Long-term follow-up of cancer and catastrophic diseases in hematopoietic stem cell donors: a comprehensive matched cohort study.

Hematopoietic stem cell (HSC) transplantation, using either bone marrow (BM) or peripheral blood stem cells (PBSC), is a well-established therapy for various hematologic and non-hematologic diseases. However, the long-term health outcomes after HSC donation remain a major concern for several potential donors. Thus, we aimed to conduct a matched cohort study of 5003 unrelated donors (1099 BM and 3904 PBSC) and randomly selected 50,030 matched controls based on age, sex, and resident area from the donor registry between 1998 and 2018. The medical insurance claims of all the participants were retrieved from the Taiwan National Health and Welfare Data Science Center after de-identification. Our findings revealed no differences in the incidence of cancer, death, and catastrophic diseases between HSC donors and matched healthy participants during long-term follow-up. Kaplan-Meier curves depicting the cumulative incidence of cancer and overall mortality throughout the follow-up period also demonstrated similar outcomes between donors and non-donors. In conclusion, our results indicate that HSC donation, whether through BM or PBSC, is safe and not associated with an increased risk of cancer, death, or catastrophic diseases. These findings provide valuable information for counseling potential HSC donors and for long-term management of HSC donor health.

Antioxidants cause rapid expansion of human adipose-derived mesenchymal stem cells via CDK and CDK inhibitor regulation.

BACKGROUND: Antioxidants have been shown to enhance the proliferation of adipose-derived mesenchymal stem cells (ADMSCs) in vitro, although the detailed mechanism(s) and potential side effects are not fully understood. RESULTS: During log-phase growth, exposure to ImF-A resulted in a higher percentage of ADMSCs in the S phase of the cell cycle and a smaller percentage in G0/G1 phase. This resulted in a significantly reduced cell-doubling time and increased number of cells in the antioxidant-supplemented cultures compared with those supplemented with FGF-2 alone, an approximately 225% higher cell density after 7 days. Western blotting showed that the levels of the CDK inhibitors p21 and p27 decreased after ImF-A treatment, whereas CDK2, CDK4, and CDC2 levels clearly increased. In addition, ImF-A resulted in significant reduction in the expression of CD29, CD90, and CD105, whereas relative telomere length, osteogenesis, adipogenesis, and chondrogenesis were enhanced. The results were similar for ADMSCs treated with antioxidants and those under hypoxic conditions. CONCLUSION: Antioxidant treatment promotes entry of ADMSCs into the S phase by suppressing cyclin-dependent kinase inhibitors and results in rapid cell proliferation similar to that observed under hypoxic conditions.

Poor harvest of peripheral blood stem cell in donors with microcytic red blood cells.

BACKGROUND: The outcome of peripheral blood stem cell (PBSC) harvest depends on mobilization and leukapheresis. Some poor harvests might not be directly related to poor mobilizations. STUDY DESIGN AND METHODS: We retrospectively analyzed the results of 793 consecutive healthy donors who underwent PBSC donation to evaluate the impact of low mean corpuscular volume (MCV) of red blood cells on the outcomes of hematopoietic stem cell mobilization and leukapheresis. RESULTS: The circulating CD34+ cells in peripheral blood after five doses of granulocyte-colony-stimulating factor injection were similar in donors with low MCV and those with normal MCV (68.0×10(6) /L vs. 69.2×10(6) /L, p=0.38). The procedural settings were not different between the two groups. However, the apheresis outcome of donors with low MCV was significantly lower in total CD34+ cells, cell dose, apheresis yield, and collection efficiency than those with normal MCV (277.6×10(6) vs. 455.0×10(6) ; 4.9×10(6) /kg vs. 8.2×10(6) /kg; 16.9×10(6) /L vs. 27.3×10(6) /L; 0.285 vs. 0.388; all p<0.0001). Similar results were noticed in subgroup analysis using the severity of microcytosis and Mentzer index for the donors with MCV of less than 80fL. The collection efficiency was significantly correlated with the MCV (r=0.30, p<0.0001). CONCLUSION: Low MCV was associated with poor apheresis outcomes in PBSC donors. This effect is not related to poor mobilization of CD34+ cells into the peripheral blood. Further studies to elucidate the detailed mechanism and develop strategy to avoid poor harvest are necessary.

The effect of different harvest strategies on the nucleated cell yields of bone marrow collection.

