c-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/ß-catenin-ATP-binding cassette G2 signaling.

Cisplatin and paclitaxel are standard chemotherapy for metastatic ovarian cancer, but with limited efficacy. Cancer stem/progenitor cells (or tumor-initiating cells, TICs) are hypothesized to be chemoresistant, and the existence of TICs in ovarian cancer has been previously demonstrated. However, the key signals and molecular events regulating the formation and expansion of ovarian tumor-initiating cells (OTICs) remain elusive. Here, we show that c-Kit is not just a marker of OTICs, but also a critical mediator of the phenotype that can be a viable target for the treatment of ovarian cancer. In contrast to non-OICs, c-Kit was overexpressed in OTICs. Moreover, the use of small interfering RNA to inhibit c-Kit expression markedly attenuated the number and size of OTIC subpopulations, inhibited the expression of stem cell markers and decreased the tumorigenic capabilities of OTICs. Imatinib (Gleevec), a clinical drug that blocks c-Kit kinase activity, also demonstrated its inhibition potency on OTICs. In addition, cisplatin/paclitaxel, which killed non-OTICs, with c-Kit knockdown or imatinib revealed that this was critically required for intervening ovarian cancer progression and recurrence in vitro and in xenograft tumors in vivo. Similar results were obtained with OTICs derived from ovarian carcinoma patients. Studies into the mechanisms suggest an important role for the activation of Wnt/ß-catenin and ATP-binding cassette G2 downstream of c-Kit. The tumor-promoting microenvironment, such as hypoxia, could promote OTICs via upregulation of c-Kit expression. These results unravel an integral role for c-Kit in ovarian neoplastic processes and shed light on its mechanisms of action.

Cost-effectiveness of postremission intensive therapy in patients with acute leukemia.

BACKGROUND: We assessed the cost-effectiveness of high-dose arabinoside (HiDAC)-based and allogeneic stem-cell transplantation (alloSCT)-based therapy in patients with acute leukemia. PATIENTS AND METHODS: We analyzed the outcome, cost and cost-effectiveness of 106 patients treated from January 1994 to January 2002 [94 acute myelogenous leukemia (AML)/12 acute lymphoblastic leukemia (ALL)]. Forty-two young patients at either intermediate or unknown cytogenetic risk received postremission intensive therapy (24 HiDAC-based/18 alloSCT-based therapy). RESULTS: After a median follow-up of 50 months, the estimated 7-year overall survival for the HiDAC-based group showed a tendency to be higher than the alloSCT-based group (48% versus 28%, P = 0.1452). The HiDAC-based group spent a significantly lower total cost ($US51,857 versus 75,474, P = 0.004) than the alloSCT-based group. Cost-effectiveness analysis showed that the mean cost per year of life saved for the HiDAC-based group is considerably less expensive than the alloSCT-based group ($US11,224 versus 21,564). The reduced total cost for the HiDAC-based group originated from lower cost in room fees, medication, laboratory and procedure, but not in blood transfusion and professional manpower fees. CONCLUSION: For the postremission therapy in young AML patients at either intermediate or unknown cytogenetic risk, cost-effectiveness of HiDAC-based therapy compares favorably with that of alloSCT-based therapy, which deserves further clinical trials.

Pretreatment prognostic factors and treatment outcome in elderly patients with de novo acute myeloid leukemia.

BACKGROUND: Elderly patients with acute myeloid leukemia (AML) generally have an unfavorable clinical course and are under-represented in clinical trials. The aim of this study was to analyze the prognosis and treatment outcome of elderly AML patients. PATIENTS AND METHODS: We studied 205 AML patients aged 65 years or older at our hospital. Prior to study initiation, we designated 13 variables to be analyzed for their impact on complete remission (CR) rate and overall survival (OS). RESULTS: Induction regimen (standard chemotherapy) and good performance status (PS) (Eastern Cooperative Oncology Group PS 0-1) independently influenced the achievement of CR. Multivariate analysis also determined five poor prognostic factors for OS: poor PS (score 2-4), presence of comorbidities, elevated serum lactate dehydrogenase level (> or =2x upper normal limit), extreme leukocytosis (> or =100 x 10(9)/l) and marked thrombocytopenia (< or =20 x 10(9)/l). Age was not an independent contributing factor in terms of either CR attainment or OS duration. Low-risk patients, who possessed one or less non-leukocytosis poor prognostic factor, had significantly longer disease-free survival and OS than their high-risk counterparts. CONCLUSIONS: Elderly AML patients should be risk-stratified at diagnosis. Anthracycline-based induction chemotherapy would be the best therapeutic option for such patients.

