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In patients with locally advanced adenocarcinoma of the oesophagogastric junction (AEG), early metabolic response defined by 18-fluorodeoxyglucose-PET ([ 18F]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. 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. 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. 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.

Background and aim Chemotactic cytokines play a role in angiogenesis and attraction of immune cells. However, their contribution to tumor formation remains incompletely understood. In a previous transcriptome study, we identified a family of structurally related chemokines of the CXC-family to be specifically up-regulated in colorectal cancer. The aim of the present study was to investigate the regulation of their expression in colon cancer cells and to test the hypothesis that altered CXC-chemokine expression is related to critical clinical parameters, such as survival or metastasis formation. Materials and methods Expression levels of interleukin-8 (CXCL-8) and growth-related oncogenes 2 and 3 (GRO-2/CXCL-2 and GRO-3/CXCL-3) were quantified using qRT-PCR in 97 patients with completely resected colon carcinoma and correlated with clinical parameters. Moreover, 16 samples of normal mucosa, nine samples of benign adenoma, and 11 samples of liver metastasis were analyzed. Next, the regulation of chemokine expression in response to various stimuli was tested in colon cancer cell lines (HT29, HCT116, CaCO2). Results Expression of GRO-2, GRO-3, and IL-8 was significantly increased in colon cancer as compared to normal colon tissue. Expression of GRO-2 and GRO-3 was already enhanced in premalignant adenomas, and GRO-3 was significantly down-regulated in liver metastasis as compared to the primary tumor. Importantly, expression of GRO-3 was significantly higher in patients with local versus systemic disease. Moreover, IL-8 expression was significantly associated to overall post-operative survival. Finally, all chemokines were strongly induced by IL-1alpha in the colon cancer cell lines tested, indicating a potential link to inflammatory processes. Conclusion In accordance with earlier findings, we report here a significantly increased expression of GRO-2, GRO-3, and IL-8 in colon carcinoma as compared to normal tissue. Furthermore, GRO-3 was related to metastasis formation, and IL-8 was associated with survival, suggesting a potential predictive power of these markers.

Background In colorectal surgery UICC/AJCC criteria require a yield of 12 or more locoregional lymph nodes for adequate staging. Neoadjuvant radiochemotherapy for rectal carcinoma reduces the number of lymph nodes in the resection specimen; the prognostic impact of this reduced lymph node yield has not been determined. Methods One hundred two patients with uT3 rectal carcinoma who were receiving neoadjuvant radiochemotherapy were compared with 114 patients with uT3 rectal carcinoma who were receiving primary surgery followed by adjuvant radiochemotherapy. Total lymph node yield and number of tumor-positive lymph nodes were determined and correlated with survival. Results After neoadjuvant radiochemotherapy both total lymph node yield (12.9 vs. 21.4, p  < 0.0001) and number of tumor-positive lymph nodes (1.0 vs. 2.3, p  = 0.014) were significantly lower than after primary surgery plus adjuvant radiochemotherapy. Reduced total lymph node yield in neoadjuvantly treated patients had no prognostic impact, with overall survival of patients with 12 or more lymph nodes the same as that of patients with less than 12 lymph nodes. Overall survival of neoadjuvantly treated patients was significantly influenced by the number of tumor-positive lymph nodes with 5-year-survival rates of 88, 63, and 39% for 0, 1–3, and more than 3 positive lymph nodes ( p  < 0.0001). Conclusion The UICC/AJCC criterion of a total lymph node yield of 12 or more should be revised for rectal carcinoma patients.

Positron emission tomography (PET) using 18F-labelled 3'-deoxy-3'-fluorothymidine (FLT) was assessed for therapy monitoring in patients with rectal cancer undergoing neoadjuvant chemoradiotherapy. Ten patients with locally advanced rectal cancer were included and underwent long-course preoperative chemoradiotherapy (total dose 45 Gy, 1.8 Gy/day, concomitant 250 mg/m2 5-fluorouracil) followed by surgery. FLT-PET was performed prior to chemoradiotherapy, 2 weeks after initiation of chemoradiotherapy and preoperatively (3-4 weeks post chemoradiotherapy). FLT uptake was correlated with histopathological tumour regression and changes in T stage. Mean tumour FLT uptake was 4.2+/-1.0 SUV before therapy and decreased significantly to 2.9+/-0.6 SUV 14 days after initiation of chemoradiotherapy (-28.6%+/-10.7%, p=0.005). The preoperative scan showed a further decrease to 1.9+/-0.4 SUV (-54.7%+/-7.6%, p=0.005). However, the degree of change in FLT uptake 2 weeks after initiation and after completion of neoadjuvant therapy did not correlate with histopathological tumour regression. FLT-PET did not seem to be a promising method for assessment of tumour response in the studied chemoradiotherapy regimen in patients with rectal cancer.

