A multi-nozzle nebuliser does not improve tissue drug delivery during PIPAC.

BACKGROUND: Multi-nozzle nebulisers for pressurised intraperitoneal aerosol chemotherapy (PIPAC) are implemented in clinical practice to improve the homogeneity of tissue drug delivery. Nonetheless, the advantages of such devices over one-nozzle nebulisers have not been demonstrated thus far. In this study, we compared the performance of multi- and one-nozzle nebulisers by conducting physical and ex vivo pharmacological experiments. METHODS: The one-nozzle nebuliser Capnopen® and the multi-nozzle nebuliser were the subjects of this study. In physical experiments, the aerosol droplet size was measured by laser diffraction spectroscopy. Spatial spray patterns were depicted on blotting paper. Pharmacological experiments were performed on the enhanced inverted bovine urinary bladder model, demonstrating real-time tissue drug delivery, aerosol sedimentation and homogeneity of doxorubicin and cisplatin tissue distribution. RESULTS: The multi-nozzle nebuliser had a sixfold greater aerosolisation flow and a threefold greater angle of aerosolisation than Capnopen®. The aerosol particle size and distribution range were higher than that of Capnopen®. Spray patterns on blotting paper were more extensive with the multi-nozzle nebuliser. Real-time tissue drug delivery with the multi-nozzle nebuliser was over 100 ml within 1 min, and the aerosol sedimentation was 48.9% ± 21.2%, which was not significantly different from that of Capnopen®. The doxorubicin and cisplatin tissue concentrations were greater with Capnopen®. Although there was no significant difference in the homogeneity of doxorubicin distribution between the two devices, the homogeneity of cisplatin distribution was significantly higher with Capnopen®. CONCLUSION: The multi-nozzle PIPAC nebuliser did not fulfil expectations. Even though the surface spray patterns were broader with the multi-nozzle nebuliser, the tissue drug homogeneity and concentration were greater with Capnopen®.

Dynamic changes of tumor gene expression during repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with peritoneal cancer.

BACKGROUND: Intraperitoneal chemotherapy is used to treat peritoneal cancer. The pattern of gene expression changes of peritoneal cancer during intraperitoneal chemotherapy has not been studied before. Pressurized intraperitoneal aerosol chemotherapy is a new form of intraperitoneal chemotherapy using repeated applications and allowing repeated tumor sampling during chemotherapy. Here, we present the analysis of gene expression changes during pressurized intraperitoneal aerosol chemotherapy with doxorubicin and cisplatin using a 22-gene panel. METHODS: Total RNA was extracted from 152 PC samples obtained from 63 patients in up to six cycles of intraperitoneal chemotherapy. Quantitative real-time PCR was used to determine the gene expression levels. For select genes, immunohistochemistry was used to verify gene expression changes observed on the transcript level on the protein level. Observed (changes in) expression levels were correlated with clinical outcomes. RESULTS: Gene expression profiles differed significantly between peritoneal cancer and non- peritoneal cancer samples and between ascites-producing and non ascites-producing peritoneal cancers. Changes of gene expression patterns during repeated intraperitoneal chemotherapy cycles were prognostic of overall survival, suggesting a molecular tumor response of peritoneal cancer. Specifically, downregulation of the whole gene panel during intraperitoneal chemotherapy was associated with better treatment response and survival. CONCLUSIONS: In summary, molecular changes of peritoneal cancer during pressurized intraperitoneal aerosol chemotherapy can be documented and may be used to refine individual treatment and prognostic estimations.

Pressurized intraluminal aerosol chemotherapy with Dbait in the distal esophagus of swine.

