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.

Diagnostic utility of bone marrow examination for the assessment of patients with fever of unknown origin: a 10-year single-centre experience.

Bone marrow (BM) examination is included in the diagnostic algorithm of fever of unknown origin (FUO), although its role is not clearly determined. The purpose of this study was to assess the role of BM studies in patients with FUO. We retrospectively reviewed 45 consecutive patients (25% human immunodeficiency virus-positive) with FUO who underwent a BM study in the University Hospital of Salamanca from 2000 to 2010. We analysed the diagnostic role of BM smears, multiparameter flow cytometry analysis, histology and microbiological cultures. Five patients (11%) were finally diagnosed by BM study (three had an infectious disease and two were found to have haematological malignancies), all of whom were immunocompetent patients. Histology was the most useful study (diagnosis was obtained in 4/5 patients), while BM cultures did not establish the final diagnosis in any patient. Flow cytometry established the diagnosis in one patient, although this patient was also diagnosed by histology. In conclusion, BM study is useful for establishing the aetiology of FUO. BM biopsy for histological examination should be always mandatory if a BM examination is performed.

Inter-comparison of hemispherical conical reflectance factors (HCRF) measured with four fibre-based spectrometers.

We describe the results of an experiment designed to compare the radiometric performance of four different spectroradiometers in ideal field conditions. A carefully designed experiment where instruments were simultaneously triggered was used to measure the Hemispherical Conical Reflectance Factors (HCRF) of four targets of varying reflectance. The experiment was in two parts. Stage 1 covered a 2 hour period finishing at solar noon, where 50 measurements of the targets were collected in sequence. Stage 2 comprised 10 rapid sequential measurements over each target. We applied a method for normalising full width half maximum (FWHM) differences between the instruments, which was a source of variability in the raw data. The work allowed us to determine data reproducibility, and we found that lower-cost instruments (Ocean Optics and PP Systems) produced data of similar radiometric quality to those manufactured by Analytical Spectral Devices (ASD -here we used the ASD FieldSpec Pro) in the spectral range 400-850 nm, which is the most significant region for research communities interested in measuring vegetation dynamics. Over the longer time-series there were changes in HCRF caused by the structural and spectral characteristics of some targets.

EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains.

Transmembrane ephrinB proteins have important functions during embryonic patterning as ligands for Eph receptor tyrosine kinases and presumably as signal-transducing receptor-like molecules. Consistent with "reverse" signaling, ephrinB1 is localized in sphingo-lipid/cholesterol-enriched raft microdomains, platforms for the localized concentration and activation of signaling molecules. Glutamate receptor-interacting protein (GRIP) and a highly related protein, which we have termed GRIP2, are recruited into these rafts through association with the C-terminal PDZ target site of ephrinB1. Stimulation of ephrinB1 with soluble EphB2 receptor ectodomain causes the formation of large raft patches that also contain GRIP proteins. Moreover, a GRIP-associated serine/threonine kinase activity is recruited into ephrinB1-GRIP complexes. Our findings suggest that GRIP proteins provide a scaffold for the assembly of a multiprotein signaling complex downstream of ephrinB ligands.

[Occult renal failure in primary care. A women's problem?]. / Insuficiencia renal oculta en atención primaria. Un problema exclusivo de mujeres?

BACKGROUND: Chronic renal failure is becoming a public health problem. The estimation of glomerular filtration rate (GFR) using the MDRD-4 equation is important to find out patients with impaired renal function. The aim of this study was to determinate the rate of patients took care in Primary Care with "occult" renal failure, defined as a GFR less than 60 mL/min/1.73m2, and serum creatinine levels in the normal range of the laboratory (< 1.3 mg/dL for men, and < 1.2 mg/dL for women). METHODS: Patients over 18 years-old took cared in Primary Care of the health area of Plasencia (Caceres), who were measured serum creatinine level between March to July 2006. We estimated GFR using MDRD-4 formula and classified the level of kidney function according to the NKF-DOQI guidelines. RESULTS: We estimated GFR in 13.784 analyses. In 1.042 the GFR was less than 60 mL/min/1.73m2, from 960 patients (6.96%). Mean age 76.8 years (range 40-98 years). 418 keep normal serum creatinine levels (43.5%). CONCLUSION: Renal impairment seems to be prevalent in the general population took care in Primary Care. An elevated rate of patients with renal failure present serum creatinine levels in the laboratory normal range, "occult" renal failure. The systematic estimation of GFR using MDRD formula is necessary to detect this patients with renal impairment.

Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma.

Flow cytometry has become a highly valuable method to monitor minimal residual disease (MRD) and evaluate the depth of complete response (CR) in bone marrow (BM) of multiple myeloma (MM) after therapy. However, current flow-MRD has lower sensitivity than molecular methods and lacks standardization. Here we report on a novel next generation flow (NGF) approach for highly sensitive and standardized MRD detection in MM. An optimized 2-tube 8-color antibody panel was constructed in five cycles of design-evaluation-redesign. In addition, a bulk-lysis procedure was established for acquisition of ⩾107 cells/sample, and novel software tools were constructed for automatic plasma cell gating. Multicenter evaluation of 110 follow-up BM from MM patients in very good partial response (VGPR) or CR showed a higher sensitivity for NGF-MRD vs conventional 8-color flow-MRD -MRD-positive rate of 47 vs 34% (P=0.003)-. Thus, 25% of patients classified as MRD-negative by conventional 8-color flow were MRD-positive by NGF, translating into a significantly longer progression-free survival for MRD-negative vs MRD-positive CR patients by NGF (75% progression-free survival not reached vs 7 months; P=0.02). This study establishes EuroFlow-based NGF as a highly sensitive, fully standardized approach for MRD detection in MM which overcomes the major limitations of conventional flow-MRD methods and is ready for implementation in routine diagnostics.

[Parry-Romberg progressive facial hemiatrophy: pathogenic and evolutionary considerations with regards to a case followed up for a long period of time]. / Hemiatrofia facial progresiva de Parry-Romberg: consideraciones patogénicas y evolutivas a propósito de un caso con seguimiento prolongado.

INTRODUCTION: The Parry-Romberg syndrome is a clinical condition in which there is progressive facial hemiatrophy which may be associated with neurological, ocular, cutaneous and auto-immune disorders. It is of unknown aetiology, although many theories have been put forward. CLINICAL CASE: We present a case of left facial hemiatrophy associated with ipsilateral lingual hemiatrophy and signs of cortico-cerebellar dysfunction, the neuroimaging findings (NMR) and clinico-radiological follow-up covered a period of over 10 years. CONCLUSION: The data on the clinical course and neuroimaging, together with our review of the literature, suggest that the Parry-Romberg syndrome may be considered to be a dysgenetic process which may originate during the first stages of CNS embryogenesis.

[Malignant middle cerebral artery infarction: medical or surgical treatment?]. / Infarto maligno de la arteria cerebral media: tratamiento médico o quirúrgico?

INTRODUCTION: Post-ischemic brain edema occurs in 10-20% of cases of infarction of the middle cerebral artery and is the main cause of early death following a completed stroke. This complication, which is known as malignant middle cerebral artery infarction (MMCI), has a mortality rate of 78% when treated medically and thus requires a different management, such as a decompressive craniectomy. The main aim of this study is to review this procedure. DEVELOPMENT: We conducted a search in the literature published over the last 20 years on this subject. Most of the studies are series of clinical cases with very favourable surgical outcomes. In non-random case-control studies the mortality rate was seen to decrease in the surgical group, and more so if the intervention was carried out early, as compared to the group that underwent medical treatment. Another study that compared decompressive craniectomy with hypothermia showed a higher survival rate in the surgical group. The post-surgery morbidity rate has not been determined, although it seems to be lower in infarction of the non-dominant hemisphere and in younger patients. CONCLUSIONS: The low degree of conclusiveness of the studies published to date only enables us to offer one practical opinion concerning this issue: decompressive craniectomy should be evaluated on an individual basis in patients with MMCI who do not respond to medical treatment. The final decision and the most appropriate moment to operate on the patient following the stroke must be based on the family's opinion and on the clinical features of the patient.

