Hanns Peter Knaebel

Early antibiotic treatment for severe acute necrotizing pancreatitis - A randomized, double-blind, placebo-controlled study

Background & Aims:In patients with severe, necrotizing pancreatitis, it is common to administer early, broad-spectrum antibiotics, often a carbapenem, in the hope of reducing the incidence of pancreatic and peripancreatic infections, although the benefits of doing so have not been proved. Methods:A multicenter, prospective, double-blind, placebo-controlled randomized study set in 32 centers within North America and Europe. Participants: One hundred patients with clinically severe, confirmed necrotizing pancreatitis: 50 received meropenem and 50 received placebo. Interventions: Meropenem (1 g intravenously every 8 hours) or placebo within 5 days of the onset of symptoms for 7 to 21 days. Main Outcome Measures: Primary endpoint: development of pancreatic or peripancreatic infection within 42 days following randomization. Other endpoints: time between onset of pancreatitis and the development of pancreatic or peripancreatic infection; all-cause mortality; requirement for surgical intervention; development of nonpancreatic infections within 42 days following randomization. Results:Pancreatic or peripancreatic infections developed in 18% (9 of 50) of patients in the meropenem group compared with 12% (6 of 50) in the placebo group (P = 0.401). Overall mortality rate was 20% (10 of 50) in the meropenem group and 18% (9 of 50) in the placebo group (P = 0.799). Surgical intervention was required in 26% (13 of 50) and 20% (10 of 50) of the meropenem and placebo groups, respectively (P = 0.476). Conclusions:This study demonstrated no statistically significant difference between the treatment groups for pancreatic or peripancreatic infection, mortality, or requirement for surgical intervention, and did not support early prophylactic antimicrobial use in patients with severe acute necrotizing pancreatitis.

Immune Response Against Frameshift-Induced Neopeptides in HNPCC Patients and Healthy HNPCC Mutation Carriers

BACKGROUND & AIMS Colorectal cancers (CRC) associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome display high-level microsatellite instability (MSI-H) as a consequence of mismatch repair deficiency. HNPCC-associated CRC frequently show features of a pronounced immune response, most likely resulting from the MSI-induced generation of novel tumor-specific carboxy-terminal frameshift peptides (FSPs). However, the role of FSP-specific immune surveillance mechanisms in HNPCC are unknown at present. METHODS The efficacy of tumor-infiltrating T cells isolated from MSI-H CRCs (n = 3) was examined by in vitro killing assays. FSP-specific T-cell responses were measured by enzyme-linked immunospot in the peripheral blood from patients with MSI-H CRC (n = 32), healthy HNPCC mutation carriers (n = 16), patients with microsatellite stable (MSS) CRC (n = 17), and healthy donors (n = 22). RESULTS Tumor-infiltrating T cells isolated from MSI-H CRCs specifically recognized MSI-induced FSPs and showed cytotoxic activity against MSI-H but not MSS CRC cells. FSP-specific T-cell responses were detected in the majority of peripheral blood samples from patients with MSI-H but not MSS CRC. Interestingly, FSP-specific T-cell reactivity was already detectable in the peripheral blood of healthy HNPCC family members with germline mutations but without history of tumor development. CONCLUSIONS These data suggest that FSPs presented by DNA mismatch repair-deficient CRC cells are effectively recognized by the patients immune system and may explain the characteristic clinicopathologic features of HNPCC-associated but also sporadic MSI-H CRCs. These observations are of high relevance for the development of FSP-based vaccination approaches, particularly for the preventive application in HNPCC mutation carriers.

Microsatellite instability of selective target genes in HNPCC-associated colon adenomas

