BACKGROUND: BCR::ABL1-like or Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) was first reported in 2009. Ph-like ALL is characterized by gene signature similar to Philadelphia chromosome ALL, but without BCR::ABL1 fusions. Molecularly, Ph-like ALL is divided into seven categories, with CRLF2 and ABL-class rearrangements being the two most common subtypes, exhibiting alterations in distinct downstream signaling cascades.
METHODS: We report a rare case of pediatric Ph-like ALL with concomitant CRLF2 and ABL1 rearrangements. CRLF2 was fused with P2RY8, its most common fusion partner, whereas ABL1 was fused with MYO18B, a novel fusion partner that has not been previously reported. The 4-year-old female patient was treated using the national multicenter CCCG-ALL-2020 protocol with the addition of dasatinib at the end of induction when ABL1 rearrangement was confirmed by RNA-seq. Morphologically and molecularly, the patient remained in continuous remission until the last follow-up. To the best of our knowledge, this is the first case of Ph-like ALL harboring two distinct rearrangement categories.
CONCLUSIONS: Our results identified that ABL1 rearrangement and CRLF2 rearrangement can coexist. The application of FISH, whole transcription sequencing, PCR can help us to have a more comprehensive understanding of ALL cytogenetics and molecular biology. Further studies are needed to explore the role of targeted therapies in such rare clinical scenarios.

Multiple isodicentric Y chromosomes [idic(Y)] is a rare cytogenetic abnormality, most exclusively described in constitutional karyotypes. Only recently has this entity been reported in hematologic neoplasms such as myeloid disorders, albeit these cases remain very scarce. The possible involvement of increasing copies of potential proto-oncogenes located on the multiple idic(Y) led to consider one of them, CRLF2, as a target for kinase inhibitors. We report here, to our knowledge, the first case of multiple idic(Y) in a patient with myelofibrosis secondary to essential thrombocythemia. The patient received ruxolitinib therapy with initial good clinical response.

Crisponi syndrome/cold-induced sweating syndrome (CS/CISS) is a rare autosomal recessive disorder with a complex phenotype, reported in the neonatal period for CS and in the evolutive one for CISS. The syndrome usually manifests at birth. The aim of this study was to report on three new patients with CS and review the Turkish patients. We report here on three patients from two related families harboring a homozygous mutation in the cytokine receptor-like factor-1 (CRLF1) gene. DNA samples of the three patients and their parents were subjected to a mutational analysis of the CRLF1 gene at the Institute of Biomedical and Genetic Research - National Research Council, Cagliari (Italy). Direct sequencing of the nine coding exons and surrounding intronic regions of CRLF1 was performed using specific primers. All three patients were found to be homozygotes for the mutation c.708_709delinsT, which leads to a frameshift in the second fibronectin type III domain (p.Pro238Argfs*6). CS should be considered in the differential diagnosis of newborns with muscle contractions, feeding and swallowing difficulties, dysmorphic facial findings, camptodactyly, and hypertermia. Neonatologists must be aware of this syndrome that, although very rare worldwide, has a higher prevalence in Turkey.

Crisponi/CISS1 syndrome (MIM#272430) is a rare autosomal recessive disease characterized by major feeding difficulties, camptodactyly, and anhidrosis in early childhood; and the subsequent development of paradoxical cold-induced sweating and scoliosis later in life. The syndrome is caused by biallelic mutations in CRLF1 or, much less commonly, CLCF1. Although genotype/phenotype correlation has been elusive, it has been suggested that the level of the mutant protein may correlate with the phenotypic severity. However, we show in this series of 12 patients from four families, all previously unpublished, that the homogeneity of the recently described c.983dupG (p.Ser328Argfs∗2) mutation in CRLF1 was associated with a highly variable degree of severity, and that the phenotype significantly overlaps with the recently described COG6-related anhidrosis syndrome (MIM#615328). Another fifth previously unpublished family is also described with a novel mutation in CRLF1, c.605delC (p.Ala202Valfs*32). In Saudi Arabia the prevalence of the syndrome is probably underestimated due to the difficulty in making the diagnosis considering the complex phenotype with typical neonatal and evolutive features.

BACKGROUND: Cut-point finding is a crucial step for clinical decision making when dealing with diagnostic (or prognostic) biomarkers. The extension of ROC-based cut-point finding methods to the case of censored failure time outcome is of interest when we are in the presence of a biomarker, measured at baseline, used to identify whether there will be the development, or not, of some disease condition within a given time point τ of clinical interest.
METHODS: Three widely used cut-point finding methods, namely the Youden index, the concordance probability and the point closest to-(0,1) corner in the ROC plane, are extended to the case of censored failure time outcome resorting to non-parametric estimators of the sensitivity and specificity that account for censoring. The performance of these methods in finding the optimal cut-point is compared under Normal and Gamma distributions of the biomarker (in subjects developing or not the disease condition). Normality ensures that estimators point theoretically to the same cut-point. Two motivating examples are provided in the paper.
RESULTS: The point closest-to-(0,1) corner approach has the best performance from simulations in terms of mean square error and relative bias.
CONCLUSIONS: We discuss the use of the Youden index or concordance probability associated to the cut-point identified through the closest-to-(0,1) corner approach to ease interpretability of the classification performance of the dichotomized biomarker. In addition, the achieved performance of the dichotomized biomarker classification associated to the estimated cut-point can be represented through a confidence interval of the point on the ROC curve.

