Impact of PIPAC-Oxaliplatin on Functional Recovery, Good Days, and Survival in a Refractory Colorectal and Appendiceal Carcinomatosis: Secondary Analysis of the US PIPAC Collaborative Phase 1 Trial.

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.

[Long-Term Survival of a Case with Peritoneal Dissemination from Appendiceal Goblet Cell Carcinoid Treated with Systemic Chemotherapy].

A 64-year-old man complained of lower abdominal pain and vomiting. The CT scan showed adhesional ileus; therefore, small bowel resection procedure was performed. Histological findings showed signet-ring cell carcinoma and poorly differentiated adenocarcinoma. We performed ileocecal resection as an additional surgery. The operative findings revealed peritoneal nodules. The histological findings suggested goblet cell carcinoid with peritoneal dissemination. mFOLFOX+bevacizumab was administered, and no progression was observed for 30 months after the surgery. Appendiceal goblet cell carcinoid is rare and its prognosis is poor. Here, we report a case of appendiceal GCC that achieved a relatively long-term survival despite peritoneal dissemination.

[A Case of Appendiceal Mucinous Carcinoma with Bladder Invasion Developed from Abscess-Forming Appendicitis, Which Was Curatively Resected after Chemotherapy].

The patient was a 35-year-old man who saw his first doctor with the chief complaint of painful urination. A contrast- enhanced CT scan of the abdomen revealed a diagnosis of abscess-forming appendicitis with inflammatory spread to the bladder, and conservative treatment was decided. Since antibiotic treatment failed to reduce the size of the abscess, he underwent surgery. The bladder wall was highly inflamed, only appendectomy was performed. Pathology revealed appendiceal mucinous carcinoma invading the bladder, so he was referred to our department. Because a total cystectomy was required for curative resection and there was concern about seeding associated with the initial surgery, he was judged to be unresectable, and received chemotherapy. After 6 courses of CAPOX+bevacizumab therapy, he was able to have a bladder- sparing curative resection because of the absence of distant metastasis and shrinkage of the tumor. He remains stable without recurrence 6 months after surgery. We herein report, with some discussion of the literature, this case of bladder-invading appendiceal mucinous carcinoma arising from abscess-forming appendicitis, for which a curative resection was possible after chemotherapy.

Nomogram to Predict Tube Occlusion During Hyperthermic Intraperitoneal Chemotherapy for Pseudomyxoma Peritonei.

OBJECTIVE: To investigate the factors contributing to the blockage of perfusion tubes during hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with appendiceal pseudomyxoma peritonei (PMP) undergoing combined cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy treatment, and to construct a nomogram for predicting the risk of tube occlusion. STUDY DESIGN: Observational study. Place and Duration of the Study: Department of Gastrointestinal Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan, China, from June 2017 to December 2023. METHODOLOGY: Tube occlusion was defined as the inability to achieve 30 minutes of continuous unobstructed perfusion. Statistical methods such as univariate analysis, multivariate analysis, and Lasso regression were employed for data analysis. RESULTS: The results revealed that 27% of the 383 hyperthermic intraperitoneal chemotherapy perfusion treatments resulted in the tube occlusion events. Multivariate logistic regression analysis identified age, CA-125, CA19-9, and pathological type as the independent risk factors. A nomogram predicting the tube occlusion was constructed and validated for its predictive accuracy and clinical utility. CONCLUSION: This study successfully developed a nomogram to predict the tube occlusion risk during cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy treatment for patients with pseudomyxoma peritonei, providing valuable guidance for clinical practice and aiding in personalised treatment decisions to improve patient prognosis. However, further research is needed to validate the reliability and clinical applicability of the model, as well as to investigate the impact of tube occlusion on treatment outcomes and corresponding management strategies. KEY WORDS: Pseudomyxoma peritonei, Cytoreductive surgery, Hyperthermic intraperitoneal chemotherapy treatment, Tube occlusion, Nomogram.

Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer.

