Impact of Body Mass Index on 5-Year Survival Rates in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Background: Cancer survival is associated with body mass index (BMI). However, the impact of patients' baseline characteristics on allogeneic hematopoietic stem cell transplantation (allo-HSCT) outcomes remains unclear. This study aimed to examine the baseline clinical factors associated with 5-year survival rates in patients undergoing allo-HSCT. Material and Methods: This was a retrospective exploratory observational study. Patients (n = 113, 52 women; average age: 55 years) who underwent allo-HSCT at the Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center, between January 2008 and March 2015, were included in the present study. Results: Patients with low BMI (<18.5 kg/m2) had significantly lower 5-year survival rates than those with normal (18.5-24.9 kg/m2) and high (⩾25.0 kg/m2) BMI. The 5-year survival rate was poorer for patients with sarcopenia (41.5%) than that for those without sarcopenia prior to allo-HSCT (P = .05). The 5-year survival rate was poorer for patients with geriatric nutritional risk index (GNRI < 98) (34.5%) than that for those without GNRI prior to allo-HSCT (P < .01). Conclusions: Low BMI before allo-HCST pre-treatment was a predictor of 5-year survival rates in this study. Patients undergoing allo-HSCT may require nutritional interventions during pre-treatment to reduce the risk of sarcopenia and GNRI (<98), which affects their survival rates.

Examination of a nutritional treatment pathway according to pretreatment health status and stress levels of patients undergoing hematopoietic stem cell transplantation.

INTRODUCTION: This study aimed to validate hematopoietic stem cell transplantation (HSCT) treatment via a tailored nutritional pathway in myeloablative conditioning (MAC), determine its efficacy in terms of remission, and explore associations between clinical outcomes and nutritional indicators. METHODS: We included patients who underwent MAC for HSCT at the Shizuoka Cancer Center Stem Cell Transplantation between 2015 and 2019. We evaluated outcomes from the day before treatment initiation (transplant date: day 0) to day 42. RESULTS: Among the 40 MAC cases (participant characteristics: 20/40 males, mean age of 52 years, and mean body mass index of 21.9 kg/m2), we found that the percent loss of body weight and loss of skeletal muscle mass were correlated with the basal energy expenditure rate (BEE rate; r = 0.70, p<0.001 and r = 0.49, p<0.01, respectively). Based on the receiver operating characteristics curves, the cutoff value for the BEE rate in terms of weight loss was 1.1. Salivary amylase levels did not significantly change during the treatment course. Continuous variables, including oral caloric intake and performance status, showed statistically significant correlations with nutrition-related adverse events during treatment (r = -0.93, p<0.01 and r = 0.91, p<0.01, respectively). Skeletal muscle mass before treatment initiation was an independent predictive variable for reduced 2-year survival (p = 0.04). CONCLUSION: Our results support the validity of a safe nutritional pathway with a BEE rate of 1.1 for HSCT patients pretreated with MAC. Specifically, we found that this pathway could prevent weight loss in response to nutrition-related adverse events. Skeletal muscle mass before treatment was identified as an independent risk factor for reduced 2-year survival.

Passive immune basophil activation test for the identification of allergic episodes from various adverse events elicited by haematopoietic cell transplantation: A pilot study.

BACKGROUND AND OBJECTIVES: Haematopoietic cell transplantation (HCT) therapy tends to be associated with various complications including engraftment failure, regimen-related toxicities, and infectious diseases. In addition, HC infusion itself occasionally elicits adverse events (AEs), one of the most common AEs is an allergic reaction. As appropriate laboratory tests have not yet been established to distinguish allergy-mediated AEs from other complications, clinical responses for HCT-related AEs can only be nonspecific. In this pilot study, using passive immune basophil activation test (pi-BAT), we attempted to distinguish an HC infusion-induced allergic reaction from various HCT-related AEs. MATERIALS AND METHODS: Using pi-BAT, we examined 34 patients who underwent HCT, that is, 11 with AEs and 23 without AEs as controls. RESULTS: Two of the eleven AE cases were pi-BAT positive and, the rest of nine AE cases were negative, while all non-AE cases were negative. Both of the two positive cases showed erythema, tachycardia, plus cough. Because erythema is one of the representative symptom of allergy, those cases could be classified as allergic reaction cases or anaphylaxis cases if tachycardia and cough were concomitant symptoms of erythema. Among the nine AEs with pi-BAT negative result, four cases showed urticaria, four showed vomiting plus diarrhoea, and one showed cough. Urticaria case was strongly suspected of allergy, however, the AE cases were pi-BAT negative. CONCLUSION: The pi-BAT may be useful as an auxiliary diagnostic tool to confirm the possible involvement of HC infusion in HCT-related AEs and identify an immunologic mechanism for HCT-related hypersensitivity reactions.

