tacrolimus and Carcinoma--Squamous-Cell

Cases of lymphoma or cutaneous cancer have been observed following use of topical calcineurin inhibitors (TCIs), but it is unclear whether TCI use increases cancer risk. We used published literature to assess the extent to which atopic dermatitis (AD) or TCI use is associated with lymphoma, melanoma, basal cell carcinoma and squamous cell carcinoma. We searched the literature and summarized the results of all studies that provided data on the absolute or relative frequency of any malignancy among patients with AD or eczema or among patients using TCIs. The relative risk for all lymphoma in broad populations of AD or eczema ranged from 0·7 to 1·8. Available data on lymphoma following TCI use were inconsistent and insufficient to draw a conclusion about the causal role of TCIs. We found no evidence indicating that melanoma or nonmelanoma skin cancer is associated with TCI use. A bias analysis showed that cutaneous T-cell lymphomas initially misdiagnosed and treated as AD would lead to overestimation of the association between TCI use and lymphoma. However, there are only sparse data on specific malignancies among TCI-treated patients. The short duration of typical TCI exposure hinders conclusions about longer exposure. There is insufficient evidence in the epidemiological literature to infer whether TCIs do or do not cause malignancy.

Topics: Administration, Topical; Calcineurin Inhibitors; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Dermatitis, Atopic; Dermatologic Agents; Humans; Lymphoma; Melanoma; Risk Factors; Skin Neoplasms; Tacrolimus

Topics: Azathioprine; Carcinoma, Squamous Cell; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Risk Factors; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Oral lichen planus (OLP) is a chronic mucosal condition commonly encountered in clinical dental practice. Lichen planus is believed to represent an abnormal immune response in which epithelial cells are recognized as foreign, secondary to changes in the antigenicity of the cell surface. It has various oral manifestations, the reticular form being the most common. The erosive and atrophic forms of OLP are less common, yet are most likely to cause symptoms. Topical corticosteroids constitute the mainstay of treatment for symptomatic lesions of OLP. Recalcitrant lesions can be treated with systemic steroids or other systemic medications. However, there is only weak evidence that these treatments are superior to placebo. Given reports of a slightly greater risk of squamous cell carcinoma developing in areas of erosive OLP, it is important for clinicians to maintain a high index of suspicion for all intraoral lichenoid lesions. Periodic follow-up of all patients with OLP is recommended.

Topics: Carboxymethylcellulose Sodium; Carcinoma, Squamous Cell; Chronic Disease; Diagnosis, Differential; Humans; Immunosuppressive Agents; Lichen Planus, Oral; Mouth Neoplasms; Precancerous Conditions; Steroids; Tacrolimus

Skin cancer is the most common malignancy arising in the posttransplantation setting. Multiple factors contribute to the high risk for cutaneous carcinoma in immunosuppressed organ-transplant recipients. We review the phenomenon of skin cancer in solid-organ transplant recipients and further delineate the problem in the context of liver transplantation. Skin cancer is a significant medical and surgical problem for organ-transplant recipients. With prolonged allograft function and patient survival, the majority of solid-organ transplant recipients will eventually develop skin cancer. Although squamous cell carcinoma is the most common cutaneous malignancy in this population, basal cell carcinoma, melanoma, and Kaposi's sarcoma, as well as uncommon skin malignancies, may occur. Highly susceptible patients may develop hundreds of squamous cell carcinomas, which may be life threatening. Management strategies focus on regular full-skin and nodal examination, aggressive treatment of established malignancies, and prophylactic measures to reduce the risk for additional photodamage and malignant transformation. Skin cancer is a substantial cause of morbidity and even mortality among solid-organ transplant recipients. As a byproduct of immunosuppression, liver transplant recipients experience a high incidence of skin cancer and should be educated and managed accordingly.

