Pharmaco-economic comparative evaluation of combination chronotherapy vs. standard chemotherapy for colorectal cancer

Results of recent trials comparing combination chemotherapy consisting of 5-fluorouracil (5-FU), folinic acid (FOL), and oxaliplatin, given either as flat (A) or chronomodulated (B) infusion for metastatic colorectal cancer, were subjected to pharmaco-economic evaluation. The overall cost of treatment with the flat and chronomodulated protocols was equivalent. The expense of the delivery of medications with the chronotherapeutic arm (B) was greater than with the standard arm (A) because it was feasible to administer more courses (requiring more frequent doctor visits) and higher doses (high cost of medications) with containment of toxic reactions. Chrono-arm B was definitively more cost-effective than standard flat-arm A treatment since it made the outcome of treatment more effective; there was greater tumor response rate and longer time to progression with less treatment-associated toxicity. Finally, selection of the Melodie brand infusion pump to deliver the chronotherapy resulted in a further 18% reduction of overall costs and made it possible for patients to enjoy increased autonomy and improved quality of life.     

A randomized phase II trial of induction chemotherapy followed by cisplatin chronotherapy versus constant rate delivery combined with radiotherapy

Chronotherapy is no longer a novel concept in cancer treatment after approximately 20 years of development. Many clinical trials have provided strong supporting evidence that chronomodulated treatment yields better results than a traditional dosage regimen. This study aimed to evaluate the adverse reactions, effect on immune functions, and therapeutic efficacy of chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) combined with intensity-modulated radiation therapy (IMRT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC). A total of 148 patients with biopsy-diagnosed untreated stage III-IVb NPC were randomly assigned to undergo two cycles of chronomodulated infusion (study group) or flat intermittent infusion (control group) of DDP (100 mg/m2 on day 1, 21 days/cycle) synchronized with radical radiotherapy. Patients in the study group received chronomodulated infusion, with peak delivery of DDP at 16:00 pm. Patients in the control group received a routine constant rate of infusion. Both groups were treated with the same radiotherapy techniques. Over a median follow-up of 20 months, the study group had better outcomes for adverse effects and immune functions compared with the control group. During the phase of concurrent chemoradiotherapy, the incidence of nausea, vomiting, and oral mucositis in the study and control groups was 66.7% and 79.5% (p < 0.05), 47.9% and 71.2% (p < 0.05), and 73.9% and 87.7% (p < 0.05), respectively. There was no significant difference in 2-year overall survival, progression-free survival, and distant metastasis-free survival between the two groups (p > 0.05). Chronochemotherapy significantly reduced the incidence of adverse reactions and enhanced the tolerance for treatment without affecting survival. It is worth mentioning that reduced destruction of immune function is a novel area of exploration in chronotherapy research.     

The Effects of Chronomodulated Therapy with 5-Fluorouracil (5-Fu) and Folinic Acid (Fa) on the Toxicity and Quality of Life in Patients with Advanced Gastric Cancer

This study was designed to assess the tolerability of chronomodulated infusion chemotherapy, individualized by the rhythm of peripheral blood cells. Twenty patients with metastatic gastric cancer were randomized to chronotherapy or day-time arms of 5-fluorouracil (FU) (600 mg/m², 8 h inf.d1-5) and folinic acid (FA) (20 mg/m², iv, d1-5) in the first cycle and crossed-over to the other arm in the following cycles. Ten of 18 evaluable patients were assigned to chronotherapy arm and eight to day-time in the first cycle. Although there was no significant difference between two arms on enrollment, chronotherapy arm yielded an improvement of 45% of QLQ-C30 scores (p = 0.021) and the day-time arm had 11% improvement (p = 0.575). After the crossing-over, chronotherapy arm, again, had a significant improvement in QLQ-C30 scores, compared to the day-time arm (14% vs. -18%, p = 0.001, respectively). Mucositis/diarrhea was significantly higher in the day-time arm compared to chronotherapy arm (p = 0.015). In conclusion, chronomodulated infusion of 5-FU might improve the quality of life.     

