Combined Infusion Research Articles

Analysis of the tumoral cytotoxicity of green tea-infusions enriched with broccoli

Broccoli has risen as rich in bioactive phytochemicals (glucosinolates and phenolic compounds) closely linked with the reduction of cancer risk. Green tea infusion is a beverage that also contains anticarcinogenic compounds, mainly represented by flavanols. The compounds present in new broccoli-enriched green tea drinks and their potential antitumoral activity in vitro were evaluated. The distinct compounds present in the prepared beverages were identified by HPLC–PAD–ESI-MSn and quantified by HPLC–PAD. Caco-2 and CCD-18Co cell lines were exposed to growing percentages (0.2–5%) of infusions of distinct combinations of plant material. The time-dependent cytotoxicity on the malignant cells was also achieved. Cell death was evaluated by trypan blue dye exclusion and a more efficient specific cytotoxic effect on Caco-2 cells was observed on the cells incubated with the mixture of broccoli and green tea than on cells exposed to control infusions. Broccoli added to green tea resulted in a combination of phytochemicals with antitumoral activity with potential for further developments in mechanistic models and the design of novel foods.

Efficacy and safety of CHG regimen (low-dose cytarabine, homoharringtonine with G-CSF priming) as induction chemotherapy for elderly patients with high-risk MDS or AML transformed from MDS

To evaluate the efficacy and toxicity of CHG regimen (low-dose cytarabine, homoharringtonine with G-CSF priming) as an induction chemotherapy for elderly patients with high-risk MDS or acute myeloid leukemia transformed from MDS (MDS-AML). Thirty-three untreated patients (21 high-risk MDS and 12 MDS-AML) were enrolled in this study. Each patient was administered with the CHG regimen comprised of low-dose cytarabine (25mg/day, days 1-14) and homoharringtonine (1mg/day, days 1-14) by intravenous continuous infusion in combination with G-CSF (300μg/day) by subcutaneous injection from day 0 until neutrophil count recovery to 2.0×10(9)/L. The overall response rate (OR) was 66.7% after one course of the CHG regimen with 19 patients reaching CR (57.6%) and 3 patients reaching partial remission (PR) (9.1%). The median overall survival (OS) was 15.0months. Patients with normal serum lactate dehydrogenase (LDH) appeared longer median OS when compared to patients with high LDH level (18months vs. 5months, P=0.011). Grade 3/4 thrombocytopenia occurred in 28% of patients, neutropenia in 34%. No treatment-related deaths occurred during the induction therapy. These data suggest that the CHG priming regimen is effective and safe as a novel induction therapy for elderly patients with high-risk MDS and MDS-AML. The results need to be conformed in further study involving a larger cohort of patients.

Regulated recovery of pulsatile growth hormone secretion from negative feedback: a preclinical investigation

Although stimulatory (feedforward) and inhibitory (feedback) dynamics jointly control neurohormone secretion, the factors that supervise feedback restraint are poorly understood. To parse the regulation of growth hormone (GH) escape from negative feedback, 25 healthy men and women were studied eight times each during an experimental GH feedback clamp. The clamp comprised combined bolus infusion of GH or saline and continuous stimulation by saline GH-releasing hormone (GHRH), GHRP-2, or both peptides after randomly ordered supplementation with placebo (both sexes) vs. E(2) (estrogen; women) and T (testosterone; men). Endpoints were GH pulsatility and entropy (a model-free measure of feedback quenching). Gender determined recovery of pulsatile GH secretion from negative feedback in all four secretagog regimens (0.003 ≤ P ≤ 0.017 for women>men). Peptidyl secretagog controlled the mass, number, and duration of feedback-inhibited GH secretory bursts (each, P < 0.001). E(2)/T administration potentiated both pulsatile (P = 0.006) and entropic (P < 0.001) modes of GH recovery. IGF-I positively predicted the escape of GH secretory burst number and mode (P = 0.022), whereas body mass index negatively forecast GH secretory burst number and mass (P = 0.005). The composite of gender, body mass index, E(2), IGF-I, and peptidyl secretagog strongly regulates the escape of pulsatile and entropic GH secretion from autonegative feedback. The ensemble factors identified in this preclinical investigation enlarge the dynamic model of GH control in humans.

