Negative association between basal oxytocin and oxytocin changes after repetitive transcranial magnetic stimulation in patients with treatment-resistant depression.

Repetitive transcranial magnetic stimulation (rTMS) is a neuromodulator effective for treating depressive symptoms in patients with treatment-resistant depression (TRD). One of the multiple mechanisms for its antidepressant effects proposed is related to the hypothalamus. Oxytocin is a neuropeptide synthesized in the hypothalamus that affects human behavior and psychology, including social and affiliative behaviors, stress regulation, and fear and emotion processing. There have been no reports on the relationship between rTMS and oxytocin for the treatment of TRD. Therefore, we aimed to investigate changes in salivary oxytocin concentrations in patients with TRD before and after 6 weeks of rTMS treatment. A total of 28 patients with TRD who received rTMS at Saga University Hospital between August 2013 and August 2020 were included. Although rTMS treatment significantly improved 24-item Hamilton Depression Rating Scale scores, rTMS treatment did not change mean salivary oxytocin after 6 weeks of treatment in patients with TRD. Multiple regression analysis revealed that the change in salivary oxytocin levels after rTMS treatment was negatively associated with basal oxytocin levels before rTMS treatment, suggesting that rTMS treatment tends to decrease oxytocin levels in patients with depression with high basal oxytocin levels while increasing them in those with low basal levels. These findings suggest that rTMS treatment improved depressive symptoms through mechanisms other than the modulatory effect on oxytocin levels in patients with TRD, while there is room for further studies to confirm these findings using a larger patient sample size and/or a sham rTMS procedure.

Total body irradiation-based versus busulfan-based myeloablative conditioning for single-unit cord blood transplantation in adults.

Comparative studies between total body irradiation (TBI)-based and busulfan-based myeloablative conditioning (MAC) regimens for cord blood transplantation (CBT) have been limited. We retrospectively analyzed the results of single-unit CBT in 333 adult patients who received either TBI-based (n = 258) or busulfan-based (n = 75) MAC regimens at our institute. After adjusting for significant variables in the univariate analysis, there were no significant differences in neutrophil recovery (hazard ratio (HR), 0.88; p = .460), grade III-IV acute graft-versus-host disease (GVHD) (HR: 1.40, p = .410), extensive chronic GVHD (HR: 0.73, p = .380), relapse (HR: 0.61, p = .270), non-relapse mortality (HR: 1.38, p = .420), overall survival (HR: 1.18, p = .637), or event-free survival (HR: 1.08, p = .773), although platelet recovery was lower with marginal significance for the busulfan-based regimen (HR: 0.67, p = .068). In subgroup analysis, TBI-based regimens were superior to busulfan-based regimens in terms of survival for acute lymphoblastic leukemia, but not for myeloid malignancies. Further investigation is warranted even for CBT.

Long-term outcomes following the addition of granulocyte colony-stimulating factor-combined high-dose cytarabine to total body irradiation and cyclophosphamide conditioning in single-unit cord blood transplantation for myeloid malignancies.

An intensified myeloablative conditioning regimen, involving the addition of granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine (12 g/m2) to standard total body irradiation and cyclophosphamide, has been performed for adult patients with myeloid malignancies in single-unit cord blood transplantation (CBT) since 1998 in our institute. We update the results of CBT, as the first allogeneic hematopoietic cell transplantation after this conditioning regimen, in 169 patients with a median long-term follow-up of 10.4 years. The median age was 43 years (range, 16 to 59 years). Ninety-four patients (56%) were in non-remission at the time of CBT, and 124 patients (73%) were acute myeloid leukemia. The median cryopreserved cord blood total nucleated cell dose and CD34+ cell dose was 2.40 × 107/kg and 0.93 × 105/kg, respectively. The cumulative incidence of neutrophil recovery at 42 days was 94.4% (95% confidence interval [CI]: 88.6-97.3%). Among the whole cohort, 105 patients were still alive at the end of the study period. The cumulative incidences of relapse and non-relapse mortality at 10 years were 26.0% (95% CI: 19.5-33.0%) and 16.9% (95% CI: 11.4-23.4%), respectively. There was an overall survival probability of 62.5% (95% CI: 54.3-69.7%) at 10 years. Higher disease risk index alone significantly affected higher overall mortality (hazard ratio 2.21, P = 0.003) in multivariate analysis. These outcomes demonstrate that G-CSF-combined myeloablative conditioning could have favorable long-term remission rates for adult patients with myeloid malignancies undergoing single-unit CBT.