INTRODUCTION: Appendiceal cancer (AC) excessive mucin production is a barrier to heated intraperitoneal chemotherapy (HIPEC) drug delivery. Bromelain is a pineapple stem extract with mucolytic properties. We explored bromelain treatment effects against mucinous AC in a patient-derived tumor organoid (PTO) model and an AC cell line. PATIENTS AND METHODS: PTOs were fabricated from tumor specimens obtained from patients with AC undergoing cytoreductive surgery with HIPEC. PTOs underwent HIPEC treatment with bromelain, cisplatin, and mitomycin C (MMC) at 37 °C and 42 °C with and without bromelain pretreatment. RESULTS: From October 2020 to May 2023, 16 specimens were collected from 13 patients with low-grade (12/16, 75%) and high-grade AC (4/16, 25%). The mucin-depleting effects of bromelain were most significant in combination with N-acetylcysteine (NAC) compared with bromelain (47% versus 10%, p = 0.0009) or NAC alone (47% versus 12.8%, p = 0.0027). Bromelain demonstrated > 31% organoid viability reduction at 60 min (p < 0.001) and > 66% in 48 h (p < 0.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (p = 0.0001) and 35.5% (p = 0.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3/7 activity and decreased Bcl-2 (p = 0.009) and Bcl-xL (p = 0.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A/B I (p < 0.03) and II (p < 0.031) were increased; while ATG7 (p < 0.01), ATG 12 (p < 0.04), and Becline 1(p < 0.03), expression decreased in bromelain-treated PTOs. CONCLUSIONS: Bromelain demonstrates cytotoxicity and mucolytic activity against appendiceal cancer organoids. As a pretreatment agent, it potentiates the cytotoxicity of multiple HIPEC regimens, potentially mediated through programmed cell death and autophagy.

Multi-Institutional Study Evaluating the Role of Circulating Tumor DNA in the Management of Appendiceal Cancers.

PURPOSE: Conventional surveillance methods are poorly sensitive for monitoring appendiceal cancers (AC). This study investigated the utility of circulating tumor DNA (ctDNA) in evaluating systemic therapy response and recurrence after surgery for AC. METHODS: Patients from two specialized centers who underwent tumor-informed ctDNA testing (Signatera) were evaluated to determine the association between systemic therapy and ctDNA detection. In addition, the accuracy of ctDNA detection during surveillance for the diagnosis of recurrence after complete cytoreductive surgery (CRS) for grade 2-3 ACs with peritoneal metastases (PM) was investigated. RESULTS: In this cohort of 94 patients with AC, most had grade 2-3 tumors (84.0%) and PM (84.0%). Fifty patients completed the assay in the presence of identifiable disease, among which ctDNA was detected in 4 of 7 (57.1%), 10 of 16 (62.5%), and 19 of 27 (70.4%) patients with grade 1, 2, and 3 diseases, respectively. Patients who had recently received systemic chemotherapy had ctDNA detected less frequently (7 of 16 [43.8%] v 26 of 34 [76.5%]; odds ratio, 0.22 [95% CI, 0.06 to 0.82]; P = .02). Among 36 patients with complete CRS for grade 2-3 AC-PM, 16 (44.4%) developed recurrence (median follow-up, 19.6 months). ctDNA detection was associated with shorter recurrence-free survival (median 11.3 months v not reached; hazard ratio, 14.1 [95% CI, 1.7 to 113.8]; P = .01) and showed high accuracy for the detection of recurrence (sensitivity 93.8%, specificity 85.0%). ctDNA was more sensitive than carcinoembryonic antigen (62.5%), CA19-9 (25.0%), and CA125 (18.8%) and was the only elevated biomarker in four (25%) patients with recurrence. CONCLUSION: This study revealed a reduced ctDNA detection frequency after systemic therapy and accurate recurrence assessment after CRS. These findings underscore the role of ctDNA as a predictive and prognostic biomarker for grade 2-3 AC-PM management.

Efficacy and Safety of Atezolizumab and Bevacizumab in Appendiceal Adenocarcinoma.

PURPOSE: Appendiceal adenocarcinoma (AA) remains an orphan disease with limited treatment options for patients unable to undergo surgical resection. Evidence supporting the efficacy of combined VEGF and PD-1 inhibition in other tumor types provided a compelling rationale for investigating this combination in AA, where immune checkpoint inhibitors have not been explored previously. EXPERIMENTAL DESIGN: We conducted a prospective, single-arm phase II study evaluating efficacy and safety of atezolizumab in conjunction with bevacizumab (Atezo+Bev) in advanced, unresectable AA. RESULTS: Patients treated with the Atezo+Bev combination had 100% disease control rate (1 partial response, 15 stable disease) with progression-free survival (PFS) of 18.3 months and overall survival not-yet-reached with median duration of follow-up of 40 months. These survival intervals were significantly longer relative to a clinically and molecularly matched synthetic control cohort treated with cytotoxic chemotherapy designed for colorectal cancer (PFS of 4.4 months, P = 0.041). CONCLUSIONS: In light of recent data demonstrating a lack of efficacy of 5-fluorouracil-based chemotherapy, Atezo+Bev is a promising treatment option for patients with low-grade unresectable AA; further study is warranted. SIGNIFICANCE: AA remains an orphan disease with limited systemic therapy options for patients who are not candidates for surgical resection. These data suggest activity from combined VEGF and PD-L1 inhibition that warrants further study.

