GX-I7 (rhIL-7-hyFc, efineptakin alfa) is a hybrid Fc-fused long-acting interleukin-7 (IL-7) with the aim of correcting T-cell deficiency, thereby strengthening the immune response to fight against cancer. This Phase 1b, dose-escalation study was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of GX-I7 in patients with locally advanced or metastatic solid tumours.

This study, conducted in patients with advanced solid tumours at three hospitals in Korea, involved intramuscular GX-I7 administration across eight dose levels (60-1700 µg/kg) in 3- and 6-week cohorts. A dose-expansion phase at 720 and 1200 µg/kg further assessed GX-I7's safety and efficacy.

Anti-tumour responses showed either stable disease (SD) or disease progression (PD). GX-I7 demonstrated dose-dependent increases in the maximum serum concentration (Cmax) and area under the curve up to the last measurable concentration (AUClast). In addition, a dose-dependent increase in circulating CD8+/CD4+ T cells was observed. In five patients who consented for biopsy, a statistically significant increase in tumour-infiltrating lymphocytes (TILs) followed GX-I7 treatment.

Findings suggest GX-I7 is a safe T cell-amplifying agent with peripheral immune activation. Ongoing studies are exploring its ability to enhance immune responses in peripheral immune cells and tumour cells when combined with other anti-cancer agents.

NCT03478995.

The purpose of the study was to explore the value of dynamic changes in inflammatory and nutritional index after comprehensive treatment in patients with stage III-IVA nasopharyngeal carcinoma (NPC). A prognostic model was also established and validated for progression-free survival (PFS) of patients.

We retrospectively selected 279 NPC patients with stage III-IVA. Their general clinical data and hematological index were collected and then calculated the changes during treatment. X-tile software was used to determine the optimal cut-off value. COX regression, Lasso method, and Boruta method were used to variable selection and model establishment. Using the bootstrap internal validation method, concordance index (C-index), calibration plot, and Kaplan-Meier curves were used to evaluate the model. To test the prognostic value of the model, we have also evaluated the performance of the nomogram against a conventional tumor metastasis staging system (TNM).

Multivariable COX regression analysis demonstrated that clinical staging, delta lymphocyte, delta monocyte, delta albumin, delta platelet-to-lymphocyte ratio and delta systemic immune inflammation index were related to the PFS of NPC patients. The C-index of the model was 0.712, and the calibration curve indicated that the model had good consistency. The C-index of the TNM staging system was 0.597, which was considerably lower compared to our model (P = 0.015).

We demonstrated the predictive value of dynamic changes in inflammatory and nutritional indices for the prognosis of NPC by successfully establishing and validating a prognostic model for predicting 1- and 3-year PFS after comprehensive treatment in patients with stage III-IVA NPC.

Radiation-induced lymphopenia (RIL) is a frequent complication in head and neck cancer (HNC) patients undergoing radiotherapy (RT), and its severity is associated with poorer survival outcomes.

This work aims to develop a patient-specific modeling method to simulate lymphocyte kinetics during and after RT and evaluate the lymphocyte-sparing effects across different RT treatment regimens.

A cohort of 17 HNC patients receiving unilateral irradiation with protons or photons were included in this study. The dose to circulating lymphocytes was calculated using the HEDOS model, considering lymph nodes on the irradiated side, the esophagus, auto-segmented bilateral carotid arteries and jugular veins, skeletal muscle, fat, skin, compact bone, spongy bone, red marrow, and other skeleton. A patient-specific model was developed to simulate lymphocyte kinetics that account for radiation-induced damage to both circulating lymphocytes and lymph nodes. The weekly absolute lymphocyte counts (ALC) before, during and after RT, were assembled to estimate the patient-specific parameters. Four different RT treatment regimens-conventional fractionation, hypofractionation, stereotactic body radiotherapy (SBRT), and FLASH-were evaluated to compare their lymphocyte-sparing effects.

Patients treated with protons had 17.1% less grade 3 and 4 RIL compared to photons. The mean dose to circulating lymphocytes was 1.28 ± 0.37 Gy(RBE) for proton therapy and 3.12 ± 0.75 Gy for photon therapy. The patient-specific model captured three distinct patterns of ALC kinetics: plateau phase, normal recovery, and incomplete recovery, with a mean squared error (MSE) of 0.024 ± 0.025 (mean ± SD) between the simulated and observed ALC values. On average, 42.72% of circulating lymphocytes received more than 0.1 Gy(RBE) in proton FLASH, significantly less than the 81.94% in photon FLASH. Hypofractionated RT, SBRT, and FLASH were 6.5%, 20.2%, and 29.9%, respectively, higher than conventional RT in term of ALC levels 3 months post-RT. At 1 year post-RT, most patients achieved at least 70% recovery of baseline ALC for all treatment regimens.

A patient-specific method has been developed for modeling lymphocyte dynamics over the course of RT and the subsequent follow-up period for HNC patients.

This systematic review and meta-analysis evaluated the effectiveness and the safety of transarterial radioembolization using Holmium-166 microspheres (Ho-166-TARE) for the treatment of primary and secondary liver tumors. The aim of the study was to offer a detailed analysis of clinical outcomes and the potential benefits of this innovative therapy.

The study was conducted according to the PRISMA 2020 guidelines. The systematic search was performed in five databases in November 2023 and updated in June 2024. All 16 eligible studies were original research that evaluated Ho-166-TARE. The endpoints analyzed were disease control rate (DCR), overall survival (OS), progression-free survival (PFS), clinical and laboratory adverse events, healthy-liver- and tumor-liver-absorbed doses. The risk of bias was assessed using the MINORS checklist.

The pooled overall disease control rate (DCR) was 72% (95% CI, 46-89%); by mRECIST, it was 93% (95% CI, 71-99%); and by RECIST 1.1, it was 54% (95% CI, 22-83%) at 3-month follow-up. Overall survival (OS) at 3, 6, 12, and 30 months was 98%, 89%, 74%, and 39%, respectively. Severe clinical adverse events were minimal, although some patients showed elevated GGT levels and lymphocytopenia. Tumor-absorbed doses were nearly three times higher than those in healthy liver tissue.

These findings suggest that Ho-166-TARE is a safe and effective locoregional treatment option for liver tumors, especially in cases where systemic therapy alone is insufficient or surgical resection is not feasible. Further studies are needed to investigate tumor-specific response, optimize dosimetry strategies, and establish standardized protocols for long-term outcome assessment.

Thoracic radiotherapy (RT) is now widely used in the treatment of advanced non-small cell lung cancer (NSCLC) as palliative, consolidative or radical therapy. However, RT adversely impacts the immune system, which can be evaluated by calculating the estimated dose of radiation to immune cells (EDRIC). We evaluated the prognostic impact of the EDRIC in patients with advanced NSCLC who received immunotherapy and thoracic RT.

