ImmuneMirror: A machine learning-based integrative pipeline and web server for neoantigen prediction.

Neoantigens are derived from somatic mutations in the tumors but are absent in normal tissues. Emerging evidence suggests that neoantigens can stimulate tumor-specific T-cell-mediated antitumor immune responses, and therefore are potential immunotherapeutic targets. We developed ImmuneMirror as a stand-alone open-source pipeline and a web server incorporating a balanced random forest model for neoantigen prediction and prioritization. The prediction model was trained and tested using known immunogenic neopeptides collected from 19 published studies. The area under the curve of our trained model was 0.87 based on the testing data. We applied ImmuneMirror to the whole-exome sequencing and RNA sequencing data obtained from gastrointestinal tract cancers including 805 tumors from colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma patients. We discovered a subgroup of microsatellite instability-high (MSI-H) CRC patients with a low neoantigen load but a high tumor mutation burden (> 10 mutations per Mbp). Although the efficacy of PD-1 blockade has been demonstrated in advanced MSI-H patients, almost half of such patients do not respond well. Our study identified a subset of MSI-H patients who may not benefit from this treatment with lower neoantigen load for major histocompatibility complex I (P < 0.0001) and II (P = 0.0008) molecules, respectively. Additionally, the neopeptide YMCNSSCMGV-TP53G245V, derived from a hotspot mutation restricted by HLA-A02, was identified as a potential actionable target in ESCC. This is so far the largest study to comprehensively evaluate neoantigen prediction models using experimentally validated neopeptides. Our results demonstrate the reliability and effectiveness of ImmuneMirror for neoantigen prediction.

Optimal glycaemic control and the reduced risk of colorectal adenoma and cancer in patients with diabetes: a population-based cohort study.

OBJECTIVE: Whether varying degrees of glycaemic control impact colonic neoplasm risk in patients with diabetes mellitus (DM) remains uncertain. DESIGN: Patients with newly diagnosed DM were retrieved from 2005 to 2013. Optimal glycaemic control at baseline was defined as mean haemoglobin A1c (HbA1c)<7%. Outcomes of interest included colorectal cancer (CRC) and colonic adenoma development. We used propensity score (PS) matching with competing risk models to estimate subdistribution HRs (SHRs). We further analysed the combined effect of baseline and postbaseline glycaemic control based on time-weighted mean HbA1c during follow-up. RESULTS: Of 88 468 PS-matched patients with DM (mean (SD) age: 61.5 (±11.7) years; male: 47 127 (53.3%)), 1229 (1.4%) patients developed CRC during a median follow-up of 7.2 (IQR: 5.5-9.4) years. Optimal glycaemic control was associated with lower CRC risk (SHR 0.72; 95% CI 0.65 to 0.81). The beneficial effect was limited to left-sided colon (SHR 0.71; 95% CI 0.59 to 0.85) and rectum (SHR 0.71; 95% CI 0.57 to 0.89), but not right-sided colon (SHR 0.86; 95% CI 0.67 to 1.10). Setting suboptimal glycaemic control at baseline/postbaseline as a reference, a decreased CRC risk was found in optimal control at postbaseline (SHR 0.79), baseline (SHR 0.71) and both time periods (SHR 0.61). Similar associations were demonstrated using glycaemic control as a time-varying covariate (HR 0.75). A stepwise greater risk of CRC was found (Ptrend<0.001) with increasing HbA1c (SHRs 1.34, 1.30, 1.44, 1.58 for HbA1c 7.0% to <7.5%, 7.5% to <8.0%, 8.0% to <8.5% and ≥8.5%, respectively). Optimal glycaemic control was associated with a lower risk of any, non-advanced and advanced colonic adenoma (SHRs 0.73-0.87). CONCLUSION: Glycaemic control in patients with DM was independently associated with the risk of colonic adenoma and CRC development with a biological gradient.

Presence of tumour capsule on contrast-enhanced CT is associated with improved outcomes of stereotactic body radiation therapy in hepatocellular carcinoma patients.

