Real-life data on improvement of survival after perioperative chemotherapy versus surgery alone on resectable adenocarcinoma of the stomach - a single-center study.

BACKGROUND: In the last decade, neoadjuvant chemotherapy has become the standard of care also for curatively resectable advanced gastric cancer. Prospective randomized studies have shown a significant benefit in disease free and overall survival rate after perioperative chemotherapy as compared to immediate surgery. However, data in the "real-life" setting are rare. In our retrospective study, we wanted to clarify the question whether this benefit is achievable under real-life conditions. METHODS: A total of 81 patients with resected adenocarcinoma of the stomach or distal esophagogastric junction (AEG III) clinical stage II-IIIc according to UICC (eighth edition) were enrolled. Forty-two patients received perioperative chemotherapy (cohort 1) and 39 patients were operated on immediately (cohort 2). Chemotherapy was carried out according to the ECF, EOX, or FLOT protocols. RESULTS: Overall 5-year survival was 35.7 % in cohort 1 and 23.7 % in cohort 2. Thus, the relative 5-year overall survival benefit was 51 %, and 12 % in absolute numbers (p = 0.083). For patients receiving perioperative chemotherapy per protocol (n = 20), a more marked absolute improvement in 5-year overall survival of 16.3 % as compared to immediately operated on patients was achieved (p = 0.05). Progression-free survival in this analysis was shown to be improved by perioperative chemotherapy also without statistical significance (p = 0.03). CONCLUSIONS: Patients with curatively resectable gastric adenocarcinoma or type III AEG tumor benefit from perioperative chemotherapy in terms of overall survival even under real-life conditions. Moreover, a benefit in progression-free survival can be demonstrated.

Neoadjuvant Therapy of Gastric Cancer: A Decisive Step Forward.

BACKGROUND: Although its incidence has been steadily decreasing in Western countries, gastric cancer remains a leading cause of cancer deaths worldwide. The detection rate of early-stage cancers is improving; nevertheless, the majority of cases is still diagnosed at later stages with a poor prognosis. Furthermore, the results that can be achieved with surgery have reached a plateau of effectiveness. SUMMARY: Neoadjuvant chemotherapy was successfully introduced first in patients with non-curatively resectable disease. In the last decade, neoadjuvant chemotherapy has also been established in potentially curatively resectable cases and has become the state-of-the-art treatment. Esophagogastric junction (EGJ) tumors are not optimally treated with chemotherapy alone, and combined radiochemotherapy (RCT) seems to yield superior outcomes. KEY MESSAGE: The use of neoadjuvant therapy has been successfully established in patients with curatively resectable disease. Neoadjuvant chemotherapy is now a cornerstone in the treatment of gastric cancer and cancer of the EGJ, although further work is needed in order to define the optimal combination regimen. PRACTICAL IMPLICATIONS: Neoadjuvant chemotherapy is currently the gold standard for the treatment of gastric cancer and cancer of the EGJ. Several independent studies have shown the benefits of using combination regimens that included cisplatin and 5-fluorouracil, though recently the use of the EOX (epirubicin, oxaliplatin and capecitabine) regimen has been widely accepted in this setting. Tumors of the EGJ benefit from neoadjuvant treatment with combined RCT. It should be noted that the optimal neoadjuvant regimen in EGJ tumors has not yet been defined, and the survival advantage of neoadjuvant RCT over neoadjuvant chemotherapy remains to be established in this patient population.

Acute cholecystitis: early versus delayed cholecystectomy, a multicenter randomized trial (ACDC study, NCT00447304).

OBJECTIVE: Acute cholecystitis is a common disease, and laparoscopic surgery is the standard of care. BACKGROUND: Optimal timing of surgery for acute cholecystitis remains controversial: either early surgery shortly after hospital admission or delayed elective surgery after a conservative treatment with antibiotics. METHODS: The ACDC ("Acute Cholecystitis-early laparoscopic surgery versus antibiotic therapy and Delayed elective Cholecystectomy") study is a randomized, prospective, open-label, parallel group trial. Patients were randomly assigned to receive immediate surgery within 24 hours of hospital admission (group ILC) or initial antibiotic treatment, followed by delayed laparoscopic cholecystectomy at days 7 to 45 (group DLC). For infection, all patients were treated with moxifloxacin for at least 48 hours. Primary endpoint was occurrence of predefined relevant morbidity within 75 days. Secondary endpoints were as follows: (1) 75-day morbidity using a scoring system; (2) conversion rate; (3) change of antibiotic therapy; (4) mortality; (5) costs; and (6) length of hospital stay. RESULTS: Morbidity rate was significantly lower in group ILC (304 patients) than in group DLC (314 patients): 11.8% versus 34.4%. Conversion rate to open surgery and mortality did not differ significantly between groups. Mean length of hospital stay (5.4 days vs 10.0 days; P < 0.001) and total hospital costs (€2919 vs €4262; P < 0.001) were significantly lower in group ILC. CONCLUSIONS: In this large, randomized trial, laparoscopic cholecystectomy within 24 hours of hospital admission was shown to be superior to the conservative approach concerning morbidity and costs. Therefore, we believe that immediate laparoscopic cholecystectomy should become therapy of choice for acute cholecystitis in operable patients. (NCT00447304).

