Haibo Qiu

Combined preoperative concentrations of CEA, CA 19-9, and 72-4 for predicting outcomes in patients with gastric cancer after curative resection

In many cancers, prognostic factors are useful for identifying high-risk patients and in individualizing treatment. We sought to determine whether a combination of tumor markers (CTM) would improve prognostic accuracy in patients with gastric cancer (GC). The CTM score, which is derived from serum concentrations of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9), and carbohydrate antigen 72-4 (CA 72-4), was tested retrospectively in 1134 patients with GC undergoing curative resection between October 2000 and December 2012. The CTM score was 2 for patients with two or three elevated markers, 1 for those with one elevated marker, and 0 for those no elevated markers. Overall survival (OS) in patients with CTM scores 0, 1, and 2 was 61.8%, 31.4%, and 15.1%, respectively (P<.001). The CTM score independently predicted OS on multivariate analysis (HR, 1.95; 95% CI, 1.73 to 2.21; P<.001). Moreover, the area under the receiver operating characteristics curve of the CTM score (0.67; 95% CI, 0.64 to 0.70) was higher than the values of any individual marker (0.63, 0.57, 0.57; P<.001 for all comparisons). The CTM score independently predicted postoperative survival in GC, and it may have better clinical utility than individual tumor markers for identifying high-risk patients with GC.

Impact of preoperative anemia on outcomes in patients undergoing curative resection for gastric cancer: a single-institution retrospective analysis of 2163 Chinese patients

We sought to evaluate whether preoperative anemia was an important determinant of survival in gastric cancer (GC). A single institution cohort of 2163 GC patients who underwent curative resection were retrospectively analyzed. Anemia was defined as a preoperative hemoglobin level <120 g/L in males and <110 g/L in females. Overall survival (OS) was analyzed using the Kaplan–Meier method, and a multivariate Cox proportional hazards model was performed to identify the independent prognostic factor. Anemic patients had a poorer OS compared with nonanemic patients after resection for tumor–nodes–metastasis (TNM) stage III tumors (5‐year OS rate: 32.2% vs. 45.7%, P < 0.001) but not stage I (P  =  0.480) or stage II (P  =  0.917) tumors. Multivariate analysis revealed that preoperative anemia was an independent prognostic factor in TNM stage III (hazard ratio [HR], 1.771; 95% CI, 1.040–3.015; P = 0.035). In a stage‐stratified analysis, preoperative anemia was still independently associated with OS in TNM stages IIIa through IIIc (P < 0.001, P = 0.075, and P = 0.012, respectively), though the association was only marginal in stage IIIb. Of note, preoperative mild anemia had a similar prognostic value in TNM stage III GC. Furthermore, preoperative anemia was significantly associated with more perioperative transfusions, postoperative complications and several nutritional‐based indices, including the prognostic nutritional index (PNI), preoperative weight loss and performance status (all P < 0.05). Preoperative anemia, even mild anemia, was an important predictor of postoperative survival for TNM stage III GC.

Gastric cancer, nutritional status, and outcome

Background We aim to investigate the prognostic value of several nutrition-based indices, including the prognostic nutritional index (PNI), performance status, body mass index, serum albumin, and preoperative body weight loss in patients with gastric cancer (GC). Materials and methods We retrospectively analyzed the records of 1,330 consecutive patients with GC undergoing curative surgery between October 2000 and September 2012. The relationship between nutrition-based indices and overall survival (OS) was examined using Kaplan–Meier analysis and Cox regression model. Results Following multivariate analysis, the PNI and preoperative body weight loss were the only nutritional-based indices independently associated with OS (hazard ratio [HR]: 1.356, 95% confidence interval [CI]: 1.051–1.748, P=0.019; HR: 1.152, 95% CI: 1.014–1.310, P=0.030, retrospectively). In stage-stratified analysis, multivariate analysis revealed that preoperative body weight loss was identified as an independent prognostic factor only in patients with stage III GC (HR: 1.223, 95% CI: 1.065–1.405, P=0.004), while the prognostic significance of PNI was not significant (all P>0.05). In patients with stage III GC, preoperative body weight loss stratified 5-year OS from 41.1% to 26.5%. When stratified by adjuvant chemotherapy, the prognostic significance of preoperative body weight loss was maintained in patients treated with surgery plus adjuvant chemotherapy and in patients treated with surgery alone (P<0.001; P=0.003). Conclusion Preoperative body weight loss is an independent prognostic factor for OS in patients with GC, especially in stage III disease. Preoperative body weight loss appears to be a superior predictor of outcome compared with other established nutrition-based indices.

