Approach to Acute Myeloid Leukemia with Increased Eosinophils and Basophils.

There is remarkable morphologic and genetic heterogeneity in acute myeloid leukemia (AML). In a small percentage of cases of AML, increased eosinophils and/or basophils are present in the bone marrow and sometimes in the peripheral blood. This is often a puzzling diagnostic situation but also an important finding that requires special investigation. Unique chromosomal rearrangements have been correlated with an increased number of eosinophils and basophils in AML. The identification of the underlying genetic lesion that promotes eosinophilia and basophilia can dramatically change both the prognosis and the treatment of the patient. Thus, clinicians must be vigilant in searching for the cause of eosinophilia and basophilia in patients with AML, since the different causes may lead to different treatments and survival outcomes. In this article, we examine the significance of increased eosinophils and/or basophils in the context of AML, provide guidance that simplifies the differential diagnosis, and give prognostic and therapeutic information about specific subtypes of AML associated with eosinophilia and/or basophilia. Evidence supporting personalized (molecularly targeted) therapy for these patients is also presented.

How to improve RCHOP as frontline therapy for diffuse large B-cell lymphoma: a systematic review and meta-analysis of 21 randomized controlled trials.

RCHOP is the standard of care for patients with diffuse large b-cell lymphoma (DLBCL) but failures occur in approximately 40% of them. We performed a meta-analysis of 21 randomized controlled trials (RCTs) comparing experimental regimens with RCHOP. We searched the database of PubMed with proper criteria, and data of efficacy (Progression Free Survival-PFS) in the ITT population were extracted and analyzed. Cross comparisons of RCTs were performed by using the CINEMA software. Odds ratio (OR) and 95% confidence intervals (95%, CI) are reported. The literature search yielded 21 RCTs including 5785 patients in the RCHOP arm and 5648 patients in the experimental arm. Odds ratio (OR) for PFS in the total cohort was OR (95%, CI): 0.87 (0.76-0.99), p=0.02. Among different strategies to improve RCHOP, addition of a novel agent on RCHOP improved PFS. In total 1740 patients in the RCHOP arm were compared with 1755 in the RCHOP plus a novel agent arm, and the OR (95% CI) for PFS was 0.84 (0.71-0.97), p=0.02. Indirect comparisons of nine studies adding a novel agent on RCHOP does not give prominence to any agent. Subgroup analysis according to cell of origin was performed for non-GC DLBCL patients. In this subgroup, 1546 patients treated with RCHOP were compared with 1538 patients treated with experimental regimens. The OR (95% CI) for PFS was 0.86 (0.73-1.02), p=0.34. Overall survival data extracted from 18 studies showed no superiority of experimental regimens over RCHOP. Efficacy of RCHOP backbone is marginally improved when adding a novel anti-lymphoma agent.

A variant of KSHV-associated inflammatory cytokine syndrome in elderly men of Mediterranean descent.

The spectrum of HHV-8-associated disorders includes Kaposi's sarcoma, primary effusion lymphoma, multicentric Castleman's disease, and the recently described KSHV inflammatory cytokine syndrome (KICS), a life-threatening disorder complicating HIV infection. There have been no reports in the literature concerning non-immunosuppressed individuals affected with KICS. We report here a KICS-like illness occurring in two elderly Greek men without HIV infection or other recognizable cause of immunosuppression.

A personalized stepwise dynamic predictive algorithm of the time to first treatment in chronic lymphocytic leukemia.

Personalized prediction is ideal in chronic lymphocytic leukemia (CLL). Although refined models have been developed, stratifying patients in risk groups, it is required to accommodate time-dependent information of patients, to address the clinical heterogeneity observed within these groups. In this direction, this study proposes a personalized stepwise dynamic predictive algorithm (PSDPA) for the time-to-first-treatment of the individual patient. The PSDPA introduces a personalized Score, reflecting the evolution in the patient's follow-up, employed to develop a reference pool of patients. Score evolution's similarity is used to predict, at a selected time point, the time-to-first-treatment for a new patient. Additional patient's biological information may be utilized. The algorithm was applied to 20 CLL patients, indicating that stricter assessment criteria for the Score evolution's similarity, and biological similarity exploitation, may improve prediction. The PSDPA capitalizes on both the follow-up and the biological background of the individual patient, dynamically promoting personalized prediction in CLL.

Progress toward Better Treatment of Therapy-Related AML.

Therapy-related acute myeloid leukemia (t-AML) comprises 10-20% of all newly diagnosed cases of AML and is related to previous use of chemotherapy or ionizing radiotherapy for an unrelated malignant non-myeloid disorder or autoimmune disease. Classic examples include alkylating agents and topoisomerase II inhibitors, whereas newer targeted therapies such as poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors have emerged as causative agents. Typically, t-AML is characterized by adverse karyotypic abnormalities and molecular lesions that confer a poor prognosis. Nevertheless, there are also cases of t-AML without poor-risk features. The management of these patients remains controversial. We describe the causes and pathophysiology of t-AML, putting emphasis on its mutational heterogeneity, and present recent advances in its treatment including CPX-351, hypomethylating agent plus venetoclax combination, and novel, molecularly targeted agents that promise to improve the cure rates. Evidence supporting personalized medicine for patients with t-AML is presented, as well as the authors' clinical recommendations.

