Tumor-associated macrophages (TAMs) as biomarkers for gastric cancer: A review.

Gastric adenocarcinoma is one of the most common types of cancer worldwide, with an incidence of a million new cases annually. In addition to having a high mortality rate due to often delayed detection and its poor response to cancer therapy, it also spreads aggressively. Inflammation has been shown to play a role in carcinogenesis. Consequently, macrophages are important in phagocytosis, antigen presenting and producing cytokines and growth factors. As a response to microenvironmental signals, they may polarize into tumor resisting M1 or tumor promoting M2 macrophages. Recently, studies have indicated that M2-type macrophage resembling tumor-associated macrophages (TAMs) might be used as an independent prognostic factor for gastric cancer. This review will discuss the possible use of TAMs as prognostic tools for gastric cancer and whether they are suitable for use in clinical environment.

Toward a Consensus on Centralization in Surgery.

OBJECTIVES: To critically assess centralization policies for highly specialized surgeries in Europe and North America and propose recommendations. BACKGROUND/METHODS: Most countries are increasingly forced to maintain quality medicine at a reasonable cost. An all-inclusive perspective, including health care providers, payers, society as a whole and patients, has ubiquitously failed, arguably for different reasons in environments. This special article follows 3 aims: first, analyze health care policies for centralization in different countries, second, analyze how centralization strategies affect patient outcome and other aspects such as medical education and cost, and third, propose recommendations for centralization, which could apply across continents. RESULTS: Conflicting interests have led many countries to compromise for a health care system based on factors beyond best patient-oriented care. Centralization has been a common strategy, but modalities vary greatly among countries with no consensus on the minimal requirement for the number of procedures per center or per surgeon. Most national policies are either partially or not implemented. Data overwhelmingly indicate that concentration of complex care or procedures in specialized centers have positive impacts on quality of care and cost. Countries requiring lower threshold numbers for centralization, however, may cause inappropriate expansion of indications, as hospitals struggle to fulfill the criteria. Centralization requires adjustments in training and credentialing of general and specialized surgeons, and patient education. CONCLUSION/RECOMMENDATIONS: There is an obvious need in most areas for effective centralization. Unrestrained, purely "market driven" approaches are deleterious to patients and society. Centralization should not be based solely on minimal number of procedures, but rather on the multidisciplinary treatment of complex diseases including well-trained specialists available around the clock. Audited prospective database with monitoring of quality of care and cost are mandatory.

Increasing the Inflammatory Competence of Macrophages with IL-6 or with Combination of IL-4 and LPS Restrains the Invasiveness of Pancreatic Cancer Cells.

Recent studies suggest that pro-inflammatory type M1 macrophages inhibit tumor progression and that anti-inflammatory M2 macrophages enhance it. The aim of this study was to examine the interaction of type M1 and M2 macrophages with pancreatic cancer cells. We studied the migration rate of fluorescein stained pancreatic cancer cells on Matrigel cultured alone or with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) differentiated macrophages or with Macrophage Colony Stimulating Factor (M-CSF) differentiated macrophages, skewing the phenotype towards pro- and anti-inflammatory direction, respectively. Macrophage differentiation was assessed with flow cytometry and the cytokine secretion in cell cultures with cytokine array. Both GM-CSF and M-CSF differentiated macrophages increased the migration rate of primary pancreatic adenocarcinoma cell line (MiaPaCa-2) and metastatic cell line (HPAF-II). Stimulation with IL6 or IL4+LPS reversed the macrophages' increasing effect on the migration rate of MiaPaCa-2 completely and partly of HPAF-II. Co-culture with MiaPaCa-2 reduced the inflammatory cytokine secretion of GM-CSF differentiated macrophages. Co-culture of macrophages with pancreatic cancer cells seem to change the inflammatory cytokine profile of GM-CSF differentiated macrophages and this might explain why also GM-CSF differentiated macrophages promoted the invasion. Adding IL6 or IL4+LPS to the cell culture with MiaPaCa-2 and GM-CSF or M-CSF differentiated macrophages increased the secretion of inflammatory cytokines and this could contribute to the reversion of the macrophage induced increase of cancer cell migration rate.