Clinical significance of preoperative serum high density lipoprotein cholesterol levels in soft tissue sarcoma.

AbstractThe prognostic value of lipid profile remains unclear in soft tissue sarcoma. The aim of the present study was to validate the prognostic value of preoperative plasma lipid profile (high density lipoprotein-cholesterol [HDL-C], low density lipoprotein-cholesterol [LDL-C], cholesterol, and triglycerides) levels on disease-free survival (DFS) and overall survival (OS) in soft tissue sarcoma (STS) patients undergoing extensive and radical surgical resection.The preoperative plasma lipid profile levels of 234 STS patients, who were operated on between 2000 with 2010, were retrospectively evaluated. Kaplan-Meier curves and multivariate Cox proportional models were calculated for DFS and OS.In univariate analysis, a decreased HDL-C level was significantly associated with decreased OS (hazard ratio [HR], 3.405; 95% confidence interval (CI), 1.445–8.021, P = 0.005) and remained significant in the multivariate analysis (HR, 5.615; 95% CI, 1.243–25.378, P = 0.025). Patients with HDL-C < 1.475 mmol/L showed a median OS of 71 months. In contrast, patients with HDL-C ≥1.475 mmol/L had a median OS of 101 months. In univariate analysis, a decreased HDL-C level was significantly associated with decreased DFS (HR, 2.085; 95% CI, 1.271–3.422, P = 0.004) and remained significant in the multivariate analysis (HR, 1.808; 95% CI, 1.118–2.924, P = 0.016). Patients with HDL-C <1.475 mmol/L presented with a median DFS of 47 months, whereas patients with HDL-C ≥1.475 mmol/L had a median DFS of 78 months. In univariate analysis and multivariate analyses regarding OS and DFS, there was no significant association between the groups in terms of LDL-C, CHO and TG.Our study investigated the potential prognostic utility of preoperative plasma HDL-C levels as an independent factor in STS patients who had undergone radical surgical resection.

A Novel Pathological Prognostic Score (PPS) to Identify “Very High-Risk” Patients: a Multicenter Retrospective Analysis of 506 Patients with High Risk Gastrointestinal Stromal Tumor (GIST)

BackgroundTo determine the better risk stratification based on surgical pathology and to assess the clinical outcomes after curative resection with a new scoring system in high risk gastrointestinal stromal tumor (GIST) patients.MethodsWe retrospectively evaluated 506 high-risk GIST patients who underwent curative resection as initial treatment at four centers from 2001 to 2015.ResultsMultivariate analysis revealed that only Ki-67 labeling index (LI) and mitotic index were independent prognostic factors of overall survival (OS). For the two tumor-related pathological factors, Ki-67 LI > 7% and mitotic index ≥ 7/50 high power fields were allocated 1 point each. The total score was defined as the Pathological Prognostic Score (PPS). When Ki-67 LI and mitotic index were replaced by PPS, a multivariate analysis still identified PPS as an independent predictor of OS (HR 2.719; 95% CI 1.309–5.650; P = 0.007). Patients with a PPS of 0, 1, or 2 had a 5-year survival of 91.8, 79.8, and 51.0%, respectively (P = 0.001). Furthermore, an elevated PPS (PPS = 2) was associated with larger tumor size, non-stomach tumor, and open resection (all P < 0.05).ConclusionThe PPS independently predicted postoperative survival in high-risk GIST, and it might facilitate the selection of appropriate treatment strategy for these patients.

Prognostic factors of primary gastrointestinal stromal tumors: a cohort study based on high-volume centers

