CXCL12-loaded-hydrogel (CLG): A new device for metastatic circulating tumor cells (CTCs) capturing and characterization.

Background: Circulating Tumor Cells (CTCs) represent a small, heterogeneous population that comprise the minority of cells able to develop metastasis. To trap and characterize CTCs with metastatic attitude, a CXCL12-loaded hyaluronic-gel (CLG) was developed. CXCR4+cells with invasive capability would infiltrate CLG. Methods: Human colon, renal, lung and ovarian cancer cells (HT29, A498, H460 and OVCAR8 respectively) were seeded on 150 µl Empty Gels (EG) or 300 ng/ml CXCL12 loaded gel (CLG) and allowed to infiltrate for 16 h. Gels were then digested and fixed with 2 % FA-HAse for human cancer cell enumeration or digested with HAse and cancer cells recovered. CLG-recovered cells migrated toward CXCL12 and were tested for colonies/spheres formation. Moreover, CXCR4, E-Cadherin and Vimentin expression was assessed through flow cytometry and RT-PCR. The clinical trial "TRAP4MET" recruited 48 metastatic/advanced cancer patients (8 OC, 8 LC, 8 GBM, 8 EC, 8 RCC and 8 EC). 10 cc whole blood were devoted to PBMCs extraction (7 cc) and ScreenCell™ filters (3 cc) CTCs evaluation. Ficoll-isolated patient's PBMCs were seeded over CLG and allowed to infiltrate for 16 h; gels were digested and fixed with 2 % FA-HAse, cells stained and DAPI+/CD45-/pan-CK + cells enumerated as CTCs. Results: Human cancer cells infiltrate CLG more efficiently than EG (CLG/EG ratio 1.25 for HT29/1.58 for A498/1.71 for H460 and 2.83 for OVCAR8). CLG-recovered HT29 cells display hybrid-mesenchymal features [low E-cadherin (40 %) and high vimentin (235 %) as compared to HT29], CXCR4 two-fold higher than HT29, efficiently migrate toward CXCL12 (two-fold higher than HT29) and developed higher number of colonies (171 ± 21 for HT29-CLG vs 131 ± 8 colonies for HT29)/larger spheres (spheroid area: 26561 ± 6142 µm2 for HT29-CLG vs 20297 ± 7238 for HT29). In TRAP4MET clinical trial, CLG-CTCs were isolated in 8/8 patients with OC, 6/8 with LC, 6/8 with CRC, 8/8 with EC, 8/8 with RCC cancer and 5/8 with GBM. Interestingly, in OC, LC and GBM, CLG isolated higher number of CTCs as compared to the conventional ScreenCell™ (CLG/SC ratio = 1.88 for OC, 2.47 for LC and 11.89 for GBM). Bland and Altman blot analysis and Passing and Bablok regression analysis showed concordance between the methodological approaches but indicate that SC and CLG are not superimposable suggesting that the two systems select cells with different features. Conclusion: CLG might represent a new and easy tool to isolate invasive CTCs in multiple cancers such as OC, LC and GBM at today orphan of reliable methods to consistently detect CTCs.

Temozolomide based treatment in glioblastoma: 6 vs. 12 months.

The Stupp regimen remains the standard treatment for newly diagnosed glioblastomas, although the prognosis remains poor. Several temozolomide alternative schedules have been studied, with extended adjuvant treatment (>6 cycles of temozolomide) frequently used, although different trials have indicated contrasting results. Survival data of 87 patients who received 6 ('6C' group) or 12 ('12C' group) cycles of temozolomide were collected between 2012 and 2022. A total of 45 patients were included in the 6C group and 42 patients were included in the 12C group. Data on isocitrate dehydrogenase mutation and methylguanine-DNA-methyltransferase (MGMT) promoter methylation status were also collected. The 12C group exhibited statistically significantly improved overall survival [OS; 22.8 vs. 17.5 months; hazard ratio (HR), 0.47; 95% CI, 0.30-0.73; P=0.001] and progression-free survival (15.3 vs. 9 months; HR, 0.39; 95% CI, 0.25-0.62; P=0.001). However, in the subgroup analysis according to MGMT status, OS in the 12C group was significantly superior to OS in the 6C group only in the MGMT unmethylated tumors. The present data suggested that extended adjuvant temozolomide appeared to be more effective than the conventional six cycles.

