Gastric gastrointestinal stromal tumors: therapeutic strategies and long-term prognosis.

OBJECTIVES: This study aimed to evaluate the clinical and prognostic characteristics of primary gastric gastrointestinal stromal tumors (GIST). METHODS: Patients who underwent resection for primary gastric GIST between January 2002 and December 2017 were included. Recurrence-free survival (RFS) was calculated by Kaplan-Meier analysis, and Cox proportional hazards model was used to identify independent prognostic factors. RESULTS: Altogether, 653 patients were enrolled. The median patient age was 59 years (range 15-86 years). Open, laparoscopic, and endoscopic resections were performed in 394 (60.3%), 105 (16.1%), and 154 (23.6%) patients, respectively. According to the modified NIH consensus classification, 132 (20.2%), 245 (37.5%), 166 (25.4%), and 88 (13.5%) patients were categorized into very low-, low-, intermediate-, and high-risk, respectively. A total of 136 (20.8%) patients received adjuvant imatinib treatment. The median follow-up time was 78 months (range 4-219 months), and the estimated 5-year RFS rate was 93.0%. In all patients, tumor size and rupture, mitotic counts, and adjuvant imatinib treatment were independent prognostic factors. The prognosis of gastric GIST treated with endoscopic resection was not significantly different from that of laparoscopic or open resection after adjusting for covariates using propensity score matching (log-rank p = .558). Adjuvant imatinib treatment (HR = 0.151, 95%CI 0.055-0.417, p < .001) was a favorable prognostic factor for high-risk patients, but was not associated with prognosis in intermediate-risk patients. CONCLUSION: Patients with small gastric GISTs who successfully underwent endoscopic resection may have a favorable prognosis. Adjuvant imatinib treatment improve the prognosis of high-risk gastric GISTs, however, its use in intermediate-risk patients remains controversial.

Efficacy and Safety of Avapritinib in Treating Unresectable or Metastatic Gastrointestinal Stromal Tumors: A Phase I/II, Open-Label, Multicenter Study.

BACKGROUND: Avapritinib is a type 1 kinase inhibitor designed to potently and selectively inhibit oncogenic KIT/PDGFRA mutants by targeting the kinase active conformation. This multicenter, single-arm, open-label, phase I/II bridging study of NAVIGATOR in Chinese patients evaluated the safety and the antineoplastic activity of avapritinib in Chinese patients with unresectable/metastatic gastrointestinal stromal tumors (GIST). METHODS: Phase I comprised dose escalation for safety and phase II dose determination. Phase II comprised dose expansion for safety/efficacy evaluations in patients with PDGFRA D842V mutations or patients having received at least 3 lines of therapy without PDGFRA D842V mutations. The primary endpoints were recommended phase II dose, safety, and Independent Radiology Review Committee (IRRC)-assessed objective response rate (ORR). RESULTS: No dose-limiting toxicities occurred (n = 10); the recommended phase II dose was avapritinib 300 mg once daily orally. Fifty-nine patients initially received avapritinib 300 mg. Common grade ≥3 treatment-related adverse events were anemia, decreased white blood cell count, increased blood bilirubin levels, and decreased neutrophil count. In patients with PDGFRA D842V mutations, IRRC- and investigator-assessed ORRs were 75% and 79%, respectively; clinical benefit rates were both 86%. Median duration of response/progression-free survival were not reached. IRCC- and investigator-assessed ORRs in patients in the fourth- or later-line setting were 22% and 35%, respectively. Median progression-free survivals were 5.6 months for both. Overall survival data were immature and not calculated. CONCLUSION: Avapritinib was generally well tolerated and showed marked anti-tumor activity in Chinese patients with GIST bearing PDGFRA D842V mutations and notable efficacy as fourth- or later-line monotherapy (ClinicalTrials.gov Identifier: NCT04254939).

CT features combined with RECIST 1.1 criteria improve progression assessments of sunitinib-treated gastrointestinal stromal tumors.

