EVITA-a double-blind, vehicle-controlled, randomized phase II trial of vitamin K1 cream as prophylaxis for cetuximab-induced skin toxicity.

Background: Acne-like skin rash is a frequently occurring adverse event associated with drugs against the epidermal growth factor receptor. This randomized vehicle-controlled study investigated the addition of vitamin K1 cream to doxycycline in patients with metastatic colorectal cancer treated with cetuximab. Patients and methods: Patients receiving first-line cetuximab + FOLFIRI were randomly assigned to prophylactic treatment with doxycylin and vitamin K1 cream or doxycycline and the vehicle. The primary end point of the study was the incidence of grade ≥ 2 skin rash (NCI CTCAE version 4.02) during 8 weeks of skin treatment. Secondary end points comprised skin rash according to a more thorough tripartite skin toxicity score (WoMo), quality of life, efficacy, and compliance. The study had 80% power to show a 20% reduction of the incidence of grade ≥ 2 skin rash. Results: A total of 126 patients were analyzed. The incidence of skin rash grade ≥ 2 was comparable between the arms. Likewise, no difference was seen in the WoMo score with respect to the percentage of skin affected. However, starting in week 5 and increasing over time patients treated with vitamin K1 cream had less severe rash and fewer fissures. Quality of life as well as efficacy and compliance with study medication and anticancer treatment was comparable in both arms. Conclusion: The primary end point of decreasing grade ≥ 2 skin rash was not met. However, using vitamin K1 cream as part of prophylactic treatment decreased the severity of acne-like skin rash according to WoMo, an alternative and more thorough skin toxicity scoring tool.

Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy.

BACKGROUND: The aim of this study was to evaluate the impact of pathologic complete response (pCR) on outcome in patients with gastric or esophagogastric junction (EGJ) adenocarcinoma after neoadjuvant docetaxel/platin/fluoropyrimidine-based chemotherapy. PATIENTS AND METHODS: Patients received at least one cycle of chemotherapy for potentially operable disease. Pretreatment clinicopathologic factors and pCR were investigated. Disease-free survival (DFS), overall survival (OS) and tumor-related death were correlated with pCR. RESULTS: One hundred twenty patients were included in this analysis. Eighteen patients (15%) achieved a pCR. Tumor localization in the EGJ was identified as the only significant predictor of pCR (P = 0.019). Median follow-up was 41.1 months. Median DFS and OS for all patients were 24.1 and 48.6 months, respectively. Median DFS for patients with a pCR was not reached versus 22.1 months non-pCR patients (hazard ratio, HR 0.38; 3-year DFS: 71.8% and 37.7%, respectively, P = 0.018). While OS was not significantly different, the risk for tumor-related death was significantly lower for pCR patients compared with non-pCR patients (3-year cumulative incidences of 6.4% and 45.4%, respectively, P = 0.009). CONCLUSION: A pCR following preoperative docetaxel/platin/fluoropyrimidine indicates favorable outcome in patients with gastric or EGJ adenocarcinoma. Tumor location in the EGJ is associated with a higher pCR rate.

Feasibility of perioperative chemotherapy with infusional 5-FU, leucovorin, and oxaliplatin with (FLOT) or without (FLO) docetaxel in elderly patients with locally advanced esophagogastric cancer.

BACKGROUND: The aim of this exploratory subgroup analysis of the fluorouracil, oxaliplatin, docetaxel (FLOT)65+ trial was to determine tolerability and feasibility of perioperative chemotherapy in elderly, potentially operable esophagogastric cancer patients. METHODS: Patients aged ≥65 with locally advanced esophagogastric adenocarcinoma were randomized to perioperative chemotherapy consisting of four pre- and four postoperative cycles of infusional 5-FU, leucovorin, and oxaliplatin (FLO) without or with docetaxel 50 mg m(-)(2) (FLOT), every 2 weeks. RESULTS: Forty-four patients with a median age of 70 years were randomized and 43 patients started preoperative chemotherapy (FLO, 22; FLOT, 21). Thirty-eight (86.4%) patients completed four cycles of preoperative chemotherapy and 32 (74.4%) proceeded to surgery, with 67.4% R0 resections on intent-to-treat analysis (90.1% of the 32 patients who underwent resection). Median overall survival was not reached and median progression-free survival (PFS) was 17.3 months. Compared with the FLO group, the FLOT group showed a trend towards an improved median PFS (21.1 vs 12.0 months; P=0.09), however, associated with increased chemotherapy related toxicity. No perioperative mortality was observed. Postoperative morbidity was observed in 46.9% of patients (FLO, 35.3%; FLOT, 60%). CONCLUSION: Neoadjuvant FLO or FLOT may offer a reasonable chance of curative surgery in elderly patients with locally advanced resectable gastroesophageal cancer. However, the increase in side effects with the FLOT regimen and postoperative morbidity should be carefully considered when an intensive chemotherapy regimen is planned.