Phase I study of irinotecan by 24-h intravenous infusion in combination with 5-fluorouracil in metastatic colorectal cancer

This study was intended to ascertain the feasibility of a combination therapy with irinotecan by 24-h intravenous infusion (24-h CPT-11) and 5-fluorouracil (5-FU) for patients with metastatic colorectal cancer, to estimate the dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD), to determine the recommended dose (RD) for the Phase II study, and to evaluate the efficacy of the combination therapy. The dosage regimen was as follows: CPT-11 was given by 24-h CPT-11 on day 1, followed by 24-h intravenous infusion of 5-FU on day 2. This regimen was repeated every 2 weeks. The dose of CPT-11 was escalated in five steps from 50 to 75, 100, 125, or 150 mg/m(2) (levels 1-5), whereas the dose of 5-FU was fixed at 800 mg/m(2). Twenty-six patients were recruited for this study, and 25 of the 26 patients were eligible for the assessment. The DLTs of 24-h CPT-11/5-FU therapy included grade 3 diarrhea in 1 patient treated at level 1, and grade 3 neutropenia in 1 patient and grade 4 neutropenia in 1 patient at level 4. In level 5, in 3 cases the next administration could not be done for 22 days or more as a consequence of anorexia. Thus, the level 5 was made a MTD and the level 4 was made a RD. The main side effects of grade 3 or higher, although nausea/vomiting occurred, were mild and tolerable in severity overall. The overall response rate was 24.0% (6PR/25). This study suggests that 24-h CPT-11/5-FU therapy is feasible and effective for treatment of metastatic colorectal cancer.

Effect of neoadjuvant chemotherapy on the postoperative pulmonary infection of patients with advanced gastric cancer

To evaluate the effect of neoadjuvant chemotherapy on the postoperative pulmonary infection of patient with gastric cancer. Between January 2009 and January 2011, 139 patients with curable stage T2N2 or T3N2 gastric cancer were randomly assigned to group 1(69 cases, neoadjuvant chemotherapy with combined preoperative intraarterial infusion and intravenous chemotherapy before gastrectomy and D2 lymphadenectomy) and group 2(70 cases,gastrectomy and D2 lymphadenectomy alone). The morbidity of postoperative pneumonia in the two groups were recorded respectively. The two groups were similar with respect to various clinical or pathological characteristics. All the patients underwent gastrectomy and D2 lymphadenectomy successfully. Eight patients in group 1 suffered from the postoperative pneumonia, accounting for 11.6%. Nine patients in group 2 suffered from the postoperative pneumonia, accounting for 12.9%. There was no significant difference between the two groups about the incidence of postoperative pneumonia. Surgery following neoadjuvant chemotherapy with combined preoperative intraarterial infusion and intravenous chemotherapy is safe with similar morbidity of postoperative pneumonia to immediate surgery in patients with locally-advanced resectable gastric carcinoma.

Efficacy and cost analysis of transrectal ultrasound-guided prostate biopsy under monitored anesthesia

Sedation may result in reduction in pain during transrectal ultrasound (TRUS)-guided prostate biopsies. We aimed to evaluate the efficacy and safety of a combination of propofol and remifentanil infusion during TRUS-guided prostate biopsy and the related increases in health care costs. From January to September 2010, 100 men undergoing a transrectal prostate biopsy were randomized into two groups. In Group 1, 50 patients received a combined infusion of propofol and remifentanil; in Group 2, 50 patients received lidocaine jelly. After TRUS-guided biopsies were performed, pain and patient satisfaction were evaluated by a 10-point visual analog scale (VAS), and a cost-related patient satisfaction questionnaire was completed by all patients. Patients were also asked whether they would be willing to undergo repeat biopsy by the same method. Patients in Group 1 showed a significantly lower VAS score than those in Group 2 (mean VAS score: 0.9±1.1 versus 6.3±2.5; P<0.001). In addition, the patient satisfaction scale was significantly higher in Group 1 (P=0.002). Although the overall cost was significantly higher in Group 1 (P=0.006), patient satisfaction scales considering cost were also higher in this group (P=0.009). A combination of propofol and remifentanil is a safe and effective way to decrease patient pain and increase patient satisfaction during TRUS-guided prostate biopsy. Although the costs were higher in the group that received sedation, as expected, the patients exhibited heightened satisfaction and willingness to repeat biopsies by the same method.

Phase I dose-finding study of trabectedin (T) in combination with cisplatin (C) in patients (pts) with advanced solid tumors.

