Azacitidine-venetoclax versus azacitidine salvage treatment for primary induction failure or first relapsed acute myeloid leukaemia patients.

OBJECTIVES: To compare the efficacy of venetoclax-azacitidine (VEN-AZA) with AZA in the real-life for patients with first relapsed or refractory acute myeloid leukaemia (R/R AML). METHODS: We retrospectively analysed R/R AML patients treated with VEN-AZA at the Institut Paoli Calmettes between September 2020 and February 2022. We compared them to a historical cohort of patients treated with AZA between 2010 and 2021. RESULTS: Thirty-five patients treated with VEN-AZA were compared with 140 patients treated with AZA. There were more favourable cytogenetics (25.7% vs. 8.6%; p = 0.01) and less FLT3-ITD mutated AML (8.8% vs. 25.5%; p = .049) in the VEN-AZA group. The overall 30-day mortality rate was 7.4% and the overall 90-day mortality was 20%, with no difference between the groups. The complete remission rate was 48.6% in the VEN-AZA group versus 15% (p < .0001). The composite complete response rate was 65.7% in the VEN-AZA group versus 23.6% (p < .0001). OS was 12.8 months in the VEN-AZA group versus 7.3 months (p = 0.059). Patients with primary refractory AML, poor-risk cytogenetics, prior hematopoietic stem-cell transplantation (HSCT) and FLT3-ITD mutated AML had lower response and survival rates. CONCLUSION: VEN-AZA was associated with a better response rate and a longer survival than AZA monotherapy in AML patients who relapsed after or were refractory to intensive chemotherapy.

A chemogenomic approach to identify personalized therapy for patients with relapse or refractory acute myeloid leukemia: results of a prospective feasibility study.

Targeted next-generation sequencing (tNGS) and ex vivo drug sensitivity/resistance profiling (DSRP) have laid foundations defining the functional genomic landscape of acute myeloid leukemia (AML) and premises of personalized medicine to guide treatment options for patients with aggressive and/or chemorefractory hematological malignancies. Here, we have assessed the feasibility of a tailored treatment strategy (TTS) guided by systematic parallel ex vivo DSRP and tNGS for patients with relapsed/refractory AML (number NCT02619071). A TTS issued by an institutional personalized committee could be achieved for 47/55 included patients (85%), 5 based on tNGS only, 6 on DSRP only, while 36 could be proposed on the basis of both, yielding more options and a better rationale. The TSS was available in <21 days for 28 patients (58.3%). On average, 3 to 4 potentially active drugs were selected per patient with only five patient samples being resistant to the entire drug panel. Seventeen patients received a TTS-guided treatment, resulting in four complete remissions, one partial remission, and five decreased peripheral blast counts. Our results show that chemogenomic combining tNGS with DSRP to determine a TTS is a promising approach to propose patient-specific treatment options within 21 days.

Real-world effectiveness and safety of apremilast in psoriasis at 52 weeks: a retrospective, observational, multicentre study by the Spanish Psoriasis Group.

BACKGROUND: Little has been published on the real-world effectiveness and safety of apremilast in psoriasis. OBJECTIVES: To evaluate the effectiveness, safety and drug survival of apremilast at 52 weeks in patients with moderate to severe plaque psoriasis or palmoplantar psoriasis in routine clinical practice. METHODS: Retrospective, multicentre study of adult patients with moderate to severe plaque psoriasis or palmoplantar psoriasis treated with apremilast from March 2016 to March 2018. RESULTS: We studied 292 patients with plaque psoriasis and 85 patients with palmoplantar psoriasis. The mean (SD) Psoriasis Area and Severity Index (PASI) score was 10.7 (7.0) at baseline and 3.0 (4.2) at 52 weeks. After 12 months of treatment, 73.6% of patients had a PASI score of 3 or less. In terms of relative improvement by week 52, 49.7% of patients achieved PASI-75 (≥75% reduction in PASI score) and 26.5% achieved PASI-90. The mean physician global assessment score for palmoplantar psoriasis fell from 4.2 (5.2) at baseline to 1.3 (1.3) at week 52. Overall drug survival after 1 year of treatment with apremilast was 54.9 %. The main reasons for treatment discontinuation were loss of efficacy (23.9%) and adverse events (15.9%). Almost half of the patients in our series (47%) experienced at least one adverse event. The most common events were gastrointestinal problems. CONCLUSIONS: Apremilast may be a suitable alternative for the treatment of moderate to severe psoriasis and palmoplantar psoriasis. Although the drug has a good safety profile, adverse gastrointestinal effects are common.

