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PURPOSE To ascertain if preoperative short-term radiotherapy followed by chemotherapy is not inferior to a standard schedule of long-term chemoradiotherapy in patients with locally advanced rectal cancer. MATERIALS AND METHODS Patients with distal or middle-third, clinical primary tumor stage 3-4 and/or regional lymph node–positive rectal cancer were randomly assigned (1:1) to short-term radiotherapy (25 Gy in five fractions over 1 week) followed by four cycles of chemotherapy (total neoadjuvant therapy [TNT]) or chemoradiotherapy (50 Gy in 25 fractions over 5 weeks, concurrently with capecitabine [chemoradiotherapy; CRT]). Total mesorectal excision was undertaken 6-8 weeks after preoperative treatment, with two additional cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) in the TNT group and six cycles of CAPOX in the CRT group. The primary end point was 3-year disease-free survival (DFS). RESULTS Between August 2015 and August 2018, a total of 599 patients were randomly assigned to receive TNT (n = 302) or CRT (n = 297). At a median follow-up of 35.0 months, 3-year DFS was 64.5% and 62.3% in TNT and CRT groups, respectively (hazard ratio, 0.883; one-sided 95% CI, not applicable to 1.11; P < .001 for noninferiority). There was no significant difference in metastasis-free survival or locoregional recurrence, but the TNT group had better 3-year overall survival than the CRT group (86.5% v 75.1%; P = .033). Treatment effects on DFS and overall survival were similar regardless of prognostic factors. The prevalence of acute grade III-V toxicities during preoperative treatment was 26.5% in the TNT group versus 12.6% in the CRT group ( P < .001). CONCLUSION Short-term radiotherapy with preoperative chemotherapy followed by surgery was efficacious with acceptable toxicity and could be used as an alternative to CRT for locally advanced rectal cancer.

Background: To date, the long-term outcomes of patients with locally advanced gastric cancer (LAGC) who achieved a pathological complete response (pCR) after neoadjuvant therapy are elusive. To evaluate the impact of pCR on the long-term survival of LAGC patients who underwent neoadjuvant therapy and evaluate the necessity of postoperative adjuvant chemotherapy. Methods: We conducted a retrospective study of clinicopathological and survival data of patients who achieved a pCR after neoadjuvant therapy and resection at the China National Cancer Center between January 2007 and December 2018. Results: Ultimately, 39 patients enrolled in the current study, with a median follow-up time was 30.4 (range 2.5–101.6) months. The 3- and 5-year overall survival (OS) rates were 88.9% and 88.9%, respectively. And the 3- and 5-year disease-free survival (DFS) rates were 88.9% and 88.9%, respectively. During the follow- up, recurrence was observed in 3 patients. Of all 39 patients, 51.3% (n=20) received postoperative adjuvant chemotherapy and 48.7% (n=19) did not. There was no significant difference in OS (P=0.48) and DFS (P=0.47) between patients who underwent postoperative adjuvant chemotherapy and patients who did not. Conclusions: Patients with LAGC who achieved a pCR after neoadjuvant therapy and resection might have a favorable OS and DFS. Our study failed to demonstrate the benefit of adjuvant chemotherapy for those patients.

Objective To investigate the related factors of pathological complete response(pCR)of patients with gastric cancer treated by neoadjuvant therapy and resection,and to analyze the risk factors of prognosis. Methods The clinical and pathological data of 490 patients with gastric cancer who received neoadjuvant therapy followed by radical gastrectomy from January to December in 2008 were retrospectively analyzed.Univariate and multivariate analyses were performed to identify the risk factors affecting pCR and prognosis. Results Among the 490 patients,41 achieved pCR,and the overall pCR rate was 8.3%(41/490).The pCR rate was 16.0% in the neoadjuvant chemoradiation group and 6.4% in the neoadjuvant chemotherapy group.The results of multivariate analysis showed that neoadjuvant chemoradiation(

BackgroundMonoclonal antibodies targeting programmed death ligand 1 (PD-L1) signaling currently approved for defective mismatch repair (dMMR)/microsatellite instability high (MSI-H) tumors must be delivered by intravenous infusion. Envafolimab, a humanized single-domain anti-PD-L1 antibody fused to an Fc fragment, represents a potential advance because it can be conveniently administered subcutaneously.MethodsThis open-label, single-arm, phase 2 study evaluated the efficacy and safety of envafolimab in patients with previously treated advanced dMMR/MSI-H tumors from 25 clinical sites across China. Adults with histologically confirmed locally advanced or metastatic malignant dMMR/MSI-H solid tumors received weekly 150 mg subcutaneous envafolimab injections in a 28-day treatment cycle. The primary efficacy endpoint was the objective response rate (assessed by a blinded independent review committee). Secondary efficacy outcomes were disease control rate, duration of response, progression-free survival, and overall survival.ResultsOne hundred and three patients (65 with colorectal cancer, 18 with gastric cancer, and 20 with other solid tumors) were enrolled. Median follow-up was 11.5 months. The objective response rate was 42.7% (95% confidence interval [CI] 33.0–52.8), and the disease control rate was 66.0% (95% CI 56.0–75.1). Median duration of response was not reached; the duration of response rate at 12 months was 92.2% (95% CI 77.5–97.4). Median progression-free survival was 11.1 months (95% CI 5.5 to not evaluable). Overall survival at 12 months was 74.6% (95% CI 64.7–82.1). Sixteen patients (16%) had at least one grade 3 or 4 related treatment-emergent adverse event. No grade 5 treatment-emergent adverse events related to envafolimab were reported. Injection site reactions, all grade 1–2, were reported in nine patients (9%), but there were no infusion reactions. Eight patients (8%) had grade 3 or 4 immune-related adverse events.ConclusionsThis is the first pivotal phase 2 study to examine the efficacy and safety of a single-domain immune checkpoint antibody in the treatment of cancer. Envafolimab was effective and had acceptable safety in the treatment of previously treated advanced dMMR/MSI-H solid tumors. As the first single-domain PD-L1-targeting antibody administered by rapid subcutaneous injection, envafolimab has the potential to be a significant advance in the treatment of cancer.Trial registrationClinicalTrials.gov, NCT03667170. Registered 10 September 2018—Retrospectively registered,https://clinicaltrials.gov/ct2/show/NCT03667170.

