Myeloid neoplasms in individuals with breast and ovarian cancer and the association with deleterious germline variants.

Historically, the increased incidence of myeloid neoplasms observed in individuals with breast and ovarian cancer has been attributed exclusively to prior exposure to cancer-directed therapies. However, as the association between deleterious germline variants and the development of hematopoietic malignancies (HMs) becomes better established, we propose the increased incidence of myeloid neoplasms in those with breast and ovarian cancer may be at least partially related to underlying germline cancer predisposition alleles. Deleterious germline variants in BRCA1/2, ATM, CHEK2, PALB2, and other related genes prevent normal homologous recombination DNA repair of double-strand breaks, leading to reliance on less effective repair mechanisms. This results in a high lifetime risk of breast and ovarian cancer, and likely also increases the risk of subsequent therapy-related myeloid neoplasms (t-MNs). These deleterious germline variants likely increase the risk for de novo HMs as well, as evidenced by the increased incidence of HMs observed in those with deleterious germline BRCA1/2 variants even in the absence of prior cancer-directed therapy. Thus, the association between poly(ADP-ribose) polymerase (PARP) inhibitors and other solid tumor directed therapies and the development of t-MNs may be confounded by the presence of deleterious germline variants which inherently increase the risk of both de novo and t-MNs, and additional data regarding the direct toxic effects of these drugs on bone marrow function are needed.

Dosing of 7 + 3 induction chemotherapy in a patient with acute myeloid leukemia (AML) and morbid obesity.

INTRODUCTION: Traditional chemotherapy dosing is based on body surface area (BSA) using standard formulas, which can pose challenges in dosing patients at body weight extremes. Studies suggest that chemotherapy dosing according to actual body weight does not increase toxicity in obese patients and current guidelines recommend full weight-based dosing of chemotherapy regardless of body mass index (BMI). However, the dosing of anthracyclines in obese patients can be challenging given limitations in maximum cumulative dosage, particularly in those at very extreme BMI. In this case, we highlight the difficulties of dosing anthracycline-based induction chemotherapy in a patient with newly diagnosed acute myeloid leukemia (AML) and BMI >90 kg/m2. CASE REPORT: A 40-year-old female with morbid obesity is diagnosed with AML (nucleophosmin 1 (NPMI) and isocitrate dehydrogenase-2 mutated, FMS-like tyrosine kinase 3-Internal tandem duplication negative). MANAGEMENT AND OUTCOME: The patient was initiated on induction therapy with 7 + 3 with dose capping of BSA at 2.75 m2 (cytarabine 200 mg/m2 continuous infusion over 24 h for 7 days, plus daunorubicin 60 mg/m2 slow intravenous push for 3 days), followed by two cycles of high-dose cytarabine consolidation therapy using actual BSA. The patient achieved morphologic complete remission; however, measurable residual disease testing for NPM1 remained positive after induction therapy. DISCUSSION: This case suggests that dose capping of anthracyclines in the treatment of newly diagnosed AML may be an effective and safe treatment alternative in those with extreme BMI elevations beyond what has been studied in the literature. Given the increasing incidence of morbid obesity, further studies are needed to confirm appropriate dosing of anthracycline-based regimens at upper BMI extremes (>60 kg/m2).

Systematic review and meta-analysis: Prognostic impact of time from diagnosis to treatment in patients with acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) has been considered an oncologic emergency that requires initiation of chemotherapy immediately after diagnosis. With the introduction of novel targeted therapies, there is a potential benefit associated with delaying definitive treatment for identification of actionable therapeutic targets. Unfortunately, cytogenetic/molecular testing can take >7 days to return, and there is not a consensus regarding the prognostic impact of time from diagnosis to treatment (TDT) in AML. METHODS: A literature review and meta-analysis of studies done to date that evaluate TDT was conducted. Studies that reported baseline characteristics, TDT, and outcomes for patients with AML were selected. Outcomes included overall survival (OS), complete remission (CR), and mortality. Studies that measured CR rates within each TDT range and data to calculate odds ratios were included in the meta-analysis. The remaining outcomes were synthesized descriptively for literature review. RESULTS: Thirteen studies were identified, which comprised a total of 14,946 patients. Median TDT values were between 1 and 8 days. Several studies found a significant association between prolonged TDT and older age and lower proliferation burden. Four of 11 studies did not detect a significant relationship between TDT and OS. No studies found a significant association between TDT and early death. Six of eight studies did not find a significant association between TDT and CR rate. The meta-analysis found a significant association between prolonged TDT and decreased achievement of CR (p < .05). CONCLUSIONS: Results were highly variable but suggest it may be feasible to pursue cytogenetic/molecular testing in patients who are clinically stable, particularly in those aged 60 years and older.

