Phase II Trial of Erlotinib and Capecitabine for Patients with Previously Untreated Metastatic Colorectal Cancer

BackgroundThis Simon 2-stage phase II trial was designed to document antitumor activity of capecitabine in combination with erlotinib in patients with previously untreated metastatic colorectal cancer (CRC).Patients and MethodsTime to tumor progression, objective response rate, and time to treatment failure were to be assessed. Secondary objectives included determination of toxicity. This trial was closed prematurely because of slower-than-expected accrual. Thirteen patients were enrolled, and all are off protocol treatment at the time of this report.ResultsNotably, 4 subjects discontinued therapy because of adverse events. Of 10 evaluable patients, 1 attained a complete response, 1 attained a partial response, 3 had stable disease, and 5 had progressive disease. Median time to disease progression was 21 weeks, with a range of 8–85 weeks. Overall survival ranged from 12 weeks to 182 weeks, with a median of 76 weeks.ConclusionThe toxicities and challenge to complete accrual observed in this trial are consistent with the experience of others attempting to develop erlotinib as part of combination treatment for advanced CRC.     

Phase II study of rituximab in combination with chop chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma.

PURPOSE: To determine the safety and efficacy of the combination of the chimeric anti-CD20 antibody Rituxan (rituximab, IDEC-C2B8; Genentech Inc, South San Francisco, CA) and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in patients with aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Thirty-three patients with previously untreated advanced aggressive B-cell NHL received six infusions of Rituxan (375 mg/m2 per dose) on day 1 of each cycle in combination with six doses of CHOP chemotherapy given on day 3 of each cycle. RESULTS: The ORR by investigator assessment confirmed by the sponsor was 94% (31 of 33 patients). Twenty patients experienced a complete response (CR) (61%), 11 patients had a partial response (PR) (33%), and two patients were classified as having progressive disease. In the 18 patients with an International Prognostic Index (IPI) score > or = 2, the combination of Rituxan plus CHOP achieved an ORR of 89% and CR of 56%. The median duration of response and time to progression had not been reached after a median observation time of 26 months. Twenty-nine of 31 responding patients remained in remission during this follow-up period, including 15 of 16 patients with an IPI score > or = 2. The most frequent adverse events attributed to Rituxan were fever and chills, primarily during the first infusion. Rituxan did not seem to compromise the ability of patients to tolerate CHOP; all patients completed the entire six courses of the combination. The bcl-2 translocation of blood or bone marrow was positive at baseline in 13 patients; 11 patients had follow-up specimens obtained (eight CR, three PR), and all had a negative bcl-2 status after therapy. Only one patient has reconverted to bcl-2 positivity, and all patients remain in clinical remission. CONCLUSION: This is the first report to demonstrate the safety and efficacy of the Rituxan chimeric anti-CD20 antibody in combination with standard-dose CHOP in the treatment of aggressive B-cell lymphoma. The clinical responses are at least comparable to those achieved with CHOP alone with no significant added toxicity. The presence or absence of the bcl-2 translocation did not affect the ability of patients to achieve a CR with this regimen. The ability to achieve sustained remissions in patients with an IPI score > or = 2 warrants further investigation with a randomized study.     

Treatment of leg ulcers with an allogeneic cultured-keratinocyte-collagen dressing

A living cellular allogeneic dressing made up of cultured keratinocytes adhering to a collagen film was used to treat 20 leg ulcers of various aetiologies in 16 patients. A reduction in pain was noted in 80% of cases, and promotion of granulation tissue in the ulcer bed in 70% of cases. In 10 patients, epithelialization of 71 +/- 29% of the ulcer was noted at Day 30.     

Total radical trapping antioxidant potential (TRAP) and exercise

The relationship between physical activity, physical fitness and total radical trapping antioxidant potential (TRAP) was examined in the Northern Ireland Health and Activity Survey. This was a cross-sectional population study (n = 1600) using a two-stage probability sample of the population. TRAP was calculated using the sum of the individual serum antioxidant concentrations (urate, protein thiols, ascorbate, alpha tocopherol and bilirubin) multiplied by their respective stoichiometric values. Physical fitness was determined by estimation of VO2max by extrapolation from submaximal oxygen uptake, and physical activity was recorded by computer-assisted interview. Mean serum TRAP concentrations were significantly higher in males (653 +/- 8.2 mumol/l, mean +/- SEM) compared to females (564 +/- 8.0 mumol/l) (p < 0.0001). Both male and female smokers had significantly lower TRAP values than non-smokers (males p < 0.0001, females p = 0.02). In females, there was a positive relationship of TRAP with age (p < 0.001) and body mass index (p < 0.001) but a negative relationship with physical fitness (p < 0.05). The known beneficial effects of exercise and activity do not appear to be directly mediated through increased antioxidant status.      

