Biological Bases of Immune-Related Adverse Events and Potential Crosslinks With Immunogenic Effects of Radiation

Immune checkpoint inhibitors have gained an established role in the treatment of different tumors. Indeed, their use has dramatically changed the landscape of cancer care, especially for tumor types traditionally known to have poor outcomes. However, stimulating anticancer immune responses may also elicit an unusual pattern of immune-related adverse events (irAEs), different from those of conventional chemotherapy, likely due to a self-tolerance impairment featuring the production of autoreactive lymphocytes and autoantibodies, or a non-specific autoinflammatory reaction. Ionizing radiation has proven to promote both positive pro-inflammatory and immunostimolatory activities, and negative anti-inflammatory and immunosuppressive mechanisms, as a result of cross-linked interactions among radiation dose, the tumor microenvironment and the host genetic predisposition. Several publications argue in favor of combining immunotherapy and a broad range of radiation schedules, based on the recent evidence of superior treatment responses and patient survival. The synergistic modulation of the immune response by radiation therapy and immunotherapeutics, particularly those manipulating T-cell activation, may also affect the type and severity of irAEs, suggesting a relationship between the positive antitumor and adverse autoimmune effects of these agents. As yet, information on factors that may help to predict immune toxicity is still lacking. The aim of our work is to provide an overview of the biological mechanisms underlying irAEs and possible crosslinks with radiation-induced anticancer immune responses. We believe such an overview may support the optimization of immunotherapy and radiotherapy as essential components of multimodal anticancer therapeutic approaches. Challenges in translating these to clinical practice are discussed

Potential Role of CXCR4 Targeting in the Context of Radiotherapy and Immunotherapy of Cancer

Cancer immunotherapy has been established as standard of care in different tumor entities. After the first reports on synergistic effects with radiotherapy and the induction of abscopal effects—tumor shrinkage outside the irradiated volume attributed to immunological effects of radiotherapy—several treatment combinations have been evaluated. Different immunotherapy strategies (e.g., immune checkpoint inhibition, vaccination, cytokine based therapies) have been combined with local tumor irradiation in preclinical models. Clinical trials are ongoing in different cancer entities with a broad range of immunotherapeutics and radiation schedules. SDF-1 (CXCL12)/CXCR4 signaling has been described to play a major role in tumor biology, especially in hypoxia adaptation, metastasis and migration. Local tumor irradiation is a known inducer of SDF-1 expression and release. CXCR4 also plays a major role in immunological processes. CXCR4 antagonists have been approved for the use of hematopoietic stem cell mobilization from the bone marrow. In addition, several groups reported an influence of the SDF-1/CXCR4 axis on intratumoral immune cell subsets and anti-tumor immune response. The aim of this review is to merge the knowledge on the role of SDF-1/CXCR4 in tumor biology, radiotherapy and immunotherapy of cancer and in combinatorial approaches

Radiation-induced breast angiosarcoma: report of two patients after accelerated partial breast irradiation (APBI) and review of the literature

BACKGROUND: Angiosarcoma may rarely complicate radiotherapy of breast cancer. This so-called radiation-induced angiosarcoma (RIAS) occurs in less than 0.3% of patients that underwent breast conservation surgeries, usually years after completion of radiotherapy. CASE PRESENTATION: we introduce two cases of invasive ductal carcinoma who underwent lumpectomy and accelerated partial breast irradiation (APBI) as an alternative protocol to whole breast irradiation (WBI). They received adjuvant partial breast radiotherapy on tumor cavity for a total dose of 38.5 Gy in 10 fractions in 5 days using 3D-external-beam RT. In both cases, RIAS occurred eight years after radiotherapy, in the sub-cicatricial area in one patient and outside the irradiated area in the other one. They both underwent radical surgery and chemotherapy was performed in one patient. DISCUSSION: The underlying mechanism for development of RIAS is not well known, but its incidence seems to be increasing. RIAS after partial breast irradiation is very rare and has been reported in two cases so far. As it may be suggested in case 2, it is still a matter of debate if the risk of radiation-induced sarcoma is radiation-dose dependent. Although mastectomy is considered as a standard treatment, choice of treatment should be made according to the patient’s specifications. CONCLUSION: There are very few studies in the literature that report RIAS after APBI. Present study is the only one reporting two cases after the external 3D technique APBI. Prognosis of RIAS remains poor. Only a careful evaluation in a multidisciplinary context can offer to the patients the best result in terms of local control and surviva

Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor

Epithelioid hemangioendothelioma is a rare vascular tumor, described for the first time in 1975 by Dail and Liebow as an aggressive bronchoalveolar cell carcinoma. The etiology is still a dilemma. Studies about suggestive hypothesis are ongoing. Most of the times it affects lung, liver and bones, although this kind of tumor may involve the head and neck area, breast, lymph nodes, mediastinum, brain and meninges, the spine, skin, abdomen and many other sites. Because of its heterogeneous presentation, as it represents less than 1% of all the vascular tumors, it is often misdiagnosed and not suitably treated, leading to a poor prognosis in some cases. Over 50-76% of the patients are asymptomatic. A small number of them complains respiratory symptoms. Bone metastases might cause pathological fractures or spine compression, if they arise in vertebrae. Imaging is necessary to determine morphological data, the involvement of surrounding tissues, and potentially the cleavage plan. It is important to recognize the expression of vascular markers (Fli-1 and CD31 are endothelial-specific markers), and the microscopic evidence of vascular differentiation to make a correct diagnosis, as many pulmonary diseases show multiple nodular lesions. Because of its rarity, there is no standard for treatment. We focused on radiotherapy as a good therapeutic option: despite the poor prognosis, evidence is in favor of radiotherapy which offers local pain control with good tolerance and better quality of life at least at a one-year follow-up in most of cases. Further studies are needed to establish the standard radiation dose to be used for locoregional control of such a complex and extremely rare disease

Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor

Epithelioid hemangioendothelioma is a rare vascular tumor, described for the first time in 1975 by Dail and Liebow as an aggressive bronchoalveolar cell carcinoma. The etiology is still a dilemma. Studies about suggestive hypothesis are ongoing. Most of the times it affects lung, liver and bones, although this kind of tumor may involve the head and neck area, breast, lymph nodes, mediastinum, brain and meninges, the spine, skin, abdomen and many other sites. Because of its heterogeneous presentation, as it represents less than 1% of all the vascular tumors, it is often misdiagnosed and not suitably treated, leading to a poor prognosis in some cases. Over 50-76% of the patients are asymptomatic. A small number of them complains respiratory symptoms. Bone metastases might cause pathological fractures or spine compression, if they arise in vertebrae. Imaging is necessary to determine morphological data, the involvement of surrounding tissues, and potentially the cleavage plan. It is important to recognize the expression of vascular markers (Fli-1 and CD31 are endothelial-specific markers), and the microscopic evidence of vascular differentiation to make a correct diagnosis, as many pulmonary diseases show multiple nodular lesions. Because of its rarity, there is no standard for treatment. We focused on radiotherapy as a good therapeutic option: despite the poor prognosis, evidence is in favor of radiotherapy which offers local pain control with good tolerance and better quality of life at least at a one-year follow-up in most of cases. Further studies are needed to establish the standard radiation dose to be used for locoregional control of such a complex and extremely rare disease

Pulmonary Epithelioid Hemangioendothelioma: Advances in Treatment Options despite a Rare Vascular Tumor

