TIGIT, a novel immune checkpoint therapy for melanoma.

Melanoma is the most aggressive and deadliest type of skin cancer. In the last 10 years, immune checkpoint blockades (ICBs) including PD-1/PD-L1 and CTLA-4 inhibitor has been shown to be effective against melanoma. PD-1/PD-L1 and CTLA-4 inhibitors have shown varying degrees of drug resistance in the treatment of melanoma patients. Furthermore, the clinical benefits of ICBs are also accompanied by severe immune toxicity. Therefore, there is an urgent need to develop new immune checkpoint inhibitors to optimize melanoma therapy and reduce cytotoxicity. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is thought to activate inhibitory receptors in T cells, natural killer (NK) cells, and regulatory T cells (Tregs), and has become a promising target for immunotherapy. Studies have found that TIGIT can be detected in different stages of melanoma, which is closely related to the occurrence, development, and prognosis of melanoma. This review mainly describes the immunosuppressive mechanism of TIGIT and its role in antitumor immunity of melanoma, so as to provide new ideas and schemes for the clinical treatment of melanoma with targeted TIGIT.

Drug therapies for treatment of idiopathic pulmonary fibrosis: a systematic review, Bayesian network meta-analysis, and cost-effectiveness analysis.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis and a high economic burden for individuals and healthcare resources. Studies of the costs associated with the efficiency of IPF medications are scarce. We aimed to conduct a network meta-analysis (NMA) and cost-effectiveness analysis to identify the optimum pharmacological strategy among all currently available IPF regimens. Methods: We first performed a systematic review and network meta-analysis. We searched eight databases for eligible randomised controlled trials (RCTs) published, in any language, between January 1, 1992 and July 31, 2022, that investigated the efficacy or tolerability (or both) of drug therapies for the treatment of IPF. The search was updated on February 1, 2023. Eligible RCTs were enrolled, with no restriction on dose, duration, or length of follow-up, if they included at least one of: all-cause mortality, acute exacerbation rate, disease progression rate, serious adverse events, and any adverse events under investigation. A subsequent Bayesian NMA within random-effects models was performed, followed by a cost-effectiveness analysis using the data obtained from our NMA, by developing a Markov model from the US payer's perspective. Assumptions were checked by deterministic and probabilistic sensitivity approaches to identify sensitive factors. We prospectively registered the protocol (CRD42022340590) in PROSPERO. Findings: 51 publications comprising 12,551 participants with IPF were analysed for the NMA, and the findings indicated that pirfenidone and N-acetylcysteine (NAC) + pirfenidone were the most efficacious and tolerable. The pharmacoeconomic analysis showed that NAC + pirfenidone was associated with the highest potentiality of being cost-effective at willingness-to-pay (WTP) thresholds of US$150,000 and $200,000, on the basis of quality-adjusted life years (QALYs), disability-adjusted life years (DALYs) and mortality, with the probability ranging from 53% to 92%. NAC was the minimum cost agent. Compared with placebo, NAC + pirfenidone improved effectiveness by increasing QALYs by 7.02, and reducing DALYs by 7.10 and deaths by 8.40, whilst raising overall costs by $516,894. Interpretation: This NMA and cost-effectiveness analysis suggests that NAC + pirfenidone is the most cost-effective option for treatment of IPF at WTP thresholds of $150,000 and $200,000. However, given that clinical practice guidelines have not addressed the application of this therapy, large well-designed and multicentre trials are warranted to provide a better picture of IPF management. Funding: None.

A phantom-based analysis for tracking intra-fraction pancreatic tumor motion by ultrasound imaging during radiation therapy.

Purpose: In this study, we aim to further evaluate the accuracy of ultrasound tracking for intra-fraction pancreatic tumor motion during radiotherapy by a phantom-based study. Methods: Twelve patients with pancreatic cancer who were treated with stereotactic body radiation therapy were enrolled in this study. The displacement points of the respiratory cycle were acquired from 4DCT and transferred to a motion platform to mimic realistic breathing movements in our phantom study. An ultrasound abdominal phantom was placed and fixed in the motion platform. The ground truth of phantom movement was recorded by tracking an optical tracker attached to this phantom. One tumor inside the phantom was the tracking target. In the evaluation of the results, the monitoring results from the ultrasound system were compared with the phantom motion results from the infrared camera. Differences between infrared monitoring motion and ultrasound tracking motion were analyzed by calculating the root-mean-square error. Results: The 82.2% ultrasound tracking motion was within a 0.5 mm difference value between ultrasound tracking displacement and infrared monitoring motion. 0.7% ultrasound tracking failed to track accurately (a difference value > 2.5 mm). These differences between ultrasound tracking motion and infrared monitored motion do not correlate with respiratory displacements, respiratory velocity, or respiratory acceleration by linear regression analysis. Conclusions: The highly accurate monitoring results of this phantom study prove that the ultrasound tracking system may be a potential method for real-time monitoring targets, allowing more accurate delivery of radiation doses.

