Effect of metformin versus placebo on metabolic factors in the MA.32 randomized breast cancer trial.

Metformin may exert anticancer effects through indirect (mediated by metabolic changes) or direct mechanisms. The goal was to examine metformin impact on metabolic factors in non-diabetic subjects and determine whether this impact varies by baseline BMI, insulin, and rs11212617 SNP in CCTG MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer (BC) trial. 3649 subjects with T1-3, N0-3, M0 BC were randomized; pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, highly sensitive C-reactive protein (hsCRP). Glucose was measured locally and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP. Absolute and relative change of metabolic factors (metformin versus placebo) were compared using Wilcoxon rank and t-tests. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Mean age was 52 years. The majority had T2/3, node positive, hormone receptor positive, HER2 negative BC treated with (neo)adjuvant chemotherapy and hormone therapy. Median baseline body mass index (BMI) was 27.4 kg/m2 (metformin) and 27.3 kg/m2 (placebo). Median weight change was -1.4 kg (metformin) vs +0.5 kg (placebo). Significant improvements were seen in all metabolic factors, with 6 month standardized ratios (metformin/placebo) of 0.85 (insulin), 0.83 (HOMA), 0.80 (leptin), and 0.84 (hsCRP), with no qualitative interactions with baseline BMI or insulin. Changes did not differ by rs11212617 allele. Metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status.

Serum metabolomic profile as a means to distinguish stage of colorectal cancer.

BACKGROUND: Presently, colorectal cancer (CRC) is staged preoperatively by radiographic tests, and postoperatively by pathological evaluation of available surgical specimens. However, present staging methods do not accurately identify occult metastases. This has a direct effect on clinical management. Early identification of metastases isolated to the liver may enable surgical resection, whereas more disseminated disease may be best treated with palliative chemotherapy. METHODS: Sera from 103 patients with colorectal adenocarcinoma treated at the same tertiary cancer center were analyzed by proton nuclear magnetic resonance (1H NMR) spectroscopy and gas chromatography-mass spectroscopy (GC-MS). Metabolic profiling was done using both supervised pattern recognition and orthogonal partial least squares-discriminant analysis (O-PLS-DA) of the most significant metabolites, which enables comparison of the whole sample spectrum between groups. The metabolomic profiles generated from each platform were compared between the following groups: locoregional CRC (N = 42); liver-only metastases (N = 45); and extrahepatic metastases (N = 25). RESULTS: The serum metabolomic profile associated with locoregional CRC was distinct from that associated with liver-only metastases, based on 1H NMR spectroscopy (P = 5.10 × 10-7) and GC-MS (P = 1.79 × 10-7). Similarly, the serum metabolomic profile differed significantly between patients with liver-only metastases and with extrahepatic metastases. The change in metabolomic profile was most markedly demonstrated on GC-MS (P = 4.75 × 10-5). CONCLUSIONS: In CRC, the serum metabolomic profile changes markedly with metastasis, and site of disease also appears to affect the pattern of circulating metabolites. This novel observation may have clinical utility in enhancing staging accuracy and selecting patients for surgical or medical management. Additional studies are required to determine the sensitivity of this approach to detect subtle or occult metastatic disease.

Approach to inflammatory breast cancer.

OBJECTIVE: To review the definition, clinical presentation, and management of inflammatory breast cancer in primary care. SOURCES OF INFORMATION: Relevant research and review articles, as well as personal experience of the authors practising in a specialized locally advanced breast cancer program at a comprehensive cancer centre. Evidence is levels II and III. MAIN MESSAGE: Inflammatory breast cancer is a rare disease that typically presents with a rapidly enlarging erythematous breast, often with no discernable breast mass. Identification of warning signs and recognition of clinical symptoms are crucial to prompt diagnosis and appropriate referral. Management in the primary care setting includes treatment of symptoms, psychosocial support, regular surveillance and follow-up, as well as palliative care. CONCLUSION: Family physicians are usually the entry point to the health care system and are well positioned to assess inflammation of the breast and recognize the warning signs of an underlying inflammatory breast cancer. They are also important members of the team that provides support for breast cancer patients and their families during treatment, follow-up, and end-of-life care.

First-in-class, first-in-human phase I results of targeted agents: highlights of the 2008 American society of clinical oncology meeting.

This review summarizes phase I trial results of 11 drugs presented at the American Society of Clinical Oncology meeting held in Chicago IL from May 30 to June 3rd 2008: BMS-663513, CT-322, CVX-045, GDC-0449, GRN163L, LY2181308, PF-00562271, RAV12, RTA 402, XL765, and the survivin vaccine.

Breast cancer in pregnancy: a literature review.

