Outcome of patients with peritoneal metastasis from ovarian cancer treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC).

Objectives: There are few data on Pressurized IntraPeritoneal Aerosol Chemotherapy with cisplatin and doxorubicin (PIPAC C/D) in women with primary unresectable or recurrent platinum-resistant peritoneal metastasis (PM) from ovarian cancer (OC). We evaluated survival, histological and cytological response, Quality of Life (QoL) and toxicity after PIPAC C/D in these patients. Methods: Retrospective analysis of patients from the prospective PIPAC-OPC1 and -OPC2 studies. The histological response was evaluated by the Peritoneal Regression Grading Score (PRGS). QoL questionnaires were collected at baseline and after third PIPAC or 60 days. Adverse events were collected until 30 days after the last PIPAC. Demographic and survival data were analysed based on intention to treat. Response, QoL and toxicity were analysed per protocol (≥1 PIPAC). Results: Twenty-nine patients were included. Five patients (17 %) were non-accessible at PIPAC 1. One patient was excluded due to liver metastases at PIPAC 1. Thus, 23 patients had 76 PIPACs (median 2, range 1-12). Median overall survival was 8.2 months (95 % CI 4.4-10.3) from PIPAC 1. Biopsy data were available for 22 patients, and seven (32 %) patients had a major/complete histological response (PRGS≤2) at PIPAC 3. No cytological conversions were registered. Symptoms and function scores worsened, while emotional scores improved. Three patients had severe adverse reactions (two ileus, one pulmonary embolism); no life-threatening reactions or treatment-related mortality was observed. Conclusions: PIPAC C/D was feasible and induced histological regression in a substantial proportion of patients with platinum-resistant PM from OC. Larger studies are needed to evaluate impact on survival.

Review on treatment of pleural metastasis and malignant pleural effusion with Pressurized IntraThoracic Aerosol Chemotherapy (PITAC).

Background: Malignant pleural effusion (MPE) is a common and debilitating condition seen in advanced cancer disease, and life-expectancy is short. Symptoms include pain and severe shortness of breath. Current first-line treatment options include pleural drainage using catheters as well as pleurodesis. However, these treatment modalities are often inefficient and patients need repeated procedures. Pressurized IntraThoracic Aerosol Chemotherapy (PITAC) is a minimally invasive procedure, where antineoplastic agents are nebulized under pressure into the pleural space. Content: We present the preliminary safety, feasibility, and response assessment data for PITAC based on a comprehensive literature review. Summary: Five retrospective studies reported data on 38 PITACs in 21 patients. Data were heterogeneous and incomplete on several important aspects such as procedure, safety, local effect and long-term outcomes. PITAC seems technically feasible with a low risk of complications and may provide some reduction in MPE in selected cases. Outlook: PITAC seems feasible, but prospective phase I and II studies are needed to define safety, indications, and efficacy.

No Effect of Methylnaltrexone on Acute Pancreatitis Severity: A Multicenter Randomized Controlled Trial.

OBJECTIVES: Opioids used to manage severe pain in acute pancreatitis might exacerbate the disease through effects on gastrointestinal and immune functions. Methylnaltrexone, a peripherally acting µ-opioid receptor antagonist, may counteract these effects without changing analgesia. METHODS: This double-blind, randomized, placebo-controlled trial included adult patients with acute pancreatitis and systemic inflammatory response syndrome at four Danish centers. Participants were randomized to receive five days of continuous intravenous methylnaltrexone (0.15mg/kg/day) or placebo added to the standard of care. The primary endpoint was the Pancreatitis Activity Scoring System score after 48 hours of treatment. Main secondary outcomes included pain scores, opioid use, disease severity, and mortality. RESULTS: In total, 105 patients (54% males) were randomized to methylnaltrexone (n=51) or placebo (n=54). After 48 hours, the Pancreatitis Activity Scoring System score was 134.3 points in the methylnaltrexone group and 130.5 points in the placebo group (difference, 3.8 [95% CI, -40.1 to 47.6]; P=0.87). At 48 hours, we found no differences between groups in pain severity (0.0 [95% CI, -0.8 to 0.9]; P=0.94), pain interference (-0.3 [95% CI, -1.4 to 0.8]; P=0.55), and morphine equivalent doses (6.5 mg [95% CI, -2.1 to 15.2]; P=0.14). Methylnaltrexone also did not affect the risk of severe disease (8% [95% CI, -11 to 28]; P=0.38) and mortality (6% [95% CI, -1 to 12]; P=0.11). The medication was well-tolerated. CONCLUSIONS: Methylnaltrexone treatment did not achieve superiority over placebo for reducing the severity of acute pancreatitis.

