Heiko Aselmann

Liver regeneration in a retrorsine/CCl4 – induced acute liver failure model: do bone marrow-derived cells contribute?

BACKGROUND/AIMS Adult bone marrow contains progenitors capable of generating hepatocytes. Here a new liver failure model is introduced to assess whether bone marrow-derived progeny contribute to liver regeneration after acute hepatotoxic liver failure. METHODS Retrorsine was used to inhibit endogenous hepatocyte proliferation, before inducing acute liver failure by carbon tetrachloride. Bone marrow chimeras were generated before inducing liver failure to trace bone marrow-derived cells. Therefore, CD45 and major histocompatibility complex (MHC) class I dimorphic rat models were applied. RESULTS Early after acute liver failure a multilineage inflammatory infiltrate was observed, mainly consisting of granulocytes. In long-term experiments small numbers of CD90+/CD45- cells of donor origin occurred in clusters associated with portal triads. Bone marrow cell infusion was not able to enhance liver regeneration. Cellular hypertrophy was the predominant way of liver mass regeneration in models applying retrorsine. CONCLUSIONS Retrorsine pretreatment did not affect sensitivity for carbon tetrachloride. A multilineage inflammatory infiltrate was observed in rats whether pretreated with retrorsine or not. Few donor cells co-expressing CD90 (THY 1) were present in recipient livers, which may resemble donor-derived hematopoietic progenitors or oval cells. No other donor cells within liver parenchyma were detected. This is in contrast to other cell infusion models of acute cell death.

Delayed low-level calcineurin inhibition promotes allospecific tolerance induction by posttransplantation donor leukocyte infusion

Background. Donor lymphocytes infused after organ transplantation can have strong immunoregulatory effects. Application of such protocols for transplant tolerance induction in a clinical setting will, however, require combination of specific immunomodulatory strategies with nonspecific immunosuppressive medication for safety reasons. The aim of this study was to analyze the effects of immunosuppressive treatment on tolerance induction protocols by posttransplantation donor lymphocyte infusion. Methods. The interaction of postoperative donor leukocyte infusion with different types, dosage, and timing of immunosuppressive drugs were studied in a rat model of heart transplantation. Results. Tolerance could be achieved if donor cell infusion was combined with delayed, but not immediate, low-dose cyclosporine treatment, and this was associated with activation and apoptosis of host lymphocytes. In contrast, combinations with an antibody against the interleukin 2 receptor led to long-term graft survival but severe chronic rejection, and combinations with high-dose cyclosporine or sirolimus led to acute rejection. Conclusions. Postoperative donor leukocyte infusion is a potential way for tolerance induction, but the type, dose, and timing of medication are highly critical for its efficacy.

Effect of incomplete parathyroidectomy preserving entire parathyroid glands on renal graft function.

HYPOTHESIS Parathyroidectomy (PT) corrects tertiary hyperparathyroidism in patients who have received renal grafts but can result in deterioration of renal function. OBJECTIVE To compare different surgical procedures for their effect on renal function and efficacy to cure tertiary hyperparathyroidism. DESIGN A retrospective cohort study. SETTING University clinic. PATIENTS Eighty-three patients with functioning renal grafts receiving PT for the first time. INTERVENTIONS Group 1 received an incomplete PT, with at least 1 entire parathyroid gland (PG) remaining in situ (n = 12). Group 2 received an incomplete PT, with the most morphologically conserved PG partially resected (n = 22). Group 3 received a complete PT, with autotransplantation of PG tissue (n = 49). MAIN OUTCOMES MEASURES The primary end point was the postoperative change in glomerular filtration rate. Secondary end points were rates of redialysis, hypercalcemia, and hyperparathyroidism within 5 years. RESULTS A decrease in glomerular filtration rate occurred postoperatively in 75 patients (90%) and correlated significantly with the extent of PG resection. Recovery of renal function at month 6 was observed in group 1, but not in groups 2 and 3 (P < .001). Seven patients (8%) needed permanent dialysis (1 in group 2 and 6 in group 3). Hypercalcemia was abrogated in 78 patients (94%), without significant differences among the groups. Assessment of parathyroid hormone levels in accordance with target ranges from the Kidney Disease Outcomes Quality Initiative guidelines did not reveal significant differences in the rates of recurrent hyperparathyroidism. CONCLUSION Incomplete PT preserving at least 1 entire PG does not cause deterioration of renal graft function and provides long-term correction of hypercalcemia and tertiary hyperparathyroidism.

