Daniel Reim

Gastric cancer represents a great challenge for healthcare providers and requires a multidisciplinary treatment approach in which surgery plays a major role. Minimally invasive surgery has been progressively developed, first with the advent of laparoscopy and recently with the spread of robotic surgery, but a number of issues are currently being debated, including the limitations in performing an effective extended lymph node dissection, the real advantages of robotic systems, the role of laparoscopy for Advanced Gastric Cancer, the reproducibility of a total intracorporeal technique and the oncological results achievable during long-term follow-up. A multi-institutional international database will be established to evaluate the role of robotic, laparoscopic and open approaches in gastric cancer, comprising of information regarding surgical, clinical and oncological features. A chart review will be conducted to enter data of participants with gastric cancer, previously treated at th...

Because neural invasion (NI) is still inconsistently reported and not well characterized within gastrointestinal malignancies (GIMs), our aim was to determine the exact prevalence and severity of NI and to elucidate the true impact of NI on patient's prognosis. The union internationale contre le cancer (UICC) recently added NI as a novel parameter in the current TNM classification. However, there are only a few existing studies with specific focus on NI, so that the distinct role of NI in GIMs is still uncertain. NI was characterized in approximately 16,000 hematoxylin and eosin tissue sections from 2050 patients with adenocarcinoma of the esophagogastric junction (AEG)-I-III, squamous cell carcinoma (SCC) of the esophagus, gastric cancer (GC), colon cancer (CC), rectal cancer (RC), cholangiocellular cancer (CCC), hepatocellular cancer (HCC), and pancreatic cancer (PC). NI prevalence and severity was determined and related to patient's prognosis and survival. NI prevalence largely varied between HCC/6%, CC/28%, RC/34%, AEG-I/36% and AEG-II/36%, SCC/37%, GC/38%, CCC/58%, and AEG-III/65% to PC/100%. NI severity score was uppermost in PC (24.9±1.9) and lowest in AEG-I (0.8±0.3). Multivariable analyses including age, sex, TNM stage, and grading revealed that the prevalence of NI was significantly associated with diminished survival in AEG-II/III, GC, and RC. However, increasing NI severity impaired survival in AEG-II/III and PC only. NI prevalence and NI severity strongly vary within GIMs. Determination of NI severity in GIMs is a more precise tool than solely recording the presence of NI and revealed dismal prognostic impact on patients with AEG-II/III and PC. Evidently, NI is not a concomitant side feature in GIMs and, therefore, deserves special attention for improved patient stratification and individualized therapy after surgery.

Although it is generally accepted that early defense mechanisms are controlled by cells of the innate immune system, T cells were found to be crucial for host resistance against acute septic peritonitis. However, the mechanisms by which T cells mediate protection are not fully understood. Here, we demonstrate mice deficient for recombinase-activating gene (RAG) 1, which lack mature B and T cells, showed enhanced susceptibility and impaired bacterial clearance in a model of acute septic peritonitis. Whereas B-cell-deficient muMT mice showed no significant difference in the survival rate after peritonitis induction, T-cell-deficient Balb/c nude mice exhibited reduced survival. Importantly, analysis of cytokine production in both RAG-1-deficient and T-cell-deficient nude mice indicated strongly attenuated production of IL-12, interferon (IFN) gamma, and IL-10 during sepsis. Reduced cytokine levels were detected both in serum and in organ extracts of septic mice. Direct analysis of T cells isolated from septic mice demonstrated that T cells respond to an acute septic challenge by increased production of IFN-gamma and IL-10. Moreover, bacterial numbers in spleens of septic RAG-1-deficient mice were significantly increased as compared with controls, suggesting that T cells are engaged in the early antibacterial immune defense during sepsis, possibly via the production of IFN-gamma. In summary, these results imply that T cells contribute to protective immune responses against acute systemic infections via their ability to produce crucial immune mediators.

