The Role of Additional Staining in the Assessment of the Peritoneal Regression Grading Score (PRGS) in Peritoneal Metastasis of Gastric Origin.

INTRODUCTION: The Peritoneal Regression Grading Score (PRGS) is a 4-tied histologic regression grading score for determining the response of peritoneal metastasis to chemotherapy. Peritoneal biopsies in every abdominal quadrant are recommended. A positive therapy response is defined as a decreasing or stable mean PRGS between 2 therapy cycles. The added value of periodic acid satin (PAS) and Ber-EP4 staining over HE staining for diagnosing PRGS1 (the absence of vital tumor cells) is unclear. MATERIALS AND METHODS: A total of 339 biopsies obtained during 76 laparoscopies in 33 patients with peritoneal metastasis of gastric cancer were analyzed. Biopsies classified as PRGS 1 (no residual tumor, n=95) or indefinite (n=50) were stained with PAS, and remaining indefinite or PRGS1 cases additionally stained with BerEP4. RESULTS: After PAS-staining tumor cells were detected in 28 out of 145 biopsies (19%), the remaining 117 biopsies were immunostained with Ber-EP4. Tumor cells were detected in 22 biopsies (19%). In total, additional staining allowed the detection of residual tumor cells in 50 out of 339 biopsies (15%) and changed the therapy response assessment in 7 out of 33 (21%) patients. CONCLUSIONS: In summary, 25% (24 out of 95) of initially tumor-free samples (PRGS1) showed residual tumor cells after additional staining with PAS and/or BerEp4. Immunohistochemistry provided important additional information (the presence of tumor cells) in 22 of all 339 biopsies (11.2%). Further staining reduced the instances of unclear diagnosis from 50 to 0 and changed the therapy response assessment in 7 out of 33 patients (21%). We recommend additional staining in PRGS1 or unclear cases.

Peritoneal regression grading score (PRGS): first evidence for independent predictive and prognostic significance.

Objectives: The peritoneal regression grading score (PRGS) is a four-tied pathologic score measuring tumor regression in biopsies from patients with peritoneal metastasis (PM) receiving chemotherapy. Methods: This retrospective analysis of a prospective registry (NCT03210298) analyses 97 patients with isolated PM under palliative chemotherapy. We examined the predictive value of the initial PRGS for overall survival (OS) and the prognostic value of PRGS in repeated peritoneal biopsies. Results: The 36 (37.1 %) patients with an initial mean PRGS≤2 had a longer median OS (12.1 months, CI 95 % 7.8-16.4) vs. 8.0 months (CI 95 % 5.1-10.8 months) in 61 (62.9 %) patients with PRGS≥3 (p=0.02) After stratification, the initial PRGS was an independent predictor of OS (Cox-regression, p<0.05). Out of 62 patients receiving≥two chemotherapy cycles, 42 (67.7 %) had a histological response (defined as a lower or stable mean PRGS in successive therapy cycles), and 20 (32.3 %) progressed (defined as an increasing mean PRGS). PRGS response was associated with a longer median OS (14.6 months, CI 5-95 % 6.0-23.2) vs. 6.9 (CI 5-95 % 0.0-15.9) months. PRGS response was prognostic in the univariate analysis (p=0.017). Thus, PRGS had both a predictive and prognostic significance in patients with isolated PM receiving palliative chemotherapy in this patient cohort. Conclusions: This is the first evidence for the independent predictive and prognostic significance of PRGS in PM. These encouraging results need validation in an adequately powered, prospective study.

Acidic ascites inhibits ovarian cancer cell proliferation and correlates with the metabolomic, lipidomic and inflammatory phenotype of human patients.

