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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 CO 2 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.

Awareness of the potential global overtreatment of patients with appendiceal neuroendocrine tumours (NETs) of 1–2 cm in size by performing oncological resections is increasing, but the rarity of this tumour has impeded clear recommendations to date. We aimed to assess the malignant potential of appendiceal NETs of 1–2 cm in size in patients with or without right-sided hemicolectomy. In this retrospective cohort study, we pooled data from 40 hospitals in 15 European countries for patients of any age and Eastern Cooperative Oncology Group performance status with a histopathologically confirmed appendiceal NET of 1–2 cm in size who had a complete resection of the primary tumour between Jan 1, 2000, and Dec 31, 2010. Patients either had an appendectomy only or an appendectomy with oncological right-sided hemicolectomy or ileocecal resection. Predefined primary outcomes were the frequency of distant metastases and tumour-related mortality. Secondary outcomes included the frequency of regional lymph node metastases, the association between regional lymph node metastases and histopathological risk factors, and overall survival with or without right-sided hemicolectomy. Cox proportional hazards regression was used to estimate the relative all-cause mortality hazard associated with right-sided hemicolectomy compared with appendectomy alone. This study is registered with ClinicalTrials.gov, NCT03852693. 282 patients with suspected appendiceal tumours were identified, of whom 278 with an appendiceal NET of 1–2 cm in size were included. 163 (59%) had an appendectomy and 115 (41%) had a right-sided hemicolectomy, 110 (40%) were men, 168 (60%) were women, and mean age at initial surgery was 36·0 years (SD 18·2). Median follow-up was 13·0 years (IQR 11·0–15·6). After centralised histopathological review, appendiceal NETs were classified as a possible or probable primary tumour in two (1%) of 278 patients with distant peritoneal metastases and in two (1%) 278 patients with distant metastases in the liver. All metastases were diagnosed synchronously with no tumour-related deaths during follow-up. Regional lymph node metastases were found in 22 (20%) of 112 patients with right-sided hemicolectomy with available data. On the basis of histopathological risk factors, we estimated that 12·8% (95% CI 6·5 –21·1) of patients undergoing appendectomy probably had residual regional lymph node metastases. Overall survival was similar between patients with appendectomy and right-sided hemicolectomy (adjusted hazard ratio 0·88 [95% CI 0·36–2·17]; p=0·71). This study provides evidence that right-sided hemicolectomy is not indicated after complete resection of an appendiceal NET of 1–2 cm in size by appendectomy, that regional lymph node metastases of appendiceal NETs are clinically irrelevant, and that an additional postoperative exclusion of metastases and histopathological evaluation of risk factors is not supported by the presented results. These findings should inform consensus best practice guidelines for this patient cohort. Swiss Cancer Research foundation.

The Chicago Consensus Working Group provides multidisciplinary recommendations for the management of appendiceal neoplasms specifically related to the management of peritoneal surface malignancies. These guidelines are developed with input from leading experts including surgical oncologists, medical oncologists, pathologists, radiologists, palliative care physicians, and pharmacists. These guidelines recognize and address the emerging need for increased awareness in the appropriate management of peritoneal surface disease. They are not intended to replace the quest for higher levels of evidence.

Purpose To compare the accuracy of MRI and CT for predicting the Peritoneal Cancer Index (PCI) preoperatively compared with the PCI tabulated at surgery. Methods Twenty-two patients underwent preoperative MRI and CT scanning followed by cytoreductive surgery for appendiceal ( n  = 17) and ovarian ( n  = 5) cancer. MR and CT examinations were retrospectively reviewed to determine the PCI. The results of these scores were compared with PCI tabulated at surgery. Patients were categorized as small volume tumor (PCI 0–9), moderate volume (PCI 10–20), and large volume (PCI > 20). Respective anatomic site scores for MRI and CT were compared with surgical findings. Results Compared with surgical PCI, MRI correctly categorized tumor volume in 20 (0.91) of 22 patients, including 3 of 4 patients with small volume tumor, 2 of 2 patients with moderate volume tumor, and 15 of 16 patients with large volume tumor. CT correctly categorized tumor volume in 11 of 22 (0.50) patients, including 2 of 4 patients with small-volume tumor, 2 of 2 patients with moderate volume tumor, and 7 of 16 patients with large-volume tumor. In 19 of 22 patients, CT underestimated the volume of tumor found at surgery. For all patients, the median PCI score at surgery was 33 compared with 36 for MRI and 15 for CT. Surgery confirmed 222 sites of tumor. MRI demonstrated per site sensitivity of 0.95, specificity 0.70, and accuracy 0.88. CT showed a corresponding per site sensitivity 0.55, specificity 0.86, and accuracy 0.63. Conclusions MRI more accurately predicts PCI preoperatively in patients undergoing evaluation for cytoreductive surgery.

