Sun Yat-sen University Cancer Center Research Articles

Prognostic value of the modified systemic inflammation score in non-small-cell lung cancer with brain metastasis

BackgroundBrain metastases (BM) from non-small-cell lung cancer (NSCLC) is the most common brain malignancy. Systemic inflammation biomarkers have recently been evaluated as prognosis indicators in several tumors. The combination of these markers has not been evaluated in NSCLC with BM yet. Here, we explored the predictive value of pretreatment inflammatory biomarkers and established a novel, clinically applicable prognostic index for NSCLC patients with BM.MethodsA retrospective investigation of 951 NSCLC patients newly diagnosed with BM at Sun Yat-sen University Cancer Center was conducted. We randomly divided patients into a training cohort (n = 674) or validation cohort (n = 277). Receiver operating characteristic (ROC) curve analysis was carried out to obtain the optimal cut-off values of pretreatment systemic inflammatory indexes. The associations between serum biomarkers and overall survival (OS) were analyzed by Kaplan–Meier curves and Cox proportional models. The resulting prediction model has been externally verified through the validation cohort.ResultsThe optimal cut-off value of the neutrophil–lymphocyte ratio (NLR) in predicting OS was 4.71, while the clinical standard of 40 mg/L was chosen as the optimal cut-off value of albumin. Univariate and multivariate analyses revealed that patients receiving local treatment, chemotherapy, a NLR < 4.71 and albumin ≥ 40 mg/l independently predicted improved survival. We combined the two inflammatory indexes (NLR and albumin level) to establish the modified systemic inflammation score (mSIS) which divides patients into low risk, medium risk or high-risk groups. The 1-year OS rates of three groups were 59.7%, 40.5% and 29.4%, respectively in the training cohort. The same result was verified in the validation cohort with the 1-year OS rates 69.7%, 47.0% and 7.7%, respectively. The mSIS exhibited better discrimination power than the American Joint Committee on Cancer’s (AJCC) 7th T + N staging system in the training cohort (Harrell’s concordance index (C-index): 0.744 vs 0.502, P < 0.05), and the discrimination was also superior to that of AJCC’s 7th T + N staging system in the validation cohort (C-index: 0.724 vs 0.527, P < 0.05). The 1-year and 2-year OS rates of the AUC also exhibited superior survival predictive ability to that of the AJCC’s 7th T + N staging system in NSCLC patients with BM.ConclusionThe pretreatment mSIS may be an independent prognostic factor for OS in NSCLC patients with BM and warrants further research.

Bladder paraganglioma: basic characteristics and new perspectives on perioperative management.

Paraganglioma and pheochromocytoma are rare neuroendocrine tumors with severe metabolic and cardiovascular complications. Bladder PGLs are rare, and their clinical management is not precise. Here, we discuss the basic characteristics and perioperative management of bladder PGLs. We retrospectively reviewed 20 bladder PGL cases diagnosed at Sun Yat-sen University Cancer Center. Case notes were reviewed, clinical presentations, therapies, and outcomes were collected, and data analysis was performed. Ten male and ten female patients with a median age of 47.5years (range 14-69years) were included. Most patients (65%) had no symptoms, and PGL was detected incidentally during medical checkups. All patients were treated surgically; 4 (20%) underwent transurethral resection of bladder tumor (TURBT), and 16 (80%) underwent partial cystectomy. Strong intraoperative blood pressure fluctuations were observed in 13 patients (65%). Two patients who were treated preoperatively with α-receptor blockers also experienced severe intraoperative blood pressure fluctuations. Postoperative measurements of troponin I were available for 3 patients, and all were significantly elevated. All patients were diagnosed with bladder PGL on postoperative pathological examination. The median follow-up time was 51months (range 2-147months), and 2 patients were lost to follow-up at 1 and 3months; 16 (88.9%) survived without recurrence, 2 patients (11.1%) experienced recurrence, and 1 patient died. Most bladder paragangliomas are easily mistaken for bladder urothelial carcinoma, and robust hemodynamic instability during surgery might be a challenge for urologists. Postoperative monitoring of troponin I, regardless of the presence of clinical symptoms, is recommended for patients with bladder PGL.

Dynamic alteration in SULmax predicts early pathological tumor response and short-term prognosis in non-small cell lung cancer treated with neoadjuvant immunochemotherapy.

