Urinary N-Acetyl-Beta-D-Glucosaminidase levels predict immunoglobulin a nephropathy remission status.

BACKGROUND: Tubulointerstitial lesions play a pivotal role in the progression of IgA nephropathy (IgAN). Elevated N-acetyl-beta-D-glucosaminidase (NAG) in urine is released from damaged proximal tubular epithelial cells (PTEC) and may serve as a biomarker of renal progression in diseases with tubulointerstitial involvement. METHODS: We evaluated the predictive value of urinary NAG (uNAG) for disease progression in 213 biopsy-proven primary IgAN patients from January 2018 to December 2019 at Zhongshan Hospital, Fudan University. We compared the results with those of serum cystatin C (sCysC). RESULTS: Increased uNAG and sCysC levels were associated with worse clinical and histological manifestations. Only uNAG level was independently associated with remission status after adjustment. Patients with high uNAG levels (> 22.32 U/g Cr) had a 4.32-fold greater risk of disease progression. The combination of baseline uNAG and clinical data may achieve satisfactory risk prediction in IgAN patients with relatively preserved renal function (eGFR ≥ 60 ml/min/1.73 m2, area under the curve [AUC] 0.760). CONCLUSION: Our results suggest that uNAG is a promising biomarker for predicting IgAN remission status.

Tumor volume as a predictive parameter in the sequential therapy (induction chemotherapy) of head and neck squamous cell carcinomas.

PURPOSE: Tumor volume in locally advanced head and neck squamous cell carcinomas (LAHNSCC) treated by induction chemotherapy (ICT) and followed by radiochemotherapy (RCT) was measured. The presence of potential correlation of initial tumor volume and volume reduction after ICT and RCT with remission status, overall survival (OS) and disease-free survival (DFS) were investigated. Furthermore, reliability of approximation of the tumor volume relying on its diameter to manual three-dimensional measurement was assessed. METHODS: Data of patients with LAHNSCC treated by ICT consisting of docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by definite RCT were retrospectively analyzed. The tumor volume was calculated slice-by-slice in contrast-enhanced CT or MRI before and after ICT as well as after complete treatment. The volume was compared to radiologic remission status, correlated with OS and DFS, and to volume estimation using tumor diameter. RESULT: 65 patients were included. Primary tumor volume did not correlate with complete remission rate (CR) after ICT and RCT, OS or DFS. The change in tumor volume between baseline imaging and post-RCT had a significant impact on OS (p = 0.026) and DFS (p = 0.028). The agreement between tumor volume and radiologic remission was 72.14%. CONCLUSION: The initial tumor volume had no influence on CR, OS or DFS. A severe response to ICT did not predict a powerful RCT outcome. The change in tumor volume post-RCT had an impact on OS and DFS. Tumor volume estimation using its diameter seems to be a reliable method.

Bone Marrow WT1 Levels in Allogeneic Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplasia: Clinically Relevant Time Points and 100 Copies Threshold Value.

The outcome of allogeneic hematopoietic stem cell transplantation (HCT) in patients with myeloid malignancies is better in those without minimal residual disease (MRD) than in those with MRD+, as assessed by multiparametric flow cytometry (MPFC). WT1 quantitation also has been used to assess the probability of relapse in acute myelogenous leukemia (AML) treated with chemotherapy. We analyzed the clinical value of normalized bone marrow WT1 levels as a measure of the expanded myeloid progenitor compartment in a consecutive series of 193 adult patients with myeloid malignancies who underwent HCT. Bone marrow WT1 levels before the HCT, at the first bone marrow aspirate after infusion, and in the follow-up samples after HCT were determined by means of real-time PCR using the European LeukemiaNet normalized method. We sought to clarify the prognostic relevance in terms of overall survival (OS), progression-free survival (PFS), and cumulative incidence of relapse (CIR). Based on earlier experience in AML, we selected a threshold of 100 copies, defining 2 groups: patients with <100 WT1 copies and those with ≥100 copies. Patients with <100 WT1 copies before HCT (median time, 36 days; range, 4 to 268 days) had a better OS, PFS, and CIR than those with ≥100 copies (40 ± 1 versus 29 ± 6 days, P = .004; 35 ± 9 versus 26 ± 6 days, P = .002; and 29 ± 7 versus 37 ± 6 days, P = .051). In the first bone marrow study after the HCT (median time, 42 days; range 14 to 157 days, respectively), patients with <100 WT1 copies also had better outcomes in terms of OS, PFS, and CIR (40 ± 7 versus 31 ± 9 days, P = .025; 36 ± 7 versus 30 ± 8 days, P = .004; and 29 ± 6 days versus 54 ± 9, P < .001, respectively). At this time point, bone marrrow samples with >100 copies also included patients who were negative for MRD as assessed by MPFC (19 of 32). During the HCT follow-up, patients with sustained WT1 levels <100 copies showed a marked benefit in terms of OS, PFS, and CIR even compared with those with only a single measurement >100 copies (mean, 68 ± 11 versus 26 ± 7 days, P < .001; 63 ± 11 versus 20 ± 8 days, P < .001; and 20 ± 8 vs. 71 ± 8 days, P < .001, respectively). Standardized bone marrow WT1 levels using a 100-copy threshold in samples obtained before HCT, at leukocyte recovery, and during follow-up provided relevant prognostic information in patients with myeloid malignacies submitted to HCT.

