Predictors of Recurrence and Progression in Poorly Differentiated Cutaneous Squamous Cell Carcinomas: Insights from a Real-Life Experience.

INTRODUCTION: Surgery represents the primary treatment option for cutaneous squamous cell carcinoma (cSCC) aiming for complete tumor resection (R0). Recurrence and metastasis significantly affect survival and outcomes, and poorly differentiated (G3) cSCC is associated with a higher risk of recurrence. However, the specific clinical and histopathological features that predict recurrence and progression in G3-cSCC remain unclear. METHODS: A retrospective analysis was conducted on a series of patients with primary G3-cSCC diagnosed at the Turin University Hospital between January 2016 and January 2021. After independent histological revision, logistic regression models were used to identify clinico-pathological predictors of cutaneous recurrence, lymphnode/metastatic progression, and both types of progression. RESULTS: Among the 161 G3-cSCC patients, 80.1% (129/161) showed no signs of local recurrence or metastatic progression, while 19.9% (32 patients) had progressed. In the univariate logistic regression, tumor clinical diameter, depth of infiltration (DOI), and lymphovascular invasion (LVI) were identified as significant predictors across the various types of progression (p < 0.05). In the context of multivariate logistic regression, distinct models proved to be significant. For skin recurrence, a 3-variable model incorporating DOI (OR 1.16, 95% CI, 1.01-1.35, p = 0.050), LVI (OR 3.61, 95% CI, 1.11-11.8, p = 0.034), and desmoplasia (OR 3.45, 95% CI, 1.25-9.5, p = 0.017) was selected. Regarding lymphnode/metastatic progression, a 3-variable model combining pT2 (OR 6.10, 95% CI, 1.15-32.35, p = 0.034), pT3 (OR 14.33, 95% CI, 2.79-73.63, p = 0.001), and LVI (OR 3.86, 95% CI, 1.10-13.62, p = 0.036) was identified. Lastly, a 2-variable model for both types of progression consisted of vertical tumor thickness (OR 5.45, 95% CI, 1.11-27.32, p = 0.039) and LVI (OR 1.15, 95% CI, 1.04-1.26, p = 0.006). CONCLUSION: Tumor size, DOI, and LVI were significant predictors of recurrence and metastatic progression. Notably, the size of histologically defined tumor-free margins did not affect the risk of recurrence, whilst LVI emerged as a key predictor of all forms of progression. These findings provide insights into risk stratification and suggest that close monitoring and potential adjuvant therapies, such as radiation therapy, may be necessary especially for patients with lymphovascular involvement.

Squamous cell histological transformation in a lung adenocarcinoma patient (hyper) progressing upon immunotherapy.

INTRODUCTION: In non-small cell lung cancer (NSCLC) histologic transformation upon immune checkpoint inhibitors (ICI) is rare. CASE PRESENTATION: We described the case of a patient with early-stage lung adenocarcinoma who relapsed after surgery. At the time of relapse, he received chemo-radiotherapy, followed by consolidation immunotherapy. After 3 cycles the patient experienced disease hyperprogression for onset of a new lung mass, which resulted in squamous cell carcinoma. The preservation of an atypical mutation in the v-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene in both the primary adenocarcinoma and the new squamous carcinoma suggests histological transformation, likely ICI-related. DISCUSSION: We reviewed similar cases in literature, highlighting common patterns and substantial differences. For a deeper insight into inherent biological mechanisms, re-biopsy in case of atypical ICI response should be encouraged.

Brain Metastases from Ovarian Cancer: Current Evidence in Diagnosis, Treatment, and Prognosis.

With this review, we provide the state of the art concerning brain metastases (BMs) from ovarian cancer (OC), a rare condition. Clinical, pathological, and molecular features, treatment options, and future perspectives are comprehensively discussed. Overall, a diagnosis of high-grade serous OC and an advanced disease stage are common features among patients who develop brain metastases. BRCA1 and BRCA2 gene mutations, as well as the expression of androgen receptors in the primary tumor, are emerging risk and prognostic factors which could allow one to identify categories of patients at greater risk of BMs, who could benefit from a tailored follow-up. Based on present data, a multidisciplinary approach combining surgery, radiotherapy, and chemotherapy seem to be the best approach for patients with good performance status, although the median overall survival (<1 year) remains largely disappointing. Hopefully, novel therapeutic avenues are being explored, like PARP inhibitors and immunotherapy, based on our improved knowledge regarding tumor biology, but further investigation is warranted.

Supramarginal resection of glioblastoma: 5-ALA fluorescence, combined intraoperative strategies and correlation with survival.

