Citations

Mutations provide an enduring record Somatic mutations pepper our cells with change, but because they are not in the germline, they do not propagate to the next generation. Bizzotto et al. leveraged data on the distribution of somatic mutations in adults to take a backward look at the earliest moments of human development. Calculation of cellular lineages on the basis of shared somatic mutations shows the number of cells from which the body will develop when the human embryo gastrulates. The lineage for forebrain cells is identifiable, as are the asymmetrical fates spun out of many of the gastrula cells. Science , this issue p. 1249

Abstract Context. —Monitoring customer satisfaction is a valuable component of a laboratory quality improvement program. Objective. —To survey the level of physician satisfaction with hospital clinical laboratory services. Design. —Participating institutions provided demographic and practice information and survey results of physician satisfaction with defined aspects of clinical laboratory services, rated on a scale of 1 (poor) to 5 (excellent). Results. —One hundred thirty-eight institutions participated in this study and submitted a total of 4329 physician surveys. The overall satisfaction score for all institutions ranged from 2.9 to 5.0. The median overall score for all participants was 4.1 (10th percentile, 3.6; 90th percentile, 4.5). Physicians were most satisfied with the quality/reliability of results and staff courtesy, with median values of excellent or good ratings of 89.9%. Of the 5 service categories that received the lowest percentage values of excellent/good ratings (combined scores of 4 and 5), 4 were related to turnaround time for inpatient stat, outpatient stat, routine, and esoteric tests. Surveys from half of the participating laboratories reported that 96% to 100% of physicians would recommend the laboratory to other physicians. The category most frequently selected as the most important category of laboratory services was quality/reliability of results (31.7%). Conclusions. —There continues to be a high level of physician satisfaction and loyalty with clinical laboratory services. Test turnaround times are persistent categories of dissatisfaction and present opportunities for improvement.

Abstract Context. —The laboratory test turnaround times (TATs) that exceed the expectations of clinicians who order those tests, the so-called outlier test reporting rates, may be responsible for perceptions of inadequate laboratory service. Objective. —To monitor outlier test reporting rates for emergency department stat potassium results and routine inpatient morning blood tests. Design. —In 2 different monitors, each conducted for 2 years, laboratory personnel in institutions enrolled in the College of American Pathologists (CAP) Q-Tracks program tracked the percentages of emergency department stat potassium results and/or the percentages of morning rounds routine test results that were reported later than self-imposed reporting deadlines. Setting. —A total of 291 hospitals participating in 2 CAP Q-Tracks monitors. Results. —Participants monitored 225 140 stat emergency department potassium TATs, of which 33 402 (14.8%) were outliers, and 1 055 040 routine morning test reporting times, of which 123 554 (11.7%) were outliers. For both monitors, there was a significant ( P < .05) downward trend in the outlier rates as the number of quarters in which participants submitted data increased. Conclusion. —Outlier reporting rates for emergency department stat potassium and routine morning test results decreased during the 2-year period of continuous monitoring. The CAP Q-Tracks program provides an effective vehicle by which providers of laboratory services may improve the timeliness with which they deliver the results of laboratory tests.

Abstract Context. —Rapid diagnosis of acute myocardial infarction in patients presenting to emergency departments (EDs) with chest pain may determine the types, and predict the outcomes of, the therapy those patients receive. The amount of time consumed in establishing diagnoses of acute myocardial infarction may depend in part on that consumed in the generation of the blood test results measuring myocardial injury. Objective. —To determine the normative rates of turnaround time (TAT) for biochemical markers of myocardial injury and to examine hospital and laboratory practices associated with faster TATs. Design. —Laboratory personnel in institutions enrolled in the College of American Pathologists Q-Probes Program measured the order-to-report TATs for serum creatine kinase–MB and/or serum troponin (I or T) for patients presenting to their hospital EDs with symptoms of acute myocardial infarction. Laboratory personnel also completed detailed questionnaires characterizing their laboratories' and hospitals' practices related to testing for biochemical markers of myocardial injury. ED physicians completed questionnaires indicating their satisfaction with testing for biochemical markers of myocardial injury in their hospitals. Setting. —A total of 159 hospitals, predominantly located in the United States, participating in the College of American Pathologists Q-Probes Program. Results. —Most (82%) laboratory participants indicated that they believed a reasonable order-to-report TATs for biochemical markers of myocardial injury to be 60 minutes or less. Most (75%) of the 1352 ED physicians who completed satisfaction questionnaires believed that the results of tests measuring myocardial injury should be reported back to them in 45 minutes or less, measured from the time that they ordered those tests. Participants submitted TAT data for 7020 troponin and 4368 creatine kinase–MB determinations. On average, they reported 90% of myocardial injury marker results in slightly more than 90 minutes measured from the time that those tests were ordered. Among the fastest performing 25% of participants (75th percentile and above), median order-to-report troponin and creatine kinase–MB TATs were equal to 50 and 48.3 minutes or less, respectively. Shorter troponin TATs were associated with performing cardiac marker studies in EDs or other peripheral laboratories compared to (1) performing tests in central hospital laboratories, and (2) having cardiac marker specimens obtained by laboratory rather than by nonlaboratory personnel. Conclusion. —The TAT expectations of the ED physicians using the results of laboratory tests measuring myocardial injury exceed those of the laboratory personnel providing the results of those tests. The actual TATs of myocardial injury testing meet the expectations of neither the providers of those tests nor the users of those test results. Improving TAT performance will require that the providers and users of laboratory services work together to develop standards that meet the needs of the medical staff and that are reasonably achievable by laboratory personnel.

