Patient Body Surface Area Research Articles

Ambulatory administration of 5-day infusion ifosfamide + mesna: a pilot study in sarcoma patients

Ifosfamide is a cornerstone of chemotherapy in bone and soft-tissue sarcoma. Results of pharmacokinetic studies indicate that the optimal schedule of ifosfamide should be repeated doses over several days. With the development of 5-day infusion devices, we developed and evaluated a 5-day infusion regimen of ifosfamide in sarcoma patients in the outpatient setting. Sarcoma patients requiring chemotherapy after at least one doxorubicin-based line were enrolled in this study. Ifosfamide+mesna was administered as 1:1 concentration for a total of 6 g/m2 of each over 5 days (i.e. 1.2 g/m2 per day as continuous infusion) every 3 weeks. Patients were treated until progression or limiting toxicity, and salvage surgery was attempted when possible. An economic study was run comparing ifosfamide plus mesna as a 5-day infusion regimen and conventional Ifosfamide regimen. Thirteen sarcoma patients were evaluable. The median number of cycles per patient was 6 (range, 1-8), for a total of 69 cycles. No acute encephalopathy or aggravation of renal function was noted. Acute grade 3 and 4 haematological toxicities were observed in 11.6 and 1.4% of patients, respectively without febrile neutropenia. Median time to progression survival and overall survival were 8.7 and 21.5 months, respectively. Total cost per cycle for a 2-m2 patient body surface area was ambulatory infusion=1,891 euros and conventional ifosfamide=6,256 euros. The combination of ifosfamide and mesna as a continuous infusion over 5 days is feasible and well tolerated in the outpatient setting using infusion device. Its very favourable cost-effectiveness invites to further develop this approach.

Mitral Valve Prolapse in Marfan Syndrome: An Old Topic Revisited

The echocardiographic features of mitral valve prolapse (MVP) in Marfan syndrome have been well described, and the incidence of MVP in Marfan syndrome is reported to be 40-80%. However, most of the original research was performed in the late 1980s and early 1990s, when the diagnostic criteria for MVP were less specific. Our goal was to investigate the characteristics of MVP associated with Marfan syndrome using currently accepted diagnostic criteria for MVP. Between January 1990 and March 2004, 90 patients with definitive diagnosis of Marfan syndrome (based on standardized criteria with or without genetic testing) were referred to Massachusetts General Hospital for transthoracic echocardiography. Patients' gender, age, weight, height, and body surface area at initial examination were recorded. Mitral valve thickness and motion, the degree of mitral regurgitation and aortic regurgitation, and aortic dimensions were quantified blinded to patients' clinical information. There were 25 patients (28%) with MVP, among whom 80% had symmetrical bileaflet MVP. Patients with MVP had thicker mitral leaflets (5.0 +/- 1.0 mm vs. 1.8 +/- 0.5 mm, P < 0.001), more mitral regurgitation (using a scale of 1-4, 2.2 +/- 1.0 vs. 0.90 +/- 0.60, P < 0.0001), larger LVEDD, and larger dimensions of sinus of Valsalva, sinotubular junction, aortic arch, and descending aorta indexed to square root body surface area, when compared with those without MVP. When echocardiographic features of patients younger than 18 years of age and those of patients older than 18 were compared, adult Marfan patients had larger LA dimension (indexed to square root body surface area), larger sinotubular junction (indexed to square root body surface area), and more mitral regurgitation and aortic regurgitation. The prevalence of MVP in Marfan syndrome is lower than previously reported. The large majority of patients with MVP have bileaflet involvement, and those with MVP have significantly larger aortic root diameters, suggesting a diffuse disease process.

Hemodynamic Energy Dissipation in the Cardiovascular System: Generalized Theoretical Analysis on Disease States

We present a fundamental theoretical framework for analysis of energy dissipation in any component of the circulatory system and formulate the full energy budget for both venous and arterial circulations. New indices allowing disease-specific subject-to-subject comparisons and disease-to-disease hemodynamic evaluation (quantifying the hemodynamic severity of one vascular disease type to the other) are presented based on this formalism. Dimensional analysis of energy dissipation rate with respect to the human circulation shows that the rate of energy dissipation is inversely proportional to the square of the patient body surface area and directly proportional to the cube of cardiac output. This result verified the established formulae for energy loss in aortic stenosis that was solely derived through empirical clinical experience. Three new indices are introduced to evaluate more complex disease states: (1) circulation energy dissipation index (CEDI), (2) aortic valve energy dissipation index (AV-EDI), and (3) total cavopulmonary connection energy dissipation index (TCPC-EDI). CEDI is based on the full energy budget of the circulation and is the proper measure of the work performed by the ventricle relative to the net energy spent in overcoming frictional forces. It is shown to be 4.01+/-0.16 for healthy individuals and above 7.0 for patients with severe aortic stenosis. Application of CEDI index on single-ventricle venous physiology reveals that the surgically created Fontan circulation, which is indeed palliative, progressively degrades in hemodynamic efficiency with growth (p<0.001), with the net dissipation in a typical Fontan patient (Body surface area=1.0 m(2)) being equivalent to that of an average case of severe aortic stenosis. AV-EDI is shown to be the proper index to gauge the hemodynamic severity of stenosed aortic valves as it accurately reflects energy loss. It is about 0.28+/-0.12 for healthy human valves. Moderate aortic stenosis has an AV-EDI one order of magnitude higher while clinically severe aortic stenosis cases always had magnitudes above 3.0. TCPC-EDI represents the efficiency of the TCPC connection and is shown to be negatively correlated to the size of a typical "bottle-neck" region (pulmonary artery) in the surgical TCPC pathway (p<0.05). Energy dissipation in the human circulation has been analyzed theoretically to derive the proper scaling (indexing) factor. CEDI, AV-EDI, and TCPC-EDI are proper measures of the dissipative characteristics of the circulatory system, aortic valve, and the Fontan connection, respectively.