BACKGROUND AND STUDY AIMS: A novel therapeutic concept, pressurized intraluminal aerosol chemotherapy (PILAC), and a corresponding device for distributing drugs to the mucosa and submucosa of the distal esophagus are presented. MATERIALS AND METHODS: The endoscopic device that was designed consisted of (i) a double-balloon catheter, similar to a Sengstaken-Blakemore tube; (ii) a carbon dioxide (CO2) line, used to create a gaseous, pressurized environment; and (iii) a micropump, used to generate a therapeutic aerosol. The device was inserted into the distal esophagus in three narcotized Landrace pigs. Dbait (short interfering DNA, or siDNA) was aerosolized under pressure (12 mmHg) in CO2 at 37 °C for 30 minutes. RESULTS: The procedure was well tolerated by all animals. At autopsy, no mucosal or muscular tear was observed. Fluorescence microscopy revealed a homogeneous intramural distribution of Dbait-cyanine 5 in the esophageal wall down to the circular muscular layer (400 - 600 µm). CONCLUSIONS: PILAC is feasible in a large animal model and appears to be safe. Therapy of the entire "tissue at risk" for the development of cancer in the distal esophagus is possible without the prior endoscopic identification of diseased tissue.

Pressurized intraperitoneal aerosol chemotherapy in women with recurrent ovarian cancer: A phase 2 study.

OBJECTIVE: Recurrent ovarian, fallopian or peritoneal cancer with peritoneal carcinomatosis (ROCPC) is resistant to systemic chemotherapy. We assessed the safety and activity of laparoscopic pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with this cancer. METHODS: In this open-label, single-arm phase 2 study, patients underwent 3 courses q 28-42 days of PIPAC with doxorubicin 1·5 mg/m(2) followed by cisplatin 7·5 mg/m(2). A pressure of 12 mm Hg and a temperature of 37 °C were applied for 30 min/course. The primary endpoint was the proportion of patients who had an objective tumor response (OTR) according to RECIST version 1.1 criteria. Analysis was by intention to treat. Secondary endpoints were tumor regression on histology, PC Index improvement on repeated video-laparoscopy, and quality of life measured with the EORTC QLQ-30 questionnaire. RESULTS: Sixty-four patients were enrolled. Laparoscopic non-access rate was 11/64 (17%). 53 patients were eligible for analyses. 33/53 (62%) patients had an OTR - three had a partial response and 30 patients had stable disease. Tumor regression on histology and PC Index improvement were observed in 26/34 (76%) and in 26/34 (76%) patients who underwent all 3 PIPACs. There were no treatment-related deaths. No grade 4 toxicity was observed. Grade 3 toxicities were trocar hernia (n=2), bowel obstruction (n=2), abdominal pain (n=2), hematoma (n=1), intraoperative bleeding (n=1), and cystitis with urosepsis (n=1). EORTC QLQ-30 global physical health scores, nausea/vomiting, appetite loss, diarrhea, and constipation improved during therapy. CONCLUSION: PIPAC is well tolerated and active in women with ROCPC and warrants further investigation in these patients.

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.

Activity of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) with cisplatin and doxorubicin in women with recurrent, platinum-resistant ovarian cancer: preliminary clinical experience.

OBJECTIVE: To assess the activity of laparoscopic Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) in women with recurrent, platinum-resistant ovarian cancer. METHODS: Prospective case series using repeated courses q 28-42 days of PIPAC containing cisplatin 7.5 mg/m(2) and doxorubicin 1.5 mg/m(2) at 12 mmHg and 37°C for 30 min. Objective tumor response was defined as tumor regression on histology and peritoneal carcinomatosis index (PCI) improvement on repeated video-laparoscopy. RESULTS: 34 PIPAC procedures were performed in 18 women, in 8 instances combined with cytoreductive surgery (CRS). Eight women had repeated PIPAC and objective tumor response was observed in 6 (complete remission: 1; partial remission: 2; stable disease: 3). Five adverse events WHO grade ≥ 2 were noted, 3 of them after combined CRS. No perioperative mortality occurred. Median follow-up was 192 days (min. 13-max. 639). Cumulative survival after 400 days was 62% and mean actuarial survival time was 442 days. In a multivariable regression analysis with objective tumor response (yes vs. no) as the dependent variable and PIPAC (1 vs.>1), patient age (<75 vs.≥75 years), serum CA-125 (<1000 vs.>1000 U/mL), and the presence of ascites (yes vs. no) as independent variables, PIPAC independently predicted objective tumor response. CONCLUSION: PIPAC has activity in women with recurrent, platinum-resistant ovarian cancer and should be investigated in prospective clinical trials.

