Maurizio Capuozzo

PIK3CA, which encodes the p110α catalytic subunit of phosphoinositide 3-kinase (PI3K), is one of the most frequently altered oncogenes in human cancer and a major driver of tumor initiation, progression, metastasis, and therapeutic resistance. Over the past two decades, advances in structural biology, cancer genomics, and translational research have substantially expanded our understanding of PIK3CA function and established the PI3K pathway as a clinically actionable therapeutic target. This review provides an overview of the structural organization and physiological functions of the PI3Kα complex, the molecular mechanisms underlying oncogenic activation, and the diverse spectrum of PIK3CA alterations across human malignancies. We also summarize the current landscape of PI3K-targeted therapies, highlighting both approved agents and emerging therapeutic strategies. Clinical evidence supports the rational integration of PI3K inhibitors with endocrine therapy, CDK4/6 inhibitors, MAPK pathway inhibitors, dual PI3K/mTOR inhibition, and immune checkpoint blockade. In addition, accumulating evidence indicates that PIK3CA plays a pivotal role in shaping the tumor immune microenvironment, providing a biological rationale for combining PI3K inhibition with immunotherapy. Finally, we discuss future directions in precision oncology, emphasizing integrated molecular profiling, liquid biopsy, single-cell and spatial technologies, functional genomics, and evolutionary approaches as complementary strategies to refine patient selection, overcome therapeutic resistance, and optimize clinical outcomes.

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases originating from hematopoietic stem cell transformation, characterized by the clonal proliferation of hematopoietic progenitors. A specific subset includes myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions, particularly involving PDGFR A or B, which are sensitive to TK inhibitor treatment. We report a case of a 21-year-old patient with a myeloproliferative/myelodysplastic neoplasm, presenting with hyperleukocytosis, anemia, thrombocytopenia, and elevated LDH. The peripheral blood smear showed hypogranular neutrophils, eosinophils, basophils, and myeloid precursors. The absence of BCR::ABL1 and mutations in JAK2, CALR, and MPL excluded common MPNs. Cytogenetic analysis revealed a rearrangement between chromosomes 5 and 14. FISH analysis confirmed an inverted insertion from chromosome 5 to chromosome 14, involving the PDGFRB gene. WGS and RNAseq identified a fusion between PDGFRB and CCDC88C, causing the constitutive activation of PDGFRB. The fusion gene was confirmed by sequencing. This allowed for targeted therapy with a tyrosine kinase inhibitor (TKI), leading to molecular remission monitored by RT-qPCR. This case highlights how a multidisciplinary approach can identify atypical transcripts in MPN, guiding targeted therapy with TK inhibitors, thus resulting in effective treatment and molecular remission.

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases originating from hematopoietic stem cell transformation, characterized by clonal proliferation of hematopoietic progenitors. A specific subset includes myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions, particularly involving PDGFR A or B, which are sensitive to TK inhibitor treatment. We report a case of a 21-year-old patient with a myeloproliferative/ myelodysplastic neoplasm, presenting with hyperleukocytosis, anemia, thrombocytopenia, and elevated LDH. Peripheral blood smear showed hypogranular neutrophils, eosinophils, basophils, and myeloid precur-sors. Absence of BCR::ABL1 and mutations in JAK2, CALR, and MPL ex-cluded common MPNs. Cytogenetic analysis revealed a rearrangement between chromosomes 5 and 14. FISH analysis confirmed an inverted insertion from chromosome 5 to chromosome 14, involving the PDGFRB gene. WGS and RNAseq identified a fusion between PDGFRB and CCDC88C, causing constitutive activation of PDGFRB. The fusion gene was confirmed by sequencing. This allowed for targeted therapy with a tyrosine kinase inhibitor (TKI), leading to molecular remission monitored by RT-qPCR. This case demonstrates how a multidisciplinary approach can identify atypical transcripts in MPN, guiding targeted therapy with TK inhibitors, resulting in effective treatment and molecular remission.

Colorectal cancer (CRC) is among the most prevalent malignancies worldwide, representing the second leading cause of cancer-related mortality and accounting for approximately 2 million new cases and nearly half a million deaths annually. Global age-standardized incidence rates are highest in Australia/New Zealand and other Western countries, and lowest in parts of sub-Saharan Africa and South Asia, reflecting variations in demographics, lifestyle exposures, and screening practices. Colon cancer constitutes the larger fraction of CRC cases, with rectal cancer contributing substantially, and early-onset CRC (<50 years) is increasing across both high-income and emerging regions. Established risk factors include age, hereditary syndromes, obesity, sedentary behavior, dietary patterns, metabolic disorders, and chronic inflammation, with notable distinctions between colon and rectal subsites. This narrative review provides a comprehensive overview of CRC epidemiology, molecular and genetic pathogenesis, staging, and modern therapeutic approaches, addressing colon and rectal cancers separately due to their distinct biology, clinical behavior, and treatment strategies. By integrating current knowledge on genetic drivers, systemic and local therapies, and patient stratification, the review aims to inform clinical practice, support clinical trial design, discuss ongoing challenges and future perspectives, and foster further research toward precision-guided management of CRC.

