First Clinical Safety and Feasibility Data of Whole-body Hyperthermia Pressurized Intraperitoneal Aerosol Chemotherapy (WBH-PIPAC) for Peritoneal Surface Malignancies.

BACKGROUND/AIM: This study evaluated the feasibility and safety of whole-body hyperthermia pressurized intraperitoneal aerosol chemotherapy (WBH-PIPAC) in patients with peritoneal surface malignancies. PATIENTS AND METHODS: This study retrospectively analyzed a database of 28 patients who had received one cycle of normothermic PIPAC prior to repetitive WBH-PIPACs. WBH (39-40°C) was induced using a Water-filtered infrared A device. Doxorubicin plus cisplatin or oxaliplatin was nebulized into a constant capnoperitoneum of 20 mmHg for 30 min at doses of 6.0 mg, 30.0 mg, or 120 mg per m2 body surface area, respectively. The primary outcome measures were feasibility and perioperative complications. RESULTS: The median age was 62 years (range=45-78 years). Primary tumor sites included the upper gastrointestinal tract (n=9), colon/rectum (n=7), hepato-pancreato-biliary system (n=3), peritoneum (n=2), ovaries (n=2), and unknown primary (n=5). The induction of WBH failed in one patient (6 liters ascites). After a median warming period of 95 min (53-117 min), the median rectal temperature (Trec) was 39.5°C (39.2-39.9°C). No hyperthermia-related side effects were observed. Twenty-seven patients received 50 WBH-PIPACs. The median time of therapeutic capnoperitoneum and treatment time with Trec ≥39°C was 39 min (37-43 min) and 66 min (53-69 min), respectively. The overall rate of postoperative procedure-related complications was 9/50, including seven grade I and two grade II complications. There were no grade III-V complications. CONCLUSION: In a highly selected group of patients, the feasibility and perioperative safety of WBH-PIPAC was comparable to normothermic PIPAC.

Safety and Feasibility of High-Pressure/High-Dose Pressurized Intraperitoneal Aerosol Chemotherapy (HP/HD-PIPAC) for Primary and Metastatic Peritoneal Surface Malignancies.

OBJECTIVE: The aim of this study was to evaluate the feasibility and perioperative safety of high-pressure/high-dose pressurized intraperitoneal aerosol chemotherapy (HP/HD-PIPAC) to manage peritoneal surface malignancies (PSM). METHODS: Retrospective analysis of a prospective database of about 130 consecutive patients scheduled for HP/HD-PIPACs for PSM. Doxorubicin plus cisplatin (PIPAC-C/D) or oxaliplatin (PIPAC-Ox) were nebulized into a constant capnoperitoneum of 20 mmHg at doses of 6, 30, or 120 mg/m2 of body surface area (BSA). Outcome criteria were perioperative complications (Clavien-Dindo). RESULTS: The median age of patients was 62 years (range 9-82), and the primary tumor site was of colorectal (CRC), upper gastrointestinal tract (UGI), unknown primary (CUP), malignant epithelioid mesothelioma of the peritoneum (MPM), hepato-pancreatic-biliary tract (HPB), and other origin in 30 (23.1%), 27 (20.8%), 16 (12.3%), 16 (12.3%), 6 (4.6%), and 35 (26.9%) patients, respectively. Abdominal access failed for a first, second, third, and fourth or more HP/HD-PIPAC in 12/130 (9.2%), 4/64 (6.3%), 6/40 (15.0%), and 2/33 (6.1%) patients. A total of 243 procedures were performed in 118 patients. No intraoperative complications related to increased capnoperitoneal pressure occurred, but an intraoperative bleeding complication was observed in 1/243 (0.4%) patients. The overall rate of postoperative procedure-related complications was 19.3% (47/243), while 15.3% (37/243), 1.6% (6/243), 1.6% (1/243), 0.4% (1/243), and 0.4% (1/243) were Grade I, II, III, IV, and V complications, respectively. CONCLUSIONS: Perioperative complications of HP/HD-PIPAC are comparable with standard pressure/dose PIPAC treatment protocols. Prospective studies are warranted to examine potential improvement in therapy outcomes.

Scintigraphic peritoneography reveals a non-uniform 99mTc-Pertechnetat aerosol distribution pattern for Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) in a swine model.

