Predictive significance of FGFR4 p.G388R polymorphism in metastatic colorectal cancer patients receiving trifluridine/tipiracil (TAS-102) treatment.

BACKGROUND: TAS-102 (Lonsurf®) is an oral fluoropyrimidine consisting of a combination of trifluridine (a thymidine analog) and tipiracil (a thymidine phosphorylation inhibitor). The drug is effective in metastatic colorectal cancer (mCRC) patients refractory to fluorouracil, irinotecan and oxaliplatin. This study is a real-world analysis, investigating the interplay of genotype/phenotype in relation to TAS-102 sensitivity. METHODS: Forty-seven consecutive mCRC patients were treated with TAS-102 at the National Cancer Institute of Naples from March 2019 to March 2021, at a dosage of 35 mg/m2, twice a day, in cycles of 28 days (from day 1 to 5 and from day 8 to 12). Clinical-pathological parameters were described. Activity was evaluated with RECIST criteria (v1.1) and toxicity with NCI-CTC (v5.0). Survival was depicted through the Kaplan-Meyer curves. Genetic features of patients were evaluated with Next Generation Sequencing (NGS) through the Illumina NovaSeq 6000 platform and TruSigt™Oncology 500 kit. RESULTS: Median age of patients was 65 years (range: 46-77). Forty-one patients had 2 or more metastatic sites and 38 patients underwent to more than 2 previous lines of therapies. ECOG (Eastern Cooperative Oncology Group) Performance Status (PS) was 2 in 19 patients. The median number of TAS-102 cycles was 4 (range: 2-12). The most frequent toxic event was neutropenia (G3/G4 in 16 patients). There were no severe (> 3) non-haematological toxicities or treatment-related deaths. Twenty-six patients experienced progressive disease (PD), 21 stable disease (SD). Three patients with long-lasting disease control (DC: complete, partial responses or stable disease) shared an FGFR4 (p.Gly388Arg) mutation. Patients experiencing DC had more frequently a low tumour growth rate (P = 0.0306) and an FGFR4 p.G388R variant (P < 0.0001). The FGFR4 Arg388 genotype was associated with better survival (median: 6.4 months) compared to the Gly388 genotype (median: 4 months); the HR was 0.25 (95% CI 0.12- 0.51; P = 0.0001 at Log-Rank test). CONCLUSIONS: This phenotype/genotype investigation suggests that the FGFR4 p.G388R variant may serve as a new marker for identifying patients who are responsive to TAS-102. A mechanistic hypothesis is proposed to interpret these findings.

Alzheimer's disease following COVID-19: a two player match?

Common pathways may underlie the association between COVID-19 and risk for Alzheimer's disease (AD). We conjecture that severe COVID-19 may contribute to AD onset in predisposed individuals through aberrant MDSCs expression and increased IL-6 expression levels leading to immunosuppression in inflamed brains. Research studies are needed to gain empirical evidence to strengthen the hypothesis of the involvement of MDSCs and IL-6 in the formation of AD following COVID-19 infection and possibly vaccination enabling a more in-depth understanding of the role of immunosuppression in the onset of neurodegenerative diseases at any age. Identifying why those who get severe COVID-19 are more likely to develop AD may offer a novel therapeutic approach to delay or prevent cognitive decline.

Potential hypothesis for the increased risk of Parkinson´s disease following COVID-19.

Patients with severe COVID-19 may be more likely to develop PD as a result of shared biological pathways including a great expansion of MDSCs and an imbalance in Th17/Tregs ratio. We think that these shared pathogenic features may mechanistically explain the COVID-19 - PD axis. Thus, we assume that patients who recovered from critical COVID-19 should be selected based upon a potential higher risk of developing PD. Further studies are needed to better define the possible relationship between COVID-19 and neuroinflammation and identify whether some people are more likely to develop PD after contracting COVID-19 than others with special emphasis to ascertain possible vulnerable genetic backgrounds or epigenetic factors acting on brain which may promote PD during SARS COV-2 infection. Finally, we think that regular physical activity should be performed and encouraged in patients with PD.

Liquid Biopsy Testing for the Management of Patient with Non-Small Cell Lung Cancer Carrying a Rare Exon-20 EGFR Insertion.