Post-remission therapy of adults aged 60 and older with acute myeloid leukemia in first complete remission: role of treatment intensity on the outcome.

Although complete remission (CR) is achieved in 50 to 70% of older fit patients with acute myeloid leukemia (AML), consolidation therapy in this age group remains challenging. In this retrospective study, we aimed to compare outcome in elderly patients treated with different post-remission modalities, including allogenic and autologous hematopoietic stem cell transplantation (HSCT), intensive chemotherapy, and standard-dose chemotherapy (repeated 1 + 5 regimen). We collected data of 441 patients ≥ 60 years in first CR from a single institution. Median age was 67 years. Sixty-one (14%) patients received allo-HSCT, 51 (12%) auto-HSCT, 70 (16%) intensive chemotherapy with intermediate- or high-dose cytarabine (I/HDAC), and 190 (43%) 1 + 5 regimen. Median follow-up was 6.5 years. In multivariate analysis, allo-HSCT, cytogenetics, and PS had a significant impact on OS and LFS. In spite of a more favorable-risk profile, the patients who received I/HDAC had no significantly better LFS as compared with patients treated with 1 + 5 (median LFS 8.8 months vs 10.6 months, p = 0.96). In transplanted patients, median LFS was 13.3 months for auto-HSCT and 25.8 months for allo-HSCT. Pre-transplant chemotherapy with I/HDAC had no effect on the outcome. Toxicity was significantly increased for both transplanted and non-transplanted patients treated with I/HDAC, with more units of blood and platelet transfusion and more time spent in hospitalization, but no higher non-relapse mortality. This study shows that post-remission chemotherapy intensification is not associated with significantly better outcome as compared with standard-dose chemotherapy in elderly patients for whom, overall results remain disappointing.

RSK2 is a new Pim2 target with pro-survival functions in FLT3-ITD-positive acute myeloid leukemia.

Acute myeloid leukemia (AML) with the FLT3 internal tandem duplication (FLT3-ITD AML) accounts for 20-30% of AML cases. This subtype usually responds poorly to conventional therapies, and might become resistant to FLT3 tyrosine kinase inhibitors (TKIs) due to molecular bypass mechanisms. New therapeutic strategies focusing on resistance mechanisms are therefore urgently needed. Pim kinases are FLT3-ITD oncogenic targets that have been implicated in FLT3 TKI resistance. However, their precise biological function downstream of FLT3-ITD requires further investigation. We performed high-throughput transcriptomic and proteomic analyses in Pim2-depleted FLT3-ITD AML cells and found that Pim2 predominantly controlled apoptosis through Bax expression and mitochondria disruption. We identified ribosomal protein S6 kinase A3 (RSK2), a 90 kDa serine/threonine kinase involved in the mitogen-activated protein kinase cascade encoded by the RPS6KA3 gene, as a novel Pim2 target. Ectopic expression of an RPS6KA3 allele rescued the viability of Pim2-depleted cells, supporting the involvement of RSK2 in AML cell survival downstream of Pim2. Finally, we showed that RPS6KA3 knockdown reduced the propagation of human AML cells in vivo in mice. Our results point to RSK2 as a novel Pim2 target with translational therapeutic potential in FLT3-ITD AML.

[Therapeutic of respiratory manifestations at the early phase of acute myeloid leukaemia]. / Prise en charge thérapeutique des manifestations pulmonaires à la phase aiguë des leucémies aiguës myéloblastiques.

The effective management of the respiratory manifestations at the early phase of acute myeloid hemopathies, especially acute myeloid leukaemia, frequently requires a close collaboration between hematologists, pulmonologists and intensivists. Dominated by infectious etiologies, there are however "specific" disease entities that should not be neglected in the diagnostic and therapeutic approach. These include lung leukostasis, leukemic lung infiltration, the cell lysis pneumopathy and the secondary alveolar proteinosis. These were the subject of a review in the Revue des Maladies Respiratoires published in 2010. We wished to review the management of these clinical situations, the severity of which mean patients frequently require intensive care unit admission. We are only able to make proposals for management here as there is little consensus, except in the metabolic care of tumour lysis syndrome. These data must therefore be reinterpreted regularly as new publications become available.

Evaluation of allogeneic hematopoietic SCT in younger adults with adverse karyotype AML.

