Increased specimen minimum volume reduces turnaround time and hemolysis.

Quantity not sufficient (QNS) specimens with minimal blood volume for testing are common in clinical laboratories. However, there is no universal definition of minimum volume for a QNS specimen and little data is available addressing the impact of QNS / low volume specimens on turnaround time (TAT) and sample hemolysis. We compared the TAT and hemolysis index from samples ≤1.0 mL to all specimens received and quantified the number of specimens with reduced blood volume. A new QNS policy requiring ≥1.5 mL of sample in a blood tube for laboratory analysis was implemented and the results were assessed by sample hemolysis and TAT. The median laboratory TAT for samples with ≤1.0 mL of blood was 61 min (Interquartile Range, IQR: 50-82), in contrast to 28 min (26-34) for all samples. The hemolysis index for samples ≤1.0 mL was 112 (65-253) and 15 (8-29) for all samples. Requirement of a minimum volume of 1.5 mL of blood resulted in the proportion of samples with TAT ≥ 60 min to decrease from 10.4% to 4.24% in the ED, and for specimens cancelled due to hemolysis to decrease from 4.24% to 3.38%. This policy was introduced hospital wide with similar effects. Together, we correlate limited specimen volume with an increase in laboratory TAT and hemolysis. Implementation of a QNS policy of ≥1.5 mL and provider education provided a significant and durable reduction in TAT and specimen hemolysis.

Preanalytical errors in a satellite stat laboratory: A Six Sigma analysis of seven years' data.

BACKGROUND: There have been few reports regarding the frequency and types of preanalytical errors in stat laboratories, in particular those occurring in the satellite laboratory setting. The impact of this error type on laboratory performance in this environment is largely unknown. We assessed the performance of a stat laboratory serving a population of predominantly elderly patients with suspected or established diagnoses of cancer using Six Sigma methodology and compared the results to previous work on this subject. METHODS: We performed an observational retrospective study using data from the period 2013-2020. The clinical setting was a satellite laboratory supporting an outpatient medical clinic. The type and frequency of each type of preanalytical error were compiled and were used to derive the quarterly error rate. Overall and quarterly performance were calculated using Six Sigma methodology. RESULTS: During the study period 1314 preanalytical errors were identified from 247,271 laboratory tests (0.5% of total test volume). There was a steady decrease in the error rate over the course of the study period, ranging from 1.4% in 2013 to 0.14% in 2020, despite a 290% increase in quarterly test volume during this period. The most common error types encountered were order error, hemolysis, collection error, and lab accident. CONCLUSION: 1) The overall performance of a satellite laboratory with a stat testing menu is comparable to hospital-based laboratory stat testing. 2) The most frequent error types encountered in satellite laboratory stat testing differ from those found in hospital-based laboratories. 3) There was an overall improvement in laboratory performance based on Six Sigma methodology.

The impact of biosafety enhancement on stat laboratory quality metrics: Lessons from the COVID-19 pandemic.

OBJECTIVE: It is unclear if implementation of biosafety action plans in response to the COVID-19 pandemic has affected laboratory quality metrics. METHODS: This retrospective study used quality data, including turnaround time (TAT) and number/type of unacceptable specimens from a stat laboratory supporting an outpatient medical clinic serving predominantly elderly cancer patients. Four months of data from the height of the COVID-19 pandemic (March-June 2020) were compared to the same months in 2019. RESULTS: March-May 2020 test volumes were decreased compared to 2019. June 2020 test volume was slightly increased compared to 2019. TATs in 2020 were similar/ slightly improved compared to the same months in 2019, due to shortened collect to receive and receive to verify TATs. The number and types of unacceptable specimens were similar in 2020 and 2019. CONCLUSIONS: Despite the challenges to the system caused by the pandemic, laboratory quality metrics were maintained.

Blast flagging of the Sysmex XN-10 hematology analyzer with supervised cell image analysis: Impact on quality parameters.

