Giulia Orsi

GD2 expression in breast cancer

Breast cancer (BC) is a heterogeneous disease, including different subtypes having diverse incidence, drug-sensitivity and survival rates. In particular, claudin-low and basal-like BC have mesenchymal features with a dismal prognosis. Disialoganglioside GD2 is a typical neuroectodermal antigen expressed in a variety of cancers. Despite its potential relevance in cancer diagnostics and therapeutics, the presence and role of GD2 require further investigation, especially in BC. Therefore, we evaluated GD2 expression in a cohort of BC patients and its correlation with clinical-pathological features. Sixty-three patients with BC who underwent surgery without prior chemo- and/or radiotherapy between 2001 and 2014 were considered. Cancer specimens were analyzed by immunohistochemistry and GD2-staining was expressed according to the percentage of positive cells and by a semi-quantitative scoring system. Patient characteristics were heterogeneous by age at diagnosis, histotype, grading, tumor size, Ki-67 and receptor-status. GD2 staining revealed positive cancer cells in 59% of patients. Among them, 26 cases (41%) were labeled with score 1+ and 11 (18%) with score 2+. Notably, the majority of metaplastic carcinoma specimens stained positive for GD2. The univariate regression logistic analysis revealed a significant association of GD2 with triple-receptor negative phenotype and older age (> 78) at diagnosis. We demonstrate for the first time that GD2 is highly prevalent in a cohort of BC patients clustering on very aggressive BC subtypes, such as triple-negative and metaplastic variants.

Heavily calcified gastrointestinal stromal tumors: Pathophysiology and implications of a rare clinicopathologic entity

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and are characterized by a broad spectrum of clinical, histological and molecular features at presentation. Although focal and scattered calcifications are not uncommon within the primary tumor mass, heavy calcification within a GIST is rarely described in the literature and the clinical-biological meaning of this feature remains unclear. Cases with such an atypical presentation are challenging and may be associated with diagnostic pitfalls. Herein, we report a gastric GIST with the unusual presentation of prominent calcifications that was identified incidentally on imaging during a post-trauma diagnostic work-up. The patient underwent laparoscopic surgery with a radical resection of the mass, which was subsequently characterized by histological analysis as spindle-shaped tumor cells, positive for CD117/c-KIT, CD34 and DOG1, and with calcified areas. Given the intermediate risk of recurrence, no adjuvant therapy was recommended and the patient underwent regular follow-up for 22 mo, with no evidence of relapse. Our case can be considered of interest because of the rarity of clinical presentation and the uniquely large size of the GIST at diagnosis (longest diameter exceeding 9 cm). In closing, we discuss the pathophysiology and clinical implications of calcifications in GISTs by reviewing the most up-to-date relevant literature.

Immunotherapy in the treatment of colorectal cancer: a new kid on the block

In the last few years, the success of anti-PD1 and anti-PDL1 drugs in solid cancers treatment and the advances in molecular biology have provided new potential treatment strategies for patients with metastatic colorectal cancer. Unfortunately, only patients with mismatch repair deficiency seem to benefit from immunotherapy and they represent a small subset of the metastatic population. New ongoing studies focus on converting an immune ignorant tumour into an inflamed one by combination therapies and on introducing an immunotherapeutic approach in earlier stages of disease (neoadjuvant and adjuvant setting). In this review we summarize the current knowledge about the molecular and immune landscape of colorectal cancer and propose new potential combination strategies to enhance the efficacy

