Theodor Junginger

Effect of Chemokine Receptors CXCR4 and CCR7 on the Metastatic Behavior of Human Colorectal Cancer

Purpose: The expression of chemokine receptors CXCR4 and CCR7 has been associated with tumor dissemination and poor prognosis in a limited number of tumor entities. However, no data are currently available on the impact of chemokine receptor expression on disease progression and prognosis in human colorectal cancer. Experimental Design: The expression of CXCR4 and CCR7 was evaluated in 96 patients with histologically confirmed colorectal cancers and in four colorectal cancer cell lines by immunohistochemical staining. Furthermore, cell migration assays were done with SW480, SW620, and LS174T cancer cells to confirm the effect of the CXCR4 ligand stromal cell–derived factor 1α on migration. Results: Human colorectal cancer specimens and cell lines displayed a CXCR4 and CCR7 expression with variable intensities. Interestingly, strong expression of CXCR4, but not of CCR7, was significantly associated with higher Union International Contre Cancer stages 3/4 (P = 0.0017), lymph node metastasis (P = 0.00375), and distant metastasis (P = 0.00003) and further correlated with a reduced 3-year survival rate (P = 0.1). Strong CXCR4 and CCR7 expression positively correlated with the location of the primary tumor in the rectum (P < 0.01). Furthermore, activation of CXCR4-expressing cancer cells by stromal cell–derived factor 1α resulted in a significant increase of cell migration (P < 0.014). Conclusion: Strong expression of CXCR4 by colorectal cancer cells is significantly associated with lymphatic and distant dissemination in patients with colorectal cancer as well as with cancer cell migration in vitro.

Comparison of results after transanal endoscopic microsurgery and radical resection for T1 carcinoma of the rectum

Abstract.Background: We compared the results of transanal endoscopic microsurgery and radical surgery in patients with T1 carcinomas of the rectum. Methods: We performed a retrospective study (1985–96) to compare the results obtained in 103 patients with T1 rectal carcinomas (low-risk T1, n= 80; high-risk T1; n= 23) undergoing transanal endoscopic microsurgery and radical surgical therapy. Results: The complication rate in patients undergoing local excision was 3.4% (two of 58); it was 18% (eight of 45) in the group treated with radical surgery. Two of 45 patients (3.8%) died after radical resection; there were no deaths after local excision. With regard to the actuarial 5-year survival rate, no difference was observed in the group with low-risk T1 carcinoma between patients treated with local excision (79%) and those who had radical resection (81%) (p= 0.72). In patients with high-risk T1 carcinoma, lymph node metastases were identified in four of 11 patients undergoing radical resection (36%). Four of 12 patients with high-risk T1 carcinoma treated by local excision developed recurrences, whereas none of the patients undergoing primary radical surgery had a recurrence. Conclusions: Transanal endoscopic microsurgery for the treatment of low-risk T1 carcinomas is associated with a significantly lower complication rate than radical surgical therapy. There is no difference in 5-year survival between local and radical surgical therapy in patients with low-risk T1 carcinoma.

Technique of transanal endoscopic microsurgery

SummarySessile adenomas are predominantly localized in the rectum and lower sigma. Surgical removal is indicated but often implies an invasive surgical procedure. Using conventional transanal surgical techniques, only the lower rectum can be reached and there are high rates of recurrence. The new technique combines an endoscopic view of the rectum under gas insufflation via a stereoscopic telescope with conventional surgical preparation and suturing. Adenomas can be excised using the mucosectomy technique or full-thickness-excision, whereas carcinomas should be excised using full-thickness excision with a sufficient border of healthy mucosa. In carcinomas of the sacral cavity, we remove the retrorectal fat up to the fascia of Waldeyer, including the regional lymph nodes. Transanal endoscopic microsurgery is the most economical and tissue-saving surgical technique for the removal of rectal adenomas and early rectal carcinomas.

