TERT promoter mutations and the outcome of patients with advanced urothelial carcinoma treated by platinum-based chemotherapy or pembrolizumab.

BACKGROUND: TERT promoter mutation is one of the most common genomic alterations in urothelial carcinoma (UC). Its prognostic role on patients' outcomes is still not clear. METHODS: We performed a single-center retrospective analysis on patients with advanced UC treated with platinum-based chemotherapy or immunotherapy to assess the presence of somatic TERT-124[C>T] and TERT-146[C>T] mutations and their association with clinicopathologic factors and survival outcomes. Patients were assessed for Overall Survival (OS), Progression-Free Survival (PFS), and Overall Response Rate (ORR). RESULTS: We analyzed 45 UC tumors; 38 of them received first-line chemotherapy and 21 second-line pembrolizumab; 6 patients (13%) harbored -146 C > T TERTp mutation and 25 patients (56%)-124 C > T. The presence of TERT promoter mutations was associated with a higher rate of lower tract UC and a lower rate of synchronous or lymph node metastases. TERT wild-type patients showed higher 12- and 24-months OS-rates in the chemotherapy subgroup and 6-, 12- and 24-months OS rates in the pembrolizumab subgroup. The presence of TERT promoter mutations was also associated with a lower 6 months-PFS rate in patients receiving chemotherapy and in all the three time points in those treated by pembrolizumab. The ORRs of pembrolizumab were 21% and 71% in patients with or without TERT promoter mutations, respectively (p < 0.001). CONCLUSIONS: Our analysis suggests that the presence of TERT promoter mutations could negatively affect the outcome of UC patients treated by chemotherapy or pembrolizumab. This hypothesis should be further evaluated in wider cohorts.

"Paradoxical" p16 overexpression in cutaneous melanoma: Molecular and immunohistochemical analysis of a rare phenomenon with a focus on cell cycle regulatory molecules.

BACKGROUND: One of the most relevant genetic alterations in cutaneous melanoma (CM) is the biallelic inactivation/loss-of-heterozygosis (LOH) of cyclin-dependent kinase inhibitor 2 A (CDKN2A), which results in the immunohistochemical loss of p16 frequently found in CM. However, we recently described a rare case of dermal/deep-seated melanoma arising in giant congenital nevus (DDM-GCN) with p16 overexpression combined with p53 loss and tumor protein 53 (TP53) mutation. Herein, we reported a case series of CM with p16 overexpression and analyzed their clinicopathologic features, immunohistochemical expression of the cell cycle regulatory molecules (CCRM: p53, p21, Cyclin D1, Rb), and mutational landscape. METHODS: We retrospectively tested for p16 all cases of CM diagnosed at our institution between January 1st 2019-April 1st 2022. In CM with p16 overexpression, we reported clinicopathologic features, immunohistochemical results for melanocytic markers and CCRM, and mutational landscape investigated with a next-generation sequencing (NGS) panel. In cases with zonal p16 overexpression, the immunohistochemical assessment for melanocytic markers and CCRM, as well as the NGS analysis have been performed in both components {with and without p16 overexpression [p16(+)c and p16(-)]}. RESULTS: Overexpression of p16 was found in 10/2879 (0.35%) CM [5/10 (50%) diffuse and 5/10 (50%) zonal]. We combined the immunohistochemical results for CCRM and molecular data to classify the cases as follows: a) Group 1 with altered expression of at least one CCRM but no TP53 mutations [3/10 (30%), all with Rb altered/lost]; b) Group 2 with altered expression of at least one CCRM and TP53 mutations [4/10 (40%), all with p53 altered]; c) Group 3 with normal expression of CCRM and no TP53 mutations [3/10 (30%), all with mutations in MAPK pathway genes (NRAS and BRAF)]. In CM with zonal p16 overexpression, the histologic appearance of p16(+)c was heterogeneous, whereas combining CCRM profiles and molecular data the cases could be categorized as follows: a) cases with the same CCRM and molecular profiles in both p16(+)c and p16(-)c; b) cases with p16(+)c showing additional genetic mutations and/or modifications of CCRM expression. CONCLUSIONS: p16 overexpression is a rare event, occurring in advanced-stage, clinically- and histologically-heterogeneous CM. These lesions may be classified into three different groups based on CCRM expression and mutational profiles (including TP53 mutation). The analysis of CM with zonal p16 overexpression suggests that, at least in a subset of cases, this phenomenon could represent a sign of "molecular progression" due to the acquisition of additional genetic mutations and/or modifications of the CCRM profile.

Targeted Genomic Profiling and Chemotherapy Outcomes in Grade 3 Gastro-Entero-Pancreatic Neuroendocrine Tumors (G3 GEP-NET).

BACKGROUND: Grade 3 gastro-entero-pancreatic neuroendocrine tumors (G3 GEP-NET) are poorly characterized in terms of molecular features and response to treatments. METHODS: Patients with G3 GEP-NET were included if they received capecitabine and temozolomide (CAPTEM) or oxaliplatin with either 5-fluorouracile (FOLFOX) or capecitabine (XELOX) as first-line treatment (chemotherapy cohort). G3 NET which successfully undergone next-generation sequencing (NGS) were included in the NGS cohort. RESULTS: In total, 49 patients were included in the chemotherapy cohort: 15 received CAPTEM and 34 received FOLFOX/XELOX. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were 42.9%, 9.0 months, and 33.6 months, respectively. Calculating a Ki67 cutoff using ROC curve analysis, tumors with Ki67 ≥ 40% had lower ORR (51.2% vs. 0%; p = 0.007) and shorter PFS (10.6 months vs. 4.4 months; p < 0.001) and OS (49.4 months vs. 10.0 months; p = 0.023). In patients who received FOLFOX/XELOX as a first-line treatment, ORR, PFS, and OS were 38.2%, 7.9 months, and 30.0 months, respectively. In the NGS cohort (N = 13), the most mutated genes were DAXX/ATRX (N = 5, 38%), MEN1 (N = 4, 31%), TP53 (N = 4, 31%), AKT1 (N = 2, 15%), and PIK3CA (N = 1, 8%). CONCLUSIONS: FOLFOX/XELOX chemotherapy is active as the first-line treatment of patients with G3 GEP-NET. The mutational landscape of G3 NET is more similar to well-differentiated NETs than NECs.

