Sarcopenia and obesity in long-term survivors of childhood leukemia/lymphoma: a report from a single institution.

BACKGROUND: The incidence and background factors of sarcopenia and obesity in long-term survivors of childhood leukemia/lymphoma were not clear in Japan. METHODS: Between August 2018 and September 2019, we recruited adults aged ≥18 years who had childhood leukemia/lymphoma. Blood sampling, body composition measurement by bioelectrical impedance analysis and grip strength test were performed. RESULTS: Among 81 adult survivors (34 men and 47 women) with a median age of 25.0 years, 9 (11%) had sarcopenia and 10 (12%) had obesity, of whom, 3 had metabolic syndrome. Sarcopenia was observed in 7 (21%) of 33 survivors with hematopoietic stem cell transplantation (HSCT) and 2 (4%) of 48 survivors without hematopoietic stem cell transplantation (P = 0.012). The incidence of obesity was significantly higher in the cranial radiotherapy (P = 0.021) and non-transplanted cases (P = 0.042). Univariate logistic regression analysis revealed that hematopoietic stem cell transplantation for sarcopenia (odds ratio, 6.19; 95% confidence interval, 1.2-32.0; P = 0.03) and cranial radiotherapy for obesity (odds ratio, 5.6; 95% confidence interval, 1.4-22.4; P = 0.015) were significantly associated. Hypertension was more prevalent among the obese survivors, and higher transaminase levels were found more in both the sarcopenia and obese survivors than in others. CONCLUSIONS: Young adult survivors of childhood leukemia/lymphoma could be at risk of developing sarcopenia after hematopoietic stem cell transplantation and obesity after cranial radiotherapy. Further studies are required to assess the body composition of long-term survivors to find detailed risk factors of sarcopenia and metabolic syndrome.

Management of elderly patients with head and neck carcinoma: analysis of outcomes for radical versus palliative treatment.

BACKGROUND: There are no universally accepted treatment recommendations for elderly patients with head and neck carcinomas. This study investigated whether radical treatment in elderly patients resulted in better survival compared with palliative treatment. METHODS: We retrospectively reviewed the medical records of 724 patients aged > 60 years who underwent treatment for primary head and neck carcinomas at Hamamatsu University Hospital. We evaluated the impact of the following: age, sex, the clinical stage, smoking history, alcohol use history, primary tumor site, performance status, and Osaka Head and Neck Comorbidity Index score on overall survival using a Cox proportional hazards model. RESULTS: The 5-year overall survival rate was significantly greater for the 646 patients initially treated with radical (curative) therapy than for the 78 patients treated with palliative therapy (p < 0.01). Patients who received palliative treatment in all age groups were more likely to die than were those in the radical treatment group, after controlling for age, sex, and clinical stage of the cancer. Information on the survival status of patients was obtained after a mean follow-up period of 46 months (range 6-205 months). CONCLUSIONS: In the absence of contraindications associated with comorbidities, radical treatment protocols should be recommended for elderly patients with head and neck carcinomas because they confer better survival.

Maintenance of long remission in adult T-cell leukemia by Tax-targeted vaccine: A hope for disease-preventive therapy.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive lymphoproliferative disease caused by human T-cell leukemia virus type 1 (HTLV-1). Multi-agent chemotherapy can reduce ATL cells but frequently allows relapses within a short period of time. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) following chemotherapy is now a standard therapy for ATL in Japan as it can achieve long-term remission in approximately one-third of recipient ATL patients; however, it also has a risk of treatment-related mortality. Allo-HSCT often induces HTLV-1 Tax-specific cytotoxic T cells (CTL) as well as graft-versus-host (GVH) response in ATL patients. This observation led to development of a new therapeutic vaccine to activate Tax-specific CTL, anticipating anti-ATL effects without GVH response. The newly developed Tax-DC vaccine consists of autologous dendritic cells pulsed with Tax peptides corresponding to CTL epitopes that have been identified in post-allo-HSCT ATL patients. In a pilot study of Tax-DC therapy in three ATL patients after various initial therapies, two patients survived for more than 4 years after vaccination without severe adverse effects (UMIN000011423). The Tax-DC vaccine is currently under phase I trial, showing a promising clinical outcome so far. These findings indicate the importance of patients' own HTLV-1-specific T-cell responses in maintaining remission and provide a new approach to anti-ATL immunotherapy targeting Tax. Although Tax-targeted vaccination is ineffective against Tax-negative ATL cells, it can be a safe alternative maintenance therapy for Tax-positive ATL and may be further applicable for treatment of indolent ATL or even prophylaxis of ATL development among HTLV-1-carriers.

