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CD59 is an abundant immuno-regulatory human protein that protects cells from damage by inhibiting the complement system. CD59 inhibits the assembly of the Membrane Attack Complex (MAC), the bactericidal pore-forming toxin of the innate immune system. In addition, several pathogenic viruses, including HIV-1, escape complement-mediated virolysis by incorporating this complement inhibitor in their own viral envelope. This makes human pathogenic viruses, such as HIV-1, not neutralised by the complement in human fluids. CD59 is also overexpressed in several cancer cells to resist the complement attack. Consistent with its importance as a therapeutical target, CD59-targeting antibodies have been proven to be successful in hindering HIV-1 growth and counteracting the effect of complement inhibition by specific cancer cells. In this work, we make use of bioinformatics and computational tools to identify CD59 interactions with blocking antibodies and to describe molecular details of the paratope–epitope interface. Based on this information, we design and produce paratope-mimicking bicyclic peptides able to target CD59. Our results set the basis for the development of antibody-mimicking small molecules targeting CD59 with potential therapeutic interest as complement activators.

Introduction: Progastrin-releasing peptide (proGRP), a precursor of GRP, has been recently reported as a putative circulating biomarker for differential diagnosis between non–small cell lung cancer (NSCLC) and SCLC. We evaluated the diagnostic effectiveness of proGRP to differentiate patients with NSCLC and SCLC and the usefulness of combined measurement of proGRP and neuron-specific enolase (NSE) for diagnosing SCLC. Methods: Serum proGRP, NSE, cytokeratin 19 fragment 21-1 (CYFRA 21.1), squamous cell carcinoma antigen (SCC Ag) and carcinoembryonic antigen (CEA) were prospectively collected and measured in patients with a new diagnosis of lung cancer. Serum proGRP was also measured in healthy subjects. The serum proGRP, NSE, CYFRA 21.1 and CEA concentrations were determined by an electrochemiluminescence immunoassay and the serum SCC Ag concentration was determined by an automated immunofluorescence assay. Differences between proGRP and NSE in patients with SCLC and NSCLC were evaluated and compared using Mann-Whitney test. Results: A total of 77 patients affected by SCLC (n = 17) and NSCLC (n = 60) were enrolled in the present study. Moreover, 50 cases of healthy subjects were analyzed for proGRP. SCLC patients showed a significantly higher proGRP (1,484 pg/mL; range 168-3,777) levels compared to NSCLC patients (45 pg/mL; range 31.7-60.6), p

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.

Learning objectives Background Findings and procedure details Conclusion Personal information and conflict of interest References, Learning objectives: Acute cholecystitis represents one of the most common surgical pathologies that should always be considered in an emergency with right upper abdominal pain. Nevertheless, a significant percentage of patients with acute cholecystitis admitted to ED...

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.

RAF family proteins are serine–threonine kinases that play a central role in the MAPK pathway which is involved in embryogenesis, cell differentiation, cell proliferation and death. Deregulation of this pathway is found in up to 30% of all human cancers and BRAF mutations can be identified in 1.5–3.5% of NSCLC patients. Following the positive results obtained through the combination of BRAF and MEK inhibitors in BRAF-mutant melanoma, the same combination was prospectively assessed in BRAF-mutant NSCLC. In cohort B of the BRF113928 trial, 57 pretreated NSCLC patients were treated with dabrafenib plus trametinib: an ORR of 68.4%, a disease control rate of 80.7%, a median PFS of 10.2 months and a median OS of 18.2 months were observed. Similar results were reported in the first-line setting (cohort C), with an ORR of 63.9%, a DCR of 75% and a median PFS and OS of 10.2 and 17.3 months, respectively. The combination was well tolerated: the main adverse events were pyrexia (64%), nausea (56%), diarrhoea (56%), fatigue (36%), oedema (36%) and vomiting (33%). These positive results led to the approval of the combination of dabrafenib and trametinib for the treatment of BRAF V600E metastatic NSCLC patients regardless of previous therapy. Ongoing research should better define the role of new generation RAF inhibitors for patients with acquired resistance, the activity of chemo-immunotherapy or the combination of TKIs with chemotherapy or with immunotherapy in patients with BRAF-mutated cancers.

