伊马替尼血浆谷质量浓度与慢性粒细胞白血病慢性期疗效相关性研究

目的评价伊马替尼血浆谷质量浓度对慢性粒细胞白血病(CML)慢性期(CP)患者疗效的影响。方法收集2009年6月至2010年2月北京大学人民医院55例经标准剂量伊马替尼治疗的CML-CP患者,于治疗后3、6或12个月后检测伊马替尼血浆谷质量浓度。对疗效欠佳或治疗失败患者予增加伊马替尼剂量后3～6个月再次检测伊马替尼血浆谷质量浓度。结果服用400 mg/d伊马替尼患者中,血浆伊马替尼谷质量浓度为981～4170μg/L,平均为(1685±637)μg/L。治疗后18个月获得主要分子学反应(MMR)患者平均伊马替尼谷质量浓度(1881±669)μg/L显著高于未获得MMR患者(1262±346)μg/L(P<0.05)。17例未获MMR患者中,7例伊马替尼加量至600 mg/d后,其谷质量浓度显著升高,中位9个月时,6例(86%)获得MMR,而10例未加量者继续治疗,3例(30%)获得MMR(P=0.05)。结论伊马替尼的血浆谷质量浓度与CML-CP患者良好的分子学疗效相关。疗效不佳患者增加伊马替尼的剂量,有助于提高伊马替尼谷质量浓度和分子学疗效。     

甲磺酸伊马替尼治疗120例慢性髓性白血病的临床研究

目的观察甲磺酸伊马替尼（IM）治疗Ph染色体阳性和（或）BCR／ABL基因阳性的慢性髓性白血病（CML）的疗效和安全性。方法对90例Ph染色体阳性和（或）BCR／ABL基因阳性CML慢性期（CP）患者,持续口服IM,400mg／d;30例CML疾病进展期（加速期／急变期）患者,持续口服IM,600mg／d。服药期间定期复查血常规、骨髓细胞学、染色体和（或）BCR／ABL基因等指标,并随访观察。结果（1）CML—CP患者总的完全血液学缓解率（CHR）、完全细胞遗传学缓解率（CCyR）和完全分子遗传学疗效（CMR）分别为73．3％（66／90）、66．7％（60／90）、54．4％（49／90）;治疗前是否接受过干扰素治疗对CHR、CCyR和CMR均无明显影响;服药前病程≤6个月的CMR优于〉6个月者。初次达到CHR的时间与首次达CCyR的时间、首次达CCyR的时间与BCR／ABL首次转阴时间之间均存在相关性,而初次达CHR的时间与BCR／ABL首次转阴时间则无明显相关性。（2）进展期CML患者的CHR、CCyR、CMR分别为43．3％（13／30）、25．9％（7／27）、25．0％（7／28）,总病死率为30．0％（9／30）。（3）年龄≤25岁患者的病死率高于〉25岁者,差异有统计学意义（P〈0．05）。（4）白细胞减少达Ⅲ级者有19例（16．0％）,发生于治疗后5～20周。血小板减少达Ⅲ级者有21例（18．0％）,发生于治疗后3～16周。主要的非血液系统毒性为双下肢水肿、骨痛和皮疹等,但均程度轻微。结论IM对初治CML及经干扰素治疗失败的CML有较高的CHR及CCyR且起效迅速,对CML—CP疗效显著优于进展期;不良反应程度轻微,患者易于耐受。     

Inv (11)(p15q21) in donor-derived Ph-negative cells in a patient with chronic myeloid leukemia in relapse successfully treated with imatinib mesylate post allogeneic stem cell transplantation

