[Two cases of systemic mastocytosis with RUNX1-RUNX1T1 positive acute myeloid leukemia treated with sequential avapritinib after allogeneic hematopoietic stem cell transplantation and literature review].

Systemic mastocytosis (SM) with RUNX1-RUNX1T1 positive acute myeloid leukemia (AML) is a rare myeloid tumor with no standard treatment. Two cases of SM patients with RUNX1-RUNX1T1 positive AML treated with sequential avapritinib after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were reported in Henan Cancer Hospital. Mast cell in bone marrow disappeared, C-KIT mutation and RUNX1-RUNX1T1 fusion gene remained negative. Allo-HSCT sequential avapritinib is an effective treatment for SM patients with RUNX1-RUNX1T1 positive AML.

[Risk factors of extramedullary relapse after allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemia].

Objective: To evaluate risk factors and available treatments of extramedullary relapse (EMR) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with myeloid leukemia. Methods: A total of 280 patients were retrospectively analyzed from January 2008 to December 2018 in Affiliated Cancer Hospital of Zhengzhou University. Clinical data were collected including disease patterns, pre-transplantation status, chromosome karyotype, conditioning regimen, types of donor, extramedullary disease before transplantation and graft-versus-host disease (GVHD). The log-rank test and Cox proportional hazard model were uesd for univariate analysis and multivariate analysis, respectively. Results: Twenty patients developed EMR (7.14%). The median time of EMR was 7.5 (1-123) months after allo-HSCT. The mortality of EMR was 80% (16/20). Univariate analysis identified disease patterns, second complete remission (CR2) or progressive disease before transplantation, extramedullary disease, abnormal karyotype and conditioning regimen without total body radiation as significant factors correlated to EMR (P<0.05). Multi-variable analysis revealed that CR2 or progressive disease (RR=3.468,95%CI 2.189-7.786), abnormal karyotype (RR=1.494,95%CI 1.020-2.189) and extramedullary disease before transplantation (RR=8.627,95%CI 3.921-18.452) were independent risk factors of EMR. Conclusions: The clinical outcome of EMR after allo-HSCT is poor.It is crucial to comprehensively assess and identify EMR as early as possible.

Altered resting-state functional connectivity and effective connectivity of the habenula in irritable bowel syndrome: A cross-sectional and machine learning study.

Irritable bowel syndrome (IBS) is a disorder involving dysfunctional brain-gut interactions characterized by chronic recurrent abdominal pain, altered bowel habits, and negative emotion. Previous studies have linked the habenula to the pathophysiology of negative emotion and pain. However, no studies to date have investigated habenular function in IBS patients. In this study, we investigated the resting-state functional connectivity (rsFC) and effective connectivity of the habenula in 34 subjects with IBS and 34 healthy controls and assessed the feasibility of differentiating IBS patients from healthy controls using a machine learning method. Our results showed significantly enhanced rsFC of the habenula-left dorsolateral prefrontal cortex (dlPFC) and habenula-periaqueductal grey (PAG, dorsomedial part), as well as decreased rsFC of the habenula-right thalamus (dorsolateral part), in the IBS patients compared with the healthy controls. Habenula-thalamus rsFC was positively correlated with pain intensity (r = .467, p = .005). Dynamic causal modeling (DCM) revealed significantly decreased effective connectivity from the right habenula to the right thalamus in the IBS patients compared to the healthy controls that was negatively correlated with disease duration (r = -.407, p = .017). In addition, IBS was classified with an accuracy of 71.5% based on the rsFC of the habenula-dlPFC, habenula-thalamus, and habenula-PAG in a support vector machine (SVM), which was further validated in an independent cohort of subjects (N = 44, accuracy = 65.2%, p = .026). Taken together, these findings establish altered habenular rsFC and effective connectivity in IBS, which extends our mechanistic understanding of the habenula's role in IBS.

[Clinical analysis of 9 patients with transplant-related thrombotic microangiopathy].