2517 Background: T is a synthetic compound originally derived from the marine organism Ecteinascidia turbinata with a mechanism of action based on DNA binding and involving the transcription-dependent nucleotide excision repair system. In vitro and in vivo preclinical data have shown a synergistic effect of the combination -T+C-. Methods: Primary Objectives: to identify the recommended dose (RD) of T given as 3-hour infusion in combination with standard dose of C every 3 weeks. Secondary: safety, antitumor activity and pharmacokinetics (PK). Pts with advanced solid tumors for whom treatment with T or platinum compounds was indicated were recruited. A maximum of 1 prior chemotherapy line and platinum sensitivity was required. T was given at escalating doses in subsequent cohorts of pts from 0.75 mg/m2 with a fixed dose of 75 mg/m2 C. The maximum tolerated dose was the dose level (DL) at which 1/3 or 2/6 pts had dose limiting toxicities (DLTs); the RD was set at 1 DL immediately below that. Results: At a T dose of 0.75 mg/m2 (DL1), 2 of 4 pts had DLTs: grade (G) 4 neutropenia >7 days and uncontrolled G 3 vomiting. T dose was reduced to 0.60 mg/m2 (DL-1) and 6 pts were recruited: 2 with ovarian carcinoma (OC) and 4 with soft tissue sarcoma (STS). No DLTs were reported. The most common adverse events were fatigue nausea, vomiting; the most common lab abnormalities were ALT elevations, G 3-4 neutropenia and G 3-4 thrombocytopenia. Out of 10 evaluable pts, 1 partial response (OC) and 5 stable disease (1 OC, 1 breast and 3 STS; 4 of them lasting ≥4 cycles) were reported. PK studies in 6 pts at 0.6 mg/m2 shown that the plasma exposure (AUC) to T and to C was about double and 60% higher, respectively, in the combination as compared to single agents in separate series. Conclusions: The RD of T given as 3-hour infusion in combination with 75mg/m2 of C is 0.6 mg/m2, 50 % lower than the RD as single agent. At these dose level and schedule the safety profile of both drugs is comparable to that of either single agent and is associated with antitumor activity. PK interaction leading to increased plasma exposure to both drugs may explain the clinical findings. Additional pts with platinum sensitive OC will be accrued at the RD to better define the PK profile.

Final results of a phase I dose-escalation study of ON 01910.Na in combination with oxaliplatin in patients with advanced solid tumors.

e13584 Background: ON 01910.Na is a novel multitargeted inhibitor of several regulatory pathways including polo-like kinase 1 (Plk1) and PI-3 kinases, with synergistic nonclinical activity when combined with oxaliplatin, prompting phase I clinical evaluation. Methods: Patients with advanced cancer received escalating doses of ON 01910.Na as 24hr weekly continuous infusions. Oxaliplatin was administered biweekly as a 85mg/m2, 2 hr infusion. The ON 01910.Na dose cohorts ranged from 250-1,350 mg/m2 based on a modified Fibonacci escalation algorithm using the accelerated titration scheme (NCI). Intrapatient dose escalation was allowed. Results: Thirty patients (pts) (22 females; ages: 29-80 yrs received an overall mean 9.4 (range=1-30) number of weeks of combination therapy: ON 01910.Na mg/m2: 250 n=10; 650 n=9; 1,050 n=8; 1,350 n=3. No dose-limiting toxicity was observed in any patient. Grade 3+ toxicities included pain (3 pts), lethargy and weakness (1 pt), pneumonia (1 pt), hyponatremia (1pt), anemia (1pt), transient ischemic attack (1pt), vomiting (1pt), urinary tract infection (1pt), shortness of breath and myocardial infarction (1pt). Confirmed partial response was observed in 1 pt with chemotherapy- refractory ovarian cancer (duration = 11 wks) and in another pt with metastatic breast cancer (duration = 13 wks). Stable disease was observed in 4 pts with colon cancer (42 wks and 12 wks), ovarian and renal cancer (12 wks). Conclusions: ON 01910.Na administered as a 24hr infusion in combination with oxaliplatin was well tolerated and resulted in objective tumor responses in advanced ovarian, breast, colon and renal cancer.

A randomized phase II study of carboplatin (C) and etoposide (E) with or without pan-BCL-2 antagonist obatoclax (Ob) in extensive-stage small cell lung cancer (ES-SCLC).

