RLPS and RLMS are not sensitive to conventional chemotherapy. We evaluated the efficacy and safety of eribulin plus anlotinib and camrelizumab for RLMS and RLPS. Patients (pts) with advanced/metastatic RLPS or RLMS treated with eribulin plus anlotinib and camrelizumab (Q3W) at Peking University Cancer Hospital Sarcoma Center were included in this retrospective analysis. Response (RECIST v1.1) was evaluated every 3 treatment cycles. Adverse event severity was graded per CTCAE v5.0. From December 17, 2020 to November 18, 2022, 60 pts (27 male; 33 female) were included. 22 pts had RLMS; RLPS subtypes were well-differentiated (n=9), de-differentiated (n=24), and myxoid (MLPS; n=5). Eribulin was given to 21 pts (35%) at 0.7–1.1 mg/m2, and 39 (65%) at 1.1–1.4 mg/m2.5 pts (RLMS, n=2; RLPS, n=3) were excluded from efficacy analyses due to drug intolerance and the COVID-19 pandemic. After a median of 5 cycles (range, 2–21), a partial response was observed in 15 pts (27.3%), stable disease in 27 (49.1%) and progressive disease in 13 (23.6%). The objective response rate (ORR) and disease control rate (DCR) were 27.3% and 76.4%, respectively. ORR and DCR in pts with RLMS were 42.1% and 84.2%, respectively; in pts with RLPS, they were 19.4% and 72.2%, respectively. After a median follow up of 11.3 months (mo), 10 pts had complete resection, 2 of whom had pathological complete response (1 with RLMS and 1 with MLPS); 3 other pts had locoregional recurrence after surgery. Median progression-free survival (mPFS) for the remaining 45 pts was 5.8 mo; mPFS for RLPS and RLMS subgroups were 5.5 and 6.2 mo, respectively. Any-grade treatment-related AEs (TRAEs) occurred in 51/60 pts (85.0%), with 22 (36.7%) experiencing grade ≥3 TRAEs. The most common TRAEs were neutropenia (58.3%), proteinuria (23.3%) and anorexia (23.3%). Due to AEs, 15 pts (25.0%) discontinued treatment and 6 (16.7%) reduced their eribulin dose. Eribulin plus anlotinib and camrelizumab demonstrated clinically meaningful efficacy and a manageable safety profile in pts with advanced or metastatic RLPS or RLMS, especially in those with RLMS.

Kit inhibitor monotherapy has moderated activity in melanoma harboring c-Kit aberrations (CKA) but with an unsatisfied objective response rate (ORR) of 23-26% and median progression free survival (mPFS) of 3.5-7.3mo. Thus we performed a phase II trial testing the imatinib mesylate/toripalimab (anti-PD-1 monoantibody) combo in pts with advanced melanoma harboring CKA. (NCT: 05274438). This is a single-arm, single-center, phase II clinical trial involving 37 pts (treatment-naive or refractory to standard therapy excluding Kit inhibitors and anti-PD-1/L1) with advanced melanoma harboring CKA including two stages: 3 pts were enrolled starting with imatinib 400mg qd for 6 weeks, followed by imatinib 400mg qd combined with toripalimab 240mg per 3 weeks until disease progression or intolerable toxicity. If dose limiting toxicity (DLT) was not observed, the original dose was extended to 37 pts in stage II; if there was 1 DLT, pts was extended to 6 in stage I; if ≥2 DLT cases occurred, imatinib was reduced to 300mg qd and the "3+3" study was restarted. The primary endpoint was PFS and the secondary endpoints included ORR, disease control rate (DCR), overall survival (OS) and safety. From March 2021 to April 2022, no DLT was observed in the first 3 pts and another 17 pts enrolled. 17 pts were radiologically evaluable. The ORR was 58.8% (95% CI: 32.7-84.9%) and DCR was 82.4% (95% CI: 56.6-96.2%). The mPFS was not reached (NR). Notably, in pts harboring exon 11 mutations (n=10), the ORR was 90.0% (95% CI: 55.5-99.7%). In 9 treatment naive pts, the ORR was 55.6% (95% CI: 21.2-86.3). The incidence of grade ≥3 treatment-related adverse events was 20% (4/20), including rash (10.0%), aspartase transaminase elevation (5.0%), fatigue (5.0%) and interstitial pneumonia (5.0%). No treatment-related deaths was observed. Imatinib mesylate/toripalimab combo was effective and well-tolerated in pts with advanced melanoma harboring c-kit aberrations. Longer follow-up and further patient recruitment are in need.

