TGFß engages MEK/ERK to differentially regulate benign and malignant pancreas cell function.

While TGFß signals are anti-proliferative in benign and well-differentiated pancreatic cells, TGFß appears to promote the progression of advanced cancers. To better understand dysregulation of the TGFß pathway, we first generated mouse models of neoplastic disease with TGFß receptor deficiencies. These models displayed reduced levels of pERK irrespective of KRAS mutation. Furthermore, exogenous TGFß led to rapid and sustained TGFBR1-dependent ERK phosphorylation in benign pancreatic duct cells. Similar to results that our group has published in colon cancer cells, inhibition of ERK phosphorylation in duct cells mitigated TGFß-induced upregulation of growth suppressive pSMAD2 and p21, prevented downregulation of the pro-growth signal CDK2 and ablated TGFß-induced EMT. These observations suggest that ERK is a key factor in growth suppressive TGFß signals, yet may also contribute to detrimental TGFß signaling such as EMT. In neoplastic PanIN cells, pERK was not necessary for either TGFß-induced pSMAD2 phosphorylation or CDK2 repression, but was required for upregulation of p21 and EMT indicating a partial divergence between TGFß and MEK/ERK in early carcinogenesis. In cancer cells, pERK had no effect on TGFß-induced upregulation of pSMAD2 and p21, suggesting the two pathways have completely diverged with respect to the cell cycle. Furthermore, inhibition of pERK both reduced levels of CDK2 and prevented EMT independent of exogenous TGFß, consistent with most observations identifying pERK as a tumor promoter. Combined, these data suggest that during carcinogenesis pERK initially facilitates and later antagonizes TGFß-mediated cell cycle arrest, yet remains critical for the pathological, EMT-inducing arm of TGFß signaling.

A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells.

The MST1R gene is overexpressed in pancreatic cancer producing elevated levels of the RON tyrosine kinase receptor protein. While mutations in MST1R are rare, alternative splice variants have been previously reported in epithelial cancers. We report the discovery of a novel RON isoform discovered in human pancreatic cancer. Partial splicing of exons 5 and 6 (P5P6) produces a RON isoform that lacks the first extracellular immunoglobulin-plexin-transcription domain. The splice variant is detected in 73% of xenografts derived from pancreatic adenocarcinoma patients and 71% of pancreatic cancer cell lines. Peptides specific to RON P5P6 detected in human pancreatic cancer specimens by mass spectrometry confirm translation of the protein isoform. The P5P6 isoform is found to be constitutively phosphorylated, present in the cytoplasm, and it traffics to the plasma membrane. Expression of P5P6 in immortalized human pancreatic duct epithelial (HPDE) cells activates downstream AKT, and in human pancreatic epithelial nestin-expressing cells, activates both the AKT and MAPK pathways. Inhibiting RON P5P6 in HPDE cells using a small molecule inhibitor BMS-777607 blocked constitutive activation and decreased AKT signaling. P5P6 transforms NIH3T3 cells and induces tumorigenicity in HPDE cells. Resultant HPDE-P5P6 tumors develop a dense stromal compartment similar to that seen in pancreatic cancer. In summary, we have identified a novel and constitutively active isoform of the RON tyrosine kinase receptor that has transforming activity and is expressed in human pancreatic cancer. These findings provide additional insight into the biology of the RON receptor in pancreatic cancer and are clinically relevant to the study of RON as a potential therapeutic target.

Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States.

BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.

Impact of prolonged antihypertensive duration of action on predicted clinical outcomes in imperfectly adherent patients: comparison of aliskiren, irbesartan and ramipril.