Autoimmune endocrine disorders, such as type 1 diabetes (T1D) and thyroiditis, at present are treated with only hormone replacement therapy. This emphasizes the need to identify personalized effective immunotherapeutic strategies targeting T and B lymphocytes. Among the genetic variants associated with several autoimmune disorders, the C1858T polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene, encoding for Lyp variant R620W, affects the innate and adaptive immunity. We previously exploited a novel personalized immunotherapeutic approach based on siRNA delivered by liposomes (lipoplexes) that selectively inhibit variant allele expression. In this manuscript, we improved lipoplexes carrying siRNA for variant C1858T by functionalizing them with Fab of Rituximab antibody (RituxFab-Lipoplex) to specifically target B lymphocytes in autoimmune conditions, such as T1D. RituxFab-Lipoplexes specifically bind to B lymphocytes of the human Raji cell line and of human PBMC of healthy donors. RituxFab-Lipoplexes have impact on the function of B lymphocytes of T1D patients upon CpG stimulation showing a higher inhibitory effect on total cell proliferation and IgM+ plasma cell differentiation than the not functionalized ones. These results might open new pathways of applicability of RituxFab-Lipoplexes, such as personalized immunotherapy, to other autoimmune disorders, where B lymphocytes are the prevalent pathogenic immunocytes.

Background The aim of the study was to investigate the performance of the Liver Imaging Reporting and Data System (LI-RADS) v2018 for combined hepatocellular-cholangiocarcinoma (cHCC-CCA) identifying the features that allow an accurate characterization. Patients and methods Sixty-two patients (median age, 63 years; range, 38–80 years), with pre-surgical biopsy diagnosis of hepatocellular carcinoma (HCC) that underwent hepatic resection, comprised our retrospective study. All patients were subject to multidetector computed tomography (MDCT); 23 patients underwent to magnetic resonance (MR) study. The radiologist reported the presence of the HCC by using LIRADS v2018 assessing major and ancillary features. Results Final histological diagnosis was HCC for 51 patients and cHCC-CCA for 11 patients. The median nodule size was 46.0 mm (range 10–190 mm). For cHCC-CCA the median size was 33.5 mm (range 20–80 mm), for true HCC the median size was 47.5 mm (range 10–190 mm). According to LIRADS categories: 54 (87.1%) nodules as defined as LR-5, 1 (1.6%) as LR-3, and 7 (11.3%) as LR-M. Thirty-nine nodules (63%) showed hyper-enhancement in arterial phase; among them 4 were cHCC-CCA (36.4% of cHCC-CCA) and 35 (68.6%) true HCC. Forty-three nodules (69.3%) showed washout appearance; 6 cHCC-CCAs (54.5% of cHCC-CCA) and 37 true HCC (72.5%) had this feature. Only two cHCC-CCA patients (18.2% of cHCC-CCA) showed capsule appearance. Five cHCC-CCA (71.4% of cHCC-CCA) showed hyperintensity on T2-W sequences while two (28.6%) showed inhomogeneous signal in T2-W. All cHCC-CCA showed restricted diffusion. Seven cHCC-CCA patients showed a progressive contrast enhancement and satellite nodules. Conclusions The presence of satellite nodules, hyperintense signal on T2-W, restricted diffusion, the absence of capsule appearance in nodule that shows peripheral and progressive contrast enhancement are suggestive features of cHCC-CCA.

Abdominal emergencies in cancer patients encompass a wide spectrum of oncologic conditions caused directly by malignancies, paraneoplastic syndromes, reactions to the chemotherapy or often represent the first clinical manifestation of an unknown malignancy. Not rarely, clinical symptoms are the tip of an iceberg. In this scenario, the radiologist is asked to exclude the cause responsible for the patient’s symptoms, to suggest the best way to manage and to rule out the underlying malignancy. In this article, we discuss some of the most common abdominal oncological emergencies that may be encountered in an emergency department.

Malignant melanoma metastases occur in about 15% of patients. The most common localizations are lymph nodes, lungs, pancreas, bones. The central nervous system and the perineural region are rarely affected. In case of distant metastases, the survival rate is lower (about 25%). Involvement of peripheral nerve metastases from melanoma is reported in the literature just in one case. We report the ultrasound (US) integrated with Color-Doppler Ultrasound (CDU), elastosonography, and magnetic resonance imaging (MRI) findings of a rare case of metastatic endo- and perineural involvement of the ulnar nerve from cutaneous melanoma. Our purpose is to increase the clinicians' and radiologists' awareness on the possibility of metastatic spread to the peripheral nervous system and improve the differential diagnosis with other peripheral nerve sheath tumors.