Spatiotemporal analysis of event-related fMRI data using partial least squares.

Partial least squares (PLS) has proven to be a important multivariate analytic tool for positron emission tomographic and, more recently, event-related potential (ERP) data. The application to ERP incorporates the ability to analyze space and time together, a feature that has obvious appeal for event-related functional magnetic resonance imaging (fMRI) data. This paper presents the extension of spatiotemporal PLS (ST-PLS) to fMRI, explaining the theoretical foundation and application to an fMRI study of auditory and visual perceptual memory. Analysis of activation effects with ST-PLS was compared with conventional univariate random effects analysis, showing general consensus for both methods, but several unique observations by ST-PLS, including enhanced statistical power. The application of ST-PLS for assessment of task-dependent brain-behavior relationships is also presented. Singular features of ST-PLS include (1) no assumptions about the shape of the hemodynamic response functions (HRFs); (2) robust statistical assessment at the image level through permutation tests; (3) protection against outlier influences at the voxel level through bootstrap resampling; (4) flexible analytic configurations that allow assessment of activation difference, brain-behavior relations, and functional connectivity. These features enable ST-PLS to act as an important complement to other multivariate and univariate approaches used in neuroimaging research.

Radiation therapy versus chemotherapy as initial treatment for localized nasal natural killer (NK)/T-cell lymphoma: a single institute survey in Taiwan.

BACKGROUND: To clarify the role of intention to treat for patients with localized nasal natural killer (NK)/T-cell lymphoma, and to determine the prognostic factors for these patients. PATIENTS AND METHODS: We conducted a retrospective review of 46 patients with localized nasal NK/T-cell lymphomas treated at a single institute between January 1988 and July 2002. RESULTS: The type of intended treatment was a significant factor for overall survival (OS) (5-year OS: RT versus CT = 83.3% versus 28.6%, P = 0.0269) or failure-free survival (FFS) (5-year FFS: RT versus CT = 83.3% versus 27.1%, P = 0.0247). In the intended chemotherapy group, salvage with radiotherapy was superior to chemotherapy alone for OS (5-year OS: 42.2% versus 20.0%, P = 0.0252) or FFS (5-year FFS: 41.0% versus 20.0%, P = 0.0352). On multivariate analysis, both N stage and serum lactate dehydrogenase level were independent factors for OS and FFS. No radiotherapy was an independent adverse factor for OS; advanced T stage and more than one extranodal involvement were independent adverse factors for FFS. CONCLUSIONS: Patients with localized nasal NK/T-cell lymphomas were better managed with radiotherapy as front-line therapy. The advantage of radiotherapy persisted even as palliative therapy after chemotherapy.

Diagnostic value of serum transferrin receptor and glycosylated hemoglobin on hemolytic anemia.

Soluble serum transferritin receptor (sTfR) is a new diagnostic tool for iron depletion and erythropoiesis. Glycosylated hemoglobin (GHb) can be used to detect hemolysis. The present study was thus conducted to compare the diagnostic value of sTfR and GHb (measured as Hb A(1)c) in patients with hemolytic anemia. Four groups of subjects entered into our study. Group A included 13 patients with hemolytic anemia with effective erythropoiesis (EE). Group B included 13 patients with hemolytic anemia with ineffective erythropoiesis (IE). Group C included 15 healthy controls and group D summated groups A and B. sTfR, serum ferritin, plasma hemoglobin, complete blood count, reticulocyte, haptoglobin, lactic dehydrogenase (LDH), Hb A(1)c, liver and renal function, direct and indirect bilirubin, and fasting blood sugar were measured. Plasma Hb, hematocrit, mean corpuscular volume (MCV), platelet, haptoglobin, LDH, indirect bilirubin, Hb A(1)c, and sTfR were found to be significantly different between the controls and the hemolytics, either with effective or ineffective erythropoiesis. Reticulocyte count was significantly different only between the two hemolytic groups. Hb A(1)c and sTfR were both good for the diagnosis of hemolysis. Reticulocyte count was a good tool for distinguishing EE from IE.