Clinical results of transanal endoscopic microsurgery

SummaryUsing the “transanal endoscopic microsurgery” technique, 140 patients were treated at the Department of Surgery in Cologne and Mainz. Of the patients with adenomas, 68.2% had typical symptoms preoperatively. The postoperative hospital attendance was 8.7 days, with an average resection size of 14.4 cm2. The postoperative complication rate was 5%, and there were no deaths related to the technique. In a prospective controlled trial, 2.2% of the patients with adenomas treated endoscopically in Mainz showed recidivation, requiring reoperation. The follow-up rate was 100%. In 30 cases, microscopic examination revealed carcinoma. Radical reoperation in 8 pT1 tumours showed neither remaining tumour nor lymph node metastases. Twelve patients with pT1 carcinoma treated by local surgery alone were recurrence-free with an average follow-up period of 12.3 months. So far, there have been no late results.

Influence of identification and preservation of pelvic autonomic nerves in rectal cancer surgery on bladder dysfunction after total mesorectal excision.

AbstractPURPOSE: Given the improvement in oncologic outcome after the introduction of total mesorectal excision for the treatment of rectal cancer, the objective of the present study was to determine the frequency of identification and preservation of the pelvic autonomic nerves and to identify a possible link between postoperative micturition disturbances and the extent of the radical resection. METHODS: Between March 1997 and December 2001, 150 patients with adenocarcinoma of the rectum (≤16 cm from the anal verge) underwent surgery, with sphincter preservation in 112 cases (74.7 percent). Sixty-three patients (42 percent) were classified as American Society of Anesthesiologists Stage III and two (1.3 percent) as Stage IV. The number of cases with complete identification, partial identification, or nonidentification of the autonomic nerves (superior hypogastric plexus, hypogastric nerve, and inferior hypogastric plexus) was documented and correlated with micturition disturbances (need for a long-term urinary catheter). Urine volumes were measured by ultrasound before and after surgery. RESULTS: The pelvic autonomic nerves were identified completely in 108 patients (72 percent), partially in 16 (10.7 percent), and not at all in 26 (17.3 percent). After the initial phase of the study (n = 50 patients), complete identification was realized in 78 percent of cases. Multivariate analysis showed that of the predetermined parameters (learning curve for Group I vs. Groups II or III, gender, T stage, blood loss, curative surgery, and previous surgery), gender (P = 0.006), learning curve (P = 0.019), and depth of penetration of the rectal wall (T1/T2 vs. T3/T4; P = 0.028) exerted an independent influence on achievement of complete pelvic nerve identification. Sixteen patients (10.7 percent) were discharged from the hospital with a urinary catheter. Identification and preservation of the pelvic autonomic nerves was associated with low bladder dysfunction rates (4.5 vs. 38.5 percent; P < 0.001). In the evaluation of preoperative and postoperative bladder function, a urologic history and residual urine volume measurements by ultrasound were essential. The information obtained from urodynamic studies was of no relevance. CONCLUSIONS: Identification and preservation of the pelvic autonomic nerves was achieved in the majority of patients and led to the prevention of urinary dysfunction. Gender (P = 0.006), learning curve (P = 0.019), and T stage are independent parameters that influence outcome.

Pseudoachalasia: a case series and analysis of the literature.

