Protective effect of immunomodulating peptide(PGPIPN) derived from beta-casomorphin in bovine milk on acute alcohol-induced liver injury / 中国药理学通报

Aim To investigate the protective effect of immunomodulating peptide(PGPIPN) on the acute al-coholic liver injury in mice. Methods Kunming mice were randomly divided into control group, model group,glutataione(GSH) group, PGPIPN low dose group, PGPIPN moderate and high dose groups. The mice were treated with different doses of PGPIPN or GSH for two weeks except control group and model group. The acute alcoholic liver injury model was in-duced by gavage with 56° alcohol for three days. The indices including the activities of AST,ALT in serum, and the contents of TNF-α, MDA, SOD and GSH-Px in liver were examined. Liver histopathological changes were examined by HE staining. Results Compared with control group,the levels of serum ALT,AST and the contents of TNF-α, MDA significantly increased, while the contents of SOD and GSH-Px significantly de-creased in model group. There was hepatocyte apopto-sis and inflammatory cell infiltration in liver tissues. Compared with model group, the activities of serum ALT, AST and the contents of TNF-α, MDA were re-markably reduced in PGPIPN high dose group. The contents of SOD and GSH-Px significantly increased in PGPIPN high dose group. PGPIPN could alleviate the injury of liver. Conclusion PGPIPN has certain pro-tective effect on acute alcoholic liver injury of mice, providing a theoretical guidance.

Efficacy and prognostic factors of induction therapy combined with autologous stem cell transplantation in 201 patients with multiple myeloma / 中华血液学杂志

<p><b>OBJECTIVE</b>To explore the efficacy and prognostic factors of induction therapy combined with autogenetic peripheral blood stem cells transplantation (APBSCT)in patients with multiple myeloma (MM).</p><p><b>METHODS</b>From January 1998 to May 2015, 201 patients with MM were enrolled. All patients received APBSCT after induction therapy. With the follow up to 20 June 2015, the overall survival (OS), progression free survival (PFS)and prognostic factor were analyzed.</p><p><b>RESULTS</b>① With a media follow up of 36.67 months, the median PFS and OS were 22.87 (17.48- 28.26)and 69.63 (63.57- 75.69)months, 5-year PFS and OS were 17% and 49%, respectively. ②After APBSCT, when the subgroup (n= 112) achieved complete response (CR)compared with the subgroup (n=89) not achieved CR, the median PFS were 32.93 (21.03-44.83) and 18.13 (14.46-21.80) months (P<0.001), respectively; And the media OS were 96.77 (71.79- 121.75)and 54.70 (49.53- 59.87) months (P=0.004), respectively. The risks for disease progression and death declined in CR subgroup. ③ Two subgroups included or not included bortezomib/thalidomide at induction therapy (123 patientsvs 21 patients), the media PFS were 31.67 (24.36- 38.98)and 15.20 (10.11- 20.29) months (P=0.013), respectively; And the media OS were 76.30 (55.44- 97.15)and 52.03 (33.76- 70.30) months (P=0.014), respectively. ④According to the ISS stage, the media OS of stageⅠ, Ⅱ, Ⅲ were 99.47 (59.58-139.36), 66.77 (52.17-81.37), 53.97 (28.71-79.23) (P< 0.001), respectively. The risk for death of stage Ⅱ, Ⅲ were 2.16 and 3.04 times higher than stage Ⅰ, with no difference in terms of PFS. ⑤ The media PFS in IgD (n=22) and IgG (n=101) type MM were 11.17 (10.27- 13.13)and 35.43 (22.69- 48.17)months (P=0.007) , respectively; The media OS were 30.83 (0.24-61.42)and 70.70 (53.52-87.88) months (P=0.039), respectively. The risk for disease progression of IgD type was 2.47 times higher than IgG type. ⑥ Patients received 1 line induction therapy (n=132) compared with more than 1 line (n=69), the media PFS were 25.43 (16.09- 34.77)and 20.27 (15.04- 25.50) months (P=0.042). ⑦Cox analysis showed that CR after APBSCT and ISS stage were independent prognostic factors for OS. IgD type MM and CR after APBSCT were independent prognosis factor for PFS.</p><p><b>CONCLUSION</b>CR after APBSCT and ISS stage were independent prognostic factors for OS in MM. CR after APBSCT was independent prognostic factor for PFS in MM. However, disease progression more likely occurred in IgD type MM, which was independent negative prognostic factor for PFS in MM.</p>

