Predictive value of perilesional edema volume in melanoma brain metastasis response to stereotactic radiosurgery.

BACKGROUND AND AIM: Stereotactic radiotherapy (SRT) is an established treatment for melanoma brain metastases (MBM). Recent evidence suggests that perilesional edema volume (PEV) might compromise the delivery and efficacy of radiotherapy to treat BM. This study investigated the association between SRT efficacy and PEV extent in MBM. MATERIALS AND METHODS: This retrospective study reviewed medical records from January 2020 to September 2023. Patients with up to 5 measurable MBMs, intracranial disease per RANO/iRANO criteria, and on low-dose corticosteroids were included. MRI scans assessed baseline neuroimaging, with PEV analyzed using 3D Slicer. SRT plans were based on MRI-CT fusion, delivering 18-32.5 Gy in 1-5 fractions. Outcomes included intracranial objective response rate (iORR) and survival measures (L-iPFS and OS). Statistical analysis involved decision tree analysis and multivariable logistic regression, adjusting for clinical and treatment variables. RESULTS: Seventy-two patients with 101 MBM were analyzed, with a mean age of 68.83 years. The iORR was 61.4%, with Complete Response (CR) in 21.8% and Partial Response (PR) in 39.6% of the treated lesions. PEV correlated with KPS, BRAF status, and treatment response. Decision tree analysis identified a PEV cutoff at 0.5 cc, with lower PEVs predicting better responses (AUC = 0.82 sensitivity: 86.7%, specificity:74.4%,). Patients with PEV ≥ 0.5 cc had lower response rates (iORR 44.7% vs. 63.8%, p < 0.001). Median OS was 9.4 months, with L-iPFS of 27 months. PEV significantly impacted survival outcomes. CONCLUSIONS: A more extensive PEV was associated with a less favorable outcome to SRT in MBM.

The role of brain radiotherapy for EGFR- and ALK-positive non-small-cell lung cancer with brain metastases: a review.

Non-small cell lung cancer (NSCLC) is frequently complicated by central nervous system (CNS) metastases affecting patients' life expectancy and quality. At the present clinical trials including neurosurgery, radiotherapy (RT) and systemic treatments alone or in combination have provided controversial results. CNS involvement is even more frequent in NSCLC patients with EGFR activating mutations or ALK rearrangement suggesting a role of target therapy in the upfront treatment in place of loco-regionals treatments (i.e. RT and/or surgery). So far clinical research has not explored the potential role of accurate brain imaging (i.e. MRI instead of the routine total-body contrast CT and/or PET/CT staging) to identify patients that could benefit of local therapies. Moreover, for patients who require concomitant RT there are no clear guidelines on the timing of intervention with respect to innovative precision medicine approaches with Tyrosine Kinase Inhibitors, ALK-inhibitors and/or immuno-oncological therapies. On this basis the present review describes the therapeutic strategies integrating medical and radiation oncology in patients with metastatic NSCLC (mNSCLC) adenocarcinoma with CNS involvement and EGFR activating mutations or ALK rearrangement.

CDK4, CDK6/cyclin-D1 Complex Inhibition and Radiotherapy for Cancer Control: A Role for Autophagy.

The expanding clinical application of CDK4- and CDK6-inhibiting drugs in the managements of breast cancer has raised a great interest in testing these drugs in other neoplasms. The potential of combining these drugs with other therapeutic approaches seems to be an interesting work-ground to explore. Even though a potential integration of CDK4 and CDK6 inhibitors with radiotherapy (RT) has been hypothesized, this kind of approach has not been sufficiently pursued, neither in preclinical nor in clinical studies. Similarly, the most recent discoveries focusing on autophagy, as a possible target pathway able to enhance the antitumor efficacy of CDK4 and CDK6 inhibitors is promising but needs more investigations. The aim of this review is to discuss the recent literature on the field in order to infer a rational combination strategy including cyclin-D1/CDK4-CDK6 inhibitors, RT, and/or other anticancer agents targeting G1-S phase cell cycle transition.

