Technology development of hyperthermic pressurized intraperitoneal aerosol chemotherapy (hPIPAC).

BACKGROUND: Optimized drug delivery systems are needed for intraperitoneal chemotherapy. The aim of this study was to develop a technology for applying pressurized intraperitoneal aerosol chemotherapy (PIPAC) under hyperthermic conditions (hPIPAC). METHODS: This is an ex-vivo study in an inverted bovine urinary bladder (IBUB). Hyperthermia was established using a modified industry-standard device (Humigard). Two entry and one exit ports were placed. Warm-humid CO2 was insufflated in the IBUB placed in a normothermic bath to simulate body thermal inertia. The temperature of the aerosol, tissue, and water bath was measured in real-time. RESULTS: Therapeutic hyperthermia (target tissue temperature 41-43 °C) could be established and maintained over 30 min. In the first phase (insufflation phase), tissue hyperthermia was created by insufflating continuously warm-humid CO2. In the second phase (aerosolization phase), chemotherapeutic drugs were heated up and aerosolized into the IBUB. In a third phase (application phase), hyperthermia was maintained within the therapeutic range using an endoscopic infrared heating device. In a fourth phase, the toxic aerosol was discarded using a closed aerosol waste system (CAWS). DISCUSSION: We introduce a simple and effective technology for hPIPAC. hPIPAC is feasible in an ex-vivo model by using a combination of industry-standard medical devices after modification. Potential pharmacological and biological advantages of hPIPAC over PIPAC should now be evaluated.

MRI-guided percutaneous thermoablation as first-line treatment of recurrent hepatic malignancies following hepatic resection: single center long-term experience.

PURPOSE: Hepatic recurrence of liver malignancies is a leading problem in patients after liver resection with curative intention. Thermoablation is a promising treatment approach for patients after hepatic resection, especially in liver-limited conditions. This study aimed to investigate safety, survival, and local tumor control rates of MRI-guided percutaneous thermoablation of recurrent hepatic malignancies following hepatic resection. MATERIAL AND METHODS: Data from patients with primary or secondary hepatic malignancies treated between 2004 and 2018 with MRI-guided percutaneous thermoablation of hepatic recurrence after prior hepatic resection were retrospectively analyzed. Disease-free survival and overall survival rates were calculated using the Kaplan-Meier method. RESULTS: A total of 57 patients with hepatic recurrence (mean tumor size = 18.9 ± 9.1 mm) of colorectal cancer liver metastases (n = 27), hepatocellular carcinoma (n = 17), intrahepatic recurrence of cholangiocellular carcinoma (n = 9), or other primary malignant tumor entities (n = 4) were treated once or several times with MR-guided percutaneous radiofrequency (n = 52) or microwave ablation (n = 5) (range: 1-4 times). Disease progression occurred due to local recurrence at the ablation site in nine patients (15.8%), non-local hepatic recurrence in 33 patients (57.9%), and distant malignancy in 18 patients (31.6%). The median overall survival for the total cohort was 40 months and 49 months for the colorectal cancer group, with a 5-year overall survival rate of 40.7 and 42.5%, respectively. The median disease-free survival was 10 months for both the total cohort and the colorectal cancer group with a 5-year disease-free survival rate of 15.1 and 14.8%, respectively. The mean follow-up time was 39.6 ± 35.7 months. CONCLUSION: MR-guided thermoablation is an effective and safe approach in the treatment of hepatic recurrences in liver-limited conditions and can achieve long-term survival.

Consensus on definition and severity grading of lymphatic complications after kidney transplantation.

BACKGROUND: The incidence of lymphatic complications after kidney transplantation varies considerably in the literature. This is partly because a universally accepted definition has not been established. This study aimed to propose an acceptable definition and severity grading system for lymphatic complications based on their management strategy. METHODS: Relevant literature published in MEDLINE and Web of Science was searched systematically. A consensus for definition and a severity grading was then sought between 20 high-volume transplant centres. RESULTS: Lymphorrhoea/lymphocele was defined in 32 of 87 included studies. Sixty-three articles explained how lymphatic complications were managed, but none graded their severity. The proposed definition of lymphorrhoea was leakage of more than 50 ml fluid (not urine, blood or pus) per day from the drain, or the drain site after removal of the drain, for more than 1 week after kidney transplantation. The proposed definition of lymphocele was a fluid collection of any size near to the transplanted kidney, after urinoma, haematoma and abscess have been excluded. Grade A lymphatic complications have a minor and/or non-invasive impact on the clinical management of the patient; grade B complications require non-surgical intervention; and grade C complications require invasive surgical intervention. CONCLUSION: A clear definition and severity grading for lymphatic complications after kidney transplantation was agreed. The proposed definitions should allow better comparisons between studies.

