[The diagnosis and treatment of contact lens-induced limbal stem cell deficiency].

Objective: To analyze the clinical features and treatment outcomes of eyes with contact lens-induced limbal stem cell deficiency (CL-iLSCD). Methods: This cross-sectional study involved patients diagnosed with CL-iLSCD at the Eye, Ear, Nose & Throat Hospital of Fudan University between October 2018 and September 2022. A total of 17 patients (25 eyes) with a mean age of (36.4±6.9) years were enrolled. Among them, 14 were females (82.4%). Corneal and limbal abnormalities, especially the range of epitheliopathy, were observed under a slit lamp biomicroscope with fluorescein staining. Anterior segment optical coherence tomography and in vivo laser scanning confocal microscopy were performed to obtain the central corneal epithelial thickness, density of basal epithelial cells and corneal nerve fiber length. The clinical features of CL-iLSCD, along with their treatment outcomes and related risk factors, were analyzed. Results: All patients wore soft contact lenses, with an average daily wearing time of (10.5±2.5) hours and a median wearing duration of 10 (4 to 30) years. Ocular symptoms, including decreased vision, ocular discomfort or pain, redness, and photophobia, were present in 22 eyes (88.0%). The most characteristic clinical sign of CL-iLSCD was comb-or whorl-pattern late fluorescein staining under cobalt blue light, which was most commonly seen at the superior limbus (25/25, 100.0%). Additionally, reductions in central corneal epithelial thickness, basal cell density, and corneal nerve fiber length were observed. A comprehensive score was assigned to each eye based on clinical findings and in vivo imaging biomarkers. LSCD was mild, moderate, and severe in 5, 11, and 8 eyes, respectively. A history of misdiagnosis was found in 20 eyes (80.0%). After discontinuing the use of contact lenses and receiving medical treatment, significant improvement was observed in all eyes, with 13 eyes fully recovered. Conclusions: The symptoms and clinical signs of CL-iLSCD can be subtle at the early stage. Discontinuing contact lens wear and medication are effective to treat CL-iLSCD.

[A preliminary study on the tear matrix metalloproteinase 9 point-of-care assay using a domestic kit].

Objective: To compare the point-of-care assays for tear matrix metalloproteinase 9 (MMP-9) using domestic and InflammaDry kits, and to evaluate the feasibility of diagnosing dry eye with the domestic kit. Methods: It was a cross-sectional study. Thirty dry eye patients and 30 age-and sex-matched normal volunteers were continuously enrolled in this cross-sectional study from June 2022 to July 2022. Both domestic and InflammaDry kits were used to detect the tear MMP-9 levels. The positive rates were recorded for qualitative analysis, and the gray ratios of bands (the gray value of detection bands to that of control bands) were collected for quantitative analysis. The correlations of MMP-9 levels with age, ocular surface disease index, fluorescence tear break-up time, tear meniscus height, Schirmer's Ⅰ test score, corneal fluorescein staining score, and meibomian gland dropout were analyzed. The Mann-Whitney U test, paired Chi-square test, Kappa test, and Spearman's correlation coefficient were used for statistical analysis. Results: There were 14 males and 16 females (30 eyes) in the control group, and their age was (39.37±19.55) years. In the dry eye group, 11 males and 19 females (30 eyes), aged (46.87±17.85) years, had moderate to severe dry eye. The positive rates of MMP-9 in tear fluid were significantly different between dry eye patients (InflammaDry: 86.67%; domestic kit: 70.00%) and controls (InflammaDry: 16.67%, P<0.001; domestic kit: 6.67%, P<0.001). Although the sensitivity of the domestic kit was lower than that of the InflammaDry kit (70.0% vs. 86.7%, P=0.001), the specificity was higher (93.3% vs. 83.3%, P=0.001). In dry eye patients, the positive coincidence rate was 80.7% (21/26), the negative coincidence rate was 100% (4/4), and the total coincidence rate was 83.3% (25/30), with no significant difference between the two kits (McNemar test: χ2=3.20, P>0.05), and the results of both kits were consistent (Kappa=0.53, P=0.001). The Spearman's correlation coefficient showed the gray ratios using both kits were positively correlated with the corneal fluorescein staining score (InflammaDry: ρ=0.48, P<0.05; domestic kit: ρ=0.52, P=0.003). Conclusion: The performances of the domestic and InflammaDry kits are consistent in the point-of-care assay for tear MMP-9, and the domestic kit has lower sensitivity but higher specificity.

