Factors affecting operational tolerance after pediatric living-donor liver transplantation: impact of early post-transplant events and HLA match.

Pediatric recipients of living-donor liver transplants (LDLT) can often discontinue immunosuppression (IS). We examined factors affecting development of operational tolerance (OT), defined as off IS for >1 year, in this population. A historic cohort analysis was conducted in 134 pediatric primary semi-allogeneic LDLT. Multivariate logistic regression analysis was used. The frequency of peripheral regulatory T cells (Tregs) was determined at >10 years post-Tx by FACS analysis. IS was successfully discontinued in 84 tolerant patients (Gr-tol), but not in 50 intolerant patients (Gr-intol). The Gr-intol consisted of 24 patients with rejection (Gr-rej) and 26 with fibrosis of grafts (Gr-fib). The absence of early rejection [odds ratio (OR) 2.79, 95% CI 1.11-7.02, P = 0.03], was a positive independent predictor, whereas HLA-A mismatch (0.18, 0.03-0.91, P = 0.04) was a negative predictor. HLA-DR mismatches did not affect OT. The Treg frequency was significantly decreased in Gr-intol (4.9%) compared with Gr-tol (7.6%) (P = 0.003). There were increased levels of tacrolimus in the first week in Gr-Tol (P = 0.02). Although HLA-B mismatch (8.73, 1.09-70.0, P = 0.04) was a positive independent predictor of OT, its clinical significance remains doubtful. In this large cohort of pediatric LDLT recipients, absence of early rejection, HLA-A match and the later predominance of Tregs are factors associated with OT.

The generation of donor-specific CD4+CD25++CD45RA+ naive regulatory T cells in operationally tolerant patients after pediatric living-donor liver transplantation.

BACKGROUND: CD4+CD25++CD45RA+ cells (naïve regulatory T cells [naïve-Tregs]) have been identified as a functionally premature form of CD4+CD25+++CD45RA(-) cells (conventional-Tregs). However, their contribution to transplant tolerance remains to be elucidated. METHOD: We examined the frequency and the function of conventional and naive-Tregs in the peripheral blood derived from operationally tolerant patients after pediatric living-donor liver transplant (Gr-tol). The data were compared with those of patients who were unable to be weaned off immunosuppression due to rejection (group-intolerance [Gr-intol]), patients in the process of weaning immunosuppression (Gr-weaning) and healthy volunteers (group-healthy volunteers [Gr-vol]). RESULTS: In Gr-tol, the frequency of conventional-Tregs was significantly higher than that in Gr-vol and tended to be higher than that in Gr-intol. The frequency of naive-Tregs was significantly decreased in Gr-intol versus those in Gr-tol, -weaning, and -vol. In mixed lymphocyte reactions, donor-specific hyporesponsiveness of CD4+ cells was observed only in Gr-tol but not in the other groups. Depletion of conventional or naive-Tregs from CD4+ cells demonstrated that the suppressive properties of donor antigen-reactive conventional and naïve-Tregs were upregulated compared with those of third-party antigen-reactive conventional and naïve-Tregs in Gr-tol only. CONCLUSIONS: This is the first report providing detailed evidence that donor-specific naïve-Tregs were generated and their suppressive properties were upregulated in the peripheral blood of tolerant patients, whereas their frequency was downregulated in intolerant patients. Therefore, we speculate that not only conventional-Tregs play a role in Tx tolerance but also the role of naïve-Tregs is critical.

Forced oscillation technique as a non-invasive assessment for lung transplant recipients.

We usually use spirometry for the medical follow-up of respiratory mechanics after lung transplantation. However, especially in the first few post-operative weeks, it is easily affected by postoperative pain and the patient's co-operation during forced breathing effort. To avoid missing out on assessing pulmonary function, we perform non-invasive forced oscillation techniques on the patients who cannot perform forced breathing maneuvers. In this paper, we discuss the application of forced oscillation techniques on a patient with suspicion of acute lung rejection, whose spirometry could not be correctly performed and seemed to be unreliable. The respiratory impedance measurements had good correlation with the patient's clinical symptoms before and after steroid therapy. Thus, postoperative pulmonary function follow-up using forced oscillation technique was useful in assessing peripheral airway condition in critically ill patients, and may be able to detect acute rejection.

Value of FOXP3 expression in peripheral blood as rejection marker after miniature swine lung transplantation.