Background Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by painful and ulcerating lesions on the skin. It rarely involves the face and is often difficult to diagnose. There are few cases reported in the literature of PG involving the face. Aim To share our experience with 5 patients in whom the final diagnosis was PG involving the face, and to review the literature. Methods We report a series of 5 patients with a final diagnosis of PG involving the face and reviewed relevant literature. We searched through PubMed and EMBASE using keywords such as “face” and “pyoderma gangrenosum,” “blastomycosis-like pyoderma gangrenosum, vegetative pyoderma gangrenosum and granulomatous pyoderma gangrenosum.” Results We report 5 patients (4 females) with pyoderma gangrenosum involving the face. All 5 had a final diagnosis of superficial granulomatous PG. All cases presented with nonhealing facial ulcer most commonly on cheeks and a common histopathology of mixed inflammatory infiltrates, multinucleated giant cells, and plasma cells with some granulomatous inflammation. Conclusions PG can involve the face, and all 5 of our patients had the superficial granulomatous as the most common form.

Abstract Objective. —To determine the frequency with which solitary blood culture samples were submitted to laboratories serving small hospitals and to ascertain whether certain hospital practices relating to the performance of blood cultures were associated with lower solitary blood culture rates (SBCRs). Design. —Participants in the College of American Pathologists Q-Probes laboratory quality improvement program collected data prospectively on the numbers of solitary blood culture sets from adult patients submitted to their laboratories and answered questions about their institutions' practice characteristics relating to the collection of blood culture specimens. Setting and Participants. —Three hundred thirty-three public and private institutions with a median occupied bed size of 57. Participants were located in the United States (n = 329), Canada (n = 3), and Australia (n = 1). Main Outcome Measure. —The solitary blood culture rate was defined as the number of instances in which only 1 blood culture venipuncture was performed on an individual patient during a 24-hour period divided by the total number of blood culture venipunctures that were performed during the study period. Results. —Participants submitted data on 132 778 adult patient blood culture sets. The SBCRs were 3.4% or less in the top-performing 10% of participating institutions (90th percentile and above), 12.7% in the midrange of participating institutions (50th percentile), and 42.5% or more in the bottom-performing 10% of participating institutions (10th percentile and below). In half the participating institutions, the SBCRs for inpatients were 8.3% or less and for outpatients, 22% or less. Solitary blood culture rates were lower for institutions in which phlebotomists rather than nonphlebotomists routinely collected blood culture specimens, in which internal policies required drawing at least 2 blood culture sets, in which hospital personnel contacted clinicians when their laboratories received requests for solitary blood culture sets, and in which quality control programs monitored SBCRs routinely. Conclusions. —Hospitals can achieve SBCRs under 5%. Those hospitals with particularly high SBCRs may lower their rates by altering certain institutional practices.

