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Abstract Purpose Implanted devices used in metastatic spine tumor surgery (MSTS) include pedicle screws, fixation plates, fixation rods, and interbody devices. A material to be used to fabricate any of these devices should possess an array of properties, which include biocompatibility, no toxicity, bioactivity, low wear rate, low to moderate incidence of artifacts during imaging, tensile strength and modulus that are comparable to those of cortical bone, high fatigue strength/long fatigue life, minimal or no negative impact on radiotherapy (RT) planning and delivery, and high capability for fusion to the contiguous bone. The shortcomings of Ti6Al4V alloy for these applications with respect to these desirable properties are well recognized, opening the field for an investigation about novel biomaterials that could replace the current gold standard. Previously published reviews on this topic have exhibited significant shortcomings in the studies they included, such as a small, heterogenous sample size and the lack of a cost-benefit analysis, extremely useful to understand the practical possibility of applying a novel material on a large scale. Therefore, this review aims to collect information about the clinical performance of these biomaterials from the most recent literature, with the objective of deliberating which could potentially be better than titanium in the future, with particular attention to safety, artifact production and radiotherapy planning interference. The significant promise showed by analyzing the clinical performance of these devices warrants further research through prospective studies with a larger sample size also taking into account each aspect of the production and use of such materials. Methods The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were used to improve the reporting of the review. The search was performed from March 2022 to September 2023. Results At the end of the screening process, 20 articles were considered eligible for this study. Polyetheretherketone (PEEK), Carbon-fibre reinforced polyetheretherketone (CFR-PEEK), long carbon fiber reinforced polymer (LCFRP), Polymethylmethacrylate (PMMA), and carbon screw and rods were used in the included studies. Conclusion CFR-PEEK displays a noninferior safety and efficacy profile to titanium implanted devices. However, it also has other advantages. By decreasing artifact production, it is able to increase detection of local tumor recurrence and decrease radiotherapy dose perturbation, ultimately bettering prognosis for patients necessitating adjuvant treatment. Nonetheless, its drawbacks have not been explored fully and still require further investigation in future studies. This does not exclude the fact that CFR-PEEK could be a valid alternative to titanium in the near future.

Abstract Compared to other malignancies, few studies have investigated the role of family history of cancer (FHC) in patients with lung cancer, yielding largely heterogeneous results. We performed a systematic literature review in accordance with PRISMA guidelines, searching the PubMed and Scopus databases from their inception to November 25, 2023, to identify studies reporting on the role of FHC in patients with lung cancer. A total of 53 articles were included, most with a retrospective design and encompassing a variety of geographical areas and ethnicities. Thirty studies (56.6%) assessed patients with non-small cell lung cancer (NSCLC), while 17 studies (32.1%) assessed patients with mixed histologies. Overall, the rates of FHC ranged from 8.3 to 68.9%, and the rates of family history of lung cancer ranged from 2 to 46.8%. Twenty-seven studies investigated FHC as a potential risk factor for lung cancer, with more than half reporting an increased risk for subjects with FHC. Five studies reported on the potential role of FHC in determining clinical outcomes, and twelve studies examined the relationship between FHC and germline mutations. Notably, only one study reported a significantly increased rate of germline mutations, including ATM, BRCA2, and TP53, for patients with a family history of lung cancer compared to those without, but both groups had a low prevalence of mutations (

Background Receptor activator of nuclear factor kappa-B ligand (RANKL) can directly promote tumor growth and indirectly support tumor immune evasion by altering the tumor microenvironment and immune cell responses. This study aimed to assess the prognostic significance of soluble RANKL in patients with advanced non-small cell lung cancer (NSCLC) receiving programmed cell death 1 (PD1)/programmed death-ligand 1 (PDL1) checkpoint inhibitor therapy.Methods Plasma RANKL levels were measured in 100 patients with advanced NSCLC without bone metastases undergoing monotherapy with PD1/PDL1 checkpoint inhibitors. To establish the optimal cut-off value, we used the Cutoff Finder package in R. Survival curves for four distinct patient groups, according to their RANKL and PDL1 levels (high or low), were generated using the Kaplan-Meier method and compared with the log-rank test. The Cox regression model calculated HRs and 95% CIs for overall survival (OS) and progression-free survival (PFS).Results The optimal RANKL cut-off was established at 280.4 pg/mL, categorizing patients into groups with high or low RANKL levels. A significant association was observed between increased RANKL concentrations and decreased survival rates at 24 months, only within the subgroup expressing high levels of PDL1 (p=0.002). Additionally, low RANKL levels in conjunction with elevated PDL1 expression correlated with improved PFS (median 22 months, 95% CI 6.70 to 50 vs median 4 months, 95% CI 3.0 to 7.30, p=0.009) and OS (median 26 months, 95% CI 20 to not reached vs median 7 months, 95% CI 6 to 13, p=0.003), indicating RANKL’s potential as an indicator of adverse prognosis in these patients. Multivariate analysis identified RANKL as an independent negative prognostic factor for both PFS and OS, regardless of other clinicopathological features.Conclusion These results highlight the prognostic and predictive value of RANKL specifically in patients with high PDL1 expression.

Abstract Background After a huge efficacy of imatinib in treating patients with gastrointestinal stromal tumors (GISTs) was proven, a maximum effort was made to make a differential diagnosis between GISTs and gastrointestinal leiomyosarcomas (GI‐LMS), showing the latter to be an extremely rare tumor entity. Limited data on GI‐LMS biology, clinical behavior and drug‐sensibility are available, and the clinical decision‐making in this subgroup of patients is usually challenging. Methods We conducted a multicenter, retrospective observational study on patients with diagnosed GI‐LMS from 2004 to 2020 within six high‐volume referral centers in Italy. Results Thirty‐three patients had diagnosis of KIT‐negative GI‐LMS confirmed by sarcoma‐expert pathologist. The most common site of origin was the intestine. Twenty‐two patients had localized disease and underwent surgery: with a median follow‐up of 72 months, median disease‐free survival was 42 months. Overall survival (OS)‐rate at 5 years was 73% and median OS was 193 months. Five out of 10 patients with local relapse received a salvage surgery, and 2/5 remained with no evidence of disease. Thirteen patients received neoadjuvant (6) or adjuvant (7) chemotherapy, and 2/13 patients remained free from relapse. The median OS for patients with metastatic LMS was 16.4 months. Conclusion GI‐LMS is very rare and extremely aggressive subgroup of sarcomas with a high tendency to systemic spread. Localized GI‐LMS at diagnosis may be cured if treated with adequate surgery with or without (neo) adjuvant chemotherapy, while de‐novo metastatic disease appeared to have a poor prognosis. Clinical effort to understand GI‐LMS biology and clinical behavior and to develop active treatment strategy, especially for metastatic‐disease, is warranted.

Abstract Background Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST. Methods Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment. Results From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST. Conclusions Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST. Trial registration ClinicalTrials.gov Identifier: NCT02638766.

IntroductionEpithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease.Study designRegistry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE.ObjectivesTo improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern.MethodsSettings and participantsIt is an hospital-based registry established in centers with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for routine patient follow-up. VariablesFull details on patients and disease features, treatment and outcome will be collected, according to common clinical practice guidelines developed and shared with all the contributing centers. In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will also be collected. Statistical methodsThe data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression.ResultsThe registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual.