INTRODUCTION: The Sysmex XN-10 automated hematology analyzer (Sysmex Corporation) is routinely used in hematology laboratories to perform complete blood cell count with differential (CBC w/ diff). The sensitivity of this system for blast detection is unclear, since many prior studies evaluating the blast flagging capabilities of Sysmex XN series used the white precursor cell (WPC) channel, which is not cleared for use in the United States. METHODS: We assessed the blast flagging capabilities of the Sysmex XN-10 compared with CellaVision (a cell image analyzer)-assisted visual hematology results. We evaluated the following flags: "blasts?/abnormal lymph?" and "immature granulocytes present" and compared differences in turnaround time between methods. RESULTS: We collected data on 2239 CBC w/ diff Sysmex automated analyzer differential and CellaVision-assisted visual differential from the inpatient hematology-oncology population of a tertiary care medical center. Solely analyzing the first CBC/diff from each unique patient, both flags had a combined sensitivity of 100%, specificity of 50.2%, PPV of 21.7%, and NPV of 100%. The mean turnaround time for the automated differential was 19.5 minutes (SD 35.9 minutes) compared with 66.4 minutes for the CellaVision-assisted visual differential (SD 68.5 minutes; P < 0.001; Figure 1). CONCLUSION: The Sysmex XN-10 abnormal lymphocyte/blast and immature granulocytes flags had excellent sensitivity and acceptable specificity in detecting circulating blasts with shorter turnaround time than the CellaVision-assisted visual differential. Our study suggests that automated differentials performed on Sysmex XN-10 can replace visual differentials as a first-line screening method for blast detection with improved turnaround time in hematology-oncology populations.

Combined Targeted Therapies for First-line Treatment of Metastatic Triple Negative Breast Cancer-A Phase II Trial of Weekly Nab-Paclitaxel and Bevacizumab Followed by Maintenance Targeted Therapy With Bevacizumab and Erlotinib.

INTRODUCTION: Angiogenesis and epidermal growth factor receptor signaling are potential therapeutic targets in triple negative breast cancer (TNBC). We hypothesized that targeting these critical pathways would prolong progression-free survival with first-line therapy for metastatic TNBC. PATIENTS AND METHODS: We conducted a phase II trial of nab-paclitaxel and bevacizumab, followed by maintenance therapy with bevacizumab and erlotinib, for patients with metastatic TNBC. During induction, the patients received nab-paclitaxel 100 mg/m2 intravenously (days 1, 8, and 15) and bevacizumab 10 mg/kg intravenously (days 1 and 15) every 28 days for 6 cycles. Patients free of progression at 24 weeks received maintenance therapy with bevacizumab 10 mg/kg intravenously every 2 weeks and oral erlotinib 150 mg/d until disease progression. The primary endpoint was progression-free survival (PFS). The secondary endpoints were best overall response, overall survival (OS), and adverse events. We explored the measurement of circulating tumor cells as a prognostic marker. RESULTS: A total of 55 evaluable patients were enrolled. The median PFS and OS for the cohort was 9.1 months (95% confidence interval, 7.2-11.1) and 18.1 months (95% confidence interval, 15.6-21.7), respectively. Of the 53 patients with measurable disease, 39 (74%) had experienced a partial response and 10 (19%) had stable disease using the Response Evaluation Criteria In Solid Tumors. The most common toxicities were uncomplicated neutropenia, fatigue, and neuropathy. Decreased circulating tumor cells from baseline to the first assessment correlated with longer PFS and OS. CONCLUSION: Nab-paclitaxel and bevacizumab, followed by maintenance targeted therapy with bevacizumab and erlotinib, resulted in PFS similar to that of other trials. Most patients experienced a partial response (74%). Most patients received maintenance therapy (55%), providing a break from cytotoxic chemotherapy.

A longitudinal study evaluating the effects of interferon-alpha therapy on cognitive and psychiatric function in adults with chronic hepatitis C.