We have developed a multifactorial histopathological prognostic score (PRSC) for patients with gastric cancer treated with neoadjuvant chemotherapy before surgery for the accurate discrimination of patient subgroups with differing outcomes. For patients with gastric cancer who undergo multimodal treatment, the postoperative staging classifications used for nontreated tumors may not accurately predict patient prognosis. We evaluated 428 gastric carcinoma specimens after a cisplatin-based chemotherapy. The factors for the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) ypT-category, ypN-category, and histopathological tumor regression were assigned a value from 1 to 3 as follows: ypT0 to 2 = 1 point; ypT3 = 2 points; ypT4 = 3 points; ypN0 = 1 point; ypN1 to 2 = 2 points; ypN3a to 3b = 3 points; less than 10% residual tumor per tumor bed = 1 point; 10% to 50% residual tumor per tumor bed = 2 points; and greater than 50% residual tumor per tumor bed = 3 points. A 3-tiered PRSC based on the sum value was established (group A: 3-4 points; group B: 5-7 points; group C: 8-9 points) and was found to correlate with patient prognosis. The PRSC showed a clear discrimination of 3 significantly different prognostic groups (group A: 76 patients; group B: 210 patients; group C: 142 patients; P < 0.001). In multivariate analyses, including the completeness of resection, tumor diameter, lymphatic vessel invasion, tumor grading, and Lauren classification, the PRSC was the only independent prognostic factor for overall survival (hazard ratio [HR] = 2.03; 95% confidence intervals [CI], 1.49-2.78; P < 0.001). It was slightly superior to the UICC/AJCC staging system (HR = 1.66; 95% CI, 1.20-2.27; P = 0.002) when analyzed with tumor regression as an additional independent factor (HR = 1.27; 95% CI, 1.01-1.62; P = 0.044) included in the analysis. The proposed PRSC reveals the most accurate prediction of survival for patients with gastric carcinoma after neoadjuvant chemotherapy followed by surgery. The PRSC clearly identifies 3 subgroups with different prognoses and may be helpful for therapeutic decisions.

Zusammenfassung  GRUNDLAGEN: Die bisher bekannten in vivo Modelle für den adenoviralen Transfer sind geprägt durch eine zeitliche Limitierung der Substanzapplikation, eine fehlende Zielorganselektion und eine, unter Umständen, methodisch bedingte artifizielle Läsion des Zielorgans durch den Versuchsaufbau selbst. Daher war das Ziel dieser experimentellen Studie ein Leberzirkulationsmodell, welches die vorbeschriebenen Nachteile umgeht, zu entwickeln und zu beschreiben. METHODIK: Es wurden männliche Lewis-(RT1)-Ratten

Effective immunosuppressive therapy is essential to prevent transplant rejection but renders patients vulnerable to opportunistic infections. The present study investigates the effects of common immunosuppressive drugs on the course of septic peritonitis in an experimental mouse model. We show that treatment with a combination of tacrolimus, mycophenolate mofetil, and methylprednisolone resulted in highly elevated lethality of septic peritonitis. When immunosuppressive drugs were combined with antibiotic therapy, however, mice were almost completely protected. The combination of mycophenolate mofetil and methylprednisolone was shown to be required and sufficient to improve outcome of septic peritonitis in the presence of antibiotic therapy. Combined immunosuppressive and antibiotic therapy, but not antibiotic therapy alone, resulted in enhanced bacterial clearance. These beneficial effects were linked to an elevated expression of activation markers and an increased production of reactive oxygen metabolites by peritoneal neutrophils and correlated with a reduced messenger RNA expression of the inhibitory cytokine IL-22. In contrast, systemic or peritoneal levels of IL-10, IL-12, TNF-alpha, keratinocyte chemoattractant, and monocyte chemoattractant protein 1, and splenic messenger RNA levels of IFN-gamma were not influenced by the immunosuppressive therapy. These results therefore suggest that combined immunosuppressive and antibiotic therapy may improve bacterial clearance and survival of septic peritonitis by a mechanism that involves enhanced activation and antimicrobial activity of neutrophils and reduced production of IL-22.

Despite sustained efforts, intensive research has not been proven successful to reveal risk factors, which relevantly influence early diagnostics or effective treatment of pancreatic carcinoma. Principally, it must be noted, that currently no ideal tumor marker exists for the (early) detection of pancreatic carcinoma. The most important imaging modalities are high-resolution computed tomography, abdominal ultrasound, and endosonography. Surgical procedures in therapy have become more and more standardised and lead to a decrease in morbidity and mortality on the one hand and to an increase in resectability on the other hand. Pylorus-preserving partial pancreaticoduodenectomy is the treatment of choice for a tumor of the pancreatic head, whereas resection of the left pancreas (including splenectomy) is the standard therapy for carcinomas of the pancreatic tail. In all cases, a local systematic lymphadenectomy is mandatory; hence the prognostic gain of an extended lymphadenectomy remai...

Background We investigated the applicability of both Acute Physiology And Chronic Health Evaluation II (APACHE II) and Mannheim Peritonitis Index (MPI) in transplant recipients with intestinal perforation as polymicrobial peritonitis is highly life-threatening in patients with impaired immunological defence and the course of abdominal sepsis is aberrant compared to non-immunosuppressed individuals. Methods In a retrospective database analysis, we validated the consistency of APACHE II and MPI in death prediction in septic peritonitis. In a matched-pair analysis we then investigated their applicability in immunosuppressed transplant recipients. The validation of the scores was performed with 125 non-immunosuppressed patients. In a matched-pair analysis 16 immunosuppressed transplant recipients were compared with 32 controls. Results In accordance with clinical observations, statistical analyses revealed significantly higher MPI scores in immunosuppressed transplant recipients (P = 0....

