Comorbidity of dementia and age-related macular degeneration calls for clinical awareness: a meta-analysis.

AIM: To determine the association between dementia and age-related macular degeneration (AMD) using meta-analysis. METHODS: We searched in the MEDLINE, EMBASE, Web of Knowledge, PsycInfo and Cochrane database of systematic reviews for studies published from March 1959 to March 2018. We included cross-sectional, case-control and cohort studies that evaluated the association of dementia/Alzheimer's disease (AD) with AMD (as outcome) and the association of AMD with dementia/AD (as outcome). Studies that compared cognitive functions between AMD and controls were also included. The summary outcomes, namely odds ratio (OR), relative risk, mean differences and corresponding 95% CIs, were estimated using random effects models. We performed sensitivity analysis based on study quality and individual study effect to control for potential biases. RESULTS: Among 2159 citation records, we identified 21 studies consisting of 7 876 499 study subjects for meta-analysis. Patients with dementia (padjusted≤0.017, OR≥1.24, I2≤9%) or AD (p=0.001, ORunadjusted=2.22, I2=50%) were at risk for AMD, particularly for late AMD (padjusted<0.001, OR=1.37, I2=0). AMD was also significantly associated with increased risk of AD/cognitive impairment (padjusted=0.037, OR=2.42, I2=38%). Moreover, patients with AMD had poorer cognitive functions when compared with controls, including Mini-Mental State Examination (p<0.001, I2≤79%) and Trail Making Test A (p<0.001, I2=0). Sensitivity analysis and Egger's test indicated our results were less likely biased. CONCLUSIONS: A significant association between dementia/AD and AMD calls for greater clinical awareness. The cost-effectiveness of routine screening for the other condition in patients with primary diagnosis of dementia/AD or AMD requires further study.

Impact of patient education on influenza vaccine uptake among community-dwelling elderly: a randomized controlled trial.

This randomized controlled trial aimed to test the effectiveness of brief face-to-face patient education in increasing influenza vaccination rate among elderly in the community. Recruitment and intervention were conducted at two general outpatient clinics in Hong Kong. 529 eligible patients were randomly assigned to intervention or control group with 1:1 allocation ratio. Patients in the intervention group received 3-min one-on-one verbal education by medical students and a pamphlet regarding influenza vaccination. Neither verbal health education nor pamphlet was given to the control group. Intention-to-treat analysis showed significantly higher vaccination rate in the intervention group compared with the control group (33.6 versus 25.0%) and the adjusted relative risk was 1.34 (95% CI 1.04-1.72; P = 0.021). Hence, brief face-to-face patient education was effective in increasing influenza vaccine uptake rate of community-dwelling elderly patients. Participants who were undecided whether to receive vaccination seemed to demonstrate larger beneficial effect (RR = 7.84; 95% CI 1.06-57.76) compared with patients who were certain of either receiving (RR = 1.16; 95% CI 0.90-1.48) or not receiving (RR = 2.18; 95% CI 0.68-6.99) the vaccine. The study also revealed that patients' intention for vaccination may not translate into action, reasons for which should be explored in future research.

Reliability of N95 respirators for respiratory protection before, during, and after nursing procedures.

BACKGROUND: The adequate fit of an N95 respirator is important for health care workers to reduce the transmission of airborne infectious diseases in the clinical setting. This study aimed to evaluate whether adequately sealed N95 respirators may provide consistent protection for the wearer while performing nursing procedures. METHODS: Participants were a group of nursing students (N = 120). The best fitting respirator for these participants was identified from the 3 common models, 1860, 1860S, and 1870+ (3M), using the quantitative fit test (QNFT) method. Participants performed nursing procedures for 10-minute periods while wearing a backpack containing the portable aerosol spectrometers throughout the assessment to detect air particles inside the respirator. RESULTS: The average fit factor of the best fitting respirator worn by the participants dropped significantly after nursing procedures (184.85 vs 134.71) as detected by the QNFT. In addition, significant differences in particle concentration of different sizes (>0.3, >0.4, >1.0, and >4.0 µm) inside the respirator were detected by the portable aerosol spectrometers before, during, and after nursing procedures. CONCLUSIONS: Body movements during nursing procedures may increase the risk of face seal leakage. Further research, including the development of prototype devices for better respirator fit, is necessary to improve respiratory protection of users.