The validation of matrix metalloproteinase-9 mRNA gene expression as a predictor of outcome in patients with metastatic gastric cancer.

BACKGROUND: The prognostic role of matrix metalloproteinase-9 (MMP-9) in metastatic gastric cancer has not been validated. PATIENTS AND METHODS: We carried out a molecular analysis in 222 metastatic gastric cancer patients obtained from clinical trials. We assessed the messenger RNA (mRNA) expression of MMP-9, vascular endothelial growth factor receptor-A, and epidermal growth factor receptor in a training cohort of 130 patients and conducted an independent validation in 92 patients. Automated RNA extraction from paraffin and RT-quantitative PCR was used. Immunohistochemistry for MMP-9 and diverse immune cell infiltrates was conducted. RESULTS: In the training cohort, only MMP-9 significantly correlated with patient's survival. At the cut-off with the highest predictive value, 19% of patients had MMP-9 expression above this cut-off and these showed a median survival of 3.6 months compared with 10.5 months (P=1.7e(-6)) in patients with lower expression. Corresponding 1- and 2-year survivals were 9% and 44% and 0 and 21%, respectively. The application of this cut-off to the validation cohort revealed similar distributions of overall survival according to MMP-9 expression on uni- (P<0.001) and multivariate analyses (P<0.001). No differences in survival according to MMP-9 below best cut-off were found. MMP-9 protein assessed by immunohistochemistry was not prognostic. CONCLUSION: MMP-9 mRNA expression above a certain cut-off level is associated with dismal survival.

Manganese superoxide dismutase (MnSOD) polymorphism, alcohol, cigarette smoking and risk of oesophageal cancer.

AIMS: Alcohol, tobacco smoke and Barrett's oesophagus as a consequence of gastro-oesophageal reflux are the main risk factors in oesophageal carcinogenesis. All risk factors may induce oxidative stress. Manganese superoxide dismutase (MnSOD) is one important repair enzyme for reactive oxidative stress (ROS)-induced damage. MnSOD polymorphisms in the -9 position of the signal sequence of the protein may lead to critical enzyme deficiency. The aim of the present study was to investigate the role of polymorphisms of MnSOD in patients with oesophageal cancer [n = 170, 61 patients with adenocarcinoma (AC), 109 patients with squamous cell carcinoma (SCC)] compared to heavy drinkers (n = 160) and healthy blood donors (n = 400). METHODS: Genotyping was performed by PCR-RFLP analysis using genomic DNA extracted from whole blood. RESULTS: The Ala/Ala genotype was 27.7% in cancer patients (29.5% AC, 26.6% SCC), 23.1% in patients with heavy alcohol abuse and 12.5% in the group of healthy blood donors. These results were not statistically significant after multivariate analysis controlling for age, sex, alcohol, cigarettes and interactions (odds ratio 0.92, 95% confidence interval = 0.63-1.36, for cancer patients versus heavy drinkers; odds ratio 1.02, 95% confidence interval = 0.51-2.03, for cancer patients versus blood donors; analysis by logistic regression). Subjects with an Ala/Ala genotype (81.3 g/day) had a significantly higher alcohol intake than those with Val/Ala (63.9 g/day) or Val/Val (53.8 g/day) genotype (P < 0.00001 by the Kruskal-Wallis test). CONCLUSIONS: MnSOD polymorphisms play no role in the genetic predisposition to oesophageal cancer. However, our data suggest a complex gene-to-phenotype interaction between the MnSOD genotype and alcohol misuse.

Clinical trial: cyclophosphamide pulse therapy - a promising therapeutic alternative in refractory Crohn's disease.

