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.

RNA expression profiling of peritoneal metastasis from pancreatic cancer treated with Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC).

Objectives: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) is an experimental treatment option in peritoneal metastasis from pancreatic cancer (PM-PC). Aims were to examine mRNA profile of fibrosis due to response after systemic chemotherapy and PIPAC (Regression) compared to treatment-naïve PM-PC and chronic cholecystitis-related peritoneal fibrosis (Controls). Methods: Peritoneal biopsies (PBs) from PM-PC patients who had undergone systemic chemotherapy and PIPAC were evaluated with Peritoneal Regression Grading Score (PRGS). We extracted RNA from PBs with Regression (PRGS 1, n=11), treatment-naïve PM-PC (n=10), and Controls (n=10). Profiling of 800 mRNAs was performed (NanoString nCounter, PanCancer Immuno-Oncology 360 (IO-360) and 30 additional stroma-related mRNAs). Results: Regression vs. PM-PC identified six up-regulated and 197 down-regulated mRNAs (FDR≤0.05), linked to TNF-α signaling via NF-kB, G2M checkpoint, epithelial-mesenchymal transition, estrogen response, and coagulation. Regression vs. Controls identified 43 significantly up-regulated mRNAs, linked to interferon-α response, and down-regulation of 99 mRNAs, linked to TNF-α signaling via NF-kB, inflammatory response, epithelial-mesenchymal transition, KRAS signaling, and hypoxia (FDR≤0.05). Conclusions: In regressive fibrosis of PM-PC after systemic chemotherapy and PIPAC (Regression), downregulation of mRNAs related to key tumor biological pathways was identified. Regression also showed transcriptional differences from unspecific, benign fibrosis (Controls). Future studies should explore whether mRNA profiling of PBs with PM from PC or other primaries holds prognostic or predictive value.

What is long-term survival in patients with peritoneal metastasis from gastric, pancreatic, or colorectal cancer? A study of patients treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Objectives: A definition of long-term survival (LTS) in patients with peritoneal metastasis (PM) from gastric cancer (GC), pancreatic cancer (PC) or colorectal cancer (CRC) treated with systemic chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC) is lacking. We aimed to define LTS and investigate characteristics and treatment response in patients who reached LTS in data from two prospective trials. Methods: Retrospective study of patients with GC-, PC-, or CRC-PM from the prospective PIPAC-OPC1 and PIPAC-OPC2 studies. The definition of LTS was based on published systematic reviews and randomized controlled trials. LTS was defined at the time point where 25 % of the patients were alive in these studies. Histology based response was evaluated by the mean Peritoneal Regression Grading Score (PRGS) using biopsies obtained prior to PIPAC 3, and defined by a mean PRGS of ≤2.0 or a decrease of mean PRGS of ≥1, compared to baseline. Results: LTS was defined at 21 (GC), 15 (PC), and 24 (CRC) months. Fifty-one (47.2 %) patients (nine GC, 17 PC, 25 CRC) reached LTS calculated from the date of PM diagnosis. All but one received palliative chemotherapy before PIPAC, and 37 % received bidirectional treatment. More than 90 % of the LTS patients had response according to PRGS. The mOS from PIPAC 1 was 23.3, 12.4, and 28.5 months for GC, PC, and CRC LTS patients. Conclusions: Patients with PM from GC, PC, and CRC treated with systemic chemotherapy and PIPAC can reach LTS and most show histological response. Causality must be further investigated.

Risk Factors, Diagnosis and Management of Chyle Leak Following Esophagectomy for Cancers: An International Consensus Statement.

This Delphi exercise aimed to gather consensus surrounding risk factors, diagnosis, and management of chyle leaks after esophagectomy and to develop recommendations for clinical practice. Background: Chyle leaks following esophagectomy for malignancy are uncommon. Although they are associated with increased morbidity and mortality, diagnosis and management of these patients remain controversial and a challenge globally. Methods: This was a modified Delphi exercise was delivered to clinicians across the oesophagogastric anastomosis collaborative. A 5-staged iterative process was used to gather consensus on clinical practice, including a scoping systematic review (stage 1), 2 rounds of anonymous electronic voting (stages 2 and 3), data-based analysis (stage 4), and guideline and consensus development (stage 5). Stratified analyses were performed by surgeon specialty and surgeon volume. Results: In stage 1, the steering committee proposed areas of uncertainty across 5 domains: risk factors, intraoperative techniques, and postoperative management (ie, diagnosis, severity, and treatment). In stages 2 and 3, 275 and 250 respondents respectively participated in online voting. Consensus was achieved on intraoperative thoracic duct ligation, postoperative diagnosis by milky chest drain output and biochemical testing with triglycerides and chylomicrons, assessing severity with volume of chest drain over 24 hours and a step-up approach in the management of chyle leaks. Stratified analyses demonstrated consistent results. In stage 4, data from the Oesophagogastric Anastomosis Audit demonstrated that chyle leaks occurred in 5.4% (122/2247). Increasing chyle leak grades were associated with higher rates of pulmonary complications, return to theater, prolonged length of stay, and 90-day mortality. In stage 5, 41 surgeons developed a set of recommendations in the intraoperative techniques, diagnosis, and management of chyle leaks. Conclusions: Several areas of consensus were reached surrounding diagnosis and management of chyle leaks following esophagectomy for malignancy. Guidance in clinical practice through adaptation of recommendations from this consensus may help in the prevention of, timely diagnosis, and management of chyle leaks.

