Clinical relevance of exosome-derived microRNAs in Ovarian Cancer: Looking for new tumor biological fingerprints.

Specific tumor-derived extracellular vesicles, called exosomes, are considered as potential key players in cross-talk between immune system and tumor microenvironment in several solid tumors. Different studies highlighted the clinical relevance of exosomes in ovarian cancer (OC) for their role in early diagnosis, prognosis, chemoresistance, targeted therapy. The exosomes are nanosize vesicles carrying lipids, proteins, and nucleic acids. In particular, exosomes shuttle a wide spectrum of microRNAs (miRNAs) able to induce phenotypic reprogramming of target cells, contributing to tumor progression. In this review, we will discuss the promising role of miRNAs shuttled by exosomes, called exosomal miRNAs (exo-miRNAs), as potential biomarkers for early detection, tumour progression and metastasis, prognosis, and response to therapy in OC women, in order to search for new potential biological fingerprints able to better characterize the evolution of this malignancy and provide a clinically relevant non-invasive approach useful for adopting, in future, personalized therapeutic strategies.

KIT/PDGFRA Variant Allele Frequency as Prognostic Factor in Gastrointestinal Stromal Tumors (GISTs): Results From a Multi-Institutional Cohort Study.

BACKGROUND: The patient selection for optimal adjuvant therapy in gastrointestinal stromal tumors (GISTs) is provided by nomogram based on tumor size, mitotic index, tumor location, and tumor rupture. Although mutational status is not currently used to risk assessment, tumor genotype showed a prognostic influence on natural history and tumor relapse. Innovative measures, such as KIT/PDGFRA-mutant-specific variant allele frequency (VAF) levels detection from next-generation sequencing (NGS), may act as a surrogate of tumor burden and correlate with prognosis and overall survival of patients with GIST, helping the choice for adjuvant treatment. PATIENTS AND METHODS: This was a multicenter, hospital-based, retrospective/prospective cohort study to investigate the prognostic role of KIT or PDGFRA-VAF of GIST in patients with radically resected localized disease. In the current manuscript, we present the results from the retrospective phase of the study. RESULTS: Two-hundred (200) patients with GIST between 2015 and 2022 afferent to 6 Italian Oncologic Centers in the EURACAN Network were included in the study. The receiver operating characteristic (ROC) curves analysis was used to classify "low" vs. "high" VAF values, further normalized on neoplastic cellularity (nVAF). When RFS between the low and high nVAF groups were compared, patients with GIST with KIT/PDGFRA nVAF > 50% showed less favorable RFS than patients in the group of nVAF ≤ 50% (2-year RFS, 72.6% vs. 93%, respectively; P = .003). The multivariable Cox regression model confirmed these results. In the homogeneous sub-population of intermediate-risk, patients with KIT-mutated GIST, the presence of nVAF >50% was statistically associated with higher disease recurrence. CONCLUSION: In our study, we demonstrated that higher nVAF levels were independent predictors of GIST prognosis and survival in localized GIST patients with tumors harboring KIT or PDGFRA mutations. In the cohort of intermediate-risk patients, nVAF could be helpful to improve prognostication and the use of adjuvant imatinib.

Theranostic biomarkers and PARP-inhibitors effectiveness in patients with non-BRCA associated homologous recombination deficient tumors: Still looking through a dirty glass window?

Breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) deleterious variants were the first and, still today, the main biomarkers of poly(ADP)ribose polymerase (PARP)-inhibitors (PARPis) benefit. The recent, increased, numbers of individuals referred for counseling and multigene panel testing, and the remarkable expansion of approved PARPis, not restricted to BRCA1/BRCA2-Pathogenic Variants (PVs), produced a strong clinical need for non-BRCA biomarkers. Significant limitations of the current testing and assays exist. The different approaches that identify the causes of Homologous Recombination Deficiency (HRD), such as the germline and somatic Homologous Recombination Repair (HRR) gene PVs, the testing showing its consequences, such as the genomic scars, or the novel functional assays such as the RAD51 foci testing, are not interchangeable, and should not be considered as substitutes for each other in clinical practice for guiding use of PARPi in non-BRCA, HRD-associated tumors. Today, the deeper knowledge on the significant relationship among all proteins involved in the HRR, not limited to BRCA, expands the possibility of a successful non-BRCA, HRD-PARPi synthetic lethality and, at the same time, reinforces the need for enhanced definition of HRD biomarkers predicting the magnitude of PARPi benefit.

