Clostridioides difficile
infection is a major cause of nosocomial and community illness. In this report from the Emerging Infections Program, associated with the U.S. CDC, the national burden of
C. ...difficile
infection is estimated from 2011 through 2017. In 2017, an estimated 462,100 cases of
C. difficile
infection occurred.
The androgen receptor (AR) remains a critical driver in metastatic castration-resistant prostate cancer (mCRPC). Profiling AR aberrations in both circulating DNA and RNA may identify key predictive ...and/or prognostic biomarkers in the context of contemporary systemic therapy.
To profile AR aberrations in circulating nucleic acids and correlate with clinical outcomes.
We prospectively enrolled 67 mCRPC patients commencing AR pathway inhibitors (ARPIs; n = 41) or taxane chemotherapy (n = 26). Using a first-in-class next-generation sequencing-based assay, we performed integrated cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling from a single 10 ml blood tube.
Kaplan-Meier survival estimates and multivariable Cox regression analyses were used to assess associations between clinical outcomes and the following AR aberrations: copy number variation, splice variants (AR-V7 and AR-V9) and somatic mutations.
Cell-free DNA and cfRNA were successfully sequenced in 67 (100%) and 59 (88%) patients, respectively. Thirty-six (54%) patients had one or more AR aberrations. AR gain and cumulative number of AR aberrations were independently associated with clinical/radiographic progression-free survival (PFS; hazard ratio HR 3.2, p = 0.01 and HR 3.0 for 0 vs ≥2, p = 0.04) and overall survival (HR 2.8, p = 0.04 and HR 2.9 for 0 vs ≥2, p = 0.03). Notably, concurrent AR gain and AR splice variant expression (AR gain/AR-V+) was associated with shorter prostate-specific antigen PFS on both ARPIs (HR 6.7, p = 0.009) and chemotherapy (HR 3.9, p = 0.04). Importantly, key findings were validated in an independent cohort of mCRPC patients (n = 40), including shorter OS in AR gain/AR-V+ disease (HR 3.3, p = 0.02). Limitations include sample size and follow-up period.
We demonstrate the utility of a novel, multianalyte liquid biopsy assay capable of simultaneously detecting AR alterations in cfDNA and cfRNA. Concurrent profiling of cfDNA and cfRNA may provide vital insights into disease biology and resistance mechanisms in mCRPC.
In this study of men with advanced prostate cancer, DNA and RNA abnormalities in the androgen receptor detected in blood were associated with poor outcomes on available drug treatments. This information could be used to better guide treatment of advanced prostate cancer.
We demonstrated, in two independent metastatic castration-resistant prostate cancer (mCRPC) cohorts, that simultaneous profiling of androgen receptor (AR) cell-free DNA and RNA aberrations provides important prognostic information in patients with mCRPC. Profiling of circulating AR aberrations may be of high clinical value, especially with increasing use of AR-targeted therapies earlier in the prostate cancer disease course.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Clostridium difficile
is an important cause of hospital-associated diarrhea. In this report from the CDC, the U.S. burden of
C. difficile
infection is estimated at nearly 500,000 cases and 30,000 ...deaths in 2011, with an increasing burden among nonhospitalized persons.
Changes in the epidemiology of
Clostridium difficile
infections have occurred since the emergence of the North American pulsed-field gel electrophoresis type 1 (NAP1) strain, which has been responsible for geographically dispersed hospital-associated outbreaks.
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3
In the United States, hospitalizations for
C. difficile
infection among nonpregnant adults doubled from 2000 through 2010 and were projected to continue to increase in 2011 and 2012, especially as laboratories transition to more sensitive
C. difficile
assays, such as the nucleic acid amplification test (NAAT).
4
–
6
On the basis of data from U.S. death certificates,
C. difficile
infection is the leading cause of gastroenteritis-associated death . . .
Background. Studies are conflicting regarding the importance of the fluoroquinolone-resistant North American pulsed-field gel electrophoresis type 1 (NAP1) strain in Clostridium difficile infection ...(CDI) outcome. We describe strain types causing CDI and evaluate their association with patient outcomes. Methods. CDI cases were identified from population-based surveillance. Multivariate regression models were used to evaluate the associations of strain type with severe disease (ileus, toxic megacolon, or pseudomembranous colitis within 5 days; or white blood cell count ≥15 000 cells/μL within 1 day of positive test), severe outcome (intensive care unit admission after positive test, colectomy for C. difficile infection, or death within 30 days of positive test), and death within 14 days of positive test. Results. Strain typing results were available for 2057 cases. Severe disease occurred in 363 (17.7%) cases, severe outcome in 100 (4.9%), and death within 14 days in 56 (2.7%). The most common strain types were NAP1 (28.4%), NAP4 (10.2%), and NAP11 (9.1%). In unadjusted analysis, NAP1 was associated with greater odds of severe disease than other strains. After controlling for patient risk factors, healthcare exposure, and antibiotic use, NAP1 was associated with severe disease (adjusted odds ratio AOR, 1.74; 95% confidence interval CI, 1.36–2.22), severe outcome (AOR, 1.66; 95% CI, 1.09–2.54), and death within 14 days (AOR, 2.12; 95% CI, 1.22–3.68). Conclusions. NAP1 was the most prevalent strain and a predictor of severe disease, severe outcome, and death. Strategies to reduce NAP1 prevalence, such as antibiotic stewardship to reduce fluoroquinolone use, might reduce CDI morbidity.
