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Targeted therapy with tyrosine kinase inhibitors (TKIs) was introduced for the suppression of BCR-ABL fusion protein in chronic myelogenic leukemia (CML) more than 50 years ago. The introduction of TKI was an elegant way to gain control over the disease and opened a horizon to the development of new and safer drugs to better manage the disease progression in CML patients. Although Imatinib (the first TKI) was highly effective for the treatment of CML, the lack of response in some patients and the development of resistance led to the introduction of a second-generation TKI, like Nilotinib (Tasigna®). This study aimed to show the molecular response to Nilotinib after a long-term monitoring of CML patients. We analyzed the molecular response rate of twenty-seven CML patients admitted to the Hematology Ward. All of them were subjected to multiple control measurements of Philadelphia chromosome once in at least three months’ period between January 2017 and March 2020. All patients showed a remarkable decrease in the level of the fusion gene’s expression. The highest drop in the expression level was detected after the first dose admission. Some of the patients even reached an expression of BCR-ABL below the detection limit and it was maintained stably low during further examinations. In our patients with CML, Nilotinib resulted in prolonged and deep molecular response. The expression level of BCR-ABL fusion gene showed a substantial decrease immediately after Nilotinib treatment, revealed as early as the third month of therapy.

Gaucher disease (GD) is a multi-systemic disease with a low population frequency. It is a lysosomal storage disorder (LSD) that causes accumulation of glucocerebroside in the so called Gaucher cells predominantly in areas like the spleen, liver and bone marrow. Type I GD (GDI) is the most common form and usually does not involve the brain and the spinal cord. The symptoms can range from mild to severe and may appear anytime from childhood to adulthood. Diagnostics can often be challenging and imposes looking at person’s medical history, symptoms, physical exam, and laboratory test results. We present a difficult to diagnose case of a 34-year-old woman admitted to the Clinic of Hematology, “Sv. I. Rilski” hospital with splenomegaly, normal laboratory findings and non-enlarged liver. She didn’t show focal neurological symptoms. A series of tests were assigned including genetic targeted analysis. The case is an example of a rare genetic disease with mild clinical symptoms. Diagnosis of Gaucher disease, type I was confirmed by measurement of a GBA enzyme activity and identification of mutations in the GBA gene inherited in an autosomal recessive manner. Thanks to the efforts of the clinical team, the assignment of adequate clinical and laboratory tests and their correct interpretation, the patient was subjected to enzyme replacement therapy (ERT). Although the diagnosis was settled relatively late (at 34 years of age), the correct therapy slowed down the invalidation and improved the quality of life of the patient.

Myelofibrosis (MF) is characterized by a presence of an extra fibrous tissue in the bone marrow and additional hematopoiesis. The somatic mutation in the Janus kinase 2 (JAK2) gene (V617F) occurs gradually and is detected in about 50.0% of myelofibrosis or essential thrombo-cytopenia (ET) patients. Our aim was to determine the genotype status according to the carriers of the V617F mutation in patients with MF at the Hematology Ward of the University Hospital "Ivan Rilski" in Sofia, Bulgaria. DNA samples were isolated from venous blood of patients with various hematological disorders. DNA was amplified by polymerase chain reaction (PCR) and subsequent restriction analysis was performed using a BsaXI restriction enzyme. The genotype status was determined on 2.0% agarose gel. We analyzed 38 patients initially suspected of carrying MF or osteomyelofibrosis (OMF). After trepanobiopsy, 20 out of 38 patients were confirmed as myelofibrotic (52.6%), 5/38 (13.2%) were diagnosed as ET, 1/38 (2.6%) was diagnosed as myeloproliferative neoplasm (MPN), 6/38 (15.8%) had polycythemia vera (PV). In six patients, the presence of disease was rejected. Patients with MF were divided into three groups according to the JAK2 V617F genotype status: homozygous for the mutation (3/20 or 15.0%), heterozygous (9/20 or 45.0%) and homozygous for the wild type allele (8/20 or 40.0%). The triggering factor of MF is still unknown. It was considered that this factor could have a genetic nature. Mutations in three genes were mainly accepted as an actual predisposing events to this disease: point mutations leading to amino acid substitutions in JAK2 (V617F) and in MPL (W515L, W515K), as well as insertion or deletion in CALK We have proven that carriers of the V617F mutation prevailed in the group of patients with MF (altogether 12 patients or 60.0%). Previous studies also showed that JAK2 V617F is present in more than half of MF patients within their blood-forming cells. Therefore, the risk of evolution to MF could be associated with V617F-mutant allele burden in patients with MPN.

