Dirk L. Stippel

Options in the management of esophageal perforation: analysis over a 12‐year period

Controversies exist about the management of esophageal perforation in order to eliminate the septic focus. The aim of this study was to assess the etiology, management, and outcome of esophageal perforation over a 12-year period, in order to characterize optimal treatment options in this severe disease. Between May 1996 and May 2008, 44 patients (30 men, 14 women; median age 67 years) with esophageal perforation were treated in our department. Etiology, diagnostic procedures, time interval between clinical presentation and treatment, therapeutic management, and outcome were analyzed retro- or prospectively for each patient. Iatrogenic injury was the most frequent cause of esophageal perforation (n= 28), followed by spontaneous (n= 9) and traumatic (n= 4) esophageal rupture (in three patients, the reasons were not determinable). Eight patients (18%) underwent conservative treatment with cessation of oral intake, antibiotics, and parenteral nutrition. Twelve (27%) patients received an endoscopic stent implantation. Surgical therapy was performed in 24 (55%) patients with suturing of the lesion in nine patients, esophagectomy with delayed reconstruction in 14 patients, and resection of the distal esophagus and gastrectomy in one patient. In case of iatrogenic perforation, conservative or interventional therapy was performed each in 50% of the patients; 89% of the patients with a Boerhaave syndrome underwent surgery. The hospital mortality rate was 6.8% (3 of 44 patients): one patient with an iatrogenic perforation after conservative treatment, and two patients after surgery (one with Boerhaave syndrome, one with iatrogenic rupture). No death occurred in the 25 patients with a diagnostic interval less than 24 hours, whereas the mortality rate in the group (n= 16 patients) with a diagnostic interval of more than 24 hours was 19% (P= 0.053). In three patients, the diagnostic interval was not determinable retrospectively. An individualized therapy depending on etiology, diagnostic delay, and septic status leads to a low mortality of esophageal perforation.

A concerted action of HNF4alpha and HNF1alpha links hepatitis B virus replication to hepatocyte differentiation.

Hepatitis B virus (HBV) is an important human pathogen, which targets the liver extremely efficient, gaining access to hepatocytes by a so far unknown receptor and replicating in a hepatocyte‐specific fashion. Cell differentiation seems to determine HBV replication. We here show that the level of hepatocyte differentiation, as indicated by hepatocyte polarization and metabolic activity, is closely correlated to the transcription of the HBV RNA pregenome. Pregenome transcription determined the level of HBV replication in various cell lines of hepatocellular origin and in primary human hepatocytes. A variety of hepatocyte‐enriched nuclear factors have been described to regulate transcription of the pregenome, but it remained unknown which factors link HBV replication to hepatocyte differentiation. We determined that high expression levels of HNF4α but not its potential cofactors or other hepatocyte‐enriched transcription factors were essential for efficient HBV replication, and link it to hepatocyte differentiation. HNF1α contributed to the control of HBV replication because it regulated the expression of HNF4α. Thus, a concerted action of HNF4α and HNF1α, which also determines morphological and functional differentiation of hepatocytes, links HBV replication to hepatocyte differentiation.

Variability of Size and Shape of Necrosis Induced by Radiofrequency Ablation in Human Livers: A Volumetric Evaluation