[The importance of differential diagnosis of superficial punctate keratopathy].

Superficial punctate keratopathy is a common ocular abnormality with the corneal epithelium and superficial corneal stroma involved. Various primary diseases can lead to superficial punctate keratopathy. Therefore, the differential diagnosis of the etiologies of superficial punctate keratopathy is crucial. Due to the absence of specific symptoms and signs, it is important to have an overall recognition of the disease and adopt necessary examinations for differential diagnosis. Acquisition of a detailed medical history, slit-lamp examination, in vivo laser scanning confocal microscopy, and other diagnostic tools should be combined to make an accurate diagnosis of the primary disease of superficial punctate keratopathy and provide objective evidences for the determination of treatment regimen.

Plant-wide investigation of sulfur flows in a water resource recovery facility (WRRF).

Even though sulfur compounds and their transformations may strongly affect wastewater treatment processes, their importance in water resource recovery facilities (WRRF) operation remains quite unexplored, notably when it comes to full-scale and plant-wide characterization. This contribution presents a first-of-a-kind, plant-wide quantification of total sulfur mass flows for all water and sludge streams in a full-scale WRRF. Because of its important impact on (post-treatment) process operation, the gaseous emission of sulfur as hydrogen sulfide (H2S) was also included, thus enabling a comprehensive evaluation of sulfur flows. Data availability and quality were optimized by experimental design and data reconciliation, which were applied for the first time to total sulfur flows. Total sulfur flows were successfully balanced over individual process treatment units as well as the plant-wide system with only minor variation to their original values, confirming that total sulfur is a conservative quantity. The two-stage anaerobic digestion with intermediate thermal hydrolysis led to a decreased sulfur content of dewatered sludge (by 36%). Higher (gaseous) H2S emissions were observed in the second-stage digester (42% of total emission) than in the first one, suggesting an impact of thermal treatment on the production of H2S. While the majority of sulfur mass flow from the influent left the plant through the treated effluent (> 95%), the sulfur discharge through dewatered sludge and gaseous emissions are critical. The latter are indeed responsible for odour nuisance, lower biogas quality, SO2 emissions upon sludge combustion and corrosion effects.

Isolation of phage-display library-derived scFv antibody specific to Listeria monocytogenes by a novel immobilized method.

AIMS: To select Listeria monocytogenes-specific single-chain fragment variable (scFv) antibodies from a phage-display library by a novel simple and cost-effective immobilization method. METHODS AND RESULTS: Light expanded clay aggregate (LECA) was used as biomass support matrix for biopanning of a phage-display library to select L. monocytogenes-specific scFv antibody. Four rounds of positive selection against LECA-immobilized L. monocytogenes and an additional subtractive panning against Listeria innocua were performed. The phage clones selected using this panning scheme and LECA-based immobilization method exhibited the ability to bind L. monocytogenes without cross-reactivity toward 10 other non-L. monocytogenes bacteria. One of the selected phage clones was able to specifically recognize three major pathogenic serotypes (1/2a, 1/2b and 4b) of L. monocytogenes and 11 tested L. monocytogenes strains isolated from foods. CONCLUSIONS: The LECA-based immobilization method is applicable for isolating species-specific anti-L. monocytogenes scFv antibodies by phage display. SIGNIFICANCE AND IMPACT OF THE STUDY: The isolated scFv antibody has potential use in development of immunoassay-based methods for rapid detection of L. monocytogenes in food and environmental samples. In addition, the LECA immobilization method described here could feasibly be employed to isolate specific monoclonal antibodies against any given species of pathogenic bacteria from phage-display libraries.

Fluoride-sulfophosphate glasses as hosts for broadband optical amplification through transition metal activators.