Role of perilesional edema and tumor volume in the prognosis of non-small cell lung cancer (NSCLC) undergoing radiosurgery (SRS) for brain metastases.

AIM: To assess the role of perilesional edema (PE) in non-small cell lung carcinoma (NSCLC) brain metastases (BM) undergoing radiosurgery (SRS). METHODS: This series includes 46 patients with 1-2 BM treated with SRS, selected out of all patients referred for radiotherapy (RT) for BMs over 5 years (2013 to 2017). Both the PE and gross tumor volume (GTV) were contoured on MRI images, and the PE/GTV ratio and PE + GTV value (TV, total volume) were calculated. Our clinical endpoints were brain recurrence free-survival, divided into local brain control (in field, LBC) and distant brain control (out of field, DBC) and overall survival (OS). We analyzed the role of the previously described volumetric parameters and of known clinical prognosticators (disease specific GPA, DS-GPA; chemotherapy, CHT) with Cox regression analyses. RESULTS: Only four patients (9%) developed in-field progression, whereas 10 patients (22%) showed new out-of-field BM and thirty-eight patients died in the follow up (83%). In univariate analysis, both volumetric parameters and clinical parameters were correlated with DBC and OS, whereas we did not find any correlation with LBC. In the multivariate analysis of DBC, the significant parameters were PE/GTV ratio (HR 0.302), sex (HR 0.131), and DS-GPA (HR 0.261). The OS multivariate analysis showed that the only significant parameters were DS-GPA (HR 0.478) and TV (HR: 1.038). CONCLUSION: Our study, although with the limitations of a monocentric retrospective study analyzing a small cohort of patients, suggests the role of PE/GTV ratio for the development of new BMs. TV also seems to be correlated with OS, together with known clinical prognosticators. These findings, if validated in a larger prospective dataset, could help in selecting patients for the most suitable RT modality (or systemic therapy approach).

Texture analysis as a predictor of radiation-induced xerostomia in head and neck patients undergoing IMRT.

PURPOSE: Image texture analysis (TA) is a heterogeneity quantifying approach that cannot be appreciated by the naked eye, and early evidence suggests that TA has great potential in the field of oncology. The aim of this study is to evaluate parotid gland texture analysis (TA) combined with formal dosimetry as a factor for predicting severe late xerostomia in patients undergoing radiation therapy for head and neck cancers. METHODS: We performed a retrospective analysis of patients treated at our Radiation Oncology Unit between January 2010 and December 2015, and selected the patients whose normal dose constraints for the parotid gland (mean dose < 26 Gy for the bilateral gland) could not be satisfied due to the presence of positive nodes close to the parotid glands. The parotid gland that showed the higher V30 was contoured on CT simulation and analysed with LifeX Software©. TA parameters included features of grey-level co-occurrence matrix (GLCM), neighbourhood grey-level dependence matrix (NGLDM), grey-level run length matrix (GLRLM), grey-level zone length matrix (GLZLM), sphericity, and indices from the grey-level histogram. We performed a univariate and multivariate analysis between all the texture parameters, the volume of the gland, the normal dose parameters (V30 and Mean Dose), and the development of severe chronic xerostomia. RESULTS: Seventy-eight patients were included and 25 (31%) developed chronic xerostomia. The TA parameters correlated with severe chronic xerostomia included V30 (OR 5.63), Dmean (OR 5.71), Kurtosis (OR 0.78), GLCM Correlation (OR 1.34), and RLNU (OR 2.12). The multivariate logistic regression showed a significant correlation between V30 (0.001), GLCM correlation (p: 0.026), RLNU (p: 0.011), and chronic xerostomia (p < 0.001, R2:0.664). CONCLUSIONS: Xerostomia represents an important cause of morbidity for head and neck cancer survivors after radiation therapy, and in certain cases normal dose constraints cannot be satisfied. Our results seem promising as texture analysis could enhance the normal dose constraints for the prediction of xerostomia.

Perilesional edema in brain metastasis from non-small cell lung cancer (NSCLC) as predictor of response to radiosurgery (SRS).