Introduction: Biomarkers predicting tumor response to neoadjuvant immunochemotherapy in non-small cell lung cancer (NSCLC) are still lacking despite great efforts. We aimed to assess the effectiveness of the immune PET Response Criteria in Solid Tumors via SULmax (iPERCIST-max) in predicting tumor response to neoadjuvant immunochemotherapy and short-term survival in locally advanced NSCLC. Methods: In this prospective cohort study, we calculated SULmax, SULpeak, metabolic tumor volume (MTV), total lesion glycolysis (TLG) and their dynamic percentage changes in a training cohort. We then investigated the correlation between alterations in these parameters and pathological tumor responses. Subsequently, iPERCIST-max defined by the proportional changes in the SULmax response (△SULmax%) was constructed and internally validated using a time-dependent receiver operating characteristic (ROC) curve and the area under the curve (AUC) value. A prospective cohort from the Sun Yat-Sen University Cancer Center (SYSUCC) was also included for external validation. The relationship between the iPERCIST-max responsiveness and event-free survival in the training cohort was also investigated. Results: Fifty-five patients with NSCLC were included in this study from May 2019 to December 2021. Significant alterations in post-treatment SULmax (p < 0.001), SULpeak (p < 0.001), SULmean (p < 0.001), MTV (p < 0.001), TLG (p < 0.001), and tumor size (p < 0.001) were observed compared to baseline values. Significant differences in SULpeak, SULmax, and SULmean between major pathological response (mPR) and non-mPR statuses were observed. The optimal cutoff values of the SULmax response rate were −70.0% and −88.0% using the X-tile software. The univariate and multivariate binary logistic regression showed that iPERCIST-max is the only significant key predictor for mPR status [OR = 84.0, 95% confidence interval (CI): 7.84–900.12, p < 0.001]. The AUC value for iPERCIST-max was 0.896 (95% CI: 0.776–1.000, p < 0.001). Further, external validation showed that the AUC value for iPERCIST-max in the SYSUCC cohort was 0.889 (95% CI: 0.698–1.000, p = 0.05). Significantly better event-free survival (EFS) in iPERCIST-max responsive disease (31.5 months, 95% CI 27.9–35.1) than that in iPERCIST-max unresponsive disease (22.2 months, 95% CI: 17.3–27.1 months, p = 0.024) was observed. Conclusion: iPERCIST-max could better predict both early pathological tumor response and short-term prognosis of NSCLC treated with neoadjuvant immunochemotherapy than commonly used criteria. Furthermore, large-scale prospective studies are required to confirm the generalizability of our findings.

The prognostic value and molecular properties of tertiary lymphoid structures in oesophageal squamous cell carcinoma.

BackgroundTertiary lymphoid structures (TLSs) play key roles in tumour adaptive immunity. However, the prognostic value and molecular properties of TLSs in oesophageal squamous cell carcinoma (ESCC) patients have not been studied.MethodsThe prognostic values of the presence and maturation status of tumour‐associated TLSs were determined in 394 and 256 ESCC patients from Sun Yat‐sen University Cancer Center (Centre A) and the Cancer Hospital of Shantou University Medical College (Centre B), respectively. A deep‐learning (DL) TLS classifier was established with haematoxylin and eosin (H&E)‐stained slides using an inception‐resnet‐v2 neural network. Digital spatial profiling was performed to determine the cellular and molecular properties of TLSs in ESCC tissues.ResultsTLSs were observed in 73.1% of ESCCs from Centre A via pathological examination of H&E‐stained primary tumour slides, among which 42.9% were TLS‐mature and 30.2% were TLS‐immature tumours. The established DL TLS classifier yielded favourable sensitivities and specificities for patient TLS identification and maturation evaluation, with which 55.1%, 39.5% and 5.5% of ESCCs from Centre B were identified as TLS‐mature, TLS‐immature and TLS‐negative tumours. Multivariate analyses proved that the presence of mature TLSs was an independent prognostic factor in both the Centre A and Centre B cohorts (p < .05). Increased proportions of proliferative B, plasma and CD4+ T helper (Th) cells and increased B memory and Th17 signatures were observed in mature TLSs compared to immature ones. Intratumoural CD8+ T infiltration was increased in TLS‐mature ESCC tissues compared to mature TLS‐absent tissues. The combination of mature TLS presence and high CD8+ T infiltration was associated with the best survival in ESCC patients.ConclusionsMature TLSs improve the prognosis of ESCC patients who underwent complete resection. The use of the DL TLS classifier would facilitate precise and efficient evaluation of TLS maturation status and offer a novel probability of ESCC treatment individualization.

PD-1-mAb Plus Regimen in the First and Second Lines of Advanced and Unresectable Biliary Tract Carcinoma: A Real-World, Multicenter Retrospective Analysis.

Advanced biliary tract carcinoma (BTC) has a poor prognosis and few treatment options. We compared the efficacy of the PD-1 monoclonal antibody (PD-1-mAb) combined regimens with the standard chemotherapy in the first-line and second-line treatment of advanced BTC. We retrospectively assessed the patients with advanced BTC, who received treatment at the First Affiliated Hospital of Sun Yat-Sen University and the Sun Yat-Sen University Cancer Center. The patients were treated with PD-1-mAb combined regimens or standard chemotherapy at the first line or treated with PD-1-mAb combined regimens or systematic therapy at the second line. Further subgroup analyses were assessed to identify superior regimens. This study included 210 patients. The first-line PD-1-mAb combination group (n = 83) achieved longer median PFS (mPFS) (7.3 vs 5.3 months, p=0.001) and median OS (mOS) (15.6 vs 11.4 months, p=0.002) than the first-line standard chemotherapy group (n=76). Similarly, the second-line PD-1-mAb combination group (n=50) yielded longer mPFS (6.1 vs 2.6 months, p<0.001) and mOS (11.7 vs 7.2 months, p=0.008) than the second-line systematic therapy group (n=51). Subgroup analyses showed that the PD-1-mAb combined with TKI group achieved better mPFS than the chemotherapy group whether in the first-line (HR = 0.468, p=0.005) or the second-line setting (HR = 0.45, p=0.009), but did not achieve superiority in mOS (both p>0.05). Compared with the chemotherapy group, the PD-1-mAb combined with chemotherapy group achieved longer mOS (HR = 0.53, p=0.023) in the first-line setting and longer mPFS in the second-line setting (HR = 0.54, p=0.044). The PD-1-mAb combination therapy is superior to the standard chemotherapy in advanced or unresectable BTC, whether as a first-line or second-line treatment. Among the combination therapy, both the PD-1-mAb combined with TKI and combined with standard chemotherapy were promising options for advanced BTC patients.