Importance of biopsy site selection for peritoneal regression grading score (PRGS) in peritoneal metastasis treated with repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC).

Objectives: The four-tiered peritoneal regression grading score (PRGS) is used for histological response evaluation in patients with peritoneal metastasis (PM) treated with pressurized intraperitoneal aerosol chemotherapy (PIPAC). Four quadrant biopsies (QBs) from the parietal peritoneum should be assessed by PRGS, but consensus on biopsy site strategy for follow-up biopsies during repeated PIPACs is lacking. We aimed to evaluate whether there is a difference between PRGS in QBs from clips marked PM (QB-CM) compared to biopsies from PM with the visually most malignant features (worst biopsy, WB). Methods: Prospective, descriptive study. During the first PIPAC, index QBs sites were marked with metal clips. During the second PIPAC, an independent surgical oncologist selected biopsy site for WB and biopsies were taken from QB-CM and WB. One blinded pathologist evaluated all biopsies according to PRGS. From each biopsy, three step sections were stained H&E, followed by an immunostained section, and another three step sections stained H&E. Results: Thirty-four patients were included from March 2020 to May 2021. Median age 64 years. Maximum mean PRGS in QB-CM at PIPAC 1 was 3.3 (SD 1.2). Maximum mean PRGS in QB-CM at PIPAC 2 was 2.6 (SD 1.2), whereas mean PRGS in WB at PIPAC 2 was 2.4 (SD 1.3). At PIPAC 2, there was agreement between maximum PRGS from QB-CM and PRGS from WB in 21 patients. Maximum PRGS from QB-CM was higher in nine and lower in four patients, compared to PRGS from WB. Conclusions: Biopsies from QB-CM did not overestimate treatment response compared to biopsies from WB.

Learning Curves of Ivor Lewis Totally Minimally Invasive Esophagectomy by Hospital and Surgeon Characteristics: A Retrospective Multinational Cohort Study.

OBJECTIVE: To describe the pooled learning curves of Ivor Lewis totally minimally invasive esophagectomy (TMIE) in hospitals stratified by predefined hospital- and surgeon-related factors. BACKGROUND: Ivor Lewis (TMIE is known to have a long learning curve which is associated with considerable learning associated morbidity. It is unknown whether hospital and surgeon characteristics are associated with more efficient learning. METHODS: A retrospective analysis of prospectively collected data of consecutive Ivor Lewis TMIE patients in 14 European hospitals was performed. Outcome parameters used as proxy for efficient learning were learning curve length, learning associated morbidity, and the plateau level regarding anastomotic leakage and textbook outcome. Pooled incidences were plotted for the factor-based subgroups using generalized additive models and 2-phase models. Casemix predicted outcomes were plotted and compared with observed outcomes. The investigated factors included annual volume, TMIE experience, clinic visits, courses and fellowships followed, and proctor supervision. RESULTS: This study included 2121 patients. The length of the learning curve was shorter for centers with an annual volume >50 compared to centers with an annual volume <50. Analysis with an annual volume cut-off of 30 cases showed similar but less pronounced results. No outcomes suggesting more efficient learning were found for longer experience as consultant, visiting an expert clinic, completing a minimally invasive esophagectomy fellowship or implementation under proctor supervision. CONCLUSIONS: More efficient learning was observed in centers with higher annual volume. Visiting an expert clinic, completing a fellowship, or implementation under a proctor's supervision were not associated with more efficient learning.

Short-term outcomes after minimally invasive oesophagectomy.