Interpregnancy Body Mass Index Change and Risk of Intrapartum Cesarean Delivery.

OBJECTIVE: This study aimed to examine the association between interpregnancy body mass index (BMI, kg/m2) change and intrapartum cesarean delivery in multiparous women without a history of cesarean delivery. STUDY DESIGN: We conducted a retrospective cohort study of all women who had more than one singleton pregnancy at 23 weeks' gestation or greater at MedStar Washington Hospital Center from January 2009 to June 2018. We excluded women who had a history of cesarean delivery, prelabor cesarean delivery, and contraindications for vaginal delivery. Interpregnancy BMI change was calculated by the change of early pregnancy BMI measured in the office. Women were categorized according to the interpregnancy BMI change (BMI loss more than 2 kg/m2, BMI change ± 2 kg/m2, and BMI gain more than 2 kg/m2). The primary outcome was an intrapartum cesarean delivery. Multivariable logistic regression was performed to calculate adjusted odds ratio (aOR) with 95% confidence interval (CI) after adjusting for predefined covariates. RESULTS: Of 2,168 women who were analyzed, 258 (12%), 1,192 (55%), and 718 (33%) had interpregnancy BMI loss more than 2 kg/m2, BMI change ± 2 kg/m2, and BMI gain more than 2 kg/m2, respectively. Women with BMI gain more than 2 kg/m2 compared with those with BMI change ± 2 kg/m2 had increased odds of intrapartum cesarean delivery (7.4 vs. 4.5%; aOR: 1.78; 95% CI: 1.10-2.86) and cesarean delivery for arrest disorders (3.1 vs. 1.1%; aOR: 3.06; 95% CI: 1.30-7.15). Women with BMI loss more than 2 kg/m2 compared with those with BMI change ± 2 kg/m2 had similar rates of cesarean delivery. CONCLUSION: Compared with interpregnancy BMI change ± 2 kg/m2, interpregnancy BMI gain 2 kg/m2 was associated with increased odds of intrapartum cesarean delivery. KEY POINTS: · BMI gain between pregnancies was associated with intrapartum cesarean delivery.. · BMI loss between pregnancies was not associated with intrapartum cesarean delivery.. · Our study suggests that at least maintaining weight between pregnancies is beneficial..

Interpregnancy body mass index change and risk of hypertensive disorders in pregnancy.

BACKGROUND: Hypertensive disorders are a common cause of maternal mortality. Whether interpregnancy BMI (body mass index kg/m2) gain is associated with hypertensive disorders in a subsequent pregnancy is not unclear. OBJECTIVES: To examine the association between interpregnancy BMI and hypertensive disorders in women without a history of hypertensive disorders in pregnancy. STUDY DESIGN: This was a retrospective cohort study of all women who had more than one singleton pregnancy at 23 weeks' gestation or greater at a single academic institution. Only the second pregnancy in the dataset was analyzed. We excluded women who had any hypertensive disorder in the index pregnancy. Interpregnancy BMI change was calculated by the change of early pregnancy BMI (within 14 weeks' gestation) measured in the office between the index pregnancy compared to that of the subsequent pregnancy. Women were categorized according to interpregnancy BMI change (BMI loss greater than 2 kg/m2, BMI change ±2 kg/m2, and BMI gain greater than 2 kg/m2). The primary outcome was any hypertensive disorder (chronic hypertension and pregnancy-associated hypertension). Multivariable logistic regression was performed to calculate adjusted odds ratios (aOR) with 95% confidence interval (95%CI) after adjusting for predefined covariates. RESULTS: Of 3068 women who were analyzed, 342 (11%), 1698 (55%), and 1028 (34%) had interpregnancy BMI loss greater than 2 kg/m2, interpregnancy BMI change ±2 kg/m2, and interpregnancy BMI gain greater than 2 kg/m2, respectively. Interpregnancy BMI gain greater than 2 kg/m2 compared to interpregnancy BMI loss more than 2 kg/m2 was associated with increased odds of hypertensive disorders (8.3% vs. 4.0%; adjusted odds ratio 2.20 [95% confidence interval 1.55-3.13]) and pregnancy-associated hypertension (adjusted odds ratio 2.25 [95% confidence interval 1.54-3.27]). Interpregnancy BMI loss greater than 2 kg/m2 compared to interpregnancy BMI change ±2 kg/m2 was not associated with increased odds of any hypertensive disorders (5.3% vs. 4.0%; adjusted odds ratio 0.58 [95% confidence interval 0.32-1.05]). CONCLUSIONS: Compared to interpregnancy BMI change ±2 kg/m2, interpregnancy BMI gain greater than 2 kg/m2 was associated with increased odds of any hypertensive disorder. Weight control after pregnancy could be a potentially modifiable factor that may reduce the risk of hypertensive disorders.

