Matthias Pross

Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: a retrospective analysis

BACKGROUND Although histone deacetylases (HDACs) are known to have an important regulatory role in cancer cells, and HDAC inhibitors (HDIs) have entered late-phase clinical trials for the treatment of several cancers, little is known about the expression patterns of HDAC isoforms in tumours. We aimed to clarify these expression patterns and identify potential diagnostic and prognostic uses of selected class I HDAC isoforms in gastric cancer. METHODS Tissue samples from a training cohort and a validation cohort of patients with gastric cancer from two German institutions were used for analyses. Tissue microarrays were generated from tumour tissue collected from patients in the training group, whereas tissue slides were used in the validation group. The tissues were scored for expression of class I HDAC isoforms 1, 2, and 3. Overall expression patterns (gHDAC) were grouped as being negative (all three isoforms negative), partially positive (one or two isoforms positive), or completely positive (all isoforms positive), and correlated with clinicopathological parameters and patient survival. The main endpoints were amount of expression of each of the three HDAC isoforms, patterns of expression of gHDAC, effect of metastasis on expression of HDAC and gHDAC, and overall survival according to HDAC expression patterns. FINDINGS 2617 tissue microarray spots from 143 patients in the training cohort and 606 tissue slides from 150 patients in the validation cohort were studied. 52 of the 143 (36%) gastric tumours in the training cohort and 32 of the 150 (21%) gastric tumours in the validation cohort showed nuclear expression of all three HDAC isoforms. 60 (42%) of tumours in the training cohort and 65 (43%) in the validation cohort expressed one or two isoforms in the nuclei, whereas 31 (22%) of tumours in the training cohort and 53 (35%) in the validation cohort were scored negative for all three proteins. gHDAC expression in both cohorts was higher when lymph-node metastases were present (p=0.0175 for the training group and p=0.0242 for the validation group). Survival data were available for 49 patients in the training group and 123 patients in the validation group. In the validation cohort, 3-year survival was 44% (95% CI 34-57) in the HDAC1-negative group, 50% (39-64) in the HDAC2-negative group, and 48% (34-67) in the gHDAC-negative group. 3-year survival decreased to 21% (11-37) when HDAC1 was positive, 16% (9-31) when HDAC2 was positive, and 5% (1-31) when gHDAC (all isoforms) were positive. Those patients highly expressing one or two isoforms (the gHDAC-intermediate group) had an estimated 3-year survival of 40% (29-56). In multivariate analyses, high gHDAC and HDAC2 expression were associated with shorter survival in the training cohort (gHDAC: hazard ratio [HR] 4.15 [1.23-13.99], p=0.0250; HDAC2: HR 3.58 [1.36-9.44], p=0.0100) and in the validation cohort (gHDAC: HR 2.18 [1.19-4.01], p=0.0433; HDAC2: HR 1.72 [1.08-2.73], p=0.0225), independent of standard clinical predictors. INTERPRETATION High HDAC expression is significantly associated with nodal spread and is an independent prognostic marker for gastric cancer. Additionally, we postulate that immunohistochemical detection of HDAC as a companion diagnostic method might predict treatment response to HDIs, thereby enabling selection of patients for this specific targeted treatment in gastric cancer.

Endoscopic treatment of thoracic esophageal anastomotic leaks by using silicone-covered, self-expanding polyester stents

BACKGROUND Surgery, as well as conservative treatment, in patients with clinically apparent intrathoracic esophageal anastomotic leaks often is associated with poor results and carries a high morbidity and mortality. The successful treatment of esophageal anastomotic insufficiencies and perforations when using covered, self-expanding metallic stents is described. METHODS The feasibility and the outcome of endoscopic treatment of intrathoracic anastomotic leakages when using silicone-covered self-expanding polyester stents were investigated. Twelve consecutive patients presented with clinically apparent intrathoracic esophageal anastomotic leak caused by resection of an epiphrenic diverticulum (n = 1), esophagectomy for esophageal cancer (n = 9), or gastrectomy for gastric cancer (n = 2), were endoscopically treated in our department. The extent of the dehiscences ranged from about 20% to 70% of the anastomotic circumference. After endoscopic lavage and debridement of the leakage at 2-day intervals (mean duration, 8.6 days), a large-diameter polyester stent (Polyflex; proximal/distal diameters 25/21 mm) was placed to seal the leakage. Simultaneously, the periesophageal mediastinum was drained by chest drains. OBSERVATIONS All 12 patients were successfully treated endoscopically without the need for reoperation. A complete closure of the leakage was obtained in 11 of 12 patients after stent removal (median time to stent retrieval, 4 weeks, range 2-8 weeks). In one patient, a persistent leak was sealed endoscopically after stent removal by using 3 clips. Distal stent migration was obtained in two patients. CONCLUSIONS The placement of silicone-covered self-expanding polyester stents seems to be a successful minimally invasive treatment option for clinically apparent intrathoracic esophageal anastomotic leaks.

