Do NPM1 and FLT3-ITD mutations modify prognosis in patients treated with non-intensive regimens?

FLT3-ITD and NPM1 mutations are key to defining the genetic risk profile of acute myeloid leukemia (AML). We aimed to assess the prognostic features of the FLT3-ITD and NPM1 mutations in old and/or unfit individuals with AML treated with non-intensive therapies in the era before azacitidine-venetoclax approbation. The results of various non-intensive regimens were also compared. We conducted a retrospective analysis that included patients treated with different non-intensive regimens, between 2007 and 2020 from PETHEMA AML registry. We compiled 707 patients with a median age of 74 years and median follow-up time of 37.7 months. FLT3-ITD patients (N = 98) showed a non-significant difference in overall survival (OS) compared to FLT3-ITD negative-patients (N = 608) (P = 0.17, median OS was 5 vs 7.3 months respectively). NPM1-mutated patients (N = 144) also showed a non-significant difference with NPM1 wild type (N = 519) patients (P = 0.25, median OS 7.2 vs 6.8 respectively). In the Cox regression analysis neither NPM1 nor FLT3-ITD nor age were significant prognostic variables for OS prediction. Abnormal karyotype and a high leukocyte count showed a statistically significant deleterious effect. Azacitidine also showed better survival compared to FLUGA (low dose cytarabine plus fludarabine). NPM1 and FLT3-ITD seem to lack prognostic value in older/unfit AML patients treated with non-intensive regimens other than azacitidine-venetoclax combination.

Observational pilot study of patients with carpal tunnel syndrome treated with Nucleo CMP Forte™.

AIM: Carpal tunnel syndrome (CTS) is a very common entrapment neuropathy characterized by pain and paresthesia in the territory of the median nerve. Although this syndrome has a considerable impact on the patient's quality of life, its medical treatment is far from optimal. MATERIAL & METHODS: We performed an observational study to evaluate Nucleo CMP ForteTM in patients with electromyography-confirmed, mild-moderate CTS. Pain was assessed using a visual analog scale, electromyogram and the SF-36. RESULTS: Pain decreased significantly after 6 months. Quality of life improved significantly in the pain dimensions. No significant differences were observed in electromyographic findings. No adverse events were reported. CONCLUSIONS: Nucleotides could prove useful for the nonsurgical treatment of CTS. Further studies are necessary to confirm this.

Contribution of JAK2 mutations to T-cell lymphoblastic lymphoma development.

The JAK-STAT pathway has a substantial role in lymphoid precursor cell proliferation, survival and differentiation. Nonetheless, the contribution of JAK2 to T-cell lymphoblastic lymphoma (T-LBL) development remains poorly understood. We have identified one activating TEL-JAK2 translocation and four missense mutations accumulated in 2 out of 16 T-LBL samples. Two of them are novel JAK2 mutations and the other two are reported for the first time in T-LBL. Notably, R683G and I682T might have arisen owing to RNA editing. Mutated samples showed different mutated transcripts suggesting sub-clonal heterogeneity. Functional approaches revealed that two JAK2 mutations (H574R and R683G) constitutively activate JAK-STAT signaling in γ2A cells and can drive the proliferation of BaF3-EpoR cytokine-dependent cell line. In addition, aberrant hypermethylation of SOCS3 might contribute to enhance the activation of JAK-STAT signaling. Of utmost interest is that primary T-LBL samples harboring JAK2 mutations exhibited increased expression of LMO2, suggesting a mechanistic link between JAK2 mutations and the expression of LMO2, which was confirmed for the four missense mutations in transfected γ2A cells. We therefore propose that active JAK2 contribute to T-LBL development by two different mechanisms, and that the use of pan-JAK inhibitors in combination with epigenetic drugs should be considered in future treatments.

Interrater reliability between scorers from eight European sleep laboratories in subjects with different sleep disorders.