Unusually stable multi-anion glasses of the fluoride-sulfophosphate type (FPS) are introduced as a new host material for optically active cation species. Despite a notoriously low polymerization grade, anion mixing in this glass system enables facile manufacture of bulk or fiber devices which combine several advantages of fluoride and phosphate glasses while using the stabilizing effect of sulfate additions. Using the example of chromium doping, we demonstrate broad red photoluminescence at 734 nm and inhomogeneous broadening of the R-line at 694 nm, originating from the 4T2 → 4A2 and 2E → 4A2 transitions of Cr3+, respectively. The luminescence mechanism is further analyzed on the basis of the corresponding Tanabe-Sugano diagram. Tailored through chemical composition, internally nucleated precipitation of a nanocrystalline fluoride phase enables switching between high-field and low-field configurations of the Cr3+ ion, resulting in the specific emission properties and setting the path towards FPS-based optical devices.

A Matched Case-Control Study of Risk Factors for Breast Cancer Risk in Vietnam.

Background. Vietnam has a low age-standardized incidence of breast cancer, but the incidence is rising rapidly with economic development. We report data from a matched case-control study of risk factors for breast cancer in the largest cancer hospital in Vietnam. Methods. 492 incident breast cancer cases unselected for family history or age at diagnosis and 1306 control women age 25-75 were recruited from the National Cancer Hospital (BVK), Hanoi. Structured interviews were conducted and pathology data was centrally reported at the National Cancer Hospital of Vietnam, in Hanoi. Results. Our analysis included 294 matched pairs. Mean age at diagnosis was 46.7 years. Lower mean parity, older age at first parity, increasing weight and BMI at age 18, and increasing BMI at diagnosis were positively correlated with breast cancer cases compared to controls. Age at first menarche and duration of breastfeeding were not statistically different between cases and controls. Conclusions. In this study we demonstrate that breast cancer in Vietnam is associated with some but not all of the published risk factors from Western populations. Our data is consistent with other studies of breast cancer in Asian populations.

Moderate oral supplementation with docosahexaenoic acid improves platelet function and oxidative stress in type 2 diabetic patients.

Platelets from patients with type 2 diabetes are characterised by hyperactivation and high level of oxidative stress. Docosahexaenoic acid (DHA) may have beneficial effects on platelet reactivity and redox status. We investigated whether moderate DHA supplementation, given as a triglyceride form, may correct platelet dysfunction and redox imbalance in patients with type 2 diabetes. We conducted a randomised, double-blind, placebo-controlled, two-period crossover trial (n=11 post-menopausal women with type 2 diabetes) to test the effects of 400 mg/day of DHA intake for two weeks on platelet aggregation, markers of arachidonic acid metabolism, lipid peroxidation status, and lipid composition. Each two week-period was separated from the other by a six-week washout. Daily moderate dose DHA supplementation resulted in reduced platelet aggregation induced by collagen (-46.5 %, p< 0.001), and decreased platelet thromboxane B2 (-35 %, p< 0.001), urinary 11-dehydro-thromboxane B2 (-13.2 %, p< 0.001) and F2-isoprostane levels (-19.6 %, p< 0.001) associated with a significant increase of plasma and platelet vitamin E concentrations (+20 % and +11.8 %, respectively, p< 0.001). The proportions of DHA increased both in plasma lipids and in platelet phospholipids. After placebo treatment, there was no effect on any parameters tested. Our findings support a significant beneficial effect of low intake of DHA on platelet function and a favourable role in reducing oxidative stress associated with diabetes.

Comparison of plasma exchange performances between Spectra Optia and COBE Spectra apheresis systems in repeated procedures considering variability and using specific statistical models.

Repeated therapeutic plasma exchange (TPE) procedures using centrifugation techniques became a standard therapy in some diseases. As the new device Spectra Optia (SPO; Terumo BCT) was available, we studied its performances in repeated procedures in 20 patients in three apheresis units. First we analysed the performance results obtained by SPO. Second we compared the performances of the SPO device to a standard device, COBE Spectra (CSP; Terumo BCT) in the same patients using statistical method of mixed effects linear regression that considers variability between patients, centres and apheresis procedures. The performances analysed were classified according to plasma removal performances and their consequences on patients whose blood disturbances were assessed. Primary outcome was plasma removal efficiency (PRE) and PRE-anticoagulant corrected which was a more accurate parameter. Secondary outcomes corresponded to the volume of ACD-A consumed, platelets content in waste bag, procedure duration and status of coagulation system observed after TPE sessions. Before comparing the performances of both devices we compared the plasma volumes (PVs) processed in both techniques which showed that the PVs processed in SPO procedures were lower than in CSP procedures. In these conditions the statistical analysis revealed similar performances in both apheresis devices in PRE (p = ns) but better performances with SPO when considering higher PRE corrected by anticoagulant volume used (p < 0.05). Comparison of secondary outcomes showed no difference after SPO and CSP. After verifying that pre-apheresis patients' coagulation blood levels were identical before SPO and CSP, we showed identical haemostasis disturbances after SPO and CSP but lower platelet losses and higher fibrinogen post-apheresis blood levels after SPO (p < 0.05). No side effects or technical complications occurred during and after SPO and CSP. This study demonstrated that the Spectra Optia device is an alternative device to today's standard, the COBE Spectra device.