BACKGROUND: Although recent data are contradictory, it is still claimed that Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) would deliver an aerosol which distributes homogeneously throughout the entire abdominal cavity. METHODS: 99mTc-Pertechnetat was administered in four postmortem swine using either PIPAC or liquid intra-peritoneal chemotherapy (IPC). The animals were examined by planar scintigraphy and SPECT/CT. Planar distribution images were divided into four regions of interest (ROIs: right/left upper and lower abdominal quadrant). SPECT/CT slices were scanned for areas of intense nuclide accumulation ("hot spots"). The percentage of relative distribution for planar scintigraphy was calculated by dividing the summed individual counts of each ROI by total counts measured in the entire abdominal cavity. The relative distribution of the "hot spots" was analyzed by dividing the counts of the local volume of interest (VOI) by the summed volume counts measured in the entire abdominal cavity. RESULTS: In all four animals, planar scintigraphy showed inhomogeneous nuclide distribution. After PIPAC only 8-10% of the delivered nuclide was detected in one ROI with a mean deviation of 40% and 74% from a uniform nuclide distribution pattern. In all animals, SPECT/CT revealed "hot spots" beneath the PIPAC Micropump, catheter tip, and in the cul-de-sac region which comprise about 25% of the total amount of delivered nuclide in 2.5% of the volume of the entire abdominal cavity. CONCLUSIONS: Our present data indicate that the intra-abdominal aerosol distribution pattern of PIPAC therapy is non-homogeneous and that the currently applied technology has still not overcome the problem of inhomogeneous drug distribution of IPC.

Cytotoxic effect of different treatment parameters in pressurized intraperitoneal aerosol chemotherapy (PIPAC) on the in vitro proliferation of human colonic cancer cells.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been recently reported as a new approach for intraperitoneal chemotherapy (IPC). By means of a patented micropump, the liquid chemotherapy is delivered into the peritoneal cavity as an aerosol which is supposed to achieve "gas-like" distribution. However, recent data report that the fraction of the submicron aerosol (gas-like) is less than 3 vol% of the total amount of aerosolized chemotherapy. Until today, possible modifications of treatment parameters during PIPAC with the aim of improving therapeutic outcomes have not been studied yet. This study aims to establish an in vitro PIPAC model to explore the cytotoxic effect of the submicron aerosol fraction and to investigate the impact of different application parameters on the cytotoxic effect of PIPAC on human colonic cancer cells. METHODS: An in vitro model using HCT8 colon adenocarcinoma wild-type cells (HCT8WT) and multi-chemotherapy refractory subline (HCT8RT) was established. Different experimental parameters such as pressure, drug dosage, time exposure, and system temperature were monitored in order to search for the conditions with a higher impact on cell toxicity. Cell proliferation was determined by means of colorimetric MTT assay 48 h following PIPAC exposures. RESULTS: Standard operational parameters applied for PIPAC therapy depicted a cytotoxic effect of the submicron aerosol fraction generated by the PIPAC micropump. We also observed that increasing pressure significantly enhanced tumor cell toxicity in both wild-type and chemotherapy-resistant cells. A maximum of cytotoxicity was observed at 15 mmHg. Pressure >15 mmHg did not show additional cytotoxic effect on cells. Increased oxaliplatin dosage resulted in progressively higher cell toxicity as expected. However, in resistant cells, a significant effect was only found at higher drug concentrations. Neither an extension of exposure time nor an increase in temperature of the aerosolized chemotherapy solution added an improvement in cytotoxicity. CONCLUSIONS: In this in vitro PIPAC model, the gas-like PIPAC aerosol fraction showed a cytotoxic effect which was enhanced by higher intra-abdominal pressure with a maximum at 15 mmHg. Similar findings were observed for drug dose escalation. A phase I dose escalation study is currently performed at our institution. However, increasing the intra-abdominal pressure might be a first and simple way to enhance the cytotoxic effect of PIPAC therapy which needs further clinical investigations.

Technical description of the microinjection pump (MIP®) and granulometric characterization of the aerosol applied for pressurized intraperitoneal aerosol chemotherapy (PIPAC).