Yin Yang 1-mediated epigenetic silencing of tumour-suppressive microRNAs activates nuclear factor-κB in hepatocellular carcinoma.

Enhancer of zeste homolog 2 (EZH2) catalyses histone H3 lysine 27 trimethylation (H3K27me3) to silence tumour-suppressor genes in hepatocellular carcinoma (HCC) but the process of locus-specific recruitment remains elusive. Here we investigated the transcription factors involved and the molecular consequences in HCC development. The genome-wide distribution of H3K27me3 was determined by chromatin immunoprecipitation coupled with high-throughput sequencing or promoter array analyses in HCC cells from hepatitis B virus (HBV) X protein transgenic mouse and human cell models. Transcription factor binding site analysis was performed to identify EZH2-interacting transcription factors followed by functional characterization. Our cross-species integrative analysis revealed a crucial link between Yin Yang 1 (YY1) and EZH2-mediated H3K27me3 in HCC. Gene expression analysis of human HBV-associated HCC specimens demonstrated concordant overexpression of YY1 and EZH2, which correlated with poor survival of patients in advanced stages. The YY1 binding motif was significantly enriched in both in vivo and in vitro H3K27me3-occupied genes, including genes for 15 tumour-suppressive microRNAs. Knockdown of YY1 reduced not only global H3K27me3 levels, but also EZH2 and H3K27me3 promoter occupancy and DNA methylation, leading to the transcriptional up-regulation of microRNA-9 isoforms in HCC cells. Concurrent EZH2 knockdown and 5-aza-2'-deoxycytidine treatment synergistically increased the levels of microRNA-9, which reduced the expression and transcriptional activity of nuclear factor-κB (NF-κB). Functionally, YY1 promoted HCC tumourigenicity and inhibited apoptosis of HCC cells, at least partially through NF-κB activation. In conclusion, YY1 overexpression contributes to EZH2 recruitment for H3K27me3-mediated silencing of tumour-suppressive microRNAs, thereby activating NF-κB signalling in hepatocarcinogenesis.

Genetic association of AKAP10 gene polymorphism with reduced risk of preterm birth.

OBJECTIVE: Preterm birth (PTB) is a multifactorial complication in which genetic and environmental factors contribute to the phenotype. The AKAP10 protein encoded by AKAP10 gene has a vital role in the maintenance of myometrial quiescence and pregnancy. This study aimed to investigate whether polymorphisms in the AKAP10 gene are associated with the risk of PTB. STUDY DESIGN: A total of 664 women (132 preterm and 532 term) with spontaneous singleton deliveries were genotyped for AKAP10 polymorphisms (rs119672, rs203462 and rs169412) using Sequenom MassARRAY platform. RESULT: A significant association was observed between the CC and AC genotypes of AKAP10 rs169412 with reduced risk of PTB (CC: adjusted odds ratio (OR) 2.95, 95% confidence interval (CI): 1.23-7.09, P=0.016. AC: adjusted OR 3.46, 95% CI: 1.38-8.68, P=0.008), respectively. Following stratification by ethnicity, a significant association was observed between the AC and CC genotypes of rs169412 and term birth in the Malay ethnic subgroup. (CC: OR 2.9, 95% CI: 1.01-8.59, P=0.041. AC: OR 3.14, 95% CI: 1.04-9.54, P=0.043). A significant association was also observed between the CT genotypes of AKAP10 rs119672 with reduced risk of PTB deliveries (CT: OR 3.2, 95% CI: 1.06-9.76 P=0.007, TT: OR 2.8, 0.98-8.34, P =.0.015) Alternatively, there was no association between AKAP10 rs169412 and rs119672 polymorphisms with PTB in the Indians and Chinese ethnic groups. CONCLUSION: This study indicates a significant association between the AKAP10 polymorphisms and reduced risk of PTB in the Malays. This demonstrates the potential role of AKAP10 polymorphisms in preterm complications.

Truncated HBx-dependent silencing of GAS2 promotes hepatocarcinogenesis through deregulation of cell cycle, senescence and p53-mediated apoptosis.