Objective We aimed to evaluate the clinicopathologic characteristics, immunohistochemical expression and prognostic factors of patients with primary gastrointestinal stromal tumors (GISTs). Methods Data from 2,570 consecutive GIST patients from four medical centers in China (January 2001-December 2015) were reviewed. Survival curves were constructed by the Kaplan-Meier method, and Cox regression models were used to identify independent prognostic factors. Results Of the included patients, 1,375 (53.5%) were male, and the patient age range was 18 to 95 (median, 58) years. The tumors were mostly found in the stomach (64.5%), small intestine (25.1%) and colorectal region (5.1%). At the time of diagnosis, the median tumor size was 4.0 (range: 0.1-55.0) cm, and the median mitotic index per 50 high power fields (HPFs) was 3 (range: 0-254). Of the 2,168 resected patients, 2,009 (92.7%) received curative resection. According to the modified National Institutes of Health (NIH) classification, 21.9%, 28.9%, 14.1% and 35.1% were very low-, low-, intermediate- and high-risk tumors, respectively. The rate of positivity was 96.4% for c-Kit, 87.1% for CD34, 96.9% for delay of germination 1 (DOG-1), 8.0% for S-100, 31.0% for smooth muscle actin (SMA) and 5.1% for desmin. However, the prognostic value of each was limited. Multivariate analysis showed that age, tumor size, mitotic index, tumor site, occurrence of curative resection and postoperative imatinib were independent prognostic factors. Furthermore, we found that high-risk patients benefited significantly from postoperative imatinib (P<0.001), whereas intermediate-risk patients did not (P=0.954). Conclusions Age, tumor size, mitotic index, tumor site, occurrence of curative resection and postoperative imatinib were independent prognostic factors in patients with GISTs. Moreover, determining whether intermediate-risk patients can benefit from adjuvant imatinib would be of considerable interest in future studies.

Preoperative nutritional deficiency is a useful predictor of postoperative outcome in patients undergoing curative resection for gastric cancer

BACKGROUND: Preoperative nutritional deficiency (ND) has been shown to be a valuable prognostic factor in urologic malignancies. We aimed to investigate the prognostic value of ND in patients with gastric cancer (GC). METHODS: A single-center cohort of 1026 GC patients undergoing curative resection between 2003 and 2012 was categorized to ND and nutritionally replete (NR) groups. Patients with body mass index <18.5 kg/m2, preoperative albumin <35 g/l, or preoperative weight loss ≥5% of body weight were defined as ND. RESULTS: Of the 1026 patients included in the study, 585 (57.0%) were categorized as ND. Overall survival (OS) at 5 years was 68.5% for ND patients and 44.0% for NR patients (P < .001). Multivariate analysis revealed that ND was a significant predictor of OS (hazard ratio: 1.954; 95% confidence interval: 1.552-2.460; P < .001). In stage-stratified analysis, it was still independently associated with OS in tumor-nodes-metastasis stage II and III (P = .004 and P < .001, respectively). Of note, the prognostic significance of ND was still maintained when stratified by age, sex, anemia, and adjuvant chemotherapy (all Ps < .05). CONCLUSION: Preoperative ND is a novel predictor of outcome in GC, especially in stage II to III GC, and may help clinicians identify high-risk patients for proactive nutritional interventions.

Clinical utility of HER2 assessed by immunohistochemistry in patients undergoing curative resection for gastric cancer

Purpose We sought to determine whether human epidermal growth factor receptor 2 (HER2) and vascular endothelial growth factor (VEGF) expression were independent prognostic factors for gastric cancer (GC). Patients and methods A total of 678 consecutive patients with GC undergoing curative surgery between October 2010 and December 2012 had resected tissue examined for HER2 and VEGF expression using immunohistochemistry. Immunohistochemical expression of HER2 was analyzed using the DAKO-HercepTest™ and scored according to published reports. VEGF expression was calculated by multiplying the score for the percentage of positive cells by the intensity score. We defined positive expression as a score of 1+, 2+, or 3+, and a score of 0 was defined as negative expression. We compared these results to clinicopathological characteristics, including overall survival (OS). Results Multivariate analysis revealed that HER2 expression was independently associated with shorter OS (hazard ratio [HR], 1.55; 95% confidence interval [CI], 1.10–2.18; P=0.01) and with higher tumor–nodes–metastasis stage (HR, 3.88; 95% CI, 2.67–5.64; P<0.001) in patients with GC. VEGF expression was not associated with OS (HR, 1.25; 95% CI, 0.86–1.82; P=0.24). HER2 expression was still identified as an independent prognostic factor in Stage II–III patients treated with surgery and adjuvant chemotherapy (P=0.004) but not in patients who received surgery alone (P=0.61). Among patients with Stage III GC, those without HER2 expression survived longer with adjuvant chemotherapy (median 43.9 vs 32.2 months, respectively; P=0.04), whereas those with HER2 expression did not (median 37.1 vs 33.9 months, respectively; P=0.67). Conclusion HER2 expression is independently associated with OS in GC, especially in patients who are at higher risk and receive adjuvant chemotherapy after curative resection. HER2 expression may have important clinical utility in directing adjuvant treatment for Stage III GC patients.

