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Toxicological Research Jul 2024Human cytochrome P450 (CYP) enzymes are composed of 57 individual enzymes that perform monooxygenase activities. They have diverse physiological roles in metabolizing... (Review)
Review
Human cytochrome P450 (CYP) enzymes are composed of 57 individual enzymes that perform monooxygenase activities. They have diverse physiological roles in metabolizing xenobiotics and producing important endogenous compounds, such as steroid hormones and vitamins. At least seven CYP enzymes are involved in steroid biosynthesis. Steroidogenesis primarily occurs in the adrenal glands and gonads, connecting each reaction to substrates and products. Steroids are essential for maintaining life and significantly contribute to sexual differentiation and reproductive functions within the body. Disorders in steroid biosynthesis can frequently cause serious health problems and lead to the development of diseases, such as prostate cancer, breast cancer, and Cushing's syndrome. In this review, we provide current updated knowledge on the major CYP enzymes involved in the biosynthetic process of steroids, with respect to their enzymatic mechanisms and clinical implications for the development of new drug candidates.
PubMed: 38911541
DOI: 10.1007/s43188-024-00237-0 -
Medicina 2024Ewing sarcoma (ES) and primitive neuroectodermal tumor (PNET) belong to the group of neoplasms called small round cell tumors. PNETs have been divided into central and...
Ewing sarcoma (ES) and primitive neuroectodermal tumor (PNET) belong to the group of neoplasms called small round cell tumors. PNETs have been divided into central and peripheral. ES and peripheral PNETs arise from bones, soft tissues, or peripheral nerves. We present a case of hepatic ES/PNET in a healthy man that began four months before consultation with abdominal symptoms and weight loss. Upper gastrointestinal endoscopy and laboratory tests revealed no notable findings. The abdominal tomography revealed an enlarged liver due to a solid lesion that involved all its segments with intravenous contrast enhancement and large areas of necrosis. It compressed and displaced neighboring structures. Core needle biopsy of the liver lesion was performed: small round cell neoplasm. Immunohistochemistry revealed negativity for CD45, CKA1/A3, chromogranin, synaptophysin, and cytokeratins CK7 and CK20. Dim CD56 expression and CD99, FLI-1, and NKX2 positivity. He underwent chemotherapy treatment with carboplatin and etoposide for 6 cycles with clinical improvement and tolerance. Control images showed reduction of the mass with involvement of the right hepatic lobe, involvement of the inferior vena cava, infiltration of the right adrenal gland and upper pole of the right kidney. He was referred to hepatobiliary surgery for surgical resection of the residual lesion. The patient rejected the proposed surgical procedure. Our objective is to highlight the clinical and histological diagnostic challenge of this entity that requires ruling out other clinical entities.
Topics: Humans; Male; Liver Neoplasms; Sarcoma, Ewing; Tomography, X-Ray Computed; Immunohistochemistry; Adult; Neuroectodermal Tumors, Primitive, Peripheral
PubMed: 38907976
DOI: No ID Found -
Virchows Archiv : An International... Jun 2024The aim of this multicenter prospective survey called PIT-EASY was to assess the relevance of the European Pituitary Pathology Group (EPPG) diagnostic tools for...
The aim of this multicenter prospective survey called PIT-EASY was to assess the relevance of the European Pituitary Pathology Group (EPPG) diagnostic tools for pituitary neuroendocrine tumors (PitNETs) to improve the quality of their histological diagnosis. Each center performed at least 30 histological cases of PitNETs using the EPPG tools and assessed their value using a scorecard with 10 questions. For each center, the histological cases were carried out by pathologists with varying levels of expertise in pituitary pathology defined as junior, intermediate, and expert. Two hundred and ninety histological cases were collected from six French and Italian centers. The three EPPG tools were validated and regarded as helpful for a more accurate and time-efficient diagnosis. The usefulness of level 2 and level 3 of the "EPPG's multi-step approach for immunohistochemistry" including pituitary transcription factors (PIT1, TPIT, and SF1) and chromogranin, SSTRs, and P53 respectively was higher in "other non-functioning" (silent plurihormonal PIT1, silent corticotroph, and null cell): 88% vs 32%, p < 10-6 and 42% vs 14%, p = 0.002, respectively. The diagnostic algorithm proved more useful for junior pathologists (p = 0.0001) and those with intermediate experience. PIT-EASY survey confirmed the importance of a standardized approach to PitNETs for an accurate and reproducible diagnosis and served as validation of the EPPG proposal. The tool appeared to be of practical value to junior participants and staff with intermediate experience for safe routine diagnostic reporting.
PubMed: 38907774
DOI: 10.1007/s00428-024-03849-x -
Science Advances Jun 2024Neuroblastoma is a childhood developmental cancer; however, its embryonic origins remain poorly understood. Moreover, in-depth studies of early tumor-driving events are...