PURPOSE: Stereotactic body radiation therapy (SBRT) is a novel local therapy for the treatment of hepatocellular carcinoma (HCC). While effective, there is currently no reliable radiological marker to guide patient selection. In this study, we investigated the prognostic value of capsule appearance on contrast-enhanced computed tomography (CT) for patients undergoing SBRT. MATERIALS AND METHODS: Between 2006 and 2017, 156 consecutive patients with Child-Pugh score class A/B and HCC ≥ 5 cm who underwent SBRT were retrospectively analysed. Baseline triple-phase CTs of the abdomen were reviewed for the presence of capsule appearances and correlated with objective response rate (ORR), overall survival (OS) and pattern of treatment failure. RESULTS: Capsule appearance on CT was present in 83 (53.2%) patients. It was associated with improved ORR by Response Evaluation Criteria in Solid Tumours (RECIST) (60.2 vs. 24.7%, p < 0.001) and Modified Response Evaluation Criteria in Solid Tumours (mRECIST) (78.3 vs. 34.2%, p < 0.001). The presence of a capsule was also associated with superior 2­year local control (89.1 vs. 51.4%, p < 0.001) and 2­year OS (34.1 vs. 14.8%, p < 0.01). Hepatic out-field failure was the dominant mode of progression, which was less common in patients with intact capsule (54.2 vs. 60.3%, p = 0.01). CONCLUSION: Capsule appearance on CT could potentially be a non-invasive prognostic marker for selecting HCC patients to undergo SBRT. A larger cohort is warranted to validate our findings.

Revisiting the formalism of equivalent uniform dose based on the linear-quadratic and universal survival curve models in high-dose stereotactic body radiotherapy.

PURPOSE: To examine the equivalent uniform dose (EUD) formalism using the universal survival curve (USC) applicable to high-dose stereotactic body radiotherapy (SBRT). MATERIALS AND METHODS: For nine non-small-cell carcinoma cell (NSCLC) lines, the linear-quadratic (LQ) and USC models were used to calculate the EUD of a set of hypothetical two-compartment tumor dose-volume histogram (DVH) models. The dose was varied by ±5%, ±10%, and ±20% about the prescription dose (60 Gy/3 fractions) to the first compartment, with fraction volume varying from 1% and 5% to 30%. Clinical DVHs of 21 SBRT treatments of NSCLC prescribed to the 70-83% isodose lines were also considered. The EUD of non-standard SBRT dose fractionation (EUDSBRT) was further converted to standard fractionation of 2 Gy (EUDCFRT) using the LQ and USC models to facilitate comparisons between different SBRT dose fractionations. Tumor control probability (TCP) was then estimated from the LQ- and USC-EUDCFRT. RESULTS: For non-standard SBRT fractionation, the deviation of the USC- from the LQ-EUDSBRT is largely limited to 5% in the presence of dose variation up to ±20% to fractional tumor volume up to 30% in all NSCLC cell lines. Linear regression with zero constant yielded USC-EUDSBRT = 0.96â€¯× LQ-EUDSBRT (r2 = 0.99) for the clinical DVHs. Converting EUDSBRT into standard 2­Gy fractions by the LQ formalism produced significantly larger EUDCFRT than the USC formalism, particularly for low [Formula: see text] ratios and large fraction dose. Simplified two-compartment DVH models illustrated that both the LQ- and USC-EUDCFRT values were sensitive to cold spot below the prescription dose with little volume dependence. Their deviations were almost constant for up to 30% dose increase above the prescription. Linear regression with zero constant yielded USC-EUDCFRT = 1.56â€¯× LQ-EUDCFRT (r2 = 0.99) for the clinical DVHs. The clinical LQ-EUDCFRT resulted in median TCP of almost 100% vs. 93.8% with USC-EUDCFRT. CONCLUSION: A uniform formalism of EUD should be defined among the SBRT community in order to apply it as a single metric for dose reporting and dose-response modeling in high-dose-gradient SBRT because its value depends on the underlying cell survival model and the model parameters. Further investigations of the optimal formalism to derive the EUD through clinical correlations are warranted.

Outcome of neoadjuvant chemoradiation in MRI staged locally advanced rectal cancer: Retrospective analysis of 123 Chinese patients.

BACKGROUND: For advanced rectal cancer with involved or threatened mesorectal fascia (MRF), current standard is pre-operative long course chemoradiotherapy (PLCRT) with either capecitabine or 5-fluorouracil (5-FU). However, few Chinese data on its clinical outcome are available, especially for those with pelvic MRI staging. METHODS: Between Jan-2009 and Oct-2014, 123 consecutive patients with biopsy proven adenocarcinoma of rectum, all with pelvic MRI staging, selected for PLCRT after multi-disciplinary team discussion were recruited. Their clinical records were retrospectively reviewed. RESULTS: Median follow-up was 1392 days (range: 48-2886) MRI defined poor risk factors as follows: MRF threatened or involved ≤1 mm 61.8% (n = 76), cT4 13.8% (n = 17), cN2 26.8% (n = 33) and low-lying tumor (≤5 cm from anal verge) 24.4% (n = 30). Five year OS and DFS were 63.9% and 68.3% respectively. Among 112 patients who received TME, 108 (96.4%) had microscopic clear resection (R0). Twelve and 32 individuals had pathological complete response and ypT0-2N0, respectively. Five local recurrences (4.5%) were detected. The incidence of grade 3 or above acute and late radiotherapy toxicity was 8.1% and 12.2% respectively. After multivariate adjustment, positive circumferential resection margin (CRM) status on pathology report was found to be significant factor for worse OS and DFS. CONCLUSION: The clinical outcomes of PLCRT in our institution are comparable with those in western literature. Our MRI staging lends support to the validity of data. CRM status is the most significant prognostic factor in OS and DFS, after multivariate adjustment.

