Global Curriculum in Research Literacy for the Surgical Oncologist.

BACKGROUND: The ability to provide optimal care to cancer patients depends on awareness of current evidence-based practices emanating from research or involvement in research where circumstances permit. The significant global variations in cancer-related research activity and its correlation to cancer-specific outcomes may have an influence on the care provided to cancer patients and their outcomes. The aim of this project is to develop a global curriculum in research literacy for the surgical oncologist. MATERIALS AND METHODS: The leadership of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in research literacy for the Surgical Oncologist. RESULTS: A global curriculum in research literacy is developed to incorporate the required domains considered to be essential to interpret the published research or become involved in research activity where circumstances permit. The purpose of this curriculum is to promote research literacy for the surgical oncologist, wherever they are based. It does not mandate direct research participation which may not be feasible due to restrictions within the local health-care delivery environment, socio-economic priorities and the educational environment of the individual institution where they work. CONCLUSIONS: A global curriculum in research literacy is proposed which may promote research literacy or encourage involvement in research activity where circumstances permit. It is hoped that this will enhance cancer-related research activity, promote awareness of optimal evidence-based practices and improve outcomes for cancer patients globally.

Consensus Conference on North American Training in Hepatopancreaticobiliary Surgery: A Review of the Conference and Presentation of Consensus Statements.

The findings and recommendations of the North American consensus conference on training in hepatopancreaticobiliary (HPB) surgery held in October 2014 are presented. The conference was hosted by the Society for Surgical Oncology (SSO), the Americas Hepato-Pancreatico-Biliary Association (AHPBA), and the American Society of Transplant Surgeons (ASTS). The current state of training in HPB surgery in North America was defined through three pathways-HPB, surgical oncology, and solid organ transplant fellowships. Consensus regarding programmatic requirements included establishment of minimum case volumes and inclusion of quality metrics. Formative assessment, using milestones as a framework and inclusive of both operative and nonoperative skills, must be present. Specific core HPB cases should be defined and used for evaluation of operative skills. The conference concluded with a focus on the optimal means to perform summative assessment to evaluate the individual fellow completing a fellowship in HPB surgery. Presentations from the hospital perspective and the American Board of Surgery led to consensus that summative assessment was desired by the public and the hospital systems and should occur in a uniform but possibly modular manner for all HPB fellowship pathways. A task force composed of representatives of the SSO, AHPBA, and ASTS are charged with implementation of the consensus statements emanating from this consensus conference.

Global Curriculum in Surgical Oncology.

BACKGROUND: The significant global variations in surgical oncology training paradigms can have a detrimental effect on tackling the rising global cancer burden. While some variations in training are essential to account for the differences in types of cancer and biology, the fundamental principles of providing care to a cancer patient remain the same. The development of a global curriculum in surgical oncology with incorporated essential standards could be very useful in building an adequately trained surgical oncology workforce, which in turn could help in tackling the rising global cancer burden. MATERIALS AND METHODS: The leaders of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in surgical oncology. RESULTS: A global curriculum in surgical oncology was developed to incorporate the required domains considered to be essential in training a surgical oncologist. The curriculum was constructed in a modular fashion to permit flexibility to suit the needs of the different regions of the world. Similarly, recognizing the various sociocultural, financial and cultural influences across the world, the proposed curriculum is aspirational and not mandatory in intent. CONCLUSIONS: A global curriculum was developed which may be considered as a foundational scaffolding for training surgical oncologists worldwide. It is envisioned that this initial global curriculum will provide a flexible and modular scaffolding that can be tailored by individual countries or regions to train surgical oncologists in a way that is appropriate for practice in their local environment. © 2016 Society of Surgical Oncology and the European Society of Surgical Oncology. Published by SpringerNature. All rights reserved.

Efficacy of caspofungin as salvage therapy for invasive aspergillosis compared to standard therapy in a historical cohort.