Increasing evidence suggests that liquid biopsy might play a relevant role in the management of metastatic non-small cell lung cancer (NSCLC) patients. Here, we show how the Molecular Tumor Board (MTB) in our cancer center employed liquid biopsy to support therapeutic decisions in a patient with NSCLC carrying a rare EGFR mutation. A 44-year-old woman, never-smoker with an EGFR, ALK, and ROS1-negative lung adenocarcinoma and multiple brain metastases received systemic therapy and surgery before being referred to our Institute. The MTB suggested NGS testing of tumor biopsy that revealed a rare exon-20 EGFR insertion (p.His773dup; c.2315_2316insCCA) and EGFR amplification. The MTB recommended treatment with erlotinib and follow-up with liquid biopsy, by using both cell-free DNA (cfDNA) and circulating tumor cells (CTCs). An increase of EGFR mutation levels in cfDNA revealed resistance to treatment about 6 months before clinical progression. Extremely low levels of EGFR p.T790M were detected at progression. Based on preclinical data suggesting activity of osimertinib against EGFR exon-20 insertions, the MTB recommended treatment with brain and bone radiotherapy and osimertinib. A dramatic reduction of EGFR mutation levels in the cfDNA was observed after 4 weeks of treatment. The PET scan demonstrated a metabolic partial remission that was maintained for 9 months. This case supports the evidence that liquid biopsy can aid in the management of metastatic NSCLC. It also suggests that treatment with osimertinib might be a therapeutic option in patients with EGFR exon-20 insertions when a clinical trial is not available.

Quantitative imaging decision support (QIDSTM) tool consistency evaluation and radiomic analysis by means of 594 metrics in lung carcinoma on chest CT scan.

OBJECTIVE: To evaluate the consistency of the quantitative imaging decision support (QIDSTM) tool and radiomic analysis using 594 metrics in lung carcinoma on chest CT scan. MATERIALS AND METHODS: We included, retrospectively, 150 patients with histologically confirmed lung cancer who underwent chemotherapy and baseline and follow-ups CT scans. Using the QIDSTM platform, 3 radiologists segmented each lesion and automatically collected the longest diameter and the density mean value. Inter-observer variability, Bland Altman analysis and Spearman's correlation coefficient were performed. QIDSTM tool consistency was assessed in terms of agreement rate in the treatment response classification. Kruskal Wallis test and the least absolute shrinkage and selection operator (LASSO) method with 10-fold cross validation were used to identify radiomic metrics correlated with lesion size change. RESULTS: Good and significant correlation was obtained between the measurements of largest diameter and of density among the QIDSTM tool and the radiologists measurements. Inter-observer variability values were over 0.85. HealthMyne QIDSTM tool quantitative volumetric delineation was consistent and matched with each radiologist measurement considering the RECIST classification (80-84%) while a lower concordance among QIDSTM and the radiologists CHOI classification was observed (58-63%). Among 594 extracted metrics, significant and robust predictors of RECIST response were energy, histogram entropy and uniformity, Kurtosis, coronal long axis, longest planar diameter, surface, Neighborhood Grey-Level Different Matrix (NGLDM) dependence nonuniformity and low dependence emphasis as Volume, entropy of Log(2.5 mm), wavelet energy, deviation and root man squared. CONCLUSION: In conclusion, we demonstrated that HealthMyne quantitative volumetric delineation was consistent and that several radiomic metrics extracted by QIDSTM were significant and robust predictors of RECIST response.

Cetuximab, irinotecan and fluorouracile in fiRst-line treatment of immunologically-selected advanced colorectal cancer patients: the CIFRA study protocol.