Hyperthermic intraperitoneal chemotherapy in patients with incomplete cytoreduction for appendiceal pseudomyxoma peritonei: a 10-year treatment experience in China.

BACKGROUND: To explore the application value of hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with incomplete cytoreduction for appendiceal pseudomyxoma peritonei (PMP). METHODS: We retrospectively analyzed the clinical data of 526 patients with incomplete cytoreduction for appendiceal PMP to discover its prognostic factors, and the therapeutic value of HIPEC. RESULTS: The 5-year and 10-year overall survival rates of patients after cytoreductive surgery (CRS) treated with HIPEC were significantly higher than those without HIPEC (5y-OS: 58% vs. 48%, 10y-OS: 37% vs. 16%, P = 0.032). The median progression-free survival (PFS) following CRS was 20 months, with a 20% 3-year PFS. The median PFS following CRS + HIPEC was 33 months, with a 60% 3-year PFS (P = 0.000). Univariate analysis indicated that HIPEC, gender, completeness of cytoreduction (CCR) and pathological grade had statistical difference. Multivariate analysis showed that CRS without HIPEC and high pathological grade were independent risk factors for poor prognosis and rapid tumor progression. CONCLUSIONS: HIPEC may prolong the survival in patients with incomplete cytoreduction for low-grade appendiceal PMP. High pathological grade indicates poor survival and rapid tumor progression.

Impact of neoadjuvant systemic chemotherapy followed by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for appendiceal adenocarcinoma.

AIM: Peritoneal dissemination of infiltrative appendiceal tumors is a rare and poorly understood phenomenon. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-recognized treatment option for selected patients. Neoadjuvant systemic chemotherapy (NAC) has been shown to be associated with improved overall survival (OS) in colorectal peritoneal metastases but little is known of the impact of this from an appendiceal adenocarcinoma perspective. METHOD: A prospective database of 294 patients with advanced appendiceal primary tumors undergoing CRS ± HIPEC between June 2009 and December 2020 was reviewed. Baseline characteristics and long-term outcomes were compared between patients with adenocarcinoma who received neoadjuvant chemotherapy or upfront surgery. RESULTS: Eighty-six (29%) patients were histologically diagnosed with an appendiceal cancer. These included intestinal-type adenocarcinoma (11.6%), mucinous adenocarcinoma (43%), and goblet cell adenocarcinoma (GCA) or signet ring cell adenocarcinoma (SRCA) (45.4%). Twenty-five (29%) of these underwent NAC, of which eight (32%) exhibited some degree of radiological response. There was no statistical difference in OS at 3 years between the NAC and upfront surgery groups (47.3% vs. 75.8%, p = 0.372). Appendiceal histology subtypes, particularly GCA and SRCA (p = 0.039) and peritoneal carcinomatosis index >10 (p = 0.009), were factors independently associated with worse OS. CONCLUSION: Administration of NAC did not appear to prolong OS in the operative management of disseminated appendiceal adenocarcinomas. GCA and SRCA subtypes display a more aggressive biological phenotype.

Fragmentation of Care in Patients with Peritoneal Metastases Undergoing Cytoreductive Surgery.