Acral melanoma responds poorly to anti-PD-1 monotherapy. Ori is a HSV-1 derived oncolytic virus expressing granulocyte-macrophage colony-stimulating factor, which has potentiated the efficacy of anti-PD-1 in acral melanoma in the metastatic setting. We conducted a phase Ib trial evaluating ori/tori in resectable stage IIIb-IV (M1a) acral melanoma (NCT04197882). Pts received the neoadjuvant intralesional ori up to 8*107pfu/mL*10mL combined with iv tori 3mg/kg every 2 wks*4–6 doses prior to surgery, followed by the adjuvant iv tori 3 mg/kg every 3 wks for 1 year. The primary endpoints included radiological (per RECIST 1.1) and pathological response rates. The secondary endpoints were 1/2-y recurrence-free survival (RFS) and safety. Thirty patients were enrolled between 07/2019 and 12/2020, with a median age of 57 y.o. (range 21-72), including 14 (47%) males; 12 (40%) with stage IIIB, 14 (47%) with IIIC, and 4 (13%) with IV (M1a) disease. By the last follow-up in 01/2022, all pts have completed the neoadjuvant part, 27 (90%) completed the surgery and tori adjuvant part (the remaining 3 abrogated surgeries due to disease progression). The median follow-up time was 19 months (IQR 15-25). The radiological and pathological (among those who underwent surgeries only) objective response rate was 36.7% (11/30) (95%CI 19.9-56.1) and 77.8% (21/27) (95%CI 57.7-91.4), and that of complete response rate was 3.3% (1/30) (95%CI 0-17.2) and 14.8% (4/27) (95%CI 4.2-33.7), respectively. The 1-y RFS rate was 80.0% (95%CI 66.9-95.7). This combo was well tolerated. Although all pts experienced adverse events (AEs), most were of grade 1/2 (25/30, 83%). Five patients (17%) developed grade 3 AEs, including 2 soft tissue infections, 1 transaminitis, 1 peripheral neuropathy and 1 neutropenia. No grade 4 AE was observed. Neoadjuvant ori/tori achieved a high pathologic response rate, an impressive 1-y RFS rate, and was well-tolerated in patients with resectable stage IIIB-IV (M1a) acral melanoma. Although longer follow-up is in need, this combo warrants further evaluation in this melanoma subtype.