Copycat Dietz, Brett W; Winston, Lisa G; Koehler, Jane E ...
The New England journal of medicine,
11/2021, Volume:
385, Issue:
19
Journal Article, Conference Proceeding
Peer reviewed
A 75-year-old man with a history of an untreated hepatitis C virus infection presented with a 4-day history of a pruritic rash on his lower legs. He noted generalized malaise and an unintentional ...weight loss of 7 kg over the past 2 months. A video showing aortic vegetation is available at NEJM.org.
IMPORTANCE Clostridium difficile infection (CDI) has been increasingly reported among healthy individuals in the community. Recent data suggest that community-associated CDI represents one-third of ...all C difficile cases. The epidemiology and potential sources of C difficile in the community are not fully understood. OBJECTIVES To determine epidemiological and clinical characteristics of community-associated CDI and to explore potential sources of C difficile acquisition in the community. DESIGN AND SETTING Active population-based and laboratory-based CDI surveillance in 8 US states. PARTICIPANTS Medical records were reviewed and interviews performed to assess outpatient, household, and food exposures among patients with community-associated CDI (ie, toxin or molecular assay positive for C difficile and no overnight stay in a health care facility within 12 weeks). Molecular characterization of C difficile isolates was performed. Outpatient health care exposure in the prior 12 weeks among patients with community-associated CDI was a priori categorized into the following 3 levels: no exposure, low-level exposure (ie, outpatient visit with physician or dentist), or high-level exposure (ie, surgery, dialysis, emergency or urgent care visit, inpatient care with no overnight stay, or health care personnel with direct patient care). MAIN OUTCOMES AND MEASURES Prevalence of outpatient health care exposure among patients with community-associated CDI and identification of potential sources of C difficile by level of outpatient health care exposure. RESULTS Of 984 patients with community-associated CDI, 353 (35.9%) did not receive antibiotics, 177 (18.0%) had no outpatient health care exposure, and 400 (40.7%) had low-level outpatient health care exposure. Thirty-one percent of patients without antibiotic exposure received proton pump inhibitors. Patients having CDI with no or low-level outpatient health care exposure were more likely to be exposed to infants younger than 1 year (P = .04) and to household members with active CDI (P = .05) compared with those having high-level outpatient health care exposure. No association between food exposure or animal exposure and level of outpatient health care exposure was observed. North American pulsed-field gel electrophoresis (NAP) 1 was the most common (21.7%) strain isolated; NAP7 and NAP8 were uncommon (6.7%). CONCLUSIONS AND RELEVANCE Most patients with community-associated CDI had recent outpatient health care exposure, and up to 36% would not be prevented by reduction of antibiotic use only. Our data support evaluation of additional strategies, including further examination of C difficile transmission in outpatient and household settings and reduction of proton pump inhibitor use.
Metastatic prostate cancer is a clonally heterogeneous disease state characterized by progressive somatic perturbations. The aim of this study was to identify cell free DNA- (cfDNA-) based ...alterations and their associations with outcomes in progressive metastatic prostate cancer.
In this longitudinal prospective cohort study plasma cfDNA/circulating tumor DNA (ctDNA) was analyzed before, during, and after androgen deprivation therapy (ADT) in 4 independent patient groups ranging from untreated metastatic hormone sensitive prostate cancer (mHSPC) to metastatic castrate resistant prostate cancer (mCRPC). Next generation sequencing was performed on ctDNA and germline DNA to characterize alterations and associations with clinical outcomes were determined for each group.
cfDNA yields were different in progressive mHSPC and mCRPC states (P < .001). In mHSPC, a higher than median ctDNA fraction was predictive of shorter time to ADT failure (HR, 2.29 95% CI, 1.13–4.65; Log-Rank P = .02). cfDNA, ctDNA taken with volume of metastatic disease in mHSPC and with alkaline phosphatase levels prognosticated survival better than clinical factors alone in mHSPC and mCRPC states (Log Rank P = 0.03). ctDNA-based AR, APC mutations were increased in mCRPC compared to mHSPC (P < ·05).TP53 mutations, RB1 loss, and AR gene amplifications correlated with poorer survival in mCRPC. Mutations in multiple DNA repair genes (ATM, BRCA1, BRCA2, CHEK2) were associated with time to ADT treatment failure and survival in mHSPC.
ctDNA fraction can further refine clinical prognostic factors in metastatic prostate cancer. Somatic ctDNA alterations have potential prognostic, predictive, and therapeutic implications in metastatic prostate cancer management.
Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Both changes in circulating lipids represented by a validated poor prognostic 3-lipid signature (3LS) and somatic tumour genetic aberrations are individually associated with worse clinical outcomes ...in men with metastatic castration-resistant prostate cancer (mCRPC). A key question is how the lipid environment and the cancer genome are interrelated in order to exploit this therapeutically. We assessed the association between the poor prognostic 3-lipid signature (3LS), somatic genetic aberrations and clinical outcomes in mCRPC.