BACKGROUND: Most patients miss occasional doses of antihypertensives. The use of 'forgiving' drugs (i.e. drugs with duration of action longer than the 24-h dosing interval) may allow an adequate blood pressure (BP) reduction to be maintained despite missed doses. AIM: To quantify the effects of adherence level and duration of action on estimated mean systolic BP (SBP) reduction and cardiovascular disease (CVD) risk. METHOD: For 1250 patients, we simulated 256-day dosing histories with realistically distributed drug holidays based on a study of electronically monitored dosing records. Adherence was set to the desired level by altering the proportion of doses missed. Mean office SBP-lowering effect (aliskiren 300 mg, -14.1 mmHg; irbesartan 300 mg, -13.3; ramipril 10 mg, -10.1 mmHg) and the rate of SBP increase after stopping treatment (off-rate; aliskiren, 1.0 mmHg/day; irbesartan, 3.6 mmHg/day; ramipril, 4.0 mmHg/day) were taken from the results of a randomised, double-blind trial. SBP was averaged over time and patient to estimate mean reductions in SBP and 10-year CVD risk (Framingham risk equation, baseline absolute 10-year CVD risk: 27%). RESULTS: Predicted reductions in SBP and CVD risk with aliskiren were larger and less affected by imperfect adherence than the reductions with irbesartan or ramipril. For aliskiren, reducing adherence from 90% to 60% led to a predicted rise in SBP of 1.0 mmHg and three additional CVD events per 1000 treated patients; larger predicted differences were observed for irbesartan (2.5 mmHg; 7.5 events/1000 treated patients) and ramipril (2.2 mmHg; 6.7 events/1000 treated patients). CONCLUSION: To offset the effects of imperfect adherence, a common challenge with antihypertensives, for better BP management it may be prudent to prescribe 'forgiving' drugs.

Oncogenic Ras/Src cooperativity in pancreatic neoplasia.

Pancreas cancer is one of the most lethal malignancies and is characterized by activating mutations of Kras, present in 95% of patients. More than 60% of pancreatic cancers also display increased c-Src activity, which is associated with poor prognosis. Although loss of tumor suppressor function (for example, p16, p53, Smad4) combined with oncogenic Kras signaling has been shown to accelerate pancreatic duct carcinogenesis, it is unclear whether elevated Src activity contributes to Kras-dependent tumorigenesis or is simply a biomarker of disease progression. Here, we demonstrate that in the context of oncogenic Kras, activation of c-Src through deletion of C-terminal Src kinase (CSK) results in the development of invasive pancreatic ductal adenocarcinoma (PDA) by 5-8 weeks. In contrast, deletion of CSK alone fails to induce neoplasia, while oncogenic Kras expression yields PDA at low frequency after a latency of 12 months. Analysis of cell lines derived from Ras/Src-induced PDA's indicates that oncogenic Ras/Src cooperativity may lead to genomic instability, yet Ras/Src-driven tumor cells remain dependent on Src signaling and as such, Src inhibition suppresses growth of Ras/Src-driven tumors. These findings demonstrate that oncogenic Ras/Src cooperate to accelerate PDA onset and support further studies of Src-directed therapies in pancreatic cancer.

Effects on blood pressure and cardiovascular risk of variations in patients' adherence to prescribed antihypertensive drugs: role of duration of drug action.

AIM: To determine the effects of imperfect adherence (i.e. occasionally missing prescribed doses), and the influence of rate of loss of antihypertensive effect during treatment interruption, on the predicted clinical effectiveness of antihypertensive drugs in reducing mean systolic blood pressure (SBP) and cardiovascular disease (CVD) risk. METHOD: The effects of imperfect adherence to antihypertensive treatment regimens were estimated using published patterns of missed doses, and taking into account the rate of loss of antihypertensive effect when doses are missed (loss of BP reduction in mmHg/day; the off-rate), which varies between drugs. Outcome measures were the predicted mean SBP reduction and CVD risk, determined from the Framingham Risk Equation for CVD. RESULTS: In patients taking 75% of prescribed doses (typical of clinical practice), only long-acting drugs with an off-rate of ∼1 mmHg/day were predicted to maintain almost the full mean SBP-lowering effect throughout the modelled period. In such patients, using shorter-acting drugs (e.g. an off-rate of ∼5-6 mmHg/day) was predicted to lead to a clinically relevant loss of mean SBP reduction of > 2 mmHg. This change also influenced the predicted CVD risk reduction; in patients with a baseline 10-year CVD risk of 27.0% and who were taking 75% of prescribed doses, a difference in off-rate from 1 to 5 mmHg/day led to a predicted 0.5% absolute increase in 10-year CVD risk. CONCLUSIONS: In patients who occasionally miss doses of antihypertensives, modest differences in the rate of loss of antihypertensive effect following treatment interruption may have a clinically relevant impact on SBP reduction and CVD risk. While clinicians must make every effort to counsel and encourage each of their patients to adhere to their prescribed medication, it may also be prudent to prescribe drugs with a low off-rate to mitigate the potential consequences of missing doses.