Radiosurgery (SRS) is widely used in the treatment of brain oligo-metastases from NSCLC. The aim of present study is to evaluate the extent of perilesional edema in brain metastases as predictive factor of treatment response. This single center retrospective study included 42 consecutive patients (January 2011-December 2014) with 1-2 brain metastasis from NSCLC treated with Radiosurgery (SRS). Extent of perilesional edema was measured as maximal extension from the edge of lesion and classified as minor (<10 mm) or major (≥10 mm). We analyzed Modality of Brain Recurrence (MBR), classified as in-field or out-of- field, and Brain Progression Free-Survival (BPFS) after treatment stratified according to extent of perilesional edema. Analyzing modality of brain recurrence and BPFS, after a median follow-up of 6 months, we found that patients with minor edema had a better radiological response to SRS with none in-field recurrences and a lower risk of the onset of new brain lesions (out-of-field recurrence). Instead, patients group with major edema had a worse response rate of lesions treated, further, a higher risk of out-of-field brain relapse. Extent of perilesional edema in brain metastasis from NSCLC could be a predictive factor of response and brain progression after SRS treatment alone.

Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients.

Thymidylate synthase (TS) poly-epitope peptide (TSPP) is a 27-mer peptide vaccine containing the amino acidic sequences of three epitopes with HLA-A2.1-binding motifs of TS, an enzyme overexpressed in cancer cells, which plays a crucial role in DNA repair and replication. Based on the results of preclinical studies, we designed a phase Ib trial (TSPP/VAC1) to investigate, in a dose escalation setting, the safety and the biological activity of TSPP vaccination alone (arm A) or in combination with GM-CSF and IL-2 (arm B) in cancer patients. Twenty-one pretreated metastatic cancer patients, with a good performance status (ECOG ≤ 1) and no severe organ failure or immunological disease, were enrolled in the study (12 in arm A, nine in arm B) between April 2011 and January 2012, with a median follow-up of 28 months. TSPP resulted safe, and its maximal tolerated dose was not achieved. No grade 4 toxicity was observed. The most common adverse events were grade 2 dermatological reactions to the vaccine injection, cough, rhinitis, fever, poly-arthralgia, gastro-enteric symptoms and, to a lesser extent, moderate hypertension and hypothyroidism. We detected a significant rise in auto-antibodies and TS-epitope-specific CTL precursors. Furthermore, TSPP showed antitumor activity in this group of pretreated patients; indeed, we recorded one partial response and seven disease stabilizations (SD) in arm A, and three SD in arm B. Taken together, our findings provide the framework for the evaluation of the TSPP anti-tumor activity in further disease-oriented clinical trials.

Challenges and Opportunities in Accessing Surgery for Glioblastoma in Low-Middle Income Countries: A Narrative Review.

Glioblastoma: a highly aggressive brain tumor, presents substantial challenges in treatment and management, with surgical intervention playing a pivotal role in improving patient outcomes. Disparities in access to brain tumor surgery arise from a multitude of factors, including socioeconomic status, geographical location, and healthcare resource allocation. Low- and middle-income countries (LMICs) often face significant barriers to accessing surgical services, such as shortages of specialized neurosurgical expertise, limited healthcare infrastructure, and financial constraints. Consequently, glioblastoma patients in LMICs experience delays in diagnosis, suboptimal treatment, and poorer clinical outcomes compared to patients in high-income countries (HICs). The clinical impact of these disparities is profound. Patients in LMICs are more likely to be diagnosed at advanced disease stages, receive less effective treatment, and have lower survival rates than their counterparts in HICs. Additionally, disparities in access to surgical care exacerbate economic and societal burdens, emphasizing the urgent need for targeted interventions and health policy reforms to address healthcare inequities. This review highlights the importance of addressing global disparities in access to brain tumor surgery for glioblastoma through collaborative efforts, policy advocacy, and resource allocation, aiming to improve outcomes and promote equity in surgical care delivery for all glioblastoma patients worldwide.

