[Update polytrauma and computed tomography in ongoing resuscitation : ABCDE and "diagnose first what kills first"]. / Update Polytrauma und Computertomographie unter Reanimationsbedingungen : ABCDE und "diagnose first what kills first".

CLINICAL ISSUE: The mean number of trauma room admissions and applied CT dose increase as the severity of injuries decreases. Therefore, appropriateness of established procedures should be re-evaluated. STANDARD RADIOLOGICAL METHODS: Considering severely injured patients with an Injury Severity Score (ISS) ≥16, whole body CT (WB-CT) compared to selective CT decreased mortality by about 25%. Thus, the ISS is a good indicator for the severity of injuries. However, since ISS can only be determined after diagnosis, it does not help with the primary assessment. METHODOLOGICAL INNOVATION AND EVALUATION: In addition to the currently used very fast WB-CT protocol with the highest diagnostic precision, a second protocol should be established applying a substantially lower dose. Under ongoing resuscitation, WB-CT often makes a substantial contribution towards targeted therapy or to justifying the discontinuation of resuscitation measures. The WB-CT findings should be performed several times and, at least in the acute emergency situation, it should follow the ABCDE scheme as close as possible. PRACTICAL RECOMMENDATIONS: In the trauma room it should be initially decided whether the classification as polytrauma is to be maintained. If yes, every institution should provide a dose-reduced WB-CT protocol in addition to the maximum variant used so far. Dose-reduced WB-CT seems to be appropriate for stable and oriented patients, who receive a CT primarily because of the trauma mechanism. Even under resuscitation conditions, WB-CT is easy to perform and medically as well as ethically of high value. The reporting and communication should be structured according to "diagnose first what kills first".

Early metabolic response evaluation by fluorine-18 fluorodeoxyglucose positron emission tomography allows in vivo testing of chemosensitivity in gastric cancer: long-term results of a prospective study.

PURPOSE: We prospectively evaluated the predictive value of positron emission tomography using fluorine-18 fluorodeoxyglucose (FDG-PET) for in vivo testing of chemosensitivity in locally advanced gastric cancer using an a priori definition of metabolic response (a decrease of >35% of the standard uptake value). The goal of the study was the definition of biologically different groups of patients prior to or early during induction therapy, with special emphasis on FDG non-avid tumors. EXPERIMENTAL DESIGN: Based on our data, which was published in 2003, at least 36 patients with metabolic response or FDG non-avid tumors had to be recruited for an analysis of the group of FDG non-avid tumors with sufficient statistical power. Seventy-one patients (32 metabolic nonresponders, 17 metabolic responders, and 22 patients with FDG non-avid tumors) underwent FDG-PET at baseline. In FDG-avid tumors, FDG-PET was repeated 14 days after the initiation of chemotherapy. RESULTS: Metabolic responders (17 of 49) showed a high histopathologic response rate (69%) and a favorable prognosis (median survival not reached), whereas metabolic nonresponders (32 of 49) had a poor prognosis (median survival, 24.1 months) and showed a histopathologic response in 17%. The histopathologic response rate (24%) for FDG-PET non-avid patients showed no significant difference compared with FDG-avid nonresponders (P=0.72). Survival of FDG non-avid patients was 36.7 months (not significantly different from FDG-avid nonresponders, 24.1 months, P=0.46). CONCLUSION: In locally advanced gastric cancer, three different metabolic groups exist. Response and survival was predicted by PET in FDG-avid tumors. Metabolic response assessment was not possible in FDG non-avid tumors; however, due to unfavorable outcome, therapy modification might also be considered in FDG non-avid tumors.

Paclitaxel in the neoadjuvant treatment for adeno carcinoma of the distal esophagus (AEG I). A comparison of two phase II trials with long-term follow-up.