OBJECTIVE: To prospectively evaluate for changes in objective cognitive performance (attention, memory, and executive function) and psychiatric symptom severity (depression, anxiety, fatigue, and pain) in patients before, during and after interferon-alpha based therapy (IFN) for chronic hepatitis C virus infection (HCV). METHODS: 33 HCV+ adults were evaluated two months before IFN initiation (baseline), three months into IFN, and six months following IFN termination (IFN+ Group). 31 HCV+ adults who did not undergo IFN therapy were evaluated at baseline and six months later (IFN- Group). At each evaluation, participants completed the Neuropsychological Assessment Battery (NAB) Attention, Memory and Executive Functions Modules, the Beck Depression Inventory, Second Edition (BDI), Generalized Anxiety Disorder Inventory (GADI), Fatigue Severity Scale (FSS), and Brief Pain Inventory (BPI). RESULTS: Compared with the IFN- Group, the IFN+ Group experienced significantly (p<0.050) increased symptoms of depression, anxiety, fatigue and pain during IFN therapy relative to baseline. In the IFN+ Group, psychiatric symptoms generally returned to baseline levels following IFN termination. Sustained viral response was associated with significantly lower depression and fatigue. No significant changes in cognitive performance were observed. CONCLUSIONS: During IFN, patients with HCV evidence significantly increased psychiatric symptoms, including symptoms of depression, anxiety, fatigue and pain. These psychiatric symptoms are generally short-term and remit following IFN termination, with increased benefit if viral clearance is achieved. However, IFN is not associated with significant declines in objective cognitive performance during or following IFN.

Pathogen reduction in human plasma using an ultrashort pulsed laser.

Pathogen reduction is a viable approach to ensure the continued safety of the blood supply against emerging pathogens. However, the currently licensed pathogen reduction techniques are ineffective against non-enveloped viruses such as hepatitis A virus, and they introduce chemicals with concerns of side effects which prevent their widespread use. In this report, we demonstrate the inactivation of both enveloped and non-enveloped viruses in human plasma using a novel chemical-free method, a visible ultrashort pulsed laser. We found that laser treatment resulted in 2-log, 1-log, and 3-log reductions in human immunodeficiency virus, hepatitis A virus, and murine cytomegalovirus in human plasma, respectively. Laser-treated plasma showed ≥70% retention for most coagulation factors tested. Furthermore, laser treatment did not alter the structure of a model coagulation factor, fibrinogen. Ultrashort pulsed lasers are a promising new method for chemical-free, broad-spectrum pathogen reduction in human plasma.

Multi-analyte profile analysis of plasma immune proteins: altered expression of peripheral immune factors is associated with neuropsychiatric symptom severity in adults with and without chronic hepatitis C virus infection.

BackgroundThe purpose of this study was to characterize hepatitis C virus (HCV)-associated differences in the expression of 47 inflammatory factors and to evaluate the potential role of peripheral immune activation in HCV-associated neuropsychiatric symptoms-depression, anxiety, fatigue, and pain. An additional objective was to evaluate the role of immune factor dysregulation in the expression of specific neuropsychiatric symptoms to identify biomarkers that may be relevant to the treatment of these neuropsychiatric symptoms in adults with or without HCV. MethodsBlood samples and neuropsychiatric symptom severity scales were collected from HCV-infected adults (HCV+, n = 39) and demographically similar noninfected controls (HCV-, n = 40). Multi-analyte profile analysis was used to evaluate plasma biomarkers. ResultsCompared with HCV- controls, HCV+ adults reported significantly (P < 0.050) greater depression, anxiety, fatigue, and pain, and they were more likely to present with an increased inflammatory profile as indicated by significantly higher plasma levels of 40% (19/47) of the factors assessed (21%, after correcting for multiple comparisons). Within the HCV+ group, but not within the HCV- group, an increased inflammatory profile (indicated by the number of immune factors > the LDC) significantly correlated with depression, anxiety, and pain. Within the total sample, neuropsychiatric symptom severity was significantly predicted by protein signatures consisting of 4-10 plasma immune factors; protein signatures significantly accounted for 19-40% of the variance in depression, anxiety, fatigue, and pain. ConclusionsOverall, the results demonstrate that altered expression of a network of plasma immune factors contributes to neuropsychiatric symptom severity. These findings offer new biomarkers to potentially facilitate pharmacotherapeutic development and to increase our understanding of the molecular pathways associated with neuropsychiatric symptoms in adults with or without HCV.

Prognostic implications of the IDH1 synonymous SNP rs11554137 in pediatric and adult AML: a report from the Children's Oncology Group and SWOG.

