Exploring RAS mutation incidence and temporal heterogeneity in metastatic colorectal cancer patients - a single-institution experience utilising circulating tumour DNA.

Introduction: Colorectal cancer (CRC) remains a significant global health challenge, ranking among the leading causes of neoplastic mortality. Despite transformative therapeutic advances, a considerable proportion of patients are diagnosed with metastatic disease, and 15-30% of those initially presenting with early-stage CRC eventually experience recurrence. Comprehensive molecular testing, especially the evaluation of microsatellite instability and mutations in KRAS/NRAS or BRAF genes, is essential upon diagnosis of stage IV disease, guiding treatment decisions. Material and methods: This manuscript explores the mutational landscape of KRAS and NRAS in patients with CRC, employing digital polymerase chain reaction (PCR) BEAMing for the detection of mutations in liquid biopsy. Our study enrolled patients with histologically confirmed CRC and stage IV disease, focusing on identifying mutations in KRAS and NRAS genes during various stages of therapy. Results: Evaluating baseline, midline, and progression samples, we found that 66.6% maintained consistent mutational status post-disease progression, while 33.3% exhibited a shift in mutational status. The application of techniques with high sensitivity, such as BEAMing Digital PCR, is pivotal for accurate circulating tumour DNA (ctDNA) mutation detection. The study underscores the significance of continuous molecular monitoring in guiding therapeutic decisions for patients with metastatic CRC. Conclusions: Our findings contribute to our understanding of the evolving mutational landscape and the potential clinical implications of ctDNA ana- lysis in the era of personalised cancer medicine.

Exploring Immune-Related Adverse Events: A Case of Febrile Neutropenia in a Melanoma Patient Receiving Immunotherapy.

Introduction: The introduction of immune checkpoint inhibitors (ICIs) has opened a new chapter in cancer treatment. Nevertheless, their use may result in immune-related adverse events (irAEs) with multifactorial determinants, complex mechanisms, and varying clinical implications. In specific cancer types, like melanoma, irAEs exhibit a complex relationship with patient outcomes. Case Presentation: We present a case of febrile neutropenia following ICI therapy in a patient with metastatic melanoma, underscoring the intricate clinical landscape associated with irAEs in the context of cancer immunotherapy. More specifically, a 68-year-old man was diagnosed with metastatic malignant melanoma and administered a combination of nivolumab and ipilimumab. However, after a single dose, the patient was hospitalized due to febrile neutropenia. The patient eventually recovered, but a diagnosis of myelosuppression related to prior immunotherapy led to treatment discontinuation. Subsequently, the patient transitioned to a second-line therapy. Conclusion: This case contributes to our comprehension of rare yet potentially severe hematological irAEs and their influence on immunotherapy outcomes. Such insights will guide future diagnostic and therapeutic strategies in the field of immunotherapy.

Longitudinal Muscle Biopsies Reveal Inter- and Intra-Subject Variability in Cancer Cachexia: Paving the Way for Biopsy-Guided Tailored Treatment.

In the rapidly evolving landscape of cancer cachexia research, the development and refinement of diagnostic and predictive biomarkers constitute an ongoing challenge. This study aims to introduce longitudinal muscle biopsies as a potential framework for disease monitoring and treatment. The initial feasibility and safety assessment was performed for healthy mice and rats that received two consecutive muscle biopsies. The assessment was performed by utilizing three different tools. Subsequently, the protocol was also applied in leiomyosarcoma tumor-bearing rats. Longitudinal muscle biopsies proved to be a safe and feasible technique, especially in rat models. The application of this protocol to tumor-bearing rats further affirmed its tolerability and feasibility, while microscopic evaluation of the biopsies demonstrated varying levels of muscle atrophy with or without leukocyte infiltration. In this tumor model, sequential muscle biopsies confirmed the variability of the cancer cachexia evolution among subjects and at different time-points. Despite the abundance of promising cancer cachexia data during the past decade, the full potential of muscle biopsies is not being leveraged. Sequential muscle biopsies throughout the disease course represent a feasible and safe tool that can be utilized to guide precision treatment and monitor the response in cancer cachexia research.