BACKGROUND: The poor prognosis of ovarian cancer patients is strongly related to peritoneal metastasis with the production of malignant ascites. However, it remains largely unclear how ascites in the peritoneal cavity influences tumor metabolism and recurrence. This study is an explorative approach aimed at for a deeper molecular and physical-chemical characterization of malignant ascites and to investigate their effect on in vitro ovarian cancer cell proliferation. METHODS: This study included 10 malignant ascites specimens from patients undergoing ovarian cancer resection. Ascites samples were deeply phenotyped by 1H-NMR based metabolomics, blood-gas analyzer based gas flow analysis and flow cytomertry based a 13-plex cytokine panel. Characteristics of tumor cells were investigated in a 3D spheroid model by SEM and metabolic activity, adhesion, anti-apoptosis, migratory ability evaluated by MTT assay, adhesion assay, flowcytometry and scratch assay. The effect of different pH values was assessed by adding 10% malignant ascites to the test samples. RESULTS:  The overall extracellular (peritoneal) environment was alkaline, with pH of ascites at stage II-III = 7.51 ± 0.16, and stage IV = 7.78 ± 0.16. Ovarian cancer spheroids grew rapidly in a slightly alkaline environment. Decreasing pH of the cell culture medium suppressed tumor features, metabolic activity, adhesion, anti-apoptosis, and migratory ability. However, 10% ascites could prevent tumor cells from being affected by acidic pH. Metabolomics analysis identified stage IV patients had significantly higher concentrations of alanine, isoleucine, phenylalanine, and glutamine than stage II-III patients, while stage II-III patients had significantly higher concentrations of 3-hydroxybutyrate. pH was positively correlated with acetate, and acetate positively correlated with lipid compounds. IL-8 was positively correlated with lipid metabolites and acetate. Glutathione and carnitine were negatively correlated with cytokines IL-6 and chemokines (IL-8 & MCP-1). CONCLUSION: Alkaline malignant ascites facilitated ovarian cancer progression. Additionally, deep ascites phenotyping by metabolomics and cytokine investigations allows for a refined stratification of ovarian cancer patients. These findings contribute to the understanding of ascites pathology in ovarian cancer.

Peritoneal regression grading score (PRGS) in peritoneal metastasis: how many biopsies should be examined?

Objectives: The four-tied peritoneal regression grading score (PRGS) is increasingly used to evaluate the response of peritoneal metastases (PM) to chemotherapy. The minimal number of peritoneal biopsies needed for PRGS determination remains unclear. Methods: A prospective cohort of 89 PM patients treated with 210 pressurized intraperitoneal aerosol chemotherapy (PIPAC) cycles was investigated. Four biopsies from every abdominal quadrant were recommended. Histological tumor response was defined as a stable or decreasing mean PRGS between therapy cycles, progression increasing. We compared the diagnostic uncertainty induced by missing biopsies to the histological response. Results: A total of 49 patients had at least two PIPAC and were eligible for therapy response assessment. Mean PRGS decreased from 2.04 (CI 5-95% 1.85-2.27) to 1.79 (CI 5-95% 1.59-2.01), p=0.14, as a proof of therapy effectiveness. 35 (71.4%) patients had a stable or decreasing PRGS (therapy response), 14 (28.6%) a PRGS increase (disease progression). Histology showed agreement between four biopsies in 42/210 laparoscopies (20%), between ≥3 biopsies in 103 (49%), and between ≥2 biopsies in 169 laparoscopies (81%). Mean loss of information with one missing biopsy was 0.11 (95% CI=0.13) PRGS points, with two missing biopsies 0.18 (95% CI 0.21). In 9/49 patients (18.3%), the loss of information with one less biopsy exceeded the change in PRGS under therapy. Conclusions: A minimum of three biopsies is needed to diagnose PM progression with an accuracy superior to 80%. Missing biopsies often result in a false diagnosis of tumor progression.

Dynamic Averaging Load Balancing on Cycles.