Exploring the prognostic value of circular RNAs in pancreatic ductal adenocarcinoma using genome-wide expression profiling.

BACKGROUND/OBJECTIVES: Median survival of pancreatic ductal adenocarcinoma (PDAC) is around eight months and new prognostic tools are needed. Circular RNAs (circRNAs) have gained interest in different types of cancer. However, only a few studies have evaluated their potential in PDAC. We aimed to identify the most differentially expressed circRNAs in PDAC compared to controls and to explore their potential as prognostic markers. METHODS: Using frozen specimens with PDAC and controls, we performed RNA sequencing and identified 20,440 unique circRNAs. A custom code set of capture- and reporter probes for NanoString nCounter analysis was designed to target 152 circRNAs, based on abundancy, differential expression and a literature study. Expression of these 152 circRNAs was examined in 108 formalin-fixed and paraffin-embedded surgical PDAC specimens and controls. The spatial expression of one of the most promising candidates, ciRS-7 (hsa_circ_0001946), was evaluated by chromogenic in situ hybridization (CISH) using multi-punch tissue microarrays (TMAs) and digital imaging analysis. RESULTS: Based on circRNA expression profiles, we identified different PDAC subclusters. The 30 most differentially expressed circRNAs showed log2 fold changes from -3.43 to 0.94, where circNRIP1 (hsa_circ_0004771), circMBOAT2 (hsa_circ_0007334) and circRUNX1 (hsa_circ_0002360) held significant prognostic value in multivariate analysis. CiRS-7 was absent in PDAC cells but highly expressed in the tumor microenvironment. CONCLUSIONS: We identified several new circRNAs with biomarker potential in surgically treated PDAC, three of which showed an independent prognostic value. We also found that ciRS-7 is absent in cancer cells but abundant in tumor microenvironment and may hold potential as marker of activated stroma.

Second annual report from the ISSPP PIPAC database.

Objectives: To monitor the results of PIPAC directed therapy based on data from the International Society for the Study of the Pleura and Peritoneum (ISSPP) PIPAC database. Methods: Analysis of data from patients entered between June 15th, 2020, and February 28th, 2023. Results: Twelve centers reported 2,456 PIPAC procedures in 809 patients (median 2, range 1-18) with peritoneal metastasis (PM) from different primary tumors. Approximately 90 % had systemic chemotherapy prior to PIPAC. Twenty-eight percent were treated in prospective protocols. Overall non-access rate was 3.5 %. Concomitant surgical procedures were performed during PIPAC in 1.6 % of the patients. Median length of stay was 2 days. A total of 95 surgical complications were recorded, but only 22 % of these were graded ≥3b. Seventeen-hundred-and-three adverse events were noted, and 8 % were classified ≥3. The rate of complete or major histological response (peritoneal regression grade score, PRGS≤2) increased between the first and the third PIPAC in the group of patients who were evaluated by PRGS, and a PRGS ≤2 or a reduction of the mean PRGS of at least 1 between first and third PIPAC were observed in 80 %. Disease progression (50 %) or technical issues (19 %) were the most important reasons for stopping PIPAC treatment. Median overall survival from first PIPAC directed treatment varied from 10.7 months (CI 8.7-12.5) in gastric cancer to 27.1 months (16.4-50.5) in mesothelioma. Conclusions: The ISSPP PIPAC database provides substantial real-world data supporting the use of PIPAC directed therapy in patients with PM from different primary tumors.

