- MRI features in solitary cerebral Langerhans cell histiocytosis : a case report and review of literature. [Journal Article]
- WNWorld Neurosurg 2018 Jun 18
- In this study, we report a case of solitary Langerhans cell histiocytosis (LCH) without skull or systemic lesions, including reviewing the initial magnetic resonance (MR) findings of cerebral LCH. A ...
In this study, we report a case of solitary Langerhans cell histiocytosis (LCH) without skull or systemic lesions, including reviewing the initial magnetic resonance (MR) findings of cerebral LCH. A 36-year-old male patient presented with generalized tonic-clonic type seizure. Brain MR imaging showed a 3cm mass lesion involving the right frontal lobe. It showed iso-intensity on T1-weighted images and hyperintensity on T2-weighted images. After gadolinium enhancement, the mass showed heterogeneous enhancement with perilesional edema and additional adjacent leptomeningeal enhancement. Special MR techniques focused on the enhanced lesion showed increased cerebral blood volume on perfusion images, no diffusion restriction on diffusion-weighted images, and a necrotic spectrum on MR spectroscopy. At surgery, we found a yellow mass and yellow tissue debris in the sulci adjacent to the mass and removed them. The final histopathological diagnosis was LCH in the frontal lobe. The patient underwent scheduled adjuvant chemotherapy with cytarabine for six months and has been regularly followed up without any neurological problem for three years. In conclusion, additional sulcal enhancement around the mass lesion might be a clue MRI feature of intracerebral LCH, and special magnetic resonance imaging (MRI) techniques such as perfusion imaging, diffusion-weighted imaging and MR spectroscopy could be helpful in differential diagnosis.
- Reformulating acute myeloid leukemia: liposomal cytarabine and daunorubicin (CPX-351) as an emerging therapy for secondary AML. [Review]
- OTOnco Targets Ther 2018; 11:3425-3434
- Despite increasing understanding of the pathobiology of acute myeloid leukemia (AML), outcomes remain dismal particularly for patients over the age of 60 years, a population enriched for therapy-rela...
Despite increasing understanding of the pathobiology of acute myeloid leukemia (AML), outcomes remain dismal particularly for patients over the age of 60 years, a population enriched for therapy-related AML (tAML) and secondary AML (sAML). For decades, the standard of care for AML has been the combination of cytarabine and daunorubicin, typically delivered in combination as "7 + 3" induction. In 2017, a liposomal-encapsulated combination of daunorubicin and cytarabine (CPX-351, Vyxeos) was approved by the US Food and Drug Administration (FDA) for use in the treatment of newly diagnosed tAML or AML with myelodysplasia-related changes (AML-MRCs). CPX-351 was designed to deliver a fixed 5:1 molar ratio of cytarabine and daunorubicin, respectively, based on the hypothesis that ratiometric dosing may be more effective than the delivery of either drug at their maximum tolerated dose. In a Phase III trial of older patients with sAML aged 60-75 years, CPX-351 was compared to "7 + 3" and was associated with a higher overall survival, event-free survival, and higher rates of complete remission (CR) and CR with incomplete hematologic recovery (CRi). These data were the basis for the approval of this new drug for use in the treatment of AML, but questions remain regarding how to best administer this agent across AML subgroups. Future directions include evaluating dose intensification with CPX-351, combining this agent with targeted therapies, and better understanding the mechanism of improved responses in tAML and AML-MRC, two entities that are historically less responsive to cytotoxic agents. In summary, CPX-351 offers an exciting new change to the landscape of AML therapy.
- Preclinical characterization of INCB053914, a novel pan-PIM kinase inhibitor, alone and in combination with anticancer agents, in models of hematologic malignancies. [Journal Article]
- PlosPLoS One 2018; 13(6):e0199108
- The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine protein kinases are overexpressed in many hematologic and solid tumor malignancies and play central roles in intr...
