Efficacy of bortezomib, cyclophosphamide, and dexamethasone for newly diagnosed POEMS syndrome patients.

Background: Due to the rarity of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, the best first-line treatment has not been established, although there are several options in guidelines. The preferred treatments vary according to the preference of the physician and anecdote. Objectives: First, to analyze the efficacy of a new treatment mode in POEMS syndrome that uses the four-cycle treatment as the induction regimen, followed by sequential transplantation as the consolidation regimen for transplantation-eligible patients, or received another two-cycle treatment for transplantation-ineligible patients. Second, to compare the efficacy and safety of regimens with a proteasome inhibitor (bortezomib-cyclophosphamide-dexamethasone, BCD) or without a proteasome inhibitor (cyclophosphamide-dexamethasone ± thalidomide, CD ± T). Design: We conducted a retrospective study using real-world data from Capital Medical University, Xuanwu Hospital. Methods: A total of 34 newly diagnosed POEMS syndrome patients met Dispenzieri's diagnostic criteria, and those who completed at least four cycles of treatment from July 2013 to March 2021 were included. Results: The overall vascular endothelial growth factor (VEGF) response rate of this new treatment mode was 100%. The cumulative VEGF complete remission (CRV) rate was 67.9%, and the cumulative complete hematological response (CRH) rate was 55.6%. During the median 49-month follow-up, the 5-year-overall survival (OS) rate was 90.7%, the 3-year-progression-free survival (PFS) rate was 78.4%, and the 5-year-PFS rate was 73.8%. The BCD regimen achieved a 75% CRV rate (median time from diagnosis to CRV = 130 days) and 66.7% CRH rate (median time from diagnosis to CRH = 218 days). In addition, the VEGF response was less than the partial remission (PRV) after four-cycle induction treatment, which, together with a decrease on the Overall Neurological Limitation Scale of less than three points 1 year after consolidation treatment, was an independent poor prognostic factor. Conclusion: Bortezomib was well-tolerated by patients with POEMS syndrome. Compared with CD ± T regimen, BCD as the induction regimen achieved better VEGF response and earlier hematological remission. Autologous stem cell transplantation used as consolidation therapy further improved the neurological and hematological remission rates, resulting in better OS and PFS.

A retrospective assessment of real-world experience with venetoclax and azacitidine therapy in elderly acute myeloid leukemia.

This study aimed to examine the effect of venetoclax coupled with azacytidine in treating older adults with relapsed and refractory (R/R) acute myeloid leukemia (AML). The clinical data of 10 senior patients with AML over 65 years old who were treated with venetoclax and azacytidine, including six patients with R/R AML, were retrospectively evaluated. This study comprised seven males and three females with a median age of 71 years. Five patients had at least one relapse, and one patient did not achieve remission after four cycles of azacytidine monotherapy, considering it resistant. AML with myelodysplasia-related changes was found in four cases. One of the 10 patients died early after 1-13 cycles of venetoclax plus azacytidine treatment due to a protracted period of neutropenia and severe lung infection induced by medications. Six of the remaining nine patients, including six R/R patients, achieved a complete remission (CR) or a CR with incomplete hematologic recovery (CRi). After two cycles of therapy, one patient did not react. Neutropenia lasted an average of 10.5 (6-15) days in all patients, with the most severe cases occurring in the second and third weeks of therapy. Three patients who tested positive for the TP53 gene mutation had the following outcomes: One relapsed patient has been in progression-free remission (PFS) for the past 24 months, whereas another has been in full remission but relapsed 2 months later. Another patient experienced complete remission in myelology for 4 months, but the variable allele fraction (VAF) value steadily rose, suggesting that the illness was on the verge of progressing. IDH2 gene alterations were found in three of four patients who obtained maintained CR for more than 18 months following recurrence. Venetoclax in combination with azacytidine is a successful and well-tolerated therapy for R/R AML in the elderly. Venetoclax and azacytidine may help patients with TP53 mutations and reduce VAF. The IDH2 mutation might be a good predictor of veneclax sensitivity. A notable adverse response in the treatment phase of the regimen is severe infection induced by neutropenia.

[Sensitivity of AML Cells with FLT3- to PKC412 In Vitro].