Thrombin generation in vitro and in vivo, and disturbed tissue factor regulation in patients with acute pancreatitis.

BACKGROUND: Being a central link between inflammation and coagulation, tissue factor (TF) and its inhibitor (TFPI) might be associated with the severity of acute pancreatitis (AP) and the development of organ failure (OF). METHODS: The study comprises 9 severe AP patients with OF and 24 reference patients (11 mild AP and 13 severe AP without OF). Plasma samples were collected on admission. TF-induced thrombin generation in plasma samples was studied using the thrombogram method. In vivo thrombin generation was estimated by prothrombin fragment F1+2. Free and total TFPI levels were measured. To evaluate coagulation status the activated partial thromboplastin time, prothrombin time, platelet count, D-dimer, fibrinogen, antithrombin (AT) 3 and protein C (PC) were determined. RESULTS: There was no significant difference in F1+2 levels between the patient groups. Patients with severe AP tended to show low platelet counts, PC and AT3 levels, and high D-dimer levels. In 11 patients the standard TF stimulation did not trigger thrombin generation in the thrombogram. All deaths occurred in these patients. Free TFPI levels and free/total TFPI ratios were significantly higher in these patients and in non-survivors. CONCLUSION: Failure of TF-initiated thrombin generation in the thrombogram assay explained by high levels of circulating free TFPI may be associated with OF and mortality in AP. and IAP.

A prospective diagnostic accuracy study of 18F-fluorodeoxyglucose positron emission tomography/computed tomography, multidetector row computed tomography, and magnetic resonance imaging in primary diagnosis and staging of pancreatic cancer.

OBJECTIVE: To prospectively compare the accuracy of combined positron emission tomography/computed tomography using F-fluorodeoxyglucose (FDG-PET/CT), multidetector row computed tomography (MDCT), and magnetic resonance imaging (MRI) in the evaluation of patients with suspected pancreatic malignancy. SUMMARY BACKGROUND DATA: FDG-PET/CT imaging is increasingly used for staging of pancreatic cancer. Preliminary data suggest a significant influence of FDG-PET/CT on treatment planning, although its role is still evolving. METHODS: Thirty-eight consecutive patients with suspicion of pancreatic malignancy were enrolled. Patients underwent a protocol including FDG-PET/CT, MDCT, and MRI combined with magnetic resonance cholangiopancreatography, all of which were blindly evaluated. The findings were confirmed macroscopically at operation and/or by histopathologic analysis (n = 29) or follow-up (n = 9). Results of TNM classification of different imaging methods were compared with clinical TNM classification. RESULTS: Pancreatic adenocarcinoma was diagnosed in 17 patients, neuroendocrine tumor in 3, mass-forming pancreatitis in 4, cystic lesion in 6, and fibrosis in 2. Six patients had a finding of a normal pancreas. The diagnostic accuracy of FDG-PET/CT for pancreatic malignancy was 89%, compared with 76% and 79% for MDCT and MRI, respectively. In the differential diagnosis of suspected malignant biliary stricture at endoscopic retrograde cholangiopancreaticography (n = 21), FDG-PET/CT had a positive predictive value of 92%. In 17 patients with advanced pancreatic adenocarcinoma, FDG-PET/CT had a sensitivity of 30% for N- and 88% for M-staging. Both MDCT and MRI had sensitivities of 30% for N- and 38% for M-staging. Furthermore, the clinical management of 10 patients (26%) was altered after FDG-PET/CT. CONCLUSION: FDG-PET/CT was more sensitive than conventional imaging in the diagnosis of both primary pancreatic adenocarcinoma and associated distant metastases. In contrast, the sensitivity of FDG-PET/CT was poor in detecting local lymph node metastasis, which would have been important for an assessment of resectability. We recommend the use of FDG-PET/CT in the evaluation of diagnostically challenging cases, especially in patients with biliary strictures without evidence of malignancy in conventional imaging.

