Blast crisis (BC) predicts dismal outcomes in patients with chronic myeloid leukaemia (CML). Although additional genetic alterations play a central role in BC, the landscape and prognostic impact of ...these alterations remain elusive. Here, we comprehensively investigate genetic abnormalities in 136 BC and 148 chronic phase (CP) samples obtained from 216 CML patients using exome and targeted sequencing. One or more genetic abnormalities are found in 126 (92.6%) out of the 136 BC patients, including the RUNX1-ETS2 fusion and NBEAL2 mutations. The number of genetic alterations increase during the transition from CP to BC, which is markedly suppressed by tyrosine kinase inhibitors (TKIs). The lineage of the BC and prior use of TKIs correlate with distinct molecular profiles. Notably, genetic alterations, rather than clinical variables, contribute to a better prediction of BC prognosis. In conclusion, genetic abnormalities can help predict clinical outcomes and can guide clinical decisions in CML.
Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains ...significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C, SETD1B, YTHDF2, and PDCD1. We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2. Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.
Posttransplant cyclophosphamide (PTCy:100 mg/kg) has been increasingly used in allogeneic hematopoietic stem cell transplantation, however, few studies compared different doses of PTCy. We conducted ...two consecutive prospective multicenter phase II studies to evaluate the safety and efficacy of 80 mg/kg of PTCy in 137 patients who underwent HLA-haploidentical peripheral blood stem cell transplantation (haploPBSCT) following reduced-intensity conditioning (RIC). GVHD prophylaxis consisted of PTCy at a dose of 40 mg/kg/day on days 3 and 4, tacrolimus, and mycophenolate mofetil. Neutrophil engraftment was achieved in 97% and 96% in the first and second studies, respectively. The incidences of grades II-IV acute GVHD, III-IV acute GVHD, all grade chronic GVHD, and moderate to severe chronic GVHD at 2 years were 26%, 5%, 35%, and 18% in the first study, and 23%, 1%, 28%, and 15% in the second study, respectively. Overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) at 2 years were 51%, 42%, and 18% in the first study, and 58%, 48%, and 16% in the second study, respectively. The rates of off-immunosuppressants in patients who survived without relapse at 2 years were 83 and 76%. Our results suggest that 80 mg/kg of PTCy is a valid option in haploPBSCT following RIC.
Transsphenoidal surgery (TSS) is commonly used for anterior skull base surgery, especially in the sella turcica (sellar) region. However, because of its anatomical position, CSF leakage is a major ...complication of this approach. The authors introduced a new grading reconstruction strategy for anterior skull base surgery with continuous dural suturing in 2013. In this paper the authors report on their methods and results.
All patients with sellar or anterior skull base lesions that were removed with TSS or extended TSS by a single neurosurgeon between April 2013 and March 2017 at Nagoya University Hospital and several cooperating hospitals were retrospectively identified. Three methods of suturing dura were considered, depending on the dural defect.
There were 176 TSS cases (141 conventional TSS cases and 35 extended endoscopic TSS cases) and 76 cases of Esposito's grade 2 or 3 intradural high-flow CSF leakage. In the high-flow CSF leak group, there were 3 cases of CSF leakage after the operation. The rates of CSF leakage after surgery corresponding to grades 2 and 3 were 2.9% (1/34) and 4.7% (2/42), respectively.
Dural suturing is a basic and key method for reconstruction of the skull base, and continuous suturing is the most effective approach. Using this approach, the frequency of cases requiring a nasoseptal flap and lumbar drainage can be reduced.
Recently neurosurgical operations have been carried out with water irrigation such as endoscopic third ventriculostomy and tumor resections in ventricles. Water irrigation is one of several published ...methods that promote hemostasis; however, not enough experimental evidence exists on its efficacy. In this study, we investigate whether hydrostatic pressure and persistent irrigation promote hemostasis in neuroendoscopic surgery. We dissected tails of 12–16-week-old C57BL/6 male mice at 5 mm proximal from the tip and checked for bleeding times under dry and wet conditions at pressures of 0 cmH2O, 10 cmH2O, 15 H2O, and 20 cmH2O without persistent irrigation to bleeding point and 10 cmH2O with persistent irrigation. We then examined the dissected edge with hematoxylin–eosin staining and measured the size of vessels. The average bleeding time of each group is as follows: dry: 203.4 sec, wet: 164.4 sec, 5 cmH2O: 138.6 sec, 10 cmH2O: 104.6 sec (P <0.001), 20 cmH2O: 56 sec (P <0.001), and 10 cmH2O with persistent irrigation: 72.8 sec (P <0.01 compared to 10 cmH2O without persistent irrigation). The maximum caliber of mice’s tail artery was 50–60 μm. Hydrostatic pressure and irrigation are important factors contributing to hemostasis.
Purpose
This study aimed to evaluate the association between clinical characteristics and development of medication-related osteonecrosis of the jaw (MRONJ) in patients who underwent dental ...examinations before the initiation of treatment with denosumab or zoledronic acid, which are bone-modifying agents (BMAs), for bone metastases. Additionally, the clinical outcomes of patients who developed MRONJ were evaluated along with the time to resolution of MRONJ.