Pharmacogenomic progress in individualized dosing of key drugs for cancer patients

Determining the correct dosage for the majority of traditional chemotherapeutic agents presents a challenge because most drugs have a narrow therapeutic index, which results in a fine balance between doses that cause significant drug toxicity and loss of efficacy. Dosing calculations for most agents use the patient's body surface area, a method that correlates poorly with drug pharmacokinetics. Genetic differences in drug-metabolizing enzymes are being evaluated in an effort to explain the pharmacokinetic and pharmacodynamic variability seen with many chemotherapeutic agents. Elucidation of the underlying reasons for this variability will enable individualization of therapy to minimize toxicity and maximize efficacy, and thus improve control over the narrow therapeutic index of these agents. Such investigations have led to Clinical Pharmacology FDA Subcommittee recommendations for changes to drug package instructions. This Review discusses the current limitations of body-surface-area-based dosing, examples of successful pharmacogenomic investigations that have used drug-metabolizing enzymes to decrease drug toxicity and/or improve efficacy, and the future promises of pharmacogenomic-directed pharmacotherapy.

Switch from Assist Device to Total Artificial Heart to Improve Cardiac Output

Left ventricular assist devices (LVADs) offer the opportunity to substantially improve the clinical condition and to interrupt the hospitalization of patients suffering from end-stage heart failure awaiting heart transplantation.We report a case of a 30-year-old patient (body surface area 2.49 m2) suffering from idiopathic dilative cardiomyopathy who was primarily given an LVAD with a free floating impeller pump and was finally switched to a total artificial heart due to the demand for a higher cardiac output.

冠動脈ＣＴＡ検査のための至適造影剤注入法の検討：テストボーラスパラメータと被検者の性差，ＢＳＡを用いた注入ヨード量調整法

The purpose of this study was to correlate test bolus (TB) parameters and patient information and cardiac function with main bolus (MB) contrast density for 64-slice computed tomography, and to evaluate MB contrast density on a fixed injection rate, in comparison with an injection rate adjusted with TB parameters and patient information. A total of 256 patients underwent coronary CT angiography. In 126 patients (group 1), contrast material was administered at a flow rate of 4 ml/sec. The peak enhancement, the time needed to reach the peak of the TB and cardiac function of the MB were calculated for each patient in this group. The dependency of MB contrast attenuation on these parameters was evaluated. Significant correlations were obtained between the peak density of the TB and the patient's body surface area (BSA) with the enhancement of MB. Furthermore, females showed a higher peak enhancement of MB than males. In view of the results of group 1, in the other 130 patients (group 2) injection protocols were computed by using regression analysis of each patient's attenuation response to a TB and patient sex and BSA. Compared with group 1, the variations of MB contrast density of group 2 were reduced. Optimized contrast injection protocols are useful to reduce variations of MB contrast density, by taking these TB parameters and patient sex and BSA into account.

Identification of Key Factors That Are Associated with the Clinical Anti-Tumor Effect of Zoledronic Acid in Multiple Myeloma

