The relationship between splenic dose and radiation-induced lymphopenia.

Lymphocytes, which are highly sensitive to radiation, play a crucial role in the body's defense against tumors. Radiation-induced lymphopenia has been associated with poorer outcomes in different cancer types. Despite being the largest secondary lymphoid organ, the spleen has not been officially designated as an organ at risk. This study hypothesizes a connection between spleen irradiation and lymphopenia and seeks to establish evidence-based dosage limits for the spleen. We retrospectively analyzed data from 96 patients with locally advanced gastric cancer who received postoperative chemoradiotherapy (CRT) between May 2010 and May 2017. Complete blood counts were collected before, during and after CRT. We established a model for predicting the minimum absolute lymphocyte count (Min ALC) and to investigate potential associations between spleen dosimetric variables and Min ALC. The median follow-up was 60 months. The 5-year overall survival (OS) and disease-free survival (DFS) were 65.2% and 56.8%, respectively. The median values of pre-treatment ALC, Min ALC and post-treatment ALC were 1.40 × 109, 0.23 × 109 and 0.28 × 109/L, respectively. Regression analysis confirmed that the primary tumor location, number of fractions and spleen V5 were significant predictors of Min ALC during radiation therapy. Changes in ALC (ΔALC) were identified as an independent predictor of both OS and DFS. Spleen V5 is an independent predictor for Min ALC, and the maximum dose of the spleen is associated with an increased risk of severe lymphopenia. Therefore, these doses should be restricted in clinical practice. Additionally, ΔALC can serve as a prognostic indicator for adjuvant radiotherapy in gastric cancer.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma: A case report.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with limited effective treatment especially after first-line chemotherapy. The human epidermal growth factor receptor 2 (HER-2) immunohistochemistry (IHC) positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC. CASE SUMMARY: We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn't have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment. A novel combination therapy PRaG 3.0 of RC48 (HER2-antibody-drug conjugate), radiotherapy, PD-1 inhibitor, granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month. She had not developed any grade 2 or above treatment-related adverse events at any point. Percentage of peripheral CD8+Temra and CD4+Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy. CONCLUSION: PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Evaluation of the efficacy and safety of a precise thymalfasin-regulated PRaG regimen for advanced refractory solid tumours: protocol for the open-label, prospective, multicentre study (PRaG5.0 study).

INTRODUCTION: The PRaG regimen, which consists of hypofractionated radiotherapy combined with a programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitor and granulocyte-macrophage colony stimulating factor (GM-CSF), has been demonstrated to have a survival benefit in patients with advanced solid tumours who have failed at least two lines of treatment. Nonetheless, lymphopenia poses an impediment to the enduring efficacy of PD-1/PD-L1 inhibitor therapy. Adequate lymphocyte reserves are essential for the efficacy of immunotherapy. Coupling the PRaG regimen with immunomodulatory agents that augment the number and functionality of lymphocytes may yield further survival benefits in this cohort of patients. OBJECTIVE: The aim of this study is to investigate the effectiveness and safety of a meticulously thymalfasin-controlled PRaG regimen in patients with advanced and chemotherapy-resistant solid tumours. METHODS AND ANALYSIS: The study has a prospective, single-arm, open-label, multicentre design and aims to recruit up to 60 patients with histologically confirmed advanced solid tumours that have relapsed or metastasised. All eligible patients will receive a minimum of two cycles of the PRaG regimen comprising thymalfasin followed by maintenance treatment with a PD-1/PD-L1 inhibitor and thymalfasin for 1 year or until disease progression. Patients will be monitored according to the predetermined protocol for a year or until disease progression after initiation of radiotherapy. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Soochow University, on 25 November 2022 (JD-LK-2022-151-01) and all other participating hospitals. Findings will be disseminated through national and international conferences. We also plan to publish our findings in high-impact peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05790447.

PD-1 inhibitor combined with radiotherapy and GM-CSF in MSS/pMMR metastatic colon cancer: a case report.

Patients with chemo-refractory metastatic colorectal cancer (mCRC) have poor prognoses. The application of programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors encouragingly improved the survival of mCRC patients with microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR). Unfortunately, it was ineffective for mCRC with microsatellite-stable (MSS)/proficient mismatch repair (pMMR), which accounted for 95% of mCRC. Radiotherapy can promote local control by directly killing tumor cells and inducing positive immune activities, which might help synergistically with immunotherapy. We present the report of an advanced MSS/pMMR mCRC patient who had progressive disease (PD) after first-line chemotherapy, palliative surgery and second-line chemotherapy combined with targeted therapy. Then the patient received the therapy of PD-1 inhibitor combined with radiotherapy and granulocyte-macrophage colony-stimulating factor (GM-CSF). According to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1), the patient showed a complete response (CR) after triple-combined therapy with progression-free survival (PFS) for more than 2 years so far. The patient had no other significant adverse reactions except for fatigue (Grade 1). The triple-combination therapy provided a promising strategy for metastatic chemo-refractory MSS/pMMR mCRC patients.