Risk Factors and Prognostic Factors of Hearing Impairment in Neonatal Intensive Care Unit-Treated Infants.

BACKGROUND: Infants admitted to the neonatal intensive care unit (NICU) have a higher incidence of congenital hearing loss compared with the healthy newborn population. OBJECTIVES: To clarify the relationship between risk factors for hearing impairment in NICU-treated infants and deterioration of the auditory brainstem response (ABR) threshold during childhood. METHOD: We screened 1,071 high-risk infants admitted to the NICU for hearing impairment. One-hundred forty-eight infants exhibited an abnormal ABR threshold of ≥40 dB nHL. We analyzed the correlation of change in ABR threshold with risk factors for future hearing impairment. RESULTS: Among infants treated in the NICU, 148 (13.8%) exhibited an ABR threshold of ≥40 dB nHL; 107 of these 148 (72.3%) showed hearing change in the process (102 showed improvement to normal hearing level, whereas 5 showed further deterioration). Our analysis showed that the factors contributing to the elevation of ABR threshold were oxygen administration and chromosomal aberrations. CONCLUSIONS: Factors related to the elevation of ABR threshold were oxygen administration and the presence of chromosomal aberrations. Awareness of risk factors that are more likely to cause hearing loss in infants may aid in follow-up treatment of these children.

Relevance of Level IIb Neck Dissection in Patients with Head and Neck Squamous Cell Carcinomas.

BACKGROUND: Cervical nodal metastasis is the most important prognostic factor in patients with head and neck cancers. Unfortunately, nodal dissection at level IIb carries a risk of damage to the spinal accessory nerve. We aimed to determine the prevalence of level IIb metastasis and the relevance of nodal dissection at level IIb in patients with head and neck squamous cell carcinomas. METHODS: During neck dissection, level IIb lymph nodes obtained from 181 patients with head and neck squamous cell carcinomas were removed, processed, and histopathologically examined. All specimens were divided into two groups according to the side (affected and unaffected sides). The number of dissected lymph nodes and prevalence of level IIb metastasis in each group were then determined and compared according to the preoperative clinical N stage (cN0 and cN+). RESULTS: The study included 158 men and 23 women with a median age of 65 years (range, 17-89 years). The prevalence of pathologically confirmed level IIb metastasis was 0% for clinically node-negative (cN0) necks on the unaffected side and 10.34% for clinically node-positive necks (cN+), with an overall prevalence of 2.4%. There was a significant association between clinically determined and pathologically confirmed node negativity at level IIb. CONCLUSION: Our findings suggest that level IIb neck dissection in patients with head and neck squamous cell carcinomas may be required only if preoperative examination reveals multilevel or level IIa metastasis or suspicious level IIb metastasis.

Difference in the generalization of response tolerance across views between the anterior and posterior part of the inferotemporal cortex.

The inferotemporal cortex consists of an anterior (cytoarchitectonic area TE) and a posterior (area TEO) part, which together constitute the final areas of the ventral visual stream, which is critical for object discrimination. Area TE receives dense projections from area TEO. We have previously identified a response tolerance in the cells in area TE in monkeys to a range of viewing angles after object discrimination at each of several views. To investigate the contribution of area TEO to the establishment of such a response tolerance in area TE, we conducted electrophysiological recordings of the responses of the single cells in area TEO after performance saturation of object discrimination at several independent views, without any association across views, and compared them with those obtained from the TE cells. The cells in area TEO showed responses to the experienced object views, but not to nearby views. Comparisons of the tunings of the TE and TEO cells to different viewing angles for the same object sets in the same animal showed that cells in area TEO had a significantly narrower tuning width, whereas the response tolerance was usually observed in the TE cells across viewing angles up to 60°. Our findings revealed a significant difference in the representation of the object views between areas TE and TEO, and suggested that such a representation in area TE may be completed through neuronal mechanisms within area TE, which is not a property of the earlier stages of the ventral visual stream.