Comparison of the efficacy of irreversible electroporation and conversional resection for locally advanced pancreatic cancer

Objective: To compare the short-term and long-term prognosis of irreversible electroporation(IRE) and conversional resection for locally advanced pancreatic cancer(LAPC). Methods: The clinical and pathological data of 98 LAPC patients who underwent IRE or conversional resection at the Department of Pancreatobiliary Surgery,Sun Yat-sen University Cancer Center from August 2015 to December 2020 were retrospectively collected and analyzed.The study comprised of 53 males and 45 females, with age(M(IQR)) of 57.5(13.5)years old(range:20 to 87 years old). Fifty-three patients received IRE treatment(IRE group) and 45 patients received surgical resection(resection group). The differences of clinical and pathological data between both groups were not significant(all P<0.05). The Mann-Whitney U test was used for quantitative data and the χ2 test was used for categorical data.Survival was analyzed using Kaplan-Meier method and compared using Log-rank test. Results: The operation time and intraoperative blood loss were 5.0(2.4)hours and 50(100) ml in the IRE group,respectively,which were significantly less than those of resection group(7.0(3.3)hours and 400(200)ml,both P<0.05).The hospital stay and hospitalization cost were 9.0(3.0)days and 79 154 (83 738) yuan in the IRE group,respectively,which were also significantly less than those in the resection group(16.0(8.5)days and 109 557(37 795)yuan,both P<0.05).The complication rate of IRE group was significantly lower than that of the resection group(18.8% vs. 55.6%,χ2=14.270,P<0.01).The median overall survival(OS) time of IRE group was 28.9 months(95%CI:23.2 to 34.6 months),with the 1-,2-,and 3-year OS rates of 91.6%,61.7%,and 24.6%,respectively.The median survival of OS of resection group was 27.1 months(95%CI:20.9 to 33.3 months),with the 1-,2-,and 3-year OS rates of 81.8%,53.9%,and 30.3%,respectively.There was no significant difference in OS between the two groups(χ2=0.900,P=0.760).The median progression free survival(PFS) time of IRE group was 18.0 months(95%CI:14.7 to 21.3 months),with the 1-,2-,and 3-year PFS rates of 68.3%,29.7%,and 9.9%,respectively.The median survival of PFS of resection group was 11.1 months(95%CI:6.1 to 16.2 months),with the 1-,2-,and 3-year PFS rates of 45.2%,21.9%,and 14.6%,respectively.There was no significant difference in PFS between the two groups(χ2=1.850,P=0.170). Conclusion: IRE can achieve similar survival for LAPC and may has less complications compared to those with conversion resection.

Study of preoperative diagnostic modalities in Chinese patients with superficial esophageal squamous cell carcinoma.

BACKGROUNDEndoscopic ultrasonography (EUS) and magnifying endoscopy (ME) reliably determine indications for endoscopic resection in patients with superficial esophageal squamous cell carcinoma (SESCC). ME is widely accepted for predicting the invasion depth of superficial esophageal cancer with satisfying accuracy. However, the addition of EUS is controversial.AIMTo evaluate the diagnostic efficiency of ME vs EUS for invasion depth prediction and investigate the influencing factors in patients with SESCC to determine the best diagnostic model in China.METHODSWe retrospectively analyzed patients with suspected SESCC who completed both ME and EUS and then underwent endoscopic or surgical resection at Sun Yat-Sen University Cancer Center between January 2018 and December 2021. We evaluated and compared the diagnostic efficiency of EUS and ME according to histological results, and investigated the influencing factors.RESULTSWe included 152 lesions from 144 patients in this study. The diagnostic accuracies of ME and EUS in differentiating invasion depth were not significantly different (73.0% and 66.4%, P = 0.24); both demonstrated moderate consistency with the pathological results (ME: kappa = 0.58, 95% confidence interval [CI]: 0.48-0.68, P < 0.01; EUS: kappa = 0.46, 95%CI: 0.34-0.57, P < 0.01). ME was significantly more accurate in the diagnosis of high-grade intraepithelial (HGIN) or carcinoma in situ (odds ratio [OR] = 3.62, 95%CI: 1.43-9.16, P = 0.007) subgroups. Using a miniature probe rather than conventional EUS can improve the accuracy of lesion depth determination (82.3% vs 49.3%, P < 0.01). Less than a quarter of circumferential occupation and application of a miniature probe were independent risk factors for the accuracy of tumor invasion depth as assessed by EUS (< 1/4 circumferential occupation: OR = 3.07, 95%CI: 1.04-9.10; application of a miniature probe: OR = 5.28, 95%CI: 2.41-11.59, P < 0.01). Of the 41 lesions (41/152, 27.0%) that were misdiagnosed by ME, 24 were corrected by EUS (24/41, 58.5%). CONCLUSIONPreoperative diagnosis of SESCC should be conducted endoscopically using white light and magnification. In China, EUS can be added after obtaining patient consent. Use of a high-frequency miniature probe or miniature probe combined with conventional EUS is preferable.

