• IL-2
• immunocytokines
• immunotoxins

• FAR2022 University of Insubria
• FAR2023 University of Insubria
• 2024 Ministry of Health of Italy, Ricerca Corrente to IRCCS MultiMedica, Milan, Italy

• CTLA-4
• PD-1
• immunotherapy
• non-small-cell lung cancer
• squamous cell lung cancer

• Humans
• Carcinoma, Non-Small-Cell Lung/therapy
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Lung Neoplasms/therapy
• Lung Neoplasms/drug therapy
• Immunotherapy/methods
• Immune Checkpoint Inhibitors/therapeutic use

• Abscopal effect
• Bystander effect
• Glioblastoma
• Macrophages
• Microglia
• Radiotherapy

• Gompertz law
• abscopal effect
• immune response
• immunotherapy
• mathematical modeling
• radiotherapy

• Humans
• Neoplasms/therapy
• Neoplasms/immunology
• Neoplasms/radiotherapy
• Immunotherapy/methods
• Combined Modality Therapy
• Models, Theoretical
• Radiotherapy/methods

• Chemoradiation
• Chemotherapy
• Esophageal Cancer
• Immunotherapy

• Hepatocellular carcinoma
• Natural killer cells
• Thermal ablation

• Animals
• Mice
• Mice, Inbred C57BL
• Liver/pathology
• Magnetic Resonance Imaging/methods
• Radiofrequency Ablation
• Macrophages
• Immunity
• Contrast Media

• R01 CA206180 NCI NIH HHS

• hepatocellular carcinoma
• microwave ablation
• natural killer cells
• radio frequency ablation
• thermal ablation

• chemotherapy
• esophageal cancer (EC)
• immune checkpoint inhibitor (ICI)
• immunotherapy
• neoadjuvant therapy
• radiotherapy

• Humans
• Neoadjuvant Therapy/methods
• Neoplasm Recurrence, Local
• Esophageal Neoplasms/pathology
• Treatment Outcome
• Immunotherapy

• Immunotherapy
• Lung cancer
• Main trials
• Radiotherapy

• HCC
• TACE
• ablation
• hepatocellular carcinoma
• immunotherapy
• interventional radiology
• locoregional therapy
• microwave ablation
• radiofrequency
• tumor immunology

• corticosteroid
• immune checkpoint inhibitors
• immune-related adverse event
• immunotherapy
• immunotoxicity
• programmed death 1 receptor (PD-1) inhibitor
• radiation

• Anaplastic thyroid cancer
• CAL-62 cell
• Caerin 1.1 peptide
• Iodine-131
• Radioimmunotherapy

• Animals
• Humans
• Mice
• Apoptosis/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Iodine Radioisotopes/therapeutic use
• Iodine Radioisotopes/chemistry
• Isotope Labeling
• Mice, Nude
• Peptides/chemistry
• Peptides/pharmacology
• Radioimmunotherapy/methods
• Thyroid Carcinoma, Anaplastic/radiotherapy
• Thyroid Carcinoma, Anaplastic/pathology
• Thyroid Neoplasms/radiotherapy
• Thyroid Neoplasms/pathology

• NO. 31971355 National Natural Science Foundation of China

• Gamma knife
• glioblastoma
• glioma
• high grade
• low grade
• pilocytic
• radiosurgery
• radiotherapy
• stereotactic

• Ablation
• COVID-19
• Hepatocellular carcinoma
• Liver
• Microwave
• Percutaneous
• Tumor