Imatinib mesylate (IM) is the standard first-line treatment for patients with chronic myeloid leukemia (CML). Surprisingly, 2-15% of patients achieving a complete cytogenetic response develop cytogenetic abnormalities in Philadelphia (Ph)-negative cells. Following hematopoietic stem cell transplantation (HSCT), IM induces complete molecular responses (CMR) in approximately 70% patients with relapsed CML, and no IM-related cytogenetic abnormalities in Ph-negative donor-derived cells have been described after HSCT. We report a 56-year-old female who presented with a relapse from CML in September 2002. She had received a matched related HSCT for CML in chronic phase. Donor lymphocyte infusion was given 3 years post-HSCT for a relapse. Sustained CMR was achieved within 3 months of initiation of IM. In October 2005, routine evaluation demonstrated continuous CMR, full male donor engraftment and an inv (11) on donor cells. Evaluation of the donor demonstrated no dysplasia or cytogenetic abnormalities. This observation reinforces the possibility that IM therapy may be casually linked to the phenomenon of secondary cytogenetic changes in diploid cells.     

Growth hormone (GH) and prolactin responses to repetitive administration of GH-releasing hormone in acromegaly

We investigated the pattern of GH secretion in response to repetitive GH-releasing hormone (GHRH) administration in patients with active acromegaly and in normal subjects. Twelve acromegalic patients (nine women and 3 men; aged 21-76 yr) were studied. Eight had never been treated, whereas four had undergone neurosurgery but still had active disease. All patients and eight normal subjects received three doses of 50 micrograms GHRH, iv, at 2-h intervals. Seven patients were retested 6-8 weeks after transsphenoidal removal of a pituitary adenoma. There was a marked serum GH rise in acromegalic patients and normal subjects after the first GHRH dose [area under the curve, 2070 +/- 532 (+/- SE) vs. 1558 +/- 612 ng/min X ml, respectively; P = NS]. Successive GHRH doses stimulated GH release only in acromegalic patients (second dose, 1123 +/- 421 ng/min X ml; third dose, 2293 +/- 1049 ng/min X ml). In normal subjects, the GH response to the second and third GHRH doses was blunted (second dose, 86 +/- 32 ng/min X ml; third dose, 210 +/- 63 ng/min X ml; P less than 0.01). PRL secretion did not change in normal subjects, whereas 6 of 12 acromegalic patients had PRL release after each GHRH dose (PRL responders to GHRH). Transsphenoidal surgery led to normalization (less than 5 ng/ml) of the preoperatively elevated GH levels in all but 2 patients, who, however, had reduction of somatomedin-C levels. The amount of GH released in the postoperative test was significantly lower than that released preoperatively (first dose, 722 +/- 209 vs. 2945 +/- 743 ng/min X ml; second dose, 358 +/- 117 vs. 1737 +/- 633 ng/min X ml; third dose, 320 +/- 144 vs. 1776 +/- 676 ng/min X ml, respectively; P less than 0.05 in all instances). Thus, patients with active acromegaly, but not normal subjects, respond to repetitive GHRH administration at 2-h intervals with an increase in GH levels. This increase may be due to a larger releasable GH pool and/or faster GH turnover in the adenomatous cell.     

Efficacy of a twice-daily antiretroviral regimen containing 100 mg ritonavir/400 mg indinavir in HIV-infected patients

