A nomogram prediction model of pseudomyxoma peritonei established based on new prognostic factors of HE stained pathological images analysis.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare clinical malignant syndrome, and its rarity causes a lack of pathology research. This study aims to quantitatively analyze HE-stained pathological images (PIs), and develop a new predictive model integrating digital pathological parameters with clinical information. METHODS: Ninety-two PMP patients with complete clinic-pathological information, were included. QuPath was used for PIs quantitative feature analysis at tissue-, cell-, and nucleus-level. The correlations between overall survival (OS) and general clinicopathological characteristics, and PIs features were analyzed. A nomogram was established based on independent prognostic factors and evaluated. RESULTS: Among the 92 PMP patients, there were 34 (37.0%) females and 58 (63.0%) males, with a median age of 57 (range: 31-76). A total of 449 HE stained images were obtained for QuPath analysis, which extracted 40 pathological parameters at three levels. Kaplan-Meier survival analysis revealed eight clinicopathological characteristics and 20 PIs features significantly associated with OS (p < 0.05). Partial least squares regression was used to screen the multicollinearity features and synthesize four new features. Multivariate survival analysis identified the following five independent prognostic factors: preoperative CA199, completeness of cytoreduction, histopathological type, component one at tissue-level, and tumor nuclei circularity variance. A nomogram was established with internal validation C-index 0.795 and calibration plots indicating improved prediction performance. CONCLUSIONS: The quantitative analysis of HE-stained PIs could extract the new prognostic information on PMP. A nomogram established by five independent prognosticators is the first model integrating digital pathological information with clinical data for improved clinical outcome prediction.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy to Treat Pseudomyxoma Peritonei of Ovarian Origin: A Retrospective French RENAPE Group Study.

BACKGROUND: Ovarian pseudomyxoma peritonei (OPMP) are rare, without well-defined therapeutic guidelines. We aimed to evaluate cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) to treat OPMP. METHODS: Patients from the French National Network for Rare Peritoneal Tumors (RENAPE) database with proven OPMP treated by CRS/HIPEC and with histologically normal appendix and digestive endoscopy were retrospectively included. Clinical and follow-up data were collected. Histopathological and immunohistochemical features were reviewed. RESULTS: Fifteen patients with a median age of 56 years were included. The median Peritoneal Cancer Index was 16. Following CRS, the completeness of cytoreduction (CC) score was CC-0 for 9/15 (60%) patients, CC-1 for 5/15 (33.3%) patients, and CC-2 for 1/15 (6.7%) patients. The median tumor size was 22.5 cm. After pathological review and immunohistochemical studies, tumors were classified as Group 1 (mucinous ovarian epithelial neoplasms) in 3/15 (20%) patients; Group 2 (mucinous neoplasm in ovarian teratoma) in 4/15 (26.7%) patients; Group 3 (mucinous neoplasm probably arising in ovarian teratoma) in 5/15 (33.3%) patients; and Group 4 (non-specific group) in 3/15 (20%) patients. Peritoneal lesions were OPMP pM1a/acellular, pM1b/grade 1 (hypocellular) and pM1b/grade 3 (signet-ring cells) in 13/15 (86.7%), 1/15 (6.7%) and 1/15 (6.7%) patients, respectively. Disease-free survival analysis showed a difference (p = 0.0463) between OPMP with teratoma/likely-teratoma origin (groups 2 and 3; 100% at 1, 5, and 10 years), and other groups (groups 1 and 4; 100%, 66.6%, and 50% at 1, 5, and 10 years, respectively). CONCLUSION: These results suggested that a primary therapeutic strategy using complete CRS/HIPEC for patients with OPMP led to favorable long-term outcomes.

Optimal peritoneal cancer index cutoff point for predicting surgical resectability of pseudomyxoma peritonei in treatment-naive patients.

