Hepatic cryosurgery precision evaluation of ultrasonography,thermometry, and impedancemetry in a pig model

One of the main problems of the use of liver cryosurgery is to be sure that a defined hepatic volume has been completely destroyed. We undertook an experimental pig study to determine histopathological evolution of cryolesions, to evaluate the value of intraoperative sonography, thermometry, and impedancemetry to monitor necrosis and to evaluate clinical and biological repercussions of hepatic cryosurgery. Forty-eight cryolesions were obtained by freezing each liver lobe of 12 experimental pigs during a 5-min contact with a flat cryoprobe cooled with liquid nitrogen. Cryolesions and the surrounding liver were monitored during cryosurgery by six thermocouple electrodes, five impedance electrodes, and intraoperative sonography. Animals were sacrificed immediately, 6 hr and between day 1 and day 32 after the procedure. Cryolesions were excised, and a full size pathological study was carried out. No morbidity or mortality was observed. At the end of the freezing time, cryolesions were hemispheric in shape, and their radius measured by sonography was 17.7 ± 1.2 mm (mean ± SD). Microscopic study showed sequential tissue alterations with edema, ischemic necrosis, tissue slough, and granulation. Cryolesions were sharply delineated from the normal liver tissue. The radius of necrosis at days 2 and 3 was 17 ± 0.3 mm (mean ± SD). It showed good correlation with the cryolesion size measured by intraoperative sonography. The temperature threshold to obtain complete normal liver necrosis was −15°C. We found impedancemetry too difficult to use and not precise enough to monitor cryonecrosis. We conclude that intraoperative sonography and thermometry are useful means to monitor the extent of cryonecrosis during liver cryosurgery. © 1996 Wiley-Liss, Inc.     

Pharmacokinetics of panitumumab in a patient with liver dysfunction: a case report

Purpose

Panitumumab is used for the treatment for metastatic RAS wild-type colorectal cancer (mCRC). It is likely that many of these patients will present with liver metastases and some with liver dysfunction. The pharmacokinetics in patients with hepatic impairment has not been investigated, and dosage adjustments are undetermined. Here, we present a case of a patient with progressive mCRC and liver dysfunction.

Methods

A heavily pretreated KRAS wild-type mCRC patient with liver disease Child-Pugh class B was treated with 2-weekly intravenous panitumumab (6 mg/kg). The patient received 2 doses of 490 mg i.v. panitumumab after which progressive disease was documented. Toxicities were graded using CTCAEv4.0. Serum samples were collected, and panitumumab concentrations were determined using a validated immunoassay. Pharmacokinetic parameters after the first dose, including dose-normalized AUC from time zero–day 14, clearance (CL), and elimination half-life (T_1/2), were estimated via trapezoidal noncompartmental methods. Data were compared to historical data from a population with adequate liver function, as reported by Stephenson (Clin Colorectal Cancer, 8:29–37, 2009). Values within the range of the mean ±1 standard deviation (SD) were considered not deviant.

Results

Calculated AUC after the first dose of 6 mg/kg panitumumab in this patient with hepatic dysfunction was 877 μg day/mL (Stephenson’s cohort 1: 744 ± 195 μg day/mL). Estimated T_1/2 was 3.58 days (5.28 ± 1.90 days), and CL was 6.9 mL/day/kg (8.21 ± 3.79 mL/day/kg). Estimated PK parameters during the first cycle were inside reported mean ±1 SD of historical controls without liver dysfunction. No toxicity was reported during treatment; particularly, no diarrhea and skin toxicity were noticed.

Conclusions

The pharmacokinetics of panitumumab in this patient suffering from metastatic colorectal cancer with liver dysfunction Child-Pugh class B was similar compared to patients with adequate liver function. Moreover, no substantial toxicity was detected. The here-presented data may help clinical decision making in real-life practice. Two-weekly panitumumab monotherapy seems to be safely applicable in patients with KRAS wild-type mCRC and hepatic dysfunction, without the need for any dose adjustments.     