The significance of tissue-agnostic biomarkers in solid tumors: the more the merrier?

INTRODUCTION: To date, several emerging biomarkers have gained considerable interest in the field of predictive molecular oncology. The advent of precision medicine has led to the development of innovative drugs targeting rare molecular pathways independently from histology, defined as tissue-agnostic drugs. AREAS COVERED: Although there is a lot of promise for this new tissue-agnostic model in the oncological scenario, crucial issues from both the diagnostic and therapeutic standpoint are emerging. This review aims to critically examine the role of tissue-agnostic biomarkers in different solid tumors, focusing on the prevalence and methods of detection of agnostic biomarkers together with drug approvals to guide clinicians in this evolving landscape. EXPERT OPINION: To strengthen the framework for tissue-agnostic approvals, the dialogue between regulatory, industrial, and academic parties should be intensified. Critical questions include the development of an efficient network system that can overcome the heterogeneity of patients' inclusion criteria along with the increasingly difficult interpretation of next-generation sequencing (NGS) profiling technologies. Cost-effectiveness and risk-benefit studies are needed in the national context considering the modalities of access to diagnostic tests and reimbursement of treatments.

Prognostic role of soluble PD-1 and BTN2A1 in overweight melanoma patients treated with nivolumab or pembrolizumab: finding the missing links in the symbiotic immune-metabolic interplay.

Individual response to immune checkpoint inhibitors (ICIs) is currently unpredictable in patients with melanoma. Recent findings highlight a striking improvement in the clinical outcomes of overweight/obese patients treated with ICIs, which seems driven, at least in part, by programmed cell death protein 1 (PD-1)-mediated T-cell dysfunction. A putative role of butyrophilins (BTNs) is under investigation as a novel mechanism of cancer immune evasion and obesity-associated inflammation. This study investigates the role of baseline plasma levels of soluble PD-1 (sPD-1), soluble programmed cell death ligand 1 (sPD-L1), BTN2A1 (sBTN2A1), BTN3A1 (sBTN3A1), along with body mass index (BMI), as predictive biomarkers of immunotherapy response in metastatic melanoma patients treated with nivolumab or pembrolizumab as first-line treatment. In all, 41 patients were included in the study. The baseline plasma level of sPD-1 was significantly lower, and the sBTN2A1 was significantly higher, in long-responder patients to nivolumab or pembrolizumab (median sPD-1: 10.3 ng/ml versus 16.6 ng/ml, p = 0.001; median sBTN2A1: 4.4 ng/ml versus 3.77 ng/ml, p = 0.004). Lower levels of sPD-1 and higher levels of sBTN2A1 were also significantly associated with better overall response rate. Notably, when we further stratified the study cohort using BMI along with sPD-1, patients with BMI ⩾ 25 and sPD-1 < 11.24 ng/ml had longer time to treatment failure after PD-1 inhibitor than other subgroups of patients (p < 0.001). Circulating sPD-1 and sBTN2A1 detection, along with BMI, could give more insights into the immune-metabolic interactions underlying the benefit observed in overweight/obese patients, improving the use of dynamic, noninvasive, biomarkers for patient selection.

Navigating the liquid biopsy Minimal Residual Disease (MRD) in non-small cell lung cancer: Making the invisible visible.