Comparison of Two Cyberknife Planning Approaches for Multiple Brain Metastases.

PURPOSE: To compare the delivery efficiency, plan quality, and planned treatment volume (PTV) and normal brain dosimetry between different Cyberknife planning approaches for multiple brain metastases (MBM), and to evaluate the effects of the number of collimators on the related parameters. METHODS: The study included 18 cases of MBM. The Cyberknife treatment plans were classified as Separate or Combined. For the Separate plan, each lesion was targeted by the collimator auto-selection method (Conformality 2/3 collimators). For the Combined plan, a PTV including all PTVs was targeted by the collimators. Monitor units (MUs), number of nodes and beams, estimated fraction treatment time (EFTT), new conformity index (nCI), dose gradient index (GI), homogeneity index (HI), PTV minimum/maximum dose (Dmax/Dmin), volume doses (D2% and D98%), maximum doses to lenses, optic nerves, and brainstem as well as normal brain 3, 6, 10, and 12 Gy (V 3Gy -V 12Gy) were compared. RESULTS: Compared to the Combined plan, the Separate plan had fewer nodes and beams, shorter EFTT, smaller PTV Dmin, normal brain dose, and GI, and larger HI. The Separate plan with 2 collimators also had worse PTV coverage. In the Combined plan, more collimators increased beams, EFTT, GI, and normal brain dose but improved the PTV Dmin. Among treatments based on the Separate approach, there were obvious differences between plans for most of the items except the nCI. Fewer collimators resulted in significantly reduced beams, EFTT, PTV D98%, and normal brain dose with improved GI, although PTV Dmin and MUs were decreased while HI was increased. CONCLUSION: Both approaches met the requirements for SRS/HFSRT. We found that Separate plans improved treatment efficiency and normal tissue dosimetry.

Comparison between flattening filter-free (FFF) and flattened photon beam VMAT plans for the whole brain radiotherapy (WBRT) with hippocampus sparing.

PURPOSE: To evaluate and investigate the feasibility of flattening filter-free (FFF) beam for the whole-brain radiotherapy (WBRT) with hippocampus sparing. METHODS: Eighteen patients with volumetric-modulated arc therapy (VMAT) plans in FFF and conventional beam modes were included in this study. The prescribed dose was 30 Gy in 10 fractions. The conformity index (CI), heterogeneity index reported by TPS (HI-M), and homogeneity index (HI) for planning target volume (PTV) were evaluated. Subsequently, the following parameters for PTV were calculated and compared: D2% , D98% ; the mean dose, maximum dose, and minimal dose for OARs. Plan modulation index, total MUs, and the gamma index were used to evaluate the plan quality. RESULTS: HI-M results were similar for the two techniques (1.239 vs. 1.247, respectively, p = 0.048); FFF beam plans yielded lower D2% compared to FF beam plans (3,416.3 cGy vs. 3,437.2 cGy, p = 0.22), mean dose (3,177.5 cGy vs. 3,195.2 cGy, p = 0.009), and CI (0.884 vs. 0.876, p = 0.001) for PTV. Significant differences were observed between the two beam modes (FF model vs. FFF model) for the maximum dose (1,612.9 cGy vs. 1,470.2 cGy, respectively, p < 0.001), minimum dose (987.6 cGy vs. 898.8 cGy, respectively, p < 0.001), and the mean dose (1144.4 cGy vs. 1047.3 cGy, respectively, p < 0.001) to the hippocampus, and the maximum dose to the eyes (2,792.6 cGy vs. 2,751.3 cGy, respectively, p < 0.001). The average total MUs for FFF-VMAT plans was significantly greater than FF-VMAT plans. However, differences for the plan modulation index and the gamma index were negligible. CONCLUSION: In comparison with FF beam, the FFF beam mode offers a clear benefit with respect to WBRT with hippocampal sparing.

Pelvic bone marrow sparing intensity modulated radiotherapy reduces the incidence of the hematologic toxicity of patients with cervical cancer receiving concurrent chemoradiotherapy: a single-center prospective randomized controlled trial.