BACKGROUND: In severe steroid-refractory Crohn's disease (CD), established therapies fail in a relevant proportion of patients. Recent pilot studies indicated the efficacy of cyclophosphamide pulse therapy in these patients. AIM: To provide further and substantial evidence for the rationale to apply cyclophosphamide pulse therapy as therapeutic option in severe courses of CD. METHODS: Fifteen patients with steroid-refractory (n = 13) or steroid-dependent (n = 2) CD received 2-6 (median 3) monthly pulses of 750 mg cyclophosphamide in an open-label fashion. Eleven patients were on concomitant immunosuppression (azathioprine/mercaptopurine n = 9; methotrexate n = 2). RESULTS: Thirteen of 15 patients (87%) had a clinical response (CDAI decrease >100). Ten patients (67%) went into remission (CDAI <150) after 8 weeks. Steroid-free remission was achieved in eight patients (54%). Two patients (13%) failed to respond. Median CDAI decreased from 420 (245-550) to 100 (26-538) at week 8. Remission lasted 16 months (median, range 4-40). In three patients, arthritis, erythema nodosum and episcleritis completely resolved. Cyclophosphamide pulse therapy administration was well tolerated in all subjects. CONCLUSIONS: Cyclophosphamide pulse therapy is safe and highly effective for induction and maintenance of remission in steroid-refractory/-dependent CD. There is a strong need for additional experience to improve the setting of the encouraging cyclophosphamide treatment in CD.

p53 Mutations in carcinoma of the esophagus and gastroesophageal junction.

BACKGROUND: Recent studies suggested p53 mutations as a prognostic factor. Tumors of the esophagus and gastroesophageal (GE) junction show raising incidence with a general poor prognosis. METHODS: p53 Mutational spectra in 103 patients (68 squamous cell carcinoma/SCC and 35 adenocarcinoma/AC) were compared to clinical and pathologic data. RESULTS AND CONCLUSIONS: p53 Mutations were found in 26 of 68 SSC (38.2%) and in 12 of 35 AC (34.5%). We only found G > T transversions in smokers with SCC. The survival of patients was not affected by p53 mutational status. In our study, the frequency and mutational spectrum of mutant p53 is similar in both histological types without prognostic relevance.

Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie.

BACKGROUND: The combination of docetaxel (Taxotere), cisplatin, and fluorouracil improved efficacy in gastric cancer, but was associated with substantial toxicity. This study was designed to incorporate docetaxel into a tolerable biweekly (once every 2 weeks) oxaliplatin-based chemotherapy regimen. PATIENTS AND METHODS: Patients with measurable, metastatic adenocarcinoma of the stomach or esophagogastric junction and no prior chemotherapy received oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil 2600 mg/m(2) as a 24-h infusion in combination with docetaxel 50 mg/m(2) (FLOT) on day 1 every 2 weeks. Prophylactic growth factors were not administered. RESULTS: Fifty-nine patients were enrolled; 54 received treatment. Patients had a median age of 60 years (range 29-76) and most (93%) of them had metastatic disease. Objective responses were observed in 57.7% of patients with a median time to treatment response of 1.54 months. Median progression-free survival (PFS) and overall survival were 5.2 and 11.1 months, respectively. Twenty-five percent of patients experienced prolonged (>12 months) PFS. Frequent (>10%) grade 3 or 4 toxic effects included neutropenia in 26 (48.1%), leukopenia in 15 (27.8%), diarrhea in 8 (14.8%), and fatigue in 6 (11.1%) patients. Complicated neutropenia was observed in two (3.8%) patients, only. CONCLUSIONS: Biweekly FLOT is active and has a favorable safety profile.

[Intermittent compression devices for swelling reduction and thrombosis prophylaxis--a pilot study after total hip replacement. Is the 2 hour daily minimum application sufficient?]. / Die intermittierende Impulskompression zur Abschwellung und Thromboseprophylaxe--Pilotstudie nach Hüft-TEP. Ist die Minimalanwendungsdauer von 2 h täglich ausreichend?

BACKGROUND: The use of intermittent compression devices for thrombosis prophylaxis and the reduction of postoperative swelling are widely accepted. The recommended minimum application of 2 h daily has never been statistically verified. Without evidence based data, the benefit of this costly equipment cannot be maximized. PATIENTS AND METHODS: A randomized clinical trial on 41 patients after total hip replacement was performed. The A-V Impulse System was applied for 2 h a day during the first 5 postoperative days to observe whether this time was sufficiently effective. RESULTS: In the control group, two deep vein thromboses occurred postoperatively, but there were none in the treatment group. Even though two patients from the treatment group had to be excluded from the study because of severe pain, all other parameters including visual analogue pain scale results and limb circumferences were comparable in both groups. CONCLUSION: These preliminary results suggest that pump systems can prevent deep venous thrombosis after hip surgery even when applied for only short intervals over a short period of time. However, large scale confirmatory studies are needed.