Background: To date, limited evidence exists on the impact of COVID-19 in patients with soft tissue sarcoma (STS), nor about the impact of SARS-CoV-2 vaccines and recent chemotherapy on COVID-19 morbidity and mortality in this specific population. Methods: We described COVID-19 morbidity and mortality among patients with STS across ‘Omicron’ (15 December 2021–31 January 2022), ‘Pre-vaccination’ (27 February 2020–30 November 2020), and ‘Alpha-Delta’ phase (01 December 2020–14 December 2021) using OnCovid registry participants (NCT04393974). Case fatality rate at 28 days (CFR 28 ) and COVID-19 severity were also described according to the SARS-CoV-2 vaccination status, while the impact of the receipt of cytotoxic chemotherapy within 4 weeks prior to COVID-19 on clinical outcomes was assessed with Inverse Probability of Treatment Weighting (IPTW) models adjusted for possible confounders. Results: Out of 3820 patients, 97 patients with STS were included. The median age at COVID-19 diagnosis was 56 years (range: 18–92), with 65 patients (67%) aged < 65 years and most patients had a low comorbidity burden (65, 67.0%). The most frequent primary tumor sites were the abdomen (56.7%) and the gynecological tract (12.4%). In total, 36 (37.1%) patients were on cytotoxic chemotherapy within 4 weeks prior to COVID-19. The overall CFR 28 was 25.8%, with 38% oxygen therapy requirement, 34% rate of complications, and 32.3% of hospitalizations due to COVID-19. CFR 28 (29.5%, 21.4%, and 12.5%) and all indicators of COVID-19 severity demonstrated a trend toward a numerical improvement across the pandemic phases. Similarly, vaccinated patients demonstrated numerically improved CFR 28 (16.7% versus 27.7%) and COVID-19 morbidity compared with unvaccinated patients. Patients who were on chemotherapy experienced comparable CFR 28 (19.4% versus 26.0%, p = 0.4803), hospitalizations (50.0% versus 44.4%, p = 0.6883), complication rates (30.6% versus 34.0%, p = 0.7381), and oxygen therapy requirement (28.1% versus 40.0%, p = 0.2755) compared to those who were not on anticancer therapy at COVID-19, findings further confirmed by the IPTW-fitted multivariable analysis. Conclusion: In this study, we demonstrate an improvement in COVID-19 outcomes in patients with STS over time. Recent exposure to chemotherapy does not impact COVID-19 morbidity and mortality and SARS-CoV-2 vaccination confers protection against adverse outcomes from COVID-19 in this patient population.

Immunotherapy has revolutionized the treatment paradigm of non-small cell lung cancer and improved patients’ prognosis. Immune checkpoint inhibitors have quickly become standard frontline treatment for metastatic non-oncogene addicted disease, either as a single agent or in combination strategies. However, only a few patients have long-term benefits, and most of them do not respond or develop progressive disease during treatment. Thus, the identification of reliable predictive and prognostic biomarkers remains crucial for patient selection and guiding therapeutic choices. In this review, we provide an overview of the current strategies, highlighting the main clinical challenges and novel potential biomarkers.

Background & Aims: Direct comparisons across first-line regimens for advanced hepatocellular carcinoma are not available. We performed a network metanalysis of phase III of trials to compare first-line systemic treatments for hepatocellular carcinoma in terms of overall survival (OS), progression-free survival (PFS), objective response rate, disease control rate, and incidence of adverse events (AEs). Methods: After performing a literature review from January 2008 to September 2022, we screened 6,329 studies and reviewed 3,009 studies, leading to identification of 15 phase III trials for analysis. We extracted odds ratios for objective response rate and disease control rate, relative risks for AEs, and hazard ratios (HRs) with 95% CIs for OS and PFS, and used a frequentist network metanalysis, with fixed-effect multivariable meta-regression models to estimate the indirect pooled HRs, odds ratios, relative risks, and corresponding 95% CIs, considering sorafenib as reference. Results: Of 10,820 included patients, 10,444 received active treatment and 376 placebo. Sintilimab + IBI350, camrelizumab + rivoceranib, and atezolizumab + bevacizumab provided the greatest reduction in the risk of death compared with sorafenib, with HRs of 0.57 (95% CI 0.43–0.75), 0.62 (95% CI 0.49–0.79), and 0.66 (95% CI 0.52–0.84), respectively. Considering PFS, camrelizumab + rivoceranib and pembrolizumab + lenvatinib were associated with the greatest reduction in the risk of PFS events compared with sorafenib, with HRs of 0.52 (95% CI 0.41–0.65) and 0.52 (95% CI 0.35–0.77), respectively. Immune checkpoint inhibitor (ICI) monotherapies carried the lowest risk for all-grade and grade ≥3 AEs. Conclusions: The combinations of ICI + anti-vascular endothelial growth factor, and double ICIs lead to the greatest OS benefit compared with sorafenib, whereas ICI + kinase inhibitor regimens are associated with greater PFS benefit at the cost of higher toxicity rates. Impact and Implications: In the last few years, many different therapies have been studied for patients with primary liver cancer that cannot be treated with surgery. In these cases, anticancer drugs (alone or in combination) are given with the intent to keep the cancer at bay and, ultimately, to prolong survival. Among all the therapies that have been investigated, the combination of immunotherapy (drugs that boost the immune system against the cancer) and anti-angiogenic agents (drugs that act on tumoural vessels) has appeared the best to improve survival. Similarly, the combination of two types of immunotherapies that activate the immune system at different levels has also shown positive results. Systematic Review Registration: PROSPERO CRD42022366330.

BackgroundAmong sarcomas, which are rare cancers with an incidence of 24 months. Nine patients had at least one grade 3/4 adverse event, mostly being bone marrow toxicity (n=6).ConclusionsTrabectedin has some anti-tumor activity in some ultra-rare and other rare sarcomas, particularly translocation-related sarcomas, with the well-known manageable safety profile.

Immune checkpoint inhibitors (ICIs) has revolutionized the treatment of different advanced solid tumors, but most patients develop severe immune-related adverse events (irAEs). Although a bi-directional crosstalk between bone and immune systems is widely described, the effect of ICIs on the skeleton is poorly investigated. Here, we analyze the changes in plasma levels of type I collagen C-terminal telopeptide (CTX-I) and N-terminal propeptide of type I procollagen (PINP), reference makers of bone turnover, in patients treated with ICIs and their association with clinical outcome.A series of 44 patients affected by advanced non-small cell lung cancer or renal cell carcinoma, without bone metastases, and treated with ICIs as monotherapy were enrolled. CTX-I and PINP plasma levels were assessed at baseline and after 3 months of ICIs treatment by ELISA kits.A significant increase of CTX-I with a concomitant decreasing trend towards the reduction of PINP was observed after 3 months of treatment. Intriguingly, CTX-I increase was associated with poor prognosis in terms of treatment response and survival. These data suggest a direct relationship between ICIs treatment, increased osteoclast activity and potential fracture risk.Overall, this study reveals that ICIs may act as triggers for skeletal events, and if confirmed in larger prospective studies, it would identify a new class of skeletal-related irAEs.

Background As management and prevention strategies against COVID-19 evolve, it is still uncertain whether prior exposure to immune checkpoint inhibitors (ICIs) affects COVID-19 severity in patients with cancer.Methods In a joint analysis of ICI recipients from OnCovid (NCT04393974) and European Society for Medical Oncology (ESMO) CoCARE registries, we assessed severity and mortality from SARS-CoV-2 in vaccinated and unvaccinated patients with cancer and explored whether prior immune-related adverse events (irAEs) influenced outcome from COVID-19.Findings The study population consisted of 240 patients diagnosed with COVID-19 between January 2020 and February 2022 exposed to ICI within 3 months prior to COVID-19 diagnosis, with a 30-day case fatality rate (CFR30) of 23.6% (95% CI 17.8 to 30.7%). Overall, 42 (17.5%) were fully vaccinated prior to COVID-19 and experienced decreased CFR30 (4.8% vs 28.1%, p=0.0009), hospitalization rate (27.5% vs 63.2%, p

Abstract Background Myxofibrosarcoma (MFS) is a rare soft tissue sarcoma with a high recurrence rate and a low risk of distant metastasis. It occurs mainly in the extremities of elderly men. Head and neck MFS is extremely rare. Surgery is the cornerstone of treatment. The role of radiotherapy (RT) and chemotherapy (CHT) on MFS is still debated. Case presentation A 67-year-old Caucasian man presented to our sarcoma referral center (SRC) with a history of MFS of the neck excised with microscopic positive surgical margins in a non-referral center. Staging imaging exams did not reveal distant metastasis. After a multidisciplinary discussion, preoperative RT was administered with a total dose of 50 Gy followed by wide surgical excision. Histological examination was negative for viable tumor cells. No relapse occurred during the 24-month postoperative follow-up. Conclusions The case described suggests the importance of planned combined treatments with both RT and surgery for high-grade soft tissue sarcoma. RT seems to be promising within this specific histotype. Close follow-up is advisable in all cases. Further studies are needed to confirm if the observed efficacy of combined treatments results in a prolonged time of disease-free survival and overall survival.