BACKGROUND: Combination of chemotherapies (fluoropirimidines, oxaliplatin and irinotecan) with biologic drugs (bevacizumab, panitumumab, cetuximab) have improved clinical responses and survival of metastatic colorectal cancer (mCRC). However, patients' selection thorough the identification of predictive factors still represent a challange. Cetuximab (Erbitux®), a chimeric monoclonal antibody binding to the Epidermal Growth Factor Receptor (EGFR), belongs to the Immunoglobulins (Ig) grade 1 subclass able to elicite both in vitro and in vivo the Antibody-Dependent Cell-mediated Cytotoxicity (ADCC). ADCC is the cytotoxic killing of antibody-coated target cells by immunologic effectors. The effector cells express a receptor for the Fc portion of these antibodies (FcγR); genetic polymorphisms of FcγR modify the binding affinity with the Fc of IgG1. Interestingly, the high-affinity FcγRIIIa V/V is associated with increased ADCC in vitro and in vivo. Thus, ADCC could partially account for cetuximab activity. METHODS/DESIGN: CIFRA is a single arm, open-label, phase II study assessing the activity of cetuximab in combination with irinotecan and fluorouracile in FcγRIIIa V/V patients with KRAS, NRAS, BRAF wild type mCRC. The study is designed with a two-stage Simon model based on a hypothetical higher response rate (+ 10%) of FcγRIIIa V/V patients as compared to previous trials (about 60%) assuming ADCC as one of the possible mechanisms of cetuximab action. The test power is 95%, the alpha value of the I-type error is 5%. With these assumptions the sample for passing the first stage is 14 patients with > 6 responses and the final sample is 34 patients with > 18 responses to draw positive conclusions. Secondary objectives include toxicity, responses' duration, progression-free and overall survival. Furthermore, an associated translational study will assess the patients' cetuximab-mediated ADCC and characterize the tumor microenvironment. DISCUSSION: The CIFRA study will determine whether ADCC contributes to cetuximab activity in mCRC patients selected on an innovative immunological screening. Data from the translational study will support results' interpretation as well as provide new insights in host-tumor interactions and cetuximab activity. TRIAL REGISTRATION: The CIFRA trial (version 0.0, June 21, 2018) has been registered into the NIH-US National Library of Medicine, ClinicalTrials.gov database with the identifier number ( NCT03874062 ).

Pembrolizumab in lung cancer: current evidence and future perspectives.

Pembrolizumab is a humanized monoclonal antibody against PD-1 capable of enhancing antitumor immune activity. The KEYNOTE-001 study showed that pembrolizumab has activity in advanced non-small-cell lung cancer patients and identified programmed death ligand 1 (PD-L1) as a companion test to select patients most likely to benefit from pembrolizumab. Five randomized clinical trials showed the efficacy of pembrolizumab in non-small-cell lung cancer: in second-line setting PD-L1 ≥1% (KEYNOTE-010), in first-line setting PD-L1 ≥50% (KEYNOTE-024 and KEYNOTE-042) and in first-line setting in combination with platinum doublets, any expression of PD-L1 (KEYNOTE-189 and KEYNOTE-407). Future challenges are the identification of the role of pembrolizumab in adjuvant, neoadjuvant, locally advanced disease or oncogene-addicted patients, in combination with radiotherapy or other biological agents.

An overview on multimodal imaging for the diagnostic workup of pleural mesothelioma.

Pleural mesothelioma (PM) is an aggressive disease that has a strong causal relationship with asbestos exposure and represents a major challenge from both a diagnostic and therapeutic viewpoint. Despite recent improvements in patient care, PM typically carries a poor outcome, especially in advanced stages. Therefore, a timely and effective diagnosis taking advantage of currently available imaging techniques is essential to perform an accurate staging and dictate the most appropriate treatment strategy. Our aim is to provide a brief, but exhaustive and up-to-date overview of the role of multimodal medical imaging in the management of PM.

Improving the quality of patient care in lung cancer: key factors for successful multidisciplinary team working.

International Guidelines as well as Cancer Associations recommend a multidisciplinary approach to lung cancer care. A multidisciplinary team (MDT) can significantly improve treatment decision-making and patient coordination by putting different physicians and other health professionals "in the same room", who collectively decide upon the best possible treatment. However, this is not a panacea for cancer treatment. The impact of multidisciplinary care (MDC) on patient outcomes is not univocal, while the effective functioning of the MDT depends on many factors. This review presents the available MDT literature with an emphasis on the key factors that characterize high-quality patient care in lung cancer. The study was conducted with a bibliographic search using different electronic databases (PubMed Central, Scopus, Google Scholar, and Google) referring to multidisciplinary cancer care settings. Many key elements appear consolidated, while others emerge as prevalent and actual, especially those related to visible barriers which work across geographic, organizational, and disciplinary boundaries. MDTs must be sustained by strategic management, structured within the entity, and cannot be managed as a separate care process. Furthermore, they need to coordinate with other teams (within and outside the organization) and join with the broad range of services delivered by multiple providers at various points of the cancer journey or within the system, with the vision of integrated care.