Clinical pharmacokinetics of 5-fluorouracil with consideration of chronopharmacokinetics

Even though 5-fluorouracil (FU) is one of the oldest anticancer drugs, its use in cancer chemotherapy continues to increase. Fluorouracil is a pro-drug that requires intracellular activation to exert its effects. This makes it difficult to associate blood drug concentration with cell toxicity directly, although data from the literature show the existence of such a relationship. The relationship between FU pharmacokinetics and patient response has been explored extensively and reports attest a link between systemic drug exposure and response and survival. This has led to the concept of maximal tolerated exposure, and strategies to achieve this rely on pharmacokinetic follow-up and individual dose adjustment. More than 80% of the administered FU dose is eliminated by catabolism through dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme. Dihydropyrimidine dehydrogenase activity is found in most tissues but is highest in the liver. Peripheral blood mononuclear cells (PBMC) are used to monitor clinically DPD activity. A significant, but weak correlation between PBMC and liver DPD activity has been observed. The relationship between PBMC-DPD activity and FU systemic clearance is weak (r²=0.10); thus, simply determining PBMC-DPD is not sufficient to predict accurately FU clearance. Population pharmacokinetic analysis identified patient co-variables that influence FU clearance; drug kinetics is significantly reduced by increased age, high serum alkaline phosphatase, length of drug infusion, and low PBMC-DPD. Autoregulation of FU metabolism also is suggested; inhibition of DPD activity was observed after FU administration in both colorectal cancer patients and an animal model. Circadian rhythmicity in DPD activity is suggested from both human and animal investigations. In patients receiving protracted low dose 5-FU infusion, the circadian rhythm in FU plasma concentration peaks at 11:00h and is lowest at 23:00h, on average. The inverse relationship observed between the circadian profile of FU plasma concentration and PBMC-DP activity in these same patients suggests a link between DPD activity and FU pharmacokinetics. The impact of the biological time of drug administration was also studied with short venous infusions; clearance was 70% greater at 13:00h than at 01:00h. Similarly, peak drug concentration occurred in the first half of the night in patients receiving constant rate 5-FU infusion for 2-5 d. Several studies describe wide interindividual variation in the timing of the peak and trough of the 24h rhythm in DPD activity. The rational for FU chronomodulated therapy has been the circadian rhythm in host drug tolerance, which is greatest during the night time when the proliferation of normal target tissue is least. A randomized study of chronomodulated FU therapy with maximal delivery rate at 04:00h was shown clearly to be significantly more effective and less toxic than control flat FU therapy. Future research must focus on easy-to-obtain markers of specific rhythms to individualize the chronomodulated FU delivery.     

Clinical pharmacokinetics of 5-fluorouracil with consideration of chronopharmacokinetics

Even though 5-fluorouracil (FU) is one of the oldest anticancer drugs, its use in cancer chemotherapy continues to increase. Fluorouracil is a pro-drug that requires intracellular activation to exert its effects. This makes it difficult to associate blood drug concentration with cell toxicity directly, although data from the literature show the existence of such a relationship. The relationship between FU pharmacokinetics and patient response has been explored extensively and reports attest a link between systemic drug exposure and response and survival. This has led to the concept of maximal tolerated exposure, and strategies to achieve this rely on pharmacokinetic follow-up and individual dose adjustment. More than 80% of the administered FU dose is eliminated by catabolism through dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme. Dihydropyrimidine dehydrogenase activity is found in most tissues but is highest in the liver. Peripheral blood mononuclear cells (PBMC) are used to monitor clinically DPD activity. A significant, but weak correlation between PBMC and liver DPD activity has been observed. The relationship between PBMC–DPD activity and FU systemic clearance is weak (r²=0.10); thus, simply determining PBMC–DPD is not sufficient to predict accurately FU clearance. Population pharmacokinetic analysis identified patient co-variables that influence FU clearance; drug kinetics is significantly reduced by increased age, high serum alkaline phosphatase, length of drug infusion, and low PBMC–DPD. Autoregulation of FU metabolism also is suggested; inhibition of DPD activity was observed after FU administration in both colorectal cancer patients and an animal model. Circadian rhythmicity in DPD activity is suggested from both human and animal investigations. In patients receiving protracted low dose 5-FU infusion, the circadian rhythm in FU plasma concentration peaks at 11:00h and is lowest at 23:00h, on average. The inverse relationship observed between the circadian profile of FU plasma concentration and PBMC–DP activity in these same patients suggests a link between DPD activity and FU pharmacokinetics. The impact of the biological time of drug administration was also studied with short venous infusions; clearance was 70% greater at 13:00h than at 01:00h. Similarly, peak drug concentration occurred in the first half of the night in patients receiving constant rate 5-FU infusion for 2–5 d. Several studies describe wide interindividual variation in the timing of the peak and trough of the 24h rhythm in DPD activity. The rational for FU chronomodulated therapy has been the circadian rhythm in host drug tolerance, which is greatest during the night time when the proliferation of normal target tissue is least. A randomized study of chronomodulated FU therapy with maximal delivery rate at 04:00h was shown clearly to be significantly more effective and less toxic than control flat FU therapy. Future research must focus on easy-to-obtain markers of specific rhythms to individualize the chronomodulated FU delivery.     