OBJECTIVE: To explore the clinical value of PKC412 (midostaurin) in treatment of AML patients with FLT3-. METHODS: The bone marrow or peripheral blood were collected and heparinized from 21 newly diagnosed FLT3- AML patients, then the mononuclear cells from bone marrow or peripheral blood were isolated by density-gradient method. The sensitivity of leukemia cells to PKC412 of 8 concentration in vitro was detected by ATP-bioluminescence-tumor chemosensitivity assay (ATP-TCA), and the relationship among sensitivity results in vitro, risk stratification and therapeutic efficacy was analyzed. RESULTS: The leukemia cells of 21 patients with AML displayed different sensitivities to PKC412 in vitro. The rate of sensitivity in vitro was 42.9%, and sensitive concentration in vitro were between 1 µmol/L and 5 µmol/L. There was no significant relationship between risk stratification and sensitivity results of PKC412 in vitro. There was also no significant relationship between clinical efficacy and sensitivity results of PKC412 in vitro. The survival of patients in low-risk and intermediate-risk groups was better than that of patients in high-risk groups (P=0.015). CONCLUSION: PKC412 can be one of the effective therapeutic method for AML patients without FLT3 mutation. The sensitivity of leukemia cells to PKC412 may become a prognostic marker for evaluating clinical efficacy of PKC412, which is independent of other factors.

Relationship between Hepatitis C Virus Infection and Iron Overload.

OBJECTIVE: The aim of this study was to summarize the interactions between hepatitis C virus (HCV) infection and iron overload, and to understand the mechanisms of iron overload in chronic hepatitis C (CHC) and the role iron plays in HCV life cycle. DATA SOURCES: This review was based on data in articles published in the PubMed databases up to January 28, 2017, with the keywords "hepatitis C virus", "iron overload", "iron metabolism", "hepcidin", "translation", and "replication". STUDY SELECTION: Articles related to iron metabolism, iron overload in patients with CHC, or the effects of iron on HCV life cycle were selected for the review. RESULTS: Iron overload is common in patients with CHC. The mechanisms involve decreased hepcidin levels caused by HCV through signal transducer and activator of transcription 3, mitogen-activated protein kinase, or bone morphogenetic protein/SMAD signaling pathways, and the altered expression of other iron-metabolism-related genes. Some studies found that iron increases HCV replication, while other studies found the opposite result. Most of the studies suggest the positive role of iron on HCV translation, the mechanisms of which involve increased expression levels of factors associated with HCV internal ribosome entry site-dependent translation, such as eukaryotic initiation factor 3 and La protein. CONCLUSION: The growing literature demonstrates that CHC leads to iron overload, and iron affects the HCV life cycle in turn. Further research should be conducted to clarify the mechanism involved in the complicated interaction between iron and HCV.

Improvement of chronic hepatitis B by iron chelation therapy in a patient with iron overload: A case report.

RATIONALE: This report describes seroconversion of hepatitis B surface antigen (HBsAg) in a patient with marked iron overload caused by chronic hepatitis B (CHB) after receiving iron chelation therapy and discusses the role of iron chelation therapy in CHB. PATIENT CONCERNS: Increased serum ferritin level for 2 months. DIAGNOSIS: Secondary iron overload and CHB. INTERVENTION: To relieve iron load of the body, the patient underwent regular phlebotomy therapy and deferoxamine (DFO) therapy. During the therapy, serum ferritin and hepatitis B virus (HBV) were monitored and the iron concentration of the liver and heart were followed by T2* of magnetic resonance imaging (MRI) scan. OUTCOMES: Serum ferritin gradually decreased. Approximately 1 year after the therapy, HBsAg turned persistently negative. LESSONS: Iron chelation therapy may attenuate HBV infection.

[Rituximab combined with EPOCH regimen for treatment of diffuse large B cell lymphoma of the gastrointestinal tract: analysis of 4 cases].

We treated 4 with a diagnosis of diffuse large B cell lymphoma involving the gastrointestinal tract with rituximab combined with adjusted dose EPOCH (R-DA-EPOCH) scheme based on a comprehensive analysis of the onset process, clinical and pathological features, and prognosis of the patients, and evaluated their treatment response. Complete remission (CR) was achieved in 3 patients after the treatment and 1 patient with diabetes and hypertension died due to severe infection. R-DA-EPOCH regimen as the first-line treatment of gastrointestinal diffuse large B cell lymphoma has a good short-term efficacy, but its long-term efficacy awaits further evaluation in future studies with larger sample sizes.

[Research Progress on Treating Acute Myeloid Leukemia by Midostaurin].