Valsartan vs. other angiotensin II receptor blockers in the treatment of hypertension: a meta-analytical approach.

OBJECTIVE: To compare the efficacy of valsartan in systolic (SBP) and diastolic blood pressure (DBP) reduction with other angiotensin II receptor blockers (ARBs) in essential hypertension. METHODS: Systematic literature search of databases between October 1997 and May 2008. Meta-analysis of short-term, double-blind, parallel group, randomised controlled trials (RCTs) for treatment of adult hypertension (DBP: 90-115 mmHg). Random-effects meta-regression adjusting for baseline blood pressure (BP) was used to analyse the data. Mean change in SBP and DBP was estimated for each individual drug and dose combination. RESULTS: In all, 31 RCTs (n = 13,110 patients) were included in the analysis. Six studies include trial arms with candesartan, six irbesartan, 13 losartan, two olmesartan, five telmisartan and 12 valsartan. The weighted average reduction in mean SBP and DBP for valsartan 160 mg was -15.32 mmHg (95% CI: -17.09, -13.63) and -11.3 mmHg (95% CI: -12.15, -10.52) and for 320 mg was -15.85 mmHg (95% CI: -17.60, -14.12) and -11.97 mmHg (95% CI: -12.81, -11.16); these are statistically significantly greater reductions compared with losartan 100 mg, which was -12.01 mmHg (95% CI: -13.78, -10.25) and -9.37 mmHg (95% CI: -10.18, -8.54) for SBP and DBP respectively. There is evidence that valsartan 160 mg reduces SBP and DBP more than irbesartan 150 mg and reduced DBP more than candesartan 16 mg. No other statistically significant difference in efficacy is demonstrated. CONCLUSION: Valsartan administered at 160 or 320 mg is more effective at lowering BP than losartan 100 mg and shows comparable efficacy to other ARBs in patients with essential hypertension.

Recognition of skin malignancy by general practitioners: observational study using data from a population-based randomised controlled trial.

Skin malignancy is an important cause of mortality in the United Kingdom and is rising in incidence every year. Most skin cancer presents in primary care, and an important determinant of outcome is initial recognition and management of the lesion. Here we present an observational study of interobserver agreement using data from a population-based randomised controlled trial of minor surgery. Trial participants comprised patients presenting in primary care and needing minor surgery in whom recruiting doctors felt to be able to offer treatment themselves or to be able to refer to a colleague in primary care. They are thus relatively unselected. The skin procedures undertaken in the randomised controlled trial generated 491 lesions with a traceable histology report: 36 lesions (7%) from 33 individuals were malignant or pre-malignant. Chance-corrected agreement (kappa) between general practitioner (GP) diagnosis of malignancy and histology was 0.45 (0.36-0.54) for lesions and 0.41 (0.32-0.51) for individuals affected with malignancy. Sensitivity of GPs for the detection of malignant lesions was 66.7% (95% confidence interval (CI), 50.3-79.8) for lesions and 63.6% (95% CI, 46.7-77.8) for individuals affected with malignancy. The safety of patients is of paramount importance and it is unsafe to leave the diagnosis and treatment of potential skin malignancy in the hands of doctors who have limited training and experience. However, the capacity to undertake all of the minor surgical demand works demanded in hospitals does not exist. If the capacity to undertake it is present in primary care, then the increased costs associated with enhanced training for general medical practitioners (GPs) must be borne.

