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.

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.

Next-Generation Sequencing of Circulating Tumor DNA Can Optimize Second-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer after Progression on anti-EGFR Therapy: Time to Rethink Our Approach.

BACKGROUND: Management of Ras wild-type colorectal cancer (CRC) patients upon disease progression after the successful use of targeted treatment with anti-EGFR monoclonal antibodies and backbone chemotherapy remains a clinical challenge. SUMMARY: Development of treatment resistance with prevalence of preexisting RAS mutated clones, RAS mutation conversion, truncation of extracellular receptor domains as well as HER2 and MET amplification are molecular events that can be difficult to follow without the use of sophisticated laboratory techniques. The clinical hurdle of re-biopsy and tumor heterogeneity can be overcome by the implementation of next-generation sequencing (NGS) to analyze circulating tumor DNA (ctDNA) and identify druggable mutations or recovery of RAS-wildness. In this opinion paper, we summarize with critical thinking the clinical approach to be followed after the failure of first-line treatment in Ras wild-type CRC tumors with the use of NGS. Rechallenge with anti-EGFR inhibitors, in case of persistent or recovery of RAS-wildness, and targeted approach of specific mutations (BRAF inhibitors), amplifications (anti-Her2 treatment), or fusion proteins (NTRK inhibitors) can by guided by the use of NGS. The use of NGS platforms for serial analysis of ctDNA is an important step to better understand the molecular landscape of metastatic CRC and guide clinical decisions. KEY MESSAGES: NGS should be considered a mainstay in clinical practice for the management of CRC patients and health authorities should consider reimbursing its use in the appropriate clinical settings.

Immunotherapy Efficacy in the Initial Lines of Treatment in Advanced Upper Gastrointestinal Malignancies: A Systematic Review of the Literature.

Background: The therapeutic role of immune checkpoint inhibitors (ICIs) has represented the cutting edge of clinical research in upper gastrointestinal (GI) malignancies, with these agents now included in the armamentarium of treatment options for advanced gastric and esophageal cancers. Methods: We performed a systematic literature review and pooled analysis to map out the currently available robust clinical evidence for the use of ICIs in upper GI cancers. Immunotherapy (IO), either as monotherapy or in combination with chemotherapy, and its role in first-line, maintenance, and second-line settings, as well as in specific clinical and biological subgroups, were critically appraised. All statistical tests were 2-sided. Results: ICIs, in combination with chemotherapy, have provided statistically significant overall survival benefit in the first-line setting in gastric and gastro-esophageal adenocarcinomas (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.76 to 0.90, P < .001; based on 4 studies) and esophageal squamous cell carcinoma (HR = 0.72, 95% CI = 0.64 to 0.81, P < .001; based on 3 studies), albeit with heterogeneous efficacy according to biomarker expression. Patients with esophageal squamous cell carcinoma, and in particular high programmed cell death ligand-1 expression, derive survival benefit when treated with IO in the second-line setting (HR = 0.74, 95% CI = 0.68 to 0.82, P < .001; for any level of programmed cell death ligand-1 expression). Clinical trials interrogating the combination of IO with chemotherapy in second-line treatment should be seriously considered in upper GI adenocarcinomas. The role of maintenance IO after initial disease control is still unclear and cannot be recommended. Impressive response rates and survival benefit from IO have been reported in patients with microsatellite instability-high tumors (HR = 0.33, 95% CI = 0.19 to 0.57, P < .001), and this warrants further prospective biomarker-driven studies. Conclusions: IO is changing the treatment landscape in upper GI malignancies. The rapidly developing evidence in the field needs to be critically appraised while further validation of the existing information from ongoing trials is awaited.

Ureteral carcinoma metastasizing to the testicle: Can misdiagnosis of orchiepididymitis be avoided?

Testicular metastases from ureteral carcinoma are rare and they are generally mimic orchiepididymitis. For this reason, these are associated to misleading diagnoses and cancer treatment delay. We believe that both timing and knowledge of genital blood and lymph reverse flow routes may represent two important parameters for avoiding misleading diagnoses and speed proper anticancer treatment. We describe a case and discuss pathophysiological data and relevant literature.

Interior Design: A New Perspective in Supportive Care of Patients with Acute Onset of Debilitating Diseases.

Background: Upon the onset of a debilitating rapidly evolving condition (such as cancer or a rapidly progressing myopathy, neuropathy, respiratory disease, or a severe traumatic injury), individuals have limited time to find a new home or make radical structural modifications in their residence. How the affected patients can continue sharing the same house with their families, while meeting their own special requirements, is thus rising as a critical issue. Household and daily routine rearrangements, either temporary or permanent, may be necessary, to ameliorate the life of patients with impairments, lasting for months or even years. Objectives: Interior design may provide a highly efficient "living" palliation for debilitating medical conditions directly at patients' home-site. Methods: Research of relevant literature, using keywords "debilitating conditions," "home care," "end of life care," "care of advanced cancer patients," "care of patients with mental disorders," "home care of covid-19 affected patients," and "care of patients with degenerative illnesses." Results: We found that patients and their relatives may not be aware of the probable interior design solutions to their daily life challenges, imposed by a disease-related impairment. In parallel, interior design experts may equally be unaware of these issues, as well as of who needs the available solutions.Similarly, medical and architectural sciences are not connected, eventually failing to meet patients' everyday needs. Conclusions: Interior architecture and health scientists are called to cooperate, aiming to provide a highly efficient and meaningful support to patients and families affected by unforeseen debilitating medical conditions.