Impact of stereotactic body radiotherapy vs palliative radiotherapy on oncologic outcomes of patients with metastatic kidney cancer concomitantly treated with immune checkpoint inhibitors: a preliminary, multicentre experience.

PURPOSE: To explore the benefit yielded by radiotherapy (RT), we report a series of metastatic renal cell carcinoma (RCC) patients treated with concomitant RT plus Nivolumab. METHODS/PATIENTS: Patients undergoing Nivolumab treatment plus concomitant RT (ablative or palliative) were included. RT was defined Ablative if >5 Gy/fraction were delivered. RESULTS: Ablative RT intent was the only independent predictor of both progression free and overall survival (HR 3.51, 95% CI 1.6-7.5, p = 0.0012 and HR 2.8, 95% CI 0.99-8.07, p = 0.05, respectively). CONCLUSION: Ablative RT may improve oncologic outcomes in selected patients with metastatic RCC treated with Nivolumab as compared to palliative RT.

Inflammatory Markers and Procalcitonin Predict the Outcome of Metastatic Non-Small-Cell-Lung-Cancer Patients Receiving PD-1/PD-L1 Immune-Checkpoint Blockade.

Peripheral-immune-checkpoint blockade (P-ICB) with mAbs to PD-1 (nivolumab and pembrolizumab) or PD-L1 (atezolizumab, durvalumab, avelumab) alone or combination with chemotherapy represents a novel active treatment for mNSCLC patients. However, this therapy can be associated to immune-related adverse events (irAEs) and high cost. Therefore, finding reliable biomarkers of response and irAEs is strongly encouraged to accurately select patients who may potentially benefit from the immuno-oncological treatment. This is a retrospective multi-institutional analysis performed on ninety-five mNSCLC patients who received real-world salvage therapy with nivolumab or atezolizumab between December 2015 and April 2020. The outcome of these patients in term of PFS and OS was evaluated in comparison with different serum levels of C-reactive protein (CRP), Erythrocyte Sedimention Rate (ESR) and Procalcitonin (PCT) by performing Kaplan-Meier and Log-rank test and multivariate analysis. We found that high baseline levels of CRP, ESR, and PCT were strongly predictive of poor outcome (P <0.05) with the worse prognosis detected in those patients with a baseline levels of both ESR and PCT over the pre-established cut off (median OS recorded in patients with no marker over the cut off vs. those with just one marker over the cut off vs. those with both markers over the cut off: 40 ± 59 vs. 15.5 ± 5.5 vs. 5.5 ± 1.6 months, respectively; P <0.0001). Our results suggest the predictive value of systemic inflammation and suggest a potential role of PCT in predicting a poor outcome in mNSCLC receiving PD-1/PD-L1 blocking mAbs. This finding also suggests a potential role of subclinical bacterial infections in defining the response to PD-1/PD-L1 blocking mAbs that deserves further and more specific investigations.

Distinctive Role of the Systemic Inflammatory Profile in Non-Small-Cell Lung Cancer Younger and Elderly Patients Treated with a PD-1 Immune Checkpoint Blockade: A Real-World Retrospective Multi-Institutional Analysis.

An immune checkpoint blockade with mAbs to PD-1 and PD-L1 is an expanding therapeutic option for mNSCLC patients. This treatment strategy is based on the use of mAbs able to restore the anti-tumor activity of intratumoral T cells inhibited by PD-1 binding to PD-L1/2 on tumor and inflammatory cells. It has been speculated that a chronic status of systemic inflammation as well as the immunosenescence physiologically occurring in elderly patients may affect the efficacy of the treatment and the occurrence of irAEs. We performed a multi-institutional retrospective study aimed at evaluating the effects of these mAbs (nivolumab or atezolizumab) in 117 mNSCLC patients younger (90 cases) and older (27 cases) than 75 years in correlation with multiple inflammatory parameters (NLR, CRP, ESR, LDH and PCT). No differences were observed when the cohorts were compared in terms of the frequency of PFS, OS, inflammatory markers and immune-related adverse events (irAEs). Similarly, the occurrence of irAEs was strictly correlated with a prolonged OS survival in both groups. On the contrary, a negative correlation between the high baseline levels of inflammatory markers and OS could be demonstrated in the younger cohort only. Overall, PD-1/PD-L1-blocking mAbs were equally effective in young and elderly mNSCLC patients; however, the detrimental influence of a systemic inflammation at the baseline was only observed in young patients, suggesting different aging-related inflammation immunoregulative effects.