High overall copy number variation burden by genome-wide methylation profiling holds negative prognostic value in surgically treated pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer with an overall 5-year survival of around 10 %. New prognostic tools to stratify patients are needed. Our main aim was to evaluate the prognostic value of overall copy number variation (CNV) burden in surgically treated PDAC. DNA extracted from 108 surgical PDAC specimens was examined to collect data on the genome-wide DNA methylation status of >850,000 CpG sites in promoter, gene body, and enhancer regions (Illumina Infinium Methylation EPIC BeadChip Kit). CNV profiles were obtained and all PDACs were stratified into one of three groups: Low, moderate, or high overall CNV burden. Tumors histologically showing a dominant conventional and/or tubulopapillary pattern in 60 %-100 % and 0-59 % were categorized as Group A and Group B as per Kalimuthu. We also performed targeted next-generation sequencing (NGS) and immunohistochemistry. High overall CNV burden held independent negative prognostic value with poor survival (HR 4.01 (95%CI 1.96-8.19), p = 0.00014) and was more frequent in Group B (p = 0.0003). Most frequent chromosomal arm-level aberrations were gains of 8q (29 %) and 1q (19 %) and losses of 17p (55 %), 18q (43 %), 6q (37 %), 9p (36 %), 6p (26 %), 19p (26 %), and 8p (25 %). Most frequent mutations found were in KRAS (95 %), TP53 (62 %), CDKN2A (24 %), SMAD4 (23 %), ATM (9 %), ARID1A (7 %), RNF43 (7 %), GNAS (6 %), and KDM6A (6 %). Group A PDACs showed more frequently KRAS variants other than Gly12Val and Gly12Asp (p = 0.012). Our data indicate that overall CNV burden using genome-wide methylation profiling may be a useful prognostic tool in surgically treated PDAC. Importantly, our approach, using data from genome-wide methylation profiling for analysis of overall CNV burden, can be performed on formalin-fixed and paraffin embedded PDAC tissues. Future studies should examine the prognostic value of overall CNV burden in unresectable PDAC.

Radiotherapy for Locally Advanced Pancreatic Adenocarcinoma-A Critical Review of Randomised Trials.

Pancreatic cancer is rising as one of the leading causes of cancer-related death worldwide. Patients often present with advanced disease, limiting curative treatment options and therefore making management of the disease difficult. Systemic chemotherapy has been an established part of the standard treatment in patients with both locally advanced and metastatic pancreatic cancer. In contrast, the use of radiotherapy has no clear defined role in the treatment of these patients. With the evolving imaging and radiation techniques, radiation could become a plausible intervention. In this review, we give an overview over the available data regarding radiotherapy, chemoradiation, and stereotactic body radiation therapy. We performed a systematic search of Embase and the PubMed database, focusing on studies involving locally advanced pancreatic cancer (or non-resectable pancreatic cancer) and radiotherapy without any limitation for the time of publication. We included randomised controlled trials involving patients with locally advanced pancreatic cancer, including radiotherapy, chemoradiation, or stereotactic body radiation therapy. The included articles represented mainly small patient groups and had a high heterogeneity regarding radiation delivery and modality. This review presents conflicting results concerning the addition of radiation and modality in the treatment regimen. Further research is needed to improve outcomes and define the role of radiation therapy in pancreatic cancer.

Decision making in the oesophageal cancer trajectory a source of tension and edginess to patients and relatives: a qualitative study.

PURPOSE: The curative oesophageal cancer continuum-diagnosis, treatment and survivorship represents different phases with its own challenges for the involved parties. The process of treatment decisions and interactions between patients with oesophageal cancer (EC), relatives and health professionals is vital yet not well described. The purpose of the study was to explore patients' and relatives' experiences with the process of decision-making through the EC illness and treatment trajectory. METHODS: Longitudinal explorative design was employed based on ethnographic fieldwork in the form of participant observations inspired by the American anthropologist James Spradley. RESULTS: Sixteen patients and 18 relatives were recruited for participant observations. In total, 184 hours of participant observations were conducted. The study showed that decision-making was filled with tension and edginess. Four themes were identified: 1) The encounter with the medical authority, 2) The need to see the big picture in the treatment trajectory, 3) A predetermined treatment decision, and 4) Meeting numerous different health professionals. CONCLUSION: The EC trajectory and decision-making were filled with anxiety. Patients and relatives lacked an overview of the treatment pathway, leading to their role in decision-making often being governed by the medical authority. Timing information and continuity are vital factors in decision-making.

Response Evaluation in Patients with Peritoneal Metastasis Treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC).