Background: Solitary fibrous tumours (SFT) are soft tissue sarcomas molecularly defined by the presence of the NAB2::STAT6 intrachromosomal fusion gene. Recently, a prospective phase II trial evaluating the role of the antiangiogenic tyrosine kinase inhibitor pazopanib in SFT has been conducted (NCT02066285). Methods: Here, we analysed the mRNA and protein expression levels of the tumour suppressor and angiogenesis regulator p53 ( TP53 ) in pre-treatment tumour samples from 22 patients with low aggressive (or typical) SFT and 28 patients with high aggressive (26 malignant and 2 dedifferentiated) SFT enrolled in the aforementioned pazopanib phase II trial. These results were correlated with radiological progression-free survival (PFS) and objective response. Univariate and multivariate Cox regression analyses were also performed, including known clinic-pathological prognostic factors. Results: Diffuse immunohistochemistry (IHC) expression of p53 was only found in patients with aggressive SFT and was associated with significantly shorter PFS [hazard ratio (HR): 4.39, 95% confidence interval (CI): 1.19–16.14). TP53 mRNA levels were significantly higher in the low aggressive SFT group. Only in the high aggressive SFT group, relatively higher levels of TP53 were significantly associated with shorter PFS (HR: 4.16, 95% CI: 1.46–11.89) as well as to a lower rate of disease control following treatment with pazopanib. In the multivariate analysis, the only independent prognostic factor in the whole cohort was mitotic count. Conclusion: Diffuse p53 IHC expression and higher TP53 mRNA levels are associated with worse prognosis in the subset of aggressive SFT patients treated with pazopanib.

Dacarbazine is an important drug in the therapeutic landscape of leiomyosarcoma (LMS). Alkylating agents are subjected to resistance mechanisms based on anti-apoptotic pathways and repair mechanisms, including the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). In this retrospective study, the methylation status of the MGMT promoter in histological tumor samples from patients with LMS, dacarbazine-based regimens-treated, was measured and correlated with clinical outcomes aimed at optimizing the use of dacarbazine in soft tissue sarcomas. The patients with unmethylated MGMT had better outcomes than those with methylated MGMT. Patients without MGMT methylation had better Progression Free Survival (PFS) when aged ≥62 years compared to those aged MGMT was less favorable independently of age (p = 0.0054). The patients without a methylated MGMT gene had higher Disease control rate (DCR). These results are not in agreement with the role of the methylated MGMT gene in other tumors, and with this study, we demonstrated the correlation between methylated MGMT and poor prognosis; despite that, sample smallness, heterogeneity of LMS and of treatment history could be selection bias. Predictive markers of response to chemotherapies in sarcomas remain an unmet need.

Adjuvant treatment with Imatinib is the standard of care for high-risk resected GISTs. Imatinib is known to have an impact on bone mineral density in patients affected by chronic myeloid leukemia, however this effect has never been investigated in GISTs.We retrospectively evaluated, on CT scans, the effect of adjuvant Imatinib (400 mg/die) on bone mineral density and muscle composition in 14 patients with surgically resected GISTs and in a control group of 8 patients who did not received any treatment. The effect of bone and muscle composition on Imatinib-tolerance was assessed as well.Overall patients receiving Imatinib experienced an increase in bone mineral density during treatment (p = 0.021); with higher increase in patients with basal values

Abstract Background This observational, retrospective effort across Europe, US, Australia, and Asia aimed to assess the activity of systemic therapies in EHE, an ultra‐rare sarcoma, marked by WWTR1‐CAMTA1 or YAP1‐TFE3 fusions. Methods Twenty sarcoma reference centres contributed data. Patients with advanced EHE diagnosed from 2000 onwards and treated with systemic therapies, were selected. Local pathologic review and molecular confirmation were required. Radiological response was retrospectively assessed by local investigators according to RECIST. Progression free survival (PFS) and overall survival (OS) were estimated by Kaplan‐Meier method. Results Overall, 73 patients were included; 21 had more than one treatment. Thirty‐three patients received anthracyclines regimens, achieving 1 (3%) partial response (PR), 25 (76%) stable disease (SD), 7 (21%) progressive disease (PD). The median (m‐) PFS and m‐OS were 5.5 and 14.3 months respectively. Eleven patients received paclitaxel, achieving 1 (9%) PR, 6 (55%) SD, 4 (36%) PD. The m‐PFS and m‐OS were 2.9 and 18.6 months, respectively. Twelve patients received pazopanib, achieving 3 (25%) SD, 9 (75%) PD. The m‐PFS and m‐OS were.2.9 and 8.5 months, respectively. Fifteen patients received INF‐α 2b, achieving 1 (7%) PR, 11 (73%) SD, 3 (20%) PD. The m‐PFS and m‐OS were 8.9 months and 64.3, respectively. Among 27 patients treated with other regimens, 1 PR (ifosfamide) and 9 SD (5 gemcitabine +docetaxel, 2 oral cyclophosphamide, 2 others) were reported. Conclusion Systemic therapies available for advanced sarcomas have limited activity in EHE. The identification of new active compounds, especially for rapidly progressive cases, is acutely needed.

In advanced or metastatic settings, Comprehensive Genomic Profiling (CGP) allows the evaluation of thousands of gene alterations with the goal of offering new opportunities for personalized treatment in solid tumors. This study evaluated the CGP Success Rate in a real-life cohort of 184 patients enrolled in a prospective clinical trial. CGP data were compared with the routine molecular testing strategy adopted in-house. Sample age, tumor area, and the percentage of tumor nuclei were recorded for CGP analysis. We found that 150/184 (81.5%) samples resulted in satisfying CGP reports. The CGP Success Rate was higher in samples from surgical specimens (96.7%) and in specimens that had been stored (sample age) for less than six months (89.4%). Among the inconclusive CGP reports, 7/34 (20.6%) were optimal samples, according to CGP sample requirements. Moreover, with the in-house molecular testing approach, we could obtain clinically relevant molecular data in 25/34 (73.5%) samples that had inconclusive CGP reports. In conclusion, despite the fact that CGP offers specific therapeutical options in selected patients, our data suggest that the standard molecular testing strategy should not be replaced in routine molecular profiling.