Objective: To analyze the clinical features, efficacy and outcomes in patients with transplantation associated thrombotic microangiopathy (TA-TMA). Methods: The clinical data of 9 patients who developed TA-TMA after allogeneic hematopoietic stem cell transplantation (allo-HSCT) were retrospectively analyzed from January 2011 to August 2018 in Affiliated Tumor Hospital of Zhengzhou University. Results: There were 6 male and 3 female patiens with a median age of 31 (12-38) years. The median time from transplantation to TA-TMA was 76 (24-155) days. The baseline blood and biochemical parameters at diagnosis of TA-TMA included median hemoglobin (Hb) 66 (58-77) g/L,platelet (PLT) count 22 (4-38) × 10(9)/L,serum lactic dehydrogenase (LDH) 655 (305-4 238) U/L,blood urine nitrogen (BUN) level 15.9 (4.8-26.2) mmol/L,blood creatinine (Cr) level 118 (24-380) µmol/L. The proportion of median peripheral blood schistocytes was 2.6%(1.2%-9%). All patients had positive urinary occult blood tests,and urinary protein was seen in 4 patients. Three patients had mental symptoms. Coombs tests were all negative. The main treatments of TA-TMA composed of reduction and withdrawal of calcineurin inhibitor,steroids and plasma exchange. Response was seen in 4 patients. Patients who did not response to the treatment had a higher proportion of schistocytes,more severe acute graft-versus-host disease (aGVHD),more elevated serum LDH and other transplant-related complications. Conclusions: TA-TMA after allo-HSCT is a serious complication with high mortality rate. The proportion of schistocytes in peripheral blood, serum LDH level and comorbidities are prognostic factors of clinical outcome.

[Effect of nilotinib on pregnancy outcome in female patients with chronic myeloid leukemia].

Objective: To observe the pregnancy outcome among patients with chronic myeloid leukemia (CML) treated with Nilotinib (NIL) . Methods: Clinical data of pregnancy delivery in CML patients treated with NIL from March 2015 to January 2019 were retrospectively collected. Results: A total of 11 patients were recruited with median pregnancy age 28 (25-40) years. The median duration of NIL treatment before pregnancy was 34 (3-48) months. There were 12 pregnancies, included 2 planned ones and 10 (83.3%) unplanned. In the 10 unplanned patients, 9 (90.0%) received NIL 600 mg/d. The median exposure time were 4 (4-7) weeks. In eight patients with delivery outcomes, 5 cases had well-developed babies, 2 had spontaneous abortion and 1 case with an baby of syndactyly deformity, whose mother was exposed to NIL 600 mg/d for 7 weeks in the early trimester of pregnancy. Seven infants were 4 boys and 3 girls with the median height at birth 50 (41-54) cm and median weight 3.2 (3.0-4.6) kg. They all grew with a normal pattern and well developed. Now the median age is 19 (4-41) months. The disease status during 12 pregnancies included 3 cases in CMR, 2 cases in MR(4.0), 3 cases in MMR, 4 cases not acquiring MMR. The median time of drug discontinuation was 35 (15-36) weeks during pregnancy. No patient lost CHR during this period. Conclusions: Female CML patients exposed to NIL 600 mg/d for 4 weeks in early pregnancy can give birth to normal babies, but there is still a risk of spontaneous abortion and congenital malformations.

[Clinical analysis of six cases with the de novo glomerulitis after allogeneic hematopoietic stem cell transplantation].

Objective: To explore the occurrence, clinical characteristics, diagnosis and treatment of glomerulitis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Analysis were carried out based on the clinical data of 6 patients with de novo glomerulitis following allo-HSCT hospitalized in Henan Tumor Hospital from January 2008 to December 2016, and the clinical manifestation, pathology, diagnosis, treatment and outcome were investigated. Results: The occurrence of glomerulitis was 1.26% (6/478). The median time was 447(272-1 495) d after allo-HSCT. Proteinuria and varying degrees of edema were present in all patients. Of the 6 patients, 4 patients with impaired renal function, 3 cases of hypertension, 5 cases of urine occult blood positive, 2 cases of hyperlipidemia. 5 patients underwent acute graft-versus-host disease (GVHD), 4 patients accompanied with chronic GVHD at diagnosis. Kidney pathology showed typical features of minimal change diseases in 1 patient, membranous nephropathy in 4 patients and mesangial proliferative glomerulonephritis in 1 case. Immunohistochemistry of glomerular lesions revealed that the immune complex deposition included IgG in 4 patients, C3 in 3 patients, IgM and C1q in 1 patient. Serum ANA was positive in 2 patients and serum IgG and IgM were in high level in 1 patient, respectively. Only 1 case was effective on glucocorticoid. 5 cases treated by low dose cyclophosphamide combined with mycophenolate mofetil (MMF), 2 cases achieved complete remission, and 3 cases were partial remission. Up to now, 2 cases died with lung infection, and 4 patients survived. Conclusion: The predominant pathological type of glomerulitis was membranous nephropathy. Low-dose cyclophosphamide combined with MMF was an effective treatment.