OBJECTIVE: To evaluate the pharmacokinetics, efficacy and tolerability of a low-dose boosted indinavir (IDV)/ritonavir (RTV) regimen [100 mg RTV/400 mg IDV twice daily (bid)] in patients previously receiving a standard IDV regimen [800 mg three times a day (tid)]. METHODS: In a prospective, open-label, cross-over trial, patients with plasma HIV RNA < 200 copies/ml receiving an IDV-containing regimen (800 mg tid) were switched to an RTV/IDV (100/400 mg bid)-containing regimen. Minimal and maximal IDV plasma concentrations ( Cmin and Cmax ) were determined before the switch (day 0), at week 2 and week 4 after the switch. The CD4 cell count and plasma HIV RNA were determined at day 0, week 2 and week 4, then every 8 weeks. The primary end-point was the percentage of patients with plasma HIV RNA below 200 copies ml at week 48. RESULTS: Twenty patients were enrolled. At baseline, on IDV 800 mg tid, median IDV Cmin was 194 ng/ml and median IDV Cmax was 8449 ng/ml. On RTV/IDV (100/400 mg), median IDV Cmin increased to 536 ng/ml at week 2 and 475 ng/ml at week 4, while Cmax decreased to 2983 ng/ml at week 2 and 2997 ng/ml at week 4 ( P < 0.001). The median area under the IDV plasma concentration-time curve measured in seven patients was 25 126 ng.h/ml, and the IDV half-life (t1/2 ) was 4.4 h. All patients had plasma HIV RNA remaining < 200 copies/ml at week 48. Tolerability of RTV/IDV was excellent. CONCLUSION: RTV/IDV (100/400 mg bid) yields significantly higher IDV plasma Cmin and lower IDV Cmax values relative to the standard IDV regimen, thereby improving both tolerability and efficacy.     

Comparison of rivaroxaban concentrations between Asians and Caucasians and their correlation with PT/INR

The objectives of this study are to compare steady-state trough (Cmin,ss) and peak (Cmax,ss) concentrations of rivaroxaban between Asians and Caucasians and to evaluate the relationship between rivaroxaban concentrations and prothrombin time/international normalized ratio (PT/INR). Recruited patients were advised on the time to take rivaroxaban. Cmin,ss and PT/INR were taken when patients arrived. Cmax,ss and PT/INR were drawn between 2 and 4 h later after the patient took rivaroxaban with food. Thirty patients were included in the analyses: 57% (n?=?17) males and 43% (n?=?13) females, 77% (n?=?23) on 20 mg and 23% (n?=?7) on 15 mg. Median PT_trough and PT_peak are moderately correlated with Cmin,ss (r²?=?0.43) and Cmax,ss (r²?=?0.49), respectively. Patients on 15 mg have lower Cmin,ss and Cmax,ss versus Caucasians [12 ng/ml vs. 57 ng/ml (Cmin,ss); 87 ng/ml vs. 229 ng/ml (Cmax,ss), p?<?0.01 for both]. Patients on 20 mg also have lower Cmin,ss and Cmax,ss versus Caucasians [14 ng/ml vs. 44 ng/ml (Cmin,ss); 101 ng/ml vs. 249 ng/ml (Cmax,ss), p?<?0.01 for both]. Subgroup analysis shows patients with BMI?≥?30 have lower Cmax,ss than patients with BMI?<?30 [80.47 ng/ml vs. 124 (p?=?0.014)]. Cmin,ss and Cmax,ss were lower in Singaporeans than Caucasians. This may have an impact on the effectiveness of rivaroxaban in Singaporeans. Patients with higher BMI may not benefit similarly as patients with lower BMI. Lastly, the Dade Innovin reagent’s measure of PT/INR is not sensitive towards changes in rivaroxaban concentrations.     

Use of piretanide, a new loop diuretic, in cirrhosis with ascites: relationship between the diuretic response and the plasma aldosterone level.

Twenty patients with cirrhosis and ascites but no renal failure were given piretanide, a new loop diuretic, in order to investigate its efficacy and to relate the diuretic response with the pretreatment plasma aldosterone concentration. Eleven patients responded to piretanide 12 mg/day (equivalent in potency to 80 mg furosemide); there was no response in nine patients. Both groups were similar with regard to liver function, plasma urea, serum creatinine, plasma electrolytes, urine volume, and urine potassium concentration. The basal urinary sodium excretion was significantly higher in those patients who responded (23.6 +/- 5.7 mmol/day vs. 4.3 +/- 1.42 mmol/day; P < 0.01) (M +/- SE). Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were normal or only slightly increased in patients who responded to piretanide (PRA = 1.22 +/- 0.20 ng/ml/h; PAC = 12.25 +/- 2.20 ng/100 ml) and very high in patients who did not respond (PRA = 8.71 +/- 1.18 ng/ml/h; PAC = 84.6 +/- 16.2 ng/100 ml) (P < 0.001). Patients unresponsive to piretanide 12 mg/day also failed to respond when the dose was increased to 24 mg/day. However, the addition of spironolactone, 150 mg/day, to piretanide was followed in these patients by a marked increase in diuresis and natriuresis. These results strongly suggest that the pre-treatment level of aldosterone is an important factor influencing the response to loop diuretics in patients with non-azotaemic cirrhosis and ascites.     

Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV

The impact of imatinib dose on response rates and survival in older patients with chronic myeloid leukemia in chronic phase has not been studied well. We analyzed data from the German CML-Study IV, a randomized five-arm treatment optimization study in newly diagnosed BCR-ABL-positive chronic myeloid leukemia in chronic phase. Patients randomized to imatinib 400 mg/day (IM400) or imatinib 800 mg/day (IM800) and stratified according to age (≥65 years vs. <65 years) were compared regarding dose, response, adverse events, rates of progression, and survival. The full 800 mg dose was given after a 6-week run-in period with imatinib 400 mg/day. The dose could then be reduced according to tolerability. A total of 828 patients were randomized to IM400 or IM800. Seven hundred eighty-four patients were evaluable (IM400, 382; IM800, 402). One hundred ten patients (29 %) on IM400 and 83 (21 %) on IM800 were ≥65 years. The median dose per day was lower for patients ≥65 years on IM800, with the highest median dose in the first year (466 mg/day for patients ≥65 years vs. 630 mg/day for patients <65 years). Older patients on IM800 achieved major molecular remission and deep molecular remission as fast as younger patients, in contrast to standard dose imatinib with which older patients achieved remissions much later than younger patients. Grades 3 and 4 adverse events were similar in both age groups. Five-year relative survival for older patients was comparable to that of younger patients. We suggest that the optimal dose for older patients is higher than 400 mg/day. ClinicalTrials.gov identifier: NCT00055874     

MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial.

AIMS: To determine in a multicentre, multivendor trial the diagnostic performance for perfusion-cardiac magnetic resonance (perfusion-CMR) in comparison with coronary X-ray angiography (CXA) and single-photon emission computed tomography (SPECT). METHODS AND RESULTS: Of 241 eligible patients from 18 centres, 234 were randomly dosed with 0.01, 0.025, 0.05, 0.075, or 0.1 mmol/kg Gd-DTPA-BMA (Omniscantrade mark, GE-Healthcare) per stress (0.42 mg/kg adenosine) and rest perfusion study. Coronary artery disease (CAD) was defined as diameter stenosis > or =50% on quantitative CXA. Five CMR and eight SPECT studies (of 225 complete studies) were excluded from analyses due to inadequate quality (three blinded readers scored per modality). The comparison of CMR vs. SPECT was based on receiver operating characteristic (ROC) analysis. Perfusion-CMR at the optimal CM dose (0.1 mmol/kg) had similar performance as SPECT, if only the SPECT studies of the 42 patients with this dose were considered [area under ROC curve (AUC): 0.86 +/- 0.06 vs. 0.75 +/- 0.09 for SPECT, P = 0.12]; however, diagnostic performance of perfusion-CMR was better vs. the entire SPECT population (AUC: 0.67 +/- 0.05, n = 212, P = 0.013). CONCLUSIONS: In this multicentre, multivendor trial, ROC analyses suggest perfusion-CMR as a valuable alternative to SPECT for CAD detection showing equal performance in the head-to-head comparison. Comparing perfusion-CMR with the entire SPECT population suggests CMR superiority over SPECT, which warrants further evaluation in larger trials.     

Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia

The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukaemia (CP‐CML) is 400 mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematological and cytogenetic response to IM400 vs. imatinib 400 mg twice daily (IM800) in 153 adult patients with CP‐CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4‐log reduction of BCR‐ABL1 mRNA: 25% vs. 10% of patients, P = 0·038; 3‐log reduction: 53% vs. 35%, P = 0·049). During the first 12 months BCR‐ABL1 levels in the IM800 arm were an average 2·9–fold lower than in the IM400 arm (P = 0·010). Complete haematological response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P = 0·040). Grade 3–4 toxicities were more common for IM800 (58% vs. 31%, P = 0·0007), and were most commonly haematological. Few patients have relapsed, progressed or died, but both progression‐free (P = 0·048) and relapse‐free (P = 0·031) survival were superior for IM800. In newly diagnosed CP‐CML patients, IM800 induced deeper MRs than IM400, with a trend for improved progression‐free and overall survival, but was associated with more severe toxicity.     

Imatinib dose escalation in two patients with chronic myeloid leukemia, with low trough imatinib plasma levels measured at various intervals from the beginning of therapy and with suboptimal treatment response, leads to the achievement of higher plasma levels and major molecular response

Despite the prognostic value of trough imatinib plasma levels (IPL) identified in some studies, no recommendations for the use of IPL results in routine management of CML patients have been issued. We report two patients in whom daily imatinib dose was increased from 400 to 600 or 800 mg because of low IPL found at various intervals from the beginning of treatment (7 measurements; mean IPL values = 616.33 and 764.5 ng/mL, respectively). Both patients achieved suboptimal response according to the European LeukemiaNet criteria (complete cytogenetic response was not achieved after 1 year of treatment in patient 1 and major molecular response after 47 months of standard-dose imatinib therapy in patient 2). In addition, we have demonstrated low hOCT-1 expression at diagnosis in both patients, retrospectively. Escalation of imatinib daily dose resulted in a significant increase of IPL (6 measurements; mean = 1790 and 1416.66 ng/mL, respectively) and in the achievement of complete cytogenetic response in patient 1 after 3 months and major molecular response within 15 and 6 months in both patients. Our cases demonstrate that low IPL identified at various non-predefined intervals from the beginning of therapy may be used for deciding on dose escalation in selected CML patients in the routine clinical setting, especially in cases with suboptimal treatment response.     

Hepatitis C viral kinetics in difficult to treat patients receiving high dose interferon and ribavirin

BACKGROUND/AIMS: Hepatitis C viral (HCV) kinetic studies have demonstrated the increased antiviral effect of higher than standard dosages of interferon and of daily treatment schedules. Since interferon has a short half-life, twice-daily administration of interferon may be even more effective. METHODS: We evaluated the HCV kinetics in daily vs. twice-daily high dose interferon (IFN) therapy in combination with ribavirin in 24 difficult to treat patients. Patients were randomised to 10 MU IFN daily or 5 MU twice-daily for 4 weeks. RESULTS: Interferon efficacy (epsilon) was similar and very high for both groups (range 99.83-99.97%). Clearance of infected cells (beta phase) tended to be slightly faster for patients on 5 MU bd (T1/2 70 vs. 90 h, ns). Clearance of infected cells was strongly related to initial viral load (T1/2 103 vs. 53 h, P = 0.002, for above versus below 2 x 10(6) copies/ml). In this study an additional phase with a temporary rise in viral load was observed between the alpha and the beta phase. CONCLUSION: Daily high induction dose is associated with nearly complete inhibition of viral replication even in difficult to treat patients. A twice-daily schedule did not lead to further improvement. Clearance rate of infected cells was significantly correlated with initial viral load.     

