Immune status of recipients following bone marrow - Augmented solid organ transplantation

It has been postulated that the resident “passenger” leukocytes of hematolymphoid origin that migrate from whole organ grafts and subsequently establish systemic chimerism are essential for graft acceptance and the induction of donor-specific nonreactivity. This phenomenon was augmented by infusing 3 × 108 unmodified donor bone-marrow cells into 40 patients at the time of organ transplantation. Fifteen of the first 18 analyzable patients had sequential immunological evaluation over postoperative intervals of 5 to 17 months, (which included 7 kidney (two with islets), 7 liver (one with islets), and one heart recipient). The evolution of changes was compared with that in 16 kidney and liver nonmarrow controls followed for 4 to5 months. The generic immune reactivity of peripheral blood mononuclear cells (PBMC) was determined by their proliferative responses to mitogens (PHA, ConA). Alloreactivity was measured by the recipient mixed lymphocyte reaction (MLR) to donor and HLA-mis-matched third-party panel cells. Based on all 3 tests,the recipients were classified as donor-specific hyporeactive, intermediate, and responsive; patients who were globally suppressed made up a fourth category. Eight (53%) of the 15 marrow-treated recipients exhibited progressive modulation of donor-specific reactivity (3 hyporeactive and 5 intermediate) while 7 remained antidonor-responsive. In the nonmarrow controls, 2 (12.5%) of the 16 patients showed donor-specific hyporeactivity, 10 (62.5%) were reactive, and 4 (25%) studied during a CMV infection had global suppression of responsiveness to all stimuli. © 1995 by Williams and Wilkins

Weaning of immunosuppression in liver transplant recipients

Immunosuppression has been sporadically discontinued by noncompliant liver allograft recipients for whom an additional 4 1/2 years of follow-up is provided. These anecdotal observations prompted a previously reported prospective drug withdrawal program in 59 liver recipients. This prospective series has been increased to 95 patients whose weaning was begun between June 1992 and March 1996, 8.4±4.4 (SD) years after liver replacement. A further 4 1/2 years follow-up was obtained of the 5 self-weaned patients. The prospectively weaned recipients (93 livers; 2 liver/kidney) had undergone transplantation under immunosuppression based on azathioprine (AZA, through 1979), cyclosporine (CsA, 1980-1989), or tacrolimus (TAC, 1989-1994). In patients on CsA or TAC based cocktails, the adjunct drugs were weaned first in the early part of the trial. Since 1994, the T cell-directed drugs were weaned first. Three of the 5 original self-weaned recipients remain well after drug-free intervals of 14 to 17 years. A fourth patient died in a vehicular accident after 11 years off immunosuppression, and the fifth patient underwent retransplantation because of hepatitis C infection after 9 drug-free years; their allografts had no histopathologic evidence of rejection. Eighteen (19%) of the 95 patients in the prospective series have been drug free for from 10 months to 4.8 years. In the total group, 18 (19%) have had biopsy proved acute rejection; 7 (7%) had a presumed acute rejection without biopsy; 37 (39%) are still weaning; and 12 (13%, all well) were withdrawn from the protocol at reduced immunosuppression because of noncompliance (n=8), recurrent PBC (n=2), pregnancy (n=1), and renal failure necessitating kidney transplantation (n=1). No patients were formally diagnosed with chronic rejection, but 3 (3%) were placed back on preexisting immunosuppression or switched from cyclosporine (CsA) to tacrolimus (TAC) because of histopathologic evidence of duct injury. Two patients with normal liver function died during the trial, both from complications of prior chronic immunosuppression. No grafts suffered permanent functional impairment and only one patient developed temporary jaundice. Long surviving liver transplant recipients are systematically overimmunosuppressed. Consequently, drug weaning, whether incomplete or complete, is an important management strategy providing it is done slowly under careful physician surveillance. Complete weaning from CsA-based regimens has been difficult. Disease recurrence during drug withdrawal was documented in 2 of 13 patients with PBC and could be a risk with other autoimmune disorders

Susceptibility of rhabdomyosarcoma cells to macrophage-mediated cytotoxicity

The prognosis of advanced stage rhabdomyosarcoma (RMS) is still sobering. In recent years, outcome has not been further improved by conventional therapy. Therefore, novel treatment options such as macrophage-directed immunotherapy have to be investigated. The aim of this study was to analyze the phagocytosis of RMS cells by macrophages and to modulate the susceptibility using monoclonal antibodies and cytotoxic drugs

Adult heart transplantation under tacrolimus (FK506) immunosuppression: Histopathologic observations and comparison to a cyclosporine-based regimen with lympholytic (ATG) induction

