bluuebunny/crossref_metadata_2025 huggingface dataset:
Return to Work After Autologous Chondrocyte Implantation of the Knee in Patients with Workers Compensation Insurance
Authors: Lane John G.
Published: November 2019

Objective

This retrospective analysis aimed to evaluate patient and defect characteristics on return to work after autologous chondrocyte implantation (ACI) for all patients with workers compensation insurance in our clinic.

Methods

Retrospective analysis of medical records of patients with workers compensation treated with ACI in our clinic over 10 years (August 2004 to November 2014). Data were collected on demographics, lesion size and location, number of defects, duration of symptoms, and outcomes.

Results

A total of 28 patients with 30 ACI procedures were included in this analysis. Patients had a mean age of 40.0 years, were mostly male, and tended to be overweight (mean body mass index = 31.5 kg/m2). Most patients were employed in occupations with high physical demand (85.7%) compared with lower physical demand jobs (14.3%). The mean number of lesions per knee = 1.73. Overall, the mean total surface area of the defect was large (12.6 cm2), with large mean individual lesion size of 7.39 cm2. All 28 patients returned to work in some capacity, with a total of 22 (79%) returning to full work, and 6 (21%) returning to modified work. There were no significant differences in the comparison of patients who returned to full versus modified work, in mean age, body mass index, high versus low physical demand occupation, or lesion characteristics (size, chronicity, or location).

Conclusions

Our results demonstrate that in a challenging workers compensation cohort, in patients with multiple large defects, treatment with ACI allows a high percentage of patients to return to their normal vigorous work activities within 9 months to 1 year following cartilage restoration. This study is a level IV retrospective case series.
Influence of tunnel blasting construction on adjacent highway tunnel: A case study in Wuhan, China
Authors: Liu Zihan , Jiang Nan , Sun Jinshan , Xia Yuqing , Lyu Guopeng
Published: November 2019

In the blasting construction of new tunnels adjacent to existing tunnels, it is important to properly evaluate and control the influence of blasting vibration. In this study, the peak particle velocity of the lining structure of the Huanglongshan highway tunnel (i.e. the existing tunnel) in Wuhan, China, which was adjacent to a tunnel under construction by blasting, was monitored and analyzed. The numerical model of the existing tunnel was established by the dynamic finite element software LS-DYNA, and the reliability of the model and parameter selections were verified based on the field monitoring data. The relationship between peak particle velocity and effective tensile stress of the tunnel lining structure was proposed based on the combination of measured peak particle velocity, dynamic stress distribution characteristics, and numerical simulations under different blasting conditions. Based on the maximum tensile stress criterion and considering the dynamic tensile strength increase factor of lining material, the safety threshold of peak particle velocity for existing tunnel lining structure and the maximum charge weight for new tunnel blasting were suggested.
Examining Behaviors Related to Retirement, Cleaning, and Storage of Turnout Gear Among Rural Firefighters
Authors: Macy Gretchen B. , Hwang Jooyeon , Taylor Ritchie , Golla Vijay , Cann Charles , Gates Brittney
Published: November 2019

Background: Although the increased occupational exposures among career firefighters are well documented, there are gaps in research related to exposures among volunteer firefighters. This study was completed in a state where the majority of firefighters are volunteers. We aimed to examine if differences existed in career versus volunteer firefighters’ behaviors related to the retirement, cleaning, and storage of turnout gear which may increase occupational exposures. Methods: A cross-sectional survey was administered to a convenience sample of 300 firefighters during a training event for both volunteer and career firefighters from one fire district in Kentucky. We measured factors that may affect behaviors related to retirement, cleaning, and storage of turnout gear, such as age of turnout gear at retirement, frequency of cleaning, and location of storage. Results: Two hundred and seventy-five firefighters out of 300 invited participants completed the survey, for a response rate of 92%. The majority of the participants were compliant with National Fire Protection Association Standards with most reporting cleaning their gear as needed, storing gear at the fire station, and retiring gear within 10 years of the manufactured date. Most of the participants (88%) were concerned about job-related exposures and felt susceptible to diseases like cancer and respiratory illness. The structural issues of cost and accessibility were identified as the primary barriers to the proper retirement and cleaning of turnout gear, especially among volunteer firefighters. Conclusions/Application to Practice: Most participants retired, cleaned, and stored turnout as recommended. The majority of participants were concerned with job-related exposures. The structural issues of cost and accessibility were identified as the primary barriers to the proper retirement and cleaning of turnout gear, especially among volunteer firefighters. By identifying differences, tailored trainings could be aimed at volunteer firefighters to help reduce their exposures.
Multiple Erythroid Isoforms of Human Long-Chain acyl-CoA Synthetases Are Produced by a Switch of the Fatty Acid Gate-Domains.
Authors: Soupene Eric , Kuypers Frans A.
Published: November 2019

In mammals, long-chain acyl-CoA synthetases (ACSL) are necessary for fatty acid degradation, phospholipid remodeling, and production of long acyl-CoA esters that regulate various physiological processes. These enzymes play a crucial role in plasma membrane phospholipid turnover in erythrocytes, maintaining the complex phospholipid molecular species composition essential for proper membrane function. The mechanism by which this highly dynamic turnover together with an ever-changing plasma fatty acid pool maintains phospholipid composition is poorly understood. We have previously cloned Acyl-CoA Synthetase Long-chain member 6 (ACSL6), the isoform responsible for activation of long-chain fatty acids in erythrocytes. Two additional transcript variants of this protein were subsequently isolated from brain and testis. We report the expression of four different variants of ACLS6 in reticulocytes, one as we originally reported, two of which are novel, one as was identified in brain cells. PCR amplifications using primers for the predicted variable regions were performed from cDNAs of CD34 positive erythroid progenitors, K562 cells, fetal blood cells, reticulocytes and placenta. ACSL variants were expressed in E. coli host BL21DE3 cells using the pET28a vector, and detected by His tag immuno detection. Sequence alignments were generated using sequences retrieved from RefSeq and GenBank databases on the NCBI site. Exon and intron definition for ACSL members were obtained using evidence viewer and model maker available at the map viewer page of each gene.