[Effect of stopping tyrosine kinase inhibitors during pregnancy on disease status and reproductive outcomes among patients with chronic myeloid leukemia].

Objective: To explore the pregnancy outcome and disease status among patients with chronic myeloid leukemia (CML) treated with tyrosine kinase inhibitor (TKI) when they stopped TKI treatment during pregnancy. Methods: The clinical characteristics, reproductive outcomes and disease status of the patients who stopped TKI due to pregnancy between November 2004 to November 2017 were retrospectively collected. Results: A total of 14 CML patients in chronic phase (CML-CP), 12 patients were Sokal-low-risk. The median time of TKI treatment was 46.5 (15-123) months before the drug was stopped. The median age at the time of pregnancy was 29 (24-32) years. The median time of TKI exposure was 4 (0-9) weeks in 12 accidental pregnancies. Outcomes were available for 13 pregnancies, 9 cases (69.2%) delivered healthy babies, 1 case (7.7%) delivered polydactylia malformation baby, 3 cases (23.1%) had spontaneous abortion. The last one was still in pregnancy (no organ malformations were observed in color Doppler ultrasound). At the end of the follow up date, 10 children developed normal, the median age was 14 (0.7-65) months. Of the 14 patients who stopped TKI, 7 in complete molecular response (CMR), 3 in MR(4) (BCR-ABL(IS) <0.01%, ABL transcript >10 000), 2 in major molecular response (MMR), 2 in complete cytogenetic response (CCyR). The median time of TKI discontinuation during pregnancy was 33.5 (4-40) weeks. At the end of pregnancy, 4 cases were in CMR, 4 in MR(4), 1 in MMR and 4 in CCyR. No patients lost CCyR and complete hematologic remission. Conclusions: During the treatment of imatinib and Nilotinib, unplanned pregnancy may have a normal infant, but may lead to spontaneous abortion and congenital malformations. Female of CML-CP who had sustained and stable MMR at least 24 months and Sokal-low-risk had higher safety factor discontinued TKI during pregnancy, but still had a risk of increasing tumor load, so monitored the level of BCR-ABL of peripheral blood monthly during pregnancy is necessary.

[The efficacy analysis of interferon combined with imatinib in chronic myelogenous leukemia patients with ABL kinase domain mutations].

To retrospectively analyze the efficacy of interferon plus imatinib (IM) in patients with chronic-phase chronic myelogenous leukemia(CML-CP)and ABL kinase domain mutations. The mutation rates of ABL kinase region in patients with Sokal score low, medium and high risk CML-CP were statistically significant (6.25%, 9.42% and 47.06%, P<0.05). The response rates of interferon plus IM versus second-generation TKI in CML-CP with non-T315I ABL kinase domain mutations were comparable (61.11% vs 65.52%, P>0.05). When CML-CP patients with ABL kinase domain mutations were resistant to TKI or not accessible to second-generation TKI, interferon plus IM can be an alternative choice.

[Compliance to imatinib therapy in patients with chronic myeloid leukemia in Henan province and its influence on cytogenetic response at 12 months].