Benefit of Reducing Body Weight Loss with A Nutritional Support Pathway in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: This retrospective, historically controlled investigative study examined the benefit of a nutritional support pathway that included nutritional education before the start of conditioning and emphasized oral nutrition in response to nutrition-related adverse events in patients undergoing hematopoietic stem cell transplantation (HSCT). MATERIAL AND METHODS: Participants were patients undergoing allogeneic HSCT; 46 were in the control group (i.e., did not follow our nutritional pathway) and 36 were in the group that underwent nutritional intervention (enhanced nutrition group). We compared the following parameters between groups from the day before the start of conditioning to the day after completion of parenteral nutrition (PN): percent loss of body weight (%LBW), percent loss of skeletal muscle mass (%LSMM), and estimated basal energy expenditure (EBEE) sufficiency rate. The relationship between each parameter and %LBW was also examined. We also compared nutritional indices, gastrointestinal graft versus host disease (GvHD) grade, oral energy intake, and %LBW between groups. RESULTS: There was a relationship between %LBW, %LSMM, and EBEE sufficiency rate in both groups. Compared with the control group, the enhanced nutrition group had significantly improved energy intake amount, EBEE sufficiency rate, PN duration, and oral energy intake over time. The enhanced nutrition group also had increased oral energy intake, no difference in gastrointestinal GvHD grade, and improved %LBW compared with the control group. CONCLUSIONS: Use of our nutritional support pathway in patients undergoing HSCT may be beneficial for %LBW and gastrointestinal GvHD grade, enabling early enhanced nutritional intervention after HSCT.

Comparison of levetiracetam with phenytoin for the prevention of intravenous busulfan-induced seizures in hematopoietic cell transplantation recipients.

PURPOSE: Busulfan is used as a conditioning regimen for hematopoietic stem cell transplantation and is known to cause seizures as a side effect. As various anticonvulsant drugs have been reported, we conducted a retrospective investigation regarding the preventive effects and adverse events associated with different anticonvulsants administered alongside intravenous busulfan (ivBu) in our institution. METHODS: We targeted 104 patients who received ivBu at our institution from May 1, 2010 to April 30, 2017. We investigated the seizure prevention rate and adverse events rate under anticonvulsant prophylaxis. RESULTS: There were 70 cases (67.3%) of phenytoin administration and 34 cases (32.7%) of levetiracetam administration for anticonvulsant therapy. The seizure prevention rate was 98.6% for phenytoin and 100% for levetiracetam; seizures occurred in one out of 104 patients. There were no significant differences in the seizure prevention rate depending on the type of anticonvulsant. Further, there were no differences in adverse events. CONCLUSIONS: Anticonvulsant prophylaxis is considered necessary for safe conditioning with ivBu. Adverse events associated with the use of levetiracetam are within an acceptable range. Further, levetiracetam is considered useful as a preventive drug against seizures during ivBu administration because it is easy to administer and has ideal pharmacokinetics for supportive care.

Nutritional risk in allogeneic stem cell transplantation: rationale for a tailored nutritional pathway.

Hematopoietic stem cell transplantation carries nutrition-related risks. Therefore, nutritional therapy needs to be initiated before transplantation even takes place. We assessed nutritional risk among patients who underwent allogeneic stem cell transplantation. We assessed nutrient supply (calorie supply and protein supply) by chart review. Assessments were made from the pretreatment phase of transplantation to after the end of parenteral nutrition in 51 patients who underwent allogeneic stem cell transplantation at Shizuoka Cancer Center between 2007 and 2012. We compared nutrition-related adverse events and parameters between two groups: those in whom % loss of body weight was ≥7.5 and those in whom % loss of body weight was <7.5. A correlation was observed between changes in weight and skeletal muscle mass (r = 0.89; P < 0.0001). A weak correlation was observed between % loss of body weight and nutrient supply of calories (r = 0.517; P = 0.0001). There were significant differences between the % loss of body weight ≥7.5 group and the % loss of body weight <7.5 group in the following variables: % loss of body weight, nutrient supply from calories and protein; orally ingested nutrient supply from calories and protein; start day of oral intake; and acute graft-versus-host disease. Orally ingested calories were negatively correlated with nutrition-related adverse events in both groups. Early and customized nutritional intervention may be optimal for all patients who undergo allogeneic stem cell transplantation to ameliorate body weight loss associated with nutrition-related adverse events.