We identified four different spliced variants of ACSL6 in erythroid cells based on a mutually exclusive exon pair. Each exon of this pair encodes a slightly different short motif that contains the fatty acid Gate domain, a conserved structural domain found in all vertebrate and invertebrate ACSL homologs. The motif differs in the presence of either the aromatic residue phenylalanine (Phe) or tyrosine (Tyr), and seems to play a role in substrate specificity. One of the new forms contained an exon not found in any other ACSL isoforms. Erythroid precursors also express the closely related ACSL1, and we characterized two additional isoforms of this protein, similar to ACSL6. When analyzed on denaturing SDS polyacrylamide gel both ACSL1 and 6 appeared to exist as a dimer. Based on our results, we propose the generation of two different Gate-domains by alternative splicing of the two exons in these proteins. One represents a switch of the Phe to the Tyr Gate-domain motif, the other resulted of the exclusion of both. Swapping of this motif appears to be common to all mammalian homologs of ACSL1 and 6. We conclude that the Phe to a Tyr substitution in the Gate-domain, or its removal, together with the formation of homo or heterodimers will allow ACSL6 the structural diversity to define substrate specificity that maintains the complex plasma membrane phospholipid molecular species composition in erythrocytes.
Variance in Outcomes by Physician Providers for Patients with Non-Hodgkin’s Lymphoma.
Authors: Dillman Robert O. , McClure Stephanie E.
Published: November 2019

We previously documented an improvement in survival for patients diagnosed with non-Hodgkin’s lymphoma at our institution during the years 1998–2003 compared to those diagnosed during 1990–1997. [Blood2005;106:242b] Because patients were being treated by several community-based practitioners, we examined the variance in lymphoma-specific survival by physician provider. The Hoag Cancer Registry data base was used to identify patients with a diagnosis of lymphoma. Observed and relative 5-year survival rates were calculated using a computer software program designed specifically for this purpose (Electronic Registry Systems, Inc., Cincinnati, OH). Relative survival was used to estimate lymphoma specific survival. The 802 patients from all practitioners had a median age of 64 years and a relative 5-year survival of 66% and observed 5-year survival of 54%. Data was reviewed for the 6 individual physicians who had managed at least 40 lymphoma patients during 1990–2003 (range 48–189), who accounted for 77% of all lymphoma patients. The observed and relative 5-year survival by these practitioners were: A 62% & 78%, B 67% & 77%, C 54% & 69%, D 51% & 65%, E 58% & 64%, and F 45% & 54%. Patient populations were dissimilar: practitioners D & E had the highest numbers of patients, B & F had the youngest patients, A & C the oldest, A the highest proportion with indolent lymphoma, and B the highest proportion with stage I disease. Combining data for physicians ABC (highest survival rates) (n=215) vs DEF (n=404) revealed a superior survival rate for ABC (p=.020), and a difference by whether systemic chemotherapy was initiated at the time of initial diagnosis (p=.016), as opposed to no therapy or local therapy only. This study demonstrated a 24 percentage point difference in relative 5-year survival rates among practitioners. There were differences in prognostic variables for specific populations of patients managed by individual physicians, but such differences were not seen for ABC vs DEF. Collectively, the three physicians whose patients had the best survival were more likely to use systemic therapy within four months of initial diagnosis rather than local therapy or no treatment. It is important to understand the impact of prognostic variables and physician-specific treatment differences on the variance of outcomes among different practitioners.
Castleman’s Disease: Four Extraordinary Presantations and Review of Literature.
Authors: Kupesiz Gokben Yildirim , Akkaya Bahar , Kupesiz O. Alphan , Karpuzoglu Gulten
Published: November 2019

Castleman’s disease is a rare disorder of the lymphoid tissue with three possible histological variants--the hyalin-vascular type, with a good prognosis, the plasma-cellular type and the mixed type; the latter two are both more aggressive than the hyalin-vascular type. Two clinical types of this disease have already been described: the localized or unifocal type and the multicentric or multifocal type. Localized and multicentric Castleman’s disease may be different clinical disorders with overlapping histologic features. Localized disease generally presented with a single enlarged lymph node or widening of the mediastinum, whereas multicentric disease is a systemic lymphoproliferative disorder characterized by lymphadenopathy, hepatosplenomegaly, constitutional symptoms, anemia, hypoalbuminemia, and hypergammaglobulinemia. Unlike the localized type, for which surgical excision is curative regardless of the histologic type, multicentric disease often necessitates aggressive systemic therapy and portends a poorer outcome. The aetiology of Castleman’s disease remains unclear. Here, we report four cases of Castleman’s disease, with extraordinary presentations. Tumors from retroperitoneum, mesenterium, bladder vicinity and nasopharenx locations were included. All of patients were taken to the surgery with different pre operative diagnosis. There were 1 female and 3 males; ages ranged from 16–62 years old; sizes ranged from 4– 9 cm (mean 5.5 cm). All patients presented with localized disease. One of the patients had previous NHL and lung cancer history. None of the patients demonstrated systemic involvement or signs of the POEMS syndrome. Hystopathologically 3 of the cases were classified as hyalin-vascular type and 1 of the cases were classified as plasma-cellular type. None of the patients had recurrences. Castleman ‘s disease is an uncommon cause of lymphadenopathy, and must be considered after all other causes have been eliminated. We also add the overview of the literature of the cases with extraordinary presentations.
Efficacy of 90Y-Ibritumomab Tiuxetan in Marginal-Zone Lymphoma (MZL).
Authors: Vanazzi Anna , Ferrucci Pier Francesco , Grana Chiara , Pruneri Giancarlo , Crosta Cristiano , Pinto Antonello , Chinol Marco , Paganelli Giovanni , Martinelli Giovanni
Published: November 2019