DPP4 Inhibitor-Induced Bullous Pemphigoid in Patients with Diabetes and Chronic Kidney Disease: Clinical Case Series.

INTRODUCTION: Dipeptidyl peptidase-4 (DPP4) inhibitors (gliptins) are commonly prescribed for glucose control in patients with advanced chronic kidney disease (CKD) in whom other oral glucose-lowering agents are contraindicated. In the past few years, new reports of drug-induced bullous pemphigoid associated with DPP4 inhibitors have emerged. However, there is not enough information about the renal function of the patients with DPP4 inhibitor-induced bullous pemphigoid, and it remains unknown whether the risk of this complication is increased among patients with CKD. CASE REPORTS: Five patients with stage 3b-5 CKD received a diagnosis of DPP4 inhibitor-associated bullous pemphigoid in our institution within a period of 17 months (between December 2018 and May 2020). All patients in the current series were male. Skin biopsies were performed in all patients. Three cases were secondary to vildagliptin, and 2 cases were attributed to linagliptin. In each of these patients, treatment consisted of permanent discontinuation of the DPP4 inhibitor and administration of corticosteroids. CONCLUSION: We report here the first single-center experience of DPP4 inhibitor-induced bullous pemphigoid in patients with CKD. Our case series highlights the importance of considering bullous pemphigoid in patients with CKD taking DPP4 inhibitors presenting with bullous or pruritic cutaneous lesions. By calling attention to this important complication, we hope to minimize the delay in diagnosing DPP4 inhibitor-induced bullous pemphigoid among patients with CKD.

The Cytogenetic Profile of Primary and Secondary Plasma Cell Leukemia: Etiopathogenetic Perspectives, Prognostic Impact and Clinical Relevance to Newly Diagnosed Multiple Myeloma with Differential Circulating Clonal Plasma Cells.

Plasma cell leukemia (PCL) is a rare and aggressive plasma cell dyscrasia that may appear as de-novo leukemia (pPCL) or on the basis of a pre-existing multiple myeloma (MM), called secondary plasma cell leukemia (sPCL). In this prospective study, we have applied a broad panel of FISH probes in 965 newly diagnosed MM (NDMM) and 44 PCL cases of both types to reveal the particular cytogenetic differences among the three plasma cell dyscrasias. In order to evaluate the frequency and patterns of clonal evolution, the same FISH panel was applied both at diagnosis and at the time of first relapse for 81 relapsed MM patients and both at MM diagnosis and during sPCL transformation for the 19 sPCL cases described here. pPCL was characterized by frequent MYC translocations and t(11;14) with a 11q13 breakpoint centered on the MYEOV gene, not commonly seen in MM. sPCL had a higher number of FISH abnormalities and was strongly associated with the presence of del(17p13), either acquired at the initial MM stage or as a newly acquired lesion upon leukemogenesis in the context of the apparent clonal evolution observed in sPCL. In clinical terms, sPCL showed a shorter overall survival than pPCL with either standard or high-risk (t(4;14) and/or t(14;16) and/or del(17p13) and/or ≥3 concomitant aberrations) abnormalities (median 5 months vs. 21 and 11 months respectively, p < 0.001), suggesting a prognostic stratification based on cytogenetic background. These observations proved relevant in the NDMM setting, where higher levels of circulating plasma cells (CPCs) were strongly associated with high-risk cytogenetics (median frequency of CPCs: 0.11% of peripheral blood nucleated cells for high-risk vs. 0.007% for standard-risk NDMM, p < 0.0001). Most importantly, the combined evaluation of CPCs (higher or lower than a cut-off of 0.03%), together with patients' cytogenetic status, could be used for an improved prognostic stratification of NDMM patients.

Fish evaluation of additional cytogenetic aberrations and hyperdiploidy in childhood Burkitt lymphoma.

Beyond MYC rearrangement, Burkitt lymphoma (BL) often presents with additional aberrations. Biopsy touch imprints from 72 children with BL were tested with interphase fluorescence in-situ hybridization (i-FISH) for MYC, BCL2, BCL6, IGH, IGK and IGL rearrangements and copy-number aberrations involving 1q21/1p32, 7cen/7q31, 9cen/9p21, 13q14/13q34 and 17cen/17p13. Diploid status deviations were investigated with chromosome enumeration probes. MYC rearrangement was demonstrated in all cases. Additional aberrations included +1q (21/72:29.2%), +7q (14/72:19.4%), 13q- (14/72:19.4%), 9p-(6/72:8.3%) and hyperdiploidy (6/72:8.3%). Advanced clinical stage IV, +7q and 9p- were associated with shorter overall survival, with stage IV and +7q retaining prognostic significance on multivariate analysis. No relapse or death was reported among the hyperdiploid cases. This i-FISH investigation provides information on the genetic profile of BL and may prove valuable for patients with no karyotype analysis. Demonstration of hyperdiploidy could evolve research on clonal evolution pathways and probably identify a subgroup of children with favorable prognosis.