OBJECTIVES: To explore the auxiliary value of combining CT features with existing response evaluation criteria in the prediction of progressive disease (PD) in gastrointestinal stromal tumors (GIST) patients treated with sunitinib. MATERIAL AND METHODS: Eighty-one patients with GISTs who received sunitinib were included in this retrospective multicenter study and divided into training and external validation cohorts. Progression at six months was determined as a reference standard. The predictive performance of the RECIST 1.1 and Choi criteria was compared. CT features at baseline and the first follow-up were analyzed. Logistic regression analyses were used to determine the most significant predictors and develop modified criteria. RESULTS: A total of 216 lesions showed a good response and 107 showed a poor response in 81 patients. The RECIST 1.1 criteria performed better than the Choi criteria in predicting progression (AUC, 0.75 vs. 0.69, p = 0.04). The expanded/intensified high-enhancement area, blurred tumor-tissue interface, and progressive enlarged vessels feeding or draining the mass (EVFDM) differed significantly between lesions with good and poor responses in the training cohort (p = 0.001, 0.003, and 0.000, respectively). Multivariate analysis revealed that the expanded/intensified high-enhancement area (p = 0.001), progressive EVFDM (p = 0.000), and RECIST PD (p = 0.000) were independent predictive factors. Modified RECIST (mRECIST) criteria were developed and showed significantly higher AUCs in the training and external validation cohorts than the RECIST 1.1 criteria (training: 0.81 vs. 0.73, p = 0.002; validation: 0.82 vs. 0.77, p = 0.04). CONCLUSION: The mRECIST criteria, combining CT features with the RECIST 1.1 criteria, demonstrated superior performance in the prediction of early progression in GIST patients receiving sunitinib. CLINICAL RELEVANCE STATEMENT: The mRECIST criteria, which combine CT features with the RECIST 1.1 criteria, may facilitate the early detection of progressive disease in GIST patients treated with sunitinib, thereby potentially guiding the timely switch to late-line medications or combination with surgical excision. KEY POINTS: • The RECIST 1.1 criteria outperformed the Choi criteria in identifying progression of GISTs in patients treated with sunitinib. • GISTs displayed different morphologic features on CT depending on how they responded to sunitinib. • Combining CT morphologic features with the RECIST 1.1 criteria allowed for the prompt and accurate identification of progressing GIST lesions.

Reassessment of the recurrence risk of primary gastrointestinal stromal tumour after complete resection.

OBJECTIVES: The modified National Institutes of Health (NIH) risk criteria for gastrointestinal stromal tumours (GISTs) have some limitations and need to be improved. METHODS: Patients who underwent radical resection of primary GIST were retrospectively reviewed. Peripheral blood indices including the neutrophil-to-lymphocyte ratio (NLR) and prognostic nutritional index (PNI) were analysed. Recurrence-free survival (RFS) was calculated and compared. Multivariate analysis was conducted. Area under the receiver operating characteristic curve (ROC) was calculated. RESULTS: A total of 492 patients were enrolled. Tumour size, mitotic index (MI), tumour location and PNI were independent prognostic factors. The modified NIH criteria could not distinguish among very low-, low- and intermediate-risk patients, and PNI was the only independent prognostic factors for them. The five-year RFS rate in the high risk (HR) group was significantly lower. A further modification to the NIH risk criteria was proposed (the 'NIH-PNI stratification'). Non-high risk (NHR) patients were divided into the NHR-PNI-H group (PNI > 48.05) and the NHR-PNI-L group (PNI ≤ 48.05), respectively. HR patients were divided according to tumour size and MI: the HR1, HR2 and HR3 groups. The five-year RFS rates of the NHR-PNI-H, NHR-PNI-L, HR1, HR2 and HR3 groups were 97.3%, 93.5%, 74.1%, 61.7% and 24.4%, respectively (p < .001). The area under the curve (AUC) for the NIH-PNI stratification, modified NIH criteria, NIH criteria (2002), AFIP criteria and nomogram were 0.857, 0.807, 0.817, 0.843 and 0.831, respectively. CONCLUSION: The proposed NIH-PNI stratification was able to distinguish among five groups in terms of risk of recurrence.

A further modification to the NIH risk criteria for GISTs was proposed ('NIH-PNI stratification'). Non-high risk (NHR) patients were divided into NHR-PNI-H and NHR-PNI-L groups. High risk (HR) patients were divided to HR1, HR2 and HR3 groups. The five-year RFS rates were 97.3%, 93.5%, 74.1%, 61.7% and 24.4%, respectively (p < .001). The AUC for the NIH-PNI stratification, modified NIH criteria, NIH criteria (2002), AFIP criteria and nomogram were 0.857, 0.807, 0.817, 0.843 and 0.831.