Neoadjuvant Versus Adjuvant Systemic Therapy in Breast Cancer: A Matched Case-control Study.

BACKGROUND/AIM: Neoadjuvant systemic therapy (NAT) in breast cancer can make tumors resectable or reduce the extent of surgery needed for locally advanced cancers. It can also better prevent distant relapse and possibly modulate drug therapy by adjusting adjuvant therapy (AD) based on the response to NAT, either by escalating or de-escalating the treatment. However, clear evidence of improved outcomes is currently missing. Here, we report on breast cancer patients treated with NAT at our institution. PATIENTS AND METHODS: One hundred twenty-seven patients treated at our Radiation Oncology department between 2004 and 2021 were retrospectively analyzed. All patients had localized or locally advanced breast cancer, were treated with NAT, and received postoperative radiotherapy. The outcomes considered were overall survival (OS), loco-regional recurrence-free survival (LRRFS), and distant metastases-free survival (DMFS). A matched patient population treated with AD during the same period and at the same center was used for comparison. RESULTS: The 5-year predicted OS was 87% in the NAT group and 81.5% in the AD group (p-value=0.179), while LRRFS was 93.2% in the NAT group and 100% in the AD group (p=0.005). The 5-year predicted DMFS was 84.6% in the NAT group and 82.1% in AD patients (p=0.367). In the NAT group, the only prognostic factor significantly related to improved outcomes was the pathological node response, with an OS of 95.6% in patients without residual node disease compared to 75.1% in patients with evidence of residual node disease. CONCLUSION: Our study, despite the limitations of a small number of patients and its retrospective nature, confirms the data of previous larger studies. In terms of DMFS and OS, NAT is at least as effective as AD. NAT represents a great opportunity for personalized modulation of treatment in node-positive breast cancer patients.

Modeling frameworks for radiation induced lymphopenia: A critical review.

Radiation-induced lymphopenia (RIL) is a frequent, and often considered unavoidable, side effect of radiation therapy (RT), whether or not chemotherapy is included. However, in the last few years several studies have demonstrated the detrimental effect of RIL on therapeutic outcomes, with conflicting findings concerning possible inferior patient survival. In addition, since immunotherapeutic treatment has become an integral part of cancer therapy, preserving the immune system is recognized as crucial. Given this background, various research groups have reported on different frameworks for modelling RIL, frequently based on different definitions of RIL itself, and discordant results have been reported. Our aim is to critically review the current literature on RIL modelling and summarize the different approaches recently proposed to improve the prediction of RIL after RT and aimed at immunity-sparing RT. A detailed description of these approaches will be outlined and illustrated through their applications as found in the literature from the last five years. Such a critical analysis represents the necessary starting step to develop an effective strategy that ultimately could harmonize the diverse modelling methods.

Management of radiation-induced oral mucositis in head and neck cancer patients: a real-life survey among 25 Italian radiation oncology centers.

AIM: Radiation-induced oral mucositis (RIOM) is the most frequent side effect in head and neck cancer (HNC) patients treated with curative radiotherapy (RT). A standardized strategy for preventing and treating RIOM has not been defined. Aim of this study was to perform a real-life survey on RIOM management among Italian RT centers. METHODS: A 40-question survey was administered to 25 radiation oncologists working in 25 different RT centers across Italy. RESULTS: A total of 1554 HNC patients have been treated in the participating centers in 2021, the majority (median across the centers 91%) with curative intent. Median treatment time was 41 days, with a mean percentage of interruption due to toxicity of 14.5%. Eighty percent of responders provide written oral cavity hygiene recommendations. Regarding RIOM prevention, sodium bicarbonate mouthwashes, oral mucosa barrier agents, and hyaluronic acid-based mouthwashes were the most frequent topic agents used. Regarding RIOM treatment, 14 (56%) centers relied on literature evidence, while internal guidelines were available in 13 centers (44%). Grade (G)1 mucositis is mostly treated with sodium bicarbonate mouthwashes, oral mucosa barrier agents, and steroids, while hyaluronic acid-based agents, local anesthetics, and benzydamine were the most used in mucositis G2/G3. Steroids, painkillers, and anti-inflammatory drugs were the most frequent systemic agents used independently from the RIOM severity. CONCLUSION: Great variety of strategies exist among Italian centers in RIOM management for HNC patients. Whether different strategies could impact patients' compliance and overall treatment time of the radiation course is still unclear and needs further investigation.