Chemotherapy-Based Stem Cell Mobilization Does Not Result in Significant Paraprotein Reduction in Myeloma Patients in the Era of Novel Induction Regimens.

Novel induction agents markedly improved remission rates in multiple myeloma (MM), and the continued use of chemotherapy for CD34+ stem cell mobilization (SCM) has been questioned. We examined the additional effect of chemotherapy in SCM regarding remission status/morbidity. We reviewed 236 consecutive MM patients (aged 36 to 75 years) with first autologous stem cell transplantation from January 2009 to March 2016 after chemotherapy-based SCM. Responses were measured by changes in intact Ig and free light chain levels before and after chemomobilization (International Myeloma Working Group [IMWG] criteria). Most patients (225/236, 95.3%) received novel induction regimens, which were bortezomib-based (n = 223) and/or lenalidomide-based (n = 19). Most patients (170/190, 89.5%) achieved at least partial remission postinduction and pre-SCM. Stem cells were mobilized with granulocyte colony-stimulating factor and cyclophosphamide-based (212/227, 93.4%) or etoposide-based (15/227, 6.6%) regimens. There were insignificant changes in serum Ig and free light chain levels before and after chemomobilization either in the whole cohort or subgroups. Significant improvements of the IMWG remission status were documented in only 7 of 236 patients (3.0%). Sixty-seven patients (28.4%) developed chemotherapy-related complications (neutropenic fever, sepsis, and others), resulting in 9 hospitalizations (3.8%). Our study suggests that although causing significant morbidity, chemotherapy-based mobilization fails to improve remission status. The value of incorporating additional chemotherapy for SCM is thus not evident.

Hematologic Recovery after Pretransplant Chemotherapy Does Not Influence Survival after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Patients.

Pretransplant remission status in patients with acute myeloid leukemia (AML) is 1 of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Most patients are in complete remission with full hematologic recovery (CR) before undergoing allo-HCT. However, some patients achieve CR without recovery of platelet count (CRp) or a morphologic leukemia-free state (MLFS), defined as meeting all CR criteria without recovery of both neutrophil and platelet counts. Currently, there is a paucity of data regarding transplant outcomes in AML patients achieving MLFS after chemotherapy. To address this question, we evaluated transplant outcomes in 270 AML patients who received 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at a single institution between 2006 and 2013. Of our 270 patients, 206 were in CR, 45 were in CRp, and 19 were in MLFS before allo-HCT. Patients in CR, CRp, or MLFS had similar 3-year overall survival rates (49%, 46%, and 47%, respectively; P = .88) and 3-year event-free survival rates (45%, 36%, and 40%, respectively; P = .53). However, the cumulative incidence of nonrelapse mortality was significantly higher in patients in MLFS compared with those in CR (58% versus 22%, P = .0004), whereas the cumulative incidence of relapse in patients in MLFS was significantly lower compared with those in CR (11% versus 36%, P = .03). Our results suggest that survival outcomes in AML patients are not influenced by degree of hematologic recovery before allo-HCT.

Outcomes after Second Hematopoietic Stem Cell Transplantations in Pediatric Patients with Relapsed Hematological Malignancies.