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is gaining acceptance in clinical practice, but detailed information about the microinjection pump (MIP®), the generated aerosol and drug distribution is missing. ANALYTICAL METHODS: Ex vivo granulometric analyses by means of laser diffraction spectrometry were performed for MIP® aerosol characterization. Beside the standard operation conditions, the impact of the volumetric liquid flow rate on the aerosol characteristics was investigated with different liquids. Granulometric results as well as the local drug distribution were verified by ex vivo gravimetric analyses. On the basis of determined MIP® characteristics, the aerosol droplet size, which is necessary for a homogenous intra-abdominal drug distribution, was calculated. RESULTS: Granulometric analyses showed that the MIP® aerosol consists of a bimodal volume-weighted particle size distribution (PSD3) with a median droplet diameter of x 50,3 = 25 µm. Calculations reveal that the droplet size for a homogenous intra-abdominal drug distribution during PIPAC therapy should be below 1.2 µm. We show that >97.5 vol% of the aerosolized liquid is delivered as droplets with ≥3 µm in diameter, which are primarily deposited on the surface beneath the MIP® by gravitational settling and inertial impaction. These findings were confirmed by ex vivo gravimetric analyses, where more than 86.0 vol% of the aerosolized liquid was deposited within a circular area with a diameter of 15 cm. CONCLUSIONS: The granulometric aerosol properties, as well as the aerodynamic conditions achieved by standard MIP® operation, do not support the idea of widespread or homogenous drug distribution in the abdominal cavity.

Hyperthermic intracavitary nanoaerosol therapy (HINAT) as an improved approach for pressurised intraperitoneal aerosol chemotherapy (PIPAC): Technical description, experimental validation and first proof of concept.

Background: The delivery of aerosolised chemotherapeutic substances into pressurised capnoperitonea has been reported to be more effective than conventional liquid chemotherapy for the treatment of peritoneal carcinomatosis. However, recent reports reveal limitations of the currently available technology. Material and Methods: A novel approach for pressurised intraperitoneal aerosol chemotherapy (PIPAC), called hyperthermic intracavitary nanoaerosol therapy (HINAT), based on extracavitary generation of hyperthermic and unipolar charged aerosols, was developed. The aerosol size distribution, the spatial drug distribution and in-tissue depth penetration of HINAT were studied by laser diffraction spectrometry, differential electrical mobility analysis, time of flight spectrometry, scintigraphic peritoneography and fluorescence microscopy. All experiments were performed contemporaneous with conventional PIPAC for the purpose of comparison. Furthermore, a first proof of concept was simulated in anesthetised German Landrace pigs. Results: HINAT provides a nanometre-sized (63 nm) unipolar-charged hyperthermic (41 °C) drug aerosol for quasi uniform drug deposition over the whole peritoneum with significantly deeper drug penetration than that offered by conventional PIPAC.

Distribution pattern and penetration depth of doxorubicin after pressurized intraperitoneal aerosol chemotherapy (PIPAC) in a postmortem swine model.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel approach delivering intraperitoneal chemotherapy by means of a pressurized aerosol. This study was conducted to evaluate the distribution pattern of doxorubicin in the abdominal cavity after PIPAC in a postmortem swine model. METHODS: Doxorubicin was aerosolized through a Micropump© (MIP) into the peritoneal cavity of two swines at a pressure of 12 mm Hg CO2 and 32 °C. To measure the distribution of the drug, 9 different positions within the abdominal cavity were sampled. In-tissue doxorubicin penetration was evaluated using fluorescence microscopy on frozen thin sections. RESULTS: A maximum of drug penetration was observed in the area around the MIP. The penetration in the small intestine reached a depth of 349 ± 65 µm. Penetration depth in the right upper abdomen and left upper abdomen were 349 ± 65 and 140 µm ± 26 µm, respectively. Distant areas to the MIP showed variable penetration rates between 50 and 150 µm. CONCLUSIONS: Doxorubicin reached all areas within the peritoneum. Highest penetration rates were measured in the area around the Micropump. Further studies are warranted to evaluate and optimize the distribution and penetration of cytotoxic agent into the tissue after PIPAC.

Evaluating the Effect of Micropump© Position, Internal Pressure and Doxorubicin Dosage on Efficacy of Pressurized Intra-peritoneal Aerosol Chemotherapy (PIPAC) in an Ex Vivo Model.