Pressurized intraperitoneal chemotherapy (PIPAC) in women with gynecologic malignancies: a review.

OBJECTIVE: The objective of this study was to provide an overview of published and ongoing trials of pressurized intraperitoneal chemotherapy (PIPAC) in ovarian cancer. DESIGN: The study comprised a systematic literature review. RESULTS: We identified 10 studies, including 2 ex vivo and in vitro studies, 6 clinical studies, and 2 ongoing clinical trials using PIPAC in women with recurrent ovarian cancer and pseudomyxoma peritonei. Experimental evidence and clinical study data demonstrate that PIPAC increases peritoneal cavity coverage and depth of peritoneal infiltration, and is technically feasible. Occupational safety has been established. PIPAC has demonstrated antitumor activity based on histological, radiological, and clinical evidence. The toxicity of PIPAC is manageable and restricted to Common Terminology Criteria for Adverse Events grade 2-3 events when used without concomitant cytoreductive surgery. Further clinical trials assessing efficacy and dose escalation are ongoing. CONCLUSIONS: PIPAC is technically feasible, has a safe local and systemic safety profile, and has antitumor activity in women with peritoneal carcinomatosis from recurrent ovarian cancer.

Current Medical Care Situation of Patients in Germany Undergoing Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

OBJECTIVE: Tailored approaches in gastrointestinal oncology have been more frequently introduced in past years and for patients with peritoneal metastases. This article attempts to overview the current strategies in surgical gastrointestinal oncology, with a focus on gastrointestinal peritoneal metastases. METHODS: In 2019, all patients undergoing PIPAC therapy in Germany were retrospectively analyzed regarding morbidity and in-hospital mortality rates. Furthermore, patients with chemotherapy-refractory peritoneal metastases from gastric cancer undergoing PIPAC-therapy at our institution were analyzed. RESULTS: In 2019, 534 patients received PIPAC treatment in german hospitals. The in-hospital mortality rate was 0%. In total, 36 patients suffered from postoperative complications (8%). From April 2016 to September 2021, a total of 44 patients underwent 93 PIPAC applications at our institution. The non-access-rate was 0%. The median PRGS was two (range, 1-4). Eleven patients (44%) showed histologically stable disease, whereas six patients (24%) showed histological regression. Median survival, calculated from the date of the first PIPAC application, was 181 days (range, 43-636 days). CONCLUSIONS: PIPAC is a safe and feasible procedure with a low in-hospital morbidity and mortality. Furthermore, PIPAC in the palliative and chemorefractory setting and is an appealing approach for patient management in the future.

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.

Consensus statement on safety measures for pressurized intraperitoneal aerosol chemotherapy.

OBJECTIVES: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a promising treatment for peritoneal cancer that entails, however, potential risks for the caregivers in the operating room (OR). This study aimed to reach a consensus within the PIPAC community on a comprehensive safety protocol. METHODS: Active PIPAC centers were invited to participate in a two-round Delphi process on 43 predefined items: concise summaries of the existing evidence were presented together with questions formulated using the population, intervention, comparator, and outcome framework. According to the Grading of Recommendations Assessment, Development, and Evaluation, the strength of recommendation was voted by panelists, accepting a consensus threshold of ≥50% of the agreement for any of the four grading options, or ≥70% in either direction. RESULTS: Forty-seven out of 66 invited panelists answered both rounds (response rate 76%). The consensus was reached for 41 out of 43 items (95.3%). Strong and weak recommendations were issued for 30 and 10 items, respectively. A positive consensual recommendation was issued to activate laminar airflow without specific strength, neither strong nor weak. No consensus was reached for systematic glove change for caregivers with a high risk of exposure and filtering facepiece mask class 3 for caregivers with low risk of exposure. CONCLUSIONS: A high degree of consensus was reached for a comprehensive safety protocol for PIPAC, adapted to the risk of exposure for the different caregivers in the OR. This consensus can serve as a basis for education and help reach a high degree of adherence in daily practice.