BACKGROUND: The peritoneal cancer index (PCI) has been used to predict surgical outcomes for pseudomyxoma peritonei (PMP). The present study aimed to establish the optimal cutoff point for PCI to predict surgical resectability of PMP. METHODS: A total of 366 PMP patients were included. The patients were divided into low-grade and high-grade groups. Based on the completeness of the cytoreduction (CC) score, both low-grade and high-grade PMP patients were further divided into complete cytoreductive surgery (CRS) and maximal tumor debulking (MTD) subgroups. The ability to predict surgical resectability of total and selected PCI (regions 2 + 9 to 12) was analyzed through receiver operating characteristic (ROC) curves. RESULTS: Both total and selected PCI demonstrated excellent discriminative ability in predicting surgical resectability for low-grade PMP patients (n = 266), with the ROC-AUC of 0.940 (95% CI: 0.904-0.965) and 0.927 (95% CI: 0.889-0.955). The corresponding optimal cutoff point was 21 and 5, respectively. For high-grade PMP patients (n = 100), both total and selected PCI exhibited good performance in predicting surgical resectability, with the ROC-AUC of 0.894 (95% CI: 0.816-0.946) and 0.888 (95% CI: 0.810-0.943); correspondingly, the optimal cutoff point was 25 and 8, respectively. The discriminative ability between total and selected PCI in predicting surgical resectability did not show a statistical difference. CONCLUSIONS: Both total and selected PCI exhibited good performance and similarity in predicting complete surgical resection for both low-grade and high-grade PMP patients. However, the selected PCI was simpler and time-saving in clinical practice. In the future, new imaging techniques or predictive models may be developed to better predict PCI preoperatively, which might assist in confirming whether complete surgical resection can be achieved.

Whole-Exome Sequencing Identifies Mutation Profile and Mutation Signature-Based Clustering Associated with Prognosis in Appendiceal Pseudomyxoma Peritonei.

Pseudomyxoma peritonei (PMP) is a rare malignant clinical syndrome with little known about the global mutation profile. In this study, whole-exome sequencing (WES) was performed in 49 appendiceal PMP to investigate mutation profiles and mutation signatures. A total of 4,020 somatic mutations were detected, with a median mutation number of 56 (1-402). Tumor mutation burden (TMB) was generally low (median 1.55 mutations/Mb, 0.12-11.26 mutations/Mb). Mutations were mainly enriched in the function of cancer-related axonogenesis, extracellular matrix-related processes, calcium signaling pathway, and cAMP signaling pathway. Mutations in FCGBP, RBFOX1, SPEG, RTK-RAS, PI3K-AKT, and focal adhesion pathways were associated with high-grade mucinous carcinoma peritonei. These findings revealed distinct mutation profile in appendiceal PMP. Ten mutation signatures were identified, dividing patients into mutation signature cluster (MSC) 1 (N = 28, 57.1%) and MSC 2 (N = 21, 42.9%) groups. MSC (P = 0.007) was one of the four independent factors associated with 3-year survival. TMB (P = 0.003) and microsatellite instability (P = 0.002) were independent factors associated with MSC 2 grouping. Taken together, our findings provided a broader view in the understanding of molecular pathologic mechanism in appendiceal PMP and may be critical to developing an individualized approach to appendiceal PMP treatment. IMPLICATIONS: This work describes exhaustive mutation profile of PMP based on WES data and derives ten mutation signatures, which divides patients into two clusters and serve as an independent prognostic factor associated with 3-year survival.

Clinical Effectiveness of Preoperative 18F-FDG PET/CT in Predicting Pathological Tumor Grade in Patients with Pseudomyxoma Peritonei Originating from Appendix: A Retrospective Cohort Study.

BACKGROUND: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is the standard treatment for patients with pseudomyxoma peritonei (PMP). In some malignancies, the standard uptake value of positron emission tomography with 2-deoxy-2-18F-fluoro-D-glucose integrated with computed tomography (18F-FDG PET/CT) is now accepted as a reliable indicator of neoplastic behavior. This study aimed to evaluate the association between the maximum standardized uptake value (SUVmax) and pathological grade in patients with PMP and to investigate the significance of SUVmax in the preoperative assessment of these patients. PATIENTS AND METHODS: In this retrospective single-center study, consecutively enrolled patients diagnosed with PMP of appendiceal origin underwent preoperative 18F-FDG PET/CT. SUVmax was calculated as the highest SUVmax value in the abdomen excluding the primary site. SUVmax was compared with the pathological grade (low or high grade) of PMP tumors according to the World Health Organization classification and further analyzed with respect to the estimated cutoff point, sensitivity, specificity, and receiver operating characteristic. RESULTS: In total, 160 patients were included. CRS was successfully performed in 93 patients and palliative debulking surgery in 67 patients. The pathological grade was high in 45 patients and low in 115. High-grade patients had a higher median SUVmax on 18F-FDG PET/CT than did low-grade patients (3.83 versus 2.34, p < 0.001). The highest area under the curve was 0.81, with a sensitivity of 77.8%, specificity of 72.3%, and cutoff point of 2.63. CONCLUSION: This study suggests that the SUVmax of preoperative 18F-FDG PET/CT is associated with the pathological grade in patients with PMP.

