Treatment of Chronic Hepatitis C in a Patient Affected by Systemic Sclerosis

The currently recommended treatment for patients infected with hepatitis C virus (HCV) is pegilated interferon α (IFN α) plus ribavirin. Despite the numerous benefits of this therapy, there is an increasing concern regarding his tolerance. Among the most common side effects, interferon may trigger the onset or exacerbation of autoimmune diseases. When chronic hepatitis C coexists with an autoimmune disorder, it is not clear whether using interferon is better than avoiding it. We evaluated the disease state of a 55-year old female affected by sistemic sclerosis (SSc), during and after therapy with IFNα pegilated plus ribavirin for chronic HCV infection. We were worried about the potential worsening of the autoimmune disease during the therapy, but we were confident that we would give our patient a short course of peginterferon and ribavirin. A mild, asymptomatic worsening of lung SSc was observed during IFN administration, without life threatening symptoms. After 24 months follow up we observed the maintenance of the virological response and a good control of the rheumatological disease. Thus, in liver disease at high risk of progression and concomitant SSc, the antiviral therapy with IFNα is a feasible approach

Sensitivity to Entrectinib Associated with a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer

In metastatic colorectal cancer (CRC), actionable genetic lesions represent potential clinical opportunities. NTRK1, 2, and 3 gene rearrangements encode oncogenic fusions of the tropomyosin-receptor kinase (TRK) family of receptor tyrosine kinases in different tumor types. The TPM3-NTRK1 rearrangement is a recurring event in CRC that renders tumors sensitive to TRKA kinase inhibitors in preclinical models. We identified abnormal expression of the TRKA protein in tumor and liver metastases of a CRC patient refractory to standard therapy. Molecular characterization unveiled a novel LMNA-NTRK1 rearrangement within chromosome 1 with oncogenic potential, and the patient was treated with the pan-TRK inhibitor entrectinib, achieving partial response with decrease in hepatic target lesions from 6.8 and 8.2cm in longest diameter to 4.7 and 4.3cm, respectively. To our knowledge, this is the first clinical evidence of efficacy for therapeutic inhibition of TRKA in a solid tumor, illuminating a genomic-driven strategy to identify CRCs reliant on this oncogene to be clinically targeted with entrectinib

Malignant mesothelioma of the tunica vaginalis testis in a petrochemical worker exposed to asbestos

Malignant mesothelioma of the tunica vaginalis testis is a rare and aggressive asbestos-related malignancy that may pose difficult diagnostic problems. After 16 years of asbestos exposure, a 38-year-old petrochemical worker came to our notice with acute right testicular pain and swelling, simulating torsion of the spermatic cord. Histopathology of surgical samples of the tunica vaginalis revealed tubulopapillary, epithelioid neoplastic proliferation. Immunohistochemical staining for the epithelial glycoprotein Ber-EP4 was negative, whereas results were positive for mesothelial markers, thus leading to the diagnosis of epithelial mesothelioma. The tumour infiltrated the testicular surface and the epididymis, but no distant metastases were found. The patient was treated with radical inguinal orchidectomy without adjuvant therapy and is free from disease 15 months after diagnosis. Tunical mesothelioma may simulate metastatic carcinoma at routine histopathological examination. Immunohistochemistry and occupational anamnesis are helpful for the correct diagnosis, which, in turn, is important for prognosis and treatment, and in relation to legal issues when asbestos is involved in the causation of the disease

Efficacy of Retreatment with Oxaliplatin-Based Regimens in Metastatic Colorectal Cancer Patients: The RETROX-CRC Retrospective Study

