Sun Yat-sen University Cancer Center Research Articles

Molecular characteristics of patients with colorectal signet-ring cell carcinoma with different ABO blood groups

BackgroundColorectal signet-ring cell carcinoma (SRCC) is a rare subtype of malignant adenocarcinoma, accounting for approximately 1 % of colorectal cancer (CRC) cases. Its biomarkers and molecular characteristics remain controversial, and there are no specific therapeutic targets or strategies for its clinical treatment. MethodsA retrospective study was conducted between January 2010 and December 2021. 1058 colorectal cancer cases from the Sun Yat-sen University Cancer Center and 489 cases from the Tumor Genome Atlas Project were included in the analysis, of which 64 were SRCC. Data extraction included patient demographics, blood types and risk factors, including clinical variables and genomics (either a 19-gene panel NGS or 1021-gene panel NGS). Univariate analyses were performed to identify factors significantly associated with overall survival. ResultsThe blood groups of 27 (42.2 %), 18 (28.1 %), 12 (18.8 %), and seven (10.9 %) patients were classified as O, A, B, and AB, respectively. We found that O was a unique blood group characterized by a low frequency of KRAS mutations, a high frequency of heterozygosity at each HLA class I locus, and a high tumor mutational burden (TMB). Patients in blood group A with high-frequency KRAS mutations and those in blood group B with anemia and metabolic abnormalities required targeted treatment. Furthermore, genetic alterations in SRCC differed from those in adenocarcinoma and mucinous adenocarcinoma. ConclusionsOur study revealed genomic changes in SRCC patients across different blood groups, which could advance the understanding and precise treatment of colorectal SRCC.

Prognostic significance of hemoglobin, albumin, lymphocyte, and platelet (HALP) score in breast cancer: a propensity score-matching study

BackgroundThe hemoglobin-albumin-lymphocyte-platelet (HALP) score functions as a comprehensive index that assesses the systemic inflammatory response, nutritional, and immune status. This study aimed to explore the relationship between preoperative HALP score and the prognosis of BC patients and to develop predictive nomograms.MethodsClinicopathological data were collected for BC patients who underwent mastectomy between December 2010 and April 2014 from Sun Yat-sen University Cancer Center. The optimal cutoff value for HALP was determined by maximally selected rank statistics for overall survival data. Propensity score matching (PSM) was applied to develop comparable cohorts of high-HALP group and low-HALP group. Kaplan–Meier curves and Cox regression analyses were performed to determine the impact of HALP on BC patients. Prognostic nomograms were developed based on the multivariate Cox regression method. Then, the concordance index (C-index), calibration plots, and decision curves analysis (DCA) were applied to evaluate the prognostic performance of the nomograms.ResultsA total of 1,856 patients were included as the primary cohort, and 1,470 patients were matched and considered as the PSM cohort. In the primary cohort, the 5-year overall survival (OS) and progression-free survival (PFS) rates for high-HALP group (≥ 47.89) and low-HALP group (< 47.89) were 94.4% vs. 91.0% (P = 0.005) and 87.8% vs. 82.1% (P = 0.005), respectively. Similar results were observed in PSM cohort (5-year OS, 94.3% vs. 90.8%, P = 0.015; 5-year PFS, 87.5% vs. 83.2%, P = 0.036). Notably, multivariate Cox regression analysis in the PSM cohort showed that HALP could independently predict BC patient prognosis in both OS (HR: 0.596, 95%CI [0.405–0.875], P = 0.008) and PFS (HR: 0.707, 95%CI [0.538–0.930], P = 0.013). OS and PFS nomograms showed excellent predictive performance with the C-indexes of 0.783 and 0.720, respectively. The calibration plots and DCA also indicated the good predictability of the nomograms. Finally, subgroup analysis further demonstrated a favorable impact of HALP on both OS and PFS.ConclusionPreoperative HALP score can be used as a reliable independent predictor of OS and PFS in BC patients, and the nomograms may provide a personalized treatment strategy.

Molecular characteristics of patients with colorectal signet-ring cell carcinoma with different ABO blood groups

BACKGROUNDColorectal signet-ring cell carcinoma (SRCC) is a rare subtype of malignant adenocarcinoma, accounting for approximately 1% of colorectal cancer (CRC) cases. Its biomarkers and molecular characteristics remain controversial, and there are no specific therapeutic targets or strategies for its clinical treatment. METHODSA retrospective study was conducted between January 2010 and December 2021. 1058 colorectal cancer cases from the Sun Yat-sen University Cancer Center and 489 cases from the Tumor Genome Atlas Project were included in the analysis, of which 64 were SRCC. Data extraction included patient demographics, blood types and risk factors, including clinical variables and genomics (either a 19-gene panel NGS or 1021-gene panel NGS). Univariate analyses were performed to identify factors significantly associated with overall survival. RESULTSThe blood groups of 27 (42.2%), 18 (28.1%), 12 (18.8%), and seven (10.9%) patients were classified as O, A, B, and AB, respectively. We found that O was a unique blood group characterized by a low frequency of KRAS mutations, a high frequency of heterozygosity at each HLA class I locus, and a high tumor mutational burden (TMB). Patients in blood group A with high-frequency KRAS mutations and those in blood group B with anemia and metabolic abnormalities required targeted treatment. Furthermore, genetic alterations in SRCC differed from those in adenocarcinoma and mucinous adenocarcinoma. CONCLUSIONSOur study revealed genomic changes in SRCC patients across different blood groups, which could advance the understanding and precise treatment of colorectal SRCC.