Background Anlotinib is a tyrosine kinase inhibitor inhibiting angiogenesis. This multicenter, randomized phase II trial aimed to investigate the efficacy and safety of anlotinib in comparison with sunitinib as first-line treatment for patients with metastatic renal cell carcinoma (mRCC). Materials and Methods Patients with mRCC from 13 clinical centers were randomly assigned in a 2:1 ratio to receive anlotinib (n = 90) or sunitinib (n = 43). Anlotinib was given orally at a dose of 12 mg once daily (2 weeks on/1 week off), and sunitinib was given orally at 50 mg once daily (4 weeks on/2 weeks off). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results The median PFS was similar with anlotinib and sunitinib (17.5 vs. 16.6 months, p > .05). The median OS (30.9 vs. 30.5 months, p > .05), ORR (30.3% vs. 27.9%), and 6-week DCR (97.8% vs. 93.0%) were similar in the two groups. Adverse events (AEs) of grade 3 or 4 were significantly less frequent with anlotinib than with sunitinib (28.9% vs. 55.8%, p Conclusion The clinical efficacy of anlotinib was similar to that of sunitinib as the first-line treatment for mRCC, but with a more favorable safety profile.

Using a modified dynamic Monte Carlo renormalization group method, the two- dimensional kinetic Ising model is studied, and the dynamic critical exponent is obtained. The critical temperature of phase transition can be obtained by the renormalization method for the correlation function. In the method we used, the correlation function is replaced with the absolute value of the magnetization, and it is found that the evolution of the absolute value of the magnetization over time satisfies the power-law form. It is found that the value of the dynamic critical exponent tends to be a stable value in the form of a power-law function as the scale of the system increases. The dynamic critical exponent obtained is z ≃ 2 . 15 . When the modified dynamic Monte Carlo renormalization group method is applied to the two-dimensional Glauber model, the obtained dynamic critical exponent is z ≃ 2 . 25 .

4572 Background: Human epidermal growth factor receptor 2 (HER2) overexpression is related to many tumor treatments. RC48-ADC, a novel humanized anti-HER2 antibody conjugated with monomethyl auristatin E, has shown a promising efficacy in patients with HER2-positive locally advanced or metastatic urothelial carcinoma (mUC). The characteristic expression and scoring systems of HER2 have existed in breast cancer, gastric cancer for many years, but not in UC. We aimed to explore the expression pattern of HER2 in UC and develop a validated HER2 scoring system. Methods: A total of 137 patients and 43 patients in two studies of cohort 1 and cohort 2 were enrolled, respectively. The patients of the cohort 2 were enrolled in the open-label, multicenter, phase II study of RC48-ADC. Formalin-fixed paraffin-embedded urothelial cancer samples were tested for HER2 status using the fluorescence in situ hybridization (FISH) PathVysion HER2 DNA probe kit (PathVysion, Abbott Molecular, USA). Immunohistochemistry (IHC) was performed using the Ventana Benchmark XT (Ventana Medical Systems, USA). The 2018 ASCO/CAP HER2 scoring system of breast cancer was adopted and modified to score HER2 expression level in UC. Results: The expression rate of HER2 (IHC 2+/3+) was 24.1% (33/137). In HER2 IHC status 3+ or 2+ patients, the HER2 amplified rate was 31% (13/42). The objective response rates in RC48-ADC treatment patients with IHC 3+, IHC 2+ and FISH +, IHC 2+ and FISH - were 58.8%, 66.7% and 40%, respectively. Heterogeneity of HER2 protein expression was 55.5% (15/27) and the objective response rate had no significant difference between patients with tumor heterogeneity and homogeneity. Conclusions: The modified HER2 testing scoring system could be applied to UC to determine which patient might benefit from anti-HER2-ADC treatment. There was a trend towards a better benefit for patients with HER2 amplification and the tumor heterogeneity did not influence the drug efficacy.

