Hydroxyurea is an antimetabolite that inhibits DNA synthesis and is used as a treatment option in chronic myeloproliferative disorders. Rarely, \"dermatomyositis (DM)-like\" skin lesions are observed after long-term therapy. In this case series, five skin biopsies of four patients were evaluated by histology, immunohistochemistry, and next-generation sequencing of the TP53 gene locus. All biopsies showed focal basal pleomorphic keratinocytes and suprabasal aberrant p53 expression as well as sparse to severe vacuolar interface dermatitis. Histopathologically, \"DM-like\" skin lesions can be clearly distinguished from DM by marked subepidermal fibrosis, vascular proliferation, and the absence of dermal mucin deposits. In 75% of the specimens multiple, partly inactivating and/or pathogenic point mutations of TP53 were found in low frequencies. \"DM-like\" skin eruptions as a long-term consequence of hydroxyurea therapy are possibly not chemotherapy-associated benign toxic changes, but rather inflammatory reactions to complex keratinocyte alterations that clinically mimic the picture of DM. Synergistic mutagenic effects of hydroxyurea and sunlight might be responsible for this unique drug side effect and could provide a pathogenic link to the known increased risk of skin cancer in these patients.

Burkitt\'s lymphoma (BL) with TP53 mutation often has poor outcome after standard chemoimmunotherapy. Adoptive chimeric antigen receptor (CAR)-T cell therapy may be a new paradigm for treating refractory/relapsed (r/r) BL, but its therapeutic effects remain inconclusive. Here, we report a patient with r/r BL who failed to achieve complete remission (CR) and progressed rapidly after multiple protocol chemotherapy. The patient achieved CR with CAR19 and CAR22 T-cell cocktail therapy and obtained long-term disease-free survival after autologous hematopoietic stem cells (ASCT) and subsequential CAR19 and CAR22 T-cell cocktail therapy. The clinical evolution and genetic features of this case may provide some guidance for CAR-T therapy in overcoming relapses associated with TP53 gene mutations.

Although the incidence of multiple primary malignancies (MPMs) is increasing, synchronous triple primary malignant tumours with prostate, bladder and lung is rarely reported. Gene mutation is thought to be a reason for MPMs, and severe cardiovascular diseases may interrupt the cancer treatment. Here we reported a 64-year-old male patient with synchronous triple primary malignant tumours of the bladder urothelial carcinoma, prostate adenocarcinoma, and non-small cell lung cancer (NSCLC) with mutations in TP53 and MEK1, all the three malignancies were diagnosed within 10 days. Although being interrupted by severe cardiovascular diseases (including myocardial infarction, venous thrombosis, and aneurism of the aortic root), he was successfully treated with radical cystoprostatectomy, chemotherapy plus pembrolizumab (a PD-1 antibody), and radiotherapy of the lung lesion, followed by maintenance monotherapy of pembrolizumab, overall survival was more than 26 months. In conclusion, a patient of synchronous triple primary malignant tumours with prostate, bladder, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases was treated successfully, which may suggest that comprehensive treatment, especially radical treatment such as operation and radiation, is very important for MPMs.

BACKGROUND: Paraganglioma occurs rarely in the sellar/parasellar region. Here, we report a patient with malignant paraganglioma with primary sellar location with unusual genetic and imaging features.
METHODS: A 31-year-old male presented with mild hypertension, headache, nausea, and vomiting. A sellar/parasellar tumor mass was revealed by magnetic resonance imaging (MRI), while an endocrine work-up found partial hypopituitarism, suggesting that it was a non-functioning pituitary tumor. Antihypertensive therapy and hormone replacement were initiated. Tumor reduction was achieved with transsphenoidal neurosurgery. However, histological diagnosis was not possible due to extensive tissue necrosis. After 4 years of stable disease, the residual tumor showed re-growth requiring gamma knife radiosurgery. Four years after the radiosurgery, MRI showed a significant tumor progression leading to a second neurosurgery. This time, pathological and immunohistochemical findings revealed paraganglioma. Plasma levels of metanephrine and normetanephrine were normal. A gene sequencing panel performed on DNA extracted from blood excluded germline mutations in 17 susceptibility genes. The patient developed new tumor masses in the neck, and the third surgery was performed. Immunohistochemistry demonstrated lack of ATRX (alpha thalassemia/mental retardation syndrome X-linked) protein in tumor cells, indicating an ATRX gene mutation. Molecular genetic analysis performed on tumor DNA revealed a combination of ATRX and TP53 gene abnormalities; this was not previously reported in paraganglioma. MRI and 68Ga-DOTANOC PET/CT revealed the full extent of the disease. Therapy with somatostatin LAR and 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) was initiated.
CONCLUSIONS: Although rare, paraganglioma should be considered in the differential diagnosis of sellar/parasellar tumor lesions, even in the absence of typical imaging features. ATRX gene mutation in paraganglioma is an early predictor of malignant behavior and a potential novel therapeutic marker when pharmacological therapy targeting mutated ATRX becomes available.