Benefit of autologous stem cell transplantation in multiple myelo-ma patients at different risks after bortezomib- and/or thalido-mide-based induction therapies / 中国肿瘤临床

Objective:To evaluate the benefit of autologous stem cell transplantation (ASCT) as a consolidation therapy in the survival of multiple myeloma (MM) patients at different risks. Methods:A total of 67 MM patients who received ASCT as consolida-tion therapy between August 2006 and July 2011 were enrolled in the retrospective study. The cases were divided into three risk groups on the basis of the International Staging System and fluorescence in situ hybridization. Another 67 patients who accepted consolidation chemotherapy at the same period were selected as case-paired controls matched in terms of age, sex, optimal response after induction, and risk stratifications. All the patients received bortezomib-and/or thalidomide-based induction therapies. Results:No statistical differ-ences in non-complete remission (nCR)/complete remission (CR) rate were observed between the ASCT and chemotherapy groups (44.8%vs. 37.3%, P=0.380) after the induction therapy. The progression-free survival (PFS) was longer in the ASCT group than in the chemotherapy group (32.4 months vs. 15.1 months, P0.05). In the low-risk subgroup, only PFS was extend-ed (median: 34.8 months vs. 17.6 months, P=0.012) after ASCT, without significant improvements in the OS (P>0.05). Conclusion:The MM patients obtained cytogenetic high-risk benefits mostly from ASCT consolidation after inductions based on novel agents.

Busulfan, cyclophosphamide and etoposide as conditioning for autologous stem cell transplantation in multiple myeloma / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy and safety of dose-reduced intravenous busulfan, cyclophosphamide and etoposide (BCV) as conditioning for autologous stem cell transplantation (ASCT) in multiple myeloma (MM).</p><p><b>METHODS</b>From September 2007 to September 2010, thirty-two ASCT-eligible patients with MM received high dose melphalan (HDM) as conditioning in our center. Median age was 53.5 (30-63) years. From October 2010 to October 2012, thirty-eight patients conditioned by BCV regimen (intravenous busulfan, total doses 9.6 mg/kg), whose median age was 54(35-64) years.</p><p><b>RESULTS</b>There were no statistical differences in clinical characteristics between the two groups, including myeloma isotype, Durie-Salmon staging, international staging system(ISS), and patients received the first line, second line or more than third line therapy. The median time to neutrophil and platelet engraftment were 10.5 vs 11 days (P=0.057) and 11 vs 12 days (P=0.100) in the BCV and HDM groups, respectively. The toxicity of two conditioning regimens had no significant difference. None of hepatic veno-occlusive disease and early transplant related mortality was observed. Although overall response rates showed no significant difference between two groups (P>0.05), the CR rates increased from 44.74% pre-ASCT to 63.18% post-ASCT in the BCV group, while 37.50% to 59.38% in the HDM group. During the median follow-up of 16 months (range 2-27) in BCV group, ten patients (26.32%) developed progressive disease and PFS at 12 months were 71.37%.</p><p><b>CONCLUSIONS</b>In this study, the dose-reduced intravenous busulfan, cyclophosphamide and etoposide (BCV) conditioning was demonstrated an effective and safety regimen for ASCT-eligible patients with MM. However, the long term observation is needed.</p>