Radio-immunotherapy (RIT) is an effective approach for patients with relapse-refractory NHL. RIT targets radiation to the tumor bulk while limiting exposure of normal tissues. Toxicity is prevalently hematologic, but transient and reversible. 90Y-Ibritumomab Tiuxetan in particular has demonstrated activity in follicular (FL) and Diffuse Large B-Cell (DLBC) NHL, but data are still lacking in MZL. 90Y-Ibritumomab Tiuxetan could offer an alternative option to those pts who relapse or do not respond to conventional treatment. We report efficacy results of a pilot study of 90Y-Ibritumomab Tiuxetan delivered at conventional activity (0,4 mCi/kg) in MZL patients. From May 2004 to July 2007, 15 patients were enrolled. Median age was 57 ys (range 36–83 ys); 9 female and 6 male. Six out of 15 pts had Helicobacter Pylori-negative gastric MALT (mucosa-associated lymphoid tissue) NHL. The remaining 9 pts had non gastric extranodal MZL. At time of treatment 6/15 pts had limited disease (stage I/II), 9/15 disseminated disease (stage III/IV; Ann-Arbor Staging System); bone marrow biopsy showed disease localization in 3/15 pts. Median number of previous therapies received was 2 (0–4): all pts except one had received prior CT, 7 prior Rituximab, 3 prior RT. Toxicities were primarily haematological, as expected, and reversible. Response evaluation was performed two months after 90Y-Ibritumomab Tiuxetan administration by upper gastrointestinal endoscopy with multiple biopsy and endoscopic ultrasonography in gastric NHL and by CT scan in the remaining pts. Ten out of 15 patients are now evaluable for response: 6 CR, 1 uCR, 3 SD. Response are durable: 5 CRs have been maintained for CR at 33, 26, 22, 15 and 14 months, respectively.

CONCLUSIONS: 90Y-Ibritumomab Tiuxetan seems to be very active in pts with MZL resistant or refractory to conventional systemic treatment. Its mechanism of action mimics conventional RT already known as valid option in MZL with localized disease. If these preliminary results are confirmed in larger number of patients, one single administration of 90Y-Ibritumomab Tiuxetan delivered at conventional activity (0,4 mCi/kg) could be considered a possible alternative option in the treatment of such indolent disease.
Methotrexate and/or Rituximab in a New Nude Rat Central Nervous System Lymphoma Model: Efficacy, Toxicity and Magnetic Resonance Imaging.
Authors: Jahnke Kristoph , Muldoon Leslie L. , Varallyay Csanad G. , Lewin Seth J. , Brown Robert D. , Kraemer Dale F. , Soussain Carole , Neuwelt Edward A.
Published: November 2019

The aim of this study was to determine the efficacy and toxicity of methotrexate (MTX) and/or rituximab treatment in a novel central nervous system (CNS) lymphoma model, using either intravenous (IV) or intraarterial (IA) drug administration in conjunction with osmotic blood-brain barrier disruption (BBBD). Female athymic nude rats (rnu/rnu) were inoculated with human MC116 B-cell lymphoma cells in the caudate putamen. On the day of treatment and first magnetic resonance imaging (MRI) (day 16–20), rats were randomized into 7 groups:

control group with saline IV (n = 15) or IA/BBBD (n = 7); rituximab 375 mg/m2 IV (n = 6) or IA/BBBD (n = 3); MTX 1000 mg/m2 IV (n = 6) or IA/BBBD (n = 6); and rituximab 375 mg/m2 IV + MTX 1000 mg/m2 IV (n = 6).

A second MRI scan was done 1 week after treatment. Study end points included tumor response on MRI (defined as ≤75% tumor volume on post-treatment MRI), toxicity, and tumor volumes on histology. In the IV groups, the percent change in tumor volume on T2/FLAIR images in the control versus rituximab group was statistically significant (p = 0.0051). In the IA/BBBD groups, there was a statistically significant difference between control and rituximab (p = 0.0167) for absolute and percent changes in tumor volumes on both T2/FLAIR and T1 with gadolinium sequences. For T1 with gadolinium, the difference between control and MTX was also significant for both absolute change (p = 0.0066) and percent change (p = 0.0043). Response rates in the IV groups differed significantly between controls and rituximab (p = 0.0017 on T2/FLAIR and p = 0.0049 on T1 with gadolinium). A good correlation between tumor volumes (in log mm3) on histology and fluid-attenuated inversion recovery (FLAIR)/T2 (R2 = 0.83) or contrast-enhanced T1 weighted images (R2 = 0.73) for tumors located in the caudate putamen was observed. Results of complete blood counts at sacrifice did not differ significantly between the groups. The MC116 CNS lymphoma model is valuable for preclinical testing of efficacy and toxicity of various treatment regimens. Rituximab and MTX were particularly effective in this model, regardless of the route of administration.
Congenital Hypothyroidism Following Maternal Exposure throughout Pregnancy to Imatinib.
Authors: Leeksma Onno C. , van Mil Edgar A.
Published: November 2019