BACKGROUND: The delivery of multimodal treatment at a high-volume center is known to optimize the outcomes of gastrointestinal malignancies. However, patients undergoing cytoreductive surgery (CRS) for peritoneal metastases often must 'fragment' their surgical and systemic therapeutic care between different institutions. We hypothesized that this adversely affects outcomes. PATIENTS AND METHODS: Adults undergoing CRS for colorectal or appendiceal adenocarcinoma at our institution between 2016 and 2022 were identified retrospectively and grouped by care network: 'coordinated care' patients received exclusively in-network systemic therapy, while 'fragmented care' patients received some systemic therapy from outside-network providers. Factors associated with fragmented care were also ascertained. Overall survival (OS) from CRS and systemic therapy-related serious adverse events (SAEs) were compared across the groups. RESULTS: Among 85 (80%) patients, 47 (55%) had colorectal primaries and 51 (60%) received fragmented care. Greater travel distance [OR 1.01 (CI 1.00-1.02), p = 0.02] and educational status [OR 1.04 (CI 1.01-1.07), p = 0.01] were associated with receiving fragmented care. OS was comparable between patients who received fragmented and coordinated care in the colorectal [32.5 months versus 40.8 months, HR 0.95 (CI 0.43-2.10), p = 0.89] and appendiceal [31.0 months versus 27.4 months, HR 1.17 (CI 0.37-3.74), p = 0.55] subgroups. The frequency of SAEs (7.8% versus 17.6%, p = 0.19) was also similar. CONCLUSIONS: There were no significant differences in survival or SAEs based on the networks of systemic therapy delivery. This suggests that patients undergoing CRS at a high-volume center may safely receive systemic therapy at outside-network facilities with comparable outcomes.

Taxane-Based Chemotherapy Is Effective in Metastatic Appendiceal Adenocarcinoma.

Appendiceal cancer is a rare, orphan disease with no therapies currently approved by the FDA for its treatment. Given the limited data regarding drug efficacy, these tumors have historically been treated with chemotherapy designed for colon cancer. However, an overwhelming body of molecular data has demonstrated that appendiceal adenocarcinoma is a distinct entity with key molecular differences from colon cancer, notably rare APC mutation. Recognizing that APC loss-of-function is thought to contribute to taxane resistance and that taxanes are effective in the treatment of other gastrointestinal tumors, including gastric, esophageal, and small bowel adenocarcinoma, we completed a single-center retrospective study to assess efficacy. In a cohort of 13 patients with metastatic appendiceal adenocarcinoma, treated with taxane chemotherapy the median overall survival was 8.8 months. Of 10 evaluable patients, we observed 3 responses, 4 patients with stable disease, and 3 with progression (30% response rate, 70% disease control rate). The results of this study showing activity of taxane-based chemotherapy in appendiceal adenocarcinoma support further clinical investigation of taxane therapy in this orphan disease.

Clinical benefits of FOLFOXIRI combined with bevacizumab for advanced-stage primary signet ring cell carcinoma of the appendix: A case report.

RATIONALE: Signet-ring cell carcinoma, which is an infrequent type of colorectal cancer. Abdominal pain is the primary presenting complaint of patients with acute appendicitis. It is difficult to diagnose patients with appendiceal carcinomas accompanying with symptoms of acute appendicitis. PATIENT CONCERNS: A 33-year-old female patient was admitted to our hospital, with chief complaints of "bilateral pelvic space-occupying lesions for 1 month, aggravated abdominal distension, and she accompanied with diarrhea for 3 days." DIAGNOSIS: The patient was with primary signet ring cell carcinoma of the appendix, presented with acute appendicitis, as well as bilateral ovarian metastasis and peritoneal implantation metastasis. INTERVENTIONS: She was then treated with irinotecan, oxaliplatin, calcium folinate, 5-FU combined with bevacizumab, surgical treatment, and postoperative adjuvant treatment with oxaliplatin, capecitabine regimen to consolidate the efficacy. OUTCOMES: The patient is in good conditions, and postoperative adjuvant chemotherapy is in progress as well. CONCLUSION: The outcomes highlighted the importance of strict histopathologic assessment for appendiceal adenocarcinoma, and provided new ideas for the diagnosis and treatment of advanced-stage signet ring cell carcinoma of the appendix.

Defining a role for systemic chemotherapy in local and advanced appendix adenocarcinoma.