We retrospectively enrolled 152 stage IV NSCLC patients who had received first-line immunotherapy and thoracic RT. EDRIC was a model developed by Jin et al., calculated using the number of radiotherapy fractions, mean lung dose, mean heart dose, and mean body dose. Spearman's rank correlation was used to assess the correlations between variables. The relationships of EDRIC (≥5.7 Gy vs. <5.7 Gy) with survival were assessed using Kaplan-Meier and Cox proportional hazard models.

The median PFS and OS were shorter in the EDRIC ≥ 5.7 Gy group (PFS: 10.2 months vs. 18.6 months, P < .0001; OS: 19.8 months vs. 30.2 months, P = .024). In the multivariate model, higher EDRIC was associated with worse PFS (HR = 2.791, P < .0001) and OS (HR = 1.823, P = .028). Additionally, bone metastasis was associated with worse OS (HR = 1.751, P = .022).

EDRIC was an independent predictor for PFS and OS in advanced NSCLC patients receiving immunotherapy and RT. These observations necessitate further exploration into techniques to optimize radiation exposure to the immune system in cancer treatment.

Radiation-induced lymphopenia (RIL) correlates with poor prognoses in solid tumors. This study aimed to investigate the post-radiation therapy (RT) longitudinal lymphocyte changes and the impact of different RT techniques on RIL in breast cancer patients.

We prospectively assessed 607 breast cancer patients who received hypofractionated postmastectomy RT in 8 hospitals. Radiation therapy techniques included integrated photon-based intensity modulated technique (integrated RT) and a combination of photon irradiation of supraclavicular nodes and electron irradiation of the chest wall and/or the internal mammary node (hybrid RT). Peripheral lymphocyte counts (PLC) were determined before RT, weekly during RT, at 1 and 2 weeks, 3 and 6 months post-RT, and then every 6 months. The primary outcome was the nadir PLC during RT, for which associated factors were analyzed. Univariate, multivariable linear regression and propensity score matching analyses were performed to evaluate the effect of different RT techniques on nadir PLC.

During RT, 121 (19.9%) patients had grade ≥3 RIL with a nadir PLC of 0.75 ± 0.33 × 109/L. The PLC started to recover at 1 week and reached pre-RT levels 1 year after RT and higher than pre-RT levels 2 years later. Multivariate analysis identified young age, low body mass index, radiation therapy targets involving multiple regions, integrated RT, and low pre-radiation therapy PLC as independent risk factors for nadir PLC (P < .005). The PLC at each time point during and after radiation therapy was lower in patients receiving integrated RT than in those receiving hybrid RT (P < .05). Before and after propensity score matching, integrated RT was significantly associated with lower nadir PLC after adjusting for radiation therapy targets and age (P < .001).

Breast cancer patients had prolonged lymphopenia post-RT. Integrated RT increased the risk of RIL and adversely affected recovery. Therefore, an appropriate RT technique should be considered to minimize RIL.

A detrimental association between radiation-induced lymphopenia (RIL) and oncologic outcomes in patients with esophageal cancer has been established. However, an optimal metric for RIL remains undefined but is important for the application of this knowledge in clinical decision-making and trial designs. The aim of this study was to find the optimal RIL metric discerning survival.

Patients with esophageal cancer treated with concurrent chemoradiation therapy (CRT; 2004-2022) were selected. Studied metrics included absolute lymphocyte counts (ALCs) and neutrophil counts-and calculated derivatives-at baseline and during CRT. Multivariable Cox regression models for progression-free survival (PFS) and overall survival (OS) were developed for each RIL metric. The optimal RIL metric was defined as the one in the model with the highest c-statistic.

Among 1339 included patients, 68% received photon-based and 32% proton-based CRT (median follow-up, 24.9 months). In multivariable analysis, the best-performing models included "ALC in week 3 of CRT" (corrected c-statistic 0.683 for PFS and 0.662 for OS). At an optimal threshold of <0.5 × 103/μL (ie, grade ≥3 RIL), ALC in week 3 was significantly associated with PFS (adjusted hazard ratio, 1.64; 95% CI, 1.27-2.13) and OS (adjusted hazard ratio, 1.56; 95% CI, 1.15-2.08), with 5-year PFS of 29% vs 40% and OS of 38% vs 51%, respectively.

Reaching grade ≥3 RIL in week 3 of CRT for esophageal cancer is the strongest RIL metric to distinguish survival outcomes. We suggest that this metric should be the target for lymphopenia-mitigating strategies and propose this metric to be included in future trials.

Radiotherapy (RT) is a cornerstone of cancer treatment. Compared with conventional high-dose radiation, low-dose radiation (LDR) causes less damage to normal tissues while potentially modulating immune responses and inhibiting tumor growth. LDR stimulates both innate and adaptive immunity, enhancing the activity of natural killer cells, dendritic cells, and T cells. However, the mechanisms underlying the effects of LDR on the immune system remain unclear.

To explore the history, research hotspots, and emerging trends in immune response to LDR literature over the past two decades.

Publications on immune responses to LDR were retrieved from the Web of Science Core Collection. Bibliometric tools, including CiteSpace and HistCite, were used to identify historical features, active topics, and emerging trends in this field.

Analysis of 1244 publications over the past two decades revealed a significant surge in research on immune responses to LDR, particularly in the last decade. Key journals such as INR J Radiat Biol, Cancers, and Radiat Res published pivotal studies. Citation networks identified key studies by authors like Twyman-Saint Victor C (2015) and Vanpouille-Box C (2017). Keyword analysis revealed hotspots such as ipilimumab, stereotactic body RT, and targeted therapy, possibly identifying future research directions. Temporal variations in keyword clusters and alluvial flow maps illustrate the evolution of research themes over time.

This bibliometric analysis provides valuable insights into the evolution of studies on responses to LDR, highlights research trends, and identifies emerging areas for further investigation.

Radiation therapy remains a cornerstone in the treatment of cancer, with the delineation of Organs at Risk (OARs), tumors, and malignant lymph nodes playing a critical role in the planning process. However, the manual segmentation of these anatomical structures is both time-consuming and costly, with inter-observer and intra-observer variability often leading to delineation errors. In recent years, deep learning-based automatic segmentation has gained increasing attention, leading to a proliferation of scholarly works on OAR and tumor segmentation algorithms utilizing deep learning techniques. Nevertheless, similar comprehensive reviews focusing solely on malignant lymph nodes are scarce. This paper provides an in-depth review of the advancements in deep learning for malignant lymph node segmentation and detection. After a brief overview of deep learning methodologies, the review examines specific models and their outcomes for malignant lymph node segmentation and detection across five clinical sites: head and neck, upper extremity, chest, abdomen, and pelvis. The discussion section extensively covers the current challenges and future trends in this field, analyzing how they might impact clinical applications. This review aims to bridge the gap in literature by providing a focused overview on deep learning applications in the context of malignant lymph node challenges, offering insights into their potential to enhance the precision and efficiency of cancer treatment planning.

