BACKGROUND Clinical reports of multiple primary malignant tumors (MPMTs) in the digestive system are increasing. In China, although the survival rate of patients with MPMTs is increasing, the quality of life is very low. Many patients have reached the advanced stage when the second primary tumor is found, resulting in no early intervention and treatment. This is due to the misunderstanding of MPMTs by clinicians, who treat such tumors as metastases. Therefore, before a patient has a second primary tumor, doctors should understand some common combinations of digestive system MPMTs to provide clinical guidance to the patient. AIM To explore the high incidence combination of digestive system MPMTs under heterochronism and synchronization. METHODS A total of 1902 patients with MPMTs at Peking Union Medical College Hospital were analyzed retrospectively. They were divided into metachronous MPMT and synchronous MPMT groups, and then the high incidence combinations of the first primary cancer and the second primary cancer in metachronous cancer and synchronous cancer were sorted. Sex and age differences between metachronous and synchronous tumors were tested by the chi square test and t test, respectively. A P value < 0.05 was considered as statistically significant, and SPSS version 26.0 (SPSS Inc., Chicago, Illinois, United States) was used for statistical analysis. RESULTS Among the 1902 patients with MPMTs confirmed by pathology, 1811 (95.2%) cases were secondary primary cancers, 89 (4.7%) cases were tertiary primary cancers, and 2 (0.1%) cases were quaternary primary cancers. Most (88.2%) of the secondary primary cancers were identified as metachronous multiple primary cancers six months after diagnosis of the first primary cancer. The top ten most common MPMTs in the first primary cancer group ranged from high to low as follows: Breast cancer, thyroid cancer, nonuterine cancer, lung cancer, colon cancer, kidney cancer, uterine cancer, bladder cancer, rectal cancer, and gastric cancer. The highest incidence rate of the first primary cancer in male metachronous cancer was lung cancer (11.6%), the highest incidence rate of the second primary cancer was still lung cancer (24.9%), the highest incidence rate of the first primary cancer in female metachronous cancer was breast cancer (32.7%), and the highest incidence rate of the second primary cancer was lung cancer (20.8%). Among them, breast cancer, nonuterine cancer and uterine cancer were female-specific malignant tumor types, and thyroid cancer also accounted for 79.6% of female patients. The top five metachronous cancer combinations, independent of female-specific malignant tumor types and thyroid cancer, were colon cancer and lung cancer (26 cases), kidney cancer and lung cancer (25 cases), rectal cancer and lung cancer (20 cases), gastric cancer and lung cancer (17 cases), and bladder cancer and lung cance...

Background A programmed cell death protein-1 (PD-1) inhibitor combined with lenvatinib and Gemox chemotherapy as first-line therapy demonstrated high anti-tumor activity against biliary tract cancer in phase II clinical trials. Herein, we aimed to investigate the efficacy and safety for advanced intrahepatic cholangiocarcinoma (ICC) in a multicenter real-world study. Methods Patients with advanced ICC who received PD-1 inhibitor combined with lenvatinib and Gemox chemotherapy were retrospectively screened at two medical centers. The primary endpoints were overall survival (OS) and progression-free survival (PFS), whereas the secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. Prognostic factors for survival were analyzed. Results Fifty-three patients with advanced ICC were included in this study. The median follow-up time was 13.7 (95% confidence interval (CI): 12.9–17.2) months. The median OS and PFS were 14.3 (95% CI: 11.3–NR) and 8.63 (95% CI: 7.17–11.6) months, respectively. The ORR, DCR, and clinical benefit rate were 52.8, 94.3, and 75.5%, respectively. In the multivariate analysis, the tumor burden score (TBS), tumor-node metastasis classification (TNM) stage, and PD-L1 expression were independent prognostic factors for OS and PFS. All patients experienced adverse events (AEs), 41.5% (22/53) experienced grade 3 or 4 AEs, including fatigue (8/53, 15.1%) and myelosuppression (7/53, 13.2%). No grade 5 AEs were reported. Conclusion PD-1 inhibitors combined with lenvatinib and Gemox chemotherapy represent an effective and tolerable regimen for advanced ICC in a multicenter retrospective real-world study. TBS, TNM stage, and PD-L1 expression can be used as potential prognostic factors for OS and PFS.