INTRODUCTION: Minimally invasive oesophagectomy (MIO) has gained increasing popularity. This study reports the results of the first patients operated using this technique at our department. METHODS: All procedures were prospectively registered in a database. Patients were followed until death, two years after surgery or 1 January 2019. RESULTS: A total of 150 procedures were performed (from 23 November 2015 to 27 February 2018). The median proced-ure time decreased from 350 minutes for the initial 75 pa-tients to 320 minutes for the final 75 patients (p < 0.05). Blood loss decreased from 200 ml to 100 ml (p < 0.05), respectively. The conversion rate for the abdominal procedure was 7% for the initial 75 patients and 8% for the final 75 patients (not significant (NS)). For the thoracic procedure, the corresponding figures were 11% and 7% (NS), respectively. Anastomotic leakage was seen in 17% (initial patients) and 11% (final patients) (NS); however, less than 20% of the leakages needed surgical treatment. The median length of post-operative stay was nine days for both groups. For all 150 patients, pulmonary complications were observed in 18% and cardiac complications in 11%. The 30-day mortality rate was 2% and the one-year survival rate was 86% (124 registered patients). CONCLUSIONS: MIO was introduced at our department with acceptable morbidity and mortality rates and the short-term oncological result was not compromised. FUNDING: none. TRIAL REGISTRATION: The study was approved as a quality project by the Region of Southern Denmark (18/37355).

[Metastasis from a malignant melanoma presenting as a gall bladder polyp].

Gall bladder polyps larger than 10 mm hold an increased risk of malignancy. In this case report, a metastasis from a superficial spreading malignant melanoma level IV presented as a large gall bladder polyp in a 52-year-old woman. The melanoma had been surgically resected eight years earlier. The most frequent distant metastatic sites of malignant melanoma are soft tissue, lung, liver, skin and brain, but metastasis to the gallbladder is rare. It is important to refer patients with large gall bladder polyps to centres with expertise in liver surgery.

[Palliative treatment of malignant gastric outlet obstruction].

In gastric outlet obstruction (GOO) the passage from the stomach to the intestine is obstructed. The condition is referred to as malignant GOO if cancer is the reason. Self-expanding metal stents (SEMS) and gastrojejunostomy (GEA) are the therapeutic options for palliation, with SEMS often being recommended as first choice. However, no major difference in terms of clinical success has been shown between SEMS and GEA in comparative studies. Thus, the choice between SEMS and GEA should be made on an individual basis. If SEMS is chosen, covered and uncovered stents offer equal success rates.

Ten years of experience with transgastric necrosectomy for walled-off necrosis in acute pancreatitis.

INTRODUCTION: The aim of this study was to report our results with open transgastric necrosectomy for walled-off necrosis in acute pancreatitis over a period of ten years. METHODS: Patients operated at the department from 2003 until 2012 were studied retrospectively. RESULTS: A total of 50 patients had surgery. The median age was 55 years (range: 17-79 years). The presumed aetiologies were: gallstones (n = 28), alcohol (n = 8) and other causes (n = 14). The median preoperative stay at hospital was 50 days (range: 2-150 days). Bacterial culture from the necrotic tissue was positive in 26 patients (52%), negative in 15 patients (30%); and in nine patients, no information on this was available. In all, 22 patients (44%) had one or more incidents (i.e. abdominal compartment syndrome, bleeding, new abscess, pleural effusion or delayed gastric emptying) where additional invasive therapy was needed. Ten patients (20%) died during their admission to our department. In total, 18 (45%) patients developed late complications defined as endocrine and/or exocrine malfunction of the pancreas (diabetes (n = 10), exocrine insufficiency (n = 4), both diabetes and exocrine insufficiency (n = 4)). CONCLUSION: Acute pancreatitis with walled-off necrosis has a high mortality rate. Need for additional therapy following necrosectomy was associated with fatal outcome. Endocrine and exocrine insufficiency was often seen at follow-up. FUNDING: none. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency via Region of Southern Denmark (case no. 13/29319).

Endoscopic ultrasonography is a valuable diagnostic tool in patients with incidental findings in the pancreas or bile ducts.

INTRODUCTION: Incidental findings are often seen at computed tomographies (CT). This study describes patients who had an endoscopic ultrasonography (EUS) because of an incidental finding in the pancreas/bile duct. METHODS: Patients referred for EUS between September 2012 and September 2013 because of an incidental finding in the pancreas/bile duct at a CT were prospectively enrolled. After EUS, the findings of this procedure were noted together with the plan for further diagnostic work-up or therapy. A follow-up was made after 6 months and 1 year after EUS was performed. RESULTS: A total of 47 patients (24 women, 23 men) were registered with an incidental finding. The median age was 69 years (range: 45-83 years). Diagnoses after performing EUS were: normal findings (n = 16), cystic lesion (n = 16), mass lesion (n = 6), inconclusive (n = 6) and other specified (n = 3). The plan after EUS was: no further evaluation (n = 27), referred for new EUS or other imaging procedures (n = 14) and referred for surgery/endoscopic retrograde cholangiopancreatography (n = 6). In total, 6 patients proved to have neoplastic diseases in the pancreas. None of the patients who were stopped from further evaluation following EUS later proved to have a malignant disease in the pancreas. CONCLUSION: EUS is a valuable diagnostic tool in patients with incidental findings in the pancreas/bile duct noted at a CT. Many patients can be stopped from further diagnostic work-up after EUS with a minimal risk of overlooking a malignant disease. FUNDING: not relevant. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency via Region of Southern Denmark (case no. 13/27,321).