The clinical characteristics and prognostic analysis of 147 cases of diffuse large B-cell lymphoma / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the relationship between the clinical features, pathogenesis, immunophenotype, different classification models and prognosis in Chinese patients with diffuse large B-cell lymphoma (DLBCL).</p><p><b>METHODS</b>A total of 147 patients with DLBCL who were treated with CHOP-like or R-CHOP were subjected to analysis. Standard two-step Envision method of immunohistochemical staining was used to assess the expression of CD10, Bcl-6, MUM1, FOXP1, GCET1, CD5, Bcl-2, Ki-67, then according to Hans algorithm, Choi algorithm and Molecular markers, we compared the differences of their prognoses.</p><p><b>RESULTS</b>(1) Kaplan-Meier univariate analysis of the clinical data of 147 DLBCL patients found that the 3-year overall survival (OS) rates were better in early stage (P=0.032), low IPI score (P=0.001), less than one extranodal involvement (P=0.014), and complete remission (P<0.01). The prognoses had no significant difference in terms of gender, age, LDH, B symptoms and treatment options (P value> 0.05). (2 )For Hans model, GCB group had 42 cases, the ABC group 85 cases; GCB were 47 cases, ABC 80 cases (according to Choi model). Choi model suggested GCB subtype showed much better prognosis than ABC subtype (P=0.047), while Hans model shed no statistically significant difference (P=0.285). (3) Ki-67 of 75% was found to significantly discriminate patients with good or bad prognosis. In R-CHOP group at the same time, low Ki-67 (P=0.017) and CD5-negative groups (P=0.012) were better. Cox proportional hazards regression model showed that IPI score (P=0.002) and Ki-67 (P=0.019) were independent adverse prognostic factors.</p><p><b>CONCLUSION</b>The Ann Arbor stage, IPI score, extranodal involvement status and Ki-67 were significantly associated with prognosis .Compared to Hans algorithm, Choi had an advantage to predict the different prognosis between subtypes, and ABC group had poor outcome. Finally, both Ki-67 and IPI score were independent adverse prognostic factors.</p>

Allogeneic peripheral blood stem cell transplantation from sibling donors for 10 patients with multiple myeloma / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy of allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from sibling donors for treatment of multiple myeloma (MM).</p><p><b>METHODS</b>Ten patients with MM received allo-PBSCT with conditioning consisting of fludarabine plus melphalan and cyclophosphamide mostly.CsA plus mycophenolate mofetil (MMF) and short-term MTX were applied to prevent graft versus host disease (GVHD) in 8 patients, FK506 plus short-term MTX in other 2 patients.</p><p><b>RESULTS</b>All patients engrafted successfully, the median time for ANC > 0.5 × 10(9)/L was 16 (12 - 24) days, and for BPC > 20 × 10(9)/L 23 (16 - 102) days. Five patients developed acute GVHD, and only one III-IV aGVHD. Of 9 patients, 7 developed chronic GVHD. The transplant-related mortality (TRM) at 100 days was 10% (1/10), mainly from heart and renal failure and severe infection. The 1-year expected overall survival (OS), 1-year disease-free survival (DFS) and relapse rate were 67.5%, 55.56% and 11.11% respectively. Up to now, 6 patients were still alive, of them 1 patient have survived over 99 months after allo-PBSCT.</p><p><b>CONCLUSION</b>Young MM patients having HLA-identical sibling donors well tolerated allo-PBSCT based on fludarabine to prolong their OS by reducing TRM, though further work is warranted.</p>

Clinical effects of autologous stem cell transplantation as consolidation treatment in 70 multiple myeloma patients: a case-controlled study / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Autologous stem cell transplantation (ASCT) is a part of the standard induction therapy of multiple myeloma (MM). This case-controlled clinical trial aimed to further evaluate the therapeutic effects of ASCT as a consolidation therapy for MM and discuss factors influencing the prognosis.</p><p><b>METHODS</b>Clinical data of 70 patients diagnosed as MM who received ASCT as a consolidation therapy in our hospital between October 1998 and August 2010 were analyzed retrospectively (ASCT group). Other 70 MM patients receiving routine chemotherapy without ASCT (non-ASCT group) during the same period were used as controls. Differences in the degree and duration of remission, progression-free survival (PFS) and overall survival (OS) were compared to explore factors that may influence the prognosis.</p><p><b>RESULTS</b>The median follow-up period was 38 months (range 1 - 128 months). The complete response (CR) rate of ASCT group increased from 27.1% (19/70) before ASCT to 51.4% (36/70) after ASCT. The median PFS of ASCT group was significantly higher than non-ASCT group (45 months vs. 25 months, P < 0.001). The median OS of ASCT group was also significantly higher (55 months vs. 30 months, P = 0.016). Single-factor analysis showed that International Staging System (ISS) stage, very good partial response (VGPR) or better outcome were significantly correlated with PFS and OS (P < 0.001). Multi-factor analysis showed that whether or not VGPR or better outcome was achieved were independent factors influencing the disease prognosis.</p><p><b>CONCLUSION</b>Used as a consolidation therapy, ASCT can achieve better responses and higher OS and PFS of MM patients.</p>

