Hiatal hernia, Barrett's esophagus, and long-term symptom control after laparoscopic fundoplication for gastroesophageal reflux.

BACKGROUND: The aim of this study was to determine the long-term symptom control after laparoscopic fundoplication for gastroesophageal reflux disease (GERD), and possible prognostic factors. METHODS: A cohort of 271 patients, operated on at a university hospital from 1996 through 2002, was eligible for evaluation after a median interval of 102 months (range = 12-158). The time between surgery and recurrence of reflux symptoms (i.e., time to treatment failure) served as the end point for statistical analysis. Putative risk factors for symptom recurrence were analyzed by univariate analysis and by using Cox's multiple-hazards regression. RESULTS: According to Kaplan-Meier estimates, the rate of reflux symptom recurrence was 15 % after 108 months, 11 % in cases without intestinal metaplasia, but 43 % in patients with long-segment (≥ 3 cm) Barrett's esophagus (BE; p < 0.0001). Reflux symptoms recurred in 22 % of cases with a hiatal hernia (HH) ≥ 3 cm before operation, but only in 7 % with smaller or absent HH (p = 0.005). Multivariate analysis revealed a relative risk of 6.6 (CI = 3.0-13.0) for long-segment BE and 3.0 (CI = 1.7-10.1) for HH ≥ 3 cm. A strong statistical interaction was found between HH ≥ 3 cm and long-segment BE: the small group (n = 18) of cases exhibiting both risk factors had an exaggerated recurrence rate of 72 % at 108 months. CONCLUSIONS: Laparoscopic fundoplication for symptomatic GERD provided a long-lasting abolition of reflux symptoms in 231 of 271 (85 %) patients. HH ≥ 3 cm and long-segment BE were shown as independent prognostic factors favoring recurrence.

Prognostic assessment and adjuvant treatment strategies within early-stage, sporadic triple negative breast cancer patients.

An adjuvant chemotherapeutic standard has not been identified in triple negative breast cancer (TNBC) yet. One hundred and forty-one adjuvant treated TNBC patients had a median follow-up of 71 months. Larger tumor size (p = .005) and positive lymph-node status (p = .033) were associated with a significant shorter overall survival. Sixty-one percent of patients received anthracycline-containing chemotherapy, 28.4% a non-anthracycline-containing regimen, and 10.6% an anthracycline/taxane-containing regimen. Overall survival, disease-free survival, local recurrence-free survival and distant disease-free survival did not differ between the chemotherapeutic groups. Non-anthracycline-containing regimen appeared to be an effective treatment in TNBC.

Detection of EpCAM positive and negative circulating tumor cells in metastatic breast cancer patients.

BACKGROUND: Immunomagnetic EpCAM based methods are used to enrich circulating tumor cells (CTCs) in metastatic breast cancer (mBC) patients. EpCAM negative CTCs may be missed. We addressed the question of the reliability of an EpCAM dependent assay to enrich CTCs. METHODS: To elucidate this issue, our study has been designed to assess two different CTC enrichment technologies (i) in EpCAM positive (+) and EpCAM negative cell lines and (ii) in mBC patients in dependency on their respective EpCAM expression. These two technologies encompass one anti-EpCAM immunomagnetic enrichment technology, MACS HEA MicroBeads(®) (MACS), and one EpCAM independent density centrifugation method, OncoQuick(®) plus (OQ+). Furthermore, the coherence between EpCAM expression in the primary tumor tissue of mBC patients and the CTC detection rates in the corresponding patients is analyzed. RESULTS: (i) MACS recovered significantly more EpCAM (+) than EpCAM (-) tumor cells (p < 0.001) in spiked blood samples. With OQ+ no significantly different recovery rates between EpCAM (+) and EpCAM (-) tumor cells (p = 0.796) were detected. (ii) In mBC patients MACS yielded a significantly higher (p = 0.024) detection rate of EpCAM (+) CTCs. No statistically significant difference (p = 0.070) was found concerning the EpCAM status-based detection rate of CTCs by OQ+. (iii) CTC detection rates are independent of the primary tumors' EpCAM expression. CONCLUSIONS: EpCAM (-) CTCs can not be detected by immunomagnetic EpCAM dependent enrichment methods. EpCAM independent enrichment technologies seem to be superior to detect the entire CTC population. Evaluation of CTCs as prognostic marker should compromise EpCAM (+) and (-) subpopulations.