Elevated preoperative controlling nutritional status (CONUT) scores as a predictor of postoperative recurrence in gastrointestinal stromal tumors.

BACKGROUND: The controlling nutritional status (CONUT) score is associated with the postoperative outcomes in various types of tumors, and its prognostic role in gastrointestinal stromal tumors (GISTs) needs to be clarified. METHODS: Patients with completely resected primary GISTs in the absence of imatinib adjuvant therapy were included. Recurrence-free survival (RFS) was estimated with the Kaplan-Meier method and compared using log-rank test. Prognostic factors were compared using Cox proportional hazards model. RESULTS: A total of 455 patients were included. The median follow-up time was 132.0 months (range: 7.0-253.0). Recurrence/metastasis developed in 92 (20.2%) patients. Patients were assigned to three groups: 219 (48.1%) were in normal nutrition group (CONUT = 0-1), 196 (43.1%) were in mild malnutrition group (CONUT = 2-4) and 40 (8.8%) were in moderate-severe malnutrition group (CONUT ≥ 5). Nongastric primary tumor site, large tumor size, high mitotic index, tumor rupture and high CONUT score were independent prognostic factors for shorter RFS using multivariate analysis (p < 0.05). CONCLUSIONS: Elevated preoperative CONUT score was a predictor of recurrence for patients with resected GIST. The clinical application of the CONUT score is simple and feasible, and might contribute to the individualized treatment of GIST patients.

Perioperative or postoperative adjuvant oxaliplatin with S-1 versus adjuvant oxaliplatin with capecitabine in patients with locally advanced gastric or gastro-oesophageal junction adenocarcinoma undergoing D2 gastrectomy (RESOLVE): an open-label, superiority and non-inferiority, phase 3 randomised controlled trial.

BACKGROUND: The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin (SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy. METHODS: We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40-60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40-60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546. FINDINGS: Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5-56·3) in the adjuvant-CapOx group, 56·5% (51·0-61·7) in the adjuvant-SOX group, and 59·4% (53·8-64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61-0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68-1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3-4 adverse events was neutropenia (32 [12%] of 258 patients in the adjuvant-CapOx group, 21 [8%] of 249 patients in the adjuvant-SOX group, and 30 [10%] of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported. INTERPRETATION: Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer. FUNDING: National Key Research and Development Program of China, Beijing Scholars Program 2018-2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Study on safety of laparoscopic total gastrectomy for clinical stage I gastric cancer: the protocol of the CLASS02-01 multicenter randomized controlled clinical trial.

BACKGROUND: The safety of laparoscopic total gastrectomy (LTG) for the treatment of gastric cancer remains lack of clinical evidence. The Chinese Laparoscopic Gastrointestinal Surgery Study (CLASS) Group recently launched a multicenter randomized clinical trial (CLASS02-01) to compare the safety of LTG for clinical stage I gastric cancer with the conventional open total gastrectomy (OTG). METHODS: This CLASS02-01 trial is a prospective, multicenter, randomized, controlled, open, and non-inferiority trial. Two hundred patients who met the inclusion criteria and did not accord with the exclusion criteria will be randomly divided into LTG group (n = 100) and OTG group (n = 100). The primary purpose of this study is to evaluate the early operative morbidity and mortality of LTG compared with OTG for clinical stage I gastric adenocarcinoma. The second purpose is to evaluate the recovery course and compare the postoperative hospital stay of the patients enrolled in this study. DISCUSSION: This CLASS02-01 trial is the first prospective randomized two-arm controlled study to determine the safety of LTG compared with OTG. Through this trial, we hope to show that experienced surgeons can safely perform LTG with lymphadenectomy for gastric cancer. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03007550 . December 30, 2016.

Clinical outcomes of imatinib dose escalation versus sunitinib in first-line imatinib-failure gastrointestinal stromal tumour.