7001 Background: Ob is a pan-BCL-2 antagonist that is synergistic in vitro with cisplatin and E. A phase I study concluded that a 3-hr Ob infusion in combination with C and E was favored over a 24-hr infusion (ASCO 2010, Ab e13531). Methods: Patients (pts) with chemotherapy-naive ES-SCLC, measurable disease, and PS 0-2 were randomized to receive six 21-day cycles of CE (C AUC 5 D1, and E 100 mg/m2 D1-3) or CEOb (CE plus Ob [30 mg as a 3-hr infusion D1-3]). 73 evaluable pts were planned for each arm. 1° endpoint was ORR (confirmed CR & PR); 2° endpoints included PFS and OS. After completing 6 cycles, responders received prophylactic cranial irradiation; pts on CEOb continued Ob as maintenance therapy. Results: 165 pts were randomized; 155 pts (77 CEOb; 78 CE) received treatment. The arms were well balanced for gender, PS, and metastatic sites; 21% in each arm had brain mets. CNS adverse events (AEs) (such as somnolence [46% all grades] and euphoric mood [31% all grades]) occurred during and shortly after the Ob infusion. The only Grade 3/4 non-heme AE with ≥ 5% increase in absolute frequency in the Ob arm was somnolence (8 vs 0%). Grade 3/4 febrile neutropenia was rare (5% both arms). Grade 3/4 hematologic lab data were similar for each arm (CEOb vs CE): anemia (8 vs 15%), neutropenia (61 vs 58%), and thrombocytopenia (17 vs 10%). 74% of the pts on the CEOb arm alive without progression after 6 cycles started maintenance therapy. Efficacy data, including death or progression during initial 6 cycles of chemotherapy (refractory rate) are summarized in the table below. Conclusions: The CEOb arm demonstrated a trend for improved ORR, PFS, 12 mo and overall survival (OS). Most importantly, consistent with its in vitro synergy, Ob markedly decreased the rate of refractoriness to the initial 6 cycles of chemotherapy by 36.5%. Pts with screening PS of 2 did poorly in either arm; OS in PS 0-1 pts will be evaluated in a phase III trial comparing CE to CEOb. Study arm ORR PFS 12-month survival OS OS (PS 0-1) Refractory rate (PS 0-1) CEOb 64.9% 6.0 mos* 45.5% 10.6 mos* 11.9 mos* 25.4% CE 53.8% 5.4 mos* 37.2% 9.9 mos* 10.1 mos* 40.0% One-sided p value 0.11 0.08 0.19 0.0506 0.052 0.05 Hazard ratio - 0.79 - 0.72 0.71 - * Median

FOLFOX4 regimen administered through combined hepatic arterial and systemic infusion for treatment of colorectal cancer with unresectable liver metastases.

e14138 Background: Liver metastasis is the most common type of metastasis of colorectal cancer (CRC), and was found in 60-70% at autopsy. Only about 10% patients are amenable to hepatectomy, which is currently the only curative treatment. Hepatic arterial chemotherapy is an attractive alternative treatment to systemic chemotherapy, since 90% of blood supply to liver metastases is through hepatic artery, and that a higher drug concentration can be delivered to the metastatic tumor. Methods: Inclusion criteria: CRC patients with unresectable hepatic metastases and no prior chemotherapy during 2006-2009 in Peking Union Medical College Hospital were included. Treatment regimen: first day: HAI of oxaliplatin over 2h and L-folinic acid over 2h, followed by a bolus HAI of 5-fluorouracil (5-FU) then continuous HAI of 5-FU over 20 h; second day: Intravenous infusion of L-folinic acid over 2h followed by 5-FU bolus then continuous infusion of 5-FU over 22 h. The patients received HAI and systemic venous administration during the odd cycles, and the intravenous administration of the same regimen during the even cycles. Results: 27 colorectal cancer patients with unresectable hepatic metastases and no prior chemotherapy were enrolled in the study. A total of 236 treatment cycles were given with a median of 10 cycles. The therapy generated the following results after 6 cycles: CR 1/27 (3.7%), PR 16/27 (63.0%), SD 6/27 (22.2%) and PD 3/27 (11.1%). Four patients had hepatectomy. A median time to progression of 11 months and a median overall survival period of 24 months were documented. The major adverse events include grade±-II nausea/vomiting, upper abdominal pain, peripheral neuropathy, neutropenia/ thrombocytopenia. Conclusions: The FOLFOX4-like chemotherapy regimen was efficacious and safe for the treatment of metastatic CRC lesions in the liver, and facilitated the control of local lesions.

