Andrew Haydon

Investigation of the Safety of Irreversible Electroporation in Humans

PURPOSE A single-center prospective nonrandomized cohort study was performed to investigate the safety of irreversible electroporation (IRE) for tumor ablation in humans. MATERIALS AND METHODS Thirty-eight volunteers with advanced malignancy of the liver, kidney, or lung (69 separate tumors) unresponsive to alternative treatment were subjected to IRE under general anesthesia. Clinical examination, biochemistry, and computed tomography (CT) scans of the treated organ were performed before, immediately after, and at 1 month and 3 months after the procedure. RESULTS No mortalities occurred at 30 days. Transient ventricular arrhythmia occurred in four patients, and electrocardiographically (ECG) synchronized delivery was used subsequently in the remaining 30 patients, with two further arrhythmias (supraventricular tachycardia and atrial fibrillation). One patient developed obstruction of the upper ureter after IRE. One adrenal gland was unintentionally directly electroporated, which produced transient severe hypertension. There was no other evidence of adjacent organ damage related to the electroporation. Other adverse events were not directly related to IRE, but two patients developed temporary neurapraxia as a result of arm extension during a prolonged period of anesthesia. Although not a primary aim of this preliminary study, complete target tumor ablation verified by CT was achieved in 46 of the 69 tumors treated with IRE (66%). Most treatment failures occurred in renal and lung tumors. Biopsy in three patients showed coagulative necrosis in the regions treated by IRE. CONCLUSIONS IRE appears to be safe for human clinical use provided ECG-synchronized delivery is used. Comparative evaluation with alternative ablative technologies is warranted.

Effect of physical activity and body size on survival after diagnosis with colorectal cancer

Background: Physical inactivity and obesity increase the risk of colorectal cancer but little is known about whether they influence prognosis after diagnosis. Methods: Incident cases of colorectal cancer were identified among participants of the Melbourne Collaborative Cohort Study, a prospective cohort study of 41 528 Australians recruited from 1990 to 1994. Participants diagnosed with their first colorectal cancer between recruitment and 1 August 2002 were eligible. At the time of study entry, body measurements were taken and participants were interviewed about their physical activity. Information on tumour site and stage, treatments given, recurrences, and deaths were obtained from systematic review of the medical records. Results: A total of 526 cases of colorectal cancer were identified. Median follow up among survivors was 5.5 years, and 208 deaths had occurred, including 181 from colorectal cancer. After adjusting for age, sex, and tumour stage, exercisers had an improved disease specific survival (hazard ratio 0.73 (95% confidence interval (CI) 0.54–1.00)). The benefit of exercise was largely confined to stage II–III tumours (hazard ratio 0.49 (95% CI 0.30–0.79)). Increasing per cent body fat resulted in an increase in disease specific deaths (hazard ratio 1.33 per 10 kg (95% CI 1.04–1.71)). Similarly, increasing waist circumference reduced disease specific survival (hazard ratio 1.20 per 10 cm (95% CI 1.05–1.37)). Conclusions: Increased central adiposity and a lack of regular physical activity prior to the diagnosis of colorectal cancer is associated with poorer overall and disease specific survival.

Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer

Detection of circulating tumor DNA in patients with resected stage II colon cancer provides evidence of residual disease. Footprints of persistent cancer Stage II colon cancer, which has spread through the wall of the colon but has not metastasized to the lymph nodes, can present a therapeutic dilemma. On one hand, these tumors can usually be completely removed by surgery, and the majority does not recur even without chemotherapy. On the other hand, it is difficult to determine which of these tumors will recur and to identify patients who would benefit from adjuvant chemotherapy after surgery. Tie et al. show that the presence of circulating tumor DNA in a patient’s blood after surgery is a sign of persistent tumor and a greatly increased risk of relapse, suggesting that this group of patients may require chemotherapy to prevent recurrence. Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing–based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

Emerging pathways in colorectal-cancer development

The past decade has seen the emergence of new pathways in the development of colorectal cancer. There is now clear evidence that subsets of these tumours do not show chromosomal instability and do not follow the suppressor pathway. Instead, about 15% of colorectal cancers are characterised by microsatellite instability (MSI). This feature arises through defective DNA mismatch repair, which is related either to a germline mutation (as in hereditary non-polyposis colorectal carcinoma) or to failure to express a mismatch-repair gene. CpG-island methylation has been linked to sporadic cancers with a high frequency of MSI. This type of methylation leads to loss of gene expression when it occurs in the promoter region of a gene. Tumours may have high or low type C (cancer-related) CpG-island methylation. When methylation affects hMLH1 (mismatch repair gene), the resultant cancer has high MSI.