Increased cancer risk in heavy drinkers with the alcohol dehydrogenase 1C*1 allele, possibly due to salivary acetaldehyde.

BACKGROUND: Chronic ethanol consumption is associated with an increased risk of upper aerodigestive tract cancer. As acetaldehyde seems to be a carcinogenic factor associated with chronic alcohol consumption, alcoholics with the alcohol dehydrogenase (ADH) 1C*1 allele seem to be particularly at risk as this allele encodes for a rapidly ethanol metabolising enzyme leading to increased acetaldehyde levels. Recent epidemiological studies resulted in contradictory results and therefore we have investigated ADH1C genotypes in heavy alcohol consumers only. METHODS: We analysed the ADH1C genotype in 107 heavy drinkers with upper aerodigestive tract cancer and in 103 age matched alcoholic controls without cancer who consumed similar amounts of alcohol. Genotyping of the ADH1C locus was performed using polymerase chain reaction based on restriction fragment length polymorphism methods on leucocyte DNA. In addition, ethanol was administered orally (0.3 g/kg body weight) to 21 healthy volunteers with the ADH1C*1,1, ADH1C*1,2, and ADH1C*2,2 genotypes, and 12 volunteers with various ADH genotypes consumed ethanol ad libitum (mean 211 (29) g). Subsequently, salivary acetaldehyde concentrations were measured by gas chromatography or high performance liquid chromatography. RESULTS: The allele frequency of the ADH1C*1 allele was found to be significantly increased in heavy drinkers with upper aerodigestive tract cancer compared with age matched alcoholic controls without cancer (61.7% v 49.0%; p = 0.011). The unadjusted and adjusted odds ratios for all cancer cases versus all alcoholic controls were 1.67 and 1.69, respectively. Healthy volunteers homozygous for the ADH1C*1 allele had higher salivary acetaldehyde concentrations following alcohol ingestion than volunteers heterozygous for ADH1C (p = 0.056) or homozygous for ADH1C*2 (p = 0.011). CONCLUSIONS: These data demonstrate that heavy drinkers homozygous for the ADH1C*1 allele have a predisposition to develop upper aerodigestive tract cancer, possibly due to elevated salivary acetaldehyde levels following alcohol consumption.

[Massive pulmonary embolism after endoscopic therapy for gastric variceal bleeding]. / Massive Lungenembolie nach endoskopischer Therapie einer Fundusvarizenblutung.

A 60-year-old woman with alcoholic cirrhosis of the liver was admitted to the ICU because of haemodynamic instability, hematemesis and presumed acute variceal bleeding. An upper endoscopy was performed and varices of the distal esophagus and an actively bleeding varix of the gastric fundus were detected. The bleeding was successfully treated with 2 consecutive injections of 0.5 ml n-butyl-2-cyanoacrylate and 0.5 ml lipiodol. The patient was intubated prior to the endoscopy to avoid blood aspiration. However, severe hypoxaemia with a need for prolonged mechanical ventilation and signs of right heart strain developed after endoscopy. A chest X-ray and CT scan of the thorax documented an extensive embolisation of the pulmonary arteries. The patient's varices were retreated with band ligation but rebleeding occurred. Finally, a TIPS application was needed to stop recurrent haemorrhage. This case demonstrates that embolisation of the pulmonary arterial bed is a rare complication of endoscopic sclerotherapy for gastric variceal bleeding. The severity of this complication may depend on the volume of liquid acrylate being injected and pre-existing lung tissue alterations. Since histoacryl is not lysable, severe pulmonary emboli with lung tissue damage and pulmonary hypertension may occur. Factors contributing to this complication are analysed and therapeutic alternatives are discussed.

[Prevention of epidural fibrosis. Initial experiences with non-resorbable membrane]. / Prävention der epiduralen Fibrose. Erste Erfahrungen mit einer nicht resorbierbaren Membran.

Scars around the neural structures after opening the spinal canal are common and severe problems in spine surgery. This paper presents the use of a special membrane to avoid epidural scarring in two cases.

[Airlimb. Initial experiences with a new immediate early management prosthesis with individually adjustable air chambers]. / Airlimb. Erste Erfahrungen mit einer neuen Sofort-Frühversorgungsprothese mit einzeln ansteuerbaren Luftkammern.