In a non-comparative study, caspofungin was effective salvage therapy for approximately half of the patients refractory to or intolerant of standard antifungal agents for invasive aspergillosis. To establish a frame of reference for these results, we compared the response to caspofungin with responses to other antifungal agents in a historical cohort of similar patients. The efficacy could be evaluated in 83 patients who received caspofungin 50 mg daily after a 70-mg loading dose. The historical control group, identified through a retrospective review of medical records, included 214 evaluable patients possibly refractory to or intolerant of ≥1 week of standard antifungal therapy. All patients had documented invasive aspergillosis. Favorable response was defined as a complete or partial response to therapy. Underlying diseases, baseline neutropenia, corticosteroid use, and sites of infection were similar in both studies. Most patients had received amphotericin B formulations and/or itraconazole, and were refractory to standard therapy. Favorable response rates were 45% with caspofungin and 16% with standard therapy. The unadjusted odds ratio for a favorable response (caspofungin/standard therapy) was 4.1 (95% confidence interval: 2.2, 7.5). After adjusting for potential imbalances in the frequency of disseminated infection, neutropenia, steroid use, and bone marrow transplantation between groups, the odds ratio remained at 4.1 (2.1, 7.9). Although only tentative conclusions about relative efficacy can be drawn from retrospective comparisons, caspofungin appeared to be at least as efficacious as an amphotericin B formulation and/or itraconazole for the treatment of invasive aspergillosis in patients refractory to or intolerant of their initial antifungal therapy.

Global curriculum in research literacy for the surgical oncologist.

BACKGROUND: The ability to provide optimal care to cancer patients depends on awareness of current evidence-based practices emanating from research or involvement in research where circumstances permit. The significant global variations in cancer-related research activity and its correlation to cancer-specific outcomes may have an influence on the care provided to cancer patients and their outcomes. The aim of this project is to develop a global curriculum in research literacy for the surgical oncologist. MATERIALS AND METHODS: The leadership of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in research literacy for the Surgical Oncologist. RESULTS: A global curriculum in research literacy is developed to incorporate the required domains considered to be essential to interpret the published research or become involved in research activity where circumstances permit. The purpose of this curriculum is to promote research literacy for the surgical oncologist, wherever they are based. It does not mandate direct research participation which may not be feasible due to restrictions within the local health-care delivery environment, socio-economic priorities and the educational environment of the individual institution where they work. CONCLUSIONS: A global curriculum in research literacy is proposed which may promote research literacy or encourage involvement in research activity where circumstances permit. It is hoped that this will enhance cancer-related research activity, promote awareness of optimal evidence-based practices and improve outcomes for cancer patients globally.

Global curriculum in surgical oncology.

BACKGROUND: The significant global variations in surgical oncology training paradigms can have a detrimental effect on tackling the rising global cancer burden. While some variations in training are essential to account for the differences in types of cancer and biology, the fundamental principles of providing care to a cancer patient remain the same. The development of a global curriculum in surgical oncology with incorporated essential standards could be very useful in building an adequately trained surgical oncology workforce, which in turn could help in tackling the rising global cancer burden. MATERIALS AND METHODS: The leaders of the Society of Surgical Oncology and European Society of Surgical Oncology convened a global curriculum committee to develop a global curriculum in surgical oncology. RESULTS: A global curriculum in surgical oncology was developed to incorporate the required domains considered to be essential in training a surgical oncologist. The curriculum was constructed in a modular fashion to permit flexibility to suit the needs of the different regions of the world. Similarly, recognizing the various sociocultural, financial and cultural influences across the world, the proposed curriculum is aspirational and not mandatory in intent. CONCLUSIONS: A global curriculum was developed which may be considered as a foundational scaffolding for training surgical oncologists worldwide. It is envisioned that this initial global curriculum will provide a flexible and modular scaffolding that can be tailored by individual countries or regions to train surgical oncologists in a way that is appropriate for practice in their local environment.

Long-term outcome of patients with American Joint Committee on Cancer stage IIB extremity soft tissue sarcomas.

PURPOSE: It has been suggested that patients with small (< 5 cm), high-grade extremity soft tissue sarcomas (STS) have an excellent overall prognosis and, consequently, may not require adjuvant therapies. PATIENTS AND METHODS: A comprehensive review of all patients with extremity STS treated at a tertiary care cancer hospital over a 9-year period (January 1984 to December 1992) was performed. Prognostic factors, treatment data, and long-term outcome were evaluated in the subset of 111 patients with American Joint Committee on Cancer stage IIB (G3/4, T1a/b) disease. RESULTS: The median tumor size was 3.0 cm (range, 0.6 to 4.9 cm), and 55 tumors (50%) were deep in location. All patients underwent surgical resection; 68 (61%) received pre- or postoperative radiotherapy, and 32 (29%) received doxorubicin-based chemotherapy. The median follow-up was 76 months. Forty patients (36%) experienced 59 recurrences. First recurrences occurred at local, regional, and distant sites in 21, five, and 14 patients, respectively. The 5-year actuarial local recurrence-free, distant recurrence-free, disease-free, and overall survival rates were 82%, 83%, 68%, and 83%, respectively. The presence of a microscopically positive surgical margin was an independent adverse prognostic factor for both local recurrence (relative risk [RR] = 3.75; 95% confidence interval [CI], 1.25 to 11.25; P =.02) and disease-free survival (RR = 2.57; 95% CI, 1.33 to 4.98; P =.005). CONCLUSION: Event-free outcome for this subset of patients with high-grade STS does not seem as favorable as previously reported by other investigators. Patients who undergo maximal surgical resection with microscopically positive margins represent a subset of T1 STS patients who warrant consideration for adjuvant therapies.

