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.

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.

Etiological analysis of infection after CRS + HIPEC in patients with PMP.

BACKGROUND: Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) is the standard treatment for pseudomyxoma peritonei (PMP). It can significantly prolong the survival of patients, but at the same time may increase the risk of postoperative infection. METHOD: Patients with PMP who underwent CRS + HIPEC at our center were retrospectively analyzed. According to PMP patients, basic clinical data and relevant information of postoperative infection, we analyzed the common sites of postoperative infection, results of microbial culture and the antibiotics sensitivity. Univariate and multivariate analysis were performed to explore infection-related risk factors. RESULT: Among the 482 patients with PMP, 82 (17.0%) patients were infected after CRS + HIPEC. The most common postoperative infection was central venous catheter (CVC) infection (8.1%), followed by abdominal-pelvic infection (5.2%). There were 29 kinds of microbes isolated from the culture (the most common was Staphylococcus epidermidis), including 13 kinds of Gram-positive bacteria, 12 kinds of Gram-negative bacteria, and 4 kinds of funguses. All the antibiotics sensitivity results showed that the most sensitive antibiotics were vancomycin to Gram-positive bacteria (98.4%), levofloxacin to Gram-negative bacteria (68.5%), and fluconazole to fungus (83.3%). Univariate and multivariate analysis revealed the infection independent risk factors as follow: intraoperative blood loss ≥ 350 mL (P = 0.019), ascites volume ≥ 300 mL (P = 0.008). CONCLUSION: PMP patients may have increased infection risk after CRS + HIPEC, especially CVC, abdominal-pelvic and pulmonary infections. The microbial spectrum and antibiotics sensitivity results could help clinicians to take prompt prophylactic and therapeutic approaches against postoperative infection for PMP patients.

Effect of standardized fluid management on cardiac function after CRS + HIPEC in patients with PMP: a single-center case-control study.

OBJECTIVE: To investigate the effects of standardized fluid management (SFM) on cardiac function in patients with pseudomyxoma peritonei (PMP) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). METHOD: Patients with PMP who underwent CRS + HIPEC at our center were retrospectively analyzed. The patients were divided into control and study groups according to whether SFM was applied after CRS + HIPEC. We compared the preoperative and postoperative cardiac and renal function parameters, daily fluid volume three days after CRS, and cardiovascular-related adverse events. Univariate and multivariate analyses were performed to identify the indicators affecting clinical prognosis. RESULT: Among the 104 patients, 42 (40.4%) were in the control group and 62 (59.6%) in the study group. There were no statistically significant differences between the two groups in the main clinicopathological characteristics, preoperative cardiac and renal function parameters, and CRS + HIPEC-related indicators. The incidences of cardiac troponin I (CTNI) > upper limit of normal (ULN), >2 × ULN, >3 × ULN, serum creatinine > ULN, and blood urea nitrogen > ULN were higher in the control group than in the study group (p < 0.05). The median daily fluid volume of the control group was higher than that of the study group 3 days after CRS (p < 0.05). Postoperative CTNI > 2 × ULN was an independent risk factor for serious circulatory adverse events. Survival analysis revealed pathological grading, completeness of cytoreduction score, and postoperative CTNI > ULN as independent prognostic factors. CONCLUSIONS: SFM after CRS + HIPEC in patients with PMP may reduce cardiovascular adverse events risk and improve clinical outcomes.

Yttrium-90 Selective Internal Radiation Therapy Plus Cryoablation for Recurrent Adrenocortical Carcinoma With Liver Metastases.

Advanced adrenocortical carcinoma (ACC) has a poor prognosis and is often resistant to the conventional regimens of mitotane administration and systemic chemotherapy. In addition to surgery, local therapeutic measures can be valuable. Here, we present the case of a 33-year-old woman who developed left retroperitoneal local recurrent ACC with hepatic and pulmonary metastases 1 year after radical adrenalectomy. The tumors progressed under chemotherapy and mitotane treatments. She was treated with yttrium-90 selective internal radiation therapy (90Y SIRT) for hepatic metastases and cryoablation of the local recurrent tumor, after which significant tumor shrinkage was observed. She then received radiofrequency ablation for the residual hepatic metastases and radiotherapy to the residual local recurrent tumor. Complete remission was achieved and maintained at least until the data cutoff day (15.8 months after the last treatment). This is the first published report of cryoablation in a patient with ACC and the third report of 90Y SIRT use for hepatic metastasis of ACC. Cryoablation and 90Y SIRT are local treatment choices for ACC that are worthy of further study.