Neuroblastoma is a childhood developmental cancer; however, its embryonic origins remain poorly understood. Moreover, in-depth studies of early tumor-driving events are limited because of the lack of appropriate models. Herein, we analyzed RNA sequencing data obtained from human neuroblastoma samples and found that loss of expression of trunk neural crest-enriched gene associates with advanced disease and worse outcome. Further, by using single-cell RNA sequencing data of human neuroblastoma cells and fetal adrenal glands and creating in vivo models of zebrafish, chick, and mouse, we show that MOXD1 is a determinate of tumor development. In addition, we found that expression is highly conserved and restricted to mesenchymal neuroblastoma cells and Schwann cell precursors during healthy development. Our findings identify as a lineage-restricted tumor-suppressor gene in neuroblastoma, potentiating further stratification of these tumors and development of novel therapeutic interventions.
Topics: Neuroblastoma; Animals; Humans; Mice; Genes, Tumor Suppressor; Gene Expression Regulation, Neoplastic; Zebrafish; Cell Line, Tumor; Cell Lineage; Neural Crest; Schwann Cells
PubMed: 38905335
DOI: 10.1126/sciadv.ado1583 -
Annales D'endocrinologie Jun 2024
PubMed: 38902161
DOI: 10.1016/j.ando.2024.05.001 -
Journal of Clinical Oncology : Official... Jun 2024Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and...
PURPOSE
Coblockade of lymphocyte activation gene-3 (LAG-3) and PD-1 receptors could provide significant clinical benefit for patients with advanced melanoma. Fianlimab and cemiplimab are high-affinity, human, hinge-stabilized IgG4 monoclonal antibodies, targeting LAG-3 and PD-1, respectively. We report results from a first-in-human phase-I study of fianlimab and cemiplimab safety and efficacy in various malignancies including advanced melanoma.
METHODS
Patients with advanced melanoma were eligible for enrollment into four cohorts: three for patients without and one for patients with previous anti-PD-1 therapy in the advanced disease setting. Patients were treated with fianlimab 1,600 mg and cemiplimab 350 mg intravenously once every 3 weeks for up to 51 weeks, with an optional additional 51 weeks if clinically indicated. The primary end point was objective response rate (ORR) per RECIST 1.1 criteria.
RESULTS
ORRs were 63% for patients with anti-PD-1-naïve melanoma (cohort-6; n = 40; median follow-up 20.8 months), 63% for patients with systemic treatment-naïve melanoma (cohort-15; n = 40; 11.5 months), and 56% for patients with previous neo/adjuvant treatment melanoma (cohort-16; n = 18, 9.7 months). At a median follow-up of 12.6 months for the combined cohorts (6 + 15 + 16), the ORR was 61.2% and the median progression-free survival (mPFS) 13.3 months (95% CI, 7.5 to not estimated [NE]). In patients (n = 13) with previous anti-PD-1 adjuvant therapy, ORR was 61.5% and mPFS 12 months (95% CI, 1.4 to NE). ORR in patients with previous anti-PD-1 therapy for advanced disease (n = 15) was 13.3% and mPFS 1.5 months (95% CI, 1.3 to 7.7). Treatment-emergent and treatment-related adverse events ≥grade 3 (G3) were observed in 44% and 22% of patients, respectively. Except for increased incidence of adrenal insufficiency (12%-G1-4, 4%-G3-4), no new safety signals were recorded.
CONCLUSION
The current results show a promising benefit-risk profile of fianlimab/cemiplimab combination for patients with advanced melanoma, including those with previous anti-PD-1 therapy in the adjuvant, but not advanced, setting.
PubMed: 38900987
DOI: 10.1200/JCO.23.02172 -
Surgical Case Reports Jun 2024No standard therapy for non-small lung cancer patients that have acquired resistance to tyrosine kinase inhibitor (TKI) therapy has been established. Some can be...
BACKGROUND
No standard therapy for non-small lung cancer patients that have acquired resistance to tyrosine kinase inhibitor (TKI) therapy has been established. Some can be effectively treated by salvage surgery, though indications for that procedure remain unclear. Reported here is the clinical course of a patient who experienced early post-operative distant metastases.
CASE PRESENTATION
A 48-year-old woman without symptoms was referred to another hospital for abnormal chest radiography findings and diagnosed with adenocarcinoma of the left lower lobe (cT2aN3M1b, stage IVB; TNM staging 7th edition). Gene mutation analysis revealed positive for epidermal growth factor receptor exon 19 deletion. Afatinib treatment was started, resulting in partial response, though regrowth of the main tumor was noted 1.5 years later. Bronchoscopic re-biopsy findings revealed a T790M point mutation and afatinib was switched to osimertinib. At 1.5 years following the start of osimertinib administration, the primary tumor was found to have regrown again and stereotactic radiation therapy was administered. Findings at 3.5 years after osimertinib administration indicated that all lymph nodes and distant metastases, excluding the primary tumor, were well controlled, and the patient was referred to our hospital for salvage surgery. Osimertinib was discontinued, and a left lower lobectomy with a left lingular segmentectomy and pleural biopsy were performed. The patient was discharged following an uneventful postoperative course. Three days after discharge, glossodynia developed and examination findings revealed tongue metastasis. The symptoms improved following re-administration of osimertinib, though right adrenal gland metastasis appeared 8 months after surgery. Radiation therapy was performed for tongue and right adrenal gland metastases, and the patient was alive 1 year after salvage surgery without out-of-control lesion appearing after the radiation therapy under the administration of osimertinib.