Value of a Protective Stoma in Low Anterior Resections for Rectal Cancer

AbstractINTRODUCTION: Anastomotic leakage is a major problem in colorectal surgery and in particular in operations for low rectal cancer. The present study investigates the question whether a protective stoma can reduce the (clinical and radiologic) anastomotic leakage rate and/or the rate of leakage requiring surgery. METHODS: The investigation took the form of a prospective multicenter study involving 75 German hospitals and was performed between January 1, 1999, and December 31, 1999. A comparison was made of the postoperative results of procedures performed with and those performed without a protective stoma in patients undergoing low anterior rectal resection. In addition, logistic regression using the target criteria, overall anastomotic leakage and anastomotic leakage requiring surgery, was applied. RESULTS: Among the 3,695 operations performed for carcinoma of the rectum or colon, 482 were low anterior resections. In 334 patients (69.3 percent) no protective stoma was constructed, whereas 148 (30.7 percent) received such protection. Age, American Society of Anesthesiologists physical status, and body mass index were identical in both groups. In the group receiving a protective stoma, however, neoadjuvant radiochemotherapy was more common, the tumors were lower—and thus the total mesorectal excision rate higher, the intraoperative complication rate was higher, and the duration of the operation was longer. The differences were all significant. The major criterion (overall anastomotic leakage rate) was identical in the two groups, but the rate of leakage requiring surgery was significantly lower in patients receiving a protective stoma (P = 0.028). The logistic regression revealed that use of a protective stoma is a predictor of protection against anastomotic leakage requiring surgery. The distance of the tumor from the anal verge and the duration of the operation are further predictors. CONCLUSION: The particular benefit of a covering stoma is reduction in the rate of leaks requiring surgery and thus in the severe consequences of an anastomotic leakage.

Immunomodulation by perioperative administration of n -3 fatty acids

It has been increasingly reported that administration of n-3 fatty acids is beneficial in patients with inflammatory processes. This effect is most likely caused by different biological characteristics, including an immunomodulating effect of the products derived from n-3 fatty acids through eicosanoid metabolism. The aim of this study was to investigate the effect of perioperative administration of n-3 fatty acids on inflammatory and immune responses as well as on the postoperative course of patients with extended surgical interventions of the abdomen. In particular, the effect of n-3 fatty acids on interleukin-6 release and on granulocyte/monocyte function (HLA-DR expression) was studied. There was a downregulation of the inflammatory response, and, simultaneously, a smaller postoperative immune suppression in the n-3 fatty acid group. In addition, we observed shorter postoperative periods in the intensive care unit and on the regular medical wards as well as lower rates of severe infections. The results suggest that perioperative administration of n-3 fatty acids may have a favourable effect on outcome in patients with severe surgical interventions by lowering the magnitude of inflammatory response and by modulating the immune response.

High Prognostic Value of p16INK4 Alterations in Gastrointestinal Stromal Tumors

PURPOSE Gastrointestinal stromal tumors (GISTs) represent a distinctive (but histologically heterogeneous) group of neoplasms, the malignant potential of which is often uncertain. To determine the prognostic relevance of p16INK4 alterations in GISTs, we investigated a larger group of GISTs and correlated the genetic findings with clinicopathological factors and patient survival. MATERIAL AND METHODS We evaluated the methylation status of the promotor by methylation-specific polymerase chain reaction (PCR), the presence of mutations by PCR-SSCP-sequencing, the loss of heterozygosity at the p16INK4 locus (using the c5.1 marker), and the immunohistochemical expression of p16INK4 protein in 43 GISTs in 39 patients. RESULTS p16INK4 alterations were found in 25 of 43 GISTs (58.1%), with benign, borderline, or malignant GISTs showing no differences in the type and frequency of alteration. p16INK4 alterations were correlated with a loss of p16INK4 protein expression (P <.01). Patients who had tumors with p16INK4 alterations had a poorer prognosis than patients with tumors without such alterations (P =.02). There was a high predictive value for p16INK4 alterations only in the group of benign and borderline GISTs (P <.01) with regard to clinical outcome. Univariate Coxs proportional hazard regression analysis revealed a strong correlation between p16INK4 alterations, tumor size, mitotic index, and overall survival (P <.02), whereas multivariate Coxs analysis confirmed only p16INK4 alterations as an independent prognostic factor. CONCLUSION We believe that the evaluation of p16INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.