We consider the following dynamic load-balancing process: given an underlying graph G with n nodes, in each step t ≥ 0 , a random edge is chosen, one unit of load is created, and placed at one of the endpoints. In the same step, assuming that loads are arbitrarily divisible, the two nodes balance their loads by averaging them. We are interested in the expected gap between the minimum and maximum loads at nodes as the process progresses, and its dependence on n and on the graph structure. Peres et al. (Random Struct Algorithms 47(4):760-775, 2015) studied the variant of this process, where the unit of load is placed in the least loaded endpoint of the chosen edge, and the averaging is not performed. In the case of dynamic load balancing on the cycle of length n the only known upper bound on the expected gap is of order O ( n log n ) , following from the majorization argument due to the same work. In this paper, we leverage the power of averaging and provide an improved upper bound of O ( n log n ) . We introduce a new potential analysis technique, which enables us to bound the difference in load between k-hop neighbors on the cycle, for any k ≤ n / 2 . We complement this with a "gap covering" argument, which bounds the maximum value of the gap by bounding its value across all possible subsets of a certain structure, and recursively bounding the gaps within each subset. We also show that our analysis can be extended to the specific instance of Harary graphs. On the other hand, we prove that the expected second moment of the gap is lower bounded by Ω ( n ) . Additionally, we provide experimental evidence that our upper bound on the gap is tight up to a logarithmic factor.

Limitations of laparoscopy to assess the peritoneal cancer index and eligibility for cytoreductive surgery with HIPEC in peritoneal metastasis.

PURPOSE: We aimed to determine the value of laparoscopy to assess the intra-abdominal tumor extent and predict complete cytoreduction. METHODS: All patients at our department in the period from 2017 to 2021 that underwent laparoscopy to assess peritoneal metastasis and subsequent open exploration with the intention to perform cytoreductive surgery (CRS) with HIPEC were retrospectively identified in a continuously maintained database. RESULTS: Forty-three patients were analyzed. Peritoneal cancer index (PCI) determination by laparoscopy compared to open surgery was overestimated in five patients (11.6%), identical in eleven patients (25.6%), and underestimated in 27 patients (62.8%). PCI differences were independent of surgeons, tumor entities, and prior chemotherapy. Thirty-four patients (79.1%) were determined eligible for CRS with HIPEC during open exploration, whereas nine patients (20.9%) underwent a non-therapeutic laparotomy. Complete or almost complete cytoreduction was achieved in 33 patients (76.7%). In one patient, completeness of cytoreduction was not documented. CONCLUSIONS: We demonstrate a moderate agreement according to weighted Cohen's kappa analysis of PCI values calculated during laparoscopy and subsequent open exploration for CRS with HIPEC. Uncertainty of PCI assessment should therefore be kept in mind when performing laparoscopy in patients with peritoneal metastasis.

Influence of pre-analytical sample preparation on drug concentration measurements in peritoneal tissue: an ex-vivo study.

OBJECTIVES: Biopsy morphology (surface/depth ratio) and sample processing might affect pharmacological measurements in peritoneal tissue. METHODS: This is an ex-vivo study on inverted bovine urinary bladders (IBUB). We compared cisplatin (CIS) and doxorubicin (DOX) concentration in 81 standardized transmural punch biopsies of different diameters (6 and 12 mm). Then, we assessed the effect of dabbing the peritoneal surface before analysis. After automatized tissue homogenization with ceramic beads followed by lyophilisation, DOX concentration was quantified by high-performance liquid chromatography (HPLC), CIS concentration by atomic absorption spectroscopy. Experiments were performed in triplicate; the analysis was blinded to the sample origin. Comparisons were performed using non-parametric tests. RESULTS: Concentrations are given in mean (CI 5-95%). Results were reproducible between experiments (for CIS p=0.783, for DOX p=0.235) and between different localizations within the IBUB (for CIS p=0.032, for DOX p=0.663). Biopsy diameter had an influence on CIS tissue concentration (6 mm biopsies: 23.2 (20.3-26.1), vs. 12 mm biopsies: 8.1 (7.2-9.2) ng/mg, p<0.001) but not on DOX: (0.46, 0.29-0.62) vs. 0.43 (0.33-0.54) ng/mg respectively, p=0.248). Dabbing the peritoneal surface reduced DOX tissue concentration (dry biopsies: 0.28 (0.12-0.43) vs. wet biopsies: 0.64 (0.35-0.93) ng/mg, p=0.025) but not CIS (23.5 (19.0-28.0) vs. 22.9 (18.9-26.9) ng/mg, respectively, p=0.735). CONCLUSIONS: Measurements of drug concentration in peritoneal tissue can be influenced by the biopsy's surface/depth ratio and after drying the biopsy's surface. This influence can reach a factor three, depending on the drug tested. The biopsy technique and the pre-analytical sample preparation should be standardized to ensure reliable pharmacological measurements in peritoneal tissue.