Stereotactic Radiation Therapy for Brain Metastases: Factors Affecting Outcomes and Radiation Necrosis.

Stereotactic radiation therapy (SRT) is a proven effective treatment for brain metastases (BM); however, symptomatic radiation necrosis (RN) is a late effect that may impact on patient's quality of life. The aim of our study was to retrospectively evaluate survival outcomes and characterize the occurrence of RN in a cohort of BM patients treated with ablative SRT at Federico II University Hospital. Clinical and dosimetric factors of 87 patients bearing a total of 220 BMs treated with SRT from 2016 to 2022 were analyzed. Among them, 46 patients with 127 BMs having clinical and MRI follow-up (FUP) ≥ 6 months were selected for RN evaluation. Dosimetric parameters of the uninvolved brain (brain without GTV) were extracted. The crude local control was 91% with neither clinical factors nor prescription dose correlating with local failure (LF). At a median FUP of 9 (1-68) months, the estimated median overall survival (OS), progression-free survival (PFS), and brain progression-free survival (bPFS) were 16, 6, and 9 months, respectively. The estimated OS rates at 1 and 3 years were 59.8% and 18.3%, respectively; bPFS at 1 and 3 years was 29.9% and 13.5%, respectively; PFS at 1 and 3 years was 15.7% and 0%, respectively; and local failure-free survival (LFFS) at 1 and 3 years was 87.2% and 83.8%, respectively. Extracranial disease status was an independent factor related to OS. Fourteen (30%) patients manifested RN. At multivariate analysis, adenocarcinoma histology, left location, and absence of chemotherapy were confirmed as independent risk factors for any-grade RN. Nine (20%) patients developed symptomatic (G2) RN, which improved or stabilized after 1-16 months of steroid therapy. With prompt recognition and, when necessary, medical therapy, RN radiological and clinical amelioration can be obtained.

Clinical activity of regorafenib in elderly patients with recurrent glioblastoma.

Glioblastoma multiforme is one of the most frequent and aggressive primary tumors in the central nervous system, representing >60% of all brain tumors in adults. Despite treatment, prognosis remains poor with most if not all patients experiencing disease recurrence and a 2-year survival rate of 27%. At present, no confirmed standard treatment exists for recurrent glioblastoma. Regorafenib is one of the few options available, based on results from the REGOMA trial. In the present study, a real-life retrospective investigation on the role of regorafenib in patients with recurrent glioblastoma (>60 years old) from two main Oncological Units in South Italy (Azienda Ospedaliera Universitaria Luigi Vanvitelli, Naples, Italy and Ospedale Civile San Giovanni di Dio, Frattamaggiore, Naples, Italy), was performed. The primary endpoint was overall survival (OS), whereas progression-free survival (PFS), objective response rate and disease control were secondary endpoints. Survival was then analyzed according to age, isocitrate dehydrogenase (IDH) and methylated methylguanine-DNA-methyltransferase (MGMT) status. A total of 56 patients met the eligibility criteria. The intention to treat population median PFS (mPFS) was 4.1 months and median OS (mOS) was 6.8 months. Age did not appear to have a significant influence on mPFS. mOS in MGMT-methylated patients was improved compared with that of the unmethylated group (7.7 months vs. 5.6 months). Both mOS and mPFS were longer in IDH-mutant patients. The present study was one of the first real life analyses of regorafenib in recurrent glioblastoma. The results were in line with the REGOMA trial. Age did not appear to be a prognostic factor, thus suggesting that treatment choice should not be different in elderly. MGMT methylation appeared to influence OS. To the best of our knowledge, this was the first report of regorafenib activity in older patients and, while the results were statistically significant, these should be confirmed in further studies.

Potential benefits of using radioactive ion beams for range margin reduction in carbon ion therapy.