PD-L1 expression as a potential predictor of immune checkpoint inhibitor efficacy and survival in patients with recurrent or metastatic nasopharyngeal cancer: a systematic review and meta-analysis of prospective trials.

Background: The predictive value of programmed death-ligand 1 (PD-L1) expression in nasopharyngeal cancer (NPC) patients receiving immune checkpoint inhibitors (ICIs) remains controversial. This study aimed to evaluate the optimal threshold of PD-L1 expression in predicting the efficacy of ICIs in patients with recurrent or metastatic (R/M) NPC. Methods: A meta-analysis was performed by retrieving relevant literature from PubMed, EMBASE, and Cochrane Library databases. Data on the pooled risk ratio (RR), mean overall survival (OS), progression-free survival (PFS), overall response rate (ORR) with 95% confidence interval, and 1%, 10%, and 25% PD-L1 expression cutoff points were obtained to examine the role of PD-L1 as a biomarker in R/M NPC patients receiving immunotherapy. Results: In total, 1,312 patients from 14 studies were included. An improvement in PFS was observed in both patients with PD-L1 ≥ 1% (RR = 0.76, 95% CI 0.62-0.92, P = 0.005) and those with PD-L1 < 1% (RR = 0.68, 95% CI: 0.35-1.32, P = 0.26) who received first-line treatment with immunotherapy, with no significant difference between these subgroups. The pooled ORR was significantly higher in patients with PD-L1 ≥ 1% (ORR = 0.37) than in those with PD-L1 < 1% (ORR = 0.22) (P < 0.01) undergoing subsequent-line treatment. However, when we used the PD-L1 cutoff values of 10% and 25%, there was no significant difference between the positive (PD-L1 expression ≥ the cutoff value) and negative (PD-L1 expression < the cutoff value) subgroups. PD-L1 ≥ 1% also tended to be associated with better PFS and OS. Conclusions: Our meta-analysis suggested that first-line immunotherapy could significantly improve PFS in R/M NPC patients, regardless of the PD-L1 expression levels. Positive PD-L1 expression (≥ 1%) might be a potential predictive biomarker for a better overall response to immunotherapy in R/M NPC patients in subsequent-line setting. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42024495841 PROSPERO, identifier CRD42024495841.

Development and usability testing of a technology-based intervention for promoting physical activity among post-treatment cancer survivors (WExercise) using the multi-process action control framework.

Background: To promote physical activity in post-treatment cancer survivors, a mobile application WExercise was developed using the Multi-Process Action Control Framework. It contains 10 weekly online lesson to facilitate reflective, regulatory, and reflexive processes to help participants to form and sustain physical activity behavior. Objectives: To test the usability and acceptability of WExercise in post-treatment cancer survivors. Methods: This study involved four phases: (1) preparing application content, (2) expert panel review (comprising oncology healthcare workers, exercise specialists, and behavior change researchers), (3) developing the app, and (4) usability test. The usability test was conducted cross-sectionally using direct observation of application navigation tasks, a quantitative survey, and qualitative interviews among 10 post-treatment cancer survivors. Results: In Phase 2, the expert panel rated the application highly on relevance, accuracy, comprehensiveness, meaningfulness, and easiness to understand (average score = 3.83 out of 4). The application was developed accordingly. In Phase 4, the System Usability Score was 75 %, greater than the cut-off point. Participants gave the items assessing acceptance of the application positive ratings (e.g., satisfaction = 4.30 out of 5). Based on the performance and feedback, the application was modified, including adjusting the font size and improving the visualization of buttons. Conclusion: Overall, experts and potential users considered the application relevant, usable, and acceptable. It has the full potential for further testing in a larger trial for its effectiveness in promoting physical activity in cancer survivors.

Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma - a bench to bed study.

