Post‐transplant Lymphoproliferative Disorders After Liver Transplantation: A Retrospective Cohort Study Including 1954 Transplants

Post-transplant lymphoproliferative disorders (PTLDs) are life-threatening neoplasms after organ transplantation. Because of their rarity and multiple grades of malignancy, the incidence, outcomes, and clinicopathological features affecting patient survival after liver transplantation (LT) remain unclear. We reviewed 1954 LTs in 1849 recipients (1990-2020), including 886 pediatric (<18 years of age) and 963 adult recipients. The following clinicopathological factors were studied: age, sex, liver etiologies, malignancy grades, Epstein-Barr virus status, performance status (PS), Ann Arbor stage, international prognostic index, and histopathological diagnosis. Of 1849 recipients, 79 PTLD lesions (4.3%) were identified in 70 patients (3.8%). After excluding 3 autopsy cases incidentally found, 67 (45 pediatric [5.1%] and 22 adult [2.3%]) patients were finally enrolled. Comorbid PTLDs significantly worsened recipient survival compared with non-complicated cases (P < 0.001). The 3-year, 5-year, and 10-year overall survival rates after PTLD diagnosis were 74%, 66%, and 58%, respectively. The incidence of PTLDs after LT (LT-PTLDs) was significantly higher (P < 0.001) with earlier onset (P = 0.002) in children, whereas patient survival was significantly worse in adults (P = 0.002). Univariate and multivariate analyses identified the following 3 prognostic factors: age at PTLD diagnosis ≥18 years (hazard ratio [HR], 11.2; 95% confidence interval [CI], 2.63-47.4; P = 0.001), PS ≥2 at diagnosis (HR, 6.77; 95% CI, 1.56-29.3; P = 0.01), and monomorphic type (HR, 6.78; 95% CI, 1.40-32.9; P = 0.02). A prognostic index, the “LT-PTLD score, ” that consists of these 3 factors effectively stratified patient survival and progression-free survival (P = 0.003 and <0.001, respectively). In conclusion, comorbid PTLDs significantly worsened patient survival after LT. Age ≥18 years and PS ≥2 at PTLD diagnosis, and monomorphic type are independent prognostic factors, and the LT-PTLD score that consists of these 3 factors may distinguish high-risk cases and guide adequate interventions

The impact of human leukocyte antigen mismatch on recipient outcomes in living‐donor liver transplantation

Donor–recipient human leukocyte antigen (HLA) compatibility has not been considered to significantly affect liver transplantation (LT) outcomes; however, its significance in living-donor LT (LDLT), which is mostly performed between blood relatives, remains unclear. This retrospective cohort study included 1954 LDLTs at our institution (1990–2020). The primary and secondary endpoints were recipient survival and the incidence of T cell–mediated rejection (TCMR) after LDLT, respectively, according to the number of HLA mismatches at all five loci: HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ. Subgroup analyses were also performed in between-siblings that characteristically have widely distributed 0–10 HLA mismatches. A total of 1304 cases of primary LDLTs were finally enrolled, including 631 adults (recipient age at LT ≥18 years) and 673 children (<18 years). In adult-to-adult LDLT, the more HLA mismatches at each locus, the significantly worse the recipient survival was (p = 0.03, 0.01, 0.03, 0.001, and <0.001 for HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ, respectively). This trend was more pronounced when multiple loci were combined (all p < 0.001 for A + B + DR, A + B + C, DR + DQ, and A + B + C + DR + DQ). Notably, a total of three or more HLA-B + DR mismatches was an independent risk factor for both TCMR (hazard ratio [HR] 2.66, 95% confidence interval [CI] 1.21–5.87; p = 0.02) and recipient survival (HR 2.44, 95% CI 1.11–5.35; p = 0.03) in between-siblings. By contrast, HLA mismatch did not affect pediatric LDLT outcomes at any locus or in any combinations; however, it should be noted that all donor–recipient relationships are parent-to-child that characteristically possesses one or less HLA mismatch at each locus and maximally five or less mismatches in total. In conclusion, HLA mismatch significantly affects not only TCMR development but also recipient survival in adult LDLT, but not in children