IDH1 SNP rs11554137 was recently reported in association with poor prognosis in normal karyotype adult acute myeloid leukemia (AML). We aimed to determine the prevalence, clinical associations, and prognostic significance of SNP rs11554137 in unselected pediatric and adult AML patients. Diagnostic marrow specimens from 527 AML patients treated on the pediatric trial Children's Oncology Group-AAML03P1 (N = 253) or adult SWOG trials (N = 274) were analyzed for the presence of the SNP. SNP rs11554137 was present in 11% of all patients. SNP status had no prognostic impact on survival in pediatric patients. In adult AML, overall survival for SNP-positive patients was 10% versus 18% for SNP-negative patients (P = .44). Among the 142 adults who achieved complete remission, 5-year relapse-free survival was significantly worse for SNP-positive patients (0% vs 25%, P = .0014). However, among adults with normal cytogenetics, FLT3/ITD was present in 90% of SNP-positive patients versus 59% of SNP-negative patients (P = .0053). In multivariate analysis, adjusting for the effects of age, cytogenetics, and FLT3/ITD, the independent prognostic effect of SNP positivity was not statistically significant (hazard ratio = 1.72, P = .18). The clinical profile of SNP-positive patients suggests that SNP rs11554137 may have biologic effects that bear further investigation. The clinical trials in this study are registered at http://www.clinicaltrials.gov as #NCT000707174 and #NCT00899171.

Evaluating hepatitis B universal birth dose vaccination at Minnesota birthing hospitals by utilizing immunization information systems, birth certificates, and chart reviews, 2007-2008.

OBJECTIVES: The Minnesota Department of Health (MDH) examined hospital practices as recommended by the Advisory Committee on Immunization Practice in 2005 that hepatitis B vaccine should be administered universally to newborn infants prior to hospital discharge and within 12 hours of birth if their mothers test positive or are admitted with unknown status for hepatitis B surface antigen. METHODS: The MDH conducted a survey of perinatal hepatitis B birth dosing policies in Minnesota birthing hospitals, which prompted (1) and investigation of hospital birth dose rates from the Immunization Information System (IIS) and (2) a chart review of three selected hospitals with low rates. RESULTS: The (IIS) records of children born in Minnesota during 2007 and the first 5 months of 2008 showed a hepatitis B birth dose rate that was lower than expected (2007: 37%; 2008: 48%). The chart review of three hospitals with low birth does rates showed rates for the first 6 months of 2008 of 94%, 89%, and 91% compared with IIS rates of 1.4%, 40%, and 39% respectively, during the same time period. CONCLUSIONS: These results prompted MDH to increase efforts to provide education to birth registrars on the importance of hepatitis B vaccine data on the birth certificate and to promote regular transmission of hospital vaccination data to the IIS.

Polymorphisms in DNA repair genes and therapeutic outcomes of AML patients from SWOG clinical trials.

Repair of damage to DNA resulting from chemotherapy may influence drug toxicity and survival in response to treatment. We evaluated the role of polymorphisms in DNA repair genes APE1, XRCC1, ERCC1, XPD, and XRCC3 in predicting therapeutic outcomes of older adults with acute myeloid leukemia (AML) from 2 Southwest Oncology Group (SWOG) clinical trials. All patients received standard chemotherapy induction regimens. Using logistic and proportional hazards regression models, relationships between genotypes, haplotypes, and toxicities, response to induction therapy, and overall survival were evaluated. Patients with XPD Gln751C/Asp312G ('D') haplotype were more likely to have complete response (OR = 3.06; 95% CI, 1.44-6.70) and less likely to have resistant disease (OR = 0.32; 95%CI, 0.14-0.72) than patients with other haplotypes. ERCC1 polymorphisms were significantly associated with lung (P = .037) and metabolic (P = .041) toxicities, and patients with the XRCC3 241Met variant had reduced risk of liver toxicity (OR = 0.32; 95%CI, 0.11-0.95). Significant associations with other toxicities were also found for variant XPD genotypes/haplotypes. These data from clinical trials of older patients treated for AML indicate that variants in DNA repair pathways may have an impact on both outcomes of patients and toxicities associated with treatments. With validation of results in larger samples, these findings could lead to optimizing individual chemotherapy options.