Interrater variability of sleep stage scorings is a well-known phenomenon. The SIESTA project offered the opportunity to analyse interrater reliability (IRR) between experienced scorers from eight European sleep laboratories within a large sample of patients with different (sleep) disorders: depression, general anxiety disorder with and without non-organic insomnia, Parkinson's disease, period limb movements in sleep and sleep apnoea. The results were based on 196 recordings from 98 patients (73 males: 52.3 +/- 12.1 years and 25 females: 49.5 +/- 11.9 years) for which two independent expert scorings from two different laboratories were available. Cohen's kappa was used to evaluate the IRR on the basis of epochs and intraclass correlation was used to analyse the agreement on quantitative sleep parameters. The overall level of agreement when five different stages were distinguished was kappa = 0.6816 (76.8%), which in terms of kappa reflects a 'substantial' agreement (Landis and Koch, 1977). For different groups of patients kappa values varied from 0.6138 (Parkinson's disease) to 0.8176 (generalized anxiety disorder). With regard to (sleep) stages, the IRR was highest for rapid eye movement (REM), followed by Wake, slow-wave sleep (SWS), non-rapid eye movement 2 (NREM2) and NREM1. The results of regression analysis showed that age and sex only had a statistically significant effect on kappa when the (sleep) stages are considered separately. For NREM2 and SWS a statistically significant decrease of IRR with age has been observed and the IRR for SWS was lower for males than for females. These variations of IRR most probably reflect changes of the sleep electroencephalography (EEG) with age and gender.

Proof of safety of drugs: focus on vigilance.

It is well accepted that all new compounds, before administration to patients, should undergo safety evaluations in healthy subjects, including central nervous system (CNS) toxicity and as such the assessment of vigilance effects a relevant hallmark. The original concept of vigilance as a phenomenon observed only under conditions of monotony and signal regularity is increasingly falling into disfavor, embracing at present a much broader spectrum of behavior. Currently, vigilance may be regarded as a "readiness to adopt the appropriate behavior in a given situation, which thus finds outward expression through the quality and quantity of the behavior occurring in response to a given (internal or external) stimulus situation". The assumption that vigilance is a multifactorial phenomenon and not merely EEG data should be taken into account in order to study it accurately. Specifically, in drug research, apart from subjective reports and psychomotor performance tests, neurophysiological evaluations are regularly used such as Multiple Sleep Latency Test, Vigilance Epoch Classification or Parameters within a continuous scale. Although with limitations, temporal patterns of changes in activity of different frequency bands, indexes as the alpha slow-wave or the alpha anteriorization, computed from the EEG quantification, yielded different definitions of the intermediate states of the transition from wakefulness to sleep through the so-called subvigil stages. Spatial patterns are less documented. The recently proposed mathematical models to explain and predict variations in alertness are presented. Examples of the effects of different classes of drugs with the methods reported and its theoretical and practical relevance to vigilance research are introduced.

A short hypoosmotic swelling test for the prediction of boar sperm fertility.

This study was designed to explore the relationship between the ejaculate response to a hypoosmotic swelling test (HOST) and in vivo fertility in a group of 38 boars The hypoosmotic test used was a modification of the HOST that involves a shorter incubation time (5 vs 120 min) and lower osmotic pressure (75 vs 150 mOsm/kg). Ejaculates containing less than 20% abnormal spermatozoa were selected and checked for percentage of motility, percentage of normal acrosomes, percentage of short ORT and percentage of cells showing positive short HOST (sHOST) results Two hundred eightyeight sows were inseminated to obtain in vivo fertility and prolificacy data. No differences were shown between technicians in the sHOST results obtained. Significant differences were recorded between boars in sHOST results (p < 0.002). Only the sHOST result presented a significant correlation with in vivo fertility (r = 0.43, p < 0.01). Short HOST data significantly improved fertility prediction of routine semen analysis tests. Unlike motility and acrosomal status, sHOST values showed a significant decrease when fresh ejaculates (37 degrees C) were stored for 24 h at 15 degrees C, indicating possible damage due to cold shock.

[Monoaminergic selectivity of the antidepressive drugs and sleep: neurophysiological implications of depression]. / Selectividad monoaminérgica de los antidepresivos y sueño: implicación neurofisiológica de la depresión.

OBJECTIVES: To obtain better understanding of the neurophysiology of sleep and of depression, together with any relationship there might be between them. DEVELOPMENT: We review the mechanisms of action of the neurotransmitters involved in the sleep-waking cycle, and also the antidepressive drugs, concentrating on those with more selective mechanisms of action, and the selective serotonin re-uptake inhibitors. CONCLUSIONS: It is well know that the disorders associated with sleep play a predominant part in the symptoms of depressed patients, and these may revert with antidepressant treatment. Antidepressants cause, often markedly, changes in the characteristics of sleep at the same time as they improve the depressive symptoms. Thus, knowing the basis of the mode of action of antidepressive drugs, not only does the understanding of the neurophysiology of sleep progress, but also the understanding of sleep.

Polyphenols as potential markers to differentiate juvenile and mature chestnut shoot cultures.