Gastric cancer: Where is the place for the surgeon, the oncologist and the endoscopist today?

Gastric cancer remains a major health issue and a leading cause of death worldwide. While the incidence is decreasing in western countries, there has been a shift to more proximal cancers of the diffuse type, which are usually more aggressive and associated with a worse prognosis. Radical surgery still offers the only chance of long term survival, but surgery has reached a plateau of effectiveness and more aggressive approaches like "ultraradical" lymphadenectomy have not improved prognosis. There are three options to improve the situation: Earlier detection, neoadjuvant chemotherapy and adjuvant therapy. Whilst systematic gastroscopic screening makes sense in countries with a high incidence of gastric cancer, in other regions targeted investigation of risk groups including first-degree relatives of cancer patients, patients with a chronic corpus-dominant gastritis or with defined genetic abnormalities may help to detect cancer at an earlier stage. Neoadjuvant chemotherapy has meanwhile proved to significantly improve the prognosis not only in patients with a locally advanced cancer who cannot be resected for cure but but also in those who are potentially amenable to curative resection. In the largest randomised study so far reported, perioperative chemotherapy raised overall survival after 5 years from 23% to 36%. The role of adjuvant chemotherapy has been discussed for over 30 years. Meta-analyses demonstrate a small but significant effect which, however, seems to be restricted to Asian patients. In a large US-study, adjuvant radiochemotherapy appeared to significantly improve outcomes. However, less than 50% of the study patients underwent a systematic lymphadenectomy and so the results of the therapy group were not better to those of "only resected" patients in two large European studies. Thus, the indication of adjuvant (radio-)chemotherapy in gastric cancer currently remains uncertain. Endoscopists have found a therapeutic role through endoscopic resection of early cancers, introduced mainly by Japanese authors. With the development of high resolution endoscopy, endosonography and adequate equipment, the endoscopic curative resection of T1a-tumors (restricted to the mucosal layer) has been established.

Current strategies in systemic treatment of gastric cancer and cancer of the gastroesophageal junction.

Gastric cancer is a major health issue and a leading cause of death worldwide. The results of standard therapy remain unsatisfactory mainly because of diagnosis at the late stage of disease. Innovative strategies such as neoadjuvant chemotherapy in locally advanced cancer have improved the outcome even in operable cases. Whether an adjuvant radiochemotherapy is of benefit after curative resection including systematic lymphadenectomy remains yet unclear. Some progress has been made in the palliative setting by introducing new substances. This review examines recent advances in the systemic treatment of gastric and gastroesophageal junction cancer.

Autoimmune hepatitis 2 years after the diagnosis of primary sclerosing cholangitis: an unusual overlap syndrome in a 17-year-old adolescent.

A 15-year-old girl was admitted in April 2004 owing to fatigue and loss of appetite. Her paediatrician had found elevated serum levels for alkaline phosphatase. The endoscopic retrograde cholangiography documented typical signs of primary sclerosing cholangitis with involvement of the small and large ducts. The liver biopsy revealed extensive septal and portal fibrosis. No evidence of inflammatory bowel disease was present. She was started on ursodeoxycholic acid therapy and improved clinically. After 22 months she presented again with rising transaminase levels up to 600 U/l. The second liver biopsy was strongly suggestive for autoimmune hepatitis besides the already known features of primary sclerosing cholangitis. Elevated levels of IgG, and elevated titres for ANA and antismooth muscle antibodies (ASMA) were also found. The duct irregularities seen on re-endoscopic retrograde cholangiography were slightly regredient as compared with the first investigation. We added prednisolone and azathioprine to the ursodeoxycholic acid and the transaminase levels dropped together with clinical improvement.

Contrast-enhanced endoscopic ultrasound in discrimination between benign and malignant mediastinal and abdominal lymph nodes.