Over half of radiotherapy-treated cancer patients develop radiation-induced lymphopenia (RIL). Severe RIL has been associated with worse prognosis and survival, and recent studies suggested that RIL also affects immunotherapy efficacy. We aimed to develop murine grade 2 (≥20 % decrease in absolute lymphocyte counts (ALC)) RIL models and to examine the effects of RIL on progression-free survival upon radiotherapy-immunotherapy treatment.

C57BL6/J mice received heart, large blood vessels (LBV) or thoracic vertebrae irradiation (10 Gy) and ALC were monitored weekly. In tumour-bearing animals, Lewis Lung Carcinoma cells were injected subcutaneously one day prior to RIL induction. When tumours reached 212 ± 45 mm3, tumours were locally irradiated (10 Gy), and animals were injected with L19-IL2 (1 mg/kg, 3 times QOD) or vehicle intravenously. Tumour growth was monitored until reaching > 4 times treatment starting volume. Flow cytometry-based immune cell profiling was performed on blood collected 2 weeks post-tumour cell injection.

Radiation treatment plans targeting lymphocyte-rich organs were optimized to achieve maximal target coverage while minimal dose to normal tissues. In naïve animals, LBV and vertebrae irradiation led to grade 2 RIL, however heart irradiation induced only grade 1 RIL. In tumour-bearing animals, RIL induction was confirmed by a 16 % and 20 % drop in ALC upon LBV and vertebrae irradiation, respectively. Grade 2 RIL did not negatively influence progression-free survival upon radiotherapy. Radiation combined with L19-IL2 induced a tumour growth delay compared to radiotherapy only (p < 0.0005). LBV or vertebrae irradiation did not affect radiotherapy-immunotherapy outcome, explained by the restored and increased lymphocyte and eosinophil counts upon L19-IL2 administration (p < 0.05). L19-IL2 increased inducible regulatory and CD8+ T cells, especially in vertebrae (p < 0.01) and LBV (p = 0.07) irradiated animals, respectively.

Collectively, utilizing the developed murine RIL models, we observed that RIL did not negatively affect radiotherapy treatment outcome. L19-IL2 can be a promising strategy to restore lymphocyte counts and revert RIL.

To develop a computational framework to investigate the implications of lymphocyte recirculation for understanding radiation-induced lymphopenia (RIL) and to compare model predictions with preclinical in vivo studies.

A whole-body compartmental model of lymphocyte migration in mice was developed, and unknown rate parameters were fitted to published experimental data. Using a stochastic representation of the model in combination with detailed mouse phantom meshes, implicit lymphocyte trajectories were computed. In parallel, a module was developed to reproduce small animal irradiation plans using either photon or proton beams. Combining these computational tools, we calculated the dose distribution of the recirculating lymphocyte pool in different irradiation scenarios and simulated the subsequent redistribution of viable lymphocytes. The relative importance of irradiation of secondary lymphoid organs (SLOs) versus the blood was investigated through in silico replications of 3 preclinical studies in which mice were locally irradiated.

Lymphocyte recirculation between the blood and SLOs attenuates lymphocyte depletion in 1 compartment by distributing the loss throughout the system. Because only a relatively small fraction (∼17% for mice) of the recirculating lymphocyte pool is in the blood at any given time, with most lymphocytes in the SLOs, the effect of SLO irradiation is greater than that of the blood. Predicted depletion trends correlated with those observed in preclinical studies but underestimated the degree of lymphopenia. The finding that proton beams can avert lymphopenia after whole-brain irradiation by sparing head and neck lymph nodes was reproduced.

The occurrence of RIL is associated with worse outcomes in patients with cancer but remains poorly understood. Therefore, a computational framework to replicate preclinical studies was developed to systematically investigate this phenomenon. Our simulations indicate that irradiation of SLOs contributes more to lymphocyte dose than blood irradiation. However, the expected cytotoxicity associated with the replicated preclinical studies could not fully account for the degree of lymphopenia observed.

This review explores the effects of ionizing radiation on blood and its components, focusing on its applications, biological impacts, and implications for medical and occupational settings. Ionizing radiation is a cornerstone of modern medicine, playing a critical role in diagnostic imaging, cancer treatment, and preventive measures, such as the irradiation of blood units to prevent transfusion-associated graft-versus-host disease. However, it also induces significant alterations in blood cells, including genetic damage, immune suppression, and changes in hematological, biochemical, and hemorheological parameters, depending on the dose, dose rate, and type of radiation. Conventional radiotherapy, hadron therapy, and the emerging FLASH modality exhibit distinct effects on blood. Hadron therapy and FLASH radiotherapy could reduce oxidative stress preserving red blood cell deformability more effectively than conventional methods, thereby minimizing systemic toxicity. However, the underlying mechanisms remain a topic of ongoing investigation. Additionally, studies reveal how different types of radiation, including gamma rays, X-rays, electron beams, and hadrons, uniquely influence blood cells, underscoring the complexity of radiobiological interactions. Challenges and controversies, such as the long-term hematological impact of radiation exposure, individual variability in response, and the potential of radioprotective strategies and immune system stimulation are also addressed. Insights into hemorheological changes and the development of personalized approaches are critical for optimizing therapeutic outcomes and safety protocols. By synthesizing current knowledge, this review emphasizes the need for further research on the effects of ionizing radiation on blood to bridge gaps in understanding and enhance clinical and practical applications.

Although the combination of radiotherapy and immunotherapy is regarded as a promising clinical treatment strategy, numerous clinical trials have failed to demonstrate synergistic effects. One of the key reasons is that conventional radiotherapies inevitably damage intratumoral effector immune cells. Boron Neutron Capture Therapy (BNCT) is a precise radiotherapy that selectively kills tumor cells while sparing adjacent normal cells, by utilizing 10B agents and neutron irradiation. Therefore, combinational BNCT-immunotherapy holds promise for achieving more effective synergistic effects. Here it develops a 10B-containing polymer that self-assembled with PD-L1 siRNA to form 10B/siPD-L1 nanoparticles for combinational BNCT-immunotherapy. Unlike antibodies, PD-L1 siRNA can inhibit intracellular PD-L1 upregulated by BNCT, activating T-cell immunity while also suppressing DNA repair. This can enhance BNCT-induced DNA damage, promoting immunogenic cell death (ICD) and further amplifying the antitumor immune effect. The results demonstrated that BNCT using 10B/siPD-L1 nanoparticles precisely killed tumor cells while sparing adjacent T cells and induced a potent antitumor immune response, inhibiting distal and metastatic tumors.