The conditional recurrence-free survival after R0 hepatectomy for locally advanced intrahepatic cholangiocarcinoma: A competing risk analysis based on inflammation-nutritional status

BackgroundConditional survival analysis can serve as a dynamic prognostic metric, which helps to estimate the real-time survival probability over time. The present study conducted a conditional recurrence-free survival (CRFS) analysis for locally advanced intrahepatic cholangiocarcinoma (ICC) after R0 hepatectomy from an inflammatory-nutritional perspective using the competing risk method. MethodsWe extracted the medical data of 164 locally advanced ICC patients after R0 resection from Sun Yat-sen University Cancer Center. The calculation formula of the CRFS rate is CRFS(y/x) = RFS(y + x)/RFS(x). Univariable and multivariable COX regression analysis and competing risk analysis were conducted to identify RFS indicators. ResultsConsidering death before recurrence as a competing risk factor, the conditional RFS rates every 6 months gradually increased over time. The 24-month RFS rate increased from 29.2 % to 49.9 %, 68.5 %, and 85.1 % given 6, 12, and 18-month already recurrence-free survival, respectively. Both in multivariate COX regression analysis and competing risk analysis, tumor diameter and number, lymph node metastasis, aggregate systemic inflammation index score (AISI), and albumin-bilirubin score (ALBI) all remained significant. For both AISI and ALBI variables, the CRFS rates in the low-value set were higher than those of the high-value set. ConclusionsConditional RFS rates of locally advanced ICC after R0 hepatectomy dynamically increased over time, which contributed to reducing survivors' psychological distress and facilitating personalized follow-up schedules. In addition, a person's inflammatory and nutritional status significantly impact the recurrence risk. Oncologists should consider the role of inflammation-nutritional status when making decisions for patients with locally advanced ICC.

Financial toxicity, coping strategies, and quality of life among Chinese patients with hematologic malignancies: a cross-sectional study.

Financial toxicity is used to describe the financial hardship experienced by cancer patients. Financial toxicity may cause negative consequences to patients, whereas little is known in Chinese context. This study aimed to explore the level of financial toxicity, coping strategies, and quality of life among Chinese patients with hematologic malignancies. We conducted a prospective, observational study among 274 Chinese patients with hematologic malignancies from November 2021 to August 2022 in Sun Yat-sen University Cancer Center. Clinical data were extracted from electronic clinical records. Data on financial toxicity, coping strategies, and quality of life were collected using PRO measures. Chi-square or independent t test and multivariate logistic regression were performed to explore the associated factors of financial toxicity and quality of life, respectively. Effects of financial toxicity on coping strategies were examined using Chi-square. The mean age of the participants was 50.2 (± 14.6) years. Male participants accounted for 57.3%. About half of the participants reported high financial toxicity. An average median of ¥200,000 on total medical expenditures since the diagnosis was reported. The average median monthly out-of-pocket health expenditure relating to cancer treatment was ¥20,000 (range ¥632-¥172,500) after reimbursement. Reduce daily living expenses (64.9%), borrowing money (55.7%), and choosing cheaper regimens (19.6%) were the commonly used strategies to cope with financial burden. Financial toxicity was negatively associated with quality of life (β = 0.071, P = 0.001). Financial toxicity was not uncommon in patients with hematological malignancies. Reducing daily living expenses, abandoning treatment sessions, and borrowing money were the strategies commonly adopted by participants to defray cancer costs. Additionally, participants with high level of financial toxicity tended to have worse quality of life. Therefore, actions from healthcare providers, policy-makers, and other stakeholders should be taken to help cancer patients mitigate their financial toxicity.

Clinical characteristics, prognosis, and immunotherapy outcome in pediatric melanoma: Analysis from a large Chinese cohort.