Efficacy and safety of neoadjuvant imatinib therapy for patients with locally advanced rectal gastrointestinal stromal tumors: A multi-center cohort study.

Background: Several issues on neoadjuvant imatinib therapy remain controversial despite its widespread application for rectal gastrointestinal stromal tumors (GIST). We aimed to describe the clinicopathological characteristics of this specific population, and compare the surgical and oncologic outcomes between patients with or without neoadjuvant imatinib therapy. Patients and methods: A cohort of 58 consecutive locally advanced rectal GIST patients receiving surgical treatment between January 2007 and July 2019 at Sun Yat-sen University Cancer Center and Yunnan Cancer Hospital was retrospectively analyzed. Recurrence-free survival (RFS) and overall survival (OS) were estimated using Kaplan-Meier method. Results: There were 33 (56.9%) patients who received neoadjuvant imatinib therapy. Among them, 20 (60.6%) patients had partial response (PR) as their best response, 11 (33.3%) patients had stable disease (SD), and 2 (6.1%) patients had progressive disease (PD). The median tumor size reduced from 5.2 to 4.0 cm after treatment (p < 0.001), and an attained “maximal response” was primarily achieved (32/33) on the 12th month after treatment. The most common adverse event was anemia. There were 27 adverse events occurred, most of which were grade 1 (19/27). With respect to intraoperative and postoperative surgical outcomes, no significant difference was found between patients with or without neoadjuvant Imatinib therapy except that patients with neoadjuvant treatment had a significant higher rate of preventive ileostomy (p = 0.004). Patients received neoadjuvant treatment had a superior 2-years RFS outcome than those without, though the difference was no significant (91.7% vs. 78.9%, p = 0.203). There were no significant differences in the 2-years OS rates (95.2% vs. 91.3%, p = 0.441). Conclusion: Neoadjuvant imatinib therapy is an effective and safe treatment for locally advanced rectal GISTs. Further studies are warranted to validate the long-term prognostic benefit for patients with rectal GISTs receiving neoadjuvant imatinib therapy.

184. THE PROGNOSTIC VALUE AND MOLECULAR PROPERTIES OF TERTIARY LYMPHOID STRUCTURES IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Tertiary lymphoid structures (TLSs) play key roles in tumor adaptive immunity. However, the prognostic value and molecular properties of TLSs in esophageal squamous cell carcinoma (ESCC) patients have not been studied. The prognostic values of the presence and maturation status of tumor-associated TLSs were determined in 394 and 256 ESCCs with hematoxylin and eosin (H&amp;E)-stained slides from Sun Yat-sen University Cancer Center (SYSUCC) and Cancer Hospital of Shantou University Medical College (SUMCCH), respectively. A deep-learning TLS classifier was established with H&amp;E-stained slides using inception-resnet-v2 neural network. Digital spatial profiling (DSP) was performed to determine the cellular and molecular characteristics of TLSs in ESCCs. Immature and mature TLSs were observed in 30.2% and 42.9% ESCCs from SYSUCC by pathological examination. The deep-learning TLSs classifier yielded an area under curve value of 0.975 for patients’ mature TLS detection in the external test set, by which 55.1% ESCCs from SUMCCH were identified with mature TLSs. The presence of mature TLSs associated with an earlier pT-stage and improved survival. Mature TLSs were characterized by increased proportions of proliferating B, plasma, and CD4+ Th cells, and increased B memory, CD4+ T activated and effector memory, and Th17 signatures. TLS-mature ESCCs were with increased intratumoral CD8+ T infiltration. Mature TLSs provide a privileged microniche for B and T cell differentiation and maturation, thereby generating an effective anti-tumor humoral and cellular immunity to improve ESCC prognosis.

Body mass index, as a novel predictor of hepatocellular carcinoma patients treated with Anti-PD-1 immunotherapy.

Immunocheckpoint inhibitors have shown significant efficacy in the treatment of hepatocellular carcinoma (HCC), but there are individual differences. The aim of this study was to explore body mass index (BMI) as a predictor of anti-PD-1 efficacy in patients with HCC. We retrospectively analyzed 101 HCC patients who treated with anti-PD-1 at Sun Yat-sen University Cancer Center from July 2018 to November 2019 and divided them into overweight (BMI > 24.9) and non-overweight (BMI ≤ 24.9) groups based on baseline BMI levels. BMI > 24.9 accounted for 22 cases (21.8%) and BMI ≤ 24.9 accounted for 79 cases (78.2%) in the study cohort. Overweight patients had higher disease control rates than non-overweight patients (P = 0.019, respectively). The mean progression-free survival (PFS) in overweight patients (10.23 months) was significantly longer than that of non-overweight patients (6.85 months; P = 0.027). Among patients with immune-related adverse events (irAEs), the mean PFS was also significantly longer in overweight patients (7.72 months) than in non-overweight patients (5.31 months, P = 0.034). Multivariate analysis showed that BMI was an independent prognostic factor for PFS in HCC patients treated with anti-PD-1 (hazard ratio: 0.47, P = 0.044). Thus, higher BMI predicts a better prognosis among HCC patients treated with anti-PD-1. In clinical practice, patients' BMI can provide a useful tool for predicting the efficacy of anti-PD-1 therapy.