Hepatocellular carcinoma is a leading and increasing contributor to cancer-related death worldwide. Recent advancements in both liver-directed therapies in the form of yttrium-90 (90Y) radioembolization (RE) and systemic therapy in the form of immune checkpoint inhibitors (ICI) have expanded treatment options for patients with an otherwise poor prognosis. Despite these gains, ICIs and 90Y-RE each have key limitations with low objective response rates and persistent hazard of out-of-field recurrence, respectively, and overall survival remains low. However, each therapy's strength may mitigate the other's weakness, making them potentially ideal partners for combination treatment strategies. This review discusses the scientific and clinical rationale for combining 90Y-RE with ICIs, highlights early clinical trial data on its safety and effectiveness, and proposes key issues to be addressed in this emerging field. With optimal strategies, combination therapies can potentially result in increasing likelihood of durable and curative outcomes in later stage patients.

The FDA-approved ClearLLab 10C Reagents Panel (Beckman Coulter) simplified the diagnosis of leukemias and lymphomas by flow cytometry. However, the requirement of using 3 × 106 cells/mL cannot be met for paucicellular samples. Therefore, we tested whether this 10-color panel can be reliably employed to analyze specimens with low cell concentrations. Serial dilutions of 16 samples (5 normal, 11 abnormal), yielding concentrations ranging from 3.0 × 106 to 0.0469 × 106 cells/mL (64-fold difference), were stained using the B-cell and T-cell panels of the ClearLLab 10C system, and mean fluorescence intensity (MFI) was measured for each antibody. For each cell dilution, the deviation from the value obtained with the FDA-approved concentration of 3.0 × 106 cells/mL was calculated. The agreement between the highest and lowest cell concentration data was evaluated by the Bland and Altman method, Pearson's and Spearman's correlation analyses, and linear regression. In all patients, the antigen expression pattern was similar at all cell concentrations tested, and the mean deviation of the MFI from the value obtained using 3.0 × 106 cells/mL never exceeded 10% for any of the antibodies. The Bland-Altman method demonstrated the similarity between results obtained with the FDA-approved cell concentration and a 64-fold diluted cell suspension, and a high positive correlation was found between MFI acquired under these two conditions. The tests utilizing the lowest density of cells yielded the same patterns of antigen expression in all patients as those performed with the FDA-approved concentration, documenting a 100% concordance between these two protocols. The ClearLLab 10C panel can reliably determine the expression of markers of leukemias and lymphomas in paucicellular samples containing as little as 0.0469 × 106 cells/mL (64-fold lower than the FDA-approved concentration). This finding markedly expands the applicability of the ClearLLab 10C platform in a clinical setting.

Radiotherapy is thought to enhance anti-tumor immunity, particularly when delivered in a hypofractionated and multisite manner. Therefore, we investigated the effects of combining radiotherapy with nivolumab in patients with advanced melanoma.

This was a multicenter, non-randomized, phase 2 trial that enrolled patients with treatment-naïve metastatic melanoma. They received nivolumab (240 mg / 2 weeks) plus radiotherapy (day 15, 6 Gy × 3). When feasible, one target from each organ was irradiated (no irradiation of all targets). The primary endpoint was 1-year overall survival (OS).

This trial included 64 patients between March 2017 and July 2019. The median follow-up was 23.5 (2.3-43.8) months. The median age was 68 (35-95) years, patients were mostly male (67 %) with an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0 (72 %), stage IV-M1c disease (47 %), and were BRAF-wild-type (67 %). The 2-year OS and 1-year PFS rates were 65.2 % and 56 %, respectively (P = 0.22 and P = 0.03, vs. 58 % and 43 %, respectively, in the Checkmate 066 study). Thirty-seven (58 %) and twenty-seven (42 %) patients were irradiated at one and multiple targets, respectively. The ECOG-PS (1 vs. 0; HR = 3.5; P = 0.005) was an independent prognostic factor for OS. Irradiating more than one site and irradiating a smaller cumulative tumor volume tended to correlate with better outcome. Grade 3-4 treatment-related adverse events occurred in 21.9 % of the patients (no grade 5).

Combined immunotherapy and hypofractionated radiotherapy did not improve survival compared to historical cohorts. The radiotherapy schedule needs to be optimized in order to improve these results.

Adult cancer survivors are at a heightened risk for secondary primary differentiated thyroid carcinoma (2-DTC). The characteristics and outcomes of 2-DTC remain poorly understood.

We aimed to explore the characteristics and outcomes of 2-DTC.

We retrospectively analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2017). 2-DTC was divided into 25 subgroups based on prior primary malignancies (PPMs). Baseline characteristics were compared using the chi-square test. Multivariable logistic analysis was used to identified if PPMs were associated with aggressive DTC characteristics. DTC-specific and cancer-specific mortality were analyzed using a univariable and multivariable competing risk regression model.

There were 138 555 1-DTC and 9253 2-DTC patients identified. 2-DTC patients were predominantly older, male, and White compared to first primary DTC (1-DTC) (all P < .05). In multivariable logistic regression analysis, only 4 types of PPMs were associated with higher rates of DTC aggressive characteristics, while 19 types exhibited lower rates (all P < .05). In multivariable competing risk analysis, 2-DTC showed no mortality risk in stages I (SHR: 1.16; 95% CI, 0.65-2.07) and II (SHR: 0.67; 95% CI, 0.45-1.01), but a protective role in stages III (SHR: 0.47; 95% CI, 0.27-0.83) and IV (SHR: 0.72; 95% CI, 0.52-0.99). Most PPMs that developed into 2-DTC had a lower risk of DTC-specific death than 1-DTC, but many PPMs had a higher risk of cancer-specific death.

Given the characteristics and outcomes of 2-DTC, aggressive treatment for 2-DTC, particularly for PPM with a high mortality risk, may not be advisable.