Objective Pseudoachalasia frequently cannot be distinguished from idiopathic achalasia by manometry, radiologic examination or endoscopy. Mechanisms proposed to explain the clinical features of pseudoachalasia include a circumferential mechanical obstruction of the distal esophagus or a malignant infiltration of inhibitory neurons within the myenteric plexus. Material and methods Between January 1980 and December 2002, the clinical features of 5 patients with pseudoachalasia and 174 patients with primary achalasia, diagnosed in a single center, were compared. A literature analysis of the etiology of pseudoachalasia for the time period 1968 to December 2002 was performed. The search concentrated on the databases and online catalogues PubMed, Web of Science, Cochrane Library and Current Contents Connect. Results In our case series, patients with pseudoachalasia reported a shorter duration of symptoms and tended to be older than patients with primary achalasia. Conventional manometry, endoscopy and radiologic examination of the esophagus proved to be of little value in distinguishing between the diseases. In the majority of cases only surgical exploration revealed the underlying cause. A coincidence of primary achalasia and disorders of the gastroesophageal junction was excluded by showing return of peristalsis following treatment. The analysis of the literature showed a total of 264 cases of pseudoachalasia in 122 publications. Most cases of were due to malignant disease (53.9% primary and 14.9% secondary malignancy), followed by benign lesions (12.6%) and sequelae of surgical procedures at the distal esophagus or proximal stomach (11.9%). In rare instances, the disease was an expression of a paraneoplastic process due to distant neuronal involvement rather than to local invasion with destruction of the myenteric plexus (2.6%). Conclusions The diagnosis of pseudoachalasia is difficult to establish by conventional diagnostic measures. The main distinguishing feature of secondary versus primary achalasia is the complete reversal of pathologic motor phenomena following successful therapy of the underlying disorder.

Large volume hepatic freezing: Association with significant release of the cytokines interleukin-6 and tumor necrosis factor a in a rat model

Although cryotherapy of liver tumors is generally considered a safe procedure, a syndrome of coagulopathy and fatal multiorgan failure has been observed in some patients and is called the cryoshock phenomenon. Our aim was to establish an animal model of this phenomenon and examine the effects of the basic parameters of freezing or cryotherapy on it. A group of 75 female Sprague-Dawley rats were allocated randomly to five groups: (1) sham laparotomy (n=15); (2) small (25% liver volume) single freeze (n=15); (3) small (25% liver volume) double freeze (n=15); (4) large (50% liver volume) single freeze (n=15); (5) large (50% liver volume) double freeze (n=15). Blood samples were collected at different postoperative times, and organs were harvested for histopathology. There was a significant release of tumor necrosis factor-α (TNFα:) and interleukin 6 (IL-6) following hepatic freezing, which was greatest in group 5. Postoperative serum cytokine levels were significantly associated with hepatocellular injury, as measured by postoperative serum aspartate transaminase (AST) concentrations. Severe hemoglobinuria and renal injury, as demonstrated by the serum creatinine level and the glomerular neutrophil count, were observed and were greatest in group 5. Hepatic cryosurgery is associated with release of IL-6 and TNFα and renal injury in a rat model. It is likely that the cryoshock phenomenon is another form of the systemic inflammatory response syndrome. Based on the results of this study, it is possibly mediated by cytokines released from the frozen liver tissue. We therefore caution against cryothérapy of large tumor volumes.RésuméAlors que la cryothérapie des tumerus du foie est généralement considérée comme un procédé sur, on peut observer quelque fois un syndrome de coagulopathie et de défaillance multiviscérale fatale, appelé le phénomène du «cryochoc». Notre but a été et d’étudier les effets de la cryothérapie sur les paramètres de base chez un modèle animal. 75 rates femelles Sprague-Dawley ont été randomisées en cinq groupes: (1) laparotomie factice «sham» (n=15); (2) un seul «gel» de petit volume (25% volume du foie) (n=15): (3) deux «gels» de petit volume (25% du volume du foie) (n=15); (4) un seul «gel» de volume important (50% du volume du foie) (n=15); (5) deux «gels» de volume important (50% du volume du foie) (n=15). Les échantillons sanguins ont été collectés à des moments postopératoires différents et les organes ont été prélevés pour examen histopathologique. On a constaté un largage significatif de TNFα: et d’IL-6 après cryothérapie du foie, plus important dans le groupe 5. Les taux de cytokines du sérum ont été significativement córreles avec les lésions hépatocellulaires, mesurées par les taux postopératoires des AST. Une hémoglobinurie et des lésions rénales sévères, mises en évidence par un taux élevé de créatinine et par la numération des neutrophils, ont été observées surtout dans le groupe 5. La cryothérapie hépatique est associée à un largage d’lL-6 et de TNFα ainsi que de lésions rénales dans le modèle du rat. 11 est probable que le phénomène du cryochoc est une manifestation du syndrome de réponse systémique inflammatoire. Basé sur les résultats de cette étude, on pense que les cytokines largués par le tissu hépatique refroidi sont les médiateurs de ce phénomène. Nous ne recommandons donc pas la cryothérapie pour les tumeurs volumineuses.ResumenAunque la crioterapia de los tumores hepáticos es una técnica bastante segura, se han descrito algunos casos en los que se produjo un sÍndrome coagulopático y fracaso multiorgánico mortal. Este sÍndrome se ha considerado como un fenómeno del crioshock (shock por congelación). El objetivo del trabajo fue conseguir un modelo animal del llamado fenómeno del crioshock y evaluar en el mismo, los efectos de la congelación o de la crioterapia sobre parámetros básicos. 75 ratas hembras Sprague-Dawley se distribuyeron de forma aleatoria en 5 grupos: (1) Laparatomía simulada ( n=15); (2) Pequeña (25% del volumen hepático) congelación única (n=15); (3) Pequeña (25% volumen hepático) congelación doble (n=15); (4) Gran (50% volumen hepático) congelación única (n=15); (5) Gran (50% volumen hepático) congelación doble (n=15). Muestras de sangre se obtuvieron en diversos momentos del periodo postoperatorio y los órganos fueron recogidos para su ulterior estudio histopatológico. Tras la congelación hepática se constato una significativa liberación de TNFα y IL-6, que fue más marcada en el grupo 5. Los niveles séricos de citocinas en el postoperatorio guardan estrecha relación con el trauma hepatocelular, como se constató midiendo las concentraciones séricas postoperatorias de la AST. Se observó grave hemoglobinuria y lesión renal, demostrada por los valores séricos de creatinina y el recuento de neutrófilos en los glomerulos, siendo estas alteraciones mucho más graves en el grupo 5. En un modelo de rata la criocirugía hepática produce una liberación de IL-6 y TNFα así como lesiones renales. Posiblemente el denominado fenómeno del crioshock no es más que una forma diferente del sÍndrome de respuesta sistémica inflamatoria. Según nuestros hallazgos los mediadores de dicho fenómeno son citocinas liberadas del tejido hepático congelado. De ahí, que se aconseje prudencia en la crioterapia de grandes tumores hepáticos.

