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Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.
Yu, S, Zhang, Y, Yu, G, Wang, Y, Shao, R, Du, X, Xu, N, Lin, D, Zhao, W, Zhang, X, et al
Journal of internal medicine. 2024;(2):216-228
Abstract
BACKGROUND Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION Clinical Trials Registry: NCT04424147.
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Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients.
Quintanilha, JCF, Wang, J, Sibley, AB, Jiang, C, Etheridge, AS, Shen, F, Jiang, G, Mulkey, F, Patel, JN, Hertz, DL, et al
British journal of cancer. 2022;(2):265-274
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Abstract
BACKGROUND Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. METHODS A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. RESULTS The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10-7). CONCLUSIONS The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00785291 (CALGB 40502); NCT00601900 (CALGB 40503); NCT00088894 (CALGB 80303) and NCT00110214 (CALGB 90401).
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Development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization/selected reaction monitoring/mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of keto-androgens in human serum.
Tamae, D, Byrns, M, Marck, B, Mostaghel, EA, Nelson, PS, Lange, P, Lin, D, Taplin, ME, Balk, S, Ellis, W, et al
The Journal of steroid biochemistry and molecular biology. 2013;:281-9
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Abstract
Prostate cancer is the most frequently diagnosed form of cancer in males in the United States. The disease is androgen driven and the use of orchiectomy or chemical castration, known as androgen deprivation therapy (ADT) has been employed for the treatment of advanced prostate cancer for over 70 years. Agents such as GnRH agonists and non-steroidal androgen receptor antagonists are routinely used in the clinic, but eventually relapse occurs due to the emergence of castration-resistant prostate cancer. With the appreciation that androgen signaling still persists in these patients and the development of new therapies such as abiraterone and enzalutamide that further suppresses androgen synthesis or signaling, there is a renewed need for sensitive and specific methods to quantify androgen precursor and metabolite levels to assess drug efficacy. We describe the development, validation and application of a stable isotope dilution liquid chromatography electrospray ionization selected reaction monitoring mass spectrometry (SID-LC/ESI/SRM/MS) method for quantification of serum keto-androgens and their sulfate and glucuronide conjugates using Girard-T oxime derivatives. The method is robust down to 0.2-4pg on column, depending on the androgen metabolite quantified, and can also quantify dehydroepiandrosterone sulfate (DHEA-S) in only 1μL of serum. The clinical utility of this method was demonstrated by analyzing serum androgens from patients enrolled in a clinical trial assessing combinations of pharmacological agents to maximally suppress gonadal and adrenal androgens (Targeted Androgen Pathway Suppression, TAPS clinical trial). The method was validated by correlating the results obtained with a hydroxylamine derivatization procedure coupled with tandem mass spectrometry using selected reaction monitoring that was conducted in an independent laboratory.
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Diethylstilbestrol and docetaxel: a Phase II study of tubulin active agents in patients with metastatic, androgen-independent prostate cancer.
Montgomery, RB, Nelson, PS, Lin, D, Ryan, CW, Garzotto, M, Beer, TM
Cancer. 2007;(5):996-1002
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BACKGROUND The addition of diethylstilbestrol to docetaxel modified tubulin composition and improved the response of prostate cancer to chemotherapy in preclinical models. An attempt was made to recapitulate the observations in a clinical trial. METHODS Twenty-nine patients with progressive, metastatic, chemotherapy-naive androgen-independent prostate cancer were treated with diethylstilbestrol 1 mg daily and 5 mg on the day before docetaxel and docetaxel 36 mg/m(2) intravenously weekly for 3 weeks of a 4-week cycle. Prophylactic anticoagulation was used in all patients. Patients were assessed by prostate-specific antigen (PSA) monthly and computed tomography (CT) and bone scans every 3 cycles. The Response Evaluation Criteria in Solid Tumors (RECIST) criteria and PSA decline by >50% maintained for 4 weeks were used to assess activity. RESULTS The median age was 68 years (range, 56-84 years), Southwest Oncology Group performance status 0 (score range, 0-2), alkaline phosphatase 120 U/L (range, 49-523), hemoglobin (Hgb) 12.6 g/dL (range, 9.2-16.3), PSA 66 ng/dL (range, 4-1962). The median number of cycles administered was 6. Soft tissue metastases were present in 51% of patients and bone metastases in 93%. Twenty-nine patients are evaluable for response. Of these, 20 patients (69%, 95% confidence interval [CI], 49%-85%) had a PSA decline of >50% and the PSA declined by >90% in 12 patients (41%, 95% CI, 23.1%-58.9%). Of 15 patients with measurable disease, 6 (40%, 95% CI, 23.5%-61%) had a partial response. Median time to progression was 6 months (range, 3-19 months). Fifteen patients (51%) suffered grade 3/4 toxicity. Two patients died of causes unrelated to therapy and another died from a steroid-induced ulcer. Six patients developed thrombosis and of those tested 75% had Factor V mutations. Pretreatment PSA, performance status, Hgb, and alkaline phosphatase had no impact on the likelihood of response. CONCLUSIONS The combination of diethylstilbestrol and docetaxel produces a significant level of activity, measured by PSA decline and measurable disease response rate, and except for venous thrombosis the toxicity appears similar to that seen with docetaxel plus prednisone. These results suggest that tubulin modulation with diethylstilbestrol may improve the therapeutic efficacy of docetaxel and the combination is worthy of further study.