BACKGROUND/AIM: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel clinical approach to the treatment of peritoneal carcinomatosis. A well-established, not anatomic ex vivo PIPAC model was used to investigate the influence of changes in internal pressure, distance of the Micropump(©) (MIP) to the distributing surface and the drug concentration on the penetration depth of doxorubicin in the target tissue. MATERIALS AND METHODS: Doxorubicin was aerosolized in an ex vivo PIPAC model using a hermetic container system mimicking the abdominal cavity. Fresh post-mortem swine peritoneum was cut into proportional samples. Tissue specimens were spatially placed at 4 different spots within the box: P1, on the distributing surface of the box, directly opposite to MIP; P2, on the side wall of the box; P3, on the ceiling of the box; P4, on the distributing surface with a partial cover. Impact of changes in the following parameters were analyzed and compared with clinically established values (CEVs) at our center: pressure (CEV=12 mmHg), distance of the MIP from the distributing surface (CEV=8 cm) and doxorubicin concentration (CEV=3 mg/50 ml). In-tissue doxorubicin penetration depth was measured using fluorescence microscopy on frozen thin sections. RESULTS: Tissue positioning in the box had a significant impact on drug penetration after PIPAC with CEV. Under CEV conditions, the highest drug penetration depth was observed in the tissue placed on the distributing surface directly opposite to the MIP (P1: 351 µm, P2: 77 µm, P3: 66 µm, P4: 34 µm). A closer positioning of the MIP lead to a significantly higher mean depth penetration of doxorubicin in the P1 in contrast to other samples in which a reduced drug penetration was observed (1 cm vs. 8 cm distance from MIP to the distributing surface, P1 at 1 cm: 469 µm vs. P1 at 8 cm: 351 µm, p<0.0001; P2 at 1 cm: 25 µm vs. P2 at 8 cm: 77 µm, p<0.0001; P3 at 1 cm: 21 µm vs. P3 at 8 cm: 66 µm, p<0.001; P4 at 1 cm: 13 µm vs. P4 at 8 cm: 39 µm, p=0.021). Higher doxorubicin concentrations led to a highly significant increase of drug penetration in P1 (1 cm vs. 8 cm, p<0.0001), but only a little significant increase in other samples. An increase of internal pressure did not show a significant increase in penetration depth of doxorubicin. CONCLUSION: Our ex vivo data suggest that a higher pressure does not increase the penetration deepness of doxorubicin. Higher drug dosage and a closer positioning of the MIP toward the target lead to a higher penetration of doxorubicin within the samples. A more homogeneous penetration within all targets cannot be achieved by changing drug concentration, position of the nozzle or pressure increase.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) as a neoadjuvant therapy before cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel drug delivery system able to induce regression of peritoneal metastasis (PM) in the salvage situation. The aim of this study was to determine the clinical characteristics, tumor histology, and extent of disease of the patients having undergone cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) after "neoadjuvant" PIPAC. METHODS: This study was performed at a single institution, tertiary center. In a prospective registry, retrospective analysis was done. PIPAC indication was restricted to patients in the salvage situation who were not eligible for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). RESULTS: Nine-hundred sixty-one PIPAC sessions were successfully performed in 406 patients: 21 patients (5.2 %) were scheduled for CRS and HIPEC. Twelve of these patients had a low PCI (mean 5.8 ± 5.6). The remaining nine patients showed an advanced peritoneal disease (mean PCI 14.3 ± 5.3) at initial laparoscopy. After repeated PIPAC (mean number of cycles 3.5 ± 0.9), radiological tumor regression was observed in 7/9 patients and major histological regression was observed in 8/9 patients, so that secondary CRS and HIPEC became possible. CONCLUSIONS: PIPAC might be used as a neoadjuvant therapy before CRS and HIPEC in order to improve the outcome of CRS and HIPEC, to select patients with chemosensitive, biologically favorable tumors, to extent the indications of CRS and HIPEC in the presence of diffuse small bowel involvement, and to reduce the extent of cytoreductive surgery.

Effect of Irradiation on Tissue Penetration Depth of Doxorubicin after Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) in a Novel Ex-Vivo Model.