Surgery is still the only curative therapy for locoregional gastric cancer. Hereby it is important to achieve negative margins (R0 resection) and to perform an adequate lymph-node dissection (D2 lymphadenectomy). Unfortunately most cases of gastric cancer are diagnosed in a locally advanced tumor stage. The poor prognosis of patients with these tumors is due to the frequent recurrences after primary resection in curative intent. This observation led to the development of (neo)adjuvant treatment concepts. Beginning with the end of the 1980s, more and more patients with locally advanced tumors were subjected to a preoperative, perioperative, or postoperative treatment in order to improve the prognosis after curative resection. However, in different regions of the world, different regiments are preferred. While adjuvant chemotherapy is the established treatment in Asia, adjuvant chemoradiotherapy is favored in the USA and perioperative chemotherapy is considered the treatment of choice...

Despite sustained efforts, intensive research has not been proven successful to reveal risk factors, which relevantly influence early diagnostics or effective treatment of pancreatic carcinoma. Principally, it must be noted, that currently no ideal tumor marker exists for the (early) detection of pancreatic carcinoma. The most important imaging modalities are high-resolution computed tomography, abdominal ultrasound, and endosonography. Surgical procedures in therapy have become more and more standardised and lead to a decrease in morbidity and mortality on the one hand and to an increase in resectability on the other hand. Pylorus-preserving partial pancreaticoduodenectomy is the treatment of choice for a tumor of the pancreatic head, whereas resection of the left pancreas (including splenectomy) is the standard therapy for carcinomas of the pancreatic tail. In all cases, a local systematic lymphadenectomy is mandatory; hence the prognostic gain of an extended lymphadenectomy remai...

Gastric cancer represents a great challenge for health care providers and requires a multidisciplinary approach in which surgery plays the main role. Minimally invasive surgery has been progressively developed, first with the advent of laparoscopy and more recently with the spread of robotic surgery, but a number of issues are currently being investigate, including the limitations in performing effective extended lymph node dissections and, in this context, the real advantages of using robotic systems, the possible role for advanced Gastric Cancer, the reproducibility of completely intracorporeal techniques and the oncological results achievable during follow-up. Searches of MEDLINE, Embase and Cochrane Central Register of Controlled Trials were performed to identify articles published until April 2014 which reported outcomes of surgical treatment for gastric cancer and that used minimally invasive surgical technology. Articles that deal with endoscopic technology were excluded. A t...

ZusammenfassungDie Diagnostik und Therapie des Magenfrühkarzinoms wurde aufgrund der hohen Inzidenz im Lande vorwiegend durch die Japaner geprägt und bestimmt. Im Lauf der Zeit wurden differenzierte Therapien zur Behandlung dieser Erkrankung entwickelt. Dabei treten die endoskopischen Resektionsverfahren immer mehr in den Vordergrund. Die vorliegende Arbeit soll die wesentlichen Eckpunkte der interdisziplinären Behandlung des Magenfrühkarzinoms aufzeigen.

Zusammenfassung  GRUNDLAGEN: Die bisher bekannten in vivo Modelle für den adenoviralen Transfer sind geprägt durch eine zeitliche Limitierung der Substanzapplikation, eine fehlende Zielorganselektion und eine, unter Umständen, methodisch bedingte artifizielle Läsion des Zielorgans durch den Versuchsaufbau selbst. Daher war das Ziel dieser experimentellen Studie ein Leberzirkulationsmodell, welches die vorbeschriebenen Nachteile umgeht, zu entwickeln und zu beschreiben. METHODIK: Es wurden männliche Lewis-(RT1)-Ratten

Effective immunosuppressive therapy is essential to prevent transplant rejection but renders patients vulnerable to opportunistic infections. The present study investigates the effects of common immunosuppressive drugs on the course of septic peritonitis in an experimental mouse model. We show that treatment with a combination of tacrolimus, mycophenolate mofetil, and methylprednisolone resulted in highly elevated lethality of septic peritonitis. When immunosuppressive drugs were combined with antibiotic therapy, however, mice were almost completely protected. The combination of mycophenolate mofetil and methylprednisolone was shown to be required and sufficient to improve outcome of septic peritonitis in the presence of antibiotic therapy. Combined immunosuppressive and antibiotic therapy, but not antibiotic therapy alone, resulted in enhanced bacterial clearance. These beneficial effects were linked to an elevated expression of activation markers and an increased production of reactive oxygen metabolites by peritoneal neutrophils and correlated with a reduced messenger RNA expression of the inhibitory cytokine IL-22. In contrast, systemic or peritoneal levels of IL-10, IL-12, TNF-alpha, keratinocyte chemoattractant, and monocyte chemoattractant protein 1, and splenic messenger RNA levels of IFN-gamma were not influenced by the immunosuppressive therapy. These results therefore suggest that combined immunosuppressive and antibiotic therapy may improve bacterial clearance and survival of septic peritonitis by a mechanism that involves enhanced activation and antimicrobial activity of neutrophils and reduced production of IL-22.