FLASH ultra-high dose rate radiotherapy (RT) can effectively exert the protective effect on normal tissue and reduce the risk of treatment-related toxicity, without compromising the killing effect on tumor tissue, resulting in a significant differential biological effect between tumor control and normal tissue damage, namely the FLASH effect. To date, the precise biological details of the FLASH effect remain uncertain. The currently mainstream mechanisms proposed by the academic community include the transient oxygen depletion hypothesis, free radical hypothesis, immune protection hypothesis, and DNA integrity hypothesis, which have attracted increasing attention in recent years. Based on these theoretical principles and numerous investigations on the FLASH effect in vivo and in vitro, the combined application of FLASH and immune checkpoint inhibitors (ICIs) has been considered synergistic and potentially practical. The primary underlying basis is that FLASH might actively preserve the number and function of circulating immune cells, thereby enhancing the efficacy of immune cell-mediated immunotherapy. Meanwhile, FLASH RT could activate the tumor immune microenvironment and transform "cold'' tumors into ''hot'' ones, consequently boosting local and systemic anti-tumor immunity and expanding the therapeutic benefits of ICIs. Moreover, FLASH might attenuate immunoinflammatory responses and minimize the incidence of radiation-related adverse events, allowing for the potentially safer and promising clinical application of combing FLASH RT with ICI therapy. Nevertheless, data on this treatment modality is currently lacking, and several barriers remain to be addressed, including the logistical bottlenecks, technical hurdles, limited availability, and unclear biological mechanisms. Further research is warranted in the future.

Neoadjuvant radiotherapy (RT) or chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal adenocarcinoma. The recent emerging data on preoperative immunotherapy as an effective therapeutic modality for mismatch repair deficient rectal carcinomas suggests that the immune system plays a significant role in tumor eradication. Although RT has been shown to stimulate anti-tumor immunity, it also leads to substantial lymphopenia, hindering the effect of immune response.

We retrospectively analyzed 33 rectal adenocarcinoma patients who underwent CRT in our department, aiming to identify the effects of CRT on the peripheral blood lymphocyte counts (LC) and the potential impact of CRT-induced lymphopenia on tumor response and prognosis of patients.

A statistically significant decrease in the LC of patients was observed after CRT (median values of 2,184/μL and 517/μL before and after treatment, respectively; p < 0.001). While no correlation between ypT-stage, ypN status, and LC was found, poor tumor regression grade was significantly associated with lower LC (p = 0.036). Moreover, lymphopenia was associated with poorer distant metastasis-free survival (p = 0.003). Distant metastases were documented in 0% of patients with post-CRT LC above 518/μL vs. 44.5% of patients with lower LC values.

Although further investigation is demanded, given the limited number of patients analyzed in the study, lymphopenia emerges as a significant adverse event that rectal adenocarcinoma patients face during treatment with neoadjuvant CRT, with subsequent implications on tumor response and prognosis. Protection of the immune system during CRT emerges as an important target for clinical research.

The absolute lymphocyte count (ALC), lymphocyte-to-monocyte ratio (LMR), and neutrophil-to-lymphocyte ratio (NLR) offer convenient means to assess systemic inflammation post-cancer treatment, which influences treatment outcomes. Understanding these biomarker variations and leukocyte subpopulation interplay is crucial for optimizing radiotherapy. Herein, leukocyte subpopulations (T-CD4+, T-CD8+, B cells, NK cells, neutrophils, monocytes) during and after brain irradiation (using X-rays or protons) in tumor-free mice were used to compute ALC, LMR, and NLR, on which radiation parameter influence was assessed by principal component analysis (PCA). NLR kinetics was further examined using modeling. Leukocyte subpopulation interplays and their response to radiation parameters were examined using PCA and correlation analysis. Under X-rays, ALC and LMR decreased, with ALC recovered to baseline after irradiation, but not LMR. Both X-rays and protons increased the NLR during irradiation, recovering in protons but not X-rays. Both irradiation volume and dose rate had a pronounced effect on the NLR. Leukocyte subpopulation interplay was observed under X-rays and protons, normalizing in the proton group by day 28. Lymphopenia was observed in all lymphocyte subpopulations under X-ray irradiation but not protons. The recovery patterns varied among the subpopulations. Neutrophil counts increased during irradiation, with the recovery of protons, but not X-rays, by day 28. Interplays between NK cells and myeloid subpopulations were evident under X-rays but not protons. Importantly, no interplay was detected between myeloid cells and T/B cells, indicating that LMR and NLR variations were primarily due to independent responses to brain irradiation. A tumor-free experimental mouse model was used to study the effects of brain radiotherapy on systemic immunity. When administering fractionated irradiation with a total dose of 20 Gy using a vertical beam to either the whole brain or hemi-brain, proton irradiation had fewer adverse impacts on the immune system compared to X-rays in tumor-free rodents.

Purpose.To provide a novel and personalized method (FLIP, FLowand Irradiation Personalized) using patient-specific circulating blood flows and individualized time-dependent irradiation distributions, to quantify the dose delivered to blood in large vessels during proton or photon external beam radiotherapy.Methods.Patient-specific data were obtained from ten cancer patients undergoing radiotherapy, including the blood velocity field in large vessels and the temporal irradiation scheme using photons or protons. The large vessels and the corresponding blood flow velocities are obtained from phase-contrast MRI sequences. The blood dose is obtained discretizing the fluid into individual blood particles (BPs). A Lagrangian approach was applied to simulate the BPs trajectories along the vascular velocity field flowlines. Beam delivery dynamics was obtained from beam delivery machine measurements. The whole IS is split into a sequence of successive IEs, each one with its constant dose rate, as well as its corresponding initial and final time. Calculating the dose rate and knowing the spatiotemporal distribution of BPs, the dose is computed by accumulating the energy received by each BP as the time-dependent irradiation beams take place during the treatment.Results.Blood dose volume histograms from proton therapy and photon radiotherapy patients were assessed. The irradiation times distribution is obtained for BPs in both modalities. Two dosimetric parameters are presented: (i)D3%, representing the minimum dose received by the 3% of BPs receiving the highest doses, and (ii)V0.5 Gy, denoting the blood volume percentage that has received at least 0.5 Gy.Conclusion.A novel methodology is proposed for quantifying the circulating blood dose along large vessels. This methodology involves the use of patient-specific vasculature, blood flow velocity field, and dose delivery dynamics recovered from the irradiation machine. Relevant parameters that affect the dose received, as the distance between large vessels and CTV, are identified.

Immunotherapy has revolutionized the field of cancer treatment, changing the standard of care to the use of immune checkpoint inhibitors. Radiotherapy can boost anti-tumour immune responses by changing the tumour microenvironment, but it also can cause radiotherapy-induced lymphopenia (RIL), a decrease in circulating lymphocyte counts. RIL has been associated with lower survival in patients undergoing radiotherapy, and new studies have suggested that it can also affect immunotherapy outcome. To study RIL's effects and to explore mitigation treatment strategies, preclinical models closely mimicking the clinical situation are needed. State-of-the-art image-guided small animal irradiators now offer the possibility to target specific organs in small animals to induce RIL, aiding research on its molecular mechanisms and prevention. This review covers the relationship between radiotherapy and RIL, its impact on patient survival, and future directions to generate models to investigate and prevent RIL.