HLA Expression Correlates to the Risk of Immune Checkpoint Inhibitor-Induced Pneumonitis.

Tumor-infiltrating T cell rescue by programmed cell death receptor-1 (PD-1)/PD-1 ligand-1 (PD-L1) immune checkpoint blockade is a recommended treatment for malignant diseases, including metastatic non-small-cell lung cancer (mNSCLC), malignant melanoma (MM), head and neck, kidney, and urothelial cancer. Monoclonal antibodies (mAbs) against either PD-1 or PD-L1 are active agents for these patients; however, their use may be complicated by unpredictable immune-related adverse events (irAEs), including immune-related pneumonitis (IRP). We carried out a retrospective multi-institutional statistical analysis to investigate clinical and biological parameters correlated with IRP rate on a cohort of 256 patients who received real-world treatment with PD-1/PD-L1 blocking mAbs. An independent radiological review board detected IRP in 29 patients. We did not find statistical IRP rate correlation with gender, tumor type, specific PD-1 or PD-L1 blocking mAbs, radiation therapy, inflammatory profile, or different irAEs. A higher IRP risk was detected only in mNSCLC patients who received metronomic chemotherapy +/- bevacizumab compared with other treatments prior PD-1/PD-L1 blockade. Moreover, we detected a strong correlation among the IRP rate and germinal expression of HLA-B*35 and DRB1*11, alleles associated to autoimmune diseases. Our findings may have relevant implications in predicting the IRP rate in mNSCLC patients receiving PD-1/PD-L1 blockade and need to be validated on a larger patient series.

Distinctive germline expression of class I human leukocyte antigen (HLA) alleles and DRB1 heterozygosis predict the outcome of patients with non-small cell lung cancer receiving PD-1/PD-L1 immune checkpoint blockade.

BACKGROUND: Nivolumab is a human monoclonal antibody against programmed cell death receptor-1 (PD-1) able to rescue quiescent tumor infiltrating cytotoxic T lymphocytes (CTLs) restoring their ability to kill target cells expressing specific tumor antigen-derived epitope peptides bound to homologue human leukocyte antigen (HLA) molecules. Nivolumab is currently an active but expensive therapeutic agent for metastatic non-small cell lung cancer (mNSCLC), producing, in some cases, immune-related adverse events (irAEs). At the present, no reliable biomarkers have been validated to predict either treatment response or adverse events in treated patients. METHODS: We performed a retrospective multi-institutional analysis including 119 patients with mNSCLC who received PD-1 blockade since November 2015 to investigate the predictive role of germinal class I HLA and DRB1 genotype. We investigated the correlation among patients' outcome and irAEs frequency with specific HLA A, B, C and DRB1 alleles by reverse sequence-specific oligonucleotide (SSO) DNA typing. RESULTS: A poor outcome in patients negative for the expression of two most frequent HLA-A alleles was detected (HLA: HLA-A*01 and or A*02; progression-free survival (PFS): 7.5 (2.8 to 12.2) vs 15.9 (0 to 39.2) months, p=0.01). In particular, HLA-A*01-positive patients showed a prolonged PFS of 22.6 (10.2 to 35.0) and overall survival (OS) of 30.8 (7.7 to 53.9) months, respectively. We also reported that HLA-A and DRB1 locus heterozygosis (het) were correlated to a worse OS if we considered het in the locus A; in reverse, long survival was correlated to het in DRB1. CONCLUSIONS: This study demonstrate that class I and II HLA allele characterization to define tumor immunogenicity has relevant implications in predicting nivolumab efficacy in mNSCLC and provide the rationale for further prospective trials of cancer immunotherapy.