Second myeloablative allogeneic stem cell transplantation (SCT) using cord blood for leukemia relapsed after initial allogeneic SCT.

There are many reports of second allogeneic stem cell transplantation (allo-SCT) using cord blood (CB) for graft failure after initial allo-SCT. However, the efficacy of second allo-SCT using CB for patients with leukemia relapsed after initial allo-SCT is unknown. We report the results of second allo-SCT using CB in seven adult patients with leukemia relapsed after initial allo-SCT. All patients received a myeloablative conditioning regimen including oral busulfan 16 mg/kg, intravenously fludarabine 100mg/m(2) and cyclophosphamide 120 mg/kg. All but one patient had myeloid reconstitution and four patients remain alive at between 4 and 40 months after second SCT. We conclude that second myeloablative allo-SCT using CB may be feasible in selected patients with the relatively younger age, less organ damage and longer time interval between first and second allo-SCT.

Myeloablative unrelated cord blood transplantation for acute leukemia patients between 50 and 55 years of age: single institutional retrospective comparison with patients younger than 50 years of age.

Increasing recipient age is a well-known risk factor for graft-versus-host disease (GVHD) and treatment-related mortality (TRM) and has a negative impact on allogeneic hematopoietic stem cell transplantation. Since the incidence of severe GVHD after cord blood transplantation (CBT) is lower than that after transplants using bone marrow or mobilized peripheral blood grafts from adult cells, we should expect better outcomes from CBT in older patients. To evaluate the feasibility and efficacy of myeloablative unrelated CBT in patients aged between 50 and 55 years, we performed a retrospective comparison of 100 patients with acute leukemia who received cord blood grafts at our institution. Nineteen older patients (median age, 52; range, 50-55) and 81 younger patients (median, 36; range, 16-49) received a myeloablative conditioning regimen including 12 Gy of total body irradiation and chemotherapy. GVHD prophylaxis included cyclosporine with (n = 96) or without (n = 4) methotrexate. There were no significant differences in the incidences of grades II to IV acute GVHD, extensive-type chronic GVHD, TRM, and the probability of overall and disease-free survival between these groups. These results suggest that, in patients with acute leukemia, myeloablative CBT might be as safe and effective in patients aged between 50 and 55 years as in younger patients.

Unrelated cord blood transplantation after myeloablative conditioning in adults with acute myelogenous leukemia.

We analyzed the disease-specific outcomes of adult acute myelogenous leukemia (AML) patients treated with unrelated cord blood transplantation (CBT) after myeloablative conditioning. Between August 1998 and February 2008, 77 adult patients with AML were treated with unrelated CBT. All patients received 4 fractionated 12 Gy total body irradiation (TBI) and chemotherapy as myeloablative conditioning. The median age was 45 years, the median weight was 55 kg, the median number of nucleated cells was 2.44 x 10(7)/kg, and the median number of CD34-positive cells was 1.00 x 10(5)/kg. All patients received a single and HLA mismatched cord blood unit. The cumulative incidence of neutrophil recovery at day 50 and platelet recovery at day 200 was 94.8% and 91.7%, respectively. A higher CD34-positive cell dose was associated with faster hematopoietic recovery. The cumulative incidence of grade III to IV acute graft-versus-host disease (aGVHD) and extensive-type chronic GVHD (cGVHD) was 25.1% and 28.6%, respectively. With a median follow-up of 78 months, the probability of event-free survival (EFS) at 5 years was 62.8%. The 5-year cumulative incidence of treatment related-mortality (TRM) and relapse was 9.7%, 25.8%, respectively. In multivariate analyses, the risk factor identified for event free survival (EFS) was disease status and cytogenetics. These results suggest that unrelated CBT after myeloablative conditioning could be safely and effectively used for adult patients with AML.

Fatal acute tumor lysis syndrome following intrathecal chemotherapy for acute lymphoblastic leukemia with meningeal involvement.

Acute tumor lysis syndrome (ATLS) is a well-recognized complication of systemic chemotherapy for rapidly proliferating neoplasms. ATLS has rarely occurred after intrathecal chemotherapy for the treatment of leukemia with meningeal involvement. Here, we report a case of fatal ATLS complicating intrathecal injections of methotrexate, cytarabine and hydrocortisone for acute lymphoblastic leukemia which relapsed with meningeal involvement after allogeneic stem cell transplantation. This case indicates that intrathecal chemotherapy alone may be sufficient to induce ATLS. Close monitoring and prevention of ATLS are also warranted following intrathecal chemotherapy alone.

Recipient-derived cells after cord blood transplantation: dynamics elucidated by multicolor FACS, reflecting graft failure and relapse.

