Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

Progressive computed tomography (CT) appearances preceding malignant spinal cord compression (MSCC) in men with castration-resistant prostate cancer.

AIM: To test the hypothesis that computed tomography (CT)-based signs might precede symptomatic malignant spinal cord compression (MSCC) in men with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: A database was used to identify suitable mCRPC patients. Staging CT images were retrospectively reviewed for signs preceding MSCC. Signs of malignant paravertebral fat infiltration and epidural soft-tissue disease were defined and assessed on serial CT in 34 patients with MSCC and 58 control patients. The presence and evolution of the features were summarized using descriptive statistics. RESULTS: In MSCC patients, CT performed a median of 28 days prior to the diagnostic magnetic resonance imaging (MRI) demonstrated significant epidural soft tissue in 28 (80%) patients. The median time to MSCC from a combination of overt malignant paravertebral and epidural disease was 2.7 (0-14.6) months. Conversely, these signs were uncommon in the control cohort. CONCLUSIONS: Significant malignant paravertebral and/or epidural disease at CT precede MSCC in up to 80% of mCRPC patients and should prompt closer patient follow-up and consideration of early MRI evaluation. These CT-based features require further prospective validation.

Effect of selective dopamine D3 and D4 receptor agonists on trunk pulmonary artery vascular reactivity from control and monocrotaline-treated rats.

Dopamine D1-like and D2-like receptors are expressed in the pulmonary arteries, however there is a little information about their effect on vascular tone in pulmonary circulation, even the vascular effect of activation of the dopamine D3 and D4 subtypes in physiological and pathological conditions such as pulmonary hypertension is unknown. The objective of this study was to evaluate the vascular response of trunk pulmonary artery rings from saline and monocrotaline-treated rats in the presence of selective dopamine receptor agonists. In trunk pulmonary artery rings with intact and denuded endothelium, cumulative concentration-response curves were performed for phenylephrine, acetylcholine, and dopamine receptor agonists (apomorphine-D2-like, SKF38393-D1, quinpirole-D2/D3, 7-OH-DPATD3, and PD168077-D4) alone and in the presence of corresponding selective dopamine receptor antagonists (SCH23390-D1, raclopride-D2/D3, U99194 maleate-D3, and L-745,870-D4). Contractile and relaxant effects generated during the activation with phenylephrine and acetylcholine, respectively, were significantly reduced in intact and denuded endothelium trunk pulmonary artery rings from monocrotaline rats in comparison with control rats. All dopamine receptor agonists, except the 7-OH-DPAT, produced significant vascular relaxation in intact trunk pulmonary artery rings precontracted with phenylephrine in both experimental groups. Also, the vascular relaxation of SKF38393, and particularly apomorphine and PD168077 was significant in denuded endothelium trunk pulmonary artery rings from control and monocrotaline groups. Furthermore, the vasorelaxation induced by these dopamine agonists was significantly reduced in pulmonary preparations from monocrotaline-treated rats in comparison to that recorded in preparations from control rats. The effect of dopamine receptor agonists decreased significantly in the presence of the corresponding antagonist in both experimental groups. The results support that dopamine D4 receptor agonist induces significant vascular relaxation, whereas dopamine D3 receptor agonist induces vasoconstriction in intact and denuded endothelium trunk pulmonary artery rings in control and monocrotaline-induced pulmonary arterial hypertension rats.

Diffuse Large B-Cell Epstein-Barr Virus-Positive Primary CNS Lymphoma in Non-AIDS Patients: High Diagnostic Accuracy of DSC Perfusion Metrics.

