tacrolimus and Uterine-Cervical-Neoplasms

Although conventional immunosuppression after liver transplantation consists of cyclosporine A (CsA), steroids, and azathioprine, recently introduced protocols entail CsA-based quadruple induction protocols or tacrolimus-based combinations. These protocols aim to reduce the rejection rate and the considerable morbidity related to the side effects of additional immunosuppressive treatment, but have not yet been analyzed regarding their long term de novo neoplastic risk.. From September 1988 to May 1994, 500 liver transplantations were performed in 458 patients. The median follow-up was 50 months (range, 0.3-97 months) for all patients. Conventional triple therapy was implemented in 25 patients, CsA-based quadruple induction therapy using an antilymphocyte globulin preparation (ATG) in 190 patients, an interleukin-2 receptor antibody (BT563) in 141 patients, and tacrolimus-based dual or triple immunosuppression in 102 patients. The different protocols were evaluated in four randomized and two nonrandomized prospective trials.. De novo neoplasias were detected in 33 patients (7.2%) and were comprised of lymphomas (n = 7), skin malignancies (n = 8 lesions in 7 patients), intraepithelial neoplasias of the cervix uteri (n = 7), breast carcinoma (n = 3), lung carcinoma (n = 3), and other malignancies (n = 6). The incidence of de novo neoplasias did not differ in the different trial arms. Only a positive T-crossmatch and a low CD4+/CD8+ ratio in patients receiving CsA-based immunosuppression demonstrated a significant correlation with the development of a de novo tumor in a multivariant logistic regression analysis.. The development of de novo neoplastic diseases after liver transplantation with the use of CsA-based quadruple induction protocols or tacrolimus-based regimens for immunosuppresion was assessed over the long term. Recently introduced immunosuppressive protocols did not alter the posttransplant de novo tumor rate. Patients with a low CD4+/CD8+ ratio during CsA-based therapy or a positive T-crossmatch were identified to be at an increased risk for the development of a de novo malignancy.

Topics: Antibodies, Monoclonal; Antilymphocyte Serum; Clinical Trials as Topic; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Transplantation; Lymphoma; Neoplasms, Second Primary; Prospective Studies; Randomized Controlled Trials as Topic; Receptors, Interleukin-2; Skin Neoplasms; Tacrolimus; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms

Transplant recipients have elevated cancer risk including risk of human papillomavirus (HPV)-associated cancers of the cervix, anus, penis, vagina, vulva and oropharynx. We examined the incidence of HPV-related cancers in 187 649 US recipients in the Transplant Cancer Match Study. Standardized incidence ratios (SIRs) compared incidence rates to the general population, and incidence rate ratios (IRRs) compared rates across transplant subgroups. We observed elevated incidence of HPV-related cancers (SIRs: in situ 3.3-20.3, invasive 2.2-7.3), except for invasive cervical cancer (SIR 1.0). Incidence increased with time since transplant for vulvar, anal and penile cancers (IRRs 2.1-4.6 for 5+ vs. <2 years). Immunophenotype, characterized by decreased incidence with HLA DRB1:13 and increased incidence with B:44, contributed to susceptibility at several sites. Use of specific immunosuppressive medications was variably associated with incidence; for example, tacrolimus, was associated with reduced incidence for some anogenital cancers (IRRs 0.4-0.7) but increased incidence of oropharyngeal cancer (IRR 2.1). Thus, specific features associated with recipient characteristics, transplanted organs and medications are associated with incidence of HPV-related cancers after transplant. The absence of increased incidence of invasive cervical cancer highlights the success of cervical screening in this population and suggests a need for screening for other HPV-related cancers.