Abstract Incidence rates for endometrial cancer (EC) are rising, particularly in postmenopausal and obese women. Our previous work has showed that the uterine and vaginal microbiome distinguishes patients with EC from those without. We now examine the impact of patient factors (such as menopause status, body mass index, and vaginal pH) in the microbiome in the absence of EC and how these might contribute to the microbiome signature in EC. We find that each factor independently alters the microbiome and identified postmenopausal status as the main driver of a polymicrobial network associated with EC (ECbiome). Of the 17 taxa we found enriched in EC patients, 8 were also enriched by postmenopause. Because postmenopausal status is a main risk factor for endometrial cancer, this system can be thought of as an ecological succession towards a disease state. Organisms within the ECbiome have been previously identified as polymicrobial associations in chronic soft tissue infections, ulcers, morbid obesity, and bacterial vaginosis. This suggests that this microbiome network is likely involved in mechanisms of host disease. Within the ECbiome, Porphyromonas somerae stands out because of its very significant and specific association with EC (p = 5.73E-6; Q = 0.009). We had previously identified this species as significantly associated with EC, and hereby validate that finding. Because the association of P. somerae with EC was robust and specific enough to potentially be considered as a biomarker for the disease (AUC 76.7%, CI: 67.9-85.5%), we developed a P. somerae-specific qPCR assay to detect this species in vaginal swabs. This becomes of particular interest because the lower tract and uterine microbiome are significantly correlated in these patients (p = 0.01), indicating that the vaginal microbiome can be used as a proxy for the uterine environment in EC. In agreement with the 16S rRNA gene sequencing data, P. somerae was detected significantly more frequently in vaginal swabs of patients with EC than those without EC (p = 3.02E-7). Overall, the test achieved a sensitivity of 74% and specificity of 63%, with a positive predictive value of 0.86 for obese and postmenopausal patients. In summary, we identify Porphyromas somerae presence as the most predictive microbial marker of EC, and we confirm this using targeted qPCR, which could be of use in detecting EC in high-risk, asymptomatic women. Given the established pathogenic behavior of P.somerae, we have also explored mechanistic routes through which this microbe and associated consortia may be involved in the mechanisms of disease. Citation Format: Marina Walther-Antonio, Dana Walsh, Alexis Hokenstad, Jun Chen, Jayeun Sung, Gregory Jenkins, Nicholas Chia, Heidi Nelson, Andrea Mariani. Postmenopause as a key factor in the composition of the Endometrial Cancer Microbiome (ECbiome): Putative role of Porphyromonas somerae in the disease [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr PR09.