Confined Low Grade Appendiceal Mucinous Neoplasm With Coexisting Distant Metastasis.

BACKGROUND/AIM: Appendiceal mucinous neoplasms (AMNs) are tumors with dysplastic mucinous epithelium, a pushing growth pattern but no infiltrative invasion to the appendiceal wall. Some AMNs are associated with pseudomyxoma peritonei, characterized by intraperitoneal mucinous involvement. Recent studies have demonstrated that LAMNs confined to the appendix have low or no risk for disease recurrence, progression, and peritoneal involvement during follow up. CASE REPORT: Here, we present two extremely rare cases with confined low grade appendiceal mucinous neoplasm (pTis and pT3) and simultaneous extraperitoneal subcutaneous or ovary involvement at the time of diagnosis. CONCLUSION: Our cases demonstrate that although the primary tumor is limited to the appendix, coexisting distant metastasis may occur on very rare occasions.

Establishment and characterization of NCC-PMP2-C1: a novel patient-derived cell line of pseudomyxoma peritonei with signet ring cells.

Pseudomyxoma peritonei (PMP) is a rare phenomenon, characterized by accumulation of mucus in the abdominal cavity due to a mucinous neoplasm. Histologically, PMP is divided into three prognostic classes, namely low-grade mucinous carcinoma peritonei (LGMCP), high-grade mucinous carcinoma peritonei (HGMCP), and high-grade mucinous carcinoma peritonei with signet ring cells (HGMCP-S); HGMCP-S exhibits the worst prognosis. Complete cytoreductive surgery and hyperthermic intraperitoneal chemotherapy have been established as the standard therapy for PMP. However, 50% of patients with PMP experience a recurrence, and 30-40% are unable to receive the standard treatment due to invasive diseases. Therefore, novel therapies are required for their treatment. Although patient-derived cell lines are important tools for basic and pre-clinical research, PMP cell lines derived from patients with HGMCP-S have never been reported. Thus, we established a novel PMP cell line NCC-PMP2-C1, using surgically resected tumor tissue from a patient with HGMCP-S. NCC-PMP2-C1 cells were maintained for more than five months and passaged 30 times under culture conditions. NCC-PMP2-C1 cells exhibited multiple deletions and somatic mutations, slow growth, histological features, and dissemination of tumor cells in nude mice. Screening for the anti-proliferative effects of anti-cancer drugs on cells revealed that bortezomib, mubritinib, and romidepsin had a significant response against NCC-PMP2-C1 cells. Thus, the NCC-PMP2-C1 cell line is the first PMP cell line harboring signet ring cells and will be a valuable resource for basic and preclinical studies of HGMCP-S.

Bland-Altman agreement analysis between CT predicted and surgical peritoneal cancer index in pseudomyxoma peritonei of appendiceal origin.