Tumor-stroma ratio as a new prognosticator for pseudomyxoma peritonei: a comprehensive clinicopathological and immunohistochemical study.

BACKGROUND: As a rare clinical tumor syndrome with an indolent clinical course and lack of pathognomonic symptoms, pseudomyxoma peritonei (PMP) is usually diagnosed at an advanced stage. In-depth pathological analysis is essential to assess tumor biological behaviors, assist treatment decision, and predict the clinical prognosis of PMP. The tumor-stroma ratio (TSR) is a promising prognostic parameter based on the tumor and stroma. This study explored the relationship between TSR and the pathological characteristics and prognosis of PMP. METHODS: PMP patients with complete data who underwent cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy were enrolled. The TSR of postoperative pathological images was quantitatively analyzed by Image-Pro Plus. Then the relationship between TSR and the clinicopathological characteristics, immunohistochemical characteristics and prognosis of PMP was analyzed. RESULTS: Among the 50 PMP patients included, there were 27 males (54.0%) and 23 females (46.0%), with a median age of 55 (range: 31-76) years. 25 (50.0%) patients were diagnosed with low-grade PMP (LG-PMP), and 25 (50.0%) were diagnosed with high-grade PMP (HG-PMP). There were 4 (8.0%) patients with vascular tumor emboli, 3 (6.0%) patients with nerve invasion, and 5 (10.0%) patients with lymph node metastasis. The immunohistochemical results showed that the Ki67 label index was < 25% in 18 cases (36.0%), 25 - 50% in 18 cases (36.0%) and > 50% in 14 cases (28.0%). The range of TSR was 2 - 24% (median: 8%). The cutoff value of TSR was 10% based on the receiver operating characteristic (ROC) curve and X-Tile analysis. There were 31 (62.0%) cases with TSR < 10% and 19 (38.0%) cases with TSR ≥ 10%. The TSR was closely related to histopathological type (P < 0.001) and Ki67 label index (P < 0.001). Univariate analysis showed that preoperative carcinoembryonic antigen (CEA), preoperative carbohydrate antigen 19-9, pathological type, vascular tumor emboli and TSR influenced the prognosis of PMP patients (P < 0.05). Multivariate analysis showed that preoperative CEA, vascular tumor emboli and the TSR were independent prognostic factors. CONCLUSIONS: The TSR could be a new independent prognosticator for PMP.

Fish-specific TLR18 in Nile tilapia (Oreochromis niloticus) recruits MyD88 and TRIF to induce expression of effectors in NF-κB and IFN pathways in melanomacrophages.

Toll-like receptors (TLRs) are evolutionarily conserved proteins of pattern recognition receptors (PRRs) and play a crucial role in innate immune systems recognition of conserved pathogen-related molecular samples (PAMPs). We identified and characterized TLR18 from Nile tilapia (Oreochromis niloticus), OnTLR18, to elucidate its role in tissue expression patterns, modulation of gene expression after microbial challenge and TLR ligands, subcellular localization in fish and human cells, and the possible effectors TLR18 induces in a melanomacrophage-like cell line (tilapia head kidney (THK) cells). OnTLR18 expression was detected in all tissues examined, with the highest levels in the intestine and the lowest in the liver. OnTLR18 transcript was up-regulated in immune-related organs after bacterial and polyinosinic-polycytidylic acid (poly I:C) challenges and in the THK cells after lipopolysaccharide (LPS) stimulation. In transfected THK and human embryonic kidney (HEK) 293 cells, OnTLR18 localizes in the intracellular compartment. OnMyD88 and OnTRIF, but not OnTIRAP, were co-immunoprecipitated with OnTLR18, suggesting that the former two molecules are recruited by OnTLR18 as adaptors. The constitutively active form of OnTLR18 induced the production of pro-inflammatory cytokines, type I interferon (IFN), and antimicrobial peptides such as tumor necrosis factor α, interferon (IFN) d2.13, tilapia piscidin (TP)2, TP3, TP4, and hepcidin in THK cells. Our results suggest that OnTLR18 plays an important role in innate immunity through initiating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and IFN signaling pathways via OnMyD88 and OnTRIF and induces the production of various effectors in melanomacrophages.