Purpose The combination of PD-1/PD-L1 inhibitors and molecular targeted agents showed promising efficacy for unresectable hepatocellular carcinoma (uHCC). This study aimed to investigate the prognostic value of metabolic parameters from 18 F-fluorodeoxyglucose positron emission tomography-computed tomography ( 18 F-FDG PET/CT) in patients with uHCC underwent the combined therapies. Patients and Methods Patients with uHCC treated with a combination of immunotherapy and targeted therapy who underwent baseline 18 F-FDG PET/CT between July 2018 and December 2021 were recruited retrospectively. The metabolic tumor volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake values (SUV max ), and clinical and biological parameters were recorded. A multivariate prediction model was developed for overall survival (OS) using these parameters together with clinical prognostic factors. Results Seventy-seven patients were finally included. The median OS was 16.8 months. We found that a high MTV (≥39.65 cm 3 as the median value) was significantly associated with OS (P<0.05). In multivariate analyses for OS, a high MTV, high Eastern Cooperative Oncology Group performance status (ECOG-PS, ≥1), Child-Pugh (B-C) grade, and the presence of bone metastasis were significantly associated with poor OS (HR 1.371, HR 3.73, HR 15.384, and HR 2.994, all P<0.05, respectively). A multivariate prognostic model including MTV and prognostic factors, such as ECOG-PS, Child-Pugh grade, and bone metastasis, further improved the identification of different OS subgroups. Conclusion High MTV is an adverse prognostic factor in patients with uHCC treated with a combination of immunotherapy and molecular targeted agents. Integrating PET/CT parameters with clinical prognostic factors could help to personalize immunotherapy.

e16155 Background: Combining lenvatinib (a multikinase inhibitor) with programmed cell death protein-1 (PD-1) inhibitor has been explored in Unresectable hepatocellular carcinoma (uHCC) in phase 1b trials. This study aimed to investigate the real-word efficacy and safety of lenvatinib plus PD-1 inhibitor for large Chinese patients uHCC cohorts. Methods: BCLC stage B or C uHCC patients were included. Data was collected from Oct 2017 to Nov 2021 retrospectively. Patients were treated with lenvatinib and PD-1 inhibitor (pembrolizumab or nivolumab or camrelizumab or sintilimab or toripalimab or tislelizumab). The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and objective response rate (ORR) evaluated by RECIST v1.1 criteria. Adverse events (AEs) were assessed using CTCAE v5.0. Prognostic factors of survival were also analyzed. Results: 378 uHCC patients of BCLC stage B (12.7%) and C (87.3%) from two medical centers were included in China. The median age was 55 (range 18-89) years and 86.5% patients were male. ECOG scores were 0 (43.7%), 1 (43.4%) and 2 (13.0%), while Child-pugh grade were A (77.5%) and B (22.5%) respectively. The median OS was 17.8 (95% CI 14.0-21.6) months. The median PFS was 6.9 (95% CI 6.0-7.9) months. The best objective response rate (ORR) and disease control rate (DCR) was 74/378 (19.6%) and 278/378 (73.5%) respectively. Child-pugh grade (A vs. B), ECOG score (0 vs. 1-2), BCLC stage (B vs. C) and achieve response (yes vs. no) were the prognostic factors for both OS and PFS. All (100%) experienced all-grade adverse events (AE). The most frequent AEs were fatigue, diarrhea, hypertension, decreased appetite. The most common ≥Grade 3 AEs were hypertension (13.2%), fatigue (7.1%), decreased platelet count (6.3%), increased blood bilirubin (6.1%), diarrhea (6.1%) and gastrointestinal hemorrhage (4.8%). Conclusions: This real-world study of lenvatinib plus PD-1 inhibitors achieved long survival and considerable ORR for uHCC patients in China. The tolerability of combination therapy was acceptable but should be still monitored closely. Clinical trial information: NCT03892577. [Table: see text]