BACKGROUND AND PURPOSE: Immunodeficiency-associated CNS lymphoma may occur in different clinical scenarios beyond AIDS. This subtype of CNS lymphoma is diffuse large B-cell and Epstein-Barr virus-positive. Its accurate presurgical diagnosis is often unfeasible because it appears as ring-enhancing lesions mimicking glioblastoma or metastasis. In this article, we describe clinicoradiologic features and test the performance of DSC-PWI metrics for presurgical identification. MATERIALS AND METHODS: Patients without AIDS with histologically confirmed diffuse large B-cell Epstein-Barr virus-positive primary CNS lymphoma (December 2010 to January 2022) and diagnostic MR imaging without onco-specific treatment were retrospectively studied. Clinical, demographic, and conventional imaging data were reviewed. Previously published DSC-PWI time-intensity curve analysis methodology, to presurgically identify primary CNS lymphoma, was used in this particular lymphoma subtype and compared with a prior cohort of 33 patients with Epstein-Barr virus-negative CNS lymphoma, 35 with glioblastoma, and 36 with metastasis data. Normalized curves were analyzed and compared on a point-by-point basis, and previously published classifiers were tested. The standard percentage of signal recovery and CBV values were also evaluated. RESULTS: Seven patients with Epstein-Barr virus-positive primary CNS lymphoma were included in the study. DSC-PWI normalized time-intensity curve analysis performed the best for presurgical identification of Epstein-Barr virus-positive CNS lymphoma (area under the receiver operating characteristic curve of 0.984 for glioblastoma and 0.898 for metastasis), followed by the percentage of signal recovery (0.833 and 0.873) and CBV (0.855 and 0.687). CONCLUSIONS: When a necrotic tumor is found in a potentially immunocompromised host, neuroradiologists should consider Epstein-Barr virus-positive CNS lymphoma. DSC-PWI could be very useful for presurgical characterization, with especially strong performance of normalized time-intensity curves.

Presurgical Identification of Primary Central Nervous System Lymphoma with Normalized Time-Intensity Curve: A Pilot Study of a New Method to Analyze DSC-PWI.

BACKGROUND AND PURPOSE: DSC-PWI has demonstrated promising results in the presurgical diagnosis of brain tumors. While most studies analyze specific parameters derived from time-intensity curves, very few have directly analyzed the whole curves. The aims of this study were the following: 1) to design a new method of postprocessing time-intensity curves, which renders normalized curves, and 2) to test its feasibility and performance on the diagnosis of primary central nervous system lymphoma. MATERIALS AND METHODS: Diagnostic MR imaging of patients with histologically confirmed primary central nervous system lymphoma were retrospectively reviewed. Correlative cases of glioblastoma, anaplastic astrocytoma, metastasis, and meningioma, matched by date and number, were retrieved for comparison. Time-intensity curves of enhancing tumor and normal-appearing white matter were obtained for each case. Enhancing tumor curves were normalized relative to normal-appearing white matter. We performed pair-wise comparisons for primary central nervous system lymphoma against the other tumor type. The best discriminatory time points of the curves were obtained through a stepwise selection. Logistic binary regression was applied to obtain prediction models. The generated algorithms were applied in a test subset. RESULTS: A total of 233 patients were included in the study: 47 primary central nervous system lymphomas, 48 glioblastomas, 39 anaplastic astrocytomas, 49 metastases, and 50 meningiomas. The classifiers satisfactorily performed all bilateral comparisons in the test subset (primary central nervous system lymphoma versus glioblastoma, area under the curve = 0.96 and accuracy = 93%; versus anaplastic astrocytoma, 0.83 and 71%; versus metastases, 0.95 and 93%; versus meningioma, 0.93 and 96%). CONCLUSIONS: The proposed method for DSC-PWI time-intensity curve normalization renders comparable curves beyond technical and patient variability. Normalized time-intensity curves performed satisfactorily for the presurgical identification of primary central nervous system lymphoma.

Mineral sequestration of CO(2) by aqueous carbonation of coal combustion fly-ash.

The increasing CO(2) concentration in the Earth's atmosphere, mainly caused by fossil fuel combustion, has led to concerns about global warming. A technology that could possibly contribute to reducing carbon dioxide emissions is the in-situ mineral sequestration (long term geological storage) or the ex-situ mineral sequestration (controlled industrial reactors) of CO(2). In the present study, we propose to use coal combustion fly-ash, an industrial waste that contains about 4.1 wt.% of lime (CaO), to sequester carbon dioxide by aqueous carbonation. The carbonation reaction was carried out in two successive chemical reactions, first, the irreversible hydration of lime. second, the spontaneous carbonation of calcium hydroxide suspension. A significant CaO-CaCO(3) chemical transformation (approximately 82% of carbonation efficiency) was estimated by pressure-mass balance after 2h of reaction at 30 degrees C. In addition, the qualitative comparison of X-ray diffraction spectra for reactants and products revealed a complete CaO-CaCO(3) conversion. The carbonation efficiency of CaO was independent on the initial pressure of CO(2) (10, 20, 30 and 40 bar) and it was not significantly affected by reaction temperature (room temperature "20-25", 30 and 60 degrees C) and by fly-ash dose (50, 100, 150 g). The kinetic data demonstrated that the initial rate of CO(2) transfer was enhanced by carbonation process for our experiments. The precipitate calcium carbonate was characterized by isolated micrometric particles and micrometric agglomerates of calcite (SEM observations). Finally, the geochemical modelling using PHREEQC software indicated that the final solutions (i.e. after reaction) are supersaturated with respect to calcium carbonate (0.7 < or = saturation index < or = 1.1). This experimental study demonstrates that 1 ton of fly-ash could sequester up to 26 kg of CO(2), i.e. 38.18 ton of fly-ash per ton of CO(2) sequestered. This confirms the possibility to use this alkaline residue for CO(2) mitigation.