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Use of noncontact mapping and saline-cooled ablation catheter for sinus node modification in medically refractory inappropriate sinus tachycardia.
Lin, D, Garcia, F, Jacobson, J, Gerstenfeld, EP, Dixit, S, Verdino, R, Callans, DJ, Marchlinski, FE
Pacing and clinical electrophysiology : PACE. 2007;(2):236-42
Abstract
BACKGROUND Inappropriate sinus tachycardia (IST) is characterized by heart rate (HR) increase out of proportion to stress level. Radiofrequency (RF) modification of the sinus node (SN) is an accepted treatment modality for medically refractory IST. We describe a new technique using noncontact mapping and a saline irrigated catheter for SN modification. METHODS Seven consecutive patients with medically refractory IST were referred for ablation. Intrinsic heart rate (IHR) was calculated with complete autonomic blockade by atropine and propranolol. Isoproterenol (ISO) 1 mcg/min was initiated and increased to 10 mcg/min. Site of earliest activation was tagged at each dose of ISO once stable HR was achieved. RF ablation to target site of earliest activation at peak HR on ISO 10 mcg/min was performed. With any change in P-wave morphology, activation was reassessed and the new site of earliest activation targeted. Endpoint was a decrease in HR and change in P-wave morphology in lead III and aVF. RESULTS Five of seven patients had abnormal IHR. Mean number of RF lesions was 25 (10-52). All patients had either flattening of the P wave or development of negative P waves in leads III and aVF post RF associated with a decrease in HR of > or = 25% from baseline off ISO. A caudal shift of the site of early activation compared with baseline was observed. One patient who had a prior SN modification developed symptomatic intermittent junctional bradycardia and required an atrial pacemaker 2 weeks later. The other 6 patients in follow-up from 6 to 24 months had no further IST. CONCLUSIONS Noncontact mapping using the described technique in conjunction with the saline-cooled ablation catheter for SN modification in the treatment of IST may provide effective HR control.
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Rectal fistulas after prostate brachytherapy.
Tran, A, Wallner, K, Merrick, G, Seeberger, J, Armstrong, J, Mueller, A, Cavanagh, W, Lin, D, Butler, W
International journal of radiation oncology, biology, physics. 2005;(1):150-4
Abstract
PURPOSE To compare the rectal and prostatic radiation doses for a prospective series of 503 patients, 44 of whom developed persistent rectal bleeding, and 2 of whom developed rectal-prostatic fistulas. METHODS AND MATERIALS The 503 patients were randomized and treated by implantation with 125I vs. 103Pd alone (n = 290) or to 103Pd with 20 Gy vs. 44 Gy supplemental external beam radiotherapy (n = 213) and treated at the Puget Sound Veterans Affairs Medical Center (n = 227), Schiffler Cancer Center (n = 242) or University of Washington (n = 34). Patients were treated between September 1998 and October 2001 and had a minimum of 24 months of follow-up. The patient groups were treated concurrently. Treatment-related morbidity was monitored by mailed questionnaires, using standard American Urological Association and Radiation Therapy Oncology Group criteria, at 1, 3, 6, 12, 18, and 24 months. Patients who reported Grade 1 or greater Radiation Therapy Oncology Group rectal morbidity were interviewed by telephone to clarify details regarding their rectal bleeding. Those who reported persistent bleeding, lasting for >1 month were included as having Grade 2 toxicity. Three of the patients with rectal bleeding required a colostomy, two of whom developed a fistula. No patient was lost to follow-up. The rectal doses were defined as the rectal volume in cubic centimeters that received >50%, 100%, 200%, or 300% of the prescription dose. The rectum was considered as a solid structure defined by the outer wall, without attempting to differentiate the inner wall or contents. RESULTS Persistent rectal bleeding occurred in 44 of the 502 patients, 32 of whom (73%) underwent confirmatory endoscopy. In univariate analysis, multiple parameters were associated with late rectal bleeding, including all rectal brachytherapy indexes. In multivariate analysis, however, only the rectal volume that received >100% of the dose was significantly predictive of bleeding. Rectal fistulas occurred in 2 patients (0.4%), both of whom had received moderate rectal radiation doses and extensive intervention for rectal bleeding. CONCLUSION Partly on the basis of data from others and data presented here, we believe that the incidence of rectal fistulas can be much lower than in our series. High rectal radiation doses should be avoided a priori, to minimize the likelihood of rectal bleeding, and hence the likelihood that invasive procedures will be performed.