PRaG Therapy of Refractory Metastatic Gastric Cancer: A Case Report.

Patients with metastatic gastric cancer had limited treatments and often had a somber prognosis, especially when patients were unable to tolerate high-intensity cytotoxic treatment due to poor physical condition or organ dysfunction after the failure of standard therapy. Here, we reported a metastatic and proficient mismatch repair (pMMR) gastric adenocarcinoma patient with the Eastern Cooperative Oncology Group (ECOG) performance status score of 2 associated with hypoproteinemia and fatigue, and poor appetite that was unable to tolerate high-intensity therapy after several chemotherapy regimens and anti-angiogenic therapy. After receiving novel triple-combination therapy, which consists of PD-1 inhibitor, Radiotherapy and Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy (PRaG for short), the patient achieved a complete response (CR) with a progression-free survival time of 14 months, and ECOG performance status score improved from 2 to 0. A significant systemic effect was observed in this case and the PRaG triple-combination therapy might provide a novel treatment strategy for metastatic pMMR gastric cancer patients.

PD-1 Inhibitor Combined With Radiotherapy and GM-CSF (PRaG) in Patients With Metastatic Solid Tumors: An Open-Label Phase II Study.

Patients with metastatic cancer refractory to standard systemic therapies have a poor prognosis and few therapeutic options. Radiotherapy can shape the tumor microenvironment (TME) by inducing immunogenic cell death and promoting tumor recognition by natural killer cells and T lymphocytes. Granulocyte macrophage-colony stimulating factor (GM-CSF) was known to promote dendric cell maturation and function, and might also induce the macrophage polarization with anti-tumor capabilities. A phase II trial (ChiCTR1900026175) was conducted to assess the clinical efficacy and safety of radiotherapy, PD-1 inhibitor and GM-CSF (PRaG regimen). This trial was registered at http://www.chictr.org.cn/index.aspx. A PRaG cycle consisted of 3 fractions of 5 or 8 Gy delivered for one metastatic lesion from day 1, followed by 200 µg subcutaneous injection of GM-CSF once daily for 2 weeks, and intravenous infusion of PD-1 inhibitor once within one week after completion of radiotherapy. The PRaG regimen was repeated every 21 days for at least two cycles. Once the PRaG therapy was completed, the patient continued PD-1 inhibitor monotherapy until confirmed disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). A total of 54 patients were enrolled with a median follow-up time of 16.4 months. The ORR was 16.7%, and the disease control rate was 46.3% in intent-to-treat patients. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.3 to 4.8), and median overall survival was 10.5 months (95% CI, 8.7 to 12.2). Grade 3 treatment-related adverse events occurred in five patients (10.0%) and grade 4 in one patient (2.0%). Therefore, the PRaG regimen was well tolerated with acceptable toxicity and may represent a promising salvage treatment for patients with chemotherapy-refractory solid tumors. It is likely that PRaG acts via heating upthe TME with radiotherapy and GM-CSF, which was further boosted by PD-1 inhibitors.

Gut Bacteria Erysipelatoclostridium and Its Related Metabolite Ptilosteroid A Could Predict Radiation-Induced Intestinal Injury.

It is difficult to study the intestinal damage induced by space radiation to astronauts directly, and few prediction models exist. However, we can simulate it in patients with pelvic tumor radiotherapy (RT). Radiation-induced intestinal injury (RIII) is common in cancer patients who receieved pelvic and abdominal RT. We dynamically analyzed gut microbiota and metabolites alterations in 17 cervical and endometrial cancer patients after pelvic RT. In patients who later developed grade 2 RIII, dysbiosis of gut microbiota and metabolites were observed. Univariate analysis showed that Erysipelatoclostridium and ptilosteroid A were related to the occurrence of grade 2 RIII. Notably, a strong positive correlation between gut bacteria Erysipelatoclostridium relative abundance and gut metabolite ptilosteroid A expression was found. Furthermore, combinations of Erysipelatoclostridium and ptilosteroid A could provide good diagnostic markers for grade 2 RIII. In conclusion, gut bacteria Erysipelatoclostridium and its related metabolite ptilosteroid A may collaboratively predict RIII, and could be diagnostic biomarkers for RIII and space radiation injury.