4031 Background: The optimal perioperative chemotherapy of locally advanced gastric or gastro-esophageal junction (G/GEJ) cancer has not been established in Asia, though FLOT was considered as standard therapy in Europe. Therefore, we aimed to assess efficacy and safety of DOS versus SOX as perioperative treatment in patients with locally advanced G/GEJ cancer in this study. Methods: This was a single center, open-label, randomized, phase 2 study. Eligible pts were aged ≥18 years with histologically diagnosed HER2 negative cT3-4 Nany M0 G/GEJ (Siewert II/III type) adenocarcinoma. Pts were randomized (1:1) to receive either 4 preoperative and 4 postoperative cycles of DOS (docetaxel 60mg/m2 D1, oxaliplatin 100mg/m2 D1, S-1 40-60mg bid D1-14 depending on body surface area (BSA), Q3W) or SOX (oxaliplatin 130mg/m2 D1, S-1 40-60mg bid D1-14 depending on BSA, Q3W). Pts underwent D2 gastrectomy after preoperative treatment. The primary endpoint was major pathological response (MPR) analyzed in the modified intention to treat (mITT) population according to Becker TRG criteria. Secondary endpoints included the 3-year progression free survival (PFS), the 3-year overall survival (OS), pathological complete response, R0 resection rate and safety. Results: From Aug, 2015, to Dec, 2019, 154 pts were enrolled, 7 pts withdrew consent, 147 pts were included as mITT population (DOS 71; SOX 76). 80.3% and 67.1% of the pts in the DOS and SOX groups accepted surgery respectively. More pts achieved MPR (25.4% vs. 11.8%, p = 0.035) and R0 resection (78.9% vs. 61.8%, p = 0.024) in the DOS group than the SOX group. With a median follow-up of 42.4 months, the 3-year PFS and the 3-year OS were 52.3% vs. 35% (p = 0.065, HR 0.667, 95%CI 0.432-1.029) and 57.5% vs. 49.2% (p = 0.114, HR 0.685, 95%CI 0.429-1.095) in the DOS and SOX groups, respectively. Pts who acquired MPR had a significant longer survival than non-MPR pts. The 3-year PFS were 89.4% vs. 38.6% (p < 0.001, HR 0.076, 95%CI 0.018-0.314). The 3-year OS were 100% vs. 50.1% (p = 0.008, HR 0.024, 95%CI 0.002-0.371). 56.1% and 60.8% of the pts completed at least 6 cycles of the perioperative chemotherapy in the DOS and SOX groups, respectively (p = 0.625). The most common grade ≥3 TRAEs included neutropenia (8.5% vs.10.5%), leucopenia (1.4% vs. 5.3%), thrombocytopenia (1.4% vs 15.8%, p = 0.002), anemia (1.4% vs. 3.9%) and diarrhea (1.4% vs. 2.6%). The incidence of grade 1-2 thrombocytopenia was also significant lower in the DOS group (15.5% vs. 31.6%, p = 0.022). No treatment-related deaths occurred. Conclusions: Perioperative DOS improved MPR significantly and tended to have better PFS compared with SOX in locally advanced G/GEJ cancer, might be regarded as a prefered option of perioperative chemotherapy. Clinical trial information: NCT02725424.

3591 Background: Raltitrexed-based chemotherapy regimen is one of the common regimens for the treatment of metastatic colorectal cancer (mCRC). This prospective observational real-world study aimed to evaluate the safety and effectiveness of raltitrexed administered to Chinese patients with mCRC in real life setting. Methods: This is a prospective, multicenter, real-world study. Prospectively registered Patients received second-line treatment of raltitrexed plus irinotecan combined with or without target therapy until progression disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), quality of life (QOL) and safety. Totally,1000 patients were required for primary point testing. Results: Between May 2018 and December 2021,a total of 1039 patients from 57 centers were screened for enrollment,among which 271 patients were treated with raltitrexed plus irinotecan, 753 patients accepted target therapy (bevacizumab or cetuximab) additionally, and 15 patients combined with other drugs. Overall mPFS was 6.8 months (95%CI: 6.5-7.1),ORR was 20.2%, and DCR was 85.7%; The ORR of combined with or without target therapy were 21.6% and 16.2% ( p = 0.038),respectively, the DCR were 88.2% and 79.0% ( p < 0.001). The mPFS of combined without or with target therapy were 5.2 months (95% CI: 4.7 to 5.7) and 7.3 months respectively (95% CI: 7.0-7.7) [HR = 0.67, 95% CI 0.56̃0.80, p < 0.001], The mPFS of combined with bevacizumab or cetuximab were 7.4 months (95% CI: 7.0 -7.8) and 6.8 months (95% CI: 5.9-7.7) [HR = 1.15, 95% CI 0.88̃1.51, p = 0.3]. mOS has not yet reached. Majority of treatment-related adverse events (TEAEs) were grade I or II. The most common grade III or IV TRAEs reported by 116 patients (11.2%) were aspartate aminotransferase increased (4.0%), alanine aminotransferase increased (3.7%), neutrocytopenia (2.7%), glutamyltransferase increased (2.5%), leukocytopenia (1.1%). Conclusions: The real-world study confirmd that raltitrexed was an effective and safe regimen for the second-line treatment in Chinese patients with mCRC, especially combined with target therapy additionally, which was aligned with previous trials. Clinical trial information: ChiCTR1800016185.

