Human cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients, and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal ...antibodies (LJP538 and LJP539) that bind to and inhibit the functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation. As would be expected in the study population, all the patients (100%) reported at least one treatment-emergent adverse event. There were 22 deaths during this study, and over 80% of the patients receiving placebo or CSJ148 developed at least one adverse event of grade 3 or higher severity. No subject who received antibody developed a hypersensitivity- or infusion-related reaction. CSJ148-treated patients showed trends toward decreased viral load, shorter median duration of preemptive therapy, and fewer courses of preemptive therapy. However, the estimated probability that CSJ148 decreases the need for preemptive therapy compared to placebo was 69%, with a risk ratio of 0.89 and a 90% credible interval of 0.61 to 1.31. The primary efficacy endpoint was therefore not met, indicating that CSJ148 did not prevent clinically significant HCMV reactivation in recipients of allogeneic hematopoietic cell transplants. (This study has been registered at ClinicalTrials.gov under identifier NCT02268526 and at EudraCT under number 2017-002047-15.).
To examine the effects of estrogen therapy on cognition, mood, and cerebral blood flow in patients with AD.
Some studies have suggested estrogen may be effective in the treatment of AD. However, most ...of these studies were not controlled adequately.
Fifty female AD patients were recruited in a randomized, double-blind, placebo-controlled 12-week trial. Each member of the estrogen-treated group received conjugated estrogen (Premarin) 1.25 mg/day. The primary outcome measures were the Cognitive Ability Screening Instrument (CASI), Clinical Dementia Rating (CDR), and Clinician Interview-Based Impression of Change (CIBIC-plus). The secondary outcome measures were Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD), Hamilton Anxiety Rating Scale (HARS), Hamilton Depression Rating Scale (HDRS), and 99mTc hexamethylpropylene amine oxime SPECT of the brain.
No meaningful differences were found between the outcome measures (CASI, CDR, CIBIC-plus, BEHAVE-AD, HARS, HDRS, and cerebral blood flow) taken from the estrogen-treated group and those from the control group.
A 1.25-mg/day dose of Premarin administered for 12 consecutive weeks does not produce a meaningful effect on cognitive performance, dementia severity, behavior, mood, and cerebral perfusion in female AD patients. Because estrogen therapy has been suspected of yielding adverse effects, and its therapeutic effectiveness is in doubt, additional evaluation of its role in AD treatment ought to be conducted.
To investigate the prevalence, risk factors, and prognosis of chronic daily headache (CDH) in a population of elderly Chinese subjects.
A community-based survey of registered residents > or =65 years ...old (n = 2,003) in two townships of Kinmen Island in 1993. A neurologist used a structured questionnaire and clinical interview to make the diagnosis of headache. Subjects who had headaches > or =15 days/month for > or =6 months in the previous year were considered to have CDH. CDH was further classified into chronic tension-type headache (CTTH), CDH with migrainous features (CDH/MF), and other CDH. Person-to-person biannual follow-up of the subjects with CDH was done in June 1995 and August 1997.
A total of 1,533 people (77%) participated in our prevalence study. Sixty subjects (3.9%) fulfilled the criteria for CDH, with a higher prevalence in women (F/M: 5.6%/1.8%, p < 0.001). Of these subjects, 42 (70%) had CTTH, 15 (25%) had CDH/MF, and 3 (5%) had other CDH. Only 23% of those with CDH had consulted physicians for their headaches in the previous year. Multivariate logistic regression revealed the significant risk factors for CDH to be analgesic overuse (OR = 79), a history of migraine (OR = 6.6), and a Geriatric Depression Scale-Short Form score of > or =8 (OR = 2.6). The follow-up results in 1995 and 1997 showed that about two-thirds of the subjects still had CDH. Analgesic overuse (relative risk = 1.6) in 1993 was a significant predictor of persistent CDH at follow-up.
A total of 3.9% of this elderly population had CDH, with CTTH being the most common subtype. Almost two-thirds of those with CDH had persistent frequent headaches at follow-up. Analgesic overuse was a significant predictor of a poor outcome.