OBJECTIVE: To observe the compliance to Imatinib (IM) 400 mg/d in 513 patients with chronic myeloid leukemia chronic phase (CML- CP) referred to Henan Province Tumor Hospital from March 2013 through March 2015 and its influence on cytogenetic response at 12 months. METHODS: Of 513 patients with CML-CP from Henan province, 456 cases covered by the new rural cooperative medical insurance, and 57 cases by other medical insurances. Patients were told the importance of regular monitoring after receiveing IM treatment, including bone marrow , BCR- ABL fusion genes and chromosomes. All patients were followed up for 12 months, according to the circumstances of the periodic review, to be subjected into good or poor compliance groups. Chi-square test was used to compare CCyR rate at 12 months and Sokal score difference of the distribution of risk between two groups. Diagnosis to IM treatment duration, level of education, personal income, convenience of residence to the hospital' s traffic, age and gender were recorded, the Cox single and multiple factors analyses were implied to probe the factors affecting CCyR 12 months. RESULTS: After receving IM 400 mg/d treatment for 12 months, the CCyR rate in good compliance group (82.2% ) was significantly higher than in poor compliance one (50.9%) (P<0.001). Sokal scores of risk stratification were 121, 132, 101, respectively in good compliance group; which were as of 58, 61, 40, respectively in poor compliance group, the difference of disease risk between the two groups was not statistical significance (P=0.721). Sokal score, annual income, level of education and diagnosis to treatment duration were positively related with the 12 months CCyR rate by the Cox single factor analysis (P<0.05). Level of education (B=0.457,P=0.018), income (B=0.267,P= 0.035) and treatment compliance (B=0.587,P=0.026) were independent risk factors for the 12 months CCyR rate by the Cox multiple factor analysis. CONCLUSIONS: Patients in CML-CP with good compliance achieved satisfactory responses when receving IM treatment for 12 months. Low education, low income and poor treatment compliance were independent risk factors for the CCyR rate at 12 months.

[The efficacy of sorafenib to prevent relapse in patients with FLT3-ITD mutation positive acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation].

To study the efficacy of sorafenib to prevent relapse in patients with FLT3-ITD mutation positive acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 7 cases with FLT3-ITD positive AML have received allo-HSCT in our department from May 2013 to January 2015. Six cases were administrated with sorafenib after hematopoietic reconstruction. Another patient relapsed on day 192 past allo-HSCT, then she started to use sorafenib after remission of re-induction regimens. Five patients survived. The median progression free survival was 280(126-366)day. This study suggests that sorafenib might prevent relapse past allo-HSCT and improve survival in patients with FLT3-ITD positive AML.

AC Electric Field Enhances Cryopreservation Efficiency of Sprague-Dawley Rat Liver During a Slow Freezing Procedure.

Slow freezing coupled with an AC electric field (ACEF) has been demonstrated to miniaturize the ice crystals of a 0.9% (w/v) NaCl solution in a prior study. The aim of this study was to assess the effect of ACEF on Sprague-Dawley (SD) rat liver in vitro during the slow cooling procedure. SD rat liver exposed to an oscillating electric field was frozen in a programmed freezer initially down to -30°C at a cooling rate of -1°C/min and continuing down to -80°C at a cooling rate of -5°C/min. The cryovials were finally transferred into liquid nitrogen for 7 days. The frequency range was 0-20 MHz, and peak field strength was 1,000 V/m. For the sham and electric-exposed groups, the freezing solution consisted of 0%, 2.5%, 5.0%, 7.5%, or 10% (v/v) dimethyl sulfoxide (DMSO) Dulbecco's modified Eagles' medium culture solution, and fresh tissue was selected as the control group. The changes in cell survival rate, adenosine triphosphate (ATP) content, and morphology of fresh and frozen-thawed liver tissue were examined. Compared with the sham group with 5.0% DMSO, the result showed that slow freezing coupled with 2.45 MHz or 5 MHz ACEF significantly increased the relative survival rate by 43.27% and 26.31% (P < 0.001), respectively. However, ACEF exposure increased the ATP content compared with the sham group. Especially in 5% and 10% DMSO with 2.45 MHz ACEF exposure, the ATP content approximated the fresh group (7.3 ± 2.7 nmol/piece), corresponding to 94.52% and 80.82%. In addition, the cellular membrane and some organelles (e.g., mitochondria) in the electric-exposed group appeared to be more intact according to the transmission electron microscopy images. The underlying mechanism might be that the ACEF affects the formation and growth of the ice crystallization, and thus inhibits cryoinjury. These results show that ACEF would provide an efficient method for cryopreservation banking with a low concentration of CPA during the slow freezing process.

HER-2-induced PI3K signaling pathway was involved in the pathogenesis of gastric cancer.