Prevention of Peritoneal Carcinomatosis from Human Gastric Cancer Cells by Adjuvant-Type Intraperitoneal Immunotherapy in a SCID Mouse Model

Purpose: We analyzed the effect of intraperitoneal immunotherapy in an animal model mimicking locoregional dissemination of tumor cells during resection of advanced tumors. Methods: We first established a tumor model with human gastric cancer cells (MKN-45) in the peritoneal cavity of CB-17-SCID mice. Three hours following the injection of tumor cells into the peritoneal cavity, mAb 17-1A alone and in combination with human LAK cells were given intraperitoneally at different dosages. The results were quantified by determining the weight of the peritoneal tumor masses. Results: After intraperitoneal administration of 17-1A mAb, a tumor reduction could be shown (median tumor mass after 10 µg mAb: 171 µg; after 100 µg: 130 µg) when compared with the control group (632 µg). Following a combined therapy with mAb and LAK cells, a statistically significant tumor reduction could be observed (after 10 µg mAb + 20–50 × 106 LAK cells: 80 µg; after 100 µg mAb + 20–50 × 106 LAK cells: 12 µg, p = 0.0005). With specific dosages of antibody and LAK cells it was even possible to achieve complete tumor clearance. Conclusions: Intraperitoneal immunotherapy reduces the peritoneal tumor masses and can even prevent the peritoneal carcinomatosis formation.

Effectiveness of peripheral hepatogastrostomy versus hepatojejunostomy in the treatment of obstructive cholestasis: results of an experimental model.

PurposeTumors of the liver hilum frequently cause obstructive cholestasis. When a curative resection of the tumor is impossible, palliative bile drainage is indicated. A hepatojejunostomy is performed if conservative treatment fails or if irresectability is proven during an initial laparotomy. In patients with peritoneal carcinosis and mesentery retraction, a hepatogastrostomy may represent a helpful alternative. An experimental study was designed to compare the bile drainage effectiveness of a hepatogastrostomy versus a hepatojejunostomy.MethodsTwo-month-old outbred piglets were used in all experiments. The animals were randomized into three groups (hepatojejunostomy, hepatogastrostomy alone, hepatogastrostomy and proton pump inhibitors). Obstructive cholestasis was induced by common bile duct ligation; hepatojejunostomy and hepatogastrostomy were performed 2 weeks later. The serum bilirubin levels were monitored weekly. All animals were killed 4 weeks after the drainage operation.ResultsFollowing a hepatojejunostomy (n = 5) all animals showed decreasing cholestasis parameters. All animals (n = 3) died within 3–5 days after a hepatogastrostomy due to gastrointestinal bleeding caused by gastric ulcers and ulcers of the liver surface. The administration of pantoprazole prevented these bleeding complications. In animals treated by hepatogastrostomy and proton pump inhibitors (n = 5), bile drainage effectiveness was similar to that following hepatojejunostomy.ConclusionA hepatogastrostomy represents an alternative treatment option for surgical bile drainage with a similar effectiveness to that of a hepatojejunostomy. To prevent postoperative gastrointestinal bleeding, proton pump inhibitors should be used.

Laparoscopic right hemicolectomy with CME: standardization using the “critical view” concept

BackgroundComplete mesocolic excision is gradually becoming an established oncologic surgical principle for right hemicolectomy. However, the procedure is technically demanding and carries the risk of serious complications, especially when performed laparoscopically. A standardized procedure that minimizes technical hazards and facilitates teaching is, therefore, highly desirable.MethodsAn expert group of surgeons and one anatomist met three times. The initial aim was to achieve consensus about the surgical anatomy before agreeing on a sequence for dissection in laparoscopic CME. This proposal was evaluated and discussed in an anatomy workshop using post-mortem body donors along with videos of process-informed procedures, leading to a definite consensus.ResultsIn order to provide a clear picture of the surgical anatomy, the “open book” model was developed, consisting of symbolic pages representing the corresponding dissection planes (retroperitoneal, ileocolic, transverse mesocolic, and mesogastric), vascular relations, and radicality criteria. The description of the procedure is based on eight preparative milestones, which all serve as critical views of safety. The chosen sequence of the milestones was designed to maximize control during central vascular dissection. Failure to reach any of the critical views should alert the surgeon to a possible incorrect dissection and to consider converting to an open procedure.ConclusionCombining the open-book anatomical model with a clearly structured dissection sequence, using critical views as safety checkpoints, may provide a safe and efficient platform for teaching laparoscopic right hemicolectomy with CME.

Robotic-assisted total mesorectal excision (TME) for rectal cancer results in a significantly higher quality of TME specimen compared to the laparoscopic approach—report of a single-center experience

AimRobotic surgery allows for a better visualization and more precise dissection especially in the narrow male pelvis and mid and lower third of the rectum. However, superiority to laparoscopic TME has yet to be proven. We therefore analyzed short-term outcomes of laparoscopic and robotic low anterior rectal resection for rectal cancer.Patients and methodsFrom 2011 to 2016, 44 robotic (RTME) and 41 laparoscopic (LTME) low anterior rectal resection with total mesorectal excision were performed at a single institution. Specimen quality was assessed and reported by an independent pathologist following international guidelines.ResultsThe groups did not differ significantly regarding gender, age, ASA stage, BMI, and distance of the lower tumor margin from the anal verge. More patients in the RTME group underwent preoperative chemoradiation (43.2 vs. 19.5%, p = 0.019). The quality of the TME specimen was significantly better in the RTME group (complete/nearly complete/incomplete for RTME 97/0/3% and for LTME 78/17/5%, p = 0.03). The conversion rate tended to be lower in the RTME group (7 vs. 17%, p = 0.143). There was no difference in CRM positivity between the groups.ConclusionRobotic surgery is safe and can improve the quality of TME for rectal cancer compared to laparoscopy. Any effect on long-term survival remains to be established.