Despite compelling preclinical data, only anecdotal reports have shown that zoledronic acid (ZOMETA, Zol) exerts an anti-multiple myeloma (MM) effect in humans. We postulate that this could be related to the dose-intensity of Zol, since anti-MM effects were clearly observed in mice given a dose equivalent of 8.0 mg (8.0 EQmg) weekly; but not in humans who received only 4.0 mg monthly. We describe 3 patients, who were treated with 2- to 3-fold higher dose-intensity of Zol; who demonstrated brisk clinical improvements. When the equivalent dose of Zol was normalized to the patient's body surface area, the maximum EQmg rate of Zol administered was between 11.4 EQmgmax and 12.0 EQmgmax per 28 days. Since the potency of Zol is measured by the degree of inhibition of differentiation of osteoclast precursors (pOC) (i.e. monocytes) to osteoclasts (OC) in vitro, we next investigated whether high-dose rate Zol had an in vivo inhibitory effect on this renewable pOC pool. We demonstrate that there was a linear relationship between the absolute monocyte count (AMCO) and the stage of MM at presentation. Specifically, patients with International Staging System (ISS) stage I disease had the lowest AMCO levels, whereas ISS stage III patients had the highest. We also show that treatment with Zol resulted in progressive decreases in AMCO levels, and these changes correlated with response to therapy. By contrast, AMCO levels increased in patients who either failed to respond to treatment or who had progressive disease. Finally, since Zol is known to induce the gamma delta T cells in vitro, we studied the recovery patterns of various T cell subsets following treatment using a high dose-intensity Zol-based regimen called “dtZ”. To our surprise, there was no difference in gamma delta T cell numbers, but instead bone marrow CD4+ CD25+ regulatory T cells were significantly decreased in patients who achieved CR, as compared to those that did not. These data suggest that high dose-intensity Zol has a very desirable anti-tumor profile in MM that could be related to inhibition of both myelomagenic processes as well as the immunosuppressive elements of host anti-tumor defense.

High Body Surface Area (BSA) Is An Independent Risk Factor for Developing Bisphosphonate-Induced Osteonecrosis of the Jaw (ONJ)

Background: Osteolytic bone disease and associated complications of pathological fractures is a major complication in patients with multiple myeloma (MM) and metastatic breast cancer (MBC). This is due to tumor cell mediated increase in osteoclastic activity. Bisphosphonates (BP) are effective in preventing skeletal events associated with osteolytic bone destruction. Improved survival of MM and MBC patients has resulted in prolonged exposure to BP therapy, which is reported to be associated with an increased incidence of osteonecrosis of the jaw (ONJ). ONJ involves destruction and necrosis of the maxillary and/or mandibular bone, etiology of which remains unclear. As treatment is usually not helpful, prevention becomes an important strategy and in this context identification of validated risk factors for development of OJN is critical. Several investigators have reported possible risk factors (including invasive dental procedures, prolonged BP therapy and renal dysfunction) that are associated with increased likelihood of ONJ development. We asked if specific patient biometric profile renders enhanced risk of ONJ development? Thus we investigated patient demographic profiles in a large cohort of patients and correlated with development of ONJ.Methods: Patients with MM or MBC with bone lesions treated with intravenous (iv) BP (zoledronic acid; Zometañ) between November 2002–December 2006 were identified using the RPCI database. Demographic, laboratory biochemical, BP-related and ONJ-related data was collected and compared between cases and controls.Results: Complete data was available for 160 patients, of whom 36 (22.5%) patients had ONJ. The remaining 124 (77.5%) patients served as controls. Of all the patients, 122 (76.2%) had MBC and 38 (23.8%) had MM. Median age for all patients was 58 years (range 35–87) while the median age at diagnosis of ONJ was 59.5 years (range 40–81). The median number of cycles with BP for the control group was 15 (range 1–80) and for the ONJ group was 23.5 (range 1–80). Cumulative median BP dose in the control and ONJ groups was 58 mg (range 2–316 mg) and 94 mg (range 4–297 mg) respectively, while the median body surface area (BSA) amongst the control group was 1.66 m2 (range 0.93–2.4) and in the ONJ group was 1.81 m2 (range 1.44–2.5). Other variables studied between cases and controls included percent deviation from ideal body weight, body mass index (BMI) serum creatinine at baseline, creatinine clearance (CrCl) at baseline and at time of diagnosis of ONJ, baseline serum calcium and baseline serum alkaline phosphatase. Amongst the variables tested, BSA was the only factor that was significantly different between the two groups (p=0.004; Wilcoxon). There was no significant difference between CrCl at baseline and at ONJ diagnosis (p=0.73; Sign test). A logistic regression model showed that BSA was significantly different between the cases and controls on univariate analysis (p=0.009) as well as a multivariate analysis incorporating BSA, cumulative BP dose, age at initiation of BP, BMI and baseline creatinine clearance (p=0.028). Using a normal adult BSA of 1.71 m2 as the cut-off, the odds ratio for developing ONJ was 2.85 times (univariate) and 2.54 times (multivariate) higher in the higher than normal BSA group (BSA 3 1.71 m2) when compared with the lesser BSA group (BSA <1.71 m2).Conclusions: ONJ is a serious complication of BP therapy. Patient's biometric profile has not been implicated as a potential risk factor in ONJ development so far. Our study, for the first time suggests that patient's BSA may be an important and independent risk factor for BP associated ONJ. Our findings warrant further investigation in prospective studies and emphasize close monitoring of patients with high BSA who are on BP treatment with careful periodic assessment of risk-benefit for BP continuation. [Display omitted]