Although anti-programmed cell death receptor-1 (PD-1) monotherapy is a standard adjuvant treatment for melanoma patients underwent definitive surgery, their efficacy is evaluated mostly in Caucasians and cutaneous melanoma, it remains unclear in other ethnic groups and melanoma subtypes. Clinical data for patients (pts) with resected stage II/III/IV melanoma treated with anti-PD-1 monotherapy both in and outside clinical trial settings between 2015 and 2021 was collected retrospectively from 6 independent institutions in the US, Australia, Japan and China. Survival outcomes (both recurrence free survival [RFS] and overall survival [OS]) were compared by ethnicity (Caucasian versus East-Asian/African) and by different melanoma subtypes (non-acral-cutaneous[NAC]/unknown primary[UP], acral and mucosal). In total 537 pts were included. Caucasians had significantly longer RFS and OS. Among different melanoma subtypes, NAC/UP had the best RFS and OS, followed by acral. Mucosal melanoma had the poorest survival outcomes. In NAC/UP subtypes, Caucasians had longer RFS (with significance) and OS (with marginal significance) than East Asian/African. In the multivariate analysis incorporating ethnicity, melanoma subtype, age, sex, stage, LDH, and BRAF mutation status, Caucasian ethnicity was independently correlated with significantly better RFS (HR 0.59; 95%CI 0.41-0.84; P=.004) and a trend towards better OS (HR 0.59, 95%CI 0.34-1.02; P=.06), while mucosal subtype independently associated with both poorer RFS (HR 2.43; 95%CI 1.55-3.80; P<.001) and OS (HR 2.97; 95%CI, 1.53-5.78; P=.001).Table: 807PEntire CohortNAC/UP subtypesEthnicityMel SubtypeEthnicityCaucasianEast-Asian /AfricanNAC/UPAcralMucosalCaucasianEast-Asian /African(n=262)(n=275)(n=352)(n=83)(n=102)(n=246)(n=106)RFS1-y rate (%, 95% CI)80 (76-86)67 (62-73)77 (73-82)79 (70-88)58 (49-69)81 (76-86)68 (60-78)2-y rate (%, 95% CI)70 (64-76)49 (44-56)66 (61-71)57 (46-70)40 (32-52)71 (65-77)53 (44-64)P value<.001<.001<.001OS2-y rate (%, 95% CI)92 (88-95)80 (75-86)90 (87-94)83 (74-92)75 (67-85)92 (89-96)85 (78-93)4-y rate (%, 95% CI)83 (78-89)55 (46-66)82 (77-87)57 (38-86)46 (36-60)84 (78-90)78 (69-88)P value<.001<.001.07 Open table in a new tab Ethnicity and melanoma subtype both contribute to survival discrepancies in melanoma patients undergoing adjuvant anti-PD-1 monotherapy. The somatic genetic and immunologic underpinning of these differences remain unclear and warrants further investigation.

To investigate the tumor volume dynamic change on short-term effect (STE) in esophageal squamous cell carcinoma (ESCC) patients underwent definitive radiotherapy. All data were retrospectively collected from 418 ESCC patients who received radiotherapy at our institution between 2015 and 2019. The tumor volume change rate (TVCR) was defined as follows: TVCR = 1 – [gross tumor volume (GTV) at the repositioned treatment planning)] / (GTV at the initial treatment planning). STE was assessed by an imaging deputy chief physician and a radiotherapy deputy chief physician according to computed tomography and esophagography before and at 1 month after radiotherapy according to Response Evaluation Criteria in Solid Tumor. Chi square test was used to compare the clinic characteristics in different TVCR groups, and the difference between primary GTV (GTVp) and repositioned GTV (GTVr) was compared using Wilcoxon's sign rank test. Logistic regression analysis and spearman correlation was performed. At 1 month after radiotherapy, 272 patients (65.1%) achieved remission and 146 patients (34.9%) achieved un-remission when assessed STE of 418 patients. Patients in the high TVCR group (≥ 6.155%) and low TVCR group (< 6.155%) were significant with GTVp (P < 0.001). In univariate analysis, age, cT-stage, TNM stage, treatment modality, primary GTV and TVCR were associated with STE (P = 0.029, 0.027, 0.009, 0.035, < 0.001, < 0.001). Among the factors affecting the STE in multivariate analysis, gender and TVCR were statistically significant (P = 0.010, < 0.001). Meanwhile, the prediction model formed by gender and TVCR has a good prediction effect, with the area under the receiver operating characteristic curve was 0.876 (P < 0.001). There was a positive correlation between primary GTV as well as reposition dose, and TVCR (r = 0.413, 0.221), whereas the curative effects primary GTV exceeded that of reposition dose. TVCR could serve to forecast STE of radiotherapy in ESCC. It was of great significance to guide the individualized treatment of ESCC.

