Interrelationships between tumor proliferative activity, leucocyte and macrophage infiltration, systemic inflammatory response, and survival in patients selected for potentially curative resection for gastroesophageal cancer.

BACKGROUND: A number of accepted criteria, including pathological tumor, node, metastasis system stage, lymph node metastasis, and tumor differentiation, predict survival in patients undergoing surgery for gastroesophageal cancer. We examined the interrelationships between standard clinicopathological factors, systemic and local inflammatory responses, tumor proliferative activity, and survival. METHODS: The interrelationships between the systemic inflammatory response (Glasgow prognostic score, mGPS), standard clinicopathological factors, local inflammatory response (Klintrup criteria, macrophage infiltration), and tumor proliferative activity (Ki-67) were examined by immunohistochemistry in 100 patients (44 esophageal [19 squamous, 25 adenocarcinoma], 19 junctional, and 37 gastric cancers) selected for potentially curative resection. RESULTS: The minimum follow-up was 59 months. On multivariate survival analysis, lymph node ratio (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.11-2.40, P < 0.05), tumor differentiation (HR 2.63, 95% CI 1.45-4.77, P = 0.001), mGPS (HR 3.91, 95% CI 1.96-8.11, P < 0.001), Klintrup score (HR 3.47, 95% CI 1.14-10.55, P < 0.05), and Ki-67 (HR 0.67, 95% CI 0.47-0.96, P < 0.05) were independently associated with cancer-specific survival. A higher lymph node ratio was associated with poor tumor differentiation (P < 0.05), low-grade Klintrup criteria (P < 0.005), and low tumor proliferative activity (P < 0.05). CONCLUSION: Tumor proliferation rate and local and systemic inflammatory responses are important predictors of survival, albeit in a heterogeneous cohort of patients including esophageal, junctional, and gastric cancers. These scores may be combined with accepted tumor-based factors to improve prediction of outcome.

Endoscopic mucosal resection for gastroesophageal cancer in a U.K. population. Long-term follow-up of a consecutive series.

BACKGROUND: Endoscopic mucosal resection (EMR) of early gastric and esophageal tumors is effective and avoids the morbidity and mortality of surgery. We report the long-term results of a consecutive series of 93 endoscopic resections, during a 7-year period, in a U.K. population. METHODS: Eighty-eight patients with 93 lesions were included. EMR was performed for 64 and 29 malignant and benign lesions, respectively. Patients with malignant disease were subgrouped into "high risk" or "low risk" for recurrence. RESULTS: Of the 35 lesions in the low-risk group, local control was achieved in 31; 29 after 1 EMR session. Two had residual invasive carcinoma, one had treatment ceased due to pancreatic cancer, and one patient did not attend follow-up. Of the 29 lesions in the high-risk group, local control was achieved in 15; 13 after 1 EMR session. Median follow-up was 53 months. Cancer specific survival for the 45 invasive cancers (T1m and T1sm) was 93%; three patients died from their disease. CONCLUSIONS: This study has shown for the first time in a U.K. population that EMR is effective in controlling disease in patients with local high grade dysplasia (HGD) and early invasive carcinoma, with no mortality and low morbidity.

Is hypoalbuminemia an independent prognostic factor in patients with gastric cancer?

BACKGROUND: Studies have indicated that hypoalbuminemia is associated with decreased survival of patients with gastric cancer. However, the prognostic value of albumin may be secondary to an ongoing systemic inflammatory response. The aim of the study was to assess the relation between hypoalbuminemia, the systemic inflammatory response, and survival in patients with gastric cancer. METHODS: Patients diagnosed with gastric carcinoma attending the upper gastrointestinal surgical unit in the Royal Infirmary, Glasgow between April 1997 and December 2005 and who had a pretreatment measurement of albumin and C-reactive protein (CRP) were studied. RESULTS: Most of the patients had stage III/IV disease and received palliative treatment. The minimum follow-up was 15 months. During follow-up, 157 (72%) patients died of their cancer. On univariate analysis, stage (p < 0.001), treatment (p < 0.001), albumin level (p < 0.001), and CRP level (p < 0.001) were significant predictors of survival. On multivariate analysis, stage (p < 0.001), treatment (p < 0.001), and CRP level (p < 0.001) remained significant predictors of survival. Albumin was no longer an independent predictor of survival. CONCLUSIONS: Low albumin concentrations are associated with poorer survival in patients with gastric cancer. However, the strength of this relation with survival is dependent on the presence of a systemic inflammatory response, as evidenced by an elevated CRP level. Therefore, it appears that the relation between hypoalbuminemia and poor survival is secondary to that of the systemic inflammatory response.

