Skin cancer is a prevalent and heterogenous disease with several subtypes, such as melanoma, basal cell carcinoma, and squamous cell carcinoma. Among them, melanoma is the most aggressive subtype, with a higher propensity to spread compared to most solid tumors. The application of OMICS approaches has revolutionized the field of melanoma research by providing comprehensive insights into the molecular alterations and biological processes underlying melanoma development and progression. This review aims to offer an overview of melanoma biology, covering its transition from primary to malignant melanoma, as well as the key genes and pathways involved in the initiation and progression of this disease. Utilizing online databases, we extensively explored the general expression profile of genes, identified the most frequently altered genes, and gene mutations, and examined genetic alterations responsible for drug resistance. Additionally, we studied the mechanisms responsible for immune checkpoint inhibitors resistance in melanoma.

Background and aims: Brain metastases are prevalent in the late stages of malignant melanoma. Multimodal therapy remains challenging. Patient-derived organoids (PDOs) represent a valuable pre-clinical model, faithfully recapitulating key aspects of the original tumor, including the heterogeneity and the mutational status. This study aimed to establish PDOs from melanoma brain metastases (MBM-PDOs) and to test the feasibility of using them as a model for in vitro targeted-therapy drug testing.Methods: Surgical resection samples from eight patients with melanoma brain metastases were used to establish MBM-PDOs. Samples were enzymatically dissociated followed by seeding into low-attachment plates to generate floating organoids. The MBM-PDOs were characterized genetically, histologically, immunohistologically and compared with the parental tissue. The MBM-PDO cultures were exposed to dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) followed by cell viability assessment.Results: Seven out of eight cases were successfully cultivated, maintaining the histological, immunhistological phenotype, and the mutational status of the parental tumors. Five out of seven cases harbored BRAF V600E mutations and were responsive to BRAF and MEK inhibitors in vitro. Two out of seven cases were BRAF wild type, one case harboring an NRAS mutation and the other harboring a KIT mutation, and both were resistant to BRAF and MEK inhibitor therapy. Conclusion:We successfully established PDOs from melanoma brain metastases surgical specimens, which exhibited a consistent histological and mutational profile with the parental tissue. Using FDA-approved BRAF and MEK inhibitors, our data demonstrates the feasibility of employing MBM-PDOs for targeted-therapy in vitro testing.

BRAF is one of the most frequently mutated oncogenes, with an overall frequency of about 50%. Targeting BRAF and its effector mitogen-activated protein kinase kinase 1/2 (MEK1/2) is now a key therapeutic strategy for BRAF-mutant tumors, and therapies based on dual BRAF/MEK inhibition showed significant efficacy in a broad spectrum of BRAF tumors. Nonetheless, BRAF/MEK inhibition therapy is not always effective for BRAF tumor suppression, and significant challenges remain to improve its clinical outcomes. First, certain BRAF tumors have an intrinsic ability to rapidly adapt to the presence of BRAF and MEK1/2 inhibitors by bypassing drug effects via rewired signaling, metabolic, and regulatory networks. Second, almost all tumors initially responsive to BRAF and MEK1/2 inhibitors eventually acquire therapy resistance via an additional genetic or epigenetic alteration(s). Overcoming these challenges requires identifying the molecular mechanism underlying tumor cell resistance to BRAF and MEK inhibitors and analyzing their specificity in different BRAF tumors. This review aims to update this information.

Background: The association of age at onset of CRC and prevalence of KRAS G12C mutation is unclear; Methods: Retrospective multicenter study evaluating metastatic CRC patients from January 2019 to July 2023 treated at Oncoclinicas units, tested for tissue-based KRAS/NRAS and BRAF mutations in a centralized genomics lab. Mismatch repair (MMR) status was retrieved from different labs and electronic medical records, as were patient demographics (age, gender) and tumor sidedness. Chi-square test was used to examine the association between clinical and molecular variables, with p value <0.05 being statistically significant; Results: A total of 858 cases were included. The median age was 63.7 years (range 22-95) and 17.4% were less than 50 years old at diagnosis of metastatic CRC. Male patients represented 50.3% of the population. Sidedness distribution was left-side 59.2%, right-side 36.8% and not specified 4%. Prevalence of KRAS mutation was 49.4% and NRAS mutation 3.9%. Among KRAS mutated tumors, the most common variants were G12V (27.6%) and G12D (23.5%), while KRAS G12C was less frequent (6.4%), which represented 3.1% of the overall population. BRAF mutant cases were 7.3%, most commonly V600E. Only 5 (<1%) non-V600E mutations were detected. MSI-high or dMMR was present in 14 cases (1.6%). In the age-stratified analysis, left-sidedness (p<0.001) and KRAS G12C mutation (p=0.046) were associated with younger age (<50 years). In the sidedness-stratified analysis, BRAF mutation (p=0.001) and MSI-high/dMMR status (p=0.009), were more common in right-sided tumors; Conclusions: Our data suggest that KRAS G12C mutations are more frequent in early-onset metastatic CRC. To the best of our knowledge, this is the largest cohort in the Latin American population with mCRC reporting RAS, BRAF and MSI/dMMR status.