Background: The rapid reduction in tumor burden by the oral B-cell lymphoma-2 inhibitor venetoclax (Ven) poses a risk of tumor lysis syndrome (TLS) for patients (pts) with chronic lymphocytic leukemia (CLL). The approved 5-week Ven dose ramp-up, along with prophylaxis and monitoring, effectively mitigate this risk of TLS but also introduce some logistical challenges to starting the drug. Moreover, the long ramp-up period may lead to clinical deterioration while pts are receiving lower doses, particularly for those with rapid disease progression after B-cell receptor pathway inhibitor (BCRi) therapy. Accelerated Ven dose ramp-up has been explored in a limited number of prior studies, including the prospective M14-032 trial (Jones et al. Lancet Oncol 2018) and a single-center retrospective study (Koenig et al. ASH 2019); these studies had conflicting results with regard to the risk of TLS. We conducted a multicenter study to systematically characterize the safety profile and feasibility of an accelerated Ven ramp-up schedule in pts with previously treated CLL. Methods: This is a retrospective chart review from 4 large academic US medical centers of 36 pts with relapsed/refractory CLL and a documented ramp-up period of &lt;5 weeks (duration at treating physician's discretion). The study period was defined from 1 month before to 1 month after ramp-up. TLS risk before Ven initiation was assessed per the label. Safety endpoints included the proportion of pts who experienced Grade ≥3 adverse events (AEs), TLS per Howard criteria (laboratory, clinical, or any reported TLS), and/or metabolic abnormalities observed during ramp-up. Feasibility of accelerated ramp-up was measured by assessing the proportion of pts who reached the target 400-mg dose or an alternative stable dose, defined as continuous/stable Ven dosing for ≥1 month after ramp-up. Descriptive statistics were calculated. Results: The median age at Ven initiation was 67.5 years (range 53-84) and 58.3% of pts had deletion 17p or TP53 mutation (Table 1). Pts were heavily pretreated (median of 3 lines of prior therapy [range 1-7]) and 88.9% had prior BCRi therapy; 27 pts (75.0%) had BCRi as immediate prior line of therapy before Ven. Before Ven initiation, 7 pts (19.4%) were at high risk of TLS, 13 (36.1%) at medium risk of TLS, and 15 (41.7%) at low risk of TLS; 1 unknown. Last line of therapy was discontinued in 30 pts (83.3%). Twenty-one pts (58.3%) received Ven monotherapy, 11 (30.6%) received Ven plus rituximab, 1 (2.8%) received Ven plus obinutuzumab, and 3 (8.3%) received Ven plus other (including ibrutinib, duvelisib, or idelalisib). Thirty-three pts (91.7%) underwent accelerated ramp-up as an inpatient, with a median hospital stay of 11 days (range 3-28). A stable dose of Ven was reached by 34 pts (94.4%), with median time of 15 days (range 3-66) to stable dose. Twenty-eight of these 34 pts (82.4%) reached the full 400 mg as their stable dose, with median time of 19.5 days (range 11-66). Overall, 15 pts (41.7%) experienced Grade ≥3 AEs and 4 (11.1%) discontinued Ven during ramp-up (2 pts due to clinical TLS, and 1 patient each due to persistent cytopenias and enrollment in hospice care). Seven pts (19.4%) had TLS (5 [13.9%] laboratory, 2 [5.6%] clinical), and 9 pts (25.0%) developed a metabolic abnormality only that did not meet Howard criteria for TLS (Table 2). Both pts with clinical TLS received Ven ramp-up while hospitalized; 1 high risk and 1 medium risk at baseline. Life-threatening (Grade 4) acute kidney injury and hypovolemic shock were reported for both. Of those pts with TLS, 4 (57.1%) required supportive medications. All AEs of TLS (including clinical events) resolved. Conclusion: In this multicenter study exploring accelerated Ven ramp-up, 82% of pts reached a stable dose of Ven 400 mg. TLS was observed in 19% of pts, including 2 pts with clinical TLS, which in both cases was reversible. Our data suggest that although the risk of TLS with an accelerated ramp-up appears to be greater than with 5-week Ven ramp-up per label, an accelerated Ven ramp-up schedule appears feasible at experienced academic centers with close inpatient monitoring. This dosing regimen may be beneficial for relapsed CLL pts with aggressive disease, particularly those progressing immediately after BCRi therapy. While promising, the approach cannot be routinely recommended until results are validated in a prospective clinical trial. Disclosures Davids: BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Ascentage Pharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; AbbVie: Consultancy; Eli Lilly: Consultancy; MEI Pharma: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Sunesis: Consultancy; Gilead Sciences: Consultancy; Zentalis: Consultancy; Syros Pharmaceuticals: Consultancy; Research to Practice: Honoraria; Merck: Consultancy; Surface Oncology: Research Funding. Shadman:TG therapeutics: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Atara Biotherapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellectar: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mustang Bio: Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Sunesis: Research Funding; Gilead: Research Funding; MophoSys: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sound Biologics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta Pharma: Ended employment in the past 24 months. Parikh:GlaxoSmithKline: Honoraria; AbbVie: Honoraria, Research Funding; Ascentage Pharma: Research Funding; Genentech: Honoraria; Verastem Oncology: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; TG Therapeutics: Research Funding; Merck: Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding. Ujjani:MorphoSys: Consultancy; Genentech: Consultancy, Honoraria; Atara: Consultancy, Honoraria; Gilead/Kite: Consultancy, Research Funding; Verastem Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding. Chen:AbbVie: Other: Institutional research grants, Research Funding. Johnson:AbbVie: Other: Institutional research grants, Research Funding. Jiang:AbbVie: Current Employment, Other: may hold stock or options. Llamas:AbbVie: Current Employment, Other: may hold stock or options. Feng:AbbVie: Current Employment, Other: may hold stock or options. Khan:ICON plc: Current Employment, Other: a company contracted by AbbVie for this study. Lamanna:MingSight: Other: Institutional research grants, Research Funding; Oncternal, Verastem, TG Therapeutics: Other: Institutional research grants, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Columbia University Medical Center: Current Employment; Juno: Other: Institutional research grants, Research Funding; Octapharma: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bei-Gene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Institutional research grants, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Loxo: Research Funding. OffLabel Disclosure: "Venetoclax is a BCL-2 inhibitor indicated: for treatment of adult patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); in combination with azacitidine, or decitabine, or low-dose cytarabine to treat adults with newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. CLL/SLL: Dosing with venetoclax begins with a 5-week ramp-up."