Hepatocellular carcinoma (HCC) is a worldwide threat to public health, especially in China, where chronic hepatitis B virus (HBV) infection is found in 80-90% of all HCCs. The HBV-encoded X antigen (HBx) is a trans-regulatory protein involved in virus-induced hepatocarcinogenesis. Although the carboxyl-terminus-truncated HBx, rather than the full-length counterpart, is frequently overexpressed in human HCCs, its functional mechanisms are not fully defined. We investigated the molecular function of a naturally occurring HBx variant which has 35 amino acids deleted at the C-terminus (HBxΔ35). Genome-wide scanning analysis and PCR validation identified growth arrest-specific 2 (GAS2) as a direct target of HBxΔ35 at transcriptional level in human immortalized liver cells. HBxΔ35 was found to bind the promoter region of GAS2 and attenuate its expression to promote hepatocellular proliferation and tumourigenicity. Further functional assays demonstrated that GAS2 induces p53-dependent apoptosis and senescence to counteract HBxΔ35-mediated tumourigenesis. Notably, GAS2 expression was significantly down-regulated in HCCs compared with the corresponding normal tissues. In conclusion, our integrated study uncovered a novel viral mechanism in hepatocarcinogenesis, wherein HBxΔ35 deregulates cell growth via direct silencing of GAS2 and thereby provides a survival advantage for pre-neoplastic hepatocytes to facilitate cancer development.

Enhancing knowledge and attitudes in pain management: a pain management education program for nursing home staff.

The aim of the study was to examine the effectiveness of a pain management program (PMP) in enhancing the knowledge and attitudes of health care workers in pain management. Many nursing home residents suffer from pain, and treatment of pain is often inadequate. Failure of health care workers to assess pain and their insufficient knowledge of pain management are barriers to adequate treatment. It was a quasiexperimental pretest and posttest study. Four nursing homes were approached, and 88 staff joined the 8-week PMP. Demographics and the knowledge and attitudes regarding pain were collected with the use of the Nurse's Knowledge and Attitudes Survey Regarding Pain-Chinese version (NKASRP-C) before and after the PMP. A deficit in knowledge and attitudes related to pain management was prominent before the PMP, and there was a significant increase in pain knowledge and attitudes from 7.9 ± SD 3.52 to 19.2 ± SD4.4 (p < .05) after the 8-week PMP. A PMP can improve the knowledge and attitudes of nursing staff and enable them to provide adequate and appropriate care to older persons in pain. PMPs for nurses and all health care professionals are important in enhancing care for older adults and to inform policy on the provision of pain management.

Pain management for older persons living in nursing homes: a pilot study.

Because the prevalence of chronic pain among the elderly in nursing homes is high and decreases their quality of life, effective nonpharmacologic pain management should be promoted. The purpose of this quasiexperimental pretest and posttest control design was to enhance pain management in nursing homes via an integrated pain management program (IPMP) for staff and residents. Nursing staff and residents from the experimental nursing home were invited to join the 8-week IPMP, whereas staff and residents from the control nursing home did not receive the IPMP. Baseline data were collected from nursing staff and residents in both groups before and after the IPMP. The IPMP consisted of eight lectures on pain assessment, drug knowledge,and nondrug strategies for the nursing staff, and 8 weeks of activities, including gardening therapy and physiotherapy exercise, for the residents. There were 48 and 42 older people in the experimental and control groups, respectively. No significant differences were found in their educational level, sleep quality, bowel habits, past and present health conditions, pain conditions and psychologic well-being parameters (p > .05) at baseline. After the IPMP, the experimental nursing staff showed a significant improvement in their knowledge of and attitudes to pain management (p < .05), and the experimental residents reported significantly lower pain scores and used more nondrug strategies for pain relief compared with the control group (p < .05). Moreover, the psychologic well-being parameters, including happiness, loneliness, life satisfaction, and geriatric depression, had significantly improved among the experimental residents (p < .05). The IPMP was effective in enhancing the knowledge and attitudes of nursing staff, as well as reducing pain conditions and enhancing psychologic well-being for older persons in nursing homes.

Helicobacter pylori causes epigenetic dysregulation of FOXD3 to promote gastric carcinogenesis.