INTRODUCTION: We report a comparative analysis of 2 sequential, prospective phase II trials on the efficacy of platinum/leucovorin/5-fluorouracil (PLF) +/- paclitaxel (T-PLF) in the neoadjuvant treatment of adenocarcinoma of the esophagus (AEG I). PATIENTS AND METHODS: Inclusion criteria were histologically proven, locally advanced AEG I stage uT3/4 anyN cM0/M1a. 67 patients were treated with either PLF (n = 32) or T-PLF (n = 35). Paclitaxel (80 mg/m(2)) was added to PLF on days 1, 15, and 29. Primary endpoint was the response. Additionally, 5-year survival was analyzed. RESULTS: The study population was well balanced, apart from an imbalance in clinical cM1a (33.3% PLF vs. 8.6% T-PLF; p = 0.01). Histopathological response rates (23.3% PLF vs. 25.0% T-PLF) showed no significant difference. Clinical response rates were improved for T-PLF (21.9 vs. 45.7%; p = 0.04). Median overall survival for clinical and histopathological responders was significantly improved for T-PLF (p = 0.005, p = 0.01), but not for PLF (p = 0.08, p = 0.25). Median overall survival was better with T-PLF without reaching statistical significance (18.9 months PLF vs. 43.1 months T-PLF; p = 0.27). Toxicity was slightly increased by paclitaxel. No treatment-related deaths occurred. CONCLUSION: Our data failed to demonstrate statistically significant superiority of the T-PLF regimen except for clinical response. However, there was a trend towards improved survival.

In vitro pyrogen test--A new test method for solid medical devices.

Medical devices manufactured for implantation into humans must be free of any contamination with viable bacteria. However, remnants of dead bacteria and bacterial components alone may induce an inflammatory immune response. Pyrogen tests for such inflammatory contaminations are generally performed either by determining the content of lipopolysaccharide in rinsing solutions of batch samples by limulus amoebocyte lysate assay, by injecting the rinsing solutions into rabbits or by implanting batch samples into rabbits and measuring change of body temperature. In this study, we show that the in vitro pyrogen test (IPT), which measures the release of the inflammatory cytokine IL-1beta in fresh or cryopreserved human whole blood, can be used to assess the pyrogenic contamination of implantable medical devices. This test was used to check neurosurgical implants, namely aneurysm clips, as a proof of principle. Owing to the direct contact of the test material with the blood cells, this test does not require rinsing procedures, which have variable efficacy. The use of human blood ensures the detection of all substances that are pyrogenic for humans and reflects their relative potency. The safety of the products as delivered could be confirmed. The effects of sterilization and depyrogenization procedures on intentional pyrogenic contaminations of samples could be followed. This new application of the already internationally validated method promises to replace further rabbit pyrogen tests. It generates extremely sensitive results with an extended range of detectable pyrogenic contaminants.

Combined GADD45A and thymidine phosphorylase expression levels predict response and survival of neoadjuvant-treated gastric cancer patients.

PURPOSE: We evaluated the expression of seven therapy-related genes to predict the clinical outcome of advanced gastric cancer patients treated with a neoadjuvant chemotherapeutic protocol. EXPERIMENTAL DESIGN: Pretherapeutic, formalin-fixed, and paraffin-embedded biopsies of 61 patients, who received a 5-fluorouracil (5-FU)- and cisplatin-based chemotherapy were studied. The expressions of the 5-FU-related genes TS, DPD, and TP and of the cisplatin-related genes ERCC1, ERCC4, KU80, and GADD45A were analyzed by quantitative real-time PCR. The expression levels of single genes and of various combinations were tested for an association with response and overall survival. RESULTS: High DPD levels were more frequently found in nonresponding patients and were associated with worse survival. GADD45A and TP levels showed weak associations with response, but GADD45A expression correlated with survival. There was no association with response for TS expression, but tumors with a high TS level were associated with worse survival. The combination of GADD45A and TP revealed the strongest predictive effect. High expression values of TP and/or GADD45A were exclusively found in nonresponding patients (P = 0.002) and were associated with a significantly poorer survival (P = 0.04). CONCLUSIONS: Combined gene expression levels of TP and GADD45A represent a new variable to predict the clinical outcome after neoadjuvant chemotherapy in gastric cancer. The association of DPD expression with response and survival underlines a predominant role of DPD to predict 5-FU sensitivity. The association of TS expression levels with survival but not with response suggests an importance of this gene for tumor progression.

Prediction of response to preoperative chemotherapy in gastric carcinoma by metabolic imaging: results of a prospective trial.