Risk and prognostic factors for multiple primary carcinomas in patients with head and neck cancer.

BACKGROUND: Unexpected multiple primary carcinomas (MPCs) that develop in patients with head and neck carcinomas complicate approaches to their management. We therefore investigated the clinical factors associated with survival outcomes after the treatment of MPCs. METHODS: We performed a retrospective review of records of 1104 patients who underwent treatment for primary head and neck carcinoma at Hamamatsu University Hospital. We evaluated clinical staging, age, sex, smoking, alcohol consumption, the primary tumor site (particularly the involvement of the mucosal epithelial lining of the aerodigestive tract), and overall survival (OS) as determined by Kaplan-Meier analysis. Information on patients' survival status was obtained after a mean follow-up period of 43.8 months (range, 1-144 months). RESULTS: Among 566 patients with mucosa-associated carcinoma arising in the epithelial lining, the 5- and 10-year OS rates (68.49% and 58.96%, respectively) were significantly shorter than those of patients with mucosa non-associated carcinoma (74.22%, and 66.76%, respectively) (log-rank P = 0.0219). Older age (P = 0.016) and male sex (P < 0.001) were likely independent risk factors for developing MPCs; smoking (P < 0.001) and alcohol consumption (P < 0.001) were also significant risk factors. CONCLUSION: Mucosa-associated carcinomas arising in the epithelial lining of the aerodigestive tract in the head and neck are a significant risk factor for developing MPC and are a poor prognostic factor. Careful follow-up and more frequent examinations of the aerodigestive tracts of these patients are recommended.

Secondary bone/soft tissue sarcoma in childhood cancer survivors: a nationwide hospital-based case-series study in Japan.

BACKGROUND: Secondary cancer is the most life-threatening late effect of childhood cancer. We investigated the clinical features of secondary bone/soft tissue sarcoma among childhood cancer survivors (CCSs). METHODS: We conducted a retrospective case-series study of 10 069 CCSs newly diagnosed with cancer between 1980 and 2009 across 15 Japanese hospitals. Twenty-one cases of pathologically diagnosed secondary bone/soft tissue sarcoma were selected, and the respective clinical courses were determined using additional questionnaires. RESULTS: The primary cancers included retinoblastoma (n = 7), acute lymphoblastic leukemia (n = 5), lymphoma (n = 5), osteosarcoma (n = 1), rhabdomyosarcoma (n = 1), brain tumor (n = 1) and Langerhans cell histiocytosis (n = 1). The median age at the primary cancer diagnosis was 2.9 years, and the male-to-female ratio was 16:5. The histological classifications of the secondary sarcoma included osteosarcoma (n = 10), malignant peripheral nerve sheath tumor (n = 4), rhabdomyosarcoma (n = 3), Ewing's sarcoma (n = 3) and primitive neuroectodermal tumor (n = 1). The median latency period to the secondary sarcoma was 10.2 years. Significant risk factors for secondary sarcoma in the multivariate Cox regression model included a history of retinoblastoma as the primary cancer (hazard ratio [HR], 20.9; 95% confidence interval [CI], 5.70-76.5) and autologous stem cell transplantation (SCT) (HR, 2.56; 95% CI, 1.08-6.03). Seventeen CCSs with secondary sarcoma underwent radiation, and nine, hematopoietic SCT. Twelve CCSs with secondary sarcoma achieved disease-free survival, while CCSs with hematological cancer or relapsed primary cancer who developed secondary sarcoma had the worst prognoses. CONCLUSION: The prognoses of CCSs with secondary sarcoma may depend on the primary cancer or prior relapse of primary cancer.

Secondary cancer after a childhood cancer diagnosis: viewpoints considering primary cancer.

