Living-donor parathyroid allotransplantation for therapy-refractory postsurgical persistent hypoparathyroidism in a nontransplant recipient - three year results: a case report.

BACKGROUND: Therapy-refractory persistent hypoparathyroidism after extensive neck surgery is a rare but severe complication. Parathyroid allotransplantation may represent a definitive treatment option. CASE PRESENTATION: A 32-year old female was referred to our hospital with intractable persistent hypocalcemia after neck surgery for papillary thyroid cancer. Despite optimal medical treatment including calcium and vitamin D supplementation and even hormonal replacement therapy hypocalcemic symptoms failed to improve. The quality of life was considered very low. In light of the unsuccessful medical therapy and the young age of the patient parathyroid allotransplantation seemed an attractive treatment option to restore normal calcium homeostasis despite of the need for immunosuppressive therapy after the procedure. Therefore, we performed living-donor allotransplantation of two healthy parathyroid glands to the recipient's left forearm. The surgical intervention was successful. Neither the donor nor the recipient showed any complications. In the postoperative course clinical symptoms of hypocalcemia significantly improved whereas serum calcium and parathyroid hormone (PTH) levels progressively increased into the normal range. Former intense replacement therapy could be discontinued completely in a stepwise fashion. To date, nearly three years after transplantation, the patient remains asymptomatic with normal serum levels of calcium and PTH. CONCLUSION: Successful living-donor parathyroid allotransplantation for postsurgical hypoparathyroidism represents an innovative therapeutic strategy that could provide the definitive treatment in those patients in which the disease is therapy-refractory. The procedure can be justified even in nontransplant recipients. Retrieval of parathyroid glands from healthy donors is feasible and safe.

IRAK-M Expression in Tumor Cells Supports Colorectal Cancer Progression through Reduction of Antimicrobial Defense and Stabilization of STAT3.

Colorectal cancer (CRC) is associated with loss of epithelial barrier integrity, which facilitates the interaction of the immunological microenvironment with the luminal microbiome, eliciting tumor-supportive inflammation. An important regulator of intestinal inflammatory responses is IRAK-M, a negative regulator of TLR signaling. Here we investigate the compartment-specific impact of IRAK-M on colorectal carcinogenesis using a mouse model. We demonstrate that IRAK-M is expressed in tumor cells due to combined TLR and Wnt activation. Tumor cell-intrinsic IRAK-M is responsible for regulation of microbial colonization of tumors and STAT3 protein stability in tumor cells, leading to tumor cell proliferation. IRAK-M expression in human CRCs is associated with poor prognosis. These results suggest that IRAK-M may be a potential therapeutic target for CRC treatment.

Peritoneal carcinomatosis of colorectal cancer is characterized by structural and functional reorganization of the tumor microenvironment inducing senescence and proliferation arrest in cancer cells.

Background : Peritoneal carcinomatosis (PC) is a terminal evolution from primary colorectal cancer (pCRC) associated with poor patient survival. Impact of the immune cell infiltrate on PC pathogenesis is unknown. Therefore, we characterized the immunological tumor microenvironment regarding proliferation, senescence and neovascularization. Methods : Formalin-fixed and paraffin-embedded (FFPE) tissue of PC and pCRC was examined by immunohistochemistry. Cells infiltrating resected tissue were isolated and analyzed by flow cytometry. PCR arrays detected the expression of genes relevant for helper T (TH) cell responses, like TH1, TH2 and TH17 response. Results : PC tumor cells demonstrate significantly lower proliferation rates than pCRC, but show significantly more senescence. PC is surrounded by significantly increased numbers of cytotoxic active Natural Killer (NK) cells, follicular helper T cells (TFH) and B cells, whereas pCRC shows more CD4+ TH cells, CD8+ cytotoxic T (TC) cells, eosinophilic granulocytes, TH17 and regulatory T (Treg) cells. PC is characterized by significantly increased interferon-γ (IFNγ), an upregulation of tumor necrosis factor (TNF) and the NK cell-regulating cytokine interleukin-15 (IL-15). An upregulation of angiogenesis-related genes, like vascular endothelial growth factor-A (VEGF-A), leads to severe neovascularization in PC. Correlations of PC results reveal that elevated numbers of interleukin-17 (IL-17) positive cells are associated with high cancer cell proliferation, whereas high numbers of IFNγ positive cells correlate with more tumor cells in senescence. Conclusion : The cellular immune reaction is modified during metastasis, inducing senescence in PC tumor cells. Immune surveillance in PC is facilitated by NK cells and high levels of IFNγ and TNF. Counteracting this effect, TFH and B cells combined with VEGF-A enhancement promote neovascularization in PC (Illustration 1). During metastasis from primary CRC to PC the immune cell infiltrate changes, accompanied by the induction of senescence in PC cancer cells (marked red): In pCRC, the antitumor immune response is facilitated by CD4+TH cells, CD8+TC cells and PRG2+ eosinophilic granulocytes. The premetastatic niche development is promoted by Treg cells and TH17 cells producing systemic factors like VEGF-A, TGF-ß and TNF. Along with TFH and B cells, as with a pro-tumor immune response, they support metastatic formation and lead to severe neovascularization in PC. This is counterbalanced by the IL-15-induced activation and proliferation of NK cells. The secreted cytokines IFNγ and TNF mediate immunosurveillance.