Optimal Sequence of Irinotecan and Oxaliplatin-Based Regimens in Metastatic Colorectal Cancer: A Population-Based Observational Study

The optimal sequence of irinotecan and oxaliplatin-based regimens for metastatic colorectal cancer remains unclear. We conducted a population-based observational study by retrospectively reviewing records from Taiwan’s National Health Insurance Research Database to explore this issue. Patients aged ≥20 years with metastatic colorectal cancer newly diagnosed between 2004 and 2008 (n = 9490) were enrolled in current study. Among these 9490 patients, 3895 patients (41.04%) did not receive any chemotherapy within the first three months after catastrophic illness registration. Patients who received best supportive care were older and had higher Charlson comorbidity indexes and incidences of comorbidities than those who received irinotecan-based regimens, oxaliplatin-based regimens, and 5-fluorouracil/capecitabine alone. Patients who received irinotecan followed by oxaliplatin-based regimens and those who received the reverse sequence were further stratified into arm A (n = 542) and arm B (n = 1156), respectively. The median first time to next treatment was not significantly different between arm A and arm B (210 days vs. 196 days; p = 0.17). However, the median second time to next treatment was longer in arm A than in arm B (155 days vs. 123 days; p = 0.006), which translated into a better overall survival (487 days vs. 454 days; p = 0.02). The crossover rate was higher in arm A than in arm B (47.84% vs. 41.61%; p<0.001). Multivariate Cox regression analyses showed that overall survival was comparable between the two chemotherapy sequences (p = 0.27). Our study suggested that irinotecan followed by oxaliplatin-based regimens might be a better chemotherapy treatment option for metastatic colorectal cancer than the reverse sequence given the higher crossover rate and potential overall survival benefit.     

Effects of aging and arm swing on the metabolic cost of stability in human walking

To gain insight into the mechanical determinants of walking energetics, we investigated the effects of aging and arm swing on the metabolic cost of stabilization. We tested two hypotheses: (1) elderly adults consume more metabolic energy during walking than young adults because they consume more metabolic energy for lateral stabilization, and (2) arm swing reduces the metabolic cost of stabilization during walking in young and elderly adults. To test these hypotheses, we provided external lateral stabilization by applying bilateral forces (10% body weight) to a waist belt via elastic cords while young and elderly subjects walked at 1.3m/s on a motorized treadmill with arm swing and with no arm swing. We found that the external stabilizer reduced the net rate of metabolic energy consumption to a similar extent in elderly and young subjects. This reduction was greater (6-7%) when subjects walked with no arm swing than when they walked normally (3-4%). When young or elderly subjects eliminated arm swing while walking with no external stabilization, net metabolic power increased by 5-6%. We conclude that the greater metabolic cost of walking in elderly adults is not caused by a greater cost of lateral stabilization. Moreover, arm swing reduces the metabolic cost of walking in both young and elderly adults likely by contributing to stability.     

Chronomodulated chemotherapy and irradiation: an idea whose time has come?

