ctDNA offers a promising, noninvasive approach to monitor therapeutic efficacy in real-time. We explored whether the quantitative percent change in ctDNA early after therapy initiation can predict ...treatment response and progression-free survival (PFS) in patients with metastatic gastrointestinal cancer.
A total of 138 patients with metastatic gastrointestinal cancers and tumor profiling by next-generation sequencing had serial blood draws pretreatment and at scheduled intervals during therapy. ctDNA was assessed using individualized droplet digital PCR measuring the mutant allele fraction in plasma of mutations identified in tumor biopsies. ctDNA changes were correlated with tumor markers and radiographic response.
A total of 138 patients enrolled. A total of 101 patients were evaluable for ctDNA and 68 for tumor markers at 4 weeks. Percent change of ctDNA by 4 weeks predicted partial response (PR,
< 0.0001) and clinical benefit CB: PR and stable disease (SD),
< 0.0001. ctDNA decreased by 98% (median) and >30% for all PR patients. ctDNA change at 8 weeks, but not 2 weeks, also predicted CB (
< 0.0001). Four-week change in tumor markers also predicted response (
= 0.0026) and CB (
= 0.022). However, at a clinically relevant specificity threshold of 90%, 4-week ctDNA change more effectively predicted CB versus tumor markers, with a sensitivity of 60% versus 24%, respectively (
= 0.0109). Patients whose 4-week ctDNA decreased beyond this threshold (≥30% decrease) had a median PFS of 175 days versus 59.5 days (HR, 3.29; 95% CI, 1.55-7.00;
< 0.0001).
Serial ctDNA monitoring may provide early indication of response to systemic therapy in patients with metastatic gastrointestinal cancer prior to radiographic assessments and may outperform standard tumor markers, warranting further evaluation.
Background
Survival in patients with metastatic colorectal cancer (mCRC) has been associated with tumor mutational status, muscle loss, and weight loss. We sought to explore the combined effects of ...these variables on overall survival.
Materials and Methods
We performed an observational cohort study, prospectively enrolling patients receiving chemotherapy for mCRC. We retrospectively assessed changes in muscle (using computed tomography) and weight, each dichotomized as >5% or ≤5% loss, at 3, 6, and 12 months after diagnosis of mCRC. We used regression models to assess relationships between tumor mutational status, muscle loss, weight loss, and overall survival. Additionally, we evaluated associations between muscle loss, weight loss, and tumor mutational status.
Results
We included 226 patients (mean age 59 ± 13 years, 53% male). Tumor mutational status included 44% wild type, 42% RAS‐mutant, and 14% BRAF‐mutant. Patients with >5% muscle loss at 3 and 12 months experienced worse survival controlling for mutational status and weight (3 months hazard ratio, 2.66; p < .001; 12 months hazard ratio, 2.10; p = .031). We found an association of >5% muscle loss with BRAF‐mutational status at 6 and 12 months. Weight loss was not associated with survival nor mutational status.
Conclusion
Increased muscle loss at 3 and 12 months may identify patients with mCRC at risk for decreased overall survival, independent of tumor mutational status. Specifically, >5% muscle loss identifies patients within each category of tumor mutational status with decreased overall survival in our sample. Our findings suggest that quantifying muscle loss on serial computed tomography scans may refine survival estimates in patients with mCRC.
Implications for Practice
In this study of 226 patients with metastatic colorectal cancer, it was found that losing >5% skeletal muscle at 3 and 12 months after the diagnosis of metastatic disease was associated with worse overall survival, independent of tumor mutational status and weight loss. Interestingly, results did not show a significant association between weight loss and overall survival. These findings suggest that muscle quantification on serial computed tomography may refine survival estimates in patients with metastatic colorectal cancer beyond mutational status.