[Inflammatory pseudotumor: differential diagnosis of tumors of the 4th ventricle]. / Pseudotumor inflamatorio: diagnóstico diferencial de los tumores del IV ventrículo.

INTRODUCTION: An inflammatory pseudotumour is a condition of unknown origin and inflammatory nature. It is rarely found in the CNS. We report a case of inflammatory pseudotumour localized to the IV ventricle and review the clinical characteristics of previously reported cases in order to outline the clinical profile of this condition. CLINICAL CASE: A 40 year old man was admitted to hospital complaining of a subacute condition involving difficulty in speaking and in moving his right arm and leg. On examination he had ocular deviation on initial gaze, a complete right Horner's syndrome, right supranuclear facial palsy, dyssynergy-asymmetry on the right finger-nose test and a dissociated sensitivity disorder of the left arm. On MR of the brain there was a space occupying lesion, nodular in form and fixed to the roof of the fourth ventricle. The histopathological report on the specimen removed by surgery stated it to be an inflammatory pseudotumour. On a MEDLINE search for reported cases of inflammatory pseudotumour of the CNS, 27 were found since 1967. Four cases, including ours, involved masses growing into the interior of the fourth ventricle. CONCLUSIONS: Inflammatory pseudotumour of the CNS is a condition affecting young adults, with a slight male predominance and some association with clinical and analytical data suggesting autoimmune dysfunction. The intraventricular site, particularly within the fourth ventricle, is relatively common (4/28) and is usually associated with clinical features of dysfunction of the posterior fossa and/or intracranial hypertension. We consider that inflammatory pseudotumour should be included in the differential diagnosis of tumours of the fourth ventricle.

[Intra-abdominal tumor in a young man]. / Tumor desmoide intraabdominal en un varón joven.

Desmoid tumor is a rare neoplasm with extra-abdominal location and female predilection. Anatomopatological analysis is necessary to establish the diagnosis unequivocally, but Magnetic Resonance is the no aggressive method with the best sensitivity and specificity. Surgical resection is the elective treatment yet, and prognosis is not so good as it could be expected in a benign tumor. We report a young male case without polyposis coli antecedents. When he was attended, he related only an abdominal bulk with no other symptom. An intra-abdominal mass 32 cm length per 25 cm width consistent with desmoid tumor was finally resected.

[Local thrombolysis in renal artery embolism]. / Fibrinolisis local en el embolismo de la arteria renal.

Renal artery embolism is an infrequent entity that occurs in patients with underlying cardiac diseases. Diagnosis is usually difficult unless the index of suspicion is high. Local thrombolysis with low-dose fibrinolytic agents is an useful therapeutic intervention. We present 2 cases of renal artery embolism treated with intra-arterial urokinase and review clinical features and therapeutic options.

[Acquired experience in anesthesia and perioperative intensive care in percutaneous nephrolithotomy. Current approach in the endoscopic treatment of lithiasis and pyelo-ureteral junction anomalies]. / Expérience acquise en anesthésie et réanimation péri-opératoire dans la néphrolithotomie percutanée. Attitude actuelle dans le traitement endoscopique de la lithiase et de l'anomalie de la jonction pyélo-urétérale.

Percutaneous endoscopic treatment of the kidney retains a place in the treatment of renal stones (percutaneous nephrolithotomy--PCNL) and ureteropelvic junction abnormalities (endopyeloplasty). It requires anaesthesia ensuring surgical comfort and safety for the patients despite changes in position and the prolonged ventral supine position. The operation carries certain iatrogenic risks related to caliceal irrigation in patients with more or less documented episodes of infection and carries risks of haemorrhage and effraction of adjacent organs. 282 patients treated by PCNL between 1984 and 1991 were reviewed in order to define the respective indications for general anaesthesia and peridural anaesthesia and to determine the modalities, to evaluate the risk and severity of absorption of irrigation fluid and to assess the risk of infection by defining the indications for prophylactic antibiotics. General anaesthesia, using etomidate and propofol via an infusion pump, ensures surgical comfort, anaesthetic safety and better control of intraoperative complications. The renewed interest in this technique must be counterbalanced by the growing incidence of anaphylactic reactions related to anaesthetic drugs. Operations lasting more than 2 hours, raised intracaliceal pressure, the initially exclusive use of glycine for irrigation induce haemodilution complications, possibly aggravated by glycine intoxication. Repeated surgery is preferable with the use of an Amplatz tube as often as possible and physiological saline, except when required by the operation. Patients with a history of urinary tract infection or infected stones should receive prolonged and effective antibiotics before, during and after the operation. Prophylactic antibiotics are reserved for those patients with no history of infection. These principles equally apply to percutaneous nephrolithotomy and endopyeloplasty.