The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia.

OBJECTIVE: The chemokine CXCL12, together with its specific receptor, CXCR4, have been shown to mediate invasiveness and metastatic behaviour in pancreatic cancer cells. The expression of CXC12/CXCR4 has not been previously examined in pancreatic intraepithelial neoplasias (PanIN), the accepted precursor lesions to pancreatic duct cancer. DESIGN: In this study we sought to characterise the expression of CXCL12 and CXCR4 during the progression of PanIN using both a murine model and human tissues. RESULTS: These studies reveal that both CXCL12 and CXCR4 are expressed in PanIN and that the frequency increases during PanIN progression (0% CXCR4 expression in normal mouse and human ducts vs 100% in mouse PanIN 3 and 77% in human PanIN 3). Next we demonstrate a dose-dependent increase in the proliferation of murine PanIN cells when exposed to CXCL12. Finally, we show that expression of CXCR4 in murine PanIN cells is partially dependent on mitogen-activated protein kinase (MAPK) signalling and that the effect of CXCL12 on PanIN proliferation can be abrogated by an MAPK inhibitor. CONCLUSIONS: Together these results demonstrate that CXCL12/CXCR4 expression begins in the pre-invasive stages of pancreatic neoplasia, and suggest that the presence of an autocrine loop that is at least partially regulated by MAPK signalling. Further studies that define the role of CXCR4 signalling in PanIN progression will determine if CXCR4 could serve as a novel target for chemoprevention and early stage therapy in pancreatic cancer.

A prospective randomised comparison of minor surgery in primary and secondary care. The MiSTIC trial.

OBJECTIVE: To determine whether there is equivalence in the competence of GPs and hospital doctors to perform a range of elective minor surgical procedures, in terms of the safety, quality and cost of care. DESIGN: A prospective randomised controlled equivalence trial was undertaken in consenting patients presenting at general practices and needing minor surgery. SETTING: The study was conducted in the south of England. PARTICIPANTS: Consenting patients presenting at general practices who needed minor surgery in specified categories for whom the recruiting doctor felt able to offer treatment or to be able to refer to a colleague in primary care. INTERVENTIONS: On presentation to their GP, patients were randomised to either treatment within primary care or treatment at their local hospital. Evaluation was by assessment of clinical quality and safety of outcome, supplemented by examination of patient satisfaction and cost-effectiveness. MAIN OUTCOME MEASURES: Two independent observers assessed surgical quality by blinded assessment of wound appearance, between 6 and 8 weeks postsurgery, from photographs of wounds. Other measures included satisfaction with care, safety of surgery in terms of recognition of and appropriate treatment of skin malignancies, and resource use and implications. RESULTS: The 568 patients recruited (284 primary care, 284 hospital) were randomised by 82 GPs. In total, 637 skin procedures plus 17 ingrowing toenail procedures were performed (313 primary care, 341 hospital) by 65 GPs and 60 hospital doctors. Surgical quality was assessed for 273 (87%) primary care and 316 (93%) hospital lesions. Mean visual analogue scale score in hospital was significantly higher than that in primary care [mean difference=5.46 on 100-point scale; 95% confidence interval (CI) 0.925 to 9.99], but the clinical importance of the difference was uncertain. Hospital doctors were better at achieving complete excision of malignancies, with a difference that approached statistical significance [7/16 GP (44%) versus 15/20 hospital (75%), chi(2)=3.65, p=0.056]. The proportion of patients with post-operative complications was similar in both groups. The mean cost for hospital-based minor surgery was 1222.24 pounds and for primary care 449.74 pounds. Using postoperative complications as an outcome, both effectiveness and costs of the alternative interventions are uncertain. Using completeness of excision of malignancy as an outcome, hospital minor surgery becomes more cost-effective. The 705 skin procedures undertaken in this trial generated 491 lesions with a traceable histology report: 36 lesions (7%) from 33 individuals were malignant or premalignant. Chance-corrected agreement (kappa) between GP diagnosis of malignancy and histology was 0.45 (95% CI 0.36 to 0.54) for lesions and 0.41 (95% CI 0.32 to 0.51) for individuals affected by malignancy. Sensitivity of GPs for detection of malignant lesions was 66.7% (95% CI 50.3 to 79.8) for lesions and 63.6% (95% CI 46.7 to 77.8) for individuals affected by malignancy. CONCLUSIONS: The quality of minor surgery carried out in general practice is not as high as that carried out in hospital, using surgical quality as the primary outcome, although the difference is not large. Patients are more satisfied if their procedure is performed in primary care, largely because of convenience. However, there are clear deficiencies in GPs' ability to recognise malignant lesions, and there may be differences in completeness of excision when compared with hospital doctors. The safety of patients is of paramount importance and this study does not demonstrate that minor surgery carried out in primary care is safe as it is currently practised. There are several alternative models of minor surgery provision worthy of consideration, including ones based in primary care that require all excised tissue to be sent for histological examination, or that require further training of GPs to undertake the necessary work. The results of this study suggest that a hospital-based service is more cost-effective. It must be concluded that it is unsafe to leave minor surgery in the hands of doctors who have never been trained to do it. Further work is required to determine GPs' management of a range of skin conditions (including potentially life-threatening malignancies), rather than just their recognition of them. Further economic modelling work is required to look at the potential costs of training sufficient numbers of GPs and GPs with special interests to meet the demand for minor surgery safely in primary care, and of the alternative of transferring minor surgery large-scale to the hospital sector. Different models of provision need thorough testing before widespread introduction.