Association between driving pressure and postoperative pulmonary complications in patients undergoing lung resection surgery: A randomised clinical trial

BackgroundIt is uncertain whether an association exists for decreases in driving pressure and the occurrence of postoperative pulmonary complications (PPCs) in patients undergoing selective lung resection surgery. Thus, we designed this study to determine whether the positive end-expiratory pressure (PEEP) titration to the lowest driving pressure compared with conventional low PEEP level during one-lung ventilation (OLV) in patients undergoing selective lung resection surgery decreases PPCs. MethodsThis single-centre, randomised trial approved by the Ethical Committee of the Sun Yat-Sen University Cancer Center involved patients who signed written consent. Patients were randomised to the PEEP titration to the lowest driving pressure group (n = 104), or to the conventional low level of PEEP group (n = 103), consisting a PEEP level of 4 cm H2O during OLV. All patients received volume-controlled ventilation with a tidal volume of 6 mL/kg of predicted body weight. The primary outcome was defined as positive if 4 or more of eight Melbourne Group Scale (MGS) variables developed within the first 3 days after surgery. The incidence of major PPCs occurring during postoperative 7 days was also recorded. ResultsAmong 222 patients who were randomised, 207 (93%) completed the trial (109 men [53%]; mean age, 56.9 years). The primary outcome occurred in 4 of 104 patients (4%) in the PEEP titration to the lowest driving pressure group compared with 13 of 103 patients (13%) in the conventional low level of PEEP group (risk ratio, 0.32 [95% CI, 0.10−0.90]; P = 0.021). ConclusionsAmong patients undergoing selective lung surgery, intraoperative OLV with PEEP titration to the lowest driving pressure compared with conventional low PEEP level (4 cm H2O) significantly reduced PPCs within the first 3 postoperative days, however, did not significantly reduce PPCs within the first 7 postoperative days.

1256P Three courses of neoadjuvant camrelizumab combined with chemotherapy in locally advanced esophageal squamous cell carcinoma (ESCC): A prospective phase II clinical trial

Neoadjuvant chemotherapy with anti-PD-1 antibody has favorable effect for locally advanced ESCC. However, these trials only applied two courses of neoadjuvant protocols. The efficacy and safety of three courses regimen are poorly known. This study explored the three courses of camrelizumab plus chemotherapy for treating locally advanced ESCC in a prospective phase II trial. We planned to recruit locally advanced ESCC patients to received three courses of camrelizumab (200mg every 3 weeks) plus nab-paclitaxel (260 mg/m2 every 3 weeks) and capecitabine (1250 mg/m2 every 3 weeks) before undergoing surgery. The first endpoint was complete pathological response. The second endpoint was safety and feasibility. To further explore the biomarkers for predicting the efficacy, we performed extensive analyses using immunohistochemistry, WES and mutiplex immunofluorescence. From May 2020 to December 2021, a total of 47 patients was enrolled in Sun Yat-sen university cancer center. The ORR was 83%, 42 patients received surgery and R0 resection was achieved in all cases. 33.3% patients had a pCR and 64.3% had an MPR. The median follow-up was 12 months (range, 3-22 months). Only one patient died at 12th month after surgery due to cardiovascular diseases, and one patient had recurrence in the left main bronchus lymph node at 12th month. 1-year OS rate and 1-year DFS rate was 97.3% and 92.1%, respectively. The most common adverse events were grade 1-2, which did not delay the operation. The density of CD56dim NK cells in pretreatment tissues was significant higher in pCR+MPR group than non-responders group(P=0.0085). And after neoadjuvant treatment, the density of CD56dimNK cells significantly decrease in pCR+MPR group (P=0.00019). However, the PD-L1 expression and TMB had no difference between the two groups (P = 0.165, P = 0.627, respectively). Three courses of neoadjuvant camrelizumab combined with chemotherapy in locally advance ESCC had a favorable pathological response, with a manageable safety profile. Three courses regimen may achieve a better survival and patients with a higher density of CD56dim NK cells might benefit greatly from the regimen.