In this pilot study, we evaluated 3'-deoxy-3'-(18)F-fluorothymidine (FLT) PET for the detection of gastric cancer and compared the diagnostic accuracy with that of (18)F-FDG PET. Forty-five patients (31 male and 14 female) with histologically proven locally advanced gastric cancer underwent attenuation-corrected whole-body (18)F-FLT PET and (18)F-FDG PET/CT (low-dose CT). (18)F-FLT emission images were acquired on a full-ring PET scanner 45 min after the injection of 270-340 MBq of (18)F-FLT. (18)F-FDG PET/CT was performed 60 min after the injection of 300-370 MBq of (18)F-FDG. Mean standardized uptake values for (18)F-FLT and (18)F-FDG were calculated using circular ROIs (diameter, 1.5 cm) in the primary tumor manifestation site, in a reference segment of the liver, and in the bone marrow and were compared on a lesion-by-lesion basis. According to the Lauren classification, 15 tumors (33%) were of the intestinal subtype and 30 (67%) of the nonintestinal subtype. (18)F-FLT PET images showed high contrast for the primary tumor and proliferating bone marrow. In all patients (45/45), focal (18)F-FLT uptake could be detected in the primary tumor. In contrast, 14 primary tumors were negative for (18)F-FDG uptake, with lesional (18)F-FDG uptake lower than or similar to background activity. The mean standardized uptake value for (18)F-FLT in malignant primaries was 6.0 +/- 2.5 (range, 2.4-12.7). In the subgroup of (18)F-FDG-positive patients, the mean value for (18)F-FDG was 8.4 +/- 4.1 (range, 3.8/19.0), versus 6.8 +/- 2.6 for (18)F-FLT (Wilcoxon test: P = 0.03). Comparison of mean (18)F-FLT and (18)F-FDG uptake in tumors with signet ring cells revealed no statistically significant difference between the tracers (6.2 +/- 2.1 for (18)F-FLT vs. 6.4 +/- 2.8 for (18)F-FDG; Wilcoxon test: P = 0.94). The results of this study indicate that imaging gastric cancer with the proliferation marker (18)F-FLT is feasible. (18)F-FLT PET was more sensitive than (18)F-FDG PET, especially in tumors frequently presenting without or with low (18)F-FDG uptake, and may improve early evaluation of response to neoadjuvant treatment.

The utility of fiberoptic bronchoscopy in the preoperative assessment of patients with esophageal cancer has not been thoroughly investigated. More accurate staging could improve the design of clinical trials and avoid inappropriate surgical decisions in individual patients. To evaluate the utility of bronchoscopy in the preoperative assessment of airway invasion by supracarinal esophageal cancer. We prospectively analyzed 220 bronchoscopies in 166 consecutive patients with supracarinal esophageal cancer and correlated the findings with operative results and survival. In 126 bronchoscopies (57.3%), no abnormal findings could be seen in the airways. Compared with histologic and cytologic results, the normal macroscopic appearance of the airways had a negative predictive value of 94.4%, but the positive predictive value of all macroscopic abnormalities for the diagnosis of airway invasion was low, particularly after radiation therapy. Endoluminal tumor mass, protrusion of the posterior tracheal wall, and signs of mucosal invasion were visible in 5.9%, 28.6%, and 4.1% of the bronchoscopies, respectively. However, in only 8.6% of the 220 bronchoscopies, cancer invasion was proved by biopsy or cytology. Bronchoscopy with biopsies and brush and washing cytology examinations was the sole decisive staging procedure, enabling the exclusion from surgery because of airway invasion in 18.1% of otherwise potentially operable patients, with an overall accuracy of 93.3% (95% confidence interval, 86.7 to 97.3%). The results of bronchoscopy were falsely negative in six patients, who all underwent surgery after neoadjuvant therapy. Fiberoptic bronchoscopy with systematic multiple biopsies and brush and washing cytology examinations is an accurate procedure in evaluating the possible invasion of supracarinal esophageal cancer into the airways. Macroscopic findings alone are not reliable; errors in sole bronchoscopic inspection would have resulted in operations that would be unlikely to help the patients or would have inappropriately excluded patients from surgery.