PURPOSE: We prospectively evaluated the predictive value of therapy-induced reduction of tumor glucose use for subsequent response and patient survival in patients with gastric cancer treated by preoperative chemotherapy. PATIENTS AND METHODS: Forty-four consecutive patients with locally advanced gastric carcinomas were studied by positron emission tomography with the glucose analog fluorine-18 fluorodeoxyglucose (FDG-PET) at baseline and 14 days after initiation of cisplatin-based polychemotherapy. On the basis of a previous study, a reduction of tumor FDG uptake by more than 35% was used as a criterion for a metabolic response. The metabolic response in FDG-PET was correlated with histopathologic response after completion of therapy (< 10% viable tumor cells in the resected specimen) and patient survival. RESULTS: Thirty-five (80%) of the 44 tumors were visualized with sufficient contrast for quantitative analysis (two of 19 intestinal and seven of 25 nonintestinal tumors showed only low FDG uptake). In the 35 assessable patients, PET imaging after 14 days of therapy correctly predicted histopathologic response after 3 months of therapy in 10 (77%) of 13 responders and 19 (86%) of 22 nonresponders. Median overall survival for patients with a metabolic response has not been reached (2-year survival rate, 90%); for patients without a metabolic response, median survival was only 18.9 months (2-year survival rate, 25%; P =.002) CONCLUSION: This study prospectively demonstrates that in patients with gastric cancer, response to preoperative chemotherapy can be predicted by FDG-PET early during the course of therapy. By avoiding the morbidity and costs of ineffective therapy, FDG-PET imaging may markedly facilitate the use of preoperative chemotherapy.

Time course of tumor metabolic activity during chemoradiotherapy of esophageal squamous cell carcinoma and response to treatment.

PURPOSE: To evaluate the time course of therapy-induced changes in tumor glucose use during chemoradiotherapy of esophageal squamous cell carcinoma (ESCC) and to correlate the reduction of metabolic activity with histopathologic tumor response and patient survival. PATIENTS AND METHODS: Thirty-eight patients with histologically proven intrathoracic ESCC (cT3, cN0/+, cM0) scheduled to undergo a 4-week course of preoperative simultaneous chemoradiotherapy followed by esophagectomy were included. Patients underwent positron emission tomography with the glucose analog fluorodeoxyglucose (FDG-PET) before therapy (n = 38), after 2 weeks of initiation of therapy (n = 27), and preoperatively (3 to 4 weeks after chemoradiotherapy; n = 38). Tumor metabolic activity was quantitatively assessed by standardized uptake values (SUVs). Results Mean tumor FDG uptake before therapy was 9.3 +/- 2.8 SUV and decreased to 5.7 +/- 1.9 SUV 14 days after initiation of chemoradiotherapy (-38% +/- 18%; P <.0001). The preoperative scan showed an additional decrease of metabolic activity to 3.3 +/- 1.1 SUV (P <.0001). In histopathologic responders (< 10% viable cells in the resected specimen), the decrease in SUV from baseline to day 14 was 44% +/- 15%, whereas it was only 21% +/- 14% in nonresponders (P =.0055). Metabolic changes at this time point were also correlated with patient survival (P =.011). In the preoperative scan, tumor metabolic activity had decreased by 70% +/- 11% in histopathologic responders and 51% +/- 21% in histopathologic nonresponders. CONCLUSION: Changes in tumor metabolic activity after 14 days of preoperative chemoradiotherapy are significantly correlated with tumor response and patient survival. This suggests that FDG-PET might be used to identify nonresponders early during neoadjuvant chemoradiotherapy, allowing for early modifications of the treatment protocol.

Clinical response to induction chemotherapy predicts local control and long-term survival in multimodal treatment of patients with locally advanced esophageal cancer.

PURPOSE: From 1991 to 1994 we performed a phase II study with intensive preoperative chemoradiation in locally advanced squamous cell carcinoma and adenocarcinoma of the esophagus. We now report on a multivariate analysis of prognostic factors based on the long-term results at a median follow-up of 6.5 years. PATIENTS AND METHODS: Eighty-eight patients were treated. Prognostic factors for overall survival and local tumor control were identified by univariate and multivariate analysis. RESULTS: Median overall survival reached 17 months, and the survival rate at 5 years was 22% (95%-confidence interval: 18-26%). Response to induction chemotherapy was the only independent factor predicting local tumor control and--beside weight loss prior to treatment--it also proved to be an independent prognostic factor for long-term survival. CONCLUSIONS: Intensive chemoradiation followed by surgery seems to be appropriate to improve long-term survival of high-risk patients with locally advanced esophageal cancer. In our trial, local tumor control and prognosis were best correlated with response to induction chemotherapy. These results may help to guide decisions regarding surgery in multimodal treatment of EC. Further efforts are needed to increase the number of treatment responders and to predict tumors not responding to chemo(radio)therapy earlier.

