Weekly oxaliplatin,high-dose folinic acid and 24h-5-fluorouracil (FUFOX) as salvage therapy in metastatic colorectal cancer patients pretreated with irinotecan and folinic acid/5-fluorouracil regimens

Irinotecan (CPT-11), oxaliplatin (OXA) and different folinic acid(FA) modulated 5-fluorouracil (5-FU) regimens are active as first-and second-line chemotherapy of metastatic colorectal cancer. However, the best palliative sequence of these substances is still unclear. After CPT-11 containing regimens the optimal salvage protocol has not yet been defined. Here, we retrospectively analysed the weekly ambulant combination of OXA with continuous FA/5-FU (FUFOX) after two different CPT-11 containing chemotherapeutic regimens. PATIENTS: During October 1999 and May 2001, 20 patients (median 62; 48-74 years) were included who had disease progression after CPT-11 /bolus FA/5-FU (Saltz; 7 patients, group A) or after FA/5-FU followed by CPT-11 alone (13 patients, group B). OXA(60 mg/m2) was given for 2 hours prior to FA (500 mg/m2) as 2 h-infusion and continuous 5-FU (2.600 mg/m2) for 24 h-infusion on day 1,8,15 and 22 (repeated after week 6). RESULTS: FUFOX was administered 252 times. About 1,203 mg OXA per patient was given. Toxicities NC-CrC grade 3 were observed in 10 patients: diarrhoea (4), mucositis (5), nausea/vomiting (2), anaemia (1), leucopenia (1), thrombopenia (1) and hand-foot-syndrome (1), 3 patients showed minor remissions, II patients stable disease. The median time to progression was 16(0-39) weeks. The median survival from start of FUFOX and from start of any palliative therapy was 33 (5-65) and 99 (44-200) weeks for all patients, respectively. CONCLUSIONS: FUFOX was efficient for additional tumour control in 70% of patients pretreated with CPT-11/5-FU based regimens. Sequential palliative treatment can lead to prolonged survival.     

Long recovery times improve the detection of cellular resistance in vitro

In vitro cytotoxicity testing is used increasingly during the development of clinical treatment protocols. These tests are influenced by many variables, not all of which have been assessed systematically yet. We analyzed the influence of the recovery time between the end of treatments and measurements on the detection of cellular resistance. The development of resistance to cisplatin and radiation was chosen as a model since the schedule of these treatments is the objective of several ongoing clinical trials. C6 rat glioma, T98G, 86HG-39, A172 human glioma and TE671 human rhabdomyosarcoma cells were pretreated with radiation or cisplatin. The cellular resistance was then compared in pretreated and wild-type cells using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. In all cell lines, apparent drug concentrations killing 50% of the cells were dependent on the recovery time. In A172 cells this concentration was 10.3 ± 02.1 μM after 48 h but decreased to 3.56 ± 0.44 μM after 120 h recovery time (P < 0.001). After recovery times of more than 168 h, 53% of all pretreated cell lines were resistant to cisplatin or radiation, 25% were unchanged and 22% were more sensitive. However, only half the resistant cells could be identified when the MTT test was done with only 48 h recovery time. The sensitivity of detection increased from 0.46 to 0.83 when the recovery time of the test system was extended from 48 h to 168 h. The specificity was not dependent on the recovery time. Experi-ments showing resistance after short recovery times are reliable, but lack of resistance can only be shown in experiments with long recovery times. Cisplatin treatment can result in resistance to radiation in glioma cells. Received: 7 March 1997 / Accepted: 18 March 1998     

BMS-747158-02: a novel PET myocardial perfusion imaging agent.