Gemcitabine combined with apatinib and toripalimab in recurrent or metastatic nasopharyngeal carcinoma

The role of a triple combination of gemcitabine (chemotherapy) plus apatinib (anti-vascular endothelial growth factor [VEGFR]) and toripalimab (anti-PD-1) (GAT) in recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) is unclear. Between August 2019 and April 2020, 41 patients with RM-NPC were enrolled and received GAT for up to 6 cycles followed by apatinib and toripalimab. The primary endpoint was the safety. The secondary endpoints included the objective response rate (ORR) and progression-free survival (PFS). Integrated genomic and transcriptional analyses were conducted to identify the patients who benefited in response to this novel combination therapy. As of April 1, 2022, treatment-related grade 3 or 4 adverse events (AEs) occurred in 23 of 41 patients (56.1%, 95% confidence interval [CI] 41%-70.1%). G3-4 nasopharyngeal necrosis was observed in 9 (9/41, 21.9%) patients. High-risk factors for necrosis included repeated radiotherapy and an interval of less than 12months from the last radiotherapy. The ORR was 90.2% (95% CI: 76.9%-97.2%). The median PFS was 25.8months (95% CI: not reached (NR)-NR), and the 24-month PFS rate was 50.7% (95% CI: 34.0%-67.4%). MAS-related GPR family member F (MRGPRF) high expression in tumors correlated with poor PFS from the GAT therapy, characterized by high epithelial mesenchymal transition signatures. Serial circulating tumor DNA (ctDNA) sequencing could predict PFS outcomes to combination therapy. GAT therapy exhibits a promising antitumor activity and manageable toxicities in patients with RM-NPC. Patients with repeated radiotherapy and an interval of less than 12months from the last radiotherapy should be carefully selected for antiangiogenic therapies. MRGPRF expression and serial ctDNA monitoring could identify patients that derive benefits from the combination therapy. ClinicalTrials.gov: NCT04073784. This research was funded by the National Natural Science Foundation of China (nos. 81772895 and 82002857), the Key-Area Research and Development of Guangdong Province (2020B1111190001), the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project (202103010001), and the National "Ten Thousand TalentsProgram" Science and Technology Innovation Leading Talents (84000-41180005).

A nomogram for predicting 10-year cancer specific survival in patients with pathological T3N0M0 rectal cancer.

BackgroundThe pathological T3N0M0 (pT3N0M0) rectal cancer is the earliest stage and has the best prognosis in the locally advanced rectal cancer, but the optimal treatment remains controversial. A reliable prognostic model is needed to discriminate the high-risk patients from the low-risk patients, and optimize adjuvant chemotherapy (ACT) treatment decisions by predicting the likelihood of ACT benefit for the target population.Patients and methodsWe gathered and analyzed 276 patients in Sun Yat-sen University Cancer Center from March 2005 to December 2011. All patients underwent total mesorectal excision (TME), without preoperative therapy, and were pathologically proven pT3N0M0 rectal cancer with negative circumferential resection margin (CRM). LASSO regression model was used for variable selection and risk factor prediction. Multivariable cox regression was used to develop the predicting model. Optimum cut-off values were determined using X-Tile plot analysis. The 10-fold cross-validation was adopted to validate the model. The performance of the nomogram was evaluated with its calibration, discrimination and clinical usefulness.ResultsA total of 188 patients (68.1%) had ACT and no patients had adjuvant radiotherapy. Age, monocyte percentage, carbohydrate antigen 19–9, lymph node dissection numbers and perineural invasion (PNI) were identified as significantly associated variables that could be combined for an accurate prediction risk of Cancer Specific Survival (CSS) for pT3N0M0 patients. The model adjusted for CSS showed good discrimination with a C-index of 0.723 (95% CI: 0.652–0.794). The calibration curves showed that the nomogram adjusted for CSS was able to predict 3-, 5-, and 10-year CSS accurately. The corresponding predicted probability was used to stratify high and low-risk patients (10-year CSS: 69.1% vs. 90.8%, HR = 3.815, 95%CI: 2.102–6.924, P < 0.0001). ACT improved overall survival (OS) in the low-risk patients (10-year OS: 91.9% vs. 83.3%, HR = 0.338, 95% CI: 0.135–0.848, P < 0.0001), while it did not exhibit a significant benefit in the high-risk patients.ConclusionThe present study showed that age, monocyte percentage, carbohydrate antigen 19–9, lymph node dissection numbers and PNI were independent prognostic factors for pT3N0M0 rectal cancer patients. A nomogram based on these prognostic factors effectively predicts CSS in patients, which can be conveniently used in clinical practice. ACT may improve overall survival in the low-risk patients. But the benefit of ACT was not seen in the high-risk patients.

Apatinib for recurrent/progressive glioblastoma multiforme: A salvage option

Purpose: The recurrent/progressive glioblastoma multiforme (GBM) carries a dismal prognosis and the definitive treatment strategy has not yet been established. This study aimed to assess the efficacy and safety of apatinib in recurrent/progressive GBM patients. Materials and methods: The clinical data of 19 recurrent/progressive GBM patients who received apatinib treatment from November 2015 to December 2019 at Sun Yat-sen University Cancer Center were collected retrospectively in this study. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (AEs) were reviewed and assessed. Results: The overall ORR was 52.6%, and the DCR was 73.7%. Median PFS and OS were 5.1 and 10.4 months, respectively. The 6-month PFS and OS rates were 38.9% and 68.4%, respectively. The 12-month PFS and OS rates were 16.7% and 36.8%, respectively. The treatment-related toxicities were generally well-tolerated. The most common grade 3/4 AEs were hand-foot syndrome (36.8%) and hypertension (21.1%). Conclusion: Our study showed that apatinib therapy provided a better salvaging option for recurrent/progressive GBM patients and the toxicity was manageable.

Identification of a novel cuproptosis-related gene signature and integrative analyses in patients with lower-grade gliomas.