Imatinib Plasma Levels Correlate with Molecular Response in CML Patients

Measurement of imatinib plasma levels is recommended for CML patients on Glivec therapy with suboptimal response or failure. Recently, reports suggesting that imatinib plasma levels correlate both with cytogenetic and molecular response of the patient and may be used for routine management of the treatment were published. We have introduced the examination of imatinib plasma levels into our laboratory follow-up of CML patients in 2007. All patients have signed informed consent before sampling. New capillary electrophoretic method was developed for determination of imatinib plasma levels. Plasma samples were deproteinated by methanol, evaporated, resuspended and directly analyzed. Separation was performed in buffer consisting of 50 mmol/L citrate adjusted with γ-amino-n-butyric acid to pH 4.0. Imatinib was quantified by UV detection in the range 250 – 270 nm (limit of detection is 10 nmol/L). BCR-ABL transcript levels were monitored by TaqMan-based real-time quantitative PCR, the baseline value of BCR-ABL/ABL% was 60%. Here we report comparison of plasma drug levels in CML patients with optimal and suboptimal molecular response. Total 238 samples from 100 CML patients were examined. Patients with major and complete molecular response (n = 68) and patients with suboptimal molecular response (n = 35) were chosen for the final comparison. The actual sample was eligible for analysis providing patient had been treated with standard dose 400 mg daily for at least one year, there was no other evident cause of the suboptimal response (presence of additional cytogenetic abnormalities or BCR/ABL mutation) and the sample was taken 24±6 hours after the ingestion of the drug. Other medication, the actual duration of the therapy (providing it was longer than one year), time interval between the dose and the meal ingestion, weight, body-mass index, body surface area and co-morbidity of patients were not taken into the account. All patients in the suboptimal group have achieved the complete cytogenetic response. Three patients in the suboptimal group have progressed, while there were any such patients in the optimal group. The results showed considerable inter-individual variability between the patients. However, the imatinib plasma levels found in the optimal group significantly higher (median of 2.34 umol/l; range of 0.46 – 6.23) than in the suboptimal group (median of 1.75 umol/l; range of 0.84 – 4.63) p < 0.003. Moreover, patients with negativity in real-time quantitative PCR testing showed a trend for even higher drug plasma levels (median of 3.18 umol/l; range of 0.46 – 6.23, n = 36) p < 0.001. We can conclude that higher imatinib plasma levels are associated with better molecular response to therapy and laboratory measurements may be used for modification of the imatinib dosage.

Irinotecan Plus Cisplatin Therapy and S-1 Plus Cisplatin Therapy for Advanced or Recurrent Gastric Cancer in a Single Institution

From the results of the JCOG9912 and SPIRITS trials, S-1 plus cisplatin (CDDP) therapy (SP) has been recognized as the standard chemotherapy for advanced gastric cancer in Japan. However, in their subsets of patients with the target lesion, irinotecan (CPT-11) plus CDDP therapy (IP) resulted in longer survival than 5-fluorouracil alone while SP exhibited a survival similar to S-1 alone. The objective of this study was to clarify the safety and efficacy of these two regimens. Forty-four patients were treated with IP and 32 with SP between September 2002 and July 2006 at Shizuoka Cancer Center. In IP, 70 mg/m(2) CPT-11 was administered on Days 1 and 15, 80 mg/m(2) CDDP on Day 1, repeated every 4 weeks. In SP, 40-60 mg S-1 depending on the patient's body surface area was given orally twice daily for 21 days and 60 mg/m(2) CDDP intravenously on Day 8, repeated every 5 weeks. The response rate, progression-free survival and median survival were 47% (17 of 36), 170 and 444 days in IP, and 80% (21 of 26), 235 and 469 days in SP. In patients with target lesions, those were 47%, 170 and 431 days in IP, and 80%, 235 and 442 days in SP. The incidence of Grade 3 or 4 toxicity was similar in both groups, but patient refusal of treatment was more frequent for IP than for SP. Our results demonstrate a better efficacy and feasibility of SP than IP for advanced gastric cancer patients, with or without a target lesion.

Serum leptin levels, skin leptin and leptin receptor expression in psoriasis

Recent studies support the relation of psoriasis with obesity and cardiovascular disease. Leptin, a peptide hormone secreted predominantly from adipose tissue, is involved in the regulation of energy intake and expenditure. Recently, it has been shown to have several immunological effects including induction of proinflammatory cytokine production. To investigate the possible role of leptin in psoriasis pathogenesis. Forty-three patients with psoriasis, 10 diseased and 10 healthy controls with normal body mass index were included. Serum fasting leptin levels of the study group were examined by enzyme-linked immunosorbent assay. Tissue leptin and leptin receptor expression of both patients and controls were investigated by immunohistochemistry. Serum leptin levels, tissue leptin and leptin receptor expression were significantly higher in patients with severe psoriasis than patients with mild-moderate psoriasis and controls (P < 0.05). Serum leptin levels showed a positive correlation with Psoriasis Area and Severity Index and involved body surface area in patients with psoriasis. In addition, serum leptin levels, tissue leptin and leptin receptor expression showed a positive correlation with disease duration in patients with psoriasis (P < 0.01, r = 0.979; P < 0.01, r = 0.691; P < 0.01, r = 0.428, respectively). We assume that leptin might serve as a marker of severity in psoriasis and also may be a pathogenetic cofactor contributing to chronicity of the disease. Consequently, its role in obesity and cardiovascular disease in patients with psoriasis deserves to be studied. In addition, drugs targeting the proinflammatory effects of leptin may be a new adjuvant therapeutic approach in psoriasis.