Relapse of hematological malignancies after hematopoietic stem cell transplantation (HCT) is associated with poor prognosis. A second HCT represents one of the few therapeutic options for these high-risk patients. For children undergoing second HCT, the outcome data are particularly limited. We, therefore, conducted a retrospective single-institution study and report the outcomes and prognostic variables associated with overall survival (OS) and relapse in 43 pediatric patients who underwent a second HCT between 2000 and 2013. Eleven of the 43 patients who underwent transplantation remain alive and disease-free at a median follow-up of 49 months (range, 5 to 127 months). The 5-year probability of OS for the entire cohort was 24%. Patients who had early relapse (<6 months) after first HCT had significantly worse OS than those who relapsed late (>6 months), with 5-year OS at 11% versus 34%, respectively (hazard ratio [HR], 2.24; 95% confidence interval [CI], 1.21 to 4.93; P = .013). Active disease at time of second HCT was also associated with a significantly increased risk of relapse (subdistribution hazard ratio [SHR], 2.36; P = .049) for the entire cohort and relapse was the most frequent cause of death (23 of 32; 72%). On subgroup analysis for the 34 patients with leukemia alone, presence of active disease was associated both with a significant decrease in OS (SHR, 2.28; 95% CI, 1.02 to 5.09; P = .044) and significant increase in the rate of relapse (SHR, 2.46; P = .046). By contrast, underlying disease, donor source, conditioning regimen, or development of GVHD did not modify OS or rate of relapse. Hence, a second HCT appears to be a useful therapeutic option in children with relapsed hematological malignancies that is most likely to benefit those individuals with late onset of relapse and with low disease burden at the time of transplantation.

Association Between High NK-Cell Count and Remission of Primary Membranous Nephropathy: A Retrospective Chart Review and Pilot Study.

PURPOSE: Primary membranous nephropathy (PMN) is the most frequent cause of nephrotic syndrome in adults. Rituximab monotherapy has emerged as a front-line treatment for patients with PMN, but potential markers for predicting the response to rituximab are unknown. METHODS: In this single-arm retrospective pilot study, 48 patients with PMN without previous immunosuppressive therapy were enrolled. All patients were treated with rituximab and were followed up for at least 6 months. The primary end point was the achievement of complete or partial remission at 6 months. The subsets of lymphocytes were collected at baseline, 1 month, 3 months and 6 months to identify prognostic factors for achieving remission of PMN with rituximab therapy. FINDINGS: A total of 58.3% of patients (28/48) achieved remission. Lower serum creatinine, greater serum albumin, and greater phospholipase A2 receptor antigen detected in kidney biopsy at baseline were found in the remission group. After multiple adjustments, a high percentage of natural killer (NK) cells at baseline, especially ≥15.7%, was strongly associated with remission (relative risk = 1.62; 95% CI, 1.00-2.62; P = 0.049), and patients with a response to rituximab had a greater mean percentage of NK cells during the follow-up period compared with nonresponders. Analysis using a receiver operating characteristic curve indicated prognostic value of the NK-cell percentage at baseline, with an area under the curve of 0.716 (95% CI, 0.556-0.876; P = 0.021). IMPLICATIONS: The findings from this retrospective pilot study suggest that a high percentage, especially ≥15.7%, of NK cells at baseline might predict a response to rituximab treatment. These findings provide a basis for designing larger-scale studies to test the predictive value of NK cells in patients with PMN undergoing rituximab treatment.

Using multiple imputation of real-world data to estimate clinical remission in pediatric inflammatory bowel disease.

Aim: To evaluate the performance of the multiple imputation (MI) method for estimating clinical effectiveness in pediatric Crohn's disease in the ImproveCareNow registry; to address the analytical challenge of missing data. Materials & methods: Simulation studies were performed by creating missing datasets based on fully observed data from patients with moderate-to-severe Crohn's disease treated with non-ustekinumab biologics. MI was used to impute sPCDAI remission statuses in each simulated dataset. Results: The true remission rate (75.1% [95% CI: 72.6%, 77.5%]) was underestimated without imputation (72.6% [71.8%, 73.3%]). With MI, the estimate was 74.8% (74.4%, 75.2%). Conclusion: MI reduced nonresponse bias and improved the validity, reliability, and efficiency of real-world registry data to estimate remission rate in pediatric patients with Crohn's disease.