Spectral evolution of GRB 060904A observed with Swift and Suzaku -- Possibility of Inefficient Electron Acceleration

We observed an X-ray afterglow of GRB 060904A with the Swift and Suzaku satellites. We found rapid spectral softening during both the prompt tail phase and the decline phase of an X-ray flare in the BAT and XRT data. The observed spectra were fit by power-law photon indices which rapidly changed from $\Gamma = 1.51^{+0.04}_{-0.03}$ to $\Gamma = 5.30^{+0.69}_{-0.59}$ within a few hundred seconds in the prompt tail. This is one of the steepest X-ray spectra ever observed, making it quite difficult to explain by simple electron acceleration and synchrotron radiation. Then, we applied an alternative spectral fitting using a broken power-law with exponential cutoff (BPEC) model. It is valid to consider the situation that the cutoff energy is equivalent to the synchrotron frequency of the maximum energy electrons in their energy distribution. Since the spectral cutoff appears in the soft X-ray band, we conclude the electron acceleration has been inefficient in the internal shocks of GRB 060904A. These cutoff spectra suddenly disappeared at the transition time from the prompt tail phase to the shallow decay one. After that, typical afterglow spectra with the photon indices of 2.0 are continuously and preciously monitored by both XRT and Suzaku/XIS up to 1 day since the burst trigger time. We could successfully trace the temporal history of two characteristic break energies (peak energy and cutoff energy) and they show the time dependence of $\propto t^{-3} \sim t^{-4}$ while the following afterglow spectra are quite stable. This fact indicates that the emitting material of prompt tail is due to completely different dynamics from the shallow decay component. Therefore we conclude the emission sites of two distinct phenomena obviously differ from each other.Comment: 19 pages, 9 figures, accepted for publication in PASJ (Suzaku 2nd Special Issue

CD146 is a potential immunotarget for neuroblastoma

Neuroblastoma, the most common extracranial solid tumor of childhood, is thought to arise from neural crest-derived immature cells. The prognosis of patients with high-risk or recurrent/refractory neuroblastoma remains quite poor despite intensive multimodality therapy; therefore, novel therapeutic interventions are required. We examined the expression of a cell adhesion molecule CD146 (melanoma cell adhesion molecule [MCAM]) by neuroblastoma cell lines and in clinical samples and investigated the anti-tumor effects of CD146-targeting treatment for neuroblastoma cells both in vitro and in vivo. CD146 is expressed by 4 cell lines and by most of primary tumors at any stage. Short hairpin RNA-mediated knockdown of CD146, or treatment with an anti-CD146 polyclonal antibody, effectively inhibited growth of neuroblastoma cells both in vitro and in vivo, principally due to increased apoptosis via the focal adhesion kinase and/or nuclear factor-kappa B signaling pathway. Furthermore, the anti-CD146 polyclonal antibody markedly inhibited tumor growth in immunodeficient mice inoculated with primary neuroblastoma cells. In conclusion, CD146 represents a promising therapeutic target for neuroblastoma

Ten-year follow-up of infliximab treatment for uveitis in Behçet disease patients: A multicenter retrospective study