Background: Biomarker profiles should represent a coherent description of the colorectal cancer (CRC) stage and its evolution. Methods: Using droplet digital PCR, we detected the allelic frequencies (AF) of KRAS, NRAS, BRAF and EGFR mutations from 60 tumors. We employed a pair-wise association approach to estimate the risk involving AF mutations as outcome variables for clinical data and as predicting variables for tumor-staging. We evaluated correlations between mutations AFs and also between the mutations and histopathology features (tumor staging, inflammation, differentiation and invasiveness). Results: KRAS G12/G13 mutations were present in all patients. KRAS Q61 was significantly associated with poor differentiation, high desmoplastic reaction, invasiveness (ypT4) and metastasis (ypM1). NRAS and BRAF were associated with the right-side localization of tumors. Diabetic patients had a higher risk to exhibit NRAS G12/G13 mutations. BRAF’s presence limited the invasiveness in the submucosa, co-existing with NRAS G12/G13 mutations. Conclusions: The associations we found and the mutational AF we reported may help to understand disease processes and may be considered as potential CCR biomarker candidates. In addition, we propose representative mutation panels associated with specific clinical and histopathological features of CRC, as a unique opportunity to refine the degree of personalization of CRC treatment.

From their discovery in 2002, BRAF mutations have been identified as clear drivers of oncogenesis in several cancer types. Currently, their incidence rate is nearly 7% of all solid tumors with BRAF V600E constituting approximately 90% of these diagnoses [1]. In melanoma, thyroid cancer, and histiocytic neoplasms, BRAF hotspot mutations are found at a rate of about 50%, while in lung and colorectal cancers they range from 3 to 10% of reported cases [2-5]. Though present in other malignancies such as breast and ovarian cancers, they constitute a small portion of diagnoses (<1%). Given their frequency along with advancements in screening technologies, various methods are used for the detection of BRAF-mutant cancers. Among these are targeted next-generation sequencing (NGS) on tumor tissue or circulating tumor DNA (ctDNA) and immunohistochemistry (IHC)-based assays. With advancements in detection technologies, several approaches have been taken for the treatment of BRAF mutant cancers. In this review we retrace the milestones that led to the clinical development of targeted therapies currently available for these tumors.

The purine nucleoside analogues cladribine and pentostatin are highly-active first-line therapeutic treatments for hairy cell leukemia (HCL), resulting in complete response rates of 80 to 90%. However, HCL patients continue to relapse, and sooner or later, most require subsequent lines of treatment. This report presents the relapsed patients with classic HCL who were treated with vemurafenib (mostly at the low dose of 240 mg twice daily for 16 weeks) combined with rituximab after the failure of several lines of therapy including cladribine with or without rituximab and moxetumomab pasudotox. Two patients achieved CR MRD (-) after combined treatment with vemurafenib and rituximab, with a hematologic response ongoing after 38 months from the end of treatment in one patient and a relapse of cytopenias occurring after 13 months in the other patient. A third patient normalized her blood counts and this hematologic response, which was not evaluated in the bone marrow at the end of treatment, was lost after 18 months. The last patient died due to infection and multi-organ failure, too early to verify response to vemurafenib. Two patients who had relapsed after vemurafenib and rituximab derived meaningful clinical benefit from retreatment with the same agents, but eventually relapsed again and started indefinite therapy with dabrafenib and trametinib with normalization of the blood counts despite heavy bone marrow infiltration in the only patient so far evaluable. The outcomes of these cases indicate that novel targeted agents, and in particular vemurafenib combined with rituximab, improve the prognosis of HCL patients, even those heavily pretreated with PNAs and moxetumomab pasudotox

