Associations between initiating antihypertensive regimens on stage I-III colorectal cancer outcomes: A Medicare SEER cohort analysis.

PURPOSE: Colorectal cancer (CRC) diagnosis is associated with high mortality in the United States and thus warrants the study of novel treatment approaches. Vascular changes are well observed in cancers and evidence indicates that antihypertensive (AH) medications may interfere with both tumor vasculature and in recruiting immune cells to the tumor microenvironment based on preclinical models. Extant literature also shows that AH medications are correlated with improved survival in some forms of cancer. Thus, this study sought to explore the impact of AH therapies on CRC outcomes. PATIENTS AND METHODS: This study was a non-interventional, retrospective analysis of patients aged 65 years and older with CRC diagnosed from January 1, 2007 to December 31st, 2012 in the Surveillance, Epidemiology, and End-Results (SEER)-Medicare database. The association between AH drug utilization on AJCC stage I-III CRC mortality rates in patients who underwent treatment for cancer was examined using Cox proportional hazards models. RESULTS: The study cohort consisted of 13,982 patients diagnosed with CRC. Adjusted Cox proportional hazards regression showed that among these patients, the use of AH drug was associated with decreased cancer-specific mortality (HR: 0.79, 95% CI: 0.75-0.83). Specifically, ACE inhibitors (hazard ratio [HR]: 0.84, 95% CI: 0.80-0.87), beta-blockers (HR: 0.87, 95% CI: 0.84-0.91), and thiazide diuretics (HR: 0.83, 95% CI: 0.80-0.87) were found to be associated with decreased mortality. An association was also found between adherence to AH therapy and decreased cancer-specific mortality (HR: 0.94, 95% CI: 0.90-0.98). CONCLUSION: Further research needs to be performed, but AH medications may present a promising, low-cost pathway to supporting CRC treatment for stage I-III cancers.

Right colectomy: a New York state of mind.

Although mortality rates attributable to colon cancer have significantly improved over the past decades, it is still one of the leading causes of death in the USA. As newer technology and surgical techniques and concepts are being introduced, substantial confusion and dissenting opinions have come into fray as well. Naturally, different practice patterns emerged in Asia, Western Europe as well as in the USA. In this special article, we focus on the right colon and examine the unique challenges and oddities of practicing academic colorectal surgery in the New York metropolitan area.

CT assessment of right colonic arterial anatomy pre and post cancer resection - a potential marker for quality and extent of surgery?

BACKGROUND: There is conflicting opinion as to the optimum extent of resection for right-sided colonic cancer, which is currently graded by pathological analysis of the resected specimen. It is not known if computed tomography (CT) analysis of residual post-resection arterial stump length could be used as an alternative in vivo marker for extent of mesenteric resection. Ileocolic artery stumps have been demonstrated previously on CT after right hemicolectomy, but only in the early postoperative period. PURPOSE: To analyze preoperative right colonic arterial anatomy using portal venous colorectal cancer staging CT and subsequently determine if post-resection arterial stumps (a potential in vivo marker of surgical resection) could be consistently identified using routine follow-up CT scans many months after cancer resection. MATERIAL AND METHODS: A retrospective analysis of routine staging and follow-up CT scans for 151 patients with right-sided colorectal cancer was performed. Preoperative right colonic arterial anatomy and postoperative arterial stumps were analyzed and measured. RESULTS: Preoperative ileocolic (98.8%), middle (94.7%), and right colic artery (23.8%) identification was comparable to catheter angiogram studies. Postoperative ileocolic stumps were consistently demonstrated (88.3%) many months (average, 2 years and 42 days) after resection and were significantly longer than expected for a standard D2 resection (paired t-test, t(127) = -11.45, P ≤ 0.001). CONCLUSION: This is the first study to successfully demonstrate ileocolic arterial stumps many months (and years) after cancer resection using routine portal venous CT. Further prospective research should assess whether arterial stumps can be used as an in vivo marker of surgical quality and extent.

Preoperative assessment of vascular anatomy by multidetector computed tomography before laparoscopic colectomy for transverse colon cancer: report of a case.

Although the safety of laparoscopic surgery for colon cancer has been reported in many randomized controlled trials, concerns about the difficulty of surgery for transverse colon cancer has not been fully resolved, mainly because of the variation in the vascular anatomy of mesenteric vessels, which leads to difficulty in determining the optimal operative procedure and the extent of lymph node dissection. We present the case of a patient with transverse colon cancer who underwent laparoscopic surgery after preoperative assessment using a combination of endoscopic clipping and three-dimensional computed tomography angiography (3DCTA). A 68-year-old man was diagnosed with transverse colon cancer, and laparoscopic surgery has been planned. 3DCTA showed right-middle and left-middle colic arteries arising independently from the superior mesenteric artery. The relationship between the clip and vessels showed that the right-middle colic artery was the feeding artery of the tumor. Operative findings were consistent with 3DCTA findings, and transverse colectomy with lymph node dissection was successfully performed.