Sharp dose gradients and high biological effectiveness make ions such as 12C an ideal tool to treat deep-seated tumors, however, at the same time, sensitive to errors in the range prediction. Tumor safety margins mitigate these uncertainties, but during the irradiation they lead to unavoidable damage to the surrounding healthy tissue. To fully exploit the Bragg peak benefits, a large effort is put into establishing precise range verification methods. Despite positron emission tomography being widely in use for this purpose in 12C therapy, the low count rates, biological washout, and broad activity distribution still limit its precision. Instead, radioactive beams used directly for treatment would yield an improved signal and a closer match with the dose fall-off, potentially enabling precise in vivo beam range monitoring. We have performed a treatment planning study to estimate the possible impact of the reduced range uncertainties, enabled by radioactive 11C ions treatments, on sparing critical organs in tumor proximity. Compared to 12C treatments, (i) annihilation maps for 11C ions can reflect sub- millimeter shifts in dose distributions in the patient, (ii) outcomes of treatment planning with 11C significantly improve and (iii) less severe toxicities for serial and parallel critical organs can be expected.

In PD-1+ human colon cancer cells NIVOLUMAB promotes survival and could protect tumor cells from conventional therapies.

BACKGROUND: Colorectal cancer (CRC) is one of the most prevalent and deadly tumors worldwide. The majority of CRC is resistant to anti-programmed cell death-1 (PD-1)-based cancer immunotherapy, with approximately 15% with high-microsatellite instability, high tumor mutation burden, and intratumoral lymphocytic infiltration. Programmed death-ligand 1 (PD-L1)/PD-1 signaling was described in solid tumor cells. In melanoma, liver, and thyroid cancer cells, intrinsic PD-1 signaling activates oncogenic functions, while in lung cancer cells, it has a tumor suppressor effect. Our work aimed to evaluate the effects of the anti-PD-1 nivolumab (NIVO) on CRC cells. METHODS: In vitro NIVO-treated human colon cancer cells (HT29, HCT116, and LoVo) were evaluated for cell growth, chemo/radiotherapeutic sensitivity, apoptosis, and spheroid growth. Total RNA-seq was assessed in 6-24 hours NIVO-treated human colon cancer cells HT29 and HCT116 as compared with NIVO-treated PES43 human melanoma cells. In vivo mice carrying HT29 xenograft were intraperitoneally treated with NIVO, OXA (oxaliplatin), and NIVO+OXA, and the tumors were characterized for growth, apoptosis, and pERK1/2/pP38. Forty-eight human primary colon cancers were evaluated for PD-1 expression through immunohistochemistry. RESULTS: In PD-1+ human colon cancer cells, intrinsic PD-1 signaling significantly decreased proliferation and promoted apoptosis. On the contrary, NIVO promoted proliferation, reduced apoptosis, and protected PD-1+ cells from chemo/radiotherapy. Transcriptional profile of NIVO-treated HT29 and HCT116 human colon cancer cells revealed downregulation of BATF2, DRAM1, FXYD3, IFIT3, MT-TN, and TNFRSF11A, and upregulation of CLK1, DCAF13, DNAJC2, MTHFD1L, PRPF3, PSMD7, and SCFD1; the opposite regulation was described in NIVO-treated human melanoma PES43 cells. Differentially expressed genes (DEGs) were significantly enriched for interferon pathway, innate immune, cytokine-mediated signaling pathways. In vivo, NIVO promoted HT29 tumor growth, thus reducing OXA efficacy as revealed through significant Ki-67 increase, pERK1/2 and pP38 increase, and apoptotic cell reduction. Eleven out of 48 primary human colon cancer biopsies expressed PD-1 (22.9%). PD-1 expression is significantly associated with lower pT stage. CONCLUSIONS: In PD-1+ human colon cancer cells, NIVO activates tumor survival pathways and could protect tumor cells from conventional therapies.

Local tumor control and treatment related toxicity after plaque brachytherapy for uveal melanoma: A systematic review and a data pooled analysis.