Systematic four-quadrant biopsy detects Barrett's dysplasia in more patients than nonsystematic biopsy.

AIMS: To compare detection of Barrett's dysplasia and adenocarcinoma by systematic versus nonsystematic surveillance biopsy protocols. METHODS: Upper GI consultation and open-access endoscopy are provided jointly at Glasgow Royal Infirmary by medical and surgical teams. The surgical team adopted annual systematic four-quadrant biopsy Barrett's surveillance in 1995. The medical team continued annual Barrett's surveillance with nonsystematic biopsy until 2004. We compare detection of Barrett's dysplasia and esophageal adenocarcinoma in unselected patients by these two biopsy strategies over 10 yr. All patients had > or = 3 cm Barrett's esophagus and histological proof of intestinal metaplasia. Patients referred for dysplasia management or with prevalent adenocarcinoma were excluded. Cohort A (N = 180) had four-quadrant biopsy every 2 cm while cohort B (N = 182) had nonsystematic biopsies. RESULTS: Cohort A versus cohort B: Median number of biopsies per endoscopy: 16 versus 4. Prevalence of low-grade dysplasia (per patient): 18.9% versus 1.6% (P << 0.001). Prevalence of high-grade dysplasia: 2.8% versus 0% (P = 0.03). Incidence of low-grade dysplasia: 2.2% versus 6.6% (NS). Incidence of high-grade dysplasia: 2.8% versus 0% (P = 0.03). Nine cohort A patients (total 5%, 1.4% per patient-year) were treated for HGD (eight endoscopically, one by esophagectomy). Two had intramucosal adenocarcinoma. No cohort A patient developed advanced cancer but three cohort B patients developed and died of invasive Barrett's adenocarcinoma (0.6% per patient-year). CONCLUSIONS: Patient age, gender, Barrett's segment length, and follow-up were similar (though not identical) in both cohorts, but confounding seems unlikely to account for a 13-fold difference in detection of prevalent dysplasia between the two groups. Our data support the hypothesis that systematic four-quadrant biopsy is considerably more effective than nonsystematic biopsy sampling in detecting Barrett's dysplasia and early adenocarcinoma. Greater biopsy numbers and the systematic pattern of biopsy taking may both contribute to this greater effectiveness.

Comparison of an inflammation-based prognostic score (GPS) with performance status (ECOG-ps) in patients receiving palliative chemotherapy for gastroesophageal cancer.

AIM: The aim of the present study was to compare an inflammation-based prognostic score (Glasgow Prognostic Score, GPS) with performance status (ECOG-ps) in patients receiving platinum-based chemotherapy for palliation of gastroesophageal cancer. METHODS: Sixty-five patients presenting with gastroesophageal carcinoma to the Royal Infirmary, Glasgow between January 1999 and December 2005 and who received palliative chemotherapy or chemo-radiotherapy were studied. ECOG-ps, C-reactive protein, and albumin were recorded at diagnosis. Patients with both an elevated C-reactive protein (>10 mg/L) and hypoalbuminemia (<35 g/L) were allocated a GPS of 2. Patients in whom only one of these biochemical abnormalities was present were allocated a GPS of 1 and patients with a normal C-reactive protein and albumin were allocated a score of 0. Toxicity was recorded using the Common Toxicity Criteria. RESULTS: The minimum follow up was 14 months. During the follow-up period, 59 (91%) of the patients died. On univariate and multivariate survival analysis, only the GPS (hazard ratios 1.65, 95% CI 1.10-2.47, P < 0.05) was a significant independent predictor of cancer survival. In addition, in comparison with patients with GPS of 0, those patients with a GPS of 1 or 2 required more frequent chemotherapy dose reduction (P < 0.05), were less likely to exhibit a clinical response to treatment (P < 0.05), and had shorter survival (P < 0.05). CONCLUSION: The presence of a systemic inflammatory response, as evidenced by the GPS, appears to be superior to the subjective assessment of performance status (ECOG-ps) in predicting the response to platinum-based chemotherapy in patients with advanced gastroesophageal cancer.

Enhancing and expansile portal vein thrombosis: value in the diagnosis of hepatocellular carcinoma in patients with multiple hepatic lesions.

OBJECTIVE: The objective of this study was to determine whether the presence of enhancing and expansile portal vein thrombus is suggestive of the diagnosis of hepatocellular carcinoma. CONCLUSION: In the presence of hepatic tumors, enhancing expansile portal vein thrombus is highly suggestive of hepatocellular carcinoma.