Immunotherapy Assessment: A New Paradigm for Radiologists.

Immunotherapy denotes an exemplar change in an oncological setting. Despite the effective application of these treatments across a broad range of tumors, only a minority of patients have beneficial effects. The efficacy of immunotherapy is affected by several factors, including human immunity, which is strongly correlated to genetic features, such as intra-tumor heterogeneity. Classic imaging assessment, based on computed tomography (CT) or magnetic resonance imaging (MRI), which is useful for conventional treatments, has a limited role in immunotherapy. The reason is due to different patterns of response and/or progression during this kind of treatment which differs from those seen during other treatments, such as the possibility to assess the wide spectrum of immunotherapy-correlated toxic effects (ir-AEs) as soon as possible. In addition, considering the unusual response patterns, the limits of conventional response criteria and the necessity of using related immune-response criteria are clear. Radiomics analysis is a recent field of great interest in a radiological setting and recently it has grown the idea that we could identify patients who will be fit for this treatment or who will develop ir-AEs.

Radiation Recall Pneumonitis: The Open Challenge in Differential Diagnosis of Pneumonia Induced by Oncological Treatments.

The treatment of primary and secondary lung neoplasms now sees the fundamental role of radiotherapy, associated with surgery and systemic therapies. The improvement in survival outcomes has also increased attention to the quality of life, treatment compliance and the management of side effects. The role of imaging is not only limited to recognizing the efficacy of treatment but also to identifying, as soon as possible, the uncommon effects, especially when more treatments, such as chemotherapy, immunotherapy and radiotherapy, are associated. Radiation recall pneumonitis is an uncommon treatment complication that should be correctly characterized, and it is essential to recognize the mechanisms of radiation recall pneumonitis pathogenesis and diagnostic features in order to promptly identify them and adopt the best therapeutic strategy, with the shortest possible withdrawal of the current oncological drug. In this setting, artificial intelligence could have a critical role, although a larger patient data set is required.

Dose Reduction Strategies for Pregnant Women in Emergency Settings.

In modern clinical practice, there is an increasing dependence on imaging techniques in several settings, and especially during emergencies. Consequently, there has been an increase in the frequency of imaging examinations and thus also an increased risk of radiation exposure. In this context, a critical phase is a woman's pregnancy management that requires a proper diagnostic assessment to reduce radiation risk to the fetus and mother. The risk is greatest during the first phases of pregnancy at the time of organogenesis. Therefore, the principles of radiation protection should guide the multidisciplinary team. Although diagnostic tools that do not employ ionizing radiation, such as ultrasound (US) and magnetic resonance imaging (MRI) should be preferred, in several settings as polytrauma, computed tomography (CT) nonetheless remains the examination to perform, beyond the fetus risk. In addition, protocol optimization, using dose-limiting protocols and avoiding multiple acquisitions, is a critical point that makes it possible to reduce risks. The purpose of this review is to provide a critical evaluation of emergency conditions, e.g., abdominal pain and trauma, considering the different diagnostic tools that should be used as study protocols in order to control the dose to the pregnant woman and fetus.

Risk Management Activities in a Lung Cancer Multidisciplinary Team at a Comprehensive Cancer Center: Results of a Prospective Analysis.

