The proportion of tumor-stroma as a strong prognosticator for stage II and III colon cancer patients: validation in the VICTOR trial.

BACKGROUND: The intra-tumor stroma percentage in colon cancer (CC) patients has previously been reported by our group as a strong independent prognostic parameter. Patients with a high stroma percentage within the primary tumor have a poor prognosis. PATIENTS AND METHODS: Tissue samples from the most invasive part of the primary tumor of 710 patients (52% Stage II, 48% Stage III) participating in the VICTOR trial were analyzed for their tumor-stroma percentage. Stroma-high (>50%) and stroma-low (≤50%) groups were evaluated with respect to survival times. RESULTS: Overall and disease-free survival times (OS and DFS) were significantly lower in the stroma-high group (OS P<0.0001, hazard ratio (HR)=1.96; DFS P<0.0001, HR=2.15). The 5-year OS was 69.0% versus 83.4% and DFS 58.6% versus 77.3% for stroma-high versus stroma-low patients. CONCLUSION: This study confirms the intra-tumor stroma ratio as a prognostic factor. This parameter could be a valuable and low cost addition to the TNM status and next to current high-risk parameters such as microsatellite instability status used in routine pathology reporting. When adding the stroma-parameter to the ASCO criteria, the rate of 'undertreated' patients dropped from 5.9% to 4.3%, the 'overtreated' increased with 6.8% but the correctly classified increased with an additional 14%.

TERC polymorphisms are associated both with susceptibility to colorectal cancer and with longer telomeres.

BACKGROUND AND AIMS: Shorter telomeres have been associated with increased risk of malignancy, including colorectal cancer (CRC). Telomere length is heritable and may be an intermediate phenotype linked to genetic susceptibility to CRC. METHODS: In a large sample, the study investigated whether candidate single nucleotide polymorphisms (SNP) in 'telomere biology' genes were associated with telomere length in leucocytes. SNP associated with an increased risk of CRC were searched for separately. RESULTS: Carriers of the common allele at SNP rs10936599, near the telomerase RNA component (TERC) locus, had significantly longer telomeres. It was independently found that the same rs10936599 allele was associated with increased risk of both CRC and colorectal adenomas. Neither telomere length nor CRC risk was associated with variation near telomerase reverse transcriptase or other telomere biology genes. In silico analysis showed that SNP rs2293607 was strongly correlated with rs10936599, mapped within TERC transcripts, had a predicted effect on messenger RNA folding and lay at a reported transcription factor binding site. TERC mRNA were expressed, differing only at the alleles of rs2293607, in CRC cell line HCT116. The long-telomere/CRC-risk allele was associated with higher levels of TERC mRNA and the formation of longer telomeres. CONCLUSIONS: Common genetic variation at TERC is associated with both longer telomeres and an increased risk of CRC, a potential mechanism being reduced levels of cell senescence or death. This finding is somewhat paradoxical, given retrospective studies reporting that CRC cases have shorter telomeres than controls. One possibility is that that association actually results from poorer survival in patients with longer telomeres.

Safety, tolerability, pharmacokinetics and pharmacodynamics of the oral cyclin-dependent kinase inhibitor AZD5438 when administered at intermittent and continuous dosing schedules in patients with advanced solid tumours.

BACKGROUND: AZD5438 is an orally bioavailable inhibitor of cyclin E-cdk2, cyclin A-cdk2 and cyclin B-cdk1 complexes. Three phase I studies assessed the clinical safety, tolerability, pharmacokinetics and pharmacodynamics of AZD5438 when administered in different dosing schedules. PATIENTS AND METHODS: AZD5438 was administered four times daily, once every 7 days (study 1), for 14 consecutive days followed by 7 days of rest (study 2), or continuously (study 3), to patients with advanced solid tumours. Dose escalation proceeded until the emergence of dose-limiting toxic effects. RESULTS: Sixty-four patients were included across the three studies (19, 17 and 28, respectively). Nausea and vomiting were the most common adverse events. When dosed continuously, 40 mg four times daily was considered intolerable, and due to safety issues, all studies were terminated prematurely. Consequently, no intolerable dose was identified during the weekly schedule. Pharmacokinetics demonstrated dose-proportional exposure, high interpatient variability and accumulation after multiple doses. Skin biopsies indicated reduced retinoblastoma protein phosphorylation at cdk2 phospho-sites; other pharmacodynamic assessments did not reveal consistent trends. CONCLUSIONS: AZD5438 was generally well tolerated in a weekly dosing schedule, but not in continuous schedules. The clinical development programme for AZD5438 was discontinued owing to tolerability and exposure data from these studies.