Resection of the mesopancreas (RMP): a new surgical classification of a known anatomical space

BackgroundPrognosis after surgical therapy for pancreatic cancer is poor and has been attributed to early lymph node involvement as well as to a strong tendency of cancer cells to infiltrate into the retropancreatic tissue and to spread along the peripancreatic neural plexuses. The objective of our study was to classify the anatomical-surgical layer of the mesopancreas and to describe the surgical principles relevant for resection of the mesopancreas (RMP). Immunohistochemical investigation of the mesopancreatic-perineural lymphogenic structures was carried out with the purpose of identifying possible routes of metastatic spread.MethodsResection of the mesopancreas (RMP) was performed in fresh corpses. Pancreas and mesopancreas were separated from each other and the mesopancreas was immunohistochemically investigated.ResultsThe mesopancreas strains itself dorsally of the mesenteric vessels as a whitish-firm, fatty tissue-like layer. Macroscopically, in the dissected en-bloc specimens of pancreas and mesopancreas nerve plexuses were found running from the dorsal site of the pancreatic head to the mesopancreas to establish a perineural plane. Immunohistochemical examinations revealed the lymphatic vessels localized in direct vicinity of the neuronal plexuses between pancreas and mesopancreas.ConclusionThe mesopancreas as a perineural lymphatic layer located dorsally to the pancreas and reaching beyond the mesenteric vessels has not been classified in the anatomical or surgical literature before. The aim to ensure the greatest possible distance from the retropancreatic lymphatic tissue which drains the carcinomatous focus can be achieved in patients with pancreatic cancer only by complete resection of the mesopancreas (RMP).