PURPOSE: The objective of the study was to highlight sources of harm that could negatively affect the lung cancer multidisciplinary team (MDT) activities to reduce the level of risk of each factor. METHODS: A modified Delphi approach was used by a board of multi-health care professionals of the lung cancer MDT to identify the main processes, subprocesses, and risk factors of the multidisciplinary pathway of patients with lung cancer. A semiquantitative matrix was built with a five-point scale for probability of harm (likelihood) and severity of harm (consequences) according to the international risk management standards (ISO 31000-2018). The risk level was calculated by multiplying likelihood × consequences. Mitigation strategies have been identified and applied by the MDT to reduce risks to acceptable levels. RESULTS: Three main processes (outpatient specialist visit, MDT discussion, and MDT program implementation), eight related subprocesses, and 16 risk factors were identified. Four risk factors (25%) were related to outpatient specialist visit, seven (43.75%) to case discussion, and five (31.25%) to program implementation. Overall, two risk factors were assigned a low-risk level (12.5%), 11 a moderate-risk level (68.75%), one (6.25%) a high-risk level, and two (12.5%) a very high-risk level. After the implementation of mitigation measures, the new semiquantitative risk analysis showed a reduction in almost all hazardous situations: two risk factors (12.5%) were given a very low level, six (37.5%) a low level, seven (43.75%) a moderate level, and one (6.25%) a very high level. CONCLUSION: An interdisciplinary risk assessment analysis is applicable to MDT activities by using an ad hoc risk matrix: if the hazard is identified and monitored, the risk could be reduced and managed in a short time.

Oligo-Metastatic Cancers: Putative Biomarkers, Emerging Challenges and New Perspectives.

Some cancer patients display a less aggressive form of metastatic disease, characterized by a low tumor burden and involving a smaller number of sites, which is referred to as "oligometastatic disease" (OMD). This review discusses new biomarkers, as well as methodological challenges and perspectives characterizing OMD. Recent studies have revealed that specific microRNA profiles, chromosome patterns, driver gene mutations (ERBB2, PBRM1, SETD2, KRAS, PIK3CA, SMAD4), polymorphisms (TCF7L2), and levels of immune cell infiltration into metastases, depending on the tumor type, are associated with an oligometastatic behavior. This suggests that OMD could be a distinct disease with specific biological and molecular characteristics. Therefore, the heterogeneity of initial tumor burden and inclusion of OMD patients in clinical trials pose a crucial methodological question that requires responses in the near future. Additionally, a solid understanding of the molecular and biological features of OMD will be necessary to support and complete the clinical staging systems, enabling a better distinction of metastatic behavior and tailored treatments.

Not only lymphadenopathy: case of chest lymphangitis assessed with MRI after COVID 19 vaccine.

BACKGROUND: To date, no paper reports cases of lymphangitis after COVID 19 vaccination. We present a case of lymphangitis after vaccination from COVID 19, in a patient with colorectal liver metastases. METHODS: We described the case of a 56-year-old woman with history of a surgical resection of colorectal cancer and liver metastases, without any kind of drug therapy for about a month. In addition, a recent administration (2 days ago) of Spikevax (mRNA-1273, Moderna vaccine), as a booster dose, on the right arm was reported. RESULTS: The magnetic resonance (MR) examination showed the effects of the previous surgical resection and five new hepatic metastases, located in the VIII, VI, V, IV and II hepatic segments. As an accessory finding the presence of lymphadenopathy in the axillary area and lymphangitis of the right breast and chest were identified. The computed tomography scan performed a week earlier, and re-evaluated in light of the MR data, did not identify the presence of lymphadenopathy in the axillary area and lymphangitis signs. CONCLUSIONS: Lymphangitis could occur after COVID 19 vaccine and it is important to know this data to avoid alarmism in patients and clinicians and economic waste linked to the execution of various radiological investigations for the search for a tumour that probably does not exist. TRIAL REGISTRATION: Not applicable.

Imaging Assessment of Interval Metastasis from Melanoma.

Interval metastasis is a particular metastatic category of metastatic localizations in the lymph nodes in patients with melanoma. Interval nodes are generally located at nonregional lymphatic stations placed along the pathway of the spread of melanoma, such as the epitrochlear lymph node station, the popliteal fossa, and the retroareolar station. Imaging techniques for evaluation of patients with interval metastasis from melanoma diseases include ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), lymphoscintigraphy (LS), and positron emission tomography (PET). A literature review was conducted through a methodical search on the Pubmed and Embase databases. The evaluation of lymph node metastases represents a critical phase in the staging and follow-up of melanoma patients. Therefore, a thorough knowledge of the imaging methods available and the interactions between the clinician and the radiologist are essential for making the correct choice for individual patients, for a better management, and to improve treatment and survival.