Oleuropein (Ole), a secoiridoid glucoside present in Olea europaea leaves, gained the interest of many scientists thanks to its several biological properties, including the anticancer one. We verified whether Ole might potentiate cytotoxicity of conventional drugs used to treat melanoma, disclosing new potential therapeutic strategy. We tested the cytotoxic action of Ole alone or in combination with chemotherapeutics on A375 human melanoma cells. We found that Ole was able, at a dose of 500 μM, to stimulate apoptosis in melanoma cells, while at a non-toxic dose of 250 μM, it affected cell proliferation and induced the downregulation of pAKT/pS6 pathway. 250 μM Ole did not potentiate the effect of Vemurafenib (PLX4032), but it succeeded in increase the cytotoxic effect of Dacarbazine (DTIC). The mayor effect was found in the association between Ole and Everolimus (RAD001), also on PLX4032-resistant BRAF melanoma cells, possibly cooperating in the inhibition of pAKT/pS6 pathway. Of interest, an olive leaf extract enriched in equimolar Ole was more effective and able to further improve DTIC and, particularly, RAD001 efficacy on BRAF melanoma cells than Ole alone. Therefore, Ole represents a natural product able to potentiate a wide array of chemotherapeutics against BRAF melanoma cells affecting pAKT/pS6 pathway.

Despite the recent advances in melanoma therapy, the need for new targets and novel approaches to therapy is urgent. We previously reported melanoma actives that work via binding and downregulating spliceosomal proteins hnRNPH1 and H2. In a separate study, we reported that these compounds were non-toxic to Balb/C mice at 50 mg/kg suggesting their utility in in vivo studies. In the present study, we aimed to determine the therapeutic potential of these compounds by testing them in A375 cell-line derived xenograft in nu/nu mice. Animals were randomized into four groups (n=12/group) to receive subcutaneous administration of vehicle, 10 mg/kg vemurafenib, and 25 mg/kg 2155-14 and 2155-18 three times per week for 15 days along with a control group. The results revealed that both 2155-14 and 2155-18 significantly decreased the growth of A375 tumors, which was comparable to vemurafenib. These results were confirmed by tumor volume, weight, and histopathological examination. In conclusion, these results suggest a therapeutic potential of targeting spliceosomal proteins hnRNPH1 and H2.

In comparison to other human cancer types, malignant melanoma exhibits the greatest amount of heterogeneity. After DNA-based detection of the BRAF V600E mutation in melanoma patients, targeted inhibitor treatment is the current recommendation. This approach, however, does not take the abundance of the therapeutic target, i.e., the B-raf V600E protein, into consideration. As shown by immunohistochemistry, the protein expression profiles of metastatic melanomas do clearly reveal the existence of inter- and intra-tumor variability. Nevertheless, the technique is only semi-quantitative. To quantitate the mutant protein there is a fundamental need for more precise techniques that are aimed at defining the currently non-existent link between the levels of the target protein and subsequent drug efficacy. Using cutting-edge mass spectrometry combined with DNA and mRNA sequencing, the mutated B-raf protein within metastatic tumors was quantitated for the first time. B-raf V600E protein analysis revealed a subjacent layer of heterogeneity for mutation-positive metastatic melanomas. These were characterized into two distinct groups with different tumor morphologies, protein profiles and patient clinical outcomes. This study provides evidence that a higher level of expression for the mutated protein is associated with a more aggressive tumor progression. Our study design that is comprised of surgical isolation of tumors, histopathological characterization, tissue biobanking, and protein analysis may enable the eventual delineation of patient responders/non-responders and the subsequent therapy of malignant melanoma.

Background Adjuvant therapy has improved the clinical prognosis for postoperative melanoma patients. but the long-term efficacy of acral and mucosal types has not been fully evaluated in previous trials. This study aimed to assess the 3-year recurrence-free survival (RFS) and overall survival (OS) of melanoma treated with anti-PD-1antibody (Ab) or the combination of dabrafenib and trametinib. Methods We retrospectively analyzed both the 3-year recurrence-free survival (RFS) and overall survival (OS). Results The median RFS was 18.4 months, with a range of 0.69 to 36 months. The 3-year RFS of the acral and mucosal types was 28.1% and 38.5%, respectively. Baseline tumor thickness (TT) and acral type were associated with the RFS in subgroup analysis. Moreover, we classified 104 acral and non-acral cutaneous patients into the anti-PD-1 Abs or dabrafenib plus trametinib combined therapies cohort in multiple analyses. The acral subtype and TT were detected as important prognostic factors. In the 3-year OS, only tumor ulceration was associated with the OS in both univariate and multiple analyses. Conclusion This study suggests that both acral and mucosal types in the adjuvant setting are less effective than non-acral cutaneous melanoma at the 3-year RFS.