INTRODUCTION: Glioblastoma treatment requires a multidisciplinary approach involving oncologists, radiotherapists and surgeons. Surgery constitutes the initial step of the therapeutic strategy and its efficacy is dependent on the extent of resection (EOR). Over the last decade, the goal of surgical treatment was the resection of the contrast enhancement on T1 MRI, defined as gross-total resection (GTR). More recently, an increasing number of studies reports a positive impact on survival parameters of a more aggressive surgical strategy aiming to resect all peri-tumoral infiltrated areas. These areas are histologically characterized by the presence of pathological cells infiltrating normal white matter and surround the neoplastic core of glioblastoma identified by gadolinium enhancement in T1-weighted MR. Intuitively, the major risk of the so called supramarginal resection is related to the possibility of resecting functionally eloquent brain tissue. Several strategies have been proposed to maximize the safety of resection and minimize the occurrence of postoperative functional deficits. The aim of this review was to focus on the clinical impact of supramarginal resection of glioblastomas, highlighting the role of image-guided surgery combined with neuromonitoring to increase surgical safety and efficacy. EVIDENCE ACQUISITION: The MEDLINE database has been queried for the literature research. EVIDENCE SYNTHESIS: Ten studies matched the inclusion criteria, reporting a global number of 3221 patients. CONCLUSIONS: The current evidence suggests a positive correlation between a more extensive resection based on FLAIR abnormal areas and overall survival.

Tentorial Angioleiomyoma: A Rare Neurosurgical Entity. Case Report and Review of the Literature.

BACKGROUND: Angioleiomyoma (ALM) is a soft tissue neoplasm rarely described in the intracranial site. Because of their uncommon presentation, atypical neuroradiologic and pathologic features, ALMs are often misdiagnosed. CASE DESCRIPTION: We describe the neuroradiologic, clinical, and pathologic data of a 37-year-old male patient suffering from a tentorial ALM. He was admitted at our hospital because of a posterior cranial fossa mass. Magnetic resonance imaging (MRI) showed a left tentorial tumor, hypointense on T1-weighted sequences, with heterogeneous contrast enhancement after gadolinium injection ("salt-and-pepper" fashion) and slightly hyperintense signal on T2-weighted sequence. After surgery, pathological examination showed a tumor composed of several thick-walled blood vessels mixed with a population of deeply eosinophilic spindle-shaped smooth muscle cells arranged in bundles. Necrosis was absent. Neither cellular pleomorphism nor mitoses were detected. Immuno-histochemical analysis confirmed the smooth muscle phenotype of the spindle cell component: diffuse and strong positivity for alpha-smooth muscle actin, desmin, and h-caldesmon. Based on both morphologic and immunohistochemical findings, a diagnosis of primary intracranial ALM was rendered. CONCLUSIONS: We add to the literature the tenth case of this exceedingly rare tumor and submit that ALM should be suspected when a tentorial mass with a "flame-like" time-dependent pattern of contrast enhancement on MRI, a "salt-and-pepper" post-contrast appearance on MRI T1-weighted sequences, and a relation with large intracranial feeding vessels are present.

CircSMARCA5 Regulates VEGFA mRNA Splicing and Angiogenesis in Glioblastoma Multiforme Through the Binding of SRSF1.

Circular RNAs are a large group of RNAs whose cellular functions are still being investigated. We recently proposed that circSMARCA5 acts as sponge for the splicing factor Serine and Arginine Rich Splicing Factor 1 (SRSF1) in glioblastoma multiforme (GBM). After demonstrating by RNA immunoprecipitation a physical interaction between SRFS1 and circSMARCA5, we assayed by real-time PCR in a cohort of 31 GBM biopsies and 20 unaffected brain parenchyma controls (UC) the expression of total, pro-angiogenic (Iso8a) and anti-angiogenic (Iso8b) mRNA isoforms of Vascular Endothelial Growth Factor A (VEGFA), a known splicing target of SRSF1. The Iso8a to Iso8b ratio: (i) increased in GBM biopsies with respect to UC (p-value < 0.00001); (ii) negatively correlated with the expression of circSMARCA5 (r-value = -0.46, p-value = 0.006); (iii) decreased in U87-MG overexpressing circSMARCA5 with respect to negative control (p-value = 0.0055). Blood vascular microvessel density, estimated within the same biopsies, negatively correlated with the expression of circSMARCA5 (r-value = -0.59, p-value = 0.00001), while positively correlated with that of SRSF1 (r-value = 0.38, p-value = 0.00663) and the Iso8a to Iso8b ratio (r-value = 0.41, p-value = 0.0259). Kaplan-Meier survival analysis showed that GBM patients with low circSMARCA5 expression had lower overall and progression free survival rates than those with higher circSMARCA5 expression (p-values = 0.033, 0.012, respectively). Our data convincingly suggest that circSMARCA5 is an upstream regulator of pro- to anti-angiogenic VEGFA isoforms ratio within GBM cells and a highly promising GBM prognostic and prospective anti-angiogenic molecule.