Chromosomal instability rather than p53 mutation is associated with response to neoadjuvant cisplatin-based chemotherapy in gastric carcinoma.

PURPOSE: The objective of the study was to evaluate microsatellite alterations [microsatellite instability (MSI) and loss of heterozygosity (LOH)] and mutation in the p53 gene in relation to response and patient survival to a cisplatin-based neoadjuvant chemotherapy in gastric cancer. EXPERIMENTAL DESIGN: Fifty-three pretherapeutic gastric carcinoma biopsies were analyzed with 11 microsatellite markers. The entire coding region of the p53 gene (exons 2-11) was analyzed for mutations by denaturing high-pressure liquid chromatography and sequencing. p53 protein expression was evaluated by immunohistochemistry. Patients were treated with a cisplatin-based, neoadjuvant chemotherapy regimen. Therapy response was evaluated by computed tomography scan, endoscopy, and endoluminal ultrasound. The median follow-up of the patients was 45.6 months. RESULTS: p53 mutations were identified in 19 of the 53 (36%) analyzed tumors. No significant association with response or survival was found for p53 mutation or for p53 protein expression. MSI (either high-grade MSI or low-grade MSI) did not show a correlation with response. With respect to LOH, LOH at chromosome 17p13 showed a significant association with therapy response (P = 0.022) but did not reach statistical significance in terms of patient survival. The global LOH rate, expressed as fractional allelic loss (FAL), was assessed, and tumors were classified into tumors with a high (>0.5), medium (>0.25-0.5), and low (0-0.25) FAL value. A statistically significant association of FAL with therapy response was found (P = 0.003), with a high FAL being related to therapy response. The sensitivity, specificity, positive predictive value, and negative predictive value for FAL > 0.5 were 45%, 93%, 82%, and 72%, respectively. CONCLUSIONS: A high level of chromosomal instability (high FAL value) defines a subset of patients who are more likely to benefit from cisplatin-based neoadjuvant chemotherapy. p53 mutation status is not significantly associated with therapy response and is not a useful marker for response prediction.

Ceramic and PMMA particles differentially affect osteoblast phenotype.

There is increasing evidence that wear debris particles present in periprosthetic tissues have direct effects on osteoblasts. The nature of the cell response varies with the chemistry of the particle and the number of particles. Most studies have used Ti, Ti-6Al-4V, and ultrahigh molecular weight polyethylene (UHMWPE) particles since these materials are most frequently used in implants and as a result, these particles predominate in peri-prosthetic tissues. Ceramics have also been used successfully as load-bearing surfaces in implants for years, although it is unknown how wear debris from these surfaces may contribute to aseptic bone loss. Further, particles resulting from polymethylmethacrylate (PMMA) cements used for fixation may also be involved in aseptic loosening of implants, but how these particles may affect bone formation is unknown. In the present study, we examined whether aluminum oxide (Al2O3), zirconium oxide (ZrO2), and PMMA particles exert effects on osteoblast proliferation, phenotypic expression, and local factor production, and if so, whether the effects were specific to the particle type. ZrO2 particles were produced in a custom-made axial mixer in which ZrO2 containers were filled with ZrO2 bars and 95% ethanol and then rotated continuously at room temperature. PMMA particles were prepared in a ZrO2 roller mill. Al2O3 was produced and provided by Aesculap AG. Particles were endotoxin-free with equivalent circle diameters <3 microm; Al2O3 particles were significantly smaller than ZrO2 or PMMA particles. Particle suspensions were added to confluent cultures of MG63 osteoblast-like cells after diluting them 1:100, 1:10, and 1:1 with culture medium. Cells were incubated with the particles for 24 h. Transmission electron microscopy showed that MG63 cells phagocytosed Al2O3 particles and exhibited ultrastructural changes consistent with cytotoxicity. This was supported by biochemical changes as well. Proliferation, alkaline phosphatase activity, and TGF-beta1 levels were decreased. ZrO2 and PMMA particles increased proliferation and alkaline phosphatase specific activity. The effect of ZrO2 on alkaline phosphatase was targeted to matrix vesicles, the effect of PMMA was greater on the cells. All particles increased prostaglandin E2 production. These results show that Al2O3, ZrO2, and PMMA particles elicit direct effects on osteoblasts and that cell response depends on the particle type. None of the particles tested had the same effect as noted previously for UHMWPE: increased proliferation and decreased alkaline phosphatase. These results may indicate that the response of peri-prosthetic tissues to wear particles may be modulated by the relative contributions of the various particle types present.