10050 Background: Malignant melanoma in children and adolescents is rare, with limited data on Chinese populations.To assess the clinical characteristics, survival, prognostic factors, and the efficacy of immunotherapy in a real-world cohort of Chinese pediatric patients with melanoma. Methods: This is a retrospective, cohort study included pediatric melanoma patients between February, 2005 and May, 2021, with a median follow-up time of 76.7 months. Data analyses were conducted in May, 2023. This study enrolled patients from Sun Yat-sen University Cancer Center, the biggest cancer institution in South China for cancer prevention, diagnosis and treatment. Inclusion criteria for this study were as follows: 1) histopathologically confirmed diagnosis of melanoma; 2) Age ≤18 year; 3) with complete clinical data on sex, age, histopathological features, etc. The exclusion criteria was secondary malignant melanoma. Main outcomes and measures were patient’s OS and EFS. Results: 43 patients were enrolled, with median age of 138.9 (range 13.1-215.0) months, including 30 cutaneous melanoma, 7 meningeal melanoma, 5 mucosal melanoma, and 1 uveal melanoma. The frequency of BRAF V600E mutation was 16.7% (4/24). Mismatch repair proteins were normally expressed (7/7), and the positive rate of programmed cell death ligand 1 expression was 55.6% (5/9). The event-free survival and overall survival of cutaneous, mucosal and meningeal melanoma were 46.7±9.1% vs 75.0±21.7% vs 16.7±15.2% ( P = 0.010), 65.5±8.9% vs 75.0±21.7% vs 16.7±15.2% (P&lt; 0.001), respectively. Survival of cutaneous melanoma were associated with pathological type, ulceration, Clark level, disease spread, sentinel lymph node status, tumor stage and Ki-67 expression. 5 of 9 patients who were treated with PD-1 inhibitors (5 with PD-1 inhibitors alone, 3 with PD-1 inhibitors plus angiogenesis inhibitors, 1 with combination of anti-PD1, anti-angiogenic inhibitors plus chemotherapy) were evaluable with the overall response rate of 20%. The most common immune-related adverse event was hypothyroidism. Conclusions: This is the largest real-world study in pediatric melanoma patients in Asia. The prognosis of mucosal melanoma was favorable, followed by cutaneous melanoma, and meningeal melanoma had the worst prognosis. PD-1 antibody combined with angiogenesis inhibitors maybe a promising choice in pediatric melanoma.

Overexpression of COX7A1 Promotes the Resistance of Gastric Cancer to Oxaliplatin and Weakens the Efficacy of Immunotherapy

Gastric cancer (GC) is one of the most common clinical malignant tumors worldwide, with high morbidity and mortality. Presently, the overall response rate to immunotherapy is low, and current methods for predicting the prognosis of GC are not optimal. Therefore, novel biomarkers with accuracy, efficiency, stability, performance ratio and wide clinical application are needed. Based on public data sets, the Chemotherapy Cohort and the Immunotherapy Cohort from Sun Yat-sen University Cancer Center, a series of bioinformatics analyses, such as differential expression analysis, survival analysis, drug sensitivity prediction, enrichment analysis, tumor immune dysfunction and exclusion (TIDE) analysis, single-sample gene set enrichment analysis (ssGSEA), stemness index calculation, immune cell infiltration analysis, were performed for screening and preliminary exploration. Immunohistochemical staining and in vitro experiments were performed for further verification. Overexpression of COX7A1 promoted the resistance of GC cells to Oxaliplatin. COX7A1 may induce immune escape by regulating the number of fibroblasts and their cellular communication with immune cells. In summary, measuring the expression levels of COX7A1 in the clinic may be useful to predict the prognosis of GC patients, the degree of chemotherapy resistance and the efficacy of immunotherapy.

Temporal dynamics and prognostic significance of cancer free status in patients with intermediate stage hepatocellular carcinoma: A multicenter cohort study.

e16236 Background: A proportion of patients with intermediate stage hepatocellular carcinoma (HCC) can achieve cancer free status (CFS) during treatment, the prognostic value of CFS across the period of dynamic surveillance and treatment remained unknown. Methods: This longitudinal cohort study examined data from the electronic medical record system of four hospitals in China between January 1, 2007 to May 31, 2019. The data from Sun Yat-sen University Cancer Center served as the derivation cohort and other centers as testing cohort. The time-series data were converted into data of time slices, with an interval of three months. Image CFS is defined as patients with no evidence of disease based on imaging exams after treatment and Image-Bio CFS is defined as achievement of Image CFS, together with normal AFP level. Based on the dynamic changes of disease during treatment, patients at specific time slice were classified into either “Arrive”, “Maintain”, or “Not reached” CFS subgroups. The correlations between CFS subgroups and overall survival (OS) were determined by Cox regression. Results: A total of 945 (42.2%) and 741 (33.1%) patients in derivation cohort reached Image CFS and Image-Bio CFS during treatment, respectively. The corresponding rates for Image CFS and Image-Bio CFS in testing cohort were 155 (37.4%) and 130 (31.4%), respectively. Maintaining Image CFS or Image-Bio CFS, rather than just arrive Image CFS or Image-Bio CFS, had stable predictive value for improved OS across different time slices. The merged Hazard ratio of Maintain Image-Bio CFS was 0.23 (95%CI, 0.20-0.25, P &lt; 0.001). The patients achieved Image-Bio CFS could be further classified into three subgroups with differential prognosis based on duration of CFS (≤ 4.5months; 4.5-18.0 months; &gt; 18.0 months). Maintaining Image-Bio CFS for more than 18.0 months predicted long term survival (5-year OS: 91.2% in derivation cohort, 94.7% in testing cohort). Conclusions: Maintaining CFS, rather than just arrive CFS, is a key marker of favorable survival during dynamic management of intermediate stage HCC. A duration of Image-Biochemical CFS for more than eighteen months predicts long-term survival.