IDH1105GGT single nucleotide polymorphism improves progression free survival in patients with IDH mutated grade II and III gliomas.

BACKGROUND: A synonymous single nucleotide polymorphism (SNP) is a substitution of a single base that does not modify the primary amino acid sequence but could influence protein function. In patients with brain tumors, the incidence of the silent SNP IDH 1 105GGT (rs11554137) is three times higher than the normal population. METHODS: Our aim was to investigate the prognostic role of the IDH 1 105GGT SNP. We selected only patients with diagnosis of IDH grade II or III mutated glioma. Additional inclusion criteria were: complete clinical data and adequate tumor samples for IDH 1 or 2 sequencing. RESULTS: 71 patients with grade II and III IDH-mutated glioma have been evaluated. Nine of 71 patients (12.7 %) presented the SNP 105GGT. Patients with SNP 105GGT had a longer Progression Free Survival (PFS - 47.3 months vs Not reached; p = 0.015). The SNP 105GGT (HR 0.240; 95 %CI 0.074-0.784, p = 0.018) was confirmed as an independent prognostic factors in multivariate analysis. CONCLUSIONS: Patients with IDH1 or 2 mutated grade II and III glioma presenting the SNP105GGT had longer PFS regardless adjuvant treatment received and extension of primary surgery. A validation is warranted to confirm our preliminary results.

miR-196B-5P and miR-200B-3P Are Differentially Expressed in Medulloblastomas of Adults and Children.

Medulloblastoma is a highly aggressive brain tumor that typically affects children, while in adults it represents ~1% of all brain tumors. Little is known about microRNA expression profile of the rare adult medulloblastoma. The main aim of this study was to identify peculiar differences in microRNA expression between childhood and adult medulloblastoma. Medulloblastomas were profiled for microRNA expression using the Exiqon Human miRNome panel (I + II) analyzing 752 microRNAs in a training set of six adult and six childhood cases. Then, the most differentially expressed microRNAs were validated in a total of 21 adult and 19 childhood cases. Eight microRNAs (miR-196b-5p, miR-183-5p, miR-200b-3p, miR-196a-5p, miR-193a-3p, miR-29c-3p, miR-33b-5p, and miR-200a-3p) were differentially expressed in medulloblastoma of adults and children. Analysis of the validation set confirmed that miR-196b-5p and miR-200b-3p were significantly overexpressed in medulloblastoma of adults as compared with those of children. We followed an in silico approach to investigate direct targets and the pathways involved for the two microRNAs (miR-196b and miR-200b) differently expressed between adult and childhood medulloblastoma. Adult and childhood medulloblastoma have different miRNA expression profiles. In particular, the differential dysregulation of miR-196b-5p and miR-200b-3p characterizes the miRNA profile of adult medulloblastoma and suggests potential targets for novel diagnostic, prognostic, or therapeutic strategies.

Should subcentimeter non-invasive encapsulated, follicular variant of papillary thyroid carcinoma be included in the noninvasive follicular thyroid neoplasm with papillary-like nuclear features category?

OBJECTIVE: In 2016, non-invasive, well-circumscribed and encapsulated, follicular variant of papillary thyroid carcinoma (NI-EFV PTC) was reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) in order to reduce overtreatment of this indolent tumor. However, the study cohort did not include subcentimeter tumors, i.e., papillary thyroid microcarcinoma (mPTC) with NI-EFV morphology, and such lesions are still regarded and staged by most pathologists as microcarcinomas. It is therefore crucial to evaluate the clinical outcome of subcentimeter NI-EFVs. METHODS: A total of 52 patients with unifocal mPTC, NI-EFV from five tertiary hospitals who had at least one year clinical follow-up (FU) without post-operative RAI administration were included in the study. A control group of 57 invasive mPTC follicular variant was also included. RESULTS: The median tumor size was 0.44 cm (range 0.1-0.9 cm). There were no distant or lymph node metastases at diagnosis in all patients. Twenty-three patients (44%) underwent lobectomy alone, while the remaining received total thyroidectomy. No recurrence was observed in the entire cohort (n = 52) including all 38 patients with at least 2 years of FU (median FU: 6.3 years). Among 25 patients with ≥5 years of FU, none recurred with a median FU of 9.6 years (range 5.2-18.1 years). In contrast, in the control group with invasive mPTC follicular variant, there were 5 (9%) patients with nodal metastasis at presentation and 1 (2%) who displayed nodal recurrence. CONCLUSION: Papillary thyroid microcarcinoma, NI-EFV, when stringently selected for, lacks metastasis at presentation and follows an extremely indolent clinical course, even when treated conservatively without RAI therapy. Provided stringent inclusion criteria are met, classification of subcentimeter mPTC, NI-EFV as NIFTP should be considered in order to avoid overtreatment of these biologically indolent lesions.

Synovial sarcoma involving the median nerve: a case report.

Synovial sarcoma may arise from different and unusual sites. Here a case of biphasic synovial sarcoma arising or invading the radial nerve in a 59-year-old female classically showing chromosomal reciprocal translocation (X; 18) is reported. The differential diagnosis from similar tumors is discussed.