The chronomodulated delivery of systemic chemotherapy given with irradiation (chemoradiation) is driven by an understanding of: the chronobiology of normal tissue response to cytotoxic insult, chronopharmacology, and by technologic advances in vascular access and in the availability of portable programmable pumps. Since circadian variation exists in the proliferative activity of acute-reacting normal tissues like the gut and bone marrow, a potential therapeutic gain can be realized by the chronomodulated administration of S-phase chemotherapeutic agents at biological times when these normal tissues are in a different cell phase and thus relatively spared (chronotolerance). The reasons for this are complex and possibly include newly described time-keeping genes that may influence the cell cycle. Another important aspect of chronotolerance is based on chronopharmacologic behavior of S-phase chemotherapeutic radiation sensitizing agents, especially 5-fluorouracil (5-FU). In this review laboratory and clinical evidence is presented for using chronomodulated 5-FU or the topoisomerase-I inhibitor, camptothecin, when best tolerated biologically. Although the main body of this work has been accomplished with pure chemotherapy schedules, there is emerging clinical evidence this approach to treatment also applies to the application of chemoradiation. This knowledge has been exploited only recently in the clinic. These data should be viewed as a call for additional studies to investigate the precise timing of systemic chemotherapeutic radio sensitizers to ameliorate toxicity and maximize treatment effect, especially with newer and potentially more toxic chemoradiation programs.     

PF化疗同步联合时辰放疗与常规放疗治疗局部晚期鼻咽癌的随机对照研究

目的:比较局部晚期鼻咽癌分别接受顺铂联合氟尿嘧啶方案(PF)化疗联合时辰放疗以及PF化疗联合常规放疗时的疗效和毒副反应。方法:将我科45例初治局部晚期鼻咽癌患者随机分为时辰放疗组和常规放疗组,分别为22例和23例。两组均采用相同放射治疗方法和治疗剂量,同步给予PF方案化疗。时辰放疗组放疗时间在20:00-22:00,而常规放疗组在8:00-10:00。结果:两组患者在放疗结束3个月和6个月进行时比较发现,时辰放疗组患者的鼻咽部及颈部的肿瘤完全消退率(CR率)均比常规放疗组高(P<0.05)。而时辰放疗组的各种急性副作用发生率较常规放疗组低,但无统计学差异。治疗后时辰组CD4/CD8升高,常规组CD4/CD8降低(P<0.05)。结论:时辰放疗联合PF同步化疗针对局部晚期鼻咽癌患者疗效好,毒副作用轻,同时可能有利于改善患者的免疫功能。     

Cost Resulting from Anti-Tuberculosis Drug Shortages in the United States: A Hypothetical Cohort Study

BackgroundFrom 2012 through 2014, the United States experienced acute shortages and price escalations of several first-line anti-tuberculosis (TB) medications. Because secondary TB drug regimens are longer and adverse events occur more frequently with them, we sought to conservatively estimate the cost, to patients and the health care system, of TB treatment and medication adverse events from alternative regimens during drug shortages.MethodsWe assessed the cost of treatment for TB disease in the absence of isoniazid (INH), rifampin (RIF), or pyrazinamide (PZA), or both INH and RIF. We simulated adverse events based on published probabilities using a monthly discrete-time stochastic model. For total costs, we summed costs of medications, routine testing, and treatment of adverse events using procedural terminology codes. We report average cost ratios of TB treatment during drug shortages to standard TB treatment.ResultsThe cost ratio of TB treatment without INH, RIF, or PZA to standard treatment was 1.7 (Range: 1.2, 2.3), 4.9 (Range: 3.2, 7.3), and 1.1 (Range: 0.7, 1.7) times higher, respectively. Without both INH and RIF, the cost ratio was 18.6 (Range: 10.0, 39.0) times higher. When the prices for INH, RIF and PZA were increased, the cost for standard treatment increased by a factor of 2.7 (Range: 1.9, 3.0). The percentage of patients experiencing at least one adverse event while taking standard therapy was 3.9% (Range: 1.3%, 11.8%). This percentage increased to 51.5% (Range: 20.1%, 83.8%) when RIF was unavailable, and increased to 82.5% (Range: 41.2%, 98.5%) when both INH and RIF were unavailable.ConclusionsOur conservative model illustrates that an interruption in first-line anti-TB medications leads to appreciable additional costs and adverse events for patients. The availability of these drugs in the United States should be ensured. Models that incorporate the effectiveness of alternative regimens, delays in treatment initiation, and TB transmission can provide broader perspectives on the impact of drug shortages.     