BACKGROUNDS: Multidisciplinary therapy has increased the risk of subsequent late effects, but detailed analyses on secondary cancers in childhood cancer survivors (CCSs) are limited in Asian countries. METHODS: This was a retrospective cohort study comprising 10,069 CCSs who were diagnosed between 1980 and 2009 across 15 Japanese hospitals. We conducted secondary analyses to estimate the incidence of secondary cancer according to each primary malignancy and to elucidate the association between primary and secondary cancers. We also explored the risk factors for the development of secondary cancer in each independent primary malignancy. RESULTS: The cumulative incidence of secondary cancer at 20 years varied among primary cancers: hematological malignancy, 3.1% (95% CI 2.2-4.3); retinoblastoma, 6.6% (95% CI 1.5-16.8); pediatric solid tumor, 2.5% (95% CI 1.3-4.2); brain tumors, 5.2% (95% CI 1.7-11.8) bone/soft tissue sarcoma, 5.2% (95% CI 2.3-10.1); and others, 3.3% (95% CI 1.6-6.0) (p = 0.015). The cumulative incidence of secondary cancers is highest in those with osteosarcoma (13.1%) followed by those with hepatoblastoma (8.4%) and retinoblastoma (6.6%). Close association between the primary and secondary cancer diagnoses was found. The risk factors for secondary cancer development depended on the primary cancer, but autologous/allogeneic stem cell transplantation was a relatively common risk factor. CONCLUSION: The cumulative incidence of secondary cancer varied among primary cancers. The primary cancer was closely associated with the secondary cancer but stem cell transplantation was a common risk factor for secondary cancers among CCSs.

Photodynamic therapy in patients with head and neck squamous cell carcinoma.

BACKGROUND: Photodynamic therapy (PDT) is a minimally invasive treatment for malignant tumors. The aim of this study was to determine the efficacy of PDT in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: Thirty-three patients with HNSCC were treated with porfimer sodium-mediated PDT followed by intraoperative light activation at 630 nm via fiber optic microlens delivered after 48 hours of injection. RESULTS: The complete response (CR) rate was 72.7%, while the efficacy (CR + partial response) rate was 97.0%. The rate of good local control (i.e., CR without recurrence after PDT) achieved after the initial PDT (82.6%) was significantly higher than that achieved after the second or third PDT (10%); this rate remained at 62.1% without functional disturbance and disfigurement even after excluding four previously untreated patients. The final local control rate following PDT plus additional therapies was 73.8%. CONCLUSIONS: PDT is an effective therapy to treat HNSCC, and leads to an improved quality of life in patients with residual or recurrent disease. Lasers Surg. Med. 50:420-426, 2018. © 2018 Wiley Periodicals, Inc.

Effect of Cytomegalovirus Reactivation on Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Acute Leukemia.

Recent studies have demonstrated the protective effect of cytomegalovirus (CMV) reactivation against relapse after allogeneic hematopoietic stem cell transplantation (HSCT) for adult myeloid malignancies. We assessed the association of CMV reactivation, defined as the development of CMV antigenemia (at least 1 pp65 antigen-positive cell per 5.0 × 10(4) WBCs) within 100 days after HSCT, with the risk of relapse in 143 patients with pediatric acute leukemia. The median age at HSCT was 7 years, and underlying diseases included acute lymphoblastic leukemia in 101 patients and acute myeloid leukemia in 42. The cumulative incidence of CMV reactivation at day 100 after HSCT was 45.4%. At a median follow-up of 88 months, patients with CMV reactivation had significantly lower 5-year cumulative incidence of relapse compared with patients without CMV reactivation. In a multivariate analysis, high-level CMV reactivation (≥10 pp65 antigen-positive cells) was an independent factor associated with reduced relapse. However, CMV reactivation was also associated with higher nonrelapse mortality (NRM), mostly caused by opportunistic infection after grades II to IV acute graft-versus-host disease (GVHD), which resulted in decreased probability of survival. High-level CMV reactivation was a risk factor for increased NRM and worse overall survival in multivariate analysis. Although CMV reactivation may reduce the risk of relapse after HSCT for pediatric acute leukemia, effective management of severe acute GVHD and better prophylaxis and treatment of opportunistic infections are required to reduce the incidence of NRM and improve survival. Further studies on pediatric HSCT that include a larger number of patients and more homogenous patient cohorts are desirable.

Differences in spatial and temporal frequency interactions between central and peripheral parts of the feline area 18.

