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Biomedical subjects

David Cunningham

Publications and source records attributed to David Cunningham.

At least 37 records · Page 2Linked to original sources
PubMed2005

Changes in gene expression associated with loss of function of the NSDHL sterol dehydrogenase in mouse embryonic fibroblasts.

Seven human disorders of postsqualene cholesterol biosynthesis have been described. One of these, congenital hemidysplasia with ichthyosiform nevus and limb defects (CHILD) syndrome, results from mutations in the X-linked gene NADH sterol dehydrogenase-like (NSDHL) encoding a sterol dehydrogenase. A series of mutant alleles of the murine Nsdhl gene are carried by bare patches (Bpa) mice, with Bpa(1H) representing a null allele. Heterozygous Bpa(1H) females display skin and skeletal abnormalities in a distribution reflecting random X inactivation, whereas hemizygous male embryos die before embryonic day 10.5. To investigate the molecular basis of defects associated with perturbations in cholesterol biosynthesis, microarray analysis was performed comparing gene expression in embryonic fibroblasts expressing the Bpa(1H) allele versus wild-type (wt) cells. Labeled cDNAs from cells grown in normal serum or lipid-depleted serum (LDS) were hybridized to microarrays containing 22,000 mouse genes. Among 44 genes that showed higher expression in the Bpa(1H) versus wt cells grown in LDS, 11 function in cholesterol biosynthesis, 7 are involved in fatty acid synthesis, 3 (Srebp2, Insig1, and Orf11) encode sterol-regulatory proteins, and 2 (Ldlr and StarD4) are lipid transporters. Of the 21 remaining genes, 16 are known genes, some of which have been implicated previously in cholesterol homeostasis or lipid-mediated signaling, and 5 are uncharacterized cDNA clones.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

Second-line therapy for advanced colorectal carcinoma.

The past decade has witnessed considerable advances in the treatment of colorectal cancer (CRC). The emergence and integration into clinical practice of new cytotoxic agents, such as irinotecan and oxaliplatin, has had a significant impact on outcomes from advanced CRC with median survivals of 18 to 21 months now achievable. Improvements in survival as a consequence of using these drugs as salvage therapies ultimately led to demonstration of efficacy for both in the first-line treatment of CRC. As the importance of second-line therapy is increasingly recognized, key issues, such as optimal schedules, chemotherapy combinations, and sequential therapy, need to be addressed. The integration of newer biologic agents, such as cetuximab and bevacizumab, for which recent data have emerged, has further added to the complexities of delivering therapy to patients with advanced CRC, heralding a new treatment era for this disease.

Antineoplastic Agents↗
PubMed2005

Longitudinal quality of life and quality adjusted survival in a randomised controlled trial comparing six months of bolus fluorouracil/leucovorin vs. twelve weeks of protracted venous infusion fluorouracil as adjuvant chemotherapy for colorectal cancer.

Longitudinal quality of life (QOL) assessment is infrequently made in adjuvant therapy for colorectal cancer (CRC). This analysis aims to assess QOL and quality adjusted survival (QAS) in patients receiving adjuvant 5-FU for stage II and III CRC. We performed a multicentre study in which 801 patients were randomised to 6 months of bolus 5-FU/leucovorin (LV n = 404) or 12 weeks of protracted venous infusion (PVI) 5-FU (n = 397). There were significant differences in the deterioration of QOL scores at week 2 with bolus 5-FU/LV compared to PVI 5-FU (P < 0.001), coinciding with toxicity peak during the first cycle. Following week 12, global QOL recovered to baseline when PVI 5-FU was stopped but this was delayed with bolus 5-FU/LV until completion at week 24. QOL scores significantly improved in both arms during follow-up (P < 0.001) and reached a plateau by year 1 without incremental improvement between years 2 and 5. There was a trend towards better QAS with PVI 5-FU. Twelve weeks of adjuvant PVI 5-FU was associated with significantly better QOL during treatment and faster time to recovery compared to 6 months of bolus 5-FU/LV.

Adult↗
PubMed2005

The frequency and pattern of cardiotoxicity observed with capecitabine used in conjunction with oxaliplatin in patients treated for advanced colorectal cancer (CRC).

We examined the cardiotoxicity in 153 patients treated with capecitabine and oxaliplatin in two prospective trials for advanced colorectal cancer. Ten patients (6.5%) developed cardiac events. One patient (0.7%) had sudden death, one patient developed cardiac failure with raised troponin I while another developed ventricular tachycardia (VT). The remaining seven patients (4.6%) experienced angina and three of the seven patients had raised troponin I, one of which developed ventricular fibrillation. Eight events occurred within cycle 1 (median cycle 1 day 10). Four patients with angina and one patient with VT recovered on stopping capecitabine, four patients required additional medical management and the remaining patient died suddenly at home. Patients with ischaemic heart disease appeared to be at increased risk. Physicians and patients need to be aware of these complications, so that prompt discontinuation of treatment and appropriate interventions may be instituted.