Peritoneal cancer index (PCI) is the surgical variable most commonly used to quantify the extent of peritoneal metastases for pseudomyxoma peritonei (PMP) patients. The present study aimed to investigate the agreement between CT predicted and surgical PCI by the Bland-Altman method for PMP of appendiceal origin. A total of 167 PMP patients of appendiceal origin were included between 2016 and 2021. Bland-Altman analysis was performed for both total PCI and selected PCI (regions 2 + 9-12). After the Bland-Altman plot was drawn, the mean bias and its 95% limit of agreements (LoAs) was quantified. Besides, the correlation coefficients between CT-PCI and surgical PCI were also been calculated. The Bland-Altman plot showed the mean bias ± SD between total CT-PCI and surgical PCI as 0.431 ± 3.005, with the LoAs from - 5.459 to 6.321. There were nine points of difference in total PCI exceeded the 95% LoAs, with the rate of 5.39% (9/167). As for selected CT-PCI, Bland-Altman plot showed the mean bias ± SD between selected CT-PCI and surgical PCI as - 0.287 ± 1.955, with the LoAs from - 4.118 to 3.544. There were ten points of difference in selected PCI exceeded the 95% LoAs, with the rate of 5.99% (10/167). The Spearman's rank correlation coefficient between total CT-PCI and surgical PCI was 0.911, P < 0.001, as for selected CT-PCI and surgical PCI, the coefficient was 0.909, P < 0.001. Although there was a strong correlation for both total and selected CT-PCI with surgical PCI, however, the agreement is still not good in Bland-Altman analysis, which suggested that CT-PCI cannot predict surgical PCI accurately even in professional PMP treatment centers. In brief explanation, CT makes it difficult to distinguish the borderline between tumor tissue and mucus and to detect tumor lesions in the small intestine regions, which caused overestimation or underestimation by CT-PCI. In the future, a multiple linear regression model based on CT-PCI might accurately predict surgical PCI preoperatively.

[Efficacy of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei].

Objective: To evaluate the efficacy and safety of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of pseudomyxoma peritonei (PMP). Methods: In this descriptive case series study, we retrospective analyzed the records of PMP patients treated with CRS and HIPEC between January 2013 and June 2023 at Affiliated Cancer Hospital and Institute of Guangzhou Medical University. The inclusion criteria were as follows: (1) Aged 18 to 75 years and nonpregnant women. (2) Histologically confirmed diagnosis of pseudomyxoma peritonei. (3) Karnofsky Performance Scale (KPS)>70. (4) The functions of major organs such as the heart, liver, lungs, and kidneys can tolerate major surgery for long periods of time. (5) No evidence of extra-abdominal metastasis. Patients with extensive intra-abdominal adhesions or severe infectious diseases were excluded. The main outcomes were overall survival (OS) and postoperative major complications. The postoperative major complications were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). We used the peritoneal cancer index (PCI) score to quantitatively assess the peritoneal metastases and the completeness of cytoreduction (CCR) score at the end of surgery (CCR-0 and CCR-1 considered to be complete CRS). Results: A total of the 186 PMP patients with a median age of 56 (interquartile range extremes (IQRE), 48-64) years were included, 65 (34.9%) males and 121 (65.1%) females. The median peritoneal cancer index (PCI) score was 28 (20-34). Appendiceal origin accounted for 91.4%. Histological types were low grade in 99 patients (53.2%), high grade in 57 patients (30.6%), and 55 patients (29.6%) received complete cytoreduction (CCR-0/1). The median operative duration was 300 (211-430) minutes for all patients. Treatment-related 30-day mortality was 2.7%; 90-day mortality 4.3%; reoperation 1.6%; and severe morbidity 43.0%. Within the entire series, anemia(27.4%), electrolyte disturbance(11.6%), and hypoalbuminemia(7.5%) were the most frequent major complications (grade 3-4). The incidences of gastrointestinal anastomotic leakage, abdominal bleeding, and abdominal infection were 2.2%, 2.2%, and 4.3%, respectively. After a median follow-up of 38.1 (95%CI:31.2-45.1) months, the 5-year OS was 50.3% (95%CI: 40.7%-59.9%) with a median survival time of 66.1 (95%CI: 43.1-89.1) months. The survival analysis showed that patients with pathological low grade, low PCI, and low CCR score had better survival with statistically significant differences (all P<0.05). Further stratified into complete and incomplete CRS subgroups, the 5-year OS of the CCR-0 and CCR-1 subgroups was 88.9% (95%CI: 68.3%-100.0%) and 77.6% (95%CI: 62.7%-92.5%), respectively; and 42.0% (95%CI: 29.5%-54.5%) in the CCR-2/3 subgroup. Conclusions: CRS and HIPEC may result in a long-term survival benefit for PMP patients with acceptable perioperative morbidity and mortality. This strategy, when complete CRS is possible, could significantly prolong survival for strictly selected patients at experienced centers.

The Cancer Diaspora: A Rare Case of Pseudomyxoma Peritonei of Appendiceal Origin.