Risk factors for failure of endoscopic stenting of biliary strictures in chronic pancreatitis: a prospective follow-up study

OBJECTIVES:The aims of this study were to investigate the value of interventional endoscopy in patients with strictures of the common bile duct (CBD) caused by chronic pancreatitis (CP), and to define the subset of patients who may be at risk for failure of endoscopic intervention, in a prospective follow-up study.METHODS:A total of 61 patients with symptomatic CBD strictures caused by alcoholic CP were treated by endoscopic stent insertion for 1 yr with scheduled stent changes every 3 months. After the treatment period, all patients entered a follow-up program.RESULTS:Initial endoscopic drainage was successful in all cases, with complete resolution of obstructive jaundice. After 1 yr from the initial stent insertion, in 19 patients (31.1%) the obstruction was resolved, and stents were removed without any need of additional procedures. During a median follow-up of 40 months (range 18–66 months), 16 patients had no recurrence of symptomatic CBD stricture (long term success rate 26.2%). Of 45 patients who needed definitive therapy, 12 patients (19.7%) were treated with repeated plastic stent insertion and three (4.9%) with insertion of a metal stent, and 30 patients (49.2%) underwent surgery. Among the variables tested, calcification of the pancreatic head was the only factor that was found to be of prognostic value. Of 39 patients with calcification of the pancreatic head, only three (7.7%) were successfully treated by a 1-yr period of plastic stent therapy, whereas in 13 of 22 patients (59.1%) without calcification, this treatment was successful (p < 0.001).CONCLUSIONS:Endoscopic drainage of biliary obstruction provides excellent short term but only moderate long term results. Patients without calcifications of the pancreatic head benefit from biliary stenting. Patients with calcifications were identified to have a 17-fold (95% CI = 4–74) increased risk of failure of a 12 month course of endoscopic stenting.

Endoscopic treatment of clinically symptomatic leaks of thoracic esophageal anastomoses

BACKGROUND The mortality of thoracic anastomotic leakage following esophageal reconstruction has been reported to be as high as 60%. Early septic fulminant suture line leaks require rethoracotomy. In addition, however, clinically symptomatic leaks may also occur 2 to 7 days after resection of the esophagus. METHODS Among 80 esophageal reconstructions performed between January 1994 and July 1998, a total of 7 (8.75%) clinically apparent leaks of thoracic anastomoses were observed. The standard treatment consisted of endoscopic lavage, drainage and subsequent closure of the defect by repeated intraluminal and submucosal applications of fibrin glue. In 2 patients a novel approach permitting rapid closure by plugging the fistula with a Vicryl-cylinder was tried. In 4 patients the effect of endoscopic treatment on the HLA-DR expression on monocytes was investigated and compared to 6 patients with intact anastomoses. RESULTS All 7 patients were successfully treated via endoscopy. The cylinder plug achieved immediate closure of the leak. The measured change in HLA-DR expression reflected the improvement in the inflammatory response and thus documented the success of endoscopic treatment. CONCLUSIONS Endoscopic management of thoracic leakages represents a safe and relatively noninvasive therapeutic option.

Prospektive Multizenterstudien “Kolon-/Rektumkarzinome” als flächendeckende chirurgische Qualitätssicherung