AIM: The majority of available data on the clinical efficacy of sunitinib in patients with imatinib-resistant or -intolerant gastrointestinal stromal tumours (GISTs) are from studies of western populations. We investigated the clinical outcomes of imatinib dose escalation versus sunitinib in first-line imatinib-failure Asian GIST patients to further guide clinical treatment. METHODS: Patients received imatinib dose escalation and a shift to sunitinib (Group A) or a direct shift to sunitinib (Group B). The objective tumour response was assessed according to Choi's criteria. Progression-free survival (PFS) and overall survival (OS) were calculated. The relationship between genetic mutation and survival was analysed. RESULTS: In total, 40 patients who fulfilled the inclusion criteria were recruited. The differences in survival between Group A and Group B were not significant for PFS (p = .776) or OS (p = .219). For patients with KIT exon 11 mutation, a trend towards a better PFS was found in Group B (p = .122), OS of Group B was better than Group A (p = .013). The median PFS and OS of sunitinib treatment were 8 and 24 months, respectively, and a clinical benefit was observed in 80%. Patients with KIT exon 11 mutations had better PFS compared to those with KIT exon 9 mutations or wild-type GISTs (p = .017, p = .040, respectively). CONCLUSIONS: Both imatinib dose escalation and sunitinib were optional in Asian patients after failure of first-line imatinib, and patients with KIT exon 11 mutation benefited more from a direct shift to sunitinib.

Value of the prognostic nutritional index in advanced gastric cancer treated with preoperative chemotherapy.

BACKGROUND: The prognostic nutritional index (PNI) is a useful parameter indicating the immune and nutritional status of cancer patients; this study investigated the prognostic value of the PNI in advanced gastric cancer patients treated with preoperative chemotherapy. MATERIALS AND METHODS: We retrospectively reviewed 117 advanced gastric cancer patients who met the inclusion criteria for preoperative chemotherapy and underwent surgical resection from July 2004 to December 2011. The patients were divided into PNI-high (PNI ≥ 45) and PNI-low (PNI < 45) groups. Clinicopathologic features, chemotherapy adverse events, and surgical complications were compared between the prechemotherapy PNI-high and PNI-low groups using the chi-square test. Survival analysis was performed using the Kaplan-Meier method and log-rank test. The Cox proportional hazard model was used to identify prognostic factors. RESULTS: Overall survival was better in the prechemotherapy PNI-high group than in the PNI-low group (hazard ratio [HR] = 2.237, 95% confidence interval [CI]: 1.271-3.393, P = 0.005), while there was no significant difference in Overall survival between the postchemotherapy PNI-high and PNI-low groups (P > 0.05). Cox regression analysis indicated that yield pathologic T (ypT), yield pathologic N (ypN) stage, and prechemotherapy PNI were independent prognostic factors (ypT: HR = 2.914, 95% CI = 1.312-6.470, P = 0.009; ypN: HR = 4.909, 95% CI = 1.764-13.660, P = 0.003; prechemotherapy PNI: HR = 1.963, 95% CI = 1.101-3.499, P = 0.022). CONCLUSIONS: The prechemotherapy PNI is a useful predictor of the long-term outcome of patients with advanced gastric cancer treated with preoperative chemotherapy.

Role of plasmacytoid dendritic cells and inducible costimulator-positive regulatory T cells in the immunosuppression microenvironment of gastric cancer.

Regulatory T cells (Tregs) and plasmacytoid dendritic cells (pDCs) play important roles in the immune escape of cancer. In this study, we investigated pDCs and pDC-induced inducible costimulator (ICOS)(+) Treg populations in peripheral blood from gastric cancer (GC) patients and healthy donors by flow cytometry. The distribution of these cells in carcinoma tissue, peritumor tissue, and normal gastric mucosa was detected by immunohistochemistry. Plasma and tissue concentration of the cytokines such as interleukin-10 and transforming growth factor-ß1 were also measured. We found that the numbers of pDCs, Tregs, and ICOS(+) Tregs in peripheral blood were increased in GC patients compared with healthy donors. In tissue, Tregs and ICOS(+) Tregs were found distributing mainly in carcinoma tissue, whereas pDCs were mainly found in peritumor tissue. Moreover, the Foxp3(+) ICOS(+) /Foxp3(+) cell ratio in carcinoma and peritumor tissue were higher than that in normal tissue. There were more ICOS(+) Tregs in tumor and peritumor tissue of late-stage GC patients. There was a positive correlation between pDCs and ICOS(+) Tregs in peripheral blood and peritumor tissue from GC patients. In conclusion, pDCs may play a potential role in recruiting ICOS(+) Tregs, and both participate in the immunosuppression microenvironment of GC.