BACKGROUND: Enlarged lymph nodes in the mediastinum reflect neoplastic, infectious or other diseases. The classification of these nodes is crucial in the management of the patient. Currently, only invasive measures obtaining tissue samples reach satisfying specificity. Contrast-enhanced endoscopic ultrasound (EUS) may offer a non-invasive alternative. MATERIALS AND METHODS: A total of 122 patients (age: 63 +/- 15 years, 92 males, 30 females) with enlarged mediastinal and/or paraaortic lymph nodes diagnosed by CT scan were included in the study. EUS-guided fine needle aspiration was performed and cytologic specimens were diagnosed as representing a malignant or benign process in case of Papanicolau IV and V, or Papanicolau I and II, respectively. RESULTS: Based on cytology results, the investigated lymph nodes were classified as neoplastic (n = 48) or non-neoplastic lymph nodes. Using the B-mode criteria the preliminary diagnosis was confirmed in 64 out of 74 benign lymph nodes (specificity 86%). Regarding malignant lymph nodes 33 of 48 were confirmed (sensitivity 68%). Using the advanced contrast-enhanced EUS criteria the diagnosis was confirmed in 68 of 74 benign lymph nodes (specificity 91%). However, in case of malignant lymph nodes the number of correct diagnoses dropped to 29 of 48 lymph nodes (sensitivity 60%). The contrast-enhanced EUS criteria to identify benign lymph nodes and node enlargement in malignant lymphoma do not differ. If those ten patients with malignant lymphoma are excluded, the sensitivity of the contrast enhanced EUS for malignant lymph nodes rises to 73%. CONCLUSION: Contrast-enhanced EUS improves the specificity in diagnosing benign lymph nodes as compared to B-mode EUS. It does not improve the correct identification of malignant lymph nodes and cannot replace EUS-guided fine-needle aspiration.

Cost-benefit analysis of screening colonoscopy in 40- to 50-year-old first-degree relatives of patients with colorectal cancer.

BACKGROUND AND AIMS: As shown previously, 40- to 50-year-old first-degree relatives of patients with colorectal cancer (CRC) have significantly more colorectal adenomas than controls of the same age. Screening colonoscopy of these persons at risk between 40 and 50 years might be cost beneficial. METHODS: We prepared a detailed cost-benefit analysis of screening colonoscopy and possible repeat endoscopies according to current expenditures for endoscopic procedures in Germany. Since screening colonoscopy is generally offered and reimbursed from 55 years on in Germany, we analysed the period between 45 and 55 years, taking an annual interest rate of 5% into account. Costs were analysed based on the results of a former study [11] depending on various participation rates in a general screening programme. FINDINGS: Based on the available 1994 figure of about 20,000 euros for diagnosis and treatment of one cancer case, screening colonoscopy is cost beneficial when participation is high. Under a more realistic assumption of currently about 40,000 euros per cancer case, screening colonoscopy is cost beneficial in any case. INTERPRETATION: Our data support that systematic screening colonoscopy in first-degree relatives of patients with CRC by the age of 45 years most likely demonstrates an economic benefit.

Screening colonoscopy in 40- to 50-year-old first-degree relatives of patients with colorectal cancer is efficient: a controlled multicentre study.

BACKGROUND AND AIMS: Persons with a familial risk of colorectal cancer (CRC) account for about 25% of all CRC cases. The adenoma prevalence in relatives of CRC patients 50-60 years of age is 17-34%; data on younger individuals are scarce. Our aim was to prospectively define the adenoma prevalence in 40- to 50-year-old first-degree relatives of CRC patients compared to controls. PATIENTS AND METHODS: CRC patients were identified via the regional cancer registry, and their 40- to 50-year-old first-degree relatives (risk group) were invited for screening colonoscopy. Additional probands and controls of the same age were recruited by newspaper articles and radio or television broadcastings. Using high-resolution video colonoscopy, each detected polyp was removed and histopathologically assessed. Each participant completed demographic and epidemiological questionnaires. RESULTS: Of 228 subjects in the risk group 36.4% had polypoid lesions compared to 20.9% of 220 controls (p<0.001). Forty-three (18.9%) subjects in the risk group had adenomas compared to 18 (8.2%) in the control group (p=0.001). High-risk adenomas (>10 mm and/or of villous type) were found in 12 persons in the risk group compared to 5 controls (not significant). In the risk group most lesions (52%) were located proximal to the sigmoid colon compared to 29% in controls. CONCLUSIONS: Subjects between 40-50 years with first-degree relatives with CRC demonstrate a significantly higher prevalence of adenomas than controls, with a tendency towards a more proximal location. These data support a screening colonoscopy in persons with familial risk already between 40 and 50 years.

