Optimizing Colorectal Cancer Care in Older Patients

Colorectal cancer is a disease affecting mainly older people, a fact that is becoming more apparent with the global population aging. However, this patient group is more likely to be subjected to suboptimal treatment due to a number of factors, but most commonly as a result of the physician’s weakness to recognize those fit for the full spectrum of cancer therapy. In this regard, clinical screening tests, such as the Comprehensive Geriatric Assessment, can be invaluable in guiding treatment decisions. Fluoropyrimidine-based adjuvant chemotherapy clearly confers a survival advantage in older individuals with node-positive disease; however, the benefit from the administration of oxaliplatin-based regimens is less clear. Palliative chemotherapy also has an important role in managing metastatic disease, and with the use of novel targeted agents it can potentially prolong survival and improve quality of life. The management of rectal cancer in this population can present a challenge, since it appears that the optimal treatment of chemoradiation followed by total mesorectal excision can be applied in select few. Indeed, the morbidity and mortality rates in older people treated with these combined modalities can be too high, guiding many physicians to opt for more conservative approaches, directed at providing palliation and local control, especially in those with limited life expectancy. In conclusion, in order to provide the best care in an older colorectal cancer patient, we need to individualize our approach, selecting the right patient for the right treatment.     

The role of mitral annulus motion in left ventricular function.

The dynamics between mitral annulus motion and left ventricular function were studied. Thirty subjects (10 normals, 10 with severe cardiac failure and 10 with mitral regurgitation) were examined. Left ventricular long and short-axis dimensions were measured in a two-dimensional apical four-chamber image. A volume was calculated as defined by cardiac cyclic changes of mitral annulus in size and motion. This volume had the approximate geometric configuration of a truncuated cone and was covered by mitral annulus motion at enddiastole and endsystole. Left ventricular ejection fraction was calculated echocardiographically using the prolate ellipsoid/area-length method. The volume defined by mitral annulus motion was 24 ml in normals, 16 ml in patients with cardiac failure and 48 ml in patients with mitral regurgitation while the ejection fraction was 51%, 19% and 53% respectively. Comparison between the volume of the truncuated cone and the ejection fraction in all 30 subjects revealed a statistically significant correlation (p less than 0.01). Thus, the bigger the volume determined by the mitral annulus motion during systole, the larger portion of the left ventricle is "atrialized", and a higher ejection fraction follows. Mitral annulus motion may provide new information about cardiac mechanics in normal and abnormal conditions.     

Incremental value of arterial wave reflections in the determination of left ventricular diastolic dysfunction in untreated patients with essential hypertension

Systemic arterial stiffness is an indicator of cardiovascular disease and an independent marker of morbidity and cardiovascular mortality. We investigated the association of arterial wave reflections with left ventricular (LV) diastolic dysfunction and their incremental value to other determinants of LV diastolic dysfunction in patients with essential hypertension. In total 143 patients and 20 controls with similar atherosclerotic risk factors were examined by applanation tonometry of the radial artery (Sphygmocor) and echocardiography. Central augmentation index (CAI%) of reflected arterial waves as well as aortic strain (AoS) assessed by echocardiography were estimated. Doppler diastolic abnormalities were defined as proposed by the European Study Group on diastolic heart failure by measurement of E/A ratio (the ratio of the mitral inflow velocities), isovolumic relaxation time, deceleration time and flow propagation velocity. AoS and CAI were impaired in patients compared with controls (4.67 +/- 2.94 vs 6.06 +/- 4.91% and 145.8 +/- 22.7 vs. 135.7 +/- 20.3%, P < 0.01) as well as in patients with LV diastolic dysfunction compared to patients without, (5.52 +/- 4.29 vs. 10.73 +/- 5.77% and 139.5 +/- 21.7 vs. 124.5 +/- 17.0%, P < 0.05). The odds ratio (OR) of AoS and CAI for diastolic dysfunction was OR:0.918, 95% confidence interval (CI):0.837-0.99, P = 0.04 and OR:1.023, 95% CI: 1.023-1.040 P = 0.010, respectively. The addition of CAI to the multivariable model including age, LV mass index, AoS and mean arterial pressure increased the power of the model for determination of LV diastolic dysfunction (-2 log likelihood = 139.368, change of chi2 = 4.2, P-value for change=0.04). In untreated patients with newly diagnosed essential hypertension, wave reflections are independent and additive determinants of LV diastolic dysfunction.     