CONCLUSION
The present patient experienced multiple instances of systemic recurrence after undergoing salvage surgery. Experience with this case indicates that systemic therapy is essential for patients with distant metastatic lung cancer even following salvage surgery for the primary tumor.
PubMed: 38898314
DOI: 10.1186/s40792-024-01950-6 -
Endocrinologia, Diabetes Y Nutricion May 2024
Topics: Humans; Pheochromocytoma; Adrenal Gland Neoplasms; Pancreatitis; Acute Disease; Male; Female; Adrenalectomy; Middle Aged
PubMed: 38897706
DOI: 10.1016/j.endien.2024.02.008 -
Innere Medizin (Heidelberg, Germany) Jul 2024In the management of solid tumours, routine concepts are increasingly being transformed into individualized patient treatment. Endocrine surgery is traditionally... (Review)
Review
BACKGROUND
In the management of solid tumours, routine concepts are increasingly being transformed into individualized patient treatment. Endocrine surgery is traditionally characterized by resection strategies that are adapted to phenotype and genotype of the underlying disease. As complication rates in surgery correlate with the extent of resection, continuous efforts are made to identify selection criteria in order to limit the extent of surgery without compromising the oncological outcome. The aim is to design risk-stratified precision endocrine surgery.
MATERIALS AND METHODS
A search was carried out in PubMed for new and modern strategies and approaches for oncological endocrine surgery.
RESULTS
Several developments in surgical technique and technology, molecular pathology, medical therapy, and study data identify the potential to adapt the surgical strategy in all areas of endocrine surgery.
CONCLUSION
According to prevalent data, limited extent of resection in thyroid cancer surgery shows a reduction in complication rates while preserving oncological outcome when adequate selection criteria are implemented. New insights and innovative technologies also influence additional areas in oncological endocrine surgery for parathyroid, adrenal, and neuroendocrine neoplasia. However, the broad practice of these new concepts needs to be evaluated with regard to long-term oncological outcome.
Topics: Humans; Endocrine Gland Neoplasms; Endocrine Surgical Procedures; Thyroid Neoplasms; Adrenal Gland Neoplasms
PubMed: 38888613
DOI: 10.1007/s00108-024-01732-0 -
JCO Precision Oncology Jun 2024Targeted therapy in translocation-associated sarcomas has been limited to oncogenic activation of tyrosine kinases or ligands while gene fusions resulting in aberrant...
PURPOSE
Targeted therapy in translocation-associated sarcomas has been limited to oncogenic activation of tyrosine kinases or ligands while gene fusions resulting in aberrant expression of transcription factors have been notoriously difficult to target. Moreover, secondary genetic alterations in sarcomas driven by translocations are uncommon, comprising mostly alterations in tumor suppressor genes (, /). Our study was triggered by an index patient showing a dramatic clinical response by targeting the secondary V600E mutation in a metastatic angiomatoid fibrous histiocytoma (AFH) harboring the typical fusion.
MATERIALS AND METHODS
The patient, a 28-year-old female, was diagnosed with an AFH of the thigh and followed a highly aggressive clinical course, with rapid multifocal local recurrence within a year and widespread distant metastases (adrenal, bone, liver, lung). The tumor showed characteristic morphologic features, with histiocytoid cells intermixed with hemorrhagic cystic spaces and lymphoid aggregates. In addition to the pathognomonic fusion, targeted DNA sequencing revealed in both primary and adrenal metastatic sites a hot spot V600E mutation and a / deletion. Accordingly, the patient was treated with a BRAF-MEK inhibitor combination (encorafenib/binimetinib) showing an excellent but short-lived response.
RESULTS
Using a CRISPR-Cas9 approach, we introduced the c.1799 T>A point mutation in human embryonic stem (hES) cells harboring a conditional (exon7):: (exon7) translocation and further differentiated to mesenchymal progenitors (hES-MP) before fusion expression. The cells maintained the fusion transcript expression and the AFH core gene signature while responding to treatment with encorafenib and binimetinib.
CONCLUSION
These results highlight that additional targeted DNA NGS in chemotherapy-resistant translocation-associated sarcomas may reveal actionable oncogenic drivers occurring as secondary genetic events during disease progression.
Topics: Humans; Female; Adult; Oncogene Proteins, Fusion; Proto-Oncogene Proteins B-raf; Histiocytoma, Malignant Fibrous; Sarcoma; Mutation
PubMed: 38885476
DOI: 10.1200/PO.23.00688