The Spectrum of FIP1L1-PDGFRA-Associated Chronic Eosinophilic Leukemia: New Insights Based on a Survey of 44 Cases

Imatinib is the treatment of choice for FIP1L1/PDGFRA (F/P)-associated chronic eosinophilic leukemia (F/P⁺ CEL), but its optimal dosing, duration, and possibility of discontinuation are still a matter of debate. A retrospective multicenter study was conducted with 44 F/P⁺ CEL patients identified in the French Eosinophil Network and treated with imatinib. The most frequently involved systems were skin (57%), spleen (52%), and lung (45%), and eosinophilic heart disease was observed in 15 patients (34%). Complete hematologic response (CHR) was obtained in all patients, and complete molecular response (CMR) in 95% of patients (average initial imatinib dose, 165 mg/d). For 29 patients the imatinib dose was tapered with a maintenance dose of 58 mg/d (±34 mg/d), allowing sustained CHR and CMR. None of the patients developed resistance during a median follow-up of 52.3 months (range, 1.4–97.4 mo). Imatinib was stopped in 11 patients; 6 of the patients subsequently relapsed, but 5 remained in persistent CHR or CMR (range, 9–88 mo). These results confirm that an initial low-dose regimen of imatinib (100 mg/d) followed by a lower maintenance dose can be efficient for obtaining long-term CHR and CMR. Our data also suggest that imatinib can be stopped in some patients without molecular relapse.     

Durable responses in chronic myeloid leukemia patients maintained with lower doses of imatinib mesylate after achieving molecular remission

In the present report, we address the question if the reduction of standard dosage of imatinib mesylate (IM) in imatinib-intolerant chronic myeloid leukemia (CML) patients with undetectable residual disease may impair their outcome. Four patients are described. The median follow up from the beginning of IM therapy was 35 months (33–59). The median duration of real-time quantitative polymerase chain reaction (RQ-PCR) negativity on IM 200 mg daily was 17months (4–37). We hypothesize that in IM intolerant CML patients with complete molecular remission, the compound dosage might be safely reduced to a lower than standard dose without to lose the response. A tight molecular monitoring of such patients should be required.     

Effect of interferon alpha and ribavirin treatment on serum levels of transforming growth factor-β1, vascular endothelial growth factor, and basic fibroblast growth factor in patients with chronic hepatitis C

AIM: To assess the role of transforming growth factor-β1(TGF-β1), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (Bfgf) in the pathogenesis of fibrosis associated with chronic hepatitis C (CHC)and to evaluate the influence of the antiviral therapy on above parameter levels depending on the treatment results (complete response or no response).METHODS: Study group included 100 patients with CHC, in whom fibrosis in liver specimens was assessed (Scheuer fibrosis score: 1-4 points). Control group included 30 subjects with antibodies anti-HCV present and persistently normal ALT level, without fibrosis (Scheuer fibrosis score: 0 points). Concentration of studied parameters was assayed in the serum by immunoenzymatic method before and after the therapy with interferon alpha-2b and ribavirin.RESULTS: TGF-β1 levels were significantly higher in the study group compared to the control group (35.89 vs 32.37ng/Ml; P=0.023). Such differences were not found in VEGF and Bfgf levels. In patients showing complete response (negative HCV RNA and normal ALT level), significant increase in VEGF (112.8 vs 315.03 pg/Ml; P＜ 0.05) and Bfgf (2.51 vs 15.79 pg/Ml; P=0.04) levels were found. Significant decrease in TGF-β1 level was observed both in responders (37.44 vs 30.02 ng/Ml; P=0.05), and in non-responders (38.22 vs 30.43 ng/Ml; P= 0.043).Bfgf levels before the treatment were significantly lower (2.51 vs 5.94 pg/Ml; P=0.04), and after the treatment significantly higher (15.79 vs 4.35 pg/Ml; P=0.01) in patients with complete response than in those with no response.CONCLUSION: Among the analyzed parameters TGF-β1 seems to play the most important role in the pathogenesis of fibrosis in CHC. Levels of this factor are significantly lower in subjects who do not have fibrosis developed in them. Good therapeutic effect in CHC patients is associated with significant changes in TGF-β1,VEGF, and Bfgf levels. Bfgf seems to have the highest usefulness in the prognosis of treatment efficacy.     