逆行肝切除治疗难切性肝癌244例报道

目的　逆行肝切除是治疗难切性肝癌的有效方法 ,本文报道了 2 44例临床经验。方法　常规肝切除方法切除困难的 2 44例巨大、显露困难或下腔静脉受累的肝癌采用逆行切肝法结合血管外科技术予以切除 (A组 ) ,同期临床特征类似的 31例肝癌采用常规切肝法切除 ,作为对照 (B组 )。结果　两组均无手术死亡 ,A组与B组相比 ,术中出血量较少 ( 12 90± 998ml比 2 2 86± 136 3ml)、术后胸水发生率 ( 2 6 /2 44比 10 /31)、腹水发生率 ( 72 /2 44比 19/31)、中度到重度黄疸率 ( 14 /2 44比 5 /31)、手术区积液率 ( 17/2 44比 7/31)、膈下感染率 ( 3/2 44比 1/31)、胆漏发生率 ( 2 /2 44比 1/31)、切口感染率 ( 3/2 44比 1/31)以及ALT恢复时间 ( 13.8± 5 .1天比 18.9± 8.9天 )均较低 ,差别具有统计学意义 (P <0 .0 1)。结论　对于难切性肝癌而言 ,逆行肝切除是安全有效的手术方法。     

Impaired liver function tests in patients treated with antithymocyte globulin: Implication for liver transplantation

Antithymocyte globulin (ATG) is traditionally used as a conventional immunosuppression agent in various pathological states including severe aplastic anaemia (SAA), graft versus host disease (GVHD), and for the prevention and treatment of graft rejection and GVHD post bone marrow and liver transplantation. We reviewed the liver functions of 16 haematological patients with no previous liver disorders who received ATG as part of their pre-bone marrow transplantation (BMT) conditioning regimen, and the liver function tests of five SAA patients who received ATG as part of their treatment. Liver functions were evaluated at day — 1 pre-, and days +3 and +10 post-ATG treatment. All patients had normal liver functions before treatment. In the haematological patients, the mean serum lactic dehydrogenase (LDH) levels increased from 408.7 ± 37.7 U/l pre-treatment to 1394.4 ± 488.7 U/l 3 days post-treatment (n = 16;p < 0.029), and then declined to 561.4 ± 61.3 U/l 10 days post-treatment (n = 16;p < 0.043). The mean alanine aminotransferase (ALT) levels increased from 51.9 ± 11.3 U to 184.6 ± 74.6 U (n = 16;p < 0.036), and then declined to 121.9 ± 61.3 U (n = 16; NS). The mean aspartate amino transferase (AST) levels increased from 31.2 ± 5.7 U to 152.0 ± 67.0 U (n = 16;p < 0.44) and then declined to 46.0 ± 14 (n = 16;p < 0.049). The mean r-glutamyltransferase (GTP) levels increased from 93.0 ± 34 to 188.0 ±36 (n = 16;p < 0.02), and were 168.0 ± 37.0 at day +10 (n = 16; NS). The mean bilirubin levels increased from 18.0 ± 1.9μM I^-1 to 22.7 ± 2.8 (n = 16); NS), at day +3 and to 31.9 ± 6.9 at day +10 (n = 16; NS). In contrast, no significant changes in liver function tests were demonstrated in the SAA patients treated with ATG. The possible pathophysiologic mechanisms and the clinical implications for liver transplantation are discussed.     

Unchanged pharmacokinetics of etoposide given by intra-arterial hepatic infusion as compared with i.v. infusion

 We investigated the pharmacokinetics of etoposide given to a patient suffering from multifocal liver metastases from an unknown primary tumor. The drug was given either by i.v. infusion or by hepatic arterial infusion (HAI). The calculated pharmacokinetic parameters (mean values ± SD) were similar after i.v. infusion and HAI, viz., 6.4±0.7 versus 6.5±0.2 h for the terminal elimination half-life (t _1/2β), 98.5±1.3 versus 101.3±5.9 mg l^-1 h for the area under the plasma concentration-time curve (AUC), 21.2±0.3 versus 20.6±1.2 ml min^-1 m^-2 for clearance (Cl), 17.7±1.9 versus 18.1±2.6 mg/l for the peak concentration, and 11.7±1.3 versus 11.6±1.0 l/m² for the volume of distribution (V _d ), respectively. We therefore conclude that administration of etoposide by HAI does not result in a significantly higher liver extraction. Hepatic extraction of etoposide is determined by the fraction of non-protein-bound (free) drug present. The lack of a difference between the two administration routes suggests that under in vivo conditions the equilibrium between free and bound drug is established before the drug reaches the hepatic arterioles. Consequently, administration by HAI does not lead to an increased exposure of the tumor in the liver to free (active) etoposide. Furthermore, the overall exposure of the liver to total (bound + free) etoposide is increased only from about 100 to 120 mg l^-1 h. These results do not favor the use of this more complex route of drug administration in the treatment of (metastatic) cancer located in the liver. Received: 5 November 1995/Accepted: 17 January 1996     