Topics: Adolescent; Adult; Anus Neoplasms; Cohort Studies; Female; Humans; Immunosuppression Therapy; Incidence; Male; Middle Aged; Organ Transplantation; Oropharyngeal Neoplasms; Papillomavirus Infections; Penile Neoplasms; Registries; Tacrolimus; United States; Uterine Cervical Neoplasms; Vulvar Neoplasms; Young Adult

Oxygen-dependent radiosensitivity of tumour cells reflects direct oxidative damage to DNA, but non-nuclear mechanisms including signalling pathways may also contribute. Mitochondria are likely candidates because not only do they integrate signals from each of the main kinase pathways but mitochondrial kinases responsive to oxidative stress communicate to the rest of the cell. Using pharmacological and immunochemical methods, we tested the role of mitochondrial permeability transition (MPT) and the Bcl-2 proteins in oxygen-dependent radiosensitivity. Drug-treated or untreated cervical cancer HeLa, breast cancer MCF-7 and melanoma MeWo cell lines were irradiated at 6.2 Gy under normoxic and hypoxic conditions then allowed to proliferate for 7 days. The MPT blocker cyclosporin A (2 microM) strongly protected HeLa but not the other two lines against oxygen-dependent radiosensitivity. By contrast, bongkrekic acid (50 microM), which blocks MPT by targeting the adenine nucleotide transporter, had only marginal effect and calcineurin inhibitor FK-506 (0.1 microM) had none. Nor was evidence found for the modulation of oxygen-dependent radiosensitivity by Bax/Bcl-2 signalling, mitochondrial ATP-dependent potassium (mitoK(ATP)) channels or mitochondrial Ca(2+) uptake. In conclusion, calcineurin-independent protection by cyclosporin A suggests that MPT but not mitoK(ATP) or the mitochondrial apoptosis pathway plays a causal role in oxygen-dependent radiosensitivity of HeLa cells. Targeting MPT may therefore improve the effectiveness of radiotherapy in some solid tumours.

Topics: Anti-Bacterial Agents; bcl-2-Associated X Protein; Bongkrekic Acid; Breast Neoplasms; Cell Line, Tumor; Cyclosporine; Female; Humans; Immunosuppressive Agents; Melanoma; Mitochondria; Oxidative Stress; Radiation Tolerance; Tacrolimus; Uterine Cervical Neoplasms

After transplantation the necessary immunosuppressive therapy predisposes to the development of de novo cancers. From January 1989 to April 1994 we collected PAR smears of 98 women before and repeatedly after liver transplantation. After surgery all women received as immunosuppressive agents either Cyclosporin A or FK 506 as long-term medication. In seven patients (8.5%) who had a normal cervical cytology before transplantation a suspicious PAP smear was found on average 11 months after transplantation. In five cases a histological verification (exploratory excision, coning of the cervix) was made. In two cases we found a CIN III. Possible causes for the higher incidence of dysplasia of the cervix observed in the transplant patients are discussed. Similar to kidney transplant recipients female liver transplant recipients are at higher risk of developing cervical dysplasias and neoplasias. Accelerated development of malignancy seems likely. The influence on the cervical cells of both immunosuppressive drugs Cyclosporin A and FK 506 seems to be of a similar nature. Recommendations for the gynaecological care of female liver transplant recipients treated with immunosuppressive therapy are given.

Topics: Adult; Aged; Cervix Uteri; Cyclosporine; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Liver Transplantation; Middle Aged; Neoplasm Staging; Papanicolaou Test; Risk Factors; Tacrolimus; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaginal Smears

During the time 1989 to 1992 we collected PAP smears of 58 women before and several times after a liver transplantation. Five of the patients (= 8.6%) showed a suspicious PAP smear, although pre-transplantation they had a normal cervical cytology. Histological one woman even had a higher grade dysplasia. 30 women received FK 506 after the liver transplantation, 28 patients Cyclosporin A as long-term medication. Likewise kidney and liver transplanted women have a higher risk to be affected by a cervical neoplasia. A acceleration of malignant growth seems to be likely. The influence on the cervical cells of both immunosuppressive drugs Cyclosporin A (Sandimmun) and FK 506 seem to be similar. It should be recommended to perform a close-meshed cervical cytology control when following -up the female liver transplant recipients.

Topics: Adolescent; Adult; Aged; Cervix Uteri; Cyclosporine; Female; Follow-Up Studies; Humans; Liver Transplantation; Middle Aged; Neoplasm Staging; Papanicolaou Test; Postoperative Complications; Precancerous Conditions; Risk Factors; Smoking; Tacrolimus; Uterine Cervical Dysplasia; Uterine Cervical Neoplasms; Vaginal Smears