Previous studies have demonstrated that the prognosis of disseminated mucinous appendiceal neoplasms is highly dependent upon tumor grade. Reflecting this, the 7th edition of the American Joint Committee on Cancer (AJCC) staging system now incorporates a three-tier grading system for prognostic staging of mucinous appendiceal tumors. However, the grading criteria are not well described. In order to address this issue, we evaluated clinicopathologic and molecular features of 219 cases from 151 patients with widely disseminated appendiceal mucinous neoplasia treated at our institution between 2004 and 2012. We identified histologic features that were associated with worse overall survival on univariate analysis: destructive invasion, high cytologic grade, high tumor cellularity, angiolymphatic invasion, perineural invasion, and signet ring cell component (all with P<0.0001). We used these morphologic characteristics to classify neoplasms into three grades: AJCC grade G1 lacked all adverse histologic features; AJCC grade G2 had at least one adverse histologic feature (except a signet ring cell component); and AJCC grade G3 were defined by the presence of a signet ring cell component. Patients with AJCC grade G2 and grade G3 adenocarcinomas had a significantly worse prognosis compared with AJCC grade G1 (P<0.0001 for each). A trend toward worse overall survival was identified for patients with AJCC grade G3 adenocarcinomas compared with AJCC grade G2 adenocarcinomas (P=0.07). Our multivariate analysis found that this three-tier grading system was a significant predictor of outcome (P=0.008), independent of other prognostic variables. After controlling for other prognostic variables, AJCC grade G2 was associated with a 2.7-fold increased risk of death (95% confidence interval (CI), 1.2–6.2) and AJCC grade G3 was associated with a 5.1-fold increased risk of death (95% CI, 1.7–14) relative to grade G1 tumors. Our results indicate that evaluation of a limited set of adverse histologic features allows for the separation of disseminated mucinous neoplasms of appendiceal origin into three morphologically defined and prognostically relevant grades as advocated by the AJCC.

There is a paucity of data to support surveillance protocols for localized, low-grade appendiceal mucinous neoplasms (LAMNs) after resection. A search strategy was developed to identify postoperative surveillance strategies for LAMNs, in the context of rates of recurrence and disease-free survival, and applied to four literature databases. Resultant citations were subject to screening in duplicate, in three stages: title, abstract, and full-text. Data was extracted from the final set of included articles and subject to descriptive statistics. A total of 16 articles, representing 1218 patients, were included. The duration of surveillance ranged from 0.1 to 294 months, and the mode surveillance interval was three months. The most common surveillance method was imaging (n ​= ​610 patients, 48.7 ​%). Thirty one patients had disease recurrence (2.7 ​%). Time to recurrence ranged from 2.5 to 68 months, and the range of five-year survival was 93.5–95.2 ​% among five studies. In the absence of strong evidence to suggest that surveillance confers a survival benefit for patients with localized LAMNs after resection, decisions about surveillance should be patient-oriented. •There is considerable practice variability in surveillance for localized, low-grade LAMNs after resection.•There is no strong evidence to suggest that surveillance confers a disease-free survival benefit for patients with localized, non-perforated LAMN resected with negative margins.•Decisions about surveillance should be patient-oriented, and informed by the patient's individual risk tolerance.

Background International consensus on classifications of appendiceal mucinous neoplasms (AMNs) and associated pseudomyxoma peritonei (PMP) have been carefully made but clinicopathological associations supporting decision making remain scarce. Objective This study aimed to assess interdependence between AMNs and PMP and provide directions for clinical management. Methods This two-center retrospective cohort study reviewed patients with PMP treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy between 2005 and 2021. The primary objective was to reassess histopathologic grade of AMNs and PMP according to the Peritoneal Surface Oncology Group International classification and to establish its interdependence. Secondary outcomes were recurrence rate, PMP grade progression, ovarian involvement, and overall survival (OS). Results Of 105 patients included, 78 (74.3%) had low-grade AMNs as the primary tumor, 8 (7.6%) had high-grade AMNs, 7 (6.7%) had mucinous adenocarcinoma (MAC), 1 (0.9%) had MAC with signet ring cells (SRC), and 11 (10.5%) had unidentified tumors. Overall, 11 patients (10.5%) had no PMP, 21 (20.0%) had acellular mucin, 56 (53.3%) had low-grade PMP, 12 (11.4%) had high-grade PMP, and 5 (4.8%) had PMP-SRC. In 11 cases (13.3%), AMNs and matching PMP grade differed. Over a 16-year follow-up, recurrence occurred in 31.8%, with three cases showing histopathologically changed PMP. Ovarian involvement was observed in 43/65 females (66.2%). Median OS was 13.8 years, and 5-year OS rates were 100%, 74.4%, 44.4%, and 20% for acellular mucin, low-grade PMP, high-grade PMP and PMP-SRC, respectively ( p  < 0.001 ). Conclusions AMN histology does not always reflects its associated PMP grade, while PMP grade strongly influences survival. Ovarian involvement and recurrent PMP showing unchanged histopathological features are common.