Continuous Interferon-α2B Infusion in Combination with Ribavirin for Chronic Hepatitis C in Treatment-Experienced Patients

Sustained virological response (SVR) rates in previous non-responders to pegylated interferon (PEG-IFN)-α and ribavirin for chronic HCV remain low (~10%). We hypothesize that continuous subcutaneous delivery of fully potent interferon (IFN)-α2b via an external pump will lead to stable blood concentrations and thereby prevent subtherapeutic trough levels associated with viral breakthrough. The aims of the study were to assess safety, tolerability and virological response in patients who were previous PEG-IFN-α/ribavirin non-responders. We randomized 30 HCV genotype 1 (n=24) and genotype 4 (n=6) patients to receive 6, 9 or 12 million units (MU) IFN-α2b daily by continuous subcutaneous administration using an insulin pump (MiniMed(®) 508; Medtronic Inc., Minneapolis, MN, USA) in combination with ribavirin (1,000-1,600 mg) for 48 weeks. The magnitude of viral decline in the 12 MU group after 4 weeks of treatment was 2.67 log HCV RNA compared with 1.21 and 1.27 log HCV RNA in the 9 and 6 MU groups, respectively (P=0.001). In the intention-to-treat analysis, the SVR rate was 20% (6/30). The per-protocol SVR rate was 25% (6/24), of which four out of six patients in the high-dose arm achieved SVR. Adverse events appeared dose-dependent, were mostly mild-to-moderate and were typical of IFN therapy. Five patients developed irritation and/or abscesses at the injection site. Six serious adverse events were reported in five patients. Continuous delivery of IFN-α2b can induce a strong dose-dependent viral suppression. This could be an effective approach in conjunction with, or as lead-in therapy prior to, treatment with a direct antiviral agent.

A Simple Modified Bicarbonate Regimen for Urine Alkalinization in Moderate Pediatric Salicylate Poisoning in the Emergency Department

A 4-year-old Indian girl was seen in our emergency department for unintentional ingestion of topical medication oil with subsequent salicylate poisoning. Serum levels were 52 mg/dL at 12 hours after ingestion.She was started on urine alkalization therapy to enhance salicylate elimination. This was achieved by a bicarbonate bolus of 1 mEq/kg for an hour and a continuous bicarbonate-potassium-dextrose combination infusion. The infusion regimen was modified from adult recommendations to tailor for pediatric physiological requirements in a young child. This consisted of a combination solution of dextrose 5%-sodium bicarbonate-potassium chloride with similar sodium content as half-strength (0.45%) saline and supplemental potassium, which is crucial for effective urine alkalinization. The combination fluid was administered at a rate 1.5 times her maintenance fluid requirement to achieve a urine output of 1.5 to 2 mL/kg per hour and a urine pH of 7.5 to 8.5. This regimen was well tolerated with good outcome.Many pediatricians and toxicologists achieve urine alkalinization by giving multiple bicarbonate boluses and have separate hydration fluids with dextrose and supplemental potassium. These regimens may involve complex calculations and multiple infusions that may lead to increased risk of calculation and medication errors especially in the busy emergency department setting. This case report highlights the use of a simple modified urine alkalinization regimen for moderate salicylate poisoning in a young child in the emergency department.

Time-reversal techniques in ultrasound-assisted deep vein thrombosis treatment: Technology development and in vitro evaluation.

We describe a thrombolysis method that combines time-reversal acoustic (TRA) focusing with an AngioJet thrombectomy catheter to improve the dissolution of thrombus in the treatment of deep venous thrombosis (DVT). Commercially available ultrasound-assisted DVT systems have been shown to accelerate thrombolysis by up to 40% and reduce the amount of thrombolytic drug required for treatment by 50%–70%. Current ultrasound-assisted DVT treatments utilize a specially designed intravascular catheter with therapeutic ultrasound transducer on the tip and side. Additionally, MRI guided high intensity focused ultrasound systems have shown to rapidly lyse thrombus. We describe a novel TRA focusing system that is used to infuse fluids into the thrombus while simultaneously exposing the clot to safe levels of 1-MHz ultrasound energy. The system includes a combined infusion catheter-hydrophone, a ten-channel ultralow-output impedance amplifier, a broad-band ultrasound resonator, and MATLAB-based, TRA control and user-interface. TRA allows easy focusing of ultrasound therapy to the catheter tip from an external source, without complex phase-correction and array design. The system has been tested in vitro in a DVT phantom model, and results show that it provides 1-mm spatial resolution focusing. We present results in using TRA focusing to lyse bovine blood clots in the physiological size DVT phantom.