e16001 Background: PD-1 inhibitor combined with chemotherapy showed remarkable objective response rate in the first line treatment of metastatic gastric cancer. While, the benefit of perioperative PD-1 inhibitor plus chemotherapy in locally advanced gastric or gastro-esophageal junction (G/GEJ) cancer was not clear. Therefore, we aimed to assess the efficacy and safety of perioperative XELOX plus toripalimab in the patients with locally advanced G/GEJ cancer in this study. Methods: This was a prospective single arm phase 2 study. Eligible patients were with histologically confirmed locally advanced G/GEJ (Siewert II/II type) adenocarcinoma (cT3-4 Nany M0 or T1-2 N2-3 M0). Patients received 4 preoperative and 2 postoperative cycles of XELOX plus toripalimab (oxaliplatin 130mg/m2 D1, capecitabine 1000mg/m2 bid D1-14, toripalimab 240mg D1, Q3W) followed by subsequent 2 cycles of toripalimab monotherapy. Patients underwent D2 gastrectomy after preoperative treatment. The primary endpoint was major pathological response (MPR) according to Becker TRG criteria. Secondary endpoints included safety, R0 resection rate, pathological complete response (pCR), 3-year disease free survival (DFS) and 3-year overall survival (OS). Results: From Jul, 2019, to Dec, 2021, 35 pts were recruited. The median age was 61 (34-72) years old. 80% of the pts were men. Acutally, all the pts had cT4 (cT4a [48.6%] & cT4b [51.4%]) and 88.6% had cN+ by CT, MRI and ultrasound gastroscopy. 2 pts suffered disease progression during neoadjuvant treatment. 4 pts have not yet completed preoperative therapy. 29 pts had received gastrectomy and 2 pts were pathologically diagnosed with large cell neuroendocrine carcinoma. Therefore, 27 adenocarcinoma pts were included in this analysis. 3 (11.1%) pts achieved pCR (TRG1a) and 4 (14.8%) pts achieved MPR (TRG1a/b). R0 resection was achieved in 96.3% (26/27) of the pts. No patient had pT4b. The most common (≥10%) grade 1-2 treatment related adverse events (TRAEs) included leucopenia (45.7%), neutropenia (42.9%), thrombocytopenia (20%), nausea (34.1%), vomiting (14.3%), anorexia (14.3%), ALT increased (40%) and AST increased (34.3%). Only 4 (11.4%) pts experienced grade 3 neutropenia. No other ≥ grade 3 TRAEs occurred. Most of the potential immune-related adverse events were grade 1-2 including hypothyroidism (8.6%), adrenal insufficiency (2.9%) and hyperglycemia (11.4%). Only one (2.9%) patient had grade 3 hyperglycemia. No serious perioperative complication and death occurred. Conclusions: Perioperative XELOX plus toripalimab preliminarily showed a favorable R0 resection rate and acceptable MPR in cT4a/T4b locally advanced G/GEJ cancer patients with a manageable safety profile. Clinical trial information: NCT04119622.

3594 Background: Irinotecan and fluorouracil are the most effective drugs in the treatment of metastatic colorectal cancer (mCRC). But XELIRI (irinotecan plus capecitabine) has not been recommended in the 1st-L setting due to the toxicity in the Western countries. While, modified 3-weekly XELIRI has been proved to be effective and safe in the 2nd-L therapy in Asian mCRC patients. Therefore, this study aimed to assess the efficacy and safety of biweekly mXELIRI with reduced dose of irinotecan in the 1st-L treatment of mCRC. Methods: This was a randomized, open-label, non-inferiority study undertaken at 11 hospitals in China. Eligible patients were aged ≥18 years with unresectable metastatic histologically diagnosed colorectal adenocarcinoma; had an ECOG of 0 or 1 and at least one measurable disease according to the RECIST v 1.1 without any systemic chemotherapy for metastatic disease. Patients were randomly assigned (1:1) stratified by the location of primary tumor (left or right site) to receive 9 cycles of mXELIRI + bevacizumab (Bev) (irinotecan 150mg/m2 D1, capecitabine 1000mg/m2 bid D1-10, Bev 5mg/kg D1, Q2W) or FOLFIRI + Bev (irinotecan 180mg/m2 D1, CF 400mg/m2 D1, 5-Fu 400mg/m2 bolus D1, 5-Fu 2400mg/m2 civ 46h D1, Bev 5mg/kg D1, Q2W) followed by maintenance treatments with capecitabine + Bev or 5-FU + CF + Bev. The primary endpoint was 12-month progression-free survival (PFS) rate. The secondary endpoints included objective response rate (ORR), PFS, overall survival (OS) and safety. Results: From May, 2018 to Apr, 2021, 264 pts were randomized (mXELIRI + Bev 132; FOLFIRI + Bev 132). The median age was 61 (29-80) years old. 62.5% of the patients were men. With a median follow-up of 17.1 months, the 12-month PFS rates were 43.9% vs. 28.8% in the mXELIRI + Bev and FOLFIRI + Bev groups, respectively. The HR was 0.72 (95%CI 0.51 -1.02) which didn’t cross the predefined non-inferiority margin of 1.18 (upper bound < 1.18). The median PFS were 10.5 months vs. 9.6 months (p = 0.056, HR 0.74, 95%CI 0.55-1.01). The median OS was still not mature. The ORR were 51.5% vs. 47.0% (p = 0.460), respectively. The incidence of treatment related adverse events (TRAEs) between these two groups were similar. The most common TRAEs were neutropenia (mXELIRI + Bev vs. FOLFIRI + Bev: 51.8% vs. 57.0%), leukopenia (43.9% vs. 55.3%), anemia (54.4% vs. 45.6%), nausea (31.6% vs. 40.4%), ALT/AST increased (22.8% vs. 23.7%), diarrhea (21.1% vs. 16.7%), fatigue (20.2% vs. 23.7%), vomiting (17.5% vs. 20.2%) and hyperbilirubinemia (14.9% vs. 17.5%). No treatment- related deaths were reported. Conclusions: Biweekly mXELIRI with reduced dose of irinotecan plus bevacizumab was noninferior to the standard dose of FOLFIRI + Bev in PFS, with similar safety profile in the patients with untreated mCRC. Clinical trial number: NCT04247984. Research Sponsor: No Clinical trial information: NCT04247984.