Discovery and validation of acetyl-L-carnitine in serum for diagnosis of major depressive disorder and remission status through metabolomic approach.

Major depressive disorder (MDD) is one of the most common psychiatric disorders that accompany psychophysiological and mood changes. However, the pathophysiology-based disease mechanism of MDD is not yet fully understood, and diagnosis is also conducted through interviews with clinicians and patients. Diagnosis and treatment of MDD are limited due to the absence of biomarkers underlying the pathophysiological mechanisms of MDD. Although various attempts have been made to discover metabolite biomarkers for the diagnosis and treatment response of MDD, problems with sample size and consistency of results have limited clinical application. In addition, it was reported that future biomarker studies must consider exposure to antidepressants, which is the main cause of heterogeneity in depression subgroups. Therefore, the purpose of this study is to discover and validate biomarkers for the diagnosis of depression in consideration of exposure to drug treatment including antidepressants that contribute to the heterogeneity of the MDD subgroup. In the biomarker discovery and validation set, the disease group consisted of a mixture of patients exposed and unexposed to drug treatment including antidepressants for the treatment of MDD. The serum metabolites that differed between the MDD patients and the control group were profiled using mass spectrometry. The validation set including the remission group was used to verify the effectiveness as a biomarker for the diagnosis of depression and determination of remission status. The presence of different metabolites between the two groups was confirmed through serum metabolite profiling between the MDD patient group and the control group. Finally, Acetylcarnitine was selected as a biomarker. In validation, acetylcarnitine was significantly decreased in MDD and was distinguished from remission status. This study confirmed that the discovered acetylcarnitine has potential as a biomarker for diagnosing depression and determining remission status, regardless of exposure to drug treatment including antidepressants.

Clinico-Haematologic Parameters And Assessment Of Post-Induction Status In Acute Lymphoblastic Leukaemia.

BACKGROUND: Acute Leukaemia is a malignant disorder characterized by an abnormal proliferation of immature cells, called blasts. Classically, acute leukaemia is classified into acute myeloid leukaemia and acute lymphoblastic leukaemia depending on the lineage of the immature cells. Objective of the study was to evaluate the clinical presentations, analyze the haematologic parameters at time of diagnosis and assess the post-induction status in newly diagnosed ALL patients. This cross-sectional study was conducted in the Department of Haematology, Armed Forces Institute of Pathology, Rawalpindi from June to November 2019. METHODS: A total of 55 newly diagnosed ALL patients were recruited including children, adults and elderly. Detailed medical history and physical findings were noted. Haematologic parameters were documented. Each patient was treated as per standard protocol and remission induction status was determined on day 29 of treatment. RESULTS: The median age of the study cohort of 55 newly diagnosed ALL patients was 8.5 years. Males were 37 (67.3%) and females were 18 (32.7%) with a male to female ratio of 2:1. Paediatric group included 31 (56.4%) patients. Nine (16.4%) patients were in the adult group and 15 (27.3%) in the elderly age group. The time from onset of symptoms to diagnosis of acute lymphoblastic leukaemia was 98.87±79.21 days. Fever was the most common symptom but body aches were common among paediatric group while pallor was the most common sign. Mean WBC was 29.1±27.9 x109/l, Hb was 8.1±2.9 g/dl and platelet count was 60±41.8 x109/l B-acute lymphoblastic leukaemia was more common than T-acute lymphoblastic leukaemia. A total of 52 patients were assessed on day 29 to evaluate for post-induction remission status. The remission rate of our cohort of patients was 82.7%. CONCLUSIONS: Most of the patients were in paediatric age group and remission rate was better in this age group compared to elderly population. B-ALL was associated with good response to induction chemotherapy while patients with BCR-ABL1 gene rearrangement did not respond well to treatment. Identification of prognostic features at diagnosis will further help our clinicians to predict outcomes of the disease.

Urinary Soluble CD163 Levels Predict IgA Nephropathy Remission Status.