The phenolic contents of eight in-vitro-cultivated chestnut clones (Castanea sativa Mill. and C. sativa x C. crenata Siebold & Zucc. hybrids) were analyzed both qualitatively and quantitatively. The aim of the work was to identify potential phenolic markers of: (i) juvenile or mature state; (ii) topophysical origin; and (iii) rooting capacity. A condensed tannin was detected in mature material but not in juvenile material, indicating that it could be used as a qualitative marker. Other qualitative phenolic differences were found between basal shoots and crown shoots of some clones, but it was not possible to discriminate among these materials in a general way. Canonical discriminant analysis was used for the study of quantitative markers. Differentiation between mature and juvenile material, and between materials differing in in vitro rooting capacity was possible according to the results of the analysis. Nevertheless, no significant quantitative differences were found between the phenolic content of material of basal shoot origin and that of crown shoot origin, indicating that the greater juvenility of material of basal origin compared with that of crown origin was not reflected in differences in phenolic content.

Absence of influence of prior treatment with interferon on the outcome of allogeneic bone marrow transplantation for chronic myeloid leukemia.

Timing of transplantation in the chronic phase of chronic myeloid leukemia (CML) and previous treatment with interferon remains controversial. We have tried to discover what influence pretreatment with interferon alpha (IFN-A) has on the results of allogeneic bone marrow transplantation for CML patients treated in a single institution. Fifty-one consecutive patients with chronic phase Ph-positive CML who received an allogeneic bone marrow transplantation from a HLA-identical familial donor were evaluated. Thirty had been treated with IFN-A (IFN+ group) prior to BMT and twenty-one had not (IFN- group). Both groups were homogeneous for clinical characteristics such as age, sex, previous chemotherapy, disease status, and time from diagnosis to transplant. No difference was found in neutrophil and platelet count recovery between the IFN+ and IFN- group. The incidence of acute and chronic GVHD, VOD and severe mucositis was not significantly different. Relapse and both overall survival and DFS were similar for both groups. No adverse effects of prior IFN exposure on the outcome of HLA-identical sibling donor BMT for chronic phase CML patients were found in this study.

The anterior inferior cerebellar artery infarcts: a clinical-magnetic resonance imaging study.

Acute infarcts of the anterior inferior cerebellar artery (AICA) are unusual. We report 15 cases of AICA infarcts and their correlation with the topography of the lesion by brain MRI. During 2 years we prospectively identified 7 cases of AICA infarcts among 770 acute strokes (0.9% of the acute strokes seen in our department). We studied these cases and also another 8 that we found retrospectively. Most patients (8/15) had a unilateral affectation of both middle cerebellar peduncle (MCP) and inferior lateral pontine area (ILP), in these cases the main symptoms were vertigo, ataxia, peripheral facial palsy and hypoacusia. Two other patients had isolated MCP infarcts and were characterized by peripheral vertigo and ataxia, without hypoacusia or facial palsy. Another 2 patients had isolated ILP territory infarct characterized by vertigo, left peripheral facial palsy without hypoacusia and mild or no ataxia. One patient had a Gasperini syndrome. Finally 3 patients had bilateral AICA infarcts due to basilar thrombosis. The etiology was atherosclerosis in 9 patients, lacunar due to hypertension in 1, cardiac embolism in 1, migraine in 1 and unknown in 3. Among the 15 patients only 2 died, both with AICA plus infarcts. In the remaining patients a follow-up during a mean of 31 months (3 months to 12 years) showed no recurrences.

Comparison of peripheral blood progenitor cell mobilization in patients with multiple myeloma: high-dose cyclophosphamide plus GM-CSF vs G-CSF alone.