THADA inhibits autophagy and increases 5-FU sensitivity in gastric cancer cells via the PI3K/AKT/mTOR signaling pathway.

Objectives: 5-Fluorouracil (5-FU) is currently the main drug used in chemotherapy for gastric cancer (GC). The main clinical problems of 5-FU therapy are insensitivity and acquired resistance to 5-FU. The mechanism of GC cell resistance to 5-FU is currently unknown. Materials and Methods: This study employed next-generation sequencing (NGS) to analyze the differentially expressed genes (DEGs) in chemotherapy-sensitive and non-sensitive GC tissues. In addition, a bioinformatics analysis was conducted using the GC dataset of GEO, and further validated and explored through in vitro experiments. Results: Thyroid adenoma-associated gene (THADA) was highly expressed in GC tissues from chemotherapy-sensitive patients and was an independent prognostic factor in GC patients receiving postoperative 5-FU adjuvant chemotherapy. Notably, heightened THADA expression in GC cells was associated with the down-regulation of autophagy-related proteins (LC-3, ATG13, ULK1, and TFEB). Furthermore, the PI3K/AKT/mTOR signaling pathway and mTORC1 signaling pathway were remarkably increased in patients with elevated THADA expression. THADA expression was associated with mTOR, the core protein of the mTOR signaling pathway, and related proteins involved in regulating the mTORC1 signaling pathway (mLST8, RHEB, and TSC2). THADA exhibited inhibitory effects on autophagy and augmented the sensitivity of GC cells to 5-FU through the PI3K/AKT/mTOR signaling pathway. Conclusion: The findings suggest that THADA may be involved in the regulatory mechanism of GC cell sensitivity to 5-FU. Consequently, the detection of THADA in tumor tissues may bring clinical benefits, specifically for 5-FU-related chemotherapy administered to GC patients with elevated THADA expression.

Blood neutrophil-lymphocyte ratio predicts survival for stages III-IV gastric cancer treated with neoadjuvant chemotherapy.

BACKGROUND: Accurate predictors of survival for patients with advanced gastric cancer treated with neoadjuvant chemotherapy are currently lacking. In this study, we aimed to evaluate the prognostic significance of the neutrophil-lymphocyte ratio (NLR) in patients with stage III-IV gastric cancer who received neoadjuvant chemotherapy. METHODS: We enrolled 46 patients in this study. The NLR was divided into two groups: high (>2.5) and low (≤2.5). Univariate analysis on progression-free survival (PFS) and overall survival(OS) was performed using the Kaplan-Meier and log-rank tests, and multivariate analysis was conducted using the Cox proportional hazards regression model. We analyzed whether chemotherapy normalized high NLR or not, and evaluated the prognostic significance of normalization on survival. RESULTS: The univariate analysis showed that PFS and OS were both worse for patients with high NLR than for those with low NLR before chemotherapy (median PFS 16 and 49 months, respectively, P = 0.012; median OS 21 and 52 months, P = 0.113). PFS and OS were also worse for patients with high NLR than for those with low NLR before surgery (median PFS 12 and 35 months, P = 0.019; median OS 21 and 52 months, P = 0.082). Multivariate analysis showed that both NLR before chemotherapy and surgery were independent prognostic factors of PFS. Neoadjuvant chemotherapy normalized high NLR in 11 of 24 patients, and these 11 patients had better median PFS and OS than the 13 patients who had high NLR both before chemotherapy and before surgery (PFS: 35.0 and 10.0 months, P = 0.003; OS: 60 and 16 months, P = 0.042). CONCLUSIONS: NLR may serve as a potential biomarker for survival prognosis in patients with stage III-IV gastric cancer receiving neoadjuvant chemotherapy.

Anti-tumor effects of Mfn2 in gastric cancer.