Imatinib mesylate has revolutionized treatment of Chronic Myeloid Leukemia. Yet for women of child bearing age problems may arise during pregnancy. While continuation of the drug is in the interest of maternal health, the safety of this approach for the fetus has been questioned. Therapy is therefore usually immediately interrupted on recognition of pregnancy. Only three successful pregnancies have been reported to date in which imatinib was continued. A 34-year-old woman of Chinese descent in complete cytogenetic and major molecular remission (i.e. 3-log reduction of BCR-ABL transcripts) of her CML in chronic phase on 400mg imatinib daily continued treatment during conception and throughout pregnancy. After an uneventful full term pregnancy she gave birth to an apparently healthy son. The mother retained her major molecular remission. Routine screening for congenital hypothyroidism of her child however repeatedly revealed an elevated TSH, rising from 11 mU/l at the age of 1 week to15 mU/l at 4 weeks, associated with a relatively low free T4 of 24.8 and 17.4 pmol/l respectively. Thyroglobulin and thyroxine binding globulin concentrations were normal for age. The mother was euthyroid and had no detectable anti-thyroid antibodies. A mild primary hypothyroidism was suspected. An ultrasound showed no developmental defect of his thyroid gland and a 123I scan with a perchlorate discharge test ruled out an intra-thyroidal iodide organification defect. There was no family history of congenital hypothyroidism. The child was put on levothyroxine and is currently doing well. Hypothyroidism has been noticed as a potential side effect of imatinib therapy in thyroidectomized patients receiving levothyroxine and has been ascribed to enhanced non-deiodination clearance of T4 (de Groot et al Clin Pharmacol Ther2005;78:433–8). An induction of uridine diphosphate-glucuronosyl transferases by imatinib was hypothesized as mechanism for an altered levothyroxine metabolism in these patients. Congenital hypothyroidism has to the best of our knowledge not been reported as a potential consequence of imatinib therapy.
RH Gene Polymorphisms Are Risk Factor for Alloimmunization in Patients with Sickle Cell Disease.
Authors: Westhoff Connie M. , Vege Sunitha
Published: November 2019

Transfusion therapy for treatment of sickle cell disease (SCD) is predicted to increase, following the significant benefit of chronic red cell transfusion demonstrated by the stroke prevention trial (STOP). Despite progress in mitigating negative effects of transfusion therapy with the use of iron chelating agents, alloimmunization remains a significant problem. Patients with SCD have a higher incidence of antibody production compared to other patient groups undergoing chronic transfusion. To limit alloimmunization, many programs transfuse SCD patients with RBCs that are phenotype-matched for the most immunogenic blood groups, Rh and K, and some programs also supply RBCs from African-American (AA) donors. Although this approach reduces the incidence of alloantibody production, it is resource- and cost-prohibitive for many programs, and, importantly, some patients (∼5%) still become alloimmunized. The development of high-throughput genotyping for blood group antigens will make antigen-matching cost effective; therefore, it is important to determine why some patients become alloimmunized despite antigen-matching. We investigated the antibody specificity and sequenced the RH genes in 46 SCD patients who were alloimmunized, despite having received Rh and K matched units. The antibodies identified included anti-D, or -C, or -e, and/or antibodies to high-prevalence antigens. None had anti-E. RH gene sequencing revealed that 20 patients had a RHD-CE(3–7)-D hybrid gene in which RHD exons 3 through 7 are replaced with reciprocal exons from RHCE. The resulting Rh protein encodes an altered C antigen. This D-CE-D gene was also linked to an RHce allele encoding altered e antigen. These patients had anti-C and/or anti-e in their serum (i.e.-hrB). We screened healthy AA donors and found that the prevalence of the hybrid RHD-CE(3–7)-D gene in this population is 5–8%. The remaining 26 patients were homozygous for mutations in RHce and had produced anti-e, and some also had mutations in RHD and had produced anti-D. These results suggest that inheritance of a RHD-CE-D gene or altered RHce, with or without altered RHD, underlies Rh alloimmunization in SCD. The altered Rh proteins are not distinguished with current serologic typing reagents. Therefore, these patients are not truly Rh antigen matched. The development of RH genotyping platforms offers a potential solution to prevent alloimmunization by identifying SCD patients who are homozygous for variant alleles and at risk for production of alloantibodies to Rh antigens. The 5–8% of donor units with the same RH genotype could be directed to these high risk patients.
Analysis of JAK2 V167F Mutation in Myelodysplastic Syndromes.
Authors: Fermo Elisa , Zaninoni Anna , Imperiali Francesca G. , Bianchi Paola , Colombi Mariangela , Barcellini Wilma , Zanella Alberto
Published: November 2019