Detailed Characterization of a High-molecular-weight Glycoprotein Secreted by Lung Cancer Cells

A cancer-associated, high-molecular-weight glycoprotein antigen (6B3·Ag) recognized by monoclonal antibody 6B3 was purified from culture medium of human large cell lung carcinoma cell line (HLC-2) and characterized biochemically and immunochemically. The 6B3·Ag was purified more than 1,200-fold with a yield of 30% by salting out, precipitation by acidification at pH 4.5, and chromatographies on Sepharose 4B and concanavalin A-Sepharose. The molecular weight of 6B3·Ag is approximately 1,000,000 and the molecule is a homodecamer of 94,000 subnnits. The 6B3·Ag is a glycoprotein containing 22.9% sugars, consisting of both N - and O -glycoside chains. The N-terminal 19 amino acids were determined and only 4 out of 19 amino acid residues were different from those of an antigen, L3, secreted by lung carcinoma cell line Calu-1. The serum level of 6B3·Ag was determined in normal adults as well as patients with various diseases by enzyme-linked immunosorbent assay. The mean serum level of 6B3-Ag was 3.1 μg/ml, ranging from 1.6 to 6.2 μg/ml in 131 healthy adults. When the cut-off value was set at 6.2 μg/ml, the incidence of positive values in the sera was elevated not only in malignant diseases such as hepatoma (73%) and leukemia (62%), but also in benign diseases such as chronic hepatitis (42%) and liver cirrhosis (63%). While the incidence of positive values was elevated in advanced liver diseases, namely, chronic hepatitis, liver cirrhosis and hepatoma, the cancer specificity of 6B3·Ag did not appear to be high.     

Metabolism of camptothecin, a potent topoisomerase I inhibitor, in the isolated perfused rat liver

Purpose: Camptothecin (CPT) is a potent topoisomerase I inhibitor that has recently been undergoing phase I clinical trials. Though CPT shows high activity against various tumor cells, its biotransformation is still unknown. To investigate the metabolism and biliary excretion of CPT, an isolated perfused rat liver system was used. Methods: CPT was added to the perfusion medium at a concentration of 20 μM, and bile and perfusate samples were collected for 90 min. CPT (lacton and carboxylate) and three novel metabolites were identified by mass spectroscopy and quantified by reversed-phase high-performance liquid chromatography (HPLC). Kinetic parameters of CPT and its biotransformation products were then estimated in bile and effluent perfusate. Results: Biliary secretion of CPT and its three metabolites reached a peak secretion of 37.6 ± 16.3, 0.94 ± 0.29, 0.19 ± 0.023 and 0.302 ± 0.076 nmol/g liver/min, respectively, after 20 min. The total amount of CPT and M1–M3 excreted into bile during 90 min of perfusion was 63.5 ± 15.4%, 1.8 ± 0.37%, 0.43 ± 0.06%, and 0.72 ± 0.15% of CPT cleared from the perfusate during 90 min, respectively. In the perfusate, only one metabolite (M3) could be detected (cumulative release into the perfusion medium: 0.37 ± 0.026 μmol/liver). Analysis of the biliary metabolites by mass spectroscopy supported the existence of dihydroxy-CPT derivatives (M1 and M2), whereas M3 appears to be a monohydroxy-analog. Conclusion: CPT is biotransformed to three novel metabolites, mainly excreted into bile. The possible pharmacological effects of these new metabolites need to be considered. Received: 16 February 1999 / Accepted: 11 June 1999     

Thermal decomposition of the amino acids glycine,cysteine, aspartic acid,asparagine, glutamic acid,glutamine, arginine and histidine

Background

The pathways of thermal instability of amino acids have been unknown. New mass spectrometric data allow unequivocal quantitative identification of the decomposition products.