AbstractIntroduction. Currently, only a small percentage of the diagnostic and therapeutic data on colonic carcinomas has been confirmed by data obtained in randomized controlled studies. For this reason, the results of prospective multicentre observational studies are extremely important. Method. Within a multicentre observational study involving 75 surgical departments carried out between 01.01. and 31.12.1999, 3,756 patients with a colorectal carcinoma (2,293 carcinoma of the colon; 1,463 carcinomas or the rectum) were investigated prospectively using a standardised questionnaire. Results. The OP rate was 98.4%, the resection rate 92.5% (colon 94.1%, rectum 89.9%). The rate of rectal extirpations was relatively high at 30.3%. General postoperative morbidity was 27.4% (colon 27.0%, rectum 27.9%); the specific postoperative morbidity was 24.6% (colon 21.8%, rectum 29.1%). The anastomotic insufficiency rate was 5.2% (colon 3.7%, rectum 9.5%). The 30-day mortality rate was 4.7%, and the postoperative mortality rate 5.7%. Conclusions. Surgical quality control in the form of prospective multicentre observational studies make possible the analysis of the therapeutic situation of a surgical disease under quality assurance aspects. At the same time, the comprehensive data material available will serve the specific planning of prospective randomized studies. With the aid of the present study, a basis for a thorough and complete evaluation of colorectal carcinoma has been created.ZusammenfassungHintergrund. Nur ein geringer Teil der Diagnostik und Therapie des kolorektalen Karzinoms ist derzeit durch prospektiv randomisierte Studiendaten abgesichert. Aus diesem Grund kommt den Ergebnissen prospektiver multizentrischer Beobachtungsstudien ein hoher Stellenwert zu. Methode. Innerhalb einer multizentrischen Beobachtungsstudie wurden vom 01.01.–31.12.1999 an 75 Kliniken 3.756 Patienten mit einem kolorektalen Karzinom (2.293 Kolonkarzinome, 1.463 Rektumkarzinome) mittels eines standardisierten Fragebogens prospektiv erfasst. Ergebnisse. Die Operationsrate betrug 98,4%. Die Resektionsquote lag bei 92,5% (Kolon 94,1%, Rektum 89,9%). Die Rektumexstirpationsquote war mit 30,3% relativ hoch. Die allgemeine postoperative Morbidität betrug 27,4% (Kolon 27,0%, Rektum 27,9%), die spezifische postoperative Morbidität 24,6% (Kolon 21,8%, Rektum 29,1%). Die Anastomoseninsuffizienzrate lag bei 5,2% (Kolon 3,7%, Rektum 9,5%). Es war eine 30-Tage-Letalität von 4,7% und eine postoperative Letalität von 5,7% zu verzeichnen. Schlussfolgerung. Chirurgische Qualitätssicherung in Form von prospektiven multizentrischen Beobachtungsstudien ermöglicht die Analyse der Behandlungssituation eines chirurgischen Krankheitsbildes unter qualitätssichernden Aspekten. Gleichzeitig wird mit dem vorliegenden umfangreichen Datenmaterial die gezielte Planung von prospektiv randomisierten Studien unterstützt. Mit dieser Studie wurden die Grundlagen für eine bundesweite Erfassung der kolorektalen Karzinome geschaffen.

Effect of caseload on the short-term outcome of colon surgery: results of a multicenter study

Abstract This prospective multicenter study investigated the effect of hospital caseload on early postoperative outcome of surgery for carcinoma of the colon in 75 German hospitals and included 2293 patients. The hospitals were divided into those with a caseload of 1–30 (group A), 31–60 (group B), and more than 60 (group C) operations. Increasing caseload was associated only with fewer general postoperative complications. It was also associated with significantly greater use of antibiotic prophylaxis. No significant differences between the groups were found in resection rates, intraoperative complications, specific postoperative complications, overall postoperative morbidity, hospital mortality, or 30-day mortality. The significance of hospital caseload for the short-term postoperative outcome following surgery on the colon should not be overestimated. Basing conclusions about the results to be expected simply on the case volume is impermissible. On the basis of the available data it is not possible to establish a threshold value, that is, a minimum number of required operations.

Procaine Hydrochloride Fails to Relieve Pain in Patients with Acute Pancreatitis

Background: Several analgesics are in use for pain control in patients with acute pancreatitis. Procaine hydrochloride (procaine) has a long tradition and is recommended by the German Society of Gastroenterology and Metabolic Diseases for pain treatment in patients with acute pancreatitis. There is no controlled trial showing that procaine could be effective for pain treatment. Methods: In an open, randomized, controlled trial, 107 patients (76 male, 31 female; mean age 45 ± 12 years) were included and randomized either to receive procaine (n = 55) or pentazocine (n = 52) for pain relief. Procaine 2 g/ 24 h was administered by continuous intravenous infusion, pentazocine 30 mg was administered every 6 h as a bolus intravenous injection. Pentazocine was additionally administered on demand whenever required in patients of both treatment groups and its total consumption was recorded. Pain scores were assessed twice daily on a visual analogue scale. Results: Patients receiving procaine were significantly more likely to request additional analgesics compared to patients treated with pentazocine alone, 98 vs. 44%, respectively (p < 0.001). Procaine did not reduce the amount of pentazocine required for pain control. The amount of pentazocine given in both groups was not statistically significantly different. Recorded pain scores were significantly lower (p < 0.001) in patients in the pentazocine group during the first 3 days of analgesic treatment. From day 4 on there was no significant difference in pain scores among the two groups. Conclusion: Thus, intravenous procaine treatment is not effective for pain control in patients with acute pancreatitis.