Reproductive Failure and Thrombophilia: Not Enough Evidence for a Tight Bond.

OBJECTIVES: The role of hereditary thrombophilia in reproductive failure (RF) is strongly debatable. In this retrospective single-center study, we analyzed pregnancy outcome in 175 women screened for thrombophilia after at least one event of RF. RESULTS: The prevalence of thrombophilia in our cohort was 33.4%. Pregnancy survival curves were not different according to severity (log-rank, p = 0.302) or type of thrombophilia (log-rank, p = 0.532). In total, 81.7% of 175 subsequent pregnancies were proceeded with LMWH. Concomitant use of ASA was prescribed in 75 pregnancies according to physician choice. The primary endpoint was live birth rate (LBR) that succeeded in 152/175 next pregnancies (86.8%) and late obstetric complications (LOBC) which occurred in 17/175 next pregnancies (9.8%). In logistic regression analysis, neither the severity nor the type of thrombophilia was important for any pregnancy outcome (LBR or LOBC). Considering therapeutic interventions, the use of LMWH ± ASA was not related to LBR or LOBC. The only factor inversely related to LBR was age above the cutoff value of 35.5 years (p = 0.049). CONCLUSIONS: Incidence of thrombophilia is increased among women with RF, but the severity or type of thrombophilia is not related to pregnancy outcome.

Approaching First-Line Treatment in Patients With Advanced CMML: Hypomethylating Agents or Cytotoxic Treatment?

Chronic myelomonocytic leukemia (CMML) is a rare clonal haematological malignancy bearing characteristics of both myelodysplastic syndromes and myeloproliferative neoplasms. It primarily affects older people (median age at diagnosis ~72 years). There are many challenges encountered in its treatment. One striking issue is the lack of strong clinical evidence from large randomized clinical trials for treating this disease. Another issue is that patients with CMML have highly variable outcomes with current treatments. Additional challenges include a wider application of current knowledge, an improved understanding of pathogenesis, development of new therapies, and management of refractory cases/disease progression. It is clear that there is still progress to be made. Here, we review the available first-line treatment options for advanced CMML. Emphasis has been placed on choosing between hypomethylating agents and cytotoxic treatments, on the basis on disease-specific and patient-specific characteristics. A proper selection between these two treatments could lead to a better quality of care for patients with CMML.

Τemporal Variation in Pesticide Residues in Citrus Fruits from Chios, Greece, before and after the Development of an Integrated Pest Management Strategy (IPMS): A Five-Year Study (LIFE13 ENV GR/000414).

The temporal variation in pesticide residues in Kampos, of Chios Island, in Greece, was determined between June 2014 and October 2019. Monitoring of residues took place before and after the development of an Integrated Pest Management Strategy (IPMS) for the sustainable control of the Mediterranean fruit fly (medfly) based on mass trapping with the non-toxic and environmentally friendly attractant Biodelear. A total of 1252 samples of citrus fruits, collected from 12 experimental citrus orchards, were analyzed for the presence of 353 active substances and metabolites of pesticides. A modified QuEChERS method and sensitive chromatographic techniques were used. During preparatory monitoring for the project, the most frequently detected pesticides were the insecticides chlorpyrifos, deltamethrin and spirotetramat; the fungicides propamocarb, dimethomorph and mepanipyrim; and the synergist piperonyl butoxide. The implementation of the IPMS to address medfly resulted in a dramatic reduction in the pesticides detected in citrus fruits during confirmatory monitoring, with no detectable residues-which may cause serious problems to human health-in any of the samples analyzed at the end of the project, thus enhancing consumer safety.

Targeted Multiresidue Method for the Analysis of Different Classes of Pesticides in Agro-Food Industrial Sludge by Liquid Chromatography Tandem Mass Spectrometry.

Sludge generated after washing of fruits and vegetables during agro-food processes is a complex matrix and selective methods for the identification and quantification of pesticides' residues are necessary in order to achieve a sustainable and effective management of the total sewage. The present work describes the development and validation of a reliable, simple and fast analytical method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the determination of 47 pesticides of different chemical classes, including organosphosphates, pyrethroids, neonicotinoids, triazoles and others, in sludge samples after QuEChERS sample preparation. The necessity of the individual steps of QuEChERS was investigated and the LC-ESI-MS/MS conditions were optimized to achieve maximum sensitivity of the target analytes. The method limits of detection (LODs) ranged between 0.0005 mg/kg (imidacloprid) and 0.05 mg/kg (beta cyfluthrin). The recoveries ranged between 71-120% and the repeatability of the method was ≤25% expressed as relative standard deviation. The method was applied to sludge samples generated after washing of fruits in an agro-fruit-packaging unit in Greece. The results showed the presence of 37 pesticides' active substances with concentrations ranging from low ppbs, such as fludioxinil (5 µg/kg) up to low ppms such as beta cyfluthrin (3.5 mg/kg) and with their sum concentration reaching up to 19 mg/kg.