BACKGROUND: Positron Emission Tomography (PET) with combined [18F]-FDG and [11C]-acetate (dual-tracer) is used for the management of hepatocellular carcinoma (HCC) patients, although its prognostic value and underlying molecular mechanism remain poorly understood. We hypothesized that radiotracer uptake might be associated with tumor hypoxia and validated our findings in public and local human HCC cohorts. METHODS: Twelve orthotopic HCC xenografts were established using MHCC97L cells in female nude mice, with 5 having undergone hepatic artery ligation (HAL) to create tumor hypoxia in vivo. Tumors in both Control and HAL-treated xenografts were imaged with [11C]-acetate and [18F]-FDG PET-MR and RNA sequencing was performed on the resected tumors. Semiquantitative analysis of PET findings was then performed, and the findings were then validated on the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and patients from our institution. RESULTS: HAL-treated mice showed lower [11C]-acetate (HAL-treated vs. Control, tumor-to-liver SUV ratio (SUVTLR): 2.14[2.05-2.21] vs 3.11[2.75-5.43], p = 0.02) but not [18F]-FDG (HAL-treated vs. Control, SUVTLR: 3.73[3.12-4.35] vs 3.86[3.7-5.29], p = 0.83) tumor uptakes. Gene expression analysis showed the PET phenotype is associated with upregulation of hallmark hypoxia signature. The prognostic value of the hypoxia gene signature was tested on the TCGA-LIHC cohort with upregulation of hypoxia gene signature associated with poorer overall survival (OS) in late-stage (stage III and IV) HCC patients (n = 66, OS 2.05 vs 1.67 years, p = 0.046). Using a local cohort of late-stage HCC patients who underwent dual-tracer PET-CT, tumors without [11C]-acetate uptake are associated with poorer prognosis (n = 51, OS 0.25 versus 1.21 years, p < 0.0001) and multivariable analyses showed [11C]-acetate tumor uptake as an independent predictor of OS (HR 0.17 95%C 0.06-0.42, p < 0.0001). CONCLUSIONS: [11C]-acetate uptake is associated with alteration of tumor hypoxia gene expression and poorer prognosis in patients with advanced HCC.

Complete Response to Locoregional Therapy Plus Immunotherapy for Hepatocellular Carcinoma.

Importance: Previous studies showed that 42% to 50% of patients with locally advanced hepatocellular carcinoma (HCC) achieved complete remission (CR) after combined locoregional therapy (LRT) plus immunotherapy (IO). However, data on predictors of CR and long-term clinical outcomes without surgery and after discontinuation of IO are lacking. Objective: To assess the long-term clinical outcomes among patients with unresectable HCC who achieved CR after LRT-IO and were placed on a watch-and-wait protocol. Design, Setting, and Participants: This cohort study included patients with unresectable HCC who achieved CR after LRT-IO in 2 prospective studies between January 2018 and December 2022. The time of data cutoff was June 2023. Radiologic CR was defined per modified Response Evaluation Criteria in Solid Tumors. All patients underwent close surveillance after CR without surgical interventions, and IO was discontinued. Exposure: All patients had received stereotactic body radiotherapy followed by anti-programmed cell death protein 1 or anti-programmed death ligand 1 therapy. Forty-nine patients had received a dose of transarterial chemoembolization before stereotactic body radiotherapy. Main Outcomes and Measures: The primary outcome was the 3-year overall survival (OS) rate. Secondary outcomes included the 3-year time-to-progression rate, 3-year local control rate, and relapse pattern. Factors associated with CR were analyzed using multivariate analyses. Results: A total of 63 patients were enrolled (58 male [92.1%]; median age, 69 years [range, 18-90 years]); 38 patients (60.3%) had macrovascular invasion, and the median tumor diameter was 10 cm (range, 3.8-31.1 cm). The median follow-up time was 34.7 months (95% CI, 6.5-64.6 months). Twenty-nine patients (46.0%) achieved CR. The patients achieving CR had a significantly better 3-year OS rate than patients not achieving CR (75.5% [95% CI, 58.2%-98.3%] vs 28.1% [95% CI, 7.4%-29.4%]; P < .001). Among the 29 patients with CR, the 3-year time-to-progression rate was 58.7% (95% CI, 38.7%-79.1%) and the 3-year local control rate was 90.5% (95% CI, 78.2%-100%). Ten patients (34.5%) developed recurrence; among them, 6 (60.0%) with solitary intrahepatic disease relapse underwent curative surgical treatment. The absence of tumor vascular invasion (odds ratio, 0.30; 95% CI, 0.10-0.89) and the sum of the largest lesion diameters of 8 cm or less (odds ratio, 0.26; 95% CI, 0.07-0.98) were associated with CR. Conclusions and Relevance: This cohort study of LRT-IO with long-term follow-up data found a durable response in patients with locally advanced unresectable HCC. Long-term survival was attainable in patients with radiologic CR. Further randomized clinical trials are warranted.