Background: Feline injection-site sarcomas (FISS) are mesenchymal tumors that can occur in cats after injections of different medical agents, and are easily prone to recurrence. Aim: The aims of this study were to report treatment outcomes for cats with feline injection site sarcomas (FISS) treated with both bleomycin and cisplatin, per adjuvant electrochemotherapy (ECT) protocol. Methods: Medical records of cats with a diagnosis of FISS that were treated with ECT using both bleomycin and cisplatin were retrospectively evaluated. Twenty-seven cats were available for statistical evaluation of their response. The cats received intravenous 20 mg/m2 bleomycin, and the tumor bed and margins were infiltrated with cisplatin at the dose of 0.5 mg/cm2. Then, trains of permeabilizing biphasic electric pulses lasting 50 + 50 µsec each, were delivered in bursts of 1,300 V/cm using caliper electrodes under sedation. A second session was performed 2 weeks later. Results: Side effects were limited to local inflammation in three cats. Three cats developed local tumor recurrence at days 180, 180 and 545, after surgery, two cats developed recurrence and metastases at 100 and 505 days after surgery and two cats experienced distant metastases. A median time to recurrence could not be calculated as over 80% of the study population remained disease-free or were censored due to death from other causes. Mean survival time was 985 days and median cumulative survival for all cases, was 1000 days. Conclusion: When compared to historical controls, the results of this study demonstrate superior rates of tumor-free survival and disease-free interval. This adjuvant therapy could be a useful addition to the current options for FISS in consideration of its efficacy, limited toxicity, and ease of administration.

Abstract In a large number of cancer types, treatment selection depends on the presence of specific tumor biomarkers. Due to the dynamic nature of cancer, very often these predictive biomarkers are not uniformly present in all cancer cells. Tumor heterogeneity represents indeed one of the main causes of therapeutic failure, and its decoding remains a major ongoing challenge in the field. Liquid biopsy is the sampling and analysis of non-solid biological tissue often through rapid and non-invasive methods, which allows the assessment in real-time of the evolving landscape of cancer. Samples can be obtained from blood and most other bodily fluids. A blood-based liquid biopsy can capture circulating tumor cells and leukocytes, as well as circulating tumor-derived nucleic acids. In this review, we discuss the current and possibly future applications of blood-based liquid biopsy in oncology, its advantages and its limitations in clinical practice. We specifically focused on its role as a tool to capture tumor heterogeneity in metastatic cancer patients.

BackgroundSDH-deficient gastrointestinal stromal tumors (GIST) account for 20–40% of all KIT/PDGFRA-negative GIST and are due to mutations in one of the four SDH-complex subunits, with SDHA mutations as the most frequent. Here we sought to evaluate the presence and prevalence of SDHA variants in the germline lineage in a population of SDHA-deficient GIST.MethodsGermline SDHA status was assessed by Sanger sequencing on a series of 14 patients with gastric SDHA-deficient GIST.ResultsAll patients carried a germline SDHA pathogenic variant, ranging from truncating, missense, or splicing variants. The second hit was the loss of the wild-type allele or an additional somatic mutation. One-third of the patients were over 50 years old. GIST was the only disease presentation in all cases except one, with no personal or familial cancer history. Seven metastatic cases received a multimodal treatment integrating surgery, loco-regional and medical therapy. The mean follow-up time was of 10 years, confirming the indolent clinical course of the disease.ConclusionSDHA germline variants are highly frequent in SDHA-deficient GIST, and the disease may occur also in older adulthood. Genetic testing and surveillance of SDHA-mutation carriers and relatives should be performed.

Patients with metastatic prostate cancer frequently develop bone metastases that elicit significant skeletal morbidity and increased mortality. The high tropism of prostate cancer cells for bone and their tendency to induce the osteoblastic-like phenotype are a result of a complex interplay between tumor cells and osteoblasts. Although the role of osteoblasts in supporting prostate cancer cell proliferation has been reported by previous studies, their precise contribution in tumor growth remains to be fully elucidated. Here, we tried to dissect the molecular signaling underlining the interactions between castration-resistant prostate cancer (CRPC) cells and osteoblasts using in vitro co-culture models. Transcriptomic analysis showed that osteoblast-conditioned media (OCM) induced the overexpression of genes related to cell cycle in the CRPC cell line C4-2B but, surprisingly, reduced androgen receptor (AR) transcript levels. In-depth analysis of AR expression in C4-2B cells after OCM treatment showed an AR reduction at the mRNA (p = 0.0047), protein (p = 0.0247), and functional level (p = 0.0029) and, concomitantly, an increase of C4-2B cells in S-G2-M cell cycle phases (p = 0.0185). An extensive proteomic analysis revealed in OCM the presence of some molecules that reduced AR activation, and among these, Matrix metalloproteinase-1 (MMP-1) was the only one able to block AR function (0.1 ng/ml p = 0.006; 1 ng/ml p = 0.002; 10 ng/ml p = 0.0001) and, at the same time, enhance CRPC proliferation (1 ng/ml p = 0.009; 10 ng/ml p = 0.033). Although the increase of C4-2B cell growth induced by MMP-1 did not reach the proliferation levels observed after OCM treatment, the addition of Vorapaxar, an MMP-1 receptor inhibitor (Protease-activated receptor-1, PAR-1), significantly reduced C4-2B cell cycle (0.1 μM p = 0.014; 1 μM p = 0.0087). Overall, our results provide a novel AR-independent mechanism of CRPC proliferation and suggest that MMP-1/PAR-1 could be one of the potential pathways involved in this process.

Background: Cancer patients are at higher risk of COVID-19 complications and mortality than the rest of the population. Breast cancer patients seem to have better prognosis when infected by SARS-CoV-2 than other cancer patients. Methods: We report a subanalysis of the OnCovid study providing more detailed information in the breast cancer population. Results: We included 495 breast cancer patients with a SARS-CoV-2 infection. Mean age was 62.6 years; 31.5% presented more than one comorbidity. The most frequent breast cancer subtype was luminal-like ( n = 245, 49.5%) and 177 (35.8%) had metastatic disease. A total of 332 (67.1%) patients were receiving active treatment, with radical intent in 232 (47.6%) of them. Hospitalization rate was 58.2% and all-cause mortality rate was 20.3%. One hundred twenty-nine (26.1%) patients developed one COVID-19 complication, being acute respiratory failure the most common ( n = 74, 15.0%). In the multivariable analysis, age older than 70 years, presence of COVID-19 complications, and metastatic disease were factors correlated with worse outcomes, while ongoing anticancer therapy at time of COVID-19 diagnosis appeared to be a protective factor. No particular oncological treatment was related to higher risk of complications. In the context of SARS-CoV-2 infection, 73 (18.3%) patients had some kind of modification on their oncologic treatment. At the first oncological reassessment (median time: 46.9 days ± 36.7), 255 (51.6%) patients reported to be fully recovered from the infection. There were 39 patients (7.9%) with long-term SARS-CoV-2-related complications. Conclusion: In the context of COVID-19, our data confirm that breast cancer patients appear to have lower complications and mortality rate than expected in other cancer populations. Most breast cancer patients can be safely treated for their neoplasm during SARS-CoV-2 pandemic. Oncological treatment has no impact on the risk of SARS-CoV-2 complications, and, especially in the curative setting, the treatment should be modified as little as possible.