Frequent MGMT (0(6)-methylguanine-DNA methyltransferase) hypermethylation in long-term survivors of glioblastoma: a single institution experience.

BACKGROUND: The aim of this retrospective study was to analyse the MGMT (0(6)-methylguanine-DNA methyltransferase) promoter methylation status in long-term surviving (≥ 3 years) patients with glioblastoma multiforme (GBM). METHODS: The methylation status of the MGMT promoter was determined by bisulfite modification of the DNA and subsequent methylation-specific polymerase-chain-reaction (MSP). DNA was extracted from routinely formalin-fixed and paraffin-embedded tumour tissue samples. RESULTS: MSP yielded interpretable results in only 14 of 33 (42%) long-term surviving patients with GBM. A methylated band was seen in 3 of 14, methylated as well as unmethylated bands in 8 of 14 and an only unmethylated band in 3 of 14 patients, thus, yielding MGMT promoter methylation in 11 of 14 patients. The two groups of patients with methylated and unmethylated MGMT promoter status were too small to draw any firm statistical conclusions. CONCLUSIONS: Long-term surviving patients with GBM have very frequently intratumoural MGMT promoter methylation. This phenomenon discriminates long-term survivors from a non-selected group of patients with GBM. The standardization of the MSP for the determination of the MGMT promoter methylation status seems to be necessary in order to make this methodology a more reliable one.

Cell cycle dysregulation influences survival in high risk breast cancer patients.

BACKGROUND: Cell cycle progression is regulated by cyclin dependent kinases (cdk) and cdk inhibitors. Recent immunohistological studies suggested that dysregulation of cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), and p27(kip1) are of prognostic value in patients with breast cancer. Our study represents the first comprehensive immunohistochemical cell cycle marker analysis for cdc25A, cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), p27(kip1), and pRb in tumor tissue and adjacent benign breast tissue from 69 primarily untreated breast cancer patients. METHODS: Immunhistochemistry using primary monoclonal antibodies to detect cdc 25A, cyclin A, cyclin D, cyclin E, p16(ink4), p21(waf1/cip1), p27(kip1), and pRb has been performed. RESULTS: Sixty-nine patients with untreated, invasive breast cancer (n = 69) were divided into a low/ intermediate and a high risk group according to the St. Gallen 2005 consensus conference. High risk patients (n = 22) had a significantly (p = 0.003) shorter mean and median survival (282.85 weeks; 383.0 weeks, respectively) than low/intermediate risk patients (375.41 weeks; not reached yet, respectively). A subgroup of high risk breast cancer patients characterized in addition by overexpression of cdc25A, cyclin A, cyclin E, p16(ink4a), and p27(kip1) experienced a shortened mean survival of 222.03, 235.71, 257.25, 239.18, and 261.94 weeks, respectively. Regarding benign breast tissue adjacent to breast cancer tissue, 59.4% of the patients investigated overexpressed cdc25A, 23.2% overexpressed pRb, and 63.2% exerted dysregulation of p27(kip1) while they proved to be negative for immunohistochemical staining regarding all other markers tested. CONCLUSION: The immunohistological analyses of cdc25A, cyclin A, cyclin E, p16(ink4a), and p27(kip1) have the potential for further refining the risk assessment in patients with untreated breast cancer who belong to the high risk category defined according to the St. Gallen 2005 consensus conference. These cell cycle markers define a subgroup of high risk patients with even higher risk of metastazation and shortened survival. For confirmation a prospective study using standardized laboratory procedures in a larger population is needed.

[Biostatistical issues]. / Biostatistische Grundlagen.