The combination of immune checkpoint inhibitors and definitive radiotherapy is investigated for the multimodal treatment of cisplatin non-eligible locally advanced head and neck cancers (HNC). In the case of recurrent and metastatic HNC, immunotherapy has shown benefit over the EXTREME protocol, being already considered the standard treatment. One of the biggest challenges of multimodal treatment is to establish the optimal therapy sequence so that the synergistic effect is maximal. Thus, superior results were obtained for the administration of anti-CTLA4 immunotherapy followed by hypofractionated radiotherapy, but the anti-PD-L1 therapy demonstrates the maximum potential of radio-sensitization of the tumor in case of concurrent administration. The synergistic effect of radiotherapy–immunotherapy (RT–IT) has been demonstrated in clinical practice, with an overall response rate of about 18% for HNC. Given the demonstrated potential of radiotherapy to activate the immune system through already known mechanisms, it is necessary to identify biomarkers that direct the “nonresponders” of immunotherapy towards a synergistic RT–IT stimulation strategy. Stimulation of the immune system by irradiation can convert “nonresponder” to “responder”. With the development of modern techniques, re-irradiation is becoming an increasingly common option for patients who have previously been treated with higher doses of radiation. In this context, radiotherapy in combination with immunotherapy, both in the advanced local stage and in recurrent/metastatic of HNC radiotherapy, could evolve from the “first level” of knowledge (i.e., ballistic precision, dose conformity and homogeneity) to “level two” of “biological dose painting” (in which the concept of tumor heterogeneity and radio-resistance supports the need for doses escalation based on biological criteria), and finally to the “third level“ ofthe new concept of “immunological dose painting”. The peculiarity of this concept is that the radiotherapy target volumes and tumoricidal dose can be completely reevaluated, taking into account the immune-modulatory effect of irradiation. In this case, the tumor target volume can include even the tumor microenvironment or a partial volume of the primary tumor or metastasis, not all the gross and microscopic disease. Tumoricidal biologically equivalent dose (BED) may be completely different from the currently estimated values, radiotherapy treating the tumor in this case indirectly by boosting the immune response. Thus, the clinical target volume (CTV) can be replaced with a new immunological-clinical target volume (ICTV) for patients who benefit from the RT–IT association (Image 1).

• ab-scopal
• head and neck cancers
• immunotherapy
• radiotherapy
• re-irradiation

• Cisplatin
• Head and Neck Neoplasms/radiotherapy
• Humans
• Immunotherapy
• Re-Irradiation
• Tumor Burden
• Tumor Microenvironment

• Animals
• Humans
• Neoplasm Metastasis/pathology
• Neoplasms/pathology
• Tumor Microenvironment

• Hepatocellular carcinoma
• chemoembolization
• interventional radiology
• radiofrequency ablation
• transarterial radioembolization

Breast cancer is the most commonly diagnosed cancer in females worldwide. If diagnosed early, patients generally have good outcomes. However, approximately 20% to 30% of all women diagnosed with breast cancer develop metastatic disease. Metastatic breast cancer is incurable, but there is growing evidence that resection or other local therapy for breast cancer liver metastases (BCLM) may improve survival. We aimed to review indications for and outcomes of perioperative liver resection and other local therapies for BCLM. In this series, we reviewed 11 articles (605 patients) focusing on surgical resection and 7 articles (266 patients) describing radiofrequency ablation (RFA) for BCLM. Median disease-free survival (DFS) after surgical resection was 23 months (range, 14–29 months) and median overall survival (OS) was 39.5 months (range, 26–82 months). One, 3- and 5-year survivals were 89.5%, 70%, and 38%, respectively. The factors favoring better outcomes are hormone receptor positive primary breast cancer status, R0 resection, no extrahepatic metastases (EHM), small BCLM, and solitary liver metastases. On the other hand, the median DFS with RFA was 11 months, median OS was 32 months, and the 3- and 5-year OS were 43% and 27%, respectively. The clinical features that are indications for RFA are smaller tumor and higher EHM rate than those favoring surgical resection (2.4 vs. 4.0 cm and 46% vs. 27%). The merits of RFA are its high technical success rate, low morbidity, short hospital stay, and that it can be repeated. Although results are as yet limited, in carefully selected patients, resection or other local therapies such as RFA, render BCLM potentially provide prognostic improvement.

• Breast cancer
• liver metastases
• radiofrequency ablation (RFA)
• surgical resection

• Chemoradioimmunotherapy
• Immunotherapy
• Multimodal treatment
• Non-small cell lung cancer

• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Carcinoma, Non-Small-Cell Lung/mortality
• Carcinoma, Non-Small-Cell Lung/therapy
• Chemoradiotherapy/methods
• Clinical Trials as Topic
• Humans
• Immune Checkpoint Inhibitors/therapeutic use
• Immunotherapy
• Lung Neoplasms/mortality
• Lung Neoplasms/therapy