Neoadjuvant chemotherapy (NAC) has been a common therapeutic approach before radiotherapy for nasopharyngeal carcinoma (NPC) patient. However, individual differences exist in tumor control rate and progression. This study aims at proposing a noninvasive and patient specific radiomics model to predict the clinical efficacy of NAC for NPC patients. A total of 65 locally advanced NPC patients having paclitaxel or gemcitabine combined with platinum drugs treatment before radiotherapy were retrospectively evaluated. All patients had MRI scans including T1-weighted (T1), T1-weighted fat-suppression (T1-fs), and T2-weighted (T2) sequences before and after NAC. The corresponding tumor regions at two time points for all sequences of MRI were delineated by an expert radiation oncologist. By analyzing the changes of tumor volume and maximum diameter due to NAC, the patients were classified into the clinical response groups (CR or PR) and non-response groups (SD) according to the RECIST 1.1 guidelines thereafter. 9 non-texture features and 41 texture features were extracted to develop an effective prediction model with multivariable Logistic regression. Specifically, we compared the performances of different extraction parameters, and took the best combination to build the final prediction model. 25 features were finally selected by an information theory-based method involving computation for Spearman's rank correlation and potential information coefficient. Besides, to further improve the credibility of the results, the imbalance-adjusted bootstrap resampling strategy was adopted during the feature set selection and reduction process, as well as the final model coefficients computation and prediction performance estimation process. For univariate analysis, the high gray-level run emphasis (HGRE) of gray-level run-length matrix (GLRLM) presented the highest predictive impact. For multivariable analysis, the texture features had higher impact on the predictive value than the non-texture features, while those extracted from T1-fs significantly outperformed those extracted from the other two sequences. The best performance was acquired from 10 texture features, which predicted the clinical response of NAC for NPC patient with an AUC of 0.954±0.004, a sensitivity of 0.898±0.005, and a specificity of 0.884±0.010, respectively. Multi-sequence MRI-based radiomics model has been validated to be valuable in predicting clinical efficacy of neoadjuvant chemotherapy for NPC patients.

We initial aimed to investigate pre/post-treatment inflammatory biomarkers (pre/post-IBs) and their dynamic changes (delta-IBs) on short-term effect (STE). Furthermore, a nomogram was built to provide accurate prediction of STE in patients with esophageal squamous cell carcinoma (ESCC) who received radiotherapy. The IBs included absolute lymphocyte counts (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR). All pre/post-IBs and delta-IBs of 398 ESCC patients at Shandong Cancer Hospital between 2015 and 2019 were analyzed. The nomogram was then constructed that forecasted STE based on logistic regression analyses. At 1 month after radiotherapy, 261 patients (65.6%) achieved remission, and 137 patients (34.4%) achieved un-remission. The pre-ALC and pre-LMR significantly increased, pre-NLR and pre-PLR significantly decreased during radiotherapy (all P<0.001). Meanwhile, there was a positive correlation between delta-NLR as well as delta-PLR and delta-LMR (r=0.621 and 0.613, respectively), whereas a negatively correlated between delta-LMR and delta-PLR (r=-0.573). Multivariate analysis indicated that gender [OR, 0.473; 95%CI, 0.274-0.816; P=0.007], pre-ALC [OR, 0.554; 95%CI, 0.335-0.915; P=0.021], pre-NLR [OR, 3.176; 95%CI, 1.733-5.823; P<0.001], post-NLR [OR, 2.418; 95%CI, 1.271-4.600; P=0.007] and delta-NLR [OR, 1.929; 95%CI, 1.035-3.595; P=0.039] were statistically significant with STE. Nomogram for STE was established by combining all independent predictors and the concordance indexes for STE were 0.770 [95%CI, 0.719–0.820]. In conclusion, pre-NLR and pre-ALC, post-NLR, and delta-NLR could predict STE in ESCC patients. Further, pre-NLR had the best predictive value, and the developed nomogram with superior prediction ability for STE could assist in patients counseling and guide to make treatment decisions.