Effect of interferon alpha and ribavirin treatment on serum levels of transforming growth factor-beta1, vascular endothelial growth factor, and basic fibroblast growth factor in patients with chronic hepatitis C

AIM: To assess the role of transforming growth factor-beta1 (TGF-beta1), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in the pathogenesis of fibrosis associated with chronic hepatitis C (CHC) and to evaluate the influence of the antiviral therapy on above parameter levels depending on the treatment results (complete response or no response). METHODS: Study group included 100 patients with CHC, in whom fibrosis in liver specimens was assessed (Scheuer fibrosis score: 1-4 points). Control group included 30 subjects with antibodies anti-HCV present and persistently normal ALT level, without fibrosis (Scheuer fibrosis score: 0 points). Concentration of studied parameters was assayed in the serum by immunoenzymatic method before and after the therapy with interferon alpha-2b and ribavirin. RESULTS: TGF-beta1 levels were significantly higher in the study group compared to the control group (35.89 vs 32.37 ng/mL; P=0.023). Such differences were not found in VEGF and bFGF levels. In patients showing complete response (negative HCV RNA and normal ALT level), significant increase in VEGF (112.8 vs 315.03 pg/mL; P<0.05) and bFGF (2.51 vs 15.79 pg/mL; P=0.04) levels were found. Significant decrease in TGF-beta1 level was observed both in responders (37.44 vs 30.02 ng/mL; P=0.05), and in non-responders (38.22 vs 30.43 ng/mL; P=0.043). bFGF levels before the treatment were significantly lower (2.51 vs 5.94 pg/mL; P=0.04), and after the treatment significantly higher (15.79 vs 4.35 pg/mL; P=0.01) in patients with complete response than in those with no response. CONCLUSION: Among the analyzed parameters TGF-beta1 seems to play the most important role in the pathogenesis of fibrosis in CHC. Levels of this factor are significantly lower in subjects who do not have fibrosis developed in them. Good therapeutic effect in CHC patients is associated with significant changes in TGF-beta1, VEGF, and bFGF levels. bFGF seems to have the highest usefulness in the prognosis of treatment efficacy.     

Plasma drug levels, genotypic resistance, and virological response to a nelfinavir plus saquinavir-containing regimen.

OBJECTIVE: To determine the importance of resistance and drug levels in the response to a dual-protease inhibitor (PI) combination. METHODS: Prospective study of 62 HIV-positive patients who switched to a salvage regimen including nelfinavir plus saquinavir. Virological response was defined as a decrease in viraemia > 0.5 log10 after 24 weeks. Optimal PI levels were defined as those above the protein binding-corrected 95% inhibitory concentration (IC95), as estimated in the presence of 50% human serum. RESULTS: Baseline median HIV load was 4.78 log10 copies/ml. The median number of mutations in the protease gene was nine (range, 2-25), predominantly at residues 82 (52%), and 90 (40%). After 24 weeks, 45% of patients had responded and 19% were < 50 copies/ml. A higher number of mutations in the protease gene (12 versus 8;P = 0.001), and the L90M mutation (36% versus 67%; P = 0.001) were associated with treatment failure. Trough levels of nelfinavir and saquinavir were two- and fivefold, respectively, greater than those reached when used as the only PI (2480 and 260 ng/ml, respectively), and they were above the estimated protein-corrected IC95 in 96% and 32% of cases. Thus, the Cmin : IC95 ratio ranged from 0.1 to 10 for nelfinavir and from 0.12 to 3.24 for saquinavir. Suboptimal PI levels were associated with a poorer response, but there was no correlation between optimal drug levels and a better response. CONCLUSION: Genotypic resistance predicts the virological response to a nelfinavir-saquinavir salvage regimen. Our data suggest that higher than optimal drug levels could be necessary to control the replication of many PI-resistant viruses.     