A novel splicing acceptor mutation of the factor VIII gene producing skipping of exon 25.

A gross deletion in the factor VIII (FVIII) mRNA was determined by reverse transcriptase polymerase chain reaction (RT-PCR) for a patient with moderately severe hemophilia A. Sequencing of the RT-PCR product depicted a 177-bp deletion ranging from nucleotide (nt) 6724 to nt 6900 of FVIII cDNA, exactly corresponding to the whole exon 25. Further study of the genomic DNA revealed the presence of a single base pair substitution (G >A) at position -1 of intron 24. The absolute consensus AG doublet of the intron 24 splicing acceptor changed to AA. In the novel splice site mutation, exon 24 was erroneously spliced to exon 26, skipping exon 25. The FVIII antigen level was normal despite the markedly reduced functional activity. Since exon 25 corresponds to part of the C2 domain, we speculate that for this patient the aberrant C2 domain markedly reduces binding affinity of FVIII protein to the phospholipid membrane, thus severely impairing the protein function.

Repeated intestinal perforation caused by an incomplete form of Behçet's syndrome.

Behçet's disease, as initially described, is a triad of recurrent oral and genital ulcers and relapsing uveitis. The incomplete form, in which there is no ocular involvement, has been described in Japan and Korea, but this is not commonly recognized in the southern Chinese. We reported herein a rare case of repeated intestinal perforations caused by an incomplete form of Behçet's syndrome in a southern Chinese man.

Intensive postremission chemotherapy in Taiwanese adults with acute myelogenous leukemia.

Intensive postremission chemotherapy has produced disease-free survival comparable to that of bone marrow transplantation in patients with acute myelogenous leukemia (AML), but its efficacy was unknown in Taiwan. We assessed the efficacy of intensive postremission chemotherapy, consisting of high-dose arabinoside-C (HiDAC) with or without transplantation of peripheral blood stem cells, in 33 AML patients from a single institute in Taiwan. Toxic reactions, treatment outcome, prognostic factors, and the size of the peripheral blood stem-cell harvest after HiDAC were analyzed. After a median follow-up of 21 months, 18 patients remained in continuous complete remission. The actuarial leukemia-free survival at 4 years was 51%. Relapse occurred in 12 patients, at a median of 12 months after initial diagnosis. All 6 patients with acute promyelocytic leukemia remained disease free after HiDAC therapy. Age, sex, and number of remission-induction or intensive consolidation chemotherapy courses had no effect on the risk of relapse. Intensive postremission chemotherapy can effectively prolong the duration of remission in young (< 60 years of age) adults with AML.

Sonographic diagnosis of a small fistulous communication between a subphrenic abscess and a perforated duodenal ulcer.

We report a case of a fistula between a subphrenic abscess and a perforated duodenal ulcer diagnosed by sonography and confirmed by CT. The sonographic findings included a subphrenic fluid collection connected to the anterior aspect of the superior duodenum by a nonpulsatile, anechoic tubular lesion. Manual compression of the upper epigastrium resulted in movement of echogenic debris from the antrum and superior duodenum through the fistulous tract into the abscess.

Angiotropic lymphoma manifesting as a solitary adrenal tumor in a case of ankylosing spondylitis.

Angiotropic lymphoma is an extremely rare disease characterized by intravascular accumulation of large neoplastic lymphocytes, with the clinical manifestations of fever, skin lesions and neurologic deficits. We report a patient who developed angiotropic lymphoma after a 10-year history of ankylosing spondylitis. The clinical disease manifested as a unilateral, solitary adrenal tumor, fever and body weight loss. The fever subsided after surgical removal of the adrenal tumor. Systemic chemotherapy was administered postoperatively. The patient was leading an uneventful life 44 months after the initial diagnosis. To our knowledge, this is the first case of angiotropic lymphoma associated with ankylosing spondylitis. It is also the second reported case manifesting with a unilateral solitary adrenal tumor without systemic involvement.