To illustrate methodological issues, we compared donor vs no-donor to transplant vs no-transplant comparisons in a cohort of 107 patients aged 50 years with adverse karyotype AML in first CR. Adverse karyotypes were defined as -7, del(7q), -5, del(5q), t(9;22), 11q23, 3q26 or complex abnormalities. Mantel-Byar estimations and hematopoietic SCT (HSCT) as a time-dependent variable were used to compare transplant vs no-transplant cumulative incidence of relapse (CIR), relapse-free survival (RFS) and OS. In all, 52 patients had a sibling donor, but only 35 of them were transplanted in first CR, whereas 9 patients received HSCT from alternative stem cell sources. Donor-based analysis showed lower CIR in the donor group, not translating in prolonged RFS or OS. Conversely, transplant-based analysis showed that HSCT in the first CR improved the three CIR (multivariate hazard ratio (HR), 0.31; P<0.001), RFS (multivariate HR, 0.57; P=0.047) and OS (multivariate HR, 0.54; P=0.03) endpoints. At 5 years, OS was estimated at 33% in transplanted vs 18% in non-transplanted patients. The positive effect of HSCT was more pronounced in patients aged 35 years and/or in those transplanted in the more recent years. These results confirm that HSCT is likely the best curative option in younger patients with adverse karyotype AML.

La importancia del cuidado de enfermería para los pacientes de cáncer de pulmón / Importance of nursing care for lung cancer patients

El objetivo de este artículo es evidenciar la importancia de los cuidados e intervenciones de Enfermería en los pacientes de cáncer de pulmón. Las intervenciones sistematizadas desde una perspectiva integral, holística, de forma individualizada y/o de forma grupal, mejoran la calidad de vida de estos enfermos produciéndoles mayor satisfacción y bienestar a lo largo del proceso del cáncer

The aim of this paper is to acknowledge the relevance of nurse care and interventions regarding lung cancer patients. Systematic interventions designed from an integrative and holistic point of view, either as individuals or as a group, may improve quality of life of these patients by increasing satisfaction and wellbeing along the process

[Evaluation of antibiotic prophylaxis in surgery]. / Evaluación de la profilaxis antibiótica en cirugía.

OBJECTIVE: To evaluate the level of compliance with antibiotic prophylaxis during surgery in a university referral hospital. PATIENTS AND METHODS: A descriptive study of 257 patients undergoing clean or clean-contaminated elective surgery was carried out in 2001. Data were gathered prospectively by three anesthesiologists in the operating room. Prophylaxis was considered to have been administered correctly if the first dose was given before the skin incision, if a second dose was given during operations lasting longer than 240 minutes, and if the antibiotic prescribed was of a wide enough spectrum to cover the type of surgical procedure performed. RESULTS: Prophylaxis was administered incorrectly to 132 patients (51.4%). The causes were administration after incision in 21.8%, long-duration surgery without a second dose in 15.6%, administration after incision plus long-duration surgery without a second dose in 3.1%, inadequate-spectrum antibiotic in 4.7%, administration after incision plus inadequate dose in 2.7%, inadequate dose in 1.9%, inadequate-spectrum antibiotic plus administration after incision in 0.8%, late second dose in 0.4%, long-duration surgery without a second dose plus inadequate dose in 0.4%. DISCUSSION: The rates of late administration of an antibiotic or failure to administer a second dose during long-duration surgery is high. CONCLUSION: To improve the low level of compliance and avoid late administration of antibiotics, we propose that the anesthetist be responsible for giving antibiotic prophylaxis and for directly monitoring compliance errors in the operating room.

[Pulmonary embolism after placement of an Esmarch bandage for ankle surgery]. / Embolismo pulmonar tras colocación de venda de Esmarch para cirugía de tobillo.

We report the case of a woman scheduled for surgical fixation of an ankle fracture who developed a pulmonary embolism during application of an Esmarch compression bandage for exsanguination of the limb. Tracheal intubation and mechanical ventilation were needed to reanimate the patient and surgery had to be postponed 15 days. Orthopedic surgery, pneumatic tourniquets for providing a bloodless field and other risk factors contribute to the development of pulmonary embolism, which is often fatal. Accurate diagnosis by plasma D-dimer determination and imaging (perfusion scintigraphy, vascular Doppler ultrasound, echocardiography and pulmonary angiography) is discussed, along with therapeutic approaches to consider when managing pulmonary embolism.