FLT3 gene mutations occurred in approximately 30% of acute myeloid leukemia (AML) patients, which is closely associated with the occurrence, development and poor prognosis of AML. The therapy targeting at FLT3 mutations might be a promising treatment for AML. Midostaurin can inhibit the activities of III receptor tyrosine kinase encoded by FLT3 gene, induce cell cycle arrest and has a apoptotic effect on primitive AML cells of FLT3 -mutant, FLT3 wild-type and the expression of FLT3 mutated receptor. In view of this, the association between FLT3 mutations and AML, and research advances and clinical applications of midostaurin on the treatment of AML especially for FLT3 mutated AML, are reviewed.

[Abnormal Karyotypes Involving 1q21 and 12p13 and Their Clinical Significance].

Many hematological malignances involve recurrent chromosomal abnormalities, and the reciprocal translocation is one of them. However, there are a lot of chromosomal abnormalities with lower incidence and unclear clinical significance. Among them, the one abnormal karyotype translocation, t (1;12) (q21; p13) is a rare karyotype change. Only 6 patients had been reported to have this karyotype and all of them suffered from hematologic diseases, including one case of acute myeloid leukemia, one case of high-risk myelodysplastic syndrome, two children with acute lymphoblastic leukemia, one case of chronic myeloid leukemia at accelerated phase and one case of multiple myeloma. Among them, the fusion gene were detectable in two cases. In this article, the common chromoscme karyotype abnormality involving 1q21 and 12p13, and genes involving in these regious are summarized, moreover the reported cases of t(1;12) (q21;p13) are reviewed.

[Genetic characteristics of human acute lymphoblastic leukemia cell line Molt-4].

This study was aimed to investigate the genetic characteristics of human acute lymphoblastic leukemia cell line Molt-4, and evaluate its application in measuring telomere length by Flow-FISH. Molt-4 cell line was cultured in suspension and subcultured regularly. Eight different passages of Molt-4 cells in exponential stage were selected.The growth curves were drawn by cell counting method, meanwhile calculating the population doubling times of cells,DNA ploidies were determined by flow cytometry,karyotypes were analyzed by G-banding and telomere lengths were measured by Southern blot. The results showed that the population doubling time of Molt-4 cell line was (1.315 ± 0.062) d, DNA ploidy index was (2.085 ± 0.0093) , and the telomere length was (32.05 ± 5.27) kb. There were no significant difference among different passages (P = 0.931,0.888 and 0.935 separately). The karyotypes showed that the chromosome numbers of Molt-4 cell line were from 91 to 99 in different metaphases, and the majority of them were hypertetraploid, and stable and recurrent structural abnormalities of chromosomes could be kept. It is concluded that the stable genetic characteristics and the longer telomere length of Molt-4 cell line makes it be a feasible control cells in measurement of telomere length by Flow-FISH.

[Application of flow cytometry-fluorescence in situ hybridization in the measurement of relative telomere length of bone marrow CD34(+) cells in patients with myelodysplastic syndrome].

This study was aimed to investigate the feasibility of flow cytometry-fluorescence in situ hybridization (Flow-FISH) in measuring the telomere length of bone marrow cell subgroups in patients with myelodysplastic syndrome (MDS). Seven newly diagnosed patients with low-risk MDS and seven nutritional anemia patients who were matched with age and sex, were enrolled in this study. Heparinized bone marrow were sampled. Taking Molt-4 cell line as internal control cells, leukocytes isolated from whole bone marrow were labeled with CD34-Alexa Fluork ® 647, then denatured by high temperature and hybridized with FITC-conjugated telomere probe. The DNA was counterstained and the relative telomere length (RTL) of nucleated cells and CD34(+) cells in bone marrow were measured by four-color flow cytometry. The results showed that CD34(+) cells could be gated for the measurement of RTL in both groups, undergoing the denaturation and hybridization. Primary analysis indicated that the RTL of bone marrow CD34(+) cells in MDS patients was significantly shorter than that of bone marrow nucleated cells (P = 0.001), and the RTL of both CD34(+) cells and nucleated cells in bone marrow of MDS patients were significantly shorter than that of control group (P = 0.020, 0.002). It is concluded that the application of Flow-FISH in the measurement of RTL of certain cell subgroup is feasible by labeling the cell with thermostable fluorescence-conjugated antibody, and this technique is worthy to be investigated further.

Clinical outcome of autologous peripheral blood stem cell transplantation in opticospinal and conventional forms of secondary progressive multiple sclerosis in a Chinese population.