e16184 Background: The combination of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitor (TKI) manifested high efficacy in front-line therapy for aHCC, which still deserves further exploration in second-line therapy. Anlotinib, an oral multi-targeted TKI that mainly blocks VEGF/VEGFR pathway, has been approved for several solid tumor types in china. Anlotinib plus TQB2450, a novel anti-PD-L1 mAb, might be a promising strategy. This study aimed to evaluate the efficacy and safety of this regimen as second-line treatment in aHCC patients (pts). Methods: Pts with aHCC, ≥18 years, Child Pugh class A-B (scores ≤ 8), ECOG PS of 0-1, BCLC stage B or C, ≥ 1 measurable lesion (per RECIST v1.1) and progressed/tolerated after first-line treatment were eligible. Pts received anlotinib (10-12 mg, p.o., qd, d1-14, q3w) plus TQB2450 (1200mg, iv, d1, q3w). In the dose-escalation stage, anlotinib dose was explored from 10mg to 12mg. Dose expansion was performed after the determination of the maximum tolerable dose. Tumor assessment was evaluated according to the RECIST 1.1 per investigators, supplemented by iRECIST. The primary endpoints were ORR and safety. Secondary endpoints included PFS, DCR and OS. Results: 19 pts were enrolled between 16 May 2019 and 16 Jan 2020. The median age of pts was 52 years (range: 37-67), 89.5% pts were male, 94.7% pts were ECOG 0 and 78.9% had BCLC staging C. Both 10mg and 12mg were tolerable during the dose-escalation stage. At the cut off date (Jan 29, 2022), the median follow-up duration was 9.13 months. Of the 19 evaluable patients, 4 had PR, 8 had SD, 5 had PD, and 2 pts were NE. Confirmed ORR was 23.5% (95%CI: 6.8-49.9), DCR was 76.5% (95%CI: 50.1-93.2). The median PFS was 5.49 (3.46-7.51) months, and median DOR of 12.95 (5.26-20.63) months was achieved. Treatment-related adverse events (TRAEs) of any grade were recorded in 73.7% pts, ≥ grade 3 TRAEs were observed in 7 patients, with gastrointestinal reaction (15.8%), leucopenia (5.3%), neutropenia (5.3%), thrombocytopenia (5.3%), ALT increased (5.3%). Conclusions: Anlotinib plus TQB2450 was tolerable and showed preliminary antitumor activity in pre-treated aHCC. Further investigation in larger population is warranted. Clinical trial information: NCT03825705.

4570 Background: Overexpression of HER-2 is associated with poor prognosis of urothelial cancer, and anti-HER-2 antibody-drug conjugate (ADC) has shown a promising efficacy among the UC patients (pts) in recently studies. MRG002 is a novel HER2-targeted ADC being investigated in the MRG002-006 trial to evaluate the efficacy and safety in HER2 positive UC pts. Methods: This is a single-arm, multicenter phase II study. Eligibility criteria included: histologically HER2-positive (IHC 2+ or 3+) UC pts confirmed by a central-laboratory, ECOG PS 0-1, prior received ≥1 standard treatment. Approximately 40 pts will be enrolled. In the initial dose finding stage, pts were assigned to receive MRG002 at a dose of 2.6 mg/kg or 2.2 mg/kg administered by intravenous infusion every 3 weeks. The dose expanding stage was subsequentially performed based on preliminary results. The primary endpoint was ORR per RECIST 1.1, secondary endpoints are safety, DOR, PFS and, OS. Results: As of December 31, 2021, a total of 39 pts were enrolled. Enrollment is estimated be completed in February 28, 2022, and results are expected to be updated before publication. Nine pts were dosed at 2.6 mg/kg and 26 pts were dosed at 2.2 mg/kg. Based on safety analysis, 2.2 mg/kg was adopted as the recommended dosage. At baseline, 80% pts (28/35) had visceral metastasis. Most pts (28/35) received ≥ 2 lines of treatment and 29 (83%) pts had prior immune checkpoint inhibitor (ICI) therapy. By the cut-off date, 23 pts were evaluable and the ORR was 65% (15/23, 95% CI: 44.9%–81.2%), with 9% CR, and the DCR was 91% (21/23, 95% CI: 73.2%–97.6%). The estimated median PFS for the 23 pts was 5.5 months (95% CI: 2.7–NR). Among the evaluable pts, 1 CR responder achieved a response duration of more than 9.5 months. Subgroup analysis indicated that the ORR was 65% among the 17 pts post ≥ 2 lines of treatment, and 78% among the 18 pts failed platinum-containing chemotherapy and ICI treatment. Most common treatment-related AEs determined by investigators were anemia (34%), alopecia (34%), AST increased (31%), neutrophil count decreased (26%), neuropathy peripheral (23%), constipation (17%), decreased appetite (17%); most were grade 1 or 2 per CTCAE 5.0. The incidence of SAE was 17% (6/35). At the dose of 2.6mg/kg, 1 pts discontinued the treatment due to hypotension and 1 pts experienced ileus, which was considered caused by neurotoxicity of MRG002. There were no similar events described above happened among the pts at the dose of 2.2mg/kg. Conclusions: Preliminary results of MRG002 demonstrated a clinically meaningful response in pretreated HER-2 positive unresectable locally advanced or metastatic UC patients, especially in those progressed after platinum-containing chemotherapy and ICI therapy. MRG002 at 2.2mg/kg showed a manageable safety profile in these pts. Further evaluation is ongoing. Clinical trial information: NCT04839510.

BackgroundTislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy.MethodsThe purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1.ResultsAs of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2–21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types.ConclusionsTislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors.Trial registration numberCTR20160872.