Background: Although the gastrointestinal stromal tumor (GIST) genotype is not currently included in risk-stratification systems, a growing body of evidence shows that the pathogenic variant (PV) type and codon location hold a strong prognostic influence on recurrence-free survival (RFS). This information has particular relevance in the adjuvant setting, where an accurate prognostication could help to better identify high-risk tumors and guide clinical decision-making. Materials and Methods: Between January 2005 and December 2020, 96 patients with completely resected GISTs harboring a KIT proto-oncogene receptor tyrosine kinase ( KIT ) exon 11 PV were included in the study. We analyzed the type and codon location of the PV according to clinicopathological characteristics and clinical outcome; the metastatic sites in relapsed patients were also investigated. Results: Tumors harboring a KIT exon 11 deletion or deletion/insertion involving the 557 and/or 558 codons, showed a more aggressive clinical behavior compared with tumors carrying deletion/deletion/insertion in other codons, or tumors with duplication/insertion/single-nucleotide variant (SNV) (7-year RFS: 50% versus 73.1% versus 88.2%, respectively; p

Abiraterone is a selective inhibitor of androgen biosynthesis approved for the treatment of metastatic patients affected by castration-resistant or castration-sensitive prostate cancer. Intriguingly, clinical data revealed that abiraterone also delayed disease progression in bone improving bone-related endpoints. Our group has previously demonstrated in vitro a direct effect of abiraterone on osteoclast and osteoblast function suggesting its ability to modulate bone microenvironment. Here, we performed an extensive proteomic analysis to investigate how abiraterone influences osteoblast cell secretome and, consequently, osteoblast/prostate cancer cells interaction. A panel of 507 soluble molecules were analyzed in osteoblast conditioned media (OCM) obtained from osteoblast treated or not with abiraterone. Subsequently, OCM was added to prostate cancer cells to investigate its potential effect on prostate cancer cell proliferation and androgen receptor (AR) activation status. Out of 507 screened molecules, 39 of them were differentially expressed in OCM from osteoblasts treated with abiraterone (OCM ABI) compared to OCM obtained from untreated OBs (OCM CTRL). Pathway enrichment analysis revealed that abiraterone down-modulated the release of specific osteoblast soluble factors, positively associated with cell proliferation pathways (false discovery rate adjusted p-value = 0.0019). In vitro validation data showed that OCM ABI treatment significantly reduced cancer proliferation in C4-2B cells (p = 0.022), but not in AR- negative PC-3 cells. Moreover, we also found a reduction in AR activation in C4-2B cells (p = 0.017) confirming the “indirect” anti-tumor AR-dependent effect of abiraterone mediated by osteoblasts. This study provides the first evidence of an additional antitumor effect of abiraterone through the modulation of multiple osteoblast proliferative signals.

Electrochemotherapy (ECT) couples the administration of anticancer drugs with the delivery of electric pulses that increase the drug uptake through the cell membranes, thus resulting in an improved efficacy. This study has evaluated the tolerability and efficacy of the combination of systemic bleomycin and local cisplatin as ECT agents for incompletely excised canine soft tissue sarcoma (STS). Thirty dogs with incompletely excised STSs were enrolled. The dogs received intravenous 20 mg/m2 bleomycin and the tumor bed and margins were infiltrated with cisplatin at the dose of 0.5 mg/cm2. Then, trains of permeabilizing biphasic electric pulses were applied under sedation. More precisely, five minutes after the injection of the chemotherapy agents, sequences of 8 biphasic pulses lasting 50+50 microseconds each, were delivered in bursts of 1300 V/cm using caliper electrodes. A second session was performed two weeks later. The treatment was well tolerated and side effects were minimal. Twenty-six dogs had no evidence of recurrence at the time of manuscript writing, four had recurrence and one of the four recurring dogs, died of lung metastases. Median estimated disease free was 857 days. Perivascular wall tumors response was compared to that of the other STSs, but the difference in outcome was not significative. ECT using combination of bleomycin and cisplatin appears to be effective in the treatment of incompletely resected STSs in dogs. This therapeutic approach could be a useful addition to the current options in consideration of its low cost, limited toxicity, and ease of administration.

Contemporary anticancer immunotherapy with chimeric antigen receptor T-cell (CAR-T) therapy has dramatically changed the treatment of many hematologic malignancies previously associated with poor prognosis. The clinical improvement and the survival benefit unveiled the risk of cardiotoxicity, ranging from minimal effects to severe cardiac adverse events, including death. Immunotherapy should also be proposed even in patients with pre-existing cardiovascular risk factors, thereby increasing the potential harm of cardiotoxicity. CAR-T therapy frequently results in cytokine release syndrome (CRS), and inflammatory activation is sustained by circulating cytokines that foster a positive feedback mechanism. Prompt diagnosis and treatment of CAR-T cardiotoxicity might significantly improve outcomes and reduce the burden associated with cardiovascular complications. Clinical and echocardiographic examinations are crucial to perform a tailored evaluation and follow-up during CAR-T treatment. This review aims to summarize the pathophysiology, clinical implications, and echocardiographic assessment of CAR-T-related cardiotoxicity to enlighten new avenues for future research.

Premisa: No obstante una general justificabilidad sobre el plano ético, la sedación paliativa (SP) presenta todavía numerosos as- pectos controvertidos que requieren un ulterior debate y aclara- ción. Desde el punto de vista práctico, además, se observa una notable variabilidad por cuanto se refiere al procedimiento clínico de la SP y un límite entre la SP al final de la vida y la eutanasia involuntaria, cada vez más angosto e incierto. Esta situación hace particularmente necesaria la elaboración de caminos decisionales trasparentes, también en la forma de líneas-guía locales, que aclaren los procedimientos y las implicaciones éticas de la seda- ción paliativa. Objetivos: La finalidad de este trabajo es la de presentar las principales características del camino decisional y asistencial para la SP elaborado en el Policlínico Universitario “Campus Bio- Médico” de Roma. Métodos: La elaboración de la propuesta presentada ha sido pre- cedida por un estudio, a través de la suministración de cuestiona- rios semiestructurados, sobre los conocimientos del personal mé- dico y de enfermería a propósito de la SP y de un estudio retros- pectivo sobre los expedientes clínicos, para verificar las modali- dades de utilización de la SP al interior del Hospital. Resultados: El camino decisional y asistencial elaborado con- sidera no sólo los aspectos farmacológicos, sino afronta con cla- ridad también las implicaciones éticas y legales del procedimiento de SP, y en particular la comunicación, la atención a los familiares y a los operadores sanitarios, la posibilidad de valerse de la con- sulta de ética clínica en los casos más complejos y en los cuales es difícil alcanzar una decisión compartida. Se subraya, además, cómo la aplicación de un camino decisional y asistencial para la SP deba ser apoyada por momentos formativos y de confronta- ción activa entre los operadores sanitarios, para favorecer la ade- cuada comprensión y la correcta utilización de esos instrumentos operativos, pero también para asegurar el respeto de la conscien- cia de los operadores sanitarios implicados. Conclusiones: Es recomendable que todas las instituciones sanitarias produzcan caminos decisionales y asistenciales para la SP, atentos no sólo a los estándares científicos, sino también a la sensibilidad ética y cultural del contexto en el cual serán utiliza- das. Caminos decisionales y asistenciales así estructurados ofre- cen no sólo una orientación operativa y formativa para el actuar clínico, sino constituyen también un obligado instrumento de tras- parencia en relación con los pacientes, con sus familiares, con la misma estructura sanitaria y con toda la sociedad.

Background Patients with cancer are particularly susceptible to SARS-CoV-2 infection. The systemic inflammatory response is a pathogenic mechanism shared by cancer progression and COVID-19. We investigated systemic inflammation as a driver of severity and mortality from COVID-19, evaluating the prognostic role of commonly used inflammatory indices in SARS-CoV-2-infected patients with cancer accrued to the OnCovid study.Methods In a multicenter cohort of SARS-CoV-2-infected patients with cancer in Europe, we evaluated dynamic changes in neutrophil:lymphocyte ratio (NLR); platelet:lymphocyte ratio (PLR); Prognostic Nutritional Index (PNI), renamed the OnCovid Inflammatory Score (OIS); modified Glasgow Prognostic Score (mGPS); and Prognostic Index (PI) in relation to oncological and COVID-19 infection features, testing their prognostic potential in independent training (n=529) and validation (n=542) sets.Results We evaluated 1071 eligible patients, of which 625 (58.3%) were men, and 420 were patients with malignancy in advanced stage (39.2%), most commonly genitourinary (n=216, 20.2%). 844 (78.8%) had ≥1 comorbidity and 754 (70.4%) had ≥1 COVID-19 complication. NLR, OIS, and mGPS worsened at COVID-19 diagnosis compared with pre-COVID-19 measurement (p

