The RAS/MAP kinase pathway has attracted attention because activating mutations of the BRAF serine/threonine kinase was described in over 50% of melanomas. Very recently, selective and potent BRAF ...inhibitors have been developed. Several other signal transduction pathways have been found to be constitutively active or mutated in other subsets of melanoma tumors that are potentially targetable with new agents. Among these, NFκB is another pathway that melanoma tumors use to achieve survival, proliferation and resistance to apoptosis. Inhibition of NF-κB activation appears to be a very promising option for anti-cancer therapies.
Oncogenic mutations in the
gene are targets of tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma (LC) patients, and their search is mandatory to make decisions on treatment strategies. Liquid ...biopsy of circulating tumour DNA (ctDNA) is increasingly used to detect EGFR mutations, including main activating alterations (exon 19 deletions and exon 21 L858R mutation) and T790M mutation, which is the most common mechanism of acquired resistance to first- and second-generation TKIs. In this study, we prospectively compared three different techniques for
mutation detection in liquid biopsies of such patients. Fifty-four ctDNA samples from 48 consecutive advanced LC patients treated with TKIs were tested for relevant
mutations with Therascreen
EGFR Plasma RGQ-PCR Kit (Qiagen). Samples were subsequently tested with two different technologies, with the aim to compare the EGFR detection rates: real-time PCR based Idylla™ ctEGFR mutation assay (Biocartis) and next-generation sequencing (NGS) system with Ion AmpliSeq Cancer Hotspot panel (ThermoFisher). A high concordance rate for main druggable
alterations was observed with the two real-time PCR-based assays, ranging from 100% for T790M mutation to 94% for L858R variant and 85% for exon 19 deletions. Conversely, lower concordance rates were found between real-time PCR approaches and the NGS method (L858R: 88%; exon19-dels: 74%; T790M: 37.5%). Our results evidenced an equivalent detection ability between PCR-based techniques for circulating
mutations. The NGS assay allowed detection of a wider range of
mutations but showed a poor ability to detect T790M.
•Separation surgery is a new concept for metastatic spinal cord compression treatment.•Stereotactic radiosurgery increased local control, overcoming radio-resistance’s idea.•The surgery goal shifted ...towards creating targets for radiations avoiding cord damages.•Minimal invasive strategies could allow quick return to systemic therapies.
The new concept of separation surgery has changed the surgical paradigms for the treatment of metastatic epidural spinal cord compression (MESCC), shifting from aggressive cytoreductive surgery towards less invasive surgery with the aim to achieve circumferential separation of the spinal cord and create a safe target for high dose Stereotactic Body Radiation Therapy (SBRT), which turned out to be the real game-changer for disease’s local control.
In this review a qualitative analysis of the English literature has been performed according to the rating of evidence, with the aim to underline the increasingly role of the concept of separation surgery in MESCC treatment. A review of the main steps in the evolution of both radiotherapy and surgery fields have been described, highlighting the important results deriving from their integration.
Compared with more aggressive surgical approaches, the concept of separation surgery together with the advancements of radiotherapy and the use of SBRT for the treatment of MESCC showed promising results in order to achieve a valuable local control while reducing surgical related morbidities and complications.
Patients with pancreatic ductal adenocarcinoma (PDCA) carrying impaired mismatch repair mechanisms seem to have an outcome advantage under treatment with conventional chemotherapy, whereas the role ...for the tumor mutation burden on prognosis is controversial. In this study, we evaluated the prognostic role of the mutated genes involved in genome damage repair in a real-life series of PDAC patients in a hospital-based manner from the main Institution deputed to surgically treat such a disease in North Sardinia.
A cohort of fifty-five consecutive PDAC patients with potentially resectable/border line resectable PDAC (stage IIB-III) or oligometastatic disease (stage IV) and tumor tissue availability underwent next-generation sequencing (NGS)-based analysis using a panel containing driver oncogenes and tumor suppressor genes as well as genes controlling DNA repair mechanisms.
Genes involved in the both genome damage repair (DR) and DNA mismatch repair (MMR) were found mutated in 17 (31%) and 15 (27%) cases, respectively. One fourth of PDAC cases (14/55; 25.5%) carried tumors presenting a combination of mutations in repair genes (DR and MMR) and the highest mutation load rates (MLR-H). After correction for confounders (surgery, adjuvant therapy, stage T, and metastasis), multivariate Cox regression analysis indicated that mutations in DR genes (HR = 3.0126, 95% CI 1.0707 to 8.4764, p = 0.0367) and the MLR (HR = 1.0018, 95%CI 1.0005 to 1.0032, p = 0.009) were significantly related to worse survival.
The combination of mutated repair genes and MLR-H, which is associated with a worse survival in our series of PDAC patients treated with conventional chemotherapy protocols, might become a predictive biomarker of response to immunotherapy in addition to its prognostic role in predicting survival.