Mucinous cancer of the appendix: challenges in diagnosis and treatment.

The authors report and discuss a case of a mucinous carcinoma of the appendix, a rare entity with a distinct natural history that poses diagnostic and therapeutic challenges. Mucinous peritoneal carcinomatosis is most commonly associated with primary tumors of the appendix and colon. Typically, spread remains confined to the abdominal cavity. Imaging assessment of these mucinous lesions is difficult, while tumor markers (CEA and CA19.9) may be surrogates for extent of disease. Treatment consists of surgical debulking, sometimes coupled with intraperitoneal drug delivery, but recurrence is universal. New treatment approaches are needed. Mucin genes are regulated in part by epidermal growth factor receptor signaling. Therefore, we initiated a phase II study of cetuximab for mucinous peritoneal carcinomatosis, that was part of this patient's treatment.

Costs of treatment of Swiss patients with HIV on antiretroviral therapy in hospital-based and general practice-based care: a prospective cohort study.

Some ambulant people with HIV are cared for primarily by their general practitioner and some in an outpatient clinic. Costs and patterns of care in these settings were studied in 65 such patients based in Zürich, from a limited societal perspective (excluding patient costs) based on medical resource use. Antiretroviral therapy (ART), other medications and patient variables were collected prospectively, and non-medication resources (professional time and investigations) and treatment history data were collected from medical records and by record linkage to the Swiss HIV Cohort Study database. Cost differences between the settings were estimated using multiple regression, controlling for differences in case-mix. ART comprised 80% of the total cost, non-medication costs 15% and non-ART medications 5%. Total costs were higher in the outpatient clinic (estimated additional cost after controlling for case-mix = 3489 Swiss Francs per year at 1999 prices, 95% confidence interval 742 to 6236, p=0.017). The difference was accounted for by higher ART costs in the outpatient clinic, not through a tendency to use more expensive drugs or higher doses but rather through the use of more drugs concurrently. Differences in ART prescribing patterns between the doctors in the outpatient clinic and the general practitioners were considerable and appear worthy of further investigation.