Causes of venous thrombosis in fifty Chinese patients.

In a whole year from July 1997 to June 1998, a total of 50 patients with sonogram-proved venous thrombosis who called on our hematology clinic consecutively entered into the study. Their mean age was 59.1 +/- 17.5 years, range 18-83 years, and 29 were male. A series of examinations were performed in order to find out the cause of venous thrombosis. These examinations included antithrombin, protein C, protein S, plasminogen, heparin cofactor II, activated protein C ratio, factor V Leiden mutation, fibrinogen, factors VIII and XII, euglobulin lysis time, 677 C-->T mutation of methylenetetrahydrofolate reductase (MTHFR), prothrombin 20210 (PT 20210) A allele mutation, lupus anticoagulant, anticardiolipin antibody, and complete blood count. Five patients (10%) were found to have malignancy; an inferior vena cava thrombosis in one patient was due to venous compression by hydronephrosis; two patients had lupus anticoagulant; two had varicose veins of legs; two had protein C deficiency; four had protein S deficiency; two had plasminogen deficiency; two had antithrombin deficiency. No activated protein C resistance, elevated factor VIII level, factor V Leiden, PT 20210 A allele or heparin cofactor II deficiency was found in the present study. Homozygous MTHFR 677 C-->T gene mutation was found in 7 patients (14%); one of them also had a plasminogen deficiency. No possible risk factor of venous thrombosis could be found in 24 patients (48%). In conclusion, malignancy and protein S deficiency were the most frequent acquired and congenital causes of venous thrombosis in the Chinese, respectively.

A comparative study of cefepime versus ceftazidime as empiric therapy of febrile episodes in neutropenic patients.

An open-label, randomized comparative study was conducted to evaluate the efficacy and safety of cefepime (2.0 g q. 8 h) and ceftazidime (2.0 g q. 8 h) in the empiric therapy of febrile neutropenic patients. A total of 45 eligible febrile episodes were randomized (1:1) to be treated with the study regimen. Nineteen febrile episodes treated with cefepime and 22 febrile episodes treated with ceftazidime were evaluable for efficacy. The two groups were comparable in terms of age, sex, height, weight, underlying neoplasm, number of pretherapy neutrophil, duration of neutropenia and types of infections. The overall therapeutic success rate of the cefepime group (53%) was comparable to the ceftazidime group (50%). It did not differ significantly (95% confidence interval: -0.28 to 0. 34, p = 0.85). Eighty-eight percent of pathogens in each group were bacteriologically eradicated. The safety profile was similar in both groups. No patients in either group discontinued the therapy because of adverse events. None (0%) of the cefepime patients and 2 (9%) of the ceftazidime patients died of infection. The results of this study suggest that cefepime is an effective and safe agent in the empiric therapy of febrile episodes in neutropenic patients.

Acute febrile neutrophilic dermatosis (Sweet's syndrome) in hairy cell leukemia: a case report.

Sweet's syndrome is a cutaneous reactive process that is usually associated with fever, but rarely occurs in patients with hairy cell leukemia (HCL). We report the case of a patient with HCL who developed typical Sweet's syndrome five months after the diagnosis of HCL. Skin eruptions and constitutional symptoms subsided rapidly after short-term systemic adrenocorticosteroid treatment without recurrence, until the patient died from disease exacerbation and uncontrolled infection. According to his manifestations, chemical allergens, microorganisms or HCL progression were unlikely to have been the precipitating factors for development of Sweet's syndrome. Because immunologic disorders and opportunistic infection are not uncommon in patients with HCL, a skin biopsy should be taken as early as possible when cutaneous lesions and fever develop in order to establish a correct diagnosis. Hence, unnecessary and prolonged use of antibiotics is avoided and prompt relief of the symptoms by appropriate management can be achieved.