To improve bone marrow (BM) harvest of the volunteer donors in our institute, we changed from the single-hole needle to the multi-side-hole needle after March 2002, and examined the midway total nucleated cell (TNC) counts during collection after September 2004. The aims of this retrospective study were to evaluate BM harvest yields obtained through different strategies and to examine the correlation between final and midway BM harvests. The distribution of BM harvesting by different strategies was 235 donors with single-hole needles (group A), 389 donors with 5-side-hole needles (group B), and 365 donors with 5-side-hole needles and midway TNC counts (group C). The nucleated cell density of the collected BM was significantly improved by modifying the harvest strategy (0.202 × 10(8)/mL in group A, 0.219 × 10(8)/mL in group B, and 0.250 × 10(8)/mL in group C; P < .001). The percentage of unacceptable TNC dose (<2 × 10(8)/kg) was also decreased in all 3 groups (to 5.9%, 3.6%, and 0%, respectively; P < .001). Multiple regression analysis revealed that donor weight, white blood cell count, and harvest strategy were positively correlated with BM TNC density (P < .001), whereas harvested BM volume was negatively correlated with TNC density (P < .001). On linear regression analysis, highly significant correlations were noted between midway and final TNC densities (r = 0.8774; P < .001) as well as between harvested BM volume and TNC count (r = 0.7937; P < .001). Changing the harvesting needle and checking the midway TNC count improved the harvest outcome.

Technetium-99m-labeled autologous serum albumin: a personal-exclusive source of serum component.

Technetium-99m human serum albumin ((99m)Tc-HSA) is an important radiopharmaceutical required in nuclear medicine studies. However, the risk of transfusion-transmitted infection remains a major safety concern. Autopreparation of serum component acquired from patient provides a "personal-exclusive" source for radiolabeling. This paper is to evaluate the practicality of on-site elusion and subsequent radiolabeling efficacy for serum albumin. Results showed that the autologous elute contained more albumin fraction than serum without extraction procedure. Good radiochemical purity and stability were demonstrated after radiolabeling. Biodistribution study showed that labeled albumin accumulated immediately in the lung, liver, and kidney. It was cleared steadily and excreted in the urine. The biologic half-life was defined, and all samples passed the pyrogenicity and sterility tests. In conclusion, autoalbumin could be extracted and radiolabeled properly in a nuclear medicine setting. Moreover, the risk of transfusion-transmitted infection associated with nonautologous, multisource (99m)Tc-HSA agents can be reduced.

Diterpenoid anthraquinones as chemopreventive agents altered microRNA and transcriptome expressions in cancer cells.

OBJECTIVE: Cryptotanshinone (CPT) and dihydrotanshinone (DHT) are diterpenoid anthraquinone compounds extracted from traditional Chinese herbal medicine (TCM). Recent studies have shown that CPT regulates the signal transduction pathways via microRNA (miRNA) alterations. However, few studies have investigated the role of DHT in miRNA alterations affecting cell-signaling pathways. This study aimed to investigate the miRNA alterations and post-transcriptional regulation activities of DHT in comparison to CPT. METHODS: HepG2 and HT-29 cells were treated with DHT or CPT for 72 h. MiRNA, transcription factor encoding mRNA, and downstream gene expression were determined using real-time quantitative PCR. Protein expression was analyzed using western blotting. RESULTS: The results revealed that CPT and DHT targeted cell proliferation and apoptosis signaling pathways via miR-15a-5p, miR-27a-5p, miR-100-5p, and miR-200a-5p alterations.In silico target predictions showed that downregulation of epidermal growth factor receptor (EGFR) mRNA expression by DHT might also suppress the expression of STAT family proteins and lead to anti-proliferation effects. We also found that, compared to CPT, DHT might possess higher potency in cell growth regulation via multi-miRNA and transcription factor alterations. CONCLUSION: This study revealed that CPT and DHT targeted cell proliferation and apoptosis signaling pathways via alterations in miRNAs and transcription factors. In addition, the findings of this study suggest that DHT is more potent than CPT in cancer chemopreventive activities. Therefore, DHT at a low dose is a TCM compound with less toxic side effects and may contribute to the development of natural medicine as a potential cancer chemopreventive agent.

Haptoglobin genotypes in nasopharyngeal carcinoma.