Response-adapted treatment with upfront high-dose chemotherapy followed by autologous stem-cell transplantation rescue or consolidation phase high-dose methotrexate for primary central nervous system lymphoma: a long-term mono-center study.

Treatment regimens for primary central nervous system lymphoma (PCNSL) include high-dose methotrexate (HD-MTX)-based chemotherapy, with or without radiotherapy and are based on studies of selected patient groups. This retrospective study assessed a consistent strategy of response-adapted protocol applied for patients including age >65 years in a cancer center for 10 years longitudinally. Case notes were studied of 61 consecutively treated patients with PCNSL histologically diagnosed between 2003 and 2013. Clinical follow-up during and after treatment included neurologic examination and magnetic resonance imaging. Of the patients studied, 14.8 % (9/61) were clinically unfit for chemotherapy; the remaining 85.2 % (52/61) of patients were treated with HD-MTX. Of these patients, 58 % (30/52) achieved an initial complete response, with a median survival of 100.1 months. Of these response-adapted patients, 33 % (10/30) were <65 years and were treated with upfront high-dose chemotherapy and autologous stem-cell transplantation (HDC-ASCT). The remaining response-adapted patients included 53 % (16/30) who were ≥65 years underwent consolidation with HD-MTX, and 14 % (4/30) who chose radiotherapy. The median survival of patients with HDC-ASCT had not yet been reached compared with 67.6 months for patients with HD-MTX consolidation treatment (p = 0.26). At the end of the study, 75 % (39/52) of patients had died mainly owing to progression or relapse of PCNSL. Multivariate analysis showed that age younger than 65 years (p = 0.02) and complete response for up-front HD-MTX (p = 0.001) were independent prognostic indicators of overall survival. In conclusion, this single-center retrospective clinical study has shown that treatment of PCNSL with upfront HDC-ASCT and consolidation phase HD-MTX monotherapy may be feasible, even for elderly patients in a routine clinical setting, using the three-step selection by eligibility and response to initial HD-MTX, and age threshold of 65 years for ASCT.

Variegated RHOA mutations in adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a distinct form of peripheral T-cell lymphoma with poor prognosis, which is caused by the human T-lymphotropic virus type 1 (HTLV-1). In contrast to the unequivocal importance of HTLV-1 infection in the pathogenesis of ATLL, the role of acquired mutations in HTLV-1 infected T cells has not been fully elucidated, with a handful of genes known to be recurrently mutated. In this study, we identified unique RHOA mutations in ATLL through whole genome sequencing of an index case, followed by deep sequencing of 203 ATLL samples. RHOA mutations showed distinct distribution and function from those found in other cancers. Involving 15% (30/203) of ATLL cases, RHOA mutations were widely distributed across the entire coding sequence but almost invariably located at the guanosine triphosphate (GTP)-binding pocket, with Cys16Arg being most frequently observed. Unexpectedly, depending on mutation types and positions, these RHOA mutants showed different or even opposite functional consequences in terms of GTP/guanosine diphosphate (GDP)-binding kinetics, regulation of actin fibers, and transcriptional activation. The Gly17Val mutant did not bind GTP/GDP and act as a dominant negative molecule, whereas other mutants (Cys16Arg and Ala161Pro) showed fast GTP/GDP cycling with enhanced transcriptional activation. These findings suggest that both loss- and gain-of-RHOA functions could be involved in ATLL leukemogenesis. In summary, our study not only provides a novel insight into the molecular pathogenesis of ATLL but also highlights a unique role of variegation of heterologous RHOA mutations in human cancers.

G17V RHOA: Genetic evidence of GTP-unbound RHOA playing a role in tumorigenesis in T cells.