Cancer cachexia has traditionally been defined using weight loss; however, loss of skeletal muscle may be a more objective measure. This article reports the results of a retrospective study that assessed whether skeletal muscle loss is associated with overall survival in patients with metastatic colorectal cancer, independent of tumor mutational status and weight loss.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
Background
The incidence of opioid-related overdose deaths has been rising for 30 years and has been further exacerbated amidst the COVID-19 pandemic. Naloxone can reverse opioid overdose, ...lower death rates, and enable a transition to medication for opioid use disorder. Though current formulations for community use of naloxone have been shown to be safe and effective public health interventions, they rely on bystander presence. We sought to understand the preferences and minimum necessary conditions for wearing a device capable of sensing and reversing opioid overdose among people who regularly use opioids.
Methods
We conducted a combined cross-sectional survey and semi-structured interview at a respite center, shelter, and syringe exchange drop-in program in Philadelphia, Pennsylvania, USA, during the COVID-19 pandemic in August and September 2020. The primary aim was to explore the proportion of participants who would use a wearable device to detect and reverse overdose. Preferences regarding designs and functionalities were collected via a questionnaire with items having Likert-based response options and a semi-structured interview intended to elicit feedback on prototype designs. Independent variables included demographics, opioid use habits, and previous experience with overdose.
Results
A total of 97 adults with an opioid use history of at least 3 months were interviewed. A majority of survey participants (76%) reported a willingness to use a device capable of detecting an overdose and automatically administering a reversal agent upon initial survey. When reflecting on the prototype, most respondents (75.5%) reported that they would wear the device always or most of the time. Respondents indicated discreetness and comfort as important factors that increased their chance of uptake. Respondents suggested that people experiencing homelessness and those with low tolerance for opioids would be in greatest need of the device.
Conclusions
The majority of people sampled with a history of opioid use in an urban setting were interested in having access to a device capable of detecting and reversing an opioid overdose. Participants emphasized privacy and comfort as the most important factors influencing their willingness to use such a device.
Trial registration
NCT04530591.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Detection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery can identify patients with minimal residual disease (MRD) who will ultimately recur. Most ctDNA MRD assays require ...tumor sequencing to identify tumor-derived mutations to facilitate ctDNA detection, requiring tumor and blood. We evaluated a plasma-only ctDNA assay integrating genomic and epigenomic cancer signatures to enable tumor-uninformed MRD detection.
A total of 252 prospective serial plasma specimens from 103 patients with colorectal cancer undergoing curative-intent surgery were analyzed and correlated with recurrence.
Of 103 patients, 84 stage I (9.5%), II (23.8%), III (47.6%), IV (19%) had evaluable plasma drawn after completion of definitive therapy, defined as surgery only (
= 39) or completion of adjuvant therapy (
= 45). In "landmark" plasma drawn 1-month (median, 31.5 days) after definitive therapy and >1 year follow-up, 15 patients had detectable ctDNA, and all 15 recurred positive predictive value (PPV), 100%; HR, 11.28 (
< 0.0001). Of 49 patients without detectable ctDNA at the landmark timepoint, 12 (24.5%) recurred. Landmark recurrence sensitivity and specificity were 55.6% and 100%. Incorporating serial longitudinal and surveillance (drawn within 4 months of recurrence) samples, sensitivity improved to 69% and 91%. Integrating epigenomic signatures increased sensitivity by 25%-36% versus genomic alterations alone. Notably, standard serum carcinoembryonic antigen levels did not predict recurrence HR, 1.84 (
= 0.18); PPV = 53.9%.
Plasma-only MRD detection demonstrated favorable sensitivity and specificity for recurrence, comparable with tumor-informed approaches. Integrating analysis of epigenomic and genomic alterations enhanced sensitivity. These findings support the potential clinical utility of plasma-only ctDNA MRD detection.
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The tools nonprofits need to measure the impact of their social mediaHaving a social media measurement plan and approach can no longer be an after-thought. It is a requirement of success. As ...nonprofits refine their social media practice, their boards are expecting reports showing results. As funders provide dollars to support programs that include social media, they too want to see results. This book offers the tools and strategies needed for nonprofits that need reliable and measurable data from their social media efforts. Using these tools will not only improve a nonprofit?s decision making process but will produce results-driven metrics for staff and stakeholders.? A hands-on resource for nonprofit professionals who must be able to accurately measure the results of their social media ventures Written by popular nonprofit blogger Beth Kanter and measurement expert Katie Delahaye Paine Filled with tools, strategies, and illustrative examples that are highly accessible for nonprofit professionalsThis important resource will give savvy nonprofit professionals the information needed to produce measurable results for their social media.