Noninvasive biomarkers of disease activity are needed to predict disease remission status in patients with IgA nephropathy (IgAN). Soluble CD163 (sCD163), shed by monocytes and macrophages, is a potential biomarker in diseases associated with excessive macrophage activation. We investigated the association of urinary sCD163 (u-sCD163) with histopathological activity and clinical manifestations in 349 patients with biopsy-diagnosed IgAN. U-sCD163 was measured via enzyme-linked immunosorbent assay. In patients with IgAN, higher u-sCD163 levels were associated with histological lesions of greater severity, as well as more proteinuria and poorer renal function. Additionally, u-sCD163 was correlated with infiltration of tubulointerstitial CD163+ macrophages. High u-sCD163 levels (>3.57 ng/mg Cr) were associated with a 2.66-fold greater risk for IgAN remission failure in adjusted analyses. Adding u-sCD163 levels to the model containing clinical data at biopsy and MEST-C score significantly improved the risk prediction of IgAN remission status (AUC 0.788). Together, our results suggest that u-sCD163 may be a useful noninvasive biomarker to evaluate disease severity and remission status of IgAN.

Impact of Pre-transplant and Post-transplant Remission Status of Patients on Survival in Newly Diagnosed Multiple Myeloma.

The overall survival (OS) in patients with multiple myeloma (MM) has increased in the last decade due to the introduction of proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies as well as an extensive combination of autologous stem cell transplantation (ASCT) for suitable patients. The objective of this study was to examine the impact of pre-transplant and post-transplant remission status of patients on survival in newly diagnosed multiple myeloma. Two hundred and four patients with newly diagnosed MM who received an ASCT in our HSC transplant center at Hacettepe University Hospital between the years of 2001 and 2018 were evaluated in a retrospective manner. The median follow-up period was 35.9 months (range 4.2-206.4) for the entire group. The 5-year OS for pre-transplant remission status CR/VGPR patients and pre-transplant remission status PR or less patients were 79% and 68%, respectively (p = 0.09). The 5-year PFS for pre-transplant remission status CR/VGPR patients and pre-transplant remission status PR or less patients were 62% and 45%, respectively (p = 0.23). The 5-year OS for post-transplant remission status CR/VGPR group was 72% and for post-transplant remission status PR or less group was 60% (p = 0.02). The 5-year PFS in post-transplant remission status CR/VGPR patients was 48% and post-transplant remission status PR or less patients was 36% (p = 0.03). This study focuses on determination of survival outcome based on the best response obtained before and after ASCT and particularly highlights the significance of reaching CR and VGPR.

Outcome of allogeneic hematopoietic stem cell transplantation for relapsed/refractory acute myeloid leukemia in NR status / 中华器官移植杂志

Objective To explore the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for relapsed/refractory acute myeloid leukemia (AML) patients in nonremission (NR) status and its related risk factors.Methods Thirty-nine relapsed/refractory AML patients in NR status who received allo-HSCT between Jan.2006 and Dec.2016 were retrospectively analyzed.Major end points of study included overall survival (OS),disease free survival (DFS),and relapse rate.Results All patients achieved hematopoietic reconstitution.Median time to neutrophil and platelet engraftment was 13 (11 20) and 16 (10-58) days,respectively.Acute graft-versus-host disease (aGVHD) occurred in 25 (64.1％) patients,and 11 (31.4％) patients developed chronic GVHD.During a median follow-up period of 9.1 (1.6-93.8) months,11 (28.9％) cases survived,10(26.3％) survived without leukemia,and 21 (53.8％) relapsed.The estimated 2 year OS and DFS were 30.0％ ± 8.0％ and 26.7％ ± 7.7％,and cumulative incidence of relapse and transplantation related mortality at 2 years was 56.63％ (95％ CI 37.84％-71.71％),19.7％ (95％ CI 8.3％-34.5％),respectively.The multivariate analysis revealed that the number of bone marrow blasts≥25％ or any level of blasts in peripheral blood was significantly associated with worse OS (HR =11.91,P=0.003),DFS (HR =10.75,P =0.002) and higher rate of relapse (70.83％ versus 20.22％,P =0.002).In addition,the development of grade Ⅱ-Ⅳ aGVHD also predicted an inferior OS (HR =3.18,P =0.039).Conclusion Salvage therapy with allo-HSCT can induce long-term survival in part refractory/relapsed AML patients.Decrease in the pre-transplant disease burden is the key to reduce relapse and improve survival.