Radiomics predicts survival of patients with advanced non-small cell lung cancer undergoing PD-1 blockade using Nivolumab.

Immune checkpoint blockade is an emerging anticancer strategy, and Nivolumab is a human mAb to PD-1 that is used in the treatment of a number of different malignancies, including non-small cell lung cancer (NSCLC), kidney cancer, urothelial carcinoma and melanoma. Although the use of Nivolumab prolongs survival in a number of patients, this treatment is hampered by high cost. Therefore, the identification of predictive markers of response to treatment in patients is required. In this context, PD-1/PDL1 blockade antitumor effects occur through the reactivation of a pre-existing immune response, and the efficacy of these effects is strictly associated with the presence of necrosis, hypoxia and inflammation at the tumour sites. It has been indicated that these events can be evaluated by specific assessments using a computed tomography (CT) texture analysis (TA) or radiomics. Therefore, a retrospective study was performed, which aimed to evaluate the potential use of this analysis in the identification of patients with NSCLC who may benefit from Nivolumab treatment. A retrospective analysis was performed of 59 patients with metastatic NSCLC who received Nivolumab treatment between January 2015 and July 2017 at Siena University Hospital (35 patients, training dataset), Catanzaro University Hospital and Reggio Calabria Grand Metropolitan Hospital, Italy (24 patients, validation dataset). Pre- and post-contrast CT sequences were used to contour the gross tumour volume (GTV) of the target lesions prior to Nivolumab treatment. The impact of variations on contouring was analysed using two delineations, which were performed on each patient, and the TA parameters were tested for reliability using the Intraclass Coefficient Correlation method (ICC). All analyses for the current study were performed using LifeX Software©. Imaging, clinical and pathological parameters were correlated with progression free survival and overall survival (OS) using Kaplan Meier analysis. An external validation testing was performed for the TA Score using the validation dataset. A total of 59 patients were included in the analysis of the present study. The reliability ICC analysis of 14 TA parameters indicated a highly reproducibility (ICC >0.70, single measure) in 12 (85%) pre- contrast and 13 (93%) post-contrast exams. A specific cut-off was detected for each of the following parameters: volume (score 1 >36 ml), histogram entropy (score 1 > 1.30), compacity (score 1 <3), gray level co-occurrence matrix (GLCM)-entropy (score 1 >1.80), GLCM-Dissimilarity (score 1 >5) and GLCM-Correlation (score 1<0.54). The global texture score allowed the classification of two subgroups of Low (Score 0-1; 36 patients; 61%) and High Risk patients (Score >1; 23 patients; 39%) that respectively, showed a median OS of 26 (mean +/- SD: 18 +/- 1.98 months; 95% CI 14-21 months) and 5 months (mean +/- SD: 6 +/- 0.99 months; 95% CI: 4-8 months; P=0.002). The current study indicated that TA parameters can identify patients that will benefit from PD-1 blockage by defining the radiological settings that are potentially suggestive of an active immune response. These results require further confirmation in prospective trials.

Is a reduction of radiation dose feasible in patients affected by glioblastoma undergoing radio-chemotherapy according to MGMT promoter methylation status without jeopardizing survival?

OBJECTIVE: To explore therapeutic results of different radiotherapy (RT) dose schedules combined to Temozolomide (TMZ)-RT treatment in newly diagnosed glioblastoma (GB), according to the O (6)-methylguanine-DNA methyltransferase (MGMT) methylation status. PATIENTS AND METHODS: Patients with newly diagnosed GB received either standard (60-59.4 Gy) or reduced (54-52 Gy) dose radiation therapy (RT) with concurrent and adjuvant TMZ between June 2010 and October 2016. We retrospectively evaluated the therapeutic effectiveness of the RT ranges schedules in terms of overall survival (OS) with univariate and multivariate analysis, after analyzing the MGMT methylation status. RESULTS: One hundred and seventeen patients were selected for the present analysis out of 146 total treated patients accrued. Seventy-two out of the selected cases received the standard RT-TMZ course (SDRT-TMZ) whereas the remaining 45 underwent the reduced dose schedule (RDRT-TMZ). The analysis according to the MGMT promoter methylation status showed that, in methylated-MGMT GB patients, SDRT-TMZ and RDRT-TMZ groups did not show different median OS (p = ns) according to the two RT schedules, independently by the extent of surgical resection. Instead, a difference in survival outcomes was confirmed in unmethylated-MGMT GB patients with better survival for patients undergoing to SDRT, particularly in sub-total resection. CONCLUSION: In our experience, a reduction of radiation dose schedule does not seem to jeopardize survival in methylated-MGMT patients independently by the extent of resection. A therapeutic approach to a standard reduction of RT dose for the methylated subset of patients may be feasible and could deserve prospective trials for validation.

