ß-Catenin-Driven Differentiation Is a Tissue-Specific Epigenetic Vulnerability in Adrenal Cancer.

Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent ß-catenin-activating mutations. Here, we demonstrated that ACC differentiation is maintained by a balance between nuclear, tissue-specific ß-catenin-containing complexes, and the epigenome. On chromatin, ß-catenin bound master adrenal transcription factor SF1 and hijacked the adrenocortical super-enhancer landscape to maintain differentiation in CIMP-high ACC; off chromatin, ß-catenin bound histone methyltransferase EZH2. SF1/ß-catenin and EZH2/ß-catenin complexes present in normal adrenals persisted through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC expelled SF1/ß-catenin from chromatin and favored EZH2/ß-catenin assembly, erasing differentiation and restraining cancer growth in vitro and in vivo. These studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities. SIGNIFICANCE: Oncogenic ß-catenin can use tissue-specific partners to regulate cellular differentiation programs that can be reversed by epigenetic therapies, identifying epigenetic control of differentiation as a viable target for ß-catenin-driven cancers.

Vitamin D and colorectal cancer - A practical review of the literature.

Colorectal cancer (CRC) is the third leading cause of cancer-related mortality in the United States and the second cause worldwide. Its incidence rates have been decreasing in the overall population in the US in the past few decades, but with increasing rates in the population younger than 50 years old. Environmental factors are supposed to be involved in the development of the disease, with strong evidence favoring an influence of the diet and lifestyle. A diet high in red meat and calories, and low in fiber, fruits and vegetables increases the risk of CRC, as well as physical inactivity. The influence of low calcium intake and low levels of vitamin D on the risk of the disease and on the clinical outcomes of CRC patients has also been investigated. Hypovitaminosis D has been highly prevalent worldwide and associated with several chronic diseases, including malignancies. Vitamin D is a steroid hormone with the main function of regulating bone metabolism, but with many other physiological functions, such as anti-inflammatory, immunomodulatory, and antiangiogenic effects, potentially acting as a carcinogenesis inhibitor. In this review, we aim to describe the relation of vitamin D with malignant diseases, mainly CRC, as well as to highlight the results of the studies which addressed the potential role of vitamin D in the development and progression of the disease. In addition, we will present the results of the pivotal randomized clinical trials that evaluated the impact of vitamin D supplementation on the clinical outcomes of patients with CRC.

Gene expression signatures in early breast cancer: Better together with clinicopathological features.

Breast cancer (BC) is a highly heterogeneous disease, characterized by a variety of subtypes with distinct biological, molecular, and clinical behavior. Standard clinicopathological and tumor biology information (as assessed by gene expression signatures-GES), have provided enhanced prognostic and predictive information in both node-negative(N0) and positive(N +), hormonal receptor positive/human epidermal growth factor 2 negative (HR+/HER2-) early breast cancer (EBC). Herein, we comprehensively review the clinical data of 5 commonly used GES, namely, Oncotype DX(ODX)®; MammaPrint (MP)®; Prosigna®; Breast Cancer Index (BCI)® and Endopredict® - with sections specifically addressing the role of GES in special histologic subtypes, premenopausal women, late recurrence and adjuvant treatment de-escalation.

Should we still be using bolus 5-FU prior to infusional regimens in gastrointestinal cancers? A practical review.

5-fluorouracil (5-FU), a pyrimidine analogue with antimetabolite activity, is one of the most widely used drugs in Oncology and many different regimens have been described regarding its use. Nowadays, the modified de Gramont is the most popular schedule of 5-FU to treat gastrointestinal cancers and may be given either alone or combined with irinotecan, oxaliplatin and monoclonal antibodies. The true clinical value of bolus 5-FU right before infusional regimens remains to be determined since no randomized trials have addressed this issue. This manuscript aims to review the history of 5-FU, its mechanism of action and the data exploring the role of bolus 5-FU.

Quantitative proteomic study reveals differential expression of matricellular proteins between fibrous dysplasia and cemento-ossifying fibroma pathogenesis.

BACKGROUND: Fibrous dysplasia (FD) and cemento-ossifying fibroma (COF) are the most common gnathic fibro-osseous lesions. These diseases exhibit remarkable overlap of several clinicopathological aspects, and differential diagnosis depends on the combination of histopathological, radiographic, and clinical aspects. Their molecular landscape remains poorly characterized, and herein, we assessed their proteomic and phosphoproteomic profiles. METHODS: The quantitative differences in protein profile of FD and COF were assessed by proteomic and phosphoproteomic analyses of formalin-fixed paraffin-embedded tissue samples. Pathway enrichment analyses with differentially regulated proteins were performed. RESULTS: FD and COF exhibited differential regulation of pathways related to extracellular matrix organization, cell adhesion, and platelet and erythrocytes activities. Additionally, these lesions demonstrated distinct abundance of proteins involved in osteoblastic differentiation and tumorigenesis and differential abundance of phosphorylation of Ser61 of Yes-associated protein 1 (YAP1). CONCLUSIONS: In summary, despite the morphological similarity between these diseases, our results demonstrated that COF and DF present numerous quantitative differences in their proteomic profiles. These findings suggest that these fibro-osseous lesions trigger distinct molecular mechanisms during their pathogenesis. Moreover, some proteins identified in our analysis could serve as potential biomarkers for differential diagnosis of these diseases after further validation.