Oral L-arginine improves endothelial dysfunction in patients with essential hypertension

BACKGROUND: L-Arginine is a nitric oxide precursor, which augments endothelium-dependent vasodilatation in hypercholesterolemic humans and animals. Endothelium-dependent vasodilation is attenuated in patients with hypertension; however the effects of oral L-arginine on endothelial function of the conduit arteries in patients with essential hypertension have not previously been investigated. METHODS: In a prospective randomized double blind trial, 35 patients with essential hypertension received either 6 g L-arginine (18 subjects) or placebo (17 subjects). Patients were examined for flow-mediated endothelium-dependent dilatation of the brachial artery before and 1.5 h after administration of L-arginine or placebo. At the end of the protocol the nitrate-induced, endothelium-independent vasodilatation was evaluated. RESULTS: Two groups of L-arginine and placebo were similar regarding age, sex, blood lipids, smoking, diabetes, coronary artery disease, body mass index, intima-media thickness of the common carotid artery, clinics blood pressure and baseline brachial artery parameters. Administration of L-arginine or placebo did not change significantly heart rate, blood pressure, baseline diameter, blood flow or reactive hyperemia. L-Arginine resulted in a significant improvement of flow-mediated dilatation (1.7+/-3.4 vs. 5.9+/-5.4%, P=0.008) while placebo did not significantly change this parameter (3.0+/-2.7 vs. 3.1+/-2.2%, P=ns). The effect of L-arginine on flow-mediated dilatation was significantly different from the effect of placebo (P=0.05). L-Arginine did not significantly influence nitrate-induced dilatation (16+/-6.9 vs. 17.7+/-6.7%, P=ns). CONCLUSIONS: Oral administration of L-arginine acutely improves endothelium-dependent, flow-mediated dilatation of the brachial artery in patients with essential hypertension. The long-term effects of L-arginine in these patients require further investigation.     

Can premenstrual syndrome affect arterial stiffness or blood pressure?

ObjectiveWe tested the hypotheses that monthly fluctuations in markers of arterial stiffness and blood pressure hemodynamics differ between women with and without premenstrual syndrome. We also assessed hypertension prevalence and arterial stiffening in postmenopausal women with or without history of premenstrual symptoms.MethodsTwenty one pre-menopausal women with premenstrual syndrome and 15 women without were prospectively examined in three distinct phases of their menstrual cycle (menses, late follicular and luteal phase). Pulse-wave velocity and analysis were used to assess arterial stiffness and wave reflection indices, respectively. Endothelial function was evaluated by flow-mediated vasodilation. In a cross-sectional substudy, 156 postmenopausal women were assessed for possible associations between retrospectively reported PMS symptoms and hypertension.ResultsIn women with premenstrual syndrome, arterial stiffness significantly increased during the luteal and menses phase (late follicular: 6.48 ± 1.07, luteal: 7.1 ± 1.26, menstruation: 7.12 ± 1.19 m/s, p = 0.003), while blood pressure peaked at the menses phase. Significant interactions between PMS and changes in arterial stiffness and blood pressure but not endothelial function, were observed. Changes in PWV were significantly associated with concomitant changes in blood pressure, C-reactive protein and the severity of PMS symptoms. The prevalence of hypertension (20.9% vs. 40.9%, p = 0.041) and pulse-wave velocity values (8.64 ± 1.52 vs. 9.37 ± 1.1, p = 0.046) were higher in postmenopausal women with 7 or more reported PMS symptoms. Arterial stiffness differences remained significant after adjustment for confounding factors.ConclusionThese results imply that PMS may affect arterial stiffness and BP monthly variability. Whether PMS is associated with new onset hypertension later in life needs further evaluation.     

EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab

Introduction

Cetuximab is a monoclonal epidermal growth factor receptor (EGFR)-targeting antibody, used in the treatment of colon cancer. KRAS mutation status is strongly predictive of cetuximab efficacy, but more predictive factors are needed for better patient selection. PTEN is a downstream inhibitor of the EGFR pathway and has been evaluated as a predictive factor of cetuximab efficacy in colorectal cancer.