Results

Calorimetry, thermogravimetry and mass spectrometry were used to follow the thermal decomposition of the eight amino acids G, C, D, N, E, Q, R and H between 185 °C and 280 °C. Endothermic heats of decomposition between 72 and 151 kJ/mol are needed to form 12 to 70% volatile products. This process is neither melting nor sublimation. With exception of cysteine they emit mainly H₂O, some NH₃ and no CO₂. Cysteine produces CO₂ and little else. The reactions are described by polynomials, AA→a NH₃+b H₂O+c CO₂+d H₂S+e residue, with integer or half integer coefficients. The solid monomolecular residues are rich in peptide bonds.

Conclusions

Eight of the 20 standard amino acids decompose at well-defined, characteristic temperatures, in contrast to commonly accepted knowledge. Products of decomposition are simple. The novel quantitative results emphasize the impact of water and cyclic condensates with peptide bonds and put constraints on hypotheses of the origin, state and stability of amino acids in the range between 200 °C and 300 °C.

     

Nelfinavir Suspension Obtained from Nelfinavir Tablets Has Equivalent Pharmacokinetic Profile

Abstract

The pharmacokinetics of nelfinavir tablets (A) and an oral simplified nelfinavir suspension (B) were studied. Twelve healthy volunteers randomly received either five 250-mg nelfinavir tablets or a simplified oral suspension obtained from tablets dissolved in water (nelfinavir 1250 mg in 100 mL of water) in a single dose before being crossed over to the second treatment after a one-week washout period. Blood samples were drawn up to 24 h after drug administration. Nelfinavir concentrations in plasma were analyzed by a specific and validated reverse-phase high-performance liquid chromatography assay (HPLC) with UV detection, and pharmacokinetic values were determined. For the AUC_0-∞with means±SD of 31.71±7.85, 30.88±10.28 (μg/L) respectively for treatments B and A, the ratio (F_B/A) was of 1.1 with a C.I. of 0.90-1.24. For Cmax with means±SD of 3.1±0.6 (treatment B) and 3.2±0.8 mg/mL (treatment A), the ratio was 1.0. with C.I. of 0.92- 1.08. The two treatments evidenced no significant differences in AUC_0-∞ and Cmax values and the two-one sided t-test showed that the two preparations are bioequivalent. There was no significant difference in Tmax between the liquid and tablets.

Nelfinavir suspension might be a option for treating HIV-infected patients with swallowing disturbances or compliance problems.     

Mouse liver free amino acids during the development of Ehrlich ascites tumour.

Sequential amino acid concentrations were determined in the liver of mice infested with a highly malignant strain of Ehrlich ascites tumour cells. The liver concentrations of a certain group of amino acids showed changes consistent with those previously reported for plasma, ascitic liquid and tumour cells during tumour growth. Shortly after tumour transplantation a significant decrease of the essential amino acids methionine, threonine, valine, isoleucine + phenylalanine, leucine, lysine and histidine, was detected. Some non-essential amino acids, mainly the gluconeogenic substrates alanine and serine, showed a strong reduction in hepatic concentrations during the first days; these amino acids remained significantly lower than controls until animal death. Interestingly, hepatic glutamine increased at days 1 and 2 after inoculation, and proline showed a sustained increase from the seventh day onwards, reaching a value double the control at the end of animal life.     

Value of apparent diffusion coefficient measurement for discrimination of focal benign and malignant hepatic masses

The purpose of our study was to investigate the value of diffusion‐weighted magnetic resonance imaging (DW‐MRI) to discriminate benign and malignant focal lesions of the liver using parallel imaging technique. A total of 77 patients and 65 healthy controls were enrolled in the study. DW‐MRI was performed with b‐factors of 0, 500 and 1000 s/mm², and the apparent diffusion coefficients (ADC) values of the normal liver and the lesions were calculated. The mean ADC value of the focal liver lesions were as follows: simple cysts (3.16 ± 0.18 × 10^?3 mm²/s), hydatid cysts (2.58 ± 0.53 × 10^?3 mm²/s), hemangiomas (1.97 ± 0.49 × 10^?3 mm²/s), metastases (1.14 ± 0.41 × 10^?3 mm²/s) and hepatocellular carcinomas (HCC) (1.15 ± 0.36 × 10^?3 mm²/s). The mean ADC values of all the disease groups were statistically significant when compared with the mean ADC value of the normal liver (1.56 ± 0.14 × 10^?3 mm²/s), (P < 0.01). There were also statistically significant differences among the ADC values of hemangiomas and HCC metastases (P < 0.01), and simple and hydatid cysts (P < 0.008). However, there was no statistically significant difference between HCC and metastases. The present study showed that ADC measurement has the potential to differentiate benign and malignant focal hepatic lesions. We propose to add DW sequence in the MR protocol for the detection and quantitative discrimination of hepatic pathologies.     