Development of model for analysing respective collections of intended hematopoietic stem cells and harvests of unintended mature cells in apheresis for autologous hematopoietic stem cell collection.

Hematopoietic stem cells (HSCs) required to perform peripheral hematopoietic autologous stem cell transplantation (APBSCT) can be collected by processing several blood volumes (BVs) in leukapheresis sessions. However, this may cause granulocyte harvest in graft and decrease in patient's platelet blood level. Both consequences may induce disturbances in patient. One apheresis team's current purpose is to improve HSC collection by increasing HSC collection and prevent increase in granulocyte and platelet harvests. Before improving HSC collection it seemed important to know more about the way to harvest these types of cells. The purpose of our study was to develop a simple model for analysing respective collections of intended CD34+ cells among HSC (designated here as HSC) and harvests of unintended platelets or granulocytes among mature cells (designated here as mature cells) considering the number of BVs processed and factors likely to influence cell collection or harvest. For this, we processed 1, 2 and 3 BVs in 59 leukapheresis sessions and analysed corresponding collections and harvests with a referent device (COBE Spectra). First we analysed the amounts of HSC collected and mature cells harvested and second the evolution of the respective shares of HSC and mature cells collected or harvested throughout the BV processes. HSC collections and mature cell harvests increased globally (p<0.0001) and their respective shares remained stable throughout the BV processes (p non-significant). We analysed the role of intrinsic (patient's features) and extrinsic (features before starting leukapheresis sessions) factors in collections and harvests, which showed that only pre-leukapheresis blood levels (CD34+cells and platelets) influenced both cell collections and harvests (CD34+cells and platelets) (p<0.001) and shares of HSC collections and mature unintended cells harvests (p<0.001) throughout the BV processes. Altogether, our results suggested that the main factors likely to influence intended HSC collections or unintended mature cell harvests were pre-leukapheresis blood cell levels. Our model was meant to assist apheresis teams in analysing shares of HSC collected and mature cells harvested with new devices or with new types of HSC mobilization.

The first results demonstrating efficiency and safety of a double-column whole blood method of LDL-apheresis.

LDL-apheresis is a treatment for familial hypercholesterolemia in addition to diet and drug therapy. In the past, LDL-apheresis techniques consisted in separating plasma from blood and adsorbing plasma LDL-C whereas recent methods remove LDL-C directly from whole blood. The whole blood system developed by Kaneka consists of a single-column (Liposorber DL-75) treatment (SCWB) but a double-column whole blood (DCWB) method has recently been developed (Liposorber DL-50 x 2). When 1.6 blood volumes (plus 1l) were processed, acute reductions of total cholesterol and LDL-C were 67.9+/-6% and 80.2+/-4.5%, respectively. The performances of the DCWB method were compared to other LDL-apheresis methods. Assessed in 10 patients, the DCWB method is more efficient than the SCWB method with higher reduction rates of LDL-C (79.7+/-4.9 vs. 68.2+/-5.0% p<0.0001) and apolipoprotein-B (79.5+/-5.4 vs. 67.4+/-5.4% p<0.0001). In a sub group of five patients having the highest LDL-C baseline levels, the LDL-C reduction rates obtained by the DCWB method are equivalent to those obtained by the conventional LDL-apheresis method consisting of preliminary plasma separation followed by plasma LDL-C adsorption and used as first line apheresis therapy (80.5+/-4.5 vs. 79.0+/-5.9%). The safety of DCWB was demonstrated in 12 patients with only a low frequency of mild and transient adverse effects (4%). In conclusion, the DCWB LDL-apheresis method provides efficient removal of LDL-C, a low level of adverse effects, and a shortened duration of the procedure.