NMDA currents and receptor protein are downregulated in the amygdala during maintenance of fear memory.

The amygdala plays a critical role in fear conditioning, a model of emotional learning and cue-induced anxiety. In the lateral amygdala, fear conditioning is associated with an enduring increase in synaptic strength mediated through AMPA receptors and with a reduction in paired-pulse facilitation, reflecting an increased probability of neurotransmitter release. Here we show that NMDA-mediated transmission in the thalamic-to-lateral amygdala pathway is not facilitated after fear conditioning, although probability of transmitter release is enhanced. Rather, the EC50 for NMDA receptor (NR)-mediated current is shifted threefold to fourfold to the right in fear-conditioned animals, suggesting a postsynaptic alteration in NMDA receptors in the maintenance phase of fear memory. Furthermore, the ability of nonselective and subunit-selective antagonists of NMDA receptors to block NMDA receptor-mediated EPSCs is reduced in lateral amygdala neurons from fear-conditioned animals, suggesting a reduction in NMDA receptors at thalamolateral amygdala synapses. In addition, Western blots show a reduction in phosphorylated-NR1, NR2A, and NR2B subunit protein expression in amygdalas from fear-conditioned animals. These data indicate that postsynaptic mechanisms are involved in synaptic plasticity in the thalamoamygdala pathway in fear conditioning and raise the possibility that: (1) downregulation of the NMDA receptor may protect against excitotoxicity of unchecked NMDA receptor recruitment during induction and consolidation of fear memories, (2) reduced NMDA current and protein may allow persistence of the "capacity to reactivate" amygdala pathways in NMDA receptor-dependent fear memories, or (3) a persistent long-term depression of NMDA transmission may occur after fear learning.

L-type voltage-gated calcium channels are involved in the in vivo and in vitro expression of fear conditioning.

Fear conditioning, a behavioral model of fear learning and cue-related anxiety, causes enhanced neuronal transmission in the thalamic to lateral amygdala pathway.(1,2) In the expression phase of learned fear, this increased transmission recorded in vitro is revealed in increased amplitudes of excitatory postsynaptic currents (EPSCs) and occlusion of paired-pulse facilitation (PPF) implicating a presynaptic increase in transmitter release. Here we examined the contribution of L-type calcium channels in fear conditioning. We measured the effect of nimodipine (Nim, 1.5-20 mg/kg), an L-type calcium channel antagonist, on fear-potentiated startle in which startle was assessed in animals receiving paired or unpaired tone and foot shock. Nim administered intraperitoneally blocked fear-potentiated startle but not baseline startle in a dose-dependent manner. We also analyzed the effect of Nim (10 micro M) in vitro on synaptic facilitation of EPSCs and PPF in slices from naïve control, unpaired control, and fear-conditioned animals. In neurons from naïve control animals, Nim had no effect on EPSC amplitude or PPF, but in slices from fear-conditioned rats, Nim reduced EPSC amplitude, suggesting the recruitment of L-type calcium channels within the fear-conditioning pathway. Nim increased PPF in slices from fear-conditioned animals, suggesting that L-type calcium channels may contribute to increased probability of release in fear conditioning. In slices from unpaired animals, Nim decreased synaptic transmission but had little effect on PPF, suggesting that stress or contextual fear learning may induce L-type channel activity in fear-conditioned and unpaired control animal groups. We also analyzed protein expression of the alpha(1C) and alpha(1D) L-type calcium channel subunits isolated from the amygdala and found that alpha(1C) protein was significantly increased in fear-conditioned animals. These findings suggest that L-type calcium channels play a role in the amygdala in cued fear conditioning and have important implications in the treatment of anxiety and in emotional learning and plasticity.

Expression of fear-conditioning is accompanied by increased paired-pulse depression within the amygdala.

Fear-conditioning is a model of fear learning and anxiety. The lateral nucleus of the amygdala (LA) provides a critical link for relaying thalamic and cortical auditory information to the rest of the amygdala during the fear conditioning process. Alterations in excitatory synaptic transmission in the thalamic to LA pyramidal cells was studied using whole-cell patch clamp recordings in brain slices from fear-conditioned animals. Following paired stimulation of the thalamic afferents, paired-pulse depression (PPD) could be recorded at 200-ms to 2-s intervals. Increasing transmitter release by decreasing the Mg2+/Ca2+ ratio enhanced PPD suggesting that PPD is reflective of changes in release probability. Analysis of the pairs of composite, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated excitatory postsynaptic currents (EPSCs) showed that there was no correlation between EPSC pairs suggesting that PPD may be mediated through a release-independent mechanism of presynaptic origin. However, AMPA and NMDA receptor mediated PPD had a different time course and magnitude suggesting postsynaptic factors may be involved in PPD. After fear-conditioning PPD of the composite and AMPA receptor-mediated EPSCs was enhanced suggesting that neurotransmitter release may be increased in learned fear. The NMDA receptor-mediated PPD was however not altered in fear-conditioned animals. The differences in response of AMPA and NMDA receptor-mediated PPD suggest that postsynaptic mechanisms may also be involved in the expression of fear conditioning.