Methods
The medical charts of patients with cancer who received denosumab or zoledronic acid for bone metastases between January 2012 and September 2016 were retrospectively reviewed. Patients were excluded if they did not undergo a dental examination at baseline.
Results
Among the 374 included patients, 34 (9.1%) developed MRONJ. The incidence of MRONJ was significantly higher in the denosumab group than in the zoledronic acid (27/215 12.6% vs 7/159 4.4%,
P
= 0.006) group. Multivariate Cox proportional hazards regression analysis revealed that denosumab treatment, older age, and tooth extraction before and after starting BMA treatments were significantly associated with developing MRONJ. The time to resolution of MRONJ was significantly shorter for patients who received denosumab (median 26.8 months) than for those who received zoledronic acid (median not reached;
P
= 0.024).
Conclusion
The results of this study suggest that treatment with denosumab, age > 65 years, and tooth extraction before and after starting BMA treatments are significantly associated with developing MRONJ in patients undergoing treatment for bone metastases. However, MRONJ caused by denosumab resolves faster than that caused by zoledronic acid.
Myelodysplastic syndrome (MDS) is a clonal hematopoietic neoplasm with high rates of leukemic transformation. MDS had been an intractable disease for which the mainstream of therapeutic approach was ...best supportive care. Recently, however, treatment of hematological malignancies has benefited from advances in molecular targeted drug discovery such as the revolutionary drug imatinib for chronic myeloid leukemia, and from the reappraisal of forgotten drugs such as thalidomide for multiple myeloma. Two azanucleotide drugs, azacitidine (AZA) and decitabine, were created as anti-neoplastic drugs in the 1960s with little success. In the 1980s, they were reassessed as hypomethylating agents (HMAs), and the introduction of low-dose schedules of them has shown dramatic effects in the delay of leukemic evolution for high-risk MDS. AZA was approved in Japan in March 2011 and has become a standard drug of choice in the treatment of high-risk MDS. Its position as a treatment for low-risk MDS remains to be established. Only half of patients with high-risk MDS can gain benefit from AZA. For example, those with complex karyotypes experience only a limited extension in survival. In addition, AZA resistance develops sooner or later. To achieve a more sustained disease control of high-risk MDS, the combined use of HMAs with other therapeutic approaches will be inevitable. Clinical trials of histone deacetylase inhibitors, lenalidomide, thrombopoietin agonists, or anticancer drugs in combination with HMAs are ongoing. In addition, HMAs are being used as a bridging therapy prior to allogeneic stem cell transplantation (AHSCT) and the salvage therapy of relapsed disease after AHSCT. Thus, HMAs will continue to be key drugs for the management of MDS.
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curable treatment option for adolescent and young adult (AYA) patients with myelodysplastic syndrome (MDS). The study aim was to ...evaluate epidemiological data and identify prognostic factors for AYA patients with MDS undergoing allogeneic HSCT. Here, 645 patients were selected from patients enrolled in a multicenter prospective registry for HSCT from 2000 to 2015. The primary endpoint was 3-year overall survival (OS). Survival rates were estimated using the Kaplan-Meier method. Prognostic factors were identified using the multivariable Cox proportional hazards model. The 3-year OS was 71.2% (95% confidence interval CI: 67.4-74.6%). In multivariable analysis, active disease status (adjusted hazard ratio: 1.54, 95% CI: 1.09-2.18, p = 0.016), poor cytogenetic risk (1.62, 1.12-2.36, p = 0.011), poor performance status (2.01, 1.13-3.56, p = 0.016), human leukocyte antigen (HLA)-matched unrelated donors (2.23, 1.39-3.59, p < 0.001), HLA-mismatched unrelated donors (2.16, 1.09-4.28, p = 0.027), and cord blood transplantation (2.44, 1.43-4.17, p = 0.001) were significantly associated with poor 3-year OS. In conclusion, in AYA patients with MDS the 3-year OS following allogeneic HSCT was 71.2%. Active disease status, poor cytogenetic risk, poor performance status, and donor sources other than related donors were associated with poor 3-year OS.
Polatuzumab vedotin (pola) is a CD79b‐targeted antibody‐drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open‐label, single‐arm study of pola ...1.8 mg/kg, bendamustine 90 mg/m2, rituximab 375 mg/m2 (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography–computed tomography (PET‐CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty‐five patients (median age 71 range 46‐86 years) were enrolled. Twenty‐three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow‐up of 5.4 (0.7‐11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval CI 19.1‐52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression‐free survival was 5.2 months (95% CI 3.6‐not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3‐4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1‐2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI‐184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.
We report the results of an open‐label, single‐arm study of polatuzumab vedotin 1.8 mg/kg, bendamustine 90 mg/m2, rituximab 375 mg/m2 in patients with transplant‐ineligible relapsed/refractory (R/R) diffuse large B‐cell lymphoma (DLBCL). A complete response rate of 34.3% at the end of the treatment and consistent safety profile with previous studies with polatuzumab vedotin were observed.
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