Sustained complete molecular remission after cessation of imatinib mesylate treatment in a patient with relapsed chronic myelogenous leukemia after allogeneic stem cell transplantation

We present a case with sustained complete molecular response (CMR) after cessation of two months of imatinib mesylate (IM) treatment for chronic myelogenous leukemia (CML) relapsed after allogeneic stem cell transplantation (Allo-SCT). A 30-year-old previously healthy woman was seen in a clinic because of left abdominal discomfort. Splenomegaly and increased leukocytes with Philadelphia chromosome led to the diagnosis of CML in the accelerated phase. She received four months of IM treatment followed by allo-SCT from her HLA-matched sibling. She achieved and maintained CMR without developing acute GVHD for six months, when hematologic relapse occurred. While reducing the immunosuppressant, she received IM; however, it was discontinued two months later due to myelosuppression. Even after the termination of IM, the positivity of chimeric BCR-ABL gene detected by FISH analysis in peripheral blood continued to decrease. The molecular analysis of bone marrow one year after allo-PBSCT revealed CMR lasting for more than two years after cessation of IM. IM may possibly enhance the graft-versus-leukemia effects by reducing tumor burden in cases relapsed after allo-SCT.     

Growth hormone (GH) responses to GH-releasing hormone-arginine testing in human immunodeficiency virus lipodystrophy

Prior studies suggest reduced overnight GH secretion in association with excess visceral adiposity among patients with HIV lipodystrophy (LIPO, i.e. with fat redistribution). We now investigate GH responses to standardized GHRH-arginine in LIPO patients (n = 39) in comparison with body mass index- and age-matched control groups [HIV patients without fat distribution (NONLIPO, n = 17)] and healthy subjects (C, n = 16). IGF-I [242 +/- 17; 345 +/- 38; 291 +/- 27 ng/ml (P < 0.05 vs. NONLIPO)] was lowest in the LIPO group. Our data demonstrate failure rates of 18% for the LIPO group vs. 5.9% for the NONLIPO group and 0% for the C group, using a stringent criterion of 3.3 ng/ml for peak GH response to GHRH-arginine (P < 0.05 LIPO vs. C). Using less stringent cutoffs, the failure rate in the LIPO group rises to 38.5% at 7.5 ng/ml. Among the LIPO patients, the peak GH response to GHRH-arginine was significantly predicted by visceral adipose tissue (P = 0.008), free fatty acid (P = 0.04), and insulin level (P = 0.007) in regression modeling controlling for age, body mass index, sc fat area, and triglyceride level. These data demonstrate increased failure rates to standardized stimulation testing with GHRH-arginine in LIPO patients, in association with increased visceral adiposity. The effects of low-dose GH should be assessed in the large subset of LIPO patients with abnormal GH stimulation testing.     

Frontline imatinib treatment of chronic myeloid leukemia: no impact of age on outcome, a survey by the GIMEMA CML Working Party

The median age of chronic myeloid leukemia (CML) patients is ~60 years, and age is still considered an important prognostic factor, included in Sokal and EURO risk scores. However, few data are available about the long-term outcome of older patients treated with imatinib (IM) frontline. We analyzed the relationship between age and outcome in 559 early chronic-phase CML patients enrolled in 3 prospective clinical trials of Gruppo Italiano Malattie Ematologiche dell'Adulto CML Working Party, treated frontline with IM, with a median follow-up of 60 months. There were 115 older patients (≥ 65 years; 21%). The complete cytogenetic and major molecular response rates were similar in the 2 age groups. In older patients, event-free survival (55% vs 67%), failure-free survival (78% vs 92%), progression-free survival (62% vs 78%), and overall survival (75% vs 89%) were significantly inferior (all P < .01) because of a higher proportion of deaths that occurred in complete hematologic response, therefore unrelated to CML progression (15% vs 3%, P < .0001). The outcome was similar once those deaths were censored. These data show that response to IM was not affected by age and that the mortality rate linked to CML is similar in both age groups. This trial was registered at www.clinicaltrials.gov as #NCT00514488 and #NCT00510926.