Cassia angustifolia is a species of plant from the Senna family that has traditionally been used as a laxative in different herbal products and commercial medicines. Even though there are few ...documented drug–plant interactions, the use of C. angustifolia with different drugs may have additive effects, such as with other laxatives or potassium‐depleting diuretics. Its use also increases peristalsis which, may reduce drug absorption. The combination with digoxin has been associated with an increased risk of digoxin toxicity, probably due to an increase in plasma digoxin concentrations and hypokalaemia. We present a case with supratherapeutic trough concentration of tacrolimus, an immunosuppressive agent, and a herbal product in a liver transplant patient after concomitant intake of tacrolimus and a herbal product based on C. angustifolia, suggesting a possible drug–lant interaction through by P‐glycoprotein. We observed an increase in the patient’s blood concentration 2.8‐fold and the area under the curve at steady state 2.1‐fold. This interaction could be of clinical relevance, given the dose‐dependent side effects of tacrolimus, such as nephrotoxicity, neurotoxicity, hypertension, hyperglycaemia, or electrolyte alterations.
Summary
Recommended genetic categorization of acute myeloid leukaemias (AML) includes a favourable‐risk category, but not all these patients have good prognosis. Here, we used next‐generation ...sequencing to evaluate the mutational profile of 166 low‐risk AML patients: 30 core‐binding factor (CBF)‐AMLs, 33 nucleophosmin (NPM1)‐AMLs, 4 biCEBPα‐AMLs and 101 acute promyelocytic leukaemias (APLs). Functional categories of mutated genes differed among subgroups. NPM1‐AMLs showed frequent variations in DNA‐methylation genes (DNMT3A, TET2, IDH1/2) (79%), although without prognostic impact. Within this group, splicing‐gene mutations were an independent factor for relapse‐free (RFS) and overall survival (OS). In CBF‐AML, poor independent factors for RFS and OS were mutations in RAS pathway and cohesin genes, respectively. In APL, the mutational profile differed according to the risk groups. High‐risk APLs showed a high mutation rate in cell‐signalling genes (P = 0·002), highlighting an increased incidence of FLT3 internal tandem duplication (ITD) (65%, P < 0·0001). Remarkably, in low‐risk APLs (n = 28), NRAS mutations were strongly correlated with a shorter five‐year RFS (25% vs. 100%, P < 0·0001). Overall, a high number of mutations (≥3) was the worst prognostic factor RFS (HR = 2·6, P = 0·003). These results suggest that gene mutations may identify conventional low‐risk AML patients with poor prognosis and might be useful for better risk stratification and treatment decisions.
Summary
The Hodgkin lymphoma (HL) genomic landscape is hardly known due to the scarcity of tumour cells in the tissue. Liquid biopsy employing circulating tumour DNA (ctDNA) can emerge as an ...alternative tool for non‐invasive genotyping. By using a custom next generation sequencing (NGS) panel in combination with unique molecule identifiers, we aimed to identify somatic variants in the ctDNA of 60 HL at diagnosis. A total of 277 variants were detected in 36 of the 49 samples (73·5%) with a good quality ctDNA sample. The median number of variants detected per patient was five (range 1–23) with a median variant allele frequency of 4·2% (0·84–28%). Genotyping revealed somatic variants in the following genes: SOCS1 (28%), IGLL5 (26%), TNFAIP3 (23%), GNA13 (23%), STAT6 (21%) and B2M (19%). Moreover, several poor prognosis features (high LDH, low serum albumin, B‐symptoms, IPI ≥ 3 or at an advanced stage) were related to significantly higher amounts of ctDNA. Variant detection in ctDNA by NGS is a feasible approach to depict the genetic features of HL patients at diagnosis. Our data favour the implementation of liquid biopsy genotyping for the routine evaluation of HL patients.
This research study analysed the effect of adding fine—fMRA (0.25% and 50%)—and coarse—cMRA (0%, 25% and 50%)—mixed recycled aggregate both individually and simultaneously in the development of ...sustainable recycled concretes that require a lower consumption of natural resources. For this purpose, we first conducted a physical and mechanical characterisation of the new recycled raw materials and then analysed the effect of its addition on fresh and hardened new concretes. The results highlight that the addition of fMRA and/or cMRA does not cause a loss of workability in the new concrete but does increase the amount of entrained air. Regarding compressive strength, we observed that fMRA and/or cMRA cause a maximum increase of +12.4% compared with conventional concrete. Tensile strength increases with the addition of fMRA (between 8.7% and 5.5%) and decreases with the use of either cMRA or fMRA + cMRA (between 4.6% and 7%). The addition of fMRA mitigates the adverse effect that using cMRA has on tensile strength. Regarding watertightness, all designed concretes have a structure that is impermeable to water. Lastly, the results show the feasibility of using these concretes to design elements with a characteristic strength of 25 MPa and that the optimal percentage of fMRA replacement is 25%.
Carcinoma of the mammary crease is a very rare variant of breast carcinoma, in which the skin lesions are usually the presenting sign. The authors present the case of an 88-year-old woman with an ...exophytic plaque in the mammary crease of approximately ten years duration. The histopathological and immunohistochemical studies confirmed the diagnosis of infiltrative breast carcinoma (carcinoma of the mammary crease variant). This case highlights the important role of the dermatologist in the early diagnosis of this rare variant of breast cancer.