Age and acute myeloid leukemia.

We conducted a retrospective analysis of 968 adults with acute myeloid leukemia (AML) on 5 recent Southwest Oncology Group trials to understand how the nature of AML changes with age. Older study patients with AML presented with poorer performance status, lower white blood cell counts, and a lower percentage of marrow blasts. Multidrug resistance was found in 33% of AMLs in patients younger than age 56 compared with 57% in patients older than 75. The percentage of patients with favorable cytogenetics dropped from 17% in those younger than age 56 to 4% in those older than 75. In contrast, the proportion of patients with unfavorable cytogenetics increased from 35% in those younger than age 56 to 51% in patients older than 75. Particularly striking were the increases in abnormalities of chromosomes 5, 7, and 17 among the elderly. The increased incidence of unfavorable cytogenetics contributed to their poorer outcome, and, within each cytogenetic risk group, treatment outcome deteriorated markedly with age. Finally, the combination of a poor performance status and advanced age identified a group of patients with a very high likelihood of dying within 30 days of initiating induction therapy. The distinct biology and clinical responses seen argue for age-specific assessments when evaluating therapies for AML.

Outcome after induction chemotherapy for older patients with acute myeloid leukemia is not improved with mitoxantrone and etoposide compared to cytarabine and daunorubicin: a Southwest Oncology Group study.

Complete remission and long-term survival rates are low for older adults treated for acute myeloid leukemia (AML). Because of favorable phase 2 data using mitoxantrone and etoposide, we conducted a phase 3 study (SWOG-9333) in which patients over 55 years of age with previously untreated AML were randomized to receive mitoxantrone (10 mg/m(2) per day x 5) and etoposide (100 mg/m(2) per day x 5) [ME], or cytarabine (200 mg/m(2) per day x 7) and daunorubicin (45 mg/m(2) per day x 3) [AD] as induction therapy. The randomization was stratified by age, onset of leukemia, and multidrug resistance phenotype. Over a 4-year period, 328 eligible patients from 66 institutions were enrolled. The complete remission rate was 34% (95% confidence interval [CI] 26%-41%) for patients in the ME and 43% (CI 35%-51%) for patients in the AD treatment arm (one-tailed P value.96). The rates of resistant disease were 43% (CI 35%-51%) and 34% (CI 27%-42%), respectively, for the 2 treatment arms (one-tailed P value.95). The estimated overall survival at 2 years was 11% (CI 6%-15%) and 19% (CI 12%-25%) for patients randomized to ME and to AD induction therapy, respectively (one-tailed P value.99). After accounting for the independent prognostic factors associated with survival (karyotype, performance status, age, white blood cell count), exploratory analysis suggested there was a worse survival for patients who received ME compared with AD induction therapy (2-tailed P value.0066). We conclude that the results of our study do not demonstrate any benefit to the use of ME induction chemotherapy instead of AD in older patients with AML.

T-cell blast crisis of chronic myelogenous leukemia manifesting as a large mediastinal tumor.

We report an unusual case of T-cell blast crisis of chronic myelogenous leukemia (CML) with a clinical presentation more typical of de novo T-cell lymphoblastic lymphoma. The patient was a 32-year-old man who presented with acute superior vena cava syndrome 19 months after an initial diagnosis of CML and 5 months after allogeneic bone marrow transplantation. The tumor was composed of primitive lymphoid cells expressing CD2, CD3, CD4, CD5, CD7, CD8, and CD10. Although the clinical features were more typical of acute lymphoblastic leukemia/lymphoma, fluorescence in situ hybridization analysis showed the bcr-abl fusion gene within blastic tumor cells. This finding confirmed that the mass represented a blastic transformation of CML. We use the unusual features of the current case and the previous reports to suggest that the development of T-cell blast crisis of CML is dependent on the presence of both marrow and extramedullary disease and a mechanism to evade apoptosis.

Hematopoietic stem cell transplantation for advanced myelodysplastic syndrome after conditioning with busulfan and fractionated total body irradiation is associated with low relapse rate but considerable nonrelapse mortality.

