Nasopharyngeal carcinoma (NPC) is a prevalent malignant tumor of the head and neck, with approximately 70 % of patients being diagnosed at a locally advanced stage. Despite the responsiveness to radiotherapy and chemotherapy, the 5-year survival rate of locally advanced NPC (LANPC) remains at approximately 80 %. Hence, there is an urgent need for novel treatment strategies to improve the prognosis of patients with LANPC. Numerous studies have illustrated the efficacy of immune checkpoint inhibitors (ICIs) in recurrent/metastatic NPC. Hence, the potential of immunotherapy for LANPC is under investigation. Using the Web of Clinical Trials, we identified 84 relevant trials exploring immunotherapy for NPC, encompassing 17 trials focusing on ICIs for LANPC. Preliminary findings from several trials suggest that adding ICIs into the primary treatment for LANPC significantly enhances the objective response rate and progression-free survival, with manageable safety profiles. However, the type, dosage, and timing of integration (induction phase, concurrent phase, and adjuvant phase) of ICIs into standard primary treatment of LANPC varies among these trials and further researches are warranted. This review provides an overview of immunotherapy principles in NPC, discusses recent advances and challenges associated with ICIs in the primary treatment for LANPC derived from published and ongoing clinical trials, and outlines the current landscape of other immunotherapies in LANPC, such as adoptive cell therapy, immunomodulatory agents, and tumor vaccines in LANPC. These insights aim to inform clinical practice and guide future researches.

Natural killer (NK) cells and dendritic cells (DCs) are critical mediators of anti-cancer immune responses. In addition to their individual roles, NK cells and DCs are involved in intercellular crosstalk which is essential for the initiation and coordination of adaptive immunity against cancer. However, NK cell and DC activity is often compromised in the tumor microenvironment (TME). Recently, much attention has been paid to one of the major components of the TME, the cancer-associated fibroblasts (CAFs), which not only contribute to extracellular matrix (ECM) deposition and tumor progression but also suppress immune cell functions. It is now well established that CAFs support T cell exclusion from tumor nests and regulate their cytotoxic activity. In contrast, little is currently known about their interaction with NK cells, and DCs. In this review, we describe the interaction of CAFs with NK cells and DCs, by secreting and expressing various mediators in the TME of adult solid tumors. We also provide a detailed overview of ongoing clinical studies evaluating the targeting of stromal factors alone or in combination with immunotherapy based on immune checkpoint inhibitors. Finally, we discuss currently available strategies for the selective depletion of detrimental CAFs and for a better understanding of their interaction with NK cells and DCs.

Breast cancer stands as the most frequently diagnosed cancer and the primary cause of cancer-related mortality among women worldwide, including Italy. With the increasing number of survivors, many are enrolled in regular follow-up programs. However, adherence to recommendations from scientific societies (such as ASCO, ESMO, AIOM) for breast cancer follow-up management varies in daily clinical practice across different cancer centers, potentially resulting in unequal management and escalating costs. To address these concerns, the Italian Association of Multidisciplinary Oncology Groups (AIGOM) orchestrated a Consensus on early Breast Cancer follow-up utilizing the Estimate-Talk-Estimate methodology. Following the identification of 18 Items and 38 statements by a select Board, 46 out of 54 (85.1%) experts comprising a multidisciplinary and multiprofessional panel expressed their degree of consensus (Expert Panel). The Expert Panel underscores the potential for the multidisciplinary team to tailor follow-up intensity based on the individual risk of recurrence. In selected cases, the general practitioner may be recommended as the clinical lead for breast cancer follow-up, both after completion of adjuvant treatment and at early initiation of endocrine therapy in low-risk patients. Throughout follow-up, and alongside oncologic surveillance, the expert panel advises osteometabolic, cardiologic, and gynecologic surveillance for the early detection and management of early and late treatment toxicities. Moreover, preserving quality of life is emphasized, with provisions for psycho-oncologic support and encouragement to adopt protective lifestyle behaviors.