Ten-year clinical outcome, toxicity and compliance of dose-dense sequential adjuvant administration of cyclophosphamide & epirubicin followed by docetaxel in patients with early breast cancer: A hellenic cooperative oncology group observational study (HE 10/10) with concurrent investigation of significance of tumor infiltrating lymphocytes.

BACKGROUND: Dose-dense sequential (dds) chemotherapy has changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a currently widely used chemotherapeutic regimen. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8+ lymphocytes were also evaluated in the same cohort. PATIENTS AND METHODS: Totally, 1054 patients were prospectively enrolled in the current study with 1024 patients being eligible, while adequate tissue was available for 596 of them. TILs, CD8+ lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8+ lymphocytes in tumor stroma (sCD8) as well as the total number of CD8+ lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry. RESULTS: Within a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. Importantly, the 10-year DFS and OS rates were 78.4% (95% CI 75.0-81.5) and 81.7% (95% CI 79.0-84.1), respectively. Interestingly, higher CD8+ T cells as well as TILs in the tumor microenvironment were associated with an improved long-term survival outcome. CONCLUSIONS: In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of TILs and infiltrating CD8+ lymphocytes in BC patients with early-stage disease.

TAMs and PD-1 Networking in Gastric Cancer: A Review of the Literature.

BACKGROUND: Gastric cancer (GC) is one of the most common and aggressive types of cancer. Immune checkpoint inhibitors (ICIs) have proven effective in treating various types of cancer. The use of ICIs in GC patients is currently an area of ongoing research. The tumor microenvironment (TME) also seems to play a crucial role in cancer progression. Tumor-associated macrophages (TAMs) are the most abundant population in the TME. TAMs are capable of displaying programmed cell death protein 1 (PD-1) on their surface and can form a ligand with programmed death ligand 1 (PD-L1), which is found on the surface of cancer cells. Therefore, it is expected that TAMs may significantly influence the immune response related to immune checkpoint inhibitors (ICIs). AIM OF THE STUDY: Understanding the role of TAMs and PD-1/PD-L1 networking in GC. METHODS: A systematic review of published data was performed using MEDLINE (PubMed), Embase, and Cochrane databases. We retrieved articles investigating the co-existence of TAMs and PD-1 in GC and the prognosis of patients expressing high levels of PD-1+ TAMs. RESULTS: Ten articles with a total of 2277 patients were included in the systematic review. The examined data suggest that the expression of PD-L1 has a positive correlation with the infiltration of TAMs and that patients who express high levels of PD-1+ TAMs may have a worse prognosis than those who express low levels of PD-1+ TAMs. CONCLUSIONS: TAMs play a pivotal role in the regulation of PD-1/PD-L1 networking and the progression of GC cells. Nevertheless, additional studies are needed to better define the role of TAMs and PD-1/PD-L1 networking in GC.

Exploring a Rarity: Incidence of and Therapeutic Approaches for Neurological Complications and Hypophysitis in Cancer Patients on Immune Checkpoint Inhibitors-A Single-Center Study.

Immune checkpoint inhibitors, such as anti-PD-1 and anti-CTLA-4 inhibitors, have become the standard of care for many cancer types. However, they induce immune-related adverse events (irAEs), including neurotoxicity and hypophysitis. The incidence and outcomes of neurotoxicity and hypophysitis in patients treated with immune checkpoint inhibitors are not well established. We conducted a retrospective study of 812 patients with solid cancers who received immune checkpoint inhibitors at the University General Hospital of Ioannina between January 2018 and January 2023. We assessed demographic and clinical data, including the severity of symptoms, treatment regimen, other irAEs, resolution type and time, and death. Two patients experienced neurotoxicity and two hypophysitis. All four patients required inpatient administration and received corticosteroids or/and hormone replacement. Three patients responded to the initial therapy, experiencing full recovery, while one patient was corticosteroid-resistant, and immunoglobin G was administered. Two patients never received immunotherapy after their toxicity due to the severity of symptoms; one patient continued monotherapy with nivolumab, changing from combination therapy with ipilimumab-nivolumab, while the fourth patient continued his initial treatment with nivolumab. Our study suggests that the incidence of neurotoxicity and hypophysitis in patients treated with immune checkpoint inhibitors is low, but careful monitoring and prompt treatment with corticosteroids are necessary for effective management.

«Juvenile» oncology - a missing subspecialty. The experience of a reference cancer centre

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