Influence of TP53 mutation on efficacy and survival in advanced EGFR-mutant non-small cell lung cancer patients treated with third-generation EGFR tyrosine kinase inhibitors.

TP53 comutation is related to poor prognosis of non-small cell lung cancer. However, there is limited study focusing on the structural influence of TP53 mutation on third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. We retrospectively analyzed the clinical and molecular data of patients treated with third-generation EGFR-TKIs in two independent cohorts. A total of 117 patients from the Sun Yat-sen University Cancer Center (SYSUCC) and 141 patients from the American Association for Cancer Research Project GENIE database were included. In the SYSUCC cohort, TP53 comutations were found in 59 patients (50.4%) and were associated with poor median progress-free survival (mPFS) and median overall survival (mOS). The additional subtype analysis found that TP53 mutation in the alpha-helix region had shorter mOS compared with those with TP53 mutations in other regions in the SYSUCC cohort (mOS, 12.2 vs. 21.7 months; p=0.027). Similar findings were confirmed in the GENIE cohort. Specifically, the presence of TP53 mutation in the alpha-helix region was an independent negative predictive factor for PFS [hazard ratio (HR) 2.05(1.01-4.18), p=0.048] and OS [HR 3.62(1.60-8.17), p=0.002] in the SYSUCC cohort. TP53 mutation in alpha-helix region was related to inferior clinical outcomes in patients treated with third-generation EGFR-TKIs.

Treatment modalities for advanced solid pseudopapillary tumor of the pancreas.

e16327 Background: Solid pseudopapillary tumor (SPT) of the pancreas is a rare low-grade malignant tumor. However, a minority of SPT patients present aggressive behavior and develop recurrent or metastatic diseases. The treatment strategies of advanced SPTs remain unclear. Our study aimed to explore the treatment modalities of aggressive SPTs and the role of endocrine therapy. Methods: The data on clinicopathologic characteristics and treatment of advanced SPT patients from Sun Yat-Sen University Cancer Center and Shen Zhen People's Hospital were collected. The treatment modalities were explored by co-analyzing our local cohort and published literatures. Single sample gene set enrichment analysis (ssGSEA) was used to explore the functional enrichment pathway (GSE43795). Fresh surgical specimens from 10 SPT patients were collected for endocrine drugs sensitive test in vitro by performing tumor histoculture end-point staining computer image analysis (TECIA). Results: A total of 77 advanced SPT patients including 14 cases in our local cohort and 63 cases from published literatures were enrolled. 60 patients received local treatment including cytoreductive surgery, interventional therapy or radiation therapy. 55 patients who had undergone cytoreductive surgery have better outcome compared with others (P = 0.046, HR = 4.12). 31 patients received systemic chemotherapy and 6 patients received targeted therapy. There were 2 patients achieved partial response after chemotherapy. In our local cohort, 5 patients received endocrine therapy with tamoxifen plus megestrol. One patient achieved partial response with duration of response (DOR) of 89 months. 4 patients showed stable disease. ssGSEA for GSE43795 showed that Wnt signaling pathway and its inhibitory pathway-progesterone receptor signaling pathway were simultaneously enriched in SPTs. The results of endocrine drug sensitive test in vitro by TECIA showed response rate of 50% (5/10) in megestrol group, 40% (4/10) in tamoxifen group, and 30% (3/10) in testosterone propionate group. Conclusions: Advanced SPTs did not appear chemosensitive. Cytoreductive surgery may improve survival. Simultaneously enriching Wnt and progesterone receptor signaling pathway may partially explain the low aggressive ability of SPT and their unbalance may lead to the aggressive behavior of SPT. Endocrine therapy with tamoxifen plus megestrol, by enhancing the progesterone signaling pathway, seems to be a promising regimen for advanced SPTs, which is worth to be noted and further studied.

Pretreatment neutrophil to lymphocyte ratio as a predictor of pathological complete response to neoadjuvant immunotherapy in early breast cancer.

e12545 Background: Neoadjuvant immunotherapy has been increasingly used in early breast cancer, while lack of accessible predictive biomarkers of response remains an open question. High pretreatment neutrophil to lymphocyte ratio (NLR) was associated with worse prognosis and treatment responses to neoadjuvant chemotherapy in multiple cancers including breast cancer. However, it remains unclear whether NLR was associated with response to neoadjuvant immunotherapy in early breast cancer. Methods: We retrospectively analyzed 89 early breast cancer patients who received neoadjuvant chemotherapy in combination with at least 4 cycles of immunotherapy and subsequent breast surgery in Sun Yat-sen University Cancer Center. Pretreatment NLR was calculated, and Miller-Payne grade 5 in primary tumor site was considered pathological complete response (pCR) to neoadjuvant therapy. Univariate and multivariate analyses were used to evaluate the associations between clinicopathological markers and pCR. Results: 49.4% (44/89) of the patients achieved pCR. Compared to non-pCR patients, pCR patients had significantly lower pretreatment NLR (1.93 vs 2.87, p&lt;0.001) and lower percentage of pretreatment cT3/T4 stage (11.4% vs 37.7%, p=0.006), and received more cycles of neoadjuvant immunotherapy (6.5 vs 6.0, p&lt;0.05). More pCR patients received TCb based neoadjuvant therapy (86.4% vs 51.1%, p&lt;0.001). In multivariate analysis, the pretreatment NLR (p=0.002) and cT3/T4 (p=0.010, as compared to cT1/T2) were independent predictive factors for pCR. Conclusions: Lower pretreatment NLR was associated with higher possibility of achieving pCR in early breast cancer treated with neoadjuvant immunotherapy. [Table: see text]

Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma.

e16184 Background: The prognosis for unresectable intrahepatic cholangiocarcinoma (ICC) is poor and the efficacy of traditional chemotherapy remains unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) is effective in patients with unresectable ICC. In this study, we determined the preliminary clinical efficacy and safety of lenvatinib plus durvalumab combined with FOLFOX-HAIC in patients with untreated, unresectable ICC. Methods: Between July 2021 and July 2023, patients with unresectable ICC who initially received lenvatinib plus durvalumab combined with FOLFOX-HAIC at the Sun Yat-Sen University Cancer Center (SYSUCC) were retrospectively reviewed for eligibility. Efficacy was evaluated by tumor response rate and survival, and safety was assessed by the frequency of key adverse events (AEs). Results: A total of 28 eligible patients were enrolled. The objective response rates (ORRs) based on mRECIST and RECIST 1.1 criteria were 65.2% and 39.1%, respectively. The median OS was 17.9 months (95% CI, 5.7–30.1) and the median PFS was 11.9 months (95% CI, 6.7–17.1). Most patients (92.9%) experienced adverse events (AEs), whereas 46.5% (13/28) experienced grade 3 or 4 AEs. Conclusions: Lenvatinib plus durvalumab combined with FOLFOX-HAIC showed promising antitumor activity and manageable AEs in patients with treatment-naive unresectable ICC. This regimen may be suitable as a novel first-line treatment option for this patient population.

Utidelone for heavily pretreated metastatic castration-resistant prostate cancer after failing docetaxel treatment: An open-label, single-arm, phase II trial.

e17036 Background: The appropriate chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) that progressed after docetaxel treatment remains unmet medical needs. Utidelone (UTD1) is a genetically engineered epothilone analog with antitumor activity in taxane-resistant cancers. UTD1 was approved for advanced breast cancer in 2021. This study was designed to evaluate the safety and efficacy of UTD1 in mCRPC. Methods: In this perspective, phase II clinical trial, men with progressive mCRPC after docetaxel and abiraterone, and/or enzalutamide, and/or apalutamide received UTD1 monotherapy treatment at a total dose of 150 mg/m2 for five days intravenous, every three weeks until disease progression, or intolerable toxicity, or death. We reported the preliminary results for potential benefits in this new treatment. The primary endpoint was prostate specific antigen (PSA) response rate, defined as a 50% or greater reduction in serum PSA. The secondary endpoint included investigators-assessed objective response rate (ORR) and disease control rate (DCR) according to RECIST v1.1, radiographic progression-free survival (rPFS) according to PCWG3 criteria, overall survival (OS), and safety. The trial was registered at Chinese Clinical Trial Registry (No. ChiCTR2200061635). Results: By January 31st, 2024, twenty-five mCRPC patients with a median age of 67 years were enrolled in this study at Sun Yat-sen University Cancer Center since March 23rd, 2022. Patients received an average of 4.2 lines of prior anticancer treatments: 100% of them received docetaxel, 96.0% of them received abiraterone, and 80.0% progressed after enzalutamide, and/or apalutamide. 28.0% of patients had visceral metastases, and 88.0% patients had bone metastases. At of the cut-off date, the PSA response rate was 16.0%. The median rPFS and OS were 4.9 months and 7.1 months, respectively. One patient had a durable response for 19.2 months and had been remaining on study treatment to date. One PR and four SD were observed in ten patients with measurable lesions, resulting in an overall ORR and DCR of 10.0% and 50.0%, respectively. The most common treatment-related adverse events (TRAEs) including peripheral sensory neuropathy (76.0%), dyspepsia (72.0%), anemia (64.0%), constipation (60.0%), fatigue (64.0%), nausea (36.0%), leukocytopenia (32.0%), arthralgia (32.0%), dizziness (32.0%), vomiting (20.0%), and diarrhea (20.0%) were manageable. The 3/4 grade TRAEs included anemia (16.0%), and diarrhea (4%). No treatment-related death occurred. Conclusions: UTD1 has demonstrated promising efficacy and favorable tolerance in heavily pretreated mCRPC patients after progression on docetaxel in the preliminary analyses. Additional randomized trials are warranted for this new regimen. Clinical trial information: ChiCTR2200061635.