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.

Enhanced intraperitoneal delivery of charged, aerosolized curcumin nanoparticles by electrostatic precipitation.

Aims: To investigate the potential of curcumin-loaded polylactic-co-glycolic acid nanoparticles (CUR-PLGA-NPs), alone and with electrostatic precipitation, for improving tissue uptake during pressurized intraperitoneal aerosol chemotherapy (PIPAC). Methods: Positively and negatively charged CUR-PLGA-NPs were delivered as PIPAC into inverted bovine urinary bladders ex vivo. The experiment was repeated with the additional use of electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (electrostatic PIPAC). Results: Positively charged CUR-PLGA-NPs increased depth of tissue penetration by 81.5% and tissue concentration by 80%. Electrostatic precipitation further improved the uptake of positively charged CUR-PLGA-NPs by 41.8%. Conclusion: The combination of positive charge and electrostatic precipitation have significant potential to improve tissue uptake of nanoparticles during intraperitoneal chemotherapy.

The ISSPP PIPAC database: design, process, access, and first interim analysis.

OBJECTIVES: Several trials have documented the favorable safety profile, and promising clinical results of pressurized intraperitoneal aerosol chemotherapy (PIPAC) directed treatment in different types of peritoneal malignancies. However, until the results of randomized trials are available, the quality of documentation and acceptance by the users may be improved through a worldwide registry. The International Society for the Study of Pleura and Peritoneum (www.ISSPP.org) facilitated this process by creating a dedicated focus group and providing the funding needed for the creation and implementation of an international database. This article describes the design and the journey of establishing this international database and the first, preliminary results from the ISSPP PIPAC online database. METHODS: In 2019 the ISSPP PIPAC Registry Group started to create a database with a minimal dataset relevant to many diseases and applicable in different framework conditions. The task was divided into three phases including design, testing, implementation, protocol, handbook, legal requirements, as well as registry rules and bylaws for the registry group. RESULTS: The ISSPP PIPAC online database has six key elements (patient, consent, treatment, complications, response evaluation and follow-up). Following design, testing and implementation the database was successfully launched in June 2020. Ten institutions reported on 459 PIPAC procedures in 181 patients during the first 6 months, and the recorded data were comparable to the present literature. CONCLUSIONS: A new international multicenter PIPAC database has been developed, tested and implemented under the auspices of ISSPP. The database is accessible through the ISSPP website (www.ISSPP.org), and PIPAC institutions worldwide are highly encouraged to participate.

Protein expression in human non-small cell lung cancer: a systematic database.

OBJECTIVES: The following database integrates results from published proteomics studies in human non-small cell lung cancer (NSCLC), with a focus on squamous cell cancers (SCC) and adenocarcinomas (AC). METHODS: Only studies on NSCLC were analyzed. Results from 12 studies were available, 5 studies on SCC, 4 on AC, 1 on AC and SCC, and 2 on NSCLC without further distinction. Human cancer tissues, paired normal tissues, paired cancer patient's sera, normal sera or human tumor cell lines were analyzed. Three technologies were applied: two-dimensional polyacrylamide gel electrophoresis (2D-PAGE), differential in-gel electrophoresis (DIGE) and serological proteome analysis (SERPA). RESULTS: The total number of NSCLC patients was 306. Out of 261 differentially expressed proteins, 192 proteins (74%) were mentioned in a single study, 40 (15%) were mentioned by 2 different studies. 18 (7%) in 3 studies, 4 (2%) in 4 studies, 2 (1%) in 5 studies, and a single protein was listed in 6 studies. CONCLUSION: Overlapping of protein expression is low between SCC and AC. However, a few proteins appear to be upregulated in SCC and AC: triosephosphate isomerase, protein disulfide isomerase and phosphoglycerate mutase (phosphoglycerate kinase 1). These three proteins might be key players in human lung cancer.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) for Peritoneal Metastases in Solid Organ Graft Recipients: First Experience.