Strong predictors for alcohol recidivism after liver transplantation: non-acceptance of the alcohol problem and abstinence of <3 months.

OBJECTIVE: Alcohol-toxic liver cirrhosis (ALC) is one of the main indications for liver transplantation (LT). The aim of the study is to define predictors for alcohol recidivism and to identify the outcome and quality of life of such patients. MATERIAL AND METHODS: From March 2003 to July 2009, 226 patients underwent LT in our centre. In 53% liver cirrhosis was caused by alcohol abuse (sole/cofactor). Outcome and alcohol recidivism were assessed using patients' records, laboratory tests and interviews (patient, family members and family doctor). Furthermore, patients received an SF-36 quality of life and a self-designed questionnaire anonymously. RESULTS: Mean follow-up after LT was 31 + 23 months. The 5-year survival rate after LT in patients with ALC was significantly better compared to patients with other indications (78 vs. 64%; p = 0.016). Quality of life of both patient groups was comparable. After LT, alcohol recidivism rate was 16%. Patients with an alcohol abstinence of <3 months before LT had a significantly higher (p = 0.012) rate of alcohol recidivism in comparison to those with an abstinence of >3 months. Another predictor for alcohol recidivism was the patients' non-acceptance of having an alcohol problem before LT (p = 0.001). CONCLUSIONS: ALC is a good indication for LT. An alcohol abstinence of <3 months before LT and a non-acceptance of having an alcohol problem are strong predictors for alcohol recidivism after LT.

Workload and quality of life of surgeons. Results and implications of a large-scale survey by the German Society of Surgery.

BACKGROUND: Quality of life is of vital importance for patients undergoing surgery. However, little is known about the quality of life of surgeons who are facing a stressful and dramatically changing working environment. For this reason, this large-scale study investigated the quality of life (QL) of surgeons in Germany in the context of occupational, private, and system-related risk factors. METHODS: The study population consisted of attendees (surgeons, non-surgical physicians, medical students) of the nine major annual conferences of the German Society of Surgery between 2008 and 2009. Participants filled in a single questionnaire including study-specific questions (demographic variables, professional position, and occupational situation) and a standardized quality of life instrument (Profiles of quality of life of the chronically ill, PLC). Surgeons' responses with regard to their professional situation and their quality of life were contrasted with those of the two controls (non-surgical physicians, medical students). Furthermore, PLC scores were compared with German population reference data and with reference data of several patient groups. RESULTS: Individuals (3,652) (2,991 surgeons, 561 non-surgical physicians, 100 medical students) participated in this study. The average age of surgeons and non-surgeons was in the low forties. In terms of professional qualifications, the majority of surgeons were residents (30%) and the majority of non-surgeons consultants in private practice (38%). Sixty-eight percent of the surgeons, only 39% of the non-surgeons worked more than 60 h per week on average (p < 0.001). Surgeons regarded their administrative workload as high (67% vs. controls 57%, p < 0.001). Surgeons reported restrictions on their private and family life due to work overload, more so than non-surgeons (74% vs. 59%, p < 0.001). Of the surgeons, 40% regarded their quality of life as worse than that of the general public (non-surgeons, 22%; p < 0.001). A third (32%) of the surgeons considered their quality of life even lower than that of their patients (non-surgeons, 17%; p < 0.001). Responses to the PLC quality of life questionnaire confirmed these results, showing score values lower than those of the German population reference data and of several patient groups. Multiple regression analyses showed that the strongest and most consistent influence variable for a low quality of life on all eight quality of life scores were restrictions in private life (range of standardized beta weights beta = 0.259 to 0.325), hierarchical and uncooperative working environment (beta = 0.057 to 0.235), lack of opportunities for continuing education (beta = 0.108 to 0.161), and inadequate salary (beta = 0.036 to 0.172). CONCLUSIONS: Improving the working conditions for surgeons requires a concerted action of all relevant parties, including hospital administrators, insurance companies, and the German Society of Surgery. The present study clearly identified measures that should be taken.