Adult↗
PubMed2005

Placental defects are associated with male lethality in bare patches and striated embryos deficient in the NAD(P)H Steroid Dehydrogenase-like (NSDHL) Enzyme.

NSDHL is a 3beta-hydroxysterol dehydrogenase that is involved in the removal of C-4 methyl groups in one of the later steps of cholesterol biosynthesis. Mutations in the Nsdhl gene are associated with the X-linked male lethal mouse mutations bare patches (Bpa) and striated (Str), as well as with most cases of human CHILD syndrome. To begin to examine the pathogenesis of these disorders, we have determined that affected male embryos for several Nsdhl alleles die in midgestation, between E10.5 and 13.5, while the majority of affected male embryos for the most severe allele, Nsdhl(Bpa1H), die prior to E9.5. Although no consistent anomalies were identified in affected male embryos themselves, the labyrinth layer of the fetal placenta was always thinner, with fewer fetal vessels and decreased proliferation of labyrinth trophoblast cells. X-inactivation is non-random in females in most lineages of the rodent placenta with preferential inactivation of the paternal X chromosome. For primary defects involving these extraembryonic lineages, heterozygous females with a mutant maternal X chromosome would be expected to have an identical placental phenotype to that found in affected male embryos. We hypothesize that abnormalities in cells of the allantoic mesoderm that undergo random X-inactivation and form the endothelial lining of the fetal vessels of the labyrinth are associated with the male lethality, perhaps through disruption of an as yet unidentified signaling pathway.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

The role of cetuximab in the therapy of previously treated advanced colorectal cancer.

Much remains to be learned about the best ways to integrate molecular-targeted therapies into the chemotherapeutic armamentarium. The epidermal growth factor receptor inhibitor cetuximab has been extensively evaluated in patients with chemotherapy-resistant metastatic colorectal cancer. In patients with irinotecan-refractory or irinotecan/oxaliplatin-refractory disease, single-agent cetuximab has produced a partial response in 9% to 11.6% of patients and stable disease in 21.6% to 36.8%. In irinotecan-resistant disease, the combination of cetuximab and irinotecan has resulted in partial responses in 17% to 22.9% of patients and stable disease in 31% to 32.6%. The degree of epidermal growth factor receptor expression has not been predictive of treatment response; severity of a characteristic acneiform rash does appear to be predictive of response. Ongoing trials in colorectal cancer are examining the combination of cetuximab and bevacizumab with or without irinotecan in irinotecan-refractory disease, irinotecan with or without cetuximab in oxaliplatin-refractory disease, and FOLFOX4 with or without cetuximab in patients receiving first-line irinotecan treatment.

Adenocarcinoma↗
PubMed2005

Cetuximab in previously treated colorectal cancer.

Within the past decade, there have been considerable advances in the first- and second-line treatment of colorectal cancer (CRC). For many years, 5-fluorouracil was the only therapeutic option for the first-line treatment of CRC, and virtually no effective salvage therapies were available. However, the advent of oxaliplatin and irinotecan has improved outcomes for advanced CRC, providing increased therapeutic choice in the first-line setting and effective salvage therapies. Many patients are now receiving multiple lines of therapy, and it is in the setting of previously treated CRC that cetuximab, a monoclonal antibody to the epidermal growth factor receptor, has been successfully developed based on sound scientific principles. The ability to integrate new biologic therapies with conventional cytotoxic agents marks a new treatment era for this disease. This review discusses the development of cetuximab in pretreated CRC to date and future directions with this novel therapy.

Antibodies, Monoclonal↗
PubMed2005

Recent data with anti-epidermal growth factor receptor antibodies and irinotecan in colon cancer.

The epidermal growth factor receptor (EGFR) is overexpressed in the majority of colorectal cancers. It is the target for a class of agents at the forefront of development for the treatment of colorectal cancer, ie, the anti-EGFR monoclonal antibodies, which include cetuximab, panitumumab, and matuzumab. At present, cetuximab is the furthest along in terms of established efficacy in the treatment of metastatic or inoperable disease and is licensed for the treatment of patients with irinotecan-refractory colorectal cancer. This article reviews the recent evidence supporting the combination of these anti-EGFR agents with the cytotoxic chemotherapeutic agent irinotecan.

Antibodies, Monoclonal↗
PubMed2004

CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma.