Causes and impacts of a mine water spill from an acidic pit lake (Iberian Pyrite Belt).

In May 2017, a spill from La Zarza pit lake (SW Spain) resulted in the release of approximately 270,000 m3 of extremely acidic waters to the Odiel River. Around 780 × 103 kg of Fe, 170 × 103 kg of Al, 2.15 × 103 kg of As and high amounts of other trace metals and metalloids were spilled. The purpose of this study is to explain the causes, consequences and impacts of the mine spill on the receiving water bodies. To this end, an extensive sampling along the mine site, river and estuary as well as a hydrological model of the pit lake was performed. Around 53 km of the Odiel River's main course, which was already contaminated by acid mine drainage (AMD), were affected. The mine spill resulted in an incremental impact on the Odiel River water quality. Thus, dissolved concentrations of some elements increased in the river up to 450 times; e.g. 435 mg/L of Fe and 0.41 mg/L of As. Due to low pH values (around 2.5), most metals (e.g., Cu, Zn, Mn, Cd) were transported in the dissolved phase to the estuary, exhibiting a conservative behavior and decreasing their concentration only due to dilution. However, dissolved concentrations of Fe, Cr, Pb, Se, Sb, Ti, V and especially As decreased significantly along the river due to Fe precipitation and sorption/coprecipitation processes. At the upper zone of the estuary, a noticeable increment of metal concentrations (up to 77 times) was also recorded. The water balance illustrates the existence of groundwater inputs (at least 16% of total) to the pit lake, due probably to local infiltration of rainwater at the mining zone. The probable existence of an ancient adit connected to the pit lake indicates that potential releases could occur again if adequate prevention measures are not adopted.

Validation of the BCR sequential extraction procedure for natural radionuclides.

Determining the availability of natural radionuclides in environmental conditions is increasingly important in order to evaluate their toxicity. A validated procedure is necessary to ensure the comparability and accuracy of the results obtained by different laboratories. For that, an optimised BCR sequential extraction procedure has been applied to the certified reference material (CRM), coded as BCR-701, and their resulting liquid and solid fractions were subjected to an exhaustive chemical and radioactivity characterisation. In this sense, several material characterisation techniques were used for chemical, mineralogical, and radioactive characterisation, in order to gain basic information about the obtained fractions. In accordance with the results of this work, the BCR sequential extraction procedure has been validated for the most significant alpha-emitter natural radionuclides (210Po, 234U, 238U, 230Th, 232Th, and 226Ra). It has been demonstrated that their mobility is related to the speciation under environmental conditions and the type of radionuclide; we have even found differences between radionuclides of the same element, such as the cases of the pairs 234U238U and 230Th232Th, for the BCR-701. In addition, we found that radium was mainly bound to the reducible fraction (Fe and Mn-oxyhydroxides), uranium to the oxidizable fraction (organic matter and sulphides), and that the polonium and thorium isotopes had a high affinity with the particulate phase (non-mobile fraction).

Assessment of natural radionuclides mobility in a phosphogypsum disposal area.