Although umbilical cord blood has been increasingly used as an alternative donor source to treat hematologic malignancies, cord blood transplantation (CBT) is frequently complicated by graft failure and relapse of primary diseases. Because persistence or increase of recipient-derived hematopoietic or malignant cells has pathogenic import under these conditions, analysis of recipient-derived cells should be useful to understand the pathogenesis of graft failure and relapse of primary disease. Because most CBT involves human leukocyte antigen (HLA)-mismatched transplantation, we developed a 9-color fluorescence activated cell sorter (FACS)-based method of mixed chimerism (MC) analysis using anti-HLA antibodies to detect mismatched antigens (HLA-Flow method). Among CD4(+) T cells, CD8(+) T cells, B cells, NK cells, monocytes, and granulocytes, donor- and recipient-derived cells alike could be individually analyzed simultaneously in a rapid, quantitative and highly sensitive manner, making the HLA-Flow method very valuable in monitoring the engraftment process. In addition, this method was also useful in monitoring recipient-derived cells with leukemia-specific phenotypes, both as minimal residual disease (MRD) and as early harbingers of relapse. Leukemia relapse can be definitively diagnosed by cytogenetic or PCR studies using recipient-derived cells sorted for leukemia markers. Multicolor HLA-fFlow analysis and cell sorting in early diagnosis of graft failure and relapse was confirmed as valuable in 14 patients who had received HLA-mismatched CBT.

Early renal injury after myeloablative cord blood transplantation in adults.

We report a retrospective analysis of acute renal failure (ARF) in a group of 54 adult patients with hematological malignancies treated with unrelated cord blood transplantation (CBT) after myeloablative conditioning. All patients received four fractionated 12 Gy total body irradiation and chemotherapy as myeloablative conditioning. ARF was defined as the doubling serum creatinine occurring within the first 100 days after CBT. A statistically significant decrement of renal function from baseline was observed in days between 11 and 20. ARF occurred in 27.8% of patients. Although no difference was seen in maximum cyclosporine trough levels, the maximum of vancomycin (VCM) trough levels were significantly higher in patients with ARF (p = 0.01). Our result suggests that it is important to monitor VCM dosing more strictly with pharmacokinetic assessment, especially in days 11 - 20, when the most frequently observed declining renal function.

Impact of cytomegalovirus serostatus on outcome of unrelated cord blood transplantation for adults: a single-institute experience in Japan.

Cytomegalovirus (CMV) disease is one of the major infectious complications after allogeneic hematopoietic stem cell transplantation (SCT). Several studies have shown that CMV-seropositive patients have a substantial survival disadvantage after bone marrow transplantation (BMT) or peripheral blood SCT (PBSCT). Between August 1998 and February 2006, 101 adult patients underwent myeloablative cord blood transplantation (CBT) from unrelated donors at our institution. Sixteen and 85 patients were CMV-seronegative and CMV-seropositive, respectively, prior to CBT. Outcomes of CBT were compared between CMV-seronegative and CMV-seropositive patients. The cumulative incidences of neutrophil engraftment at 60 d after CBT did not differ between CMV-seronegative and CMV-seropositive patients (100% and 94%, P = 0.09); however, the cumulative incidence of platelet engraftment at 100 d was higher in CMV-seronegative patients than CMV-seropositive patients (100% vs. 86%, P < 0.005). The cumulative incidence of CMV antigenemia at 100 d was lower in CMV-seronegative patients than CMV-seropositive patients (0% vs. 77%, P < 0.001); however, the cumulative incidences of CMV disease did not differ between CMV-seronegative and CMV-seropositive patients (0% vs. 1%, P = 0.84). The probabilities of disease-free survival at 2 yr also did not differ between CMV-seronegative and CMV-seropositive patients (92% vs. 72%, P = 0.16). The outcomes of CBT for CMV-seropositive patients as well as CMV-seronegative patients in our series were favorable. This might be due to effective antiviral therapy for CMV infection. Large-scale studies are needed to determine the impact of recipient CMV serostatus on the outcome of CBT for adults.

Bacterial bloodstream infection in neutropenic adult patients after myeloablative cord blood transplantation: experience of a single institution in Japan.