AIM: Haptoglobin polymorphisms are associated with different cancers; however, the occurrence of nasopharyngeal carcinoma (NPC) in relation to haptoglobin polymorphisms has not been reported. In this study, the distribution of haptoglobin genotypes among patients with NPC was investigated and the prognostic significance of haptoglobin genotypes was further analyzed. MATERIAL AND METHODS: Haptoglobin genotypes were analyzed using polymerase chain reaction and electrophoresis. The genotypes were determined in the sera of 49 NPC patients and in 134 controls. RESULTS: The haptoglobin genotypes of patients with NPC were as follows: Hp 1-1, 2%; Hp 2-1, 39%; Hp 2-2, 59%. The frequency of the Hp 2-2 genotype was much higher in NPC patients than in control individuals (p=0.044). Furthermore, NPC patients with the Hp 2-2 genotype had advanced T stages (p=0.001) and larger primary tumor volumes (p=0.035) than those with Hp 2-1 or 1-1. CONCLUSION: An increased frequency of the Hp 2-2 genotype was associated with NPC. The Hp 2 allele was also overexpressed in NPC patients. NPC patients with the Hp 2-2 genotype had advanced T stage and a larger primary tumor volume. Hp 2-2 may be a negative prognostic factor in NPC.

Is a boosting dose of granulocyte-colony-stimulating factor necessary for healthy PBSC donors undergoing secondary apheresis? An institute's experience.

Successful allogeneic PBSC transplantation depends upon the infusion of an adequate number of CD34+ cells to patients. Granulocyte-colony-stimulating factors (G-CSF) mobilized PBSC were harvested on 5th day after stimulation from donors. When the CD34+ cell target yield was not achieved; secondary apheresis was performed the following day. Before September 2006, 67 donors (Group A) received five doses of G-CSF. After September 2006, a sixth dose of G-CSF was administered to 35 donors (Group B) to improve CD34+ yield. The mean CD34+-cell concentration of the second PBSC harvest was significantly higher in Group B (1,087 x 10(6)/l vs. 767 x 10(6)/l; P = 0.031).

hSNF5 /INI1 mutation analysis in acute myeloid leukemia.

Previous studies indicated that region 11.2 of the long arm of chromosome 22 (22q11.2) might be a locus encoding a tumor suppressor gene, since its deletion is a recurrent genetic characteristic of aggressive pediatric cancer. This region is found in the human immunodeficiency virus integrase interactor 1 (hSNF5/INI1) gene. To investigate whether the hSNF5/INI1 gene is involved in leukemogenesis, mutation analysis of the hSNF5/INI1 gene was performed in the present study using 5 hematopoietic cell lines, acute myeloid leukemia (AML) specimen and normal control. We found two single nucleotide polymorphisms at the hSNF5/INI1 gene in exon 4 and exon 9. The results of this study suggest that the hSNF5/INI1 gene does not play an important role in the leukemogenesis of AML.

Primary effusion lymphoma involving both pleural and abdominal cavities in a patient with hepatitis B virus-related liver cirrhosis.

Primary effusion lymphoma (PEL) is an unusual form of non-Hodgkin's lymphoma, which is characterized by lymphomatous effusion in body cavities, but no associated mass lesions. It is usually associated with an immunodeficient state most often with the human immunodeficiency virus (HIV). We describe a 54-year-old man with HIV-negative PEL, with a history of hepatitis B virus-related liver cirrhosis. Both abdominal and pleural cavities were involved; no solid tumor masses were found and bone marrow investigations were normal. The ascites and pleural effusion contained numerous pleomorphic lymphoid cells. Immunophenotyping was positive for CD138. Chromosome study showed complex cytogenetics. The genomic human herpesvirus-8 was detected in the lymphoma cells. It is postulated that the immunosuppressed state in this patient may have been caused by cirrhosis. The patient received four cycles of chemotherapy of CHOP and Picibanil (OK-432) intraperitoneal administration. However, no durable remission was achieved. Adefovir failed to halt the progressive liver failure after the development of YMDD mutant related to lamivudine. He died of sepsis and hepatic failure.

Prognostic significance of flow cytometric residual disease, dysregulated neutrophils/monocytes, and hematogones in adult acute myeloid leukemia in first remission.

