Neurologic complications after allogeneic hematopoietic stem cell transplantation: risk factors and impact.

Neurologic complications (NCs) may be a significant source of morbidity and mortality after hematopoietic cell transplantation (HCT). We performed a retrospective study of 263 consecutive patients undergoing allogeneic HCT for hematological malignancies to determine the incidence, risk factors and clinical impact of NCs in the first 5 years after HCT. We determined the incidence of central nervous system (CNS) infection, intracranial hemorrhage, ischemic stroke, metabolic encephalopathy, posterior reversal encephalopathy syndrome, seizure and peripheral neuropathy. In all, 50 patients experienced 63 NCs-37 early (⩽day +100), 21 late (day +101 to 2 years) and 5 very late (2 to 5 years). The 1- and 5-year cumulative incidences of all NCs were 15.6% and 19.2%, respectively, and of CNS complication (CNSC; all of the above complications except peripheral neuropathy) were 12.2 and 14.5%. Risk factors for CNSC were age (hazard ratio (HR)=1.06 per year, P=0.0034), development of acute GvHD grade III-IV (HR=2.78, P=0.041), transfusion-dependent thrombocytopenia (HR=3.07, P=0.025) and delayed platelet engraftment (>90th centile; HR=2.77, P=0.043). CNSCs negatively impacted progression-free survival (HR=2.29, P=0.0001), overall survival (HR=2.63, P<0.0001) and non-relapse mortality (HR=8.51, P<0.0001). NCs after HCT are associated with poor outcomes, and usually occur early after HCT.

Primary pulmonary actinomycosis: a retrospective analysis of 145 cases in mainland China.

OBJECTIVE: To improve our understanding of pulmonary actinomycosis. METHODS: A retrospective analysis of 145 cases in mainland China was conducted. RESULTS: The male:female ratio was 2.7:1. Mean age at diagnosis was 48 years (± 12). Main symptoms were cough (87.6%), expectoration (40%), blood-stained sputum (37.2%), fever (26.9%), chest pain (24.8%) and haemoptysis (16.6%). Eighty-eight (60.7%) patients had no underlying disease. Only five patients received a correct initial diagnosis; 60 patients were misdiagnosed with lung cancer, followed by pulmonary tuberculosis (TB) and lung abscess. Most patients were diagnosed using surgical resection, transthoracic needle aspiration or flexible bronchoscopy. Sixty-seven patients received penicillin G, and one patient did not receive any antibiotics after surgery. The mean duration of treatment with antibiotics was 4.5 months (±3.7). Overall, 110 (75.9%) patients were fully cured, 4 died, 1 was lost to follow-up, and a record of the prognosis was not available for 30 patients. Mean duration of follow-up was 26 months (± 32). CONCLUSION: Pulmonary actinomycosis is a rare bacterial infection and is often misdiagnosed as lung cancer or pulmonary TB. The definitive diagnosis depends on pathology; sulfur granules are suggestive, but not specific. Penicillin G is the standard treatment. The optimal duration of antibiotic treatment merits further investigation.

G-CSF Indirectly Induces Apoptosis of Osteoblasts During Hematopoietic Stem Cell Mobilization.

The objective of this study was to explore the mechanism underlying osteoblast suppression in the process of hematopoietic stem cells mobilization induced by granulocyte colony-stimulating factor (G-CSF). The apoptosis of human and mouse osteoblasts was examined by detecting caspase 3. The levels of serum DKK1 and osteocalcin in the supernatant of co-culture of mouse osteoblasts and mouse bone marrow nucleated cells were measured. The number of mouse osteoblasts co-cultured with mouse bone marrow nucleated cells was measured and the osteocalcin mRNA level was also measured. The G-CSF-induced decrease in osteoblast function was partly due to the apoptosis of osteoblasts. There was no significant difference in the level of serum DKK1 in healthy donors before and 5 days after mobilization. The osteocalcin gene and protein expression was significantly different in co-cultured osteoblasts with bone marrow nucleated cells treated with and without G-CSF. Osteoblasts undergo apoptosis during mobilization and G-CSF affects osteoblasts through bone marrow nucleated cells.

GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes.

Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (⩾18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.

Does quality of life impact the decision to pursue stem cell transplantation for elderly patients with advanced MDS?

