Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms.

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), -17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS ('EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.

Dysplastic squamous cells are frequently present in urine cytology specimens of patients with high-grade urothelial carcinoma.

BACKGROUND: In urothelial carcinoma (UCA), squamous differentiation (SqD) occurs mainly in high-grade UCA with invasion. Therefore, we sought to determine the frequency of dysplastic squamous cells (DSC) in urine specimens obtained from patients with high-grade UCA asking if DSC could serve as a surrogate marker for high-grade UCA. DESIGN: We searched for cases with a histologic diagnosis of high-grade UCA and available concurrent cytology, yielding 93 surgical specimens (including 71 biopsies, 12 cystectomies, 5 nephrectomies, 4 ureterectomies, and 1 urethrectomy) from 68 patients with 98 urine cytology samples. Both cytology and histologic specimens were evaluated for the presence of any SqD on histology and the presence of DSC on cytology besides urothelial cells. RESULTS: Forty-three of 68 patients (63%) had a cytologic diagnosis of 'positive/suspicious'. Twenty-one patients (30%) had surgical specimens that showed SqD. Seventeen patients had urine cytology specimens showing DSC (25%). Thirteen of these 17 patients showed DSC with concurrent malignant urothelial cells, while 4 patients displayed only isolated DSC. CONCLUSION: SqD is common in patients with high-grade UCA. DSC were detected in a subset of specimens from patients with high-grade UCA. In some instances, isolated DSC on cytology may represent the only evidence of an unsampled high-grade malignancy.

Donor cell myeloid sarcoma.

Donor cell derived malignancies are a rare and interesting complication of allogeneic bone marrow transplantation. We present a case of a 56-year-old male with donor cell myeloid sarcoma of the stomach and myocardium.

FOXP3 expression and nodal metastasis of breast cancer.

PURPOSE: T regulatory cells, a subset of T lymphocytes, function to suppress immune responses. FOXP3, a member of the forkhead family of transcription factors, is a good marker for T regulatory cells. Since sentinel nodes are important sites of immunomodulation in breast cancer, we studied the association between T regulatory cells and nodal metastasis using FOXP3 expression in sentinel nodes with and without metastatic breast carcinoma. METHODS: Following sample size calculations, we selected 140 sentinel nodes from breast cancer patients; 70 with metastasis (sentinel node+) and 70 without metastasis (sentinel node-). FOXP3 expression in sentinel nodes was studied by immunohistochemistry. Cortical cells expressing FOXP3 were counted in 10 high power fields. RESULTS: In the evaluable cases, the node positive (n = 66) and negative (n = 69) groups were well balanced for all clinicopathological parameters except histological type. The mean number of T regulatory cells expressing FOXP3 (per 10 hpf) was 139 in the node positive and 132 in the node negative group (P = 0.540). The mean number of T regulatory cells was 162 in patients ≤35 years of age (n = 8) compared to 133 in older patients (P = 0.250). Primary tumor pathological characteristics like tumor type, grade, size, and ER, PR, and HER2 status did not correlate with FOXP3 expression. CONCLUSIONS: The number of FOXP3-expressing T regulatory cells does not differ significantly between sentinel node+ and sentinel node- samples. It was also not affected by primary tumor characteristics like tumor type, grade, size, hormone receptor, and HER2 status.

Chronic myelomonocytic leukemia monocytes uniformly display a population of monocytes with CD11c underexpression.

OBJECTIVES: To examine the utility of CD11c expression on monocytes in normal controls and patients with chronic myelomonocytic leukemia (CMML) (n = 23) with flow cytometric immunophenotyping. METHODS: Twenty-three CMML samples and 10 control bone marrows submitted for lymphoma staging without evidence of disease were examined. RESULTS: Monocytes in CMML samples ranged from 4% to 35%. Expression of at least one aberrant monocytic marker was found on the monocytes in 18 (82%) of 22 evaluable cases. The most common aberrancy was underexpression of CD11c (n = 15), while none of the bone marrow controls showed underexpression of CD11c. CONCLUSIONS: A distinct heterogeneous population of monocytic cells with underexpression of CD11c was identified in all these cases. CD11c underexpression was independent of other aberrancies, including HLA-DR underexpression (n = 14), aberrant CD56 expression (n = 11), and underexpression of CD33, CD38, and CD14 (n = 6, 5, and 5, respectively), supporting the utility of CD11c expression status on monocytes in establishing a CMML diagnosis.