Assessment of acute antivascular effects of vandetanib with high-resolution dynamic contrast-enhanced computed tomographic imaging in a human colon tumor xenograft model in the nude rat.

Tumor size is not a reliable marker for the assessment of early antivascular effects of antiangiogenics. In the present study, we used 200-microm in-plane high-resolution dynamic contrast-enhanced computed tomography (DCE-CT) to noninvasively assess the immediate antivascular effects of vandetanib in a subcutaneous human colon cancer (LoVo) xenograft model in nude rats and to investigate correlation between changes in CT perfusion parameters and tumor volume or immunohistochemical end points. At 3 to 4 weeks after LoVo cell implantation, the animal was gavaged with either vandetanib (50 mg/kg) or vehicle twice (22 hours apart) and scanned with a preclinical DCE-CT scanner before (0 hour) and after treatment (24 hours). Quantitative maps of blood flow (BF) and volume (BV) of the tumor were calculated from the acquired DCE-CT images. The rats were divided into nonhypovascular, hypovascular, and combined (regardless of vascularity) groups. In the nonhypovascular group, significant decreases in both tumor BF and BV were observed in the vandetanib-treated rats compared with increases in the vehicle-treated rats. A significant decrease in BV was detected in the vandetanib-treated rats in the combined group as well. No differences in tumor growth, vascular endothelial growth factor expression, microvessel density, or apoptosis were observed between vandetanib- and vehicle-treated rats in all three groups. These results demonstrate that BF and BV imaging biomarkers from DCE-CT imaging can be used for rapid monitoring of immediate (24 hours after) antimicrovascular effects of vandetanib on tumors, even in the absence of significant changes of tumor volume or clinically relevant immunohistochemical end points.

Assessment of blood supply in superficial tissue by polarization-gated elastic light-scattering spectroscopy.

We report the feasibility of monitoring both hemoglobin oxygen saturation and hemoglobin concentration in the superficial layer of tissue using polarization-gated elastic light-scattering spectroscopy. We detail our analysis technique, the experimental validation of our analysis, and the detection of an early increase in blood supply to the superficial layer of colon tissue in human patients with colonic adenomas as well as in an animal model of colon carcinogenesis. To the best of our knowledge, this study represents the first evidence that polarization gating can be used as a spectroscopic tool to quantify hemoglobin concentration as well as oxygen saturation in the uppermost tissue layer.

Vascular endothelial growth factor assessment in different blood fractions of gastrointestinal cancer patients and healthy controls.

Vascular endothelial growth factor (VEGF) is known to play a central role in tumour angiogenesis. Up to now inconclusive data have been published on the clinical-biological significance of circulating VEGF and on the most suitable blood fraction for measuring it. The aims of this pilot study were to assess VEGF in blood compartments of 16 healthy control volunteers and 56 gastrointestinal cancer patients, prospectively collected, to identify the most suitable blood fraction for the determination of VEGF and to evaluate its possible clinical-biological significance. Samples of serum (S) and plasma (P) in both sodium citrate (SC) and sodium citrate-theophylline-adenosine-dipyridamole (CTAD) were collected from venous blood. After the centrifugation and separation methods VEGF levels were detected by ELISA in: S, plasma-platelets poor (P-PP), plasma-activated platelets rich (P-APR) and blood-lysed whole (B-LW). The best differentiation between healthy control volunteers and cancer patients in VEGF level was seen for P-APRCTAD (mean value: 278 pg/ml vs 77 pg/ml; p=0.0036 by t-test). No significant correlation among the blood fractions of VEGF analysed and clinical-pathological features was found. Our data suggest that P-APRCTAD blood fraction, obtained according to well standardised conditions, could represent the most suitable compartment for the assessment of VEGF. We suggest that VEGF levels in P-APRCTAD could play a role as an angiogenic marker of malignant gastrointestinal transformation. Further studies on a larger series of patients and healthy controls with the same experimental methodological conditions are required to confirm our preliminary conclusions.

Quantitative assessment of angiogenesis and tumor vessel architecture by computer-assisted digital image analysis: effects of VEGF-toxin conjugate on tumor microvessel density.