Amputations of the lower extremity are still a common problem in diabetic feet and peripheral vasculopathies. The presented paper introduces a new device for an easier and faster mobilization of below-the-knee amputees. It is based on a new modular prostheses with individual inflatable air bladders. The compliance rate is higher with this device and it could be used from the day of surgery until the definitive prostheses is made. A biomechanical cadaver study with the prostheses will also be presented.

The post-discectomy syndrome. Aetiology, diagnosis, treatment, prevention.

The post-discectomy syndrome (PDS) is a common diagnosis in patients with problems following a disc operation. The different causes of PDS make the establishment of the correct diagnosis and its corresponding efficient treatment difficult. A general overview published in the bibliographical data covering the entity of PDS is rare. The following paper aims to specify PDS according to its aetiology, diagnosis, treatment and prevention. The diagnosis should be made efficiently, so that the patient can receive prompt adequate therapy.

Increased rectal cell proliferation following alcohol abuse.

BACKGROUND: Epidemiological data indicate an increased risk for rectal cancer following chronic alcohol consumption. As chronic ethanol ingestion leads to rectal hyperregeneration in experimental animals, indicating a state of increased susceptibility to carcinogens, we studied cell proliferation in alcohol abusers. METHODS: Rectal biopsies were taken from 44 heavy drinkers and 26 controls. Cell proliferation, including proliferative compartment size, was measured by immunohistological staining for proliferative cell nuclear antigen (PCNA) and Ki67, and by in situ hybridisation for histone H3. Quantification of cell proliferation using PCNA staining was evaluated in 27 alcohol abusers and 12 controls. In addition, immunohistology was performed for cytokeratins and gene products of Rb1, bcl-2, and p53. RESULTS: Heavy drinking resulted in increased cell proliferation of the rectal mucosa, as shown by increased detection of different proliferation markers. However, cell differentiation regarding cytokeratin expression patterns was unchanged as well as regulatory factors involved in carcinogenesis and/or apoptosis. CONCLUSION: Chronic alcohol abuse leads to rectal mucosal hyperproliferation in humans, a condition associated with an increased cancer risk.

Alcohol and cancer.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Helmut K. Seitz and Shohei Matsuzaki. The presentations were (1) Alcohol dehydrogenase-2 and aldehyde dehydrogenase-2 genotype and cancer risk for upper aerodigestive tract in Japanese alcoholics, by Akira Yokoyama; (2) The role of acetaldehyde in alcohol-associated carcinogenesis, by Nils Homann; (3) High salivary acetaldehyde levels after a moderate dose of alcohol in ALDH2-deficient subjects, by Satu Väkeväinen; (4) Alcohol and vitamin A interactions, by Xian Dong Wang; and (5) Alcohol and colorectal cancer, by Helmut K. Seitz.

Overexpression of p53 in tumor-distant epithelia of head and neck cancer patients is associated with an increased incidence of second primary carcinoma.

Second primary carcinoma is a peculiar feature of head and neck cancer and represents a form of treatment failure distinct from the recurrence of the primary tumor. Whether altered p53 expression in tumor-distant epithelia at the time of diagnosis is of clinical value as a biomarker for second primary carcinoma development has not been rigorously answered because of the lack of long-term follow-up studies involving a sufficiently large patient cohort. In this prospective study, we have investigated p53 expression in tumor-distant epithelia and in the corresponding primary tumors of 105 head and neck cancer patients by immunohistochemistry on frozen sections. After a median follow-up of 55 months, the clinical course of disease parameters, i.e., local recurrences, lymph node and distant metastasis, incidence of second primary carcinoma, and survival, was evaluated. Overexpression of p53 in tumor-distant epithelia was found in 49 patients (46.7%), and it was independent of the p53 protein status of the primary tumor and of the tumor site, size, stage, and grading. Mucosal p53 overexpression was not associated with local primary recurrences, lymph node or distant metastases, or overall survival. Importantly, mucosal p53 overexpression, but not overexpression in the primary tumors, was significantly associated with an increased incidence of second primary carcinomas (P = 0.0001; Fisher's exact test). When the times to second primary tumor occurrence were analyzed by the Kaplan-Meier method, the difference remained significant (P = 0.005; log rank test). We conclude that IHC staining for p53 overexpression in tumor-distant epithelia provides a simple and rapid tool to identify head and neck cancer patients at increased risk of developing second primary tumors. Because p53 overexpression in these epithelia in our patient cohort was specifically associated with second primary cancer but not with recurrences, at least a fraction of the second primary cancers appears to have resulted from genetic events in the mucosa ("field cancerization").