Dedifferentiated liposarcoma (DDLPS) is a malignant mesenchymal neoplasm in desperate need of novel therapeutic approaches. Often occurring in conjunction with well-differentiated liposarcoma (WDLPS), DDLPS can behave more aggressively and exhibits a significant risk for developing recurrence or metastatic disease when compared to its well-differentiated counterpart. A multidisciplinary approach is critically important, particularly for patients with localized disease, as disease presentations are often complex, and the management of patients has become increasingly nuanced as treatment approaches have become more refined. Expert pathology review and appropriate application of diagnostic molecular techniques are key components of DDLPS diagnosis and also reflect an improved understanding of the underlying pathogenesis of the disease. Systemic therapies remain limited for DDLPS, but novel therapies targeting important underlying molecular drivers have resulted in ongoing clinical trials aiming to improve outcomes for patients with advanced disease. In recognition of the increased activity and interest within the DDLPS field, a multidisciplinary group of nationally recognized experts in medical oncology, surgical oncology, radiation oncology, and pathology was convened to summarize key insights. This position paper highlights important points from the meeting and provides evidence-based recommendations for practicing clinicians.

Since the introduction of immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4 receptors, survival has improved significantly for patients with irresectable and metastatic skin cancer, including cutaneous squamous cell cancer and melanoma. However, systemic administration of these drugs is associated with immune related adverse events (irAEs), which can be severe, irreversible and even fatal. To reduce the risk of irAEs associated with systemic exposure to immunotherapeutic drugs, local administration of low doses could be considered. This systematic review provides an overview of early phase clinical trials with drugs that are currently under investigation for intratumoral administration in patients with melanoma and non-melanoma skin cancer.

Combining antibody-drug conjugate (ADCs) with immune checkpoint inhibitors (ICIs) is emerging as a promising treatment option to increase efficacy outcomes. However, concerns arise regarding the safety of these combinations, as some toxicities may overlap. Currently, there is still limited information about the safety profiles of this strategy.

Traditional chemotherapy and immunotherapy-based systemic treatments for locally advanced or metastatic cholangiocarcinoma have been associated with poor clinical outcomes driven partly by molecular heterogeneity promoting early treatment resistance and a higher toxicity profile associated with these regimens. Few patients are eligible for upfront surgical resection and clinical studies have been traditionally difficult to conduct due to the orphan nature of this disease. However, increasing use of genomic profiling in clinical practice have led to active investigations of aberrant albeit promising mechanistic therapeutic targets such as IDH-1, FGFRs, BRAF, HER-2 and NTRK. This review article aims to highlight the complex genomic landscape of this difficult-to-treat disease, followed by a discussion of evidence-based biological mechanisms that can be actioned using targeted agents. We explore the clinical rationale behind a targeted therapeutic strategy, the role of liquid biopsies in guiding clinical decisions and future treatment pathways for cholangiocarcinoma management. We also discuss the challenges and opportunities originating from recent clinical trials evaluating targeted treatments and our own institutional experience at UCLH that have aimed to address some of these biological complexities and have translated into improved patient outcomes via effective molecularly driven patient selection strategies. We also provide perspectives on emerging novel, next generation targeted inhibitors overcoming treatment resistance to previous targeted agents with demonstrated clinical value in a challenging patient population.