BACKGROUND: This study was performed to assess the impact of irradiation on the tissue penetration depth of doxorubicin delivered during Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC). METHODS: Fresh post mortem swine peritoneum was cut into 10 proportional sections. Except for 2 control samples, all received irradiation with 1, 2, 7 and 14 Gy, respectively. Four samples received PIPAC 15 minutes after irradiation and 4 other after 24 hours. Doxorubicin was aerosolized in an ex-vivo PIPAC model at 12 mmHg/36°C. In-tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. RESULTS: Doxorubicin penetration after PIPAC (15 minutes after irradiation) was 476 ± 74 µm for the control sample, 450 ± 45µm after 1 Gy (p > 0.05), 438 ± 29 µm after 2 Gy (p > 0.05), 396 ± 32 µm after 7 Gy (p = 0.005) and 284 ± 57 after 14 Gy irradiation (p < 0.001). The doxorubicin penetration after PIPAC (24 hours after irradiation) was 428 ± 77 µm for the control sample, 393 ± 41 µm after 1 Gy (p > 0.05), 379 ± 56 µm after 2 Gy (p > 0.05), 352 ± 53 µm after 7 Gy (p = 0.008) and 345 ± 53 after 14 Gy irradiation (p = 0.001). CONCLUSIONS: Higher (fractional) radiation dose might reduce the tissue penetration depth of doxorubicin in our ex-vivo model. However, irradiation with lower (fractional) radiation dose does not affect the tissue penetration negatively. Further studies are warranted to investigate if irradiation can be used safely as chemopotenting agent for patients with peritoneal metastases treated with PIPAC.

Exploring the Spatial Drug Distribution Pattern of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel approach to delivering intraperitoneal chemotherapy (IPC) as a pressurized aerosol. One of the assumed advantages is the homogeneous drug distribution in the intraperitoneal cavity compared with conventional liquid in situ chemotherapy. However, to date, the spatial drug distribution pattern of PIPAC has not been investigated in detail. METHODS: Doxorubicin was aerosolized in an ex vivo PIPAC model containing native fresh tissue samples of swine peritoneum at a pressure of 12 mmHg CO2 at 36 °C. In the center of the top cover of the PIPAC chamber, a PIPAC micropump was installed. Tissue specimens were placed as follows: (A) bottom of the plastic box, (B) margin of the aerosol jet covered with a bilaterally open tunnel, (C) side wall, and (D) top cover, respectively. In-tissue doxorubicin penetration was measured using fluorescence microscopy on frozen thin sections. RESULTS: The depth of doxorubicin penetration was found to be significantly higher in tissues directly exposed to the aerosol jet (A: 215 ± 79 µm) compared with the side wall (C: 77 ± 18 µm; p < 0.01) and the top of the box (D: 65 ± 17 µm; p < 0.01). The poorest penetration was observed for peritoneal tissue covered under a bilaterally open plastic tunnel (B: 34 ± 19 µm; p < 0.001). CONCLUSIONS: The study data suggest that the spatial drug distribution pattern of ex vivo PIPAC is heterogeneous.

Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy.

BACKGROUND: Peritoneal carcinomatosis (PC) is an unmet medical need. Despite recent improvements, systemic chemotherapy has limited efficacy. We report the first application of intraperitoneal chemotherapy as a pressurized aerosol in human patients. METHODS: Three end-stage patients with advanced PC from gastric, appendiceal, and ovarian origin were treated as a compassionate therapy. All patients had received previous systemic chemotherapy. A pressurized aerosol of CO2 loaded with doxorubicin 1.5 mg/m(2) and cisplatin 7.5 mg/m(2) (pressurized intraperitoneal aerosol chemotherapy, PIPAC) was applied into the abdomen for 30 min at a pressure of 12 mmHg and a temperature of 37 °C. RESULTS: No side-effects >2 CTCAE were observed, and the procedures were well tolerated. Early hospital discharge was possible (days 2-5). Nuclear presence of doxorubicin was documented throughout the peritoneum, reaching high local concentration (≤4.1 µmol/g) and plasma concentration was low (4.0-6.2 ng/ml). PIPAC created no significant adhesions, could be repeated, and was applied 6×, 4×, and 2×. Two patients showed a complete and one a partial histological remission. Mean survival after the first PIPAC was 288 days. One patient is alive after 567 days. CONCLUSIONS: PIPAC shows superior pharmacological properties with high local concentration and low systemic exposure. PIPAC can induce regression of PC in chemoresistant tumors, using 10% of a usual systemic dose.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC): occupational health and safety aspects.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel approach for treating peritoneal carcinomatosis. First encouraging results have been obtained in human patients. However, delivering chemotherapy as an aerosol might result in an increased risk of exposure to health care workers, as compared with other administration routes. METHODS: PIPAC was applied in two human patients using chemotherapeutic drugs (doxorubicin and cisplatin), and air contamination levels were measured under real clinical conditions. Air was collected on a cellulose nitrate filter with a flow of 22.5 m(3)/h. To exclude any risk for health care workers, both procedures were remote controlled. Toxicological research of cisplatin was performed according to NIOSH 7300 protocol. Sampling and analysis were performed by an independent certification organization. RESULTS: The following safety measures were implemented: closed abdomen, laminar airflow, controlled aerosol waste, and protection curtain. No cisplatin was detected in the air (detection limit < 0.000009 mg/m(3)) at the working positions of the surgeon and the anesthesiologist under real PIPAC conditions. CONCLUSIONS: For the drugs tested, PIPAC is in compliance with European Community working safety law and regulations. Workplace contamination remains below the tolerance margin. The safety measures and conditions as defined above are sufficient. Further protecting devices, such as particulate (air purifying) masks, are not necessary. PIPAC can be used safely in the clinical setting if the conditions specified above are met. However, a toxicological workplace analysis must be performed to confirm that the procedure as implemented complies with local regulations.