Background: Definite size and shape of radiofrequency-induced ablations (RFAs) cannot be evaluated intraoperatively. Instead, surgeons choose a radiofrequency device that is supposed to cause a necrosis of a determined size greater than the malignant lesion. The aim of this study was to measure the variability of the induced necroses postoperatively and to define a reproducible ablation volume in human liver.Methods: In 24 patients, 34 RFA procedures were performed with single applications of the device. The deployment was 3 cm (n = 16), 4 cm (n = 5), or 5 cm (n = 13). The induced necroses were analyzed by volumetric reconstructions of computed tomography (CT) scans. Measured volumes were compared with the expected volumes. Furthermore, the shape of the necrosis was classified according to an index of the diameters.Results: The measured volumes of postoperative necroses were 14 ± 8 cm3 (deployment, 3 cm), 24 ± 12 cm3 (4 cm), and 45 ± 42 cm3 (5 cm). The diameter of a sphere fitted into the necroses reached 2.9 ± .5 cm (3 cm), 3.5 ± .7 cm (4 cm), and 4.1 ± 1.1 cm (5 cm), at P < .02, significantly smaller than the deployment. The classification of shapes yielded a spherical shape (n = 14), a teardrop shape (n = 13), or an irregular shape (n = 7). The energy consumption was 2.1 ± 1.5 kJ/cm3 (3 cm), 2.6 ± .5 kJ/cm3 (4 cm), or 3.5 ± 2.0 kJ/cm3 (5 cm).Conclusions: The diameter of RFA-induced liver necrosis is significantly smaller than expected from needle deployment, especially with full-needle deployment. The shape of the lesion differs in more than half of the cases from the anticipated spherical pattern. The upper limit for reproducible necrosis induction is a tumor diameter of 3.4 cm.

Transanal endoscopic microsurgery in large, sessile adenomas of the rectum

The clinical and long-term results of 286 cases encountered from 1983 to 1993 in our Department of Surgery regarding the local excision of large, sessile rectal adenomas (>2cm2) by the endoscopic surgical method and the influence of this selected series of adenomas on age, sex, size, grade of dysplasia, and architecture are subjects of this study. Histologically proven rectal carcinomas as well as nonneoplastic polyps were excluded from this trial.Early postoperative complications amounted to 3.4%. The 1-year and 5-year recurrence rates ±SE of adenomas were 1.2±0.7% and 7.0±1.9%, respectively. Remarkably, there was no significant relationship between the histological type of the adenoma and the grade of dysplasia nor between the size and grade of dysplasia. However, there was a significant relationship between the size and histological type of the adenoma (P<0.01).With the endoscopic minimal-invasive system, we are able to achieve a superior rate of recurrence compared to any other local treatment as well as a more favorable operative result compared to extensive surgical procedures.

Experimental and clinical radiofrequency ablation: Proposal for standardized description of coagulation size and geometry

BackgroundRadiofrequency (RF) ablation is used to obtain local control of unresectable tumors in liver, kidney, prostate, and other organs. Accurate data on expected size and geometry of coagulation zones are essential for physicians to prevent collateral damage and local tumor recurrence. The aim of this study was to develop a standardized terminology to describe the size and geometry of these zones for experimental and clinical RF.MethodsIn a first step, the essential geometric parameters to accurately describe the coagulation zones and the spatial relationship between the coagulation zones and the electrodes were defined. In a second step, standard terms were assigned to each parameter.ResultsThe proposed terms for single-electrode RF ablation include axial diameter, front margin, coagulation center, maximal and minimal radius, maximal and minimal transverse diameter, ellipticity index, and regularity index. In addition a subjective description of the general shape and regularity is recommended.ConclusionsAdoption of the proposed standardized description method may help to fill in the many gaps in our current knowledge of the size and geometry of RF coagulation zones.

Intraoperative Radiofrequency Ablation Using a 3D Navigation Tool for Treatment of Colorectal Liver Metastases

Background: Resection as the only potential cure for colorectal liver metastasis is limited by the size and the intrahepatic localization of lesions. Radiofrequency ablation (RFA) may extend the limitations of surgery. Patients and Methods: 23 consecutive patients suffering from a total of 128 colorectal liver metastases were treated by resection and intraoperative RFA. All of these patients were irresectable by standard surgery due to volume and distribution of the lesions. 17 patients were treated by chemotherapy before RFA, with only 1 patient showing partial regression of liver metastases. In 12 lesions a new 3D navigation tool was used, that allows a virtual overlay of the RFA probe in real-time. Results: 60 metastases were resected, 68 metastases were treated by RFA. There was no mortality, and complications occurred in 4 patients only (1??temporary encephalopathy, 3x cholangitis). Local tumor control according to CT scan was achieved by RFA in 93% of lesions up to 30 mm diameter (n = 45) and in 44% of lesions larger than 30 mm (n = 23). All ablations using the navigation tool were successful. After a mean follow-up of 8 ± 5 months 12 patients are free of disease, 8 patients have either recurrent or new metastases, and 3 patients died of progressive disease. The estimated median survival time is 18 months (95% confidence interval 13–22 months). Conclusions: Intraoperative RFA of colorectal liver metastases in combination with hepatic resection is safe. Up to a lesion size of 30 mm a reliable treatment with RFA is possible. The navigation aid increases the reproducibility of the procedure.