Uveal melanoma (UM) represents the most common primary intraocular tumor, and nowadays eye plaque brachytherapy (EPB) is the most frequently used visual acuity preservation treatment option for small to medium sized UMs. The excellent local tumor control (LTC) rate achieved by EPB may be associated with severe complications and adverse events. Several dosimetric and clinical risk factors for the development of EPB-related ocular morbidity can be identified. However, morbidity predictive models specifically developed for EPB are still scarce. PRISMA methodology was used for the present systematic review of articles indexed in PubMed in the last sixteen years on EPB treatment of UM which aims at determining the major factors affecting local tumor control and ocular morbidities. To our knowledge, for the first time in EPB field, local tumor control probability (TCP) and normal tissue complication probability (NTCP) modelling on pooled clinical outcomes were performed. The analyzed literature (103 studies including 21,263 UM patients) pointed out that Ru-106 EPB provided high local control outcomes while minimizing radiation induced complications. The use of treatment planning systems (TPS) was the most influencing factor for EPB outcomes such as metastasis occurrence, enucleation, and disease specific survival, irrespective of radioactive implant type. TCP and NTCP parameters were successfully extracted for 5-year LTC, cataract and optic neuropathy. In future studies, more consistent recordings of ocular morbidities along with accurate estimation of doses through routine use of TPS are needed to expand and improve the robustness of toxicity risk prediction in EPB.

Biological Rationale and Clinical Evidence of Carbon Ion Radiation Therapy for Adenoid Cystic Carcinoma: A Narrative Review.

Adenoid cystic carcinoma (ACC) is a rare, basaloid, epithelial tumor, arising mostly from salivary glands. Radiation therapy can be employed as a single modality for unresectable tumors, in an adjuvant setting after uncomplete resection, in case of high-risk pathological features, or for recurrent tumors. Due to ACC intrinsic radioresistance, high linear energy transfer (LET) radiotherapy techniques have been evaluated for ACC irradiation: while fast neutron therapy has now been abandoned due to toxicity concerns, charged particle beams such as protons and carbon ions are at present the beams used for hadron therapy. Carbon ion radiation therapy (CIRT) is currently increasingly used for ACC irradiation. The aim of this review is to describe the immunological, molecular and clinicopathological bases that support ACC treatment with CIRT, as well as to expose the current clinical evidence that reveal the advantages of using CIRT for treating ACC.

FKBP51 Affects TNF-Related Apoptosis Inducing Ligand Response in Melanoma.

Melanoma is one of the most immunogenic tumors and has the highest potential to elicit specific adaptive antitumor immune responses. Immune cells induce apoptosis of cancer cells either by soluble factors or by triggering cell-death pathways. Melanoma cells exploit multiple mechanisms to escape immune system tumoricidal control. FKBP51 is a relevant pro-oncogenic factor of melanoma cells supporting NF-κB-mediated resistance and cancer stemness/invasion epigenetic programs. Herein, we show that FKBP51-silencing increases TNF-related apoptosis-inducing ligand (TRAIL)-R2 (DR5) expression and sensitizes melanoma cells to TRAIL-induced apoptosis. Consistent with the general increase in histone deacetylases, as by the proteomic profile, the immune precipitation assay showed decreased acetyl-Yin Yang 1 (YY1) after FKBP51 depletion, suggesting an impaired repressor activity of this transcription factor. ChIP assay supported this hypothesis. Compared with non-silenced cells, a reduced acetyl-YY1 was found on the DR5 promoter, resulting in increased DR5 transcript levels. Using Crispr/Cas9 knockout (KO) melanoma cells, we confirmed the negative regulation of DR5 by FKBP51. We also show that KO cells displayed reduced levels of acetyl-EP300 responsible for YY1 acetylation, along with reduced acetyl-YY1. Reconstituting FKBP51 levels contrasted the effects of KO on DR5, acetyl-YY1, and acetyl-EP300 levels. In conclusion, our finding shows that FKBP51 reduces DR5 expression at the transcriptional level by promoting YY1 repressor activity. Our study supports the conclusion that targeting FKBP51 increases the expression level of DR5 and sensitivity to TRAIL-induced cell death, which can improve the tumoricidal action of immune cells.

Radiation Pneumonitis in Thoracic Cancer Patients: Multi-Center Voxel-Based Analysis.