Outcome of patients with ischemic-like cholangiopathy with secondary sclerosing cholangitis after liver transplantation.

BACKGROUND AND AIMS: Sclerosing cholangitis in critically ill patients (SC-CIP) with sepsis and acute respiratory distress syndrome (ARDS) is a cholestatic liver disease with a rapid progression to liver cirrhosis and hepatic failure. Data on outcome of these patients after liver transplantation (LT) are sparse. PATIENTS AND METHODS: Eleven patients (46 ± 12 years; mean labMELD-score: 27 ± 7) with SC-CIP underwent LT. Six patients had severe polytrauma with multiple bone fractures, sepsis and ARDS. Five non-traumatic patients acquired SC-CIP during long-term intensive-care-unit stays due to sepsis and ARDS. Time to diagnosis, the microbiologic results and the survival rates after LT were evaluated. RESULTS: SC-CIP was diagnosed by endoscopic retrograde cholangiopancreatography (ERCP) within 3 ± 1 months after manifestation of cholestasis and histologically confirmed in explanted livers. The predominant microorganisms isolated in bile were: Enterococcus and Candida albicans. Mean follow-up after LT was 28 ± 20 months. One female patient (non-traumatic) died due to sepsis 26 days after LT. All other patients left the hospital alive, but two (non-traumatic) patients died from sepsis, and one (traumatic) patient died in a hemorrhagic shock, thereafter. Seven of 11 patients (5 with polytrauma) are still alive and have a good quality of life. The survival of the SC-CIP patients after LT was comparable with that of patients transplanted due to alcoholic liver cirrhosis. CONCLUSION: SC-CIP develops rapidly within several months. Enterococcus and C. albicans were the main isolated microorganisms in the bile. Sepsis was the main cause of death after LT. Overall, SC-CIP is a good indication for LT in selected patients.

Patient selection for a curative approach to carcinomatosis.

There is an increasing evidence showing that in selected patients with peritoneal carcinomatosis cytoreductive surgery and hyperthermic intraperitoneal chemotherapy may improve survival. Adequate patient selection is crucial to obtain a complete macroscopic cytoreduction, a leading predictor of patient outcome. However, selection is a very difficult process and is associated with a significant learning curve. Many selection criteria have to be assessed in each patient: performance status, comorbiditites, response to previous chemotherapies, histology grading, and presence of extra-abdominal or liver metastases, small bowel involvement, and tumor volume assessed by the peritoneal cancer index. All these factors have to be discussed interdisciplinary and with the patient to create an individualized treatment strategy. It is difficult to decide the relative importance of each selection criteria. However, completeness of cytoreduction, tumor volume, and histology grading are most important in many multivariate analysis independent prognostic factors. For appropriate selected patients with peritoneal carcinomatosis arising from appendiceal and colon cancer, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy should be considered standard of care.

Safety of gastric resections during cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal carcinomatosis.

BACKGROUND: Cytoreductive surgery (CRS) including gastric resection combined with hyperthermic intraperitoneal chemotherapy (HIPEC) can improve the prognosis of selected patients with peritoneal surface malignancies. Perioperative morbidity of this aggressive treatment strategy is high; however, overall mortality can be low in specialized centers. The aim of this study was to assess the safety of gastric resections with anastomosis during CRS and HIPEC. METHODS: Between 2005 and 2008, 204 patients underwent CRS and HIPEC at our tertiary referral centre. Of these, 37 procedures (male/female 24/13, median age 55 years) included gastric resections. The clinical data of all patients were introduced into a database and analyzed with respect to the morbidity associated with the gastric resections. RESULTS: Of all patients included, 16 had pseudomyxoma peritonei, 11 gastric carcinoma, 4 ovarian carcinoma, 3 malignant peritoneal mesothelioma, and 3 colon carcinoma. Twenty-seven patients had previous surgery (n = 22) and/or systemic chemotherapy (n = 18). Fifteen total gastrectomies, 3 subtotal gastrectomies, 12 distal gastrectomies, and 7 gastric wedge resections were performed during CRS. The overall postoperative morbidity was 45%; main surgical complications were pancreatitis (n = 6), abdominal abscess (n = 4), bile leakage (n = 2), and digestive fistula (leakage of ileorectostomy and small bowel perforation) (n = 2). However, no complications occurred at the site of the esophageal anastomosis (n = 15), gastric anastomosis (n = 15) or gastric suture (n = 7). No patient died postoperatively during the hospitalization period. CONCLUSIONS: CRS in combination with HIPEC is associated with high postoperative morbidity; however, anastomosis following total or subtotal gastrectomy is safe in experienced centers. No leakages related to gastric resections occurred in this high-risk patient group.