Neoadjuvant treatment of esophageal cancer: Immunosuppression following combined radiochemotherapy.

BACKGROUND: The biologic effects of neoadjuvant tumor therapies on the immune system of cancer patients are largely unknown. Immune deviations may be particularly detrimental if they occur in conjunction with postoperative immunosuppression. The effects of combined radiochemotherapy (RCTx) on T cell functions in patients with squamous cell carcinoma of the esophagus were investigated. METHODS: T cell proliferation was stimulated by incubation of peripheral blood mononuclear cells with bacterial superantigens or by exposure of enriched T cells to superantigens presented by B lymphoma cells. Cytokine production of enriched T cells was induced by cross-linking of CD3 and CD28 and the secretion of interleukin (IL)-2, IL-4, IL-10, and interferon-gamma was measured by enzyme-linked immunosorbent assay. T cell expression of human leukocyte antigen-DR (HLA-DR) molecules was determined by flow cytometry. RESULTS: T lymphocytes from patients having undergone RCTx exhibited a significantly reduced proliferative response following stimulation with 3 independent superantigens. Cytokine production of T cells and the antigen presenting capacity of patient's peripheral blood mononuclear cells was not diminished following RCTx. T cell expression of HLA-DR was increased following RCTx. CONCLUSIONS: RCTx of patients with squamous cell carcinoma of the esophagus results in the suppression of T lymphocyte functions. The proliferative defects of T cells after RCTx may be linked to an impaired immune surveillance of cancer and to a higher risk of surgical complications associated with esophagectomy.

Emergency diagnosis with spiral CT angiography in case of suspected ventral perforation following lumbar disc surgery.

BACKGROUND: Ventral perforation and vascular lesions are rare but life-threatening complications in lumbar disc surgery. In some cases, however, it remains unclear from the clinical situation whether a laparotomy is necessary to save the patient. The goal of this study is to demonstrate the value of spiral CT (computed tomography) angiography for emergency vascular diagnosis in two cases. METHODS: Spiral CT angiography with an intravenous bolus contrast medium injection and reconstruction with images in sagittal, coronal, and oblique planes was performed. RESULTS: Spiral CT angiography confirms or excludes a vascular lesion, as demonstrated in two case reports. CONCLUSION: In unclear cases when ventral perforation in lumbar disc surgery is suspected, the need for emergency laparotomy can be confirmed quickly by noninvasive spiral CT angiography.

Long-lasting improvement of arterial hypertension after surgical treatment of a foramen magnum meningioma: case report.

BACKGROUND: Neurogenic arterial hypertension has been proposed to be caused by neurovascular compression in many cases. However, there is little reference to tumors causing hypertension by local compression of the vagal nerve or the ventrolateral medulla oblongata. The following case illustrates the effects of surgery for a meningioma of the foramen magnum on arterial hypertension. CASE DESCRIPTION: A 54-year-old woman suffered from arterial hypertension for at least 7 months, for which she required a combined medical treatment regime. She suffered for 6 months from dizziness and tinnitus, more in the left ear than in the right. Neurologic examination revealed a horizontal fixation nystagmus and a mild left-sided hearing loss. Magnetic resonance imaging and computed tomographic angiography showed a contrast-enhancing tumor on the left side of the foramen magnum compressing the medulla oblongata close to the vertebral artery and vascularized by branches of the left PICA. Complete surgical extirpation was performed using a medial craniocervical approach. The tinnitus and dizziness were gone and hearing improved. Postoperatively, the arterial hypertension showed a long-lasting improvement (observation period 8 months) with only minimal medical treatment. CONCLUSION: Based on our case, we conclude that tumors in close proximity to the ventrolateral medulla oblongata may induce neurogenic hypertension, similar to neurovascular compression.

Incidence and long-term follow-up of silent cerebral lesions after pulmonary vein isolation using a remote robotic navigation system as compared with manual ablation.