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) directed therapy emerged as a treatment of peritoneal metastasis (PM) a decade ago. The response assessment of PIPAC is not uniform. This narrative review describes non-invasive and invasive methods for response evaluation of PIPAC and summarizes their current status. PubMed and clinicaltrials.gov were searched for eligible publications, and data were reported on an intention-to-treat basis. The peritoneal regression grading score (PRGS) showed a response in 18-58% of patients after two PIPACs. Five studies showed a cytological response in ascites or peritoneal lavage fluid in 6-15% of the patients. The proportion of patients with malignant cytology decreased between the first and third PIPAC. A computed tomography showed stable or regressive disease following PIPAC in 15-78% of patients. The peritoneal cancer index was mainly used as a demographic variable, but prospective studies reported a response to treatment in 57-72% of patients. The role of serum biomarkers of cancer or inflammation in the selection of candidates for and responders to PIPAC is not fully evaluated. In conclusion, response evaluation after PIPAC in patients with PM remains difficult, but PRGS seems to be the most promising response evaluation modality.

Phase I study of intraperitoneal aerosolized nanoparticle albumin based paclitaxel (NAB-PTX) for unresectable peritoneal metastases.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel method to treat patients with peritoneal metastases (PM). We aimed to study the tolerability, safety, pharmacokinetics, and tumour response of nanoparticle albumin bound paclitaxel (NAB-PTX) during PIPAC in a Phase I study. METHODS: Eligible patients with biopsy-proven PM from ovarian, breast, gastric, hepatobiliary, or pancreatic origin underwent three PIPAC treatments using NAB-PTX with a four-week interval. The dose of NAB-PTX was escalated from 35 to 140 mg/m2 using a Bayesian design to estimate the maximum tolerated dose (MTD). FINDINGS: Twenty-three patients were included; thirteen (65%) patients combined PIPAC therapy with continued systemic chemotherapy. The most frequent toxicities were liver toxicity and anaemia. Treatment resulted in seven (35%) responders, six (30%) non-responders and seven (35%) patients with stable PM. Systemic absorption of NAB-PTX was slow, with median peak plasma concentrations reached after 3 to 4 h. Median NAB-PTX tumour tissue concentrations suggested accumulation: 14.6 ng/mg, 19.2 ng/mg and 40.8 ng/mg after the first, second and third PIPAC procedure respectively. EORTC QoL and VAS scores remained stable. Overall survival after one year was 57%. INTERPRETATION: PIPAC with NAB-PTX results in a favourable PK profile and promising anticancer activity in patients with unresectable PM. The MTD and recommended Phase II clinical trial dose are 140 mg/m2. In patients with impaired hepatobiliary function, a dose of 112.5 mg/m2 is recommended. FUNDING: Kom op tegen Kanker (Flemish League against Cancer).

Accuracy and clinical outcomes of pancreatic EUS-guided fine-needle biopsy in a consecutive series of 852 specimens.

Background and Objectives: Pancreatic EUS-guided fine needle biopsy (EUS-FNB) is increasingly used. Accuracy of EUS-FNB, particularly for benign diseases, utility of additional EUS-FNB if malignancy is suspected but initial diagnosis is inconclusive, and complication rate are not fully elucidated. We evaluated operating characteristics of EUS-FNB overall and for different diagnostic categories, value of additional EUS-FNB if malignancy is suspected but initial diagnosis is inconclusive, and frequency and type of complications. Methods: A retrospective tertiary single-center study including 852 consecutive pancreatic SharkCore EUS-FNBs from 723 patients between 2015 and 2020. EUS-FNB diagnoses were applied according to Papanicolaou Society's system and each category was further subcategorized. Results: Sufficient tissue cylinders for a histologic diagnosis were obtained in 93.4% (796/852). Accuracy was overall, for malignant, and benign entities 85.6% (confidence interval [CI]: 83.2%-87.9%), 88.3% (CI: 85.9%-90.4%), and 94% (CI: 92.2%-95.5%). Sensitivity and accuracy of EUS-FNB for autoimmune pancreatitis (AIP) (n = 15) was 83.3% (CI: 58.6%-96.4%) and 99.2% (CI: 98.3%-99.7%). Of patients in whom malignancy was suspected but initial EUS-FNB diagnosis was inconclusive, 7.3% (53/723) underwent one or two additional EUS-FNBs, and in 54.7% (29/53) of these, a malignant diagnosis was established. The frequency of hospitalization following EUS-FNB was 4.7%, with 0.2% (n = 2) incidents needing active intervention. Conclusions: We found a high accuracy of pancreatic EUS-FNB across all diagnostic categories including rare entities, such as AIP. In patients with a clinical suspicion of malignancy, additional EUS-FNB resulted in a conclusive diagnosis in more than half of cases. Complications necessitate hospitalization in almost 5%, but the majority are self-limiting.