The visual system demonstrates significant differences in information processing abilities between the central and peripheral parts of the visual field. Optical imaging based on intrinsic signals was used to investigate the difference in stimulus spatial and temporal frequency interactions related to receptive field eccentricity in the cat area 18. Changing either the spatial or the temporal frequency of grating stimuli had a significant impact on responses in the cortical areas corresponding to the centre of the visual field and more peripheral parts at 10 degrees eccentricity. The cortical region corresponding to the centre of the gaze was tuned to 0.4 cycles per degree (c/deg) for spatial frequency and 2 Hz for temporal frequency. In contrast, the cortical region corresponding to the periphery of the visual field was tuned to a lower spatial frequency of 0.15 c/deg and a higher temporal frequency of 4 Hz. Interestingly, when we simultaneously changed both the spatial frequency and the temporal frequency of the grating stimuli, the responses were significantly different from those estimated with an assumption of independence between the spatial and temporal frequency in the cortical region corresponding to the periphery of the visual field. However, in the cortical area corresponding to the centre of the gaze, spatial frequency showed significant independence from temporal frequency. These properties support the notion of relative specialization of visual information processing for peripheral representations in cortical areas.

Secondary cancers after a childhood cancer diagnosis: a nationwide hospital-based retrospective cohort study in Japan.

BACKGROUND: The epidemiology of secondary cancers in childhood cancer survivors has been unknown in Asian countries. Our aim is to assess the incidence and risk factors for secondary cancers through a nationwide survey in Japan. METHODS: A retrospective cohort study comprising 10,069 children who were diagnosed with cancer between 1980 and 2009 was conducted in 15 Japanese hospitals. The cumulative incidence rate was calculated using death as the competing risk and compared by the Gray method. The standardized incidence ratio (SIR) was defined as the ratio of the number of observed cancers divided by the number of expected cancers. The risk factors were analyzed using Cox regression analysis. RESULTS: One hundred and twenty-eight patients (1.3 %) developed secondary cancers within a median follow-up of 8.4 years. The cumulative incidence rate was 1.1 % (95 % confidence interval [CI] 0.9-1.4) at 10 years and 2.6 % (95 % CI 2.1-3.3) at 20 years after primary cancer diagnosis. Sensitivity analysis, limited to 5-year survivors (n = 5,387), confirmed these low incidence rates. The SIR of secondary cancers was 12.1 (95 % CI 10.1-14.4). In the Cox analysis, the hazard ratios for secondary cancers were 3.81 (95 % CI 1.53-9.47) for retinoblastoma, 2.78 (95 % CI 1.44-5.38) for bone/soft tissue sarcomas, and 1.81 (95 % CI 1.16-2.83) for allogeneic stem cell transplantation. CONCLUSIONS: The cumulative incidence of secondary cancers in children in Japan was not high; however, the SIR was relatively high. Retinoblastoma or sarcoma in addition to allogeneic stem cell transplantation were significant risk factors for secondary cancers.

Central nervous system EBV lymphoproliferative disorder in a patient with rhabdomyosarcoma.

Epstein-Barr virus associated lymphoproliferative disorder (EBV-LPD) occurs in patients with immunodeficiency, but it has not been well described in patients who have received chemotherapy for solid tumors. We describe a child with rhabdomyosarcoma who developed isolated central nervous system (CNS) EBV-LPD during combination chemotherapy with vincristine, actinomycin D and cyclophosphamide. The patient was treated with high-dose methotrexate (HD-MTX) for CNS EBV-LPD and then treated with rituximab in addition to HD-MTX because of the emergence of LPD in the liver. I.v. rituximab combined with HD-MTX might be effective therapy for CNS EBV-LPD.

Neural substrates of view-invariant object recognition developed without experiencing rotations of the objects.