Analysis of internal tandem duplications of FLT3 (FLT3/ITD) was performed on bone marrow samples obtained at diagnosis and relapse from 108 adult patients with de novo acute myeloid leukemia (AML) to ...determine the role of this mutation in leukemic relapse. Eighty-three patients had wild-type FLT3 at both diagnosis and relapse, 16 had FLT3/ITD at both stages, whereas 8 had acquired the mutation and 1 had lost it at relapse. Using Genescan analysis, we found that FLT3/ITD levels at first relapse were significantly higher than those at diagnosis (mean +/- SE, 40.5% +/- 4.8% versus 17.9% +/- 3.6%, P <.001). The increase in mutation levels at relapse as compared with diagnosis did not correlate with the difference in blast cell percentages at both stages (P =.777). A hemizygous deletion of wild-type FLT3 was found in 4 patients at relapse compared to none at diagnosis. Nine of the 11 patients carrying a single mutation at diagnosis relapsed with an identical mutation. All 6 patients with more than one FLT3/ITD mutation at diagnosis showed changes in mutation patterns and levels at first relapse; however, each patient retained at least one mutation in the relapse sample. The changes of mutation patterns had implications for the monitoring of minimal residual disease. Our results suggest that FLT3/ITD may contribute as the initial transforming event in AML, and relapse can reflect the selection and outgrowth of a mutant clone or evolution of a new clone harboring this mutation.
The role of internal tandem duplication of fms-like tyrosine kinase 3 (FLT3/ITD), mutations at tyrosine kinase domain (FLT3/TKD) and N-ras mutations in the transformation of myelodysplastic syndrome ...(MDS) to AML was investigated in 82 MDS patients who later progressed to AML; 70 of them had paired marrow samples at diagnosis of MDS and AML available for comparative analysis. Five of the 82 patients had FLT3/ITD at presentation. Of the 70 paired samples, seven patients acquired FLT3/ITD during AML evolution. The incidence of FLT3/ITD at diagnosis of MDS was significantly lower than that at AML transformation (3/70 vs 10/70, P<0.001). FLT3/ITD(+) patients progressed to AML more rapidly than FLT3/ITD(-) patients (2.5+/-0.5 vs 11.9+/-1.5 months, P=0.114). FLT3/ITD(+) patients had a significantly shorter survival than FLT3/ITD(-) patients (5.6+/-1.3 vs 18.0+/-1.7 months, P=0.0008). After AML transformation, FLT3/ITD was also associated with an adverse prognosis. One patient had FLT3/TKD mutation (D835Y) at both MDS and AML stages. Additional three acquired FLT3/TKD (one each with D835 H, D835F and I836S) at AML transformation. Five of the 70 matched samples had N-ras mutation at diagnosis of MDS compared to 15 at AML transformation (P<0.001), one lost and 11 gained N-ras mutations at AML progression. Coexistence of FLT3/TKD and N-ras mutations was found in two AML samples. N-ras mutations had no prognostic impact either at the MDS or AML stage. Our results show that one-third of MDS patients acquire activating mutations of FLT3 or N-ras gene during AML evolution and FLT3/ITD predicts a poor outcome in MDS.
The fusion transcripts of MLL rearrangement MLL(+) in acute myeloid leukemia (AML) and their clinicohematologic correlation have not be well characterized in the previous studies. We used Southern ...blot analysis to screen MLL(+) in de novo AML. Reverse transcriptase-polymerase chain reaction was used to detect the common MLL fusion transcripts. cDNA panhandle PCR was used to identify infrequent or unknown MLL partner genes. MLL(+) was identified in 114 (98 adults) of 988 AML patients. MLL fusion transcripts comprised of 63 partial tandem duplication of MLL (MLL-PTD), 14 MLL-AF9, 9 MLL-AF10, 9 MLL-ELL, 8 MLL-AF6, 4 MLL-ENL and one each of MLL-AF1, MLL-AF4, MLL-MSF, MLL-LCX, MLL-LARG, MLL-SEPT6 and MLL-CBL. The frequency of MLL-PTD was 7.1% in adults and 0.9% in children (P<0.001). 11q23 abnormalities were detected in 64% of MLL/t11q23 and in none of MLL-PTD by conventional cytogenetics. There were no differences in remission rate, event-free survival and overall survival between adult MLL-PTD and MLL/t11q23 groups. Adult patients had a significantly poorer outcome than children. The present study showed that cDNA panhandle PCR can identify all rare or novel MLL partner genes. MLL-PTD was rare in childhood AML. MLL(+) adults had a poor outcome with no difference in survival between MLL-PTD and MLL/t11q23 groups.