Chronomodulated chemotherapy and irradiation: an idea whose time has come?

The chronomodulated delivery of systemic chemotherapy given with irradiation (chemoradiation) is driven by an understanding of: the chronobiology of normal tissue response to cytotoxic insult, chronopharmacology, and by technologic advances in vascular access and in the availability of portable programmable pumps. Since circadian variation exists in the proliferative activity of acute-reacting normal tissues like the gut and bone marrow, a potential therapeutic gain can be realized by the chronomodulated administration of S-phase chemotherapeutic agents at biological times when these normal tissues are in a different cell phase and thus relatively spared (chronotolerance). The reasons for this are complex and possibly include newly described time-keeping genes that may influence the cell cycle. Another important aspect of chronotolerance is based on chronopharmacologic behavior of S-phase chemotherapeutic radiation sensitizing agents, especially 5-fluorouracil (5-FU). In this review laboratory and clinical evidence is presented for using chronomodulated 5-FU or the topoisomerase-I inhibitor, camptothecin, when best tolerated biologically. Although the main body of this work has been accomplished with pure chemotherapy schedules, there is emerging clinical evidence this approach to treatment also applies to the application of chemoradiation. This knowledge has been exploited only recently in the clinic. These data should be viewed as a call for additional studies to investigate the precise timing of systemic chemotherapeutic radio sensitizers to ameliorate toxicity and maximize treatment effect, especially with newer and potentially more toxic chemoradiation programs.     

Effect of Rapid Intravenous Infusion on Serum Concentrations of Amphotericin B

The magnitude of the concentrations of amphotericin B produced in serum of patients with systemic mycoses may significantly influence the outcome of therapy with this drug. Since amphotericin B is conventionally administered in intravenous infusions lasting 4 to 6 hr, we asked whether faster infusions of this drug might yield higher serum concentrations without an increase in dose. This question was studied in three patients who received 16 infusions of this drug: eight infusions administered slowly (5 hr) and eight administered rapidly (45 min). Serum concentrations after each rapid infusion were compared with those after a slow infusion administered to the same patient. The mean serum concentration of amphotericin B 1 hr after the rapid infusions (2.02 mug/ml) was significantly higher (P < 0.001) than the mean serum concentration of amphotericin B 1 hr after the slow infusions of this drug (1.18 mug/ml). Mean serum concentrations 18 and 42 hr after rapid infusion remained slightly but not significantly higher than respective mean concentrations after slow infusions. By yielding higher initial serum concentration, rapid intravenous infusion may be therapeutically more effective than slow infusion of amphotericin B. Although rapid infusions caused no more toxicity than did slow infusions, the lack of greater toxicity with rapid infusion of amphotericin B should be further documented prior to extensive clinical application of this procedure.     

Construction and study of leaf rust-resistant common wheat lines with translocations of Aegilops speltoides Tausch

Genotyping was performed for the leaf rust-resistant line 73/00i (Triticum aestivum x Aegilops speltoides). Fluorescence in situ hybridization (FISH) with probes Spelt1 and pSc119.2 in combination with microsatellite analysis were used to determine the locations and sizes of the Ae. speltoides genetic fragments integrated into the line genome. Translocations were identified in the long arms of chromosomes 5B and 6B and in the short arm of chromosome 1B. The Spelt1 and pSc119.2 molecular cytological markers made it possible to rapidly establish lines with single translocation in the long arms of chromosomes 5B and 6B. The line carrying the T5BS x 5BL-5SL translocation was highly resistant to leaf rust, and the lines carrying the T6BS x 6BL-6SL translocation displayed moderate resistance. The translocations differed in chromosomal location from known leaf resistance genes transferred into common wheat from Ae. speltoides. Hence, it was assumed that new genes were introduced into the common wheat genome from Ae. speltoides. The locus that determined high resistance to leaf rust and was transferred into the common wheat genome from the long arm of Ae. speltoides chromosome 5S by the T5BS x 5BL-5SL translocation was preliminarily designated as LrAsp5.     