The Cancer Genome Atlas (TCGA) has classified papillary thyroid carcinoma (PTC) into indolent RAS-like and aggressive BRAF-like based on its distinct driver gene mutations. This study aimed to assess clinicopathology and pERK1/2 expression variations between BRAF-like and RAS-like PTCs and establish predictive models for BRAFV600E and RAS-mutated PTCs. A total of 222 PTCs underwent immunohistochemistry staining to assess pERK1/2 expression and Sanger sequencing to analyze the BRAF and RAS genes. Multivariate logistic regression was employed to develop prediction model. Independent predictors for the BRAFV600E mutation include a nuclear score of 3, the absence of capsules, an aggressive histology variant, and pERK1/2 levels exceeding 10% (X2=0.128, P&gt;0.05, AUC=0.734, P&lt;0.001). RAS mutation predictive model includes follicular histology variant and pERK1/2 expression &gt;10% (X2=0.174, P&gt;0.05, AUC=0.8, P&lt;0.001). We proposed using the prediction model concurrently with four potential combination group outcomes. PTC cases included in combination of low BRAFV600E-scoring group and high RAS-scoring group are categorized as RAS-like (adjOR=4.857, P=0.01, 95% CI=1.470-16.049). PTCs included in combination of high BRAFV600E-scoring group and low RAS-scoring group are categorized as BRAF-like PTCs (adjOR=3.091, P=0.001, 95% CI=1.594-5.995). The different prediction models indicate variations in biological behaviour between BRAF-like and RAS-like PTCs, necessitating adjustments in treatment approaches.

Background: This study assessed the nephrotoxicity of oral BRAF inhibitors (BRAFi), regorafenib (REG) and encorafenib (ENC), in metastatic colorectal cancer (mCRC), through an analysis of re-ports from the US Food and Drug Administration's Adverse Event Reporting System (FAERS) da-tabase. Methods: A descriptive and disproportional analyses were performed for all reports with ENC and REG as the primary suspect. Results: A total of 379 reports had at least one renal ADR, mainly related to REG (93.1%). Potential safety signals for REG particularly included chromaturia (n = 44; ROR = 12.00, CI 95% = 8.92-16.16; IC = 2.36, IC025-IC075 = 2.06-2.66), hydronephrosis (10; 8.70, 4.67-16.19; 1.85, 1.23-2.47), nephrotic syn-drome (7; 5.73, 2.73-12.03; 1.47, 0.73-2.21), renal impairment (53; 4.16, 3.17-5.45; 1.39, 1.12-1.66), dys-uria (19; 3.06, 1.95-4.81; 1.06, 0.61-1.52), renal failure (38; 1.66, 1.20-2.28; 0.49, 0.17-0.81), and acute kidney injury (AKI) (43; 1.46, 1.08-1.97; 0.37, 0.07-0.67). For ENC, consistent disproportionalities were observed for AKI (n = 11; ROR = 3.79, CI 95% = 2.09-6.90; IC = 1.32, IC025-IC075 = 0.72-1.91) and dysuria (4; 6.50, 2.43-17.39; 1.86, 0.88-2.85). Conclusions: These findings highlighted some not extensively reported renal ADRs that required further investigations to better characterize the safety profile of BRAFi in patients with mCRC.

The incidence of melanoma, the most lethal form of skin cancer, has increased due to ultraviolet exposure. The molecular characterization of melanomas has shown a high mutational burden led to the identification of some recurrent genetic alterations. BRAF gene is mutated in 40-50% of melanomas and its role in melanoma development is paramount. BRAF mutations confer constitutive activation of MAPK signalling. The large majority (abou 90%) of BRAF mutations occur at amino acid 600; the majority are BRAFV600E mutations and less frequently BRAFv600K, V600D and V600M. The introduction of drugs that directly target BRAF-mutant protein (BRAF inhibitors) and of agents that stimulate immune response through targeting of immune check inhibitor consistently improved the survival of melanoma BRAFV600-mutant patients with unresectable/metastatic disease. In parallel, studies in melanoma stage II-III patients with resectable disease have shown that adjuvant therapy with ICIs and/or targeted therapy improves PFS and RFS, but not OS compared to placebo; however, neoadjuvant therapy plus adjuvant therapy improved therapeutic response compared to adjuvant therapy alone.