The significance and clinical factors associated with a subcentimeter resection of colorectal liver metastases.

BACKGROUND: Prognosis after resection of colorectal liver metastases is influenced by various factors. A positive margin of resection (MOR) has been shown to adversely influence prognosis. Although a 1-cm MOR has been accepted as adequate, the data to support this guideline are sparse. METHODS: Our hepatobiliary database was queried for patients who underwent liver resection for colorectal metastases between January 1992 and July 2003. All patients were divided into three groups: MOR <.5 cm (group A), .5 to 1 cm (group B), and >1 cm (group C). Operative reports from each hepatic resection were analyzed to determine local factors that may have contributed to a subcentimeter MOR. RESULTS: A total of 112 patients (67 men and 45 women) underwent liver resection for colorectal metastases with negative margins. Fifty-three patients were in group A, 26 patients were in group B, and 33 patients were in group C. Group C demonstrated decreased local recurrence (LR; P = .003), distant recurrence (DR; P = .008), and disease-free recurrence (P = .002). A significant difference in the overall time to LR (P = .003), time to DR (P = .003), and disease-free survival (P = .002) was also demonstrated. Factors associated with a subcentimeter MOR included nonanatomical resection (P = .043), proximity to a major vessel (P = .003), and central location (P = .002). CONCLUSIONS: A <1-cm resection for colorectal liver metastases is associated with increased LR and DR, as well as decreased disease-free survival. When a nonanatomical resection is performed, a MOR >1 cm should be attempted, because an adequate margin is often underestimated. Considerations should be made for extended resections when tumors are centrally located or near major vessels.

Effects of cerivastatin on forearm vascular responses, blood pressure responsiveness and ambulatory blood pressure in type 2 diabetic men.

OBJECTIVE: The objective of the study was to investigate the effects of cerivastatin therapy on forearm endothelial dependent acetylcholine (ACH) and independent (nitroprusside) vasodilator responses, blood pressure (BP) responses to intravenous infusions of angiotensin II (AII) and noradrenaline (NA) and on 24-h ambulatory BP recordings in type 2 diabetic men. DESIGN: Eleven type 2 diabetic men aged 59 +/- 9 years with total cholesterol levels of 5.0 +/- 1.26 mmol/l, triglycerides of 2.23 mmol/l and high-density lipoprotein cholesterol levels of 1.24 mmol/l completed a double-blind, randomized, crossover trial comparing 8 weeks of cerivastatin therapy (800 microg of nocte) with placebo. Forearm vascular resistance (FVR) responses to intrabrachial-arterial infusions of ACH (3-24 microg/min), nitroprusside (2-16 microg/min), the nitric oxide(NO) synthase inhibitor l-nitro-mono-methyl arginine (l-nmma) (8 micromol/min), ACH during l-NMMA infusion and BP responses to intravenous infusions of AII (12.5-50 ng/min) and NA (20-400 ng/min) were measured at the end of each treatment period. Twenty-four-hour ambulatory BP recordings were also performed. RESULTS: FVR responses to ACH during l-NMMA infusion were significantly (p = 0.026) greater during cerivastatin than during placebo therapy. In contrast, FVR responses to ACH in the absence of NO synthase inhibition did not differ significantly between cerivastatin and placebo therapies (p = 0.81). FVR increased by 31.4 +/- 57.3% in response to l-NMMA infusion during cerivastatin therapy compared with 6.1 +/- 41.2% during placebo therapy (p = 0.20). FVR responses to nitroprusside did not differ between cerivastatin and placebo therapies (p = 0.28), nor did BP responses to AII (systolic BP, p = 0.99; diastolic BP, p = 0.98) or NA (systolic BP, p = 0.21; diastolic BP, p = 0.48). Mean 24-h BP was similar during cerivastatin (123 +/- 10 or 70 +/- 7 mmHg) and placebo therapies (129 +/- 11 or 74 +/- 7 mmHg) (systolic BP, p = 0.26; diastolic BP, p = 0.41). CONCLUSION: Cerivastatin increases FVR responses to ACH in type 2 diabetic men with mild dyslipidaemia but only following NO synthase inhibition. This may indicate an improvement in endothelium-derived hyperpolarizing factor-mediated responses.

SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer.

The gene for the transducer of transforming growth factor-beta/bone morphogenetic protein signalling SMAD4, a potential suppressor of colorectal carcinogenesis, is located at the chromosomal region 18q21. In order to evaluate the clinical relevance of SMAD4 deletion, gene copy alterations were determined by copy dosage using real-time quantitative PCR in 202 colorectal tumour biopsies from a previous randomised study of adjuvant chemotherapy. Patients with normal SMAD4 diploidy turned out to have a three-fold higher benefit of 5-fluorouracil-based adjuvant chemotherapy with a border line significance (overall survival: 3.23, P=0.056; disease-free survival: 2.89, P=0.045). These data are consistent with the previous observation that patients whose cancer had retention of the 18q21 region had a significantly higher benefit from 5-fluorouracil-based therapy. Moreover, these results may provide a refinement at the gene level of the clinical relevance of 18q21 deletion, thereby suggesting SMAD4 as a predictive marker in colorectal cancer. This data also indicate that integrity of this component of the transforming growth factor-beta/bone morphogenetic protein signalling pathway may be a critical factor for benefit of chemotherapy in patients with colorectal cancer.

Response shift in the perception of health for utility evaluation. an explorative investigation.

We previously showed that patients with newly diagnosed colon cancer change the internal standards on which they base their quality of life estimation. In the present investigation, we explored whether this response shift similarly affects the perception of health for utility evaluation in cancer clinical trials. After radical resection of adenocarcinoma of the colon (pT1-4 pN>0 M0 and pT3-4 pN0 M0) and perioperative chemotherapy, patients were randomised to three treatment arms: observation only (A), 5-fluorouracil (5-FU) 450 mg/m(2) plus levamisol (B), or 5-FU 600 mg/m(2) (C). Subjective health was assessed by a linear analogue self-assessment (LASA) scale anchored at 'perfect health-worst health' developed for serial assessment of utility values (Hürny C, van Wegberg B, Bacchi M, et al. Subjective health estimations (SHE) in patients with advanced breast cancer: an adapted utility concept for clinical trials. Br J Cancer 1998, 77, 985-991). Patients estimated their pre-surgery health among various quality of life indicators both before surgery and retrospectively thereafter, and their pre-adjuvant health both at the beginning of randomly assigned chemotherapy or observation and retrospectively approximately 2 months later. Thereafter, current subjective health was assessed. Paired t-tests were used to test the hypotheses of no change. Patients' estimated pre-surgery health was worse after surgery than before (n=127, mean change=-6.7, standard deviation (S.D.)=30, P=0.01), and their estimated pre-adjuvant health was worse under treatment or observation than at the beginning (n=132, mean change=-7.1, S.D.=23.8, P=0.001), in agreement with the quality of life indicators. Chemotherapy had no impact on these changes attributed to a response shift. Conventionally assessed changes between the beginning of adjuvant treatment or observation and 2 months later indicated no change in subjective health. Change scores relative to patients' retrospective estimation revealed an improvement (n=122, mean change=6.6, S.D.=24.8, P=0.004) in this period. Patients with colon cancer substantially reframe their internal standard of health as they do for quality of life. This explorative finding questions the assumption, generally made in decision models, that health estimates for utility evaluation are independent of time. Given that patients may change their standards, comparisons of health estimates across different populations and clinical situations are to be interpreted with caution.

Independent influences of central fat and skeletal muscle lipids on insulin sensitivity.