Altered tissue repair in hevin-null mice: inhibition of fibroblast migration by a matricellular SPARC homolog.

Matricellular proteins such as hevin, secreted protein acidic and rich in cysteine, and thrombospondin-2 play an important role during tissue repair through their influence on fundamental cellular activities such as adhesion, migration, proliferation, and extracellular matrix synthesis/reorganization. We have investigated the role played by hevin during excisional and incisional cutaneous wound repair in hevin-null mice. Hevin-null animals both close and heal their skin wounds faster than wild-type animals, as evidenced by enhanced macrophage infiltration of wound beds at early time points, the earlier appearance of mature extracellular matrix, and the overall higher maturity score. In addition, fibrovascular invasion of polyvinyl alcohol sponges was more robust in hevin-null mice, a result indicating that differences in cell migration might underlie the observed alterations in wound repair. Experiments in vitro showed that hevin induced the deadhesion and inhibited the migration of primary dermal fibroblasts in a Rac-1-dependent manner. These findings indicate that the differences in wound repair between hevin-null and wild-type animals can be attributed in part to the deadhesive function of hevin and reduced cell migration within dermal wound beds in which this protein is expressed.

Early assessment of pancreatic infections and overall prognosis in severe acute pancreatitis by procalcitonin (PCT): a prospective international multicenter study.

BACKGROUND: Pancreatic infections and sepsis are major complications in severe acute pancreatitis (AP) with significant impact on management and outcome. We investigated the value of Procalcitonin (PCT) for identifying patients at risk to develop pancreatic infections in severe AP. METHODS: A total of 104 patients with predicted severe AP were enrolled in five European academic surgical centers within 96 hours of symptom onset. PCT was measured prospectively by a semi-automated immunoassay in each center, C-reactive protein (CRP) was routinely assessed. Both parameters were monitored over a maximum of 21 consecutive days and in weekly intervals thereafter. RESULTS: In contrast to CRP, PCT concentrations were significantly elevated in patients with pancreatic infections and associated multiorgan dysfunction syndrome (MODS) who all required surgery (n = 10) and in nonsurvivors (n = 8) early after onset of symptoms. PCT levels revealed only a moderate increase in patients with pancreatic infections in the absence of MODS (n = 7), all of whom were managed nonoperatively without mortality. A PCT value of > or =3.5 ng/mL on 2 consecutive days was superior to CRP > or =430 mg/L for the assessment of infected necrosis with MODS or nonsurvival as determined by ROC analysis with a sensitivity and specificity of 93% and 88% for PCT and 40% and 100% for CRP, respectively (P < 0.01). The single or combined prediction of the two major complications was already possible on the third and fourth day after onset of symptoms with a sensitivity and specificity of 79% and 93% for PCT > or =3.8 ng/mL compared with 36% and 97% for CRP > or =430 mg/L, respectively (P = 0.002). CONCLUSION: Monitoring of PCT allows early and reliable assessment of clinically relevant pancreatic infections and overall prognosis in AP. This single test parameter significantly contributes to an improved stratification of patients at risk to develop major complications.

Evaluation of procalcitonin for predicting septic multiorgan failure and overall prognosis in secondary peritonitis: a prospective, international multicenter study.