BackgroundToripalimab shows antitumor efficacy in cholangiocarcinoma. Radiotherapy (RT) may enhance systemic responses of PD-1 inhibitors and lenvatinib. This study was designed to assess the safety and feasibility of toripalimab plus lenvatinib with or without RT in advanced BTC.MethodsThis study involved 88 patients with advanced BTC receiving toripalimab plus lenvatinib with or without RT from the clinical trials (NCT03892577). Propensity score matching (PSM) (1:1) analysis was used to balance potential bias. The overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) were evaluated.ResultsAfter PSM, the final analysis included 40 patients: 20 receiving toripalimab plus lenvatinib without RT (NRT); 20 receiving toripalimab plus lenvatinib with RT. The AEs were more frequent in the RT group than in the NRT group without treatment-associated mortality. The addition of RT did not cause specific AEs. The median PFS was significantly longer with RT (10.8 versus 4.6 months, p&lt;0.001). The median OS was 13.7 months with RT versus 9.2 months in the NRT group (p=0.008). The ORR was 35% (95% CI: 12.1-57.9) in the RT group versus 20% (95% CI: 0.8-39.2) in the NRT group.ConclusionsThe addition of RT may enhance the efficacy of toripalimab plus lenvatinib. Toripalimab plus lenvatinib with RT have a good safety profile without an increase in specific toxicities in advanced BTC patients.

Background. Gastric cancer (GC) is a major cause of cancer-related death in China. Immunotherapies based on PD-1/PD-L1 inhibitors have improved the survival of some patients with GC. Epstein–Barr virus (EBV) infection, mismatch repair (MMR) deficiency, and tumor immune microenvironment (TIME) markers (such as CD3, CD8, and PD-L1) may help to identify specific patients who will respond to PD-1/PD-L1 inhibitors. Considering racial heterogeneity, the pattern of TIME markers in Tibetan patients with GC is still unclear. We aimed to identify the prevalence of EBV infection and the MMR status and their association with immune markers in Tibetan GC to aid in patient selection for immunotherapy. Materials and Methods. From 2001 to 2015, we retrospectively collected 120 tissue samples from consecutive Tibetan GC patients and constructed tissue microarrays. EBV infection was assessed by Epstein–Barr-encoded RNA (EBER) in situ hybridization, and MMR protein levels were measured. Immune markers (including CD3 and CD8) in intraepithelial, stromal, and total areas were detected by immunohistochemistry (IHC). PD-L1 expression was assessed by the combined positive score (CPS). We also analyzed the relationships of EBV infection and MMR status with immune markers. Results. Of the 120 samples, 11 (9.17%) were EBV positive (+), and 6 (5%) were MMR deficient (dMMR). PD-L1 CPS ≥1% was found in 32.5% (39/120) of Tibetan GC patients. EBV infection was associated with higher numbers of CD3+ T cells ( P < 0.05 ) and CD8+ T cells ( P < 0.05 ) and higher PD-L1 expression ( P < 0.05 ). For the limited number of dMMR patients, no significant relationship was observed between dMMR and TIME markers ( P > 0.05 ). Conclusions. In Tibetan GC patients, the rates of EBV infection, dMMR, and positive PD-L1 expression were 9.17%, 5%, and 32.5%, respectively. EBV infection was associated with the numbers of CD3+ T cells and CD8+ T cells and PD-L1 expression within the tumor. These markers may guide the selection of Tibetan GC patients for immunotherapy.