Background Gain of function mutations in NRAS occurs in 15-25% of patients with melanoma, leading to activation of Ras/Raf/MEK/ERK signaling pathway results in unconstrained cell growth and cell transformation. The MEK inhibitor targets this signaling pathway, inhibiting cell proliferation and inducing apoptosis. NRAS mutation status was identified as an independent poor prognostic factor in stage IV melanoma. It is also reported that the survival of patients with high copy number (>4) was significantly worse than that of NRAS patients with 2-4 copy number (P = 0.002). No drug was approved to treat melanoma patients with NRAS mutation or amplification until now. FCN-159, an oral and potent MEK1/2 inhibitor, has more than 10 folds higher selectivity against activated MEK1 and MEK2 compared with trametinib, and has demonstrated significant antitumor growth inhibition in two patient-derived xenograft (PDX) models with NRAS mutation. This is the first in human study to evaluate the safety and anti-tumor activity of FCN-159 in patients. Trial design This is a phase Ia/Ib, open label, dose-escalation study with expansion cohort that will evaluate the safety, pharmacokinetics (PK), and preliminary anti-tumor activity of FCN-159 in up to 37 patients with locally advanced or metastatic melanoma harboring NRAS-aberrant including both NRAS amplification and mutation (Ia) and NRAS-mutation only (Ib). In this study, the dose escalation utilizes 3 + 3, accelerated titration design with starting dose of 0.2 mg, QD, orally; the dose will be escalated until Maximum-Tolerated Dose (MTD) or the Recommended phase II dose (RP2D) being identified. The dose level will be considered to expand up to 6 patients if an objective response is observed, intending to collect more clinical data to support the RP2D determination. Once the MTD or RP2D is identified, an expansion cohort will be followed to further evaluate the safety and efficacy of FCN-159 in patients with NRAS-mutant melanoma. As of April 22, 2019, one patient has been dosed. Legal entity responsible for the study Shanghai Fosun Pharmaceutical Development Co, Ltd. Funding Shanghai Fosun Pharmaceutical Development Co, Ltd. Disclosure All authors have declared no conflicts of interest.

To propose a novel plan difficulty index (PDI) and an optimal PDI-based evaluation criterion and evaluate their applications in external beam radiotherapy (EBRT) of lung cancer, in order to provide quality assurance (QA) in EBRT planning. Thirty-four EBRT plans of lung cancer with intensity-modulated radiation therapy (IMRT) technique were retrospectively analyzed in this paper, and the prescription dose was 60 Gy in 30 fractions to the planning target volume (PTV). To obtain an optimal evaluation criterion of plan quality, four scoring models were investigated to mark these plans, segmented uniform score (SU), segmented non-uniform score (SNU), non-segmented uniform score (NSU), non-segmented non-uniform score (NSNU). Every evaluation model with a total score of 100 contained 12 metrics. For PTV, there were 5 metrics (V60, V57, V66, Conformation Number (CN) [57 Gy] and Dmax). For organs at risk (OARs), there were 6 metrics (V5, V20, V30 of lung, V30, V40 of heart and Dmax of spinal cord), And 1 metric of 'Global Max Location' indicated the anatomic location of global maximum of dose. Given the anatomic location of PTV and OARs, a novel PDI was defined firstly in our study. Also, the relationship between PDI and corresponding plan score was evaluated. The average PDI of 34 IMRT plans was 4.19 (2.64-7.25) for the uniform score model or 4.45 (2.89-7.96) for the non-uniform score model. There were significant differences in the plan scores between different models, and these scores were 72.34±10.10, 69.40±12.06, 53.11±10.44 and 50.30±11.67 for SU, SNU, NSU and NSNU model, respectively. The pass rate of plans with quality scores of ≥70 in the SU model was superior to the other three models, 64.7% vs. 38.2% (SNU), 5.9% (NSU), or 2.9% (NSNU). The PDI and quality score of plan showed a negative correlation, regardless of which model was used. The Pearson coefficients were -0.52 (P<0.05), -0.49 (P<0.05), -0.59 (P<0.05) and -0.53 (P<0.05) for SU, SNU, NSU and NSNU model, respectively. The negative correlation between the PDI and plan score demonstrates the feasibility of PDI and evaluation criterion in planning QA for EBRT in lung cancer. Due to the highest pass rate, the evaluation model of segmented uniform score was recommended to mark the EBRT plan in future clinical practice.