HYPOTHESIS: Infections and sepsis are major complications in secondary peritonitis and still represent a diagnostic challenge. We hypothesized that the laboratory marker procalcitonin would provide an early and reliable assessment of septic complications. DESIGN: Prospective, international, multicenter inception cohort study. SETTING: Five European surgical referral centers. PATIENTS: Eighty-two patients with intraoperatively proven secondary peritonitis were enrolled within 96 hours of symptom onset. MAIN OUTCOME MEASURES: Procalcitonin and the laboratory routine marker C-reactive protein (CRP) were prospectively assessed and monitored for a maximum of 21 consecutive days. RESULTS: Procalcitonin concentrations were most closely correlated with the development of septic multiorgan dysfunction syndrome (MODS), with peak levels occurring early after symptom onset or during the immediate postoperative course. No such correlation was observed for CRP. According to receiver operating characteristic analysis, a procalcitonin value of 10.0 ng/mL or greater on 2 consecutive days was superior to a CRP level of 210 mg/L or greater for predicting septic MODS, with sensitivity, specificity, and positive and negative predictive values of 65%, 92%, 83%, and 81% for procalcitonin and 67%, 58%, 49%, and 74% for CRP, respectively (P<.001). Assessment of septic MODS was already possible on the first 2 postoperative days, with similar sensitivity and specificity. Persisting procalcitonin levels greater than 1.0 ng/mL beyond the first week after disease onset strongly indicated nonsurvival and were significantly better than CRP in assessing overall prognosis (P<.001). CONCLUSIONS: Procalcitonin monitoring is a fast and reliable approach to assessing septic MODS and overall prognosis in secondary peritonitis. This single-test marker improves stratification of patients who will develop clinically relevant complications.

SPARC-thrombospondin-2-double-null mice exhibit enhanced cutaneous wound healing and increased fibrovascular invasion of subcutaneous polyvinyl alcohol sponges.

Secreted protein acidic and rich in cysteine (SPARC) and thrombospondin-2 (TSP-2) are structurally unrelated matricellular proteins that have important roles in cell-extracellular matrix (ECM) interactions and tissue repair. SPARC-null mice exhibit accelerated wound closure, and TSP-2-null mice show an overall enhancement in wound healing. To assess potential compensation of one protein for the other, we examined cutaneous wound healing and fibrovascular invasion of subcutaneous sponges in SPARC-TSP-2 (ST) double-null and wild-type (WT) mice. Epidermal closure of cutaneous wounds was found to occur significantly faster in ST-double-null mice, compared with WT animals: histological analysis of dermal wound repair revealed significantly more mature phases of healing at 1, 4, 7, 10, and 14 days after wounding, and electron microscopy showed disrupted ECM at 14 days in these mice. ST-double-null dermal fibroblasts displayed accelerated migration, relative to WT fibroblasts, in a wounding assay in vitro, as well as enhanced contraction of native collagen gels. Zymography indicated that fibroblasts from ST-double-null mice also produced higher levels of matrix metalloproteinase (MMP)-2. These data are consistent with the increased fibrovascular invasion of subcutaneous sponge implants seen in the double-null mice. The generally accelerated wound healing of ST-double-null mice reflects that described for the single-null animals. Importantly, the absence of both proteins results in elevated MMP-2 levels. SPARC and TSP-2 therefore perform similar functions in the regulation of cutaneous wound healing, but fine-tuning with respect to ECM production and remodeling could account for the enhanced response seen in ST-double-null mice.

Bifidobacterium Lactis sp. 420 up-regulates cyclooxygenase (Cox)-1 and down-regulates Cox-2 gene expression in a Caco-2 cell culture model.

Cyclooxygenases (Cox) -1 and -2 play important roles in gastrointestinal health; chronic overexpression of Cox-2 is associated with inflammatory and cancerous disease, whereas Cox-1 is expressed constitutively. We studied the effects of two probiotic (Bifidobacterium lactis sp. 420 and Lactobacillus acidophilus) and two control microorganisms (Escherichia coli and Salmonella enteritidis) and four microbial metabolites (acetate, butyrate, lactate and propionate) on the expression levels of the Cox isoforms in the enterocyte-like cell line Caco-2. Butyrate, which is anticarcinogenic, resulted in an 85% down-regulation of Cox-2 and a 37-fold increase in Cox-1 transcription. Propionate gave similar results (72% reduction of Cox-2, 23-fold induction of Cox-1), but lactate and acetate had no effect on Cox expression profile. Bifidobacterium sp. 420, which produces acetate and lactate but no butyrate or propionate, shared the Cox-1-increasing and Cox-2-silencing properties of butyrate and propionate, whereas L. acidophilus was similar to E. coli and S. enteritidis in having no effect on the Cox-1/Cox-2 ratio. For the first time, we therefore demonstrate evidence for a direct relationship between a probiotic bacterial strain and host Cox expression profile, suggesting that modulation of Cox expression may be an important factor in the potential anti-inflammatory and anticarcinogenic properties of some probiotics.