455 Background: The combination of immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) antibodies manifested high efficacy in advanced hepatocellular carcinoma (HCC), which still needs to be further verified. We aimed to evaluate the safety and activity of this strategy with different doses, as well as to explore potential predictive biomarkers. Methods: In this two-part phase Ib study, patients with advanced or metastatic HCC were enrolled. Part 1 was dose escalation trial with sintilimab plus bevacizumab biosimilar (IBI305) 7.5 mg/kg (initial dose) or 15 mg/kg (escalated dose). Part 2 was extension in each tolerable dose group. Peripheral blood samples and tumor tissue specimens were collected before treatment to detect serum cytokines and tumor immune microenvironment (TiME) by multiplexed bead immunoassays and multicolor immunofluorescence. Results: Fifty patients were enrolled in final analysis. Among all, IBI305 7.5 mg/kg was administered in 29 patients and 21 patients with 15 mg/kg. The most common adverse event suspected to be treatment-related was hypertension (32%), proteinuria (26%) and fever (26%). The incidence of the grade 3-5 adverse events in group 15 mg/kg was 28.6%, while 13.8% in 7.5 mg/kg group. Overall, the ORR was 34% (17/50) and the DCR reached to 78% (39/50). The median PFS was 10.5 months (95%CI, 8.4-12.7) and the median OS was 20.2 months (95%CI, 16.1 -24.3). The ORR for 7.5 mg/kg and 15 mg/kg were 31% and 38%, respectively. Further analysis showed that responder patients (CR+PR+SD≥12 weeks) had significantly higher level of serum CD137 than those with non-responder group (PD+SD≥12weeks) (median, 32.8 versus 19.8 pg/mL, P = 0.034). Patients with a high level of CD137 ≥ 31.8 pg/mL had longer PFS (mPFS:14.2 vs. 4.1months, P = 0.001) and OS (mOS: NR vs.15.6months, P = 0.023). In addition, the TiME analysis demonstrated that the density of M1 macrophages (CD68+CD163-) in stroma was related to efficacy (P = 0.033), longer PFS (P = 0. 024) and OS (P = 0.046). Conclusions: The sintilimab plus IBI305 is well tolerated and effective, IBI305 of 7.5 mg/kg could be also optional to some patients. The serum CD137 and M1 macrophages are potential predicting biomarkers for the combination therapy Clinical trial information: NCT04072679.

Although PIWI-interacting RNAs (piRNAs) have recently been linked to human diseases, their roles and functions in malignancies remain unclear. This study aimed to investigate the significance of some piRNAs in colorectal cancer (CRC). Methods: We first analyzed the expression profile of piRNAs in CRC using the TCGA and GEO databases. The top 20 highly expressed piRNAs were selected and tested in our CRC tumor and non-tumor tissue samples. We then examined the relevance of the significantly differentially expressed piRNA to the CRC outcomes in 218 patients receiving postoperative chemotherapy and 317 patients receiving neoadjuvant chemotherapy. A series of biochemical and molecular biological assays were conducted to elucidate the functional mechanism of a piRNA of interest in CRC. Furthermore, experiments with mice xenografts were performed to evaluate the therapeutic effect of an inhibitor specific to the piRNA. Results: We found that among the examined 20 piRNAs, only piRNA-54265 was overexpressed in CRC compared with non-tumor tissues and higher levels in tumor or in serum were significantly associated with poor survival in patients. Functional assays demonstrated that piRNA-54265 binds PIWIL2 protein and this is necessary for the formation of PIWIL2/STAT3/phosphorylated-SRC (p-SRC) complex, which activates STAT3 signaling and promotes proliferation, metastasis and chemoresistance of CRC cells. Treatment with a piRNA-54265 inhibitor significantly suppressed the growth and metastasis of implanted tumors in mice. Conclusion: These results indicate that piRNA-54265 is an oncogenic RNA in CRC and thus might be a therapeutic target.

In this study, hierarchical porous boron nitride nanosheets (hp-BNNSs) were prepared by pyrolyzing the mixture of boron acid and urea at 1000 °C for 5 h. The prepared hp-BNNSs exhibited hierarchical porous structure with the pores in the range of 1.1 nm–40 nm and a higher specific surface area of 1145 m2/g. hp-BNNSs showed versatile adsorption capacity to industrial dyes (methylene blue (MB) and rhodamine B (RhB)), heavy metal ions (Cu2+ and Ni2+), and antibiotic (tetracycline (TC)). The adsorption capacities for MB, RhB, Cu2+, Ni2+, and TC were 201 mg/g, 385 mg/g, 417 mg/g, 280 mg/g, and 263 mg/g, respectively. Besides that, hp-BNNSs also exhibited a fast adsorption rate for industrial dyes as 99 % MB and RhB were removed from the solution within 20 min. Significantly, this excellent performance of hp-BNNSs demonstrated its great potential in versatile water treatment.

For theoretical study, blood can be regarded as a viscous electrically conducting fluid of negative ions and protons. Zakharov equations including viscosity are relevant for describing the behaviour of blood plasma. The dispersion formula is derived from the perturbation method and is solved numerically. It turns out that the imaginary part of one root of the perturbation frequency is greater than zero, and modulation instability occurs. This would lead to the formation of blood clot. The viscous force can suppress the occurrence of instability and prevent thrombosis. One can find that the chaotic state of blood signals human health.