The Biological Synthesis and the Function of Mucin 2 in Pseudomyxoma Peritonei.

Excessive mucus secretion is the most prominent feature of pseudomyxoma peritonei (PMP), which often leads to significant increase in abdominal circumference, intractable abdominal pain, progressive intestinal obstruction, abdominal organ adhesions, and cachexia. Excessive mucus secretion is also the main cause of death. Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is the recommended treatment for PMP. However, recurrence is frequently observed even after CRS and HIPEC, presenting similar clinical manifestations. Mucin 2 (MUC2) is the main type of mucin in PMP and plays a key role in the progressive sclerosis of mucus. To comprehensively demonstrate the biosynthetic process and molecular features of MUC2 and to provide new directions for the development of PMP mucolytic strategies, this review systematically summarizes the molecular biology of MUC2, including MUC2 gene structure, transcription, translation, post-translational modification, tertiary structure, and factors regulating mucus viscoelasticity. The results show that MUC2 is a highly glycosylated protein, with glycan accounts for 80% to 90% of the dry weight. The assembly pattern of MUC2 is highly complicated, presenting a bead-like filament. Salt concentration, pH, mucin concentration and trefoil factor family may contribute to the increase in mucus viscoelasticity and sclerosis, which could be used to develop drugs to soften or even dissolve mucus in the future.

Consensuses and controversies on pseudomyxoma peritonei: a review of the published consensus statements and guidelines.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a clinical malignant syndrome mainly originating from the appendix, with an incidence of 2-4 per million people. As a rare disease, an early and accurate diagnosis of PMP is difficult. It was not until the 1980s that the systematic study of this disease was started. MAIN BODY: As a result of clinical and basic research progress over the last 4 decades, a comprehensive strategy based on cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) has been established and proved to be an effective treatment for PMP. Currently, CRS + HIPEC was recommended as the standard treatment for PMP worldwide. There are several consensuses on PMP management, playing an important role in the standardization of CRS + HIPEC. However, controversies exist among consensuses published worldwide. A systematic evaluation of PMP consensuses helps not only to standardize PMP treatment but also to identify existing controversies and point to possible solutions in the future. The controversy underlying the consensus and vice versa promotes the continuous refinement and updating of consensuses and continue to improve PMP management through a gradual and continuous process. In this traditional narrative review, we systemically evaluated the consensuses published by major national and international academic organizations, aiming to get a timely update on the treatment strategies of CRS + HIPEC on PMP. CONCLUSION: Currently, consensuses have been reached on the following aspects: pathological classification, terminology, preoperative evaluation, eligibility for surgical treatment, maximal tumor debulking, CRS technical details, and severe adverse event classification system. However, controversies still exist regarding the HIPEC regimen, systemic chemotherapy, and early postoperative intraperitoneal chemotherapy.

Establishment and histopathological study of patient-derived xenograft models and primary cell lines of epithelioid malignant peritoneal mesothelioma.

Malignant peritoneal mesothelioma (MPM) is a rare malignancy with few experimental models. This study used the human surgical specimen to establish MPM patient-derived xenograft (PDX) models and primary cell lines to provide a study platform for MPM in vitro and in vivo, and conducted histopathological analysis. Our study used the experimental peritoneal cancer index (ePCI) score to evaluate gross pathology, and the results showed that the ePCI score of the female and male nude mice were 8.80 ± 1.75 and 9.20 ± 1.81 (P=0.6219), respectively. The Hematoxylin and eosin (HE) staining of animal models showed that the tumor was epithelioid mesothelioma and invaded multiple organs. Immunohistochemistry (IHC) staining showed that Calretinin, Cytokeratin 5/6, WT-1 and Ki-67 were all positive. The Swiss-Giemsa and Immunofluorescence (IF) staining of primary cell lines were also consistent with the pathological characteristics of mesothelioma. We also performed the whole-exome sequencing (WES) to identify the mutant genes between models and the patient. And the results showed that 21 mutant genes were shared between the two groups, and the genes related to tumorigenesis and development including BAP1, NF2, MTBP, NECTIN2, CDC23, LRPPRC, TRIM25, and DHRS2. In conclusion, the PDX models and primary cell lines of MPM were successfully established with the epithelioid mesothelioma identity confirmed by histopathological evidence. Moreover, our study has also illustrated the shared genomic profile between models and the patient.