Current practice and perceptions of safety protocols for the use of intraperitoneal chemotherapy in the operating room: results of the IP-OR international survey.

OBJECTIVES: To assess the risk perception and the uptake of measures preventing environment-related risks in the operating room (OR) during hyperthermic intraperitoneal chemotherapy (HIPEC) and pressurized intraperitoneal aerosol chemotherapy (PIPAC). METHODS: A multicentric, international survey among OR teams in high-volume HIPEC and PIPAC centers: Surgeons (Surg), Scrub nurses (ScrubN), Anesthesiologists (Anest), Anesthesiology nurses (AnesthN), and OR Cleaning staff (CleanS). Scores extended from 0-10 (maximum). RESULTS: Ten centers in six countries participated in the study (response rate 100%). Two hundred and eleven responses from 68 Surg (32%), 49 ScrubN (23%), 45 Anest (21%), 31 AnesthN (15%), and 18 CleanS (9%) were gathered. Individual uptake of protection measures was 51.4%, similar among professions and between HIPEC and PIPAC. Perceived levels of protection were 7.57 vs. 7.17 for PIPAC and HIPEC, respectively (p<0.05), with Anesth scoring the lowest (6.81). Perceived contamination risk was 4.19 for HIPEC vs. 3.5 for PIPAC (p<0.01). Information level was lower for CleanS and Anesth for HIPEC and PIPAC procedures compared to all other responders (6.48 vs. 4.86, and 6.48 vs. 5.67, p<0.01). Willingness to obtain more information was 86%, the highest among CleanS (94%). CONCLUSIONS: Experience with the current practice of safety protocols was similar during HIPEC and PIPAC. The individual uptake of protection measures was rather low. The safety perception was better for PIPAC, but the perceived level of protection remained relatively low. The willingness to obtain more information was high. Intensified, standardized training of all OR team members involved in HIPEC and PIPAC is meaningful.

Endoscopic Negative Pressure Therapy (ENPT) Is Superior to Stent Therapy for Staple Line Leak After Sleeve Gastrectomy: a Single-Center Cohort Study.

PURPOSE: Staple line leak (SLL) is a serious complication after sleeve gastrectomy (SG). Common endoscopic treatment options include self-expandable metallic stent (SEMS), endoscopic internal drainage (EID), and endoscopic closure. The endoscopic negative pressure therapy (ENPT) is a promising treatment option combining temporary sealing of the defect with drainage of the inflammatory bed. In this study, we compare the outcome of ENPT and SEMS for the treatment of SLL following SG. MATERIALS AND METHODS: A retrospective cohort of 27 patients (21 females) treated at a single center for SLL after SG was included. ENPT was primary therapy for 14 patients and compared with 13 patients treated primarily using SEMS. RESULTS: ENPT was associated with a significant reduction of hospital stay (19 ± 15.1 vs. 56.69 ± 47.21 days, p = 0.027), reduced duration of endoscopic treatment (9.8 ± 8.6 vs. 44.92 ± 60.98 days, p = 0.009), and shorter transabdominal drain dwell time (15 (5-96) vs. 45 (12-162) days, p = 0.014) when compared to SEMS. Whereas endoscopic management was successful in 12/14 (85.7%) of patients from the ENPT group, SEMS was successful in only 5/13 (38.5%) of patients (p = 0.015). Furthermore, ENPT was associated with a significant reduction of endoscopic adverse events compared with SEMS (14.3% vs. 76.92% p = 0.001). CONCLUSION: Compared with SEMS, ENPT is effective and safe in treating SLL after SG providing higher success rates, shorter treatment duration, and lower adverse events rates.