BACKGROUND Therapy of peritoneal metastases (PM) in solid organ transplant recipients is challenging. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) might constitute a new therapeutic opportunity for these patients. MATERIAL AND METHODS This was a single-center, retrospective analysis of prospective registry data (NCT03210298) in a tertiary care center between 1.7.2016 and 31.12.2017. Intraperitoneal administration of oxaliplatin 92 mg/m² body surface or a combination of cisplatin 7.5 mg/m² and doxorubicin 1.5 mg/m², repeated every 6 weeks. Objective tumor response was documented via histology (Peritoneal Regression Grading Score, PRGS), adverse events according to Common Terminology Criteria for Adverse Events (CTCAE) 4.0. RESULTS Out of 71 consecutive patients treated with PIPAC, 2 patients (2.8%) were solid organ transplant recipients. The first patient had metachronous PM of colonic cancer origin after liver transplantation. The second patient had synchronous PM of pancreatic cancer origin after combined kidney-pancreas transplantation. After repeated combined systemic and PIPAC chemotherapy, objective histological response was documented in both patients. No adverse events >CTCAE 2 were recorded. There was no measurable liver or renal toxicity. PIPAC procedures could be repeated (2, resp. 3 cycles) without any interruption of immunosuppressive medication or impairment of respective plasmatic drug levels. The first patient passed away 7 months after the first PIPAC, the second patient was still alive after 8 months. CONCLUSIONS PIPAC can induce objective regression of PM in solid organ transplant recipients without inducing organ toxicity or interfering with immunosuppressive therapy.

Lost in translation? A systematic database of gene expression in breast cancer.

Ten years of translational research in breast cancer (BC) using high-throughput technologies such as cDNA arrays have produced an impressive amount of results. However, it is difficult for a single researcher to overview these results, since no critical synthesis is provided in the literature. This is a meta-analysis of gene expression in BC. Thirteen translational studies fulfilled the inclusion criteria, involving 553 BC patients and 79 controls. Large cohorts of patients and well-defined samples were rare. A total of 1,350 genes were reported at least once to be deregulated in BC. Out of these findings, 1,212 (90%) were not confirmed by other authors. A cohort of 138 genes of particular interest remained for further analysis. Of these, 79 were consistently reported to be overexpressed in BC, 41 to be underexpressed and in 18 cases results were contradictory. The most frequently reported deregulated genes in BC include: GATA binding protein 3, arylamine N-acetyltransferase, Myb-related protein B and zinc transporter SLC39A6 precursor (overexpressed); cadherin-3 precursor, keratin type I cytoskeletal 17 and type II cytoskeletal 5 (underexpressed). These genes obviously correlate with the presence and/or development of BC. More efforts should be devoted to the establishment of common standards in translational BC research.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal metastases of pancreas and biliary tract cancer.