Background Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a novel, minimally invasive, safe, and repeatable method to treat carcinomatosis. Evidence regarding the clinical benefit (quality of life and survival) of PIPAC compared with that of conventional standard therapy (ST) is lacking. Methods This is the secondary analysis of the phase 1 US-PIPAC trial for refractory colorectal and appendiceal carcinomatosis. A PIPAC cohort was compared with a retrospective cohort of consecutive patients receiving ST. The primary outcome was number of good days (number of days alive and out of the hospital). The secondary outcomes were overall survival (OS), progression-free survival (PFS), health-related quality of life (HRQoL), and objective functional recovery (daily step count). Results The study included 32 patients (PIPAC, 12; ST, 20) with similar baseline characteristics. Compared with the ST cohort, the PIPAC cohort had lower median inpatient hospital stays (> 24 h) within 6 months (0 vs 1; p = 0.015) and 1 year (1 vs 2; p = 0.052) and higher median good days at 6 months (181 vs 131 days; p = 0.042) and 1 year (323 vs 131 days; p = 0.032). There was no worsening of HRQoL after repeated PIPACs. Step counts diminished immediately after PIPAC but returned to baseline within 2–4 weeks. Kaplan–Meier analysis demonstrated a favorable association between receipt of PIPAC and OS (median, 11.3 vs 5.1 months; p = 0.036). Conclusion Compared with ST, PIPAC was associated with higher number of good days, reduced hospitalization burden, and longer OS without a negative impact on HRQoL with repeated PIPACs. These findings are foundational for evaluation of PIPAC in a randomized clinical trial.

Purpose Appendiceal cancer is a rare and potentially aggressive malignancy. The objectives of this study were to characterize secular demographic patterns of disease and to determine survival by using a population-based data source. Methods Using the Surveillance, Epidemiology, and End Results database, we conducted a retrospective cohort analysis of patients treated from 2000–2009. Results We identified 4765 patients with appendiceal cancer. The incidence of appendiceal cancer increased by 54 % from 2000 (0.63 per 100,000) to 2009 (0.97 per 100,000 population). Incidence rates increased across all tumor types, stages, age groups, and gender. The most common malignancies were mucinous adenocarcinoma (38 %), followed by carcinoids (28 %), adenocarcinoma-not otherwise specified (NOS) (27 %), and signet ring cell adenocarcinoma (7 %). Larger tumor size and older patient age were significantly associated with higher relative odds of distant disease at diagnosis ( P  < 0.0001). Patient and demographic characteristics were significantly associated with higher relative hazard of death ( P  < 0.0001). Conclusions Although appendiceal cancer is rare, the incidence increased significantly in the USA from 2000 to 2009. The cause of this trend is not obvious. We did not observe increases differentially associated with stage, histology, or demographic characteristics. Further investigation is needed to examine factors underlying this increase.

Background The selection of hyperthermic intraperitoneal chemotherapy (HIPEC) or early postoperative intraperitoneal chemotherapy (EPIC) for peritoneal metastases from colorectal cancer or appendiceal neoplasms following cytoreductive surgery (CRS) depends on the surgeon’s discretion. This study was designed to compare postoperative and oncologic outcomes of HIPEC and EPIC using inverse probability of treatment weighting (IPTW). Methods This study included 175 patients who received HIPEC or EPIC following CRS at a single tertiary university hospital between December 1999 and December 2020. Inverse probability of treatment weighting analysis was performed to control for pretreatment characteristics between the two groups. Multivariate analysis was performed to determine factors associated with postoperative and survival outcomes. Results After IPTW, no significant differences in baseline demographics and tumor characteristics were observed between the two groups. The HIPEC group had a significantly longer operation time than the EPIC group. The EPIC group showed a significantly higher postoperative mortality rate than the HIPEC group. Operation time (odds ratio [OR] 1.01; 95% confidence interval [CI] 1.01–1.02; p < 0.001), bowel anastomosis (OR 7.25; 95% CI 1.16–45.2; p = 0.034), neoadjuvant chemotherapy (OR 7.62; 95% CI 1.85–31.4; p = 0.005), and EPIC (OR 8.76; 95% CI 2.16–35.5; p = 0.002) were independent risk factors for major surgical complications. No association was observed between intraperitoneal chemotherapy type and major hematologic toxicity, overall survival, progression-free survival, or peritoneal progression-free survival. Conclusions EPIC was a risk factor for major surgical complications. Survival outcomes were similar between the two types of intraperitoneal chemotherapy.