No prospective data were available prior to 2021 to inform selection between combination BRAF and MEK inhibition versus dual blockade of programmed cell death protein-1 (PD-1) and cytotoxic T ...lymphocyte antigen-4 (CTLA-4) as first-line treatment options for BRAFV600-mutant melanoma. SECOMBIT (NCT02631447) was a randomized, three-arm, noncomparative phase II trial in which patients were randomized to one of two sequences with immunotherapy or targeted therapy first, with a third arm in which an 8-week induction course of targeted therapy followed by a planned switch to immunotherapy was the first treatment. BRAF/MEK inhibitors were encorafenib plus binimetinib and checkpoint inhibitors ipilimumab plus nivolumab. Primary outcome of overall survival was previously reported, demonstrating improved survival with immunotherapy administered until progression and followed by BRAF/MEK inhibition. Here we report 4-year survival outcomes, confirming long-term benefit with first-line immunotherapy. We also describe preliminary results of predefined biomarkers analyses that identify a trend toward improved 4-year overall survival and total progression-free survival in patients with loss-of-function mutations affecting JAK or low baseline levels of serum interferon gamma (IFNy). These long-term survival outcomes confirm immunotherapy as the preferred first-line treatment approach for most patients with BRAFV600-mutant metastatic melanoma, and the biomarker analyses are hypothesis-generating for future investigations of predictors of durable benefit with dual checkpoint blockade and targeted therapy.
Recently the 8th version of the American Joint Committee on Cancer (AJCC) classification has been introduced, and has attempted to define a more accurate and precise definition of prognosis in line ...with the major progresses in understanding the biology and pathogenesis of melanoma. This new staging system introduces major changes in the stage III staging system. Indeed, surgical practice is changing in stage III patients, since, according to recent evidence, there is no survival benefit in radical lymph node dissection following a positive sentinel lymph node dissection. Therefore, some patients currently staged IIIB-C after dissection could be downgraded to IIIA (as in the case of patients with metastatic non-sentinel lymph nodes) since many completion lymph node dissections will no longer be performed. Moreover, new and effective targeted and immune strategies are being introduced in the pharmacological armamentarium in the adjuvant setting, showing major efficacy.
This article provides the authors' personal view on the above-mentioned topics.
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In the era of personalized medicine, BRAF mutational assessment is mandatory in advanced-stage melanoma and non-small cell lung cancer (NSCLC) patients. The identification of ...actionable mutations is crucial for the adequate management of these patients. To date various drugs have been implemented in clinical practice. Similarly, various methods may be adopted for the identification of BRAF mutations. Here, we briefly review the current literature on BRAF in melanoma and NSCLC, focusing attention in particular on the different methods and drugs adopted in these patients. In addition, an overview of the real-world practice in different Italian laboratories with high expertise in molecular predictive pathology testing is provided.
Primary mucosal melanomas (MMs) are uncommon tumors originating from melanocytes located in the mucous membranes at various anatomic sites within the body. MM significantly differs from cutaneous ...melanoma (CM) regarding epidemiology, genetic profile, clinical presentation, and response to therapies. Despite these differences, that have important implications for both disease diagnosis and prognosis, MMs are usually treated in the same way as CM but exhibit a lower response rate to immunotherapy leading to a poorer survival rate. Furthermore, a high inter-patient variability can be observed in relation to therapeutic response. Recently, novel "
" techniques have evidenced that MM lesions have different genomic, molecular, and metabolic landscapes as compared with CM lesions, thus explaining the heterogeneity of the response. Such specific molecular aspects might be useful to identify new biomarkers aimed at improving the diagnosis and selection of MM patients who could benefit from immunotherapy or targeted therapy. In this review, we have focused on relevant molecular and clinical advancements for the different MM subtypes in order to describe the updated knowledge relating to main diagnostic, clinical, and therapeutic implications as well as to provide hints on likely future directions.
Cutaneous angiosarcoma (CAS) is the most common type of angiosarcoma that predominantly affects older Caucasians. The outcomes of immunotherapy in CAS are currently under investigation in relation to ...the expression of programmed death ligand 1 (PD-L1) and other biomarkers. We performed a systematic review and metanalysis of data from the current literature reporting on PD-L1 immunohistochemistry expression. A systematic search of publications in the electronic databases PubMed, Web of Science, and Scopus was conducted using the following terms: "PD-L1" and "angiosarcomas". A total of ten studies reporting on 279 cases were identified and included in the meta-analysis. The pooled prevalence of PD-L1 expression in CAS was 54% (95% CI 36-71%), with high heterogeneity (I
= 84.81%,
< 0.001). In sub-group analysis, the proportion of PD-L1 expression in CAS was significantly (
= 0.049) lower in Asian studies (ES = 35%, 95% CI 28-42%, I
= 0.0%,
= 0.46) than in European studies (ES = 71%, 95% CI 51-89%, I
= 48.91%,
= 0.12).
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