ANTECEDENTES: La incidencia de complicaciones linfáticas tras el trasplante renal (post-kidney-transplantation lymphatic, PKTL) varía considerablemente en la literatura. Esto se debe en parte a que no se ha establecido una definición universalmente aceptada. Este estudio tuvo como objetivo proponer una definición aceptable para las complicaciones PKTL y un sistema de clasificación de la gravedad basado en la estrategia de tratamiento. MÉTODOS: Se realizó una búsqueda sistemática de la literatura relevante en MEDLINE y Web of Science. Se logró un consenso para la definición y la clasificación de gravedad de las PKTL entre veinte centros de trasplante de alto volumen. RESULTADOS: En 32 de los 87 estudios incluidos se definía la linforrea/linfocele. Sesenta y tres artículos describían como se trataban las PKTL, pero ninguno calificó la gravedad de las mismas. La definición propuesta para la linforrea fue la de un débito diario superior a 50 ml de líquido (no orina, sangre o pus) a través del drenaje o del orificio cutáneo tras su retirada, más allá del 7º día postoperatorio del trasplante renal. La definición propuesta para linfocele fue la de una colección de líquido de tamaño variable adyacente al riñón trasplantado, tras haber descartado un urinoma, hematoma o absceso. Las PKTL de grado A fueron aquellas con escaso impacto o que no requirieron tratamiento invasivo; las PKTL de grado B fueron aquellas que precisaron intervención no quirúrgica y las PKTL de grado C aquellas en que fue necesaria la reintervención quirúrgica. CONCLUSIÓN: Se propone una definición clara y una clasificación de gravedad basada en la estrategia de tratamiento de las PKTLs. La definición propuesta y el sistema de calificación en 3 grados son razonables, sencillos y fáciles de comprender, y servirán para estandarizar los resultados de las PKTL y facilitar las comparaciones entre los diferentes estudios.

[Role of the radiologist in surgery of colorectal liver metastases : What should be removed and what must remain]. / Rolle des Radiologen in der Chirurgie kolorektaler Lebermetastasen : Was soll weg und was muss übrig bleiben.

BACKGROUND: The radical resection of colorectal liver metastases is the only curative option for affected patients. If properly performed, surgery provides the chance of long-term tumor-free survival. OBJECTIVE: Summary of the critical interaction points between radiology and surgery in the planning and performance of (complex) liver resections. RESULTS: There are many interaction points between radiology and surgery in the treatment of patients with colorectal liver metastases. Radiology supports surgery by providing detailed information of the localization of metastases, information on liver inflow and outflow as well as basic information on liver quality and function. Perioperatively, it provides interventional treatment options for postoperative complications as well as ablation of non-resectable metastases. CONCLUSION: Complex liver resections can only be performed properly and successfully after thorough planning by an interdisciplinary board of surgeons, radiologists and associated disciplines.

Comparison of clinical outcome of laparoscopic versus open appendectomy for complicated appendicitis.

BACKGROUND: Laparoscopic appendectomy is now the treatment of choice in uncomplicated appendicitis. To date its importance in the treatment of complicated appendicitis is not clearly defined. METHODS: From January 2005 to June 2013 a total of 1762 patients underwent appendectomy for the suspected diagnosis of appendicitis at our institution. Of these patients 1516 suffered from complicated appendicitis and were enrolled. In total 926 (61 %) underwent open appendectomy (OA) and 590 (39 %) underwent laparoscopic appendectomy (LA). The following parameters were retrospectively analyzed: age, sex, operative times, histology, length of hospital stay, 30-day morbidity focusing on occurrence of surgical site infections, intraabdominal abscess formation, postoperative ileus and appendiceal stump insufficiency, conversion rate, use of endoloops and endostapler. RESULTS: A statistically significant difference in operative time was observed between the laparoscopic and the open group (64.5 vs. 60 min; p = 0.002). Median length of hospitalization was significantly shorter in the laparoscopic group (p < 0.000). Surgical site infections occurred exclusively after OA (38 vs. 0 patients). Intraabdominal abscess formation occurred statistically significantly more often after LA (2 vs. 10 patients; p = 0.002). There were no statistical significances concerning the occurrence of postoperative ileus (p = 0.261) or appendiceal stump insufficiencies (p = 0.076). CONCLUSIONS: The laparoscopic approach for complicated appendicitis is a safe and feasible procedure. Surgeons should be aware of a potentially higher incidence of intraabdominal abscess formation following LA. Use of endobags , inversion of the appendiceal stump and carefully conducted local irrigation of the abdomen in a supine position may reduce the incidence of abscess formation.