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A functional polymorphism in the SULT1A1 gene (G638A) is associated with risk of lung cancer in relation to tobacco smoking.
Liang, G, Miao, X, Zhou, Y, Tan, W, Lin, D
Carcinogenesis. 2004;(5):773-8
Abstract
Sulfotransferase 1A1, an important member of sulfotransferase superfamily, is involved in the biotransformation of many compounds including tobacco carcinogens. A single nucleotide polymorphism (G638A) in the sulfotransferase 1A1 (SULT1A1) gene causes Arg213His amino acid change and consequently results in significantly reduced enzyme activity and thermostability. We thus hypothesized that the variant SULT1A1 allele may protect against the risk of lung cancer related to tobacco smoking. To examine this hypothesis, we analyzed 805 patients with lung cancer and 809 controls for this polymorphism in a hospital-based, case-control study. We observed that, compared with the GG genotype, the variant SULT1A1 genotype (638GA or AA) was associated with a significantly increased risk for overall lung cancer [odds ratio (OR) 1.85; 95% confidence interval (CI) 1.44-2.37]. Stratification analysis showed that the increased risk of lung cancer related to the variant SULT1A1 genotypes was more pronounced in younger subjects and limited to smokers but not non-smokers [OR 2.28 (95% CI 1.66-3.13) versus OR 1.35 (95% CI 0.91-1.99); P for homogeneity = 0.000]. Furthermore, the risk of lung cancer for the variant genotypes was increased consistently with cumulative smoking dose, with the ORs being 1.66 (95% CI, 0.75-3.68), 2.28 (95% CI, 1.47-3.54) and 3.35 (95% CI, 1.71-6.57) for those who smoked <15 pack-years, 15-36 pack-years and >36 pack-years, respectively (P for trend = 0.000). When analysis was stratified by histological subtypes of lung cancer, consistent results were observed for all three major types of the cancer, i.e. squamous cell carcinoma, adenocarcinoma and other types. Our results, which are against the original hypothesis, demonstrate that the variant SULT1A1 638A allele is associated with susceptibility to lung cancer in relation to tobacco smoking.
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[Study on effect of Astragalus injection in treating congestive heart failure].
Zhou, ZL, Yu, P, Lin, D
Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine. 2001;(10):747-9
Abstract
OBJECTIVE To observe the clinical efficacy and side-effects of Astragalus Injection (AI) in treating congestive heart failure (CHF). METHODS Eighty-three patients of CHF with heart function of II-IV grade assessed by NYHA (New York Heart Association) classification were randomly divided into 2 groups. The 42 patients in the treated group were treated with AI 40 ml (equivalent to 80 g crude drug) by adding in 5% glucose solution 500 ml for intravenous dripping, once a day and the 41 patients in the control group were treated by nitrolingual injection 15 mg by adding in 5% glucose solution 500 ml for intravenous dripping once a day. The therapeutic course in both groups was 2 weeks and the patients were followed-up for 1-6 months. RESULTS The clinical heart function improvement rate and the total effective rate in the treated group after 1 month treatment were 26.2% and 78.6%, and after 6 months were 34.2% and 81.6% respectively, which were superior to those in the control group significantly (P < 0.05 or P < 0.01). The levels of left ventricular ejection fraction (LVEF), fractional shortening of left ventricular short axis (FS), the ratio of maximum blood flow between the advanced and early atrial systole (E/A), stroke volume (SV), cardiac output (CO) and the cardiac index (CI) were all improved in both groups (P < 0.01 or P < 0.05), but better improvement was shown in the treated group. Follow-up study showed that the incidence of cardiac event was lower in the treated group than that in the control group (P < 0.05). CONCLUSION AI can be took as one of the important auxiliary drugs for treatment of CHF especially in severe cases.