BACKGROUND: BMS-747158-02 is a fluorine 18-labeled pyridaben derivative designed as a new myocardial perfusion imaging agent for use with positron emission tomography (PET). This study evaluated BMS-747158-02 in animal models of cardiac perfusion and compared it with established single photon emission computed tomography agents. METHODS AND RESULTS: In a rat biodistribution study, BMS-747158-02 (15 microCi) had substantially higher myocardial uptake than technetium 99m sestamibi (100 microCi) at 15 minutes (3.5% +/- 0.3% %ID/g vs 1.9% +/- 0.1% %ID/g) and 120 minutes (3.2% +/- 0.4% of injected dose per gram vs 1.8% +/- 0.0% of injected dose per gram) after intravenous administration. Uptake ratios of heart to lung and liver at 60 minutes were also higher for BMS-747158-02 (12.7 +/- 1.4 and 3.7 +/- 0.2, respectively) than Tc-99m sestamibi (5.9 +/- 0.5 and 2.4 +/- 0.4, respectively). In an isolated rabbit heart model at flow rates of 1.66 to 5.06 mL x min(-1).g(-1) wet left ventricular weight, the net BMS-747158-02 heart uptake increased proportionally (0.93 +/- 0.15 to 2.44 +/- 0.40 mL.min(-1) x g(-1)) and to a greater extent than that of thallium 201 (0.76 +/- 0.02 to 1.11 +/- 0.02 mL x min(-1) x g(-1)) or Tc-99m sestamibi (0.49 +/- 0.03 to 0.77 +/- 0.08 mL x min(-1) x g(-1)). PET imaging with BMS-747158-02 showed a clear and sustained cardiac uptake in rats, rabbits, and nonhuman primates with minimal lung interference and rapid liver clearance. Myocardial perfusion deficit zones created by either permanent left coronary ligation or reperfusion after ligation in rats were both clearly identified on PET cardiac images of BMS-747158-02 and had good agreement with in vitro histology. CONCLUSIONS: BMS-747158-02 exhibited high and sustained cardiac uptake that was proportional to blood flow, and it represents a new class of PET myocardial perfusion imaging agent.     

ASCO-Update 2005--Highlights of the 41st Meeting of the American Society of Clinical Oncology/ASCO 2005

Currently, the treatment of gastrointestinal cancers is rapidly changing due to the implementation of novel chemotherapeutic agents as well as the introduction of targeted therapies into treatment protocols. The following review provides an overview of the most important clinical trials in esophageal, gastric, colorectal, pancreatic and hepatobiliary cancer that were presented at the annual meeting of the American Society of Clinical Oncology.     

Feasibility of reduced intensity hematopoietic stem cell transplantation from an HLA-matched unrelated donor

To evaluate the feasibility of reduced intensity stem cell transplantation (RIST) with bone marrow from a matched unrelated donor (MUD), we retrospectively investigated 20 patients with hematological disorders who received RIST in the Tokyo SCT consortium from January 2000 to October 2002. The preparative regimens were fludarabine-based (150-180 mg/m(2), n=18) or cladribine-based (0.77 mg/kg, n=2). To enhance engraftment, antithymocyte globulin (ATG) and 4 or 8 Gy total body irradiation (TBI) were added to these regimens in nine and 11 patients, respectively. GVHD prophylaxis was cyclosporine with or without methotrexate. In all, 19 achieved primary engraftment. Three developed graft failure (one primary, two secondary), and five died of treatment-related mortality within 100 days of transplant. Seven of the 19 patients who achieved initial engraftment developed grade II-IV acute GVHD, and seven of 13 patients who survived >100 days developed chronic GVHD. At a median follow-up of 5.5 months, estimated 1-year overall survival was 35%. Compared with a TBI-containing regimen, an ATG-containing regimen was associated with a high risk of graft failure (30 vs 0%, P=0.0737). This study supports the feasibility of RIST from MUD; however, procedure-related toxicities remain significant in its application to patients.     

Evaluation of cytomegalovirus-specific cytotoxic T-lymphocytes in patients with the HLA-A*02 or HLA-A*24 phenotype undergoing hematopoietic stem cell transplantation