Molecular characterization of hepatitis B virus among chronic hepatitis B patients from Pointe Noire,Republic of Congo

Background

Chronic Hepatitis B infection is a major health problem in Republic of Congo therefore molecular analysis of HBV strains is important to detect the patients at high risk of disease progression.

Methods

Serum samples were obtained from 111 chronic HBV patients in Pointe Noire. HBsAg, HBeAg and HBeAb were detected. A fragment of the preS1 region of HBV was amplified and sequenced to determine genotypes, subgenotypes and to identify mutations.

Results

Of the 111 samples analyzed, 35 patients were asymptomatic carriers (ASC), 24 with a chronic active hepatitis (CAH), 33 with liver cirrhosis (LC) and 19 have a hepatocellular carcinoma (HCC). The mean age were 45?±?13 year, 88 (79.3 %) were male and 23 (20.7 %) female. The prevalence of HBeAg was 15.3 % and 73 % of subjects were anti-HBe positive. The mean serum level of alanine aminotransferase transaminase (ALT) and aspartate transaminase (AST) was 25.1?±?9 IU/L and 28.6?±?10 IU/L respectively. Eighty two samples out of 111 (73.9 %) were genotyped by the analyzing of the S region of HBV, 58 (70.7 %) cases belonged to HBV genotype E and 24 (29.3 %) were genotype A with three subgenotypes; A3 (66.7 %), A4 (20.8 %) and A6 (12.5 %). Prevalence of genotype A was relatively high in CAH (33.3 %) and HCC (31.6 %) patients in comparison with other groups. The most prevalent amino acids substitutions were R38K found in 14 (17.1 %) sequences, following by H44L in 11 (13.4 %), K13E in 8 (9.8 %), N29K in 8 (9.8 %), A35E in 8 (9.8 %), V80I in 7 (8.5 %) and in 6 (7.3 %) sequences for S90T. Different substitutions located in the hepatocyte binding site were higher among patients with LC and HCC (p?<?0.05).

Conclusions

This study have shown that HBV genotype E and A were the most frequent strains circulating in Republic of Congo patients. HBV pres1 substitutions found in this study were associated with severe clinical forms of liver diseases. This data have shown the importance of implementing an effective program to fight HBV infection.

     

半胱氨酸酶在NS-398诱导HepG2细胞凋亡中的作用

目的 探讨选择性环氧合酶(COX-2)抑制剂NS-398诱导肝癌HepG2细胞凋亡的分子机制。方法 采用流式细胞术测定细胞凋亡情况;Western blot法检测不同浓度NS-398处理后凋亡相关蛋白Bcl-2、Caspase3表达的变化; 并以流式细胞术检测半胱氨酸酶-3(Caspase-3) 酶活性的变化。结果 流式细胞术显示NS-398(0、100、200、300、400μmol/L)作用HepG2细胞24h后,对照处理组没有出现凋亡峰,其余各组(100、200、300、400μmol/L)出现明显的凋亡峰,其凋亡率分别为(10.51±1.04)%、(27.79±2.40)%、(45.72±3.32)%,(60.22±2.03)%(P<0.01),不同浓度NS-398处理后凋亡相关蛋白Bcl-2表达下降,Caspase-3蛋白表达增加,随着NS-398处理浓度的增加,表达活性Caspase3的细胞百分率分别为(2.67±0.22)%、(9.53±0.15)%、(21.28±0.43)%、(39.63±0.8)%、(63.40±0.69)%(P<0.01)。结论 选择性COX-2 抑制剂可能通过调节Bcl-2蛋白表达活化Caspase3,从而诱导肝癌细胞HepG2凋亡。     

Yttrium-90 (Y-90) Resin Microsphere Therapy for Patients with Unresectable Hepatocellular Carcinoma: a Single-Center Experience

Background/Aim

Selective intraarterial radionuclide therapy (SIRT) with yttrium-90 (Y-90) resin microspheres presently has successful results in primary or metastatic inoperable liver tumors. This procedure, which is also known as radioembolisation, delivers high doses of radiation selectively to hepatic tumors while minimum healthy liver exposure. The aim of this study was to present our clinical experience of radiomicrosphere therapy for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Methods