Peak bone mineral density in Vietnamese women.

SUMMARY: This cross-sectional study showed that peak bone mineral density in Vietnamese women is comparable to that in Caucasian women; however, the prevalence of osteoporosis in post-menopausal Vietnamese women was slightly higher than in Caucasian women. The age of achieving peak bone mass in Vietnamese women was between 26 and 30 years. INTRODUCTION: While peak bone mass and its determinants have been well-documented in Caucasian populations, little has been studied in Asian populations. The present study was designed to estimate the peak bone mineral density (BMD), age of its attainment, and to examine the prevalence of osteoporosis in Vietnamese women aged 50+. METHODS: The study was designed as a cross-sectional study with 328 women aged between 10 and 65 years (average age: 41) who were randomly selected from two districts around Hanoi city according to a stratified sampling scheme. BMD at the lumbar spine, femoral neck and total hip was measured by a DXA instrument (GE Lunar Prodigy, WI, USA). BMD was modeled as a cubic function of age, from which peak BMD and age at peak BMD were estimated. Bootstrap method was utilized to estimate the 95% confidence interval of peak BMD and age at peak BMD. From the peak BMD, T-score was calculated for each woman, and using the World Health Organization criteria, any woman with femoral neck BMD T-score

Effect of priming with granulocyte-macrophage colony-stimulating factor in younger adults with newly diagnosed acute myeloid leukemia: a trial by the Acute Leukemia French Association (ALFA) Group.

In a multicenter trial, 259 young adults (15-49 years) with newly diagnosed acute myeloid leukemia (AML) were first randomized to receive a timed-sequential induction regimen given either alone (135 patients) or concomitantly with granulocyte-macrophage colony-stimulating factor (GM-CSF) (124 patients). Patients reaching complete remission (CR) were then randomized to compare a timed-sequential consolidation to a postremission chemotherapy including four cycles of high-dose cytarabine followed by maintenance courses. In the appropriate arm, GM-CSF was given concurrently with chemotherapy during all cycles of consolidation. CR rates were significantly better in the GM-CSF arm (88 vs 78%, P<0.04), but did not differ after salvage. Patients receiving GM-CSF had a higher 3-year event-free survival (EFS) estimate (42 vs 34%), but GM-CSF did not impact on overall survival. Patients with intermediate-risk cytogenetics benefited more from GM-CSF therapy (P=0.05) in terms of EFS than patients with other cytogenetics. This was also confirmed when considering only patients following the second randomization, or subgroups defined by a prognostic index based on cytogenetics and the number of courses required for achieving CR. Priming of leukemic cells with hematopoietic growth factors is a means of enhancing the efficacy of chemotherapy in younger adults with AML.

Mutation status and clinical outcome of 89 imatinib mesylate-resistant chronic myelogenous leukemia patients: a retrospective analysis from the French intergroup of CML (Fi(phi)-LMC GROUP).

The emergence of ABL point mutations is the most frequent cause for imatinib resistance in chronic myelogenous leukemia (CML) patients and can occur during any phase of the disease; however, their clinical impact remains controversial. In this study, we retrospectively analyzed the predictive impact of 94 BCR-ABL kinase domain mutations (18 T315I, 26 P-loop, 50 in other sites) found in 89 imatinib-resistant CML patients. At imatinib onset, 64% of patients (57/89) were in chronic phase (CP), 24% (21/89) in accelerated phase (AP) and 12% (11/89) in blastic phase (BP). T315I and P-loop mutations were preferentially discovered in accelerated phase of BP CML, and other types of mutations in CP (P=0.003). With a median follow-up of 39.2 months (6.3-67.2), since imatinib initiation, overall survival (OS) was significantly worse for P-loop (28.3 months) and for T315I (12.6 months), and not reached for other mutations (P=0.0004). For CP only, multivariate analysis demonstrated a worse OS for P-loop mutations (P=0.014), and a worse progression-free survival (PFS) for T315I mutations (P=0.014). Therefore, P-loop and T315I mutations selectively impair the outcome of imatinib-resistant CML patients, in contrast to other mutations, which may benefit from dose escalation of imatinib, able to improve or stabilize disease response.

Stress activation and genomic impact of Tnt1 retrotransposons in Solanaceae.