PURPOSE: Breast cancer in pregnancy is a clinically challenging situation for patients and their physicians. A review of the literature was performed to help identify optimal treatment strategies. METHODS: A Medline search between 1966 to the present using the keywords "breast", "carcinoma", and "pregnancy" revealed numerous hits, from which English-language articles including epidemiologic studies, case series, and general summaries were reviewed. RESULTS: There is a paucity of prospective studies regarding diagnosis and treatment of breast cancer in pregnancy due to its rarity. However a general review of the literature database reveals that women diagnosed with breast cancer during pregnancy have similar disease characteristics to age-matched controls. Surgery remains the mainstay of treatment of breast cancer during pregnancy, and in some circumstances breast-conserving surgery is an acceptable option. Adjuvant treatment can proceed with some modifications that minimize harm to the fetus, namely limiting radiation exposure and timing chemotherapy properly. Post-partum decisions regarding lactation and future fertility should be addressed on a per-patient basis. CONCLUSION: Breast cancer in pregnancy is an uncommon phenomenon but one which poses dilemmas for patients and their physicians. A multi-disciplinary approach is recommended for optimal clinical-decision making.

Changes in dielectric properties at 460 kHz of kidney and fat during heating: importance for radio-frequency thermal therapy.

We have developed a system to measure the changes due to heating to high temperatures in the dielectric properties of tissues in the radio-frequency range. A two-electrode arrangement was connected to a low-frequency impedance analyser and used to measure the dielectric properties of ex vivo porcine kidney and fat at 460 kHz. This frequency was selected as it is the most commonly used for radio-frequency thermal therapy of renal tumours. Tissue samples were heated to target temperatures between 48 and 78 degrees C in a hot water bath and changes in dielectric properties were measured during 30 min of heating and 15 min of cooling. Results suggest a time-temperature dependence of dielectric properties, with two separate components: one a reversible, temperature-dependent effect and the other a permanent effect due to structural events (e.g. protein coagulation, fat melting) that occur in tissues during heating. We calculated temperature coefficients of 1.3 +/- 0.1% degrees C(-1) for kidney permittivity and 1.6% degrees C(-1) for kidney conductivity, 0.9 +/- 0.1% degrees C(-1) for fat permittivity and 1.7 +/- 0.1% degrees C(-1) for fat conductivity. An Arrhenius model was employed to determine the first-order kinetic rates for the irreversible changes in dielectric properties. The following Arrhenius parameters were determined: an activation energy of 57 +/- 5 kcal mol(-1) and a frequency factor of (6 +/- 1) x 10(34) s(-1) for conductivity of kidney, an activation energy of 48 +/- 2 kcal mol(-1) and a frequency factor of 6 x 10(28) s(-1) for permittivity of kidney. A similar analysis led to an activation energy of 31 +/- 4 kcal mol(-1) and a frequency factor of (4.43 +/- 1) x 10(16) s(-1) for conductivity of fat, and an activation energy of 40 +/- 4 kcal mol(-1) and a frequency factor of 4 x 10(22) s(-1) for permittivity of fat. Structural events occurring during heating at different target temperatures as determined by histological analyses were correlated with the changes in the measured dielectric properties.

Diagnostic potential of near-infrared Raman spectroscopy in the colon: differentiating adenomatous from hyperplastic polyps.

BACKGROUND: Near-infrared Raman spectroscopy is a promising optical technique for GI tissue diagnosis. This study assessed the diagnostic potential of near-infrared Raman spectroscopy in the colon by evaluating its ability to distinguish between adenomatous and hyperplastic polyps. METHODS: Ex vivo and in vivo Raman spectra of colon polyps were collected by using a custom-built, fiber-optic, near-infrared Raman spectroscopic system. Multivariate statistical techniques, including principal component analysis and linear discriminant analysis, were used to develop diagnostic algorithms for classifying colon polyps based on their spectral characteristics. With the number of samples available, spectral classification of polyps was tested by using a leave-one-out, cross-validation method. RESULTS: Fifty-four ex vivo Raman spectra were analyzed (20 hyperplastic, 34 adenomatous). The spectral-based diagnostic algorithms identified adenomatous polyps with 91% sensitivity, 95% specificity, and 93% accuracy. In vivo, adenomas (n = 10) were distinguished from hyperplastic polyps (n = 9) with 100% sensitivity, 89% specificity, and 95% accuracy. CONCLUSIONS: Near-infrared Raman spectroscopy differentiated adenomatous from hyperplastic polyps with high diagnostic accuracy. To our knowledge, this is the first demonstration of the potential of near-infrared Raman spectroscopy for differentiation of colonic polyps during GI endoscopy.