Matricellular homologs in the foreign body response: hevin suppresses inflammation, but hevin and SPARC together diminish angiogenesis.

Implanted foreign materials, used to restore or assist tissue function, elicit an initial acute inflammatory response followed by chronic fibrosis that leads to the entrapment of the biomaterial in a thick, poorly vascularized collagenous capsule. Matricellular proteins, secreted macromolecules that interact with extracellular matrix proteins but do not in themselves serve structural roles, have been identified as important mediators of the foreign body response that includes inflammation, angiogenesis, and collagen synthesis and assembly. In this report we delineate functions of hevin and SPARC, two homologs of the SPARC family of matricellular proteins, in the foreign body response. Despite their sequence similarity, hevin and SPARC mediate different aspects of this fibrotic response. Using mice with targeted gene deletions, we show that hevin is central to the progression of biomaterial-induced inflammation whereas SPARC regulates the formation of the collagenous capsule. Although vascular density within the capsule is unaltered in the absence of either protein, SPARC-hevin double-null capsules show substantially increased numbers of vessels, indicating compensatory functions for these two proteins in the inhibition of angiogenesis. These results provide important information for further development of implant technology.

Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis.

SPARC, a matricellular glycoprotein, modulates cellular interaction with the extracellular matrix (ECM). Tumor growth and metastasis occur in the context of the ECM, the levels and deposition of which are controlled in part by SPARC. Tumor-derived SPARC is reported to stimulate or retard tumor progression depending on the tumor type, whereas the function of host-derived SPARC in tumorigenesis has not been explored fully. To evaluate the function of endogenous SPARC, we have examined the growth of pancreatic tumors in SPARC-null (SP(-/-)) mice and their wild-type (SP(+/+)) counterparts. Mouse pancreatic adenocarcinoma cells injected s.c. grew significantly faster in SP(-/-) mice than cells injected into SP(+/+) animals, with mean tumor weights at sacrifice of 0.415 +/- 0.08 and 0.086 +/- 0.03 g (P < 0.01), respectively. Lack of endogenous SPARC resulted in decreased collagen deposition and fiber formation, alterations in the distribution of tumor-infiltrating macrophages, and decreased tumor cell apoptosis. There was no difference in microvessel density of tumors from SP(-/-) or SP(+/+) mice. However, tumors grown in SP(-/-) had a lower percentage of blood vessels that expressed smooth muscle alpha-actin, a marker of pericytes. These data reflect the importance of ECM deposition in regulating tumor growth and demonstrate that host-derived SPARC is a critical factor in the response of host tissue to tumorigenesis.

Predicting fatal outcome in the early phase of severe acute pancreatitis by using novel prognostic models.

BACKGROUND/AIMS: Survival in acute pancreatitis and particularly in severe acute and necrotizing pancreatitis is a combination of therapy-associated and patient-related factors. There are only few relevant methods for predicting fatal outcome in acute pancreatitis. Scores such as Ranson, Imrie, Blamey, and APACHE II are practical in assessing the severity of the disease, but are not sufficiently validated for predicting fatal outcome among patients with severe acute pancreatitis. The aim of this study was to construct a novel prediction model for predicting fatal outcome in the early phase of severe acute pancreatitis (SAP) and to compare this model with previously reported predictive systems. METHODS: Hospital records of 253 patients with SAP were retrospectively analyzed. 234 patients with adequate data were included to the test set to construct five logistic regression and three artificial neural network (ANN) models. Two models were tested in an independent prospective validation set of 60 consecutive patients with SAP and compared with previously reported predictive systems. RESULTS: The prediction model considered optimal was a logistic model with four variables: age, highest serum creatinine value within 60-72 h from primary admission, need for mechanical ventilation, and chronic health status. In the validation set, the predictive accuracy, determined by the area under the receiver operating characteristic curve value, was 0.862 for the chosen model, 0.847 for the ANN model using eight variables, 0.817 for APACHE II, 0.781 for multiple organ dysfunction score, 0.655 for Ranson, and 0.536 for Imrie scores. CONCLUSIONS: Ranson and Imrie scores are inaccurate indicators of the mortality in SAP. A novel predictive model based on four variables can reach at least the same predictive performance as the APACHE II system with 14 variables.