Human epidermal growth factor receptor-2 (HER-2) overexpression was closely associated with the tumor growth and invasion, we here aimed to investigate the mechanism of HER-2 mediation in the pathogenesis of gastric cancer (GC). We first detected the expression of HER-2 in GC cell line SGC-7901 and then examined the levels of nuclear factor-κB (NF-κB), matrix metalloproteinase-9 (MMP-9) and intercellular adhesion molecule-1 (ICAM-1) and the association between them by molecular methods. Statistical analysis was used to compare the significance. We further detected the possible molecular mechanism involved in their relationship in the SGC-7901 genesis. The MMP-9, NF-κB and secretory type (s-ICAM-1) levels were significantly greater in peripheral blood serum from SGC-7901 than healthy control GES-1 (P<0.01). ICAM-1, MMP-9 and NF-κB mRNA and protein levels were more highly expressed in SGC-7901 than healthy control GES-1. The expression levels of NF-κB, MMP-9 and ICAM-1 were positively related in GC cell line SGC-7901, which was HER-2 positive. The HER-2 positive SGC-7901 secreted more transforming growth factor beta 1 (TGF-ß1) and resultantly activated MMP-9 to enhance s-ICAM-1 secretion and further studies showed that phosphatidylinositol-3 kinase (PI3K)/Akt/NF-κB signaling pathway was involved in GC pathogenesis. The GC cells that express the HER-2 oncogene spur the activation of NF-κB that can upregulate the expression of ICAM-1 and induce the expression of MMP-9, which hydrolyzes ICAM-1 into s-ICAM-1 to promote tumor immune escape. TGF-ß1-induced PI3K/Akt/NF-κB signaling pathway was involved in the pathogenesis of GC and they could be a new target for cancer therapy. The GC cells that express the HER-2 oncogene spur the activation of NF-κB that can upregulate the expression of ICAM-1 and induce the expression of MMP-9, which hydrolyzes ICAM-1 into s-ICAM-1 to promote tumor immune escape. TGF-ß1-induced PI3K/Akt/NF-κB signaling pathway was involved in the pathogenesis of GC and they could be a new target for cancer therapy.

Tacrolimus dosing in Chinese renal transplant patients is related to MDR1 gene C3435T polymorphisms.

Tacrolimus is an immunosuppressive drug with narrow therapeutic range and wide interindividual variations in its pharmacokinetics. P-glycoprotein (P-gp) plays an important role in the absorption metabolism of tacrolimus. The polymorphism C3435T of MDR1, the gene coding P-gp, may influence the expression and activity of P-gp. The aim of this study was to evaluate whether C3435T polymorphism was associated with the tacrolimus concentration/dose ratio. Sixty-six Chinese renal transplant patients enrolled in this study were surveyed for body weight and dosage and concentration of tacrolimus as well as MDR1 genotype by polymerase chain reaction followed by restriction fragment length polymorphism analysis. The results showed a significant association between tacrolimus levels per dose mg/kg/d and MDR1 gene C3435T polymorphism (P < .05). The CC patients displayed a lower tacrolimus level per dose than CT/TT patients. Pharmacogenetic methods might be employed prospectively to help dose selection and to individualize immunosuppressive therapy.

A study on the standard for forensic anthropologic identification of skull - image superimposition

By means of X ray photography tests were made of 224 (100 males and 124 females) volunteer Chinese adults of han nationality to study the related regular patterns of superimposed projection of face landmarks onto the skull. On the basis of these tests, the present article reveals from a forensic antropology angle the related regular patterns of plane projection of the human face with its skull. Study shows that there exist a strict individual identity and exclusiveness in relation between the human face and skull (AU)

A study on the standard for forensic anthropologic identification of skull-image superimposition.

By means of X-ray photography tests were made of 224 (100 males and 124 females) volunteer Chinese adults of Han nationality to study the related regular patterns of superimposed projection of face landmarks onto the skull. On the basis of these tests, the present article reveals from a forensic anthropology angle the related regular patterns of plane projection of the human face with its skull. Study shows that there exist a strict individual identity and exclusiveness in relation between the human face and skull. The related regularity of displacement of face landmarks appears in projection of the skull with the human head at different photographic positions and angles. On the basis of this discovery, 52 indexes in 4 groups were established as a standard for judging the identification of a skull's body origin by means of skull-image superimposition. Based on forensic anthropology, the technique has raised to a great extent the credibility of unknown skull identification. In the past 8 years, 89 unknown skulls have been identified with their body origins which provided important and accurate evidence for the solution of murders with dismembered bodies, skeletonized bodies, and unidentified dead bodies.