Microsatellite instability (MSI) occurs in most hereditary nonpolyposis colorectal cancers (HNPCC) and less frequently in sporadic tumors as the result of DNA mismatch repair (MMR) deficiency. Instability at coding microsatellites (cMS) in specific target genes causes frameshift mutations and functional inactivation of affected proteins, thereby providing a selective growth advantage to MMR deficient cells. At present, little is known about Selective Target Gene frameshift mutations in preneoplastic lesions. In this study, we examined 30 HNPCC-associated MSI-H colorectal adenomas of different grades of dysplasia for frameshift mutations in 26 cMS-bearing genes, which, according to our previous model, represent Selective Target genes of MSI. About 30% (8/26) of these genes showed a high mutation frequency (⩾50%) in colorectal adenomas, similar to the frequencies reported for colorectal carcinomas. Mutations in one gene (PTHL3) occurred significantly less frequently in MSI adenomas compared to published mutation rates in MSI carcinomas (36.0 vs 85.7%, P=0.023). Biallelic inactivation was observed in nine genes, thus emphasizing the functional impact of cMS instability on MSI tumorigenesis. Some genes showed a high frequency of frameshift mutations already at early stages of MSI colorectal tumorigenesis that increased with grade of dysplasia and transition to carcinoma. These include known Target Genes like BAX and TGFBR2, as well as three novel candidates, MACS, NDUFC2, and TAF1B. Overall, we have identified genes of potential relevance for the initiation and progression of MSI tumorigenesis, thus representing promising candidates for novel diagnostic and therapeutic approaches directed towards MMR-deficient tumors.

Comprehensive Genetic Counseling for Families At Risk for HNPCC: Impact on Distress and Perceptions

The aim of the study was to explore distress and health beliefs before and after comprehensive interdisciplinary counseling in families at risk for hereditary non-polyposis colorectal cancer (HNPCC). Results reported here were derived from a consecutive sample of 65 counselees [31 patients with colorectal cancer (CRC) and 34 unaffected at-risk persons] who participated in interdisciplinary counseling provided by human geneticists, surgeons, and psycho-oncologists before genetic testing. Data were collected from self-administered questionnaires before, as well as 4-6 weeks after, counseling. Distress and perceptions specific to HNPCC were assessed at both timepoints using standardized as well as author-derived instruments. Distress declined after counseling, as did worries related to HNPCC. An increase was found in personal belief in control of cancer risk, for instance, in the perceived efficacy of early detection of CRC. We also observed a trend toward greater anticipated ability to cope with a positive gene test after counseling. Changes after counseling were generally more pronounced for persons at risk, as compared to patients with cancer. The decrease in distress was partly attributable to an increase in personal self-confidence. One-third of the sample reported enhanced communication specific to hereditary disease within the family after counseling. A substantial minority, however, said they experienced increased worry and physical symptoms after counseling. Overall, counselees demonstrated less stress and perceived cancer threat as well as enhanced beliefs regarding personal control over cancer, suggesting an overall beneficial impact of comprehensive counseling. Further research is needed to identify those individuals most at risk for increased fear and worry related to HNPCC so that they may be most appropriately counseled.

Expression of an endogenous retroviral sequence from the HERV-H group in gastrointestinal cancers

Human endogenous retroviruses (HERVs) account for approximately 8% of the human genome. Since the majority of HERV elements have accumulated inactivating mutations in the viral genes, only few expressed viral open reading frames (ORFs) have been described. In this study, we have analyzed the expression of a HERV‐H copy located on Xp22.3 encompassing a potential ORF immediately downstream of the viral promoter. Conventional and real time RT‐PCR based expression analysis of this specific HERV‐H sequence showed overexpression in 16 of 34 (47%) colorectal, 25 of 63 (40%) gastric and 2 of 12 (17%) pancreatic cancers, whereas no overexpression was detected in bronchial and cervical cancers. Normal human testis, placenta and breast tissue did not show expression of this sequence. CpG methylation analysis of the viral promoter revealed a loss of methylation in cell lines expressing the HERV‐H sequence as compared to nonexpressing cell lines and lymphocyte DNA derived from healthy individuals. Further investigations of the HERV‐H long terminal repeat and the HERV‐H RNA are necessary to assess the functional relevance of the HERV‐H expression.