Arterial endothelial barrier dysfunction: actions of homocysteine and the hypoxanthine-xanthine oxidase free radical generating system.

1. Endothelial barrier function was assessed by use of an in vitro model in which transfer of trypan blue-labelled albumin was measured across monolayers of bovine aortic endothelial cells grown on polycarbonate membranes. 2. Addition of either hypoxanthine (0.2 mM) or xanthine oxidase (20 mu ml-1) alone during a 90 min incubation did not affect albumin transfer across endothelial cell monolayers, but a combination of both increased transfer. 3. The increase in albumin transfer induced by hypoxanthine and xanthine oxidase was abolished by catalase (3 u ml-1), reduced by allopurinol (4 mM), but unaffected by superoxide dismutase (6000 u ml-1), the hydroxyl radical scavengers, mannitol (15 mM), dimethylthiourea (10 mM) and N-(2-mercaptopropionyl)-glycine (1 mM), the iron chelator, deferoxamine (0.5 mM), ferric chloride (50 microM), an inhibitor of nitric oxide synthase, NG-nitro-L-arginine (30 microM), or the antioxidant, dithiothreitol (3 mM). 4. Hydrogen peroxide (0.1-30 mM) itself increased albumin transfer across endothelial cell monolayers, exhibiting a biphasic concentration-response curve. The increase induced by 0.1 mM hydrogen peroxide was abolished in the presence of 0.3 u ml-1 catalase whilst that induced by 10 mM hydrogen peroxide was abolished by 3000 u ml-1 catalase. 5. Homocysteine (0.5-1.5 mM) did not affect albumin transfer across endothelial monolayers when added alone, but when added in combination with copper sulphate (50 microM), which catalyses its oxidation, a significant increase in albumin transfer was observed. 6. The increase in albumin transfer induced by the combination of homocysteine (1.5 mM) and copper sulphate was abolished by catalase (1 u ml-1), but was unaffected by superoxide dismutase (6000 u ml-1), mannitol (15 mM), dimethylthiourea (1 mM) or deferoxamine (0.5 mM).7. The data suggest that the endothelial barrier dysfunction induced by the combination of hypoxanthine and xanthine oxidase is mediated solely by the action of hydrogen peroxide and not by superoxide anion, hydroxyl radical, peroxynitrite anion or hypochlorous acid. The copper-catalysed oxidation of homocysteine also induces endothelial barrier dysfunction through the generation of hydrogen peroxide.These findings may have relevance to the endothelial barrier dysfunction associated with ischaemia reperfusion injury and the atherogenic actions of homocysteine.

Differential actions of charybdotoxin on central and daughter branch arteries of the rabbit isolated ear.