Pharmacologic and phenotypic study of docetaxel in patients with ovarian or primary peritoneal cancer

The objectives of this study were to determine whether the midazolam clearance predicted docetaxel pharmacokinetics, CA-125 change, and response and to assess the impact of cytochrome P450 (CYP) 3A5 and ATP-binding cassette, subfamily B, member 1 (ABCB1) genotypes on docetaxel pharmacokinetics and pharmacodynamics in ovarian or primary peritoneal cancer patients. Thirty-four patients with advanced ovarian and primary peritoneal cancer were administered docetaxel at 75mg/m(2) as a 1-h infusion in combination with carboplatin IV over 30min at a target AUC of 5mg/mlmin. Cycles were repeated every 21days for 6 cycles. Midazolam was administered at 2mg as a 30-min IV infusion the day prior to cycle one of docetaxel administration. Pharmacokinetic studies of docetaxel and CYP3A5 and ABCB1 genotype studies were performed. There was an inverse relationship between midazolam clearance (CL) and CA-125 level after cycle 6 where a higher midazolam CL was associated with a CA-125<10U/ml (P=0.007) and CA-125<15U/ml (P=0.048). The CA-125 categories were associated with response achieved (complete response/partial response) (CR/PR), stable disease (SD), and progressive disease (PD) at the end of therapy (P=0.0173). Docetaxel CL was not related to midazolam CL or genotype. Docetaxel exposure and genotypes were not related to toxicity or response (P>0.05). The midazolam CL predicted CA-125 levels and response that was independent of other factors including docetaxel pharmacokinetics. Future studies need to evaluate the mechanism for the relationship between midazolam CL and response in patients with ovarian cancer.

Protection against β adrenoceptor agonist reduction of plasma potassium in severe but not in moderate hypokalemia

K-depleted and control rats were anesthetized and infused with terbutalin. In controls, plasma K concentration (pK) decreased by 0.7 mm (P = 0.01). In moderate hypokalemia terbutalin-induced decrease in pK was reduced by 0.3 mm for each 1 mm decrease in pK (n = 8, R(2) = 0.82, P = 0.002) and by 0.2 mm for each 10 mmol/g wet wt. decrease in muscle K content (n = 8, R(2) = 0.66, P = 0.01). Hence, for baseline pK of 4, 3 and 2 mm, decrease in pK was 0.7, 0.4 and 0.1 mm, respectively. In severe hypokalemia (1.7 mm), terbutain induced no further reduction in pK. The combined infusion of insulin and terbutalin showed no additive effect. Normalization of pK by KCl infusion in severe hypokalemia immediately abolished protection against terbutalin induced further pK reduction. Hence, terbutalin clamped pK at around 4 mm, whereas it continued to increase to around 5 mm without terbutalin infusion. Major new findings are: Protection against terbutalin induced further reduction in pK in severe pre-existing hypokalemia (<2 mm) and blunted but nevertheless severe further reduction in pK in more moderate pre-existing hypokalemia; immediate abolishment of protection by normalization of pK; protection against additive reduction in pK by terbutalin and insulin in severe hypokalemia. It may be advisable to avoid hypokalemia when using β adrenoceptor agonists and to maintain pK in the upper normal range if at the risk of arrhythmia.

The impact of adenosine pharmacologic stress combined with low-level exercise in patients undergoing myocardial perfusion imaging (BIWAKO adenosine-Ex trial)

The combination of adenosine infusion with low-level exercise has become a common approach for inducing stress during stress myocardial perfusion imaging (MPI). We investigated stress MPI performed by combined low-level exercise and adenosine infusion. This combined protocol can decrease adverse reactions and reduce the effect of scattered rays from the liver. Subjects were clinically referred for a 53-min rest-stress Tc-99m Sestamibi MPI procedure using BIWAKO PROTOCOL. Ninety-eight patients (44.5%) underwent adenosine infusion with ergometer exercise testing and 122 patients (55.5%) underwent adenosine infusion without exercise testing. We evaluated the liver/heart (L/H) uptake ratio, background activity in the upper mediastinum, and adverse reactions. The L/H ratio and background activity were lower in the adenosine-exercise group than in the adenosine-non-exercise group (1.8±0.54 vs. 2.1±0.62, P<0.0056; 43.1±12.2 vs. 61.5±15.4, P<0.0001). The adenosine-exercise group had fewer adverse reactions than the adenosine-non-exercise group (11.2 vs. 19.7%). All of the adverse reactions were minor, with the exception of severe back pain in one case. The incidence of adverse reactions in our study was lower than that in previous studies for unknown reason. Adenosine infusion in combination with low-level exercise seems to result in higher-quality images and fewer adverse reactions than adenosine infusion without exercise. The combined protocol decreases adverse reactions and improves the quality of myocardial perfusion images by decreasing background activity.

Low-dose versus standard-dose gemcitabine infusion and cisplatin for patients with advanced bladder cancer: A randomized phase II trial.