Renal and hepatic toxicities after pressurized intraperitoneal aerosol chemotherapy (PIPAC).

BACKGROUND: Both in animal models and in human patients, pressurized intraperitoneal aerosol chemotherapy (PIPAC) has been shown to improve local bioavailability of chemotherapy in peritoneal nodules, as compared with conventional peritoneal lavage. Pharmacokinetic studies show a low drug concentration in peripheral venous blood. However, hepatic and renal toxicities induced by delivering chemotherapeutic drugs into the abdomen as a pressurized aerosol have not yet been investigated. METHODS: Liver and renal function as well as toxicity parameters were monitored after eight PIPAC applications with doxorubicin (1.5 mg/m(2) body surface) and cisplatin (7.5 mg/m(2) body surface) in three end-stage patients suffering therapy-resistant peritoneal carcinomatosis. PIPAC was repeated at 4-week intervals (three times in two patients, twice in one patient). Peripheral venous blood was collected preoperatively and then daily until the 5th postoperative day, and sent to the hospital's clinical chemistry laboratory. Statistical analysis was performed by analysis of variance (ANOVA). RESULTS: Gamma-glutamyltransferase was significantly elevated (p < 0.05) in the early postoperative phase. Glutamic oxaloacetic transaminase [aspartate aminotransferase], glutamic pyruvic transaminase [alanine aminotransferase], and bilirubin levels were not influenced by the procedure. Quick-test remained normal. Serum creatinine levels were not altered. CONCLUSIONS: Under the above conditions, PIPAC did not induce clinically relevant liver cytotoxicity. Liver metabolism and function were not altered. Renal function remained within the normal range. No cumulative toxicity was observed after repeated PIPAC. PIPAC appears to be associated with very limited hepatic and renal toxicity, which might be a significant advantage over other administration routes.

Can pre-endoscopic assessment predict active upper gastrointestinal bleeding? A retrospective study in patients with symptoms of upper gastrointestinal bleeding outside regular working hours.

BACKGROUND/AIMS: To evaluate the usefulness of pre-endoscopic assessment for predicting active up-per gastrointestinal bleeding (UGI-B) at emergency esophagogastroduodenoscopy (E-EGD, within 6 hours). METHODOLOGY: We retrospectively analysed the medical records of patients that had an E-EGD performed outside working hours and considered 15 pre-endoscopic variables in a univariate analysis. Active UGI-Bat E-EGD was taken as end-point. RESULTS: Of 228 E-EGD performed during 75 months, 195 were motivated by the suspicion of UGI-B. We excluded 83 cases as they were hospitalised at the time of first symptoms of bleeding. Thus, 112 cases were included. The following clinical signs triggered E-EGD: hematemesis (56/50%),melena (55/49.1%), hematochezia (20/17.8%), anae- mia (7/6.2%). Patients' age was 65.5+14.2 years. Sixty nine (61.6%) cases were male. The relative risk and p-value of the variables for the presence of active bleeding at E-EGD were as follows: hematemesis: 1.54/0.3; malignancy and cirrhosis: 1.73/0.07; haemoglobin <8g/dL: 1.38/0.3; white blood count >12,000/tL: 1.18/0.6;systolic blood pressure (SBP) <100 mmHg: 0.53/0.03;pulse >100/min: 1.42/0.2; platelets <14000/nL:1.5/0.2; INR >1.17: 1.89/0.049. In the multivariate analysis none of these variables independently predicted UGI-B. CONCLUSIONS: No relevant pre-endoscopic variables for the prediction of active UGI-B at E-EGD could be found. Our data suggest that pre-endoscopic evaluation cannot replace rapid endoscopy.

