality rates were calculated and compared using Cox regression and propensity score-matched analyses. Results We identified 76,623 patients who underwent surgery (78% lobectomy, 20% sublobar resection, 2% pneumonectomy) and 8,216 patients who received SBRT. In the unmatched cohort, mortality rates were moderately increased with surgery versus SBRT (30 days, 2.07% v 0.73% absolute difference (Δ), 1.34%; P < .001; 90 days, 3.59% v 2.93% Δ, 0.66%; P < .001). Among the 27,200 propensity score-matched patients, these differences increased (30 days, 2.41% v 0.79% Δ, 1.62%; P < .001; 90 days, 4.23% v 2.82% Δ, 1.41%; P < .001). Differences in mortality between surgery and SBRT increased with age, with interaction P < .001 at both 30 days and 90 days (71 to 75 years old: 30-day Δ, 1.87%; 90-day Δ, 2.02%; 76 to 80 years old: 30-day Δ, 2.80%; 90-day Δ, 2.59%; > 80 years old: 30-day Δ, 3.03%; 90-day Δ, 3.67%; all P ≤ .001). Compared with SBRT, surgical mortality rates were higher with increased extent of resection (30-day and 90-day multivariate hazard ratio for mortality: sublobar resection, 2.85 and 1.37; lobectomy, 3.65 and 1.60; pneumonectomy, 14.5 and 5.66; all P < 0.001). Conclusion Differences in 30- and 90-day post-treatment mortality between surgery and SBRT increased as a function of age, with the largest differences in favor of SBRT observed among patients older than 70 years. These representative mortality data may inform shared decision making among patients with early-stage NSCLC who are eligible for both interventions.
There is growing interest in the role of local therapies, including external beam radiotherapy (RT), for men with metastatic prostate cancer (mPCa). We used the National Cancer Database (NCDB) to ...evaluate the overall survival (OS) of men with mPCa treated with androgen deprivation (ADT) with and without prostate RT.
The NCDB was queried for men with newly diagnosed mPCa, all treated with ADT, with complete datasets for RT, surgery, prostate-specific antigen (PSA) level, Gleason score, and Charlson-Deyo comorbidity score. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses.
From 2004 to 2012, 6,382 men with mPCa were identified, including 538 (8.4%) receiving prostate RT. At a median follow-up of 5.1 years, the addition of prostate RT to ADT was associated with improved OS on univariate (P < .001) and multivariate analysis (hazard ratio, 0.624; 95% CI, 0.551 to 0.706; P < .001) adjusted for age, year, race, comorbidity score, PSA level, Gleason score, T stage, N stage, chemotherapy administration, treating facility, and insurance status. Propensity score analysis with matched baseline characteristics demonstrated superior median (55 v 37 months) and 5-year OS (49% v 33%) with prostate RT plus ADT compared with ADT alone (P < .001). Landmark analyses limited to long-term survivors of ≥1, ≥3, and ≥5 years demonstrated improved OS with prostate RT in all subsets (all P < .05). Secondary analyses comparing the survival outcomes for patients treated with therapeutic dose RT plus ADT versus prostatectomy plus ADT during the same time interval demonstrated no significant differences in OS, whereas both therapies were superior to ADT alone.
In this large contemporary analysis, men with mPCa receiving prostate RT and ADT lived substantially longer than men treated with ADT alone. Prospective trials evaluating local therapies for mPCa are warranted.
The optimal role for postoperative radiotherapy (PORT) for thymoma and thymic carcinoma remains controversial. We used the National Cancer Data Base to investigate the impact of PORT on overall ...survival (OS).
Patients who underwent an operation for thymoma or thymic carcinoma were categorized into Masaoka-Koga stage groups I to IIA, IIB, III, and IV. Patients who did not undergo an operation or those who received preoperative radiation were excluded. Kaplan-Meier estimates of OS and univariate and multivariate Cox proportional hazards regression analyses were performed. Propensity score–matched analyses were performed to further control for baseline confounders.