Impact of surgical resection extension on outcome for primary well-differentiated thyroid cancer-a retrospective analysis.

BACKGROUND: The surgical resection extension in well-differentiated thyroid cancer is controversially discussed with the possibility of an overtreatment on the one hand against the risk of local disease recurrence. The aim of this study is to evaluate how the surgical resection extension with the adjunction of radioiodine therapy affects postoperative morbidity and the oncologic outcome of patients primarily treated for well-differentiated thyroid cancer. METHODS: All patients undergoing primary surgery for a well-differentiated, non-recurrent thyroid cancer from January 2005 to April 2013 at Tuebingen University Hospital were retrospectively analyzed. RESULTS: Papillary thyroid cancer (PTC) was present in 73 patients (including 27 papillary microcarinoma) and follicular thyroid cancer in 14 patients. Fifty-six of 87 patients (64%) underwent one-stage surgery, of which 26 patients (30%) received simultaneous lymph node dissection (LND). The remaining 31 patients (36%) underwent a two-stage completion surgery (29 patients with LND). Only in three patients a single lymph node metastasis was newly detected during two-stage completion surgery. Patients with LND at either one-stage and two-stage completion surgery had a significant higher rate of transient postoperative hypocalcemia. Postoperative adjuvant radioiodine therapy was performed in 68 of 87 patients (78%). After a median follow-up of 69 months [range 9-104], one local recurrence was documented in a patient suffering from PTC 23 months after surgery. CONCLUSION: No prophylactic two-stage lymphadenectomy should be performed in case of well-differentiated thyroid cancer to avoid unnecessary complication without any proven oncologic benefit.

Pancreas-preserving surgical management of grade-C pancreatic fistulas after pancreatic head resection by external wirsungostomy.

PURPOSE: Completion pancreatectomy for grade-C pancreatic fistula is associated with unacceptably high mortality and therefore this strategy should be reassessed. This study presents an update of our experience with a pancreas-preserving technique in the course of salvage re-laparotomy in terms of closure of the open jejunum via segmental resection and external drainage of the pancreas. METHODS: Between April 2004 and January 2015, 292 pancreaticoduodenectomies (PD) with pancreaticojejunostomy (PJ) were performed. Thirteen patients (5 %) underwent salvage re-laparotomy for symptomatic grade-C fistulas, and clinical data were retrospectively analyzed. RESULTS: In all patients, the preservation of the pancreas remnant and external drainage of the pancreatic juice was feasible. Median hospital stay was 58 days (range, 21-142 days). In 4/13 patients (31 %), further reoperations were necessary. In-hospital mortality was 15 % (2/13). 3/13 patients (23 %) were readmitted and two received inpatient non-surgical treatment. To date re-pancreaticojejunostomy was performed in seven of the remaining 11 patients (63 %) after 168 days in median. In 1/7 patients (14 %), a re-operation after re-PJ was necessary. In one patient, externalization of the pancreas juice was chosen as a definite option. In another patient, secretion ceased spontaneously without stasis and normal endocrine function. Neither before nor after re-anastomosis impairment of endocrine function was observed. CONCLUSIONS: Closure of the intestinum and preservation of the pancreas remnant in grade-C pancreatic fistula is easy to perform and can be categorized as a life-saving procedure. Prevention of total pancreatectomy associated with high morbidity and mortality was achieved in all cases.

[Surgical Management of Peritoneal Surface Malignancy with Respect to Tumour Type, Tumour Stage and Individual Tumour Biology]. / Chirurgische Therapie der peritonealen Metastasierung in Abhängigkeit von Tumorentität, -stadium und -charakteristik(a).