266 Background: Bladder carcinoma is the foremost oncologic problem in Egypt. Prolonged infusion of gemcitabine and cisplatin is an effective treatment for advanced bilharzial-related bladder cancer based on a previously published phase II trial. Methods: To compare efficacy and safety of both prolonged infusion and standard gemcitabine-cisplatin combination, this phase II randomized study of 60 untreated patients with stage III/IV bladder cancer was conducted. Patients were randomized to receive either gemcitabine (250 mg/m2) 6-hour infusion on days 1 and 8, and cisplatin (70 mg/m2) on day 2 every 21-day cycle (Arm1) or gemcitabine (1,250 mg/m2) 30-min infusion on days 1 and 8, and cisplatin (70 mg/m2) on day 2 every 21-day cycle (Arm 2). Results: The 47 males and 13 females had a median age of 60 years (range 40-73 years). A total of 44 patients had transitional cell, 12 had squamous cell, and 4 had undifferentiated cell carcinoma. Among the 53 evaluable patients (26 patients in arm1 and 27 patients in arm 2), complete response rate was achieved in 19.3% (5/26 patients of arm 1) and 7.4% (2/27 patients of arm 2). Eight patients in arm 1 (30.7%) and 7 patients (25.9%) in arm 2 had partial response on therapy. Thus the overall response rate of patients in arm1 and arm 2 was 50% (13/26 patients) and 33.3% (9/27patients), respectively (p = 0.21). No significant difference in median time to disease progression (6.7 months versus 7.9 months, p = 0.42), median survival (9.7 months versus 8.8 months, p = 0.3), and 1-year survival (27% versus 6%, p = 0.3) was detected between arms 1 and 2, respectively. No treatment- related deaths occurred. Main hematologic and nonhematologic toxicities were similar in both arms with no statistically significant differences. Conclusions: In the treatment of advanced bilharzial bladder cancer, gemcitabine in low dose and prolonged infusion in combination with cisplatin is not inferior to high-dose short infusion gemcitabine and cisplatin in terms of overall survival, time to disease progression, and response rates with favorable toxicity profile and less financial costs. No significant financial relationships to disclose.

Continuous infusion of 5-FU with split-dose cisplatin: An effective treatment for advanced squamous-cell carcinoma of the head and neck

The purpose of this study was to determine if a combination chemotherapy, using continuous intravenous infusion of fluorouracil (5-FU) in combination with split-dose cisplatin, in patients with recurrent or metastatic head and neck squamous-cell could improve previously reported clinical outcomes. Forty-two patients with recurrent or metastatic head and neck squamous-cell cancer were treated by cisplatin (25 mg/m(2)/day on days 1-3) and 5-FU (750 mg/m(2)/day for 120 hours; continuous intravenous infusion on days 1 through 5) with a cycle that repeated every 3 weeks. Of the 42 patients, 8 (19.1%) showed complete response and 12 (28.5%) demonstrated a partial response, giving an overall response rate of 47.6%. Response rates were significantly different for patients undergoing initial treatment vs. re-treatment:73.6% (14/19) vs. 25.9% (6/23), respectively (χ(2)=9.45, P < 0.05). Median time to progression was 7.2 months and median overall survival was 13.7 months. The 1 year survival was 57.1%. Toxicity mainly included myelo-suppression, mucositis, nausea and vomiting. Chemotherapy with 5-FU by continuous intravenous infusion in combination with split-dose cisplatin is effective with a tolerable toxicity profile in patients with recurrent, or metastatic squamous-cell carcinoma of head and neck. The overall response was significantly higher in patients undergoing initial treatment in comparison with patients undergoing re-treatment after relapse.

Phase II study of fixed-dose-rate infusion of gemcitabine and UFT combination chemotherapy in patients with advanced bile duct cancer: Daegu Gyeoungbuk Oncology Group.