[Medical treatment of prostate cancer]. / Traitement médical du cancer de la prostate.

Hormone dependence of prostate cancer is well known. In 80% of cases with metastases, hormone suppression leads to the reduction of tumour volume and related disorders. However the treatment is generally palliative because malignant process recurs after about around 16 months. Mean survival is less than 3 years in these forms. Lack of response come always together with a poor prognosis, and there is 90% mortality at 2 years. Advanced prostatic cancer should not be treated with hormones if the patient has few symptoms and his quality of life is satisfactory. Symptomatic forms require hormone manipulation. Orchidectomy or LH-RH are recommended. Total androgen ablation (combined treatment) leads rapidly to more relief of symptoms, but its drawbacks and especially high cost indicate that its use should be weighed individually. Estramustine is not a first-lune treatment. Presently, there is no criteria to predict response to treatment.

Risk factors for thrombotic microangiopathy in allogeneic hematopoietic stem cell recipients receiving GVHD prophylaxis with tacrolimus plus MTX or sirolimus.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a feared complication of allogeneic hematopoietic SCT (HSCT) owing to its high mortality rate. The use of calcineurin inhibitors or sirolimus (SIR) for GVHD prophylaxis has been suggested as a potential risk factor. However, the impact of tacrolimus (TAC) and SIR combinations on the increased risk of TA-TMA is currently not well defined. We retrospectively analyzed the incidence of TA-TMA in 102 allogeneic HSCT recipients who consecutively received TAC plus SIR (TAC/SIR) (n=68) or plus MTX (TAC/MTX)±ATG (n=34) for GVHD prophylaxis. No significant differences were observed in the incidence of TA-TMA between patients receiving TAC/SIR vs TAC/MTX±ATG (7.4% vs 8.8%, P=0.8). Only grade III-IV acute GVHD, previous HSCT and serum levels of TAC >25 ng/mL were associated with a greater risk of TA-TMA. Patients developing TA-TMA have significantly poorer survival (P<0.001); however, TA-TMA ceased to be an independent prognostic factor when it was included in a multivariate model. In conclusion, the combination of TAC/SIR does not appear to pose a higher risk of TA-TMA. By contrast, we identified three different risk groups for developing TA-TMA.

Multiple cranial neuropathy and intracranial hypertension associated with all-trans retinoic acid treatment in a young adult patient with acute promyelocytic leukemia.

All-trans retinoic acid (ATRA) induces complete remission in 64-100 % of patients with acute promyelocytic leukemia (APL), and is considered to be a safe agent. Pseudotumor cerebri is a neurological side effect of ATRA reported in pediatric patients, and which is characterized by raised cerebrospinal fluid pressure in the absence of any intracranial pathology or secondary causes of intracranial hypertension. Involvement of cranial nerves other than II and VI is very uncommon in idiopathic intracranial hypertension (IIH); peripheral facial nerve palsy is exceptional and has rarely been described in the context of treatment with ATRA. We describe the case of a 15-year-old female patient with APL who developed an IIH and involvement of cranial nerves (bilateral papilledema, left facial and right sixth nerves) after receiving induction therapy including ATRA. Viral infections and other causes of secondary cranial nerve lesions were excluded. Symptoms completely subsided with the temporary withdrawal of ATRA and did not recur after reintroducing the drug. To date, the patient has managed to receive the treatment as per protocol. In conclusion, we report an atypical presentation of IIH that merits consideration, especially with respect to young patients with APL receiving ATRA; our most important observation is that the drug could be safely reintroduced once the symptoms had resolved.