The Proviral Integration site of Moloney murine leukemia virus (PIM) serine/threonine protein kinases are overexpressed in many hematologic and solid tumor malignancies and play central roles in intracellular signaling networks important in tumorigenesis, including the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways. The three PIM kinase isozymes (PIM1, PIM2, and PIM3) share similar downstream substrates with other key oncogenic kinases and have differing but mutually compensatory functions across tumors. This supports the therapeutic potential of pan-PIM kinase inhibitors, especially in combination with other anticancer agents chosen based on their role in overlapping signaling networks. Reported here is a preclinical characterization of INCB053914, a novel, potent, and selective adenosine triphosphate-competitive pan-PIM kinase inhibitor. In vitro, INCB053914 inhibited proliferation and the phosphorylation of downstream substrates in cell lines from multiple hematologic malignancies. Effects were confirmed in primary bone marrow blasts from patients with acute myeloid leukemia treated ex vivo and in blood samples from patients receiving INCB053914 in an ongoing phase 1 dose-escalation study. In vivo, single-agent INCB053914 inhibited Bcl-2-associated death promoter protein phosphorylation and dose-dependently inhibited tumor growth in acute myeloid leukemia and multiple myeloma xenografts. Additive or synergistic inhibition of tumor growth was observed when INCB053914 was combined with selective PI3Kδ inhibition, selective JAK1 or JAK1/2 inhibition, or cytarabine. Based on these data, pan-PIM kinase inhibitors, including INCB053914, may have therapeutic utility in hematologic malignancies when combined with other inhibitors of oncogenic kinases or standard chemotherapeutics.
- SAMHD1 modulates in vitro proliferation of acute myeloid leukemia-derived THP-1 cells through the PI3K-Akt-p27 axis. [Journal Article]
- CCCell Cycle 2018 Jun 18
- Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a mammalian dNTP hydrolase that acts as a negative regulator in the efficacy of cytarabine treatment against acute myeloid leukemia ...
Sterile alpha motif and HD domain-containing protein 1 (SAMHD1) is a mammalian dNTP hydrolase that acts as a negative regulator in the efficacy of cytarabine treatment against acute myeloid leukemia (AML). However, the role of SAMHD1 in AML development and progression remains unknown. We have reported that SAMHD1 knockout (KO) in the AML-derived THP-1 cells results in enhanced proliferation and reduced apoptosis, but the underlying mechanisms are unclear. Here we show that SAMHD1 KO in THP-1 cells increased PI3K activity and reduced expression of the tumor suppressor PTEN. Pharmacological inhibition of PI3K activity reduced cell proliferation specifically in SAMHD1 KO cells, suggesting that SAMHD1 KO-induced cell proliferation is mediated via enhanced PI3K signaling. However, PI3K inhibition did not significantly affect SAMHD1 KO-reduced apoptosis, implicating the involvement of additional mechanisms. SAMHD1 KO also led to enhanced phosphorylation of p27 at residue T157 and its mis-localization to the cytoplasm. Inhibition of PI3K activity reversed these effects, indicating that SAMHD1 KO-induced changes in p27 phosphorylation and localization is mediated via PI3K-Akt signaling. While SAMHD1 KO significantly enhanced THP-1 cell migration in vitro, SAMHD1 KO attenuated the ability of THP-1 cells to form subcutaneous tumors in xenografted immunodeficient mice. This effect correlated with significantly increased expression of tumor necrosis factor α (TNF-α) in tumors, which may suggest that TNF-α-mediated inflammation could account for the decreased tumorigenicity in vivo. Our findings implicate that SAMHD1 can regulate AML cell proliferation via modulation of the PI3K-Akt-p27 signaling axis, and that SAMHD1 may affect tumorigenicity by downregulating inflammation.
- Recombinant human thrombopoietin (rh-TPO) for the prevention of severe thrombocytopenia induced by high-dose cytarabine: a prospective, randomized, self-controlled study. [Journal Article]
- LLLeuk Lymphoma 2018 Jun 18; :1-8
- The aim of this randomized phase II study was to investigate the optimal timing of the administration of thrombopoietin to prevent cytarabine-induced thrombocytopenia. Fifty-two patients who were sch...
The aim of this randomized phase II study was to investigate the optimal timing of the administration of thrombopoietin to prevent cytarabine-induced thrombocytopenia. Fifty-two patients who were scheduled for high-dose cytarabine treatment were randomly assigned to receive either the standard prophylactic mode (starting thrombopoietin, 15,000 units/day on days 2-11) or the pre-chemo mode (starting thrombopoietin, 15,000 units/day on days -4, -2, and 2-9) during the first cycle of chemotherapy with a switch to the other mode in the second cycle. The thrombocytopenia rate in the standard mode and the pre-chemo mode were PLT < 50 × 109/L, 67.3% versus 46.2% (p = .001); and PLT < 25 × 109/L, 48.1% versus 26.9% (p = .001). The platelet transfusion rate was reduced in pre-chemo mode, with 7 patients requiring 10 units of platelets, whereas 13 patients required 24 units in standard mode (p = .038). Grade III/IV thrombopoietin-related toxicity was not observed. The prophylactic use of thrombopoietin was effective and safe.