Balancing selected medication costs with total number of daily injections: a preference analysis of GnRH-agonist and antagonist protocols by IVF patients

ABSTRACT: BACKGROUND: During in vitro fertilization (IVF), fertility patients are expected to self-administer many injections as part of this treatment. While newer medications have been developed to substantially reduce the number of these injections, such agents are typically much more expensive. Considering these differences in both cost and number of injections, this study compared patient preferences between GnRH-agonist and GnRH-antagonist based protocols in IVF. METHODS: Data were collected by voluntary, anonymous questionnaire at first consultation appointment. Patient opinion concerning total number of s.c. injections as a function of non-reimbursed patient cost associated with GnRH-agonist [A] and GnRH-antagonist [B] protocols in IVF was studied. RESULTS: Completed questionnaires (n = 71) revealed a mean +/[MINUS SIGN] SD patient age of 34 +/[MINUS SIGN] 4.1 yrs. Most (83.1 %) had no prior IVF experience; 2.8 % reported another medical condition requiring self-administration of subcutaneous medication(s). When out-of-pocket cost for [A] and [B] were identical, preference for [B] was registered by 50.7 % patients. The tendency to favor protocol [B] was weaker among patients with a health occupation. Estimated patient costs for [A] and [B] were $259.82 +/[MINUS SIGN] 11.75 and $654.55 +/[MINUS SIGN] 106.34, respectively (p < 0.005). Measured patient preference for [B] diminished as the cost difference increased. CONCLUSIONS: This investigation found consistently higher non-reimbursed direct medication costs for GnRH-antagonist IVF vs. GnRH-agonist IVF protocols. A conditional preference to minimize downregulation (using GnRH-antagonist) was noted among some, but not all, IVF patient sub-groups. Compared to IVF patients with a health occupation, the preference for GnRH-antagonist was weaker than for other patients. While reducing total number of injections by using GnRH-antagonist is a desirable goal, it appears this advantage is not perceived equally by all IVF patients and its utility is likely discounted heavily by patients when nonreimbursed medication costs reach a critical level.     

Trade-offs between cost and accuracy in active case finding for tuberculosis: A dynamic modelling analysis

BackgroundActive case finding (ACF) may be valuable in tuberculosis (TB) control, but questions remain about its optimum implementation in different settings. For example, smear microscopy misses up to half of TB cases, yet is cheap and detects the most infectious TB cases. What, then, is the incremental value of using more sensitive and specific, yet more costly, tests such as Xpert MTB/RIF in ACF in a high-burden setting?Methods and findingsWe constructed a dynamic transmission model of TB, calibrated to be consistent with an urban slum population in India. We applied this model to compare the potential cost and impact of 2 hypothetical approaches following initial symptom screening: (i) ‘moderate accuracy’ testing employing a microscopy-like test (i.e., lower cost but also lower accuracy) for bacteriological confirmation and (ii) ‘high accuracy’ testing employing an Xpert-like test (higher cost but also higher accuracy, while also detecting rifampicin resistance). Results suggest that ACF using a moderate-accuracy test could in fact cost more overall than using a high-accuracy test. Under an illustrative budget of US$20 million in a slum population of 2 million, high-accuracy testing would avert 1.14 (95% credible interval 0.75–1.99, with p = 0.28) cases relative to each case averted by moderate-accuracy testing. Test specificity is a key driver: High-accuracy testing would be significantly more impactful at the 5% significance level, as long as the high-accuracy test has specificity at least 3 percentage points greater than the moderate-accuracy test. Additional factors promoting the impact of high-accuracy testing are that (i) its ability to detect rifampicin resistance can lead to long-term cost savings in second-line treatment and (ii) its higher sensitivity contributes to the overall cases averted by ACF. Amongst the limitations of this study, our cost model has a narrow focus on the commodity costs of testing and treatment; our estimates should not be taken as indicative of the overall cost of ACF. There remains uncertainty about the true specificity of tests such as smear and Xpert-like tests in ACF, relating to the accuracy of the reference standard under such conditions.ConclusionsOur results suggest that cheaper diagnostics do not necessarily translate to less costly ACF, as any savings from the test cost can be strongly outweighed by factors including false-positive TB treatment, reduced sensitivity, and foregone savings in second-line treatment. In resource-limited settings, it is therefore important to take all of these factors into account when designing cost-effective strategies for ACF.

In this modeling study, Lucia Cilloni and colleagues simulate the cost and epidemiologic impact of active case-finding for tuberculosis in high-burden settings such as India.     