Optimizing the Treatment Schedule of Radiotherapy Combined With Anti-PD-1/PD-L1 Immunotherapy in Metastatic Cancers.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1), and programmed cell death ligand-1 (PD-L1) have been approved for a variety of malignant tumors and are widely used to treat patients with metastatic disease. However, the efficacy of PD-1 inhibitors is limited due to tumor heterogeneity, high tumor burden, and "cold" tumor microenvironment. Radiotherapy can improve the anti-tumor effects of PD-1/PD-L1 inhibitors in various ways. As a new radiotherapy method, stereotactic body radiotherapy (SBRT) or hypofractionated radiotherapy (HFRT) provides higher doses per fraction to the target lesions, thus achieving immune activation effects and overcoming tumor resistance to anti-PD-1/PD-L1 treatment, which significantly improves the local and distant control of tumors. However, for different metastatic situations, radiotherapy plays different roles in the combination therapy. In oligometastatic status, radiotherapy can be used as a local radical treatment aiming to eliminate cancers in cooperation with systemic PD-1 inhibitors. In other circumstances, like bulky metastasis or multiple metastatic tumors, radiotherapy can be used as adjuvant to systemic immunotherapy. This review focuses on the underlying mechanisms and optimization strategies for the combination of radiotherapy and anti-PD-1/PD-L1 therapy in metastatic disease.

Anti-PD-1 Immunotherapy Combined With Stereotactic Body Radiation Therapy and GM-CSF as Salvage Therapy in a PD-L1-Negative Patient With Refractory Metastatic Esophageal Squamous Cell Carcinoma: A Case Report and Literature Review.

Esophageal squamous cell carcinoma (ESCC) is a malignancy with poor prognosis, which is often diagnosed at a late stage. Effective treatment options are limited when patients fail standard systemic therapy. The application of PD-1 inhibitors have led to a paradigm shift in the treatment of ESCC, but its efficacy as monotherapy is limited. Previous studies have shown that the antitumor effects may be reinforced when a PD-1 inhibitor is combined with radiotherapy or GM-CSF. This study aimed to report a case of a patient about advanced unresectable ESCC negative expression of PD-L1, who experienced tumor progression after chemoradiotherapy and targeted therapy.A significant systemic effect was seen after PD-1 inhibitor combined with GM-CSF and stereotactic body radiotherapy (SBRT) for metastatic lesions, however, severe pneumonia occurred after the triple-combination therapy. This study also reviewed several reports about the efficacy and safety of combination therapy.

A dosimetric study on the use of 3D-printed customized boluses in photon therapy: A hydrogel and silica gel study.

PURPOSE: The aim of the study was to compare the dose differences between two kinds of materials (silica gel and hydrogel) used to prepare boluses based on three-dimensional (3D) printing technologies and commercial bolus in head phantoms simulating nose, ear, and parotid gland radiotherapy. METHODS AND MATERIALS: We used 3D printing technology to make silica gel and hydrogel boluses. To evaluate the clinical feasibility, intensity modulated radiation therapy (IMRT) plans were created for head phantoms that were bolus-free or had a commercial bolus, a silica gel bolus, or a hydrogel bolus. Dosimetry differences were compared in simulating nose, ear, and parotid gland radiotherapy separately. RESULTS: The air gaps were smaller in the silica gel and hydrogel bolus than the commercial one. In nose plans, it was shown that the V95% (relative volume that is covered by at least 95% of the prescription dose) of the silica gel (99.86%) and hydrogel (99.95%) bolus were better than the commercial one (98.39%) and bolus-free (87.52%). Similarly, the homogeneity index (HI) and conformity index (CI) of the silica gel (0.06; 0.79) and hydrogel (0.058; 0.80) bolus were better than the commercial one (0.094; 0.72) and bolus-free (0.59; 0.53). The parameters of results (HI, CI, V95% ) were also better in 3D printing boluses than in the commercial bolus or without bolus in ear and parotid plans. CONCLUSIONS: Silica gel and hydrogel boluses were not only good for fit and a high level of comfort and repeatability, but also had better parameters in IMRT plans. They could replace the commercial bolus for clinical use.

[Design of Individualized Oral Radiotherapy Stent Based on 3D Printing Technique].

This paper introduces the individual design of oral radiotherapy stent based on 3D printing technology, and expounds its design principle. The modeling of the device is based on CT images and Mimics software, which builds a set of 3D printing oral stent technology. The instrument has more advantage in high precision, fast modeling, individualized production and digital storage. The results show that the construction of 3D printed dental stent is feasible, which provides a new idea and method for the production of oral stents.