BACKGROUND & AIMS: Deregulation of forkhead box (Fox) proteins, an evolutionarily conserved family of transcriptional regulators, leads to tumorigenesis. Little is known about their regulation or functions in the pathogenesis of gastric cancer. Promoter hypermethylation occurs during Helicobacter pylori-induced gastritis. We investigated whether the deregulated genes contribute to gastric tumorigenesis. METHODS: We used integrative genome-wide scans to identify concomitant hypermethylated genes in mice infected with H pylori and human gastric cancer samples. We also analyzed epigenetic gene silencing in gastric tissues from patients with H pylori infection and gastritis, intestinal metaplasia, gastric tumors, or without disease (controls). Target genes were identified by chromatin immunoprecipitation microarrays and expression and luciferase reporter analyses. RESULTS: Methylation profile analyses identified the promoter of FOXD3 as the only genomic region with increased methylation in mice and humans during progression of H pylori-associated gastric tumors. FOXD3 methylation also correlated with shorter survival times of patients with gastric cancer. Genome demethylation reactivated FOXD3 expression in gastric cancer cell lines. Transgenic overexpression of FOXD3 significantly inhibited gastric cancer cell proliferation and invasion, and reduced growth of xenograft tumors in mice, at least partially, by promoting tumor cell apoptosis. FOXD3 bound directly to the promoters of, and activated transcription of, genes encoding the cell death regulators CYFIP2 and RARB. Levels of FOXD3, CYFIP2, and RARB messenger RNAs were reduced in human gastric tumor samples, compared with control tissues. CONCLUSIONS: FOXD3-mediated transcriptional control of tumor suppressors is deregulated by H pylori infection-induced hypermethylation; this could perturb the balance between cell death and survival. These findings identify a pathway by which epigenetic changes affect gastric tumor suppression.

The effectiveness of an integrated pain management program for older persons and staff in nursing homes.

This study examined the effects of an 8-week integrated pain management program (IPMP) on enhancing the knowledge and attitude toward pain management among staff; and improving the pain, quality of life, physical and psychosocial functions, and use of non-drug therapies for the elderly in nursing homes. Nursing home staff (N=147) and residents (N=535) were recruited from ten nursing homes. Nursing homes were randomly assigned into an experimental group (N=296) with IPMP or control group (N=239) without IPMP. The IPMP consisted of pain education for staff and physical exercise and multisensory stimulation art and craft therapy for residents. Data were collected before and after the IPMP. The staff demonstrated a significant improvement in knowledge and attitude to pain management, with the survey score increasing from 8.46±3.74 to 19.43±4.07 (p<0.001). Among the residents, 74% had experienced pain within the previous 6 months, with pain intensity of 4.10±2.20. Those in the experimental group showed a significantly better reduction in pain scores than the control group, from 4.19±2.25 to 2.67±2.08 (p<0.001). Group differences were also found in psychological well-being, including happiness, loneliness, life satisfaction and depression (p<0.05), and the use of non-drug methods (p<0.05). These results suggested that IPMP is beneficial for staff, and is effective in reducing geriatric pain and negative impacts. Management support and staff involvement in the program are important for its long-term continuation.

Benchmarking dosimetric quality assessment of prostate intensity-modulated radiotherapy.

PURPOSE: To benchmark the dosimetric quality assessment of prostate intensity-modulated radiotherapy and determine whether the quality is influenced by disease or treatment factors. PATIENTS AND METHODS: We retrospectively analyzed the data from 155 consecutive men treated radically for prostate cancer using intensity-modulated radiotherapy to 78 Gy between January 2007 and March 2009 across six radiotherapy treatment centers. The plan quality was determined by the measures of coverage, homogeneity, and conformity. Tumor coverage was measured using the planning target volume (PTV) receiving 95% and 100% of the prescribed dose (V(95%) and V(100%), respectively) and the clinical target volume (CTV) receiving 95% and 100% of the prescribed dose. Homogeneity was measured using the sigma index of the PTV and CTV. Conformity was measured using the lesion coverage factor, healthy tissue conformity index, and the conformity number. Multivariate regression models were created to determine the relationship between these and T stage, risk status, androgen deprivation therapy use, treatment center, planning system, and treatment date. RESULTS: The largest discriminatory measurements of coverage, homogeneity, and conformity were the PTV V(95%), PTV sigma index, and conformity number. The mean PTV V(95%) was 92.5% (95% confidence interval, 91.3-93.7%). The mean PTV sigma index was 2.10 Gy (95% confidence interval, 1.90-2.20). The mean conformity number was 0.78 (95% confidence interval, 0.76-0.79). The treatment center independently influenced the coverage, homogeneity, and conformity (all p < .0001). The planning system independently influenced homogeneity (p = .038) and conformity (p = .021). The treatment date independently influenced the PTV V(95%) only, with it being better at the start (p = .013). Risk status, T stage, and the use of androgen deprivation therapy did not influence any aspect of plan quality. CONCLUSION: Our study has benchmarked measures of coverage, homogeneity, and conformity for the treatment of prostate cancer using IMRT. The differences seen between centers and planning systems and the coverage deterioration over time highlight the need for every center to determine their own benchmarks and apply clinical vigilance with respect to maintaining these through quality assurance.