质子泵抑制剂兰索拉唑和奥美拉唑对胃溃疡患者MDA，SOD及NO的影响

目的:探讨兰索拉唑和奥美拉唑两种不同质子泵抑制剂对胃溃疡患者治疗效果及对丙二醛(MDA)、超氧化物歧化酶(SOD)及一氧化氮(NO)水平的影响。方法:收取2013年9月至2015年6月之间于我院接受治疗的胃溃疡患者98例作为研究对象,根据随机数字表法将98例患者平均分为A、B两组,两组各包含患者49例。A组患者使用兰索拉唑治疗,B组患者使用奥美拉唑治疗,两组均进行连续30 d治疗。对两组患者治疗效果、症状缓解情况、MDA、SOD及NO水平、不良反应以及治疗费用进行比较。结果:A组患者痊愈率及总有效率分别为63.27%及91.84%,B组患者痊愈率及总有效率分别为61.22%及93.88%。两组患者治疗效果比较无显著差异(P0.05)。治疗后,两组患者腹胀、腹痛、上腹部烧灼及反酸症状与治疗前相较有显著差异(P0.05),但治疗后组间比较无明显差异(P0.05)。治疗后两组MDA显著降低,SOD及NO显著升高,其中A组变化幅度大于B组,差异有统计学意义(P0.05)。A组患者不良反应发生率为20.41%,明显高于B组的6.12%(P0.05)。B组患者质子泵抑制剂治疗费用明显低于A组。结论:兰索拉唑和奥美拉唑两种质子泵抑制剂对胃溃疡患者疗效相当,兰索拉唑在MDA、SOD及NO水平改善上具有优势,但奥美拉唑安全性更高且治疗费用相对较低。应当结合患者具体情况选择适宜的治疗方案。     

DNA immunization against tissue-restricted antigens enhances tumor immunity after allogeneic hemopoietic stem cell transplantation

Malignant relapse remains a major problem for recipients of allogeneic hemopoietic stem cell transplantation (HSCT). We hypothesized that immunization of allogeneic HSCT recipients against tissue-restricted Ags using DNA vaccines would decrease the risk of relapse without enhancing graft-vs-host disease (GVHD). Using the mouse B16 melanoma model, we found that post-HSCT DNA immunization against a single tumor Ag induces tumor rejection that is significantly greater than HSCT alone in a T cell-depleted MHC-matched minor Ag-mismatched allogeneic HSCT model (LP --> B6). In treatment models, post-HSCT DNA immunization provides significantly greater overall survival than the vaccine alone. Donor leukocyte infusion further enhances tumor-free survival, including in treatment models. There was no GVHD in HSCT recipients treated with DNA vaccination and donor leukocyte infusion. Further analysis demonstrated that these effects are dependent on CD8+ T cells of donor origin that recognize multiple epitopes. These results demonstrate that DNA immunization against tissue-restricted Ags after allogeneic T cell-depleted HSCT can induce potent antitumor effects without causing GVHD.     

A Multicenter,Randomized Clinical Trial Comparing the Three-Weekly Docetaxel Regimen plus Prednisone versus Mitoxantone plus Prednisone for Chinese Patients with Metastatic Castration Refractory Prostate Cancer

Purpose

To explore the feasibility and efficacy of docetaxel plus prednisone for Chinese population with metastatic castration refractory prostate cancer (mCRPC).

Patients and methods

A total of 228 patients recruited from 15 centers were randomized to receive 10 cycles of D3P arm (docetaxel: 75 mg/m², intravenous infusion, every three weeks; Prednisone 10mg orally given daily) or M3P arm (mitoxantrone: 12 mg/m², intravenous infusion, every three weeks; Prednisone 10mg orally given daily). Primary end point was overall survival, and secondary end points were events progression-free survival (PFS), response rate, response duration. Quality of life (QoL) was also assessed in both treatment groups.