Liquid biopsy has gained increasing interest in the growing era of precision medicine as minimally invasive technique. Recent findings demonstrated that detecting minimal or molecular residual disease (MRD) in NSCLC is a challenging matter of debate that need multidisciplinary competencies, avoiding the overtreatment risk along with achieving a significant survival improvement. This review aims to provide practical consideration for solving data interpretation questions about MRD in NSCLC thanks to the close cooperation between biologists and oncology clinicians. We discussed with a translational approach the critical point of view from benchside, bedside and bunchside to facilitate the future applicability of liquid biopsy in this setting. Herein, we defined the clinical significance of MRD, focusing on relevant practical consideration about advantages and disadvantages, speculating on future clinical trial design and standardization of MRD technology.

Clinical Potential of Circulating Cell-Free DNA (cfDNA) for Longitudinally Monitoring Clinical Outcomes in the First-Line Setting of Non-Small-Cell Lung Cancer (NSCLC): A Real-World Prospective Study.

BACKGROUND: Despite the increasing implementation of targeted and immunotherapy-based treatments, the prognosis of patients with advanced NSCLC remains dismal. We prospectively evaluated longitudinal plasma cfDNA kinetics as an early marker of therapeutic efficacy in patients with advanced NSCLC undergoing standard first-line treatments. METHODS: From February 2020 to May 2022, treatment-naïve patients with advanced NSCLC were consecutively enrolled at the Medical Oncology Unit of the Paolo Giaccone University Hospital, Palermo (Italy). We quantified cfDNA in terms of ng/µL using a QubitTM dsDNA HS Assay Kit. The agreement between the cfDNA and radiologic response was evaluated from baseline (T0) to the radiologic evaluation (T1). RESULTS: A total of 315 liquid biopsy samples were collected from 63 patients at baseline, with a total of 235 paired plasma samples from 47 patients at disease re-evaluation. A fair concordance was observed between early and durable radiographic and cfDNA response (Cohen's kappa coefficient = 0.001); 11 and 18 patients receiving TKI (Pearson's chi-squared test = 4.278; Cohen's kappa coefficient = 0.039) and IO treatments (Pearson's chi-squared test = 7.481; Cohen's kappa coefficient = 0.006) showed a significant and durable association between cfDNA dynamics and the first radiologic evaluation, whereas among the 18 patients undergoing CT, no significant correlation was observed (Pearson's chi-squared test = 0.720; Cohen's kappa coefficient = 0.396). The ECOG-PS 2 patients presented with the mean baseline cfDNA levels 2.6-fold higher than those with ECOG-PS 0-1 (1.71 vs. 0.65 ng/µL; p = 0.105). CONCLUSIONS: Our real-world study demonstrates that quantitative changes in cfDNA values correlated with responses to therapy and relapse of disease in treatment-naïve patients with advanced NSCLC undergoing TKI- and IO-based treatments.

The diagnostic accuracy of PIK3CA mutations by circulating tumor DNA in breast cancer: an individual patient data meta-analysis.

Background: The circulating tumor DNA (ctDNA) diagnostic accuracy for detecting phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations in breast cancer (BC) is under discussion. We aimed to compare plasma and tissue PIK3CA alterations, encompassing factors that could affect the results. Methods: Two reviewers selected studies from different databases until December 2020. We considered BC patients with matched tumor tissue and plasma ctDNA. We performed meta-regression and subgroup analyses to explore sources of heterogeneity concerning tumor burden, diagnostic technique, sample size, sampling time, biological subtype, and hotspot mutation. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and the related area under the curve (AUC) were elaborated for the overall population and each subgroup. Results: The pooled analysis was carried out on 25 cohorts for a total of 1966 patients. The overall ctDNA sensitivity and specificity were 0.73 (95% CI: 0.70-0.77) and 0.87 (95% CI: 0.85-0.89). The AUC was 0.93. Pooled concordance, negative predictive value and positive predictive value values were 0.87 (95% CI: 0.82-0.92), 0.86 (95% CI: 0.81-0.90), and 0.89 (95% CI: 0.81-0.95) with pooled PLR, NLR, and DOR of 7.94 (95% CI: 4.90-12.86), 0.33 (95% CI: 0.25-0.45), and 33.41 (95% CI: 17.23-64.79), respectively. The pooled results consistently favored next-generation sequencing (NGS)- over polymerase chain reaction-based methodologies. The best ctDNA performance in terms of sensitivity, specificity, and AUC (0.85, 0.99, and 0.94, respectively) was observed in the low-time sampling subgroup (⩽18 days between tissue and plasma collection). Meta-regression and subgroup analyses highlighted sampling time as a possible major cause of heterogeneity. Conclusions: These findings reliably estimate the high ctDNA accuracy for the detection of PIK3CA mutations. A ctDNA-first approach for the assessment of PIK3CA mutational status by NGS may accurately replace tissue tumor sampling, representing the preferable strategy at diagnosis of metastatic BC in patients who present with visceral involvement and at least two metastatic lesions, primarily given low clinical compliance or inaccessible metastatic sites.

Extracellular Vesicles-ceRNAs as Ovarian Cancer Biomarkers: Looking into circRNA-miRNA-mRNA Code.

Ovarian cancer (OC) is one of the most lethal gynecologic malignancies in females worldwide. OC is frequently diagnosed at an advanced stage due to a lack of specific symptoms and effective screening tests, resulting in a poor prognosis for patients. Age, genetic alterations, and family history are the major risk factors for OC pathogenesis. Understanding the molecular mechanisms underlying OC progression, identifying new biomarkers for early detection, and discovering potential targets for new drugs are urgent needs. Liquid biopsy (LB), used for cancer detection and management, consists of a minimally invasive approach and practical alternative source to investigate tumor alterations by testing extracellular vesicles (EVs), circulating tumor cells, tumor-educated platelets, and cell-free nucleic acids. EVs are nanosize vesicles shuttling proteins, lipids, and nucleic acids, such as DNA, RNA, and non-coding RNAs (ncRNAs), that can induce phenotypic reprogramming of target cells. EVs are natural intercellular shuttles for ncRNAs, such as microRNAs (miRNAs) and circular-RNAs (circRNAs), known to have regulatory effects in OC. Here we focus on the involvement of circRNAs and miRNAs in OC cancer progression. The circRNA-microRNA-mRNA axis has been investigated with Circbank and miRwalk analysis, unraveling the intricate and detailed regulatory network created by EVs, ncRNAs, and mRNAs in OC.

BRCA1/2 variants of unknown significance in hereditary breast and ovarian cancer (HBOC) syndrome: Looking for the hidden meaning.

Hereditary breast and ovarian cancer syndrome is caused by germline mutations in BRCA1/2 genes. These genes are very large and their mutations are heterogeneous and scattered throughout the coding sequence. In addition to the above-mentioned mutations, variants of uncertain/unknown significance (VUSs) have been identified in BRCA genes, which make more difficult the clinical management of the patient and risk assessment. In the last decades, several laboratories have developed different databases that contain more than 2000 variants for the two genes and integrated strategies which include multifactorial prediction models based on direct and indirect genetic evidence, to classify the VUSs and attribute them a clinical significance associated with a deleterious, high/low or neutral risk. This review provides a comprehensive overview of literature studies concerning the VUSs, in order to assess their impact on the population and provide new insight useful for the appropriate patient management in clinical practice.

Can the tumor-agnostic evaluation of MSI/MMR status be the common denominator for the immunotherapy treatment of patients with several solid tumors?

Alterations in short-repetitive DNA sequences, known as microsatellite instability (MSI), can reflect deficiencies in Mismatch Repair (MMR) system which represents a major player in DNA integrity maintenance. The incidence of MSI-H/dMMR has been shown to be variable depending on the tumor type. Several studies confirmed that dMMR/MSI status, although less frequent than PD-L1 expression, may better predict response to immune-checkpoint inhibitors (ICIs) in patients with solid tumors. In October 2016, the FDA granted pembrolizumab as breakthrough therapy for the treatment of non-CRC, MSI-H/dMMR tumors, providing, for the first time, a tumor-agnostic indication. In the next future, the tissue-agnostic evaluation of MSI-H/dMMR could become the common denominator for the immunotherapy treatment of patients with different advanced solid tumors, in order to select patient subgroups which may benefit from this therapy. In this Review we provided an overview of the main clinical studies describing the association between MSI-H/dMMR tumors and immunotherapy response.

Exploring the Dynamic Crosstalk between the Immune System and Genetics in Gastrointestinal Stromal Tumors.

Gastrointestinal Stromal Tumors (GISTs) represent a paradigmatic model of oncogene addiction. Despite the well-known impact of the mutational status on clinical outcomes, we need to expand our knowledge to other factors that influence behavior heterogeneity in GIST patients. A growing body of studies has revealed that the tumor microenvironment (TME), mostly populated by tumor-associated macrophages (TAMs) and lymphocytes (TILs), and stromal differentiation (SD) have a significant impact on prognosis and response to treatment. Interestingly, even though the current knowledge of the role of immune response in this setting is still limited, recent pre-clinical and clinical data have highlighted the relevance of the TME in GISTs, with possible implications for clinical practice in the near future. Moreover, the expression of immune checkpoints, such as PD-L1, PD-1, and CTLA-4, and their relationship to the clinical phenotype in GIST are emerging as potential prognostic biomarkers. Looking forward, these variables related to the underlying tumoral microenvironment in GIST, though limited to still-ongoing trials, might lead to the potential use of immunotherapy, alone or in combination with targeted therapy, in advanced TKI-refractory GISTs. This review aims to deepen understanding of the potential link between mutational status and the immune microenvironment in GIST.

Is there any room for PD-1 inhibitors in combination with platinum-based chemotherapy as frontline treatment of extensive-stage small cell lung cancer? A systematic review and meta-analysis with indirect comparisons among subgroups and landmark survival analyses.

BACKGROUND: The addition of PD-L1 inhibitors to platinum-based chemotherapy (CT) has newly received United States Food and Drug Administration (FDA) approval in extensive stage-small cell lung cancer (ES-SCLC). PD-1 agents similarly improved survival rates, even if not yet supported by international regulatory agencies. The current work aims to assess different efficacy and safety profiles among chemoimmunotherapy plus immuno-oncology (CT+IO) approaches according to different immune checkpoint inhibitor (ICI) subtypes. MATERIAL & METHODS: We included in our meta-analysis six first-line randomised controlled trials (RCTs) comparing the association of single-agent ICI with CT versus CT alone in ES-SCLC. Pooled hazard ratios (HRs) and risk ratios (RRs) for progression-free survival (PFS), overall survival (OS), objective response rates (ORR), 12-month duration of response rate (DORR), disease control rate (DCR), treatment-related adverse events (TRAEs) and discontinuation rates (DRs) were obtained. Moreover, we performed indirect comparisons according to ICI subtypes, also among subgroups and landmark survival analyses. RESULTS: Although no ORR benefit was observed, our results showed how CT+IO significantly improved DORR, resulting in improved PFS and OS with no differences in TRAEs; however, CT+IO led to a significant increase in DR. Interestingly, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 1, the use of cisplatin, and the absence of brain metastases seem to be associated with a survival gain using CT+IO in ES-SCLC. Indirect comparisons suggested a slight advantage in favour of programmed cell death-1 (PD-1) and programmed death ligand 1 (PD-L1) over anti-CTLA-4 agents in terms of efficacy with no additional safety concerns. No further differences were observed between PD-1 and PD-L1 inhibitors among subgroups and landmark survival analyses with benefit trends towards anti-PD-1 in terms of DORR and DR. CONCLUSION: While confirming a survival advantage of CT+IO in selected patients, these results suggested the association of PD-1 inhibitors with CT as a viable option for novel therapeutic approaches in the frontline management of ES-SCLC. Further trials evaluating anti-CTLA-4 agents should be carefully studied in biomarker-selected patients.

Not all KIT 557/558 codons mutations have the same prognostic influence on recurrence-free survival: breaking the exon 11 mutations in gastrointestinal stromal tumors (GISTs).

Background: Although the gastrointestinal stromal tumor (GIST) genotype is not currently included in risk-stratification systems, a growing body of evidence shows that the pathogenic variant (PV) type and codon location hold a strong prognostic influence on recurrence-free survival (RFS). This information has particular relevance in the adjuvant setting, where an accurate prognostication could help to better identify high-risk tumors and guide clinical decision-making. Materials and Methods: Between January 2005 and December 2020, 96 patients with completely resected GISTs harboring a KIT proto-oncogene receptor tyrosine kinase (KIT) exon 11 PV were included in the study. We analyzed the type and codon location of the PV according to clinicopathological characteristics and clinical outcome; the metastatic sites in relapsed patients were also investigated. Results: Tumors harboring a KIT exon 11 deletion or deletion/insertion involving the 557 and/or 558 codons, showed a more aggressive clinical behavior compared with tumors carrying deletion/deletion/insertion in other codons, or tumors with duplication/insertion/single-nucleotide variant (SNV) (7-year RFS: 50% versus 73.1% versus 88.2%, respectively; p < 0.001). Notably, among 18 relapsed patients with 557 and/or 558 deletion or deletion/insertion, 14 patients (77.8%) harbored deletions simultaneously involving 557 and 558 codons, while only 4 patients (22.2%) harbored deletions involving only 1 of the 557/558 codons. Thus, when 557 or 558 deletions occurred separately, the tumor showed a prognostic behavior similar to the GIST carrying deletions outside the 557/558 position. Remarkably, patients with GISTs stratified as intermediate risk, but carrying the 557/558 deletion, showed a similar outcome to the high-risk patients with tumors harboring deletions in codons other than 557/558, or duplication/insertion/SNV. Conclusion: Our data support the inclusion of the PV type and codon location in routine risk prediction models, and suggest that intermediate-risk patients whose GISTs harbor 557/558 deletions may also need to be treated with adjuvant imatinib like the high-risk patients.

Is there any place for PD-1/CTLA-4 inhibitors combination in the first-line treatment of advanced NSCLC?-a trial-level meta-analysis in PD-L1 selected subgroups.

BACKGROUND: The advent of immuno-oncology (IO) represented a breakthrough in non-small cell lung cancer (NSCLC) therapy over the last few years. However, establishing the optimal therapeutic options among programmed death-ligand 1 (PD-L1) selected subgroups still addresses an unmet need in the clinical setting. METHODS: We performed a systematic review and finally included eleven first-line randomized controlled trials to compare efficacy and safety outcomes among first-line IO treatment strategies versus standard platinum-based chemotherapy (CT) according to PD-L1 expression level (<1%, 1-49%, ≥50%). Pooled hazard ratios (HRs) and risk ratios (RRs) for progression-free survival (PFS), overall survival (OS), objective response rates (ORR), treatment-related adverse events (TRAEs), and discontinuation rates were obtained. RESULTS: Our results demonstrated that among the different IO-based strategies (single-agent IO, Combo-IO, IO + CT) the IO + CT approach resulted in a significant increase of the ORR, albeit with no relevant improvement of survival in patients with PD-L1 ≥50%. As regards patients with negative PD-L1 expression, no significant differences in terms of activity and efficacy profile have been detected between the IO + CT and the dual checkpoint blockade. Of note, in the PD-L1 1-49% subgroup, the use of anti-PD-1 agents in association with CT led to a statistically significant gain in OS. As concerns safety, the dual checkpoint blockade seemed to be better tolerated than IO + CT. CONCLUSIONS: This meta-analysis suggested the current limited role of PD-1/CTLA-4 inhibitors combination in PD-L1-high and/or -low advanced NSCLC patients while emerging as a potentially effective and tolerable option in particular PD-L1 negative subgroups.

Detection of Germline Mutations in a Cohort of 139 Patients with Bilateral Breast Cancer by Multi-Gene Panel Testing: Impact of Pathogenic Variants in Other Genes beyond BRCA1/2.

Patients with unilateral breast cancer (UBC) have an increased risk of developing bilateral breast cancer (BBC). The annual risk of contralateral BC is about 0.5%, but increases by up to 3% in BRCA1 or BRCA2 pathogenic variant (PV) carriers. Our study was aimed to evaluate whether all BBC patients should be offered multi-gene panel testing, regardless their cancer family history and age at diagnosis. We retrospectively collected all clinical information of 139 BBC patients genetically tested for germline PVs in different cancer susceptibility genes by NGS-based multi-gene panel testing. Our investigation revealed that 52 (37.4%) out of 139 BBC patients harbored germline PVs in high- and intermediate-penetrance breast cancer (BC) susceptibility genes including BRCA1, BRCA2, PTEN, PALB2, CHEK2, ATM, RAD51C. Nineteen out of 53 positively tested patients harbored a PV in a known BC susceptibility gene (no-BRCA). Interestingly, in the absence of an analysis performed via multi-gene panel, a significant proportion (14.4%) of PVs would have been lost. Therefore, offering a NGS-based multi-gene panel testing to all BBC patients may significantly increase the detection rates of germline PVs in other cancer susceptibility genes beyond BRCA1/2, avoiding underestimation of the number of individuals affected by a hereditary tumor syndrome.

Analysis of systemic inflammatory biomarkers in neuroendocrine carcinomas of the lung: prognostic and predictive significance of NLR, LDH, ALI, and LIPI score.

BACKGROUND: Lung neuroendocrine carcinoma (NEC) is characterized by aggressive clinical behavior and lack of treatment advances. We evaluate the prognostic and the predictive roles of systemic inflammatory biomarkers in patient circulating blood: neutrophil-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), advanced lung cancer inflammation index (ALI), and the Lung Immune Prognostic Index (LIPI) score. METHODS: A total of 120 patients with small-cell lung cancer (SCLC) (n = 110) and large cell neuroendocrine carcinoma (LCNEC) (n = 10) were enrolled. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS while χ2 test was used for categorical data. RESULTS: NLR cutoff value was 1.93. NLR was measured before and after first-line chemotherapy; 25 (21%) patients had higher NLR (delta NLR >1), whereas NLR was lower in 37 (31%). At the univariate analysis, median OS was 12 months: OS for SCLC and LCNEC were 11 months and 14 months, respectively. OS had a prognostic positive value in patients with pre-treatment NLR <1.93 (p = 0.0002), LDH <600 U/L (p = 0,03) and ALI ⩾34 (p = 0,0065). At the multivariate analysis, Eastern Cooperative Oncology Group performance status, LDH levels and response after first-line chemotherapy were independently associated with OS. Median OS for good, intermediate, and poor LIPI was 15 months, 11 months, and 9 months, respectively(p = 0.091). Patients with higher NLR (>1.93) had an increased probability of tumor progression (p = 0.045, χ2 test). CONCLUSION: This study demonstrated that systemic inflammatory biomarkers could facilitate the understanding of survival differences in the clinical management of lung NEC patients, underlying the need for prospective biomarker-driven studies in the immune checkpoint inhibitors setting.

Hereditary Breast and Ovarian Cancer in Families from Southern Italy (Sicily)-Prevalence and Geographic Distribution of Pathogenic Variants in BRCA1/2 Genes.

Recent advances in the detection of germline pathogenic variants (PVs) in BRCA1/2 genes have allowed a deeper understanding of the BRCA-related cancer risk. Several studies showed a significant heterogeneity in the prevalence of PVs across different populations. Because little is known about this in the Sicilian population, our study was aimed at investigating the prevalence and geographic distribution of inherited BRCA1/2 PVs in families from this specific geographical area of Southern Italy. We retrospectively collected and analyzed all clinical information of 1346 hereditary breast and/or ovarian cancer patients genetically tested for germline BRCA1/2 PVs at University Hospital Policlinico "P. Giaccone" of Palermo from January 1999 to October 2019. Thirty PVs were more frequently observed in the Sicilian population but only some of these showed a specific territorial prevalence, unlike other Italian and European regions. This difference could be attributed to the genetic heterogeneity of the Sicilian people and its historical background. Therefore hereditary breast and ovarian cancers could be predominantly due to BRCA1/2 PVs different from those usually detected in other geographical areas of Italy and Europe. Our investigation led us to hypothesize that a higher prevalence of some germline BRCA PVs in Sicily could be a population-specific genetic feature of BRCA-positive carriers.

Moving the Target on the Optimal Adjuvant Strategy for Resected Pancreatic Cancers: A Systematic Review with Meta-Analysis.

Combination regimens have shown superiority over single agents in the adjuvant treatment of resected pancreatic cancer (PC), but there are no data supporting definition of the best regimen. This work aimed to compare the efficacy and safety of mFOLFIRINOX, gemcitabine+capecitabine, and gemcitabine+nab/paclitaxel in PC patients. A meta-analysis was performed for direct comparison between trials comparing combination regimens and gemcitabine monotherapy. Subsequently, an indirect comparison was made between trials investigating the efficacy and safety of mFOLFIRINOX, gemcitabine+capecitabine, and gemcitabine+nab/paclitaxel because of the same control arm (gemcitabine). A total of three studies met the selection criteria and were included in our indirect comparison. Indirect comparisons for efficacy outcomes showed a benefit in terms of DFS (disease-free survival)/EFS (event-free survival)/RFS (relapse-free survival) for both mFOLFIRINOX versus gemcitabine+capecitabine (HR 0.69, 95% CI 0.52-0.91) and versus gemcitabine+nab/paclitaxel (HR 0.67, 95% CI 0.50-0.90). No significant advantage was registered for OS (overall survival). Indirect comparisons for safety showed an increase in terms of G3-5 AEs (with the exception of neutropenia) for mFOLFIRINOX versus gemcitabine+capecitabine (RR 1.24, 95% CI 1.03-1.50), while no significant differences were observed versus gemcitabine+nab/paclitaxel. According to our results, mFOLFIRINOX is feasible and manageable and could represent a first option for fit PC resected patients.

TTF-1/p63-Positive Poorly Differentiated NSCLC: A Histogenetic Hypothesis from the Basal Reserve Cell of the Terminal Respiratory Unit.

TTF-1 is expressed in the alveolar epithelium and in the basal cells of distal terminal bronchioles. It is considered the most sensitive and specific marker to define the adenocarcinoma arising from the terminal respiratory unit (TRU). TTF-1, CK7, CK5/6, p63 and p40 are useful for typifying the majority of non-small-cell lung cancers, with TTF and CK7 being typically expressed in adenocarcinomas and the latter three being expressed in squamous cell carcinoma. As tumors with coexpression of both TTF-1 and p63 in the same cells are rare, we describe different cases that coexpress them, suggesting a histogenetic hypothesis of their origin. We report 10 cases of poorly differentiated non-small-cell lung carcinoma (PD-NSCLC). Immunohistochemistry was performed by using TTF-1, p63, p40 (ΔNp63), CK5/6 and CK7. EGFR and BRAF gene mutational analysis was performed by using real-time PCR. All the cases showed coexpression of p63 and TTF-1. Six of them showing CK7+ and CK5/6- immunostaining were diagnosed as "TTF-1+ p63+ adenocarcinoma". The other cases of PD-NSCLC, despite the positivity for CK5/6, were diagnosed as "adenocarcinoma, solid variant", in keeping with the presence of TTF-1 expression and p40 negativity. A "wild type" genotype of EGFR was evidenced in all cases. TTF1 stained positively the alveolar epithelium and the basal reserve cells of TRU, with the latter also being positive for p63. The coexpression of p63 and TTF-1 could suggest the origin from the basal reserve cells of TRU and represent the capability to differentiate towards different histogenetic lines. More aggressive clinical and morphological features could characterize these "basal-type tumors" like those in the better known "basal-like" cancer of the breast.