The phosphogypsum (PG) stacks located at Huelva (SW Spain) store about 100 Mt of PG, and covers a surface of 1000 ha. It has been very well established in many studies that this waste contains significant U-series radionuclides concentrations, with average activity concentrations rounding the 650, 600, 400 and 100 Bq kg-1 for 226Ra, 210Po, 230Th and 238U, respectively. However, the radionuclide transfer from this repository into the environment by the aquatic pathway will depend on the mobility of each radionuclide. The mobility of the natural radionuclides (U-isotopes, Th-isotopes, 226Ra, and 210Po) contained in the PG piles were evaluated by using the optimized BCR sequential extraction procedure (BCR "Community Bureau of Reference"). The radionuclides were measured in the liquid fractions by alpha-particle spectrometry with semiconductor PIPS detectors. In addition, to validate the obtained results, waters from different locations of the PG piles (pore-water, perimeter channel and edge outflow leachates) were taken and the alpha emitter radionuclides determined. Uranium presents the highest mobility, being its total mobile fraction in the PG around 70%, while 210Po and 226Ra present an intermediate mobility of (around 50% and 30%, respectively). And finally, the Th-isotopes have very low mobility (mobile fraction < 5%), being fixed to the residual fraction. It is noteworthy that this behaviour has been also found in the water samples taken from the stacks, demonstrating that this sequential leaching operational methodology is a useful tool for assessing the release capacity of radionuclides by inorganic wastes.

Metal and acidity fluxes controlled by precipitation/dissolution cycles of sulfate salts in an anthropogenic mine aquifer.

Underground mine drainages are extremely difficult to study due to the lack of information about the flow path and source proximity in relation to the outflow adit. Geochemical processes controlling metals and acidity fluxes in a complex anthropogenic mine aquifer in SW Spain during the dry and rainy season were investigated by geochemical and statistical tools. High concentrations of acidity, sulfate, metals and metalloids (e.g. Fe, Cu, Zn, As, Cd, Ni, Co) were observed due to intense sulfide oxidation processes. The high residence time inside the anthropogenic aquifer, around 40days, caused the release of significant quantities of metals linked to host rocks (e.g. Al, Ca, Ge, Li, Mg, REE). The most outstanding characteristic of the acid mine drainage (AMD) outflows is the existence of higher Fe/SO4 molar ratios than those theoretical of pyrite (0.50) during most of the monitored period, due to a fire which occurred in 1949 and remained active for decades. Permanent and temporal retention mechanisms of acidity and metals were observed in the galleries. Once released from sulfide oxidation, Pb and As are sorbed on Fe oxyhydroxysulfate or precipitated as low solubility minerals (i.e. anglesite) inside the galleries. The precipitation of evaporitic sulfate salts during the dry season and the subsequent re-dissolution after rainfall control the fluxes of acidity and main metals (i.e. Fe, Mg, Al) from this anthropogenic aquifer. Some elements, such as Cd, Cu, Ni, REE and Zn, are retained in highly soluble sulfate salts while other elements, such as Ge, Pb and Sc, have a lower response to washout processes due to its incorporation in less soluble sulfate salts. In this way, metal concentration during the washout processes would be controlled by the proportion and solubility of each type of evaporitic sulfate salt stored during the dry season. The recovery of metals of economic interest contained in the AMD could help to self-finance the remediation of these waters in derelict mines worldwide.

Long-term evolution of liver histopathology in patients with chronic hepatitis C and sustained response.

OBJECTIVE: To evaluate the evolution of histological changes observed in patients with chronic hepatitis C (CHC) and sustained response (SR) compared to non-responders (NR) to antiviral treatment. METHODS: A retrospective study was performed in a total of 176 patients with CHC. These were divided into two groups: 132 SR and 44 NR. All had undergone a basal liver biopsy prior to treatment onset. A second biopsy was performed in 143 patients, 104 SR and 39 NR. Inflammatory activity and the degree of liver fibrosis was measured by Metavir units (MU). The progression and regression index of fibrosis was calculated before and after treatment. The time elapsed between the two biopsies was 5.9 +/- 0.3 years for SR and 6.6 +/- 0.3 years for NR (NS). RESULTS: At baseline, 53% of SR patients had mild, chronic active hepatitis (CAH), while this was moderate in 43% of NR patients (p < 0.0001). The time elapsed between baseline and post-treatment liver biopsies was 5.9 +/- 0.3 years for SR subjects and 6.6 +/- 0.4 years for NR subjects (NS). After antiviral treatment 47% of SR subjects presented a normal liver or minimal changes, whilst mild CAH persisted in 34.4% and moderate CAH in 37.5% of NR subjects. Necro-inflammatory activity decreased by 50% in SR subjects and by 15% in NR subjects (p < 0.0001), and fibrosis decreased by 82% in SR subjects (p < 0.0001) and by 66% in NR subjects (p < 0.001). Fibrosis progression index was 0.14 MU/year in SR subjects and 0.21 MU/year in NR subjects (NS). Fibrosis regression index was -0.11 in SR subjects and -0.14 in NR subjects (NS). CONCLUSIONS: In our series of patients with CHC and SR, we observed histological normalization in approximately fifty per cent of cases during long-term follow-up. NR subjects also showed improvement, especially in the fibrosis score. Both groups showed a marked regression of liver fibrosis after treatment.