We have already discussed about dail and liebow describing pulmonary epithelioid hemangioendothelioma (PEH) as an aggressive bronchoalveolar cell carcinoma with a remarkable propensity to invade adjacent blood vessels and small airways, the following Weiss and Enzinger description of epithelioid hemangioendothelioma (EHE) as a vascular bone and soft tissues tumor showing intermediate malignancy between hemangioma and angiosarcoma, and the final confirmation from Weldon-Linne of a factor-VIII-related antigen onto malignant cells [1]. The recent World Health Organization (WHO 2002) classification has described EHE as lesions that fall into the category of locally aggressive tumors with metastatic potential [2,3]. The etiology of EHE is still a dilemma, as several clonal abnormalities in tumor cells, and different angiogenic stimulators may act as promoters of endothelial cell proliferation [4-8]. A new etiopathogenetic hypothesis suggests a causal relationship between chronic Bartonella infection and the development of this rare vascular tumor: if this was confirmed, it would be plausible that eradicating the bacterial infection or interrupting Bartonella-induced angiogenic and proliferative cell signals could slow the tumor progression and improve patient outcomes [9]. Due to its rarity (EHE represents less than 1% of all vascular tumors), because of EHE clinical presentation is as heterogeneous as its clinical localization can be, there is no standard for treatment and few therapeutic options are available. As the most common presentations are liver alone (21%), liver plus lung (18%), lung alone (12%) and bone alone (14%), the available literature focuses above all on these three directions [10]. The general issue seems to be that, when bone or pulmonary lesions are small and limited in number, surgical, curative resection (that is amputation, en-bloc resection, wedge resection) achieves good outcomes [11,12]. Locally advanced hepatic EHE seems to benefit from transplantation, with good results [13]. However, a complete surgical resection is not usually feasible: Pinet et al. reported a case of an aggressive form of pleural EHE resulting in complete remission after treatment with carboplatin plus etoposide [14], as well as bilateral multicentric PEH seems to respond well to interferon 2α, with some partial spontaneous regression [7]. Nonetheless, when a pathological fracture occurs, a great alternative to plate-and-screws surgical stabilization is radiofrequency ablation: by creating small, carefully controlled, thermal injuries of bone, the extent of resection can be reduced [15]. On the other side, with the aim of controlling residual desease given the recurrence of EHE, radiation therapy (RT) is chosen for localized EHE, while chemotherapy is preferred for widespread disease. In any case, the beneficial effect of both is still not confirmed [14,16-19]. Given the vascular origin of this tumor, the use of antiangiogenetic molecules like thalidomide and lenalidomide reasonably might achieve good outcomes (partial response and several stable diseases), even if using bevacizumab and nanoparticle albuminbound paclitaxel (nab-paclitaxel) produced higher percentages of progression disease [20]. RT has proven to be ineffective for PEH because of the tumor’s radiobiological characteristics (slow growth of the tumor cells), while a good local control has been obtained in EHE of bone [19, 21] Since EHE has been correctly defined, several research groups have dealt with EHE bone irradiation, in order to define the volume and the dose distribution achieving the greatest results for local disease control, together with the greatest tolerance to the treatment and the lowest incidence of side effects [19,21-24]. A 6400 cGy adjuvant RT was also performed against an axillary form of EHE, resulting in the absence of lymph nodes metastases but pleural and pulmonary widespread [18]. In our experience, at our Institute we observed systemic progression of EHE after 4-month-PEG-IFN-α therapy in spite of stable pulmonary disease; then, lumbar pain control with good tolerance and better quality of life at 1-year-follow-up from a symptomatic, normofractionated RT onto the L3-L5 vertebral tract, consolidated outcome through Ifosfamide and Epirubicin chemotherapy soon after RT, and surgical removal of EHE spleen lesions, showing 1-year survival [1]. All this considered, despite the rarity of this vascular tumor and its extremely complex and heterogeneous patterns of presentation, actually we are capable of performing more treatment lines, combined in a multimodal strategy or sequencially adopted, so that we are able to reach good outcomes in most of cases. In this regard, taking into account the EHE radiobiological characteristics, no doubt evidence is all in favour of RT obtaining local pain control with good tolerance and better quality of life at least one-year-follow up. The literature reveals certain discordance about the radiation dose to be used for this purpose, maybe attributable to the very small number of patients and to the limited survival that EHE typically shows. As a result, further studies are needed to answer the question