In recent years there has been increased interest in exploring the therapeutic efficacy of cannabis for the management of chronic pain among adult patients. However, the use of cannabis for chronic pain is still a matter of debate and uncertainty. This opinion paper carried out a short overview of the literature with the aim of evaluating data on efficacy and safety of cannabis-based medicines, to fill the existing gaps in understanding the role of cannabis in therapy and to identify the critical issues associated with their use. The analysis of existing literature has clearly highlighted the potential benefits of cannabis-based preparations for the management of chronic pain. However, several criticalities have been identified. These include the lack of standardization of preparations and the insufficient clinical evidence to establish cannabis as the therapy of choice for chronic pain. As a result, although the potential benefits of cannabis preparations for the management of chronic pain are clear, further research is needed to address existing limitations and establish a solid scientific basis, especially through real-world data collection.

Summary Background Biosimilar drugs offer a valuable opportunity for healthcare systems worldwide, providing significant cost savings and ensuring the same level of effectiveness and safety in the treatment of chronic conditions. These savings can be reinvested into continuous medical innovations. Methods A search was carried out to assess the use of key biosimilar medications across various therapeutic areas within an Italian health authority that serves a population of over 1 million people. Data on usage, costs, and the number of patients treated were obtained from the company databases. In addition, a comparison with the year 2022 was performed, aiming to identify any increase in the use of biosimilar drugs during 2023. Results The analysis of 2023 revealed that a large majority of the studied active ingredients are administered as biosimilar medications, with only a few exceptions. Resistance remains in the prescription of adalimumab and etanercept, with spending on the originators of close to 3 million euros. Conclusion The comparison between 2023 and 2022 highlighted the growing adoption of biosimilar medications. This positive trend suggests the potential for achieving full utilization in the near future. Such a result would significantly benefit the national healthcare system and the public, ensuring a healthcare approach that is both effective and sustainable.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with metastatic disease posing significant therapeutic challenges. While anti-EGFR therapy has improved outcomes for patients with RAS and BRAF wild-type tumors, resistance remains a major hurdle, limiting treatment efficacy. The concept of negative hyperselection has emerged as a refinement of molecular profiling, identifying additional genomic alterations—such as HER2 and MET amplificationsand MAP2K1 mutations—that predict resistance to anti-EGFR agents. Studies incorporating these expanded assessments have demonstrated that nearly half of patients with RAS/BRAF wild-type tumors harbor alternative resistance biomarkers, underscoring the need for expanded selection criteria. Liquid biopsies, particularly circulating tumor DNA (ctDNA) analysis, have revolutionized precision oncology by providing a minimally invasive, real-time assessment of tumor dynamics. ctDNA-based hyperselection enables the detection of resistance-associated alterations, guiding treatment decisions with greater accuracy than conventional tissue biopsies. Recent trials support the predictive value of ctDNA-defined negative hyperselection, revealing superior outcomes for patients stratified through liquid biopsy. This narrative review explores the evolving role of molecular hyperselection in first-line anti-EGFR therapy, emphasizing the integration of ctDNA to refine patient selection, enhance therapeutic efficacy, and pave the way for personalized treatment strategies in metastatic CRC.

Hypercholesterolemia is a major risk factor in the development of cardiovascular diseases. Statins have been the primary treatment for reducing LDL cholesterol for years; however, adverse events related to their use have led to the development of alternative therapies, such as ezetimibe, bempedoic acid, and PCSK9 inhibitors, including alirocumab, evolocumab, and inclisiran. The study is aimed at comparing the consumption and costs of lipid-lowering drugs in the first half of 2023 (21,446,011.54 DDD and 10,974,495.47 €) and 2024 (19,493,540.71 DDD and 12,260,634.95 €) to assess the economic impact of new therapies in the management of dyslipidemia and adherence to guidelines. Dispensing data, without access to patient data, were collected from private community pharmacies and hospital and district pharmacies. Drug consumption was measured using the ATC classification system and the defined daily dose (DDD). The study revealed a trend toward a reduction in the use of traditional statin monotherapy and an increase in more recent and combined therapies. Statins showed a significant reduction from 42% in the first half of 2023 to 30% in the first half of 2024. Combined therapies, such as statins with ezetimibe, showed no change in trend, maintaining a 17% share in both periods. New therapies, such as PCSK9 inhibitors, demonstrated an increase from 33% in the first half of 2023 to 40% in the first half of 2024, while bempedoic acid, either as monotherapy or in combination with ezetimibe, remained below 2%. In recent years, the treatment of dyslipidemia has seen the introduction of many therapeutic alternatives. Bempedoic acid, recently introduced and less expensive, when used as an adjunct therapy with statins and ezetimibe, could reduce side effects and improve therapeutic efficacy without immediately resorting to higher-cost injectable drugs such as evolocumab, alirocumab, and inclisiran. Monitoring prescription trends and costs is essential to maintain the sustainability of the healthcare system, enabling investments in innovation and effective therapies without waste.