Experimental evaluation of icodextrin delivery as pressurized aerosol (PIPAC): Antiadhesive and cytotoxic effects.

BACKGROUND: Icodextrin (IDX) is an antiadhesive polymer that can be used as a carrier solution for intraperitoneal (IP) delivery of chemotherapeutic drugs. METHODS: We investigated the suitability of IDX solution as a carrier of Cisplatin and Doxorubicin for delivery as pressurized intraperitoneal aerosol chemotherapy (PIPAC). We examined the sprayability of IDX, the aerosol characteristics, the stability of the molecule after aerosolization, the effects of IDX on the adhesion of MKN45 human gastric cancer cells, the synergistic effect of aerosolized IDX with Cisplatin and Doxorubicin, and the chemical stability of IDX, Cisplatin, and Doxorubicin in combination. RESULTS: Delivery of IDX as PIPAC is feasible with no particular restrictions. The median droplet size of 35.7 µm did not change at increasing concentrations. IDX withstood the shear forces applied by the nebulizer and remained stable after aerosolization (ANOVA, p = 0.97). IDX did not impair the cytotoxic effects of Cisplatin and Doxorubicin (ns). IDX had a significant antiadhesive impact alone (p < 0.03) and in combination with Cisplatin and Doxorubicin (p < 0.02). IDX as a carrier for Cisplatin and Doxorubicin remained stable at 4 °C for three months and did not cause degradation of those two substances. CONCLUSION: The proposed combination takes advantage of the antiadhesive properties of IDX, the cytotoxic effect of Cisplatin and Doxorubicin, and an advanced drug delivery system.

Comparison between microcatheter and nebulizer for generating Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC).

BACKGROUND: This study compares an endoscopic microcatheter and a nebulizer for delivering Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC). METHODS: This is an in vitro and ex vivo study in an established model (inverted bovine urinary bladder). Four parameters were compared to determine the performance of a micro-perforated endoscopic spray catheter vs. state-of-the art, nozzle technology: (1) surface coverage and pattern with methylene blue on blotting paper at three different distances; (2) median aerodynamic diameter (MAD) of aerosol droplets with three different solutions (H2O, Glc 5% and silicon oil); (3) depth of tissue penetration of doxorubicin (DOX) and (4) tissue concentration of cisplatin (CIS) and DOX using standard clinical solutions. RESULTS: The spray area covered by the microcatheter was larger (p < 0.001) but its pattern was inhomogenous than with the nozzle technology. We found that aerosol droplets were larger in the test group than in the control group for all three solutions tested. Median tissue penetration of DOX was lower (980 µm) with the microcatheter than with the nebulizer (1235 µm) and distribution was more heterogeneous ( = 0.003) with the microcatheter. The median tissue concentration of DOX and CIS was lower and concentration of DOX was more heterogeneous with the microcatheter (p = 0.002). CONCLUSIONS: This investigation has revealed that microcatheter technology generates larger aerosol droplet size, less drug tissue penetration and lower drug tissue concentration than the current nozzle technology. In the absence of clinical studies, use of microcatheters for delivering PIPAC can not be recommended at this stage.

In-Hospital Mortality and Complication Rates According to Health Insurance Data in Patients Undergoing Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Surface Malignancies in Germany.