Evaluación de la profilaxis antibiótica en cirugía / Evaluation of antibiotic prophylaxis during surgery

OBJETIVO: Evaluar el nivel de cumplimiento de la antibiótico profilaxis en cirugía en un hospital universitario de tercer nivel. PACIENTES Y MÉTODOS: Durante el año 2001 se realizó un estudio descriptivo que incluyó a 257 enfermos sometidos a intervenciones quirúrgicas electivas limpias o limpias contaminadas. La recogida de datos fue realizada en quirófano, de forma prospectiva por tres anestesiólogos. Se consideró que la profilaxis se administró correctamente si la primera dosis fue administrada antes de la incisión de la piel; si se administró una segunda dosis en intervenciones de duración superior a 240 minutos y si se administró un antibiótico de espectro adecuado según el tipo de intervención quirúrgica . RESULTADOS: En 132 pacientes (51,4 por ciento) la profilaxis se realizó incorrectamente. Las causas fueron: 21,8 por ciento administración después de la incisión; 15,6 por ciento cirugía larga sin 2ª dosis; 3,1 por ciento administración después de la incisión y cirugía larga sin 2ª dosis; 4,7 por ciento antibiótico inadecuado; 2,7 por ciento administración después de la incisión y dosis inadecuada; 1,9 por ciento dosis inadecuada; 0,8 por ciento antibiótico inadecuado y administración después de la incisión; 0,4 por ciento 2ª dosis tarde; 0,4 por ciento cirugía larga sin 2ª dosis y dosis inadecuada. DISCUSIÓN: Existe un alto porcentaje de incumplimiento relacionado con la administración tardía del antibiótico y la no administración de una segunda dosis en cirugías de larga duración .CONCLUSIÓN: Para mejorar el bajo nivel de cumplimiento y evitar la administración tardía del antibiótico proponemos al anestesiólogo como responsable de la antibiótico profilaxis, así como la evaluación directa en quirófano para detectar este tipo de error (AU)

Embolismo pulmonar tras colocación de venda de Esmarch para cirugía de tobillo / Pulmonary embolism following application of an Esmarch bandage for ankle surgery

Una paciente de 63 años que iba a ser intervenida de fractura de tobillo presentó, durante la colocación de una venda de Esmarch para la isquemia de la extremidad, un embolismo pulmonar agudo que requirió intubación traqueal y ventilación mecánica para reanimar a la paciente y obligó a posponer la intervención 15 días. La cirugía ortopédica, las maniobras de exanguinación y otros factores de riesgo contribuyen a que se produzca este cuadro, muchas veces mortal. El correcto diagnóstico mediante pruebas analíticas (dímero D) y técnicas de imagen (gammagrafía de perfusión, eco-Doppler vascular, ecocardiografía y angiografía pulmonar), son analizadas, así como las posibles estrategias terapéuticas a considerar frente a esta patología (AU)

Synthesis and CD studies of an 88-residue peptide containing the main receptor binding site of HTLV-I SU-glycoprotein.

Essential HTLV-1 biological functions, like host-cell receptor recognition, depend on the structural motives on the surface glycoprotein gp46. We defined a peptide of 88 amino acids [Arg147-Leu234] corresponding to the central part of the protein sequence, where major neutralizing epitopes are localized. After evaluating the feasibility of its chemical synthesis, the chosen sequence was realized using the stepwise solid-phase methodology. Multiple chromatographic purification steps were required to obtain a sample suitable for structural analysis. Correct folding was supported by strong binding of monooclonal antibodies, recognizing known exposed immunodominant regions. Circular dichroism studies confirmed a non-random conformation of at least 70-80% of the synthetic peptide. Investigation of the 3D-structure of the synthetic peptide will provide useful information for future vaccine and drug-design strategies.

Chemical synthesis of a 7 kDa insect gonadotropic neurohormone.

An original insect neurohormone of 65 residues was synthesized by the solid-phase methodology using t-Boc strategy and Boc-Val-PAM-resin. The purification, conducted by several steps of liquid chromatography having mass, polarity or charge as separative criteria, yielded the product with the correct molecular weight of 6922 Da determined by mass spectrometry. The synthetic peptide had both the same affinity for the anti-native neurohormone serum and the same biological activity as the native neurohormone.

Inhibition of activity of the protease from bovine leukemia virus.

In view of the close similarity between bovine leukemia virus (BLV) and human T-cell leukemia virus type I (HTLV-I) we investigated the possibility of developing specific inhibitors of the proteases of these retroviruses using the purified enzyme from BLV. We tested the ability of this protease to specifically cleave various short oligopeptide substrates containing cleavage sites of BLV and HTLV-I proteases, as well as a recombinant BLV Gag precursor. The best substrate, a synthetic decapeptide bearing the natural cleavage site between the matrix and the capsid proteins of BLV Gag precursor polyprotein, was used to develop an inhibition assay. We determined the relative inhibitory effect of synthetic Gag precursor-like peptides in which the cleavable site was replaced by a non-hydrolyzable moiety. The encouraging inhibitory effect of these compounds indicates that potent non-peptidic inhibitors for retroviral proteases are not unattainable.

