The high morbidity and mortality of colorectal cancer (CRC) remain a worldwide challenge, despite the advances in prevention, diagnosis, and treatment. RAS alterations have a central role in the pathogenesis of CRC universally recognized both in the canonical mutation-based classification and in the recent transcriptome-based classification. About 40% of CRCs are KRAS mutated, 5% NRAS mutated, and only rare cases are HRAS mutated. Morphological and molecular correlations demonstrated the involvement of RAS in cellular plasticity, which is related to invasive and migration properties of neoplastic cells. RAS signaling has been involved in the initiation of epithelial to mesenchymal transition (EMT) in CRC leading to tumor spreading. Tumor budding is the morphological surrogate of EMT and features cellular plasticity. Tumor budding is clinically relevant for CRC patients in three different contexts: (i) in pT1 CRC the presence of tumor buds is associated with nodal metastasis, (ii) in stage II CRC identifies the cases with a prognosis similar to metastatic disease, and (iii) intratumoral budding could be useful in patient selection for neoadjuvant therapy. This review is focused on the current knowledge on RAS in CRC and its link with cellular plasticity and related clinicopathological features.

CONTEXT The oral glucose tolerance test (OGTT) is considered the most useful method for diagnosing active acromegaly and for patient follow-up after neurosurgery. Despite its widespread use, only a few small studies have so far focused on patients’ clinical features associated with different GH responsiveness to OGTT. OBJECTIVE We aimed to investigate the association between glucose-induced GH response and endocrine profiles, clinical manifestations, and response to therapy in a large cohort of patients with acromegaly. PATIENTS Based on GH response to the OGTT, patients were grouped as paradoxical (GH-Par) or non-paradoxical (GH-NPar), and their clinical and pathological features were compared in terms of pituitary tumor size, invasiveness, biochemical profiles, and response to therapy. RESULTS The study concerned 496 acromegalic patients. At diagnosis, GH-Par patients (n=184) were older than GH-NPar patients (n=312) (mean 44.1±13.7 years vs 40.5±12.7, p<0.01), and had smaller tumors (0.82 vs 1.57 cm³, p<0.01), that less frequently invaded the cavernous sinus (15% vs 27%, p<0.01). The GH-Par group also had a higher basal GH per volume ratio (14.3 vs 10.5 μg/L⋅cm³, p<0.05) and a lower incidence of hyperprolactinemia (17% vs 30%, p<0.01) than the GH-NPar patients. Importantly, the GH-Par group had a higher rate of remission in response to somatostatin analogs (52% vs 26%, p<0.01), and a more marked drop in IGF-1 and GH after six months of therapy. CONCLUSIONS Our data strongly suggest that serum GH responsiveness to oral glucose challenge reflects some significant biological features of pituitary tumors and the OGTT may have some prognostic value.

The use of adjuvant radiotherapy is controversial in patients with atypical meningiomas treated with gross total resection (GTR). This study aimed to determine whether clinico-pathological features could be helpful to predict the recurrence risk in this group of patients and to identify high-risk ones who could benefit from adjuvant treatment. We collected 200 patients with primary atypical meningiomas treated with GTR but with no adjuvant radiotherapy from 5 different centers. A risk score, formulated by assigning 1 point for the presence and 0 points for the absence of 5 high-risk parameters (male sex, parasagittal site, Simpson grade 3, mitotic index ≥ 6/10 HPF, and sheeting), was the most significant predictor of recurrence. A score ≥2 was associated with 4.7 risk of shorter disease-free survival (p < 0.0001). Our findings indicate that the presence of at least 2 clinico-pathological high-risk factors predicts recurrence of totally resected primary atypical meningiomas and could be helpful for identifying patients who could benefit from adjuvant radiotherapy.