The combination of cyclophosphamide, vincristine, and prednisone (CVP) is one of several standard treatment options for advanced follicular lymphoma. This, like similar chemotherapeutic regimens, induces response rates of 60% to 80%, with a median response duration of under 2 years. Rituximab, a chimeric monoclonal antibody against CD20, is active in follicular lymphoma, both as monotherapy and in combination with chemotherapy. Previously untreated patients with stages III to IV follicular lymphoma were randomly assigned to receive either 8 cycles of CVP plus rituximab (R-CVP; n = 162) or CVP (n = 159). Overall and complete response rates were 81% and 41% in the R-CVP arm versus 57% and 10% in the CVP arm, respectively (P < .0001). At a median follow-up of 30 months, patients treated with R-CVP had a very significantly prolonged time to progression (median 32 months versus 15 months for CVP; P < .0001). Median time to treatment failure was 27 months in patients receiving R-CVP and 7 months in the CVP arm (P < .0001). Rituximab did not add significantly to the toxicity of CVP. The addition of rituximab to the CVP regimen significantly improves the clinical outcome in patients with previously untreated advanced follicular lymphoma, without increased toxicity.

Adult↗
PubMed2004

A randomized trial comparing defined-duration with continuous irinotecan until disease progression in fluoropyrimidine and thymidylate synthase inhibitor-resistant advanced colorectal cancer.

PURPOSE: Irinotecan given until disease progression is an accepted standard treatment for advanced colorectal cancer (CRC) resistant to fluoropyrimidines. It is not known whether a predefined period of irinotecan treatment would result in similar duration of disease control. We performed a multicenter phase III trial to compare the two policies of defined-duration versus continuous irinotecan treatment. PATIENTS AND METHODS: Three hundred thirty-three eligible patients with advanced CRC progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospectively registered. After receiving eight cycles of irinotecan given at 350 mg/m2 once every 3 weeks, 55 patients with responding or stable disease were randomly assigned to stop irinotecan (n = 30) or continue until disease progression (n = 25). Registered patients were not randomly assigned predominantly due to disease progression (n = 236) and intolerable toxicity (n = 38). RESULTS: From the time of random assignment, there were no differences in failure-free survival (P = .999) or overall survival (P = .11) between the two arms. No difference was seen in mean global health status quality-of-life score between the two arms at 12 weeks after random assignment. No grade 3 diarrhea and febrile neutropenia was seen in the continue-irinotecan arm after random assignment. CONCLUSION: For most patients, the decision to continue on irinotecan beyond 24 weeks is influenced by disease progression or treatment-related toxicity. However, for 17% of patients in whom this decision is clinically relevant, there seems to be little benefit from continuing irinotecan, though the drug was well tolerated without any deterioration in quality of life.

Adult↗
PubMed2004

Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.

BACKGROUND: The epidermal growth factor receptor (EGFR), which participates in signaling pathways that are deregulated in cancer cells, commonly appears on colorectal-cancer cells. Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We compared the efficacy of cetuximab in combination with irinotecan with that of cetuximab alone in metastatic colorectal cancer that was refractory to treatment with irinotecan. METHODS: We randomly assigned 329 patients whose disease had progressed during or within three months after treatment with an irinotecan-based regimen to receive either cetuximab and irinotecan (at the same dose and schedule as in a prestudy regimen [218 patients]) or cetuximab monotherapy (111 patients). In cases of disease progression, the addition of irinotecan to cetuximab monotherapy was permitted. The patients were evaluated radiologically for tumor response and were also evaluated for the time to tumor progression, survival, and side effects of treatment. RESULTS: The rate of response in the combination-therapy group was significantly higher than that in the monotherapy group (22.9 percent [95 percent confidence interval, 17.5 to 29.1 percent] vs. 10.8 percent [95 percent confidence interval, 5.7 to 18.1 percent], P=0.007). The median time to progression was significantly greater in the combination-therapy group (4.1 vs. 1.5 months, P<0.001 by the log-rank test). The median survival time was 8.6 months in the combination-therapy group and 6.9 months in the monotherapy group (P=0.48). Toxic effects were more frequent in the combination-therapy group, but their severity and incidence were similar to those that would be expected with irinotecan alone. CONCLUSIONS: Cetuximab has clinically significant activity when given alone or in combination with irinotecan in patients with irinotecan-refractory colorectal cancer.

Adenocarcinoma↗
PubMed2004

Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer--pooled analysis from three multicenter, randomized, controlled trials using individual patient data.