Circulating tumour DNA (ctDNA) allows genotyping and minimal residual disease (MRD) detection in lymphomas. Using a next-generation sequencing (NGS) approach (EuroClonality-NDC), we evaluated the ...clinical and prognostic value of ctDNA in a series of R-CHOP-treated diffuse large B-cell lymphoma (DLBCL) patients at baseline (n = 68) and after two cycles (n = 59), monitored by metabolic imaging (positron emission tomography combined with computed tomography PET/CT). A molecular marker was identified in 61/68 (90%) ctDNA samples at diagnosis. Pretreatment high ctDNA levels significantly correlated with elevated lactate dehydrogenase, advanced stage, high-risk International Prognostic Index and a trend to shorter 2-year progression-free survival (PFS). Valuable NGS data after two cycles of treatment were obtained in 44 cases, and 38 achieved major molecular response (MMR; 2.5-log drop in ctDNA). PFS curves displayed statistically significant differences among those achieving MMR versus those not achieving MMR (2-year PFS of 76% vs. 0%, p < 0.001). Similarly, more than 66% reduction in ΔSUVmax by PET/CT identified two subgroups with different prognosis (2-year PFS of 83% vs. 38%; p < 0.001). Combining both approaches MMR and ΔSUVmax reduction, a better stratification was observed (2-year PFS of 84% vs. 17% vs. 0%, p < 0.001). EuroClonality-NDC panel allows the detection of a molecular marker in the ctDNA in 90% of DLBCL. ctDNA reduction at two cycles and its combination with interim PET results improve patient prognosis stratification.
We performed targeted next-generation sequencing of 62 genes, previously described as being mutated in T-cell lymphomas, in 15 formalin-fixed paraffin-embedded samples from patients with primary ...cutaneous CD4+ small/medium T-cell lymphoproliferative disorder.
The addition of monoclonal antibodies to chemotherapy has significantly improved treatment of chronic lymphocytic leukemia (CLL). Based on excellent results with the chemotherapy-only regimen ...fludarabine, cyclophosphamide, and mitoxantrone (FCM), we built a new chemoimmunotherapy combination--rituximab plus FCM (R-FCM). We report a phase II clinical trial consisting of an initial treatment with R-FCM followed by rituximab maintenance.
Seventy-two untreated CLL patients age 70 years or younger received rituximab 500 mg/m(2) on day 1 (375 mg/m(2) the first cycle), fludarabine 25 mg/m(2) IV on days 1 to 3, cyclophosphamide 200 mg/m(2) on days 1 to 3, and mitoxantrone 6 mg/m(2) IV on day 1, given at 4-week intervals with up to six cycles supported with colony-stimulating factor. Patients achieving response received maintenance with rituximab 375 mg/m(2) every 3 months for 2 years.
The overall response, minimal residual disease (MRD) -negative complete response (CR), MRD-positive CR, and partial response rates were 93%, 46%, 36%, and 11%, respectively. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Advanced clinical stage, del(17p), or increased serum beta2-microglobulin levels correlated with a lower CR rate.
R-FCM is highly effective in previously untreated CLL, with an 82% CR rate and a high proportion of MRD-negative CRs (46%). Treatment toxicity is acceptable. Parameters correlating with a lower response rate were advanced clinical stage, high serum beta2-microglobulin levels, and del(17p). Based on these results, R-FCM warrants further investigation in randomized clinical trials.
Differentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid (ATRA). Detailed ...knowledge about DS has remained limited. We present an analysis of the incidence, characteristics, prognostic factors, and outcome of 739 APL patients treated with ATRA plus idarubicin in 2 consecutive trials (Programa Español de Tratamientos en Hematología PETHEMA LPA96 and LPA99). Overall, 183 patients (24.8%) experienced DS, 93 with a severe form (12.6%) and 90 with a moderate form (12.2%). Severe but not moderate DS was associated with an increase in mortality. A bimodal incidence of DS was observed, with peaks occurring in the first and third weeks after the start of ATRA therapy. A multivariate analysis indicated that a WBC count greater than 5 × 109/L and an abnormal serum creatinine level correlated with an increased risk of developing severe DS. Patients receiving systematic prednisone prophylaxis (LPA99 trial) in contrast to those receiving selective prophylaxis with dexamethasone (LPA96 trial) had a lower incidence of severe DS. Patients developing severe DS showed a reduced 7-year relapse-free survival in the LPA96 trial (60% vs 85%, P = .003), but this difference was not apparent in the LPA99 trial (86% vs 88%).
Fulfilment of the progressive environmental normative involves a singular challenge for Short Sea Shipping (SSS), since it must maintain its competitiveness versus other transport alternatives. For ...this reason, over the last decade SSS vessels have been the subject of numerous analyses, in terms of operative research, and optimizations, from the marine engineering standpoint. Despite widespread awareness about the impact of a vessel’s resistance on environmental performance, many of the previous analyses were based on resistance prediction methods with low accuracy levels. This fact necessarily involves deviations regarding the expected sustainability of vessels. This paper attempts to quantify (in monetary terms) the environmental consequences due to this low level of accuracy. To meet this aim, it analyzes the environmental performance of an SSS feeder vessel, which was obtained from an optimization process based on standard resistance prediction techniques, when its propulsion power requirements for sailing at optimized speed were assessed through the Reynolds Averaged Navier–Stokes method in Computational Fluid Dynamic simulations. The findings show that standard resistance prediction methods without consideration of hull shape must be avoided, not only in the optimization process, but also for operative research, especially in free sailing analysis.
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