We performed plasma lipidomic analysis and cell-free DNA (cfDNA) sequencing on 106 men with mCRPC commencing docetaxel, cabazitaxel, abiraterone or enzalutamide (discovery cohort) and 94 men with mCRPC commencing docetaxel (validation cohort). Differences in lipid levels between men ± somatic genetic aberrations were assessed with t-tests. Associations between the 3LS and genetic aberrations with overall survival (OS) were examined using Kaplan-Meier methods and Cox proportional hazard models.
The 3LS was associated with shorter OS in the discovery (hazard ratio HR 2.15, 95% confidence interval CI 1.4-3.3, p < 0.001) and validation cohorts (HR 2.32, 95% CI 1.59-3.38, p < 0.001). Elevated plasma sphingolipids were associated with AR, TP53, RB1 and PI3K aberrations (p < 0.05). Men with both the 3LS and aberrations in AR, TP53, RB1 or PI3K had shorter OS than men with neither in both cohorts (p ≤ 0.001). The presence of 3LS and/or genetic aberration was independently associated with shorter OS for men with AR, TP53, RB1 and PI3K aberrations (p < 0.02). Furthermore, aggressive-variant prostate cancer (AVPC), defined as 2 or more aberrations in TP53, RB1 and/or PTEN, was associated with elevated sphingolipids. The combination of AVPC and 3LS predicted for a median survival of ~12 months. The relatively small sample size of the cohorts limits clinical applicability and warrants future studies.
Elevated circulating sphingolipids were associated with AR, TP53, RB1, PI3K and AVPC aberrations in mCRPC, and the combination of lipid and genetic abnormalities conferred a worse prognosis. These findings suggest that certain genotypes in mCRPC may benefit from metabolic therapies.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Few data suggest that Clostridioides difficile infections (CDIs) detected by toxin enzyme immunoassay (EIA) are more severe and have worse outcomes than those detected by nucleic acid amplification ...tests (NAATs) only. We compared toxin- positive and NAAT-positive-only CDI across geographically diverse sites.
A case was defined as a positive C. difficile test in a person ≥1 year old with no positive tests in the prior 8 weeks. Cases were detected during 2014-2015 by a testing algorithm (specimens initially tested by glutamate dehydrogenase and toxin EIA; if discordant results, specimens were reflexed to NAAT) and classified as toxin positive or NAAT positive only. Medical charts were reviewed. Multivariable logistic regression models were used to compare CDI-related complications, recurrence, and 30-day mortality between the 2 groups.
Of 4878 cases, 2160 (44.3%) were toxin positive and 2718 (55.7%) were NAAT positive only. More toxin-positive than NAAT-positive-only cases were aged ≥65 years (48.2% vs 38.0%; P < .0001), had ≥3 unformed stools for ≥1 day (43.9% vs 36.6%; P < .0001), and had white blood cell counts ≥15 000 cells/µL (31.4% vs 21.4%; P < .0001). In multivariable analysis, toxin positivity was associated with recurrence (adjusted odds ratio aOR, 1.89; 95% confidence interval CI, 1.61-2.23), but not with CDI-related complications (aOR, 0.91; 95% CI, .67-1.23) or 30-day mortality (aOR, 0.95; 95% CI, .73-1.24).
Toxin-positive CDI is more severe, but there were no differences in adjusted CDI-related complication and mortality rates between toxin-positive and NAAT-positive-only CDI that were detected by an algorithm that utilized an initial glutamate dehydrogenase screening test.
To determine whether assignment to a multiple-bed room increased the risk of hospital-onset C. difficile diarrhea (HO-CDI).
Case-control study.
San Francisco General Hospital and Trauma ...Center.PopulationAdult general medical and surgical inpatients.
Consecutive cases of HO-CDI were identified between January 1, 2010, and December 31, 2015. To investigate the effect of multiple-bed room exposure both at admission and at the time of symptom onset, 2 sets of controls were selected from the general medical/surgical inpatient population using incidence density sampling. Conditional logistic regression was used to estimate the relationship between room assignment (single bed vs multiple beds) and the development of HO-CDI.
In total, 187 cases were identified and matched with 512 and 515 controls for the admission and at-diagnosis analyses, respectively. The adjusted rate ratio (RR) associated with the development HO-CDI associated with multiple-bed room exposure during the 7 and 14 days immediately prior to HO-CDI diagnosis were 1.08 (95% confidence interval CI, 0.93-1.25; P=.31) and 0.96 (95% CI, 0.93-1.18; P=.12), respectively. Furthermore, no significant association was detected in the analysis of the first 7 and 14 days after case admission or among patients with Charlson comorbidity scores ≥4 in either period.
Assignment of patients to multiple-bed rooms on general medical and surgical wards was not associated with an increased risk in the development of HO-CDI. Future investigation should be performed with larger cohorts in multiple sites to more definitively address the question because this issue could have implications for patient room assignment and hospital design.
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