The best method for peripheral blood progenitor cell (PBPC) mobilization in patients with multiple myeloma (MM) remains controversial. We report the results of two different methods of PBPC collection for autologous transplantation in 40 patients with stage II or III MM. In group I (n = 18), HD-CY, 4 g/m2 i.v., was administered followed by GM-CSF, 8 microg/kg/day s.c., until the end of collection, starting the leukaphereses after hematological recovery (>1 x 10(9)/l WBC). In group II (n = 22), G-CSF, 10 microg/kg/day s.c., was used alone until the last day of collection, starting consecutive aphereses on the 5th day. A minimum of two aphereses were performed to collect at least 2 x 10(6)/kg CD34+ cells. Both patient groups were comparable for age, sex and clinical prognostic features as well as previous therapies. In group I, the median yields per pheresis were: MNC 1.47 (1.38-2.32) x 10(8)/kg, CFU-GM 0.82 (0.18-13.2) x 10(4)/kg and CD34+ cells 1.98 (0.96-6.96) x 10(6)/kg. In group II these results were: MNC 2.44 (2.06-3.6 x 10(8)/kg) (P = 0.03), CFU-GM 0.75 (0.16-7.8) x 10(4)/kg and CD34+ 1.05 (0.32-3.4) x 10(6)/kg (P = 0.02). The median number of aphereses performed in each group was 5 (4-12) with a median of 5.24 +/- 2.51 in group I and 3 (2-6) with a median of 3.1 (+/- 0.91) in group II (P = NS). Hospitalization for PBPC mobilization was required in all patients in group I and the treatment-related toxicity was greater in this group: 12 patients (66%) developed fever requiring antibiotics during the neutropenic period after HD-CY and six (33%) patients required transfusion support. After receiving busulfan 12 mg/kg p.o. and melphalan 140 mg/m2 i.v., as the conditioning regimen, the median periods to reach granulocytes (>0.5 x 10(9)/l) and platelet (>20 x 10(9)/l) engraftment were 12 and 11 days respectively (ranges 8-20 and 10-16) in group I (HD-CY plus GM-CSF group), and 11 and 13 days respectively (ranges 7-42 and 10-38) in group II (G-CSF group) (P = NS). In conclusion, these data suggest that although HD-CY plus GM-CSF is superior to G-CSF alone based on mean CD34+ cell yield per pheresis, adequate CD34+ cell collections can be achieved with G-CSF alone in most MM patients with less toxicity and with simplification of the procedure.

Results of a pilot study of 40 patients using high-dose therapy with hematopoietic rescue after standard-dose adjuvant therapy for high-risk breast cancer.

The study was designed to determine the toxicity, feasibility, and effectiveness of high-dose cyclophosphamide (6 g/m2), thiotepa (500 mg/m2) and carboplatin (800 mg/m2 (CTCb) with hematopoietic rescue as consolidation after standard-dose adjuvant chemotherapy treatment of primary high-risk breast cancer. From October 1991 to September 1994, 40 patients with stage II or III breast cancer involving 10 or more nodes were treated with CTCb after six cycles of adjuvant therapy with an anthracycline-containing regimen. Bone marrow (BM) was used as the source hematopoietic stem cell in the first 23 patients and G-CSF-mobilized peripheral blood progenitor cells (PBPC) in the other 17. No therapy-related deaths occurred, but three life-threatening Complications were recorded which resolved: bilateral pulmonary hemorrhage, veno-occlusive disease of the liver and pulmonary thromboembolism. PBPC result in faster hemopoietic reconstitution with significantly lower transfusion requirements. With a median follow-up of 35 months (23-59) actuarial event-free survival for the study patients at 3 years is 72% (CI 95%: 66-81%). Even in patients over 50-60 years, CTCb is a relatively well tolerated regimen which appears, after a median follow-up of nearly 3 years, to decrease relapse frequency as compared with historical series, although a definite role of HDT in the treatment of high-risk primary breast cancer needs confirmation in prospective randomized trials.

Urodynamically based modification of Mitrofanoff procedure.

This paper reviews our experience with the Mitrofanoff principle as applied in eight patients. Of four patients with post-traumatic urethral stricture, three required the appendix as continent catheterizable conduit, with a modified appendicovesical anastomosis technique-that is, without a submucosal tunnel- and in one patient, the remnant ureter of a previous simple nephrectomy was used. Of the four remaining patients, one with a hypotonic bladder and three with urethral stricture, a complete laparoscopic approach was used to perform the same modified Mitrofanoff procedure with the appendix. With a mean follow-up of 19.5 months, all patients were completely dry. Only three patients had persistently positive urine cultures, but without evidence of renal function impairment. The modified direct appendicovesical anastomosis technique reduces the operative time, has a lower complication rate, and allows us to use a laparoscopic approach with the resulting benefits of a minimally invasive surgical procedure. As shown in urodynamic tests, urinary continence is preserved.

[Imipenem combined with teicoplanin or vancomycin in the initial empirical treatment of febrile neutropenia. Analysis of the primary response and of a global sequential strategy in 126 episodes]. / Imipenem combinado con teicoplanina o vancomicina en el tratamiento empírico inicial de la neutropenia febril. Análisis de la respuesta primaria y de una estrategia secuencial global en 126 episodios.