Chronic myeloid leukemia (CML) is one of the most common hematological malignancies and accounts for 15-20% of all leukemia cases. The cytogenetic marker of CML is the presence of Philadelphia chromosome (Ph) in >95% of patients. The current case reports a 83-year old woman who was directed to the genetic laboratory for a cytogenetic and molecular-genetic analysis suspected to be Ph positive [(+)]. Karyotype analysis of a bone marrow sample revealed a hyperdiploid karyotype in a part of Ph (+) cells with additional chromosomes 8, 10 and 12. Restriction analysis for V617F JAK2 mutation was negative, while the quantitative RT-qPCR assay indicated BCR-ABL/ABL transcript at the level of 120% International Scale (IS). Generally cytogenetic complexities are important in the prognostic evaluation of CML. Besides the Ph chromosome, a variet of chromosomal aberrations may be associated with CML. A total of 5-10% of these cases show complex translocations involving another chromosome. The current case is Ph(+) demonstrating an additional hyperdiploid karyotype clone with three additional autosomes (8, 10 and 12). This case highlights the significance of cytogenetic abnormalities on the prognosis of CML.

BACKGROUND: Modern drugs could sometimes be a good solution even to problematic patients. The cutaneous and systemic forms of the CD30 positive anaplastic large T-cell lymphoma could often be described as a suitable target for therapy with Brentuximab vedotin.CASE REPORT: We present the first case of a Bulgarian patient with a histologically confirmed primary cutaneous T-cell CD30+/ALK- large anaplastic cell lymphoma-cALCL (therapeutically resistant to therapy with Methotrexate, radiation therapy and systemic corticosteroid therapy) who was successfully treated with Brentuximab vedotin. In several years, the patient has developed a comparatively fast skin progression as well as an initial systemic one which impacts inguinal and mediastinal nodes. After the implementation of 4 therapy cycles with Brentuximab vedotin, complete regression of the described by previous hospitalisations lymph nodes as well as 80% reduction of the cutaneous and subcutaneous located tumour formations were observed.CONCLUSION: The therapy of CD30+/ALK- anaplastic large T-cell lymphoma is a significant challenge for oncologists and dermatologists because it requires maximally efficient and minimally traumatic treatment in parallel. Therapy with Brentuximab is a new direction which shows extremely good clinical results and can be applied to the cutaneous as well as to the systemic form of anaplastic large-cell CD30 positive lymphoma. The key element by treatment with Brentuximab is suppression of the CD30- expression which, in turn, could be the cause of relapses. On that ground, patients with these lymphomas should be strictly monitored.

Summary Background Patients who are immunocompromised because of malignancy have an increased risk of herpes zoster and herpes zoster-related complications. We aimed to investigate the efficacy and safety of an inactivated varicella zoster virus (VZV) vaccine for herpes zoster prevention in patients with solid tumour or haematological malignancies. Methods This phase 3, two-arm, randomised, double-blind, placebo-controlled, multicentre trial with an adaptive design was done in 329 centres across 40 countries. The trial included adult patients with solid tumour malignancies receiving chemotherapy and those with haematological malignancies, either receiving or not receiving chemotherapy. Patients were randomly assigned (1:1) to receive four doses of VZV vaccine inactivated by γ irradiation or placebo approximately 30 days apart. The patients, investigators, trial site staff, clinical adjudication committee, and sponsor's clinical and laboratory personnel were masked to the group assignment. The primary efficacy endpoint was herpes zoster incidence in patients with solid tumour malignancies receiving chemotherapy, which was assessed in the modified intention-to-treat population (defined as all randomly assigned patients who received at least one dose of inactivated VZV vaccine or placebo). The primary safety endpoint was serious adverse events up to 28 days after the fourth dose in patients with solid tumour malignancies receiving chemotherapy. Safety endpoints were assessed in all patients who received at least one dose of inactivated VZV vaccine or placebo and had follow-up data. This trial is registered ( NCT01254630 and EudraCT 2010-023156-89). Findings Between June 27, 2011, and April 11, 2017, 5286 patients were randomly assigned to receive VZV vaccine inactivated by γ irradiation (n=2637) or placebo (n=2649). The haematological malignancy arm was terminated early because of evidence of futility at a planned interim analysis; therefore, all prespecified haematological malignancy endpoints were deemed exploratory. In patients with solid tumour malignancies in the modified intention-to-treat population, confirmed herpes zoster occurred in 22 of 1328 (6·7 per 1000 person-years) VZV vaccine recipients and in 61 of 1350 (18·5 per 1000 person-years) placebo recipients. Estimated vaccine efficacy against herpes zoster in patients with solid tumour malignancies was 63·6% (97·5% CI 36·4 to 79·1), meeting the prespecified success criterion. In patients with solid tumour malignancies, serious adverse events were similar in frequency across treatment groups, occurring in 298 (22·5%) of 1322 patients who received the vaccine and in 283 (21·0%) of 1346 patients who received placebo (risk difference 1·5%, 95% CI −1·7 to 4·6). Vaccine-related serious adverse events were less than 1% in each treatment group. Vaccine-related injection-site reactions were more common in the vaccine group than in the placebo group. In the haematological malignancy group, VZV vaccine was well tolerated and estimated vaccine efficacy against herpes zoster was 16·8% (95% CI −17·8 to 41·3). Interpretation The inactivated VZV vaccine was well tolerated and efficacious for herpes zoster prevention in patients with solid tumour malignancies receiving chemotherapy, but was not efficacious for herpes zoster prevention in patients with haematological malignancies. Funding Merck & Co, Inc.