Mitofusin-2 (Mfn2) is a mitochondrial outer membrane protein involved in mitochondrial fusion. Its mutation can cause Charcot-Marie-Tooth disease. Recent studies of Mfn2 in cancer research have not included gastric cancer. We confirmed that Mfn2 expression was lower in tumor tissue than in normal gastric mucosal tissue and that it was negatively correlated with tumor size, indicating an anti-tumor role for Mfn2. In vitro experiments showed that Mfn2 overexpression suppressed gastric cancer cell proliferation and colony formation, weakened the invasion and migratory ability of cancer cells by downregulating MMP-2 and MMP-9, halted the cell cycle and induced apoptosis. Western blotting indicated the likely involvement of P21 and PI3K/Akt signaling. Therefore, Mfn2 is a potential anti-tumor gene and a potential therapeutic target for treating gastric cancer. The progress of gastric cancer may be delayed by controlling Mfn2 expression.

Advances in the diagnosis of non-occlusive mesenteric ischemia and challenges in intra-abdominal sepsis patients: a narrative review.

Non-occlusive mesenteric ischemia (NOMI) is a type of acute mesenteric ischemia (AMI) with a high mortality rate mainly because of a delayed or misdiagnosis. Intra-abdominal sepsis is one of the risk factors for developing NOMI, and its presence makes early diagnosis much more difficult. An increase in routine abdominal surgeries carries a corresponding risk of abdominal infection, which is a complication that should not be overlooked. It is critical that physicians are aware of the possibility for intestinal necrosis in abdominal sepsis patients due to the poor survival rate of NOMI. This review aims to summarize advances in the diagnosis of NOMI, and focuses on the diagnostic challenges of mesenteric ischemia in patients with intra-abdominal sepsis.

CCR9-CCL25 mediated plasmacytoid dendritic cell homing and contributed the immunosuppressive microenvironment in gastric cancer.

OBJECTIVES: Plasmacytoid dendritic cells (pDCs) play a crucial role in the microenvironment of tumor. Evidences has been shown that chemokine receptor 9 (CCR9) is an important molecule that attracts pDCs homing to the digestive tract and the latter are involved in the formation of digestive tract immune tolerance. The aim of this study was to explore the role of CCR9-CCL25 interaction in pDC-mediated immunosuppression microenvironment of gastric cancer (GC). MATERIALS AND METHODS: Regulatory T cells (Tregs) and pDCs were detected by immunohistochemistry. CCR9, which expressed on pDC was visualized by immunofluorescence. Western Blot was applied to evaluate the expression of CCL-25. Total pDCs, CCR9+pDCs, CCR9-pDCs, total Tregs, inducible costimulator + (ICOS) Tregs and ICOS-Tregs in peripheral blood and draining lymph nodes were analyzed by flow cytometry. Plasma concentration of the cytokines were measured by enzyme-linked immunosorbent assay RESULTS: Total Tregs, pDCs and CCR9+pDCs were higher in GC tissue. CCL-25 was over-expressed in carcinoma tissue. Peripheral total pDCs, CCR9-pDCs, total Tregs, ICOS+ Tregs, ICOS- Tregs were significantly increased in GC patients. More total pDCs, CCR9+ pDCs, total Tregs, ICOS+ Tregs were found in metastatic lymph nodes. Plasma concentrations of IL-6 and IL-10 were significantly higher in GC patients. More CCR9+ pDCs were found infiltrating carcinoma tissue in patients with later T staging and lymph node metastasis and conferred a poor prognosis. CONCLUSION: CCR9-CCL25 interaction might play an important role in mediating PDC homing to metastatic lymph nodes and carcinoma tissue, which contributed to the formation of tumor immunosuppressive microenvironment and poor prognosis.

The prognostic role of gastrointestinal bleeding in patients with a primary gastrointestinal stromal tumor: a long-term follow-up study.