• HCC
• MWA
• RFA
• ablation
• immunomodulation
• liver

• Carcinoma, Hepatocellular/therapy
• Clinical Trials as Topic
• Combined Modality Therapy
• Humans
• Immunotherapy/methods
• Liver Neoplasms/therapy
• Microwaves/therapeutic use
• Neoplasm Recurrence, Local
• Radiofrequency Ablation/methods
• Treatment Outcome

• 2019 Dotation Agir pour les Maladies Chroniques

• NSCLC
• abscopal effect
• checkpoint inhibitors
• immunotherapy
• lung cancer
• radiotherapy

• Immunomodulation
• check point inhibitors
• hepatocellular carcinoma
• radiofrequency

• CEA
• IL-2
• antibody
• breast cancer
• immunocytokine
• stereotactic radiation

The standard treatment for patients with unresectable locally advanced (LA) non‐small cell lung cancer (NSCLC) is chemoradiotherapy (CRT). Consolidation therapy with durvalumab after CRT demonstrated survival benefits and was approved in Japan in July 2018. The use of immune checkpoint inhibitors (ICIs) is entering routine oncological practice, and here we investigate the feasibility of concurrent CRT for LA‐NSCLC patients based on the PACIFIC criteria.

We performed a retrospective study to evaluate the feasibility and efficacy of concurrent CRT prior to the approval of durvalumab. We assessed consecutive patients with LA‐NSCLC treated with CRT between January 2012 and June 2018.

We analyzed a total of 108 consecutive patients who received radical thoracic radiotherapy and concurrent platinum‐based chemotherapy. Of those patients, 105 (97%) completed the planned radiotherapy. Radiation pneumonitis was observed in 93 patients (85%), with a median of 130 days (range: 41–317 days) from the initiation of radiation to the onset of the complication. Among the patients, 74 (69%) were considered eligible for consolidation therapy with durvalumab. The overall response rate was 64%, and the two‐year survival rate was 63%. Patients who received an ICI after relapse were associated with significantly better survival than those who did not receive an ICI (two‐year survival rate: 87% vs. 41%, respectively; P = 0.001).

Prior to the approval of durvalumab, the clinical application of ICIs improved the outcome of patients with relapsed NSCLC after CRT for LA‐NSCLC. The management of radiation pneumonitis remains a challenge following the approval of durvalumab.

• Chemoradiotherapy
• immune checkpoint inhibitor
• locally advanced
• non-small cell lung cancer
• radiation pneumonitis

Treatment with ionizing radiation (IR) remains the cornerstone of therapy for multiple cancer types, including disseminated and aggressive diseases in the palliative setting. Radiotherapy efficacy could be improved in combination with drugs that regulate the ubiquitin-proteasome system (UPS), many of which are currently being tested in clinical trials. The UPS operates through the covalent attachment of ATP-activated ubiquitin molecules onto substrates following the transfer of ubiquitin from an E1, to an E2, and then to the substrate via an E3 enzyme. The specificity of ubiquitin ligation is dictated by E3 ligases, which select substrates to be ubiquitylated. Among the E3s, cullin ring ubiquitin ligases (CRLs) represent prototypical multi-subunit E3s, which use the cullin subunit as a central assembling scaffold. CRLs have crucial roles in controlling the cell cycle, hypoxia signaling, reactive oxygen species clearance and DNA repair; pivotal factors regulating the cancer and normal tissue response to IR. Here, we summarize the findings on the involvement of CRLs in the response of cancer cells to IR, and we discuss the therapeutic approaches to target the CRLs which could be exploited in the clinic.

• DNA-damage
• E3-ligases
• cullin ring ligases (CRLs)
• cullins
• double-strand breaks (DSBs)
• ionizing radiation (IR)