The somatic mutation JAK2 V617F has been identified as a pathogenic factor in typical chronic myeloproliferative diseases (MPD) such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis with myeloid metaplasia (MMF). In typical forms of myelodysplastic syndromes (MDS), JAK2 V617F mutation is rarely present (2–5%); on the contrary, it has been found with higher prevalence in patients with RARS-T (i.e. MDS/MPD-U with platelet count >600×109/L and ringed sideroblasts more than 15%) and in a subgroup of MDS patients with isolated 5q deletion and a proliferative bone marrow. In this study we analysed the JAK2 V617F mutational status in 53 MDS patients (26 males, 27 females; median age at the time of the study 76 years, range 45–91). Patients were classified as follows: 4 cases 5q- syndrome, 3 RCMD, 5 MDS/MPD, 1 MDS-U, 23 RA, 12 RARS, 5 RAEB. DNA was extracted from purified granulocytes; all samples were analyzed by allele-specific polymerase chain reaction (PCR), according to Baxter el al (2005). DNA samples were further subjected to direct sequencing for confirmatory testing. The JAK2 V617F mutation was present in 3 cases, with an overall frequency of 5%. With respect to MDS subtype, 1 patient had RA and 2 RARS. Among the 12 RARS patients, the two V617F postive displayed thrombocytosis (680×109/L and 649×109/L), whereas none of the 10 RARS V617F negative patients showed high platelet counts (median Plt 157×109/L, range 5–422×109/L). In one JAK2 mutant case, thrombocytosis required treatment with hydroxyurea. Moreover, the two V617F positive RARS patients displayed higher WBC count (6.2×109/L and 8.5×109/L) than the V617F negatives (median WBC 4.05×109/L); no difference was observed in Hb levels. The JAK2 positive RA patient had 10% of sideroblasts in bone marrow, normal platelet and WBC count and no proliferative characteristics; since the occurrence of the mutation may be an early event and preceed the classical manifestations of MDS/MPD, a longer follow-up is necessary to determine its possible prognostic significance. Considering the V617F negative MDS cases, only one patient, diagnosed as MDS/MPD, showed a platelet count >600×109/L. In conclusion, we confirmed recent reports showing that JAK2 V617F is present with low prevalence (about 5%) in MDS; in particular, the JAK2 mutation identifies a subset of MDS patients with and “overlap” syndrome, characterised by proliferative bone marrow morphology and frequent thrombocytosis and leucocytosis, who may benefit from JAK2 specifically targeted therapies.
Copper and Iron Status in Myelodysplastic Syndromes.
Authors: Saouli Zoi , Kontoninas Zisis , Girtovitis Fotios , Kaiafa Georgia , Ntaios George , Andreadis Charalambos , Tsoukali Helen , Haztitolios Apostolos , Papadopoulos Athanasios
Published: November 2019

Introduction: Copper is an essential mineral found in many tissues. It is involved in iron incorporation into hemoglobin, hemolytic syndromes, while copper deficiency provokes iron overload and induces dysplastic changes to erythrocytes. On the other hand, there are references that iron overload can result in mild copper deficiency. There seems to be equivocal relationship between these two elements.

Aim: The aim of this study is to determine copper and iron status in myelodysplastic patients and to investigate if copper deficiency correlates with the type of myelodysplastic syndrome.

Materials and methods: We studied 52 patients with myelodysplastic syndrome, 29 men and 23 women(mean age 67,05± years). No other simultaneous disease was confirmed which could contribute to copper disorders. Patients were categorized in two groups. Group A, composed of 21 patients frequently transfused(approximately once monthly), suffering from RAEB, RAEB-t AND CMML. Group B included 31 patients, who either didn’t often need transfusion, or responded to erythropoietin, suffering from RA and RARS. Copper, iron and ferritin levels measurments were performed. Copper was measured by flame atomic absorption spectrometry (normal range: 0,8–1,3mg/l).

Results:

Nine patients of group A revealed copper deficiency(mean value 0,66±0,06mg/L). Mean copper value was 0,8±0,11mg/L for that group. All of them had elevated iron levels (average:602,23±160,46μg/dl) and high ferritin levels(average:1769±693,85ng/ml) All group B patients were found to have normal copper levels(Mean value was 1,15±0,09), indicating a statistically significant difference compared to group A patients(p<0,0001). Iron and ferritin levels were within normal range(average105,22±28,63 and 82,9±28,42 respectively)

Conclusions: Copper levels, in multitransfused patients with poor prognosis myelodysplastic syndrome and iron overload, are significantly lower than in oligotransfused ones with good prognosis who consequently present normal iron burden.
Circulating Dendritic Cells of the Patients with Myelodysplastic Syndromes.
Authors: Shao Zonghong , Wang Huaquan , Xing Limin , Fu Rong , Tu Fengmei
Published: November 2019

Objective To investigate the quantity, subsets of dendritic cells(DC) and costimulatory molecule expression in peripheral blood(PB) of the patients with myelodysplastic syndromes(MDS).

Methods Total DC(Lin1+HLA-DR+), myeloid DC(mDC) (Lin1+HLA-DR+ CD11c+) and plasma DC(Lin1+HLA-DR+CD123+) in fresh whole PB samples of 38 MDS patients and 19 normal controls were assayed with flow cytometer and the monoclonal antibodies. The expression of CD80, CD86 and CD40, the costimulatory molecules on these DC were also assayed in the same way.

Results. Total DC in PB of MDS patients was more than that of normal controls significantly [(41.4±10.9)×106/L vs (12.1±1.4)×106/L](P<0.05). mDC in PB of MDS patients was more than that of normal controls too [(20.8±7.2)×106/L vs (5.5±0.9)×106/L](P<0.05). pDC in PB of MDS patients was not significantly more than that of normal controls [(9.5±2.8)×106/L vs (6.6±0.7)×106/L] (P>0.05). The percentage of total DC in PB mononuclear cells(PBMNC) of MDS patients was higher than that of normal controls[(2.78±0.59)% vs (0.68±0.08)%](P<0.05). The percentage of mDC in PBMNC of MDS cases was also higher than that of normal controls[(1.15±0.33)% vs (0.32±0.05)%](P<0.05). The percentage of pDC in PBMNC of MDS cases was not significantly higher than that of normal controls[(0.64±0.19)% vs (0.37±0.04)%](P>0.05).