Results

The median overall survival was 21.88 months in D3P arm and 13.67 months in M3P arm (P = 0.0011, hazard ratio = 0.63, 95% confidence interval, 0.46–0.86). Subgroup analysis was consistent with the results of overall analysis. Events progression-free survival (pain, PSA, tumor and disease) were significantly improved in D3P arm compared with M3P arm. PSA response rate was 35.11% for patients treated by D3P arm and 19.39% for M3P arm (P = 0.0155). Pain response rate was higher in D3P arm (61.11%, P = 0.0011) than in M3P (23.08%) arm. No statistical differences were found between D3P arm and M3P arm for QoL, tumor response rate and response duration of PSA and pain. The tolerability and overall safety of D3P arm were generally comparable to that of M3P arm.

Conclusions

Compared with M3P arm, D3P arm significantly prolonged overall survival for the Chinese patients with mCRPC and improved the response rate for PSA and pain.

Trial Registration

clinicaltrials.gov NCT00436839     

Neo-adjuvant chemo-(immuno-)therapy of advanced squamous-cell head and neck carcinoma: a multicenter, phase III, randomized study comparing cisplatin + 5-fluorouracil (5-FU) with cisplatin + 5-FU + recombinant interleukin 2

We carried out an open, randomized, phase III, multicenter clinical trial to compare, in neo-adjuvant setting, the clinical response and toxicity of the combination chemotherapy cisplatin + 5-FU with the same combination plus s.c. recombinant interleukin-2 (rIL-2) in patients with advanced (stage III–IV) head and neck squamous-cell carcinoma (HNSCC). Regimen A was the classical Al Sarraf treatment: 100 mg/m² cisplatin i.v. on day 1 plus 1000 mg m⁻² day⁻¹ 5-FU on days 1–5 as a continuous infusion. Regimen B was the same as regimen A plus 4.5 MIU/day rIL-2 s.c. on days 8–12 and 15–19. Treatment was repeated every 3 weeks for three cycles. A total of 33 patients were enrolled in the study; 30 were evaluable for toxicity and 28 for response. Seventeen patients were assigned to group A and 16 were assigned to group B. Three patients (20%) of group A and 4 (31%) of group B had a complete response, 9 patients (60%) of group A and 6 (46%) of group B had a partial response, with an overall response rate of 12 patients (80%) for group A and 10 patients (77%) for group B. Two patients (13%) of group A and 3 patients (23%) group B had stable disease; 1 patient (7%) of group A had progressive disease. Thus, there was not a statistically significant difference in response rate between the two groups and therefore there was no benefit from the addition of immunotherapy with rIL-2 to the standard chemotherapy. Both regimens were well tolerated. There were 2 toxic deaths (6.7%), 1 from hematological causes in group A and 1 from cardiac causes in group B. Myelosuppression and gastrointestinal toxicity, mainly nausea/vomiting and stomatitis, were the most frequent toxicities. The calculated number of patients for the sample has not yet been reached; however, the projection of our present results suggests that it is highly improbable that a clinically significant difference between the two treatment groups will be observed even if the calculated patient sample size is achieved. Received: 9 April 1998 / Accepted: 30 June 1998     

The effects of step width and arm swing on energetic cost and lateral balance during running

In walking, humans prefer a moderate step width that minimizes energetic cost and vary step width from step-to-step to maintain lateral balance. Arm swing also reduces energetic cost and improves lateral balance. In running, humans prefer a narrow step width that may present a challenge for maintaining lateral balance. However, arm swing in running may improve lateral balance and help reduce energetic cost. To understand the roles of step width and arm swing, we hypothesized that net metabolic power would be greater at step widths greater or less than preferred and when running without arm swing. We further hypothesized that step width variability (indicator of lateral balance) would be greater at step widths greater or less than preferred and when running without arm swing. Ten subjects ran (3m/s) at four target step widths (0%, 15%, 20%, and 25% leg length (LL)) with arm swing, at their preferred step width with arm swing, and at their preferred step width without arm swing. We measured metabolic power, step width, and step width variability. When subjects ran at target step widths less (0% LL) or greater (15%, 20%, and 25% LL) than preferred, both net metabolic power demand (by 3%, 9%, 12%, and 15%) and step width variability (by 7%, 33%, 46%, and 69%) increased. When running without arm swing, both net metabolic power demand (by 8%) and step width variability (by 9%) increased compared to running with arm swing. It appears that humans prefer to run with a narrow step width and swing their arms so as to minimize energetic cost and improve lateral balance.