Peritoneal tumour dissemination is still considered as a terminal disease. For the last two decades, cytoreductive surgery (CRS) combined with intraoperative hyperthermic chemotherapy (HIPEC) has been popularised by Paul Sugarbaker almost doubling survival in selected patients compared with systemic chemotherapy alone. Nowadays, this particular treatment protocol is available in comprehensive cancer centres with reasonable mortality and morbidity. However, patient selection is still challenging. In general, CRS and HIPEC is indicated in primary peritoneal tumours such as mesothelioma and pseudomyxoma peritonei as well as in peritoneal metastases derived from gastrointestinal malignancies and ovarian cancers. Since systemic tumour spread is uncommon in patients with peritoneal metastases, peritoneal tumour dissemination was defined as localised disease within the "compartment abdomen". However, CRS and HIPEC are only beneficial as long as complete cytoreduction is achieved (CC-0 or CC-1). Histopathological parameters, the Sugarbaker peritoneal carcinomatosis index (PCI) and general condition of the patient have been established as patient selection criteria. In primary peritoneal cancers, individual tumour biology is the predominant criterium for patient selection as opposed to intraabdominal tumour load in peritoneal metastases derived from gastrointestinal cancers. In gastric cancer, CRS and HIPEC should be restricted to synchronous limited disease because of its biological aggressiveness. In patients with free floating cancer cells without macroscopic signs of peritoneal spread, however, CRS and HIPEC following preoperative "neoadjuvant" chemotherapy preserves chances for cure. So far, there is no general recommendation for CRS and HIPEC by clinical practice guidelines. In the recent S3 guideline for treatment of colorectal cancer, however, CRS and HIPEC have been included as possible treatment options.

Liver fluke-infested graft used for living-donor liver transplantation: case report and review of the literature.

Clonorchiasis is a cholangiopathy caused by foodborne trematode parasites, also known as liver flukes. Clonorchiasis is endemic in a wide geographical area extending from Eastern Europe to Southeast Asia. Infested hosts may remain asymptomatic for decades and consequently their liver can become available as a graft. To date, 20 liver transplantations with liver fluke-infested grafts have been reported in the literature. All of them occurred in Asian countries. We, here, report the first case to our knowledge in the Western world of living-donor liver transplantation (LDLT) with an Opisthorchis felineus-infested graft, and present a review of the literature. A 6-month-old girl with decompensated secondary biliary cirrhosis underwent an LDLT with a left lateral graft infested with O. felineus. After prompt diagnosis and adequate therapy, both donor and recipient had an uneventful postoperative course and long-term follow-up. Liver grafts infested with liver flukes do not pose a contraindication to liver donation from deceased or living donors, provided that a correct diagnosis and treatment are performed in a timely fashion.

[Recurrent Peritoneal Metastases after Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Colorectal Cancer]. / Rezidive nach zytoreduktiver Chirurgie und hyperthermer intraperitonealer Chemotherapie (HIPEC) beim kolorektalen Karzinom.

BACKGROUND: Peritoneal recurrences after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer are challenges in conservative and surgical oncology. METHODS: Surgical concepts are discussed in this review on the basis of the current literature. RESULTS: The majority of patients suffer from recurrent disease after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in colorectal cancer. In most cases, a palliative chemotherapy is performed. Repeated surgery with the aim of complete cytoreduction may be done in selected cases. CONCLUSIONS: New concepts are necessary to treat patients with recurrent disease as early as possible.

Indications and limits for associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). Lessons Learned from 15 cases at a single centre.