Localized Well-Differentiated Rectal Neuroendocrine Tumors - Where Are We in 2021?

Neuroendocrine tumors (NETs) are slow-growing malignancies with distinct biologic and clinical characteristics. Most rectal-NETs are localized and well-differentiated, usually carrying an excellent prognosis. In this review, we aim at describing the epidemiology, clinical characteristics and therapeutic approaches for well-differentiated rectal NETs.

Thyroid collision tumor containing oncocytic carcinoma, classical and hobnail variants of papillary carcinoma and areas of poorly differentiated carcinoma

SUMMARY Collision tumors are rare and may comprise components with different behavior, treatments, and prognosis. We report an unprecedented case of aggressive thyroid collision tumor containing widely invasive oncocytic carcinoma (OC), classical and hobnail (HPTC) variants of papillary carcinoma, and poorly differentiated carcinoma (PDTC). The patient underwent total thyroidectomy, radioactive iodine therapy, and within months progressed with local recurrence, and pulmonary metastases requiring neck dissection, external radiotherapy and systemic treatment with sorafenib. The rapid progression, dedifferentiated metastatic lesions, and failure to treatments resulted in the patient´s death. The great variety of histological types and the evolution of this case were a challenge for the management of metastatic disease. Widely invasive OC, HPTC and PDTC are considered to have a worse prognosis. HPTC has never been reported as a component of a collision tumor. HPTC and PDTC should call attention to a possible higher-grade transformation.

Thyroid collision tumor containing oncocytic carcinoma, classical and hobnail variants of papillary carcinoma and areas of poorly differentiated carcinoma.

Collision tumors are rare and may comprise components with different behavior, treatments, and prognosis. We report an unprecedented case of aggressive thyroid collision tumor containing widely invasive oncocytic carcinoma (OC), classical and hobnail (HPTC) variants of papillary carcinoma, and poorly differentiated carcinoma (PDTC). The patient underwent total thyroidectomy, radioactive iodine therapy, and within months progressed with local recurrence, and pulmonary metastases requiring neck dissection, external radiotherapy and systemic treatment with sorafenib. The rapid progression, dedifferentiated metastatic lesions, and failure to treatments resulted in the patient's death. The great variety of histological types and the evolution of this case were a challenge for the management of metastatic disease. Widely invasive OC, HPTC and PDTC are considered to have a worse prognosis. HPTC has never been reported as a component of a collision tumor. HPTC and PDTC should call attention to a possible higher-grade transformation.

Malignant bowel obstruction: effectiveness and safety of systemic chemotherapy.

OBJECTIVES: Although systemic chemotherapy is often administered to patients with malignant bowel obstruction (MBO), its benefit remains unknown. This study assessed the outcomes of patients who received systemic chemotherapy as part of MBO treatment. METHODS: For this retrospective cohort study, data were extracted from records of patients hospitalised due to MBO in a tertiary cancer centre from 2008 to 2020. Eligible patients were not candidates for surgery and received systemic chemotherapy targeting the underlying malignancy causing MBO. Primary objective was to assess patient outcomes after chemotherapy; secondary objectives were rates of intestinal function recovery, hospital discharge and grade ≥3 toxicities. The primary endpoint was overall survival (OS). RESULTS: A total of 167 patients were included: median age was 55 (18-81) years, 91% had an Eastern Cooperative Oncology Group (ECOG) performance status ≥2, 75.5% had gastrointestinal tumours and 70% were treatment-naive. The median OS after chemotherapy was 4.4 weeks (95% CI 3.4 to 5.5) in the overall population. No OS difference was observed according to treatment line (p=0.24) or primary tumour (p=0.13). Intestinal function recovery occurred in 87 patients (52%), out of whom 21 (24.1%) had a reobstruction. Hospital discharge was possible in 74 patients (44.3%). Grade≥3 adverse events occurred in 26.9% of the patients, and a total of 12 deaths (7%) attributed to toxicities were observed after chemotherapy. CONCLUSIONS: MBO was associated with a dismal prognosis in this mostly treatment-naive population. The administration of chemotherapy yielded a significant risk of toxicities, whereas it did not appear to provide any relevant survival benefit in this scenario.

Metabolic landscape of oral squamous cell carcinoma.