The CDK4/6 inhibitors (CDKi) palbociclib, ribociclib, and abemaciclib are currently approved in combination with anti-estrogen therapy for the treatment of advanced and/or metastatic hormone receptor-positive/HER2-neu-negative breast cancer patients. Given the high incidence of bone metastases in this population, we investigated and compared the potential effects of palbociclib, ribociclib, and abemaciclib on the breast cancer bone microenvironment. Primary osteoclasts (OCs) and osteoblasts (OBs) were obtained from human monocyte and mesenchymal stem cells, respectively. OC function was evaluated by tartrate-resistant acid phosphatase assay and real-time PCR; OB activity was assessed by an alizarin red assay. OB/breast cancer co-culture models were generated via the seeding of MCF-7 cells on a layer of OBs, and tumor cell proliferation was analyzed using flow cytometry. Here, we showed that ribociclib, palbociclib, and abemaciclib exerted similar inhibitory effects on the OC differentiation and expression of bone resorption markers without affecting OC viability. On the other hand, the three CDKi did not affect the ability of OB to produce bone matrix, even if the higher doses of palbociclib and abemaciclib reduced the OB viability. In OB/MCF-7 co-culture models, palbociclib demonstrated a lower anti-tumor effect than ribociclib and abemaciclib. Overall, our results revealed the direct effects of CDKi on the tumor bone microenvironment, highlighting differences potentially relevant for clinical practice.

Introduction Angiosarcomas constitute approximately 2% to 3% of all soft tissue sarcomas, are characterised by an aggressive clinical behaviour and poor outcome. Optimal management of localised angiosarcomas consists of complete surgical resection with or without radiation. However, due to the infiltrating nature of this disease, complete resection is often not possible. Despite optimal management, the outcome of patients with localised disease remains poor. The role of (neo)adjuvant chemotherapy in angiosarcomas remains undefined. The aim of this study is to document the outcome of patients treated with (neo)adjuvant chemotherapy and assess the feasibility of performing a prospective trial by evaluating the number of patients treated at sarcoma referral centres.Methods A retrospective search within participating EORTC (European Organisation for Research and Treatment of Cancer) sites for patients treated with (neo)adjuvant chemotherapy was made. Patients treated between January 2007 and January 2016 were included.Results A total of 15 institutions participated and 86 patients were evaluable, 43 were treated with neoadjuvant, 27 with adjuvant chemotherapy and 16 with both. At the time of analysis, the median follow-up from diagnosis was 4.6 years. Median overall survival (OS) was 4.9 years (2.9 N) and the percentage alive at 4 years was 57.9 (45.5 to 68.4). The median disease-free survival was 1.4 years (0.9 to 1.7) and the percentage disease-free at 4 years was 26.8% (17.9 to 36.5).Conclusion The outcome of angiosarcoma patients treated with (neo)adjuvant chemotherapy in this case series compares favourably with previously published data. Due to the aggressive nature of angiosarcoma, a prospective trial of neoadjuvant chemotherapy should be considered.

Cancer immunotherapy has become a stronghold in modern oncology. Immune checkpoint inhibitors, in particular anti-PD-1 and anti-PD-L1 antibodies, are approved for the treatment of several solid cancers. In the near future, an increasing number of patients will be eligible for immunotherapy. Therefore, the management of immune-related adverse events is a daily challenge in clinical practice, among which hepatic immune-related toxicity has been described as a rare adverse event. We report the case of a patient treated with nivolumab (an anti-PD-L1 antibody) for a stage IV resected melanoma who developed recurrence of steroid-refractory liver toxicity that was later discovered to be associated with acute exacerbation of chronic undiagnosed hepatitis B. The patient significantly benefited from antiviral treatment. We conclude that serological viral screening is strongly recommended before starting immune checkpoint inhibitor treatment.

Background: Due to the relative rarity of small bowel adenocarcinoma (SBA), prospective trials, helping to guide therapeutic decisions, are lacking and the optimal therapy for advanced SBA is unknown. The role of targeted agents, such as anti–epidermal growth factor receptor (EGFR) and anti–vascular endothelial growth factor (VEGF), is unknown. Patients and Methods: This is a retrospective multicenter observational study that included patients with metastatic SBA treated with anti-EGFR antibodies (cetuximab or panitumumab) ± chemotherapy in the first (I) or second (II) line. Results: Thirteen patients with metastatic SBA, recruited from 5 Italian referral institutions, were included in the present retrospective analysis. All patients received anti-EGFR inhibitors as a single agent or in association with chemotherapy. More common G2 treatment–related side effects were skin reaction (8 patients, 53.8%), hypomagnesemia (6 patients, 46.2%), and diarrhea (8 patients, 61.5%). Grade 3 diarrhea was observed in only 1 patient. Conjunctivitis was not reported in any patients. Grade 4 toxicity was not reported. In the overall population, median progression-free survival was 5.526 months (95% confidence interval [CI]: 3.684-12.467). Median overall survival was 15.86 months (95% CI: 14.43-24.30). Complete response was observed in 15% of patients, partial response in 39% of patients, stable disease in 23% of patients, and progression disease in 15% of patients. Conclusions: In this retrospective analysis, anti-EGFR inhibitors showed to be a suitable addendum to chemotherapy in the I and II line, with an excellent tolerance and safety profile both in I and II line.

Bone is one of the preferential sites of distant metastases from malignant tumors, with the highest prevalence observed in breast and prostate cancers. Patients with bone metastases (BMs) may experience skeletal-related events, such as severe bone pain, pathological fractures, spinal cord compression, and hypercalcemia, with negative effects on the quality of life. In the last decades, a deeper understanding of the molecular mechanisms underlying the BM onset has been gained, leading to the development of bone-targeting agents. So far, most of the research has been focused on the pathophysiology and treatment of BM, with only relatively few studies investigating potential predictors of risk for BM development. The ability to select such “high-risk” patients could allow early identification of those most likely to benefit from interventions to prevent or delay BM. This review summarizes several evidences for the potential use of specific biomarkers able to predict early the BM development.

Background: Gastrointestinal stromal tumors (GIST) are known to carry oncogenic KIT or PDGFRA mutations, or less commonly SDH or NF1 gene inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 10% of GISTs are devoid of any of such mutations and are characterized by very limited therapeutic opportunities and poor response to standard treatments.Methods: Twenty-six sporadic KIT/PDGFRA/SDH/RAS-pathway wild type GIST were profiled for the molecular status of genes frequently altered in GIST by a targeted next generation sequencing (NGS) approach. Molecular findings were validated by alternative amplicon-based targeted sequencing, immunohistochemistry, gene expression profiling and Sanger sequencing.Results: Three patients harboring NF1 inactivating mutations were identified and excluded from further analysis. Intriguingly, five patients carried cryptic KIT alterations, mainly represented by low-allele-fraction mutations (12–16% allele ratio). These mutations were confirmed by another targeted NGS approaches and supported by CD117 immuno-staining, gene expression profiling, Sanger sequencing, with peak signals at the level of background noise, and by the patients' clinical course assessment.Conclusion: This study indicates that ~20% patients diagnosed with a KIT/PDGFRA/SDH/RAS-pathway wild-type GIST are bona-fide carriers of pathogenic KIT mutations, thus expected to be eligible for and responsive to the various therapeutic lines of TK-inhibitors in use for KIT/PDGFRA-mutant GIST. The centralization for a second level molecular analysis of GIST samples diagnosed as wild-type for KIT and PDGFRA is once again strongly recommended.