Impact of the COVID-19 Pandemic on Radiotherapy Supply

Background. The impetuous entrance of the COVID-19 pandemic in Italy in March 2020, after the onset and diffusion in China, found the health system widely unfit to face the large amount of infected patients. The matter of this investigation was to evaluate how pandemic fear and guidelines for limiting the diffusion of SARS-CoV-2 virus could have impacted the regular supply of radiotherapy (RT) and the outcome of the treatments. Materials and Methods. From March 9, 2020, to May 29, 2020, a register has been established to record patients that cancelled or postponed the RT appointment. The reasons were as follows: (1) patients whose appointments were postponed by the staff according to national guidelines; (2) patients who asked themselves to postpone the appointment; (3) patients who interrupted the treatment for causes directly or indirectly related to the pandemic; (4) patients who cancelled their care path. Results. A total number of 277 patients started regular RT, and 384 respected their computed tomography (CT) simulation appointment, but 60 of them had alteration of their therapeutic pathway. Among these, 18 cancelled their appointment. 42 patients asked to postpone their procedure. Twenty-seven out of 42 adduced directly or indirectly SARS-CoV-2 infection-related reasons. Conclusions. The COVID-19 pandemic affected the regular RT delivery to oncologic patients, owing to the delay or cancellation of procedures with the likely effect to observe worsening of local disease control and reduced survival rates in the future

Intracranial Solitary Fibrous Tumor: A “New” Challenge for PET Radiopharmaceuticals

Solitary fibrous tumor (SFT) of the central nervous system, previously named and classified with the term hemangiopericytoma (HPC), is rare and accounts for less than 1% of all intracranial tumors. Despite its benign nature, it has a malignant behavior due to the high rate of recurrence and distant metastasis, occurring in up to 50% of cases. Surgical resection of the tumor is the treatment of choice. Radiotherapy represents the gold standard in the case of post-surgery residual disease, relapse, and distant metastases. In this context, imaging plays a crucial role in identifying the personalized therapeutic decision for each patient. Although the referring imaging approach in SFT is morphologic, an emerging role of positron emission tomography (PET) has been reported in the literature. However, there is still a debate on which radiotracers have the best accuracy for studying these uncommon tumors because of the histological or biological heterogeneity of SFT

Stratification of Oligometastatic Prostate Cancer Patients by Liquid Biopsy: Clinical Insights from a Pilot Study

11noWe propose a pilot, prospective, translational study with the aim of identifying possible molecular markers underlying metastatic prostate cancer (PC) evolution with the use of liquid biopsy. Twenty-eight castrate sensitive, oligometastatic PC patients undergoing bone and/or nodal stereotactic body radiotherapy (SBRT) were recruited. Peripheral blood samples were collected before the commencement of SBRT, then they were processed for circulating cell free DNA (cfDNA) extraction. Deep targeted sequencing was performed using a custom gene panel. The primary endpoint was to identify differences in the molecular contribution between the oligometastatic and polymetastatic evolution of PC to same-first oligo-recurrent disease presentation. Seventy-seven mutations were detected in 25/28 cfDNA samples: ATM in 14 (50%) cases, BRCA2 11 (39%), BRCA1 6 (21%), AR 13 (46%), ETV4, and ETV6 2 (7%). SBRT failure was associated with an increased risk of harboring the BRCA1 mutation (OR 10.5) (p = 0.043). The median cfDNA concentration was 24.02 ng/mL for ATM mutation carriers vs. 40.04 ng/mL for non-carriers (p = 0.039). Real-time molecular characterization of oligometastatic PC may allow for the identification of a true oligometastatic phenotype, with a stable disease over a long time being more likely to benefit from local, curative treatments or the achievement of long-term disease control. A prospective validation of our promising findings is desirable for a better understanding of the real impact of liquid biopsy in detecting tumor aggressiveness and clonal evolution.noneColosini, Antonella; Bernardi, Simona; Foroni, Chiara; Pasinetti, Nadia; Guerini, Andrea Emanuele; Russo, Domenico; Bresciani, Roberto; Tomasi, Cesare; Magrini, Stefano Maria; Bardoscia, Lilia; Triggiani, LucaColosini, Antonella; Bernardi, Simona; Foroni, Chiara; Pasinetti, Nadia; Guerini, Andrea Emanuele; Russo, Domenico; Bresciani, Roberto; Tomasi, Cesare; Magrini, Stefano Maria; Bardoscia, Lilia; Triggiani, Luc