INTRODUCTION: The ALPSS procedure has been recently introduced as an alternative to PVE for liver volume augmentation in cases of planned right trisectionectomy with small future RLV and high risk of PHLF. We retrospectively analysed our single centre experience with 15 ALPPS procedures in order to better assess the limits and indications of the procedure. PATIENTS AND METHODS: The following volumetric parameters were evaluated: total liver volume (TLV), remnant liver volume (RLV), remnant liver volume to total liver volume ratio (RLV/TLV), remnant liver volume to body weight ratio (RLV/BWR) and median volume gain. The ALPPS procedure was usually considered when RLV/TLV < 25 % or RLV/BWR < 0.5. The ALPPS procedure consisted of phase 1 (in situ splitting of the liver), interphase (waiting for liver regeneration) and phase 2 (completion of right trisectionectomy). Postoperative complications were reported according to the Dindo-Clavien classification. Patient survival, late complications and tumour recurrence were analysed. RESULTS: Between November 2010 and September 2013, we performed 15 ALPPS procedures in 10 patients with primary liver tumours (5 h-CCA, 4 i-CCA and 1 HCC) and in 5 with CRLM. The preoperative RLV/TLV ratio was 22.6 % (15.7 - 29.2) and the RLV/BWR 0.46 (0.22 - 0.66). After 10 days (range 8 - 16) the RLV/TLV ratio and RLV/BWR increased up to 36.3 % (30 - 59.2 %) and 0.67 (0.5 - 1.2) respectively, with a median volume gain of 87.2 % (23.8 - 161 %). The time interval between phases 1 and 2 was 13 days (9 - 18). An R0 status was reached in 13 patients and R1 in 2. The overall postoperative morbidity was 66.7 %. After phase 1, 8 patients experienced 19 complications and 7 none. After phase 2, 11 patients experienced 36 complications and 4 none. Four patients died postoperatively after 22 days (9 - 36 days) resulting in a postoperative mortality of 28.7 %. After a median follow-up of 17 months (1 - 33), 10 out of 15 patients are still alive (survival rate 66.6 %). Four patients (2 i-CCA, 1 CRLM, 1 HCC) developed tumour recurrences (2 intrahepatic and 2 extrahepatic). One patient with i-CCA died at POM 4 secondary to peritoneal carcinosis. DISCUSSION: The actual high morbidity and mortality rates related to the ALPPS procedure should lead us to a more cautious selection of the candidates for this operation and restriction of the indications through an accurate work-up based on interdisciplinary cooperation among hepatologists, oncologists, radiologists and surgeons.

[Gastrointestinal stromal tumours bigger than 20 cm: experience with imatinib chemotherapy in neoadjuvant intention]. / Gastrointestinale Stromatumore größer als 20 cm: Erfahrungen mit Imatinib in neoadjuvanter Intention.

The size of the primary tumour is considered the most important risk factor for the development of metastasis or local recurrence in case of gastrointestinal stromal tumour (GIST). Until now no prospective data are available in the literature about the role of neadjuvant therapy with Imatinib. Between 2009 and 2012 seven patients with a giant GIST > 20 cm underwent a neadjuvant treatment with Imatinib, a radical operation, followed by an adjuvant therapy. These patients were controlled with regard to peri- and postoperative morbidity and disease-free survival. Two patients were considered not resectable and one patient showed liver metastasis at the time of diagnosis. RECIST responses to the neoadjuvant Imatinib were: 2/7 patients with stable disease, 3/7 partial response, 2/7 partial response with down-staging (resectable disease). Because of the following tumour localisations (6 gastric and 1 rectal), six gastrectomies (one en-bloc with left pancreas) and one Holm operation were performed. The patient with simultaneous liver metastasis developed a tumour progression during the follow-up but the others are still tumour free after 2 years. We detected a significant tumour volume regression due to the neadjuvant chemotherapy in cases of GIST > 20 cm (30 %). Our series showed good results for a neadjuvant therapy in cases of giant GIST with the achievement of 100 % R0 resection without a high morbidity rate (in the literature a tumor size > 10 cm and poor localisation is associated to a high risk of R1 - 2 and high morbidity). Peri- and postoperative morbidity are acceptable and the tumour free survival at 2 years is 85 %.

Transpapillary retrieval of a proximally migrated stent using a three-prong polyp retrieval device in a 2-years-old girl.

Endoscopic retrieval of proximally migrated biliary stents is sometimes challenging. We report on the successful use of a three-prong colon polyp retrieval device in a two year old child.

How much oxidative stress exists without the liver?

BACKGROUND: Oxidative stress (OS) represents an important pathogenetic factor of acute liver failure and chronic liver diseases. To elucidate whether the liver itself is a major source of OS, the present study was performed to assess OS and antioxidant status in an anhepatic porcine model. METHODS: Six pigs underwent a total hepatectomy, five pigs were sham operated. OS and antioxidant status were evaluated by measuring plasma concentrations of malondialdehyde (MDA), xanthine oxidase (XO), superoxide dismutase (SOD) and the ferric reducing ability of plasma (FRAP). They were sampled at the start of the experiment, immediately after surgery, and then at 8 and 16 hours post hepatectomy. RESULTS: Increased concentrations of MDA were observed in anhepatic pigs postoperatively (p < 0.02) and 8 hours after hepatectomy (p < 0.003) compared to controls. XO activity increased soon after hepatectomy (22.6 ±â€Š5.4 mU/L versus 3.3 ±â€Š2.1 mU/L in sham animals, p < 0.03) but returned to normal values in the further course. SOD levels did not change during the observational period in both groups. FRAP values rose significantly in the anhepatic animals compared to control (p < 0.015). A significant positive correlation was observed between MDA levels and FRAP levels (Spearman's ρ = 0.62; p < 0.0001). CONCLUSIONS: These findings show that hepatectomy does not completely prevent the occurrence of OS because the production and regulation of OS are also located outside the liver.