Fractionation and fluxes of metals and radionuclides during the recycling process of phosphogypsum wastes applied to mineral CO2 sequestration.

The industry of phosphoric acid produces a calcium-rich by-product known as phosphogypsum, which is usually stored in large stacks of millions of tons. Up to now, no commercial application has been widely implemented for its reuse because of the significant presence of potentially toxic contaminants. This work confirmed that up to 96% of the calcium of phosphogypsum could be recycled for CO2 mineral sequestration by a simple two-step process: alkaline dissolution and aqueous carbonation, under ambient pressure and temperature. This CO2 sequestration process based on recycling phosphogypsum wastes would help to mitigate greenhouse gasses emissions. Yet this work goes beyond the validation of the sequestration procedure; it tracks the contaminants, such as trace metals or radionuclides, during the recycling process in the phosphogypsum. Thus, most of the contaminants were transferred from raw phosphogypsum to portlandite, obtained by dissolution of the phosphogypsum in soda, and from portlandite to calcite during aqueous carbonation. These findings provide valuable information for managing phosphogypsum wastes and designing potential technological applications of the by-products of this environmentally-friendly proposal.

A comparison between two induction regimes for the interferon treatment of chronic hepatitis C. Response related factors.

Treatment of chronic hepatitis C with alfa interferon for 6 months achieves sustained responses in 15-25% of the patients. The initial induction with higher doses and the prolongation of treatment can improve the results. A randomized, prospective study was carried out to compare the efficacy of a short term induction schedule of interferon alfa-2b (group A) versus a long term one (group B). 106 patients with chronic hepatitis C were included: 54 received 5 megaunits tiw for 8 weeks and 52 for 16 weeks; afterwards, interferon was reduced to 3 megaunits up to 9 months. The percentage of sustained responses, transient responses and non responses were 18.5%, 24% and 57.4% in group A and 23.1%, 28.8% and 48.1% in group B (NS). The following factors were related to a poor response in the univariate analysis: an increase of serum iron levels, ferritin, Gamma-GT and bilirubin, anti-nuclear antibody positivity, presumed non-parenteral infection, an AST/ALT ratio greater than 0.75, a higher Knodell's index and a greater necrosis and fibrosis score. The multivariate analysis revealed that elevated serum iron and ferritin and anti-nuclear antibody positivity had an independent predictive value related to a non response. Our results appear to suggest that an induction with higher doses and the treatment over nine months are more efficient than the classic schedule. The prolongation of the induction period does not provide additional advantages.

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.

Assessment of the dissolved pollutant flux of the Odiel River (SW Spain) during a wet period.

The abandoned mining districts of the Iberian Pyrite Belt (IPB, SW Spain) are an extreme source of pollution by acid mine drainage (AMD) to the Tinto and Odiel rivers. The pollutant flux transported by the Odiel River during a high stage period was assessed using concentration-discharge relationships and concentration-conductivity relationships, for the hydrological year 2009/10 (which was especially wet). Both correlations were high (R(2)>0.80) for most of the elements studied. The two methods for flux calculation gave similar results with differences generally lower than 10%. The dissolved contaminant flux transported by the Odiel River just before its mouth mainly includes sulphate (257,534±13,464 t/yr), Al (13,259±1071 t/yr), Zn (4265±242 t/yr), Mn (2532±146 t/yr) and Cu (1738±136 t/yr), and minor amounts of other elements. These findings confirm that, up to our knowledge, the Odiel River can be considered to be the largest contributor of mining-related pollutants to the world's oceans.

Procedure to use phosphogypsum industrial waste for mineral CO2 sequestration.

Industrial wet phosphoric acid production in Huelva (SW Spain) has led to the controversial stockpiling of waste phosphogypsum by-products, resulting in the release of significant quantities of toxic impurities in salt marshes in the Tinto river estuary. In the framework of the fight against global climate change and the effort to reduce carbon dioxide emissions, a simple and efficient procedure for CO(2) mineral sequestration is presented in this work, using phosphogypsum waste as a calcium source. Our results demonstrate the high efficiency of portlandite precipitation by phosphogypsum dissolution using an alkaline soda solution. Carbonation experiments performed at ambient pressure and temperature resulted in total conversion of the portlandite into carbonate. The fate of trace elements present in the phosphogypsum waste was also investigated, and trace impurities were found to be completely transferred to the final calcite. We believe that the procedure proposed here should be considered not only as a solution for reducing old stockpiles of phosphogypsum wastes, but also for future phosphoric acid and other gypsum-producing industrial processes, resulting in more sustainable production.