BACKGROUND: The incidence of silent cerebral lesions (SCL) after atrial fibrillation (AF) ablation is highly variable, depending on the technology used. Recently, an increased risk for SCL has been described for a novel, nonirrigated ablation tool using multielectrode phased radiofrequency (PVAC). The aim of this prospective study was to evaluate the incidence and long-term follow-up of SCL in patients undergoing robotically assisted pulmonary vein isolation (RA-PVI) as compared with manual PVI. METHODS AND RESULTS: Circumferential PVI using irrigated radiofrequency current was performed on 70 patients (41 patients with paroxysmal AF, 59%). Fifty patients underwent RA-PVI and 20 patients underwent a manual approach. Cerebral MRI was performed the day before and the day after the ablation procedure; follow-up MRI was performed on 9 of 12 (75%) patients after a follow-up period of 21 months. SCLs were found in 12 of 70 (17%) patients in this study; the incidence of SCLs was similar in patients undergoing RA-PVI as compared with manually ablated patients (n=9, 18% versus n=3, 15%; probability value=1.0). In 1 patient undergoing manual PVI (1%), an SCL with asymptomatic subarachnoid hemorrhage was detected; the bleeding completely resolved within 1 month. Transient ischemic attack occurred in 1 (1%) patient 2 days after manual PVI. After a median follow-up period of 21 months, no residual SCLs were detected. CONCLUSIONS: The incidence of SCL using the robotic navigation system was 18% in this study. Incidence and size of SCL appears to be similar after RA-PVI as compared with manual PVI. Repeat MRI showed no residual SCLs at long-term follow-up.

Patch test reactivity to a cobalt-chromium-molybdenum alloy and stainless steel in metal-allergic patients in correlation to the metal ion release.

Nickel, chromium, and cobalt released from stainless steel and CoCrMo alloys have been postulated to trigger hypersensitivity reactions. The objective of this study was to assess the ion release from a CoCrMo alloy and stainless steel in vitro and the cutaneous reactivity to it by patch test. 52 metal-allergic patients and 48 non-allergic controls were patch tested to stainless steel and CoCrMo discs. In addition, using atomic absorption spectrometry, the release of nickel, cobalt, and chromium from both materials was assessed upon 2-day exposure to distilled water, artificial sweat (AS), and cell culture medium. There was low nickel ion release from stainless steel (0.3-0.46 microg/cm(2)/2 days) and CoCrMo discs (up to 0.33 microg/cm(2)/2 days) into the different elution media. Chromium release from the 2 materials was also very low (0.06-0.38 microg/cm(2)/2 days from stainless steel and 0.52-1.36 microg/cm(2)/2 days from CoCrMo alloy). In contrast, AS led to abundant cobalt release (maximally 18.94 microg/cm(2)/2 days) from the CoCrMo discs, with concomitant eczematous reaction upon patch testing: 0 of the 52 metal-allergic patients reacted to stainless steel discs and 5 of the 52 patients to CoCrMo discs (all 5 patients were cobalt allergic and 3 also nickel and chromium allergic). None of the controls reacted to the discs. Apart from nickel being a focus of allergological research, our results point to the possibly underestimated association of cobalt release and potential hyperreactivity to CoCrMo alloy.

Induction chemotherapy in Barrett cancer: influence on surgical risk and outcome.

OBJECTIVE: To study the impact of induction chemotherapy on surgical risk and outcome in locally advanced Barrett cancer. BACKGROUND: Induction chemotherapy has become an accepted choice for the treatment of locally advanced adenocarcinoma of the esophagus and the esophagogastric junction. It has been shown that early assessment of metabolic response using positron emission tomography predicts response to chemotherapy. Metabolic response has also been revealed to be an independent prognostic factor. METHODS: Surgical risk and outcome in metabolic responders were compared with those in nonresponders. The study design predefined a 12-week multicourse preoperative chemotherapy regimen in metabolic responders. In contrast, chemotherapy was stopped after a 2-week induction period in metabolic nonresponders. All patients were scheduled for surgical resection. RESULTS: Of 110 evaluable patients, 50 metabolic responders and 54 nonresponders underwent resection. Postoperative complications occurred in 34%. Two patients (1.8%) died. There were no significant differences between responders and nonresponders in terms of postoperative morbidity and mortality. Major histologic remissions were seen in 58% of metabolic responders. Metabolic responders had an increased chance of having an R0 resection (96% vs. 74%; P=0.002) and a decreased risk of developing hematogenous or distant lymphatic recurrence (32% vs. 54%, P=0.019). This translated into better recurrence-free and overall survival. CONCLUSIONS: Induction chemotherapy and early metabolic response assessment is a new concept in the treatment of locally advanced Barrett cancer. Metabolic responders undergoing multicourse preoperative chemotherapy have a good prognosis. The best treatment strategy for nonresponders remains to be defined.