The factors that influence utilization of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (HCT) among medically fit older patients with advanced myelodysplastic syndromes (MDS) are largely unknown. The MDS Transplant-Associated Outcomes (MDS-TAO) study is an ongoing prospective observational study at the Dana-Farber Cancer Institute and Massachusetts General Hospital that enrolls transplant-eligible fit patients aged 60-75 years with advanced MDS and follows them through RIC HCT vs non-HCT treatment. In this analysis of 127 patients enrolled from May 2011 to June 2014, we examined the influence of age, gender, cytogenetics, International Prognostic Scoring System (IPSS) category, performance status, distance from HCT center and baseline patient-reported quality of life (QOL) from the EORTC QLQ-C30 (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire) on the likelihood of receiving RIC HCT using competing risk regression modeling. With a median follow-up of 16 months, 44 patients (35%) had undergone RIC HCT. In multivariable analyses, age (hazard ratio (HR) 0.87 per year, 95% confidence interval (CI): 0.81-0.92, P<0.001) and higher IPSS (intermediate-2/high; HR 2.29, 95% CI: 1.25-4.19, P=0.007) were significantly predictive of receipt of RIC HCT; neither global QOL score nor any QOL subscales scores were predictive. These data suggest that baseline patient-reported QOL has little influence on the decision to undergo RIC HCT for older patients with advanced MDS.

Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma.

Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors.

Decreased circulating neopterin is associated with increased arterial elasticity: a beneficial role of periodontal treatment.

BACKGROUND: The aim of this study was to evaluate the effect of periodontal treatment on arterial elasticity and circulating neopterin in patients with moderate to severe periodontitis in a Chinese population. METHODS: One hundred and eight patients with moderate to severe periodontitis were eligible to take part in the study and were randomized into two groups. The treatment group received intensive periodontal treatment, while the control group received control periodontal treatment. All parameters, including brachial-ankle pulse wave velocity (baPWV), ankle brachial index (ABI), serum neopterin (NP), high-sensitivity C-reactive protein (hs-CRP), Interleukin-6 (IL-6), were evaluated before treatment and 1 month after treatment. RESULTS: The parameters including NP, hs-CRP, IL-6 and baPWV decreased significantly after 1 month in the treatment group (p < 0.05 for all comparisons) but not in the control group (p > 0.05). There was no significant difference in the change of ABI between the two groups (p = 0.231). A positive correlation was found between the decreased circulating NP and increased arterial elasticity in the treatment group (r = 0.947, p < 0.001). CONCLUSIONS: This study demonstrates for the first time that the fall in circulating NP induced by periodontal treatment contributes to increased arterial elasticity in patients with moderate and severe periodontitis.

INFLUENCE OF miR-373 ON THE INVASION AND MIGRATION OF BREAST CANCER AND THE EXPRESSION LEVEL OF TARGET GENES TXNIP.

An increasing number of people die from breast cancer every year. Consequently, more research has been concentrated on the study of this type of tumour, and miR-373 resulted as an important gene for treating breast cancer. To explore the influence of miR-373 on the invasion and migration of breast cancer and the expression level of target gene TXNIP, a set of therapeutic methods were designed based on miR-373. The transfection was performed using miR-373 inhibitor; the concentration of miR-373 was controlled by inhibitor, and it was transfected into MCF-7 cell by lipofectin. Fluorescent quantitative polymerase chain reaction was used to detect the expression level of miR-373 in cells after transfection as well as that of Caspase-3 and Caspase-8. MTT assay was used to detect the influence of miR-373 inhibitor on MCF-7 cells. The expression quantity of miR-373 in cell and tissue of breast cancer with high-low invasion and migration ability was detected by qRT-PCR (quantitative real-time polymerase chain reaction), thus the influence of the expression quantity of miR-373 on the invasion and migration of cell was determined. The expression of miR-373, EMT and TXNIP was determined by Western blot. Through the identification of proteomics and bioinformatics, it was finally found that TXNIP was regulated by miR-373. The protein expression level of TXNIP was negatively correlated with the level of miR-373. Thus it was concluded that miR-373 could promote the invasion and migration of breast cancer. In addition, in the tissue and cell of breast cancer with different invasion and migration abilities, the expression level of TXNIP was negatively correlated with the level of miR-373.

miR-145 regulates chemoresistance in hepatocellular carcinoma via epithelial mesenchymal transition.

Resistance to chemotherapeutic drugs is a major obstacle in hepatocellular carcinoma (HCC) therapy. MicroRNA—145 (miR—145) has been shown to be down—regulated in several cancers and may be involved in the process of carcinogenesis. The present study aimed to evaluate the effects of miR—145 in adriamycin (ADM)—resistant human HCC cells. We found that miR—145 was significantly reduced in HepG2/ADM and HuH7/ADM cells compared with the chemosensitive parental cells. Up—regulation of miR—145 increased the ADM cytotoxicity in chemoresistant tumor cells. In addition, Smad3 was identified as the target of miR—145 and miR—145 overexpression inhibited Smad3 expression both at the mRNA and protein levels. The luciferase reporter assay confirmed that Smad3 was a direct target of miR—145. Moreover, up—regulation of miR—145 suppressed Smad3 related EMT features as shown by increased expression of E—cadherin and reduced vimentin level in HepG2/ADM and HuH7/ADM cells. Our study demonstrated that miR—145 modulated both chemoresistance and EMT in HCC cells, and up—regulation of miR—145 might be a potential therapeutic strategy for treatment of chemoresistant HCC.