RHOA is a member of RHO family small GTPases. Over the past 2 decades, numerous biochemical and cell biological studies on RHOA have demonstrated signalings such as activation of RHO-associated coiled-coil forming kinases through guanine nucleotide exchange and GTP hydrolysis, cellular responses such as actin fiber formation and myocin activation, biological consequences such as cell motility and cytokineses, etc. There have also been a plenty of active discussion on the roles of RHOA in tumorigenesis, primarily based on gain- and loss-of-function experiments. However, cell-type-specific functions of RHOA have only recently been delineated by conditional gene targeting strategies. Furthermore, very little information had been available on human cancer genetics until we and others recently reported frequent somatic RHOA mutations in a distinct subtype of T-cell-type malignant lymphoma called angioimmunoblastic T-cell lymphoma (AITL), and other T-cell lymphoma with AITL-like features. The RHOA mutations were very specific to these types of lymphoma among hematologic malignancies, and a single hotspot, glycine at the 17th position, was affected by the replacement with valine (G17V). Remarkably, G17V RHOA did not bind GTP, and moreover, it inhibited the GTP binding to wild-type RHOA. How G17V RHOA contributes to T-cell lymphomagenesis needs to be clarified.

Age-Dependent Decrease of DNA Hydroxymethylation in Human T Cells.

Hydroxymethylcytosine (hmC) is a natural nucleobase, which is converted from methylcytosine (mC) by tet methylcytosine dioxygenase (TET) family (TET1-3) enzymes. Decrease of genomic hmC is postulated to confer a risk for myeloid-lineage as well as T-cell neoplasms, based on the fact that loss-of-function mutations in the TET2 gene were frequently identified in these diseases. The relationship between hmC and aging remains to be elucidated. Here, we demonstrated that hmC content decreased with age in the peripheral blood T cells of 53 human volunteers. We further identified that the mRNA expression levels of TET1 and TET3 decreased with age, while those of TET2 were not influenced by age. The genomic hmC content was correlated with the mRNA expression level of TET3, but not those of TET1 and TET2. Our study suggests the presence of new epigenetic regulatory mechanisms in aging T cells.

Detection of the G17V RHOA mutation in angioimmunoblastic T-cell lymphoma and related lymphomas using quantitative allele-specific PCR.

Angioimmunoblastic T-cell lymphoma (AITL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) are subtypes of T-cell lymphoma. Due to low tumor cell content and substantial reactive cell infiltration, these lymphomas are sometimes mistaken for other types of lymphomas or even non-neoplastic diseases. In addition, a significant proportion of PTCL-NOS cases reportedly exhibit features of AITL (AITL-like PTCL-NOS). Thus disagreement is common in distinguishing between AITL and PTCL-NOS. Using whole-exome and subsequent targeted sequencing, we recently identified G17V RHOA mutations in 60-70% of AITL and AITL-like PTCL-NOS cases but not in other hematologic cancers, including other T-cell malignancies. Here, we establish a sensitive detection method for the G17V RHOA mutation using a quantitative allele-specific polymerase chain reaction (qAS-PCR) assay. Mutated allele frequencies deduced from this approach were highly correlated with those determined by deep sequencing. This method could serve as a novel diagnostic tool for 60-70% of AITL and AITL-like PTCL-NOS.

Disease-specific mutations in mature lymphoid neoplasms: recent advances.

Mature lymphoid neoplasms (MLN) are clinically and pathologically more complex than precursor lymphoid neoplasms. Until recently, molecular characterization of MLN was mainly based on cytogenetics/fluorescence in situ hybridization, allele copy number, and mRNA expression, approaches that yielded scanty gene mutation information. Use of massive parallel sequencing technologies has changed this outcome, and now many gene mutations have been discovered. Some of these are considerably frequent in, and substantially specific to, distinct MLN subtypes, and occur at single or several hotspots. They include the V600E BRAF mutation in hairy cell leukemia, the L265P MYD88 mutation in Waldenström macroglobulinemia, the G17V RHOA mutation in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified, and the Y640F//D661Y/V/H/I//N647I STAT3 mutations in T-cell large granular lymphocytic leukemia. Detecting these mutations is highly valuable in diagnosing MLN subtypes. Defining these mutations also sheds light on the molecular pathogenesis of MLN, furthering development of molecular targeting therapies. In this review, we focus on the disease-specific gene mutations in MLN discovered by recent massive sequencing technologies.

Somatic RHOA mutation in angioimmunoblastic T cell lymphoma.

Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma characterized by generalized lymphadenopathy and frequent autoimmune-like manifestations. Although frequent mutations in TET2, IDH2 and DNMT3A, which are common to various hematologic malignancies, have been identified in AITL, the molecular pathogenesis specific to this lymphoma subtype is unknown. Here we report somatic RHOA mutations encoding a p.Gly17Val alteration in 68% of AITL samples. Remarkably, all cases with the mutation encoding p.Gly17Val also had TET2 mutations. The RHOA mutation encoding p.Gly17Val was specifically identified in tumor cells, whereas TET2 mutations were found in both tumor cells and non-tumor hematopoietic cells. RHOA encodes a small GTPase that regulates diverse biological processes. We demonstrated that the Gly17Val RHOA mutant did not bind GTP and also inhibited wild-type RHOA function. Our findings suggest that impaired RHOA function in cooperation with preceding loss of TET2 function contributes to AITL-specific pathogenesis.