In this contribution we discuss some fundamental aspects of biostatistics in the context of research in clinical oncology. Starting with a general presentation of basic principles of confirmatory statistics we deal with specific questions which typically arise in practical situations. This covers the importance of prespecification of statistical analyses before looking at the data as well as the judgment of multiple p-values and the interpretation of subgroup analyses. Subsequently we propose essential principles and techniques for the design and analysis of controlled clinical trials, which are relevant to achieve valid results with regard to cause-effect relationships from clinical observations. We specifically point out that an exact definition of the whole research design together with the methods of analysis and evaluation as well as planning of interim analyses and possible termination strategies have to be defined clearly in advance. General hints with regard to reporting standards conclude this chapter. In the final chapter we discuss general ideas behind meta-studies and demonstrate by means of a small example some basic analytical techniques for the summarization of single study results.

Chemoembolization with cisplatin, lipiodol and Gelfoam and subsequent systemic chemotherapy with cisplatin and interferon in patients with hepatocellular carcinoma: a non-randomized prospective study.

Arterial chemoembolization with subsequent systemic chemotherapy was assessed prospectively. Of 94 consecutive patients with HCC, 31 patients were considered to have inoperable disease and were selected for chemoembolization. Twenty-two of the 31 patients underwent chemoembolization. In eight patients, technical problems with catheterization prevented the application of therapy, and one patient rejected further treatment. Regimen: Three monthly cycles of chemoembolization with cisplatin 20 mg/m(2) mixed with lipiodol delivered intraarterially with Gelfoam or collagen on day 1, followed by intravenous chemotherapy with cisplatin 60 mg/m(2) on day 2; interferon alpha-2c 30 microg (10 M IU) subcutaneously on days 2, 5, 9, and 12. Three percent of the patients (1/31) (CI 95% 0.08; 16.7) experienced a partial clinical response, in 53% alpha-fetoprotein levels decreased by more than 50%. On univariate analysis, performance status, Child score, Okuda stage, albumin levels, and lactate dehydrogenase were found to have an effect on survival. Postchemoembolization syndrome occurred in 68% of the patients, nausea/vomiting grades 3/4 (according to the World Health Organization WHO) in six patients, anemia grade 3 in three patients, leukopenia grade 3 in one patient and thrombocytopenia grade 3 in one patient. This treatment regimen is a very selective procedure. Because of the low response rate it is not recommended for routine clinical use.

Circulating tumor cells in metastatic colorectal cancer: efficacy and feasibility of different enrichment methods.

Comprehensive in vitro and in vivo studies comparing EpCAM-based methods with other cytometric CTC enrichment technologies in metastatic colorectal cancer (mCRC) patients are lacking. We compare four manual cytometric methods to detect CTCs in vitro and in mCRC patients. The EpCAM-based technology, MACS HEA MicroBeads((R)), showed a significant better tumor cell recovery rate compared to other cytometric methods (p-value<0.0001). CTCs of 38 mCRC patients were enriched with MACS HEA MicroBeads(R). Progression-free survival did significantly differ between mCRC patients without detectable and with >or= 1 CTCs (p=0.007). CTC enrichment with EpCAM coupled antibodies is superior to other cytometric methods and is a feasible method for CTC detection in mCRC patients.

A phase II trial of docetaxel (Taxotere) as second-line chemotherapy in patients with metastatic breast cancer.

The efficacy and tolerability of docetaxel 100 mg/m(2) every 3 weeks as second-line chemotherapy in patients with metastatic breast cancer was investigated. In addition, the efficacy of a 3-day prophylaxis against cumulative dose-related fluid retention was examined with methylprednisolone 32 mg twice daily for 3 days starting 12 and 3 h before the docetaxel infusion together with oral cetirizine 10 mg 12 and 3 h before start of docetaxel for prevention of acute hypersensitivity reactions. According to the intent to treat-analysis 35% (95%CI: 25; 46) of the 94 patients entered responded to therapy. Their median survival was 12 months (range 0-20 months). The respective response rate for the 87 patients eligible for response evaluation was 37% (95%CI: 27; 48). Their median duration of response was 8 months (range 3-12 months), their median time to progression was 4 months (range 1-12 months). The corresponding response rate in the eligible patient cohort with anthracycline-resistant disease was 28% (95%CI: 15; 45) and increased to 44% (95%CI: 30; 59) in the cohort with non-anthracycline-resistant disease. Patients with visceral metastases responded in 36% and patients with > or = 3 organs involved in 33%. In a retrospective analysis, the 3-day premedication of corticosteroids and antihistamines proved to be as effective as the established but more toxic 5-day regimen in delaying and preventing the occurrence of docetaxel derived toxicities especially the cumulative fluid retention. In conclusion, docetaxel represents one of the most active agents for second-line treatment of metastatic breast cancer, especially for anthracycline-resistant patients. Due to comparable effectiveness of the 5-day regimen which is widely used by others and the 3-day premedication tested in this trial the latter proved to be more favourable and was therefore recommended for future therapies.