- The FOSSIL Study: FLAG or standard 7+3 induction therapy in secondary acute myeloid leukemia. [Journal Article]
- LRLeuk Res 2018 Jun 01; 70:91-96
- Patients with secondary acute myeloid leukemia (sAML) have poor outcomes, with CR/CRi rates of 25-35% with standard 7 + 3 induction chemotherapy, while single center non-comparative analyses suggest ...
Patients with secondary acute myeloid leukemia (sAML) have poor outcomes, with CR/CRi rates of 25-35% with standard 7 + 3 induction chemotherapy, while single center non-comparative analyses suggest promising outcomes with FLAG. We conducted a single-center, retrospective cohort study assessing outcomes in treatment-naïve patients with sAML treated with fludarabine, high-dose cytarabine, and granulocyte colony-stimulating factor (FLAG, n = 40) compared with 7 + 3 (n = 66). Median patient age was 63 years (range: 27-82) in the FLAG group and 60 years (range: 21-76) in the 7 + 3 group (P = 0.968). Patients treated with FLAG achieved higher overall response rates (CR + CRi + MLFS) compared to 7 + 3 (70% vs. 48%, P = 0.043). FLAG was well tolerated, with only one induction death (30-day mortality rate, 3% vs. 8%, P = 0.405) and no cases of cerebellar toxicity. Duration of neutropenia was significantly shorter with FLAG (median 16 vs. 23 days, P < 0.001). Half of the FLAG-treated patients proceeded to consolidative therapy compared with only 27% of those who received 7 + 3 (P = 0.022). Overall survival was comparable between groups (8.5 mos, FLAG vs. 9.1 mos, 7 + 3; P = 0.798). Thus, FLAG may represent a low-cost treatment strategy in sAML that produces higher response rates and promising survival outcomes with minimal treatment-related toxicity. Further studies are required to prospectively compare FLAG to the newly FDA-approved CPX-351 in sAML.
- Design, synthesis and anticancer activity of fluorocyclopentenyl-purines and - pyrimidines. [Journal Article]
- EJEur J Med Chem 2018 Jun 05; 155:406-417
- Based on the potent anticancer activity of 6'-fluorocyclopentenyl-cytosine 2b in phase IIa clinical trials for the treatment of gemcitabine-resistant pancreatic cancer, we carried out a systematic st...
Based on the potent anticancer activity of 6'-fluorocyclopentenyl-cytosine 2b in phase IIa clinical trials for the treatment of gemcitabine-resistant pancreatic cancer, we carried out a systematic structure-activity relationship study of 6'-fluorocyclopentenyl-pyrimidines 3a-i and -purines 3j-o to discover novel anticancer agents. We also synthesized the phosphoramidate prodrug 3p of adenine derivative 1b to determine if the anticancer activity depended on the inhibition of DNA and/or RNA polymerase in cancer cells and/or on the inhibition of S-adenosylhomocysteine (SAH) hydrolase. All of the synthesized pyrimidine nucleosides exhibited much less potent anticancer activity in vitro than the cytosine derivative 2b, acting as RNA and/or DNA polymerase inhibitor, indicating that they could not be efficiently converted to their triphosphates for anticancer activity. Among all the synthesized purine nucleosides, adenine derivative 1b and N6-methyladenine derivative 3k showed potent anticancer activity, showing equipotent inhibitory activity as the positive control, neplanocin A (1a) or Ara-C. However, the phosphoramidate prodrug 3p showed less anticancer activity than 1b, indicating that it did not act as a RNA and/or DNA polymerase inhibitor like 2b. This result also demonstrates that the anticancer activity of 1b largely depends on the inhibition of histone methyltransferase, resulting from strong inhibition of SAH hydrolase. The deamination of the N6-amino group, the addition of the bulky alkyl group at the N6-amino group, or the introduction of the amino group at the C2 position almost abolished the anticancer activity.