EZH2-mediated concordant repression of Wnt antagonists promotes ß-catenin-dependent hepatocarcinogenesis.

Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb-repressive complex 2 (PRC2) that represses gene transcription through histone H3 lysine 27 trimethylation (H3K27me3). Although EZH2 is abundantly present in various cancers, the molecular consequences leading to oncogenesis remain unclear. Here, we show that EZH2 concordantly silences the Wnt pathway antagonists operating at several subcellular compartments, which in turn activate Wnt/ß-catenin signaling in hepatocellular carcinomas (HCC). Chromatin immunoprecipitation promoter array and gene expression analyses in HCCs revealed EZH2 occupancy and reduced expression of Wnt antagonists, including the growth-suppressive AXIN2, NKD1, PPP2R2B, PRICKLE1, and SFRP5. Knockdown of EZH2 reduced the promoter occupancy of PRC2, histone deacetylase 1 (HDAC1), and H3K27me3, whereas the activating histone marks were increased, leading to the transcriptional upregulation of the Wnt antagonists. Combinatorial EZH2 and HDAC inhibition dramatically reduced the levels of nuclear ß-catenin, T-cell factor-dependent transcriptional activity, and downstream pro-proliferative targets CCND1 and EGFR. Functional analysis revealed that downregulation of EZH2 reduced HCC cell growth, partially through the inhibition of ß-catenin signaling. Conversely, ectopic overexpression of EZH2 in immortalized hepatocytes activated Wnt/ß-catenin signaling to promote cellular proliferation. In human HCCs, concomitant overexpression of EZH2 and ß-catenin was observed in one-third (61/179) of cases and significantly correlated with tumor progression. Our data indicate that EZH2-mediated epigenetic silencing contributes to constitutive activation of Wnt/ß-catenin signaling and consequential proliferation of HCC cells, thus representing a novel therapeutic target for this highly malignant tumor.

Physical exercise: does it help in relieving pain and increasing mobility among older adults with chronic pain?

AIM: To provide a physical exercise programme for older adults living in nursing homes. BACKGROUND: Pain is common among older persons and for those already in long-term care and having difficulty in coping with pain will be at risk of further reducing their optimal independent function. DESIGN: A quasi-experimental single group pretest-posttest design. METHOD: Older persons from a nursing home were invited to join an eight-week physical exercise programme. Each session lasted an hour and sessions were conducted once a week by physiotherapist and nurses. Physical exercise programme consisted of stretching, strengthening, balancing, towel dancing and self-administered massage to various acupressure points. On completion of each session, older persons were given a pamphlet with pictures to illustrate the exercise of the day and they were encouraged to practise these exercises by themselves. Outcome measures including pain intensity, range of movement, activities of daily living and mobility were collected before and after the physical exercise programme. RESULTS: There were 75 older adult participants (57 female and 18 male, mean age 85.14 SD 5.30). Seventy-three percent (n = 55) of them had pain in the previous three months and were referred as pain group, while 25% (n = 20) were no pain group. Pain scores of 4.89 (on a 10-point scale) indicated medium pain intensity before the intervention for the pain group; the location of pain was mainly in the knee, back and shoulder. On completion of the physical exercise programme, there was a significant decrease in pain intensity to 2.89 (SD 2.14) (p < 0.01). There was a significant increase in range of movement in the neck, shoulder, back, hip and knee rotation, flex and abduction (p < 0.01). Mobility level was significantly increased post intervention, yet activities of daily living remained unchanged. CONCLUSIONS: The present study demonstrated the effectiveness of a physical exercise programme in relieving pain and enhancing functional mobility for older persons. Relevance to clinical practice. It is important to educate older persons, especially those living in nursing homes, on the importance of engaging in regular physical exercise and maintaining mobility.

Risk classification for large cell lymphoma using lactate dehydrogenase, beta-2 microglobulin, and thymidine kinase.