暂无摘要。

暂无摘要。

New polymorphisms have been recently identified in CX3CR1, a coreceptor for some HIV-1 strains, one of which was associated with a strong acceleration of HIV disease progression. This effect was observed both by a case-control study involving 63 nonprogressors (NP) from the asymptomatic long-term (ALT) cohort and Kaplan-Meier analysis of 426 French seroconverters (SEROCO cohort). These results prompted us to analyze these polymorphisms in 244 nonprogressors (NPs) and 80 rapid progressors (RPs) from the largest case-control cohort known to date, the GRIV cohort. Surprisingly, the genetic frequencies found were identical for both groups under all genetic models (p >.8). The discrepancy with the previous work stemmed only from the difference between GRIV NPs versus ALT NPs. We hypothesized this might be due to the limited number of NPs in ALT (n = 63) and in this line we reanalyzed the data previously collected on GRIV for over 100 different genetic polymorphisms: we effectively observed that the genetic frequencies of some polymorphisms could vary by as much as 10% (absolute percentage) when computing them on the first 50 NP subjects enrolled, on the first 100, or on all the NPs tested (240 study subjects). This observation emphasizes the need for caution in case-control studies involving small numbers of subjects: p values should be low or other control groups should be used.However, the association of the CX3CR1 polymorphism with progression seems quite significant in the Kaplan-Meier analysis of the SEROCO cohort (426 individuals), and the difference observed with GRIV might be explained by a delayed effect of the polymorphism on disease. Further studies on other seroconverter cohorts are needed to confirm the reported association with disease progression.

A 65-year-old Japanese woman presented with disseminated erythematous patches, plaques, and nodules on the trunk and limbs. Histological examination showed diffuse and dense infiltrates located in the dermis and subcutis, composed of large pleomorphic T lymphocytes. Immunohistochemically, neoplastic cells were positive for blastic T-cell markers, but negative for CD30 (Ki-1) antigen. Based on the clinicopathological findings, a diagnosis of primary cutaneous large T-cell lymphoma was made. Despite systemic chemotherapy, the patient died 7 months after diagnosis. Gene expression profiling using complementary DNA microarrays indicated significantly increased expression of an apoptosis-inhibitory protein and certain cyokines and cytokine receptors (e.g. MCP-1, MCP-2, IP-10, and IL-2R gamma) in the tumour-indurated skin. Comprehensive gene expression patterning in additional cases may provide useful information regarding the biological and clinical behaviour of aggressive cutaneous lymphomas such as CD30-negative large T-cell lymphoma.

BACKGROUND: The cytokine receptor CD30 is an activation marker of T cells which preferentially associates with the production of the TH2 cytokine IL-4. Therefore, it may potentially be a candidate marker for atopic disorders and a target molecule for new therapeutic approaches.
OBJECTIVE: To test the hypothesis that elevated levels of soluble CD30 (sCD30) are significantly associated with atopic disorders after adjustment for other predictors of atopy.
METHODS: The presence of elevated sCD30 (> or = 20 U/mL) in atopic disorders was evaluated in a nested case-control study. Cases (n = 60) were blood donors with specific IgE antibodies, total serum levels of IgE > or = 100kU/L and presence or history of allergic symptoms. Controls (n = 59) were blood donors without presence or history of allergic symptoms and serum levels of IgE < 50 kU/L. sCD30 was determined from serum samples by an enzyme-linked immunosorbent assay. Odds ratios (OR) and confidence intervals (CI) were calculated from logistic regression coefficients.
RESULTS: Mean sCD30 levels for cases were 75 U/mL (SD 110U/mL) as compared with 35 U/mL (SD 59 U/mL) for controls. Serum levels of sCD30 were elevated in 65% of cases and 32% of controls (OR 3.9, 95% CI 1.8-8.4). The odds ratio for elevated sCD30 as a predictor of atopic disorders slightly decreased to 3.7 after controlling for smoking, age and gender. Blood eosinophilia which was a strong predictor of atopy (OR 11.7) was a weak confounder of the association between sCD30 levels and atopic disorders. Family history of allergy, another strong predictor of atopy (OR 8.6), did not confound the association.
CONCLUSIONS: The results are consistent with the hypothesis that CD30 is involved in the pathogenesis of atopic disorders independent of eosinophilia and family history of allergy.