Clinical features of multiple myeloma invasion of the central nervous system in Chinese patients / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Although neurologic manifestations often complicate the course of patients with multiple myeloma, direct central nervous system invasion is rare. This study explored the neurologic symptoms, signs, clinical features, therapy and prognosis of Chinese patients with central nervous system myeloma invasion.</p><p><b>METHODS</b>The diagnosis, therapy and prognosis were analyzed retrospectively in 11 Chinese multiple myeloma patients with central nervous system infiltration from a total of 625 patients who have been treated at Changzheng Hospital (Shanghai, China) between January 1993 and May 2009. Survival curve was constructed with the use of Kaplan-Meier estimates.</p><p><b>RESULTS</b>There were 11 patients with central nervous system involvement from 625 multiple myeloma patients. The occurrence rate was 1.8%. Ten of the 11 patients had other extramedullary diseases. Symptoms included cerebral symptoms, cranial nerve palsies, and spinal cord or spinal nerve roots symptoms. Cerebrospinal fluid was abnormal in 7 patients, usually exhibiting pleocytosis and elevated protein content, plus positive cytologic findings. Specific magnetic resonance imaging findings suggestive of central nervous system invasion were found in 9 patients. After a median follow-up of 19 months, 3 patients were alive. The median overall survival for all patients was 23 months, while the median overall survival for patients after central nervous system invasion was merely 6 months.</p><p><b>CONCLUSIONS</b>It is exceedingly rare for there to be central nervous system infiltration in multiple myeloma patients. When it occurs, the prognosis is extremely poor despite the use of aggressive local and systemic treatment including stem cell transplantation.</p>

Establishment of a bortezomib-resistant myeloma cell line and differential proteins analysis by MALDI-OF-MS / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To establish a bortezomib-resistant myeloma cell line and to investigate its mechanism.</p><p><b>METHODS</b>Bortezomib-resistant NCI-H929 cell line (NCI-H929B) was obtained by stepwise increasing extracellular concentrations of bortezomib over a period of 8 months. The biological characteristics of NCI-H929 and NCI-H929B were observed. Proteins from NCI-H929B cell and NCI-H929 cell were extracted, run on two-dimensional gel electrophoresis. Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) and mass spectrometry (MS) were used to identify proteins. Western blot was used to further verify differential proteins.</p><p><b>RESULT</b>Bortezomib-resistant cell line NCI-H929B was established. NCI-H929B exhibits a 23.5-fold level of resistance to bortezomib as compared to the parental cell line NCI-H929. There were no significant differences in cellular biology of cell growth curve and cell cycle distribution between NCI-H929 and NCI-H929B cell lines.Whole proteins of NCI-H929 and NCI-H929B myeloma cell lines were extracted by two-dimensional gel electrophoresis. Gel-image analysis revealed that there were 17 differential protein spots. A total of 14 differential protein spots were successfully identified by MALDI-TOF-MS. The result of Western blot was consistent with 2-DE.</p><p><b>CONCLUSION</b>A bortezomib-resistant human myeloma cell line NCI-H929B was successfully established. The differentially expression of proteomes may be useful for study of the bortezomib-resistant mechanisms and the molecular markers of MM.</p>

The impact of autologous stem cell transplantation on the prognosis in multiple myeloma / 中华血液学杂志