Growing clinical evidence for the interaction of the p53 genotype and response to induction chemotherapy in advanced non-small cell lung cancer.

OBJECTIVE: The objective of this study is to establish clinical evidence that the p53 genotype can serve as a predictive marker for response to cisplatin-based induction therapy. METHODS: Patients with advanced non-small cell lung cancer who had received neoadjuvant chemotherapy in the context of a prospective phase II trial were analyzed for the p53 genotype of their tumors. Response to induction therapy was then correlated to the p53 genotype as assessed by complete direct DNA sequencing. Patients had received 3 cycles of cisplatin and etoposide, and 1 cycle of simultaneous radiochemotherapy. All 3 treatment components mediate their cytotoxic effect through induction of apoptosis, which is suggested to require an intact p53 gene. In addition, the results from a previously published hypothesis-finding study are updated to demonstrate the consistency of clinical results and summarize currently available clinical evidence. RESULTS: In the phase II trial, 35 patients underwent resection after induction chemotherapy, allowing a pathohistologic response assessment. The presence of a mutant p53 genotype was highly indicative of resistance to induction chemotherapy (P < .002). The sensitivity of a mutant p53 genotype to identify nonresponders was 94% (71.3-99.9 confidence interval). A normal p53 gene was significantly associated with radical resection (P < .004) and survival advantage (P = .02). CONCLUSION: This is the second clinical evaluation demonstrating a significant relation between p53 genotype and response to induction therapy in non-small cell lung cancer. We conclude that the p53 genotype should be evaluated as a predictive marker for response to induction therapy in prospective randomized protocols.

Docetaxel/cisplatin as first-line chemotherapy in patients with head and neck carcinoma: a phase II trial.

BACKGROUND: The objective of this Phase II study was to assess the clinical activity and toxicity of docetaxel (D) and cisplatin (P) in patients with locally advanced unresectable, metastatic, or recurrent squamous cell carcinoma of the head and neck (SCCHN). PATIENTS: Of 34 patients, 30 were eligible for treatment with D 80 mg/m(2) on Day 1 and P 70 mg/m(2) on Day 2. Therapy was repeated every 3 weeks. At the start of chemotherapy, the tumors had the following extensions: locoregional, n = 15; distant metastatic, n = 2; and relapse, n = 13. RESULTS: Overall, the rate of objective responses in the population of all eligible patients based on an intention-to-treat analysis was 53%, with a 95% confidence interval (CI; 34.33-71.66%). Two patients had complete disease remission (pathologic), 4 patients had complete disease remission (clinical), 10 patients had partial disease remission, 3 patients had no change in disease status, and 7 patients had disease progression. The duration of objective response was median 5+ months (range 3-8+ months). Eleven patients (37%) had Grade 4 granulocytopenia and three patients (10%) had Grade 3 granulocytopenia (grades were based on the classification of the National Cancer Institute of Canada-Common Toxicity Criteria). Six patients died of septicemia. CONCLUSIONS: Overall, the combination of D and P represents a highly active chemotherapeutic regimen for the treatment of patients with SCCHN. However, because of the high toxicity of this regimen, prophylactic administration of antibiotics and hematopoietic growth factors is essential as is a three-day corticosteroid premedication regimen. Above all, this combination of drugs is not recommended for treatment of patients with a World Health Organization performance status of >1.