Tnt1 elements are a superfamily of LTR-retrotransposons distributed in the Solanaceae plant family and represent good model systems for studying regulatory and evolutionary controls established between hosts and transposable elements. Tnt1 retrotransposons tightly control their activation, by restricting expression to specific conditions. The Tnt1A element, originally discovered in tobacco, is expressed in response to stress, and its activation by microbial factors is followed by amplification, demonstrating that factors of pathogen origin can generate genetic diversity in plants. The Tnt1A promoter has the potential to be activated by various biotic and abiotic stimuli but a number of these are specifically repressed in tobacco and are revealed only when the LTR promoter is placed in a heterologous context. We propose that a tobacco- and stimulus-specific repression has been established in order to minimize activation in conditions that might generate germinal transposition. In addition to tight transcriptional controls, Tnt1A retrotransposons self-regulate their activity through gradual generation of defective copies that have reduced transcriptional activity. Tnt1 retrotransposons found in various Solanaceae species are characterized by a high level of variability in the LTR sequences involved in transcription, and have evolved by gaining new expression patterns, mostly associated with responses to diverse stress conditions. Tnt1A insertions associated with genic regions are initially favored but seem subsequently counter-selected, while insertions in repetitive DNA are maintained. On the other hand, amplification and loss of insertions may result from more brutal occurrences, as suggested by the large restructuring of Tnt1 populations observed in tobacco compared to each of its parental species. The distribution of Tnt1 elements thus appears as a dynamic flux, with amplification counterbalanced by loss of insertions. Tnt1 insertion polymorphisms are too high to reveal species relationships in the Nicotiana genus, but can be used to evaluate species relationships in the Lycopersicon and Capsicum genera. This also demonstrates that the behavior of Tnt1 retrotransposons differs between host species, most probably in correlation to differences in expression conditions and in the evolutionary and environmental history of each host.

Outcome and long-term follow-up of alloreactive donor lymphocyte infusions given for relapse after myeloablative allogeneic hematopoietic stem cell transplantations (HSCT).

In order to study efficacy, toxicity and the long-term results of donor lymphocyte infusions (DLI), we retrospectively analyzed DLI given for relapse after conventional allogeneic hematopoietic stem cell transplantation (HSCT) in 30 patients with a median delay of 107.5 months after transplant and 58 months after DLI. After DLI, 15 patients established full donor chimerism, three patients developed grade III and one grade IV acute GVHD. A total of 15 patients achieved a disease response. Among the 14 patients with chronic myeloid leukemia (CML), 11 are alive at the last follow-up: five are in complete molecular response (CMR) and two in complete cytogenetic response (CCR) with no other intervention after DLI, three in CMR after imatinib mesylate given after DLI and one in complete hematological response after imatinib mesylate and reduced-intensity conditioning allogeneic SCT performed after DLI. At the time of the last follow-up, 19 (63%) patients died and 11 (37%) remain alive. The 3-year probability of survival for the entire population, CML patients and non-CML patients, was 60, 93, 62% after transplantation, and 48, 80 and 48% after DLI, respectively. A multivariate analysis demonstrated a significantly worse survival rate after transplantation for female recipients, advanced disease and acute leukemia before transplantation.

Subclinical late cardiomyopathy after doxorubicin therapy for lymphoma in adults.

PURPOSE: To assess the cardiac status of the long-term survivors and to estimate the incidence and the features of subclinical cardiotoxicity induced after conventional treatment with doxorubicin for non-Hodgkin's lymphoma or Hodgkin's lymphoma. PATIENTS AND METHODS: We analyzed a group of patients who previously received doxorubicin-based chemotherapy for lymphoma. Echocardiograms were performed at least 5 years after therapy with anthracyclines. Clinical cardiomyopathy was defined by the presence of clinical signs of congestive heart failure (CHF). Subclinical cardiomyopathy was defined by decrease of left ventricular fractional shortening (FS) without clinical signs of CHF. Cumulative dose of doxorubicin, male sex, older age, relapse, radiotherapy (mediastinal or total-body irradiation), autologous stem-cell transplantation, high-dose cyclophosphamide, and cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia, familial history of cardiac disease, being overweight, and smoking history) were evaluated as potential risk factors for the development of cardiac dysfunction. RESULTS: Of 141 assessable patients (median age, 54 years; median cumulative dose of doxorubicin, 300 mg/m(2)), only one developed CHF. Criteria of subclinical cardiomyopathy were found in 39 patients. In multivariate analysis, factors that contributed to decreased FS were male sex (P <.01), older age (P <.01), higher cumulative dose of doxorubicin or association with another anthracycline (P =.04), radiotherapy (P =.04), and being overweight (P =.04). CONCLUSION: Cardiac abnormalities can occur in patients treated with doxorubicin for lymphoma in the absence of CHF, even in patients who received moderate anthracycline doses. Male sex, older age, higher dose of doxorubicin, radiotherapy, and being overweight were risk factors for the development of cardiomyopathy.