Radioiodinated phenylalanine derivatives to image pancreatic cancer: a comparative study with [18F]fluoro-2-deoxy-D-glucose in human pancreatic carcinoma xenografts and in inflammation models.

This work validated an in vivo model of human pancreatic cancer for preclinical studies and evaluated p-amino-3-[123I]iodo-L-phenylalanine (AIPA) and p-[123I]iodo-L-phenylalanine (IPA) as potential imaging agents for pancreatic cancer. The primary human pancreatic adenocarcinoma PaCa44 and PanC1 cells (1.5-2.5x10(6)) were inoculated either subcutaneously into the flank or orthotopically into the pancreas of severe combined immunodeficient (SCID) mice. Tumor formation was recorded by palpation and monitored by magnetic resonance imaging (MRI). After intravenous injection, tumor affinity and organ distribution of AIPA and IPA were compared with those of [18F]fluoro-2-deoxy-D-glucose (FDG) in tumor-bearing SCID mice and in concanavalin A (ConA)-induced inflammation models. All SCID mice developed a pancreatic tumor 2-4 weeks after cell implantation. All subcutaneously transplanted tumors were detected by MRI and confirmed histologically, whereas 90% and 68% of the histopathologically confirmed orthotopic PaCa44 and PanC1 tumors were accurately demonstrated by MRI. Tumor formation and spread after orthotopic implantation showed invasion into adjacent organs and metastases in different sites of the abdomen. In contrast, no organ invasion or metastases were demonstrated by subcutaneous implantation. In vivo, AIPA and IPA displayed high affinity for pancreatic tumors. Radioactivity uptake into a tumor at 60 and 240 min amounted to 7.2+/-2.1% and 10.7+/-2.5% I.D./g for AIPA and 13.3+/-3.5% and 15.2+/-3.8% I.D./g for IPA in heterotopic tumors as compared with 11.8+/-3.2% and 15.2+/-2.4% I.D./g for AIPA and 16.7+/-3.5% and 22.5+/-4.3% I.D./g for IPA in orthotopically implanted tumors. In comparison, the FDG uptake was 10.8+/-2.9% and 2.5+/-0.6% I.D./g into heterotopic tumors and 12.5+/-3.8% and 3.5+/-1.2% I.D./g into the orthotopic ones at 60 and 240 min postinjection. The FDG uptake markedly increased (>400%) in the area of inflammation, whereas accumulation of AIPA and IPA in inflammation remained moderate and comparable with that determined in muscle. In summary, the orthotopic implantation model, more than the heterotopic one, reflects more closely the clinical course of the disease, thus representing the appropriate in vivo model for preclinical studies. The specific and high-level targeting of AIPA and IPA to human pancreatic tumor xenografts, with marked tumor-to-background ratios, indicate that AIPA and IPA are interesting candidates as radiotracers for noninvasive imaging of pancreatic cancer. IPA has the advantage of relatively low renal uptake and thus presents as the most promising candidate.

Low toxic neoadjuvant cisplatin, 5-fluorouracil and folinic acid in locally advanced gastric cancer yields high R-0 resection rate.

PURPOSE: Neoadjuvant chemotherapy in locally advanced gastric cancer is effective, but is often associated with severe side effects, including fatal outcome. This study evaluates a combination of cisplatin, folinic acid and 5-fluorouracil (PLF) in terms of efficacy (R-0 resection rate) and toxicity. METHODS: Twenty-five patients with locally advanced gastric cancer who after extensive staging were deemed not suitable for curative resection underwent neoadjuvant chemotherapy. Three or four cycles of cisplatin (50 mg/m(2) days 1 and 15), folinic acid (200 mg/m(2) days 1, 8, 15 and 22), and 5-fluorouracil (2,000 mg/m(2 ) days 1, 8, 15 and 22) were administered. Cases with progressive disease were taken off the study. Two weeks after finishing chemotherapy resection was performed and all patients were enrolled in a structured follow-up. RESULTS: Of the patients, 22/25 finished chemotherapy and 20 of those underwent laparotomy. In 13/25 patients (52%) a R-0 resection and in three cases a R-1 resection were achieved. Four patients stayed irresectable. During 76 completed cycles of chemotherapy we observed five cases of WHO grade-III toxicity and no grade-IV toxicity. CONCLUSIONS: The presented PLF protocol yields R-0 resection rates comparable to protocols like EAP (etoposide, adriamycin, platinum), but with a better safety profile allowing administration in an outpatient setting. Our study supports PLF as a reference neoadjuvant treatment for gastric cancer even outside of clinical studies.