Reliability of Morphological and PCR Methods for the Official Diagnosis of Aethina tumida (Coleoptera: Nitidulidae): A European Inter-Laboratory Comparison.

The Small Hive Beetle (Aethina tumida Murray, 1867) is an invasive scavenger of honeybees. Originally endemic in sub-Saharan Africa, it is regulated internationally in order to preserve the areas still free from this species. To ensure the reliability of official diagnoses in case of introduction, an inter-laboratory comparison was organised on the identification of A. tumida by morphology and real-time PCR. Twenty-two National Reference Laboratories in Europe participated in the study and analysed 12 samples with adult coleopterans and insect larvae. The performance of the laboratories was evaluated in terms of sensitivity and specificity. Sensitivity was satisfactory for all the participants and both types of methods, thus fully meeting the diagnostic challenge of confirming all truly positive cases as positive. Two participants encountered specificity problems. For one, the anomaly was minor whereas, for the other, the issues concerned a larger number of results, especially real-time PCR, which probably were related to inexperience with this technique. The comparison demonstrated the reliability of official diagnosis, including the entire analytical process of A. tumida identification: from the first step of the analysis to the expression of opinions. The performed diagnostic tools, in parallel with field surveillance, are essential to managing A. tumida introduction.

Characteristics and Outcomes of COVID-19 Infection from an Urban Ambulatory COVID-19 Clinic-Guidance for Outpatient Clinicians in Triaging Patients.

BACKGROUND: Coronavirus infection (COVID) presents with flu-like symptoms and can cause serious complications. Here, we discuss the presentation and outcomes of COVID in an ambulatory setting along with distribution of positive cases amongst healthcare workers (HCWs). METHOD: Patients who visited the COVID clinic between 03/11/2020 and 06/14/2020 were tested based on the CDC guidelines at the time using PCR-detection methods. Medical records were reviewed and captured on a RedCap database. Statistical analysis was performed using both univariate and bivariate analysis using Fischer's exact test with 2-sided P values. RESULTS: Of the 2471 evaluated patients, 846 (34.2%) tested positive for COVID. Mean age of positivity was 43.4 years (SD ± 15.4), 60.1% were female and 49% were Black. 58.7% of people tested had a known exposure, and amongst those with exposure, 57.3% tested positive. Ninety-four patients were hospitalized (11.1%), of which 22 patients (23.4%) required ICU admission and 10 patients died. The overall death rate of patients presenting to clinic was 0.4%, or 1.2% amongst positive patients. Median length of hospital stay was 6 days (range 1-51). Symptoms significantly associated with COVID included: anosmia, fever, change in taste, anorexia, myalgias, cough, chills, and fatigue. Increased risk of COVID occurred with diabetes, whereas individuals with lung disease or malignancy were not associated with increased risk of COVID. Amongst COVID positive HCWs, the majority were registered nurses (23.4%), most working in general medicine (39.8%) followed by critical care units (14.3%). DISCUSSION/CONCLUSION: Blacks and females had the highest infection rates. There was a broad range in presentation from those who are very ill and require hospitalization and those who remain ambulatory. The above data could assist health care professionals perform a targeted review of systems and co-morbidities, allowing for appropriate patient triage.

An international inter-laboratory study on Nosema spp. spore detection and quantification through microscopic examination of crushed honey bee abdomens.