Glycaemic control is a modifiable risk factor for hepatocellular carcinoma and liver-related mortality in patients with diabetes.

BACKGROUND: Optimal glycaemic control has well-established health benefits in patients with diabetes mellitus (DM). It is uncertain whether optimal glycaemic control can benefit liver-related outcomes. AIMS: To examine the association of optimal glycaemic control with hepatocellular carcinoma (HCC) and liver-related mortality. METHODS: In a population-based cohort, we identified patients with newly diagnosed DM between 2001 and 2016 in Hong Kong. Optimal glycaemic control was defined as mean haemoglobin A1c (HbA1c) <7% during the 3-year lead-in period after DM diagnosis. By applying propensity score matching to balance covariates, we analysed glycaemic control via competing risk models with outcomes of interest being HCC and liver-related mortality. RESULTS: We identified 146,430 patients (52.2% males, mean age 61.4 ± 11.8 years). During a median follow-up duration of 7.0 years, 1099 (0.8%) and 978 (0.7%) patients developed HCC and liver-related deaths. Optimal glycaemic control, when compared to suboptimal glycaemic control, was associated with reduced risk of HCC (subdistribution hazard ratio [SHR] 0.70, 95% CI 0.61-0.79). The risk of HCC increased with incremental HbA1c increases beyond >7% (SHR 1.29-1.71). Significant associations with HCC were also found irrespective of age (SHR 0.54-0.80), sex (SHR 0.68-0.69), BMI <25 or ≥25 kg/m2 (SHR 0.63-0.75), smoking (SHR 0.61-0.72), hepatic steatosis (SHR 0.67-0.68) and aspirin/statin/metformin use (SHR 0.67-0.75). A lower risk of liver-related mortality in relation to optimal glycaemic control was also observed (SHR 0.70, 95% CI 0.61-0.80). CONCLUSIONS: Glycaemic control is an independent risk factor for HCC and liver-related mortality, and should be incorporated into oncoprotective strategies in the general DM population.

Using the genomic adjusted radiation dose (GARD) to personalize the radiation dose in nasopharyngeal cancer.

BACKGROUND: Locally advanced nasopharyngeal cancer (NPC) patients undergoing radiotherapy are at risk of treatment failure, particularly locoregional recurrence. To optimize the individual radiation dose, we hypothesize that the genomic adjusted radiation dose (GARD) can be used to correlate with locoregional control. METHODS: A total of 92 patients with American Joint Committee on Cancer / International Union Against Cancer stage III to stage IVB recruited in a randomized phase III trial were assessed (NPC-0501) (NCT00379262). Patients were treated with concurrent chemo-radiotherapy plus (neo) adjuvant chemotherapy. The primary endpoint is locoregional failure free rate (LRFFR). RESULTS: Despite the homogenous physical radiation dose prescribed (Median: 70 Gy, range 66-76 Gy), there was a wide range of GARD values (median: 50.7, range 31.1-67.8) in this cohort. In multivariable analysis, a GARD threshold (GARDT) of 45 was independently associated with LRFFR (p = 0.008). By evaluating the physical dose required to achieve the GARDT (RxRSI), three distinct clinical subgroups were identified: (1) radiosensitive tumors that RxRSI at dose < 66 Gy (N = 59, 64.1 %) (b) moderately radiosensitive tumors that RxRSI dose within the current standard of care range (66-74 Gy) (N = 20, 21.7 %), (c) radioresistant tumors that need a significant dose escalation above the current standard of care (>74 Gy) (N = 13, 14.1 %). CONCLUSION: GARD is independently associated with locoregional control in radiotherapy-treated NPC patients from a Phase 3 clinical trial. GARD may be a potential framework to personalize radiotherapy dose for NPC patients.

Dual-tracer PET/CT in the management of hepatocellular carcinoma.