Low sensitivity of the ki-ras polymerase chain reaction for diagnosing pancreatic cancer from pancreatic juice and bile: a multicenter prospective trial.

PURPOSE: Early detection of pancreatic cancer using molecular markers may improve outcome. Mutations of the ki-ras oncogene are detected in 70% to 90% of pancreatic adenocarcinomas. A prospective, partially blinded, multicenter diagnostic trial was performed to test the sensitivity and specificity of the ki-ras polymerase chain reaction (PCR) analysis of pancreatic juice and bile specimens. PATIENTS AND METHODS: Specimens of pancreatic juice and bile were collected from 532 consecutive patients. Mutations in codon 12 of the ki-ras gene were identified by two independent enrichment PCRs and confirmed by direct sequencing. RESULTS: One hundred seventy-four of 532 patients were excluded from the final analysis (reasons: no amplifiable DNA, no specimen or only duodenal juice sent, lost to follow-up). Sixty-three of 358 patients had ductal pancreatic cancer. In 24 (38.1%) of 63 patients, a mutated ki-ras gene was identified in pancreatic juice and/or bile. Ki-ras mutations were found in four (8%) of 50 cases of chronic pancreatitis, in 10 (18.7%) of 53 cases of other malignancies of the pancreaticobiliary tree, and in 14 (7.3%) of 192 cases of benign diseases or normal findings. Sensitivity and specificity of the ki-ras PCR analysis for the detection of pancreatic cancer was 38.1% and 90.5%, respectively. CONCLUSION: In this prospective trial performed in nonselected patients, mutations of the ki-ras gene were detected in 38.1% of cases with pancreatic cancer. This test in its present form is not appropriate to confirm or screen for pancreatic cancer. More sensitive and/or quantitative PCR tests may improve the molecular diagnosis of pancreatic cancer.

The influence of the suppression of gastrooesophageal reflux on the gene expression pattern in Barrett's oesophagus.

About 10% of Barrett's patients develop an adenocarcinoma in the course of life. There is increasing evidence that persistent gastrooesophageal reflux is involved in carcinogenesis. We investigated whether the gene expression pattern of Barrett's epithelium cells changes upon suppression of gastrooesophageal reflux compared to unsuppressed reflux. Biopsies from various regions of Barrett's segments and, further, during and without proton pump inhibitor therapy were collected in 5 patients. The reflux profile was assessed by simultaneous 24-h oesophageal pH and bile reflux testing. m-RNA was extracted from the specimens, and integrity and absence of DNA proven by gel electrophoresis and ALU-PCR. Using the micro array technique 1,176 genes were analysed and assigned an expression level. The number of genes detected in each experiment varied from 86 to 136. There was a 91% concordance of the gene expression pattern in distal and proximal biopsies from an individual Barrett's segment. Concordance was much less (68%) between biopsies of the same patient taken during and without proton pump inhibitor therapy. The gene expression pattern in a Barrett's oesophagus varies dependent upon different reflux situations. Other factors like the location of biopsy are of minor importance. The micro array technique allows for selection of candidate genes important in carcinogenesis.

Expression of CD44v5 and -v6 in Barrett's carcinoma is not increased compared to that in nondysplastic Barrett's mucosa.

Barrett's adenocarcinoma currently shows the highest increase in the incidence of all malignant tumors. Reliable molecular markers to identify Barrett's patients at risk are still missing. Our own results demonstrate that the expression of CD44v6 correlates with the development of dysplasia in colorectal neoplasms. Therefore, we examined the expression of CD44 variants v5 and v6 in normal esophageal mucosa, non-dysplastic Barrett's mucosa, and Barrett's carcinoma. mRNA from biopsy specimens of patients with Barrett's esophagus (n = 19) or Barrett's carcinoma (n = 15) and patients without esophageal diseases (controls; n = 9) were extracted and used as templates for cDNA synthesis. CD44 variants were detected by RT-PCR with primers hybridizing with CD44 sequences up- and downstream of variable exons. CD44v6 expression was found in 36 of 56 biopsy specimens (64%) of non-dysplastic Barrett's mucosa, in 100% of squamous epithelium, and in none of the gastric mucosa specimens. Eleven of 15 specimens (73%) of Barrett's carcinoma tested positive for v6 expression. The identification of v5 expression did not give additional information. There was no correlation between CD44v5 or -v6 expression and staging or grading of the tumors. Expression of CD44v5 and -v6 seems to be independent of the development of cancer in Barrett's mucosa.