Clinicopathological features and genomic profiles of prostate cancer with elevated carbohydrate antigen 19-9.

e17003 Background: The elevated carbohydrate antigen 19-9 (CA199) is commonly observed in digestive system tumors, but rarely in prostate cancer (PCa). Due to the rarity and the poor understanding of the special subtype of PCa, the clinicopathological and genomic characteristics and survival outcomes in PCa patients with elevated CA199 in our center were analyzed. Methods: Cases were collected retrospectively from 2012 to 2023 in Sun Yat-sen University Cancer Center. The tumor genomic profiles were analyzed by R (http://www.rproject.org). Kaplan-Meier survival analyses were performed to compare survival outcomes. All statistical analyses were performed using SPSS version 26.0 and GraphPad Prism version 8.0. All analyses were two‐tailed, and the significance level was set at P&lt;0.05. Results: A total of 137 PCa patients with elevated CA199 (&gt;35ng/ml) were identified, with an exclusion of 47 patients with secondary cancers and 40 patients with other diseases that may cause elevated CA199, finally 50 cases (22 with primary and 28 with secondary elevated CA199) were included. The median initial PSA and the median time from diagnosis to CRPC were 102ng/ml and 14 months. Most patients were with a high GS score (GS≥8: 82%) and an advanced stage (M1: 84%). Poorly differentiated adenocarcinoma (22%) was frequently observed. Compared with patients with primary elevated CA199, patients with secondary elevated CA199 had higher levels of CA199 (102ng/ml vs. 78ng/ml, p=0.0456), lower levels of PSA at diagnosis (65ng/ml vs. 132ng/ml, p=0.0131) and higher proportion of poorly differentiated adenocarcinoma (36% vs. 5%, p=0.0138). The level of CA199 in patients with primary elevated CA199 was correlated with the level of CEA (R2=0.2658, p=0.0168), but not with the level of NSE or PSA. At a median follow-up of 31 months, the median OS of the whole group, primary elevated CA199 and secondary elevated CA199 subgroups was 49 months, 31 months and not reached. Secondary elevated CA199 (p=0.0009), abiraterone treatment (p&lt;0.0001) and chemotherapy treatment (p=0.0331) were significant prognostic factors of OS. To study the genomic characteristics of PCa patients with elevated CA199, 29 PCa patients with normal CA199 were included as a control (genomic data available in 13 and 29 cases respectively). Patients with elevated CA199 were more likely to have mutations in castration resistant associated genes (AR, FOXA1, ASXL1, KMT2B, JAK2 and AKT1), malignant progression associated genes (RARA, BLM, PIK3R1) and CA199 metabolism associated gene (ERBB2). Conclusions: PCa with elevated CA199 is highly malignant and with poor prognosis. Intensive treatment with abiraterone and chemotherapy could benefit such patients. Poor pathological differentiation and the gene mutation profile may partly explain the clinical outcome.

Comparing clinical outcomes between PD-1 and PD-L1 inhibitors plus bevacizumab combined with hepatic arterial interventional therapies in unresectable hepatocellular carcinoma: A single-center real-world study.

e16229 Background: Systemic therapies combined with locoregional therapies were considered a potent therapeutic strategy in treating patients with unresectable hepatocellular carcinoma (uHCC). Given the A+T strategy became the first-line treatment for advanced HCC patients, the roles of programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) inhibitors in the combination therapies for treating patients with uHCC needed to be further discussed. The current study compared the clinical outcomes between PD-1 and PD-L1 inhibitors plus bevacizumab combined with hepatic arterial interventional therapies (HAIT) among patients with uHCC. Methods: From October 2019 to May 2023, 142 uHCC patients were retrospectively analyzed in Sun Yat-sen University Cancer Center, including 73 or 69 patients treated with either PD-1 (PD-1 group) or PD-L1 (PD-L1 group) inhibitors, respectively, combined with HAIT plus bevacizumab. The progression-free survival (PFS) and tumor responses were analyzed per mRECIST. Results: At the data cut-off, the median PFS was 5.5 months (95% CI 5.3-7.1 months) in the PD-1 group and 7.5 months (95% CI 7.0-9.6 months) in the PD-L1 group, respectively ( P=0.280; HR=0.74; 95%CI 0.43-1.28). The PD-L1 group showed a significantly better median intrahepatic PFS (8.1 months, 95%CI 7.6-10.2 months) than the PD-1 group (6.5 months, 95%CI 6.2-9.0 months; P=0.014; HR=0.35; 95%CI 0.16-0.81). The overall response rate (ORR; 49.3% vs. 66.7%, P=0.054), intrahepatic control rates (53.4% vs. 69.6%, P=0.070) and overall disease control rate (DCR; 68.5% vs. 78.3%, P=0.261) showed no significant difference in both groups, while the PD-L1 group demonstrated significantly higher intrahepatic disease control rate than the PD-1 group (76.7% vs. 92.6%, P=0.016). Conclusions: PD-1 and PD-L1 plus bevacizumab combined HAIT shared similar PFS, DCRs, and ORRs in treating uHCC patients. The PD-L1 plus bevacizumab combined with HAIT demonstrated a better intrahepatic control than those of PD-1, which needed further validation at a higher evidence level.