Determination of initial i.v. CYA dosage to achieve target AUC values in pediatric hematopoietic stem cell transplant patients

In solid organ transplantation, CYA dosing is based on the area under the concentration vs time curve (AUC(inf)). This study aimed to develop a guideline for the initial i.v. CYA dose for pediatric hematopoietic SCT (HSCT) patients to achieve the target AUC(inf) recommended in solid organ transplantation. Whole-blood CYA concentrations were determined in 24 patients (0.5-16.9 years) after the first i.v. dose given over 2 h, 1 day before HSCT. The i.v. CYA dose predicted to achieve an AUC(inf) of 4200 microg x h/l was calculated for each patient and expressed as a function of each patient's actual weight and body surface area (BSA). In patients <or=9 and >9 years of age, the mean i.v. CYA dose predicted to achieve the target AUC was 2.6+/-0.94 and 2.1+/-1.21 mg/kg, respectively. When these doses were expressed in terms of BSA, the mean dose was 65+/-23.1 and 68+/-35.0 mg/m(2) in children <or=9 and >9 years of age, respectively. In children 0.5-17 years of age undergoing HSCT, we recommend an initial i.v. CYA dose of 65 mg/m(2) infused over 2 h to achieve an AUC(inf) of approximately 4200 microg x h/l.

Does the Use of Stentless Aortic Valves in a Subcoronary Position Prevent Patient-Prosthesis Mismatch for Small Aortic Annulus?

Freestyle stentless bioprostheses have shown excellent hemodynamic performance. However, small size subcoronary implants have yet to prove their clinical usefulness. The aim of this study was to determine the incidence of patient-prosthesis mismatch [PPM = Indexed Effective Orifice Area (iEOA) < or = 0.85 cm2/m2] after aortic valve replacement (AVR) with 19-mm and 21-mm stentless bioprostheses and to evaluate clinical and hemodynamic outcomes. From January 1993 to December 2000, 419 patients who had undergone Freestyle bioprostheses implantation were prospectively followed. Sixty-eight patients (16%) received a 19-21-mm prosthesis. The EOA was calculated and indexed to the patient's body surface area to obtain the iEOA. Clinical as well as echographic measures were recorded at discharge and at one and five years. PPM was present in 91% and 80% of patients with 19-mm and 21-mm prostheses, respectively. Severe mismatch (iEOA < or = 0.65 cm2/m2) was present in 58% and 17%. Mean gradients at discharge were 22 +/- 11 mmHg for the 19-mm prostheses and 14 +/- 7 mmHg for the 21-mm prostheses. Perioperative mortality was 33% (4/12 pts) for 19-mm prosthesis and 7% (4/56 pts) for 21-mm prostheses. Five-year actuarial survival was 58% for patients with 19-mm prosthesis and 82% for patients with 21-mm prosthesis (p = 0.04). AVR with small size Freestyle subcoronary implants is associated with a high incidence of PPM and high mortality.

Normal Thoracic Aorta Diameter on Cardiac Computed Tomography in Healthy Asymptomatic Adults: Impact of Age and Gender