Intraportal injection of porcine multipotent mesenchymal stromal cells augments liver regeneration after portal vein embolization.

UNLABELLED: Portal vein embolization (PVE) can be used prior to liver surgery to increase the volume of the remaining liver tissue after an extensive resection. However, the application of PVE is limited and new strategies to augment liver regeneration by cellular therapy are promising alternatives. MATERIALS AND METHODS: The influence of syngeneic multipotent mesenchymal stromal cells (MSC) on liver regeneration was analysed after the ligation of the right portal vein branches in a porcine model, closely mimicking the situation of human surgery. Liver regeneration was monitored by ultrasonography, immunohistological analysis and serum biochemistry. RESULTS: The volume of the contra-lateral, non-ligated liver lobe increased in all piglets after portal vein ligation. This hyperplasia occurred earlier and was more pronounced in those piglets receiving MSC infusions as compared to non-treated controls. Biochemical liver function was stable in all pigs. Only solitary transplanted MSC were detected in recipient livers two weeks after the infusion. CONCLUSION: The infusion of porcine MSC into the portal vein in a setting of liver regeneration after surgical resection leads to accelerated and augmented hyperplasia. This effect is most likely due to bystander effects of the transplanted MSC.

Dual inhibition of Raf and VEGFR2 reduces growth and vascularization of hepatocellular carcinoma in an experimental model.

BACKGROUND AND AIMS: Activation of the mitogen-activated protein kinase-extracellular-signal-regulated kinase (ERK) pathways plays an important role in the progression of hepatocellular carcinoma (HCC). Importantly, Raf kinases are principal effectors within this oncogenic signaling cascade. We hypothesized that concomitant inhibition of Raf and vascular endothelial growth factor receptor 2 (VEGFR2) will affect tumor growth and angiogenesis of HCC. MATERIALS AND METHODS: Human HCC cell lines, endothelial cells (EC), and vascular smooth muscle cells (VSMC) were used. For blocking Raf kinase and VEGFR2, the small molecule inhibitor NVP-AAL881 (Novartis, USA) was used. Activation of signaling intermediates was assessed by Western blotting, and changes in cell motility were evaluated in migration assays. Effects of NVP-AAL881 on HCC growth were determined in a subcutaneous tumor model. RESULTS: NVP-AAL881 disrupted activation of ERK and STAT3 in HCC cells and reduced cancer cell motility. In addition, the migration of ECs and VSMC was also significantly impaired. In ECs, HCC-conditioned media-induced activation of STAT3 was diminished by NVP-AAL881 treatment. In vivo, NVP-AAL881 significantly reduced tumor growth, CD31-vessel area, and numbers of BrdU-positive proliferating tumor cells. CONCLUSIONS: Combined inhibition of Raf and VEGFR2 disrupts oncogenic signaling and efficiently reduces tumor growth and vascularization of HCC. Hence, this strategy could prove valuable for therapy of HCC.

Delayed visceral arterial hemorrhage following Whipple's procedure: minimally invasive treatment with covered stents.

BACKGROUND: Delayed visceral arterial hemorrhage caused by inflammatory vessel erosion represents a rare but life-threatening complication after pancreatic head resection. Therapeutic options include reoperation or endovascular minimally invasive techniques such as embolization or stent graft placement. The present article describes our experiences with implantation of newly developed low-profile stent grafts. METHODS: The findings of four patients with delayed visceral arterial hemorrhage are described. All patients were treated with placement of low-profile stent grafts. The patients' medical records, radiological reports, and images were retrospectively reviewed. Technical success was defined as immediate cessation of hemorrhage. Clinical success was defined as hemodynamic stability. RESULTS: A total of seven stent grafts were implanted in four arteries. In detail, one stent graft was placed in the splenic artery of the first and second patients. In the third patient one stent graft was initially implanted in the common hepatic artery. The patient developed recurrent hemorrhages of the common hepatic artery, treated one time surgically and two times by deployment of a second and third stent graft. In the fourth patient two stent grafts were placed in the proper hepatic artery. Technical and clinical success was achieved at every procedure. Apart from recurrent hemorrhage of patient No. 3 there were no major complications. CONCLUSIONS: Minimally invasive therapy using low-profile stent grafts is an effective and safe procedure for the treatment of delayed visceral arterial hemorrhage following Whipple's procedure. The technique is a promising alternative to standard procedures such as surgical repair or embolization.