1. By use of rabbit isolated perfused intact ears and isolated perfused segments of central and first generation daughter branch ear arteries, we investigated the actions of charybdotoxin (ChTX), a blocker of calcium-activated K+ channels (KCa channels), and N omega-nitro-L-arginine methyl ester (L-NAME) on pressure-flow and diameter-flow relationships. 2. ChTX (1 nM) induced an upwards shift in the pressure-flow curve in the rabbit intact isolated ear preconstricted with 5-hydroxytryptamine (5-HT; 100 nM) with subsequent administration of L-NAME (100 microM) inducing a further upwards shift. L-NAME itself induced an upwards shift in the pressure-flow curve, but subsequent administration of ChTX was without significant effect. 3. Microangiographic analysis revealed a tendency of ChTX (1 nM) to decrease vessel diameter in the central ear artery (G0) with little effect on the first two generations of daughter branch arteries (G1 and G2) in the intact ear. Subsequent addition of L-NAME (100 microM) did not significantly further decrease vessel diameter in G0, but did decrease vessel diameter in G1 and G2. L-NAME itself showed a tendency to decrease vessel diameter in G0, G1 and G2 vessels with subsequent addition of ChTX being without significant effect. 4. In an isolated G0 preparation which was preconstricted with 5-HT (100 nM), ChTX (1 nM) caused an upwards shift in the pressure-flow curve which was augmented by subsequent addition of L-NAME (100 microM). L-NAME (100 microM) itself caused an upwards shift in the pressure-flow curve but subsequent addition of ChTX (1 nM) had no significant effect. 5. In comparison, in an isolated G1 preparation which was preconstricted with 5-HT (100 nM), ChTX (1 nM) had no significant effect on the pressure-flow curve relative to control, but subsequent addition of L-NAME (100 microM) caused an upwards shift. L-NAME (100 microM) itself induced an upwards shift in the pressure-flow curve with subsequent addition of ChTX (1 nM) being without significant effect. 6. ChTX (10 pM-10 nM) caused a concentration-dependent increase in perfusion pressure in isolated G0 and G1 preparations at fixed flow rates of 2 ml min-1 and 0.5 ml min-1, respectively. These responses were enhanced in the presence of L-NAME (100 microM) in G1 but not G0 preparations. 7. We conclude that at 1 nM, ChTX exhibits differential actions on central and daughter branch arteries of the intact ear of the rabbit, which are also apparent in the corresponding arteries when studied in isolation. The action of 1 nM ChTX in G0 vessels may reflect inhibition of either the release or action of nitric oxide as it was blocked in the presence of L-NAME. At higher concentrations of ChTX, there would appear to be a direct constrictor effect on vascular smooth muscle which is apparent in both G0 and G1 vessels. This observed heterogeneity could reflect different distributions of KCa channels between central and daughter branch arteries at either the endothelial or smooth muscle levels, or both.

Spatial heterogeneity in the mechanisms contributing to acetylcholine-induced dilatation in the rabbit isolated ear.

1. Using an X-ray microangiographic technique in rabbit isolated perfused ears preconstricted with 5-HT (300 nM) and histamine (300 nM), we investigated the combined actions of N(omega)-nitro-L-arginine methyl ester (L-NAME) and indomethacin on acetylcholine-induced depressor responses. 2. Under control conditions, acetylcholine (10 nM-30 microM) induced a concentration-dependent reversal of the pressor response, reaching a maximum of 66.0+/-13.6% (n = 6). In the presence of L-NAME (300 microM) and indomethacin (10 microM), this depressor action was reduced, reaching a maximum of 38.6+/-5.9% (n = 6). 3. The control response was associated with substantial vasodilatation in the central ear artery (G0), a smaller dilatory action on first generation branch arteries (G1) and no effect on second generation branch arteries (G2). In the presence of L-NAME and indomethacin, vasodilatation occurred in G2 with no effect in G0 or G1. 4. Two calcium-activated K+ channels blockers, charybdotoxin (ChTX; 10 nM) and penitrem A (100 nM), further inhibited, but did not abolish, the L-NAME- and indomethacin-resistant response to acetylcholine (10 nM-300 microM). Both agents abolished the vasodilatory action of acetylcholine in G2. 5. In conclusion, L-NAME and indomethacin induced a shift in acetylcholine-induced vasodilatation from G0 and G1 to G2. This is consistent with the suggestion that nitric oxide dominates in larger vessels whilst other mechanisms dominate in smaller vessels. The L-NAME- and indomethacin-resistant component was inhibited by ChTX and penitrem A, suggesting it is mediated, at least in part, by activation of K(Ca) channels and could therefore involve a hyperpolarising mediator such as endothelium-derived hyperpolarising factor.

Endotoxin-induced arterial endothelial barrier dysfunction assessed by an in vitro model.

Using an in vitro model in which albumin transfer across monolayers of bovine aortic endothelial cells (BAEC) was measured, we have shown that lipopolysaccharide (LPS) induces a concentration-dependent increase in endothelial permeability. This increase was biphasic, having an early peak at 2 h and rising again by 24 h. Both peaks were abolished by polymixin B (PMB) but were unaffected by N omega-monomethyl-L-arginine, N omega-nitro-L-arginine methyl ester or dexamethasone. Furthermore, LPS did not stimulate nitric oxide production by BAEC following 24 h exposure. Thus, the LPS-induced increase in permeability may account for the vascular leakage of septic shock, but the L-arginine-nitric oxide system does not appear to be involved.

Pharmacodynamic activity of intravenous E-3174, an angiotensin II antagonist, in patients with essential hypertension.