Conclusion DC, mainly mDC, increased significantly in MDS, but pDC did not. The costimulatory molecules(CD80 and CD86) except CD40 expressed more on the DC of MDS patients. It was suggested that the APC relating the inflammatory injury increased in MDS, but the APC relating to antitumour immunity did not. What we found here might be involved into the pathogenesis of MDS.
Activation of Nuclear Factor KappaB in ETV6/FLT3-Transformed Ba/F3 Cells Depends on the FLT3 Tyrosine 591.
Authors: Vu Hoang Anh , Xinh Phan Thi , Kano Yasuhiko , Ishida Takaomi , Watanabe Toshiki , Tokunaga Katsushi , Sato Yuko
Published: November 2019

The FLT3 gene is one of the most frequently mutated genes in hematologic malignancies. Mutated FLT3 has been found to lead to strong constitutive activation of several signaling proteins such as STAT5, CBL, VAV, SHP2, NF-kB, and AKT. Recently, we have reported that FLT3 contributed to leukemogenesis through generating a ETV6/FLT3 fusion gene in a patient with myeloproliferative disorder and a t(12;13)(p13;q12) translocation, which is the first report to show that FLT3 fusion gene can be involved in leukemogenesis. The ETV6/FLT3 which contained the helix-loop-helix oligomerization domain of ETV6 fused to the juxtamembrane (JM) domain plus tyrosine kinase (TK) domains of FLT3, conferred interleukin-3-independent growth on Ba/F3 cells (Vu HA, et al. LEUKEMIA20:1414–21, 2006). To assess a role of the JM domain of FLT3 in the ETV6/FLT3 protein, we generated a series of ETV6/FLT3 mutants (tyrosine to phenylalanine substitution and deletion of the JM domain or N-terminal region of the TK1 domain). Each mutant was introduced into Ba/F3 cells and downstream signaling as well as cell proliferation was investigated. We found that the wild-type ETV6/FLT3 in Ba/F3 cells was a constitutively activated tyrosine kinase that led to activation of STAT5, AKT, MAPK, and NF-kB pathways as well as up-regulation of PIM-1. Deletion of the JM domain retained compatible level of autophosphorylation of the fusion protein as well as activation of STAT5, AKT and MAPK, suggesting that the JM domain is dispensable for STAT5, MAPK and AKT activations. In contrast, deletion of the JM domain did abrogate interleukin-3-independent growth of Ba/F3 cells, PIM-1 up-regulation, and activation of NF-kB. Importantly, while substitutions of other 3 tyrosines (589, 597, and 599) had no affect on NF-kB activation, the substitution of tyrosine 591 to phenylalanine abrogated this activation. Our results suggest that the tyrosine 591 in JM domain of FLT3 in ETV6/FLT3 is critical for NF-kB activation to support cell survival and PIM-1 up-regulation.
p53 in B Cell Chronic Lymphocytic Leukemia (CLL) and Lymphoma with Peripheral Blood Expression along Treatment with Fludarabine and Other Treatment Regimens.
Authors: Barragan Carlos Sergio , Hansson Silvia B. , Cicchini Silvina A. , Tamashiro Monica , Dinardi Pablo G.
Published: November 2019

Objective: To determine the expression of mutated p53 at diagnosis, along the treatment and after relapse and correlation itself with rapid disease progression. Mutated p53 was established as marker of disease progression and poor prognosis. Fludarabine is one of the standard treatments for both diseases despite the fact that it promotes p53 gene subset activating apoptosis system.

Patients Materials and method: Forty four patients were enrolled throughout two years. They were studied before, along and after treatment with immunocytochemistry for establishing the frequency of mutated p53 protein. The treatment regimens given were CHOP, one patients with Anaplastic B large cell Lymphoma; CHOP-R (Rituximab tm), one Mantle cell Lymphoma and one B Diffuse Large cell Lymphoma and Cyclophosfamide + Fludarabine oral 20 CLL patient. One patient had a follicular Lymphoma and undergo Autologous Bone Marrow transplantation (ABMT). Other prognosis markers were analyzed, such as p38 and zap 70.

Results: We detected twelve positive cases, two of them CLL both were first negative and then became positive; one spontaneously and the other after second line treatment with fludarabine and relapse. Seven patients with CLL were positive at diagnosis. Three positive p53 patients with Lymphoma, one of them HIV-AIDS the other after ABMT had a rapid progression and promptly died. All the patients with CLL are still alive two of them, the younger patients have a fast duplication of cellular counts and tumor burden.

Conclusion: It is necesary more cases to assert that p53 alone at diagnosis predict bad evolution at least in older patients with CLL who in our experience had a good development, otherwise all the Lymphoma patients and CLL after treatment p53 + had a worts outcome.
Malignant B Cells from Hairy Cell Leukemia Express an Innate Phenotype and Undergo IgD Class Switching in Response to Innate Environmental Factors, Including BAFF and APRIL.
Authors: Chiu April , Chen Kang , He Bing , Dillon Stacey , Chadburn Amy , Knowles Daniel M. , Xu Weifeng , Cerutti Andrea
Published: November 2019