BACKGROUND: Appendix adenocarcinomas (AAs) are rare tumours that often present late, with a propensity for peritoneal metastases (PMs). This study aimed to evaluate outcomes of AA patients undergoing cytoreductive surgery (CRS) with curative intent and determine the role of systemic chemotherapy. MATERIALS AND METHODS: Data were collected from a prospective database and classified according to World Health Organization (WHO) 2019 classification. Tumour clearance from CRS was described using a completeness of cytoreduction (CC) score ranging from 0 [no residual disease (RD)] to 3 (>2.5 cm RD). Patients with CC0-2 CRS received hyperthermic intraperitoneal chemotherapy (HIPEC). Systemic chemotherapy was categorised as 'prior' (>6 months before), 'neoadjuvant' (<6 months before), 'adjuvant' (<6 months after CC0-1 CRS) or 'palliative' (after CC2-3 CRS). Analyses used Kaplan-Meier and Cox regression methods. RESULTS: Between January 2005 and August 2021, 216 AA patients were identified for inclusion. Median age was 59 years (21-81 years). CRS/HIPEC was carried out in 182 (84%) patients, of whom 164/182 (76%) had mitomycin C HIPEC. CC0-1 was achieved in 172 (80%) patients. Systemic chemotherapy was given to 97 (45%) patients from the whole cohort and to 37/46 (80%) patients with positive nodes. Median overall survival (OS) was 122 months (95% confidence interval 61-182 months). After multivariate analysis, patients with acellular and lower-grade PM had similar OS to those with localised (M0) disease (P = 0.59 and P = 0.19). For patients with positive nodes, systemic chemotherapy was associated with reduced risk of death compared to no chemotherapy (P < 0.0019). CONCLUSION: This study identifies AA patients with positive lymph nodes derive the most benefit from systemic chemotherapy. We confirm the prognostic importance of stage and peritoneal grade, with excellent outcomes in patients with acellular mucin and lower-grade PM.

Safety and Efficacy of Oxaliplatin Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Colorectal and Appendiceal Cancer with Peritoneal Metastases: Results of a Multicenter Phase I Trial in the USA.

BACKGROUND: Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a laparoscopic locoregional treatment for peritoneal metastases (PM) from colorectal cancer (CRC) or appendiceal cancer (AC) in patients who cannot undergo cytoreductive surgery (CRS). While PIPAC has been studied in Europe and Asia, it has not been investigated in the USA. PATIENTS AND METHODS: We evaluated PIPAC with 90 mg/m2 oxaliplatin alone (cycle 1) and preceded by systemic chemotherapy with fluorouracil (5-FU) and leucovorin (LV) (cycle 2-3) as a multicenter prospective phase I clinical trial (NCT04329494). The primary endpoint was treatment-related adverse events (AEs). Secondary endpoints included survival and laparoscopic, histologic, and radiographic response. RESULTS: 12 patients were included: 8 with CRC and 4 with AC. Median prior chemotherapy cycles was 2 (interquartile range (IQR) 2-3). All patients were refractory to systemic oxaliplatin-based chemotherapy. Median peritoneal carcinomatosis index (PCI) was 28 (IQR 19-32). Six (50%) of twelve patients completed three PIPAC cycles. No surgical complications or dose-limiting toxicities were observed. Two patients developed grade 3 treatment-related toxicities (one abdominal pain and one anemia). Median overall survival (OS) was 12.0 months, and median progression-free survival (PFS) was 2.9 months. OS was correlated with stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria but not with laparoscopic response by PCI or histologic response by peritoneal regression grading system (PRGS). CONCLUSIONS: This phase I trial in the USA demonstrated safety, feasibility, and early efficacy signal of PIPAC with oxaliplatin and chemotherapy in patients with PM from AC or CRC who are refractory to standard lines of systemic chemotherapy.

Oral administration of bromelain and acetylcysteine in pseudomyxoma peritonei (PMP) caused by low-grade appendiceal mucinous neoplasm (LAMN): a case report.

BACKGROUND: Pseudomyxoma Peritonei (PMP) is a severe neoplastic clinical syndrome characterised by secretion of mucin from tumors often originating in the appendix. The standard treatment includes cytoreductive surgery (CRS) combined with heated intraperitoneal chemotherapy (HIPEC). A new perspective in PMP treatment aims at the mucins themselves as a therapeutic target. CASE PRESENTATION: Here we report the first case of PMP with peritoneal dissemination of mucinous implants caused by low-grade appendiceal mucinous neoplasm (LAMN) in a 58-year-old white male exclusively treated by appendectomy and oral administration of bromelain and acetylcysteine in the context of a medical self-experimentation (by co-author T.R.). Observation so far covers a period of 48 months including regular magnetic resonance imaging (MRI) with stable findings. CONCLUSIONS: Oral administration of bromelain and acetylcysteine can be used in the treatment of PMP caused by LAMN without relevant clinical side effects.