<p><b>OBJECTIVE</b>To evaluate the efficacy of autologous stem cell transplantation (ASCT) in the treatment of multiple myeloma (MM) and its impact on the prognosis of MM.</p><p><b>METHODS</b>Retrospective analysis was performed in 28 patients with MM (group A) treated with ASCT in our hospital from October 1998 to February 2007, compared with those not received ASCT in the same time period including 23 patients with near complete response (nCR) or better (group B) and 25 patients with partial response (PR) (group C). The duration of response (DOR), time to progression (TTP) and overall survival (OS) were compared by Kaplan-Meier method in the 3 groups.</p><p><b>RESULTS</b>Eight patients without nCR or better (7 in PR and 1 in MR) after ASCT achieved CR (2 cases) and nCR (5 cases). Complete response (CR) rate was 10.7% (3 cases) and 42.9% (12 cases) before and after ASCT respectively in group A. DOR was 33 months for group A, 17 months for group B and 18 months for group C, and TTP was 45, 43 and 28 months respectively. After a median follow-up of 30 months, patients in group A and in group B had a trenel of longer OS than in group C although there was no statistically significant difference.</p><p><b>CONCLUSIONS</b>ASCT can further enhance the response, prolong the DOR and TTP and probably OS, and therefore improve the quality of life in MM. MM patients not achieved good response by non-ASCT therapy may benefit from ASCT.</p>

Bortezomib-based combination therapy for relapsed or refractory multiple myeloma / 中华内科杂志

Objectives To investigate the efficacy and toxicity of bortezomib based combination therapy for Chinese patients with relapsed or refractory multiple myeloma(MM),and to determine the combination regimen,dosage and cycles in application of bortezomib for MM therapy.Methods Forty-six patients with refractory or relapsed myeloma were treated with bortezomib(1.3 mg/m2)as an intravenous bolus twice weekly for 2 weeks on day 1,4,8,and 11 in a 3-4 week cycle,in combination with dexamethasone,dexamethasone plus thalidomide, CD(C-cytoxan,D-dexamethasone),MD(M- mitoxsnteone),DCEP(E-etoposide,P-platinol),and DT-PACE regimens(T-thalidomide,A-adriamycin). Response to bortezomib was evaluated according to the criteria of the International Myeloma Working Group (IMWG)before initiation of each cycle.Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria,version 3.0.Forty-nine matched patients with relapsed and refractory MM who received thalidomide based combination therapy were used as a historical control group.Results Among 43 of the 46 patients whom could be evaluated,the overall response rate was 72.1%(the control group was 51.0%,P＜0.05),including complete response in 5 patients(11.6%),very good partial response in 12 patients(27.9%),and partial response in 14 patients(32.6%).The overall response rate after one and two cycles was 30.2%and 58.1%(P＜0.05),respectively.The frequent adverse events were thromboeytopenia(62.8%),fatigue(55.8%),nausea(51.2%)and peripheral neuropathy (30.2%);all of the events could be tolerated.The most common adverse event in the control group was constipation(69.4%),followed by fatigue(59.2%)and dizziness(46.9%).Conclusions Bortezomib based combination therapy is a new effective therapy in relapsed or refractory myeloma patients with a higher response rate and difierent toxicities as compared with thalidomide based combinations.

Bortezomib in combination with dexamethasone for the treatment of relapsed or refractory multiple myeloma / 中华血液学杂志

<p><b>OBJECTIVE</b>To investigate the efficacy and toxicity of bortezomib in combination with dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma(MM).</p><p><b>METHODS</b>Sixteen patients(9 males, 7 females, mean age 57. 5 yrs) with refractory or relapsed MM were treated with bortezomib (1. 3 mg/m(2) ) by intravenous bolus twice a week for 2 weeks, or 3. 5 mg once a week in a 21-day cycle, followed by an intravenous injection of dexamethasone 30 - 40 mg. The patients had received one to four courses at least. Response to bortezomib was evaluated according to the criteria of the European Group for Blood and Marrow Transplantation (EBMT) before initiation of each bortezomib chemotherapy course. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria, version 3. 0.</p><p><b>RESULTS</b>The median follow-up duration from the beginning of bortezomib treatment was 6 months. Clinical response was observed in 14 patients (87.5%), including near complete response in 6, partial response in 5, minimal response in 3 and no response in 2. The most common adverse events were gastrointestinal symptoms (nausea and vomiting in 12, constipation in 3, severe diarrhea in 3 patients), thrombocytopenia (8 patients) and fatigue(3 patients). The adverse events were subsided on routine supportive care.</p><p><b>CONCLUSIONS</b>Bortezomib in combination with dexamethasone is an effective therapy with a high response rate and manageable toxicities for patients with relapsed or refractory myeloma.</p>