PURPOSE: To identify baseline prognostic factors and assess whether pretreatment quality of life (QoL) predicts survival in patients with locally advanced or metastatic esophago-gastric cancer. PATIENTS AND METHODS: Between 1992 and 2001, 1,080 patients were enrolled into three randomized, controlled trials assessing fluorouracil-based combination chemotherapy. All patients were required to complete the European Organization for Research and Treatment of Cancer core QoL questionnaire before random assignment. RESULTS: Of the 1080 patients randomly assigned, 979 (91%) died. Four independent poor prognostic factors were identified by multivariate analysis: performance status >or= 2 (hazard ratio [HR], 1.58; 99% CI, 1.25 to 1.98), liver metastases (HR, 1.41; 99%CI, 1.14 to 1.74), peritoneal metastases (HR, 1.33; 99%CI, 1.01 to 1.74) and alkaline phosphatase >or= 100 U/L (HR, 1.41; 99% CI, 1.14 to 1.76). A prognostic index was constructed dividing patients into good (no risk factor), moderate (one or two risk factors) or poor (three or four risk factors) risk groups. One-year survival for good, moderate, and poor risk groups were 48.5%, 25.7%, and 11%, respectively, and the survival differences among these groups were highly significant (P <.00001). Compared with the good risk group, the moderate risk group had nearly twice the risk of death, and the poor risk group had 3.5-fold increased risk of death. Pretreatment physical (P =.003), role functioning (P <.001), and global QoL (P <.001) predicted survival. CONCLUSION: Four poor prognostic factors were identified and a simple prognostic index was devised. Information from this analysis can be used to aid clinical decision-making, help individual patient risk stratification, and serve as benchmark for the planning for future phase III trials.

Adult↗
PubMed2004

Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses.

We have assessed autologous stem cell transplantation after treatment with fludarabine in previously untreated patients with chronic lymphocytic leukemia (CLL). This study is the first to enroll previously untreated patients and follow them prospectively. The initial response rate to fludarabine was 82% (94 of 115 patients). Stem cell mobilization was attempted in 88 patients and was successful in 59 (67%). Overall 65 of 115 patients (56%) entered into the study proceeded to autologous transplantation. The early transplant-related mortality rate was 1.5% (1 of 65 patients). The number of patients in complete remission after transplantation increased from 37% (24 of 65) to 74% (48 of 65), and 26 of 41 patients (63%) who were not in complete remission at the time of their transplantation achieved a complete remission after transplantation. The 5-year overall and disease-free survival rates from transplantation were 77.5% (CI, 57.2%-97.8%) and 51.5% (CI, 33.2%-69.8%), respectively. None of the variables examined at study entry were found to be predictors of either overall or disease-free survival. Sixteen of 20 evaluable patients achieved a molecular remission on a polymerase chain reaction (PCR) for immunoglobulin heavy-chain gene rearrangements in the first 6 months following transplantation. Detectable molecular disease by PCR was highly predictive of disease recurrence. It is of concern that 5 of 65 (8%) patients developed posttransplant acute myeloid leukemia/myelodysplastic syndrome.

Adult↗
PubMed2004

The value of routine serum carcino-embryonic antigen measurement and computed tomography in the surveillance of patients after adjuvant chemotherapy for colorectal cancer.

PURPOSE: This analysis aims to evaluate routine carcino-embryonic antigen (CEA) and computed tomography (CT) of thorax, abdomen, and pelvis as part of protocol-specified follow-up policy for colorectal cancer (CRC). PATIENTS AND METHODS: Patients with resected stage II and III CRC were randomly assigned to bolus fluorouracil/leucovorin or protracted venous infusion fluorouracil. Following completion of chemotherapy, patients were seen in clinic at regular intervals for 5 years. CEA was measured at each clinic visit, and CT of thorax, abdomen, and pelvis was performed at 12 and 24 months after commencement of chemotherapy. RESULTS: Between 1993 and 1999, 530 patients were recruited. The median follow-up was 5.6 years. Disease relapses were observed in 154 patients. Relapses were detected by symptoms (n = 65), CEA (n = 45), CT (n = 49), and others (n = 9). Fourteen patients, whose relapses were detected by CT, had a concomitant elevation of CEA and were included in both groups. The CT-detected group had a better survival compared with the symptomatic group from the time of relapse (P =.0046). Thirty-three patients (21%) proceeded to potentially curative surgery for relapse and enjoyed a better survival than those who did not (P <.00001). For patients who underwent hepatic or pulmonary metastatic resection, 13 (26.5%) were in the CT group, eight (17.8%) in the CEA group, and only two (3.1%) in the symptomatic group (CT v symptomatic, P <.001; CEA v symptomatic, P =.015). CONCLUSION: Surveillance CT and CEA are valuable components of postoperative follow-up in stage II and III colorectal cancer.

Adult↗