Fifty-one consecutive non-M3 acute myeloid leukemia (AML) patients who had achieved morphologic complete remission (mCR) after induction chemotherapy were enrolled in the present study. Three characteristics of bone marrow (BM) composition analyzed by flow cytometry were combined to determine the prognostic impact. A standardized panel of reagents was used to detect residual disease of aberrant myeloid progenitor cells (RD), identify neutrophils/monocytes with dysregulated immunophenotype (dysregulated neutro/mono) and quantify the appearance of CD34(+) B-progenitor-related cluster (hematogones) simultaneously in post-induction BM of adult AML patients. Patients who had detectable RD ≥0.2 % exhibited significantly lower median leukemia-free survival (LFS) than those who did not (13.5 vs. 48.0 months; P = 0.042). Dysregulated neutro/mono abnormalities assessed by this flow cytometric scoring system (FCSS ≥2) predicted shorter LFS (8.0 vs. 39.0 months; P = 0.008). While B-progenitor-related cluster size ≥5 % predicted improved outcome, with longer LFS (not reached vs. 13.5 months; P = 0.023) and better overall survival (not reached vs. 24.0 months; P = 0.027). The proposed RD/dysregulated neutro/mono/hematogones score showed a new risk groups with different LFS in the overall patients (P = 0.0006) as well as in the subgroup of intermediate cytogenetic risk (P = 0.001). The RD/dysregulated neutro/mono/hematogones score assessed by flow cytometry for adult AML in mCR may offer a rapid and practical risk assessment providing better refinement in risk-adapted management after induction chemotherapy.

Flow cytometric scoring system as a diagnostic and prognostic tool in myelodysplastic syndromes.

The aim of this study is to validate the clinical utility of the flow cytometric scoring system (FCSS), quantifying phenotypic aberrancies in the myelomonocytic lineages, in the diagnosis and prognosis for conventionally treated myelodysplastic syndromes (MDS) patients. The bone marrow samples from 56 consecutive newly diagnosed MDS patients were characterized by the FCSS and compared with findings in 27 non-MDS cytopenic patients. The FCSS scores were significantly higher in patients with MDS than those in the non-MDS control. A flow score of 2 or more allowed for a specificity of 100% with 75% sensitivity in distinguishing these two groups. The FCSS scores correlated directly with validated prognostic systems including WHO classification, International Prognostic Scoring System (IPSS), WHO-adjusted prognostic scoring system (WPSS) and transfusion dependency. The median survival of conventionally treated MDS patients was directly related to FCSS group; severe: 6 months; moderate: 19 months and normal/mild: not reached. The multivariate analyses suggested the FCSS risk categories were an independent prognostic factor after adjustment for sex, age (above or below 70 years), IPSS or WPSS risk categories. These results confirm that quantifying aberrancies in the myelomonocytic lineage by FCSS is useful in MDS diagnosis and extends the prognostic utility for conventionally treated/untreated patients, especially among patients classified within the refractory cytopenia with multilineage dysplasia (RCMD) subgroup.

The role of donor characteristics and post-granulocyte colony-stimulating factor white blood cell counts in predicting the adverse events and yields of stem cell mobilization.

Granulocyte colony-stimulating factor (G-CSF) is now widely used for stem cell mobilization. We evaluated the role of post-G-CSF white blood cell (WBC) counts and donor factors in predicting adverse events and yields associated with mobilization. WBC counts were determined at baseline, after the third and the fifth dose of G-CSF in 476 healthy donors. Donors with WBC ≥ 50 × 10(3)/µL post the third dose of G-CSF experienced more fatigue, myalgia/arthralgia, and chills, but final post-G-CSF CD34(+) cell counts were similar. Although the final CD34(+) cell count was higher in donors with WBC ≥ 50 × 10(3)/µL post the fifth G-CSF, the incidence of side effects was similar. Females more frequently experienced headache, nausea/anorexia, vomiting, fever, and lower final CD34(+) cell count than did males. Donors with body mass index (BMI) ≥ 25 showed higher incidences of sweat and insomnia as well as higher final CD34(+) cell counts. Donor receiving G-CSF ≥ 10 µg/kg tended to experience bone pain, headache and chills more frequently. Multivariate analysis indicated that female gender is an independent factor predictive of the occurrence of most side effects, except for ECOG > 1 and chills. Higher BMI was also an independent predictor for fatigue, myalgia/arthralgia, and sweat. Higher G-CSF dose was associated with bone pain, while the WBC count post the third G-CSF was associated with fatigue only. In addition, one donor in the study period did not complete the mobilization due to suspected anaphylactoid reaction. Observation for 1 h after the first injection of G-CSF is required to prevent complications from unpredictable side effects.