Neoadjuvant immune checkpoint blockade (ICB) combined with chemotherapy has improved survival outcomes in locally-advanced non-small cell lung cancer (NSCLC). However, its impact on surgery has not been fully elucidated. We performed a systematic review and meta-analysis to compare surgical outcomes between neoadjuvant chemoimmunotherapy and chemotherapy alone in resectable NSCLC. PubMed and Embase were searched to select randomized controlled trials (RCTs) evaluating neoadjuvant ICB therapy for resectable NSCLC. The risk difference (RD) and odds ratio (OR) of outcomes such as surgical and R0 resection rates, overall complication rates, treatment-related adverse events (TRAEs), and AEs leading to cancellation of surgery were pooled using the random-effect model meta-analysis. We also evaluated the correlations between overall survival (OS) and surgical and safety outcomes. Eight RCTs with 3,387 patients were analyzed. Neoadjuvant chemoimmunotherapy was associated with improved surgical resection (RD 4.52 %, 95 % confidence interval [CI] 0.95 %-8.09 %, p = 0.01) and R0 resection (RD 4.04 %, 95 % CI 1.69 %-6.40 %, p = 0.0008) without increasing overall complications (RD -0.13 %, 95 % CI -5.14 %-4.88 %, p = 0.96), but an increase in surgery cancellation due to AEs (RD 1.15 %, 95 % CI 0.25 %- 2.05 %; p = 0.01) and grade 3-4 TRAEs (RD 3.42 %, 95 % CI 0.33 %-6.52 %, p = 0.03). OS did not show a direct significant correlation with surgical outcomes or TRAEs. Neoadjuvant chemoimmunotherapy improves resection rates but increases high-grade TRAEs and AEs leading to surgery cancellation. Nevertheless, incorporating ICB into neoadjuvant approach appears reasonable by improving surgical outcomes, potentially leading to improved survival in patients with locally-advanced NSCLC.

Cutaneous malignant melanoma (CMM) is increasing in prevalence and possesses the highest mortality rate of any skin cancer. Positron Emission Tomography and Computed Tomography (PET-CT) may be utilised in either radiological staging or surveillance, primarily in stage III-IV disease. False positive (FP) results lead to patient distress, increased costs, and unnecessary follow-up. The FP rate in CMM literature varies widely, altering calculations of positive predictive value and has not undergone pooled meta-analytic.

Gliomas are the most common primary malignant brain tumours in adults. Despite decades of research into novel therapeutic approaches, the prognosis remains poor. PARP1-2 are critical for DNA repair, cell survival and genomic stability and PARP inhibition (PARPi) may be a promising therapeutic approach for gliomas. Inhibition of PARP activity leads to homologous recombination deficiency (HRD), which, in combination with DNA damage, results in cell death. This review summarises the current knowledge and future perspectives of PARPi in glioma. The available literature was reviewed using PubMed, recent major international oncology congresses were consulted, and ongoing clinical trials were searched using ClinicalTrials.gov. In translational research, PARPi have demonstrated a strong scientific rationale for their use in the treatment of glioma. They have been evaluated both alone and in combination with radiotherapy, temozolomide, anti-angiogenic agents, immunotherapy and other new drugs in newly diagnosed or recurrent glioma. Most studies were open-label, non-randomised, dose-escalation phase I-II trials. Early results show promising anti-tumour activity, and key challenges include identifying predictive biomarkers, elucidating synergistic effects in combination therapies, addressing the development of resistance, and managing hematological toxicity. In conclusion, early phase studies have shown promising anti-tumour activity of PARPi that should be confirmed in larger prospective and randomised trials. In addition, the development of novel PARPi with improved blood brain barrier (BBB) penetration and PARP inhibitor activity with new synergistic treatment combinations seems promising and needs to be further explored.

Primary acinic cell carcinoma (PACC) of the breast is a rare oncological entity that mimics acinar cell differentiation similar to that observed in salivary glands. This distinct subtype is characterized by low-grade malignancy and has only been documented in a limited number of cases. Despite its classification frequently as TNBC, PACC of the breast typically shows a comparatively favorable prognosis. Our study aims to enrich the current understanding of PACC through a comprehensive review of cases managed at our institution, analyzing their clinical, histopathological, and therapeutic profiles including chemotherapy and radiation therapy, and patient outcomes and allows us to compile a comprehensive dataset for in-depth analysis of treatment responses and long-term survival rates, contributing to a broader understanding of the disease's natural history.