Roboterassistierte, pyloruserhaltende partielle Duodenopankreatektomie nach Kausch-Whipple

BACKGROUND The surgical treatment of pancreatic head tumours is one of the most complex procedures in general surgery. In contrast to colorectal surgery, minimally-invasive techniques are not very commonly applied in pancreatic surgery. Both the delicate dissection along peri- and retropancreatic vessels and the extrahepatic bile ducts and subsequent reconstruction are very demanding with rigid standard laparoscopic instruments. The 4-arm robotic surgery system with angled instruments, unidirectional movement of instruments with adjustable transmission, tremor elimination and a stable, surgeon-controlled 3D-HD view is a promising platform to overcome the limitations of standard laparoscopic surgery regarding precise dissection and reconstruction in pancreatic surgery. INDICATION Pancreatic head resection for mixed-type IPMN of the pancreatic head. PROCEDURE Robot-assisted, minimally-invasive pylorus-preserving pancreaticoduodenectomy (Kausch-Whipple procedure). CONCLUSION The robotic approach is particularly suited for complex procedures such as pylorus-preserving pancreatic head resections. The fully robotic Kausch-Whipple procedure is technically feasible and safe. The advantages of the robotic system are apparent in the delicate dissection near vascular structures, in lymph node dissection, the precise dissection of the uncinate process and, especially, bile duct and pancreatic anastomosis.

Is there a Benefit from Rescue-Allocated Organs for HCCPatients Staged outside the Milan Criteria?

Objective: For hepatocellular carcinoma (HCC) a 5-year survival rate over 75% is achieved within Milan-criteria (MC), but expanded criteria (UCSF- and Bologna-criteria) show similar survival rates.Management of the waiting list remains controversial and living donation and rescue allocation may help to reduce waiting time for patients outside MC in Germany. Methods: 110 Patients listed for liver transplantation at UKSH Kiel from 1998 - 2014 with HCC were analysed. Assuming that patients outside the MC had a longer waiting time for primary-donor organs, we compared the outcome of patients with rescue-allocated organs outside the MC and primary-allocated organs. Studied parameters were impact of MC, allocation-mode, waiting time, radiological and histological tumour-assessment and the impact of bridging therapy on the outcome after transplantation. Results: Radiological tumour-assessment compared to pathological report of the explant liver differed in 28%. Patients allocated by rescue-allocated donor organs had a significant shorter waiting time, but 5-year tumour free survival was significantly worse compared to primarily allocated organs. Patients within and beyond MC but within UCSF-criteria as well as patients receiving TACE inside and outside MC showed no significant difference in survival rates. Multilocular tumour lesions and a cumulative tumour size >8 cm had a significant impact on 5-year survival and tumour-free survival. Conclusion: Rescue-allocated organs may help to reduce waiting time for patients with a no-progressive tumour disease outside MC. Radiological assessment was not optimal to stratify HCC-patients on the waiting list. Besides MC and TACE standardized radiological assessment, additional parameters and biomarkers could help to improve survival and select patients for transplantation by monitoring the aggressiveness of tumour growth.

Roboterassistierte, minimalinvasive abdominothorakale Ösophagusresektion mit intrathorakaler Anastomose

BACKGROUND Ivor Lewis oesophagectomy is one of the approaches used worldwide for treating oesophageal cancer. The adoption of minimally invasive oesophagectomy has increased worldwide since its first description more than 15 years ago. However, minimally invasive oesophagectomy with a chest anastomosis has advantages. By using a four-arm robotic platform, not only the preparation of the gastric tube and mobilisation of the oesophagus but also the intrathoracic anastomosis of the oesophagogastrostomy can be performed in a comfortable and safe way. INDICATION The indication for oesophageal resection is oesophageal cancer. PROCEDURE The operative procedure comprises robotic-assisted abdominothoracal oesophageal resection with reconstruction by a gastric tube and intrathoracic anastomosis (Ivor Lewis procedure). CONCLUSION Robotic abdominal and thoracic minimally invasive esophagectomy is feasible, and safe with a complete lymph node dissection. Especially the intrathoracic anastomosis of the oesophagogastrostomy can be performed in a comfortable and safe way.