Improving dynamic prognostication of patients with hepatocellular carcinoma by node fusion algorithm equipped survival path mapping.

e13594 Background: Patients with hepatocellular carcinoma (HCC) always require routine surveillance and repeated treatment. Our previous work (1) developed a machine learning methodology called “Survival Path Mapping”, which converted the time series data into a cascading survival map to facilitate dynamic prognosis prediction and treatment planning. However, in previous work, the exponential growth of paths raised challenges of exhausting limited cohort and over-fitting risk. Novel algorithm enhancing data utilization in the Survival Path Mapping was in urgent need. Methods: A node fusion algorithm was designed. First, feature selection algorithm bifurcated each parent-nodes into temporary child-nodes, which constitutes temporary child-nodes set. Then, clustering was performed within temporary child-nodes set according to key features of each child-node. Finally, in each cluster, multiple child-nodes would be merged into one if there was no significant difference in survival. For nodes with bifurcation, a treatment recommendation algorithm was developed. A total of 19446 patients with newly diagnosed primary HCC at Sun Yat-sen University Cancer Center (SYSUCC) between 2008 and 2023 were retrospectively included as internal cohort (divided into internal train and holdout validation cohort); meanwhile 1135 patients from five hospitals were included as multicenter external validation cohort. Dedicated natural language processing program was developed to extract structured features from medical imaging reports. The time series data of patients were converted into data of time slices, with an interval of 3 months. Results: The original survival path mapping (raw-SP) consists of 463 different nodes, while the node fusion survival path mapping (fusion-SP) consisted of 84 nodes (81.8% decrease from raw-SP). The 3-year c-index of fusion-SP were 0.745 (95% CI 0.717-0.772), significantly better (p&lt;0.001) than that of raw-SP: 0.725 (95% CI 0.696-0.755), in the internal holdout validation. Both raw-SP and fusion-SP significantly (p &lt; 0.001) outperformed conventional BCLC and CNLC staging. In the multicenter external validation, the fusion-SP also demonstrated better performance than raw-SP and BCLC staging system. The recommended therapy calculated based fusion-SP system for patients receiving second-line or subsequent treatment had superior or non-inferior efficacy compared to BCLC guideline’s recommendation. Conclusions: The proposed node fusion algorithm solved exponential growth of paths in previous survival path algorithm, improving the accuracy and external validity of dynamic prognosis prediction for HCC patients. The fusion-SP model also retained its transparency and could be used to guide dynamic treatment planning, with its effectiveness in treatment guidance evaluated in prospective trials in the future. 1. Nat Commun 9, 2230; 2018.

PD-1 inhibitor combined with paclitaxel and cisplatin in the treatment of recurrent and metastatic hypopharyngeal/laryngeal squamous cell carcinoma: efficacy and survival outcomes.

This retrospective study analyzed the efficacy of PD-1 inhibitors combined with albumin-bound paclitaxel and cisplatin (TP regimen) in the treatment of recurrent and metastatic hypopharyngeal/laryngeal squamous cell carcinoma (RMHSCC/RMLSCC). Patients diagnosed and treated at the Sun Yat-sen University Cancer Center from August 1, 2020, to August 15, 2023, with histologically confirmed RMHSCC/RMLSCC were included. All patients received PD-1 inhibitors combined with albumin-bound paclitaxel (260mg/m2) and cisplatin (60mg/m2) for 3-4 cycles. The primary endpoints were overall survival (OS) and progression-free survival (PFS). A total of 50 patients with RMHSCC/RMLSCC who received TP+PD-1 inhibitor therapy were included, with an objective response rate (ORR) of 56.0% (28/50). The 1-year and 2-year OS rates were 80.2% (95% CI: 69.3%-92.9%) and 68.6% (95% CI: 52.6%-89.5%), respectively, while the 1-year and 2-year PFS rates were 44.7% (95% CI: 31.9%-62.5%) and 26.0% (95% CI: 12.6%-53.4%), respectively. Treatment-related adverse events mainly included rash, myelosuppression, gastrointestinal reactions, and hypothyroidism. In the treatment of RMHSCC/RMLSCC with TP + PD-1 inhibitors, survival rates of patients can be improved while ensuring the safety of the treatment regimen.