Consensus statement for treatment protocols in pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Objectives: Safe implementation and thorough evaluation of new treatments require prospective data monitoring and standardization of treatments. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a promising alternative for the treatment of patients with peritoneal disease with an increasing number of suggested drug regimens. The aim was to reach expert consensus on current PIPAC treatment protocols and to define the most important research topics. Methods: The expert panel included the most active PIPAC centers, organizers of PIPAC courses and principal investigators of prospective studies on PIPAC. A comprehensive literature review served as base for a two-day hybrid consensus meeting which was accompanied by a modified three-round Delphi process. Consensus bar was set at 70% for combined (strong and weak) positive or negative votes according to GRADE. Research questions were prioritized from 0 to 10 (highest importance). Results: Twenty-two out of 26 invited experts completed the entire consensus process. Consensus was reached for 10/10 final questions. The combination of doxorubicin (2.1 mg/m2) and cisplatin (10.5 mg/m2) was endorsed by 20/22 experts (90.9%). 16/22 (72.7%) supported oxaliplatin at 120 with potential reduction to 90 mg/m2 (frail patients), and 77.2% suggested PIPAC-Ox in combination with 5-FU. Mitomycin-C and Nab-paclitaxel were favoured as alternative regimens. The most important research questions concerned PIPAC conditions (n=3), standard (n=4) and alternative regimens (n=5) and efficacy of PIPAC treatment (n=2); 8/14 were given a priority of ≥8/10. Conclusions: The current consensus should help to limit heterogeneity of treatment protocols but underlines the utmost importance of further research.

Whole genome sequencing identifies rare genetic variants in familial pancreatic cancer patients.

Pancreatic ductal adenocarcinoma (PDAC) represents one of the most lethal malignancies with very high mortality and short survival time. About 5-10% of the PDAC patients have a familial predisposition to the disease designated as familial pancreatic cancer (FPC), suggesting genetic modulation of FPC pathogenesis. It is estimated that currently identified sequence variants account for less than 20% of the genetic basis of FPC leaving the majority of the genetic architecture unclarified. We performed whole genome sequencing (WGS) analysis on benign formalin-fixed paraffin-embedded (FFPE) tissues from 35 FPC patients focusing on genes enriched by rare and functional sequence variants. We identified 40 genes hosting at least 2 protein truncating variants (PTVs). Significant overlaps of the 40 genes were found (p < 1 × 10-22 ) with cancer genes, cancer driver genes and genes found in previous studies on cancer, including ATM, POLE, BRCA2, TYR03, PABPC1 and SSC5D. The PTV genes are significantly overrepresented in biological pathways in cancer development and progression including extracellular matrix organization, signaling by RHO GTPases and RHO GTPase cycle. Association analysis using external controls detected 6 genes with p < 0.05. The WGS analysis revealed high heterogeneity in the detected rare variants among FPC patients and provides novel genes harboring potential mutational hotspots for future validation and replication.

Confusion with the definition and diagnostic criteria for acute on chronic pancreatitis: review and recommendations.

OBJECTIVES: Chronic pancreatitis (CP) is a fibroinflammatory disease complicated by episodes of acute inflammation (acute on chronic pancreatitis (ACP)). This entity is common, variably defined and can reflect different pathological mechanisms that requires different interventions. The aim of this study is to conduct a systematic review of how ACP is described, defined and diagnosed in the literature. METHODS: A systematic search was conducted from January 1993 to June 2020. All articles that used a term to describe ACP in adults were reviewed and definitions and diagnostic criteria were sought. RESULTS: After reviewing 2271 abstracts, 848 articles included a term to describe ACP. The most common descriptions were 'acute on/in CP' (374), 'acute exacerbation of CP' (345) and 'flare(-up) of CP' (43). Among the 848 articles, 14 included a pragmatic definition of ACP, and only 2 papers stated diagnostic criteria. These covered both acute inflammation and acute exacerbation of chronic abdominal pain. CONCLUSION: There is no universally accepted term, definition or diagnostic criteria for ACP. A consensus definition is needed to improve quality and comparability of future articles as well as clinical management.