Prediction of tumor response by FDG-PET: comparison of the accuracy of single and sequential studies in patients with adenocarcinomas of the esophagogastric junction.

PURPOSE: Positron-emission-tomography with the glucose analog fluorodeoxyglucose (FDG-PET) has shown encouraging results for prediction of tumor response to chemotherapy. However, there is no consensus as to what time after initiation of therapy FDG-PET should be performed. To address this question we studied the time course of changes in tumor FDG-uptake in patients with locally advanced adenocarcinomas of the esophagogastric junction (AEG) treated with preoperative chemotherapy. METHODS: Twenty-four patients with AEG were included and underwent FDG-PET prior to therapy (PET1), 2 weeks after initiation of therapy (PET2), and preoperatively (PET3). Tumor metabolic activity was assessed by standardized uptake values (SUV) and correlated with histopathologic response and patient survival. RESULTS: Baseline tumor SUV was 8.3 +/- 3.5 and decreased to 5.0 +/- 1.8 at PET2 (p < 0.0001). At PET3 there was further decrease to 3.5 +/- 1.9 (p < 0.0001). The relative decrease of tumor FDG-uptake from PET1 to PET2 and from PET1 to PET3 were both significantly correlated with histopathologic response. Reduction of tumor SUV from PET1 to PET2 was significantly correlated with survival (p = 0.03) and there was a similar trend for changes from PET1 to PET3 (p = 0.09). In contrast, absolute SUVs did not demonstrate a significant correlation with histopathological response or patient survival at any of the studied time points. CONCLUSION: In patients with AEG, relative changes in tumor FDG uptake are better predictors for treatment outcome than absolute SUVs. Metabolic changes within the first 2 weeks of therapy are at least as efficient for prediction of histopathologic response and patient survival as later changes.

PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial.

BACKGROUND: In patients with locally advanced adenocarcinoma of the oesophagogastric junction (AEG), early metabolic response defined by 18-fluorodeoxyglucose-PET ([(18)F]FDG-PET) during neoadjuvant chemotherapy is predictive of histopathological response and survival. We aimed to assess the feasibility of a PET-response-guided treatment algorithm and its potential effect on prognosis. METHODS: Between May 27, 2002, and Aug 4, 2005, 119 patients with locally advanced adenocarcinoma of AEG type 1 (distal oesophageal adenocarcinoma) or type 2 (gastric cardia adenocarcinoma) were recruited into this prospective, single-centre study. All patients were assigned to 2 weeks of platinum and fluorouracil-based induction chemotherapy (evaluation period). Those with decreases in tumour glucose standard uptake values (SUVs), predefined as decreases of 35% or more at the end of the evaluation period and measured by PET, were defined as metabolic responders. Responders continued to receive neoadjuvant chemotherapy of folinic acid and fluorouracil plus cisplatin, or folinic acid and fluorouracil plus cisplatin and paclitaxel, or folinic acid and fluorouracil plus oxaliplatin for 12 weeks and then proceeded to surgery. Metabolic non-responders discontinued chemotherapy after the 2-week evaluation period and proceeded to surgery. The primary endpoint was median overall survival of metabolic responders and non-responders. Secondary endpoints were median event-free survival, postoperative complications and mortality, number of residual tumour-free (R0) resections, and histopathological responses. This study has been registered in the European Clinical Trials Database (EudraCT) as trial 2007-003356-11. FINDINGS: 110 patients were evaluable for metabolic responses. 54 of these patients had metabolic responses (ie, decrease of 35% or more in tumour glucose SUV) after 2 weeks of induction chemotherapy, corresponding to a response of 49% (95% CI 39-59). 104 patients had tumour resection (50 in the responder group and 54 in the non-responder group). After a median follow-up of 2.3 years (IQR 1.7-3.0), median overall survival was not reached in metabolic responders, whereas median overall survival was 25.8 months (19.4-32.2) in non-responders (HR 2.13 [1.14-3.99, p=0.015). Median event-free survival was 29.7 months (95% CI 23.6-35.7) in metabolic responders and 14.1 months (7.5-20.6) in non-responders (hazard ratio [HR] 2.18 [1.32-3.62], p=0.002). Major histological remissions (<10% residual tumour) were noted in 29 of 50 metabolic responders (58% [95% CI 48-67]), but no histological response was noted in metabolic non-responders. INTERPRETATION: This study confirmed prospectively the usefulness of early metabolic response evaluation, and shows the feasibility of a PET-guided treatment algorithm. These findings might enable tailoring of multimodal treatment in accordance with individual tumour biology in future randomised trials.