BACKGROUND: Morbidity and in-hospital mortality rates of patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in Germany are not known. METHODS: From 2009 to 2018 all patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in Germany were retrospectively analyzed regarding morbidity and in-hospital mortality rates according to nationwide hospital billing data based on diagnosis-related groups (DRG). The "failure to rescue" (FTR) index, characterizing patients who died after severe but potentially manageable complications, was calculated. RESULTS: In total, 8463 patients were included and analyzed. Female sex predominated (1.5:1). Colonic origin of peritoneal metastasis was highest throughout all years, reaching its highest level in 2017 (55%; n = 563) and its lowest level in 2012 (40%; n = 349). Median length of hospital stay reached its maximum in 2017 at 23.9 days and its minimum in 2010 at 22.0 days. Analysis of the total FTR index showed a noticeable improvement over the years, reaching its lowest values in 2017 (9.8%) and 2018 (8.8%). The FTR index for sepsis, peritonitis, and pulmonary complications significantly improved over time. Of the 8463 included patients, 290 died during hospital stay, reflecting an in-hospital mortality rate of 3.4%. CONCLUSION: In-hospital mortality after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is reasonably low compared with other surgical procedures. The improvement in the FTR index reflects efforts to centralize treatment at specialized high-volume centers.

Endoscopic Vacuum Therapy for Staple Line Leaks after Sleeve Gastrectomy.

PURPOSE: Management of staple line leaks (SLL) after sleeve gastrectomy (SG) is challenging. The aim of this study was to evaluate the effectiveness of a novel endoscopic vacuum therapy (EVT) modality in the management of sleeve leaks. MATERIALS AND METHODS: Eight patients were treated with EVT for SLL. Therapy data and outcome measures including duration of therapy, therapy success, and change of treatment strategy were collected and analyzed. RESULTS: During the study period, SLL occurred in 1.6% of patients who underwent SG. After 9.8 ± 8.6 days of EVT, 3.3 ± 2.2 endoscopies, and 19 ± 15.1 days of hospitalization, endoscopic treatment using EVT was successful in seven out of eight patients (87.5%). CONCLUSIONS: EVT is an effective method for the management of staple line leaks after sleeve gastrectomy. The use of the intraluminal open-pore film drainage (OFD) could be considered as an advantageous modality of EVT, regarding placement and complications.

Overcoming Drug Resistance by Taking Advantage of Physical Principles: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

Theoretical considerations as well as comprehensive preclinical and clinical data suggest that optimizing physical parameters of intraperitoneal drug delivery might help to circumvent initial or acquired resistance of peritoneal metastasis (PM) to chemotherapy. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is a novel minimally invasive drug delivery system systematically addressing the current limitations of intraperitoneal chemotherapy. The rationale behind PIPAC is: 1) optimizing homogeneity of drug distribution by applying an aerosol rather than a liquid solution; 2) applying increased intraperitoneal hydrostatic pressure to counteract elevated intratumoral interstitial fluid pressure; 3) limiting blood outflow during drug application; 4) steering environmental parameters (temperature, pH, electrostatic charge etc.) in the peritoneal cavity for best tissue target effect. In addition, PIPAC allows repeated application and objective assessment of tumor response by comparing biopsies between chemotherapy cycles. Although incompletely understood, the reasons that allow PIPAC to overcome established chemoresistance are probably linked to local dose intensification. All pharmacological data published so far show a superior therapeutic ratio (tissue concentration/dose applied) of PIPAC vs. systemic administration, of PIPAC vs. intraperitoneal liquid chemotherapy, of PIPAC vs. Hyperthermic Intraperitoneal Chemotherapy (HIPEC) or PIPAC vs. laparoscopic HIPEC. In the initial introduction phase, PIPAC has been used in patients who were quite ill and had already failed multiple treatment regimes, but it may not be limited to that group of patients in the future. Rapid diffusion of PIPAC in clinical practice worldwide supports its potential to become a game changer in the treatment of chemoresistant isolated PM of various origins.

Staging laparoscopy and Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) for peritoneal metastasis: safe access to the abdomen.