Identification of unbalanced genome copy number abnormalities in patients with multiple myeloma by single-nucleotide polymorphism genotyping microarray analysis.

Single-nucleotide polymorphism genotyping microarray (SNP array) analysis provides detailed information on chromosomal copy number aberrations. To obtain detailed information on genomic abnormalities related to pathogenesis or prognosis of multiple myeloma (MM), we performed 250K SNP array analysis in 39 MM patients and 11 cell lines. We identified an accumulation of deletions and uniparental disomies at 22q12.1. Among the hyperdiploid MM cases, chromosomal imbalance at this locus was associated with poor prognosis. On sequencing, we also found a mutation in the seizure-related 6 homolog (mouse)-like (SEZ6L) gene located at ch.22q12.1 in an MM cell line, NOP1. We further found isolated deletions in 17 genes, five of which are known tumor suppressor genes. Of these, deletion of protein tyrosine phosphatase, receptor type D (PTPRD) was found in three samples, including two patients. Consistent with previous reports, non-hyperdiploid MM, deletion of 13q (del13q) and gain of 1q in non-hyperdiploid MMs were predictive of poor prognosis (p = 0.039, p = 0.049, and p = 0.013, respectively). However, our analysis revealed that unless accompanied by gain of 1q, the prognosis of non-hyperdiploid MM was as good as that of hyperdiploid MM. Thus, SNP array analysis provides significant information useful to understanding the pathogenesis and prognosis of MM.

Treatment outcome of adult Burkitt Lymphoma in Japanese patients with modified LMB protocol : a single center retrospective analysis.

The prognosis of adult Burkitt lymphoma (BL) has improved in western countries since the introduction of high-dose methotrexate (HD-MTX)-containing chemotherapy. Here we analyzed nine consecutive Japanese patients diagnosed with BL at our institution. All except for the three elderly (> 70 years) patients were treated with a regimen including 13 g/m(2) HD-MTX in total, divided into 3 cycles. The median follow-up period was 56 months (range 38-118). All the nine patients achieved complete remission and have not shown any disease progression, including the three elderly patients who received reduced doses or alternative treatments. These observations suggest that chemotherapy including 13 g/m(2) HD-MTX in total is tolerable and effective in Japanese adult BL patients aged < 70 and that BL is curable even if developed in those who are > 70 years.

Blood flow analysis of the head and lower limbs by the laser Doppler blood flowmeter during LDL apheresis.

The presence of peripheral arterial disease substantially increases the risk for both morbidity and mortality among end-stage renal disease patients. Low-density lipoprotein (LDL) apheresis has been also applied for the treatment of peripheral arterial disease to reduce LDL levels, resulting in the improvement of the blood flow to the ischemic limbs. In this study, we investigated the continuous changes of the tissue blood flows in the lower limbs and head during LDL-apheresis treatment by a non-invasive method (the non-invasive continuous monitoring method (NICOMM) system). In this study, the tissue blood flow in both the head and lower limbs showed a significantly enhancement from before to after treatment. The tissue blood flow in the lower limbs showed a significantly larger improvement than that in the head. The short-term effects of LDL apheresis were confirmed by using the NICOMM system; thus, this system will be useful for the determination of the appropriate schedule of LDL apheresis for long-term effectiveness.

Successful treatment of refractory thrombotic thrombocytopenic purpura with cyclosporine and corticosteroids in a patient with systemic lupus erythematosus and antibodies to ADAMTS13.

A 46-year-old woman with systemic lupus erythematosus was hospitalized for purpura, hematochezia and hematuria. One week after admission, she developed grand mal seizures and coma and was diagnosed with thrombotic thrombocytopenic purpura (TTP) when fragmented red cells were found on the peripheral blood smear. Laboratory findings showed severe ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) deficiency and anti-ADAMTS13 antibodies, which in recent reports have indicated a poor prognosis. She was refractory to methylprednisolone pulse therapy and plasma exchange, but administration of cyclosporine induced remission without adverse effects. We propose that cyclosporine may be an effective treatment for cases of refractory TTP.