Lenvatinib as a therapy for unresectable hepatocellular carcinoma

ABSTRACT Introduction: Since 2007 Sorafenib has represented the only approved drug for first-line treatment of advanced hepatocellular carcinoma (HCC). Lenvatinib, an orally active inhibitor of multiple receptor tyrosine kinases (VEGFR 1–3, FGFR 1–4, PDGFRa, RET and KIT), showed preclinical and clinical activity in the treatment of solid tumors, including HCC. Areas covered: In this review, we summarize the current therapeutic paradigm for the systemic treatment of advanced HCC, focusing on Lenvatinib pre-clinical and clinical development. Keywords ‘Lenvatinib’, ‘ Target therapy’, ‘REFLECT trial’, ‘Hepatocellular carcinoma’, ‘HCC’, ‘Sorafenib’ were used for literature search on PubMed. Expert commentary: In Phase-III multicentric REFLECT trial Lenvatinib demonstrated a non-inferior overall survival (OS) compared to Sorafenib in the first-line treatment of advanced HCC, with a manageable toxicity profile, becoming a valid alternative option in the therapeutic repertoire of this disease. Nevertheless, the potential role of Lenvatinib in real-life clinical practice has still to be defined, especially in the light of the positive results that have been achieved with other new therapeutic agents (e.g. immunotherapy).

To resect or not to resect: The hamletic dilemma of primary tumor resection in patients with asymptomatic stage IV colorectal cancer

Primary tumor resection (PTR) in advanced asymptomatic colorectal cancer (CRC) has been a matter of intense debate for long time. With the advances in systemic treatments, this practice has decreased over the years, although it remains still pervasive. Although the removal of primary tumor has been extensively interrogated both in retrospective and prospective studies, it still remains a clinical conundrum. There are many arguments for and against PTR in CRC both from the preclinical and the clinical point of view. Two scoring models have been published aiming at identifying patients who are suitable candidate for PTR, but they deserve further investigations in larger datasets. While awaiting the results of ongoing randomized clinical trials (RCTs) on this controversial topic, both upfront systemic treatment and PTR followed by chemotherapy should be considered valid options in patients with asymptomatic mCRC. Clinical selection and a shared-decision making approach are the keys to success.

Resistance to EGFR inhibitors in non-small cell lung cancer: Clinical management and future perspectives

In the last few years, the development of targeted therapies for non-small cell lung cancer (NSCLC) expressing oncogenic driver mutations (e.g. EGFR) has changed the clinical management and the survival outcomes of this specific minority of patients. Several phase III trials demonstrated the superiority of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) over chemotherapy in EGFR-mutant NSCLC patients. However, in the vast majority of cases EGFR TKIs lose their clinical activity within 8-12 months. Many genetic aberrations have been described as possible mechanisms of EGFR TKIs acquired resistance and can be clustered in four main sub-groups: 1. Development of secondary EGFR mutations; 2. Activation of parallel signaling pathways; 3. Histological transformation; 4. Activation of downstream signaling pathways. In this review we will describe the molecular alterations underlying each of these EGFR TKIs resistance mechanisms, focusing on the currently available and future therapeutic strategies to overcome these phenomena.

Inducible Caspase9-mediated suicide gene for MSC-based cancer gene therapy

Cellular therapies based on mesenchymal stromal/stem cells (MSC) are promising strategies in regenerative medicine and oncology. Despite encouraging results, there is still some level of concerns on inoculating MSC in cancer patients. To face this issue, one possibility resides in engineering MSC by incorporating a suicide gene in order to control their fate once infused. Strategies based on Herpes Simplex Virus Thymidine Kinase (HSV-TK) and the Cytosine Deaminase genes have been developed and more recently a novel suicide gene, namely, iCasp9, has been proposed. This approach is based on a variant of human Caspase9 that binds with high affinity to a synthetic, bioinert small molecule (AP20187) leading to cell death. Based on this technology so far marginally applied to MSC, we tested the suitability of iCasp9 suicide strategy in MSC to further increase their safety. MSC have been transfected by a lentiviral vector carrying iCasp9 gene and then tested for viability after AP20187 treatment in comparison with mock-transfected cells. Moreover, accounting our anti-tumor approaches based on MSC expressing potent anti-cancer ligand TNF-Related Apoptosis-Inducing Ligand (TRAIL), we generated adipose MSC co-expressing iCasp9 and TRAIL successfully targeting an aggressive sarcoma type. These data show that anti-cancer and suicide mechanisms can coexist without affecting cells performance and hampering the tumoricidal activity mediated by TRAIL. In conclusion, this study originally indicates the suitability of combining a MSC-based anti-cancer gene approach with iCasp9 demonstrating efficiency and specificity.