BackgroundCuproptosis is a newly discovered unique non-apoptotic programmed cell death distinguished from known death mechanisms like ferroptosis, pyroptosis, and necroptosis. However, the prognostic value of cuproptosis and the correlation between cuproptosis and the tumor microenvironment (TME) in lower-grade gliomas (LGGs) remain unknown.MethodsIn this study, we systematically investigated the genetic and transcriptional variation, prognostic value, and expression patterns of cuproptosis-related genes (CRGs). The CRG score was applied to quantify the cuproptosis subtypes. We then evaluated their values in the TME, prognostic prediction, and therapeutic responses in LGG. Lastly, we collected five paired LGG and matched normal adjacent tissue samples from Sun Yat-sen University Cancer Center (SYSUCC) to verify the expression of signature genes by quantitative real-time PCR (qRT-PCR) and Western blotting (WB).ResultsTwo distinct cuproptosis-related clusters were identified using consensus unsupervised clustering analysis. The correlation between multilayer CRG alterations with clinical characteristics, prognosis, and TME cell infiltration were observed. Then, a well-performed cuproptosis-related risk model (CRG score) was developed to predict LGG patients’ prognosis, which was evaluated and validated in two external cohorts. We classified patients into high- and low-risk groups according to the CRG score and found that patients in the low-risk group showed significantly higher survival possibilities than those in the high-risk group (P<0.001). A high CRG score implies higher TME scores, more significant TME cell infiltration, and increased mutation burden. Meanwhile, the CRG score was significantly correlated with the cancer stem cell index, chemoradiotherapy sensitivity–related genes and immune checkpoint genes, and chemotherapeutic sensitivity, indicating the association with CRGs and treatment responses. Univariate and multivariate Cox regression analyses revealed that the CRG score was an independent prognostic predictor for LGG patients. Subsequently, a highly accurate predictive model was established for facilitating the clinical application of the CRG score, showing good predictive ability and calibration. Additionally, crucial CRGs were further validated by qRT-PCR and WB.ConclusionCollectively, we demonstrated a comprehensive overview of CRG profiles in LGG and established a novel risk model for LGG patients’ therapy status and prognosis. Our findings highlight the potential clinical implications of CRGs, suggesting that cuproptosis may be the potential therapeutic target for patients with LGG.

A novel quantitative prognostic model for initially diagnosed non-small cell lung cancer with brain metastases

BackgroundThe prognosis of non-small cell lung cancer (NSCLC) with brain metastases (BMs) had been researched in some researches, but the combination of clinical characteristics and serum inflammatory indexes as a noninvasive and more accurate model has not been described.MethodsWe retrospectively screened patients with BMs at the initial diagnosis of NSCLC at Sun Yat-Sen University Cancer Center. LASSO-Cox regression analysis was used to establish a novel prognostic model for predicting OS based on blood biomarkers. The predictive accuracy and discriminative ability of the prognostic model was compared to Adjusted prognostic Analysis (APA), Recursive Partition Analysis (RPA), and Graded Prognostic Assessment (GPA) using concordance index (C-index), time-dependent receiver operating characteristic (td-ROC) curve, Decision Curve Analysis(DCA), net reclassification improvement index (NRI), and integrated discrimination improvement index (IDI).Results10-parameter signature's predictive model for the NSCLC patients with BMs was established according to the results of LASSO-Cox regression analysis. The C-index of the prognostic model to predict OS was 0.672 (95% CI = 0.609 ~ 0.736) which was significantly higher than APA,RPA and GPA. The td-ROC curve and DCA of the predictive model also demonstrated good predictive accuracy of OS compared to APA, RPA and GPA. Moreover, NRI and IDI analysis indicated that the prognostic model had improved prediction ability compared with APA, RPA and GPA.ConclusionThe novel prognostic model demonstrated favorable performance than APA, RPA, and GPA for predicting OS in NSCLC patients with BMs.

SYST-04 PRELIMINARY REPORT OF A CLINICAL TRIAL EVALUATING THE SAFETY AND EFFICIENCY OF NEOADJUVANT CAMRELIZUMAB AND APATINIB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMAS: A PROSPECTIVE, PHASE II, SINGLE-ARM STUDY

High-grade glioma is the most common malignant primary brain tumor in the central nervous system. Multiple strategies such as surgery, radiotherapy, and chemotherapy have been used, but the prognosis of patients with high-grade glioma remains poor. No standard treatment exists for recurrent gliomas; however, combination therapies of programmed cell death protein 1 blockades with antiangiogenic agents have demonstrated promising effects in different solid tumors. We have initiated a clinical trial designed to evaluate the safety and efficiency of neoadjuvant therapy using camrelizumab and apatinib in patients with recurrent highgrade gliomas. In this prospective, Phase II, singlearm study, patients with recurrent highgrade gliomas will receive singledose intravenous injection of camrelizumab (200 mg) and daily oral administration of apatinib (250 mg/day for 7 days) 14 days before surgery for recurrent tumor. Sequential therapy will begin 2 weeks after surgery with the biweekly injection of camrelizumab and 4 weeks after surgery with the daily administration of apatinib. Treatment of camrelizumab and apatinib will be continued until disease progression or unacceptable toxicity or death. The trial is planned to enroll 30 patients. Up-to date (March 31, 2022), 12 patients had been enrolled, in which, 9 were GBM. Three patients died, while 4 cases on trial more than 6 months, the longest already 1 year. Although an evaluation is still impossible to be conducted yet, some patients have shown a promising outcome. We will present updated results on the meeting. These preliminary data suggest that this study would be worthwhile. This study was approved by the Ethics Committee of Sun Yatsen University Cancer Center (Guangzhou, China; approval No. SLB202014901). This study was registered with ClinicalTrials.gov under identifier NCT04588987.