Tumor-infiltrating lymphocytes (TILs) have prognostic significance in several cancers, including breast cancer. Despite interest in combining radiation therapy with immunotherapy, little is known about the effect of radiation therapy itself on the tumor-immune microenvironment, including TILs. Here, we interrogated longitudinal dynamics of TILs and systemic lymphocytes in patient samples taken before, during, and after neoadjuvant radiation therapy (NART) from PRADA and Neo-RT breast clinical trials.

We manually scored stromal TILs (sTILs) from longitudinal tumor samples using standardized guidelines as well as deep learning-based scores at cell-level (cTIL) and cell- and tissue-level combination analyses (SuperTIL). In parallel, we interrogated absolute lymphocyte counts from routine blood tests at corresponding time points during treatment. Exploratory analyses studied the relationship between TILs and pathologic complete response (pCR) and long-term outcomes.

Patients receiving NART experienced a significant and uniform decrease in sTILs that did not recover at the time of surgery (P < .0001). This lymphodepletive effect was also mirrored in peripheral blood. Our SuperTIL deep learning score showed good concordance with manual sTILs and importantly performed comparably to manual scores in predicting pCR from diagnostic biopsies. The analysis suggested an association between baseline sTILs and pCR, as well as sTILs at surgery and relapse, in patients receiving NART.

This study provides novel insights into TIL dynamics in the context of NART in breast cancer and demonstrates the potential for artificial intelligence to assist routine pathology. We have identified trends that warrant further interrogation and have a bearing on future radioimmunotherapy trials.

To analyze the changes of immune function-related indicators with newly diagnosed glioblastoma before and after radiotherapy and their clinical significance. Clinical data of 104 patients were analyzed. The independent samples t-test or chi-square test was used to compare changes in immune function indicators and to ascertain the differences between groups with different doses or volumes. The grading of the lowest lymphocyte count during radiotherapy was compared. The log-rank (Mantel - Cox) test of the Kaplan - Meier method was used to compare the survival rate, and the relationship of radiotherapy-related parameters, with the survival rate was evaluated by using the Spearman correlation coefficient. A Cox regression model was used to determine the relationship between various immune function indicators and prognosis. The percentages of total T lymphocytes and CD4+ T cells, the CD4-to-CD8 subset ratio, and the percentages of B cells and NKT cells showed an overall decreasing trend, whereas the percentages of CD8+ T cells and NK cells displayed an overall increasing trend. The lower CD4+ T cell percentage and CD4/CD8 ratio after radiotherapy were independent risk factors for OS. Short OS was observed in patients with grade 3 or 4 lymphopenia or with low levels of hemoglobin and serum albumin before radiotherapy. The percentage of CD4+ T cells and the CD4/CD8 ratio were higher in patients with the low tumor-irradiated volume and irradiated volume and dose of the OAR, than in patients from the corresponding high indicator group. Different irradiation dose or volume can differentially alter various immune function indicators.

The role of adaptive immunity in long-term outcomes in early breast cancer is increasingly recognised. Standard (neo)adjuvant chemotherapy can have adverse effects on immune cells. We conducted a retrospective longitudinal study of full blood counts (FBC) of 200 patients receiving (neo)adjuvant chemotherapy for early breast cancer at a single institution. FBC results at four time points from pre-treatment to 12 months post-chemotherapy were analysed. Flow cytometry was performed for patients with matched pre- and post-chemotherapy peripheral blood mononuclear cell samples. A significant decrease in absolute lymphocyte count at 12 months post-chemotherapy was observed (p < 0.01), most pronounced in pre-menopausal patients (n = 73; p < 0.01), patients receiving dose-dense chemotherapy regimens (n = 60; p < 0.01) and patients receiving adjuvant radiotherapy (n = 147, p < 0.01). In pre-menopausal patients, significant changes in CD4+ T cells subsets post-chemotherapy were observed. Further investigation, including long-term clinical outcomes, is needed to meaningfully improve long-term anti-tumour immunity.

This phase I/II trial (ChiCTR2000032879) assessed the safety and efficacy of toripalimab combined with chemoradiotherapy for locally advanced cervical squamous cell carcinoma.

Twenty-two patients, regardless of their programmed death ligand-1 (PD-L1) status, received toripalimab combined with concurrent chemoradiotherapy (CCRT). CCRT included cisplatin (40 mg/m2, once weekly for 5 weeks), radiotherapy (45-50.4 Gy/25-28 Fx, 5 fractions weekly), followed by brachytherapy (24-30 Gy/3-5 Fx) and toripalimab (240 mg, intravenous) on days 1, 22 and 43 during CCRT. The primary endpoints were safety and 2-year progression-free survival (PFS). The secondary endpoints included 2-year local control (LC), local regional control and overall survival (OS).

All patients successfully completed CCRT and toripalimab treatment. Grade III and higher adverse events (AEs) were observed in 11 patients (11/22, 50%), and no patient experienced grade V AEs. The objective response rate (ORR) was 100%. At the data cutoff (June 30, 2023), the median follow-up was 31.8 months (9.5 to 37.8 months). The 2-year PFS rate was 81.8%. The 2-year LC and local regional control rates were both 95.5%, and the 2-year OS rate was 90.9%.

Toripalimab combined with CCRT achieved good tolerance and showed promising anti-tumor effects in patients with locally advanced cervical cancer.

Radiotherapy (RT)-induced lymphopenia may hinder the anti-tumor immune response. Preoperative RT or chemo-RT (CRT) for locally advanced rectal cancer is a standard therapeutic approach, while immunotherapy has been approved for mismatch repair-deficient rectal tumors. We retrospectively analyzed 98 rectal adenocarcinoma patients undergoing neoadjuvant CRT with VMAT (groups A, B, C) or IMRT (group D) techniques, with four different RT schemes: group A (n = 24): 25 Gy/5 Gy/fraction plus a 0.2 Gy/fraction rectal tumor boost; group B (n = 22): 34 Gy/3.4 Gy/fraction, with a 1-week treatment break after the first five RT fractions; group C (n = 20): 46 Gy/2 Gy/fraction plus a 0.2 Gy/fraction rectal tumor boost; group D (n = 32): 45 Gy/1.8 Gy/fraction followed by 5.4 Gy/1.8 Gy/fraction to the rectal tumor. We examined the effect of the time-corrected normalized total dose (NTD-T) to the BM on lymphopenia. Groups A and B (hypofractionated RT) had significantly higher lymphocyte counts (LCs) after RT than groups C and D (p < 0.03). An inverse association between the LCs after RT and NTD-T was demonstrated (p = 0.01). An NTD-T threshold of 30 Gy delivered to 30% of the BM volume emerged as a potential constraint for RT planning, which could be successfully integrated in the RT plan. Hypofractionated and accelerated RT schemes, and BM-sparing techniques may reduce lymphocytic damage and prove critical for immuno-RT clinical trials.