In this paper, the thermodynamics and kinetics of nature rutile carbochlorination in a fluidized-bed were investigated. The thermodynamic calculations of TiO2–C–Cl2 system show that when C is excess in the solid phase, titanium tetrachloride and carbon monoxide can exist stably. At high temperature, the reaction with CO as the product is the dominant reaction. The appropriate reaction conditions are as follows: reaction temperature of 950 °C, reaction time of 40 min, carbon ratio of 30 wt% of rutile, natural rutile particle size of −96 μm, petroleum coke size of −150 μm, and chlorine flow of 0.036 m3·h−1. Under the above conditions, the reaction conversion rate of TiO2 can reach about 95 %. This paper proposed a reaction rate model, and got a rutile chlorination rate formula, which is generally consistent with the experimental data. For the TiO2–C–Cl2 system, the reaction rate is dependent on the initial radius of rutile particle, density, and the partial pressures of Cl2. From 900 to 1,000 °C, the apparent activation energy is 10.569 kJ·mol−1, and the mass diffusion is found to be the main reaction-controlling step. The expression for the chlorine reaction rate in the C–Cl2 system is obtained, and it depends on the degree of reaction, the partial pressure of Cl2, and the size of rutile particle.

4509 Background: Urothelial carcinoma (UC) is the third largest cancer type with HER2 positive cancer. RC48-ADC is a novel humanized anti-HER2 antibody-drug conjugate (ADC). This study was to evaluate the activity of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma (mUC). Methods: This study is an open-label, multicenter, single-arm, non-randomized phase II study. Eligibility criteria include: histologically confirmed UC, HER2-positive (IHC 2+ or 3+), ECOG PS 0-1, treated with ≥1 prior systemic treatment. The patients received RC48-ADC treatment alone (2 mg/kg IV infusion, q2w) until disease progression, unacceptable toxicity, withdrawal, or study termination. The primary endpoint was objective response rate (ORR). Progress-free survival (PFS), overall survival (OS), and safety was also assessed. Results: Patient enrollment for this study was completed in November 2018. A total of 43 patients were enrolled, with a median age of 64 years old. At baseline, most patients (37/43) had visceral metastasis. Fourteen (32.6%) patients had received ≥ 2 lines treatment and 8 (18.6%) patients had prior immune checkpoint inhibitor (CPI) therapy in second line treatment. The objective response rate was 60.5% (95% CI: 44.4%, 75.0%) and the DCR was 90.7% (39/43). As of Jan 23, 2019, the median PFS for the overall study population was not yet reached, and the median PFS was 7.8 months (95% CI: 4.9, 10.7) for the 9 patients who started RC48-ADC prior to Jun 30, 2018. The ORR was 70.6% (12/17) in patients with HER2 FISH+ or IHC3+. The ORR was 64.9% (24/37) in patients with visceral metastasis and was 70.0% (14/20) in liver metastasis patients especially. The ORR was 64.3% in patients post to ≥ 2 lines treatment and 75.0% in patients post to immunotherapy. Common treatment-related AEs were leukopenia (51.2%), hypoesthesia (41.9%), alopecia (41.9%), neutropenia (37.2%), fatigue (34.9%), ALT increase (32.6%), and AST increase (32.6%); Most were Grade 1 or 2. Conclusions: RC48-ADC has demonstrated a clinically meaningful ORR of 60.5% in pretreated HER-2 positive mUC patients including those who underwent failure to the immunotherapy. Clinical trial information: NCT03507166.

The structure and stability of a magnetized accretion disk are numerically examined with anomalous viscosity. The temperature, surface density and radial velocity all decrease with increasing radius r. The results show that the existence of the magnetic field B has an impact on the structure of the disk, which directly results in the variation of the growth rate and the damping rate of the unstable and stable modes. For Inward-moving mode, the magnetic field greatly enhances the instability at short wavelength and acts as a factor of stability at long wavelength. The growth rate of outward-moving unstable mode decreases, while the damping rate of thermally stable mode increases significantly owing to the magnetic field.

By the intake wind performance experiment study of the pipe with high pressure spray, it is pointed out that under experimental conditions the intake wind efficiency of the pipe with high pressure spray is closely related to the spray nozzle and the pipe's structure and the size.The relationship between pipe's intake wind volume and spray nozzle's water consumption is linear, and the relationship between spraying spread angle and the hydraulic pressure becomes nonlinear.The main parameters of reducing dust equipment with high pressure spray is the intake wind volume and controlled zone.Under the conditions of certain structure, the adjustment of hydraulic pressure will make the equipment with high pressure spray run under the optimum condition of the highest intake wind efficiency.

On the basis of hydrodynamic equations and the new anomalous viscosity, we numerically calculate the steady state of geometrically thin accretion disk around a black hole, including surface density, temperature and radial velocity distribution. We found the density distribution, especially in the inner region, is greatly different from the one with conventional α-viscosity. The stability of the accretion disks with anomalous viscosity is also examined. The results show that the Outward–moving mode is unstable, and the viscous mode is stable throughout the disk. The instability of the Inward–moving mode depends on the wavelength. The results show that the prescription of viscosity has some influence on the stability properties of the disk.

Considering bamboo as a 2-phase natural composite made up of vascular bundles (reinforcement or fiber) and matrixes (ground tissues) on the scale of micromechanics. By test of bamboo specimens and analysis of microscopic images of their cross sections, the distribution of vascular bundles along the axial and radial of bamboo culm were investigated. The relations between tensile properties of bamboo and its distribution of vascular bundles were studied. The results show that the vascular bundles are graded distributing along the radius of bamboo culm. The volume fraction of vascular bundles is larger near the outside, and attenuates rapidly to about 40 percent of that at the location away from outer side about 1/3 thickness of bamboo culm, and than slowly reduces to 0 near the inner side of culm. In axial direction, the volume fraction of vascular bundles in the bottom culm is smaller than that in the middle culm where the volume fraction is less variation, and reaches the largest value at the top culm. The tensile moduli and strength of bamboo are linearly related to the volume fraction of vascular bundles. The tensile moduli and the strength of vascular bundle are largely grater than that of matrix. The stiffness and the strength of bamboo are mainly offered by vascular bundles.