Hairy cell leukemia (HCL) is a rare chronic lymphoproliferative disorder characterized by massive infiltration of the spleen by malignant B cells displaying a distinctive “hairy” morphology. These hairy cells (HCs) often contain hypermutated Ig genes, suggesting an ontogenetic relationship with post-germinal center memory B cells. However, unlike memory B cells, HCs usually express CD11c and CD103, two molecules typically associated with mucosal innate immune cells. The goal of this study was to elucidate the ontogeny and growth mechanisms of HCs. We found that HCs interacted with splenic endothelial cells expressing B cell-activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL), two innate B cell-stimulating factors involved in T cell-independent antibody responses, including Ig class switching. In agreement with prior studies indicating that BAFF and APRIL play an important role in B cell tumors, HCs expressed transmembrane activator and calcium modulator and cyclophylin ligand interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R), three receptors that bind BAFF and APRIL. In addition, HCs expressed microbial carbohydrate and endocytic receptors usually expressed by innate immune cells, including DEC-205 (CD205), mannose receptor (CD206), langerin (CD207) and dendritic cell-specific ICAM-3-grabbing non-integrin (CD209). This phenotype was different from that of naïve, germinal center, memory and plasmacytoid B cells, but similar to that of a subset of splenic marginal zone and mucosal B cells. Like these innate B cells, HCs contained activation-induced cytidine deaminase, a DNA-editing enzyme required for class switching, and showed signs of ongoing IgM-to-IgD class switching, a mucosal Ig diversifying process typically triggered by BAFF and APRIL. Our findings suggest that HCL may emerge as a result of chronic stimulation of an innate B cell precursor through a T-cell independent pathway involving microbial carbohydrates, BAFF and APRIL.
A Retrospective Analysis of Response to High Dose Rituximab Monotherapy in CLL/NHL Patients Who Received Prior Standard Dose Rituximab Therapy.
Authors: Moffa Casey A. , Thatikonda Chandana , Pathe Neeta , Rossetti James M. , Shadduck Richard K. , Lister John
Published: November 2019

Background: Rituximab at standard dose (375 mg/m2) in combination with chemotherapy has been used to treat CLL and NHL. We retrospectively evaluated the response and toxicity of high dose rituximab (HDR) (500 mg/m2 thrice weekly for 2 weeks, total dose 3 gm/m2) in patients with CLL or NHL, who had received prior treatment with standard rituximab as either monotherapy or in combination chemotherapy, to determine if there was a dose response relationship.

Methods: Eight patients with either CLL or NHL who had received HDR therapy were evaluated. Patients received HDR because they refused conventional treatment or failed to respond to prior combination chemotherapy. Seven of the patients had prior combination therapy, whereas 1 had received standard dose rituximab alone. Response to HDR was evaluated based upon absolute lymphocyte count approximately 21 days after the final treatment in CLL patients and PET/CT scan after the final treatment for NHL.

Results: Mean age at treatment: 70 yrs (range = 57–83), males (n=7) and female (n=1), CLL (n=5) and NHL (n=3). One patient with CLL had Richter’s transformation. Patients received prior treatments with rituxan alone (n=1), combination therapy for CLL with FCR, FR or PCR (n=5) or combination therapy for NHL with hyperCVAD-R, CHOP-R or RICE (n=2). Of the 5 patients with CLL treated with HDR, 3 achieved partial remission (PR) while the remaining 2 patients developed progressive disease. Complete remission, however, could not be assessed secondary to lack of a post treatment bone marrow biopsy. All 3 patients with NHL developed progressive disease. One patient developed rigors during the infusion of HDR requiring IV steroids. No infusion was stopped secondary to toxicity.

Conclusions: Based upon our findings, HDR was active in patients with relapsed CLL but not in relapsed NHL. Further exploration of this dose-response relationship is warranted in patients with CLL.
Epidemiology of Plasma Cell Disorders in a General Hospital: A Retrospective Study of 102 Patients.
Authors: Ricca Irene , Tamponi Giacomo , Arnò Celeste , Bosio Angelo , Cerrato Flavio , Coggiola Marisa , Epifani Giuseppe , Giacometto Fiorella , Monaco Gabriele , Pallisco Ottavio , Scalabrino Elisa , Varvello Loris , Raucci Carlo A. , Salomone Attilio , Pascale Claudio
Published: November 2019

INTRODUCTION Plasma cell disorders are a group of diseases characterized by the proliferation of a plasma cell clone which produces a monoclonal protein (M protein). The most common type is Monoclonal Gammopathies of Undetermined Significance (MGUS), followed by multiple myeloma (MM) and Waldenstrom’s Macroglobulinemia (WM). In particular, the frequency of MGUS increases with age and its rate of progression is approximately 1% per year. Because of the high prevalence and the different fields of clinical practice in which these patients are followed, it could be of great interest to know the epidemiology of these diseases out of the Hematology Units.

AIM OF THE STUDY to describe the frequency and the progression risk of plasma cell disorders in a General Hospital during more than a twenty-year period.

METHODS We retrospectively reviewed the medical records of patients with diagnosis of MGUS, MM or WM seen at our center from 1984 through 2006. Statistical analysis were performed using GraphPad Prism 4 (GraphPad Software, Inc.).

RESULTS The study included 102 patients: 78 affected by MGUS (76%), 14 by MM (14%) and 10 by WM (10%). Patients’ clinical features are summarized in the Table. Median follow-up was 48 months (range:12–280). Among the 89 patients with a first diagnosis of MGUS, malignant transformation occurred in 11 patients (7 MM and 4 WM). The median time from diagnosis of MGUS to diagnosis of a lymphoplasma cell proliferative disorder was 60 months (range 12–196). Median time to progression (TTP) was 167 months, as shown in Figure. The cumulative probability of progression was 13.5% at 5 years and 29.2% at 10 years. The amount of serum M protein at diagnosis was a significant predictor of progression.

CONCLUSIONS MGUS are very common in clinical practice, accounting in our study for more than 75% of plasma cell disorders. The premalignant nature of this condition is comfirmed by the rate of transformation in lymphoplasma cell proliferative disorders (50% of MM and 40% of WM, in this study). Even if our results may be biased by the short follow-up period, the only significant predictor of progression was the size of serum M protein at presentation.