Downstaged ypT0-2N0 rectal cancer after neoadjuvant chemoradiation therapy may not need adjuvant chemotherapy: a retrospective cohort study.

PURPOSE: Current guidelines suggest that adjuvant chemotherapy (AC) be administered to all locally advanced (clinically T3-4 or N-positivity) rectal cancer patients undergoing neoadjuvant chemoradiotherapy (nCRT) and radical surgical resection regardless of the final pathological staging (yp staging). This study aimed to evaluate the necessity of AC for ypT0-2N0 rectal cancer. METHODS: Patients with ypT0-2N0 rectal cancer, who received nCRT and radical surgical resection, were recruited retrospectively at a university hospital. The main outcome was to evaluate the 5-year overall survival (OS) and disease-free survival (DFS) between ypT0-2N0 rectal cancer patients with AC and those without AC. We also identified potential independent prognostic factors associated with poor outcomes. RESULTS: One hundred and ten ypT0-2N0 rectal cancer patients (ypT0: n = 6; ypT1: n = 44; ypT2: n = 60) were followed up for a median of 60 months. No significant difference was observed in DFS and 5-year OS between patients with AC and those without AC. The risk of recurrence was associated with the postoperative pathological staging (0% with ypT0, 2.4% with ypT1, and 10% with ypT2). In the multivariate analysis, retrieval of < 12 lymph nodes was an independent favorable prognostic factor, which correlated with a higher OS (HR: 2.263; 95% CI: 1.093-4.687, P = 0.028). Intra-tumor lymphovascular and perineural invasion were poor prognostic markers for shorter DFS (HR: 5.940; 95% CI: 1.150-30.696, P = 0.033). CONCLUSION: Postoperative AC is not required for patients with ypT0-2N0 rectal cancer downstaged by nCRT, especially in those without poor prognostic factors.

Trifluridine/tipiracil in combination with local therapy may be a favorable option for refractory metastatic colorectal cancer patients: A case report.

RATIONALE: Currently, the 5-year survival rate remains poor for patients with metastatic colorectal cancer (mCRC), and the purpose of therapy is to prolong survival while maintaining the quality of life. Trifluridine/tipiracil, an oral drug combining trifluorothymidine and a thymidine phosphorylase inhibitor, is indicated as salvage therapy for mCRC patients who have progressed after all available regimens. Combination of local treatments with systemic therapy such as trifluridine/tipiracil represents an apt management strategy for mCRC patients. PATIENT CONCERNS: A 72-year-old man diagnosed with stage IV rectal adenocarcinoma (KRAS mutation) with peritoneal carcinomatosis and liver metastases developed resistance to 2 lines of treatment (bevacizumab/irinotecan/S-1 and bevacizumab/oxaliplatin/HDFL [high-dose 24-hour infusion of 5-fluorouracil and leucovorin regimen]) within 5 months. DIAGNOSIS: Refractory stage IV rectal adenocarcinoma. INTERVENTIONS: Systemic treatment of trifluridine/tipiracil has been given for approximately 15 months in addition to radiotherapy, Yttrium-90 radioembolization, and trans-arterial chemoembolization for peritoneal and liver metastases. OUTCOMES: After 15 months, the patient was still taking trifluridine/tipiracil for disease control with a good quality of life. LESSONS: Trifluridine/tipiracil plus other appropriate local therapy may significantly prolong patients survival with a satisfactory quality of life for patients with refractory mCRC. The favorable safety profile of trifluridine/tipiracil renders it a suitable option to be combined with other local therapies for metastatic lesions.