Patients and methods

Formalin-fixed paraffin-embedded tumor tissue samples were collected from 226 patients with advanced or metastatic colorectal cancer that had been treated with cetuximab. Clinical information was collected retrospectively from the patients’ medical records. After central evaluation, 147 cases with adequate material were eligible for further evaluation. EGFR and PTEN status was evaluated with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Data were associated with cetuximab treatment outcome. Additional analysis was performed with previously published data on PIK3CA, BRAF and KRAS mutation status and EGFR ligand amphiregulin (AREG) and epiregulin intratumoral mRNA expression levels. PIK3CA mutation status and PTEN protein expression were also analyzed as a single complex parameter, to evaluate the predictive value of PI3K/PTEN axis dysfunction as one entity.

Results

Analysis showed a borderline association of overall response rate (ORR) and time to progression (TTP) with EGFR protein overexpression by IHC (p = 0.059 and p = 0.057, respectively) and a positive association of EGFR gain by FISH (found in only five cases) with longer TTP (p = 0.026). No association was found between ORR or TTP and PTEN IHC or FISH status. Comparative analysis with previously published data showed that PTEN protein expression is associated with longer TTP in patients with wild-type (WT) KRAS (p = 0.036) and especially in the ones with elevated AREG levels (p = 0.046), as well as in patients with both KRAS and BRAF WT (p = 0.019). Patients with both PIK3CA WT and PTEN protein expression had significantly longer TTP (p = 0.010) versus all others, in the absence of BRAF and KRAS mutations, a finding which persisted in the KRAS WT/AREG high subgroup (p = 0.046).

Conclusions

In this cetuximab-treated colorectal cancer population, EGFR gain was associated with better outcome and PTEN protein expression with longer TTP in KRAS WT, KRAS WT/AREG high and KRAS/BRAF WT subpopulations. Cetuximab efficacy is greater with intact and activated EGFR signaling, without activating mutations of KRAS/BRAF and in the presence of preserved PTEN inhibitory activity upon the PI3K/AKT pathway. These results reflect a solid biological rationale and warrant further evaluation of the predictive role of PTEN in prospective studies.     

Wives of patients with acute myocardial infarction are at an increased risk of developing coronary artery disease

BACKGROUND: The present study was carried out to investigate risk factors for developing coronary artery disease in wives of patients with acute myocardial infarction. SUBJECTS AND METHODS: Risk factors for developing coronary artery disease were investigated in 50 wives of patients who developed an acute myocardial infarction (group A) and were compared with those of 50 wives of normal healthy men (group B). The average age was 50.20 +/- 1.56 years (mean +/- SD) and 50.20 +/- 1.53 years for group A and group B respectively. The parameters assessed were: plasma cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), systolic and diastolic blood pressure, smoking habits and body mass index (BMI). RESULTS: The levels of LDL-C in the wives of patients with myocardial infarction were higher than those of the wives of normal healthy men (167.8 +/- 5.84 mg/dl and 148.4 +/- 4.85 mg/dl, respectively, P < 0.01). Moreover, HDL-C concentrations were lower in the wives of the patients (51.34 +/- 0.92 mg/dl) than in the wives of the healthy men (58.14 +/- 1.39 mg/dl), (P < 0.001). Finally, TG levels were higher in the wives of the patients (132.2 +/- 7.9 mg/dl) than in the wives of the normal healthy men (96.9 +/- 5.94 mg/dl) (P < 0.01). CONCLUSIONS: Although plasma lipid levels themselves were not excessively high, the wives of patients with an acute myocardial infarction are at a higher risk of developing coronary artery disease than the wives of normal healthy men, in the long term, due to higher levels of LDL-C and TG as well as lower levels of HDL-C.     

Cetuximab plus FOLFOX6 or FOLFIRI in metastatic colorectal cancer: CECOG trial

AIM: To investigate efficacy and safety of cetuximab combined with two chemotherapy regimens in patients with unresectable metastatic colorectal cancer (mCRC). METHODS: Randomized patients received cetuximab with 5-fluorouracil (5-FU), folinic acid (FA) and oxaliplatin (FOLFOX) 6 (arm A, n = 74) or 5-FU, FA and irinotecan (FOLFIRI) (arm B, n = 77). KRAS mutation status was determined retrospectively in a subset of tumors (n = 117). RESULTS: No significant difference was found between treatment arms A and B ...