Table: Patients’ characteristics Characteristics MGUS MM WM Gender male/female 41/37 4/10 7/3 Age at diagnosis median (range) 69 yrs (30–91) 72 yrs (51–90) 75 yrs (67–85) Serum M protein median (range) 1.26 g/dl (0.17–2.92) 3.85 g/dl (0.62–8.10) 3.20 g/dl (2.22–4.9) Isotype IgG 46 8 - IgA 14 6 - IgM 15 - 10 biclonal 3 - - Immunoparesis yes/no 20/58 14/0 10/0 BJ proteinuria pos/neg 11/67 11/3 1/9 Figure Figure
New Zealand (NZ) Pacific Peoples and Maori Have a Higher Risk of Developing Multiple Myeloma Than Other New Zealanders.
Authors: Phillips Julia K. , Purdie Gordon L.
Published: November 2019

The incidence of multiple myeloma shows ethnic variation, myeloma age-standardized incidence being higher in African Americans at 11.3 per 100,000 than White Americans in whom the incidence is 5.1 per 100,000 (standardized to US 2000 census population)[Ries et al (2007) http://seer.cancer.gov/csr/1975_2004/]. NZ has a number of ethnic minorities, which includes Maori and Pacific peoples. New diagnoses of multiple myeloma in NZ are reported to a national cancer registry. Since 1994 this has been a legal requirement. We examined data from the cancer registry for 1996 to 2004 to establish the relative incidence of multiple myeloma in NZ ethnic groups. During this period ICD-9 (multiple myeloma and immunoproliferative neoplasms) was used for coding until 2000 when it was replaced by ICD-10 (multiple myeloma and malignant plasma cell neoplasms). Between 1996 and 2004 there were 2101 myeloma registrations. Median age was between 70 and 75yrs. M:F ratio was 1.3. Maori accounted for 160 patients (7.6%), Pacific peoples 81 (3.8%). Mean age-standardized annual incidence rates per 100,000 and 95% confidence intervals (WHO world standard population (WSP)) for the 9 year period were as follows:-

All Male Female Maori 6.4 (5.4–7.6) 7.9 (6.3–9.8) 4.9 (3.8–6.3) Pacific Peoples 8.4 (6.6–10.8) 10.9 (7.8–15.2) 6.0 (4.3–8.4) Non-Maori, non-Pacific 4.4 (4.2–4.6) 5.4 (5.1–5.7) 3.4 (3.1–3.6) All ethnicities 4.6 (4.4–4.8) 5.7 (5.4–6.0) 3.6 (3.3–3.8)

The population adjusted incidence of multiple myeloma was significantly higher in Pacific peoples (ratio 1.93 (95% CI 1.50–2.48)) and Maori (ratio 1.46 (95% CI 1.23–1.74)) than in the non Maori, non Pacific population.

Conclusion: The overall incidence of myeloma in NZ (4.6 per 100,000, 95%CI 4.4–4.8 WSP) is higher than that reported for a UK population (3.3 per 100,000 WSP) [Phekoo et al (2004) Brit J Haem 127:299]. The incidence of myeloma in NZ Pacific peoples is especially high at 8.4 per 100,000. The incidence of myeloma in NZ Maori at 6.4 per 100,000 is intermediate between that of the NZ non Maori, non Pacific population and that of Pacific peoples.
The Green Tea Polyphenol Epigallocatechin Gallate (EGCG) Antagonizes the Inhibitory Effect of Bortezomib on Myeloma Cells.
Authors: Burger Renate , Czekalla Hanna , Ahrens Tanja , Richter Kathrin , Guenther Andreas , Gramatzki Martin
Published: November 2019

Dietary plant polyphenols are known to have antitumor, antiinflammatory, and antioxidant activity and as such may sensitize tumor cells to chemotherapeutic agents. We have evaluated the effects of the green tea polyphenol epigallocatechin gallate (EGCG) alone and in combination with other drugs on human myeloma cells. The compound is currently under investigation in several phase I/II clinical trials including for treatment of patients with early stage chronic lymphocytic leukemia. EGCG inhibited the in vitro growth of human myeloma cell lines in a time and dose-dependent manner. IC50 concentrations were between 12.5 μM and 50 μM as measured in a colorimetric tetrazolium (MTS) based assay and by trypan blue exclusion. Excess amounts of IL-6, bone marrow stromal cells, or overexpression of Mcl-1 and Bcl-xL could not protect from EGCG induced cytotoxicity. Pretreatment of INA-6 cells with EGCG resulted in a dose-dependent inhibition of IL-6 induced STAT3 tyrosine phosphorylation. In accordance with the essential role of STAT3 for INA-6 cell survival, EGCG induced apoptosis as determined by flow cytometry upon 7-amino-actinomycin D/annexin-V staining. In cell lines not dependent on exogenous IL-6, EGCG induced growth inhibition was abolished by pretreating the cells with 200 U/ml catalase, an enzyme which reduces reactive oxygen species (ROS). The combination of EGCG with doxorubicin, dexamethason, or rapamycin did not result in increased growth inhibition. In contrast, growth inhibition by bortezomib was antagonized with EGCG at concentrations that were not inhibitory when used alone (1–10 μM). In conclusion, EGCG exerts its effects on myeloma cells through several mechanisms including inhibition of IL-6 mediated signalling pathways via STAT3 and induction of oxidative stress. Notably, at pharmacologically achievable concentrations, EGCG antagonized bortezomib activity. Thus, the intake of natural polyphenols (high consumption of green tea or taking green tea extracts) may be critical during therapy with bortezomib.