On the basis of analyzing the structure characteristics of the Isometric Polygonal Profile (IPP) hole, equations of the track for grinding wheel center and the formula of calculating node coordinates according to equal-error linear approximation method are established and the determination method of grinding technology parameters value and problems to be attention at grinding process are discussed. Grinding experiments show that both processing precision and surface roughness can reach with the fit requirements of IPP connection according to these principles. It is available for reference that grinding complex non-circular column surface is ground by CNC machine tools.

In order to solve the optimization problems of discrete variable in mechanism design, beginning vertexes to meet all of performance restriction conditions can be given by the technician from upper boundary of design variables by means of man-machine interactive method. Objective function of each beginning vertex is calculated and arranged from small to large, the vertex of maximum and minimum of objective function are found. The difference between the vertex of minimum and maximum of objective function are calculated and new point is made up from the minimum point and the difference. The new point is used in stead of the vertex of the maximum objective function if the objective function of the new point is less than the maximum of beginning vertexes. The new composite figure is made up again and the new point is calculated until all design variables reach to under boundary. Then the vertex of minimum objective function is regarded to as the optimization point. This method is very fit for the optimization of discrete variables of low dimension and is higher calculation efficiency because the hominine brightness is combined with the high speed calculation ability.

Ti-Ga co-doped ZnO thin films (TGZO) have been successfully prepared on glass substrates by DC magnetron sputtering at room temperature. The X-ray diffraction (XRD) patterns show that all the deposited films are polycrystalline with a hexagonal structure and have a preferred orientation along the c-axis perpendicular to the substrate. The distance between target and substrate was varied from 41 to 75 mm. The crystallinity increases obviously and the electrical resistivity decreases when the distance between target and substrate decreases from 75 to 46 mm. However, as the distance decreases further, the electrical resistivity increases. It is obtained that the lowest resistivity is 2.0610-4cm when the distance between target and substrate is 46 mm. In the visible region, the TGZO films show a high average transmittance of above 90 %.

We study the Auger effect in the presence of strong x-ray free-electron lasers (XFELs) propagating through resonant argon vapors by solving the Maxwell-Bloch equations numerically. The simulations ...

In order to study the grinding technology of Isometric Polygonal Profile (IPP), NC grinding accessory of IPP is developed, which is driven by Program Logic Controller (PLC) and step-motors. On the basis of the principle of coordinate conversion and envelope curve, formative motions of IPP are discussed in detail. Because the relationship between the rotation of parts and synchronization motion in both x and y axes of coordinates frame is of the proportional transmission, and the synchronization motion is harmonic motion in both x and y axes of coordinates frame, the relationship of them is of the proportional transmission too, but the frequency of the synchronization motion is low and the displacement is small, so the eccentric mechanism is used in the grinding accessory. The grinding process of three axes linkage of IPP can be translated into process of two axes linkage between three coordinates on machine tools by means of combination of PLC and the eccentric mechanism. It has been found by grinding experiment that the NC grinding accessory is available used for grinding IPP and other polygonal profile.

Purpose A Phase I study was conducted to determine the maximal tolerated dose and the dose-limiting toxicity (DLT) of oxaliplatin (OXA) combined with capecitabine and radiotherapy as adjuvant treatment in patients with operable rectal cancer. Patients and Methods A total of 21 patients with Stage II or III rectal adenocarcinoma after curative surgery were treated with radiotherapy to a total dose of 50 Gy in 5 weeks. OXA was administered at a dosage of 40 ( n = 6), 50 ( n = 3),60 ( n = 3), 70 ( n = 3), or 80 mg/m 2 ( n = 6) once a week for 2 weeks (first cycle) followed by a second cycle after a 7-day break. Capecitabine at a fixed dose of 1,300 mg/m 2 /d was administered orally at the same schedule as for OXA. DLT was defined as Grade 3 or 4 hematologic and nonhematologic toxicity. Results Grade 1–3 leukopenia, diarrhea, and nausea/vomiting were the most common toxic side effects, and most were Grade 1-2. A DLT was first observed in 1 of 3 patients at 40 mg/m 2 (Grade 3 diarrhea) but was not observed in the next 3 patients at the same level or in patients who received a dose level of 50–70 mg/m 2 . At 80 mg/m 2 , DLT occurred in 3 of 6 patients (1 Grade 4 leukopenia and 2 Grade 3 diarrhea). Conclusions OXA combined with a fixed dose of capecitabine at 625 mg/m 2 twice daily by mouth plus radiotherapy in the adjuvant setting was tolerable and clinically feasible. The maximal tolerated dose of OXA in this setting was 80 mg/m 2 , comparable to the maximal tolerated dose of OXA in the neoadjuvant setting.

This paper studies the NC grinding process for Isometric Polygonal Profiles (IPP) with self-made machine tools accessories, and establishes the time series model of the grinding process by means of measuring and analyzing the vibratory signal in the grinding process. The grinding experiment indicates that the surface formative motions of IPP can be achieved with the step-motor-driven accessories and it is reasonable to design the grinding machine for IPP according to the principle. This method solves the technical problems in IPP NC processing and can act as an important elicitation and illustration for NC processing other polygonal profiles.