This study investigates the dose-response patterns associated with radiation pneumonitis (RP) in patients treated for thoracic malignancies with different radiation modalities. To this end, voxel-based analysis (VBA) empowered by a novel strategy for the characterization of spatial properties of dose maps was applied. Data from 382 lung cancer and mediastinal lymphoma patients from three institutions treated with different radiation therapy (RT) techniques were analyzed. Each planning CT and biologically effective dose map (α/ß = 3 Gy) was spatially normalized on a common anatomical reference. The VBA of local dose differences between patients with and without RP was performed and the clusters of voxels with dose differences that significantly correlated with RP at a p-level of 0.05 were generated accordingly. The robustness of VBA inference was evaluated by a novel characterization for spatial properties of dose maps based on probabilistic independent component analysis (PICA) and connectograms. This lays robust foundations to the obtained findings that the lower parts of the lungs and the heart play a prominent role in the development of RP. Connectograms showed that the dataset can support a radiobiological differentiation between the main heart and lung substructures.

Mastectomy alone for pT1-2 pN0-1 breast cancer patients: when postmastectomy radiotherapy is indicated.

PURPOSE: To assess outcome of breast cancer (BC) stages pT1-2 N0-1 after mastectomy alone and to identify prognostic factors calling for the need of postmastectomy radiotherapy. METHODS: Patients who were not eligible for breast conserving surgery (BCS) were operated on with mastectomy between 1998 and 2008. Locoregional (LRR), distant (DM) control and breast cancer specific survival (BCSS) were retrospectively evaluated. Cumulative incidence (CI) of events was estimated according to Kalbfleisch and Prentice while Gray's test tested difference. Kaplan-Meier method for survival and Cox proportional hazards model for univariable and multivariable analysis were used. A matched pair analysis between mastectomy alone and BCS plus whole breast irradiation (WBI), using the propensity score method, was performed. RESULTS: 1281 pT1-2 N0 and 1081 pT1-2 N1 were identified. Median follow-up was 8.2 years (9.2 years for survival). Overall, LRR rate was low for both N0 and N1 subgroups (10-year CI, 8.8% and 10.9%, respectively). Young age, lymphovascular invasion and Ki-67 ≥ 20% were proved to be statistically significant prognostic factors at multivariable analysis. The combination of ≥ 2 risk factors increased LRR rate to ≥ 15%. Risk factors combination weighed on LRR rate more than nodal status itself. DM rate doubled moving from negative to positive nodal status (10-year CI 10.5% versus 20.3%, respectively). BCSS remained high in both N0 and N1 subgroups (10-year CI 92.4% versus 84.5%, respectively). Remarkably, all the molecular subtypes except Luminal A significantly affected DM and BCSS both in the N0 and N1 subgroups. Nodes number significantly impacted on DM and BCSS but not on locoregional control. In the matched pair analysis, WBI decreased nodal recurrence rate and improved distant control, without affecting survival. CONCLUSIONS: Selected patients, namely those with at least two additional risk factors, presented high enough LRR risk to support the use of postmastectomy radiotherapy in both N0 and N1 subgroups. Moreover, the observation that radiotherapy may provide benefits that go beyond local control deserves to be further investigated.

New CXCR4 Antagonist Peptide R (Pep R) Improves Standard Therapy in Colorectal Cancer.

The chemokine receptor CXCR4 is overexpressed and functional in colorectal cancer. To investigate the role of CXCR4 antagonism in potentiating colon cancer standard therapy, the new peptide CXCR4 antagonist Peptide R (Pep R) was employed. Human colon cancer HCT116 xenograft-bearing mice were treated with chemotherapeutic agents (CT) 5-Fluorouracil (5FU) and oxaliplatin (OX) or 5FU and radio chemotherapy (RT-CT) in the presence of Pep R. After two weeks, CT plus Pep R reduced by 4-fold the relative tumor volume (RTV) as compared to 2- and 1.6-fold reductions induced, respectively, by CT and Pep R. In vitro Pep R addition to CT/RT-CT impaired HCT116 cell growth and further reduced HCT116 and HT29 clonal capability. Thus, the hypothesis that Pep R could target the epithelial mesenchyme transition (EMT) process was evaluated. While CT decreased ECAD and increased ZEB-1 and CD90 expression, the addition of Pep R restored the pretreatment expression. In HCT116 and HT29 cells, CT/RT-CT induced a population of CD133+CXCR4+ cells, supposedly a stem-resistant cancer cell population, while Pep R reduced it. Taken together, the results showed that targeting CXCR4 ameliorates the effect of treatment in colon cancer through inhibition of cell growth and reversal of EMT treatment-induced markers, supporting further clinical studies.