A phase II trial of lomeguatrib and temozolomide in metastatic colorectal cancer.

To evaluate the tumour response to lomeguatrib and temozolomide (TMZ) administered for 5 consecutive days every 4 weeks in patients with metastatic colorectal carcinoma. Patients with stage IV metastatic colorectal carcinoma received lomeguatrib (40 mg) and TMZ (50-200 mg m(-2)) orally for 5 consecutive days every 4 weeks. Response was determined every two cycles. Pharmacokinetics of lomeguatrib and TMZ as well as their pharmacodynamic effects in peripheral blood mononuclear cells (PBMC) were determined. Nineteen patients received 49 cycles of treatments. Despite consistent depletion of O(6)-methylguanine-DNA methyltransferase in PBMC, none of the patients responded to treatment. Three patients had stable disease, one for the duration of the study, and no fall in carcinoembryonic antigen was observed in any patient. Median time to progression was 50 days. The commonest adverse effects were gastrointestinal and haematological and these were comparable to those of TMZ when given alone. This combination of lomeguatrib and TMZ is not efficacious in metastatic colorectal cancer. If further studies are to be performed, emerging data suggest that higher daily doses of lomeguatrib and a dosing period beyond that of TMZ should be evaluated.

A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan.

BACKGROUND: This study determined the optimally tolerated regimen (OTR) of oral lapatinib administered in combination with infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) and assessed the safety, tolerability and pharmacokinetics of the combination. PATIENTS AND METHODS: Twenty-five patients were enrolled; 12 patients were treated at three dose levels to determine OTR; then 13 patients were treated at OTR to evaluate the pharmacokinetics of the combination. RESULTS: The 2-weekly OTR comprised lapatinib 1250 mg/day with irinotecan 108 mg/m(2) (day 1) and leucovorin 200 mg/m(2), 5-FU bolus 240 mg/m(2) and 5-FU infusion 360 mg/m(2) (days 1 and 2); doses of 5-FU and irinotecan represent a 40% reduction in dose compared to conventional FOLFIRI. Dose-limiting toxicities were grade 3 diarrhoea and grade 4 neutropenia. Co-administration of lapatinib increased the area under the plasma concentration-time curve of SN-38, the active metabolite of irinotecan, by an average of 41%; no other pharmacokinetic interactions were observed. Of 19 patients evaluable for disease response assessment, four patients had partial response and nine patients had stable disease. CONCLUSION: The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan. This regime may be further tested in a phase II trial.

Systemic treatment of colorectal cancer.

Palliative and adjuvant treatment for colorectal cancer has been, until recently, largely dependent on 5-fluorouracil (5-FU)-based chemotherapy. Oral fluoropyrimidines have been evaluated in the advanced disease setting and they appear to be as effective as 5-FU, but are safer and more convenient for most patients. Irinotecan and oxaliplatin are new cytotoxic agents, which are active in 5-FU-resistant disease, but which may also be combined with 5-FU as initial therapy in advanced disease. Initial combination therapy leads to improved response rates and more prolonged progression-free survival compared with 5-FU monotherapy. Standard regimens for adjuvant therapy usually involve 6 months of chemotherapy using 5-FU and folinic acid. Recent trials of capecitabine, oxaliplatin and irinotecan in the adjuvant setting are ongoing, or have recently completed accrual, and may lead to a change in future clinical practice. Biological therapies are playing an increasing role in the management of colorectal cancer. Farnesyl transferase inhibition, inhibition of the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) are undergoing evaluation in advanced disease. In the adjuvant setting, both passive and active immunotherapeutic approaches have been studied. In addition, a large trial will evaluate the role of cyclo-oxygenase(COX)-2 inhibitors as adjuvant therapy. Further research is required in order to define the optimal sequence and combination of these different cytotoxic and biological therapies, in order to secure the best possible outcome for various subgroups of patients with both early and advanced stage colorectal cancer.

Conventional cytotoxic and novel therapeutic concepts in colorectal cancer.

Colorectal cancer (CRC) is a major cause of death, particularly in the Western world, leading to 400,000 deaths each year. Of the patients, 30% have advanced disease at presentation, either locally or at distant sites and chemotherapy in this setting has an established role in improving survival and palliating symptoms. In addition, approximately 50% of those patients initially believed to be cured by surgery, subsequently relapse and die of their disease. Adjuvant chemotherapy administered for six months after surgery for Dukes C colon cancer improves absolute survival by 5-10%. However, the role of adjuvant chemotherapy in Dukes B colon or Dukes B/C rectal tumours is still controversial and is only recommended within the scope of a randomised clinical trial. Cytotoxic drug development for colorectal cancer has traditionally followed the established pathway of Phase I, Phase II and then Phase III trials in advanced disease, with subsequent translation into the adjuvant setting. For the purpose of this review current conventional chemotherapy for advanced CRC is described, followed by an explanation of newer developments that are predicated upon our increasing understanding of the molecular processes underpinning malignant transformation, invasion and metastasis. Paradigm shifts in trial design necessitated by a mechanistic approach to drug development are also discussed.