About one third of patients with Non-Small Cell Lung Cancer (NSCLC) presents at diagnosis with localized or locally advanced disease amenable to curative surgical resection. Surgical operability refers to stage I to IIIA and selected stage IIIB NSCLC. One of the main challenges in the management of early-stage resectable NSCLC is the optimization of available therapeutic strategies to prevent local and distant disease relapse, thus improving survival outcomes. There is evidence supporting the clinical use of both adjuvant and neoadjuvant immunotherapy-based strategies for resected/resectable, stage IB-IIIA NSCLC. Available data from randomized phase III trials have led to the incorporation of several immune checkpoint blockers (ICBs) into the international guidelines for early-stage NSCLC. Preclinical rationale of targeting specific subsets of T-cells by acting early on immune checkpoint receptors (e.g., PD-(L)1 and CTLA-4) is strong. Recent evidence is in favor of the neoadjuvant approach alone or as a part of perioperative strategy, demonstrating survival benefit. Combining neoadjuvant chemotherapy and immunotherapy before surgery results in both pathologic complete response (pCR) and major pathologic response (MPR) improvement, and survival outcomes, with no major safety issues. In this review, we summarize the rationale behind neoadjuvant/perioperative immunotherapy strategies and, due to the clinical relevance of immunotherapy in resectable NSCLC, we provide current evidence of this cutting-edge approach among special populations including older adults, women, and oncogene addicted NSCLC. To conclude, we present future perspectives in the use of immunotherapy for operable NSCLC with a special focus on novel investigational combinations underway.

Human epidermal growth factor receptor 2 (HER2) overexpression and/or ERBB2 gene amplification occurs in approximately 15-20% of breast cancers and is associated with poor prognosis. While the introduction of HER2-targeted therapies has significantly improved survival in patients with HER2-positive metastatic breast cancer, the incidence of brain metastases has increased due to patients living longer. Current recommendations sequence treatments by line of therapy, as well as by the status of brain metastases in patients with HER2-positive breast cancer. However, in the third-line treatment setting and beyond, there is a lack of clarity of the preferred choice of therapy. In clinical practice, clinicians may also encounter challenging scenarios where the optimal therapeutic approach has not been defined by clinical studies, so there is a need for clarity in such situations. Two consensus meetings of expert oncologists (12 from Europe and one from Canada) were convened to discuss these scenarios. We subsequently developed this article to present an overview of current treatment recommendations for HER2-positive metastatic breast cancer and give practical guidance on addressing challenging scenarios in a real-world setting. Based on our clinical experience, we provide a unanimous consensus concerning the treatment of elderly patients as well as those with brain-only metastases, leptomeningeal disease, oligometastatic disease, central nervous system oligo-progressive disease or ERBB2-mutant disease. We also discuss how to combine HER2-targeted therapy with endocrine therapy in patients with HER2-positive/hormone-receptor-positive disease, considerations for potential discontinuation of HER2-targeted therapy in patients with long-term remission and how to treat patients whose metastatic biopsy no longer confirms their HER2-positive status.

Neoadjuvant chemoimmunotherapy (NACIT) has been shown to improve pathologic complete response (pCR) rates and survival outcomes in stage II-III triple-negative breast cancer (TNBC). Promising pCR rate improvements have also been documented for selected patients with estrogen receptor-positive (ER+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC). However, one size does not fit all and predicting which patients will benefit from NACIT remains challenging. Accurate predictions would be useful to minimize immune-related toxicity, which can be severe, irreversible, and potentially impact fertility and quality of life, and to identify patients in need of alternative treatments. This review aims to capitalize on the existing translational and clinical evidence on predictors of treatment response in patients with early-stage BC treated with neoadjuvant chemotherapy (NACT) and NACIT. It summarizes evidence suggesting that NACT/NACIT effectiveness may correlate with pre-treatment tumor characteristics, including mutational profiles, ER expression and signaling, immune cell presence and spatial organization, specific gene signatures, and the levels of proliferating versus quiescent cancer cells. However, the predominantly qualitative and descriptive nature of many studies highlights the challenges in integrating various potential response determinants into a validated, comprehensive, and multimodal predictive model. The potential of novel multi-modal approaches, such as those based on artificial intelligence, to overcome current challenges remains unclear, as these tools are not free from bias and shortcut learning. Despite these limitations, the rapid evolution of these technologies, coupled with further efforts in basic and translational research, holds promise for improving treatment outcome predictions in early HER2- BC.