We have previously proposed a staging system for large cell lymphoma using the two serum markers beta-2-microglobulin (B2M) and lactate dehydrogenase (LDH). We recently tested this model in a different cohort of patients with large cell lymphoma and also examined the possible contribution of thymidine kinase (TK), a previously reported serologic prognostic factor. Using an inclusion criteria in the multivariate analysis for both forward and backward selection of p < 0.15, only LDH, B2M, and TK were significant independent prognostic factors for both time to treatment failure (TTF) and survival. Inclusion of TK in the serologic model resulted in three significantly different risk groups for both TTF and survival. Corresponding endpoints at three years were: 1) good risk (no markers elevated, n = 43): 78%, 91%; 2) intermediate risk (1 or 2 markers elevated, n = 47): 41%, 36%; 3) poor risk (3 markers elevated, n = 11): 0%, 0%. This analysis extends the observation of the independent prognostic significance of B2M and LDH. The addition of TK permits a more precise estimate of risk, contributing to the utility of a serological staging system for large cell lymphoma.

High-dose chemotherapy with BEAC regimen and autologous bone marrow transplantation for intermediate grade and immunoblastic lymphoma: durable complete remissions, but a high rate of regimen-related toxicity.

Forty-eight adult patients with recurrent or refractory intermediate grade or immunoblastic lymphoma received high-dose carmustine (BCNU), etoposide, Ara C and cyclophosphamide (BEAC), followed by autologous bone marrow transplantation (BMT). Median follow-up is 906 days (range 613-2067 days). The complete remission rate was 42% and 22% had a partial response. Actuarial failure-free survival is 30% +/- 6.6%. Twenty one patients relapsed or progressed. Only one relapse occurred > 1 year after autologous BMT. Adverse prognostic factors for failure-free survival include high LDH at the time of autologous BMT, chemotherapy-refractory disease and multiple prior relapses. Patients with chemotherapy responsive first salvage (those achieving first CR only with salvage chemotherapy and those with first relapse, responding to salvage chemotherapy) had a failure-free survival of 52% +/- 10% vs 12% +/- 6% for those with more advanced disease. Of 13 patients who had no adverse factors, only two relapsed. Treatment-related mortality occurred in 23%, including infection (n = 4), cardiac toxicity (n = 4), pulmonary toxicity (n = 2) and hemorrhage (n = 1). Pulmonary toxicity was more common among patients who had received prior radiation-therapy to the chest. BEAC chemotherapy with autologous BMT is an effective but relatively toxic regimen for patients with relapsed or refractory lymphomas. The combination of chemotherapy-responsive disease after failure of one chemotherapy regimen and normal LDH identifies patients with a favorable prognosis. Alternative cytotoxic regimens require evaluation, with the goal of reducing treatment related mortality. More effective cytoreductive therapy is required for patient with poor prognostic features.

Fludarabine and cytosine arabinoside in the treatment of refractory or relapsed acute lymphocytic leukemia.

BACKGROUND: The objectives of the study were to evaluate the antileukemic efficacy and toxicity profiles of the combination of fludarabine and intermediate-dose cytosine arabinoside (ara-C) in refractory or relapsed adult acute lymphocytic leukemia (ALL). PATIENTS AND METHODS. Thirty adults with refractory or relapsed ALL were treated. Their median age was 45 years, 60% were in second or subsequent relapse, and 37% had Philadelphia chromosome-positive disease. Treatment consisted of ara-C 1 g/m2 during a period of 2 hours daily for 6 days, and fludarabine 30 mg/m2 during a period of 30 minutes daily for 5 days on days 2-6. Fludarabine was given 4 hours before ara-C to increase the rate of ara-C 5'-triphosphate (ara-CTP) accumulation in leukemic cells. Courses were repeated every 3 weeks or longer, depending on patient response and side effects. RESULTS: Nine (30%) patients achieved a complete remission (CR), 8 (27%) died during remission induction, and 13 (43%) had resistant disease. The median CR duration was 22 weeks, and the median survival was 12 weeks for all patients, and 34 weeks for those who had a response to treatment. Except for low platelet counts, which predicted shorter survival time, no other prognostic factors were demonstrated, considering the small number of patients treated. Myelosuppression-associated febrile episodes were the most common side effects, occurring in 28 (93%) patients. Neurotoxicity was noted in two (7%) patients. CONCLUSIONS: Fludarabine and ara-C are an active and relatively safe antileukemic combination in refractory or relapsed ALL. Future studies will incorporate other anti-ALL agents, such as topoisomerase II-reactive drugs, to improve the overall efficacy, and growth factors, to reduce myelosuppression-related complications.