BACKGROUND: Head and neck cancers are the seventh most common type of cancer worldwide, with almost half of the cases affecting the oral cavity. Oral squamous cell carcinoma (OSCC) is the most common form of oral cancer, showing poor prognosis and high mortality. OSCC molecular pathogenesis is complex, resulting from a wide range of events that involve the interplay between genetic mutations and altered levels of transcripts, proteins, and metabolites. Metabolomics is a recently developed sub-area of omics sciences focused on the comprehensive analysis of small molecules involved in several biological pathways by high throughput technologies. AIM OF REVIEW: This review summarizes and evaluates studies focused on the metabolomics analysis of OSCC and oral premalignant disorders to better interpret the complex process of oral carcinogenesis. Additionally, the metabolic biomarkers signatures identified so far are also included. Moreover, we discuss the limitations of these studies and make suggestions for future investigations. KEY SCIENTIFIC CONCEPTS: Although many questions about the metabolic features of OSCC have already been answered in metabolomic studies, further validation and optimization are still required to translate these findings into clinical applications.

Gastric cancer molecular classification and adjuvant therapy: Is there a different benefit according to the subtype?

BACKGROUND: Gastric cancer (GC) has been defined in distinct molecular subtypes with different therapeutic implications. However, its clinical significance and prognosis regarding standard chemotherapy (CMT) remains unclear. This study aimed to analyze the impact of perioperative or adjuvant treatment among subtypes of GC. METHODS: We retrospectively evaluated all stage II/III patients with GC who underwent a curative gastrectomy. Based on immunohistochemistry and in situ hybridization techniques, GC was classified into five subtypes: Epstein-Barr virus (EBV) positive, microsatellite instability (MSI), e-cadherin aberrant, p53-aberrant, and p53-normal. RESULTS: Among the 178 CG included, 111 patients received CMT and 67 were treated with surgery alone. Survival analysis showed that p53-aberrant GC treated with CMT had better disease-free survival (DFS) compared with surgery alone (P = .001).There was no significant difference in DFS between patients who received CMT and those with surgery alone for EBV, MSI, E-cadherin, and p53-normal GC. An improvement in overall survival was observed only for E-cadherin (P = .001) and p53-aberrant (P < .001) patients who received CMT. CONCLUSIONS: CMT showed different impact on the survival of CG according to the molecular subtype. No survival benefit was observed for EBV and MSI groups who received CMT. GC with p53-aberrant had a significant benefit in survival with standard therapy.

Oral pyogenic granulomas show MAPK/ERK signaling pathway activation, which occurs independently of BRAF, KRAS, HRAS, NRAS, GNA11, and GNA14 mutations.

BACKGROUND: Pyogenic granuloma (PG) is a benign nodular lesion with a prominent vascular component which may affect different sites. Recently, BRAF, KRAS, HRAS, NRAS, GNA11, and GNA14 mutations were reported on PGs of the skin. The present study assessed the role of the MAPK/ERK pathway in oral PG pathogenesis. METHODS: Mutations in hotspot regions of genes involved in the MAPK/ERK pathway activation were investigated by Sanger sequencing. The expression of phospho-ERK1/2 was evaluated by immunohistochemistry. RESULTS: Oral PGs did not show mutations in the sequenced regions of the genes BRAF, KRAS, HRAS, NRAS, GNA11, or GNA14. Our results also showed activation of the MAPK/ERK pathway demonstrated by phospho-ERK1/2 immunohistochemical positivity. CONCLUSIONS: Although oral PG shows MAPK/ERK pathway activation, the driver molecular event remains to be elucidated.

Doença sistêmica relacionada à IgG4 com linfopenia: relato de caso e breve revisão de literatura / IgG4-related systemic disease associated with lymphopenia: case report and brief literature review

A doença sistêmica relacionada à IgG4 é uma doença emergente, recentemente descrita, caracterizada clinicamente por aumento parcial ou total de um órgão, e, por isso, com amplo espectro de manifestações clínicas. Esta é uma doença sistêmica fibroinflamatória, patologicamente provocada pela infiltração de plasmoblastos IgG4 positivos que levam à inflamação eosinofílica do tecido e, consequentemente, fibrose estoriforme. Quando o diagnóstico é precoce, a melhora clínica e resposta sustentada com corticosteroides sistêmicos é impressionante. O diagnóstico é baseado em critérios patológicos, mas, recentemente, alguns trabalhos têm descrito que plasmoblastos no soro podem servir como um fator independente para auxiliar no diagnóstico da doença. Este artigo descreve uma apresentação atípica da doença relacionada à IgG4, em um paciente linfopênico com medição inconclusiva de plasmoblastos no soro.

IgG4-related systemic disease is a recently described, emerging condition, clinically characterized by partial or total enlargement of an organ, with a broad spectrum of clinical manifestations. It is a systemic fibroinflammatory condition caused by the infiltration of IgG4-positive plasmablasts that lead to eosinophilic inflammation of tissues and consequently storiform fibrosis. When diagnosis is early, clinical improvement and maintained response achieved with systemic corticosteroids is impressive. Diagnosis is based on pathological criteria, but recent papers have described that serum plasmablasts may serve as an independent factor to aid in diagnosis. This paper describes an atypical presentation of IgG4-related disease in a lymphopenic patient with inconclusive serum plasmablast measurement.