To establish the normal criterion of ascending aortic diameter (AAOD) measured by 64 multidetector computed tomography (MDCT) and electron beam computed tomography (EBT) based on gender and age. A total of 1442 consecutive subjects who were referred for evaluation of possible coronary artery disease underwent coronary computed tomographic (CT) angiography (CTA) and coronary artery calcium scanning (CACS) (55 + 11 years, 65% male) without known coronary heart disease, hypertension, chronic pulmonary and renal disease, diabetes, and severe aortic calcification. The AAOD aortic diameter, descending aortic diameter (DAOD), pulmonary artery (PAD), and chest anteroposterior diameter (CAPD), posterior border of the sternal bone to the anterior border of the spine, were measured at the slice level of mid-right pulmonary artery using end systolic trigger imaging. The volume of four chambers, ejection fraction of left ventricle, and cardiac output were measured in 56% of the patients. Patients' demographic information, age, gender, weight, height, and body surface area were recorded. The mean value and age-specific and gender-adjusted upper normal limits (mean +/- 2 standard deviation) were calculated. The linear correlation analysis was done between AAOD and all parameters. The reproducibility, wall thickness, and difference between end-systole and end-diastole were calculated. AAOD has significant linear association with age, gender, DAOD, and pulmonary artery diameter (P < .05). There is no significant correlation between AAOD and body surface area, four-chamber volume, left ventricular ejection fraction, cardiac output, and CAPD. The mean intraluminal AAOD was 31.1 +/- 3.9 and 33.6 +/- 4.1 mm in females and males, respectively. The upper normal limits (mean +/- 2 standard deviations) of intraluminal AAOD, were 35.6, 38.3, and 40 mm for females and 37.8, 40.5, and 42.6 mm for males in age groups 20-40, 41-60, and older than 60 years, respectively. Intraluminal aortic diameters should parallel echocardiography and invasive angiography. Traditional cross-sectional imaging (with CT and magnetic resonance imaging) includes the vessel wall. The mean total AAOD was 33.5 and 36.0 mm in females and males, respectively. The upper normal limits (mean +/- 2 standard deviations) of intraluminal AAOD were 38.0, 40.7 and 42.4 mm for females and 40.2, 42.9, and 45.0 mm for males in age group 20 to 40, 41 to 60, and older than 60 years, respectively. The inter- and intraobserver, scanner, and repeated measurement variabilities were low (r value >0.91, P < .001, coefficient variation <3.2%). AAOD was 1.7 mm smaller in end-diastole than end-systole (P < .001). The AAOD increases with age and male gender. Gender-specific and age-adjusted normal values for aortic diameters are necessary to differentiate pathologic atherosclerotic changes in the ascending aorta. Use of intraluminal or total aortic diameter values depends on the comparison study employed.

Implications on chemotherapy dose selection of the 4-variable Modification of Diet in Renal Disease equation (MDRD) for estimating renal function

2553 Background: Cockcroft and Gault equation (CG) has been utilised for estimating renal function (RF) in cancer patients. MDRD (Ann Intern Med 2006; 145: 247–254) has been recently advocated as the routine method of estimating RF from serum creatinine, however it was developed in patients with chronic renal disease. The aim was to determine concordance of dose selection between CG and MDRD for renally excreted chemotherapy drugs. Methods: This retrospective study was conducted utilising data from hospitalised patients undergoing pharmacokinetic drug dose monitoring at a single institution. CG was calculated using actual body weight. Serum creatinine (SeCr) was measured using Jaffe method and rounded up to 0.06mmol/L. Comparison was made with MDRD adjusted for patient body surface area. Impact on drug dosing was assessed through examination of concordance across renal function ranges utilised in practice for dose selection (<30mL/min, 30–49mL/min, ≥50mL/min). Results: 4,123 patients were included; 62% male; mean age 52.5yrs (range: 18–96yrs), weight 76.8kg (range: 28.9–245kg), height 174.9cm (range: 137–198cm), SrCr 0.085mmol/L (range: 0.06–0.98mmol/L). Mean creatinine clearance (CrCl) was 107.5mL/min (range: 5.7–362mL/min) using CG and mean GFR was 103.9mL (range: 4.7–173mL/min) using MDRD. Concordance between CG and MDRD, adjusted for patient body surface area, is shown in Table 1. Clinical application of MDRD rather than CG would result in 1 in 70 patients receiving a higher dose of chemotherapy and 1 in 200 a lesser dose. Concordance was less with increasing body mass index (BMI) and incorporation of ideal body weight (IBW) in CG. Gender did not influence concordance. Conclusions: There was a high level of concordance in chemotherapy dose selection using MDRD or CG. Impact on dose selection is greater for obese patients and when IBW is utilised in CG. Concordance between CG and MDRD for dose selection of renally excreted chemotherapy MDRD <30ml/min ≥30–49.9mls/min ≥50mls/min CG <30ml/min 72 pts (1.7%) 61 pts (1.5%) 3 pts (0.1%) ≥30–49.9 mls/min 19 pts (0.5%) 213 pts (5.2%) 208 pts (5.0%) ≥50mls/min 0 pts (0%) 71 pts (1.7%) 3,476 pts (84.3%) No significant financial relationships to disclose.