Post-operative MRI synthesis from pre-operative MRI and post-operative CT using conditional GAN for the assessment of degree of resection

BackgroundMagnetic resonance imaging (MRI) is an essential part of assessing the extension of resection after craniotomy, allowing for accurate assessment of the brain. However, the application of MRI within 72 h after surgery is limited, owing to its high cost, long time duration, and patients’ limited mobility. Besides, MRI excludes people with contraindications, in which sceneries computerized tomography (CT) is the only available choice. To overcome these limitations, we investigated the use of a deep learning model for synthesizing post-operative MRI images. MethodsWe employed Cross-domain Correspondence Learning for Exemplar-based Image Translation Network (CoCosNet), an exemplar-based image translation model to synthesize T1 contrast-enhanced (T1ce) MRI images by combining post-operative T1ce and post-operative CT images. 233 cases were retrospectively collected at Sun Yat-sen University Cancer Center and underwent complete MRI and CT scans. ResultsAfter 200 epochs and a batch size of 10, CoCosNet achieved comparable results compared to other existing models, with objective indicators structural similarity index = 0.75, peak signal to noise ratio = 21.68, and mean absolute error = 0.007. Furthermore, assessments of the extension of resection between the true and synthesized T1ce images achieve great consistency. ConclusionsOur study demonstrates the effectiveness of the CoCosNet model in synthesizing post-operative MRI images from pre-operative MRI and post-operative CT scans. Quantitative analysis indicates that the synthesized images have comparable quality to real MRI images and can accurately discriminate the extent of resection. This approach has a promising future by providing a reliable alternative to traditional post-operative MRI.

Efficacy and safety of lenvatinib plus durvalumab combined with hepatic arterial infusion chemotherapy for unresectable intrahepatic cholangiocarcinoma.

The prognosis for unresectable intrahepatic cholangiocarcinoma (ICC) is poor and the efficacy of traditional chemotherapy remains unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC) with oxaliplatin, leucovorin, and 5-fluorouracil (FOLFOX) is effective in patients with unresectable ICC. In this study, we determined the preliminary clinical efficacy and safety of lenvatinib plus durvalumab combined with FOLFOX-HAIC in patients with untreated, unresectable ICC. Between July 2021 and July 2023, patients with unresectable ICC who initially received lenvatinib plus durvalumab combined with FOLFOX-HAIC at the Sun Yat-Sen University Cancer Center (SYSUCC) were reviewed for eligibility. Efficacy was evaluated by tumor response rate and survival, and safety was assessed by the frequency of key adverse events (AEs). A total of 28 eligible patients were enrolled. The objective response rates (ORRs) based on mRECIST and RECIST 1.1 criteria were 65.2% and 39.1%, respectively. The median OS was 17.9 months (95% CI, 5.7-30.1) and the median PFS was 11.9 months (95% CI, 6.7-17.1). Most patients (92.9%) experienced adverse events (AEs), whereas 46.5% (13/28) experienced grade 3 or 4 AEs. Lenvatinib plus durvalumab combined with FOLFOX-HAIC showed promising antitumor activity and manageable AEs in patients with treatment-naive unresectable ICC. This regimen may be suitable as a novel first-line treatment option for this patient population.

Choline metabolism reprogramming mediates an immunosuppressive microenvironment in non-small cell lung cancer (NSCLC) by promoting tumor-associated macrophage functional polarization and endothelial cell proliferation

IntroductionLung cancer is a prevalent malignancy globally, and immunotherapy has revolutionized its treatment. However, resistance to immunotherapy remains a challenge. Abnormal cholinesterase (ChE) activity and choline metabolism are associated with tumor oncogenesis, progression, and poor prognosis in multiple cancers. Yet, the precise mechanism underlying the relationship between ChE, choline metabolism and tumor immune microenvironment in lung cancer, and the response and resistance of immunotherapy still unclear.MethodsFirstly, 277 advanced non-small cell lung cancer (NSCLC) patients receiving first-line immunotherapy in Sun Yat-sen University Cancer Center were enrolled in the study. Pretreatment and the alteration of ChE after 2 courses of immunotherapy and survival outcomes were collected. Kaplan–Meier survival and cox regression analysis were performed, and nomogram was conducted to identify the prognostic and predicted values. Secondly, choline metabolism-related genes were screened using Cox regression, and a prognostic model was constructed. Functional enrichment analysis and immune microenvironment analysis were also conducted. Lastly, to gain further insights into potential mechanisms, single-cell analysis was performed.ResultsFirstly, baseline high level ChE and the elevation of ChE after immunotherapy were significantly associated with better survival outcomes for advanced NSCLC. Constructed nomogram based on the significant variables from the multivariate Cox analysis performed well in discrimination and calibration. Secondly, 4 choline metabolism-related genes (MTHFD1, PDGFB, PIK3R3, CHKB) were screened and developed a risk signature that was found to be related to a poorer prognosis. Further analysis revealed that the choline metabolism-related genes signature was associated with immunosuppressive tumor microenvironment, immune escape and metabolic reprogramming. scRNA-seq showed that MTHFD1 was specifically distributed in tumor-associated macrophages (TAMs), mediating the differentiation and immunosuppressive functions of macrophages, which may potentially impact endothelial cell proliferation and tumor angiogenesis.ConclusionOur study highlights the discovery of ChE as a prognostic marker in advanced NSCLC, suggesting its potential for identifying patients who may benefit from immunotherapy. Additionally, we developed a prognostic signature based on choline metabolism-related genes, revealing the correlation with the immunosuppressive microenvironment and uncovering the role of MTHFD1 in macrophage differentiation and endothelial cell proliferation, providing insights into the intricate workings of choline metabolism in NSCLC pathogenesis.