• liver cancer
• liver resection
• radiofrequency based device

In preclinical studies with model animals, intravenous administration of a derivative of chemokine CCL3, named eMIP, after local electron-beam irradiation, not only enhanced tumor growth inhibition at a target site but also induced tumor killing beyond the treated site (a phenomenon known as the abscopal effect). eMIP works with alarmins such as high mobility group box 1 (HMGB1) and heat shock protein 70 (HSP70) released from overexpressed tumor cells by irradiation. These alarmins at the irradiated tumor bed trap injected eMIP and, by forming complexes with eMIP, play a key role to recruit and activate tumor inhibitory natural killer (NK) cells and CD4⁺ and CD8⁺ T cells. Tumor type-specific secretion of gamma interferon from splenocytes was also demonstrated, which may also activate NK cells. During Phase 1 clinical studies using X-rays, however, no apparent abscopal effect was observed. Instead, we saw frequent reduction in numbers of lymphocytes in the peripheral blood of irradiated patients. The reduced number of lymphocytes recovered poorly once depleted, in contrast to neutrophils, and persisted for months after the treatment. This might have affected outcome after combination treatment of irradiation and eMIP. To enhance host defense mechanisms during and after photon-beam (X-ray) radiotherapy of a deep-seated tumor, it seems essential to keep lymphocytes undamaged by eliminating reactive oxygen species that are formed in the peripheral blood during irradiation.

• alarmins
• ccl3 derivative
• chemokine
• electron beams
• hmgb1
• hsp70
• nk cells
• reactive oxygen species
• t cells
• x-rays

Innovation has been the cornerstone of interventional radiology since the early years of the founders, with a multitude of new therapeutic approaches developed over the last 50 years. What is the future holding for us? This article presents an overview of the in-coming developments that are catching on at this moment, particularly focusing on three items: the new applications of existing techniques, particularly embolotherapy and interventional oncology; the cutting-edge devices; the imaging technologies at the forefront of the image-guidance. Besides this, clinical vision and patient relation remain crucial for the future of the discipline.

• Embolization
• Image Fusion
• Innovation
• Interventional Oncology
• Interventional Radiology

Preclinical and clinical studies have shown that prior receipt of radiotherapy enhances antitumor immune responses, a phenomenon we call the “radio-memory effect.” However, all of the evidence regarding this effect to date comes from work with PD1/PDL1 inhibitors. Here we explored whether this effect also occurs with other forms of immune therapy, specifically interleukin-2 (IL-2). We retrospectively assessed outcomes in patients with malignant pleural effusion (MPE) who had previously received radiotherapy for non-small-cell lung cancer (NSCLC) within 18 months before the intrapleural infusion of IL-2 or cisplatin. Radiotherapy sites included lungs, thoracic lymph nodes, and intracranial. All patients received intrapleural infusion of IL-2 or cisplatin, and most had had several cycles of standard chemotherapy for NSCLC. We identified 3,747 patients with MPE (median age 64 years [range 29–88)) treated at one of several institutions from August 2009 through February 2015; 642 patients had been treated with IL-2 and 1102 with cisplatin and had survived for at least 6 months afterward. Among those who received IL-2, 288 had no radiotherapy, 324 had extracranial (i.e., thoracic) radiotherapy, and 36 had intracranial radiotherapy. The median follow-up time for surviving patients was 38 months. Patients who had received extracranial radiotherapy followed by IL-2 had significantly longer PFS than patients who had not received extracranial radiotherapy (i.e., either no radiotherapy or intracranial radiotherapy). Patients who had received intracranial or extracranial radiotherapy followed by IL-2 had significantly longer OS than did other patients. No survival advantage was noted for prior radiotherapy among patients who received intrapleural cisplatin. We speculate that previous radiotherapy could enhance the efficacy of subsequent intrapleural infusion of IL-2, a “radio-memory” effect that could be beneficial in future studies.

• immunotherapy
• interleukin-2 (IL-2)
• malignant pleural effusion (MPE)
• non-small-cell lung cancer (NSCLC)
• radio-memory effect
• radiotherapy

• Hepatocellular carcinoma
• Liver transplantation
• Recurrence

• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Clinical Protocols
• Combined Modality Therapy/methods
• Humans
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Liver Transplantation
• Neoplasm Recurrence, Local/mortality
• Neoplasm Recurrence, Local/pathology
• Neoplasm Recurrence, Local/therapy
• Patient Care Team/organization & administration
• Survival Rate
• Treatment Outcome

Plasma TGF-β1 protein levels reportedly may predict the treatment outcomes of lung cancer. We hypothesized that in patients with lung cancer treated with radiation therapy (RT), TGF-β1 levels may correlate with the percentages of CD4⁺ T cells, CD8⁺ T cells, and the CD4⁺/CD8⁺ T cell ratio in peripheral blood.