Biomarkers are crucial in cancer diagnostics, prognosis, and surveillance. Extensive research has been dedicated to identifying biomarkers that are broadly applicable across multiple cancer types and can be easily obtained from routine investigations such as blood cell counts. One such biomarker, the neutrophil-to-lymphocyte ratio (NLR), has been established as a prognostic marker in cancer. However, due to the dynamic nature of cancer diagnosis and treatment, periodic updates are necessary to keep abreast of the vast amount of published data. In this review, we searched the PubMed database and analyzed and synthesized recent literature (2018-February 2024) on the role of NLR in predicting clinical outcomes in nonhematologic malignancies. The search was conducted using the PubMed database. We included a total of 88 studies, encompassing 28,050 human subjects, and categorized the findings into four major groups: gastrointestinal cancer, cancers of the urinary tract and reproductive system, lung cancer, and breast cancer. Our analysis confirms that NLR is a reliable prognostic indicator in cancer, and we discuss the specific characteristics, limitations, and exceptions associated with its use. The review concludes with a concise Q&A section, presenting the most relevant take-home messages in response to five key practical questions on this topic.

Stereotactic body radiation therapy (SBRT) is known to modulate the immune system and contribute to the generation of anti-tumor T cells and stimulate T cell infiltration into tumors. Radiation-induced immune suppression (RIIS) is a side effect of radiation therapy that can decrease immunological function by killing naive T cells as well as SBRT-induced newly created effector T cells, suppressing the immune response to tumors and increasing susceptibility to infections.

RIIS varies substantially among patients and it is currently unclear what drives this variability. Models that can accurately predict RIIS in near real time based on treatment plan characteristics would allow treatment planners to maintain current protocol specific dosimetric criteria while minimizing immune suppression. In this paper, we present an algorithm to predict RIIS based on a model of circulating blood using early stage lung cancer patients treated with SBRT.

This Python-based algorithm uses DICOM data for radiation therapy treatment plans, dose maps, patient CT data sets, and organ delineations to stochastically simulate blood flow and predict the doses absorbed by circulating lymphocytes. These absorbed doses are used to predict the fraction of lymphocytes killed by a given treatment plan. Finally, the time dependence of absolute lymphocyte count (ALC) following SBRT is modeled using longitudinal blood data up to a year after treatment. This model was developed and evaluated on a cohort of 64 patients with 10-fold cross validation.

Our algorithm predicted post-treatment ALC with an average error of0.24 ± 0.21 × 10 9 $0.24 \pm 0.21 \times {10}^9$ cells/L with 89% of the patients having a prediction error below 0.5 × 109 cells/L. The accuracy was consistent across a wide range of clinical and treatment variables. Our model is able to predict post-treatment ALC < 0.8 (grade 2 lymphopenia), with a sensitivity of 81% and a specificity of 98%. This model has a ∼38-s end-to-end prediction time of post treatment ALC.

Our model performed well in predicting RIIS in patients treated using lung SBRT. With near-real time model prediction time, it has the capability to be interfaced with treatment planning systems to prospectively reduce immune cell toxicity while maintaining national SBRT conformity and plan quality criteria.

Differences in radiation-induced lymphopenia and prognosis between methods of radiotherapy (RT) for brain metastases remain unclear.

In this retrospective analysis of patients who underwent whole-brain radiotherapy (WBRT) or stereotactic radiosurgery/radiotherapy (SRS/SRT) for brain metastases, baseline total lymphocyte count (TLC) data were obtained within 2 weeks before RT initiation. Follow-up TLC data were evaluated at 0-2, 2-4, and 4-8 weeks after RT completion. Persistent lymphopenia was defined as <800/μL at any time point.

Overall, 138 RT courses in 128 patients were eligible (94 WBRT; 44 SRS/SRT). In the WBRT courses, the median baseline TLC was 1325/μL (IQR: 923-1799). Follow-up TLC decreased significantly to 946/μL (626-1316), 992/μL (675-1291), and 1075/μL (762-1435) (p < 0.001). SRS/SRT courses showed no significant TLC decrease. Multivariate analysis revealed female sex, prior RT, baseline TLC < 800/μL, and WBRT use were significantly associated with persistent lymphopenia. In the WBRT group, overall survival was significantly different between those with and without persistent lymphopenia (median, 2.6 and 6.1 months; p < 0.001). However, there was no significant difference in survival in the SRS/SRT group (p = 0.60).

This study suggests SRS/SRT might be preferable for lymphocyte preservation in brain metastasis patients.

Radiation induced lymphopenia (RIL) deteriorate survival and diminishes the benefit of immune checkpoint inhibitors in combined treatment of lung cancer. Given the inconsistent data across various studies on the predictors of RIL, we aim to methodically elucidate these predictors and formulate a practical guide for clinicians.

We conducted observational cohort study in four tertiary cancer centers. Patients with non-small cell lung cancer and small cell lung cancer, without lymphopenia grade >1, who underwent standalone radiotherapy (RT) in minimum 15 fractions were eligible. Dose-volume parameters of structures and clinical factors were comprehensively analyzed using various predictors selection methods and statistical models (Linear Regressors, Elastic Net, Bayesian Regressors, Huber Regression, regression based on k-nearest neighbors, Gaussian Process Regressor, Decision Tree Regressor, Random Forest Regressor, eXtreme Gradient Boosting, Automated Machine Learning) and were ranked to predict lymphocytes count nadir (alc_nadir).

Two hundred thirty eight patients (stage I-3.4%, II-17.6%, III-75.2%, IV-3.8%) who underwent RT to median dose of 60 Gy were analyzed. Median alc_nadir was 0.68K/mm3. The 60 feature sets were evaluated in 600 models (RMSE 0.27-0.41K/mm³). The most important features were baseline lymphocyte count (alc_1), mean lung_dose, lung v05, lung v10, heart v05 and effective dose to immune cells (edic). In patients with alc_1 ≤ 2.005K/mm3, median alc_nadir predictions were 0.54K/mm3 for lung_v05p > 51.8% and 0.76K/mm3 for lung_v05p ≤ 51.8%. Lymphopenia was rare in patients with alc_1 > 2.005K/mm3.

RIL was most severe in patients with low early lymphocyte counts, primarily triggered by low RT doses in the heart and lungs.