This study was undertaken to investigate the outcome and prognostic factors in patients with ovarian germ cell malignancies (OGCMs).
A total of 93 patients with OGCMs were retrospectively reviewed, ...among whom 84 patients had primary treatment at Chang Gung Memorial Hospital (CGMH) between 1984 and 2003. The other nine patients were primarily treated outside and referred for follow-up (
n = 1), adjuvant chemotherapy (
n = 4), or salvage therapy after recurrence (
n = 4). The clinicopathological and treatment-related characteristics were analyzed for association with the occurrence of tumor persistence/recurrence or death.
Of the study patients, 32 had dysgerminoma (DSG), 29 immature teratoma (IMT), 23 endodermal sinus tumor, 7 mixed germ cell tumors, and 1 each had choriocarcinoma and embryonal carcinoma. The median follow-up of survivors was 66 months (range, 12–236 months). The median time to recurrence or progression was 8 months. There were 11 treatment failures with 6 died of cancer. The 5-year survival rate was 97.4% for those primarily treated at CGMH. Histology (DSG/IMT versus non-DSG/IMT) (
P < 0.0001) and International Federation of Gynecology and Obstetrics stage (
P = 0.001) were significantly associated with treatment failure, while histology (
P = 0.0004), salvage high-dose chemotherapy (HD-CT) after primary chemotherapy failed (
P = 0.0405), and residual tumor after salvage surgery (
P = 0.0014) were significant prognostic factors for overall survival.
Prognosis of OGCMs is excellent if managed with standard treatment initially. Aggressive HD-CT with salvage surgery needs to be applied for recurrent/persistent disease after primary chemotherapy.
To investigate prospectively the influence of patient characteristics upon, and the association of postoperative measurements with, the requirements for postoperative morphine and the assessment of ...resting pain and pain upon movement in Chinese patients.
From January 1998 to December 1999, patients receiving patient-controlled iv morphine subsequent to general anesthesia and surgery at our institute (Kaohsiung Veterans General Hospital), were enrolled in the study. Demographic data (such as gender, age, weight, height and education level) and postoperative measurements, including pain scores at rest or during movement, sedation scores and morphine consumption, were recorded.
In total 2,298 patients were recruited. Females consumed significantly less morphine via patient-controlled analgesia (PCA) in the first three postoperative days than was the case for males (P <0.05). Gender was the strongest predictor for postoperative morphine requirements. Postoperative pain upon movement was another effective predictor for morphine requirement (P <0.05). Age, body height, body weight, education and operation sites were not associated with morphine consumption.
Gender and postoperative pain upon movement are the major factors influencing morphine requirement for patient-controlled iv morphine analgesia during the first three postoperative days in Chinese patients.
The purpose of this study of dementia screening was to obtain different cutoff scores of the Cognitive Abilities Screening Instrument, Chinese versions (CASI C-2.0) for subjects with different ...educational backgrounds. The diagnosis of dementia was based on the Diagnostic and Statistical Manual of Mental Disorders, ed 3 revised or ed 4 criteria. To diagnose Alzheimer's disease, the guidelines of the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association was followed. The severity of dementia was determined on the Clinical Dementia Rating scale. Altogether 2,096 subjects, aged 65 years and more, were included. Of them, 1,178 were normal and 918 were demented. Their performance on CASI C-2.0 was influenced by their education and age. Gender difference on CASI C-2.0 scores was only significant in the illiterate, but not in the literate group. We recommend that the population be divided into three levels, namely those who (1) had no formal education (Edu = 0); (2) received 1-5 years of schooling (Edu = 1-5), and (3) received 6 or more years of education (Edu >/=6). The cutoff scores of CASI C-2.0 in the diagnosis of dementia in these three educational groups were as follows: Edu = 0: 49/50 (sensitivity = 0.83; specificity = 0.85); Edu = 1-5: 67/68 (sensitivity = 0.83; specificity = 0.91), and Edu >/=6: 79/80 (sensitivity = 0.89; specificity = 0.90).
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