Eighty-two lung cancer patients satisfied the inclusion criteria. Platelet-poor plasma was obtained before RT, at the second and fourth weeks during RT, and at the end of RT (pre-, during-, and post-RT, respectively). TGF-β1 was measured via ELISA, while recording the percentages of lymphocyte subsets in peripheral blood. Short-term efficacy was categorized as complete response, partial response, stable disease, or progressive disease.

Patients who had significantly lower TGF-β1 protein levels after RT than pre-RT seemed to have a better short-term effect (P<0.05) than those who had higher TGF-β1 levels. There was a significant association between the TGF-β1 levels and percentages of CD4⁺ T cells, CD8⁺ T cells, or CD4⁺/CD8⁺ T cell ratio during and at the end of RT. Changes in CD3⁺ T cells, B cells, or natural killer cells were not statistically related to the changes in TGF-β1 levels.

Lung cancer patients with TGF-β1 levels in plasma after RT that are below pre-RT levels may experience better short-term efficacy. The underlying mechanism may be related to the influence of TGF-β1 on antitumor immunity.

• TGF-β1
• lung cancer
• lymphocytes
• prognosis
• radiotherapy

• abscopal effect
• combination immunotherapy-radiotherapy
• heavy-ion radiotherapy
• radiation-induced immunogenic cell death

Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short- and long-term cancer eradication, with significant tumour and normal tissue consequences. Therefore, the role of radiation in modulating the inflammatory response is highly topical given the current wave of targeted and immuno-therapeutic treatments for cancer. This review provides a general overview of how radiation modulates the inflammatory and immune response—(i) how radiation induces the inflammatory/immune system, (ii) the cellular changes that take place, (iii) how radiation dose delivery affects the immune response, and (iv) a discussion on research directions to improve patient survival, reduce side effects, improve quality of life, and reduce financial costs in the immediate future. Harnessing the benefits of radiation on the immune response will enhance its maximal therapeutic benefit and reduce radiation-induced toxicity.

This case represents the challenge and creativity necessary when treating patients with metastatic renal cell carcinoma who have been exposed to multiple lines of therapy. At present, treatment with immune checkpoint inhibition has stabilized and improved the metastatic disease of this patient with the exception of hepatic lesions. This isolated progression within the liver led the employment of radioembolization, which successfully treated those metastases. This is the first documented case of metastatic renal cell carcinoma controlled with concurrent use of immune checkpoint inhibition and radioembolization for both extrahepatic and hepatic metastases, respectively. This case can be construed as a potential example of the abscopal effect and may provide the basis for understanding this type of response in select patients.

• Immune checkpoint inhibition
• Immunotherapy
• Internal radiotherapy
• Metastatic renal cell carcinoma
• Radioembolization

Cancer cells subjected to ionizing radiation may release signals which can influence nearby non-irradiated cells, termed bystander effects. The transmission of bystander effects among cancer cells involves the activation of inflammatory cytokines, death ligands, and reactive oxygen/nitrogen species. In addition to bystander effects, two other forms of non-target effects (NTEs) have been identified in radiotherapy, as one is called cohort effects and the other is called abscopal effects. Cohort effects represent the phenomenon where irradiated cells can produce signals that reduce the survival of neighboring cells within an irradiated volume. The effects suggest the importance of cellular communication under irradiation with non-uniform dose distribution. In contrast, abscopal effects describe the NTEs that typically occur in non-irradiated cells distant from an irradiated target. These effects can be mediated primarily by immune cells such as T cells. Clinical trials have shown that application of radiation along with immunotherapy may enhance abscopal effects and improve therapeutic efficacy on non-target lesions outside an irradiated field. According to NTEs, cell viability is reduced not only by direct irradiation effects, but also due to signals emitted from nearby irradiated cells. A clinical consideration of NTEs could have a revolutionary impact on current radiotherapy via the establishment of more efficient and less toxic radiobiological models for treatment planning compared to conventional models. Thus, we will review the most updated findings about these effects and outline their mechanisms and potential applications in cancer treatment with a special focus on the brain, lung, and breast cancers.

• non-targeted effects
• non-uniform irradiation
• p53
• radiation therapy
• reactive oxygen species

• Pancreatic cancer
• immunotherapy
• targeted therapies
• tumor microenvironment (TME)

• Abscopal effect
• bone metastases
• breast cancer spontaneous regression
• radiotherapy