Recent data found a correlation between lymphopenia occurring early during craniospinal radiation therapy (RT) and risk of disease recurrence in newly diagnosed childhood medulloblastoma. However, the population included patients who received chemotherapy prior to or during RT. Here, we investigate the effect of lymphopenia during RT in patients with newly diagnosed pediatric medulloblastoma who were chemotherapy-naïve.

We analyzed 79 patients with newly diagnosed medulloblastoma (ages 2-21 years) treated between 1997 and 2013 with craniospinal RT. Log-rank tests were used to determine survival differences, and Cox proportional hazards regression was used to assess associations between patient characteristics and lymphopenia with disease recurrence risk.

Eighty-three percent of patients (62/75) had grade ≥3 lymphopenia by RT Week 3, with 95% developing grade ≥3 lymphopenia at some point during therapy. There was no difference in incidence of lymphopenia between those who received proton beam RT (93%) versus photon (97%). Twenty-four of 79 (30%) patients developed disease recurrence at an average 27.0 months after diagnosis. There was higher risk of disease recurrence in patients with grade ≥3 lymphopenia during RT Week 4 (log-rank p = .016; Cox p = .03) and Week 5 (log-rank p = .024; Cox p = .032); after adjusting for clinical risk group, only grade ≥3 lymphopenia at Week 4 remained prognostic (Cox p = .04). No correlation was found between risk of tumor recurrence and early lymphopenia (RT Weeks 0-3) or absolute lymphocyte count (ALC) below the median at any time during RT.

Lymphopenia during RT Weeks 4 and 5 correlates with increased risk of tumor recurrence in pediatric patients with newly diagnosed medulloblastoma.

In the multidisciplinary management of oligometastatic, persistent, or recurrent (MPR) ovarian cancer, radiotherapy (RT) is becoming a more and more worthwhile treatment to potentially improve the chronicity of the disease. Particle beam RT has proved to be effective in several gynecological malignancies, but so far no data are available for ovarian cancer.

This is a real-world, retrospective, bi-institutional, single-arm study aimed to assess the effectiveness and the safety of carbon ion RT (CIRT) in this setting. The co-first endpoints are 1-year and 2-year actuarial local control (LC) rates and the objective response rate (ORR) defined on a "per lesion" basis. The secondary endpoint was toxicity. Actuarial outcomes were evaluated using the Kaplan-Meier method while potential predictors were explored using the Log-rank test. Bi-variable logistic regression was employed in the analysis of factors predicting the complete response on a per-lesion basis.

26 patients accounting for a total of 36 lesions underwent CIRT with a total median dose of 52.8 Gy[RBE] (range: 39-64 Gy[RBE]). Five patients received CIRT for re-irradiation. No concomitant systemic therapies were administered during CIRT. Within 12 months after the treatment, 17 lesions (47 %) achieved complete response while 18 (50 %) obtained a partial response with an ORR of 97 %. The achievement of a complete response is related to the dose per fraction (>4.2 Gy[RBE], p = 0.04) and total dose (>52,8 Gy[RBE], p = 0.05). The 1-year LC was 92 % and the 2-year LC was 83 %, according to the achievement of a CR (p = 0.007) and GTV ≤ 14 cm3 (p = 0.024). No grade > 3 toxicities were recorded both in naïve and re-irradiated patients. PARP-i and anti-VEGF seemed not to exacerbate the risk of severe toxicities.

CIRT was effective and safe in MPR ovarian cancers, even in the case of re-irradiation. Largest cohort studies and longer follow-up are needed to confirm these data.

This study aimed to develop a normal tissue complication probability (NTCP) model to estimate the risk of severe radiation-induced lymphopenia (SRIL; absolute lymphocyte count [ALC] < 500/μL) by using the blood dose of patients with hepatocellular carcinoma (HCC).

We retrospectively collected data from 75 patients with HCC who received radiation therapy (RT) between 2015 and 2018. The hematological dose framework calculated blood dose-volume histograms (DVHs) using a predefined blood flow model, organ DVHs, the number of treatment fractions, and beam delivery time. A Lyman-Kutcher-Burman model with a generalized equivalent dose was used to establish the NTCP model, reflecting the whole-blood DVHs. Optimization of the Lyman-Kutcher-Burman parameters was conducted by minimizing a negative log-likelihood function.

There were 6, 4, 18, 33, and 14 patients in the groups with radiation-induced lymphopenia grades 0, 1, 2, 3, and 4, respectively. The median pre- and post-RT ALC values were 1410/μL (range, 520-3710/μL) and 470/μL (range, 60-1760/μL), respectively. There was a correlation between mean blood dose and ALC depletion (Pearson r = -0.664; P < .001). The average mean blood doses in each radiation-induced lymphopenia group were 2.90 Gy (95% CI, 1.96-3.85 Gy) for grade 0 to 1, 5.29 Gy (95% CI, 4.12-6.45 Gy) for grade 2, 8.81 Gy (95% CI, 7.55-10.07 Gy) for grade 3, and 11.69 Gy (95% CI, 9.82-17.57 Gy) for grade 4. When applying the developed NTCP model to predict SRIL, the area under the receiver operating characteristic curve and Brier score values were 0.89 and 0.12, respectively.

We developed the first NTCP model based on whole-blood DVHs for estimating SRIL after abdominal RT in patients with HCC. Our results showed a strong correlation between blood dose and ALC depletion, suggesting the potential to predict the risk of SRIL occurrence using blood dose.

Ionizing radiation can have a wide range of impacts on tumor-immune interactions, which are being studied with the greatest interest and at an accelerating pace by the medical community. Despite its undeniable immunostimulatory potential, it clearly appears that radiotherapy as it is prescribed and delivered nowadays often alters the host's immunity toward a suboptimal state. This may impair the full recovery of a sustained and efficient antitumor immunosurveillance posttreatment. An emerging concept is arising from this awareness and consists of reconsidering the way of designing radiation treatment planning, notably by taking into account the individualized risks of deleterious radio-induced immune alteration that can be deciphered from the planned beam trajectory through lymphocyte-rich organs. In this review, we critically appraise key aspects to consider while planning immunologically fitted radiotherapy, including the challenges linked to the identification of new dose constraints to immune-rich structures. We also discuss how pharmacologic immunomodulation could be advantageously used in combination with radiotherapy to compensate for the radio-induced loss, for example, with (i) agonists of interleukin (IL)2, IL4, IL7, IL9, IL15, or IL21, similarly to G-CSF being used for the prophylaxis of severe chemo-induced neutropenia, or with (ii) myeloid-derived suppressive cell blockers.

Given the substantial lack of knowledge, we aimed to assess clinical/dosimetry predictors of late hematological toxicity on patients undergoing pelvic-nodes irradiation (PNI) for prostate cancer (PCa) within a prospective multi-institute study.