Objective This study explored the application of four-dimensional cone beam computed tomography (4D CBCT) in lung cancer patients, seeking to improve the accuracy of radiotherapy and to establish a uniform protocol for the application of 4D CBCT in radiotherapy for lung cancer. Methods 4D CBCT was applied to evaluate tumor volume response (TVR), motion, and center coordinates during radiotherapy in 67 eligible individuals with lung cancer diagnoses. The differences between 4D CBCT and 3D CBCT in different registration methods were compared. Results TVR was observed during treatment in 41% of patients (28/67), with a mean volume reduction of 41.7% and a median time to TVR of 19 days. Tumor motion was obvious in 16 patients, with a mean value of 0.52 cm (0.22 to 1.34 cm), and in 3 of 6 tumors close to the diaphragm (0.28 to 0.66 cm). Gray value registration based on mean density projection could still achieve close results to the 4D gray value registration. However, when the registration was based on bone alone, partial off-targeting occurred in the treatment in 41.8% of cases. The off-target rate was 19.0% when the tumor motion was ≤ 0.5 cm and 52.2% when the motion was > 0.5 cm. Conclusion Tumor volume and motion of intrapulmonary lesions in individuals diagnosed with lung cancer varied significantly in the third week of radiotherapy. 4D CBCT may be more advantageous for isolated lesions without reference to relative anatomical structures or those near the diaphragm. Grayscale registration based on mean density projection is feasible.

4101 Background: Microsatellite instability-high (MSI-H) status is a unique genomic state with encouraging effects of PD-1-based therapy in patients with advanced cancer. Cholangiocarcinoma is often driven by genetic mutations. However, the genomic characterization and translational medicine of MSI-H are not clear. Methods: In this study, 881 Chinese patients with cholangiocarcinoma (582 intrahepatic cholangiocarcinoma and 299 extrahepatic cholangiocarcinoma) were enrolled and their genomes were investigated using panel sequencing or whole-exome sequencing. Clinicopathological and genomic features as well as PD-1 inhibitor-based immunotherapy were analyzed by MSI status in patients with cholangiocarcinoma. Results: Overall, 47 (5.3%) cholangiocarcinoma patients were identified as MSI-H patients after enrichment enrollment. Intrahepatic cholangiocarcinoma (ICC) accounted for 74.47% (35/47) of MSI-H patients. Clinicopathological parameters showed younger, ICC-dominated, and more positive PD-L1 expression in MSI-H patients. In the genome of MSI-H cholangiocarcinoma, ACVR2A (75.00%), ARID1A (75.0%), KMT2D (72.2%), TGFBR2 (63.9%), PBRM1 (58.3%), RNF43 (55.6%), TP53 (52.8%) ), ARID1B (47.2%) had a higher mutation frequency. Comparing the SNV and INDEL mutation in the genome, the differential genes between MSI-H and MSS were ARID1A, ACVR2A, KMT2D, TGFBR2, PBRM1, RNF43, LRP1B, ARID1B, etc., respectively. In addition, the differential mutation pathways of MSI-H showed that the mutation rate of DDR, SWI/SNF CellCycle, HRD and other pathways was significantly higher than that of MSS samples. The tumor mutation burden (TMB) in MSI-H patients was significantly higher than that in MSS (P<0.001). In a cohort of 151 CCA patients who received PD-1 inhibitor-based immunotherapy, 19 patients with MSI-H cholangiocarcinoma were found to have a favorable prognosis (1-year survival rate 68.4%). Compared with 132 MSS cholangiocarcinoma patients, Patients with MSI-H cholangiocarcinoma had significantly prolonged OS (Not reach vs. 13.4m, P<0.001, HR=0.17, P <0.001) and high clinical benefit (CBR) (OR=8.16, P <0.001). In this immunotherapy cohort, ≥2 DDR pathway genes and ≥2 SWI/SNF pathway genes mutations, positive PD-L1 expression and TMB-H were also associated with better OS and CBR (both P<0.05). Conclusions: MSI-H cholangiocarcinoma has distinct genomic features, and the effect of PD-1 inhibitors immunotherapy is excellent to these patients. Clinical trial information: NCT03892577.