Study on the hepatocellular carcinoma model with metastasis.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death around the world due to advanced clinical stage at diagnosis, high incidence of recurrence and metastasis after surgical treatment. It is in urgent need to create appropriate animal models to explore the mechanism, patterns, risk factors, and therapeutic strategies of HCC metastasis and recurrence. However, most of the established models lack the phenotype of invasion and metastasis in patient, or have unstable phenotype. To establish HCC models with stable metastasis phenotype requires profound understanding in cancer metastasis biology and scientific methodology. Over the past 3 decades, HCC models with stable metastasis have been extensively studied. This paper reviewed the history and development of HCC animal models and cell models, focusing on the screening and maintaining of metastatic potential and phenotype. In-depth studies using these models vastly promote the understanding of cellular and molecular mechanisms and development of therapeutic strategies on HCC metastasis.

Molecular structure and phylogenetic analyses of the complete chloroplast genomes of three original species of Pyrrosiae Folium.

Pyrrosia petiolosa, Pyrrosia lingua and Pyrrosia sheareri are recorded as original plants of Pyrrosiae Folium (PF) and commonly used as Chinese herbal medicines. Due to the similar morphological features of PF and its adulterants, common DNA barcodes cannot accurately distinguish PF species. Knowledge of the chloroplast (cp) genome is widely used in species identification, molecular marker and phylogenetic analyses. Herein, we determined the complete cp genomes of three original species of PF via high-throughput sequencing technologies. The three cp genomes exhibited a typical quadripartite structure with sizes ranging from 158 165 to 163 026 bp. The cp genomes of P. petiolosa and P. lingua encoded 130 genes, whilst that of P. sheareri encoded 131 genes. The complete cp genomes were compared, and five highly divergent regions of petA-psbJ, matK-rps16, ndhC-trnM, psbM-petN and psaC-ndhE were screened as potential DNA barcodes for identification of Pyrrosia genus species. The phylogenetic tree we obtained indicated that P. petiolosa and P. lingua are clustered in a single clade and, thus, share a close relationship. This study provides invaluable information for further studies on the species identification, taxonomy and phylogeny of Pyrrosia genus species.

The biological basis and function of GNAS mutation in pseudomyxoma peritonei: a review.

PURPOSE: Pseudomyxoma peritonei (PMP) is a rare clinical malignancy syndrome characterized by the uncontrollable accumulation of copious mucinous ascites in the peritoneal cavity, resulting in "jelly belly". The mechanism of tumor progression and mucin hypersecretion remains largely unknown, but GNAS mutation is a promising contributor. This review is to systemically summarize the biological background and variant features of GNAS, as well as the impacts of GNAS mutations on mucin expression, tumor cell proliferation, clinical-pathological characteristics, and prognosis of PMP. METHODS: NCBI PubMed database (in English) and WAN FANG DATA (in Chinese) were used for literature search. And NCBI Gene and Protein databases, Ensembl Genome Browser, COSMIC, UniProt, and RCSB PDB database were used for gene and protein review. RESULTS: GNAS encodes guanine nucleotide-binding protein α subunit (Gsα). The mutation sites of GNAS mutation in PMP are relatively stable, usually at Chr20: 57,484,420 (base pair: C-G) and Chr20: 57,484,421 (base pair: G-C). Typical GNAS mutation results in the reduction of GTP enzyme activity in Gsα, causing failure to hydrolyze GTP and release phosphoric acid, and eventually the continuous binding of GTP to Gsα. The activated Gsα could thus continuously promote mucin secretion through stimulating the cAMP-PKA signaling pathway, which is a possible mechanism leading to elevated mucin secretion in PMP. CONCLUSION: GNAS mutation is one of the most important molecular biological features in PMP, with major functions to promote mucin hypersecretion.

Expression profile, subcellular localization and signaling pathway analysis of fish-specific TLR25 in Nile tilapia (Oreochromis niloticus).