The objectives of this study were to develop transplantation regimens for patients with advanced myelodysplastic syndrome (MDS) that would be associated with low transplantation-related mortality and improved relapse-free survival. Sixty patients with advanced MDS or acute myeloid leukemia evolving from MDS (sAML), 12 to 62 years old (median, 40 years), were conditioned with busulfan (7 mg/kg) and TBI (6 x 200 cGy) (BU/TBI) and received transplants from related (n = 20) or unrelated donors (n = 40). By French-American-British (FAB) criteria, 21 patients had refractory anemia with excess blasts (RAEB), 16 had RAEB in transformation (RAEB-T), 15 had sAML, and 8 had chronic myelomonocytic leukemia (CMML). By International Prognostic Scoring System (IPSS) criteria, 1 patient had low, 10 had intermediate-1, 13 had intermediate-2, and 31 had high-risk MDS (5 patients had proliferative CMML). All evaluable patients achieved sustained engraftment. The cumulative incidence (CI) of acute GVHD grades II to IV was 83% with unrelated donors and 85% with related donors. The CI of relapse was 25% at 3 years. The incidence of nonrelapse mortality (NRM) at 100 days was 38%. The Kaplan-Meier estimate of survival was 26% at 3 years. Major causes of death were relapse, organ failure, GVHD, and infection. In multivariate analysis, improved relapse-free survival was associated with good cytogenetic risk (P = .002) and shorter disease duration (P = .004). NRM was increased with longer disease duration (P = .0002), positive cytomegalovirus serology (P = .02), and male sex (P = .02). Relapse was associated with poor cytogenetic risk (P = .0004). Thus, BU/TBI conditioning as used in this trial was associated with relapse rates comparable to those observed with a previously used more intensive regimen combining BU/TBI with cyclophosphamide. However, despite the omission of cyclophosphamide, transplantation-related morbidity and mortality were considerable, particularly with transplants from unrelated donors. Future trials should explore the efficacy and tolerability of reduced-intensity conditioning regimens.

Use of local anesthesia by dental hygienists who completed a Minnesota CE course.

PURPOSE: This study assessed the use of local anesthesia administered by dental hygienists who completed continuing education (CE) courses in Minnesota in 1996. The aims of the study were to: evaluate the use of local anesthesia by these participants; the level of effective injections; the value the dental hygienists placed on this skill; and to provide data in areas less studied, such as injection techniques utilized, and the incidence of complications. METHODS: A pretested, 34-item questionnaire; cover letter; and return self-addressed, stamped envelope were sent in 1997 to dental hygienists (N = 355) who completed a CE course in local anesthesia offered by Minnesota dental hygiene programs between January and September 1996. A reminder postcard was sent to nonrespondents two weeks after the initial return date. The survey assessed the administration experience of dental hygienists including implementation of this skill, frequency of administration, types of clients receiving local anesthesia, treatments requiring local anesthesia, choice of injection techniques, level of successful anesthesia, complications observed, and value to practice. Data were analyzed using JMP version 3.1, Pearson's chi-square and one-way ANOVA. RESULTS: The response rate was 77.7% (N = 273). Ninety-five percent of the dental hygienists who responded reported delegation of local anesthesia to them by employers. A majority of respondents (64%) implemented this new skill within one week following completion of course work. Dental hygienists in periodontal specialty practice provided local anesthesia to adult clients more frequently than those in general practice. Respondents used nerve block techniques more frequently than supraperiosteal or infiltration techniques. In general, respondents reported high success rates in achieving adequate anesthesia with a very low incidence of complications. Dental hygienists most frequently administered local anesthesia for root planing or debridement (92%). A majority of respondents also administered local anesthesia to adults and children who were treated by the dentist. The frequency of administrations was strongly related (P = 0.00) to value placed on this skill and positive outcomes to their practice. CONCLUSIONS: Dental hygienists who completed required CE course work in local anesthesia, provided safe, effective injections and reported this service to be of value to their practice. These data support the incorporation of local anesthesia into dental hygiene curricula to prepare future practitioners to provide this service to clients. Also, dental hygienists working in states not currently allowing this service, should consider these results when proposing change to their state practice acts.