From 2004 to 2012, 4056 patients were eligible for inclusion, 2001 of whom (49%) received PORT. On multivariate analysis of OS in the thymoma cohort adjusted for age, WHO histologic subtype, Masaoka-Koga stage group, surgical margins, and chemotherapy administration, PORT was associated with superior OS (hazard ratio HR = 0.72, p = 0.001). Propensity score–matched analyses confirmed the survival advantage associated with PORT. Subset analysis indicated longer OS in association with PORT for patients with stage IIB thymoma (HR = 0.61, p = 0.035), stage III (HR = 0.69, p = 0.020), and positive margins (HR = 0.53, p < 0.001). The impact of PORT for stage I to IIA disease did not reach significance (HR = 0.76, p = 0.156).
In this large database analysis of PORT for thymic tumors, PORT was associated with longer OS, with the greatest relative benefits observed for stage IIB to III disease and positive margins. In the absence of randomized studies assessing the value of PORT, these data may inform clinical practice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody–drug conjugate (ADC) ...could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.
Complementing the genome with an understanding of the human exposome is an important challenge for contemporary science and technology. Tens of thousands of chemicals are used in commerce, yet cost ...for targeted environmental chemical analysis limits surveillance to a few hundred known hazards. To overcome limitations which prevent scaling to thousands of chemicals, we develop a single-step express liquid extraction and gas chromatography high-resolution mass spectrometry analysis to operationalize the human exposome. We show that the workflow supports quantification of environmental chemicals in human plasma (200 µL) and tissue (≤100 mg) samples. The method also provides high resolution, sensitivity and selectivity for exposome epidemiology of mass spectral features without a priori knowledge of chemical identity. The simplicity of the method can facilitate harmonization of environmental biomonitoring between laboratories and enable population level human exposome research with limited sample volume.
Purpose: Multiphoton-based intravital imaging has shown that invasive carcinoma cells in mouse and rat mammary tumors intravasate
when associated with perivascular macrophages, identifying a ...potential tumor microenvironment of metastasis (TMEM). We define
TMEM as the tripartite arrangement of an invasive carcinoma cell, a macrophage, and an endothelial cell. The aim of this study
was to determine if TMEM density in human breast carcinoma samples predicts the development of systemic, hematogenous metastases.
Experimental Design: A case-control study of 30 patients who developed metastatic breast cancer and 30 patients without metastatic disease was
done. Cases were matched to controls based on currently used prognostic criteria. Paraffin-embedded primary breast cancer
samples were stained using a triple immunohistochemical method allowing simultaneous identification of carcinoma cells, macrophages,
and endothelial cells. Two pathologists, blinded to outcome, evaluated the number of TMEM per 20 high-power fields.
Results: No association was seen between TMEM density and tumor size or grade, lymph node metastasis, lymphovascular invasion, or
hormone receptor status. TMEM density was greater in the group of patients who developed systemic metastases compared with
the patients with only localized breast cancer (median, 105 versus 50, respectively; P = 0.00006). For every 10-unit increase in TMEM density, the odds ratio for systemic metastasis was 1.9 (95% confidence interval,
1.1-3.4).
Conclusions: TMEM density predicted the development of systemic, hematogenous metastases. The ability of TMEM to predict distant metastasis
was independent of lymph node status and other currently used prognosticators. Quantitation of TMEM may be a useful new prognostic
marker for breast cancer patients.
Jones et al review the recommendations for the use of fecal immunochemical testing (FIT) to help diagnose colorectal cancer among symptomatic patients in primary care made by the ACPGBI/BSG and ...consider what they mean for primary care clinicians in the UK. The Association of Coloproctology of Great Britain and Ireland and the British Society of Gastroenterology have published a new guideline around fecal immunochemical testing in patients with signs or symptoms of suspected colorectal cancer. The guideline was written by a multidisciplinary team including GPs and patient representatives, and includes recommendations for both primary and secondary care. NHS England has subsequently written to all GP practices in England recommending they implement this guideline "in full."
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