Tumor growth is angiogenesis dependent. As a consequence, strategies aimed at disrupting this mechanism are heavily investigated. Several angiogenesis assays are used to directly compare the efficacy of anti-angiogenic compounds. However, objective assessment of new vascular growth has been difficult to achieve. The aim of this study was to test and develop a computer-assisted image analysis method that would give an unbiased quantification of the microvessel density. Human tumors were grown in athymic mice and tumor biopsies were taken after a weeklong treatment with VEGF-toxin conjugate. Frozen tumor sections were prepared and stained with PE-conjugated anti-CD-31 antibodies and vessels were imaged with a fluorescence microscope. Vessel density was analyzed by quantifying PE-positive pixels per recorded field. In addition, images were further processed to investigate morphological differences by an automated binarization and skeletonization protocol. This procedure allowed the computer-assisted estimation of important angiogenic parameters such as total vessel number, length, and branch points. Based on these indices, differences in the angiogenic response between control tumors and those treated with VEGF-toxin conjugate were readily detected (P < 0.007 for all parameters). More importantly, computer-generated measurements correlated well with manual microvessel counts and showed significantly less variation. Our results suggest that computer-assisted image analysis represents a rapid, objective, and alternative method for the quantitative assessment of tumor angiogenesis and vessel architecture.

Expression of Von Willebrand factor, an endothelial cell marker, is up-regulated by angiogenesis factors: a potential method for objective assessment of tumor angiogenesis.

von Willebrand factor (vWF), a glycoprotein produced uniquely by endothelial cells and megakaryocytes, is routinely used to identify vessels in tissue sections. Vessel density in tumor specimens, as determined by immuno-histochemical staining for vWF or other endothelial cell markers, is a negative prognostic factor for many solid tumors. vWF is heterogeneously distributed throughout the vasculature, transcriptional control in response to the tissue microenvironment being responsible for local variations in endothelial cell levels of vWF. Here, we report that fibroblast growth factor-2 and vascular endothelial growth factor, potent angiogenesis inducers expressed in a variety of tumors, up-regulate expression of vWF mRNA and protein in cultured endothelial cells with a synergistic effect. Our data support the measurement of vWF mRNA in tumors to detect activated endothelium or angiogenesis. For this purpose, we developed a semi-quantitative RT-PCR for vWF mRNA. Preliminary results obtained with specimens from colon carcinoma and the corresponding normal colonic mucosa showed higher vWF mRNA levels in most tumors than in their normal counterparts. The differences in vWF mRNA levels were much larger than the differences in vessel counts between a tumor and the corresponding normal mucosa, indicating that high vWF mRNA levels in tumors may indeed be an early sign of activation of the endothelium. The rapidity, objectivity, sensitivity and specificity of this technique make it suitable for routine clinical application to identify aggressive, highly angiogenic tumors.

Assessment of human colon cancer protein kinetics in vivo.

BACKGROUND: Malignancies enlarge because protein synthesis exceeds the rate of breakdown; however, the specific protein kinetic pattern remains unknown. Determining in vivo protein kinetic rates for a tumor may be useful for quantifying individual responses to a specific therapy. The aim of this study was to assess whether the growth of tumors is related to an increase in protein synthesis or an inhibition of protein breakdown. METHODS: Five patients (age, 59 +/- 3 years) with adenocarcinoma of the colon undergoing colonoscopy were studied. Tissue protein synthesis and breakdown rates were measured in vivo for both segments of colon cancer and adjacent normal-appearing colonic mucosa by using a primed, continuous infusion of 1(13)C leucine with tissue biopsy and quantitation of regional blood flow by laser Doppler flowmetry. RESULTS: Segments of colon cancer had a significantly (p < 0.05) greater rate of protein synthesis as quantitated by both the fractional rate of protein synthesis (Ca 45.4% +/- 5.0%/day versus nl mucosa 35.7% +/- 3.1%/day; mean +/- SEM) and by the tissue synthesis rate (Ca 69.4 +/- 9.0 versus nl mucosa 51.6 +/- 5.2 mumol/L leucine/day/100 gm tissue). Regional blood flow was significantly elevated in the cancer (Ca 110.9 +/- 5.8 versus nl mucosa 91.2 +/- 2.9 ml/min/100 gm), which contributed to commensurate rates of tissue breakdown (Ca 28.6 +/- 2.0 versus nl mucosa 28.2 +/- 2.4 mumol/L leucine/day/100 gm). CONCLUSIONS: These results illustrate that human colon cancers grow in vivo as a result of increases in protein synthesis. Furthermore, increases in regional blood flow limit the rate of tissue protein breakdown of colon cancer, thereby contributing to growth of the malignancy. These findings support the contention that therapeutic strategies aimed at negating this inherent increase in protein synthesis or limiting blood flow may effectively limit the growth of malignancies. This methodology may also provide an index for evaluating the effectiveness of future therapies aimed at reducing tumor growth for individual patients.