Intraoperative Computed Tomography and Awake Craniotomy: A Useful and Safe Combination in Brain Surgery.

BACKGROUND: Awake surgery is an effective technique to improve safety in surgical resection of lesions involving eloquent areas of the brain. Intraoperative imaging guidance and neuronavigation are widely applied in neurosurgical procedures. However, data on the application of intraoperative imaging to awake craniotomies are limited. We report our experience with intraoperative computed tomography (i-CT) during awake surgery, focusing on technical feasibility and effectiveness. METHODS AND RESULTS: Four patients with a lesion located in an eloquent area of the brain-1 with a cavernous hemangioma, 1 with a high-grade glioma, and 2 with a low-grade glioma (LGG)-underwent awake surgery with neuronavigation guidance. In all patients, i-CT was used to evaluate the completeness of resection or the extent of residual tumor. Intraoperative ultrasound was also used during microsurgery to verify the presence of residual tumor. The use of i-CT us allowed to obtain updated images for neuronavigation and to correct for brain shift. CONCLUSIONS: i-CT in awake surgery is reliable and effective. It does not significantly affect the duration of surgery and does not add stress for the patient. The possibility to correct for brain shift also in awake patients can increase the precision and accuracy of surgery, particularly in cases of LGG, avoiding the resection of normal white matter or tumor remnants in noneloquent areas.

CircSMARCA5 Inhibits Migration of Glioblastoma Multiforme Cells by Regulating a Molecular Axis Involving Splicing Factors SRSF1/SRSF3/PTB.

Circular RNAs (circRNAs) have recently emerged as a new class of RNAs, highly enriched in the brain and very stable within cells, exosomes and body fluids. To analyze their involvement in glioblastoma multiforme (GBM) pathogenesis, we assayed the expression of twelve circRNAs, physiologically enriched in several regions of the brain, through real-time PCR in a cohort of fifty-six GBM patient biopsies and seven normal brain parenchymas. We focused on hsa_circ_0001445 (circSMARCA5): it was significantly downregulated in GBM biopsies as compared to normal brain tissues (p-value < 0.00001, student's t-test), contrary to its linear isoform counterpart that did not show any differential expression (p-value = 0.694, student's t-test). Analysis of a public dataset revealed a negative correlation between the expression of circSMARCA5 and glioma's histological grade, suggesting its potential negative role in the progression to malignancy. Overexpressing circSMARCA5 in U87MG cells significantly decreased their migration, but not their proliferation rate. In silico scanning of circSMARCA5 sequence revealed an enrichment in binding motifs for several RNA binding proteins (RBPs), specifically involved in splicing. Among them, serine and arginine rich splicing factor 1 (SRSF1), a splicing factor known to be a positive controller of cell migration and known to be overexpressed in GBM, was predicted to bind circSMARCA5 by three different prediction tools. Direct interaction between circSMARCA5 and SRSF1 is supported by enhanced UV crosslinking and immunoprecipitation (eCLIP) data for SRSF1 in K562 cells from Encyclopedia of DNA Elements (ENCODE). Consistently, U87MG overexpressing circSMARCA5 showed an increased expression of serine and arginine rich splicing factor 3 (SRSF3) RNA isoform containing exon 4, normally skipped in a SRSF1-dependent manner, resulting in a non-productive non-sense mediated decay (NMD) substrate. Interestingly, SRSF3 is known to interplay with two other splicing factors, polypyrimidine tract binding protein 1 (PTBP1) and polypyrimidine tract binding protein 2 (PTBP2), that positively regulate glioma cells migration. Collectively, our data show circSMARCA5 as a promising druggable tumor suppressor in GBM and suggest that it may exert its function by tethering the RBP SRSF1.

Cefaléia / eadache

Cefaléia é um dos sintomas mais comum na prática médica, sendo uma queixa usual no consultório médico de generalistas e de muitos especialistas. É considerada uma importante causa de falta ao trabalho ou diminuição da capacidade produtiva de muitas pessoas, interferindo na qualidade de vida e determinando um impacto socioeconômico importante, especialmente considerando custos aos serviços de saúde, perda de dias no trabalho e redução da eficiência do mesmo. Estima-se que 90 a 100% das pessoas terão algum tipo de dor de cabeça ao longo da vida . É com este pano de fundo que os autores deste artigo escrevem sobre a temática. O objetivo deste artigo é proporcionar aos médicos um melhor entendimento da cefaléia e uma maneira adequada de como abordar esse sintoma tão prevalente . Serão enfatizados os sinais de alerta que o clínico geral deverá ter em mente frente a um paciente com cefaléia, visando descartar doenças graves.