Magnetic-Resonance-Imaging Texture Analysis Predicts Early Progression in Rectal Cancer Patients Undergoing Neoadjuvant Chemoradiation.

BACKGROUND: We hypothesized that texture analysis (TA) from the preoperative MRI can predict early disease progression (ePD), defined as the percentage of patients who relapsed or showed distant metastasis within three months from the radical surgery, in patients with locally advanced rectal cancer (LARC, stage II and III, AJCC) undergoing neoadjuvant chemoradiotherapy (C-RT). METHODS: This retrospective monoinstitutional cohort study included 49 consecutive patients in total with a newly diagnosed rectal cancer. All the patients underwent baseline abdominal MRI and CT scan of the chest and abdomen to exclude distant metastasis before C-RT. Texture parameters were extracted from MRI performed before C-RT (T1, DWI, and ADC sequences) using LifeX Software, a dedicated software for extracting texture parameters from radiological imaging. We divided the cohort in a training set of 34 patients and a validation set of 15 patients, and we tested the data sets for homogeneity, considering the clinical variables. Then we performed univariate and multivariate analysis, and a ROC curve was also generated. RESULTS: Thirteen patients (26.5%) showed an ePD, three of whom with lung metastases and ten with liver relapse. The model was validated based on the prediction accuracy calculated in a previously unseen set of 15 patients. The prediction accuracy of the generated model was 82% (AUC = 0.853) in the training and 80% (AUC = 0.833) in the validation cohort. The only significant features at multivariate analysis was DWI GLCM Correlation (OR: 0.239, p < 0.001). CONCLUSION: Our results suggest that TA could be useful to identify patients that may develop early progression.

Early blood rise in auto-antibodies to nuclear and smooth muscle antigens is predictive of prolonged survival and autoimmunity in metastatic-non-small cell lung cancer patients treated with PD-1 immune-check point blockade by nivolumab.

Immune-checkpoint blockade by Nivolumab, a human monoclonal antibody to programmed cell death receptor-1, is an emerging treatment for metastatic non-small cell lung cancer (mNSCLC). In order to prolong patient survival, this treatment requires a continuous cross-priming of tumor derived-antigens to supply fresh tumor-specific immune-effectors; a phenomenon that may also trigger auto-immune-related adverse events (irAEs). The present study therefore investigated the prognostic value of multiple autoimmunity-associated parameters in patients with mNSCLC who were undergoing Nivolumab treatment. This retrospective study included 92 mNSCLC patients who received salvage therapy with Nivolumab (3 mg/kg, biweekly) between September 2015 and June 2018. Log-rank test, Mantel-Cox and McPherson analyses were conducted to correlate patient progression-free survival (PFS) and overall survival (OS) with different parameters including blood cell counts, serum inflammatory markers and auto-antibodies (AAbs). A median PFS and OS of 10 [inter-quartile range (IQR): 5.8-14.2] and 16 [IQR: 6.2-25.8] months, respectively, were recorded, which did not correlated with age, histology or the number of previous chemotherapy lines. Male gender, the type of therapeutic regimens received prior to Nivolumab, and the occurrence of irAEs were revealed to be positive predictors of prolonged survival (P<0.05). Early detection (within 30 days) of >1AAbs among anti-nuclear antigens (ANAs), extractable nuclear antigens (ENAs) and anti-smooth cell antigens (ASMAs) correlated with prolonged PFS [hazard ratio (HR)=0.23; 95% confidence interval (CI): 0.08-0.62; P=0.004] and OS [HR=0.28 (95% CI: 0.09-0.88), P=0.03], with the type of treatment received prior to nivolumab (P=0.007) and with the risk of irAEs (P=0.002). In conclusion, increased serum levels of ANA, ENA and/or ASMA are consequential to Nivolumab administration and are predictive of a positive outcome in mNSCLC patients.