Inhibition of apoptosis reduces immunogeneic potential of adenoviral-treated syngeneic liver grafts.

Effects of adenoviral therapy and reduced apoptosis on immune response were investigated in a rat liver transplantation model after prolonged ischemia-reperfusion. Liver donors were treated i.v. either with an adenoviral construct, expressing bcl-2, green-fluorescent-protein, or doxycyclin. Intrahepatic apoptosis was assessed by terminal transferase dUTP nick end labeling assay. The intrahepatic presence of CD4, CD8a, CD163, immunoglobulin (Ig)beta, tumor necrosis factor (TNF)-alpha and myeloperoxidase (MPO) was quantified by realtime polymerase chain reaction at 24 hours and seven days after transplantation. Bcl-2 expression abrogated the TNF-alpha elevation and reduced apoptosis of hepatocytes and sinusoidal endothelial cells as compared to advCMV green fluorescent protein. No effects on CD4, CD8a, CD163 and MPO expression were noticed in bcl-2 pretreated livers, whereas Igbeta was slightly enhanced compared to controls. Adenoviral infected liver grafts trigger an immune response but reduced apoptosis resulted in down-regulation of TNF-alpha. Thus, bcl-2 transfer might simultaneously reduce graft ischemia reperfusion injury and immunogenicity.

Total mesorectal excision for middle and lower rectal cancer: a single institution experience with 337 consecutive patients.

BACKGROUND AND OBJECTIVES: There have been reports on improved prognosis after TME for middle and lower rectal cancer. No prospective randomized studies have yet been performed. This is a large single institution series evaluating its own results of TME. METHODS: This retrospective study analyses data of 337 patients with middle and lower rectal cancer, treated with either curative or palliative intention between 1990 and 1998. RESULTS: Of all patients, 212 had lower rectal and 125 middle rectal carcinomas. The rate of rectal resections with TME was 96%. A total of 223 patients were treated by anterior rectal resection; 92 patients had to undergo abdomino-perineal resection. Ten patients were operated by a Hartmann resection. Postoperative morbidity was 35% with a leakage rate of 9%. Postoperative mortality was 4%. The rate of local recurrence was 8.6%. The 5-year survival rate after curative resection was 69.3%. The multivariate analysis outlined the tumor stage as independent prognostic factor. CONCLUSIONS: In our experience, TME is feasible with acceptable postoperative morbidity and low mortality. The local recurrence rate can be decreased to lower than 10%. The almost 70% 5-year survival rate indicates a clear benefit for the patients. These findings recommend TME as standard procedure for middle and lower rectal cancer.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal carcinomatosis from ovarian cancer.

BACKGROUND: In selected patients with peritoneal carcinomatosis from ovarian cancer prognosis can be improved by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: Between September 1995 and February 1999, 19 patients (mean age 52 years, range 30-72 years) with peritoneal carcinomatosis from primary or recurrent epithelial ovarian carcinoma were operated with the aim of complete macroscopical cytoreduction. Surgery was followed by intraoperative HIPEC. The data was analyzed retrospectively. RESULTS: Eleven patients had recurrent and 8 primary ovarian cancer. The median progression free interval was 18 months (range 6-36 months). Macroscopically complete cytoreduction was achieved in 9 patients. Cisplatin (n = 16) or mitoxantrone (n = 3) were used for the intraoperative chemotherapy. The median intraabdominal inflow temperature was 41.5 degrees C. Complications occurred in seven patients. Most frequent complications were anastomotic leakage (2/19) and intraabdominal abscess formation (2/19). One patient died postoperatively. The mean (+/- SD) overall survival time was 33(+/- 6) months with a 5-year survival rate of 15%. The survival was found to be influenced by the completeness of cytoreduction (44 +/- 11 vs. 25 +/- 6 months, p = 0.40), tumor volume (54 +/- 10 versus 16 +/- 4, p = 0.002) and presence of lymph node (38 +/- 8 vs. 20 +/- 8 months, p= 0.2) or liver metastases (51 +/- 9 vs. 21 +/- 6 months, p = 0.06). CONCLUSIONS: Cytoreductive surgery combined with HIPEC is feasible and is associated with a reasonable morbidity and mortality. Complete cytoreduction may improve survival in select group of patients with low tumor volume and no organ metastases.