Hypermethylation of hMLH1, HPP1, p14(ARF), p16(INK4A) and APC in primary adenocarcinomas of the small bowel.

Small bowel adenocarcinoma (SB-AC) is a very rare tumor entity. Epigenetic alterations, including hypermethylation of DNA mismatch repair genes and tumor suppressor genes, seem to be important for carcinogenesis in tumors of the gastrointestinal tract, but have not yet been investigated in SB-AC. In the current study, the prevalence of hypermethylation in a panel of genes involved in gastrointestinal carcinogenesis (hMLH1, HPP1, p14(ARF), p16(INK4A), APC) was determined in a series of SB-AC. Paraffin-embedded tumor samples from 56 patients with SB-AC who underwent surgical resection between January 1985 and December 2003 were investigated for hypermethylation by means of methylation-specific real-time PCR, and compared with our findings in a previously investigated series of 50 gastric adenocarcinomas. In comparison with adenocarcinomas of the stomach, SB-AC revealed a significantly higher rate of hypermethylation of HPP1 (86% versus 54%, p = 0.0003), p16(INK4A) (32% versus 10%, p = 0.0006), and a significantly lower rate of hypermethylation of APC (48% versus 84%, p = 0.0001). Hypermethylation of hMLH1 and p14(ARF) was present in 23% and 9% of SB-AC, respectively. Locally advanced tumor categories (pT3/4) showed a higher rate of hypermethylation of HPP1 (90%) than did early tumor categories (pT1/2 categories, 40%; p = 0.0036). This was also reflected by the correlation between the HPP1 hypermethylation and high UICC stage (p = 0.02). No correlation was found between hypermethylation and other clinicopathologic parameters such as age, tumor grade and nodal status. Our findings suggest that hypermethylation of hMLH1, HPP1, p16(INK4A) and APC is frequent in primary adenocarcinomas of the small bowel. The differences in the hypermethylation spectrum of small bowel and stomach cancer indicate significant epigenetic differences between these tumors.

Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction.

PURPOSE: A previous study suggested that measurement of therapy-induced changes in tumor glucose metabolism by positron emission tomography (PET) with the glucose analog [18F]fluorodeoxyglucose (FDG) allows to select patients most likely to benefit from preoperative chemotherapy in adenocarcinomas of the esophagogastric junction (AEG). The aim of this study was to prospectively validate these findings by using an a priori definition of metabolic response. PATIENTS AND METHODS: Sixty-five patients with locally advanced AEGs were included. Tumor glucose utilization was quantitatively assessed by FDG-PET before chemotherapy and 14 days after initiation of therapy. Patients were classified as metabolic responders when the metabolic activity of the primary tumor had decreased by more than 35% at the time of the second PET. RESULTS: Metabolic responders showed a high histopathologic response rate (44%) with a 3-year survival rate of 70%. In contrast, prognosis was poor for metabolic nonresponders with a histopathologic response rate of 5% (P = .001) and a 3-year survival rate of 35% (P = .01). A multivariate analysis (covariates: ypT-, ypN-category, histopathologic response) demonstrated that metabolic response was the only factor predicting recurrence (P = .018) in the subgroup of completely resected (R0) patients. CONCLUSION: This study prospectively demonstrates that changes in tumor metabolic activity during chemotherapy predict response, prognosis, and recurrence. These data provide the basis for clinical trials in which preoperative treatment is changed for patients without a metabolic response early in the course of therapy. PET-guided induction therapy may even be applicable to earlier tumor stages because surgery is only minimally delayed in nonresponding patients.