Early administration of dobutamine in the treatment of septic shock patients with tumor-a retrospective comparative cohort study.

BackgroundStudies have found that dobutamine may be beneficial to protect organs function in patients with septic shock, but there is still a lack of relevant research in septic shock patients with tumor. The study sought to explore the role of the early administration of dobutamine in the treatment of septic shock patients with tumors.MethodsWe retrospectively collected the data of tumor patients who developed septic shock at Sun Yat-sen University Cancer Center between June 2008 and November 2021. All the patients were divided into the following 3 groups: (I) the early administration group (<3 days, n=15); (II) the late administration group (≥3 days, n=22); and (III) the non-administration group (n=85). The primary observation indicator was 28-day mortality, and the secondary observation indicators included the shock reversal rate, the length of stay in the intensive care unit (ICU) and the duration of mechanical ventilation. There was no statistical difference in the basic data of the three groups.ResultsThe early administration group had a significant decrease in 28-day mortality compared to the late and non-administration groups (log-rank P=0.018). The comparison between the groups showed that the 28-day mortality of the early administration group was significantly lower than that of the non-administration group [20.0% vs. 58.8%, P=0.013, hazard ratios (HRs) =0.248, 95% confidence intervals (CIs): 0.077–0.796]. There was no statistically significant difference in 28-day mortality between the late administration group and the non-administration group (63.6% vs. 58.8%, P=0.682, HR =0.983, 95% CI: 0.543–1.778). Additionally, the early administration group had a significantly increased shock reversal rate (P=0.014), shortened length of stay in the ICU (P<0.001), and reduced duration of mechanical ventilation (P=0.049).ConclusionsEarly use of dobutamine may be beneficial to reduce the in-hospital mortality of septic shock patients with tumor, but the sample size of this study was small, which still needs to be confirmed by a multi-center randomized controlled clinical study.

Association of Intratumoral Microbiota With Prognosis in Patients With Nasopharyngeal Carcinoma From 2 Hospitals in China

Microbiota-tumor interactions have qualified microbiota as a promising prognostic biomarker in various types of cancers. Although the nasopharynx acts as a crucial niche of the upper respiratory tract microbiome, whether the intratumoral microbiota exists and its clinical significance in nasopharyngeal carcinoma (NPC) remain uncertain. To evaluate the clinical significance of intratumoral microbiota for individual prognostication in patients with NPC. This retrospective cohort study included NPC biopsy samples from 2 hospitals: Sun Yat-sen University Cancer Center (Guangzhou, China) and Zhejiang Cancer Hospital (Hangzhou, China) between January 2004 and November 2016, with follow-up through November 2020. A total of 802 patients were included according to the following criteria: with histologically proven NPC, without distant metastasis at initial diagnosis, had not received antitumor treatment before biopsy sampling, aged between 18 and 70 years, with complete medical records and regular follow-up, without a history of cancer, and successfully extracted enough DNA for experiments. The primary end point was disease-free survival, and the secondary end points included distant metastasis-free survival and overall survival. To assess the existence and load of intratumoral microbiota in 96 patients with NPC with or without tumor relapse, 16S rRNA sequencing and quantitative polymerase chain reaction were used. The associations between intratumoral bacterial load and clinical outcome were evaluated in 241 fresh-frozen NPC samples (training cohort) and validated in paraffin-embedded NPC samples of internal (n = 233) and external (n = 232) validation cohorts. Metagenomic and transcriptome analyses were performed to ascertain the origin and underlying mechanism of intratumoral bacteria. A total of 802 patients with NPC (mean [SD] age, 46.2 [10.6] years; 594 [74.1%] male) were enrolled. Microbiota presented within NPC tumor tissues, among which Corynebacterium and Staphylococcus predominated. Patients with a high bacterial load in the training cohort had inferior rates of disease-free survival (hazard ratio [HR], 2.90; 95% CI, 1.72-4.90; P < .001), distant metastasis-free survival (HR, 3.18; 95% CI, 1.58-6.39; P < .001), and overall survival (HR, 3.41; 95% CI, 1.90-6.11, P < .001) than those with a low bacterial load, a finding that was validated by the internal and external validation cohorts. Single-nucleotide variant analysis revealed that the nasopharyngeal microbiota was the main origin of NPC intratumoral bacteria. Transcriptome and digital pathology analyses demonstrated that a higher intratumoral bacterial load was negatively associated with T-lymphocyte infiltration. Intratumoral bacterial load was a robust prognostic tool for patients with NPC in this cohort study, indicating potential guidance for treatment decisions in patients at different levels of risk of malignant progression.