Management of mutilating injuries of the hand.

In the devastating destruction of parts associated with mutilating injuries of the hand, it is often not possible to salvage the elements essential to normal function of the hand. The objective of primary treatment is re-establishment of circulation to the devitalized part, realignment of the remaining skeletal structures, and skin cover of the denuded portions. Definitive reconstruction has to be delayed until survival of the salvaged parts is assured. Occasionally, complex procedures have to be carried out to convert a marginal remnant of the hand into a useful functional unit. These may comprise rearrangement of bony elements to provide a radial digit with intervening space to permit pinch and grasp. Lack of sensibility can be corrected by shifting neurovascular pedicle or by immediate transfer of free neurovascular flap from a distance. Challenge met by skill, tempered by knowledge and sound judgment, comprise the elements of reconstructive hand surgery in the face of mutilating trauma. It is a field in which the surgeon is continually reminded of humility and yet it is filled with rewards for both patient and plastic surgeon.

Observer variability in upper gastrointestinal endoscopy.

An analysis of the observer variation between 4 endoscopists was made assessing the frequency of visual interpretative discrepancies in the areas of the esophagus, stomach and duodenum. The observer variation in relation to the experience of the endoscopist was compared. The trial was carried out in 104 patients. Two observers were staff members with a minimum of 5 years experience in endoscopy. The other two were fellows with one year experience in endoscopy. The procedure was carried out by one endoscopist while the other observed the procedure through the teaching attachment. The findings were immediately recorded on a protocol. Discrepancies observed were classified in two categories: "Major" and "Minor" discrepancies. Results were evaluated in subgroups according to the different endoscopist's training (staff vs fellow, staff vs staff, fellow vs fellow). An analysis of the lesions where discrepancies occurred was made. The minor discrepancies per case was 2.18 +/- 1.32. Major discrepancies were reduced to 1.19 +/- 1.08. There was a significantly decreased incidence of minor and major discrepancies in the comparison of the staff vs staff as opposed to cases performed by fellow vs fellow (p less than 0.01 and p less than 0.005). The diagnoses where discrepancies occurred most often in order of decreasing frequency included. Esophagitis, hiatal hernia, gastritis, gastric ulcer, erosions and duodenal mucosal lesions.

A reappraisal of percutaneous liver biopsy in clinical practice.

The diagnostic yield of 101 consecutive percutaneous liver biopsies was assessed. Adequate tissue was obtained in most specimens. Even in the presence of an adequate specimen, other procedures were often necessary to rule out other diagnostic possibilities not explained nor completely ruled out by percutaneous liver biopsy alone. With the current diagnostic procedures available to the clinician which have low morbidity and low mortality, the use of blind percutaneous liver biopsy as an initial diagnostic step in certain types of liver disease should be reassessed.

A phase I trial of lomeguatrib and irinotecan in metastatic colorectal cancer.

BACKGROUND: Expression of the DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) correlates with resistance to irinotecan in colorectal cancer cell lines. This phase I study evaluated the maximum tolerated dose (MTD) of lomeguatrib, an inactivating pseudosubstrate of MGMT, in combination with irinotecan in patients with metastatic colorectal cancer and assessed the safety, toxicity and clinical pharmacology of combination treatment. PATIENTS AND METHODS: Patients with metastatic colorectal cancer received lomeguatrib (10-80 mg PO) on days 1-5 with irinotecan (250-350 mg/m(2) IV) on day 4 of a 21-day cycle. RESULTS: Twenty-four patients, pre-treated with a median of 2 lines of chemotherapy, received 104 cycles of treatment. The MTD was defined as 80 mg/day lomeguatrib with 300 mg/m(2) irinotecan. The main toxicities observed were neutropaenia and diarrhoea. Lomeguatrib of 80 mg/day produced complete MGMT depletion in all available peripheral blood mononuclear cells (PBMCs) and paired tumour biopsies (one patient). There was no pharmacokinetic interaction between the drugs. In 22 patients assessable for tumour response, one achieved a partial response and 16 had stable disease. CONCLUSION: This study defined a tolerable dose of irinotecan in combination with lomeguatrib in patients with metastatic colorectal cancer. Combination treatment gave a similar response rate to irinotecan monotherapy in this heavily pre-treated patient group.