Background & Aims: Combined 18F-fluorodeoxyglucose (FDG) and 11C-acetate (dual-tracer) positron-emission tomography/computed tomography (PET/CT) is being increasingly performed for the management of hepatocellular carcinoma (HCC), although its role is not well defined. Therefore, we evaluated its effectiveness in (i) staging, (ii) characterization of indeterminate lesions on conventional imaging, and (iii) detection of HCC in patients with unexplained elevations in serum alpha-fetoprotein (AFP) levels. Methods: We retrospectively assessed 525 consecutive patients from three tertiary centers between 2014 and 2020. For staging, we recorded new lesion detection rates, changes in the Barcelona Clinic Liver Cancer (BCLC) classification, and treatment allocation due to dual-tracer PET/CT. To characterize indeterminate lesions and unexplained elevation of serum AFP levels, the sensitivity and specificity of dual-tracer PET/CT in diagnosing HCC were evaluated. A multidisciplinary external review and a cost-benefit analysis of patients for metastatic screening were also performed. Results: Dual-tracer PET/CT identified new lesions in 14.3% of 273 staging patients, resulting in BCLC upstaging in 11.7% and treatment modifications in 7.7%. It upstaged 8.1% of 260 patients undergoing metastatic screening, with estimated savings of US$495 per patient. It had a sensitivity and specificity of 80.7% (95% CI 71.2-88.6%) and 94.8% (95% CI 90.4-98.6%), respectively, for diagnosing HCC in 201 indeterminate lesions. It detected HCC in 45.1% of 51 patients with unexplained elevations in serum AFP concentrations. External review revealed substantial agreement between local and external image interpretation and patient assessment (n = 273, κ = 0.822; 95% CI 0.803-0.864). Conclusions: Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP. Impact and implications: Compared to CT or MRI, dual-tracer positron-emission tomography/computed tomography (PET/CT) led to upstaging in 12% of patients with hepatocellular carcinoma (HCC) undergoing staging, resulting in treatment modification in 8% of cases and a cost saving of US$495 per patient. It also accurately detected HCC in high-risk cases where CT or MRI were equivocal or normal. Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP.

Survival Outcome Analysis of Stereotactic Body Radiotherapy and Immunotherapy (SBRT-IO) versus SBRT-Alone in Unresectable Hepatocellular Carcinoma.

Introduction: While combination of stereotactic body radiotherapy (SBRT) and immunotherapy are promising, their efficacy and safety have not been compared with SBRT-alone in patients with unresectable hepatocellular carcinoma (HCC). Methods: This retrospective study included 100 patients with nonmetastatic, unresectable HCC in two hospitals. Eligible patients had tumor nodules ≤3 and Child-Pugh liver function score of A5 to B7. Seventy patients received SBRT-alone, and 30 patients underwent combined SBRT and immunotherapy (SBRT-IO). Overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicity were analyzed. We adjusted for the potential confounding factors using propensity score matching. Results: The median tumor size was 7.3 cm (range, 2.6-18 cm). Twenty-five (25%) of patients had vascular invasion. Before propensity score matching, the 1-year and 3-year OS rate was 89.9% and 59.8% in the SBRT-IO group and 75.7% and 42.3% in SBRT-alone group (p = 0.039). After propensity score matching (1:2), 25 and 50 patients were selected from the SBRT-IO and SBRT-alone group. The 1-year and 3-year OS was 92.0% and 63.9% in the SBRT-IO group versus 74.0% and 43.3% in the SBRT-alone group (p = 0.034). The 1-year and 3-year TTP was better in SBRT-IO group (1-year: 68.9% vs. 58.9% and 3-year: 61.3% vs. 32.5%, p = 0.057). The ORR of 88% (complete response [CR]: 56%, partial response [PR]: 22%) in SBRT-IO arm was significantly better than 50% (CR: 20%, PR: 30%) in the SBRT-alone arm (p = 0.006). Three patients (12%) developed ≥grade 3 immune-related treatment adverse events (n = 2 hepatitis, n = 1 dermatitis) leading to permanent treatment discontinuation. Conclusion: Adding immunotherapy to SBRT resulted in better survival with manageable toxicities. Prospective randomized trial is warranted.

Ninth Version of the AJCC and UICC Nasopharyngeal Cancer TNM Staging Classification.

Importance: Accurate staging is a fundamental step in treating patients with nasopharyngeal carcinoma (NPC) worldwide; this is crucial not only for prognostication, but also for guiding treatment decisions. The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) system is the global language for clinicians, researchers, and cancer registries. Continual improvement that aligns with contemporary pattern of care is essential. Objective: To improve the prognostic accuracy and clinical applicability of the eighth edition (TNM-8) for NPC. Design, Setting, and Participants: This multicenter study analyzed patients with NPC with detailed tumor features during January 2014 and December 2015 and was reviewed by experienced radiologists. The data analysis was completed in December 2023. The findings were further confirmed with internal and external validation. Statistical analyses and clinical considerations were reviewed by the AJCC/UICC multidisciplinary head and neck panels and attained consensus. The recommendations were evaluated by the AJCC Evidence-Based Medicine Committee before final endorsement as the ninth version (TNM-9). Main Outcomes and Measures: The primary end point was overall survival. Adjusted hazard ratios of different subgroups were then assessed for confirmation of optimal stage grouping. Results: Of the 4914 patients analyzed, 1264 (25.7%) were female and 3650 (74.3%) were male; the median (SD) age was 48.1 (12.0) years. Advanced radiological extranodal extension (with involvement of adjacent muscles, skin, and/or neurovascular bundles) was identified as an independent adverse factor for all end points: this was added as a criterion for N3. Patients with nonmetastatic disease were regrouped into stages I to III instead of TNM-8 stages I to IVA. Significant hazard discrimination was achieved by grouping T1-2N0-1 as stage I, T3/N2 as stage II, and T4/N3 as stage III. Although the T1-2N0-1 subgroups had comparable 5-year overall survival, subdivisions into IA (T1-T2N0) and IB (T1-T2N1) were recommended due to the distinction in adjusted hazard ratios following adjustment for chemotherapy use. Metastatic disease was exclusively classified as stage IV, and prognostication was further refined by subdivision into IVA (M1a, ≤3 lesions) and IVB (M1b, >3 lesions). TNM-9 demonstrated superiority compared with TNM-8 in major statistical aspects. Conclusion and Relevance: The results of this diagnostic study suggest that the ninth version of TNM staging for NPC, based on robust analyses and a comprehensive review by the AJCC/UICC staging committees, provides an improved staging system for global application and a framework for future incorporation of nonanatomical factors. This will be launched for global application in January 2025.