BACKGROUND: Outcome for highly immunogenic lung transplantation remains unsatisfactory despite the development of potent immunosuppressants. The poor outcome may be the result of a lack of minimally invasive methods to detect early rejection. There is emerging clinical evidence that, paradoxically, expression of forkhead box P3 (FOXP3, a specific marker for the regulatory T cells) is upregulated within rejecting grafts. METHODS: Orthotopic lung transplantation was performed using miniature swine without immunosuppression. Rejection was monitored by chest radiography and open lung biopsy. Expressions levels of FOXP3, perforin, Fas-L and IP-10 mRNA were quantified in the peripheral blood. In addition, rescue immunosuppressive therapy (steroid plus tacrolimus) was administered on post-operative day (POD) 4 or 6. RESULTS: Early rejection was detected by open lung biopsy, but misdiagnosed by chest radiography on POD 4. Expression of FOXP3 in the peripheral blood reached its highest value as early as POD 4, followed by a decline. Such an increase of FOXP3 was not observed in recipients given high-dose tacrolimus. Neither perforin, Fas-L or IP-10 in the peripheral blood exhibited significant fluctuations in the early phase of rejection. Rescue immunosuppressive therapy from POD 4, when peak FOXP3 was seen, prolonged graft survival (27.2 days, versus 9.1 days without immunosuppression, p < 0.001), in contrast to POD 6, when rejection was suspected by chest radiography (11.5 days, p = not statistically significant [NS]). CONCLUSIONS: In a miniature swine lung transplantation model, the FOXP3 mRNA level in the peripheral blood was upregulated at an early phase of rejection. The clinical implication of this finding remains to be elucidated.

Importance of a comprehensive geriatric assessment in prediction of complications following thoracic surgery in elderly patients.

BACKGROUND: The prevalence of comorbidities and functional impairment among elderly patients may enhance the risk of operation-related complications, but the importance of these conditions in elderly patients undergoing thoracic surgery remains unclear. METHODS: One hundred twenty patients >/= 60 years of age who underwent thoracic surgery were registered prospectively and examined. A comprehensive geriatric assessment (CGA) that evaluated such diverse areas as functional status (ie, performance status and activities of daily living [ADLs] using the Barthel index), comorbidity, nutrition (ie, body mass index, arm-muscle circumference, albumin level, transferrin level, lymphocyte count, and cholinesterase level), and cognitive function (ie, mini-mental state examination [MMSE] and negative emotions for operation) was performed in the 2 weeks before patients underwent the operation. RESULTS: The diseases of the 120 patients were as follows: lung cancer, 85 patients; mediastinal tumor, 14 patients; bullas, 12 patients; and other diseases, 9 patients. Postoperative complications developed in 20 patients (16.7%). The patients with dependence for performing the ADLs, and dementia were more likely to develop postoperative complications (p = 0.041, and p = 0.0065, respectively). The patients who experienced longer operation times (ie, >/= 300 min; p = 0.018) were more likely to have complications. The incidence of prolonged air leak in the patients with malnutrition increased seven-fold (p = 0.045) and that of postoperative infectious diseases in those patients with obesity increased 24-fold (p = 0.0013), while all patients who developed delirium had low scores in the MMSE preoperatively (p = 0.0003). Using multiple logistic regression, the best model was obtained with a combination of MMSE (p = 0.031) and the Barthel index (p = 0.04). When the operation variables were added to this model, the operation time had the strongest effect (p = 0.016). CONCLUSIONS: Dependence for the performance of ADLs and impaired cognitive conditions are important predictors of postoperative complications, especially when the operation time is long. CGA is necessary in addition to the conventional cardiopulmonary functional assessment in elderly patients.

[A case of sarcoidosis with superior vena cava syndrome diagnosed by mediastinoscopy].

A bilateral hilar lymphadenopathy on the chest radiograph of a 30-year-old man was pointed out in a medical examination. Four months later, he was admitted to our hospital because of exacerbation of a bilateral hilar lymphadenopathy on the chest radiograph with high fever. Physical examination revealed a marked swelling of the face and upper arms as well as a dilated jugular vein. The fever, which was his chief complaint, responded to antibiotic therapy. A CT scan of the chest confirmed the presence of bilateral mediastinal lymphadenopathy and hilar lymphadenopathy, which caused pulmonary artery and superior vena cava stenosis. A superior vena cavagram demonstrated narrowing of the vessel. Mediastinoscopy was performed for definite diagnosis. Pathologic examination of the specimen revealed noncaseating epithelioid cell granuloma consistent with sarcoidosis. He was asymptomatic. Pulmonary function and arterial blood gas studies yielded almost normal results. A roentgenographic stage of intrathoracic change was Stage I. On the basis of these findings, he was observed carefully without systemic corticosteroid therapy. One month later, the swelling of his face and upper arms was improved, and the pulmonary functions and arterial blood gases remained almost normal. Only seven cases of sarcoidosis causing superior vena cava syndrome have been reported. This is the first case reported in Japan.

[A case of primary lung cancer with initial symptoms due to orbital metastases].

We encountered a case of lung cancer in which symptoms due to orbital metastasis were recognized. A 55-year-old man presented with a chief complaint of double vision. Orbital MR image demonstrated a right intraorbital mass with bone destruction, which resulted in oculomotor nerve palsy and optic nerve disturbance. Chest CT scan showed a 4 cm mass in the right S6, which was diagnosed on biopsy as a poorly differentiated adenocarcinoma. A whole-body scintigram revealed multiple bone metastases: the right orbital wall, the lower cervical spine, the left knee joint, and so on. Based on the clinical findings, we believed that the orbital tumor was a metastasis from the lung. Systemic chemotherapy and irradiation of the right orbital tumor and the left knee joint were performed. Though a favorable response was achieved in ocular movement, the patient died 3 months after initial treatment because of progression of the primary lesion. Including this case, seventeen reported cases in which lung cancer metastasized to the orbit in Japan were also reviewed.