Background: Tacrolimus (FK506) is an effective immunosuppressant for human heart transplantation, but information about its effects on cardiac allograft and nonallograft kidney and liver histopathologic study is limited. Methods: We therefore reviewed 1145 endomyocardial biopsy specimens and eight autopsy results from 80 heart transplant recipients who received tacrolimus as baseline immunosuppression. These were compared with 619 endomyocardial biopsy specimens and four autopsy results from 51 patients treated with cyclosporine-based immunosuppression with lympholytic induction (CLI) by use of rabbit anti-thymocyte globulin. Twenty-one histologic features including the International Society for Heart and Lung Transplantation histopathologic grade were retrospectively assessed without knowledge of the treatment regimen. The lymphocyte growth index on biopsy specimens obtained from these patients was also compared. Results: In general, there were no qualitative differences in the histopathologic appearance of various allograft syndromes between tacrolimus- and CLI-treated patients. Thus histopathologic criteria used to diagnose various graft syndromes are applicable under tacrolimus immunosuppression. However, early (between 10 and 30 days) after transplantation, biopsy specimens from patients treated with tacrolimus showed a significantly higher percentage of inflamed fragments (p = 0.02), the inflammation tended to be more severe (p = 0.09), and the rejection grade tended to be slightly higher (p = 0.08). In contrast, during the late transplantation period (275 to 548 days), biopsy specimens from patients treated with CLI showed a significantly higher percentage of inflamed fragments (p = 0.03), more severe inflammation (p = 0.03), higher rejection grades (p = 0.01), and a higher frequency of Quilty lesions (p = 0.05). Although overall freedom from any grade 3A or higher rejection was greater in the CLI-treated arm, tacrolimus was successfully used to treat refractory rejection in three patients from the CLI-treated arm. Concern has been raised in the literature about the possibility of tacrolimus being a direct hepatotoxin and an accelerant of allograft obliterative arteriopathy. However, no evidence to support either of these contentions was detected in this patient population. In contrast, tacrolimus is clearly nephrotoxic, although similar to cyclosporine in this regard. Conclusions: Tacrolimus is an effective immunosuppressive drug for heart transplantation. The cardiac allograft histopathologic study of patients treated with tacrolimus immunosuppression does not significantly differ from those given conventional, cyclosporine-based triple therapy with lympholytic induction

Unusual association of alveolar rhabdomyosarcoma with pancreatic metastasis: emerging role of PET-CT in tumor staging

Pancreatic metastases in childhood cancer have been rarely reported in the radiology literature although ample evidence exists in pathology reports for its occurrence in patients with alveolar rhabdomyosarcomas (RMS). Assess the occurrence of pancreatic metastases in alveolar rhabdomyosarcomas, increase awareness of this association and reassess current staging protocols. Three major oncology centers reviewed their records and imaging examinations. Patients’ history and demographics, primary tumor site and histology, presence of tumor recurrence, and presence and location of other metastases were reviewed. Pancreatic metastases occurred in eight patients with alveolar RMS. Four of these presented at diagnosis and four with disease recurrence. In recurrent disease, the duration between the diagnosis of the primary tumor and pancreatic metastases varied from 8 months to 6 years (mean ± SD: 2.38 ± 2.49 years). In all patients who received PET scans, pancreatic metastases showed a marked FDG-uptake, but had variable detectability with CT. Pancreatic metastases were not associated with certain primary tumor locations or presence of other metastases, mandating an evaluation of the pancreas in all cases of alveolar rhabdomyosarcomas. Radiologists should be sensitized and actively evaluate the pancreas in patients with alveolar RMS. Optimizing CT and PET-CT protocols may increase the diagnostic yield

Alveolar soft part sarcoma: clinicopathological findings in a series of 11 cases

<p>Abstract</p> <p>Background</p> <p>Alveolar sarcoma of the soft parts (ASPS) represents a very rare entity of soft tissue sarcoma with special features such as young peak age incidence and frequent metastasis to the brain. The aim of this study was a clinicopathological analysis with special reference to treatment and outcome.</p> <p>Methods</p> <p>From the database of the BG-University Hospital Bergmannsheil, 1597 soft tissue sarcoma (STS) cases were reviewed and 11 consecutive patients with ASPS were isolated. Data was acquired from patients' charts and contact to patients, their relatives or general practitioners, with special reference to treatment and clinical course. The average follow up time from the time of the definite operation for the primary tumor was 6.5 years. Kaplan-Meier method was used to calculate survival.</p> <p>Results</p> <p>Patients with localized disease who received complete resection and adjuvant radiation and who did not develop recurrence or metastatic disease within 2 years after surgery had a positive outcome. The size of the tumor, its localization, and the time of untreated growth before treatment did not influence the long-term results. All patients who developed recurrent disease also suffered from distant metastasis, reflecting the aggressive biology of the tumor. All patients with distant metastasis had the lungs and the brain affected.</p> <p>Conclusion</p> <p>Due to the limited number of patients with ASPS, prospective studies would have to span decades to gather a significant collective of patients; therefore, it is not possible to comment meaningfully on a possible benefit of neoadjuvant or adjuvant therapy.</p> <p>We recommend wide surgical excision and, in the absence of data telling otherwise, adjuvant radiation. In cases with recurrent disease or metastasis, the prognosis is bad and further treatment will be restricted to palliation in most cases.</p

Oral Insulin

Oral insulin is an exciting area of research and development in the field of diabetology. This brief review covers the various approaches used in the development of oral insulin, and highlights some of the recent data related to novel oral insulin preparation

The functional maturation of M cells is dramatically reduced in the Peyer's patches of aged mice

The transcytosis of antigens across the follicle-associated epithelium (FAE) of Peyer's patches by microfold cells (M cells) is important for the induction of efficient immune responses to mucosal antigens. The mucosal immune response is compromised by ageing, but effects on M cells were unknown. We show that M-cell density in the FAE of aged mice was dramatically reduced. As a consequence, aged Peyer's patches were significantly deficient in their ability to transcytose particulate lumenal antigen across the FAE. Ageing specifically impaired the expression of Spi-B and the downstream functional maturation of M cells. Ageing also dramatically impaired C-C motif chemokine ligand 20 expression by the FAE. As a consequence, fewer B cells were attracted towards the FAE, potentially reducing their ability to promote M-cell maturation. Our study demonstrates that ageing dramatically impedes the functional maturation of M cells, revealing an important ageing-related defect in the mucosal immune system's ability to sample lumenal antigens