Cytomegalovirus-specific cytotoxic T-lymphocytes (CMV-CTL) are essential for the control of CMV reactivation. To monitor the quantity and function of CMV-CTL after hematopoietic stem cell transplantation (HSCT), two CMV epitopes that bind to HLA-A*0201 NLVPMVATV (A*02NLV) and HLA-A*2402 QYDPVAALF (A*24QYD) were evaluated for their immunological potential. Samples from patients with the HLA-A*02 or HLA-A*24 serotype were analyzed by tetramer, intracellular cytokine staining and enzyme-linked immunospot (ELISPOT) assay. There were significantly more A*02NLV-specific CMV-CTL than A*24QYD (23 x 10(6) vs 0.4 x 10(6)/l). The frequency of IFN-gamma-producing cells was also higher upon stimulation with A*02NLV than with A*24QYD (2.5 vs 0.1%/CD8). Furthermore, the magnitude of CMV-CTL expansion was two- to 50-fold when cells were cultured with A*02NLV, while only an insignificant increase was observed in culture with A*24QYD. Although the number of A*24QYD-specific CMV-CTL was very low in most of the HLA-A*24 patients, the incidence of CMV reactivation did not differ between those with HLA-A*02 and HLA-A*24 serotype alone. These results suggest that an epitope other than A*24QYD plays a major role in patients with HLA-A*24. Our study also showed that A*02NLV may be a useful epitope for monitoring CMV-CTL not only in patients with HLA-A*0201 but also in those with the A*0206 genotype.     

A brain‐potential correlate of task‐set conflict

Brain‐potential correlates of response conflict are well documented, but those of task conflict are not. Task‐switching studies have suggested a plausible correlate of task conflict—a poststimulus posterior negativity—however, in such paradigms the negativity may also reflect poststimulus task‐set reconfiguration postulated in some models. Here, participants alternated between single‐task blocks of classifying letters and digits; hence, no within‐block task‐set reconfiguration was required. Presenting letters alongside digits slowed responses to the digits and elicited an ERP negativity from ～350 ms, relative to task‐neutral symbols presented alongside digits, consistent with task conflict. The negativity was also present for congruent digit‐letter stimuli; this and the lack of behavioral response congruency effects indicate conflict at the level of task‐set rather than response selection.     

Monitoring respiration in wheezy preschool children by pulse oximetry plethysmogram analysis

The aim of this study was to investigate whether respiratory information can be derived from pulse oximetry plethysmogram (pleth) recordings in acutely wheezy preschool children. A digital pulse oximeter was connected via ‘Bluetooth’ to a notebook computer in order to acquire pleth data. Low pass filtering and frequency analysis were used to derive respiratory rate from the pleth trace; the ratio of heart rate to respiratory rate (HR/RR) was also calculated. Recordings were obtained during acute wheezy episodes in 18 children of median age 31 months and follow-up recordings from 16 of the children were obtained when they were wheeze-free. For the acutely wheezy children, frequency analysis of the pleth waveform was within 10 breaths/min of clinical assessment in 25 of 29 recordings in 15 children. For the follow-up measurements, frequency analysis of the pleth waveform showed similarly good agreement in recordings on 15 of the 16 children. Respiratory rate was higher (p < 0.001), and HR/RR ratio was lower (p = 0.03) during acute wheeze than at follow-up. This study suggests that respiratory rate can be derived from pleth traces in wheezy preschool children.     

Non-linear adaptive controllers for an over-actuated pneumatic MR-compatible stepper

Pneumatics is one of the few actuation principles that can be used in an MR environment, since it can produce high forces without affecting imaging quality. However, pneumatic control is challenging, due to the air high compliance and cylinders non-linearities. Furthermore, the system’s properties may change for each subject. Here, we present novel control strategies that adapt to the subject’s individual anatomy and needs while performing accurate periodic gait-like movements with an MRI compatible pneumatically driven robot. In subject-passive mode, an iterative learning controller (ILC) was implemented to reduce the system’s periodic disturbances. To allow the subjects to intend the task by themselves, a zero-force controller minimized the interaction forces between subject and robot. To assist patients who may be too weak, an assist-as-needed controller that adapts the assistance based on online measurement of the subject’s performance was designed. The controllers were experimentally tested. The ILC successfully learned to reduce the variability and tracking errors. The zero-force controller allowed subjects to step in a transparent environment. The assist-as-needed controller adapted the assistance based on individual needs, while still challenged the subjects to perform the task. The presented controllers can provide accurate pneumatic control in MR environments to allow assessments of brain activation.