Long-term evolution of serum and liver viral markers in patients treated for chronic hepatitis C and sustained response.

Few studies have analysed the evolution of HCV markers in chronic hepatitis C (CHC)-treated patients. We have evaluated the presence or absence of serum and liver HCV-RNA, the core antigen (HCV-cAg) and the loss of specific antibodies (anti-HCV), in long-term sustained responders (SR). One hundred and seventy-six patients (132 SR and 44 nonresponders (NR) were included in the study. HCV-RNA was determined in serum and liver by a commercial PCR-kit. HCV-Ag was determined by ELISA and specific antibodies against HCV by means of a commercial line immunoblot assay (LIA) technique. Serum HCVcAg was found positive in three (4.2%) SR and in one (4%) NR (NS). Four SR (3.6%) and 44 NR (100%) were also HCV-RNA (+) in liver tissue. Two patients were HCV-cAg (+). A good correlation was found between the serum levels of HCV-cAg and HCV-RNA (r = 0.847, P < 0.001). Specific antibodies (anti-HCV) were determined by LIA in 45 patients. A decrease was found in the number of patients who presented reactivity to bands E2 and NS4 when we compared SR with a follow-up of more than 5 years with NR and SR with a follow-up <5 years (P < 0.01 and 0.005). A good correlation was found between the HCV-cAg and HCV-RNA serum levels in CHC-treated patients (P < 0.001). Few SR (3.6%) had HCV-RNA in the liver, and HCV-cAg (1.8%) in serum. In SR with more than 5 years of follow-up a clear tendency exists in the trend to clarify the bands E2 and NS4 of anti-HCV in serum.

Lorazepam and diazepam in the treatment of neurotic anxiety: a double-blind trial.

Fifty-eight neurotic patients with intense anxiety were treated with either lorazepam or diazepam in a double blind between-patients trial. Statistical analysis indicated that the two groups were homogeneous before treatment and that the results of treatment were similar for both drugs. According to the global rating of illness week after week, after four weeks of treatment more patients on lorazepam than on diazepam were normal or had mild illness (82.1% vs. 70.8%). In the investigators' judgment, 71.9% of the patients treated with lorazepam had an excellent or good response compared with 56.7+ of those treated with diazepam. The mean reduction in score on the Hamilton Anxiety Scale was 17.7 for lorazepam and 16.5 for diazepam. However, none of the above differences in results were statistically significant. The largest dose of lorazepam required in treatment was 6 mg, compared with 30 mg of diazepam. Two patients treated with lorazepam had side effects, against six with diazepam. Six patients in the diazepam group did not complete the trial, including three who discontinued because of side effects (rash, tremors, agitation); no patients in the lorazepam group dropped out.

Sarcoidosis in two patients with chronic hepatitis C treated with interferon, ribavirin and amantadine.

We report two patients with chronic hepatitis C, both nonresponders to a previous course of interferon (IFN), who developed or suffered an exacerbation of sarcoidosis while under treatment with IFN-alpha2a, ribavirin and amantadine. Patient 1: symptoms appeared after week 4 and treatment was withdrawn at month 9 due to severe weight loss, marked dyspnea, muscular weakness, dryness of mouth and facial paralysis. Stage III pulmonary sarcoidosis and polyneuropathy were confirmed. The patient had become steroid dependent and nine months after cessation of the treatment dyspnea and muscular weakness still persisted. She achieved a complete sustained response of hepatitis C. Patient 2: presented with a previous diagnosis of granulomatous hepatitis with chronic active hepatitis C and chronic dermatitis. The treatment exacerbated a cutaneous sarcoidosis. Furthermore, hiliar adenopathies consistent with stage I sarcoidosis became evident. Sarcoidosis responded to corticosteroids, but elevated transaminases and hepatitis C viraemia resisted. Hence, the combination of amantadine with ribavirin and IFN can develop or exacerbate subclinical sarcoidosis. A synergistic effect of these three drugs is suggested.