Long-term health-related quality of life in survivors of severe acute pancreatitis.

OBJECTIVE: To evaluate the health-related quality of life (HRQL) and postdischarge outcome after severe acute pancreatitis. DESIGN AND SETTING: Observational study in a department of surgery (surgical and general intensive care unit) in a tertiary care hospital. PATIENTS AND PARTICIPANTS: Of 283 patients with severe acute pancreatitis 211 survived; during a follow-up period an additional 27 died. The Rand 36-item Health Survey with accessory question was mailed to 174 eligible patients. The final study population comprised 145 patients (83% response rate). Age- and sex-matched Finnish population scores were compared with the study population; accessory questions were analyzed separately. RESULTS: No clinically significant differences were found in long-term HRQL between study patients and the general population. Of the 145 patients 87% returned to work, 27% suffered recurrent pancreatitis, and 43% developed diabetes. Of 113 patients with alcohol-induced severe acute pancreatitis 30% were abstinent and 28% problem drinkers, alcohol-dependent, or alcoholics. CONCLUSIONS: Up to 13% of severe acute pancreatitis patients surviving initial hospitalization die within a few years. Among the survivors long-term HRQL is comparable to that of the normal population. The majority return to work and reduce their alcohol consumption markedly.

Multiple organ dysfunction associated with severe acute pancreatitis.

OBJECTIVE: To compare three different multiple organ dysfunction scores in predicting hospital mortality rates and to discover which one best assesses organ dysfunction/failure in patients with severe acute pancreatitis in a general intensive care unit. DESIGN: Retrospective, observational study. SETTING: Surgical department and a ten-bed general intensive care unit in a tertiary care hospital. PATIENTS: Among the 178 consecutive patients admitted to the surgical department with severe acute pancreatitis from 1994 to 1998, 113 patients treated in the general intensive care unit underwent study. INTERVENTIONS: None. MEASUREMENT AND MAIN RESULTS: Clinical and laboratory data were collected during a period of 35 days. Acute Physiology and Chronic Health Evaluation (APACHE) II, Multiple Organ Dysfunction (MOD) score, Sequential Organ Failure Assessment (SOFA) score, and Logistic Organ Dysfunction (LOD) score were calculated and compared regarding hospital mortality rate. In addition, daily maximum score and a total maximum score (sum of the highest values for each organ dysfunction) were calculated for all three scores. The area under the receiver operating characteristic curve was used as a measure of accuracy of the scores. The highest accuracy was revealed with daily maximum scores with the area under the receiver operating characteristic curve 0.847 for SOFA, 0.844 for MOD, and 0.836 for LOD. According to the maximum SOFA score, the highest mortality rate was associated with liver (83%, p <.001) and renal (63%, p <.001) failures. The mortality ratio with two organ failures ranged from 50% to 91%. The highest mortality rate (91%) was for a combination of hepatic and renal failure. In multiple logistic regression analysis, only hepatic, renal, and cardiovascular failure and previous cardiovascular medication were independent risk factors for hospital mortality. CONCLUSION: In patients with severe acute pancreatitis, organ dysfunction scores (MOD, SOFA, LOD) show good accuracy, comparable with APACHE II in predicting hospital mortality. The maximum daily organ dysfunction scores were simple and useful in assessing multiple organ dysfunction and in predicting hospital mortality rates of patients with severe acute pancreatitis.