PurposeTo evaluate 10-year outcome of infliximab (IFX) treatment for uveitis in Behçet disease (BD) patients using a standardized follow-up protocol.DesignRetrospective longitudinal cohort study.Participants140 BD uveitis patients treated with IFX enrolled in our previous study.MethodsMedical records were reviewed for demographic information, duration of IFX treatment, number of ocular attacks before IFX initiation, best corrected visual acuity (VA) at baseline and 1, 2, 3, 4, 5, and 10 years after IFX initiation, uveitis recurrence after IFX initiation and main anatomical site, concomitant therapies, and adverse events (AEs).Main outcome measures10-year IFX continuation rate and change in LogMAR VA.ResultsOf 140 BD patients, 106 (75.7%) continued IFX treatment for 10 years. LogMAR VA improved gradually after initiation of IFX, and the improvement reached statistical significance from 2 years of treatment. Thereafter, significant improvement compared with baseline was maintained until 10 years, despite a slight deterioration of logMAR VA from 5 years. However, eyes with worse baseline decimal VA &lt; 0.1 showed no significant improvement from baseline to 10 years. Uveitis recurred after IFX initiation in 50 patients (recurrence group) and did not recur in 56 (non-recurrence group). Ocular attacks/year before IFX initiation was significantly higher in the recurrence group (2.82 ± 3.81) than in the non-recurrence group (1.84 ± 1.78). In the recurrence group, uveitis recurred within 1 year in 58% and within 2 years in 74%. Seventeen patients (34%) had recurrent anterior uveitis, 17 (34%) had posterior uveitis, and 16 (32%) had panuveitis, with no significant difference in VA outcome. In addition, logMAR VA at 10 years did not differ between the recurrence and non-recurrence groups. AEs occurred among 43 patients (30.7%), and 24 (17.1%) resulted in IFX discontinuation before 10 years.ConclusionsAmong BD patients with uveitis who initiated IFX, approximately 75% continued treatment for 10 years, and their VA improved significantly and was maintained for 10 years. Uveitis recurred in one-half of the patients, but visual acuity did not differ significantly from the patients without recurrence

Peripapillary and macular choroidal area in patients with normal-tension glaucoma.

PURPOSE:To evaluate normal and normal-tension glaucoma (NTG) eyes for differences in peripapillary and macular choroidal area measurements. METHODS:This cross-sectional comparative study enrolled 52 normal subjects and 35 NTG patients. Peripapillary and macular choroidal images were recorded by enhanced depth imaging optical coherence tomography (EDI-OCT), with conversion of the luminal and interstitial areas to binary images performed using the Niblack method. RESULTS:While there was a significant difference between normal subjects and NTG patients for the peripapillary choroidal area (1,853,672 ± 626,501 μm2 vs. 1,606,448 ± 418,214 μm2, P = 0.047), there were no significant differences between the normal subjects and NTG patients observed for the macular choroidal area (345,365 ± 119,248 μm2 vs. 316,442 ± 85,732 μm2, P = 0.23). In the NTG patients, multivariate regression analysis demonstrated a correlation between the macular choroidal area and the axial length (β = -0.345, P = 0.04). Furthermore, there was also a significant correlation between the peripapillary choroidal area and the age of the NTG patients (β = -0.469, P = 0.004). In addition, there was no relationship between the glaucoma severity and the peripapillary and macular choroidal areas in the NTG patients. CONCLUSIONS:There was no correlation between the peripapillary choroidal area and glaucoma severity in NTG patients, even though the area was smaller in these patients

Assessment of primary open-angle glaucoma peripapillary and macular choroidal area using enhanced depth imaging optical coherence tomography.

PURPOSE:The current study investigated differences in the peripapillary and macular choroidal areas between patients with primary open-angle glaucoma (POAG) and healthy controls because the choroid may potentially play a role in glaucoma pathophysiology. METHODS:We assessed 57 healthy controls and 42 POAG patients in a cross-sectional comparative study. We used enhanced depth imaging optical coherence tomography (EDI-OCT) and then converted the luminal and interstitial areas to binary images using the Niblack method to obtain peripapillary and macular choroidal images. The relationship between the choroidal area and demographic and ocular characteristics were determined with univariate and multivariate linear regression analysis. RESULTS:Regarding the peripapillary choroidal area, no significant differences were noted between healthy controls and POAG patients (1,836,336 ± 605,617 μm2 vs. 1,775,566 ± 477,317 μm2, respectively, P = 0.60). There were also no differences found for the macular choroidal area (controls: 347,220 ± 115,409 μm2, patients: 342,193 ± 104,356 μm2, P = 0.83). Multivariate regression analysis in the POAG patients revealed there was a significant relationship between the macular choroidal area and age (β = -0.525, P = 0.002) and axial length (β = -0.458, P = 0.005). In contrast, no correlation was found between peripapillary choroidal areas and various attributes in the POAG patients. CONCLUSIONS:EDI-OCT showed no differences in the peripapillary or macular choroidal area in healthy individuals compared to POAG patients

Changes in choroidal area after intraocular pressure reduction following trabeculectomy.