Chemotherapy Associated Ovarian Failure.

As the incidence of malignancies in young adults is increasing, fertility preservation in cancer survivors arises as a major concern. Especially among female cancer patients, pregnancy rates are estimated to be 40% lower compared to women of the same age. Nowadays oncologists are to be preoccupied not only with their patients' successful treatment, but also with the maintenance of the potential of the latter to conceive and obtain children. Chemotherapy associated ovarian failure (COF), refers to disruption of ovarian function both as an endocrine gland and as a reproductive organ, due to previous exposure to chemotherapy agents. Although the underlying mechanism is not fully understood, it is supposed that chemotherapy agents may induce either DNA damage of premature ovarian follicle or early activation and apoptosis of them, resulting into early exhaustion of available follicle deposit. Various chemotherapy agents have been associated with COF with the highest incidence being reported for patients undergoing combination regimens. Although a variety of alternatives in order to maintain ovarian function and fertility in female cancer survivors are available, adequately established practices to do so are lacking. Thus, it is of major importance to investigate further and collect sufficient evidence, aiming to guide patients and physicians in everyday clinical practice.

Old Player-New Tricks: Non Angiogenic Effects of the VEGF/VEGFR Pathway in Cancer.

Angiogenesis has long been considered to facilitate and sustain cancer growth, making the introduction of anti-angiogenic agents that disrupt the vascular endothelial growth factor/receptor (VEGF/VEGFR) pathway an important milestone at the beginning of the 21st century. Originally research on VEGF signaling focused on its survival and mitogenic effects towards endothelial cells, with moderate so far success of anti-angiogenic therapy. However, VEGF can have multiple effects on additional cell types including immune and tumor cells, by directly influencing and promoting tumor cell survival, proliferation and invasion and contributing to an immunosuppressive microenvironment. In this review, we summarize the effects of the VEGF/VEGFR pathway on non-endothelial cells and the resulting implications of anti-angiogenic agents that include direct inhibition of tumor cell growth and immunostimulatory functions. Finally, we present how previously unappreciated studies on VEGF biology, that have demonstrated immunomodulatory properties and tumor regression by disrupting the VEGF/VEGFR pathway, now provide the scientific basis for new combinational treatments of immunotherapy with anti-angiogenic agents.

Fluoropyrimidine-induced toxicity and DPD deficiency.. A case report of early onset, lethal capecitabine-induced toxicity and mini review of the literature. Uridine triacetate: Efficacy and safety as an antidote. Is it accessible outside USA?

Fluoropyrimidine-based regimens are among the most commonly used chemotherapy combinations for the treatment of solid tumors. Several genetic polymorphisms that are implicated with fluoropyrimidine anabolism and catabolism have been associated with the development of life-threatening toxicities. Uridine triacetate is an FDA-approved antidote for 5-fluorouracil or capecitabine overdose and early-onset, life-threatening toxicity within 96 h of last chemotherapy dose. To date, it is not accessible for Greek patients as per the current summary of product characteristic's time restrictions. We report and discuss the course and outcome of capecitabine toxicity in a 66-year-old female colorectal cancer patient with heterozygous dihydropyrimidine dehydrogenase deficiency. This paper highlights the difficulty in timely access of this lifesaving medication for Greek and possibly other European patients.

Effect of Methamphetamine Hydrochloride on Pregnancy Outcome: A Systematic Review and Meta-analysis.

BACKGROUND: Methamphetamine hydrochloride is 1 of the most widespread psycho-stimulants in the world. Nevertheless, its effect on pregnant women and their neonates has not been investigated extensively. OBJECTIVE: To systematically review the literature for the effect of methamphetamine exposure during pregnancy to neonatal and pregnancy outcomes. MATERIALS AND METHODS: A meta-analysis of retrospective, case-control studies was conducted. Inclusion criteria were women who have used methamphetamine during pregnancy, determined by self-report, maternal or neonatal urine test, and/or meconium toxicology, compared with control women not taking methamphetamine. Main study outcomes were gestational age at birth, neonatal characteristics (birth weight, head circumference, body length), and prevalence of gestational hypertensive disorders. RESULTS: Eight studies involving 626 women taking methamphetamine during pregnancy and 2626 controls were included in the meta-analysis. Pregnancies complicated by the use of methamphetamine resulted in younger gestational age at birth (mean difference [MD] -0.90 weeks, 95% confidence interval [CI] -0.11, -1.69), lower birth weight (MD -245 g, 95% CI -137, -353), head circumference (MD -0.88 cm, 95% CI -0.48, -1.28), body length (MD -0.94 cm, 95% CI -0.55, -1.32), and Apgar score (MD -0.94, 95% CI -0.33, -1.54) compared with control pregnancies. On the contrary, there was no statistical difference on the incidence of pre-eclampsia (risk ratio [RR] 1.77, 95% CI 0.75, 4.14) and hypertensive complications (RR 1.62, 95% CI 0.37, 7.06). CONCLUSIONS: Use of methamphetamine during pregnancy results in a deterioration of neonatal somatometric characteristics (birth weight, head circumference, body length), but not in excessive pregnancy complications (hypertension).