Background: oxaliplatin with fluoropyrimidine is a “mainstay” regarding the upfront treatment of metastatic colorectal cancer (mCRC). In contrast, the efficacy and safety of oxaliplatin-based regimens in late-care settings have been poorly reported. Methods: we identified a real-world mCRC patient cohort who were re-treated with oxaliplatin, and in which clinicopathological features were retrospectively analyzed to identify efficacy–predictive determinants (RETROX-CRC study). Results: of 2606 patients, 119 fulfilled the eligibility criteria. Oxaliplatin retreatment response rate (RR) and disease control rate (DCR) were 21.6% (CI 14.4–31.0%), and 57.8% (CI 47.7–67.4). A trend towards better RR and DCR was observed among patients who had first oxaliplatin in an adjuvant setting; a poorer outcome was observed if two or more intervening treatments were delivered. Median progression-free survival (PFS) was 5.1 months (95%CI 4.3–6.1), reducing to 4.0 months (95%CI 3.07–5.13) if oxaliplatin was readministered beyond third-line (HR 2.02; 1.25–3.25; p = 0.004). Safety data were retrieved in 65 patients (54.6%); 18.5% (12/65) and 7.7% (5/65) had G3–4 toxicities. Toxicities led to discontinuation in 34/119 (28.6%). Conclusions: oxaliplatin retreatment produced further RR in around one-fifth of patients and DCR 57.8%. Efficacy decreased in more pre-treated patients and around one-third of patients discontinued treatment due to adverse events. Translational studies improving patient selection are warranted

The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer

The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients

Liquid Biopsy for Small Cell Lung Cancer either De Novo or Transformed: Systematic Review of Different Applications and Meta-Analysis

Background: The potential added value of liquid biopsy (LB) is not well determined in the case of small cell lung cancer (SCLC), an aggressive tumor that can occur either de novo or from the histologic transformation of non-small cell lung cancer (NSCLC). Methods: A systematic review of studies adopting LB in patients with SCLC have been performed to assess the clinical utility of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs). Results: After a screening of 728 records, 62 studies (32 evaluating CTCs, 27 ctDNA, and 3 both) met predetermined eligibility criteria. Only four studies evaluated LB in the diagnostic setting for SCLC, while its prognostic significance was evaluated in 38 studies and prominently supported by both ctDNA and CTCs. A meta-analysis of 11 studies as for CTCs enumeration showed an HR for overall survival of 2.63 (1.71–4.05), with a potential publication bias. The feasibility of tumor genomic profiling and the predictive role of LB in terms of response/resistance to chemotherapy was assessed in 11 and 24 studies, respectively, with greater consistency for those regarding ctDNA. Intriguingly, several case reports suggest that LB can indirectly capture the transition to SCLC in NSCLC treated with EGFR tyrosine kinase inhibitors. Conclusions: While dedicated trials are needed, LB holds potential clinical roles in both de novo and transformed SCLC. CtDNA analysis appears the most valuable and practicable tool for both disease monitoring and genomic profiling

Preclinical Characterization and Phase 1 Study of the Anti-HER2-TLR7 Immune Stimulator Antibody Conjugate NJH395 in Patients with HER2-positive Malignancies

Immune stimulator antibody conjugates (ISACs) combining tumor-targeting monoclonal antibodies with potent immunostimulatory agents allow targeted delivery of immune activators in tumors. NJH395 is a novel, first-in-class ISAC comprising a Toll‐like receptor 7 (TLR7) agonist conjugated to an anti-HER2 antibody via a non-cleavable linker-payload. Preclinical characterization showed ISAC-mediated activation of myeloid cells in the presence of antigen-expressing cancer cells, with antigen targeting and TLR7 agonism contributing to antitumor activity. Safety, efficacy, immunogenicity, pharmacokinetics, and pharmacodynamics were investigated in a phase 1, multicenter, open-label study in patients with HER2-positive malignancies (NCT03696771). Data from 18 patients enrolled in single ascending dose escalation demonstrated delivery of the TLR7 agonist payload in HER2-positive tumor cells and induction of type I IFN response, which interrelated with preferential immune modulation in the tumor microenvironment. Cytokine release syndrome was a common but manageable drug-related adverse event. Antidrug antibody formation and neuroinflammation at high doses represented significant clinical challenges