Prosthesis–patient mismatch affects long-term survival after mechanical valve replacement

We sought to examine the relationship between the degree of prosthesis-patient mismatch and long-term survival after mechanical aortic valve replacement. Prospectively collected long-term follow-up data from 469 consecutive patients who underwent aortic valve replacement between 1995 and 1998 were reviewed. The indexed effective orifice area was derived from the reference normal values of effective orifice area divided by the patient's body surface area. Outcome was stratified according to the severity of prosthesis-patient mismatch: moderate mismatch was defined as 0.65 to 0.85 cm(2)/m(2) and severe mismatch as less than 0.65 cm(2)/m(2). The Cox proportional-hazards model with propensity score adjustment was used to adjust for the observed differences in baseline characteristics between the mismatch groups. The degree of prosthesis-patient mismatch was minimal in 57% of patients, moderate in 39%, and severe in 4%. Predictors of clinically significant mismatch included small aortic valve sizes (19 and 21 mm), obesity, age greater than 65 years, and class III or IV heart failure. During a median follow-up period of approximately 7.9 years, overall survival was 77% in patients with minimal mismatch, 63% in those with moderate mismatch, and only 47% in those with severe mismatch (P < .001). Moderate or severe mismatch was a significant predictor of poorer survival (hazard ratio, 1.6; 95% confidence interval, 1.4-2.3; P < .01), even after adjustment for all significant clinical predictors (ie, propensity score; hazard ratio, 1.2; 95% confidence interval, 1.0-1.5; P = .05). In a large aortic valve surgery population, prosthesis-patient mismatch occurred in 43% of patients, and those with significant mismatch had worse long-term outcomes than those with minimal mismatch.

S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial

Phase I/II clinical trials of S-1 plus cisplatin for advanced gastric cancer have yielded good responses and the treatment was well tolerated. In this S-1 Plus cisplatin versus S-1 In RCT In the Treatment for Stomach cancer (SPIRITS) trial, we aimed to verify that overall survival was better in patients with advanced gastric cancer treated with S-1 plus cisplatin than with S-1 alone. In this phase III trial, chemotherapy-naive patients with advanced gastric cancer were enrolled between March 26, 2002, and Nov 30, 2004, at 38 centres in Japan, and randomly assigned to S-1 plus cisplatin or S-1 alone. In patients assigned to S-1 plus cisplatin, S-1 (40-60 mg depending on patient's body surface area) was given orally, twice daily for 3 consecutive weeks, and 60 mg/m(2) cisplatin was given intravenously on day 8, followed by a 2-week rest period, within a 5-week cycle. Those assigned to S-1 alone received the same dose of S-1 twice daily for 4 consecutive weeks, followed by a 2-week rest period, within a 6-week cycle. The primary endpoint was overall survival. Secondary endpoints were progression-free survival, proportions of responders, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00150670. 305 patients were enrolled; seven patients were ineligible or withdrew consent, therefore, 148 patients were assigned to S-1 plus cisplatin and 150 patients were assigned to S-1 alone. Median overall survival was significantly longer in patients assigned to S-1 plus cisplatin (13.0 months [IQR 7.6-21.9]) than in those assigned to S-1 alone (11.0 months [5.6-19.8]; hazard ratio for death, 0.77; 95% CI 0.61-0.98; p=0.04). Progression-free survival was significantly longer in patients assigned to S-1 plus cisplatin than in those assigned to S-1 alone (median progression-free survival 6.0 months [3.3-12.9] vs 4.0 months [2.1-6.8]; p<0.0001). Additionally, of 87 patients assigned S-1 plus cisplatin who had target tumours, one patient had a complete response and 46 patients had partial responses, ie, a total of 54% (range 43-65). Of 106 patients assigned S-1 alone who had target tumours, one patient had a complete response and 32 had partial responses, ie, a total of 31% (23-41). We recorded more grade 3 or 4 adverse events including leucopenia, neutropenia, anaemia, nausea, and anorexia, in the group assigned to S-1 plus cisplatin than in the group assigned to S-1 alone. There were no treatment-related deaths in either group. S-1 plus cisplatin holds promise of becoming a standard first-line treatment for patients with advanced gastric cancer.

Effects of Leucine Administration in Diamond-Blackfan Anemia Patients.