Non-small-cell lung cancer (NSCLC) is the second most common cancer worldwide, resulting in 1.8 million deaths/year. Most of the patients are diagnosed with a metastatic disease. Central Nervous System is one of the major metastatic sites. Brain metastases are associated with severe neurological symptoms, shorter survival and worst clinical outcomes. Brain radiotherapy and systemic oncological therapies are currently used for controlling both cancer progression and neurological symptoms. Brain radiotherapy includes stereotactic brain ablative radiotherapy (SBRT) or whole brain radiotherapy (WBRT). SBRT is applied for single or multiple (≤ 4) small lesions (&lt; 3 cm), while WBRT represents the best treatment choice in case of multiple and large brain metastases. In both cases radiotherapy application can represent an overtreatment causing severe toxicities without achieving a significant clinical benefit. So far, some scores have been proposed to define the potential clinical benefits derived from brain radiotherapy. However, most of them are not well validated into clinical practice. In this article, by presenting a clinical case of a patient with advanced NSCLC carrying a BRAFV600E mutation and brain metastases, we review the variables as well as the potential applicable scores to be considered in order to predict clinical outcomes and benefits from brain radiotherapy in patients with NSCLC and brain metastases.

Non-small-cell lung cancer (NSCLC) is the second most common cancer worldwide, resulting in 1.8 million deaths/year. Most of the patients are diagnosed with a metastatic disease. Central Nervous System is one of the major metastatic sites. Brain metastases are associated with severe neurological symptoms, shorter survival and worst clinical outcomes. Brain radiotherapy and systemic oncological therapies are currently used for controlling both cancer progression and neurological symptoms. Brain radiotherapy includes stereotactic brain ablative radiotherapy (SBRT) or whole brain radiotherapy (WBRT). SBRT is applied for single or multiple (≤ 4) small lesions (&lt; 3 cm), while WBRT represents the best treatment choice in case of multiple and large brain metastases. In both cases radiotherapy application can represent an overtreatment causing severe toxicities without achieving a significant clinical benefit. So far, some scores have been proposed to define the potential clinical benefits derived from brain radiotherapy. However, most of them are not well validated into clinical practice. In this article, by presenting a clinical case of a patient with advanced NSCLC carrying a BRAFV600E mutation and brain metastases, we review the variables as well as the potential applicable scores to be considered in order to predict clinical outcomes and benefits from brain radiotherapy in patients with NSCLC and brain metastases.

Colorectal cancer (CRC) arises through a combination of genetic and epigenetic alterations that affect key pathways involved in tumor growth and progression. This review examines the major molecular pathways driving CRC, including Chromosomal Instability (CIN), Microsatellite Instability (MSI), and the CpG Island Methylator Phenotype (CIMP). Key mutations in genes such as APC, KRAS, NRAS, BRAF, and TP53 activate signaling pathways like Wnt, EGFR, and PI3K/AKT, contributing to tumorigenesis and influencing responses to targeted therapies. Resistance mechanisms, including mutations that bypass drug action, remain challenging in CRC treatment. The review highlights the role of molecular profiling in guiding the use of targeted therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitors. Novel combination treatments are also discussed as strategies to improve outcomes and overcome resistance. Understanding these molecular mechanisms is critical to advancing personalized treatment approaches in CRC and improving patient prognosis.