Pseudomyxoma peritonei (PMP) is a rare clinical entity characterized by widespread mucinous implants in the peritoneal cavity. Commonly seen in females in their 50s, PMP typically originates from ruptured appendiceal mucoceles that find refuge in the peritoneal space. Rarely, PMP may originate from the ovary, stomach, colon, or pancreas. Pseudomyxoma peritonei of colorectal origin is more malignant and has a lower survival rate. We report a case of a 59-year-old Hispanic woman with PMP who presented to the emergency room with a 3-month history of progressive abdominal distention. Pseudomyxoma peritonei was confirmed by computed tomography (CT) scan of the abdomen and pelvis and histopathology, and the patient underwent partial cytoreductive surgery. Given her Eastern Cooperative Oncology Group (ECOG) performance status of 1 despite extensive carcinomatosis, our patient may benefit from hyperthermic intraperitoneal chemotherapy (HIPEC) in the future.

Analysis of the characteristics and outcomes of patients with pseudomyxoma peritonei of appendiceal origin treated with curative-intent surgery.

BACKGROUND: There are no previous studies on pseudomyxoma peritonei regarding the details of surgical procedures included in cytoreductive surgery and quantitative evaluation for peritoneal metastases by region in the abdominal cavity. This study aimed to describe the characteristics and procedural details involved in cytoreductive surgery, and survival outcomes of patients with pseudomyxoma peritonei originating from appendiceal mucinous neoplasm, and identify differences in the difficulty of cytoreductive surgery based on tumor location. METHODS: Patient characteristics and survival outcomes were studied through a retrospective review. The complete cytoreduction rate (i), the 5-year survival rate for patients with complete cytoreduction (ii), and an index as a complement (i × ii × 100) were described for patients who had tumors larger than 50 mm in one of the 13 regions of the abdominal cavity. RESULTS: A total of 989 patients were treated with curative-intent cytoreductive surgery. The median peritoneal cancer index was 18 (interquartile range, 6-29), with complete cytoreduction achieved in 702 patients (71%); the major complication rate was 17%. The median overall survival was 92.9 months, compared to 53.8 months for patients who underwent total gastrectomy and 30.4 months for those who underwent total colectomy. In the 13 abdominal regions, the index scores indicating cytoreduction difficulty were categorized into three risk groups: upper and mid-abdominal (>20), lateral abdominal (10-20), and small bowel (<10). CONCLUSIONS: Cytoreductive surgery offered favorable survival outcomes, even in cases involving total gastrectomy. The difficulty of achieving complete cytoreduction varied across abdominal regions and was classified into three levels.

Long-term survival in patients with PMP: a single-institutional retrospective study from China.

BACKGROUND: As the standard treatment for pseudomyxoma peritonei (PMP), cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) can significantly prolong the survival of PMP patients, and some patients can even achieve long-term survival (LTS) or clinical cure. The purpose of this study was to analyze the clinicopathological and treatment features of PMP patients with LTS and to explore the survival benefit factors of PMP patients. METHODS: The clinicopathological and prognostic data of PMP patients who received CRS + HIPEC at our center from December 2004 to May 2023 were retrospectively analyzed. PMP patients were divided into LTS group (≥ 10 years) and short-term survival (STS) group (< 5 years) according to the length of natural history. Univariate and multivariate analyses were performed to explore the beneficial factors of PMP patients with LTS. RESULTS: A total of 609 patients with PMP received CRS + HIPEC treatment at our center. Two-hundred one patients with PMP were included in the study after screening, including 39 patients (19.4%) in the LTS group and 162 patients (80.6%) in the STS group. In STS group and LTS group, median overall survival based on natural history was 29.2 (2.4-59.9) vs. 138.9 (120.3-416.7) months. Univariate analysis revealed 8 factors (P < 0.05) with statistically significant differences between the two groups: gender, chemotherapy history, previous surgical score, Karnofsky Performance Status score, pathological diagnosis, lymphatic metastasis, peritoneal cancer index, and completeness of cytoreduction (CC). Multivariate analysis identified only two factors independently associated with LTS of PMP patients: CC and pathological diagnosis. CONCLUSION: Complete CRS and pathological features are two key factors affecting LTS in PMP patients.