Impact of perioperative immunosuppressive medication on surgical outcome in Crohn's Disease (CD).

INTRODUCTION: Patients with Crohn's disease [CD] carry an 80 - 90 % lifetime risk of undergoing surgery. Many of these patients are on immunosuppressive medication at the time of surgery. The aim of this study was to evaluate the effect of immunosuppression on the surgical outcome in CD patients. METHODS: We retrospectively analyzed 484 consecutive abdominal operations for CD from 1995 to 2008 for surgical complications. RESULTS: A total of 241 operations (= 49.8 %) were performed under perioperative immunosuppression (corticoids and thiopurine). The overall complication rate was 18.6 %, the major complication rate was 8.7 % and the anastomotic leakage rate was 3.3 %. No differences were observed between patients without immunosuppression compared to those with immunosuppression. Patients with colo-rectal resections showed a higher complication rate than patients with small bowel resection independently of immunosuppression. CONCLUSION: Nearly 50 % of the patients undergoing abdominal surgery for CD are receiving immunosuppressive medication during surgery. However, perioperative immunosuppression with corticoids, thiopurine or the combination of both does not significantly alter the surgical complication rate. Therefore the decision of a required surgery should not be delayed due to the fact that the patient is under immunosuppressive medication.

Treatment of recurrent genotype 1 hepatitis C post-liver transplantation: single center experience with telaprevir-based triple therapy.

Recurrent HCV infection post-liver transplantation (post-LT) is still a major challenge in the treatment of hepatitis C virus (HCV) infection. In this retrospective analysis we gathered data about treatment response and safety of all 14 post-LT patients who were treated between 2011 and 2013 at our centre with a telaprevir (TVR)-based triple therapy. Seven out of 14 patients completed the full treatment course of 48 weeks. Five patients achieved a SVR 24, while 3 additional HCV RNA-negative patients are still in follow-up (end of treatment, SVR 12 and 22). Four patients discontinued treatment prematurely due to side effects. A virological non-response at TW 4 was seen in 1 patient. Virological breakthrough was observed in 2 patients at TW 16 and 28, respectively; 1 patient displayed a virological relapse after the end of treatment (EOT). Patients with a complicated course post-LT accumulated most of the severe side effects, largely infections. One patient with cholestatic hepatitis died 11 weeks after discontinuation of treatment due to progressive graft failure. In conclusion, TVR-based triple therapy in post-LT patients reveals an acceptable antiviral efficacy. Unfortunately, severe side effects are frequent and often require therapeutic interventions. Therefore, with the approval of less straining DAA like sofosbuvir in sight, TVR-based triple therapy in post-LT patients should be, if possible avoided.

[Cytoreductive surgery and HIPEC for peritoneal malignancies in children]. / Zytoreduktive Chirurgie und HIPEC bei peritoneal-metastasierten Tumoren im Kindesalter.

Peritoneal tumour dissemination represents an advanced tumour stage and survival rates are usually low. In the past, cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been established in adults leading to increased survival rates in comparison to chemotherapy alone. CRS and HIPEC are indicated in primary peritoneal tumours such as mesothelioma and pseudomyxoma peritonei, and in peritoneal metastases from gastrointestinal and ovarian cancers in adults. The incidence of peritoneal surface malignancies in children seems to be lower than in adults, but the incidence is unknown. Nevertheless, peritoneal carcinomatosis/sarcomatosis may occur in patients suffering from desmoplastic small round cell tumour (DSRCT), soft tissue sarcoma (rhabdomyosarcoma, leiomyosarcoma, GIST or liposarcoma), as well as in patients with gastrointestinal cancers. CRS and HIPEC have been established as a novel treatment option in children suffering from peritoneal carcinomatosis/sarcomatosis in very few centres worldwide. This paper reviews the indications, treatment regimens, and pitfalls of this approach in children.

A non-comparative phase II study of dose intensive chemotherapy with doxorubicin and ifosfamide followed by high dose ICE consolidation with PBSCT in non-resectable, high grade, adult type soft tissue sarcomas.