[Malignant lymphoma perforating the small intestine].

A rare cause of acute abdominal pain: lymphoma making its debut by perforation of the small intestine. Lymphomas localised to the gastrointestinal tract are rare. A case is presented where the initial symptom of the disease was acute abdominal pain because of perforation of one of the lymphomas in the small intestine. The diagnostic and therapeutic options in such emergency cases are discussed.

[Diagnostic workup for incidentally found thickening of the stomach wall]. / Udredning af tilfældigt opdaget fortykkelse af ventriklens væg.

Thickened stomach wall is sometimes found incidentally in abdominal CT scans. A review of the literature supports our general perception that normal findings or benign diseases are found in the majority of the cases. Gastroscopy seems to be sufficient for making the diagnosis in most patients; and endoscopic ultrasonograhy is only indicated for those patients in whom malignant diseases or benign submucosal lesions with need for therapy are still suspected after standard upper endoscopy has been performed.

Potential impact of adding endoscopic ultrasound to standard imaging procedures in the preoperative assessment of resectability in patients with liver tumors.

OBJECTIVE: The value of endoscopic ultrasonography (EUS) in patients with liver diseases is limitedly described. The aim of this study was to evaluate the potential impact of adding EUS to standard imaging procedures in the evaluation of resectability in patients with liver tumors. MATERIAL AND METHODS: Patients who, based on the findings of CT and/or MRI, had been referred for curative resection of liver tumours were studied. Each patient underwent EUS before the final assessment of resectability, which was done by laparoscopic ultrasound or laparotomy. RESULTS: Sixty-four patients were included. Intended curative resection was performed in 19 (30%) patients. Thirty-five (55%) patients were considered to have non-curative malignant disease. In 10 (15%) patients, the tumor was judged to be benign and surgery was not performed. There were no complications related to EUS. The sensitivity, specificity, positive predictive value, and negative predictive value of EUS regarding prediction of non-resectability were 0.24, 0.94, 0.80 and 0.56 (tumor in right lobe), 0.50, 1.0, 1.0 and 0.75 (tumor in left lobe), and 0.60, 0.67, 0.86 and 0.33 (tumors in both lobes), respectively. Sixteen patients (25%) would have had changed their further management, if decision regarding non-resectability had been taken after EUS. DISCUSSION: Addition of EUS to a standard imaging set-up based on CT and/or MRI would have changed the management in 25% of the patients otherwise scheduled for resection of suspected liver tumors.

Combined pretherapeutic endoscopic and laparoscopic ultrasonography may predict survival of patients with upper gastrointestinal tract cancer.

BACKGROUND: The combination of endoscopic and laparoscopic ultrasonography (EUS-LUS) is accurate for resectability assessment of patients with upper gastrointestinal cancer (UGIC). But neither the ability of EUS/LUS to predict long-term prognosis nor the potential impact on patient survival using this selection strategy has been investigated. This prospective, single-center study evaluated whether pretherapeutic EUS-LUS stratification related to the prognosis in UGIC patients and whether patient selection by this strategy provided a prognostic outcome comparable with survival data from the literature. METHODS: Each patient had a pretherapeutic tumor node metastasis (TNM) stage and a resectability assessment assigned based on EUS-LUS findings. Survival curves were constructed and compared for each of the EUS-LUS TNM stage and resectability groups at the end of the observation period. Finally, the R0 resection rate, median, and 5-year survival rates were compared with the literature. RESULTS: This study enrolled 936 consecutive patients with esophageal (n = 256), gastric (n = 273), or pancreatic (n = 407) cancer. A statistically significant survival difference (p < 0.01) between the different TNM stages and resectability groups predicted by EUS-LUS was observed regardless of the cancer type. The poor prognosis for the patients with irresectable or disseminated UGIC was accurately predicted by EUS and LUS. The R0 resection rate as well as the median and 5-year survival rates were comparable with data from the literature. CONCLUSION: The pretherapeutic EUS-LUS patient stratification related significantly to the final prognosis for UGIC patients. An EUS-LUS-based patient selection strategy seemed to provide a prognostic outcome similar to data from computed tomography (CT)-based populations.