The results of empiric antibiotic therapy in 126 episodes of febrile neutropenia in patients with hematologic neoplasms postchemotherapy and bone marrow transplantation are presented. The main objective of this work was the study of the initial control of infection comparing two glycopeptidic antibiotics: vancomycin and teicoplanin combined with imipenem in first line of empiric therapy. The secondary objective was to analyze the overall control of infection during the complete episode of neutropenia using a sequential empiric antibiotic therapy course which included the addition of amikacin followed by intravenous amphotericin B when fever persisted or recurred without microbiological documentation. Both initial courses (no guidelines), imipenem + vancomycin (arm A) and imipenem + teicoplanin (arm B) resulted in a similar percentage of response at 72 hours, both in episodes of fever of unknown origin (FUO) (55% and 68%, respectively; p = NS) and in those microbiologically documented (54% and 34.5%, p = NS); 58% and 79% of these episodes, respectively, were caused by gram-positive organisms. About 60% of patients in both arm ultimately required the empiric addition of amikacin, with or without amphotericin B, because of persistence or recurrence of fever; the percentage of overall responses in both arm did not differ significantly, both in FUO (70% and 86%, p = NS) and in microbiologically documented episodes (71% and 45%, p = NS). The overall infectious mortality for the whole group was 1.58%. In conclusion, no significant differences were observed in the clinical response or in toxicity between the combination of imipenem with any of the two glycopeptides: vancomycin or teicoplanin, for the initial empiric therapy of febrile neutropenia. The sequential empiric use of amikacin followed by amphotericin B assured an adequate overall control of infection in a group of patients with prolonged severe neutropenia.

Autologous or allogeneic bone marrow transplantation for acute myeloblastic leukemia in second complete remission. Importance of duration of first complete remission in final outcome.

Between May 1983 and March 1994, 31 patients with AML in second CR underwent BMT. Fifteen underwent allogeneic BMT from an HLA-identical sibling donor and 16 without a donor, unpurged ABMT. Two different preparative regimens were used: CY (120 mg/kg) and 12 Gy of fractioned TBI (19 patients), and Bu (16 mg/kg) and Cy (120 mg/kg) (BuCy2) in 12 patients. Main clinical characteristics including age, sex, length of first remission, FAB type, and number of leukocytes at diagnosis were similar in both groups. A combination of MTX and CsA was used in 13 cases whereas either CsA or MTX alone was employed in the other two patients. With a median follow-up of 5 years the actuarial 5 year probability of disease-free survival (DFS) for the whole group was 39.8% (95% CI: 29.5-50.1%). The 5 year DFS was equivalent for those who received either ABMT (41.6 +/- 14.2%) or allogeneic BMT (40 +/- 15%). Probabilities of relapse and non-relapse mortality for ABMT and allo BMT patients were 48.7 +/- 16.1 and 18.7 +/- 14.3, and 30.1 +/- 19.2 and 40.7 +/- 16.9, respectively. DFS was better in those patients with a longer duration of first CR (> 18 months) 62.5 +/- 14.4 vs 30.4 +/- 17.9%, attributable to a significantly lower relapse rate in this group of patients 16.6 +/- 12.8 vs 57.8 +/- 22.7 (P 0.05). In conclusion, similar results were observed when ABMT and allo BMT were compared for AML in CR2. A higher antileukemic effect associated with the allo BMT is balanced by an increase in transplant-related mortality. Duration of first remission was the most important factor affecting DFS and better outcome was observed for patients with longer CR1.

Fludarabine in resistant or relapsing B-cell chronic lymphocytic leukemia: the Spanish Group experience.

Fludarabine produces high response rates in patients with B-cell chronic lymphocytic leukemia (CLL). Nevertheless, response to fludarabine of patients with previously treated CLL varies from 17% to 74% (0% to 38% CR). In 68 patients with heavily pretreated and advanced CLL, an overall response rate to fludarabine of 28% (4% CR) was observed. Response correlated with sensitivity of the disease to previous treatments (relapsing vs. refractory disease) (62% vs. 20%; p = 0.005) and, albeit not significantly, with the number of cycles of fludarabine (>3 vs. < or = 3) that patients could receive (36% vs. 15%; p = NS). Responding patients had a longer survival (median, not reached) than those not responding (median, 11 months) (p = 0.03). Severe toxicity was observed in some cases. It is concluded that fludarabine is a highly useful agent in CLL. However, in order to improve its effectiveness and decrease its toxicity, fludarabine should be given as soon as a lack of response to front-line therapy is observed and before the disease becomes completely resistant to therapy.