To evaluate clinical outcomes of autologous peripheral blood stem cell transplantation (APBCST) between opticospinal multiple sclerosis (OSMS) and conventional multiple sclerosis (CMS) during disease progressive stage in a Chinese population. Thirty-six secondary progressive MS patients, among whom 21 were with OSMS and 15 with CMS, underwent APBSCT and were followed up for an average of 48.92 months (range, 10-91 months). Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony-stimulating factor. Modified BEAM conditioning regimen (Tiniposide, melphalan, carmustin, and cytosine arabinoside) were administered. Outcomes were evaluated using the expanded disability status scale (EDSS). No maintenance treatment was administered if there was no disease progression. No treatment-related mortality occurred. Among the 36 patients, one OSMS patient dropped during the follow-up. Among the 22 relapse-free patients, 20 were with continuous neurological improvement without any relapse events, and two remained in neurologically stable states. Among the 13 relapse patients, seven had experienced of neurological relapse, but with no progression during the follow-up period; and six experienced neurological deterioration after transplantation and needed further immunosuppressant treatment. The confirmed relapse-free survival rate was 62.9% and progression-free survival rate was 83.3% after 91 months according to Kaplan and Meier survival curves. Eleven of the 20 OSMS patients (55%) and two of the 15 CMS patients (13.3%) stayed in disease active group (P = 0.014). For the 20 OSMS patients, the overall EDSS score decreased significantly after transplantation (P = 0.016), while visual functions had no significant improvement (P = 0.716). Progressive OSMS has a higher relapse rate than CMS following APBSCT.

Ex vivo expansion and long-term hematopoietic reconstitution ability of sorted CD34+CD59+ cells from patients with paroxysmal nocturnal hemoglobinuria.

Autologous bone marrow transplantation (ABMT) for paroxysmal nocturnal hemoglobinuria (PNH) remains difficult so far. To expand residual normal CD34(+)CD59(+) cells isolated from patients with PNH and observe the long-term hematopoietic reconstruction ability of the expanded cells both ex vivo and in vivo, CD34(+)CD59(+) cells from 13 PNH patients and CD34(+) cells from 11 normal controls were separated from bone marrow mononuclear cells first by immunomagnetic microbeads and then by flow cytometry autoclone sorting. The cells were then cultivated under different conditions. The long-term hematopoietic supporting ability of expanded CD34(+)CD59(+) cells was evaluated by long-term culture in semi-solid medium in vitro and long-term engraftment in irradiated severe combined immunodeficiency (SCID) mice in vivo. The best combination of hematopoietic growth factors for ex vivo expansion was SCF + IL-3 + IL-6 + FL + Tpo + Epo. The most suitable time for harvest was on day 7. CD34(+)CD59(+) PNH cells retained strong colony-forming capacity even after expansion. The survival rate, complete blood cell count recovery on day 90, and human CD45 expression in different organs were similar between the irradiated SCID mice transplanted with expanded CD34(+)CD59(+) PNH cells and those with normal CD34(+) cells (P > 0.05) both in primary and secondary transplantation. These data provided a new potential way of managing PNH with ABMT.

[Multiparameter flow cytometric evaluation of bone marrow involvement in B cell non-Hodgkin's lymphoma].

The objective of study was to evaluate the clinical values of multiparameter flow cytometry (MPFC) and cytomorphology of bone marrow aspiration(BMA) in detecting bone marrow involvement in patients with B cell Non-Hodgkin's lymphoma (B-NHL). 96 bone marrow samples from the patients with B-NHL were measured by MPFC using CD45/SSC and CD20/SSC gating strategy combined with anti-kappa and anti-lamda monoclonal antibodies, and then compared with results acquired by cytomorphologic analysis of BMA. The results showed that the bone marrow involvement was confirmed by MPFC in 38 cases (39.6%), while it was detected by cytomorphologic analysis of BMA only in 12 cases (12.5%). There was a significant difference between the two methods (p<0.05). 12 positive cases detected by cytomorphologic analysis of BMA were also positive by MPFC. There was no difference of 3-year overall survival rate between negative and positive cases detected by MPFC, but their 4-year overall survival rate was 73.18+/-6.65% and 44.13%+/-19.55% respectively (p<0.05). It is concluded that the MPFC is a more sensitive method for detecting bone marrow involvement in patients with B-NHL than cytomorphologic analysis of BMA. The 4-year overall survival rate of the patients without bone marrow involvement was significant higher than those of patients with bone marrow involvement. Bone marrow involvement in B-NHL detected by MPFC can be useful for clinical evaluation and prognosis prediction.

[Application of interphase FISH on cell smears in detection of hematological diseases].