Losartan potassium (DuP 753), an orally active angiotensin II receptor antagonist, is metabolized to a more potent active metabolite, E-3174, which contributes to losartan's long duration of action. The acute pharmacodynamic actions of intravenous (i.v.) E-3174 (20 mg infused over 4 h) were compared to placebo (vehicle) in two groups of patients with essential hypertension. Patients with supine diastolic blood pressure (SuDBP) of 100 to 120 mm Hg entered a 2-day inpatient phase and received vehicle on day 1. Patients with SuDBP > or = 95 mm Hg were randomized to double-blind treatment the next day. E-3174 significantly (P < .05) reduced SuDBP compared to placebo, beginning at approximately 100 min after the start of the infusion, with a maximum hypotensive effect at 8 h. Supine systolic blood pressure was also reduced by E-3174. Supine and standing heart rates did not differ between treatments. Mean E-3174 plasma levels were 324.6 ng/mL at 20 min and approximately 1000 ng/mL at the end of the 4-h infusion; during this time there was a modest decrease in blood pressure. Following the infusion, the relationship between plasma E-3174 levels and SuDBP was confounded by much larger decreases in blood pressure, which occurred as plasma drug concentrations declined. Urinary excretions of sodium, potassium, or chloride were not significantly altered by E-3174 nor was the fractional excretion of uric acid significantly different between groups. There were no drug-related or serious adverse experiences and no patient discontinued treatment due to an adverse experience.(ABSTRACT TRUNCATED AT 250 WORDS)

Histiocytosis-X: in situ characterization of cutaneous infiltrates with monoclonal antibodies.

Cutaneous lesions in three cases of histiocytosis-X were studied by light microscopy, electron microscopy, and immunoperoxidase technics. In each case, Birbeck granule-containing histiocytosis-X cells infiltrated the epidermis and were apposed to lymphocytes. The histiocytosis-X cells and normal Langerhans cells stained with anti-T6 and anti-I1 (Ia-like) antibodies but were negative with anti-T3, anti-T8, anti-M1, and anti-lysozyme antibodies. In addition, the histiocytosis-X cells also stained with anti-T4 antibodies, which react with T-cells associated with helper/inducer phenotype. This study supports the hypothesis that histiocytosis-X cells are abnormal Langerhans cells. The presence of T4/T6-positive cells in cutaneous disease may be a marker for abnormal Langerhans cells.

How many lymph nodes are enough during sentinel lymphadenectomy for primary melanoma?

BACKGROUND: Sentinel lymph node (SLN) biopsy has been shown to reliably identify nodal metastases and the subsequent need for further surgical and adjuvant therapy in patients with cutaneous melanoma. Although SLN identification rates have improved with the addition of radioactive colloid to the blue dye technique, it remains unclear how many lymph nodes should be removed to accurately determine the histologic status of the nodal basin. The objective of this study was to determine the optimal extent of SLN biopsy in these patients. METHODS: The records of 633 consecutive patients with melanoma (765 nodal basins) whose primary treatment included SLN biopsy with the use of a combination of blue dye and technetium Tc 99 labeled sulfur colloid were reviewed. SLN biopsy consisted of the removal of all of the blue-stained nodes and all nodes with radiotracer uptake activity of at least twice background. RESULTS: SLN biopsy was successful in 765 of 772 basins (99%). A mean of 1.9 SLNs (median, 2 SLNs) per basin were excised. At least 3 SLNs were removed in 176 basins (23%). The overall histologic status of a basin was always established by the first or second SLN harvested (ie, in no patient was the third or subsequent SLN positive when 1 of the first 2 was not). Of the 124 basins containing lymphatic metastases, the SLN that contained the maximal radiotracer uptake (hottest) and/or stained blue was pathologically positive in 118 basins (95%). In only 6 of the 124 positive basins (5%) was the sole evidence of occult nodal metastases identified in an SLN that was neither blue-stained nor the hottest. All but 1 of these SLNs had counts that were at least 66% of the hottest node in the basin. CONCLUSIONS: With a combined modality approach to SLN biopsy, removal of more than 2 SLNs did not provide information that upstaged any patient with primary melanoma. Removal of additional nonblue SLN(s) that contained radioactive counts of at least twice background but lower than two thirds of the SLNs with maximal radiotracer uptake affected patient management in less than 0.2% of all cases. These findings may be helpful in minimizing the extent of surgery and perhaps in reducing the costs and resource use associated with operating room time and pathologic examination.

Hydrochlorothiazide pharmacokinetics and pharmacologic effect: the influence of indomethacin.