280 Background: This phase II study evaluated efficacy of fixed dose rate (FDR) infusion of gemcitabine (10mg/m2/min) and UFT combination in chemo-naïve patients with advanced bile duct cancer. Methods: This was an open-label, single-arm, multicenter, phase II study with a Simon two-stage minimax design. Patients received the FDR gemcitabine 1,000mg/m2 for 3 consecutive weeks and UFT 400 mg/m2 on days 1-21. The cycle was repeated every 28 days. The primary end point was Response Evaluation Criteria in Solid Tumors (RECIST) -defined objective response rate. Secondary end points included clinical benefit response (CBR), safety, progression-free survival (PFS), and overall survival (OS). Clinical characteristics including four single nucleotide polymorphisms in DNA repair genes (RecQ1, RAD54L, XRCC1, ATM) were evaluated whether these influence the overall survival. Results: Between December 2006 and February 2008, fifty-one patients were enrolled, with a median age of 58 years. The majority of patients (76%) had intra-hepatic disease. Fourteen patients (27%) had a RECIST investigator-assessed, partial response (PR); disease control rate (PR + stable disease) was 55%. CBR was 14% among 37 evaluable patients. Hematologic toxicity was main grade 3 or 4 treatment-related adverse events. Median PFS was 4.0 months (95% CI, 2.9 to 5.1 months). Median OS was 7.0 months (95% CI, 3.5 to 10.5 months). Intrahepatic disease, poor performance, and, XRCC1 R194W C/C type were predictive markers of poor overall survival. Conclusions: FDR gemcitabine and UFT demonstrated apparent activity in patients with advanced bile duct cancer. However, this activity did not translate to prolong survival. The location of disease, performance status, and, polymorphic variants of DNA repair genes may affect clinical outcome of patients with advanced bile duct cancer. No significant financial relationships to disclose.

Alloreactive Nk Cells to Augment Antileukemia Cytotoxicity with Allogeneic Stem Cell Transplantation for Aml/Mds: A Phase I Study

AbstractAbstract 489Relapse remains the major cause of treatment failure after allogeneic hematopoietic transplantation for AML and MDS. Alloreactive NK cells mediate a potent antileukemic effect and may also enhance engraftment and reduce GVHD. We performed a phase I study infusing “third party” alloreactive NK cells from a haploidentical related donor as a component of the preparative regimen for allotransplantation from a separate HLA identical donor. The goal was to augment the antileukemia cytotoxicity of the preparative regimen by infusion of alloreactive NK cells and improve the overall outcome of hematopoietic transplantation.Patients with advanced AML or high risk MDS in relapse or beyond first remission were eligible. They received the busulfan-fludarabine preparative regimen, followed by infusion of NK cells predicted to be alloreactive by KIR:KIR ligand incompatibility. The NK cell enriched product was produced from a steady state apheresis product by depleting CD3+ cells using the CliniMACS device (Miltenyi Corp). A second step positively selecting CD56+ cells was performed for the first dose level, but discontinued thereafter in order to increase the cell yield. The NK cell product was then cultured in complete media containing rIL-2 for 16 hours and infused intravenously following completion of the busulfan-fludarabine chemotherapy. After 5 days, ATG was administered followed by PBSC infusion from the HLA identical sibling or unrelated donor. Patients received tacrolimus and methotrexate for GVHD prophylaxis. Patients were treated in 4 dose levels of the NK cell enriched product; 1) 106 cells/kg, 2) 5 × 106/kg, 3) 3 × 107/kg, and 4) 3 × 107/kg followed by systemic interleukin-2 0.5 million units/m2 SQ daily for 5 days. CD3+ cells in the NK cell product were required to be <105/kg (median infused 1.1 x104/kg). Median CD56+ cells infused (x106/kg) were from 0.9 (level 1), 1.5 (level 2), and 4.9 (levels 3 and 4).13 patients were entered. Median age was 51 years (range 2–60). 11 had active disease and 2 were in a second remission. Only mild infusion toxicity occurred with the NK cell infusion. Other toxicities were similar to that experienced with the preparative regimen without NK cells. The 2 patients at dose level 4 tolerated interleukin-2 systemic treatment without fever or increased toxicity. The haploidentical NK cells were transiently detected in the blood by chimerism studies in one patient. Rapid engraftment and hematologic recovery uniformly occurred from the HLA matched PBPC donor in all patients. None had graft failure. Grade 2 acute GVHD developed in 3 patients; all responded to corticosteroid treatment. None developed grade 3 or 4 acute GVHD. 9 of 11 patients with active disease achieved a complete remission. Only one patient died of nonrelapse mortality; she died in remission from infection 2 months post transplant.This trial confirms the feasibility of producing the haploidentical NK cell product, and the lack of major toxicity attributable to the NK cell infusion in combination with an HLA compatible allogeneic transplantation. Infusion of haploidentical alloreactive NK cells was well tolerated and did not interfere with engraftment or increase the rate of GVHD after allogeneic hematopoietic transplantation. This approach merits further phase II and III study designed to reduce relapse and improve the outcome of allogeneic hematopoietic transplantation for AML/MDS.NNK cell doseCells/kggrade 2 GVHDRelapseNRMAlive in CR4106140045 × 1060301 (27+ m)33 × 1072111 (11+ m)23 × 107 + IL-20002 (9+ m, 4+ m) Disclosures:No relevant conflicts of interest to declare.