Platelet membrane glycoprotein changes during the preparation and storage of platelet concentrates

Previous studies of platelet membrane glycoproteins during blood bank storage have reported conflicting results. This study assessed two major plasma membrane glycoproteins (GP Ib and GP IIb), an alpha-granule membrane protein (GMP-140), and the concentration of platelet membrane microparticles in cell-free plasma during routine hospital blood bank platelet storage. 125I-monoclonal antibody binding was used to measure membrane glycoproteins on the surface of intact platelets and to measure the concentration of membrane microparticles in cell-free plasma. Platelet concentrates were stored at room temperature in polyolefin bags for 7 days. In this blood bank, two types of rotators are routinely used for platelet concentrate storage: a 2-rpm circular tumbler rotator and a 6-rpm elliptical rotator. Different results were obtained with the rotators. With the tumbler rotator, there was no loss of platelets and antibody binding to GP Ib remained normal. With the elliptical rotator, one third of platelets were lost into clumps during storage, and a 50 percent decrease of antibody binding to GP Ib occurred in the remaining single platelets. There was no loss of antibody binding to GP IIb with either rotator. Antibody binding to GMP-140 increased equally in both rotators indicating that the remaining single platelets had secreted about 16 percent of their alpha-granule contents. The plasma concentration of platelet membrane microparticles was greater in the bags stored in the elliptical rotator. These results indicate that it is possible to maintain the normal concentration of platelet membrane glycoproteins Ib and IIb during 7 days of room-temperature blood bank storage.(ABSTRACT TRUNCATED AT 250 WORDS)     

A human monoclonal macroglobulin with specificity for alpha(2----8)- linked poly-N-acetyl neuraminic acid, the capsular polysaccharide of group B meningococci and Escherichia coli K1, which crossreacts with polynucleotides and with denatured DNA

We have described an IgM antibody from a patient with macroglobulinemia specifically reacting with poly-alpha(2----8)N-acetyl neuraminic acid (NeuNAc) the capsular polysaccharide of two important human pathogens, group B meningococcus and E. coli K1. This antibody has a narrowly defined specificity in its interactions with polysaccharides, being unable to bind poly-alpha(2----9)NeuNAc or alternating poly-alpha(2----8)alpha(2----9)NeuNAc. However, it shows interesting crossreactivity with seemingly unrelated polynucleotides and denatured DNA, supporting the hypothesis that charged groups with a given spacing may determine the specificity of antigen-antibody interactions on otherwise dissimilar molecular structures. Despite the crossreactivity with denatured DNA and polynucleotides, the antibody does not appear to have adverse effects in the patient. The antibody protects newborn rats against E. coli K1 infection, as well as the standard horse antiserum H46, and one would expect it to prove useful in humans as an adjunct to antibiotic therapy in infections with group B meningococcus and E. coli K1. We have attempted to clone the antibody-producing cells from peripheral blood, and have shown that the relevant cells are present and can be cultured.     

In Vivo Feedback Predicts Parent Behavior Change in the Attachment and Biobehavioral Catch-up Intervention

Understanding mechanisms and active ingredients of intervention is critical to training clinicians, particularly when interventions are transported from laboratories to communities. One promising active ingredient of parenting programs is clinicians’ in vivo feedback regarding parent–child interactions. The present study examined whether a form of in vivo feedback, in the moment commenting, predicted treatment retention and parent behavior change when the Attachment and Biobehavioral Catch-up (ABC) intervention was implemented in a community setting. Observational data were collected from 78 parent–child dyads (96% mothers; M age = 29 years; 81% minority; infants’ M age = 12 months; 90% minority) across 640 sessions conducted by 9 clinicians (100% female, M age = 39; 67% minority) in Hawaii. Parental behavior was assessed with a semistructured play task before and after intervention. Clinicians’ in-the-moment feedback to parents was assessed from intervention session videos. Clinicians’ frequency and quality of in-the-moment feedback predicted change in parental intrusiveness and sensitivity at posttreatment. Frequency of in-the-moment feedback also predicted likelihood of retention. Hierarchical linear modeling demonstrated strong support for these associations at the between-clinician level, and limited additional support at the within-clinician (i.e., between-case) level. Thus, a hypothesized active ingredient of treatment, in-the-moment feedback, predicted community-based ABC outcomes. The results complement lab-based evidence to suggest that in vivo feedback may be a mechanism of change in parenting interventions. Helping clinicians to provide frequent, high-quality in vivo feedback may improve parenting program outcomes in community settings.     

Mouse A6-positive hepatic oval cells also express several hematopoietic stem cell markers

Hepatic oval cells (HOC) are thought to be a type of facultative stem cell that arises as a result of certain forms of hepatic injury. A new and more efficient model has been established to activate the oval cell compartment in mice by incorporating 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC) in a standard chow at a concentration of 0.1%. At the present time, very few markers exist for the mouse oval cells. One accepted marker is A6, an uncharacterized epitope recognized by mouse hepatic oval cells and it is accepted to be an oval cell marker. Sca-1 is a cell surface marker used to identify hematopoietic stem cells in conjunction with Thy-1+, CD34+, and lineage-specific markers. Both the CD34 and Sca-1 antigens are not normally expressed in adult liver, but are expressed in fetal liver, presumably on the hematopoietic cells. We report herein that mouse oval cells express high levels of Sca-1 and CD34, as well as CD45 surface proteins. Immunohistochemistry revealed that the cells expressing Sca-1/CD34/CD45 were indeed oval cells because they co-expressed the oval cell-specific marker A6 (94.57% +/- 0.033%), as well as alpha-fetoprotein (AFP) (75.92% +/- 0.071%). By using Sca-1 antibody in conjunction with magnetic activated cell sorting (MACS), followed with a flow cytometric cell sorting (FACS) method for CD34 and CD45, we have developed a rapid oval cell isolation protocol with high yields of greater than 90%. In conclusion, we have an efficient murine model for the production and isolation of large numbers of highly purified oval cells. Our system works with most strains of mouse, which will facilitate both in vivo and in vitro studies of mouse hepatic oval cells.