One fails to recognize an unfamiliar object across changes in viewing angle when it must be discriminated from similar distractor objects. View-invariant recognition gradually develops as the viewer repeatedly sees the objects in rotation. It is assumed that different views of each object are associated with one another while their successive appearance is experienced in rotation. However, natural experience of objects also contains ample opportunities to discriminate among objects at each of the multiple viewing angles. Our previous behavioral experiments showed that after experiencing a new set of object stimuli during a task that required only discrimination at each of four viewing angles at 30° intervals, monkeys could recognize the objects across changes in viewing angle up to 60°. By recording activities of neurons from the inferotemporal cortex after various types of preparatory experience, we here found a possible neural substrate for the monkeys' performance. For object sets that the monkeys had experienced during the task that required only discrimination at each of four viewing angles, many inferotemporal neurons showed object selectivity covering multiple views. The degree of view generalization found for these object sets was similar to that found for stimulus sets with which the monkeys had been trained to conduct view-invariant recognition. These results suggest that the experience of discriminating new objects in each of several viewing angles develops the partially view-generalized object selectivity distributed over many neurons in the inferotemporal cortex, which in turn bases the monkeys' emergent capability to discriminate the objects across changes in viewing angle.

Hematopoietic stem cell transplantation in children with refractory cytopenia of childhood: single-center experience using high-dose cytarabine containing myeloablative and aplastic anemia oriented reduced-intensity conditioning regimens.

Refractory cytopenia of childhood (RCC) is the most common subtype of myelodysplastic syndrome in children, and the clinical course of RCC is heterogeneous. A certain proportion of RCC patients need allogeneic hematopoietic stem cell transplantation (HSCT); however, data on HSCT outcomes are not abundant, and the optimal intensity of a preparative conditioning regimen remains uncertain. In this study, we evaluated the outcomes of HSCT in 24 patients with RCC. Eleven patients received myeloablative conditioning (MAC) consisting of high-dose cytarabine, cyclophosphamide, and either total body irradiation (TBI) or busulfan. Nine patients (38%) received a reduced-intensity conditioning (RIC) regimen; of these, 7 received low-dose TBI and cyclophosphamide (200 mg/kg) with or without antithymocyte globulin or fludarabine, and 2 patients received low-dose TBI, fludarabine, and melphalan (140 mg/m(2)). The remaining 4 patients had disease progression before HSCT and received the MAC regimen. With a median follow-up of 91 months (range, 6 to 263), the probability of overall survival at 5 years was 81.1% (95% CI, 57.0 to 92.5). The 5-year overall survival for the 15 patients who received MAC was 73.3% (95% CI, 43.6 to 89.1), and all 9 patients with RIC are alive without any events. Further study is needed to evaluate the efficacy of RIC for children with RCC with an expectation for reduction of late effects such as growth retardation and infertility.

Long-Term Morbidity and Mortality in Children with Chronic Graft-versus-Host Disease Classified by National Institutes of Health Consensus Criteria after Allogeneic Hematopoietic Stem Cell Transplantation.

We report the long-term morbidity and mortality of 105 pediatric patients who developed chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). According to the consensus criteria of the National Institutes of Health, the global severity of cGVHD was mild in 26 patients (25%), moderate in 30 patients (29%), and severe in 49 patients (47%). Patients with severe cGVHD had a significantly lower cumulative incidence of cGVHD remission and higher probability of continuing cGVHD at 8 years from cGVHD diagnosis compared with those with mild or moderate cGVHD. The 10-year cumulative incidence of nonrelapse mortality in severe cGVHD patients was significantly higher and the probability of disease-free survival was significantly lower than those among patients with mild and moderate cGVHD. Of the 59 patients who survived for more than 5 years, 20 (34%) (4 with moderate and 16 with severe cGVHD) had persistent functional impairment caused by cGVHD with a Karnofsky/Lansky performance score of 90% in 3 patients, 80% in 4 patients, and below 70% in 13 patients at the time of relapse, death, or last follow-up. Better therapeutic strategies are needed to lower the incidence of severe cGVHD, considering the longer life expectancy of pediatric HSCT survivors.

Clinical outcomes of a novel therapeutic vaccine with Tax peptide-pulsed dendritic cells for adult T cell leukaemia/lymphoma in a pilot study.