Randomized Trial of the Combination of Lomeguatrib and Temozolomide Compared With Temozolomide Alone in Chemotherapy Naive Patients With Metastatic Cutaneous Melanoma

PURPOSE To evaluate tumor response, pharmacodynamic effects, and safety of a combination of lomeguatrib (LM), an O6-methylguanine DNA-methyltransferase (MGMT) inactivator, and temozolomide (TMZ), TMZ alone, and LM/TMZ after disease progression on TMZ alone in patients with advanced melanoma. PATIENTS AND METHODS Patients with unresectable stage III or IV cutaneous melanoma who had no prior systemic chemotherapy were randomly assigned to receive either 40 to 80 mg LM and 125 mg/m2 TMZ or 200 mg/m2 TMZ on days 1 through 5 of each 28-day treatment cycle. Drugs were administered orally for up to six cycles of treatment. Patients on TMZ alone were offered LM/TMZ at progression, if fit enough to receive treatment. RESULTS One hundred four patients were enrolled, with 52 in each trial arm. Twenty-seven TMZ-treated patients received LM/TMZ after progression on TMZ. Unexpectedly, analysis of tumor biopsies showed rapid recovery of MGMT after LM/TMZ with 40 mg/d LM. Therefore, doses of LM were escalated to 60 then 80 mg/d. Tumor response rates were 13.5% with LM/TMZ and 17.3% with TMZ alone. No patient responded to LM/TMZ having progressed through TMZ. Median time to disease progression was 65.5 days for LM/TMZ and 68 days for TMZ. All treatments were well tolerated, although hematologic and gastrointestinal adverse events were common. A higher incidence of hematological adverse events was observed in the LM/TMZ combination arm. CONCLUSION The efficacy of LM and TMZ in the current dosing schedule is similar to that of TMZ alone. To maintain MGMT depletion in tumor dosing of LM needs to be continued beyond that of TMZ.

Ethnicity and risk for colorectal cancers showing somatic BRAF V600E mutation or CpG island methylator phenotype

Colorectal cancers arising from serrated polyps are characterized by the CpG island methylator phenotype (CIMP) and somatic mutation (V600E) in the BRAF proto-oncogene. Few epidemiologic studies have investigated risk factors for these tumors. We conducted a cohort study of 41,328 residents of Melbourne, Australia that included 9,939 participants of southern European origin and 31,389 of Anglo-Celtic origin. Colorectal adenocarcinomas were identified from population-based cancer registries. BRAF V600E mutation in tumors was determined using a PCR-based allelic discrimination method. Tumors were classified as CIMP positive when at least three of five markers (RUNX3, CACNA1G, SOCS1, NEUROG1, and IGF2) were methylated according to MethyLight analysis. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox regression with adjustment for risk factors for colorectal cancer. During follow-up, 718 participants were diagnosed with colorectal cancer. CIMP assays were done for 579 and BRAF V600E mutation testing for 582. After adjustment for other risk factors, when compared with people of Anglo-Celtic origin, those of southern European origin had lower incidence of colorectal cancer that had CIMP (HR, 0.32; 95% CI, 0.16-0.67) or BRAF mutations (HR, 0.30; 95% CI, 0.16-0.58) but similar incidence of colorectal cancer without CIMP (HR, 0.86; 95% CI, 0.70-1.05) or BRAF (HR, 0.90; 95% CI, 0.74-1.11). People of southern European origin had lower risk of colorectal cancers with CIMP and BRAF mutation than people of Anglo-Celtic origin, which may in part be due to genetic factors that are less common in people of southern European origin. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1774–80)

Body size and composition and colon cancer risk in women.

Studies of colon cancer risk in males have reported strong positive associations with obesity, particularly with central adiposity. The association has been weaker and less consistent for women. In a prospective cohort study of women, body measurements were taken directly; fat mass and fat‐free mass being estimated by bioelectrical impedance analysis and central adiposity by waist circumference and waist‐to‐hip ratio (WHR). Among 24,072 women followed on average for 10.4 years, 212 colon cancers were ascertained via the population cancer registry. We reviewed medical records of all cases and classified them according to anatomic site and stage. The central adiposity measures of WHR (hazard ratio per 0.1 unit increase = 1.31, 95% confidence interval (CI) 1.08–1.58) and waist circumference (hazard ratio per 10 cm increase = 1.14, 95% CI 1.02–1.28) were positively associated with colon cancer risk. There was little or no association between other anthropometric measures and risk of colon cancer. There was some evidence that the associations were stronger for proximal tumors, but no evidence that risk differed by stage for any of the anthropometric measures. Central adiposity appears to be associated with colon cancer risk in women.