Background: The presence of bone metastases in renal cell carcinoma (RCC) negatively affects patients’ survival. Data from clinical trials has highlighted a significant benefit of cabozantinib in bone metastatic RCC patients. Here, we evaluated the antitumor effect of cabozantinib in coculture models of renal cell carcinoma (RCC) and osteoblasts (OBs) to investigate whether and how its antiproliferative activity is influenced by OBs. Methods: Bone/RCC models were generated, coculturing green fluorescent protein (GFP)-tagged Caki-1 and 786-O cells with human primary OBs in a “cell–cell contact” system. RCC proliferation and the OB molecular profile were evaluated after the cabozantinib treatment. Results: The Caki-1 cell proliferation increased in the presence of OBs (p < 0.0001), while the 786-O cell growth did not change in the coculture with the OBs. The cabozantinib treatment reduced the proliferation of both the Caki-1 (p < 0.0001) and 786-O (p = 0.03) cells cocultured with OBs. Intriguingly, the inhibitory potency of cabozantinib was higher when Caki-1 cells grew in presence of OBs compared to a monoculture (p < 0.001), and this was similar in 786-O cells alone or cocultured with OBs. Moreover, the OB pretreatment with cabozantinib “indirectly” inhibited Caki-1 cell proliferation (p = 0.040) without affecting 786-O cell growth. Finally, we found that cabozantinib was able to modulate the OB gene and molecular profile inhibiting specific proliferative signals that, in turn, could affect RCC cell growth. Conclusions: Overall, the “direct” effect of cabozantinib on OBs “indirectly” increased its antitumor activity in metastatic RCC Caki-1 cells but not in the primary 786-O model.

In 2018 there were over 1.8 million new cases worldwide of colorectal cancer and relapses after clinical treatments. Many studies ascribe the risk of the appearance of this cancer to the Western life style : a sedentary life, obesity, and low -fiber, high -fat diets can promote the onset of disease. Several studies have shown supplement phytochemicals to have an inhibiting effect on the growth of various cancers through the activation of apoptosis. Our goal was to prove the effectiveness of a natural compound in the combined therapy of colorectal cancer. Trigno M supplement was an optimal candidate as anticancer product for its high concentrations of phenolic acids, flavonoids and anthocyanins. Our work showed the antitumor activity of Trigno M, extract of Prunus spinosa drupes combined with the nutraceutical activator complex (NAC), in 2D, 3D and in vivo colorectal cancer models. The cellular model we used both in vitro and in vivo was the HCT116 cell line, particularly suitable for engraftment after inoculation in mice. Trigno M inhibited the growth and colony formation of HCT116 cells (35%) as compared to the chemotherapy treatment with 5-fluorouracil (80%) used in clinical therapy. The reduction of the morphological dimensions in the spheroid cells after Trigno M, was compared with 5-fluorouracil demonstrating the efficacy of the Trigno M compound also in 3D models. Flow cytometric analysis on 3D cells showed a significant increase in the apoptotic cell fraction after Trigno M treatment (44.8%) and a low level of necrotic fraction (6.7%) as compared with control cells. Trigno M and 5-fluorouracil induced the apoptosis in a comparable percentage. Monotherapy with Trigno M in severely immunodeficient mice, carrying colon rectal cancer xenografts, significantly reduced tumor growth. The histopatological analysis of the ectopic tumors showed a lower level of necrosis after Trigno M treatment compared with the control. We conclude that Trigno M is well tolerated by mice, delays colorectal cancer growth in these animals and should be weighed up for integration of the current multi-drug protocols in the treatment of colon carcinoma.

Background: Tissue evaluation for RAS (KRAS or NRAS) gene status in metastatic colorectal cancer (mCRC) patients represent the standard of care to establish the optimal therapeutic strategy. Unfortunately, tissue biopsy is hampered by several critical limitations due to its invasiveness, difficulty to access to disease site, patient’s compliance and, more recently, neoplastic tissue spatial and temporal heterogeneity. Methods: The authors performed a systematic literature review to identify available trials with paired matched tissue and ctDNA RAS gene status evaluation. The authors searched EMBASE, MEDLINE, Cochrane, www.ClinicalTrials.gov , and abstracts from international meetings. In total, 19 trials comparing standard tissue RAS mutational status matched paired ctDNA evaluated through polymerase chain reaction (PCR), next generation sequencing (NGS) or beads, emulsions, amplification and magnetics (BEAMing) were identified. Results: The pooled sensitivity and specificity of ctDNA were 0.83 (95% CI: 0.80–0.85) and 0.91 (95% CI: 0.89–0.93) respectively. The pooled positive predictive value (PPV) and negative predictive value (NPV) of the ctDNA were 0.87 (95% CI: 0.81–0.92) and 0.87 (95% CI: 0.82–0.92), respectively. Positive likelihood ratio (PLR) was 8.20 (95% CI: 5.16–13.02) and the negative likelihood ratio (NLR) was 0.22 (95% CI: 0.16–0.30). The pooled diagnostic odds ratio (DOR) was 50.86 (95% CI: 26.15–98.76), and the area under the curve (AUC) of the summary receiver operational characteristics (sROC) curve was 0.94. Conclusion: The authors’ meta-analysis produced a complete and updated overview of ctDNA diagnostic accuracy to test RAS mutation in mCRC. Results provide a strong rationale to include the RAS ctDNA test into randomized clinical trials to validate it prospectively.

Background: Hyponatremia in cancer patients is often caused by the syndrome of inappropriate antidiuretic hormone secretion (SIADH). The aim of this observational multicenter study was to analyze the medical and economic implications of SIADH in this setting. Methods: This study included 90 oncological patients from 28 Italian institutions that developed SIADH between January 2010 and September 2015. Data on clinical–pathological characteristics, anticancer therapies, hyponatremia, and related treatments were statistically analyzed. Results: The majority were lung cancer patients (73%) with metastatic disease at the onset of hyponatremia (83%). A total of 76 patients (84%) were hospitalized because of SIADH and less than half (41%) received tolvaptan for SIADH treatment. The duration of hospitalization was significantly longer in patients who did not receive tolvaptan and in those who do not reach sodium normalization during hospitalization. Patients who experienced a second episode of hyponatremia following tolvaptan dose modification/discontinuation presented a significantly lower serum sodium value at the time of hospitalization and minimum sodium value during hospitalization compared with patients who had not experienced another episode. The severity of hyponatremia, defined as minimum sodium value during hospitalization with a cut-off value of 110 mmol/l, and not obtaining sodium correction during hospitalization significantly correlated with overall survival rate. Conclusions: Hyponatremia due to SIADH could result in longer hospitalization and in a decreased overall survival when not adequately treated, and tolvaptan represents an effective treatment with a potential effect of both improving overall survival and decreasing duration of hospitalization.

The tyrosine kinase inhibitor (TKI) imatinib has radically changed the natural history of KIT-driven gastrointestinal stromal tumours (GISTs). Approved second-line and third-line medical therapies are represented by the TKIs sunitinib and regorafenib, respectively. While imatinib remains the cardinal drug for patients with GISTs, novel therapies are being developed and clinically tested to overcome the mechanisms of resistance after treatments with the approved TKI, or to treat subsets of GISTs driven by rarer molecular events. Here, we review the therapy of GISTs, with a particular focus on the newest drugs in advanced phases of clinical testing that might soon change the current therapeutic algorithm.

Background: The immune response in melanoma patients is locally affected by presence of tumor-infiltrating lymphocytes (TILs), generally divided into brisk, nonbrisk, and absent. Several studies have shown that a greater presence of TILs, especially brisk, in primary melanoma is associated with a better prognosis and higher survival rate. Patients and Methods: We investigated by enzyme-linked immunosorbent assay (ELISA) the correlation between PD-1 levels in plasma and the presence/absence of TILs in 28 patients with metastatic melanoma. Results: Low plasma PD-1 levels were correlated with brisk TILs in primary melanoma, whereas intermediate values correlated with the nonbrisk TILs, and high PD-1 levels with absent TILs. Although the low number of samples did not allow us to obtain a statistically significant correlation between the plasma PD-1 levels and the patients’ overall survival depending on the absence/presence of TILs, the median survival of patients having brisk type TILs was 5 months higher than that of patients with absent and nonbrisk TILs. Conclusions: This work highlights the ability of measuring the plasma PD-1 levels in order to predict the prognosis of patients with untreated metastatic melanoma without a BRAF mutation at the time of diagnosis.