We performed 40 Y-90 microsphere therapies in 28 patients (5 females, 23 males; mean age ± SD 48 ± 8) with HCC during the period from April 2008 through December 2016. Pretreatment Tc-99m microaggregated albumin (MAA) scintigraphy was performed to all patients in order to detect eligibility for SIRT. All patients had pre- and post-biochemical tests (hemogram and serologic tests) and imaging methods (CT or MRI or PET/CT) at regular intervals to detect any possible complication and determine response rates.

Results

The mean shunting to the lungs on MAA scan was 6.5% and the mean ± SD administered dose of Y-90 was 1.55 ± 0.32 GBq in all patients. The estimated doses to the target tumors, normal liver parenchyma and lungs were 105.7 ± 55.3, 25.5 ± 8.2 and 5.8 ± 1.7 Gy, respectively. No significant complication was observed during or early after (first week) the treatment procedure and it was well tolerated by all the patients. Only one patient developed a treatment-related gastroduodenal ulcer 3 weeks after the treatment. In control imaging tests (MRI or FDG PET/CT) performed 2.5 months after the treatment, we observed complete response in 2 (7%) patients, partial response in 10 (36%) patients, stable disease in 5 (18%) patients and progressive disease in 11 (39%) patients.

Conclusion

According to our clinical experience, we can conclude that Y-90 microsphere therapy is a safe and effective treatment option for the patients with unresectable HCC without any serious side effects.

     

Adriamycin Thermotherapy through the Hepatic Artery Using VX2 Carcinoma in Rabbit liver as a Model

OBJECTIVE It has been reported that heating can enhance sensitivity of rabbit VX2 cells to adriamycin and increase the intracellular concentration of adriamycin. This study was designed to evaluate the anti-tumor effect of interventional hyperthermia and interventional thermochemotherapy on VX2 carcinoma in rabbit liver. METHODS VX2 carcinoma cells were surgically implanted into the right liver lobe of 60 male New Zealand white rabbits, which were randomly divided into 4 groups (15 per group). The 4 groups (designated as 1, 2, 3, 4 respectively) were injected with 10 ml of the following via the hepatic artery: physiological saline (37℃); adriamycin (37℃); physiological saline (60℃); adriamycin (60℃). One week later, the tumor volume, serum level of aspartate transaminase (AST) and the survival of the rabbits bearing VX2 were observed and compared among the different treated groups. RESULTS The tumor growth rate in group 4 (ADM 60℃) (0.53±0.21)% was significantly lower than that in group 1 (3.48±1.17)%, in group 2 (1.09±0.26)% and group 3 (3.32±1.28)% (P<0.05, P<0.05, P<0.01, respectively). The days of survival days for group 4 (87.0±2.0) were significantly more than that in group 1 (40.0±3.0). Group 4 showed a significantly higher increase in serum AST compared to group 1 (P<0.05), but without significant differences compared to the other groups (P>0.05). CONCLUSION Adriamycin treatment at 60℃ significantly deceased the tumor growth, prolonged the survival period and resulted in reversible liver damage.     

Prevention of Tamoxifen-related Nonalcoholic Fatty Liver Disease in Breast Cancer Patients

Background

Tamoxifen is commonly used to prevent breast cancer recurrence. Studies have confirmed the association between tamoxifen and nonalcoholic fatty liver disease (NAFLD), with the results indicating the need for aggressive management of this side effect. We assessed the potential risk factors for and identified the possible protective factors of tamoxifen-related fatty liver.