The Nile tilapia (Oreochromis niloticus) is one of the major food fish species produced in tropical and subtropical regions. However, this industry has been facing significant challenges from microbial infections. Understanding how hosts initiate immune responses against invading microbes is the first requirement for addressing disease outbreak prevention and disease resistance. Toll-like receptors (TLRs) are a family of evolutionarily conserved proteins that can recognize pathogen-associated molecular patterns (PAMPs). They thus play an essential role in innate immunity. TLR25 is a newly identified fish-specific member of the TLR1 subfamily. In this study, we investigate the molecular and functional characteristics of O. niloticus TLR25 (OnTLR25) via tissue expression patterns, gene expression modulation after challenge with bacteria and TLR ligands, subcellular localization in human and fish cells, and the signaling pathways TLR25 may induce. Transcriptional levels of OnTLR25 are high in immune-related organs such as the spleen and head kidney, and are increased following bacterial challenges. In addition, we show that OnTLR25 preferentially localizes to the intracellular compartment in transfected tilapia head kidney (THK) cell line. Furthermore, overexpression of the truncated form of OnTLR25 in THK cell line induced the expression of proinflammatory cytokines, such as tumor necrosis factor α, interleukin (IL)-1ß, IL-8, IL-12a, and interferon-d2.13. Combined, our results suggest that TLR25 is likely to play an important role in the antimicrobial responses of the innate immune system of Nile tilapia.

Perioperative safety after cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei from appendiceal origin: Experience on 254 patients from a single center.

OBJECTIVE: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a standard treatment for pseudomyxoma peritonei (PMP) recommended by Peritoneal Surface Oncology Group International (PSOGI). The study is to analyze the incidence of perioperative serious adverse events (SAEs) of CRS + HIPEC to treat PMP patients, and identify the risk factors, for guiding the prevention of SAEs. METHODS: This is a retrospective study on the PMP database established at our center. The clinicopathological features, treatment details and SAEs information on the PMP patients are systematically established in this database. The incidence, organ system distribution and severity of perioperative SAEs are analyzed. Univariate and multivariate analyses are performed to identify the independent risk factors. RESULTS: Among the 272 CRS + HIPEC procedures for 254 PMP patients, there are 93 (34.2%) SAEs. Six systems are involved in the SAEs, including infections (9.6%), digestive system (8.1%), respiratory system (6.3%), cardiovascular system (5.5%), hematological system (2.9%), and urinary system (1.5%), in terms of frequency. In terms of severity, the majority is grade III SAEs (27.9%), followed by grade IV SAEs (4.8%) and grade V SAEs (1.5%). Univariate analysis reveals 4 risk factors for perioperative SAEs: HIPEC regimens (P = 0.020), PCI (P = 0.025), intraoperative red blood cell transfusion volume (P = 0.004), and intraoperative blood loss volume (P = 0.002). Multivariate and logistic regression model analysis identifies only one independent risk factor for perioperative SAEs: intraoperative blood loss volume (P = 0.001, OR = 0.344, 95%CI: 0.182-0.649). CONCLUSIONS: PMP patients treated by CRS + HIPEC at experienced centers could have acceptable safety. Improving the surgical techniques and developing the integrated hemostasis techniques are essential to reduce intraoperative blood loss and decrease SAEs rate.

Establishment of patient-derived xenograft model of peritoneal mucinous carcinomatosis with signet ring cells and in vivo study on the efficacy and toxicity of intraperitoneal injection of 5-fluorouracil.

BACKGROUND: Pseudomyxoma peritonei (PMP) is an indolent malignancy and insensitive to systemic chemotherapy. The authors established patient-derived xenograft (PDX) model of PMP, and evaluated the efficacy and toxicity of intraperitoneal (i.p.) administration of 5-fluorouracil (5-FU) in this model. METHODS: Human PMP sample was collected to establish subcutaneous (s.c.) and i.p. MODEL: In vivo study of i.p. injection of 5-FU was performed in i.p. model, with experimental peritoneal cancer index (ePCI) score and pathological examinations for evaluating the efficacy and toxicity. RESULTS: Both s.c. and i.p. models were constructed. The average passage interval of s.c. model was 44.2 ± 5.2 days, and the i.p. model was characterized by disseminated solid tumor nodules in abdominal-pelvic cavity. Both models were diagnosed as peritoneal mucinous carcinomatosis with signet ring cells (PMCA-S). Immunohistochemical characteristics was similar to human. GNAS mutation was detected in both model and patient. In the in vivo study, average ePCI of treatment group was lower than control and vehicle group (P = .004). Histopathology revealed obvious tumor necrosis in treatment group, and decreased Ki67 positive rate (P = .010). In toxicity study, 5-FU significantly influenced body weight (P = .010) and 1 animal from treatment group died on day 14. Congestive splenomegaly was observed (88.9%). Hepatotoxicity presented as acidophilic body (55.6%), cholestasis (100%), bile canaliculus hyperplasia and obstruction (22.2%), and lymphocyte accumulation (77.8%). CONCLUSIONS: PDX model of PMCA-S was established successfully, and i.p. 5-FU could inhibit tumor proliferation and progression, with decreased Ki67 positive rate and ePCI score. Hepatotoxicity was the main side effect.