Prognostic understanding, quality of life and mood in patients undergoing hematopoietic stem cell transplantation.

Little is known about how patients undergoing hematopoietic stem cell transplantation (HCT) and their family caregivers (FC) perceive their prognosis. We examined prognostic understanding in patients undergoing HCT and their FC and its relationship with quality of life (QOL) and mood. We conducted a longitudinal study of patients (and FC) hospitalized for HCT. We used a questionnaire to measure participants' prognostic understanding and asked the oncologists to estimate patients' prognosis prior to HCT. We assessed QOL and mood weekly and evaluated the relationship between prognostic understanding, and QOL and mood using multivariable linear mixed models. We enrolled 90 patients undergoing (autologous (n=30), myeloablative (n=30) or reduced intensity allogeneic (n=30)) HCT. About 88.9% of patients and 87.1% of FC reported it is 'extremely' or 'very' important to know about prognosis. However, 77.6% of patients and 71.7% of FC reported a discordance and more optimistic prognostic perception compared to the oncologist (P<0.0001). Patients with a concordant prognostic understanding with their oncologists reported worse QOL (ß=-9.4, P=0.01) and greater depression at baseline (ß=1.7, P=0.02) and over time ((ß=1.2, P<0.0001). Therefore, Interventions are needed to improve prognostic understanding, while providing patients with adequate psychological support.

Alternative donors extend transplantation for patients with lymphoma who lack an HLA matched donor.

Alternative donor transplantation is increasingly used for high-risk lymphoma patients. We analyzed 1593 transplant recipients (2000-2010) and compared transplant outcomes in recipients of 8/8 allele HLA-A, -B, -C and DRB1 matched unrelated donors (MUDs; n=1176), 7/8 allele HLA mismatched unrelated donors (MMUDs; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared with MUD (35%; P=0.004), but similar to UCB recipients (37%; P=0.19), although UCB had lower rates of neutrophil and platelet recovery compared with unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, P=0.003) but similar between UCB and MUD (30% vs 33%; P=0.48). In multivariate analysis, UCB recipients had lower risks of acute and chronic GVHD compared with adult donor groups (UCB vs MUD: hazard ratio (HR)=0.68, P=0.05; HR=0.35; P<0.001). Adjusted 3-year OS was comparable (43% MUD, 37% MMUD and 41% UCB). These data highlight the observation that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can extend the curative potential of allotransplant to patients who lack suitable HLA matched sibling or MUD.

Inheritance of the complete mitochondrial genomes in three different ploidy fishes.

Diploid natural gynogenetic goldfish (2nGRCG), triploid hybrids (3nRB) and tetraploid hybrids (4nRB) are generated by distant hybridization of red common goldfish (RCG, Carassius auratus red var.) and blunt snout bream (BSB, Megalobrama amblycephala). In the present study, we obtained the complete mitochondrial DNA (mtDNA) sequences of the hybrid offspring and compared them with the homologous sequences of RCG and BSB. All mtDNA sequences of these hybrids were 16,580bp in length, and the genes number, size, and order were quite similar to that of RCG. Genetic analysis revealed that the mtDNA sequences of these hybrids had high similarity (>99%) and low divergence (<2%) to their maternal RCG, yet lower similarities (84%) and higher divergences (16%) to their paternal BSB. The phylogenetic analysis also showed that the sequences of 2nGRCG, 3nRB and 4nRB were clustered with RCG rather than with BSB. These results indicate that the mitochondrial genomes of 2nGRCG, 3nRB and 4nRB remain maternally inherited after hybridization and polyploidization. Moreover, clade separation of hybrid offspring from their paternal BSB in the phylogenetic tree implies that phylogenetic analysis of mtDNA is incomplete for elucidating the true relationships between different species, particularly when they have undergone hybridization or allopolyploidization. Our study provides significant information for both evolution and genetic studies of mtDNA for hybrid species and allopolyploidization species.

Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease.

The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)(neg) pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27-52) vs 35% (95% CI 27-44); P=0.62). Patients MRD(pos) pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRD(pos) (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRD(neg) status is preferred pre-HCT.

Biomarkers for acute GVHD: can we predict the unpredictable?