- Inferior survival in high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements is not associated with MYC/IG gene rearrangements. [Journal Article]
- HHaematologica 2018 Jun 14
- High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-/triple-hit lymphoma) has an aggressive clinical course. We investigated prognostic value of transformation from low-gr...
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-/triple-hit lymphoma) has an aggressive clinical course. We investigated prognostic value of transformation from low-grade lymphoma, cytologic features (high grade versus large cell), MYC gene rearrangement partners (immunoglobulin versus nonimmunoglobulin gene), and treatment. We evaluated 100 adults with double-/triple-hit lymphoma, reviewing cytologic features; cell of origin; and rearrangements of MYC, BCL2, and BCL6 using MYC, BCL2, and BCL6 break-apart and IGH/MYC, IGL/MYC, IGK/MYC, and IGH/BCL2 dual-fusion interphase fluorescence in situ hybridization probes. Outcome analysis was restricted to patients, de novo or at transformation, who received anthracycline-based chemotherapy. Among them, 60% had high-grade cytologic features; 91%, germinal center B-cell phenotype, and 60%, MYC/immunoglobulin gene rearrangement. Germinal center B-cell phenotype was associated with BCL2 rearrangements (P<.001). Mean (95% CI) 5-year overall survival was 49% (37%-64%). Transformation from previously treated and untreated low-grade lymphoma was associated with inferior overall survival (hazard ratio [HR], 2.99; P=.008). Patients with high-grade cytologic features showed a nonsignificant tendency for inferior outcome (HR, 2.32; P=.09). No association was observed between MYC rearrangement partner and overall survival (HR, 1.00; P=.99). Compared with patients receiving rituximab, cyclophosphamide, doxorubicin, and vincristine (R-CHOP) and dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), patients receiving rituximab, cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfamide, etoposide, and cytarabine (R-CODOX-M/IVAC) had a nonsignificant tendency for better overall survival (HR, 0.37; P=.10). In conclusion, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements had heterogeneous outcomes and MYC/immunoglobulin gene rearrangements were not associated with inferior overall survival.
- The safety and efficacy of clofarabine in combination with high-dose cytarabine and total body irradiation myeloablative conditioning and allogeneic stem cell transplantation in children, adolescents, and young adults (CAYA) with poor-risk acute leukemia. [Journal Article]
- BMBone Marrow Transplant 2018 Jun 13
- Acute leukemias in children with CR3, refractory relapse, or induction failure (IF) have a poor prognosis. Clofarabine has single agent activity in relapsed leukemia and synergy with cytarabine. We s...
Acute leukemias in children with CR3, refractory relapse, or induction failure (IF) have a poor prognosis. Clofarabine has single agent activity in relapsed leukemia and synergy with cytarabine. We sought to determine the safety and overall survival in a Phase I/II trial of conditioning with clofarabine (doses 40 - 52 mg/m2), cytarabine 1000 mg/m2, and 1200 cGy TBI followed by alloSCT in children, adolescents, and young adults with poor-risk leukemia. Thirty-seven patients; Age 12 years (1-22 years); ALL/AML: 34:3 (18 IF, 10 CR3, 13 refractory relapse); 15 related, 22 unrelated donors. Probabilities of neutrophil, platelet engraftment, acute GvHD, and chronic GvHD were 94%, 84%, 49%, and 30%, respectively. Probability of day 100 TRM was 8.1%. 2-year EFS (event free survival) and OS (overall survival) were 38.6% (CI95: 23-54%), and 41.3% (CI95: 25-57%). Multivariate analysis demonstrated overt disease at time of transplant (relative risk (RR) 3.65, CI95: 1.35-9.89, P = 0.011) and umbilical cord blood source (RR 2.17, CI95: 1.33-4.15, P = 0.019) to be predictors of worse EFS/OS. This novel myeloablative conditioning regimen followed by alloSCT is safe and well tolerated in CAYA with very poor-risk ALL or AML. Further investigation in CAYA with better risk ALL and AML undergoing alloSCT is warranted.
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- Outcome of relapsed or refractory acute myeloid leukemia treated with intensive salvage chemotherapy in real life in comparison to intermediate dose cytarabine in phase 3 studies. [Journal Article]
- LLLeuk Lymphoma 2018 Jun 12; :1-4