Association of Multi-Phasic MR-Based Radiomic and Dosimetric Features with Treatment Response in Unresectable Hepatocellular Carcinoma Patients following Novel Sequential TACE-SBRT-Immunotherapy.

This study aims to investigate the association of pre-treatment multi-phasic MR-based radiomics and dosimetric features with treatment response to a novel sequential trans-arterial chemoembolization (TACE) plus stereotactic body radiotherapy (SBRT) plus immunotherapy regimen in unresectable Hepatocellular Carcinoma (HCC) sub-population. Twenty-six patients with unresectable HCC were retrospectively analyzed. Radiomic features were extracted from 42 lesions on arterial phase (AP) and portal-venous phase (PVP) MR images. Delta-phase (DeltaP) radiomic features were calculated as AP-to-PVP ratio. Dosimetric data of the tumor was extracted from dose-volume-histograms. A two-sided independent Mann-Whitney U test was used to assess the clinical association of each feature, and the classification performance of each significant independent feature was assessed using logistic regression. For the 3-month timepoint, four DeltaP-derived radiomics that characterize the temporal change in intratumoral randomness and uniformity were the only contributors to the treatment response association (p-value = 0.038-0.063, AUC = 0.690-0.766). For the 6-month timepoint, DeltaP-derived radiomic features (n = 4) maintained strong clinical associations with the treatment response (p-value = 0.047-0.070, AUC = 0.699-0.788), additional AP-derived radiomic features (n = 4) that reflect baseline tumoral arterial-enhanced signal pattern and tumor morphology (n = 1) that denotes initial tumor burden were shown to have strong associations with treatment response (p-value = 0.028-0.074, AUC = 0.719-0.773). This pilot study successfully demonstrated associations of pre-treatment multi-phasic MR-based radiomics with tumor response to the novel treatment regimen.

Dosimetric benefits of 3D-printed modulated electron bolus following lumpectomy and whole-breast radiotherapy for left breast cancer.

Radiotherapy with electrons is commonly applied to the tumor bed after whole-breast radiotherapy following breast conservation surgery for breast cancer patients. However, the radiation dose to adjacent organs-at-risk (OARs) and conformity of planning target volume (PTV) cannot be optimized. In this study, we examine the feasibility of using modulated electron bolus (MEB) to improve PTV conformity and reduce the dose to these OARs. Twenty-seven patients with left breast cancer were retrospectively selected in this study. For each patient, a tangential photon plan in RayStation treatment planning system with prescription of 26 Gy in 5 fractions was created as base plan. Two electron plans, one without bolus and one with MEB using Adaptiiv software based on the PTV were created. Various dosimetric parameters of OARs including left lung, heart, left anterior descending artery (LAD) and ribs and the conformity indices of PTV of these 2 electron plans together with the base plans were compared. Statistically significant decreases in the dosimetric parameters (V5Gy, V10Gy, V20Gy, and mean dose) of the ipsilateral left lung and the heart were observed with MEB. The median maximum dose to the LAD and the ribs decreased by 6.2% and 4.5% respectively. The median conformity index was improved by 14.3% with median increases of monitor units by 1.7%. Our results show that MEB is feasible resulting in reduction of doses to the predefined OARs and an improved conformity of PTV. By using 3D printing, MEB might be considered as an alternative to conventional electron boost.

Efficacy and feasibility of 3D printed redesigned Venezia™ applicator for treating advanced cervix and recurrent endometrial cancer.