BACKGROUND: Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) is an innovative drug delivery technique. Most common indication is palliative therapy of peritoneal metastasis of gastrointestinal and gynecological origin in the salvage situation. Access to the abdomen is the critical step of the procedure, since most patients had previous surgery. Potential pitfalls include non-access because of adhesions, bowel access lesions and postoperative subcutaneous toxic emphysema. METHODS: We propose a technique, the "finger-access technique" that might prevent largely these pitfalls. A minilaparotomy of 3 cm is performed in the midline, a finger introduced into the abdomen and a 5-mm double-balloon trocar (no Hasson trocar) is placed under finger protection at some distance of the first incision. The fascia of the minilaparotomy, not the skin, is then closed. The abdomen is insufflated with CO2 and tightness is controlled with saline solution in the minilaparotomy. A second 10-12 mm trocar is then introduced under videoscopic control. The first trocar is then visualized through the second one to exclude a bowel lesion during first access. RESULTS AND CONCLUSIONS: In our hands, this access technique has shown to be safe and effective.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with Low-Dose Cisplatin and Doxorubicin in Gastric Peritoneal Metastasis.

BACKGROUND: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel technique of intraperitoneal chemotherapy. First results obtained with PIPAC in patients with advanced peritoneal metastasis (PM) from gastric cancer (GC) are presented. METHODS: Retrospective analysis: Sixty PIPAC were applied in 24 consecutive patients with PM from GC. 67 % patients had previous surgery, and 79 % previous platinum-based systemic chemotherapy. Mean Peritoneal Carcinomatosis Index (PCI) of 16 ± 10 and 18/24 patients had signet-ring GC. Cisplatin 7.5 mg/m(2) and doxorubicin 1.5 mg/m(2) were given for 30 min at 37 °C and 12 mmHg at 6 week intervals. Outcome criteria were survival, adverse events, and histological tumor response. RESULTS: Median follow-up was 248 days (range 105-748), and median survival time was 15.4 months. Seventeen patients had repeated PIPAC, and objective tumor response was observed in 12 (12/24 = 50 %): no vital tumor cells = 6, major pathological response = 6, minor response = 3. Postoperative adverse events > CTCAE 2 were observed in 9 patients (9/24, 37.5 %). In 3/17 patients, a later PIPAC could not be performed due to non-access. Two patients (ECOG 3 and 4) died in the hospital due to disease progression. CONCLUSION: PIPAC with low-dose cisplatin and doxorubicin was safe and induced objective tumor regression in selected patients with PM from recurrent, platinum-resistant GC. First survival data are encouraging and justify further clinical studies in this indication.

Description of a novel approach for intraperitoneal drug delivery and the related device.

BACKGROUND: Two significant limitations of intraperitoneal drug therapy are limited drug distribution and poor penetration into peritoneal nodules. A possible solution is the application of the so-called "therapeutic pneumoperitoneum," taking advantage of the gaseous nature and the pressure of capnoperitoneum during laparoscopy. Our objective was to develop a device able to apply such therapeutic pneumoperitoneum. METHODS: The technology presented here is a spraying device and can be introduced through a trocar. It is driven by mechanical pressure and consists of an injector, a line, and a nozzle. An in vivo experimental study was performed in five pigs. A transvaginal cholecystectomy was performed. At the end of the procedure, a standard dose of methylene blue was sprayed/infused into the abdominal cavity for 30 min (4 test animals w/therapeutic pneumoperitoneum (12 mmHg CO(2)) and 1 control animal w/conventional lavage (2 l intra-abdominal volume with extracorporeal circulation)). At the end of the procedure, all animals were autopsied and the peritoneum was analyzed. Outcome criteria were: (1) drug distribution (as assessed by the stained peritoneal surface at autopsy), and (2) diffusion into the peritoneum (presence or not of macroscopic staining of the outer aspect of the peritoneum immediately after surgery). RESULTS: Stained peritoneal surface was larger after aerosol application compared with peritoneal lavage, and staining more intense. Hidden peritoneal surfaces and the anterior abdominal wall were stained only in the aerosol group. In contrast to peritoneal lavage, the outer aspect of peritoneal membrane was immediately stained after pressurized spraying. CONCLUSIONS: This device and the related approach significantly improve both distribution and penetration of a test substance into the peritoneal cavity in a large animal model. This might be a significant progress in treating intraperitoneal disease, in particular peritoneal carcinomatosis.