Background: Gastrointestinal (GI) bleeding is one of the common symptoms of GI stromal tumor (GIST). Although several studies have highlighted its prognostic role, conclusions have been inconsistent. This study aimed to investigate the prognosis of GIST patients with GI bleeding. Methods: Primary GIST patients who underwent complete resection and did not receive adjuvant imatinib therapy from January 2003 to December 2008 were reviewed. The Kaplan-Meier method was used to estimate recurrence-free survival (RFS), and multivariate analysis was performed using the Cox proportional hazard model. Propensity score matching (PSM) was conducted to reduce confounders. A systematic review of the published articles in the PubMed, Embase, Cochrane Collaboration, and Medline databases was also conducted, and the inclusion criteria were determined using PICOS (patients, intervention, comparison, outcomes, and study design) principles. Results: In total, 84 patients presenting with GI bleeding and 90 patients without GI bleeding were enrolled in this study. The median time of follow-up was 140 months (range, 10-196 months), and 38 patients developed tumor recurrence/metastasis. For all patients, the multivariate analysis indicated that tumor location [hazard ratio (HR) =3.48, 95% confidence interval (CI): 1.78-6.82, P<0.001], tumor size (HR =1.91, 95% CI: 1.05-3.47, P=0.035), mitotic index (MI; HR =5.69, 95% CI: 2.77-11.67, P<0.001), and age (HR =2.68, 95% CI: 1.49-4.82, P=0.001) were the independent prognostic factors for poor RFS. However, GI bleeding was not associated with RFS (HR =1.21, 95% CI: 0.68-2.14, P=0.518). After PSM, 45 patients from each group were included, and it was found that GI bleeding was still not the independent prognostic factor (HR =1.23, 95% CI: 0.51-2.97, P=0.642). Moreover, the pooled results of our study and six previously reported studies showed that GI bleeding was not the independent prognostic factor (HR =1.45, 95% CI: 0.73-2.86, P=0.287). Conclusions: In this study, tumor location, tumor size, MI, and age were independent prognostic factors in primary GIST patients who underwent radical resection. However, GI bleeding was not associated with worse RFS.

Large-Scale, Multicenter, Prospective Registry Study of Ripretinib in Advanced GIST: A Real-World Study from China.

INTRODUCTION: Tyrosine-kinase inhibitors (TKIs) have become the standard treatment for patients with advanced gastrointestinal stromal tumor (GIST); however, secondary mutations can still drive disease progression. Studies have shown that ripretinib, a novel switch-control TKI, inhibits various primary and secondary drug-resistant mutations. There is a paucity of data on the effectiveness and safety of ripretinib in a real-world setting. This prospective, large-scale, real-world registry study aimed to evaluate the effectiveness and safety of ripretinib as a fourth-line treatment in Chinese patients with advanced GIST. METHODS: Patients ≥ 18 years of age having recurrent/metastatic GIST were enrolled. Key endpoints were median progression-free survival (mPFS), median overall survival (mOS), and adverse events (AEs) incidence. Univariate and multivariate analyses were conducted to identify various parameters associated with PFS. RESULTS: A total of 240 patients were enrolled. After a median follow-up period of 6.5 months, the mPFS [95% confidence interval (CI)] was 7.70 (6.60, 8.60) months and the mOS was not reached. Multivariate analysis revealed association of Eastern Cooperative Oncology Group (ECOG) performance status score with PFS and superior benefits for non-gastric was observed as compared to gastric GISTs [hazard ratio (HR) 0.58, 95% CI (0.39-0.86)]. Disease control rate and tumor shrinkage (any magnitude) was 73% and 43%, respectively. Ripretinib was also effective in the subgroup of patients with different gene mutations. The toxicities were tolerable, and most reported AEs were alopecia (17.1%) and hand-foot syndrome (15.4%). CONCLUSION: Ripretinib demonstrated effectiveness and a tolerable safety profile, making it a viable option as a fourth- or later-line treatment in Chinese patients with advanced GISTs, especially for non-gastric GISTs. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05697107.

Co-targeting of ACK1 and KIT triggers additive anti-proliferative and -migration effects in imatinib-resistant gastrointestinal stromal tumors.