Background/Aim: To evaluate the association between baseline [18F]FDG-PET/CT tumor burden parameters and disease progression rate after first-line target therapy or immunotherapy in advanced melanoma patients. Materials and Methods: 44 melanoma patients who underwent [18F]FDG-PET/CT before first-line target therapy (28/50) or immunotherapy (16/50) were retrospectively analyzed. Whole-body and per-district metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated. Therapy response was assessed according to RECIST 1.1 on CT scan at 3 (early) and 12 (late) months. PET parameters were compared with Mann-Whitney test. Optimal cut-offs for predicting progression were defined using the ROC curve. PFS and OS were studied using Kaplan-Meier analysis. Results: Median(IQR) MTVwb and TLGwb were 13.1 mL and 72.4 respectively. Non-responders patients were 38/44, 26/28 and 12/16 at early evaluation, and in 33/44, 21/28 and 12/16 at late evaluation in the whole-cohort, target and immunotherapy subgroup respectively. At late evaluation, MTVbone and TLGbone were higher in non-responders compared to responder patients (all p<0.037) in the whole-cohort and target subgroup and also MTVwb and TLGwb (all p<0.022) in target subgroup. No significant differences were found for immunotherapy subgroup. No metabolic parameters were able to predict PFS. Controversy, MTVlfn, TLGlfn, MTVsoft+lfn, TLG-soft+lfn, MTVwb and TLGwb were significantly associated (all p<0.05) with OS in both the whole-cohort and target therapy subgroup. Conclusion: Higher values of whole-body and bone metabolic parameters were correlated with poorer outcome, while higher values of whole-body, lymph node and soft tissue metabolic parameters were correlated with OS.

Introduction: The repertoire of microRNAs (miRNAs) in thyroid carcinomas starts to be elucidated. Among differentiated thyroid carcinomas (DTC), papillary thyroid carcinoma (PTC) is the most common. The assessment of miRNAs expression may contribute to refine the pre-surgical diagnosis, in order to obtain a personalized and more effective treatment of patients. Aims: This study aims to evaluated 1) miRNAs expression in a series of DTC, and the association with the presence of selected genetic mutations, in order to improve diagnosis and predict biologic behavior of DTC/PTC. 2) the reliability of molecular tests in Ultrasound-guided Fine Needle Aspiration Cytology (US-FNAC) for a more precise preoperative diagnosis. Material and methods: This series includes 176 samples (98 cytology samples and 78 formalin-fixed paraffin embedded (FFPE) tissues) obtained from 106 patients submitted to surgery, being 13 benign lesions (controls) and 93 DTCs (cases). The microRNA expression was assessed for miR-146b, miR-221, miR-222, and miR-15a by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and the results were analyzed using the 2- ΔΔCT method, using miR16 as an endogenous control. The discriminative ability of miRNAs expression regarding PTC diagnosis was evaluated using the area under the Receiver Operating Characteristic Curve (AUC). The association of miRNAs expression, clinicopatological features and genetic alterations (BRAF, RAS and TERTp) was evaluated in PTCs. Results/Discussion: All the analyzed miRNAs showed a tendency to be over expressed in DTCs/PTCs when compared with benign lesions, both in cytology and histology samples. In cytology, miRNAs expression levels were higher in malignant than in benign tumors. In histology, corresponding discriminative abilities regarding PTC diagnosis were: miR-146b (AUC0.94, 95%CI 0.87-1), miR-221 (AUC0.79, 95%CI 0.68-0.9), miR-222 (AUC0.76, 95%CI 0.63-0.89) and miR-15a (AUC0.85, 95%CI 0.74-0.97). miR-146b showed 89% sensitivity (se) and 87% specificity (sp); mi-R221 se=68.4, sp=90; miR222 se=73, sp=70, and mi-R15a se=72, sp=80. MicroRNAs were associated with aggressive clinicopathological features and tumor progression in PTCs (p &lt; 0.05), particularly for miR-222. Our data reveals a significant association between higher expression levels of miR-146b, miR-221 and miR-222, with the presence of BRAF mutation (p&lt;0.001), and miR-146b (p=0.016) and miR-221 (p=0.010) with the presence of RAS mutation, suggesting an interplay of these mutations with miRNAs expression. Although this study has a relatively small sample size, over expression of miRNAs in cytology may contribute to a more precise preoperative diagnosis. The miRNAs showed a good discriminative ability in PTC diagnosis. The association between the miRNAs expression profile and genetic alterations results could be useful for an accurate diagnosis of DTCs/PTCs in FNAC.