Interleukin-6 and Tumor Necrosis Factor-α Levels following Hepatic Cryotherapy: Association with Volume and Duration of Freezing

Abstract. Although morbidity following cryotherapy is usually minor, a syndrome of multiorgan failure and disseminated intravascular coagulation (DIC) has been described and referred to as the cryoshock phenomenon. We hypothesized that mediators similar to those in septic shock may be involved in this syndrome. In this study we aimed to assess the plasma concentrations of the cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) following hepatic cryotherapy and to relate them to the duration and volume of freezing and to hepatocellular injury. Between April and December 1997 blood samples were taken preoperatively and at different times postoperatively from patients undergoing hepatic artery catheter-insertion (HAC) (n= 15), cryotherapy (n= 5), liver resection (n= 9), liver resection and edge cryotherapy (n= 7), or liver resection and cryotherapy of additional lesions (n= 9). They were analyzed for serum aspartate transaminase (AST) and plasma TNF-α and IL-6 levels. There was a significant association (Pearson correlation) of serum AST levels 1 hour postoperatively with plasma TNF-α and IL-6 levels at the end of the procedure. In patients undergoing cryotherapy or resection with cryotherapy of additional lesions (n= 14), the volume and duration of hepatic freezing were significantly associated with postoperative serum AST and plasma TNF-α and IL-6 levels at various postoperative times. Hepatic cryotherapy is followed by cytokine release, with postoperative plasma TNF-α and IL-6 levels associated with the degree of hepatic cryotrauma. These mediators may be involved in the occurrence of cryoshock following large-volume hepatic freezing.

Reduction of interstitial cells of Cajal (ICC) associated with neuronal nitric oxide synthase (n-NOS) in patients with achalasia.

BACKGROUND:The etiology of achalasia is still unknown. The current theories of chronic inflammation leading to autoimmune response with destruction and loss of the inhibitory myenteric ganglion cells enlighten its pathogenesis in a limited way only. Interstitial cells of Cajal (ICC) have been shown to be involved in nitrergic neurotransmission of the lower esophageal sphincter (LES).AIM:To investigate the significance of ICC and neuronal nitric oxide synthase (n-NOS) in esophageal wall tissue of patients undergoing surgery for achalasia.METHODS:In 53 patients with a median age of 45 (6–78) yr undergoing surgery for achalasia, the immunoreactivity of ICC (CD117/c-kit) and n-NOS was assessed. In 42 patients, biopsies were taken from the LES high-pressure zone during Heller myotomy, whereas in 11 patients with end-stage achalasia and a decompensated megaesophagus, the complete esophagus was resected. A semiquantitative analysis was carried out and ICC and n-NOS impairments were classified into four grades. Staining intensity was correlated with preoperative clinical, radiologic, and manometric findings and with long-term postoperative Eckardt score.RESULTS:Grade III/IV ICC reduction (severe reduction to complete loss) was seen in 59.5% of all biopsy specimens of the LES high-pressure zone. Patients with grade III/IV ICC reduction had a significantly longer duration of achalasia symptoms (3 [0–43] yr) than patients with minor to marked (grade I/II) impairment (1 [0–16] yr, P = 0.028). A majority (72.5%) of tissue samples revealed severe reduction to complete loss of n-NOS immunoreactivity. The preoperative Eckardt score was statistically significantly different between patients with grade I/II and those with grade III/IV n-NOS reductions (P = 0.031). CD117 (c-kit) positivity was statistically significantly correlated with n-NOS staining intensity (correlation coefficient r = 0.781, P < 0.0001).CONCLUSION:The present results suggest that in the pathogenesis of achalasia, especially in the development of the LES high-pressure zone, depletion of ICC networks and potential changes in the electrical activity of smooth muscle cells may play a crucial role. The reduction in CD117-positive ICC in a few patients also seemed to be of relevance, even if the cells of Auerbachs plexus were unscathed. The associated reduced NOS release might underlie the profound ICC impairment and could possibly be responsible for the lack of LES relaxation, because of missing inhibitory neurotransmission. It is unclear, however, whether the ICC loss is primarily caused by the accelerated attrition of mature cells or their impaired regeneration.