OBJECTIVE: Insulin resistance is closely associated with two disparate aspects of lipid storage: the intracellular lipid content of skeletal muscle and the magnitude of central adipose beds. Our aim was to determine their relative contribution to impaired insulin action. RESEARCH METHODS AND PROCEDURES: Eighteen older (56 to 75 years of age) men were studied before elective knee surgery. Insulin sensitivity (M/Delta I) was determined by hyperinsulinemic-euglycemic clamp. Central abdominal fat (CF) was assessed by DXA. Skeletal muscle was excised at surgery and assayed for content of metabolically active long-chain acyl-CoA esters (LCAC). RESULTS: Significant inverse relationships were observed between LCAC and M/Delta I (R(2) = 0.34, p = 0.01) and between CF and M/Delta I (R(2) = 0.38, p = 0.006), but not between CF and LCAC (R(2) = 0.0005, p = 0.93). In a multiple regression model (R(2) = 0.71, p < 0.0001), both CF (p = 0.0006) and LCAC (p = 0.0009) were independent statistical predictors of M/Delta I. Leptin levels correlated inversely with M/Delta I (R(2) = 0.60, p = 0.0002) and positively with central (R(2) = 0.41, p = 0.006) and total body fat (R(2) = 0.63, p = 0.0001). DISCUSSION: The mechanisms by which altered lipid metabolism in skeletal muscle influences insulin action may not be related directly to those linking central fat and insulin sensitivity. In particular, it is unlikely that muscle accumulation of lipids directly derived from labile central fat depots is a principal contributor to peripheral insulin resistance. Instead, our results imply that circulating factors, other than nonesterified fatty acids or triglyceride, mediate between central fat depots and skeletal muscle tissue. Leptin was not exclusively associated with central fat, but other factors, secreted specifically from central fat cells, could modulate muscle insulin sensitivity.

Numerous colonic adenomas in an individual with Bloom's syndrome.

Bloom's syndrome (BS) is a rare recessive disorder caused by germline mutation of the BLM gene. Individuals with BS manifest growth retardation, immunodeficiency, and a predisposition to cancer. In this report, we describe an individual with BS and multiple colonic adenomas reminiscent of familial adenomatous polyposis coli (FAP). Molecular studies revealed APC mutations in 4 of 6 adenomas, including 2 adenomas with the identical APC mutation and microsatellite instability in 1 of 6 adenomas. These results demonstrate similar pathways to colorectal neoplasia in BS as in the normal population and suggest that individuals with BS may be particularly susceptible to colorectal neoplasia.

A pilot study of preoperative chemoradiotherapy for resectable gastric cancer.

BACKGROUND: The goals of this study were to assess the feasibility and toxicity of a regimen of preoperative chemoradiotherapy, surgery, and intraoperative radiotherapy in the treatment of patients with potentially resectable gastric cancer. A secondary objective was to assess pathologic response to chemoradiotherapy in the treated tumors. METHODS: Twenty-four patients were entered in the protocol. Treatment regimen consisted of 45 Gy of external beam radiotherapy with concurrent 5-FU given as a continuous infusion at a dose of 300 mg/m2. Patients were restaged 4-6 weeks after chemoradiotherapy and then underwent surgical resection and intraoperative radiotherapy to a dose of 10 Gy. RESULTS: Twenty-three patients (96%) completed chemoradiotherapy in accordance with the study protocol. Nineteen (83%) of 23 patients who completed chemoradiotherapy underwent surgical resection with D2 lymphadenectomy. Four patients (17%) had progressive disease and were not resected. The morbidity and mortality rates were 32% and 5%, respectively. Of the resected patients, two (11%) had complete pathologic responses while 12 (63%) had pathologic evidence of significant treatment effect. CONCLUSIONS: Preoperative chemoradiotherapy for gastric cancer can be delivered safely and is well tolerated. The rate of surgical complications is consistent with that of other recently reported prospective trials of gastrectomy alone. Preoperative chemoradiotherapy resulted in significant pathologic responses in the majority of treated tumors, and complete pathologic responses were achieved in some patients.