Salvage by timed sequential chemotherapy in primary resistant acute myeloid leukemia: analysis of prognostic factors.

Primary resistant acute myeloid leukemia (AML) has a very poor prognosis. Etoposide-mitoxantrone-cytarabine (EMA) timed sequential chemotherapy including a first sequence combining mitoxantrone (12 mg/m(2) per day over 3 days) with cytarabine (500 mg/m(2) per day over the same period), and a second sequence consisting in etoposide (200 mg/m(2) per day for 3 days) and cytarabine as in the first sequence, has been proposed as a salvage regimen. Over a 10-year period, 66 primary resistant AML patients have been treated by EMA salvage chemotherapy. All patients displayed intermediate- or high-risk karyotypic abnormalities. Of the 66 patients, 24 [36%, 95% confidence interval (CI): 25-49%] achieved complete remission (CR). Thirty-eight patients were resistant to EMA chemotherapy and four patients died from toxicity during aplasia. After CR achievement, 18 patients received consolidation therapy. Five patients with an HLA-identical sibling donor underwent allogeneic stem cell transplantation (SCT), one patient received autologous SCT, two patients received a second course of EMA chemotherapy, and ten were scheduled for 6-monthly maintenance courses (mini-EMA). Median follow-up was 7.3 years. At the time of analysis, 21 of the 24 patients (87%) who achieved CR have relapsed. Median disease-free survival (DFS) was 5 months (95% CI: 4.3-7.7 months). Median overall survival (OS) was 5 months (95% CI: 3.8-6.7 months). There were only two long-term remitters (3%). In the univariate analysis, CR achievement was mainly related to white blood cell (WBC) count at the time of starting salvage therapy with poorer outcome for patients with more aggressive leukemia (WBC count > or =10 x 10(9)/l) (CR rates: 50% vs 10%, p<0.001). Overall survival was also influence by WBC count (median OS: 7.2 months vs 2.8 months, respectively, for WBC or =10 x 10(9)/l, p<0.0001). Initial karyotype was not a significant prognostic factor either for CR achievement or for DFS or OS when comparing patients with normal karyotype and those with chromosomal abnormality. In multivariate analysis, WBC count less than 10 x 10(9)/l with the absence of circulating blasts at the time of starting salvage therapy appeared to be of favorable prognostic value for CR achievement ( p=0.002), while WBC count less than 10 x 10(9)/l appeared to be of favorable prognostic value for survival ( p<0.0001). Using these two objective parameters of proven significance, we devised a prognostic system of immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices. Patients with both factors (WBC count <10 x 10(9)/l and no circulating blasts) or with at least one at the time of starting salvage therapy had a CR rate of 50% and were therefore candidates for intensified post-remission therapy. All other patients displayed a very poor outcome and must be oriented after failure of first-line therapy to alternate therapeutic programs based on investigational drugs.

Anthracycline-related toxicity requiring cardiac transplantation in long-term disease-free survivors with acute promyelocytic leukemia.

We describe three cases of acute promyelocytic leukemia (APL) with long-term disease-free survival who developed congestive heart failure (CHF) requiring cardiac transplantation. All three patients presented late-onset cardiotoxicity. Cardiac failure occurred progressively after 31-month, 32-month, and 14-month intervals, respectively, following completion of first anthracycline therapy. Cumulative anthracycline doses were 585 mg of daunorubicin and 64 mg of mitoxantrone in case 1, 1779 mg of daunorubicin in case 2, and 825 mg of daunorubicin in case 3. The questions relating to the pathogenesis of cardiac failure are discussed. We also discuss the prophylactic measures required for such treatment-related side effects.