Health related quality of life is excellent and sustained at two decades after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in survivors of pseudomyxoma peritonei of appendiceal origin.

INTRODUCTION: Optimal management of pseudomyxoma peritonei (PMP) is by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), which can achieve 20-year disease-free, and overall survival. There is limited information on the health-related quality of life (HRQOL) of PMP survivors beyond five years. We report longitudinal HRQOL in patients with PMP of appendiceal origin up to 17-years after their CRS and HIPEC in 2003-2004. METHODS: Patients had HRQOL assessed with EORTC QLQ-C30 questionnaires pre-operatively, and at 1-, 10- and 17-years post-operatively. Comparisons in global health-related QOL (global-HRQOL) measures were made with (1) an age- and sex-matched normal European population, (2) between patients who underwent complete cytoreduction (CRS CC0/1) versus maximal tumor debulking (MTD), and (3) between those with and without peritoneal recurrence. RESULTS: Forty-six patients underwent CRS & HIPEC for appendiceal PMP. One patient withdrew from the study. Of the 45 patients, 23 patients were alive at ten and 15 patients at 17-years post-operatively. 21/23 (91%) and 14/15 patients (93%) completed questionnaires respectively. Pre-operatively, patients had significantly lower global-HRQOL compared with the reference population. Over follow-up, patients experienced improvements in their global-HRQOL. By post-operative year-10 and -17, there was no difference between the global-HRQOL of patients and reference population. As expected, patients with CC0/1 and without peritoneal tumor recurrence had better global-HRQOL at ten- and 17-years post-operatively compared with those with MTD or recurrence. CONCLUSIONS: Optimal CRS and HIPEC is an effective treatment for appendiceal PMP that can achieve long-term survival. HRQOL is excellent and maintained, in those who have CC0/1 without recurrence.

Low-grade appendiceal mucinous neoplasm encountered during risk-reducing salpingo-oophorectomy: A case of laparoscopic surgery.

Low-grade appendiceal mucinous neoplasm (LAMN) is a rare epithelial malignancy of the appendix. If it perforates the abdominal cavity, it can cause a serious clinical syndrome called pseudomyxoma peritonei. In the present case, we laparoscopically removed a LAMN encountered during risk-reducing salpingo-oophorectomy (RRSO). The patient was a 53-year-old woman who was diagnosed with hereditary breast and ovarian cancer syndrome. RRSO was planned, and magnetic resonance imaging revealed a large cystic tumor in the right lower abdomen. We expected an ovarian cyst; however, it was a primary tumor of the appendix. Partial cecal resection was performed laparoscopically by a surgical oncologist. The pathological diagnosis was LAMN. Gynecologists may encounter this disease incidentally. Mucinous appendiceal neoplasm (MAN) may be encountered during RRSO. If a right lower abdominal mass is found near a normal ovary preoperatively, gynecologists should consider MAN as well as paraovarian cyst.

Mytomicin-C, Metronomic Capecitabine, and Bevacizumab in Patients With Unresectable or Relapsed Pseudomyxoma Peritonei of Appendiceal Origin.

INTRODUCTION: Pseudomyxoma peritonei (PMP) is a rare, slow growing tumor, traditionally considered chemoresistant. The only curative approach is cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC). At disease relapse, or in patients with inoperable disease at diagnosis, no standard treatment has been defined, though nonrandomized series showed promising results with fluoropyrimidine-based regimens. PATIENTS AND METHODS: We conducted a prospective study in patients with relapsed or unresectable PMP and confirmed disease progression at baseline. Patients received MMC (7 mg/m2 every 6 weeks, up to a maximum of 4 cycles) plus metronomic capecitabine (625 mg/sqm/day b.i.d.) and bevacizumab (7.5 mg/kg every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint was progression-free survival (PFS); secondary endpoints were overall survival (OS), overall response rate according to RECIST v1.1 criteria, serum markers response and safety. RESULTS: Fifteen patients were included. At a median follow-up of 26.1 months (IQR, 17.7-49.6), median PFS was 17.9 months (95% CI, 11.0-NE), with 1-year PFS and OS rates of 73% and 87%. Safety profile was manageable, with only 13% G3/G4 treatment-related adverse events. CONCLUSION: Metronomic capecitabine, bevacizumab, and MMC are an active regimen in advanced and progressive PMP and favorably compares with historical series.