Primary and acquired endocrine resistance remains a major issue in the treatment of hormone receptor positive breast cancer. Acquired resistance often results from estrogen receptor 1 (ESR1) mutations leading to estrogen independent estrogen receptor activation. Selective estrogen receptor degraders (SERDs) induce degradation of this receptor, thereby overcoming this resistance. The intramuscular administration and modest efficacy of fulvestrant, the first SERD, triggered development of oral, more potent SERDs. This narrative review gives an overview of the current evidence regarding this new drug class.

Patients with HER2-positive breast cancer have a significant risk of developing brain metastases (BrM), which have detrimental effects on survival outcomes and quality of life. Although there are several systemic treatment options available that may delay the appearance of BrM and secondary progression of previously treated BrM, there are still substantial unmet needs for this patient population and primary prevention remains elusive.

The PRODIGE-23 study showed a higher benefit for FOLFIRINOX (5-fluorouracil, irinotecan and oxaliplatin) as induction chemotherapy followed by long-course chemoradiotherapy (CTRT) respect to neoadjuvant CTRT alone both followed by total mesorectal excision (TME) in terms of disease-free survival (DFS) and overall survival (OS) in locally advanced rectal cancer (LARC). The added value of treatment intensification with irinotecan, over the doublet induction with fluoropyrimidine and oxaliplatin is still debated.

Third-generation EGFR tyrosine kinase inhibitor (TKIs) have revolutionized the treatment landscape for patients with non-small cell lung cancer (NSCLC) harboring EGFR activating mutations, with improved long-term outcomes compared to first-generation TKIs. Nevertheless, disease progression inevitably occurs, limiting osimertinib long-term efficacy. Indeed, the molecular biology underlying acquired resistance to first-line osimertinib is multifaceted and includes the emergence of on-target and off-target alterations. EGFR-C797S mutation represents the most frequent mechanism of on-target resistance and hinders drug binding to the target site. EGFR-independent resistance includes the activation of alternative signaling pathways, such as MET amplification and HER2 mutations, and histological transformation. In this setting, chemotherapy is the current therapeutic option, with modest clinical outcomes. Therefore, the development of novel therapeutic strategies to overcome resistance to osimertinib is a major challenge. In this setting, fourth-generation TKIs are emerging as an interesting therapeutic option to overcome on-target resistance. Preclinical drug development has led to the discovery of thiazole-amid inhibitors, which activity is mediated by the allosteric inhibition of EGFR, resulting in high specificity towards mutant-EGFR. Early phase 1/2 clinical trials are ongoing to elucidate their activity also in the clinical setting. Aim of this review is to provide a state-of-the-art analysis on preclinical development of fourth-generation EGFR-TKIs and promising preliminary clinical data.

This review focuses on the immune checkpoint inhibitors (ICIs) in the context of breast cancer (BC) management. These innovative treatments, by targeting proteins expressed on both tumor and immune cells, aim to overcome tumor-induced immune suppression and reactivate the immune system. The potential of this approach is the subject of numerous clinical studies. Here, we explore the key studies and emerging therapies related to ICIs providing a detailed analysis of their specific and combined use in BC treatment.

Ascites formation is a common complication of cancer with a significant symptomatic burden for patients. Malignant ascites (MA) is defined by the presence of tumor cells within the ascitic fluid. It does not only cause substantial morbidity, but is also associated with impaired survival. Considering the frequent occurrence of MA, it still represents a clinical challenge for physicians with limited therapy options, mainly comprising of the treatment of the primary tumor and effusion drainage. Particularly the lack of pathophysiological insight limits the development of effective, causative therapies. Causes of MA development such as lymphatic vessel obstruction and the effects of tumor secreted vascular endothelial growth factor (VEGF) have been known for decades. Novel research suggests that the intraperitoneal immune system may also induce and maintain MA accumulation. In this review, we assess current knowledge on the pathophysiology of MA and summarize available evidence of treatment approaches. Also, factors contributing to ascites formation without proof of tumor cells in the peritoneal cavity, defined as paramalignant ascites, with potential treatment strategies are discussed. We further focus on novel findings in the pathophysiology of MA that might lead to treatment improvement in the near future and discussed relevant knowledge gaps in this field.