BACKGROUND: Tumor protein 53 (TP53) gene mutations are identified in up to 37% of breast tumors especially in HER-2 positive and basal-like subtype. Previous studies have indicated TP53 mutations as a prognostic biomarker in breast cancer. However, most of these studies performed immunohistochemistry (IHC) for the detection of TP53 mutations.
OBJECTIVE: The purpose of our study is to evaluate the role of TP53 somatic mutations detected via next-generation sequencing (NGS) as a potential prognostic marker in patients with breast cancer.
METHODS: 82 female patients with Stage I-III breast cancer underwent NGS in paraffin blocks and blood samples during the period 25/09/2019 through 25/05/2021. 23 cases of somatic TP53 mutations and 23 cases of healthy controls were matched on age at diagnosis, menopausal status, histological subtype, histological grade, ki67 expression and disease stage.
RESULTS: Mean age at diagnosis was 52.35 (SD; 11.47) years. The somatic TP53 mutation NM_000546.5:c.824G>A p.(Cys275Tyr) was most frequently detected. Co-existence of PIK3CA mutation was a common finding in somatic TP53-mutant tumors (4/23; 17.4%). Disease-free survival was shorter in TP53-mutated cases (16.3 months vs. 62.9 months). TP53 pathogenic somatic mutations were associated with a 8-fold risk of recurrence in the univariate Cox regression analysis (OR = 8.530, 95% CI: 1.81-40.117; p = 0.007).
CONCLUSIONS: Our case-control study suggests that TP53 somatic mutations detected by next-generation sequencing (NGS) are associated with an adverse prognosis in breast cancer.

Anaplastic thyroid carcinoma (ATC) is a rare and highly aggressive fatal tumor. Most ATC patients using traditional surgery or radio-chemotherapy have poor prognosis and experience recurrence in a very short time. There is no optimal therapy for ATC, and the median survival time is about 5 months. We report a 67-year-old ATC patient, who experienced rapid local recurrence after radical thyroidectomy. The resected tumor tissue was sent for immunohistochemistry analysis and targeted next-generation sequencing. The results indicated high PD-L1 expression, a tumor mutation burden of 0.48 muts/Mb, microsatellite stable, and somatic mutations of TERT promoter, EIF1AX, NRAS and TP53. However, none of the mutations indicated corresponding target therapy. An immediate operation was unsuitable because of rapid recurrence after surgery. The patient was also not in a condition to tolerate chemotherapy. Based on the high expression of PD-L1, an optimum strategy was used, combining immunotherapeutic agent, sintilimab, with an anti-angiogenesis drug, anlotinib. The patient obtained remarkable tumor shrinkage and an 18.3-month-sustained remission period. This is an effective case of using immunotherapy and anti-angiogenesis agent in the first-line treatment of ATC. It demonstrates a feasible and novel therapeutic option for future treatment of ATC patients.

UNASSIGNED: The 2011 WHO Classification for lung adenocarcinoma enlightened the need for a wise use of immunohistochemistry to preserve tissue for both diagnosis and molecular studies. The current recommendation is to use a panel comprising TTF1 and p40 to classify tumors with no clear squamous or glandular differentiation as many studies have showed the higher specificity of p40 over p63 as marker of squamous differentiation. However, the co-expression of both markers opens a new scenario with subsequent classification and potentially treatment issues.
UNASSIGNED: We report a case of a non-small lung cell carcinoma (NSCLC) with coexistent expression of TTF1 and p40 in the same tumour cells. To our knowledge, this peculiar immunohistochemical profile is very rare, and thus a review of the clinical and molecular features including molecular variances of the tumour was performed. Review of the pertinent literature was also carried out.
UNASSIGNED: Two additional articles describing unusual cases of NSCLC with coexistent expression of TTF1 and p40 were found and compared to our case. Interestingly, they all carried out aberrant mutation in TP53 oncogene and were of advance stage.
UNASSIGNED: The positivity for both \"squamous\" and \"adenocarcinomatous\" markers and mutations of TP53 could be the expression of a not fully recognized variant of NSCLC with possible implications for classification, diagnosis and therapy.

BACKGROUND: Myelodysplastic syndromes are heterogeneous disorders. Patients with myelodysplastic syndrome disease often have ineffective hematopoiesis, cytopenias, blood cell dysplasia in one or more cell types, and are at high risk for developing acute myeloid leukemia. In myelodysplastic syndrome, mutations of TP53 gene are usually associated with complex karyotype and confer a worse prognosis. In the present study, two mutations in this gene are presented and discussed with the clinical evolution of the patients.
METHODS: The first case is a 77-year-old Brazilian woman diagnosed as having multiple lineage dysplasia myelodysplastic syndrome according to World Health Organization 2016 and classified as very low-risk by Revised International Prognostic Scoring. The second case is an 80-year-old Brazilian man also diagnosed as having multiple lineage dysplasia myelodysplastic syndrome and classified as low risk. The mutation described in the first case was already identified in some neoplasias and it is associated with a poor prognosis, but it had never been reported before in myelodysplastic syndrome. The second mutation has never been described.
CONCLUSIONS: This is a novel report for the scientific community and may be very helpful as we can better understand the disease and the impact of mutations through the follow-up of these patients and others in the future. Both patients are in a good clinical condition, suggesting that these mutations may not alter the clinical course of the disease or may be associated with a good prognosis, but their role in the disease must be investigated more deeply in a larger population.