It is known that nonsteroidal antiinflammatory drugs such as indomethacin can attenuate the pharmacologic effect of loop diuretics such as furosemide and ethacrynic acid and that indomethacin may also reduce the pharmacologic response to chlorothiazide. To examine further this potential drug-drug interaction, we administered 50- an 100-mg single oral doses of hydrochlorothiazide with and without indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin to 10 healthy, normal subjects. We observed no significant influence of indomethacin either on the pharmacokinetics of hydrochlorothiazide or the pharmacologic response to this diuretic. The adsorption and disposition of hydrochlorothiazide demonstrate that this drug is rapidly absorbed and produces a diuretic and natriuretic response that peaks at approximately 2 hours after dosing and is essentially terminated 12 hours after dosing. There appeared to be no greater pharmacologic response to the 100-mg than to the 50-mg hydrochlorothiazide dose in the ten subjects in this study.

Acid suppression by famotidine 20 mg twice daily or 40 mg twice daily in preventing relapse of endoscopic recurrence of erosive esophagitis.

Control of esophageal acid exposure is important in treating patients with gastroesophageal reflux disease (GERD). After complete healing of esophagitis, most patients will relapse within 6 months if left untreated. This multicenter, randomized, double-masked, placebo-controlled trial, conducted in the United States, examined whether two famotidine dosing regimens are effective in extending the time in remission for patients with moderate-to-severe erosive esophagitis. Of 172 patients enrolled, 31 received placebo, 69 received famotidine 20 mg twice daily (BID) , and 72 received famotidine 40 mg BID. Endoscopy was scheduled at baseline and at months 3 and 6. Patients assessed global heartburn and symptom relief at months 3 and 6 relative to the start of the study. Life table (Kaplan-Meier) relapse rates at 6 months were 22% (P < 0.001 vs placebo) for famotidine 20 mg BID, 11% (P < 0.001 vs placebo) for famotidine 40 mg BID, and 62% for placebo. Compared with placebo, patients in the famotidine groups were significantly less likely to note global symptomatic deterioration, as measured by the distribution of global assessment responses. The incidence of clinical and laboratory adverse experiences was similar among treatment groups. For maintenance treatment of GERD, famotidine 20 mg BID and 40 mg BID are more effective than placebo in extending the time in remission.

Neutrophilic eccrine hidradenitis. A distinctive type of neutrophilic dermatosis associated with myelogenous leukemia and chemotherapy.

On two occasions, erythematous edematous plaques developed on the left side of the neck and the left shoulder of a man undergoing induction chemotherapy for acute myelogenous leukemia. The lesions resolved after several days in both instances. Histologically, numerous neutrophils surrounded and focally infiltrated the eccrine secretory coils, in which epithelial necrosis was observed. The "fixed" nature of the plaques and temporal relationship to chemotherapy suggest that the lesions represent an unusual reaction to chemotherapeutic agents. It is possible that this unique clinicopathologic picture represents a neutrophilic dermatosis associated with leukemia.

Molecular determinants of colon cancer metastasis.

Colon cancer metastasis is a tightly regulated process that requires a cancer cell to express genes that allow progression through various distinct steps. Aberrations in gene expression by cancer cells leads to transformation, growth, angiogenesis, invasion, dissemination and survival in the circulation, attachment in the organ of metastasis, and again invasion, growth, and angiogenesis. In addition to the genotype/phenotype of the tumor cell, for a tumor cell to become a clinically relevant metastasis, it must be able to respond appropriately to the environment. This includes being able to utilize growth factors and blood vessels from the organ of metastasis for the benefit of the tumor mass. Understanding the molecular and biologic mechanisms of colon cancer metastasis will allow the development of rationale therapeutic strategies that are more likely to impact the natural history of this disease than current therapies.

Biology of liver metastases.

A primary goal of cancer research is an increased understanding of the molecular mechanisms mediating the process of cancer metastasis. Analyses of colon cancer cells (the seeds) and the microenvironment (the soil) have increased our understanding of the biologic mechanisms mediating metastasis formation. Insight into the molecular mechanisms regulating the pathobiology of colon cancer metastasis, as well as a better understanding of the interaction between the metastatic cell and the host environment (including the vasculature), should provide a foundation for new therapeutic approaches. To the clinician, it is readily apparent that by the time metastases form, most steps in the metastatic cascade have completed. Therefore, therapy to down-regulate or interrupt the last stages of metastasis, proliferation and angiogenesis as well as mechanisms to disrupt cell survival signals seems the most promising areas of investigation.