Bacterial infection is one of the most important causes of morbidity and mortality after unrelated cord blood transplantation (CBT). In the present study, we studied 101 adult patients with respect to the incidence, outcome, and risk factors for bacterial bloodstream infection (BSI) within 30 days after CBT using a myeloablative conditioning regimen. Bacterial BSI occurred in 12 patients within 30 days after CBT. The cumulative incidence of bacterial BSI was 12%. The median time of onset was day +6 (range, day -1 to day +13) after CBT. In all patients, the neutrophil count was 0/microL at the onset of bacterial BSI. Eight (67%) and 4 (33%) of the isolates were Gram-positive and Gram-negative bacteria, respectively. Only 2 (17%) of the 12 patients who had bacterial BSI died within 100 days after CBT. No risk factors for the occurrence of bacterial BSI within 30 days after CBT were identified. The low mortality rate for bacterial BSI in the neutropenic period appeared to be associated with the low incidence (6%) of transplantation-related death at day +100 in our study patients. Early diagnosis of bacterial BSI and prompt treatment with effective antibiotics are necessary for neutropenic adult patients after myeloablative CBT.

Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen.

We studied the clinical outcomes of 171 adults with hematologic malignancies who received unrelated cord blood transplantation (CBT) as a primary unrelated stem-cell source (n=100), or bone marrow transplant (BMT) or peripheral blood stem-cell transplant (PBSCT) from related donors (n=71, 55 BMT and 16 PBSCT). All patients received myeloablative regimens including 12 Gy total body irradiation. We analyzed the hematologic recovery, and risks of graft-versus-host disease (GVHD), transplantation-related mortality (TRM) and relapse, and disease-free survival (DFS) using Cox proportional hazards models. Significant delays in engraftment occurred after cord blood transplantation; however, overall engraftment rates were almost the same for both grafts. The cumulative incidences of grades III to IV acute and extensive-type chronic GVHDs among CBT recipients were significantly lower than those among BMT/PBSCT recipients. Multivariate analysis demonstrated no apparent differences in TRM (9% in CBT and 13% in BMT/PBSCT recipients), relapse (17% in CBT and 26% in BMT/PBSCT recipients), and DFS (70% in CBT and 60% in BMT/PBSCT recipients) between both groups. These data suggest that unrelated cord blood could be as safe and effective a stem-cell source as related bone marrow or mobilized peripheral blood for adult patients when it is used as a primary unrelated stem-cell source.

Pancreatic hyperamylasemia and hyperlipasemia in association with cytomegalovirus infection following unrelated cord blood transplantation for acute myelogenous leukemia.

Cytomegalovirus (CMV)-associated pancreatitis is rare after allogeneic hematopoietic stem cell transplantation (SCT). We describe a patient who developed pancreatic hyperamylasemia and hyperlipasemia in association with CMV infection after cord blood transplantation (CBT). A 31-year-old man with acute myelogenous leukemia underwent CBT. A neutrophil count consistently greater than 500/microL was achieved on day +21. Positive results for CMV antigenemia on days +35 and +67 prompted 2 courses of preemptive therapy with ganciclovir or foscarnet. The CMV antigenemia value again became positive on day +134. On day +141, serum amylase and lipase activities markedly increased to 1221 IU/L and 894 IU/L, respectively. The patient had no abdominal symptoms. Ultrasonography and computed tomography results showed no abnormalities of the pancreas. A diagnosis of possible pancreatitis was made. After the initiation of foscarnet therapy, the CMV antigenemia results soon became negative, and serum amylase and lipase activities returned to normal. Therefore, CMV infection was considered to play a major role in the development of pancreatic hyperamylasemia and hyperlipasemia in our patient. The present report indicates that CMV infection should be included in the differential diagnosis for patients with pancreatic hyperamylasemia after SCT.

Posttransplantation engraftment and safety of cord blood transplantation with grafts containing relatively low cell doses in adults.

The cell dose of a graft is a critical determinant of hematopoietic recovery and survival following unrelated cord blood transplantation. Most studies have found that the minimum acceptable nucleated cell dose should be between 1.5 X 10(7) and 2.0 X 10(7) nucleated cells per kilogram of body weight to reduce the time to myeloid recovery and increase the probability of engraftment. For some patients who have indications for hematopoietic cell transplants and for whom no other graft source except cord blood is available, it is difficult to decide whether they can receive cord blood grafts containing lower cell doses. In our study, patients who received cord blood grafts containing 1.0 X 10(7) to 2.0 X 10(7) cells/kg (n = 7) exhibited slower neutrophil and platelet recoveries compared with patients who received grafts containing total nucleated cell doses of 2.0 X 10(7) cells/kg and above (n = 93); however, 4 of those low-cell-dose recipients survived with a longer follow-up. Based on these preliminary results, cord blood grafts containing less than 2.0 X 10(7) cells/kg may be useful for cases where no grafts with higher cell doses or other stem cell sources are available.