Fighting the Host Reaction to SARS-COv-2 in Critically Ill Patients: The Possible Contribution of Off-Label Drugs.

The severe acute respiratory syndrome coronavirus 2 (SARS-COv-2) is the etiologic agent of the 2019 coronavirus disease (COVID19). The majority of infected people presents flu like symptoms and among them 15-20% develops a severe interstitial pneumonitis (IP) that may eventually evolve in acute respiratory distress syndrome (ARDS). IP is caused by the viral glycoprotein spike (S) binding to the angiotensin converting enzyme 2 (ACE2) expressed on the surface of alveolar pneumocytes. The virus is recognized by the "pattern recognition receptors" (PRR) of the immune cells that release cytokines activating more immune cells that produce a large number of pro-inflammatory cytokines, tissue factors and vasoactive peptides. Affected patients might develop the "cytokine storm syndrome," a fulminant and fatal hypercytokinaemia with multiorgan failure. In patients infected by SARS-COv-2 increase in T-helper 2 (TH2) cytokines (IL-4 and IL10) are reported in addition to the T-helper 1 (TH1) cytokines (IL1B, IFNγ, IP10, and MCP1) previously detected in other coronavirus infections. Cytokines and other molecules involved in immune response and inflammation are conceivable therapeutic targets for IP and ARDS, improving symptoms and decreasing intensive care unit admissions. To this aim off label drugs may be used taking into consideration the window timing for immunosuppressive drugs in virus infected patients. Some off label therapeutic options and preclinical evidence drugs are herein considered.

COVID-19 outbreak and cancer radiotherapy disruption in Italy: Survey endorsed by the Italian Association of Radiotherapy and Clinical Oncology (AIRO).

Italy experienced one of the world's deadliest COVID-19 outbreaks and healthcare systems had to instantly reorganise activity. The Italian Radiation Oncology Departments adapted numerous solutions to minimize the disruptions. Information technologies, treatment prioritization and implementation of hypofractionation and protection procedures allowed balancing between cancer patient care and patient/healthcare workers safety.

CAF-1 Subunits Levels Suggest Combined Treatments with PARP-Inhibitors and Ionizing Radiation in Advanced HNSCC.

Oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinomas show high morbidity and mortality rates. We aimed to investigate the role of the "Chromatin Assembly Factor-1" (CAF-1) p60 and p150 subunits, involved in DNA repair and replication, in OSCC and OPSCC progression and in response to Poly(ADP-ribose) polymerase (PARP)-inhibitors and exposure to ionizing radiation (IR). We immunostained tissue microarrays (TMAs), including 112 OSCC and 42 OPSCC, with anti-CAF-1/p60 and anti-CAF-1/p150 specific antibodies, correlating their expression with prognosis. Moreover, we assessed the sensitivity to PARP inhibitors and the double-strand breaks repair proficiency by cell viability and HR reporter assays, respectively, in HPV-positive and HPV-negative cell lines upon CAF-1/p60 and CAF-1/p150 depletion. The immunohistochemical analysis revealed a significant prognostic value of both tissue biomarkers combined expression in OSCC but not in OPSCC. In in vitro studies, the p60/150 CAF-1 subunits' depletion impaired the proficiency of Homologous Recombination DNA damage repair, inducing sensitivity to the PARP-inhibitors, able to sensitize both the cell lines to IR. These results indicate that regardless of the prognostic meaning of p60/p150 tissue expression, the pharmacological depletion of CAF-1 complex's function, combined to PARP-inhibitors and/or IR treatment, could represent a valid therapeutic strategy for squamous cell carcinomas of head and neck region.

Normal tissue complication probability (NTCP) models for modern radiation therapy.

Mathematical models of normal tissue complication probability (NTCP) able to robustly predict radiation-induced morbidities (RIM) play an essential role in the identification of a personalized optimal plan, and represent the key to maximizing the benefits of technological advances in radiation therapy (RT). Most modern RT techniques pose, however, new challenges in estimating the risk of RIM. The aim of this report is to schematically review NTCP models in the framework of advanced radiation therapy techniques. Issues relevant to hypofractionated stereotactic body RT and ion beam therapy are critically reviewed. Reirradiation scenarios for new or recurrent malignances and NTCP are also illustrated. A new phenomenological approach to predict RIM is suggested.