Prevalence of factor V Leiden in the Chinese population.

BACKGROUND: Thromboembolic diseases remain a major cause of morbidity and mortality in most countries. Factor V Leiden was found to be a major cause of thromboembolic disease in Western countries. Chinese have proved to be less prone to thromboembolic diseases, therefore investigation of the prevalence of factor V Leiden is necessary among a Chinese population. METHODS: From May, 1997, to April, 1998, a total of 1,261 subjects, including 420 healthy subjects, 719 patients with nonthrombotic hematologic disorders, 77 patients with diabetes mellitus and 45 patients with deep vein thrombosis, different in age and sex, were consecutively entered into our study to determine the prevalence of factor V Leiden in the Chinese population (mean age, 50.1 +/- 18.3 years; range, 1-99 years). Of this population, 873 were male and 388 were female. RESULTS: None of the subjects was found to have factor V Leiden mutation (Arg 506-Gln mutation). Activated protein C resistance was also measured in 827 patients; none of them had an activated protein C ratio of less than 2.0. CONCLUSIONS: We suggest that factor V Leiden mutation is rare among the Chinese.

Diagnostic and prognostic values of plasma levels of fibrinolytic markers in gastric cancer.

In the present study, we determined the plasma and tissue concentrations of tissue-type plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2 and urokinase-type plasminogen activator receptor in 32 patients with pathology-proved gastric cancer. The plasma levels of the same markers were compared in 37 patients with benign gastric ulcer in order to find out if these plasma levels could be used to evaluate the prognostic value in patients with gastric cancer. Plasma plasminogen activator inhibitor-1 was significantly higher in gastric cancer than in benign gastric disease (p < 0.0005), whereas plasma urokinase-type plasminogen activator was significantly lower in patients with gastric cancer than in those with benign ulcer (p = 0.003). There was no significant correlation between tissue and plasma concentrations of the same parameters. The plasma and tissue levels of fibrinolytic parameters were not affected by tumor size or distant metastasis, whereas tumor tissue concentration of urokinase-type plasminogen activator receptor and plasminogen activator inhibitor-2 were significantly higher in N0 than in N1 and N2, and tissue plasminogen activator inhibitor-1 was significantly higher in N0 than in N1. Plasma levels of the five fibrinolytic parameters could not take the place of the corresponding tissue concentrations on the diagnosis and prediction of prognosis in patients with gastric cancer. Tissue concentrations of urokinase-type plasminogen activator receptor and plasminogen activator inhibitor-2, especially the latter, can be used to predict lymph node involvement in patients with gastric cancer.

Improved sonographic visualization by fluid challenge method of renal lithiasis in the nondilated collecting system. Experience in seven cases.

Ultrasound is an effective means of detecting renal stones in patients with hydronephrosis. The filled urinary bladder in a normal person under hydration frequently results in the sonographic appearance of minimal or moderate hydronephrosis. For optimal visualization of stones and associated acoustic shadows, six patients with radiographically opaque renal stones were evaluated with fluid-loaded renal ultrasonography, which was compared to conventional renal sonogram in basal state. Although ultrasound in basal state can be used for detection of intrarenal lithiasis, fluid-challenged renal sonogram appears more accurate for the determination of contour, location, size, and number of small stones. In one case, this fluid-loaded ultrasound well demonstrated the tramline appearance of an isolated renal artery, which mimics stone before fluid challenge.

Real time ultrasound diagnosis of non-vaterian duodenal adenoma--a brief case report.

Non-vaterian duodenal adenomas are rare lesions, usually present with bleeding and abdominal pain. Sonography is often the first imaging procedure in patients with vague upper abdominal complaints, unsuspected duodenal pathology may be encountered. It is now widely accepted as the first choice for the investigation of abdominal masses. Oral water load is recognised as a good procedure for the detection of a bowel-related mass during sonographic examination. In our case, we used the real-time ultrasound with water ingestion to detect the location of the duodenal lesion and its relationship to the neighboring structure. This report demonstrates that conventional real-time ultrasound is still a simple method to diagnose duodenal lesions.