To characterize cytogenetic alterations found in Barrett's adenocarcinoma (BA) and, more importantly, its premalignant stages, we studied chromosomal imbalances in various lesions in the histologically proposed metaplasia-dysplasia-carcinoma sequence using comparative genomic hybridization (CGH). Using 30 esophageal adenocarcinoma resection specimens, we were able to study 30 areas of Barrett's adenocarcinoma and 8 lymph node metastases (LN). In addition, we investigated 25 premalignant lesions adjacent to BA derived from a subset of 14 resection specimens including 11 areas of high grade dysplasia (HGD), 8 areas of low grade dysplasia (LGD), and 6 areas of intestinal metaplasia (IM), which were laser-microdissected and studied with CGH. To validate the CGH findings, fluorescence in situ hybridization analysis on 13 BA with probes specific for HER-2/ neu and 20q13.2 were performed. The chromosomal alterations most often identified in BA were: gains on 8q (80%), 20q (60%), 2p, 7p and 10q (47% each), 6p (37%), 15q (33%) and 17q (30%). Losses were observed predominantly on the Y-chromosome (76%), 4q (50%), 5q and 9p (43. each), 18q (40%), 7q (33%) and 14q (30%). High-level amplifications were observed on 8q23-qter, 8p12-pter, 7p11-p14, 7q21–31, 17q11-q23. Recurrent chromosomal changes were also identified in metaplastic (gains on 8q, 6p, 10q, losses on 13q, Y, 9p) and dysplastic epithelium (gains on 8q, 20q, 2p, 10q, 15q, losses on Y, 5q, 9p, 13q, 18q). Novel amplified chromosomal regions on chromosomes 2p and 10q were detected in both Barrett's adenocarcinoma and premalignant lesions. An increase of the average number of detected chromosomal imbalances from IM (7.0 ± 1.7), to LGD (10.8 ± 2.2), HGD (13.4 ± 1.1), BA (13.3 ± 1.4), and LN (22 ± 1.2) was seen. Although the detection of common chromosomal alterations in premalignant lesions and adjacent carcinomas suggest a process of clonal expansion, the occurrence of several chromosomal changes in an apparently random order relative to one another is striking evidence that clonal evolution is more complex than would be predicted by linear models. This is probably a reflection of the existence of many divergent neoplastic subpopulations and highlights one of the main problems associated with surveillance of Barrett's patients, namely sampling error.

E-Cadherin alterations have been reported frequently in sporadic diffuse type gastric and lobular breast carcinomas. Germline mutations of this gene have been identified recently in several gastric cancer families. We analyzed seven patients with a family history of the disease who had diffuse type gastric cancer diagnosed before the age of 45 for germline mutations in CDH1, the gene encoding the E-cadherin protein. We identified a frameshift mutation in exon 3 in one patient with a strong family history of gastric cancer. The same germline mutation was found in the patient's mother, who had metachronous development of lobular breast and diffuse type gastric carcinomas. Immunohistochemistry for E-cadherin protein expression revealed an abnormal staining pattern in both of these tumors, suggesting complete inactivation of the cell adhesion molecule. Thus, our finding suggests that besides diffuse type gastric cancer, lobular breast carcinomas may be associated with germline CDH1 mutations.

The prognostic importance of uPA and PAI-1 in relapse-free survival has been shown in breast cancer. The survival of 76 totally resected gastric cancer patients were examined in a prospective study.

The alarming rise in the incidence of esophageal adenocarcinomas in the Western world has focused interest on so-called Barrett's esophagus. Barrett's esophagus is characterized by specialized intestinal epithelium replacing the normal squamous epithelium in the distal esophagus and is considered a consequence of long-lasting and severe gastroesophageal reflux disease. A metaplasia-dysplasia-carcinoma sequence links Barrett's esophagus with adenocarcinoma of the distal esophagus (Barrett's cancer). Despite intensive research, many questions concerning the pathogenesis, diagnosis, and treatment of Barrett's esophagus and associated adenocarcinoma are still unanswered. Based on current data, the malignant progression of Barrett's esophagus cannot be substantially prevented by medical or surgical therapy for reflux. Although no firm data are available to show that surveillance strategies can reduce overall mortality from Barrett's cancer, early detection and cure are possible. Management of Barrett's esophagus and carcinoma is reviewed with reference to the sequence of disease from metaplasia to carcinoma.