Purpose:The purpose of this study was evaluate the position error of multileaf collimator in volumetric modulated arc therapy of nasopharyngeal carcinoma via MLC logs from Varian machines and to provide a method for detecting the leaf position accuracy.Methods:Thirty one patients with nasopharyngeal carcinoma were randomly selected. Each patient was created with two 358° arcs. The MLC errors for all arcs, arc1 and arc2, left‐bank and right‐bank leafs of each arc were evaluated.Results:99.99% of the leaf position errors of all plans were within ± 2mm. The proportion of the leaf position errors within ± 1.5mm,± 1mm and ± 0.5mm were 99.90%, 98.98% and 94.17%,respectively. The leaf position errors range of ARC1 and ARC2 were −2.95 ∼ 2.99mm and −0.22 ∼ 0.23mm (t = 2.35, P = 0.00), The proportion of the leaf position errors within ± 1mm were 98.08% and 100% for ARC1 and ARC2. The leaf position errors range of Bank A and Bank B were −2.95 ∼ 2.68mm and −2.92 ∼ 2.99mm (t = 1.64, P = 0.31), The proportion of the leaf position errors within ± 1mm were 98.97% and 99.01%.Conclusion:During the VMAT treatment for NPC, it was found that the leaf positions were in control, the Dynalog files can be used as an effective way to analysis the leaf position errors.

Stage IV ESCC carries a poor prognosis with a median survival of 6-9 months. The standard treatment has traditionally been chemotherapy. Palliative radiation therapy was used for symptom relief. The optimal treatment for stage IV ESCC has not yet been established. The aim of this study was to compare the efficacy and safety of CCRT versus chemotherapy alone in patients with stage IV ESCC. Patients with stage IV ESCC were randomly assigned to the CCRT group and the chemotherapy group. Both groups of patients received at least 2 cycles of chemotherapy with cisplatin and docetaxel every 3 weeks. Patients in CCRT group received 50-60 Gy/ 25-30 fractions/ 5-6 weeks of concurrent radiation therapy to the esophageal primary tumor. The primary end point was overall survival (OS). The secondary end points were progression-free survival (PFS), object response rate (ORR) of primary tumor and toxicity. Between August 2013 and October 2015, 60 patients were enrolled and divided into the CCRT group (n = 30) and the chemotherapy group (n = 30). The 60 patients were comprised of 48 male and 12 female patients, with a median age of 56 years (range 36 - 70 years). The baseline clinical characteristics of the 2 groups were similar. Patients in the CCRT group received a mean 54.7 Gy of radiation therapy and a mean 3.6 cycles of chemotherapy, whereas patients in the chemotherapy group received a mean 3.8 cycles. The ORR of the primary tumor was higher in the CCRT group than in the chemotherapy group (83.3% vs. 46.7%, P = 0.001). At a median follow-up of 18 months, median PFS (9.3 vs. 4.7 months, P = 0.021) and median OS (18.3 vs. 10.2 months, P = 0.001) were significantly longer in the CCRT than that in the chemotherapy group. Overall survival rates at 1and 2 years were 73.3% and 43.3% respectively, in the CCRT group, and 46.6%and 26.7% respectively in chemotherapy group (P = 0.030) Although ≥ grade 3 neutropenia was significantly more frequent in the CCRT group than that in the chemotherapy group (33.3% vs. 20.0%, P < 0.05), the rates of other toxicities did not differ. Concurrent chemoradiation therapy was well tolerated and associated with longer PFS and OS than chemotherapy alone in patients with stage IV ESCC. Controlled randomized, multi-center trials are required to determine whether CCRT is a primary treatment option for patients with stage IV ESCC.