Development of a duodenal gallstone ileus with gastric outlet obstruction (Bouveret syndrome) four months after successful treatment of symptomatic gallstone disease with cholecystitis and cholangitis: a case report.

INTRODUCTION: Cases of gallstone ileus account for 1% to 4% of all instances of mechanical bowel obstruction. The majority of obstructing gallstones are located in the terminal ileum. Less than 10% of impacted gallstones are located in the duodenum. A gastric outlet obstruction secondary to a gallstone ileus is known as Bouveret syndrome. Gallstones usually enter the bowel through a biliary enteral fistula. Little is known about the formation of such fistulae in the course of gallstone disease. CASE PRESENTATION: We report the case of a 72-year-old Caucasian woman born in Germany with a gastric outlet obstruction due to a gallstone ileus (Bouveret syndrome), with a large gallstone impacted in the third part of the duodenum. Diagnostic investigations of our patient included plain abdominal films, gastroscopy and abdominal computed tomography, which showed a biliary enteric fistula between the gallbladder and the duodenal bulb. Our patient was successfully treated by laparotomy, duodenotomy, extraction of the stone, cholecystectomy, and resection of the fistula in a one-stage surgical approach. Histopathological examination showed chronic and acute cholecystitis, with perforated ulceration of the duodenal wall and acute purulent inflammation of the surrounding fatty tissue. Four months prior to developing a gallstone ileus our patient had been hospitalized for cholecystitis, a large gallstone in the gallbladder, cholangitis and a small obstructing gallstone in the common biliary duct. She had been treated with endoscopic retrograde cholangiopancreatography, endoscopic biliary sphincterotomy, balloon extraction of the common biliary duct gallstone, and intravenous antibiotics. At the time of her first presentation, abdominal ultrasound and endoscopic examination (including esophagogastroduodenoscopy and endoscopic retrograde cholangiopancreatography) had not shown any evidence of a biliary enteral fistula. In the four months preceding the gallstone ileus our patient had been asymptomatic. CONCLUSION: In patients known to have gallstone disease presenting with symptoms of ileus, the differential diagnosis of a gallstone ileus should be considered even in the absence of preceding symptoms related to the gallbladder disease. Gallstones large enough to cause intestinal obstruction usually enter the bowel by a biliary enteral fistula. During the formation of such a fistula, patients can be asymptomatic.

Flank hernia and bulging after open nephrectomy: mesh repair by flank or median approach? Report of a novel technique.

Flank incisions may be associated with flank hernias, which may be complicated with incarceration and strangulation. Furthermore, they may cause a significant limitation of the patient's quality of life. In the period 1997-2006 we performed 15 flank hernia repairs with a prosthetic mesh implantation. From 1997 to 2001 hernias were managed with a standardized mesh implantation through the initial flank incision (seven cases, flank group). Since 2001 we have adopted a novel operative approach in eight patients. Through a median laparotomy and following a transabdominally reduction of the hernia sac, a prosthetic polypropylene mesh [Prolene, Vypro or UltraPro, Ethicon Endo-Surgery (Europe) GmbH, Norderstedt, Germany] overlapping the midline was placed in a sublay technique (median group). The perioperative complication rate was comparable and they consisted mostly of postoperative seromas. A patient from the flank group developed a hernia recurrence two months after surgery. Thirteen patients participated in the annual follow-up for a total follow-up time of five years. In this period we observed only one additional case of hernia recurrence: a patient of the flank group presented with a 3 cm hernia recurrence at the proximal end of the previous operative incision. No recurrence was observed in the median group. As a result the novel technique for open repair of flank incisional hernias we present permits a remodelling of the abdominal wall and is associated with excellent postoperative results.