Low levels of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, and stress, which potentiates catecholamine release from sympathetic nerves, are fundamental to chronic ...functional pain syndromes and comorbid depression, which predominantly affect females. Here, we sought to examine the independent and joint contributions of low COMT and stress to chronic functional pain and depression at the behavioral and molecular level. Male and female C57BL/6 mice received sustained systemic delivery of the COMT inhibitor OR486 over 14 days and underwent a swim stress paradigm on days 8 to 10. Pain and depressive-like behavior were measured over 14 days, and brain-derived neurotrophic factor (BDNF; a factor involved in nociception and depression) and glucocorticoid receptor (GR; a stress-related receptor) expression were measured on day 14. We found that stress potentiates the effect of low COMT on functional pain and low COMT potentiates the effect of stress on depressive-like behavior. The joint effects of low COMT and stress on functional pain and depressive-like behavior were significantly greater in females vs males. Consistent with behavioral data, we found that stress potentiates COMT-dependent increases in spinal BDNF and low COMT potentiates stress-dependent decreases in hippocampal BDNF in females, but not males. Although low COMT increases spinal GR and stress increases hippocampal GR expression, these increases are not potentiated in the OR486 + stress group and are not sex-specific. These results suggest that genetic and environmental factors that enhance catecholamine bioavailability cause abnormalities in BDNF signaling and increase risk of comorbid functional pain and depression, especially among females.
Background
Patient‐reported outcomes (PROs) assessing quality of life (QOL) and symptom burden correlate with clinical outcomes in patients with cancer. However, to the authors' knowledge, data ...regarding associations between PROs and treatment response are lacking.
Methods
The authors prospectively approached consecutive patients with advanced gastrointestinal cancer who were initiating a new treatment. Prior to treatment, patients reported their QOL (Functional Assessment of Cancer Therapy‐General FACT‐G, 4 subscales: Functional, Physical, Emotional, Social; higher scores indicate better QOL) and symptom burden (Edmonton Symptom Assessment System ESAS, Patient Health Questionnaire‐4 PHQ‐4; higher scores represent greater symptoms). Regression models were used to examine associations of baseline PROs with treatment response (clinical benefit or progressive disease PD at time of first scan), healthcare utilization, and survival.
Results
From May 2019 to April 2020, a total of 112 patients with advanced gastrointestinal cancer were enrolled. For treatment response, 64.3% had CB and 35.7% had PD. Higher baseline ESAS‐Physical (odds ratio, 1.04; P = .027) and lower FACT‐G Functional (odds ratio, 0.92; P = .038) scores were associated with PD. Higher ESAS‐Physical (hazard ratio HR, 1.03; P = .044) and lower FACT‐G Total (HR, 0.96; P = .005), FACT‐G Physical (HR, 0.89; P < .001), and FACT‐G Functional (HR, 0.87; P < .001) scores were associated with a greater hospitalization risk. Lower FACT‐G Total (HR, 0.96; P = .009) and FACT‐G Emotional (HR, 0.86; P = .012) scores as well as higher ESAS‐Total (HR, 1.03; P = .014) and ESAS‐Physical (HR, 1.04; P = .032) scores were associated with worse survival.
Conclusions
Baseline PROs are associated with treatment response in patients with advanced gastrointestinal cancer, namely physical symptoms and functional QOL, in addition to health care use and survival. The findings of the current study support the association between PROs and important clinical outcomes, including the novel finding of treatment response.