PURPOSE: Venezia™ is an interstitial brachytherapy applicator for treating advanced cervical and vaginal vault recurrent cancer. However, there are limitations that lead to suboptimal target coverage. 3D printing introduction allows the redesign of Venezia™ for bulky and irregular-shaped tumors. METHODS: This study first describes three new designs included: 1) add-on needles template allowed for an extra layer of straight and oblique needles, 2) redesigned vaginal cap so straight and oblique needles can be used together and 3) redesigned central tube allowed vaginal vault interstitial needle insertion. Drawbacks to original Venezia™ and rationale for using these new designs were discussed. Dosimetric analysis by comparing the original Venezia™ with new design for 10 cases in Oncentra treatment planning system v4.5 (Elekta, Stockholm, Sweden) to observe the dose differences in gross tumor volume (GTV), high risk clinical target volume (HRCTV), intermediate clinical target volume (IRCTV) and organs at risk. RESULTS: For the dosimetric comparison, there were statistically significantly increased median minimal dose to 98% (D98%) of GTV, 90% (D90%) of HRCTV, and IRCTV for the new design with p-value of 0.008, 0.005 and 0.0018, respectively. Comparing the physical dose of D98% of GTV, D90% of HRCTV, and IRCTV when using the new design, it averagely increased by 11.7%, 8.0%, 19.4%, respectively per fraction. CONCLUSIONS: Dosimetric comparison revealed the new designs increased the dose to GTV, HRCTV and IRCTV and fulfilled the dose constraints of bladder, rectum and sigmoid. The 3D printed new design is biocompatible, inexpensive and can be patient specific.

Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase 2 trial.

BACKGROUND: The synergy between locoregional therapies and immune checkpoint inhibitors has not been investigated as conversion therapy for unresectable hepatocellular carcinoma. We aimed to investigate the activity of sequential transarterial chemoembolisation (TACE) and stereotactic body radiotherapy followed by avelumab (an anti-PD-L1 drug) for locally advanced, unresectable hepatocellular carcinoma. METHODS: START-FIT was a single-arm, phase 2 trial in patients with locally advanced hepatocellular carcinoma who were not suitable for curative treatment, conducted in two hospitals in Hong Kong and one in Shenzhen, China. Eligible patients were those aged 18 years or older with an Eastern Cooperative Oncology Group performance status 0-1, Child-Pugh liver function score A5 to B7, tumour size of at least 5 cm, a maximum of three tumour lesions, and adequate hepatic, renal, and bone marrow function. Participants received TACE on day 1, followed by stereotactic body radiotherapy (27·5-40·0 Gy in five fractions) at day 28. Avelumab (10 mg/kg) was administered 14 days following stereotactic body radiotherapy and every 2 weeks thereafter. The primary endpoint was the proportion of patients deemed amenable to curative treatment, defined as those who had a sustained complete or partial treatment response for at least 2 months and if curative treatment could be performed (ie, resection, radiofrequency ablation, or transplantation), analysed by intention to treat. Safety was also analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT03817736) and has been completed. FINDINGS: Between March 18, 2019, and Jan 27, 2021, 33 patients (32 [97%] men and one [3%] woman) were enrolled. The median sum of the largest diameters of lesions was 15·1 cm (IQR 8·3-14·9). 21 (64%) patients had macrovascular invasion (hepatic vein [n=13], branched portal vein [n=3], or both [n=5]). Median follow-up was 17·2 months (IQR 7·8-25·8). 18 (55%) patients were deemed amenable to curative treatment: four (12%) of 33 patients had curative treatment (resection [n=2] or radiofrequency ablation [n=2]), and 14 (42%) had a radiological complete response and opted for close surveillance. 11 (33%) of 33 patients had treatment-related adverse events that were grade 3 or worse. The most common treatment-related grade 3 or worse adverse event was transient increase in alanine aminotransferase or aspartate aminotransferase (five [15%]) after TACE. Five (15%) patients developed immune-related adverse events of grade 3 or worse (three had hepatitis, two had dermatitis). INTERPRETATION: To our knowledge, this is the first prospective trial using the combination of immunotherapy and locoregional treatment as conversion therapy for locally advanced unresectable hepatocellular carcinoma, with promising results. Future randomised trials with larger cohorts of patients are warranted. FUNDING: Merck.

Efficacy, safety, and correlative biomarkers of bintrafusp alfa in recurrent or metastatic nasopharyngeal cancer patients: a phase II clinical trial.

Background: The strategy of dual blockade of TGF-ß and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This study aimed to evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients. Methods: In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Findings: Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n = 2; partial response, n = 7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFß1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, P = 0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR. Interpretation: Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning. Funding: The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA.