Low PD-L1 expression in immune cells predicts the presence of nodal metastasis in early invasive (pT1) colorectal cancer: a novel tool to tailor surgical treatment.

AIMS: The current criteria for surgical treatment after endoscopic resection of a pT1 colorectal carcinoma (CRC) are unsatisfactory because nodal involvement is rarely present. This study investigates the correlation between PD-L1 expression and nodal metastasis in pT1 CRCs to enable its use for tailoring surgical treatment after endoscopic removal. METHODS AND RESULTS: Histopathological features of 81 surgically resected pT1 CRC, 19 metastatic and 62 non-metastatic cases were assessed. PD-L1 expression was evaluated by immunohistochemistry (clone 22C3) and independently assessed by two pathologists using tumour proportion score (TPS), combined positive score (CPS) and immune cell score (ICS). The correlation between PD-L1 expression and nodal metastasis, the optimal cut-off values, interobserver agreement and impact upon patients' surgical management were determined. PD-L1 expression in terms of CPS and ICS independently correlated with lymph node metastasis (PD-L1CPS : OR = -2.5, 95% CI = -4.11 to -0.97, P = 0.008 and PD-L1ICS : OR = -1.85, 95% CI = -2.90 to -0.79, P = 0.004) and < 1.2 CPS and <1.3% ICS were identified as the optimal cut-off values to discriminate between metastatic and non-metastatic patients. In our cohort, the implementation of these cut-off values would have avoided a significant rate of unnecessary surgeries in pN0 patients (PD-L1CPS = 43.2; PD-L1ICS = 51.9%). Ultimately, PD-L1 evaluation showed good interpathologist concordance in absolute terms [PD-L1CPS interclass correlation coefficient (ICC) = 0.91; PD-L1ICS ICC = 0.793] and using the identified cut-off values (PD-L1CPS ICC = 0.848; PD-L1ICS ICC = 0.756). CONCLUSIONS: Our study shows that PD-L1 expression is an effective predictor of nodal status and could improve patient selection for surgery after endoscopic removal of pT1 CRCs.

FISH Diagnostic Assessment of MDM2 Amplification in Liposarcoma: Potential Pitfalls and Troubleshooting Recommendations.

MDM2 amplification represents the leading oncogenic pathway and diagnostic hallmark of liposarcoma, whose assessment is based on Fluorescence In Situ Hybridization (FISH) analysis. Despite its diagnostic relevance, no univocal interpretation criteria regarding FISH assessments of MDM2 amplification have been established so far, leading to several different approaches and potential diagnostic misinterpretations. This study aims to address the most common issues and proposes troubleshooting guidelines for MDM2 amplification assessments by FISH. We retrospectively retrieved 51 liposarcomas, 25 Lipomas, 5 Spindle Cell Lipoma/Pleomorphic Lipomas, and 2 Atypical Spindle Cell Lipomatous Tumors and the corresponding MDM2 FISH analysis. We observed MDM2 amplification in liposarcomas cases only (43 out of 51 cases) and identified three MDM2-amplified patterns (scattered (50% of cases), clustered (14% of cases), and mixed (36% of cases)) and two nonamplified patterns (low number of signals (82% of cases) and polysomic (18% of cases)). Based on these data and published evidence in the literature, we propose a set of criteria to guide MDM2 amplification analysis in liposarcoma. Kindled by the compelling importance of MDM2 assessments to improve diagnostic and therapeutic liposarcoma management, these suggestions could represent the first step to develop a univocal interpretation model and consensus guidelines.

Ependymomas.

Ependymal neoplasms are a heterogenous group of neoplasms arising from the progenitors of the cells lining the ventricular system and the spinal central canal. During the last few years, significant novel data concerning oncogenesis, molecular characteristics and clinical correlations of these tumours have been collected, with a strong relevance for their pathological classification. The recently published 5th edition of WHO Classification of Central Nervous System Tumours integrates this novel knowledge and represents a substantial update compared to the previous edition. Concerning supratentorial ependymomas, the previous RELA fusion-positive ependymoma has been renamed into ZFTA fusion-positive and the novel YAP1 fusion-positive ependymoma subtype has been added. Posterior fossa ependymomas should now be allocated either to the Type A or Type B subtypes based on molecular profiling or using the H3 K27me3 immunohistochemical surrogate. Regarding spinal ependymomas, a novel subtype has been added based on a distinctive molecular trait, presence of MYCN amplification, and on the unfavourable outcome. Finally, myxopapillary ependymoma is now classified as a grade 2 tumour in accordance with its overall prognosis which mirrors that of conventional spinal ependymomas. The aim of this review is to present these changes and summarize the current diagnostic framework of ependymal tumours, according to the most recent updates.

Molecular neuropathology: an essential and evolving toolbox for the diagnosis and clinical management of central nervous system tumors.

Molecular profiling has transformed the diagnostic workflow of CNS tumors during the last years. The latest WHO classification of CNS tumors (5th edition), published in 2021, pushed forward the integration between histopathological features and molecular hallmarks to achieve reproducible and clinically relevant diagnoses. To address these demands, pathologists have to appropriately deal with multiple molecular assays mainly including DNA methylation profiling and DNA/RNA next generation sequencing. Tumor classification by DNA methylation profiling is now a critical tool for many diagnostic tasks in neuropathology including the assessment of complex cases, to evaluate novel tumor types and to perform tumor subgrouping in hetereogenous entities like medulloblastoma or ependymoma. DNA/RNA NGS allow the detection of multiple molecular alterations including single nucleotide variations, small insertions/deletions (InDel), and gene fusions. These molecular markers can provide key insights for diagnosis, for example, if a tumor-specific mutation is detected, but also for treatment since targeted therapies are progressively entering the clinical practice. In the present review, a brief, but comprehensive overview of these tools will be provided, discussing their technical specifications, diagnostic value, and potential limitations. Moreover, the importance of molecular profiling will be shown in a representative series of CNS neoplasms including both the most frequent tumor types and other selected entities for which molecular characterization plays a critical role.

COVID-19 and Breast Cancer: Analysis of Surgical Management of a Large Referral Center during the 2020-2021 Pandemic Period.

BACKGROUND: Coronavirus disease-19 (COVID-19) has spread worldwide since December 2019 and was officially declared a pandemic in March 2020. Due to the rapid transmission and the high fatality rate, drastic emergency restrictions were issued, with a negative impact on routine clinical activities. In particular, in Italy, many authors have reported a reduction in the number of breast cancer diagnoses and critical problems in the management of patients who accessed the breast units during the dramatic first months of the pandemic. Our study aims to analyze the global impact of COVID-19 in the two years of the pandemic (2020-2021) on the surgical management of breast cancer by comparing them with the previous two years. METHODS: In our retrospective study, we analyzed all cases of breast cancer diagnosed and surgically treated at the breast unit of "Città della Salute e della Scienza" in Turin, Italy, making a comparison between the 2018-2019 pre-pandemic period and the 2020-2021 pandemic period. RESULTS: We included in our analysis 1331 breast cancer cases surgically treated from January 2018 to December 2021. A total of 726 patients were treated in the pre-pandemic years and 605 in the pandemic period (-121 cases, 9%). No significant differences were observed regarding diagnosis (screening vs. no screening) and timing between radiological diagnosis and surgery for both in situ and invasive tumors. There were no variations in the breast surgical approach (mastectomy vs. conservative surgery), while a reduction in axillary dissection compared to the sentinel lymph node in the pandemic period was observed (p-value < 0.001). Regarding the biological characteristics of breast cancers, we observed a greater number of grades 2-3 (p-value = 0.007), pT stage 3-4 breast cancer surgically treated without previous neoadjuvant chemotherapy (p-value = 0.03), and a reduction in luminal B tumors (p-value = 0.007). CONCLUSIONS: Overall, we report a limited reduction in surgical activity for breast cancer treatment considering the entire pandemic period (2020-2021). These results suggest a prompt resumption of surgical activity similar to the pre-pandemic period.

Exploring Psoriasis Inflammatory Microenvironment by NanoString Technologies.

Psoriasis is a chronic inflammatory skin disease whose molecular mechanisms and microenvironment are poorly understood. We performed gene expression analysis through the nCounter® PanCancer Immune Profiling Panel (NanoString Technologies, Seattle, WA, USA) on 22 FFPE punch biopsies from 19 psoriasis-affected patients. A subset of five cases was analyzed before (T0) and after 6 months (T6) of treatment with dimethyl fumarate (DMF) to address immune microenvironment changes. Molecular comparisons according to biopsy site and age of onset showed a different distribution of innate immune cells (mast cells, macrophages, NK cells, and DC cells) and pathways (complement regulation and transporter functions). The analysis according to PASI (Psoriasis Area and Severity Index) led to non-significant results, suggesting no link between molecular expression profile and clinical amount of skin disease. In DMF-treated patients, we observed a strong immunomodulatory effect after treatment: A subversion of exhausted CD8 T cells, NK CD56dim cells, Tregs, neutrophils, CD45+ cells, T cells, B cells, and macrophages was reported between the two analyzed time-points, as well as the reduction in pro-inflammatory pathways and molecules, including cytotoxicity, pathogen defense, antigen processing, adhesion, cell cycle, chemokines, cytokines, and interleukins. The inflammatory psoriatic microenvironment can be modulated using DMF with encouraging results, achieving an immune-tolerant and non-inflammatory condition through the regulation of both innate and adaptive immunity.

Modern Stereotactic Radiotherapy for Brain Metastases from Lung Cancer: Current Trends and Future Perspectives Based on Integrated Translational Approaches.

Brain metastases (BMs) represent the most frequent metastatic event in the course of lung cancer patients, occurring in approximately 50% of patients with non-small-cell lung cancer (NSCLC) and in up to 70% in patients with small-cell lung cancer (SCLC). Thus far, many advances have been made in the diagnostic and therapeutic procedures, allowing improvements in the prognosis of these patients. The modern approach relies on the integration of several factors, such as accurate histological and molecular profiling, comprehensive assessment of clinical parameters and precise definition of the extent of intracranial and extracranial disease involvement. The combination of these factors is pivotal to guide the multidisciplinary discussion and to offer the most appropriate treatment to these patients based on a personalized approach. Focal radiotherapy (RT), in all its modalities (radiosurgery (SRS), fractionated stereotactic radiotherapy (SRT), adjuvant stereotactic radiotherapy (aSRT)), is the cornerstone of BM management, either alone or in combination with surgery and systemic therapies. We review the modern therapeutic strategies available to treat lung cancer patients with brain involvement. This includes an accurate review of the different technical solutions which can be exploited to provide a "state-of-art" focal RT and also a detailed description of the systemic agents available as effective alternatives to SRS/SRT when a targetable molecular driver is present. In addition to the validated treatment options, we also discuss the future perspective for focal RT, based on emerging clinical reports (e.g., SRS for patients with many BMs from NSCLC or SRS for BMs from SCLC), together with a presentation of innovative and promising findings in translational research and the combination of novel targeted agents with SRS/SRT.

Prognostic Analysis of the IDH1 G105G (rs11554137) SNP in IDH-Wildtype Glioblastoma.

The G105G SNP (rs11554137) in the IDH1 gene is observed in about 10-15% of patients with a diffuse glioma. Data regarding its impact on gliomas are poor and partially conflicting, possibly due to the evolving classification of CNS tumors. The aim of this study was to investigate the G105G SNP prognostic significance in a homogenous cohort of IDH-wildtype glioblastomas, in agreement with the 2021 WHO classification. The study analyzed 211 patients by collecting several clinico-pathological and molecular characteristics, including the age, lesion localization, number of involved lobes, type of surgical treatment, disease outcome and MGMT promoter methylation status. PFS and DSS curves were plotted according to the Kaplan-Meier method and statistical analyses were performed using parametric and non-parametric tests. A total of 32 patients out of 211 (15.2%) were found to be G105G SNP carriers. No significant impact of the IDH1 G105G SNP on patients' outcomes was observed in terms of PFS and DSS, while MGMT promoter methylation and gross total resection resulted as key prognostic factors in our cohort as expected. No prognostic impact of the IDH1 G105G SNP was detected in this strict cohort of IDH-wildtype glioblastomas. Analysis of larger cohorts is warranted to address the sample size limitations.