ERK5 is activated by oncogenic BRAF and promotes melanoma growth

Malignant melanoma is among the most aggressive cancers and its incidence is increasing worldwide. Targeted therapies and immunotherapy have improved the survival of patients with metastatic melanoma in the last few years; however, available treatments are still unsatisfactory. While the role of the BRAF-MEK1/2-ERK1/2 pathway in melanoma is well established, the involvement of mitogen-activated protein kinases MEK5-ERK5 remains poorly explored. Here we investigated the function of ERK5 signaling in melanoma. We show that ERK5 is consistently expressed in human melanoma tissues and is active in melanoma cells. Genetic silencing and pharmacological inhibition of ERK5 pathway drastically reduce the growth of melanoma cells and xenografts harboring wild-type (wt) or mutated BRAF (V600E). We also found that oncogenic BRAF positively regulates expression, phosphorylation, and nuclear localization of ERK5. Importantly, ERK5 kinase and transcriptional transactivator activities are enhanced by BRAF. Nevertheless, combined pharmacological inhibition of BRAFV600E and MEK5 is required to decrease nuclear ERK5, that is critical for the regulation of cell proliferation. Accordingly, combination of MEK5 or ERK5 inhibitors with BRAFV600E inhibitor vemurafenib is more effective than single treatments in reducing colony formation and growth of BRAFV600E melanoma cells and xenografts. Overall, these data support a key role of the ERK5 pathway for melanoma growth in vitro and in vivo and suggest that targeting ERK5, alone or in combination with BRAF-MEK1/2 inhibitors, might represent a novel approach for melanoma treatment

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

Folliculosebaceous Cystic Hamartoma with Spindle Cell Lipomatous and Neural Components

Folliculosebaceous cystic hamartoma is a cutaneous malformation composed of a cystic folliculosebaceous structure associated with mesenchymal elements, generally consisting of fibrous stroma, adipocytes and small vascular channels. We report the case of a 55-year-old female patient with a cutaneous nodule of the right nasal wing. Microscopically, the lesion showed a dilated hair follicle with multiple sebaceous glands, surrounded by a mesenchymal component composed of fibromyxoid stroma, spindle cells, mature-appearing adipocytes and collagen bundles, resembling spindle cell lipoma, associated with an additional neural component, consisting of small nerve bundles. In folliculosebaceous cystic hamartoma, the association of spindle cell lipomatous and neural components has not previously reported

Conceptual Evolution and Current Approach to Spitz Tumors

Over the past several decades, the study of Spitz neoplasms has flourished, with expanded conceptualization and refined terminology, providing a framework for the assessment and classification of Spitz nevi, atypical Spitz Tumors, and Spitz melanoma. Cancer genomics have generated concepts such as driver and passenger genes and clonal evolution, which can be applied to Spitz tumors. Herein, we provide a historical perspective, followed by a summary of current knowledge and clinical approaches for these challenging tumors

18 F-Choline Versus 68 Ga-PSMA-11 PET/CT Imaging Comparison in Incidental Clear Cell Renal Cell Carcinoma

: Few articles in literature describe the potential usefulness of 18 F-choline PET/CT and particularly 68 Ga-PSMA-11 PET/CT in imaging of clear cell renal cell carcinoma (ccRCC). We report a unique comparison in literature between the 2 radiotracers in a patient who underwent left nephrectomy with diagnosis of ccRCC, grade 3. 68 Ga-PSMA-11 PET/CT confirmed its emerging role in imaging ccRCC, as the incidentally detected renal neoplasm showed a significant higher uptake in comparison to 18 F-choline PET/CT, inducing surgical indication

A pilot study of a combined dermoscopic–pathological approach to the telediagnosis of melanocytic skin neoplasms

We examined a combined (dermoscopic–pathological) approach to the telediagnosis of melanocytic skin lesions. A store-and-forward teleconsultation was simulated. Dermoscopic and histopathology images from 12 melanocytic lesions were stored in a telepathology workstation. A dermoscopy consultant, a histopathology consultant and an expert in dermoscopic–pathological correlation gave their diagnoses and comments on the images. The consensus diagnosis between two teleconsultants on the original histological slides was regarded as the gold standard. The diagnostic accuracy was 83% (including one false negative diagnosis of malignancy) for teledermoscopy and 100% for teledermatopathology. The combined approach detected one case that showed a much greater atypia on dermoscopy than on histopathology. In this case step-sections of the sample were deemed to be required for definite diagnosis. The combined approach was helpful in detecting macroscopic and microscope sampling errors of melanocytic lesions during teleconsultation

18F-FDG PET/MRI for Rectal Cancer TNM Restaging After Preoperative Chemoradiotherapy: Initial Experience

OBJECTIVE: F-18-FDG-PET/MRI is a novel hybrid techinque that has been recently introduced in oncological imaging, showing promising results. The aim of this study is to assess the value of whole-body F-18-FDG-PET/MRI for predicting the pathological stage of locally advanced rectal cancer after preoperative chemoradiotherapy. DESIGN: This was a prospective observational study. SETTINGS: The study was conducted at a tertiary care hospital. PATIENTS: Thirty-six patients with locally advanced rectal cancer (25 male, median age 68.5 years) were prospectively assessed with PET/MRI and thoracoabdominal CT before and after preoperative chemoradiotherapy. Twenty-seven patients underwent low anterior or abdominoperineal resection. Nine patients with a complete clinical response underwent organ-preserving treatment (8 local excision and 1 watch-and-wait approach) with > 1-year follow-up. MAIN OUTCOME MEASURES: One radiologist evaluated pelvic MRI and CT. A second radiologist and a nuclear medicine physician jointly assessed PET/MRI. The imaging was compared with histology or follow-up (ypT0 vs T >= 1 and ypN0 vs ypN+ categories). Metastases were confirmed with biopsy or a follow-up CT scan at least at 1 year after preoperative chemoradiotherapy. The sensitivity, specificity, and accuracy values of the imaging techniques were calculated using standard formulas. RESULTS: The accuracy for ypT staging was 89% and 92%, and the accuracy for ypN was 86% and 92% for MRI and PET/MRI. Compared with CT, PET/MRI correctly diagnosed 4 of 5 metastases, but it did not detect a lung metastatic nodule. In 11% of the patients, the PET/MRI changed the treatment strategy. LIMITATIONS: This study is limited by its small sample size. CONCLUSIONS: Although the whole-body PET/MRI was more accurate than the pelvic MRI alone for the prediction of tumor and node response to preoperative chemoradiotherapy, the technique performed worse than CT in detecting small lung metastasis