[Incidental finding of appendiceal mucinous neoplasms]. / Zufallsbefund muzinöse Neoplasie der Appendix.

Low-grade appendiceal mucinous neoplasms (LAMN) are rare and are diagnosed in at least 0.13% of appendectomies in Germany, although significant underreporting is likely. Perforation of the tumors can result in abdominal mucinous collections, so-called pseudomyxoma peritonei (PMP). The challenge in the treatment of LAMN is the adequate approach to the incidental finding of these tumors. If a mucinous neoplasm is preoperatively suspected in cases of an acute condition, usually appendicitis, it must be weighed up whether a conservative approach is justifiable or whether immediate appendectomy is necessary. If this is the case, an intraoperative perforation of the appendix must be avoided and the complete abdominal cavity must be inspected for mucin deposits. If conservative treatment is possible, further treatment should take place at a specialized center. If the neoplasm is first found incidentally during surgery, perforation of the appendix should also be avoided and the entire abdominal cavity should be inspected for a PMP. If a PMP is present cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) should be performed in a specialized center. If LAMN are found during the postoperative histological work-up, it should be evaluated whether a perforation was present and mucin collections are noted in the surgical report. In the case of LAMN without evidence of a PMP, appendectomy is the adequate treatment. In cases of intra-abdominal mucinous collections, samples should be taken and further treatment should be performed at a center with sufficient expertise. An ileocecal resection or oncological hemicolectomy is not indicated. After adequate treatment, all patients should receive a follow-up using cross-sectional imaging (preferably magnetic resonance imaging, MRI) and determination of the tumor markers CEA, CA 19-9 and CA 125.

A Novel Assessment of Metabolic Pathways in Peritoneal Metastases from Low-Grade Appendiceal Mucinous Neoplasms.

BACKGROUND: There is a paucity of targeted therapies for patients with pseudomyxoma peritonei (PMP) secondary to low-grade appendiceal mucinous neoplasms (LAMNs). Dysregulated metabolism has emerged as a hallmark of cancer, and the relationship of metabolomics and cancer is an area of active scientific exploration. We sought to characterize phenotypic differences found in peritoneal metastases (PM) derived from LAMN versus adenocarcinoma. METHODS: Tumors were washed with phosphate-buffered saline (PBS), microdissected, then dissociated in ice-cold methanol dried and reconstituted in pyridine. Samples were derivatized in tert-butyldimethylsilyl (TBDMS) and subjected to gas chromatography-coupled mass spectrometry. Metabolites were assessed based on a standard library. RNA sequencing was performed, with pathway and network analyses on differentially expressed genes. RESULTS: Eight peritoneal tumor samples were obtained and analyzed: LAMNs (4), and moderate to poorly differentiated adenocarcinoma (colon [1], appendix [3]). Decreases in pyroglutamate, fumarate, and cysteine in PM from LAMNs were found compared with adenocarcinoma. Analyses showed the differential gene expression was dominated by the prevalence of metabolic pathways, particularly lipid metabolism. The gene retinol saturase (RETSAT), downregulated by LAMN, was involved in the multiple metabolic pathways that involve lipids. Using network mapping, we found IL1B signaling to be a potential top-level modulation candidate. CONCLUSIONS: Distinct metabolic signatures may exist for PM from LAMN versus adenocarcinoma. A multitude of genes are differentially regulated, many of which are involved in metabolic pathways. Additional research is needed to identify the significance and applicability of targeting metabolic pathways in the potential development of novel therapeutics for these challenging tumors.