Diamond-Blackfan anemia (DBA) attracts much attention, since the symptoms of the disease are associated with mutations in ribosomal protein (RP) S19 in 25% of patients and in RPS17 and RPS24 in other DBA patients, indicating a possible relationship between ribosomal function, translation level and erythropoiesis. Indeed, translational efficiency has been found to be lowered in most DBA patients, and the amino acid leucine was tested in vitro as a potential modulator of protein synthesis with promising results. We therefore decided to evaluate the effects of leucine administration in several DBA patients. For leucine therapy, 4 patients with the lowest levels of translation (patients 1, 2, 4 and 6; see Table) and 2 others were selected from the Czech DBA registry. Due to iron overload, all patients were receiving iron chelation therapy at the start of the leucine therapy. A total dose of 2000 mg/m2/day of L-leucine was administered orally in three subdoses in the form of a capsule prepared by the hospital pharmacy. The doses were based on the leucine content in sports dietary protein supplements, and reduced according to each patient's body surface area. Two and 4 hours after administration, serum leucine levels doubled, but did not exceed normal values. Changes in other amino acids serum levels were not observed. After 8 weeks of leucine supplementation, all patients reported a noticeable increase in appetite and weight gain. Over a period of 6 months of follow-up, a gradual improvement in reticulocyte counts, hemoglobin levels and a reduction of serum ferritin levels were observed in all patients (see Table). One patient became transfusion independent, and is currently still in remission (>5 months); in two other transfusion dependent patients, the inter-transfusion period doubled; in steroid-dependent patients, the steroid dose could be reduced. The patient with the RPS17 mutation significantly improved in weight and well-being, and the iron chelation therapy was stopped. Our results thus show for the first time that leucine administration can greatly improve the quality of life of DBA patients in at least two ways - it can reduce the need for iron chelation; and it can gradually enhance erythropoiesis, reducing the steroid dose or the frequency of transfusions.Patients' characteristicsPatient No.Age (y) / SexStatus before LeuLevel of translation (% of controls)*Duration of Leu administration (mo)Serum ferritin level before Leu/current (μg/l)Reticulocyte count before Leu/current (%)Effect of Leu administration1 NM7 / FTD21121220 / 3810.1 / 3.3Remission2 NM8 / MTD4791311 / 4920.1 / 0.4PTP (3 / 6 weeks)3 NM11 / FTDND21950 / ND0.1 / NDIncreased appetite4 MUT31 / MLDS398860 / 4961.1 / 1.5Steroid dose reduction5 NM13 / MTD7761427 / 11100.6 / 1.4PTP (4 / 8 weeks)6 NM18 / MHDS42121605 / 8620.4 / 0.8Steroid dose reductionMUT: mutation in RPS17; NM: no mutation in RPS17, RPS19 or RPS24; TD: transfusion dependent; HDS: high dose steroid treatment; LDS: low dose steroid treatment; ND: not done; PTP: prolongation of the transfusion period (before Leu/ current); *: Haematologica 91: 1456(2006)

Pulmonary homograft muscle reduction to reduce the risk of homograft stenosis in the Ross procedure

The Ross procedure has gained increasing interest as an attractive alternative for aortic valve replacement. Despite its advantages, there is a certain risk of structural valve deterioration, especially of the pulmonary homograft as a result of shrinkage and subsequent stenosis predominantly at the muscular annulus. Theoretically, reduction of homograft muscle tissue could reduce this risk. From February 1996 through December 2002, a total of 238 patients (mean age 44 +/- 13.2 years) underwent the Ross procedure with the subcoronary technique with follow-up investigations before discharge and after 12 and 24 months. To estimate the importance of homograft muscle reduction within our institution-specific risk factor scale for change of transhomograft pressure gradient with time, we performed a generalized estimating equation approach, which identified homograft muscle reduction, higher body surface area in male patients, younger patient age, smaller homograft diameter, blood transfusions, and follow-up time as independent risk factors demonstrating a high beta value (-2.8638) for muscle reduction. To find out whether muscle reduction influences transhomograft pressure gradient, we compared patients with (group A, n = 39) and without (group B, n = 199) muscle reduction. The other mentioned independent risk factors were not different between groups, except for blood transfusions (group A greater than B, P < .01), indicating a negative bias for group A. The maximum pressure gradient across the homograft was lower in patients with muscle reduction before discharge (4.5 +/- 2.8 mm Hg group A vs 6.2 +/- 3.8 mm Hg group B, P = .004) and after 1 (9.3 +/- 5.8 vs 13.1 +/- 8.4 mm Hg, P = .028) and 2 years (10.8 +/- 7.6 vs 13.7 +/- 7.5 mm Hg, P = .013). No significant differences were found concerning homograft insufficiency. We provide some evidence that transhomograft pressure gradient can be reduced significantly within the first 2 years after operation by homograft muscle reduction. Longer term follow-up is necessary to evaluate this promising operative technique further.

Chemotherapy Dosing Part I: Scientific Basis for Current Practice and Use of Body Surface Area

Cytotoxic chemotherapy is characterised by a low therapeutic index and significant variability in therapeutic and toxic effects. In an attempt to reduce this variability, most chemotherapy doses are individualised according to patient body surface area (BSA). This practice, which was introduced almost 50 years ago, clearly has practical and economic implications for the healthcare system. Furthermore, the clinical value of this approach has, in recent years, been questioned. Despite established practice, chemotherapy dose selection remains complicated, partly because treatment effects are difficult to measure, partly because drugs are used in combination with other treatment modalities, and also because the patient's condition may change with disease progression. Various patient-related factors can affect drug pharmacokinetics (PK) and pharmacodynamics (PD), for example organ function, expression and activity of metabolising enzymes, drug resistance, body size, gender, age, concomitant disease and co-administration of other drugs. These factors may be of clinical significance in chemotherapy dose determination and measures of PK, PD or both feature in attempts to devise more rigorous methods for chemotherapy dosing. Part I of this series of two reviews describes the history and clinical impact of BSA-based chemotherapy, and examines the scientific evidence to support BSA dosing. It evaluates the factors affecting PK and PD for specific drugs that could inform and refine dose determination.