Prognostic nutritional index is an independent prognostic factor for gastric cancer patients with peritoneal dissemination

Objective The predictive and prognostic role of prognostic nutritional index (PNI) in gastric cancer patients with peritoneal dissemination remains unclear. This study aims to explore the role of the PNI in predicting outcomes of gastric cancer patients with peritoneal dissemination. Methods A total of 660 patients diagnosed with gastric adenocarcinoma with peritoneal metastasis between January 2000 and April 2014 at Sun Yat-sen University Cancer Center and the Sixth Affiliated Hospital of Sun Yat-sen University were retrospectively analyzed. The clinicopathologic characteristics and clinical outcomes of patients with peritoneal dissemination were analyzed. Results Compared with PNI-high group, PNI-low group was correlated with advanced age (P=0.036), worse performance status (P<0.001), higher frequency of ascites (P<0.001) and higher frequency of multisite distant metastasis (P<0.001). Kaplan-Meier survival curves showed that PNI-high group had a significantly longer median overall survival than PNI-low group (13.13 vs. 9.03 months, P<0.001). Multivariate survival analysis revealed that Borrmann type IV (P=0.014), presence of ascites (P=0.017) and lower PNI (P=0.041) were independent poor prognostic factors, and palliative surgery (P<0.001) and first-line chemotherapy (P<0.001) were good prognostic factors. For patients receiving palliative surgery, the postoperative morbidity rates in the PNI-low group and PNI-high group were 9.1% and 9.9%, respectively (P=0.797). The postoperative mortality rate was not significantly different between PNI-low and PNI-high groups (2.3% vs. 0.9%, P=0.362). Conclusions PNI is a useful and practical tool for evaluating the nutritional status of gastric cancer patients with peritoneal dissemination, and is an independent prognostic factor for these patients.

Abstract 1979: HQP1351, a novel multikinase inhibitor in clinical development, overcomes drug resistance for the treatment of gastrointestinal stromal tumors in preclinical models

Gastrointestinal stromal tumors (GIST) harbor driver mutations of signal transduction kinases such as KIT. Besides surgical resection for primary localized tumors, imatinib remains the first-line treatment for advanced and metastatic GISTs. Imatinib targets a few kinases including KIT that often carries the primary driver mutations commonly located on exon 11 and exon 9. Unfortunately, a large proportion of the patients ultimately develop progressive disease owing to the secondary resistance mutations in KIT gene. We have developed an orally bioavailable multikinase inhibitor HQP1351, which is currently in clinical trials for the treatment of T315I mutant CML. Here, we demonstrated that HQP1351 inhibited both wild type and mutant (i.e., KITL576P, KITV559D, and KITV559D/T670I) KIT in biochemical assays. Using a panel of imatinib-resistant and sensitive GIST cancer cell lines derived from patient samples, we showed that HQP1351 exhibited more potent anti-proliferative activities than ponatinib (range of IC50 values: 0.027-0.133 µM vs. 0.021-0.730 µM), the latter of which is currently in clinical development in GIST to overcome the resistance to imatinib (NCT03171389). In addition, the treatment of GIST cancer cells with HQP1351 in vitro led to more profound inhibition of pharmacodynamic markers, including p-c-KIT, p-AKT, p-ERK1/2, and p-AKT, in comparison with ponatinib. Correspondingly, in multiple xenograft tumor models derived from these GIST cancer cell lines carrying the secondary mutations of KIT, HQP1351 exhibited superior antitumor activities to ponatinib. Collectively, considering that HQP1351 has already been in clinical trials, the above results suggest that therapeutic application of HQP1351 in imatinib-resistant GIST patients deserves further investigation in human. Citation Format: Guangfeng Wang, Haibo Qiu, Ping Min, Miaoyi Wu, Shuo Dang, Chunyang Yang, Fei Zhang, Wei Zhuang, Zhiwei Zhou, Douglas D. Fang, Dajun Yang, Yifan Zhai. HQP1351, a novel multikinase inhibitor in clinical development, overcomes drug resistance for the treatment of gastrointestinal stromal tumors in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1979.