Role of immunohistochemistry for interobserver agreement of Peritoneal Regression Grading Score in peritoneal metastasis.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC)-directed therapy is a new treatment option for peritoneal metastasis (PM). The 4-tiered Peritoneal Regression Grading Score (PRGS) has been proposed for assessment of histological treatment response. We aimed to evaluate the effect of immunohistochemistry (IHC) on interobserver agreement of the PRGS. Hematoxylin and eosin (H&E)-stained and IHC-stained slides (n = 662) from 331 peritoneal quadrant biopsies (QBs) taken prior to 99 PIPAC procedures performed on 33 patients were digitalized and uploaded to a web library. Eight raters (five consultants and three residents) assessed the PRGS, and Krippendorff's alpha coefficients (α) were calculated. Results (IHC-PRGS) were compared with data published in 2019, using H&E-stained slides only (H&E-PRGS). Overall, agreement for IHC-PRGS was substantial to almost perfect. Agreement (all raters) regarding single QBs after treatment was substantial for IHC-PRGS (α = 0.69, 95% confidence interval [CI] = 0.66-0.72) and moderate for H&E-PRGS (α = 0.60, 95% CI = 0.56-0.64). Agreement (all raters) regarding the mean PRGS per QB set after treatment was higher for IHC-PRGS (α = 0.78, 95% CI = 0.73-0.83) than for H&E-PRGS (α = 0.71, 95% CI = 0.64-0.78). Among residents, agreement was almost perfect for IHC-PRGS and substantial for H&E-PRGS. Agreement (all raters) regarding maximum PRGS per QB set after treatment was substantial for IHC-PRGS (α = 0.61, 95% CI = 0.54-0.68) and moderate for H&E-PRGS (α = 0.60, 95% CI = 0.53-0.66). Among residents, agreement was substantial for IHC-PRGS (α = 0.66, 95% CI = 0.57-0.75) and moderate for H&E-PRGS (α = 0.55, 95% CI = 0.45-0.64). Additional IHC seems to improve the interobserver agreement of PRGS, particularly between less experienced raters.

Effects of the peripherally acting µ-opioid receptor antagonist methylnaltrexone on acute pancreatitis severity: study protocol for a multicentre double-blind randomised placebo-controlled interventional trial, the PAMORA-AP trial.

BACKGROUND: Moderate to severe acute pancreatitis (AP) is associated with a high rate of complications and increased mortality, yet no targeted pharmacologic treatment currently exists. As pain is a dominant symptom in AP, patients are exposed to excess levels of both endo- and exogenous opioids, which may have harmful effects on the course of AP. This trial investigates the effects of the peripherally acting µ-opioid receptor antagonist (PAMORA) methylnaltrexone on disease severity and clinical outcomes in patients with moderate to severe AP. METHODS: PAMORA-AP is a multicentre, investigator-initiated, double-blind, randomised, placebo-controlled, interventional trial, which will be conducted at four referral centres for acute pancreatitis in Denmark. Ninety patients with early-onset AP (pain onset within 48 h) as well as predicted moderate to severe disease (two or more systemic inflammatory response syndrome criteria upon admission) will be prospectively included. Subsequently, participants will be randomised (1:1) to intravenous treatment with either methylnaltrexone or matching placebo (Ringer's lactate) during 5 days of admission. The primary endpoint will be the group difference in disease severity as defined and measured by the Pancreatitis Activity Scoring System (PASS) score 48 h after randomisation. Secondary endpoints include daily PASS scores; disease severity according to the Atlanta classification; quantification of need for analgesics, nutritional support, intravenous fluid resuscitation and antibiotics; duration of hospital admissions, readmission rates and mortality. Pain intensity and gut function will be self-reported using validated questionnaires. Exploratory endpoints include circulating levels of pro-and anti-inflammatory markers, polyethylene glycol recovery from the urine, circulating levels of blood markers of intestinal permeability, the prevalence of pancreatic complications on computed tomography (CT) scans, and colon transit time assessed using a CT-based radiopaque marker method. DISCUSSION: This trial aims to evaluate the PAMORA methylnaltrexone as a novel targeted pharmacotherapy in patients with moderate to severe AP with the potential benefit of improved patient outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT04743570 . Registered on 28 January 2021. EudraCT 2020-002313-18.

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.