In the current study, the authors investigate associations between patient‐reported outcomes (PROs), health care use, and clinical outcomes in a prospectively enrolled cohort of patients with advanced gastrointestinal cancer. Baseline PROs are associated with important clinical outcomes, including the novel finding of treatment response, in patients with advanced gastrointestinal cancer.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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Background: PROs assessing quality of life (QOL) and physical symptoms often correlate with clinical outcomes in patients (pts) with cancer. Yet, data are lacking about the use of ...PROs to predict treatment response. We evaluated associations of baseline PROs with treatment response, healthcare use, and survival among pts with advanced gastrointestinal cancer. Methods: We prospectively enrolled pts with metastatic gastrointestinal cancer prior to initiating chemotherapy at Massachusetts General Hospital. At baseline (start of treatment), pts reported their QOL (Functional Assessment of Cancer Therapy General FACT-G, subscales assess QOL across 4 domains: functional, physical, emotional, social well-being) and symptom burden (Edmonton Symptom Assessment System ESAS). Higher scores on FACT-G indicate better QOL, while higher scores on ESAS represent a greater symptom burden. We used regression models to examine associations of baseline PRO scores with treatment response (clinical benefit CB or progressive disease PD at the time of first scan based on clinical documentation), healthcare use (unplanned hospital admissions), and survival. Results: From 5/2019-3/2020, we enrolled 112 of 131 (85.5% enrollment) consecutive pts (median age = 62.8, 61.6% male, 45.5% pancreatobiliary cancer). For treatment response, 64.3% had CB and 35.7% had PD. Higher ESAS-physical (B = 1.04, p = .027) and lower FACT-G functional (B = 0.92, p = .038) scores at baseline were significant predictors of PD. On the specific ESAS items, pts who experienced PD were more likely to report moderate/severe poor well-being (57.9% vs 29.7%; p = .001), pain (44.7% vs 25.0%; p < .050), drowsiness (42.1% vs 20.3%; p = .024), and diarrhea (23.7% vs 4.7%; p = .008) at baseline. Lower FACT-G total (HR = 0.96, p = .003), FACT-G physical (HR = 0.89, p < .001), FACT-G functional (HR = 0.87, p < .001), and higher ESAS-physical (HR = 1.03, p = .028) scores at baseline were significantly associated with greater risk of hospital admission. Lower FACT-G total (HR = 0.96, p = .009), FACT-G emotional (HR = 0.87, p = .014), as well as higher ESAS-total (HR = 1.03, p = .018) and ESAS-physical (HR = 1.03, p = .040) scores at baseline were significantly associated with greater risk of death. Conclusions: We found that baseline PROs predict treatment response in pts with advanced cancer, namely physical symptoms and functional QOL, in addition to healthcare use and survival outcomes. These findings further support the use of PROs to predict important clinical outcomes, including the novel finding of treatment response.
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Background: Nearly half of patients with G/GE cancer do not receive or complete post-operative chemotherapy and/or chemoradiation (CRT). Total neoadjuvant therapy (TNT) is as an ...emerging alternate treatment strategy. We have previously reported a 28% pCR with FOLFIRINOX followed by CRT. However, TNT outcomes with FLOT or FOLFOX followed by CRT are lacking. Methods: We retrospectively analyzed patients after resection of locally advanced G/GE after receiving TNT. Patient received neoadjuvant FOLFOX or FLOT x 8 cycles, CRT (G 45 Gy, GE 50.4 Gy) with concurrent chemotherapy (5FU, carboplatin/paclitaxel). The primary aim was to explore TNT completion rates. Secondary aims included pCR and toxicity. We performed descriptive statistics, t-test, chi-squared, and Fisher’s exact tests as appropriate. Results: From 12/2015 to 8/2019, 57.1% (40/70) completed TNT and resection (15.7% active treatment, 15.7% progressive disease, 11% treated elsewhere). Median age was 66.0 (range:27-79) and 73% male. Tumor locations included 57.5% G, 30.0% GE, and 12.5% overlapping. Neoadjuvant chemotherapy included FLOT 22.5% (n = 9) or FOLFOX 77.5% (n = 31). Overall we found a 25% pCR without significant differences between type of neoadjuvant chemotherapy. Conclusions: TNT followed by resection is feasible with acceptable rates of treatment completion and toxicity. Notable limitations include the retrospective analysis, small sample size, and heterogenous treatment. The pCR rate is promising and warrants further prospective study to optimize TNT approaches. Table: see text
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