Experimental bile duct protection by intraductal cooling during radiofrequency ablation.

The use of radiofrequency ablation (RFA) for liver tumours is limited by the proximity of large bile ducts to the targeted lesion. The aim of this randomized study was to evaluate intraductal cooling as a mean of protecting the bile ducts during RFA.

Mixed hepatoblastoma in an adult

We report a case in an elderly adult of a highly malignant liver tumor with blastoid features that resembled hepatoblastoma. A liver tumor with a diameter of 23 cm was removed in a 78-year-old woman. The tumor showed highly differentiated epithelial hepatocellular and poorly differentiated epithelial and mesenchymal components. The blastoid nature and pluripotent differentiation potential were supported by immunohistologic analysis and suggest an origin of a poorly differentiated pluripotent hepatic cell with the potential to mature. We believe that this case of a mixed hepatoblastoma in an adult should be added to the growing number of presumed hepatic precursor cell neoplasms in adults.

Liver cell transplantation in severe infantile oxalosis—a potential bridging procedure to orthotopic liver transplantation?

BACKGROUND The infantile form of primary hyperoxaluria type I (PHI) is the most devastating PH subtype leading to early end-stage renal failure and severe systemic oxalosis. Combined or sequential liver-kidney transplantation (LKTx) is the only curative option but it involves substantial risks, especially in critically ill infants. The procedure also requires resources that are simply not available to many children suffering from PHI worldwide. Less invasive and less complex therapeutic interventions allowing a better timing are clearly needed. Liver cell transplantation (LCT) may expand the narrow spectrum of auxiliary measures to buy time until LKTx for infants can be performed more safely. METHODS We performed LCT (male neonate donor) in a 15-month-old female in reduced general condition suffering from systemic oxalosis. Renal replacement therapy, initiated at the age of 3 months, was complicated by continuous haemodialysis access problems. Living donor liver transplantation was not available for this patient. Plasma oxalate (Pox) was used as the primary outcome measure. RESULTS Pox decreased from 104.3±8.4 prior to 70.0±15.0 μmol/L from Day 14 to Day 56 after LCT. A significant persistent Pox reduction (P<0.001) comparing mean levels prior to (103.8 μmol/L) and after Day 14 of LCT until LKTx (77.3 μmol/L) was seen, although a secondary increase and wider range of Pox was also observed. In parallel, the patients clinical situation markedly improved and the girl received a cadaveric LKTx 12 months after LCT. However, biopsy specimens taken from the explanted liver did not show male donor cells by amelogenin polymerase chain reaction. CONCLUSIONS With due caution, our pilot data indicate that LCT in infantile oxalosis warrants further investigation. Improvement of protocol and methodology is clearly needed in order to develop a procedure that could assist in the cure of PHI.

Overcoming tumor-mediated immunosuppression

Mechanisms of tumor-mediated immunosuppression have been described for several solid and hematological tumors. Tumors inhibit immune responses by attraction of immunosuppressive lymphocytic populations, secretion of immunosuppressive cytokines or expression of surface molecules, which inhibit immune responses by induction of anergy or apoptosis in tumor-infiltrating lymphocytes. This tumor-mediated immunosuppression represents a major obstacle to many immunotherapeutic or conventional therapeutic approaches. In this review we discuss how tumor-mediated immunosuppression interferes with different immunotherapeutic approaches and then give an overview of strategies to overcome it. Particular emphasis is placed on agents or approaches already transferred into clinical settings. Finally the success of immune checkpoint inhibitors targeting CTLA-4 or the PD-1 pathway highlights the enormous therapeutic potential of an effective overcoming of tumor-mediated immunosuppression.