复方青黄散治疗骨髓增生异常综合征的临床效果、安全性及其与血砷浓度的 相关性

目的 分析复方青黄散治疗骨髓增生异常综合征(MDS)的临床效果、安全性及其与血砷浓度的关系.方法 40例MDS患者给予复方青黄散治疗,于治疗后6、9个月分析临床疗效、安全性及其与血砷浓度的关系.结果 治疗6个月时,血液学进步率32.5%(13/40),总有效率87.5%(35/40).21例患者治疗前依赖输血,治疗后6例(28.5%)完全脱离输血,6例(28.5%)输血量减少50%以上;中性粒细胞由治疗前的(0.50±0.13)×109/L上升到(0.93±0.33)×109/L(t=4.130,P=0.0008),血红蛋白由(71.06±14.82)g/L上升到(80.41±27.35)g/L(t=2.233,P=0.0321),治疗前后血小板计数差异无统计学意义(P>0.05).治疗9个月时,76.2%(16/40)的患者摆脱输血或输血量减少50%以上;血小板计数由治疗前的(45.04±24.38)×109/L上升到(60.65±29.46)×109/L(t=2.241,P=0.0335).40例患者治疗1、3、6个月时消化道不良反应发生率分别为12.5%(5/40)、10.0%(4/40)、5.0%(2/40),均为轻度.12例治疗前肝功能异常患者中,6例治疗后恢复正常,6例明显减轻,无新增肝功能异常病例.10例治疗前心肌酶增高患者中,1例治疗后恢复正常,9例明显减轻,无新增心肌酶增高病例.治疗前后均未见肾功能指标异常病例.患者治疗前血砷浓度(7.71±5.65)μg/L,低于治疗1、3、6个月时血砷浓度[(29.27±9.07)μg/L、(27.79±10.18)μg/L、(31.98±12.55)μg/L,均P<0.0001],治疗1、3、6个月时血砷浓度维持稳定(P>0.05).治疗有效组血砷浓度[(33.48±12.56)μg/L]高于无效组[(21.46±6.00)μg/L](t=2.089,P=0.035).治疗第1个月时有12.5%(5/40)的患者发生轻度消化道不良反应,血砷浓度[(16.93±1.80)μg/L]低于未发生不良反应者[(31.78±1.39)μg/L](P<0.0001);治疗3、6个月时消化道不良反应发生率逐渐降低,血砷浓度逐渐提高.结论 复方青黄散治疗MDS疗效显著,消化道不良反应轻微,无需停药,对心、肝、肾脏器功能无损伤.减轻消化道不良反应及维持有效血砷浓度是复方青黄散治疗MDS有效的关键.     

Influence of creatine, amino acids and water on the formation of the mutagenic heterocyclic amines found in cooked meat

Creatine or one of 15 amino acids were mixed with minced pork before broiling at 200 degrees C. Total mutagenic activity and reversed-phase HPLC-separated mutagenicity profiles were determined for the crust and pan residue of all samples and also in the aerosol fraction of the smoke formed during cooking of the creatine-fortified samples. Addition of 5% (w/w) creatine increased the total mutagenicity 4-fold without changing the mutagenicity profile of either crust, pan residue or aerosol. Amino acid addition (1% w/w) increased the total mutagenicity between 1.5 (lysine) and 43 times (threonine). In most cases the mutagenicity profiles of crust and pan residues were changed by amino acid addition. Dry-heated mixtures of amino acids and creatine were all mutagenic with a 250-fold range between the amino acids. The production of known food mutagens in these mixtures was analyzed by LC-MS of HPLC-fractionated mutagenic peaks. Serine, threonine, phenylalanine, alanine, leucine and tyrosine were all shown to give rise to one of the known food mutagens 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) or 2-amino-trimethylimidazopyridine (TMIP). Lyophilized and subsequently fried meat patties and a heated powder of lyophilized meat juice were both mutagenic, with mutagenicity profiles similar to the regular meat crust, showing that water is not a prerequisite for mutagen formation in meat. MeIQx, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (4,8-di-MeIQx) and PhIP were shown, by LC-MS, to be present in the dry-heated meat juice. It is concluded that creatine and free amino acids are the main reactants of the mutagen-forming reactions that occur during frying of meat. Creatine is probably a necessary part of all of these reactions; what specific compounds are formed in each case therefore depends upon the levels in the meat of certain free amino acids and their interactions with other, as yet unknown, compounds in the meat.     