A multicenter, phase I/II trial of biweekly S-1, leucovorin, oxaliplatin and gemcitabine in metastatic pancreatic adenocarcinoma-TCOG T1211 study.

BACKGROUND: This phase I/II study evaluated the feasibility and efficacy of S-1, leucovorin, oxaliplatin and gemcitabine (SLOG), a triplet regimen, for treating patients with metastatic pancreatic ductal adenocarcinoma (PDAC). METHODS: Patients with chemo-naive, metastatic PDAC were eligible to receive fixed-rate infusion (10 mg/m2/min) of gemcitabine of 800 mg/m2 followed by oxaliplatin of 85 mg/m2 on day 1 plus oral S-1 and leucovorin (20 mg/m2) twice daily from days 1 to 7 in a 2-week cycle. The dose of S-1 would be escalated from 20, 30, 35 to 40 mg/m2 in a 3 + 3 designed phase I part to determine the maximum tolerated dose (MTD) for phase II study, in which the primary end-point was objective response rate (ORR). The recommended dose of S-1 was from phase I. This trial is registered at ClinicalTrials.gov: NCT01415713. RESULTS: Seventy-three patients were enrolled. In the phase I study (n = 19), the MTD of S-1 was 35 mg/m2 twice daily. Of 54 patients in phase II, the ORR was 40.7% (95% confidence interval [CI], 28%-55%). The median progression-free survival and overall survival were 7.6 (95% CI, 5.6-11.0) and 11.4 (95% CI, 8.1-16.3) months, respectively. The most common grade III/IV adverse event was neutropenia (40.7%). Twenty-four percent of patients had SLOG treatment for more than 1 year. The mean relative dose intensities of gemcitabine, oxaliplatin, and S-1 were 92%, 92% and 89%, respectively. CONCLUSION: Biweekly SLOG is a feasible regimen with promising activity and safety profiles. A randomised study comparing SLOG versus modified folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) in advanced PDAC is ongoing (ClinicalTrials.gov: NCT03443492).

Traditional Serrated Pathway-associated Colorectal Carcinoma: Morphologic Reappraisal of Serrated Morphology, Tumor Budding, and Identification of Frequent PTEN Alterations.

The phenotypic characteristics of traditional serrated adenoma (TSA)-associated malignancies remain obscure. This study was a morphologic reappraisal of 27 colorectal carcinomas arising from TSA (TSA-CRCs) and 53 BRAF-mutated/microsatellite-stable colorectal carcinomas (BRAF-mut/MSS CRCs). Makinen's criteria for serrated adenocarcinoma were applied to assess the morphologic similarity of the 2 entities. Tumor budding, another histologic feature of serrated adenocarcinoma, was also evaluated. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a commonly mutated gene in the serrated pathway, was assessed with immunohistochemistry. Tumors with aberrant PTEN expression were subjected to molecular analysis using quantitative methylation assay, exon sequencing, and fluorescence in situ hybridization. Most cases (>90%) of TSA-CRCs and BRAF-mut/MSS CRCs exhibited a constellation of serrated morphology, including epithelial serrations, abundant eosinophilic cytoplasm, and discernible/vesicular nuclei. A majority (65%) of them qualified for the diagnosis of serrated adenocarcinoma. High-grade tumor budding was closely associated with serrated morphology and was a significant independent factor for poor patient survival in multivariate analysis (P=0.008). Aberrant PTEN expression was detected in nearly half of the cases of both entities (P=0.501). Among the 44 samples with aberrant PTEN expression, 8 harbored PTEN somatic mutations, which were characterized by random distribution without hotspot clustering, 12 had promoter hypermethylation, and 14 had deleted alleles. These findings support a unique model of colorectal carcinogenesis that is similar between TSA-CRCs and BRAF-mut/MSS CRCs. Both entities exhibited common histologic patterns and similar molecular alterations and may well constitute the TSA pathway.