External multicentre validation of pseudomyxoma peritonei PSOGI-Ki67 classification.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare malignant disease. Adding of the Ki67 proliferation index to the PSOGI PMP classification provided two different subcategories of the extensive HG-PMP group (HG-PMP ≤15% and HG-PMP >15%) with different survival in a previous unicentric study. This study aims to carry out an external and multicentre validation of this new proposed classification. METHOD: It was a prospective analysis of samples from a historical and international cohort of patients. A representative area with higher cellular density was used to determine the Ki67%. The Ki67 proliferation index (%) was determined in all the HG-PMP patients. A Cox proportional hazard models and multivariable COX models were used. The Kaplan-Meier method and the two-tailed log-rank test were used to analyse the effect of different PSOGI-Ki67 categories on OS and DFS. Its predictive accuracy was analysed using Harrel's C-index and the ROC curve. The calibration was performed using the calibration plots matching. RESULTS: After exclusions, 349 patients were available for analysis. The 5-years OS were 86% for LG-PMP, 59% for HG-PMP≤15, 38% for HG-PMP>15 and 42% for SRC-PMP (p = 0.0001). The 5-years DFS were 49% for LG-PMP, 35% for HG-PMP≤15, 16% for HG-PMP>15 and 18% SRC-PMP (p = 0.0001). The discrimination capability of PSOGI-Ki67 was validated. CONCLUSION: the PSOGI-Ki67 classification discriminates and predicts the OS and DFS in patients with PMP dividing the HG-PMP category into two well-defined sub-categories. The Ki67 proliferation index should be incorporated routinely in the pathology report for these patients.

Four cases of pseudomyxoma peritonei with ovarian tumors at our hospital.

We describe four cases of pseudomyxoma peritonei (PMP) that were diagnosed and treated at our hospital.Case 1: A 26-year-old woman with a large multicystic ovarian tumor and massive ascites was diagnosed with PMP originating from a borderline mucinous ovarian tumor. She underwent fertility-preserving staging laparotomy and was treated with three courses of intraperitoneal chemotherapy. There has been no recurrence in the 15 years since her first operation. Case 2: A 72-year-old woman with a giant ovarian tumor and massive ascites was diagnosed with PMP originating from low-grade appendiceal mucinous neoplasm (LAMN). After laparotomy, the patient was managed conservatively because she did not want aggressive treatment. She has remained asymptomatic with a small amount of ascites for 3 years. Case 3: A 82-year-old woman with ovarian tumors, massive ascites, and suspected PMP underwent emergency laparotomy due to appendiceal perforation and pan-peritonitis. She was diagnosed with PMP originating from LAMN. She has remained asymptomatic with a small amount of ascites for 2 years. Case 4: A 42-year-old woman with multicystic ovarian tumors and massive ascites underwent laparotomy. She was diagnosed with PMP originating from LAMN. Since multidisciplinary treatment was indicated and desired, the patient was referred to a specialized facility where cytoreductive surgery and hyperthermic intraperitoneal chemotherapy was performed. The patient has done well since the treatment.Although most cases of PMP originate from mucinous tumors of the appendix, female patients with PMP often present with ovarian tumors and are commonly referred to gynecology clinics. It is therefore important for gynecologists to be familiar with PMP and to be able to diagnose it accurately and select the most suitable management including multidisciplinary treatments.

The genetic profile and molecular subtypes of human pseudomyxoma peritonei and appendiceal mucinous neoplasms: a systematic review.

Pseudomyxoma peritonei (PMP) is a rare, progressive, slowly growing neoplastic condition which is poorly understood, with a 5-year progression-free survival rate as low as 48%. PMP is most commonly caused by appendiceal mucinous neoplasms (AMN), and understanding their genetic biology and pathogenicity may allow for the development of better novel systemic treatments to target key deleterious mutations and the implicated pathways. The primary aim of this systematic review was to identify the genetic profile of histologically confirmed human PMP or AMN samples. The secondary aim was to identify whether genetic marks could be used to predict patient survival. Ovid EMBASE, Ovid MEDLINE, PubMed, and Web of Science were searched to identify studies investigating the genetic profile of histologically-confirmed human PMP or AMN samples. We review findings of 46 studies totalling 2181 tumour samples. The most frequently identified somatic gene mutations in patients with PMP included KRAS (38-100%), GNAS (17-100%), and TP53 (5-23%); however, there were conflicting results of their effect on survival. Three studies identified molecular subtypes based on gene expression profiles classifying patients into oncogene-enriched, immune-enriched, and mixed molecular subtypes with prognostic value. This review summarises the current literature surrounding genetic aberrations in PMP and AMNs and their potential utility for targeted therapy. Given the recent advances in clinical trials to directly target KRAS and GNAS mutations in other cancers, we propose a rationale to explore these mutations in future pre-clinical studies in PMP with a view for a future clinical trial.