Pharmacokinetic comparison of oral and intravenous etoposide in patients treated with the CHOEP-regimen for malignant lymphomas

Background The addition of etoposide to the CHOP protocol (CHOEP) has been shown to improve outcome in patients with aggressive non-Hodgkin’s lymphoma. The intravenous administration of etoposide on three consecutive days represents a logistic problem and needs resources particular in the outpatient setting. This could be avoided by using etoposide capsules on days 2 and 3. However, the oral administration of cytotoxic agents is often affected by variable absorption and drug interactions. Patients and methods We investigated the pharmacokinetic equivalency of oral and intravenous etoposide in ten patients (male, n = 7; female, n = 3; median age 56 years) with aggressive lymphomas. Treatment consisted of standard CHOP plus etoposide 100 mg/m² given intravenously on day 1, and 200 mg/m² orally on days 3 and 4. Samples from blood and urine were taken on days 1 (i.v. study) and 3 (p.o. study) before and after etoposide administration. Etoposide levels were determined by high-performance liquid chromatography (HPLC), and pharmacokinetic parameters were calculated with the TOPFIT computer program. Results Mean peak plasma level after intravenous etoposide was significantly higher compared to oral administration (16.3 ± 3.7 vs. 12.0 ± 4.2 μg/ml; P = 0.015). The mean bioavailability of oral etoposide was 58 ± 15% with an interpatient variability of 26%. Significant differences of bioavailability of oral etoposide between the used dose levels (350, 400 and 450 mg) were not observed. Mean AUC after a 100 mg/m² intravenous and a 200 mg/m² oral dose of etoposide were 74.0 ± 18.3 and 84.9 ± 29.6 μg h/ml (P = 0.481). Interpatient variability of AUC was 25% for the intravenous route and 35% after oral intake. Urinary etoposide excretion as percentage of administered dose was 39.4 ± 10.6% after intravenous infusion versus 35.4 ± 9.4% after oral intake (P = 0.422). Renal clearance was also very similar with intravenous and oral route (18.5 ± 7.4 vs. 16.7 ± 6.6 ml/min; P = 0.546). Conclusion The equivalency of AUC after 200 mg/m² of oral and 100 mg/m² of intravenous etoposide support the use of the oral preparation in patients treated with the CHOEP regimen, which makes the chemotherapy more convenient for the patients and help to reduce costs.     

Randomized trial of one versus two adjuvant hyperthermia treatments per week in patients with superficial tumours

One test for thermotolerance development in a clinical situation is to evaluate the effects of altering the hyperthermia fractionation interval on tumour response to thermo-radiotherapy. Between 1983 and 1990 44 evaluable advanced superficial tumours of miscellaneous origin in 41 patients were randomized to receive either once-weekly or twice-weekly external microwave hyperthermia treatments combined with radiation therapy. The mean age of patients was 62 years, and 85% had failed previous therapy. All lesions were less than 8×8×4 cm (L×W×D) and were heated by external 915 MHz microwaves. The mean radiation dose was 44 ±3 Gy (mean ± SE) in the once-weekly group and 46±3 Gy in the twice-weekly group =0.64). The mean volume of the lesions heated once weekly was 17 ± 6 versus 23 × 5 cm³ for those heated twice weekly (p=0.45). Hyperthermia was administered once weekly for 4.6±0-2 sessions (range 3-7) or twice weekly for 8 1 ± 0 3 sessions (range 4-10). Thermometry was performed using 3–4 ± 0.2 catheters and 5 - 1 × 0 6 thermal sensors per tumour in the once-weekly group, and 2 7 ± 0–2 catheters and 5–8 ± 0–3 thermal sensors per tumour in the twice-weekly group. Of the 44 evaluable randomized lesions a complete response (CR) at 2 months post-treatment was observed in 59% (13/22) heated once weekly and 55% (12/22) in those heated twice weekly. The prognostic factors predictive of tumour complete response were found by logistic regression analysis to be radiation dose and tumour volume, while the prognostic factors predictive of duration of response (Cox proportional hazards analysis) were median minimum tumour temperature (T_min), minimum tumour temperature during the first heat treatment (T_minl) and tumour volume. The duration of local control in lesions with T_min &lt; 39 5°C was 11 7 ± 1 a 9 months while for lesions with T_min39.5°C it was 23.0±4.2 months (p=0.01). The ED₅₀ was calculated by logistic regression to be 40 Gy (95% CI=22-54 Gy) for once-and twice-weekly heated lesions. There was not a significant difference in tumour response or duration of response between populations randomized to receive once- versus twice-weekly hyperthermia treatments. There was also no difference in skin reaction rates between once- and twice-weekly hyperthennia treatments, nor could a correlation be found between any thermal parameter and skin reactions. It is concluded that similar complete response rates, similar duration of response and similar skin reaction rates can be obtained with once- or twice-weekly hyperthermia regimens.