The objective was to determine the role of dose intensive induction chemotherapy in patients with soft tissue sarcomas (STS) that were considered unresectable. Treatment consisted of 2-3 cycles of doxorubicin (Dox) and ifosfamide (Ifo) followed by high dose chemotherapy with ifosfamide, carboplatin, etoposide (HD-ICE) plus peripheral blood stem cell transplantation (PBSCT). 30 out of 631 consecutive patients, median age 46 years (21-62), with high grade STS were included. 29 patients completed at least 2 cycles of Dox/Ifo. HD-ICE was withheld because of progressive disease (PD) in 5 patients, neurotoxicity in 6 cases, insufficient peripheral blood stem cell (PBSC) mobilization, complete remission (CR) and refusal in 1 patient each. HD-ICE was associated with non-haematological grade III toxicity including emesis, mucositis, fever, neurotoxicity, and transaminase level elevation. Two additional patients attained a partial response after HD-ICE. Overall, 24 of 30 (80%) patients underwent surgery, with complete tumor resections in 19 patients (63% of all patients, 79% of the operated subgroup); however, 2 of these required amputation. After a median follow up period of 50 months in surviving patients (range, 26-120), 5-year PFS and OS rates were 39% and 48%, respectively. Induction chemotherapy plus consolidation HD-ICE is generally feasible, but is associated with significant neurotoxicity. The advantage of HD-ICE over conventional dose chemotherapy plus external beam radiation therapy (EBRT) in non-resectable disease remains unproven.

Successful ganciclovir treatment of primary cytomegalovirus infection containing the UL97 mutation N510S in an intestinal graft recipient.

In solid organ transplantation, human cytomegalovirus (HCMV) is considered to be the most important viral pathogen. We report a case of a CMV R-/D+ small intestine transplant recipient with a primary CMV infection on valganciclovir prophylaxis. Sequencing of the HCMV DNA for drug resistance-associated mutations revealed the UL97 mutation N510S. This mutation has been initially reported to confer ganciclovir resistance. Based on in vitro recombinant phenotyping, this assumption has recently been questioned. Switching the antiviral treatment to an intravenous regimen of ganciclovir eliminated HCMV DNAemia, showing the in vivo efficacy of ganciclovir for the UL97 mutation N510S. Hence, knowledge of drug efficacy is crucial for an adequate choice of antiviral medication, carefully balancing antiviral potency versus the risk of harmful side effects.

The secretion pattern of perivascular fat cells is different from that of subcutaneous and visceral fat cells.

AIMS/HYPOTHESIS: We have previously found that the mass of perivascular adipose tissue (PVAT) correlates negatively with insulin sensitivity and post-ischaemic increase in blood flow. To understand how PVAT communicates with vascular vessels, interactions between perivascular, subcutaneous and visceral fat cells with endothelial cells (ECs) were examined with regard to inflammatory, metabolic and angiogenic proteins. To test for possible in vivo relevance of these findings, circulating levels of the predominant secretion product, hepatocyte growth factor (HGF), was measured in individuals carefully phenotyped for fat distribution patterns. METHODS: Mono- and co-cultures of human primary fat cells with ECs were performed. mRNA expression and protein production were studied using Luminex, cytokine array, RealTime Ready and ELISA systems. Effects of HGF on vascular cells were determined by WST assays. In patients, HGF levels were measured by ELISA, and the mass of different fat compartments was determined by whole-body MRI. RESULTS: In contrast with other fat cell types, PVAT cells released higher amounts of angiogenic factors, e.g. HGF, acidic fibroblast growth factor, thrombospondin-1, serpin-E1, monocyte chemotactic protein-1 and insulin-like growth factor-binding protein -3. Cocultures showed different expression profiles from monocultures, and mature adipocytes differed from pre-adipocytes. HGF was preferentially released by PVAT cells and stimulated EC growth and smooth muscle cell cytokine release. Finally, in 95 patients, only PVAT, not visceral or subcutaneous mass, correlated independently with serum HGF levels (p = 0.03; r = 0.225). CONCLUSIONS: Perivascular (pre-)adipocytes differ substantially from other fat cells with regard to mRNA expression and protein production of angiogenic factors. This may contribute to fat tissue growth and atherosclerotic plaque complications. Higher levels of angiogenic factors, such as HGF, in patients with increased perivascular fat mass may have pathological relevance.