The study was aimed to investigate the application value of interphase fluorescence in situ hybridization (FISH) on cell smears in hematological diseases. Both interphase FISH on peripheral blood smears and bone marrow smears treated by methanol/acetic acid, and routine interphase FISH of bone marrow cells dropped on slides were done at the same time, in order to detect Ph chromosome by BCR/ABL dual color, dual fusion probe in 20 patients with chronic myelogenous leukemia or acute lymphoblastic leukemia which had been proven to display Ph chromosome positive. The results indicated that as compared with routine interphase FISH, the interphase FISH on cell smears could also offer reliable result. It is concluded that interphase FISH on cell smears is a kind of reliable and time-saving technique, which is also suitable for retrospective research and worthy to further apply in clinic.

Successful antiangiogenic combination therapy for pseudomyxoma peritonei with bevacizumab and capecitabine.

Effective systemic therapy for advanced pseudomyxoma peritonei (PMP) is the focus of investigation. We describe a case of PMP arising from an adenoma of the appendix in a 58-year-old man. First, the patient underwent explorative laparotomy with ileocoecal resection, but without possibility of major tumor debulking due to adhesive gross tumor masses. Subsequently, six cycles of Folfox IV chemotherapy were administered, without response, but with severe side effects. Upon progressive disease, a combination of bevacizumab and capecitabine led to a long term stabilization of disease and obvious improvement of performance status. Our case suggests that modulation of tumor microenvironment and angiogenesis by bevacizumab, potentially augmented by moochemotherapy, may be beneficial in borderline tumors such as PMP.

[Detection of deletion of the long arm of chromosome 13 and translocation of immunoglobulin heavy chain gene by interphase fluorescence in situ hybridization in patients with multiple myeloma].

OBJECTIVE: To investigate the clinical significance of the deletion of the long arm of chromosome 13 [del (13 q) ] and translocation of immunoglobulin heavy chain gene [t (14 q) I in multiple myeloma (MM) patients. METHODS: Myeloma cells were isolated from hone marrow by direct immunomagnetic cell sorting and interphase fluorescence in situ hybridization (FISH) was performed in 24 MM patients to detect del (l3q) and t (l4q). RESULTS: The positive rates of del (l3q) and t (l4q) were 45.83% and 37.50% respectively. Five patients (20.83%) had both two abnormalities and 15 patients (62.50%) had at least one abnormality. Univariate analysis showed that the positive rates of del (l3q) were 35.71% and 66.67% in responders and non-responders (P = 0.214) and the positive rates of t (l4q) were 21.43% and 66. 67% in responders and non-responders (P = 0.077). Multivariate analysis showed that del (13q) (OR = 5.761, 95% CI 0.500-66.391, P = 0.160), t (14q) (OR = 6.576, 95% CI 0.580-74.614, P = 0.129), and corrected serum calcium level (OR = 8.080, 95% CI 0.738-88.427, P = 0.087) were relatively independent negative factors for response to therapy, with the corrected serum calcium level being the strongest reversely-correlated factor. CONCLUSIONS: Interphase FISH is a sensitive method to investigate the cytogenetics of MM. Del (13q), t (14q), and corrected serum calcium level can be used to predict treatment response and prognosis.

[DNA content and cell cycle analysis of myeloma cells in patients with multiple myeloma].

The study was aimed to investigate the genetic background and proliferation characteristics of multiple myeloma (MM). Myeloma cells were isolated from bone marrow of 19 MM patients by direct immunomagnetic cell sorting and the DNA content and cell cycle analysis were carried out by flow cytometry. The results showed that in 4 patients the myeloma cells were found to be hyperdiploid and in 15 patients those were found to be diploid respectively by DNA content analysis; the proportion of plasm cells from normal controls in S + G(2)/M phase was (1.15 +/- 0.60)%, and that of myeloma cells from MM patients was (10.06 +/- 12.60)% which was significantly higher than that in the former (p = 0.001). The incidence of hyperdiploid in newly diagnosed patients was 11.76%, and that of treated patients was 100.00% which was significantly higher than that in the former (p = 0.035); the proportion of myeloma cells from newly diagnosed patients in S + G(2)/M phase was (7.12 +/- 4.98)%, and that of treated patients was (35.10 +/- 32.56)% which was also significantly higher than that in the former (p = 0.001). It is concluded that the variety of myeloma cells in DNA content and cell cycle suggests the complicated genetic background and abnormal proliferation of MM, which relate with the course of disease to some extent.