Physical activity, insulin-like growth factor 1, insulin-like growth factor binding protein 3, and survival from colorectal cancer

Background: Recent reports have shown that physical activity improves the outcome of patients with colorectal cancer as well as breast and prostate cancer. However, the mechanisms whereby physical activity reduces cancer mortality are not well established. Methods: Incident cases of colorectal cancer were identified among participants of the Melbourne Collaborative Cohort Study, a prospective cohort study of 41 528 Australians recruited from 1990 to 1994. Information on tumour site and stage, treatments given, recurrences, and deaths were obtained from systematic review of the medical records. Baseline assessments of physical activity and body size were made, and cases with available plasma had pre-diagnosis insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) levels measured. We assessed associations between these hormones and colorectal cancer specific deaths with respect to physical activity. Results: A total of 526 cases of colorectal cancer were identified, of which 443 had IGF-1/IGFBP-3 levels measured. Median follow up among survivors was 5.6 years. For the physically active, increasing IGFBP-3 by 26.2 nmol/l was associated with a 48% reduction in colorectal cancer specific deaths (adjusted hazard ratio (HR) 0.52 (0.33–0.83); p = 0.006). No association was seen for IGF-1 (adjusted HR 0.90 (0.55–1.45); p = 0.65). For the physically inactive, neither IGF-1 nor IGFBP-3 was associated with disease specific survival. Conclusions: This study supports the hypothesis that the beneficial effects of physical activity in reducing colorectal cancer mortality may occur through interactions with the insulin-like growth factor axis and in particular IGFBP-3.

Phase III Randomized, Placebo-Controlled Study of Cetuximab Plus Brivanib Alaninate Versus Cetuximab Plus Placebo in Patients With Metastatic, Chemotherapy-Refractory, Wild-Type K-RAS Colorectal Carcinoma: The NCIC Clinical Trials Group and AGITG CO.20 Trial

PURPOSE The antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer. The addition of brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity. PATIENTS AND METHODS Patients with metastatic colorectal cancer previously treated with combination chemotherapy were randomly assigned 1:1 to receive cetuximab 400 mg/m(2) intravenous loading dose followed by weekly maintenance of 250 mg/m(2) plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). The primary end point was overall survival (OS). RESULTS A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .12). Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). Partial responses observed (13.6% v 7.2%; P = .004) were higher in arm A. Incidence of any grade ≥ 3 adverse events was 78% in arm A and 53% in arm B. Fewer patients received ≥ 90% dose-intensity of both cetuximab (57% v 83%) and brivanib/placebo (48% v 87%) in arm A versus arm B, respectively. CONCLUSION Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.

Expression of MUC2, MUC5AC, MUC5B, and MUC6 mucins in colorectal cancers and their association with the CpG island methylator phenotype.

Mucinous differentiation is associated with both CpG island methylator phenotype and microsatellite instability in colorectal cancer. The mucinous phenotype derives from abundant expression of the colonic goblet cell mucin, MUC2, and de novo expression of gastric foveolar mucin, MUC5AC. We, therefore, investigated the protein expression levels of MUC2 and MUC5AC, as well as MUC5B and MUC6, in molecular subtypes of colorectal cancer. Seven-hundred and twenty-two incident colorectal carcinomas occurring in 702 participants of the Melbourne Collaborative Cohort Study were characterized for methylator status, MLH1 methylation, somatic BRAF and KRAS mutations, microsatellite-instability status, MLH1, MSH2, MSH6, and PMS2 mismatch repair, and p53 protein expression, and their histopathology was reviewed. Protein expression levels of MUC2, MUC5AC, MUC5B, MUC6, and the putative mucin regulator CDX2 were compared with molecular and clinicopathological features of colorectal cancers using odds ratios and corresponding 95% confidence intervals. MUC2 overexpression (>25% positive tumor cells) was observed in 33% colorectal cancers, MUC5B expression in 53%, and de novo MUC5AC and MUC6 expression in 50% and 39%, respectively. Co-expression of two or more of the mucins was commonly observed. Expression of MUC2, MUC5AC and MUC6 was strongly associated with features associated with tumorigenesis via the serrated neoplasia pathway, including methylator positivity, somatic BRAF p.V600E mutation, and mismatch repair deficiency, as well as proximal location, poor differentiation, lymphocytic response, and increased T stage (all P<0.001). Overexpression was observed in tumors with and without mucinous differentiation. There were inverse associations between expression of all four mucins and p53 overexpression. CDX2 expression was inversely associated with MUC2, MUC5AC and MUC6 expression. Our results suggest that, in methylator-positive tumors, mucin genes on chromosome 11p15.5 region undergo increased expression via mechanisms other than direct regulation by CDX2.