Multimodality Imaging Assessment of Desmoid Tumors: The Great Mime in the Era of Multidisciplinary Teams.

Desmoid tumors (DTs), also known as desmoid fibromatosis or aggressive fibromatosis, are rare, locally invasive, non-metastatic soft tissue tumors. Although histological results represent the gold standard diagnosis, imaging represents the fundamental tool for the diagnosis of these tumors. Although histological analysis represents the gold standard for diagnosis, imaging represents the fundamental tool for the diagnosis of these tumors. DTs represent a challenge for the radiologist, being able to mimic different pathological conditions. A proper diagnosis is required to establish an adequate therapeutic approach. Multimodality imaging, including ultrasound (US), computed tomography (CT) and Magnetic Resonance Imaging (MRI), should be preferred. Different imaging techniques can also guide minimally invasive treatments and monitor their effectiveness. The purpose of this review is to describe the state-of-the-art multidisciplinary imaging of DTs; and its role in patient management.

Lurbinectedin in small cell lung cancer.

Few treatment options are available for patients with small cell lung cancer (SCLC) in progression after a first-line therapy. A novel therapeutic approach is represented by lurbinectedin, a synthetic derivative of trabectedin that works by inhibiting oncogenic transcription and promoting apoptosis in tumor cells. A phase II basket trial demonstrated the activity of lurbinectedin at the dose of 3.2 mg/m2 in patients with SCLC who had failed a previous chemotherapy, with a response rate of 35.2%, a median progression-free survival (mPFS) of 3.5 months, and a median overall survival (mOS) of 9.3 months. Common severe adverse events (grades 3-4) were hematological disorders, including anemia (9%), leukopenia (29%), neutropenia (46%), and thrombocytopenia (7%). On the basis of the positive results of this phase II study, on June 2020, lurbinectedin was approved by the Food and Drug Administration as second line for SCLC patients in progression on or after platinum-based therapy. The subsequent phase III trial comparing the combination of lurbinectedin plus doxorubicin vs. CAV (cyclophosphamide, Adriamycin, and vincristine) or topotecan did not demonstrate an improvement in overall survival, although the experimental arm showed a superior safety profile. Combinations of lurbinectedin with other drugs, cytotoxic agents and immune checkpoint inhibitors, are currently under investigation. The results of these studies should better define the optimal clinical application of lurbinectedin.

Genetic landscape of colorectal cancer patients manifesting tumor shrinkage during SARS-Cov-2 infection.

We previously described three patients affected by metastatic colorectal cancer (mCRC) who experienced spontaneous tumour shrinkage during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Thereafter, the patients were closely monitored and no systemic treatments were applied. Here, we report follow-up clinical information about these patients as well as genetic characterization of their primary tumours through the TruSigt™Oncology 500 Next Generation Sequencing test targeting 523 cancer-relevant genes. An Illumina NovaSeq 6000 platform was used to perform sequencing. Time-to-progression was 23 and 2 months, respectively, in Patients 2 and 3 while it was not reached in Patient 1. Patients 1 and 2 had the greatest anti-SARS-CoV-2 IgG titres. Assessment of genetic landscapes evidenced common mutation in BARD1 gene (p.Val507Met) in Patients 1 and 2. Although our report is descriptive in its nature, we suggest that complex and unexplored interactions between genetic background and components of the immune response to SARS-CoV-2 infection could be responsible of unexpected rare mCRC shrinkage.

Unexpected tumor reduction in metastatic colorectal cancer patients during SARS-Cov-2 infection.

Herein, we describe three patients affected by metastatic colorectal cancer (mCRC) experiencing infection by severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) and reduction of disease burden during coronavirus disease 2019 (COVID-19) course. Insights into tumor-associated angiotensin-converting enzyme (ACE)-2 expression and lymphocyte function suggest a correlation between host/SARS-Cov-2 infection and tumor burden reduction. This may shed new light into (a) the infection mechanism of SARS-CoV-2 virus and (b) the multiple aspects of a composite antiviral immune response with potential paradoxical and unexpected applications.