Diagnostik und Therapie von Lebermetastasen neuroendokriner Tumoren

Summary. Neuroendocrine tumors are rare and slowly progressing malignancies developing predominantly in the gastrointestinal tract. Often symptoms caused by excessive hormone production lead to diagnosis, especially when active metabolites are released from hepatic metastases to reach the systemic circulation before they are inactivated in the liver. Preoperative diagnosis of specific tumors relies on demonstration of the respective hormones in serum or urine rather than on histological diagnosis. Localization of primaries or their metastases can be accomplished by CT-AP, somatostatin receptor scintigraphy, SPECT or PET studies with high sensitivity. At the time of diagnosis more than 60 % of tumors have already spread to the liver. Potentially curative resection of liver metastases can achieve 5-year survival rates of more than 60 %. Since excess hormone production may be incapacitating and even life-threatening, effective palliation is highly important. Five-year survival following palliative liver resection was calculated to be almost 40 %. Palliative liver resection may therefore be considered an alternative to liver transplantation with 5-year survival of 34 % in a collected series. If liver resection is not possible, at least temporary palliation of symptoms and retardation of tumor growth can effectively be achieved with somatostatin analogues.Zusammenfassung. Neuroendokrine Tumoren entstehen vorwiegend im Gastrointestinaltrakt und sind vergleichsweise selten. Sie zeichnen sich durch langsames Wachstum aus und werden oft erst durch ihre spezifischen hormonellen Stoffwechselprodukte symptomatisch, wenn bei entsprechend großer hormonproduzierender Tumormasse aus dem portalen Stromgebiet anflutende stoffwechselaktive Metaboliten in der Leber nicht mehr ausreichend abgebaut werden können. Das gleiche gilt bei der sehr häufigen Metastasierung in die Leber selbst, wenn hormonell aktive Substanzen den systemischen Kreislauf erreichen bevor sie abgebaut werden können. Die präoperative artspezifische Diagnostik beruht auf dem Nachweis der jeweiligen Hormone in Serum oder Urin und weniger auf der histologischen Sicherung. Die Lokalisationsdiagnostik erreicht durch spezielle Untersuchungsverfahren wie CT-AP, Somatostatinrezeptorszintigraphie, SPECT und PET eine sehr hohe Sensitivität. Über 60 % der Patienten haben bei Erstdiagnose bereits Lebermetastasen. Bei potentiell kurativer Resektion der Lebermetastasen werden 5-Jahres-Überlebensraten von über 60 % erreicht. Wegen der starken Beeinträchtigung des Allgemeinbefindens durch die – möglicherweise sogar lebensbedrohliche – hormonelle Überproduktion kommt auch palliativen Maßnahmen eine sehr große Bedeutung zu. Nach palliativer Leberresektion beträgt die 5-Jahres-Überlebensrate fast 40 %. Damit kann die palliative Leberresektion als Alternative zur Transplantation mit einer 5-Jahres-Überlebensrate von 34 % in einer Sammelstatistik erwogen werden. Falls eine Leberresektion nicht möglich ist, kann eine wirksame Palliation der Symptome und eine Wachstumsverlangsamung durch Somatostatinanaloga zumindest vorübergehend erreicht werden.

To whom do the results of the multicenter, randomized, controlled INSECT trial (ISRCTN 24023541) apply?--assessment of external validity.

A response to Seiler et al: Interrupted or continuous slowly absorbable sutures for closure of primary elective midline abdominal incisions: a multicenter randomized trial (INSECT: ISRCTN24023541). Ann Surg 2009, 249(4):576-582.BackgroundExisting evidence suggests that the transfer of results of randomized controlled trials into clinical practice may be limited. Potential reasons can be attributed to aspects of external validity. The aim of this study is to investigate issues related to the external validity of the INSECT trial.MethodsAll participating surgical departments were categorized and the clinical and baseline characteristics of randomized patients were evaluated. In addition, demographic and clinical data of all screened and randomized patients at the Departments of Surgery in Heidelberg and Erlangen were analyzed.ResultsTwenty-five centers enrolled a total of 625 patients. These centers included eight primary, 11 secondary, and six tertiary care centers. The tertiary care centers enrolled the most patients (n = 237, 38%) followed by the primary care centers (n = 199, 32%) and the secondary care centers (n = 189 patients; 30%). The mean number and baseline data of randomized patients did not differ between the three types of care centers (p = 0.09). Overall, the treatment according to protocol was at least 92%. At the Department of Surgery, University of Heidelberg, 307 patients were screened and 60 out of 130 eligible patients were randomized. There were no differences in demographic and clinical baseline data between included and non-included patients. In Erlangen, 351 patients were screened and 57 out of 106 eligible patients randomized.ConclusionsResults of the INSECT trial are applicable to a broad spectrum of patients treated at different hospital levels.