Acute GVHD remains an important complication after allogeneic hematopoietic cell transplantation (HCT). Many efforts have been devoted to identifying potential noninvasive peripheral blood biomarkers to help improve the diagnosis or management of acute GVHD while avoiding invasive tissue biopsies. Early attempts to identify biomarkers focused on inflammatory cytokines, especially IL-2 or TNF-α, however, both of these and others were not specific for GVHD, often being elevated in the setting of generalized inflammation, accompanying other major complications of HCT as well. More recent efforts have focused on additional cytokines and other cell-surface molecules, which function in leukocyte trafficking and activation with the hope that these can also serve as targets for novel therapeutic approaches. Modern proteomic methods have allowed the screening of large numbers of patient samples and yielded several novel candidate biomarkers, including elafin and reg3α, which may not be directly involved in the immunological pathogenesis of GVHD, but may be unique biomarkers for end-organ injury. Combining these new molecules with traditionally identified cytokines to form an acute GVHD biomarker panel has recently shown the ability to predict outcomes in patients who develop acute GVHD. The ultimate goals of identifying a specific biomarker are to refine diagnosis, guide therapy and develop risk-adapted approaches in order to better treat patients and improve outcomes after allogeneic HCT. These approaches include differential treatment for patients who develop acute GVHD with a high-risk biomarker profile as well as pre-emptive therapy in patients after HCT prior to the development of symptoms. With the recent progress summarized below, these goals may soon be realized.

Expression of α4ß7 integrin on memory CD8(+) T cells at the presentation of acute intestinal GVHD.

Acute intestinal GVHD remains a major source of morbidity after allogeneic hematopoietic cell transplantation (HCT). α4ß7 integrin is a cell surface molecule that mediates lymphocyte trafficking to intestinal tissue. In this analysis, peripheral blood was collected at the time of presentation of symptoms of acute GVHD and before any treatment. In all, 45 samples were collected and divided into three groups on the basis of subsequent evaluation: intestinal GVHD (n=15), skin GVHD (n=20) and no GVHD (n=10). Two patients developed intestinal GVHD after DLI. The no-GVHD group comprised 10 patients who presented with suspicious symptoms, but evaluation yielded other etiologies. Analysis by flow cytometry showed that intestinal GVHD patients had a significantly higher percentage of α4ß7 integrin-expressing memory CD8(+) T cells (median 7.69%; lower and upper quartiles, 1.06% and 11.64%, respectively) compared with patients with skin GVHD (1.26%; 0.57% and 2.49%) and no GVHD (0.96%; 0.44% and 1.85%), P=0.03. No differences were found in α4ß7 expression in any CD4(+) T-cell subsets or naive CD8(+) T cells. This study adds to the evidence that α4ß7 integrin is involved in lymphocyte trafficking in acute intestinal GVHD.

Grating profile optimization for narrow-band or broad-band infrared emitters with differential evolution algorithms.

A stochastic method and its variants, differential evolution (DE) and micro-DE, were employed to optimize profiles of omnidirectional gratings for desired emittance spectra. Both narrow-band and broad-band infrared emitters were developed successfully from assigned profile types with different complexity and dimension constraints. The efficiency in determining profiles from each method was compared to demonstrate that the superiority of each method is dependent on the number of parameters (dimensions). The performance of the proposed emitters was further discussed considering the emission orientation and fabrication tolerance.

Surface waves between metallic films and truncated photonic crystals observed with reflectance spectroscopy.

We have analyzed and demonstrated surface-wave excitations, by propagating waves in air, at the interface between a truncated photonic crystal (PC) and a silver film in the near-infrared. The truncated PC was fabricated with several unit cells of alternating SiO(2) and Si(3)N(4) layers. The dispersion relation of surface waves was calculated using the supercell method. A Fourier-transform infrared spectrometer measured the spectral reflectance of the fabricated sample at different incidence angles. An angle-resolved laser scatterometer measured the reflectance as a function of the incidence angle at the wavelength of 891 nm. The agreement between the resonance conditions obtained from experiments and the calculated dispersion relation manifests that surface waves at the PC-Ag interface may be utilized to build coherent thermal-emission sources.

Current status of reduced-intensity allogeneic stem cell transplantation using alternative donors.

The optimal donor for a patient undergoing reduced-intensity stem cell transplantation remains a human leukocyte antigen (HLA)-matched relative. Alternative donors such as matched unrelated donors (MUDs), mismatched related donors (haploidentical), or unrelated umbilical cord blood (UCB) units have emerged as options as well. The most experience thus far has been with MUD donors, mostly attributed to the development of allele-specific DNA-based HLA-typing methods. The biggest drawback remains the significant delay needed to locate a donor. Haploidentical donors exist for almost all patients, and offer the convenience of a living related donor. However, significant rates of graft-versus-host disease (GVHD) and other toxicities continue to complicate such HLA mismatching. UCB is the most recent option for source of stem cells. Frozen cord blood units can be acquired almost immediately and are able to safely traverse 1 or 2-HLA antigen mismatch barriers. The experience with UCB has been limited by the low cell dose, although recent innovations are attempting to overcome this. In this review, we summarize the current experience and knowledge with alternative donors as stem cell sources for reduced-intensity transplantation.