We describe an original electroporation protocol for in vivo plasmid DNA transfection. The right hind limbs of C57 mice are exposed to a specifically designed train of permeabilizing electric pulses by transcutaneous application of tailored needle electrodes, immediately after the injection of pEGFP-C1 plasmid encoding GFP (Green Fluorescente Protein). The electroporated rodents show a greater GFP expression than the controls at three different time points (4, 10, and 15 days). The electroporated muscles display only mild interstitial myositis, with a significant increase in inflammatory cell infiltrates. Finally, mild gait abnormalities are registered in electroporated mice only in the first 48 h after the treatment. This protocol has proven to be highly efficient in terms of expression levels of the construct, is easy to apply since it does not require surgical exposure of the muscle and is well tolerated by the animals because it does not cause evident morphological and functional damage to the electroporated muscle.

An amendment to this paper has been published and can be accessed via the original article.

Background: Rechallenge with imatinib is an option in advanced gastrointestinal stromal tumor (GIST) patients following progression with standard tyrosine-kinase inhibitors (TKIs), imatinib, sunitinib and regorafenib. We retrospectively collected data from metastatic Italian GIST patients treated with imatinib resumption after progression to conventional TKIs. Methods: A total of 104 eligible advanced GIST patients, previously treated with imatinib, sunitinib and regorafenib, were collected from six referral Italian institutions. Mutational analysis was recorded and correlated with survival and response according to RECIST 1.1 or CHOI criteria. Results: Overall, 71 patients treated with imatinib 400 mg as rechallenge were included. Mutational status was available in all patients. The median follow up was 13 months. In patients who received a rechallenge therapy, the median time to progression (TTP) was 5.4 months [95% confidence interval (CI) 1.9–13.5] and overall survival (OS) was 10.6 months (95% CI 2.8–26.9). A correlation between mutational status, response rate, TTP and OS was not found but comparing deleted versus nondeleted KIT exon 11 patients, a significant difference was identified in terms of TTP and OS ( p = 0.04 and p = 0.02, respectively). Conclusions: Our retrospective data confirm that imatinib rechallenge is a reasonable option in advanced GIST. The prognostic value of the specific KIT mutations was confirmed in our series.

Abstract The use of direct oral anticoagulant in cancer patients is an emerging issue, which seems to be an alternative to low molecular weight heparin. Every year several new drugs are approved as anticancer treatment with possible drug-drug interaction with other drugs such as oral anticoagulant. We describe, for the first time, a case of neutropenia and thrombocytopenia in a patient in treatment with cabozantinib, a novel anticancer treatment used in metastatic renal cell carcinoma, and apixaban with promptly resumption of the toxicity after the interruption of cabozantinib. This case suggest a possible interaction between these two pharmaceutical agents, which merit caution considering the spreading of the two drugs.

Background: Regorafenib (REG) has now been approved as the standard third-line therapy in metastatic gastrointestinal stromal tumour (GIST) patients at the recommended dose and schedule of 160 mg once daily for the first 3 weeks of each 4-week cycle. However, it has a relevant toxicity profile that mainly occurs within the first cycles of therapy, and dose and schedule adjustments are often required to reduce the frequency or severity of adverse events and to avoid early treatment discontinuation. To date, large amounts of data on the use of REG in metastatic GIST patients in daily clinical practice are not available, and we lack information about how this treatment personalization really affects the quality of life (QoL) of patients. The aim of the present retrospective study is to build a comprehensive picture of all alternative REG strategies adopted in daily clinical practice for use in metastatic GIST patients. Methods: Metastatic GIST patients treated with dose adjustment or alternative schedules of REG at seven reference Italian centres were retrospectively included. Results: For a total of 62 metastatic GIST patients, we confirmed that REG treatment adjustment is common in clinical practice and that it is very heterogeneous, with approximately 20 different strategies being adopted. Independent of which strategy is chosen, treatment personalization has led to a clinical benefit defined as complete or partial resolution of side effects in almost all patients, affecting the duration of REG treatment. Conclusions: The personalization of REG, even if it is heterogeneous, seems to be crucial to maximize the overall treatment duration.

The development of bone metastases requires multistep and multicellular machinery consisting not only of processes shared with any type of metastases (formation of a pre-metastatic niche, chemotaxis of tumor cells into the host tissue, tumor cells escape from the microvasculature), but also biological interactions that are strictly related to the particular bone microenvironment (bone marrow colonization by cancer cells, osteomimicry, deregulation of bone homeostasis). MiRNAs are highly conserved, small RNAs molecules that regulate gene expression. The functional consequence of miRNA deregulation lies in the mRNA targets whose expression is altered. MiRNA networks acting as upstream regulators of these genes interfere with the initial steps of tumor local invasion and cancer cell intravasation, mainly by regulating the epithelial-mesenchymal transition, the motility, invasiveness and survival abilities of these cells. The miRNA-mediated regulation on the steps of bone tropism, anchorage, homing and finally bone colonization is more tissue specific, being dependent on the expression pattern of target miRNAs in bone marrow sinusoids, bone cells and microenvironment. In that, miRNA specific expression signatures that can distinguish between primary tumors from their corresponding bone metastases might be determinants of clinical aggressiveness. In this review, we focus on the current advances on functions and molecular mechanisms by which miRNAs exert their biological roles in regulating bone metastases development.

Bisphosphonate therapy has become a standard of therapy for patients with malignant bone disease. In vivo pre-clinical data suggest that bisphosphonates may exert an antitumor effect and preliminary clinical data show promising activity on metastatic disease in cancer patients. This review will describe the pre-clinical evidence of action of bisphosphonates on osteoclasts and tumor cells, in both in vitro and animal models. In addition, the effects of principal bisphosphonates on skeletal disease progression in patients with cancers in different sites, including breast cancer, prostate cancer and non-small cell lung cancer will be reported. The preliminary clinical data from retrospective trials on the effect of bisphosphonates on survival will be described and the ongoing adjuvant phase III trial will be analyzed. This review will describe the preliminary clinical evidences from prospective studies on the effect of zoledronic acid treatment on the prevention of bone metastases.

The European Association for the Study of the Liver (EASL) criteria and the modified Response Evaluation Criteria in Solid Tumors (mRECIST) are currently adopted to evaluate radiological response in patients affected by HCC and treated with loco-regional procedures. Several studies explored the validity of these measurements in predicting survival but definitive data are still lacking.To conduct a systematic review of studies exploring mRECIST and EASL criteria usefulness in predictive radiological response in HCC undergoing loco-regional therapies and their validity in predicting survival.A comprehensive search of the literature was performed in electronic databases EMBASE, MEDLINE, COCHRANE LIBRARY, ASCO conferences and EASL conferences up to June 10, 2014. Our overall search strategy included terms for HCC, mRECIST, and EASL. Loco-regional procedures included transarterial embolization (TAE), transarterial chemoembolization (TACE) and cryoablation. Inter-method agreement between EASL and mRECIST was assessed using the k coefficient. For each criteria, overall survival was described in responders vs. non-responders patients, considering all target lesions response.Among 18 initially found publications, 7 reports including 1357 patients were considered eligible. All studies were published as full-text articles. Proportion of responders according to mRECIST and EASL criteria was 62.4% and 61.3%, respectively. In the pooled population, 1286 agreements were observed between the two methods (kappa statistics 0.928, 95% confidence interval 0.912-0.944). HR for overall survival (responders versus non responders) according to mRECIST and EASL was 0.39 (95% confidence interval 0.26-0.61, p