PURPOSE:To investigate changes of the macular and peripapillary choroidal areas after trabeculectomy. METHODS:This prospective and interventional study examined 74 eyes of 74 patients with glaucoma uncontrolled by medical therapy. Enhanced depth imaging optical coherence tomography (EDI-OCT) recorded macular and peripapillary choroidal images at 1 day before trabeculectomy and at 2 weeks after surgery. The Niblack method was used to covert luminal and interstitial areas to binary images. RESULTS:At baseline, the mean intraocular pressure (IOP) was 17.6±6.3 mmHg, while it was 6.5±2.9 mmHg after trabeculectomy (P < 0.001). Increases were observed for the macular choroidal area after the surgery, with the total area increasing from 317,853±95,728 μm2 to 368,597±104,393 μm2, while the luminal area increased from 210,355±73,650 μm2 to 249,464±77,195 μm2, and the interstitial area increased from 107,498±27,613 μm2 to 119,133±31,811 μm2 (all P < 0.001). Increases were also observed after the surgery for the peripapillary choroidal area, with the total area increasing from 1,629,440±460,429 μm2 to 1,974,289±500,496 μm2, while the luminal area increased from 920,141±328,690 μm2 to 1,179,843±357,601 μm2, and the interstitial area increased from 709,299±153,179 μm2 to 794,446±169,029 μm2 (all P < 0.001). There was a significant increase in the ratio of the luminal to choroidal area in the macular area (67.2%) and in the peripapillary area (59.1%). Factors associated with the changes in the peripapillary choroidal area included decreases in the diastolic blood pressure and IOP. CONCLUSIONS:A reduction in the IOP after trabeculectomy led to increases in the macular and peripapillary choroidal areas. Observed changes in the choroidal area after trabeculectomy are primarily due to increases in the luminal areas

Effectiveness of Sirolimus in Combination with Cyclosporine against Chronic Rejection in a Pediatric Liver Transplant Patient

The patient is a 3-year-old boy who received living-donor liver transplantation (LDLT) for hepatoblastoma, with his mother as the donor. Oral tacrolimus was started at a dose of 0.3 mg every 12 h from day 1, with the dosage adjusted on the basis of trough concentrations. The levels of aspartate aminotransferase (AST), alanine transferase (ALT), and total bilirubin (T-bil) were 110 U/L, 182 U/L, and 12.6 mg/dL, respectively, when chronic rejection (CR) was pathologically diagnosed. Then, sirolimus at a dose of 1.0 mg/d was added to the tacrolimus-based regimen. The T-bil level rapidly decreased to 5.4 mg/dL, without changes in AST and ALT. Because the intracellular receptor of sirolimus and tacrolimus is FK506-binding protein 12, we switched tacrolimus to cyclosporine at a dose of 60 mg/d to avoid competitive inhibition between these 2 drugs. The target trough concentration of sirolimus and cyclosporine was set to around 15 ng/mL and 180 ng/mL, respectively. The concentration/dose ratio of sirolimus was significantly correlated with the blood cyclosporine level (r=0.5293, p<0.05), suggesting the pharmacokinetic interaction between these 2 drugs. Thereafter, the levels of AST and ALT as well as the T-bil were successfully decreased to 73 U/L, 83 U/L, and 3.0 mg/dL, respectively. These results suggest that sirolimus therapy in combination with cyclosporine may be an effective treatment against CR after liver transplantation