Critical and progressive cachexia may be observed in numerous medical disciplines, but in patients with various diseases several pathways overlap (endocrine, inflammatory and kidney diseases, heart failure, cancer). A case-control analysis is presented of patients with initial immune-mediated thyroiditis complicated with cachexia, pulmonary pa-thology coexisting with opportunistic infection, finally diagnosed cancer (thyroid cancer, misdiagnosed as NSCLC). Contrary to other patients with lung cancer the presented pa-tients were not active smokers, exclusively women who developed cachexia with existing autoimmune process in the first phase. Furthermore, coexistence of short overall survival without cancer progression in the most seriously ill patients, correlation with sex (con-trary to history of smoking) and predisposition to mycobacterial disease are very sug-gestive. The unique sequence shed light on immune-mediated thyroid disease as a sub-clinical paraneoplastic process modified by various therapeutic regimens, however, with systemic consequences and a sequel, requiring holistic approach. Differential diagnosis of severe cachexia, adenocarcinoma with pulmonary localization and tuberculosis reac-tivation require analysis of immunological and genetic background. Contrary to highly specialized teams (e.g. lung cancer units) the immunotherapy and general medicine in aging populations require multidisciplinary observation, holistic and inquiring approach. Lack of differentiation, confusing bias as well as discrepancy in literature are the main obstacles in statistical research, that indicate correlation of common factors only. Such time-lapse case studies may be first to build evidence of a pathway and association be-tween immune parameters, comorbidity and cancer.

Introduction – Molecular tests can contribute to improve the preoperative diagnosis of thyroid nodules. Tests available are expensive and not adapted to different population. Aim – This study aimed to compare the cyto-histological genetic profile, and to evaluate the reliability of molecular tests on Ultrasound-guided Fine Needle Aspiration Cytology (US-FNAC) in accurately diagnosing differentiated thyroid carcinomas (DTCs) and predicting biologic behavior of papillary thyroid carcinomas (PTCs). Material and methods – The series included 259 patients with paired cyto-histological samples totalizing 518 samples. The genetic alterations were analyzed by PCR/Sanger sequencing. The association with clinicopathologic features was evaluated in PTCs. Results/Discussion – From the 259 patients included, histologies were 50 (19.3%) benign controls and 209 (80.7%) DTCs cases, from which 182 were PTCs; cytologies were 5.8% non-diagnostic, 18.2% benign, 39% indeterminate and 37.1% malignant. In histology, indeterminate nodules (n=101) were 22.8% benign and 77.2% malignant. Mutation frequencies in cytology and histology specimens were, respectively, TERTp: 3.7% vs. 7.9%; BRAF: 19.5% vs. 25.1%; RAS: 11% vs. 17.5%. The overall cyto-histological agreement of the genetic mutations was 94.9%, Cohen’s k=0.67, and in indeterminate nodules 95.7%, k=0.64. The identified mutations exhibited a discriminative ability in diagnosing DTC with a specificity of 100% for TERTp and BRAF, and of 94% for RAS, albeit with low sensitivity. TERTp and BRAF mutations were associated with aggressive clinicopathological features and tumor progression in PTCs (p<0.001). The obtained good cyto-histological agreement suggests that molecular analysis in US-FNAC may anticipate the genetic profile and the behavior of thyroid tumors, confirming malignancy and contributing to refer patients towards surgery.

Borderline ovarian tumors (BOTs) show intriguing characteristics distinguishing them from other ovarian tumors. This unique type of non-invasive neoplasms is characterized by atypical growth of epithelial cells, nuclear atypia, and a moderate-level mitotic activity that places BOTs between benign tumors and invasive cancers. Similar to invasive carcinomas, BOTs can be categorized into six histological subtypes based on the type of epithelial cells present. The most prevalent subtypes are serous and mucinous BOTs, whereas endometrioid, clear cell, seromucinous, and borderline Brenner tumors are diagnosed less often. Noticeably, molecular changes found in BOTs can vary on a case-by-case basis, which warrants further research on the molecular landscape of these tumors. Identifying carcinogenic mutations through molecular analysis and developing targeted therapies represent significant advancements in the diagnosis and treatment of ovarian malignancies. A growing body of evidence indicates that BOTs often remain clinically dormant for extended periods before a molecular trigger initiates increased cell replication, potentially leading to carcinoma development or recurrence. Continued research in this area is crucial for improving risk assessment and developing personalized treatment approaches. While molecular studies have contributed significantly to our understanding of BOT pathogenesis, substantial research is still required to elucidate the relationship between ovarian neoplasms and extraneous disease, identify accurate prognostic indicators, and develop targeted therapeutic approaches. The aim of the present systematic review was to analyze the spectrum of molecular changes found in BOTs and discuss their significance in the context of the overall therapeutic approach.