Altres ajuts: This work was supported by Celyad, SA (Mont-Saint-Guibert, Belgium). Celyad has received research grants from the Walloon Region (Belgium, DG06 funding). Cardiopoietic cells, produced through cardiogenic conditioning of patients' mesenchymal stem cells, have shown preliminary efficacy. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial aimed to validate cardiopoiesis-based biotherapy in a larger heart failure cohort. This multinational, randomized, double-blind, sham-controlled study was conducted in 39 hospitals. Patients with symptomatic ischaemic heart failure on guideline-directed therapy (n = 484) were screened; n = 348 underwent bone marrow harvest and mesenchymal stem cell expansion. Those achieving > 24 million mesenchymal stem cells (n = 315) were randomized to cardiopoietic cells delivered endomyocardially with a retention-enhanced catheter (n = 157) or sham procedure (n = 158). Procedures were performed as randomized in 271 patients (n = 120 cardiopoietic cells, n = 151 sham). The primary efficacy endpoint was a Finkelstein–Schoenfeld hierarchical composite (all-cause mortality, worsening heart failure, Minnesota Living with Heart Failure Questionnaire score, 6-min walk distance, left ventricular end-systolic volume, and ejection fraction) at 39 weeks. The primary outcome was neutral (Mann–Whitney estimator 0.54, 95% confidence interval [CI] 0.47–0.61 [value > 0.5 favours cell treatment], P = 0.27). Exploratory analyses suggested a benefit of cell treatment on the primary composite in patients with baseline left ventricular end-diastolic volume 200–370 mL (60% of patients) (Mann–Whitney estimator 0.61, 95% CI 0.52–0.70, P = 0.015). No difference was observed in serious adverse events. One (0.9%) cardiopoietic cell patient and 9 (5.4%) sham patients experienced aborted or sudden cardiac death. The primary endpoint was neutral, with safety demonstrated across the cohort. Further evaluation of cardiopoietic cell therapy in patients with elevated end-diastolic volume is warranted.

The omega-alkynals yielded macrocyclic (S)-allylic alcohols in a one-pot reaction sequence involving alkyne monohydroboration, boron to zinc transmetalation, and ((+)-DAIB)-catalyzed enantioselective intramolecular ring closure to the aldehyde function. A general study of this macrocyclization methodology is presented with respect to ligand type, size, and nature of the formed rings.

ω-Alkynal ester 3 , prepared from ( S )-propylene oxide 4 , yields the macrocyclic (6 R )-allylic alcohol 2 (60% yield, 83% d.e.) in one operation via monohydroboration, boron/zinc-transmetalation and (−)-DAIB “catalyzed” intramolecular alkenylzinc/aldehyde addition. Introduction of the C(2)–C(3) double bond by selenoxide elimination ( 2 → 8 ), hydroxy-directed epoxidation ( 8 → 9 ), acetate assisted α-epoxide opening ( 10 → 12 ) and acidic methanolysis provides pure (+)-aspicilin ( 1 ) in 22% overall yield from 4 .

Hydroboration of aliphatic 1-alkynes with freshly prepared dicyclohexylborane (1 mol-equiv., hexane), treatment of the resulting [(E)-1-alkenyl]boranes 5 with Et2Zn or Me2Zn (1.05 mol-equiv.) followed by addition of (−)-3-exo-(dimethylamino)isoborneol (DAIB, 8; 0.01 mol-equiv.), subsequent addition of a solution of an aromatic or aliphatic aldehyde (1 mol-equiv., hexane), and quenching with aq. NH4Cl provided (E)-allyl alcohols 6 usually in 70–95% yield with 79–98% enantiomeric excess (Scheme 3 and Table).