Most gastrointestinal stromal tumors (GIST) harbor mutated receptor tyrosine kinase (RTK) KIT/PDGFRA, which provides an attractive therapeutic target. However, a majority of GISTs ultimately develop resistance to KIT/PDGFRA inhibitor imatinib, multiple therapeutic targets will be identified as a reasonable strategy in imatinib-resistant GISTs. Biological mechanisms of non-RTK activated CDC42 associated kinase 1 (ACK1) are still unclear, which has been found to be activated in GISTs. In the current report, ACK1 overexpression is demonstrated in GIST cell lines and biopsies. RNA-seq analysis and immunoblotting show that ACK1 expression is dependent on imatinib treatment time in GIST-T1 cell line. The colocalization/complex of KIT and ACK1 in GIST cells are observed, and ACK1 activation is in a partially KIT and CDC42 dependent manner. Treatment with a specific ACK1 inhibitor AIM-100 or ACK1 siRNA, mildly suppresses cell viability, but markedly inhibits cell migration in imatinib sensitive and in imatinib resistant GIST cell lines, which is associated with inactivation of PI3K/AKT/mTOR and RAF/MAPK signaling pathways, and inhibition of epithelial-mesenchymal transition, evidencing upregulation of E-cadherin and downregulation of ZEB1, N-cadherin, vimentin, snail, and/or ß-catenin after treatment with AIM-100 or ACK1/CDC42 shRNAs. Combination inhibition of ACK1 and KIT results in additive effects of anti-proliferation and pro-apoptosis as well as cell cycle arrest, and inhibition of invasiveness and migration in vitro and in vivo, compared to either intervention alone through dephosphorylation of KIT downstream intermediates (AKT, S6, and MAPK). Our data suggest that co-targeting of ACK1 and KIT might be a novel therapeutic strategy in imatinib-resistant GIST.

Efficacy and safety of ripretinib in Chinese patients with advanced gastrointestinal stromal tumors: a real-world, multicenter, observational study.

Introduction: Mutations in KIT proto-oncogene, receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor-α (PDGFRA) render the available tyrosine kinase inhibitors (TKI) ineffective in treating advanced gastrointestinal stromal tumors (GIST). Ripretinib, a broad-spectrum switch-control kinase inhibitor, has shown increased efficacy and manageable safety, but real-world evidence remains scarce. This study evaluates the efficacy and safety of ripretinib among Chinese patients in a real-world setting. Methods: Advanced GIST patients (N=23) receiving ripretinib following progression on previous lines of TKI treatment were enrolled to determine the efficacy [progression-free survival (PFS) and overall survival (OS)]. Safety was assessed by the incidence and severity of adverse events (AEs). All statistical analyses were performed using SPSS version 20.0 and a p-value of <0.05 was considered significant. Results: The median PFS (mPFS) of efficacy analysis set (EAS) (N=21) was 7.1 months. mPFS of patients receiving ripretinib following ≤2 lines of previous TKI treatment and ≥3 prior lines of therapy were 7.1 and 9.2 months, respectively. The median OS (mOS) was 12.0 months and shorter interval between the end of the latest TKI and ripretinib therapy was correlated with longer median PFS and OS (p=0.054 and p=0.046), respectively. Alopecia and asthenia were the most common AEs observed. Conclusion: Compared to previous lines of TKI in advanced GIST patients, ripretinib showed superior efficacy with clinically manageable AEs. Real-world results are comparable to that of phase III INVICTUS study and its Chinese bridging study. Hence, ripretinib can be used for the clinical management of advanced GIST patients.

Robotic thyroidectomy versus endoscopic thyroidectomy: a meta-analysis.

BACKGROUND: To conduct a meta-analysis to determine the relative merits of robotic thyroidectomy (RT) and endoscopic thyroidectomy (ET). METHODS: A literature search was performed to identify comparative studies reporting peri-operative outcomes for RT and ET. Pooled odds ratios (ORs) and weighted mean differences (WMDs) with 95% confidence interval (95% CI) were calculated using either a fixed-effects or a random-effects model. RESULTS: Six studies matched the selection criteria, which reported on 2048 subjects, of whom 978 underwent RT and 1070 underwent ET. Comparing the outcomes of RT with ET, this meta-analysis indicated that RT was associated with more complications (WMD = 1.51, 95% CI 1.18 to 1.94) and greater amount of drainage fluid (WMD = 17.10, 95% CI 5.69 to 28.51). Meanwhile, operating time (WMD = 1.50, 95% CI -39.59 to 42.58), conversion (WMD = 0.63, 95% CI 0.07 to 6.17), post-operative hospital stay (WMD = -0.05; 95% CI -0.18 to 0.08), and the number of lymph nodes harvested (WMD = 0.62, 95% CI -0.29 to 1.53) were similar for both procedures. CONCLUSION: The results of this meta-analysis indicated that RT is associated with an increased risk of complications and a greater amount of drainage fluid. Therefore, RT does not appear to have any advantage over ET. Further studies are required to confirm these results.