Adult T cell leukaemia/lymphoma (ATL) is a human T cell leukaemia virus type-I (HTLV-I)-infected T cell malignancy with poor prognosis. We herein developed a novel therapeutic vaccine designed to augment an HTLV-I Tax-specific cytotoxic T lymphocyte (CTL) response that has been implicated in anti-ATL effects, and conducted a pilot study to investigate its safety and efficacy. Three previously treated ATL patients, classified as intermediate- to high-risk, were subcutaneously administered with the vaccine, consisting of autologous dendritic cells (DCs) pulsed with Tax peptides corresponding to the CTL epitopes. In all patients, the performance status improved after vaccination without severe adverse events, and Tax-specific CTL responses were observed with peaks at 16-20 weeks. Two patients achieved partial remission in the first 8 weeks, one of whom later achieved complete remission, maintaining their remission status without any additional chemotherapy 24 and 19 months after vaccination, respectively. The third patient, whose tumour cells lacked the ability to express Tax at biopsy, obtained stable disease in the first 8 weeks and later developed slowly progressive disease although additional therapy was not required for 14 months. The clinical outcomes of this pilot study indicate that the Tax peptide-pulsed DC vaccine is a safe and promising immunotherapy for ATL.

Hematopoietic stem cell transplantation following unsuccessful salvage treatment for relapsed acute lymphoblastic leukemia in children.

BACKGROUND: For children who experience a re-induction failure or multiple recurrences following the first relapse of acute lymphoblastic leukemia (ALL), it is uncertain whether additional intensive chemotherapy aimed at hematopoietic stem cell transplantation (SCT) in complete remission (CR) or immediate SCT even in non-CR should be performed. This study aimed to investigate the impact of disease status at SCT on the outcomes of SCT for these children, whose prognosis is considered unquestionably poor even with SCT. PROCEDURE: The medical records of 55 children with ALL who underwent SCT following the experience of re-induction failure (n = 25) or multiple relapses (n = 30) were retrospectively analyzed. RESULTS: Twenty-one patients underwent SCT in CR (delayed CR2, CR3, and CR4) and 34 in non-CR (first or subsequent relapse). The probability of overall survival of patients with CR and with non-CR at SCT was 42.9% and 23.5% (P = 0.15), leukemia-free survival was 38.1% and 20.6% (P = 0.18), and the cumulative incidence of relapse at 2 years was 23.8% and 50%, respectively (P = 0.05). In multivariate analysis, non-CR at SCT was a significant risk factor for higher relapse incidence and male sex was a significant risk factor for lower survival. CONCLUSIONS: Our results indicated that in case of tolerable patient condition, further re-induction chemotherapy might be reasonable so that SCT could be performed in CR, which might result in a low incidence of relapse after SCT. Novel approaches are required to induce CR for the treatment of children with relapsed/refractory ALL.

Potential contribution of a novel Tax epitope-specific CD4+ T cells to graft-versus-Tax effect in adult T cell leukemia patients after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). We previously reported that Tax-specific CD8(+) cytotoxic T lymphocyte (CTL) contributed to graft-versus-ATL effects in ATL patients after allo-HSCT. However, the role of HTLV-1-specific CD4(+) T cells in the effects remains unclear. In this study, we showed that Tax-specific CD4(+) as well as CD8(+) T cell responses were induced in some ATL patients following allo-HSCT. To further analyze HTLV-1-specific CD4(+) T cell responses, we identified a novel HLA-DRB1*0101-restricted epitope, Tax155-167, recognized by HTLV-1-specific CD4(+) Th1-like cells, a major population of HTLV-1-specific CD4(+) T cell line, which was established from an ATL patient at 180 d after allo-HSCT from an unrelated seronegative donor by in vitro stimulation with HTLV-1-infected cells from the same patient. Costimulation of PBMCs with both the identified epitope (Tax155-167) and known CTL epitope peptides markedly enhanced the expansion of Tax-specific CD8(+) T cells in PBMCs compared with stimulation with CTL epitope peptide alone in all three HLA-DRB1*0101(+) patients post-allo-HSCT tested. In addition, direct detection using newly generated HLA-DRB1*0101/Tax155-167 tetramers revealed that Tax155-167-specific CD4(+) T cells were present in all HTLV-1-infected individuals tested, regardless of HSCT. These results suggest that Tax155-167 may be the dominant epitope recognized by HTLV-1-specific CD4(+) T cells in HLA-DRB1*0101(+)-infected individuals and that Tax-specific CD4(+) T cells may augment the graft-versus-Tax effects via efficient induction of Tax-specific CD8(+) T cell responses.