Lichen planus with predominant plasma cell infiltrate.

We herein report the case of a patient with lichenoid plaques on the lower extremities and anonychia of all toenails. Histologically, the eruption showed typical features of lichen planus, with the exceptional finding of a lichenoid infiltrate composed mostly of plasma cells. Only two other similar cases have been reported. The explanation for the numerous plasma cells remains unknown although such cases may represent a new histologic variant.

Modelling, synthesis and biological activity of a BLV proteinase, made of (only) 116 amino acids.

Bovine leukaemia virus (BLV) is the aetiological agent of Leukosis enzootica bovis [Viral Oncology (1980), G. Klein (Ed.) Raven Press, New York, pp. 231-238], a widely spread disease in cattle. BLV is reported as the animal model of human T-cell leukaemia virus (HLTV) which is the causative agent of adult T-cell leukaemia and tropical spastic paraparesis. Like the viruses themselves, the two retroviral proteinases (PR) are very closely related [Virology 142 (1985) 357-377]. BLV and HTLV-I PR are reported as putative proteins made of 126 [J. Virol. 57 (1986) 826-832] and 125 [FEBS Lett. 293 (1991) 106-110] amino acids, respectively (long sequences), belonging to the aspartyl proteinase family [Nature 329 (1987) 351-354], with the aid of molecular modelling, we show that BLV and HTLV-I proteinases made of only 116 and 115 amino acids, respectively (short sequences), display three-dimensional structures similar to that observed for other retroviral aspartyl proteinases. The models are based on three-dimensional structures of Rous sarcoma virus (RSV PR) and the human immunodeficiency virus (HIV-1 PR). We used solid phase peptide synthesis to produce the putative proteolytic enzyme of BLV (116 amino acids). In this study, we show that the folded synthetic protease accurately hydrolyzes a decapeptide corresponding to the sequence of the Matrice-Capside (MA/CA) cleavage site of the gag polyprotein. In addition, the proteolytic activity is inhibited by a statine ((4S,3S)-4-amino-3-hydroxyl-6-methylheptanoic acid) containing an analogous sequence.

Bovine leukemia virus: purification and characterization of the aspartic protease.

To develop efficient bovine leukemia virus (BLV) protease (PR) inhibitors, pure enzyme is required. For this, we have developed a two-step chromatographic nondenaturing purification protocol of PR from virions. As expected, the purified protein presents a molecular weight (14 kDa) and a NH2 terminal end fitting with previously reported data. The enzymatic activity of BLV PR was characterized using a synthetic peptide containing a potential cleavage site of the BLV gag-pro polypeptide precursor as substrate. The protease was most active at pH 6, 40 degrees, and high salt concentration (1-2 M NaCl or ammonium sulfate). In contrast, using a natural substrate such as a human T-cell leukemia virus recombinant gag precursor, BLV PR activity was higher at a low salt concentration (0.5 M NaCl). Besides, the use of different potentially cleavable molecules revealed that PR activity may be influenced by the substrate conformational structure around the cleavage site. Replacement of the two amino acids of a synthetic substrate cleavable site by a statin residue completely inhibited the enzymatic activity of the BLV PR.

Monoclinic uncomplexed double-stranded, antiparallel, left-handed beta 5.6-helix (increases decreases beta 5.6) structure of gramicidin A: alternate patterns of helical association and deformation.

A comparison of the monoclinic and orthorhombic crystal structures of the uncomplexed double-stranded, antiparallel, left-handed beta-helix (5.6 amino acid residues per turn) (increases decreases beta 5.6) conformers of gramicidin A reveals marked differences in the tryptophan side-chain orientations and the degree of helical uniformity of the dimer and in the manner in which these helical dimers associate with one another in the crystal. The helix of the orthorhombic dimer exhibits a regular pattern of bulges and constrictions that appears to be induced by crystal packing forces affecting tryptophan side chains that are aligned parallel to the helix axis. The monoclinic dimer is more uniform than the orthorhombic dimer as a consequence of pi stacking interactions between dimers in which orientation of tryptophan side chains is normal to the helix axis to relieve the lateral crystal packing forces that may locally twist and deform the helix. It may be inferred from these observations that lipid interactions may be expected to destabilize the increases decreases beta 5.6 helix when it is inserted into a membrane bilayer.