GOLFIG Chemo-Immunotherapy in Metastatic Colorectal Cancer Patients. A Critical Review on a Long-Lasting Follow-Up.

Background: GOLFIG is a chemo-immunotherapy regimen established in preclinical models that combines gemcitabine + FOLFOX (fluoropyrimidine backbone coupled to oxaliplatin) poly-chemotherapy with low-dose s. c. recombinant interleukin-2 (rIL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF). Promising antitumor effects in metastatic colorectal cancer (mCRC) patients were obtained in previous phase II and III trials. Here we report the results of 15 years of follow-up. Methods: This is a multi-institutional retrospective analysis including 179 mCRC patients receiving GOLFIG regimen between June 2002 and June 2018. Sixty-two of them received the treatment as frontline (enrolled in the GOLFIG-2 phase III trial) and 117 as second/third line (49 enrolled in the GOLFIG-1 phase II trial and 68 as compassionate use). One hundred twelve patients showed a primary left side and 67 a primary right side; K/N-ras mutational status was available in 74 cases, and an activating mutation was detected in 33. Kaplan-Meier and Cox regression analyses were carried out to relate PFS and OS with different parameters. Results: Overall, we recorded a mean PFS and OS of 15.28 (95% CI: 10.36-20.20) and 24.6 (95% CI: 19.07-30.14) months, respectively, with 14 patients surviving free of progression for 10 years. This regimen, in our updated survey of the GOLFIG-2 trial, confirmed superiority over FOLFOX in terms of PFS (hazard ratio (HR) = 0.58, p = 0.006) with a trend to a longer OS (HR = 0.69, P = 0.06) in the first line. Our analysis also confirmed significant antitumor activity in pre-treated patients, reporting a mean PFS and OS of 12.55 (95% CI: 7.19-17.9) and 20.28 (95% CI: 14.4-26.13) months, respectively. Immune-related adverse events (irAEs) were recorded in 24% of the cases and were related to a longer survival (HR = 0.36; P = 0.0001). Finally, patients' outcome was not correlated to sex, sidedness, and MT-K/N-ras. Conclusions: The GOLFIG regimen is a reliable underestimated therapeutic option in pre-treated mCRC patients and offers a strong rationale to design further trials.

The effects of radiotherapy on the survival of patients with unresectable non-small cell lung cancer.

INTRODUCTION: Lung cancer represents the leading cause of cancer mortality across the worlds. At present, less than 30% of the patients can undergo curative surgery, while the majority of them (65%) are diagnosed with metastatic disease and directed to systemic treatments. In this context there is a subset of patients (25%) with locally advanced stage disease whose outcome might be improved by using combined strategies of treatment including chemotherapy, radiotherapy and surgery. Areas covered: Here we reviewed possible combination strategies aimed to improve the outcome of lung cancer patients, focusing on the role of radiotherapy both in the adjuvant and oligo-metastatic setting and in synergy with immunotherapy, and finally, we afforded the new challenges concerning the advanced RT and precision oncology. We carried out a focused analysis concerning the key clinical management weaknesses as well as the potential that current research holds. Expert commentary: We believe that the most promising clinical trials in this specific patient subset will build their rationale on the results of well-designed translational models aimed to test the combination of cytotoxic drugs, radiobiology, and immune-pharmacology. In this context, remarkable investigational fields are focused on the attempt to combine radiotherapy with chemo-immunological strategies and precision medicine protocols.