Data on the effectivness of PIPAC in patients with peritoneal metastases of pancreaticobiliary origin is scarce. We here present further proof of treatment efficacy in this subset of patients. Repetitive PIPAC treatment with low-dose cisplatin 7.5 mg/m2 and doxorubicin 1.5 mg/m2 body surface area every 6 weeks and prospective data collection. Documentation included microscopic histological regression, median overall survival and treatment-related adverse events. Twelve patients with a median age of 57 years (range 43-78 years) were included. Six patients suffered from pertioneal metastases of pancreatic adenocarcinoma (PDAC) and six patients from cholangiocarcinoma (CC). In total 23 cycles of PIPAC were adminstered with the median number of PIPAC cycles being two (range 1-4). Complete tumor regression was found in four patients and major regression in one patient. Median overall survival after the first PIPAC cycle was 12.7 months for PDAC patients and 15.1 months for CC patients. 11 of the 12 patients are still alive after a median follow-up of 438 days. There were no CTCAE Grade 3 or 4 complications. PIPAC is an innovative and attractive treatment option in the salvage situation for patients with peritoneal metastases of pancreaticobiliary tumors after failure of systemic chemotherapy. In 40% of the patients histological regression can be induced. Further studies are warranted to further elucidate treatment efficacy.

Hyperthermic intraperitoneal chemotherapy for women with granulosa cell tumors of the ovary: a systematic review of the literature.

Background: Adult and juvenile granulosa cell tumors of the ovary are rare functional sex-cord-stromal ovarian neoplasms characterized by low malignant potential and late relapse. Evidence-based management options for primary and recurrent juvenile (JGCT) and adult (AGCT) granulosa cell tumors are limited and treatment options have not been standardized. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may be an option to treat these women effectively. Methods: Systematic literature review using PubMed and the Cochrane Central Register of Controlled Trials. Results: No reports of HIPEC among women with a first diagnosis of AGCT were identified. We identified 5 reports on the safety and therapeutic efficacy of CRS and HIPEC in 19 patients with recurrent AGCT and one patient with JGCT. The pooled rate of complete cytoreduction was 95 % (18/19) with 16 % (3/19) severe morbidity and no procedure-related mortality. The median time of follow-up was 30 (range, 3 to 72) months, during which 6/19 (31 %) patients experienced a recurrence and two patients (10 %) died of the disease. Conclusion: CRS and HIPEC are a safe and potentially effective treatment option for selected women with recurrent AGCT limited to the abdomen.

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.

Pressurized Intraperitoneal Aerosol Chemotherapy with Cisplatin and Doxorubicin in Women with Peritoneal Carcinomatosis: A Cohort Study.

AIM: We aimed to assess the objective tumor response (OTR) to laparoscopic pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with peritoneal carcinomatosis (PC). PATIENTS AND METHODS: We carried-out a retrospective cohort study of women with PC undergoing repeated courses of PIPAC with 7.5 mg/m(2) of cisplatin and 1.5 mg/m(2) of doxorubicin. OTR was defined as histological regression. Peritoneal carcinomatosis index (PCI) improvement on video-laparoscopy and ascites volume reduction were secondary outcomes. Quality of life was assessed by the European Organization for Research & Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-30+3. RESULTS: A total of 252 PIPACs were performed in 99 women with PC and ovarian (n=84), primary peritoneal (n=6), cervical (n=3), endometrial (n=3), fallopian tube (n=1), and breast (n=1) cancer and pseudomyxoma peritonei (n=1). Laparoscopic non-access rate was 17% (17/99). Fifty women had more than one PIPAC procedures, with an OTR of 76% (38/50) and PCI improvement in 64% (32/50). Ascites volume significantly decreased from 762±1170 ml to 167±456 ml (p=0.02). A high initial Karnofsky Index was correlated with receiving more than one PIPAC (p<0.0001) and a high number of previous surgeries with laparoscopic non-access (p=0.01). Twenty adverse events of Common Terminology Criteria for Adverse Events grade 3 or more were noted. Absence of ascites (odds ratio=8.45, 95% confidence interval=1.9-3.6; p<0.0001), but not patient age, serum cancer antigen-125, and Karnofsky Index independently predicted OTR. EORTC QLQ-30+3 scores for global physical health, nausea/vomiting, appetite loss, and constipation improved during therapy. CONCLUSION: PIPAC with cisplatin and doxorubicin is an active treatment in women with PC and preserves quality of life. Appropriate patient selection regarding performance status and the number of prior surgeries is important.