PURPOSE: To test the efficacy and feasibility of pelvic bone marrow sparing intensity modulated radiotherapy (PBMS-IMRT) in reducing grade 2 or higher hematological toxicity (HT2+) for patients with cervical cancer treated with concurrent chemoradiotherapy. METHODS AND MATERIALS: A total of 164 patients with Stage Ib2-IIIb cervical cancer were prospectively enrolled from March 2018 to March 2019 at a single center and were randomly allocated into the PBMS group or the control group. The control group received weekly cisplatin concurrently with IMRT, followed by intracavitary brachytherapy. The PBMS group additionally received PBM dose constraint. The dosimetric parameters of the pelvic bone (PB) and the subsites including hip bone (HIP) and lumbosacral spine (LSS) and the corresponding bone marrow were recorded. The endpoint of the trial was acute hematologic or gastrointestinal toxicity. Receiver operating characteristic curves were used to derive optimal dosimetric planning constraints. RESULTS: Eighty-two patients in the PBMS group and 82 in the control group were enrolled for statistical analysis. The incidence of HT2+ in the PBMS group was 50.0%, significantly lower than the 69.5% incidence in the control group (P = 0.02). Patients with PB V40 ≥ 28% were more likely to experience HT2+ (OR = 2.85, P = 0.006), while the incidence of grade 2 or higher gastrointestinal toxicity (GT2+) events did not differ significantly between the two groups (P > 0.05). Dosimetric parameters of LSS showed stronger associations with HT2+ than other subsites. The patients with LSS V10 ≥ 87% and LSS mean ≥ 39 Gy were more likely to experience HT2+ (OR = 3.13, P = 0.001;OR = 3.03, P = 0.002, respectively). CONCLUSION: PBMS-IMRT reduced HT compared with IMRT alone. Efforts to maintain LSS V10 < 87%, LSS mean < 39 Gy and PB V40 < 28% simultaneously may reduce the risk of HT2 +. TRIAL REGISTRATION: The trial was registered with Chinese clinical trial registry ( ChiCTR1800015069 ).

Clinical, dosimetric, and position factors for radiation-induced acute esophagitis in intensity-modulated (chemo)radiotherapy for locally advanced non-small-cell lung cancer.

PURPOSE: The purpose of this study was to estimate the relation between acute esophagitis (AE) and clinical, dosimetric, and position factors in patients with locally advanced non-small-cell lung cancer (NSCLC) receiving intensity-modulated (chemo)radiotherapy. MATERIALS AND METHODS: A retrospective cohort analysis was performed to identify factors associated with Common Toxicity Criteria for Adverse Events grade 2 or worse AE (AE2+). A multivariable model was established including patient- and treatment-related variables and esophageal dose-volume histogram parameters. The esophagus was divided according to physiological anatomy, and logistic regression was used to analyze the position parameter for its correlation with AE2+. RESULTS: The incidence of AE2+ was 27.5%. All models included gender, concurrent chemo-radiotherapy (CCRT), position parameter, and one of the dosimetric variables. The model with mean dose showed the best goodness of fit. Gender (OR=2.47, P=0.014), CCRT (OR=3.67, P=0.015), mean dose (OR=1.33, P<0.001), and maximum radiation position (OR=1.65, P=0.016) were significantly related to AE2+. CONCLUSION: Gender, concurrent chemotherapy, maximum radiation position, and mean dose were independent risk factors for AE2+. The upper part of the esophagus showed a higher sensitivity to radiation toxicity.

The risk and predictors for severe radiation pneumonitis in lung cancer patients treated with thoracic reirradiation.

BACKGROUND: Thoracic reirradiation (re-RT) is increasingly administered. However, radiation pneumonitis (RP) remains to be the most common side effect from retreatment. This study aimed to determine the risk and predictors for severe RP in patients receiving thoracic re-RT. METHODS: Sixty seven patients with lung cancer received thoracic re-RT for recurrent or metastatic disease. Three-dimensional conformal radiotherapy (3D-CRT)/intensity modulated radiotherapy (IMRT) was used for 60 patients, and stereotactic body radiation therapy (SBRT) was used in 7 patients. Deformable image registration (DIR) was performed to create a composite plan. Severe (grade ≥ 3) RP was graded according to Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Eighteen patients (26.9%) developed grade ≥ 3 RP (17 of grade 3, and 1 of grade 4). In univariate analyses, V5 and mean lung dose (MLD) of initial RT or re-RT plans, V5 and V20 of composite plans, and the overlap between V5 of initial RT and V5 of re-RT plans/V5 of re-RT plans (overlap-V5/re-V5) were significantly associated with grade ≥ 3 RP (P < 0.05 for each comparison). Multivariate analysis revealed that MLD of the initial RT plans (HR = 14.515, 95%CI:1.778-118.494, P = 0.013), V5 of the composite plans (HR = 7.398, 95%CI:1.319-41.495, P = 0.023), and overlap-V5/re-V5 (P = 0.041) were independent predictors for grade ≥ 3 RP. Out-of-field failures with medium overlap-V5/re-V5 of 0.4-0.8 was associated with higher risk of grade ≥ 3 RP compared with in-field failures (18.3% vs. 50%, P = 0.014). CONCLUSIONS: The risk of grade ≥ 3 RP could be predicted not only by dose-volume variables from re-RT plan, but also by some from initial-RT and composite plans. Out-of-field failures was associated with higher risk of severe RP compared with in-field failures in some cases.