Nosemosis is a microsporidian disease causing mortality and weakening of honey bee colonies, especially in the event of co-exposure to other sources of stress. As a result, the disease is regulated in some countries. Reliable and harmonised diagnosis is crucial to ensure the quality of surveillance and research results. For this reason, the first European Interlaboratory Comparison (ILC) was organised in 2017 in order to assess both the methods and the results obtained by National Reference Laboratories (NRLs) in counting Nosema spp. spores by microscopy. Implementing their own routine conditions of analysis, the 23 participants were asked to perform an assay on a panel of ten positive and negative samples of crushed honey bee abdomens. They were asked to report results from a qualitative and quantitative standpoint. The assessment covered specificity, sensitivity, trueness and precision. Quantitative results were analysed in compliance with international standards NF ISO 13528 (2015) and NF ISO 5725-2 (1994). Three results showed a lack of precision and five a lack of trueness. However, overall results indicated a global specificity of 98% and a global sensitivity of 100%, thus demonstrating the advanced performance of the microscopic methods applied to Nosema spores by the NRLs. Therefore, the study concluded that using microscopy to detect and quantify spores of Nosema spp. was reliable and valid.

Association between long interpregnancy intervals and cesarean delivery due to arrest disorders.

BACKGROUND: It is hypothesized that pregnancy causes time-limited physiologic adaptations of the reproductive system, such as increased blood flow to the uterus. With long interpregnancy intervals, those adaptations may regress, and maternal physiologic characteristics may revert to those of primigravid women. Therefore, it is plausible that long interpregnancy interval is associated with cesarean delivery, especially due to arrest disorders (failed induction of labor, arrest of dilation, or arrest of descent). OBJECTIVE: To examine the association between interpregnancy interval and cesarean delivery due to arrest disorders in multiparous women without a history of cesarean delivery. MATERIALS AND METHODS: This was a retrospective cohort study of all women who had more than 1 singleton pregnancy at 23 weeks' gestation or greater at MedStar Washington Hospital Center from January 2009 to June 2018. We defined the interpregnancy interval as the duration from the birth of the preceding offspring to the date of conception of the index offspring. We a priori decided to categorize women based on the interpregnancy interval (less than 18 months, 18-59 months, and 60 months or greater). Our primary outcome was cesarean delivery due to arrest disorders. We also examined overall cesarean delivery and cesarean delivery due to nonreassuring fetal heart tracing. Multivariable logistic regression was performed to calculate adjusted odds ratios and 95% confidence intervals, controlling for predefined covariates. RESULTS: Of 2741 women, 1143 (41.7%), 1369 (49.9%), and 229 (8.4%) had an interpregnancy interval of less than 18 months, 18-59 months, and 60 months or more, respectively. After adjusting for confounders, an interpregnancy interval of 60 months or more compared to an interpregnancy interval of 18-59 months was associated with increased odds of cesarean delivery due to arrest disorders (4.8% vs 1.3%; adjusted odds ratio, 3.06; 95% confidence interval, 1.34-6.97) and cesarean delivery due to arrest of dilation (3.1% vs 0.7%; adjusted odds ratio, 3.24; 95% confidence interval, 1.10-9.59). An interpregnancy interval of less than 18 months compared to an interpregnancy interval of 18-59 months was associated with decreased odds of cesarean delivery due to nonreassuring fetal heart tracing (2.4% vs 4.1%; adjusted odds ratio, 0.55; 95% confidence interval, 0.32-0.92). CONCLUSION: An interpregnancy interval of 60 months or greater compared to an interpregnancy interval of 18-59 months was associated with increased odds of cesarean delivery due to arrest disorders. Beneficial effects on postpartum adaptations in the reproductive system may regress as interpregnancy interval increases.

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma.

Efforts to reduce immunosuppression in the solid tumor microenvironment by blocking the recruitment or polarization of tumor associated macrophages (TAM), or myeloid derived suppressor cells (MDSCs), have gained momentum in recent years. Expanding our knowledge of the immune cell types, cytokines, or recruitment factors that are associated with high-grade disease, both within the tumor and in circulation, is critical to identifying novel targets for immunotherapy. Furthermore, a better understanding of how therapeutic regimens, such as Dexamethasone (Dex), chemotherapy, and radiation, impact these factors will facilitate the design of therapies that can be targeted to the appropriate populations and retain efficacy when administered in combination with standard of care regimens. Here we perform quantitative analysis of tissue microarrays made of samples taken from grades I-III astrocytoma and glioblastoma (GBM, grade IV astrocytoma) to evaluate infiltration of myeloid markers CD163, CD68, CD33, and S100A9. Serum, flow cytometric, and Nanostring analysis allowed us to further elucidate the impact of Dex treatment on systemic biomarkers, circulating cells, and functional markers within tumor tissue. We found that common myeloid markers were elevated in Dex-treated grade I astrocytoma and GBM compared to non-neoplastic brain tissue and grade II-III astrocytomas. Cell frequencies in these samples differed significantly from those in Dex-naïve patients in a pattern that depended on tumor grade. In contrast, observed changes in serum chemokines or circulating monocytes were independent of disease state and were due to Dex treatment alone. Furthermore, these changes seen in blood were often not reflected within the tumor tissue. Conclusions: Our findings highlight the importance of considering perioperative treatment as well as disease grade when assessing novel therapeutic targets or biomarkers of disease.

Development and validation of a real-time two-step RT-qPCR TaqMan(®) assay for quantitation of Sacbrood virus (SBV) and its application to a field survey of symptomatic honey bee colonies.

Sacbrood virus (SBV) is the causal agent of a disease of honey bee larvae, resulting in failure to pupate and causing death. The typical clinical symptom of SBV is an accumulation of SBV-rich fluid in swollen sub-cuticular pouches, forming the characteristic fluid-filled sac that gives its name to the disease. Outbreaks of the disease have been reported in different countries, affecting the development of the brood and causing losses in honey bee colonies. Today, few data are available on the SBV viral load in the case of overt disease in larvae, or for the behavioural changes of SBV-infected adult bees. A two-step real-time RT-PCR assay, based on TaqMan(®) technology using a fluorescent probe (FAM-TAMRA) was therefore developed to quantify Sacbrood virus in larvae, pupae and adult bees from symptomatic apiaries. This assay was first validated according to the recent XP-U47-600 standard issued by the French Standards Institute, where the reliability and the repeatability of the results and the performance of the assay were confirmed. The performance of the qPCR assay was validated over the 6 log range of the standard curve (i.e. from 10(2) to 10(8) copies per well) with a measurement uncertainty evaluated at 0.11log10. The detection and quantitation limits were established respectively at 50 copies and 100 copies of SBV genome, for a template volume of 5µl of cDNA. The RT-qPCR assay was applied during a French SBV outbreak in 2012 where larvae with typical SBV signs were collected, along with individuals without clinical signs. The SBV quantitation revealed that, in symptomatic larvae, the virus load was significantly higher than in samples without clinical signs. Combining quantitation with clinical data, a threshold of SBV viral load related to an overt disease was proposed (10(10) SBV genome copies per individual).

Demographics of the European apicultural industry.

Over the last few years, many European and North American countries have reported a high rate of disorders (mortality, dwindling and disappearance) affecting honeybee colonies (Apis mellifera). Although beekeeping has become an increasingly professional activity in recent years, the beekeeping industry remains poorly documented in Europe. The European Union Reference Laboratory for Honeybee Health sent a detailed questionnaire to each Member State, in addition to Kosovo and Norway, to determine the demographics and state of their beekeeping industries. Based on data supplied by the National Reference Laboratory for honeybee diseases in each European country, a European database was created to describe the beekeeping industry including the number and types of beekeepers, operation size, industry production, and health (notifiable diseases, mortalities). The total number of beekeepers in Europe was estimated at 620,000. European honey production was evaluated at around 220,000 tons in 2010. The price of honey varied from 1.5 to 40 €/kg depending on the country and on the distribution network. The estimated colony winter mortality varied from 7 to 28% depending on the country and the origin of the data (institutional survey or beekeeping associations). This survey documents the high heterogeneity of the apicultural industry within the European Union. The high proportion of non-professional beekeepers and the small mean number of colonies per beekeeper were the only common characteristics at European level. The tremendous variation in European apicultural industries has implication for any comprehensive epidemiological or economic analysis of the industry. This variability needs to be taken into account for such analysis as well as for future policy development. The industry would be served if beekeeping registration was uniformly implemented across member states. Better information on the package bee and queen production would help in understanding the ability of the industry to replace lost honey bee stocks.