Comparison of pre-treatment clinical prognostic factors in patients with gastro-oesophageal cancer and proposal of a new staging system.

BACKGROUND: Clinical staging in patients with gastro-oesophageal cancer, is of crucial importance in determining the likely benefit of treatment. Despite recent advances in clinical staging, overall survival remains poor. The aim of the present study was to examine the relationship between pre-treatment clinical prognostic factors and cancer-specific survival. METHODS: Two hundred and seventeen patients, undergoing staging investigations including host factors (Edinburgh Clinical Risk Score (ECRS)) and the systemic inflammatory response (Glasgow Prognostic score (mGPS)), in the upper GI surgical unit at Glasgow Royal Infirmary, were studied. RESULTS: During the follow-up period, 188 (87%) patients died; 178 of these patients died from the disease. The minimum follow-up was 46 months, and the median follow-up of the survivors was 65 months. On multivariate survival analysis of the significant factors, only cTNM stage (HR 1.84, 95% CI 1.56-2.17, p < 0.001), mGPS (HR 1.67, 95% CI 1.35-2.07, p < 0.001) and treatment (HR 2.12, 95% CI 1.73-2.60, p < 0.001) were independently associated with survival. An elevated mGPS was associated with advanced cTNM stage, poor performance status, an elevated ECRS and more conservative treatment. CONCLUSIONS: Pre-treatment mGPS improves clinical staging in patients with gastro-oesophageal cancer. Therefore, it is likely to aid clinical decision making for these difficult to treat patients.

Are plain radiographs of the spine necessary during evaluation after blunt trauma? Accuracy of screening torso computed tomography in thoracic/lumbar spine fracture diagnosis.

BACKGROUND: Fracture of the thoracolumbar (TL) spine is reported in 8 to 15% of victims of blunt trauma. Current screening of these patients is done with conventional radiography. This may require repeated sets of films and take hours to days. It is imperative that these patients get timely, accurate evaluation to allow for treatment planning and early mobilization; alternatives to plain films would aid in this. The objective of this study is to determine whether the data obtained from admission chest/abdomen/pelvis (CAP) computed tomography (CT) scans after blunt trauma has utility in thoracolumbar spine evaluation. METHODS: The records of all patients admitted to a Level I trauma center over a 2-month period who underwent CAP CT were reviewed for the presence of TL spine fracture, time to completion of plain film evaluation, and clinical course. Admission CT scans were reviewed by an attending radiologist who was blinded to any previously diagnosed spine fractures. The two tests were compared for diagnostic accuracy and their discriminatory ability was compared using receiver operating characteristic (ROC) curves. Significance was defined as p < 0.05. RESULTS: In all, 103 patients were admitted from January 1, 2003 to February 28, 2003 and underwent CAP CT scan as part of their initial trauma evaluation. Of these, 26 (25%) had thoracolumbar fractures. Seven (27%) thoracolumbar fractures were not seen on plain radiographs taken during the trauma evaluation. Average time until plain film completion in this group was 8 hours (range, 44 minutes to 38 hours). All 26 (100%) patients with fractures, however, were diagnosed on CT scan performed shortly after admission. Of the remaining 77 patients, two (2.6%) were falsely read as positive for fracture on CT. Sensitivity and specificity of CT scan for thoracolumbar fracture were excellent at 100% and 97%, respectively, with a negative predictive value of 100%. Plain radiographs were 73% sensitive, 100% specific, and had a negative predictive value of 92%. Area under the ROC curve for CT was 0.98, but for plain film was 0.86 (p < 0.02). CONCLUSION: Admission CAP CT obtained as part of the routine trauma evaluation in these high-risk patients is more sensitive than plain radiographs for evaluation of the TL spine after blunt trauma. In addition, CAP CT can be performed faster. Omission of plain radiographs will expedite accurate evaluation allowing earlier treatment and mobilization.