Tadalafil is a phosphodiesterase 5 (PDE5) inhibitor with a long half-life, high selectivity, and rapid onset of action. Because the safety of using PDE5 inhibitors as therapeutic agents for fetal growth restriction (FGR) has been a problem worldwide, this paper primarily focuses on the safety assessments performed in the Tadalafil Treatment for Fetuses with Early-Onset Growth Restriction (TADAFER) II population. Neonatal and maternal adverse events were analyzed, in addition to fetal, neonatal, and infant death cases, six months after stopping the trial. Eighty-nine pregnant women with FGR were studied between September 2016 and March 2018 (45 and 44 in the tadalafil and conventional treatment groups, respectively). Seven (16%) deaths (four fetal, one neonatal, and two infant) in the control group, whereas only one neonatal death occurred in the tadalafil group. Although headache, facial flushing, and nasal hemorrhage occurred more frequently in the tadalafil group, these symptoms were Grade 1 and transient. In conclusion, this trial showed that tadalafil decreased the fetal and infant deaths associated with FGR. This is thought to be primarily due to pregnancy prolongation. Further studies are warranted to evaluate the efficacy of tadalafil in treating early-onset FGR.
The gene expression profile of peripheral ␥␦ T-cell lymphoma (␥␦TCL) has not been investigated. Using oligonucleotide microarrays, we analyzed total RNA from 7 patients with ␥␦TCL (4 hepatosplenic, 1 cutaneous, 1 intestinal, and 1 thyroidal) and 27 patients with ␣TCL (11 peripheral TCL-unspecified, 15 angioimmunoblastic TCL, and 1 hepatosplenic). Unsupervised microarray analyses classified all hepatosplenic ␥␦TCLs into a single cluster, whereas other ␥␦TCLs were scattered within the ␣TCL distribution. We identified a T-cell receptor signature gene set, which accurately classified ␥␦TCL and ␣TCL. A classifier based on gene expression under supervised analysis correctly identified ␥␦TCL. IntroductionT cells expressing the ␥␦ T-cell receptor (TCR) heterodimer comprise only a small fraction of the peripheral blood T-cell population and differ from those expressing the ␣ TCR in terms of development, tissue distribution, and function. 1,2 Mature T-cell lymphomas (TCLs) with the ␥␦ T-cell immunophenotype can be divided into hepatosplenic ␥␦TCL 3 and nonhepatosplenic ␥␦TCL. 4 The third World Health Organization (WHO) classification system describes hepatosplenic ␥␦TCLs and hepatosplenic ␣TCLs as a single disease entity (hepatosplenic TCL) as they exhibit nearly identical clinicopathologic and cytogenetic features. [4][5][6] In contrast, nonhepatosplenic ␥␦TCL occurs in only a limited number of anatomic sites, including cutaneous, nasopharyngeal, gastrointestinal, pulmonary, and thyroidal regions. [7][8][9][10] This disease has also been called mucocutaneous ␥␦TCL because the majority of patients show some involvement of mucocutaneous sites. Among nonhepatosplenic ␥␦TCLs, the cutaneous form is most common and overlaps with subcutaneous panniculitis-like TCL. 11,12 Whereas primary cutaneous ␥␦TCL is categorized as a single disease entity in the new WHO scheme, 13 other nonhepatosplenic ␥␦TCLs remains an enigma.␥␦TCLs are rare lymphoid malignancies and are difficult to diagnose, resulting from the lack of available monoclonal antibodies against ␥␦TCR for use with paraffin-embedded tissue. Several studies have elucidated the gene expression profile of peripheral TCLs (PTCLs) 14-17 but did not evaluate ␥␦TCL. In our current study, we performed gene expression profiling in 34 PTCLs, including 7 cases of ␥␦TCL. Methods Patients/samplesOur present study assessed 34 cases of PTCL, including 11 PTCLunspecified with ␣ T-cell immunophenotype, 15 angioimmunoblastic TCLs, 1 hepatosplenic ␣TCL, 4 hepatosplenic ␥␦TCLs, 1 cutaneous ␥␦TCL, 1 intestinal ␥␦TCL, and 1 thyroidal ␥␦TCL. All specimens were collected between 1987 and 2002 at Mie University Hospital and diagnosed according to the third WHO classification. 6 Tumor cell expression of cellsurface antigens and TCR heterodimer (␣ or ␥␦) was confirmed by immunohistochemistry using frozen sections as described previously. 9 DNA microarray studies using specimens from patients with hematopoietic malignancies were approved by the Institutional Review Committee of Mie University ...
CD5-positive (CD5(+)) diffuse large B-cell lymphoma (DLBCL) has a poor prognosis and high incidence of central nervous system (CNS) relapse, even in the rituximab era. To determine the gene expression profile of CD5(+) DLBCL, total RNA from 90 patients with DLBCL, including 33 CD5(+) DLBCL and 57 CD5-negative (CD5(-)) DLBCL patients, was examined using Agilent human oligo microarrays. These cases were separated into 78 activated B-cell-like (ABC) DLBCLs and 12 germinal center B-cell-like (GCB) DLBCLs. All cases of CD5(+) DLBCL were classified as ABC DLBCLs. The classifier based on gene expression used in a supervised analysis correctly identified CD5 expression in the DLBCL and ABC DLBCL samples. The gene most relevant to CD5 expression was SH3BP5. Enriched GO categories in the CD5(+) ABC DLBCL signature gene set included multicellular organismal signaling, transmission of nerve impulse, and synaptic transmission. The present study, which includes the largest reported number of patients with CD5(+) DLBCL, confirmed that most CD5(+) DLBCLs are ABC DLBCLs, suggesting that therapeutic strategies for ABC DLBCL may be effective for the treatment of CD5(+) DLBCL. Our CD5(+) ABC DLBCL signature gene set may provide insights into the cause of the high frequency of CNS relapse in CD5(+) DLBCL.
CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.)
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