Since the recent MAGIC trial neoadjuvant chemotherapy has been considered as treatment option for patients with advanced gastric cancer for tumor-downsizing and increasing R0 resection rates. Morbidity was reported in 45% of the patients treated within this randomized trial. Due to myelotoxicity under chemotherapy a part of the patients might undergo surgery with preoperative leucopenia. As leucopenia causes adverse events such as opportunistic infections and fever, it might be considered as a relevant risk factor in the course of surgical treatment. We analyzed a cohort of neoadjuvantly treated patients (n = 214), which had a clinically inapparent but proven leucopenia (n = 58) before undergoing surgery due to advanced stage gastric cancer. Statistical analysis by Fisher's exact test showed, that there was no significant effect neither on general (P = 0.191) nor on surgery-dependant postoperative complications (P = 0.75). Conclusively patients with clinically inapparent leucopenia after neoadjuvant chemotherapy due to advanced stage gastric cancer can be safely operated on without putting them in danger of relevant surgical complications.

PURPOSEValidity of the seventh edition of the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) staging systems for gastric cancer has been evaluated in several studies, mostly in Asian patient populations. Only few data are available on the prognostic implications of the new classification system on a Western population. Therefore, we investigated its prognostic ability based on a German patient cohort.Patients And methodsData from a single-center cohort of 1,767 consecutive patients surgically treated for gastric cancer were classified according to the seventh edition and were compared using the previous TNM/UICC classification. Kaplan-Meier analyses were performed for all TNM stages and UICC stages in a comparative manner. Additional survival receiver operating characteristic analyses and bootstrap-based goodness-of-fit comparisons via Bayesian information criterion (BIC) were performed to assess and compare prognostic performance of the competing ...

It has been postulated that an early systemic inflammatory response syndrome (SIRS) and a subsequent compensatory anti-inflammatory response syndrome (CARS) occur sequentially in sepsis. Co-existence of both is referred to as mixed antagonist response syndrome (MARS). Pro- and anti-inflammatory cytokine production was investigated in patients with postoperative sepsis, a murine peritonitis model and in vitro to further delineate the interaction of hyper- and hypo-inflammation in sepsis. IL-6 and IL-10 were measured in serum samples from 80 patients on d1 and d2 of postoperative sepsis and were similarly determined at various time points after induction of septic peritonitis in mice. Cytokine production of RAW264 macrophages was stimulated in vitro using TLR agonists. IL-6 and IL-10 were measured in supernatants. All cytokine measurements were performed by ELISA. In patients, the initial phase of the immune response to sepsis was characterized by a concomitant elevation of serum IL-6 and IL-10 levels. IL-10 levels were correlated with IL-6 levels in an exponential manner (p<0.001), which could be confirmed in a mouse model of septic peritonitis. In vitro experiments revealed that the observed exponential correlation may occur as function of TLR signaling intensity. Early postoperative sepsis seems to be characterized by a primary MARS. Sepsis severity was positively correlated with a disproportionate elevation of the anti-inflammatory response relative to the pro-inflammatory response, a pattern reminiscent of TLR-driven responses. Detailed characterization of immune responses in sepsis may help to direct standard therapies and to develop effective immunomodulatory strategies.

The incidence of adenocarcinoma of the esophagogastric junction is increasing. This study aims to evaluate the clinicopathological features of Chinese patients with adenocarcinoma of the esophagogastric junction and to define prognostic factors. We retrospectively reviewed a database of 382 consecutive patients with adenocarcinoma of the esophagogastric junction at the First Affiliated Hospital of Xi'an Jiaotong University from January 2005 to March 2010. All patients were classified according to the Siewert's classification and staged according to the latest edition of the American Joint Committee on Cancer categories. Six of the 382 patients had type I adenocarcinoma, 220 had type II, and 156 had type III. There was no significant difference in the overall survival of different Siewert subtypes. According to the multivariate analysis, pathological lymph node stage, age, and the existence of lymphovascular invasion were the independent factors of prognosis of adenocarcinoma of the esophagogastric junction following surgery. On the data, the distribution of the three types of tumor was found to be different from that reported in Western countries. Lymph node metastasis, lymphovascular invasion, and age were significant and independent factors for poor prognosis after R0 resection for adenocarcinoma of the esophagogastric junction.