Topics: Animals; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Cyclosporine; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Keratosis; Liver Transplantation; Postoperative Complications; Skin Neoplasms; Tacrolimus

Transplant recipients in whom cutaneous squamous-cell carcinomas develop are at high risk for multiple subsequent skin cancers. Whether sirolimus is useful in the prevention of secondary skin cancer has not been assessed.. In this multicenter trial, we randomly assigned transplant recipients who were taking calcineurin inhibitors and had at least one cutaneous squamous-cell carcinoma either to receive sirolimus as a substitute for calcineurin inhibitors (in 64 patients) or to maintain their initial treatment (in 56). The primary end point was survival free of squamous-cell carcinoma at 2 years. Secondary end points included the time until the onset of new squamous-cell carcinomas, occurrence of other skin tumors, graft function, and problems with sirolimus.. Survival free of cutaneous squamous-cell carcinoma was significantly longer in the sirolimus group than in the calcineurin-inhibitor group. Overall, new squamous-cell carcinomas developed in 14 patients (22%) in the sirolimus group (6 after withdrawal of sirolimus) and in 22 (39%) in the calcineurin-inhibitor group (median time until onset, 15 vs. 7 months; P=0.02), with a relative risk in the sirolimus group of 0.56 (95% confidence interval, 0.32 to 0.98). There were 60 serious adverse events in the sirolimus group, as compared with 14 such events in the calcineurin-inhibitor group (average, 0.938 vs. 0.250). There were twice as many serious adverse events in patients who had been converted to sirolimus with rapid protocols as in those with progressive protocols. In the sirolimus group, 23% of patients discontinued the drug because of adverse events. Graft function remained stable in the two study groups.. Switching from calcineurin inhibitors to sirolimus had an antitumoral effect among kidney-transplant recipients with previous squamous-cell carcinoma. These observations may have implications concerning immunosuppressive treatment of patients with cutaneous squamous-cell carcinomas. (Funded by Hospices Civils de Lyon and others; TUMORAPA ClinicalTrials.gov number, NCT00133887.).

Topics: Adult; Aged; Aged, 80 and over; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Cyclosporine; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Sirolimus; Skin Neoplasms; Tacrolimus

Topical tacrolimus has been shown to be beneficial in the treatment of oral lichen planus (OLP). However, long-term effects and its optimal application protocol with gradual reduction have not been studied. Accordingly, we analysed the clinical response of OLP to tacrolimus in our daily clinical practice with a focus on the optimal long-term therapeutic scheme.. Retrospective analysis of all consecutive patients diagnosed with OLP and treated with topical tacrolimus (0.03% oral rinse) in a clinical setting between 2015 and 2020. The objective clinical response was measured by a 4-point scale (complete remission, major remission, partial remission and no response), and subjective impairment by a 3-point scale (severe, moderate and none).. Fifty-seven patients (74% women; median age: 66 years) were included. Fifty-six (98%) patients had prior treatment with topical steroids. After introduction of tacrolimus, objective remission (major or complete) was reached by 28%, 62%, 87% and 97% of patients after 3, 6, 12 and 24 months respectively. Subjective remission was reported by 16%, 48%, 69% and 83% after 3, 6, 12 and 24 months of treatment respectively. The treatment frequency could be gradually reduced from initially twice daily to once daily or less in 28%, 61%, 78% and 87% after 3, 6, 12 and 24 months respectively; 41% of patients completely suspended the treatment at one point, but 67% of them experienced a relapse after a median time of 3.3 months. Four patients (7%) developed a squamous cell carcinoma (SCC) during the observation period. Otherwise, there were only few and minor side-effects.. Topical tacrolimus can be an effective second-line therapy for OLP refractory to potent topical corticosteroids. The therapy frequency can often be reduced during the maintenance period. Both signs of clinical activity and subjective impairment should guide therapy. Regular follow-up is necessary to recognize possible SCC.

Topics: Administration, Topical; Aged; Carcinoma, Squamous Cell; Clinical Protocols; Female; Humans; Immunosuppressive Agents; Lichen Planus, Oral; Male; Neoplasm Recurrence, Local; Retrospective Studies; Tacrolimus; Treatment Outcome

A 74-year-old man was administered nivolumab to treat recurrent squamous cell carcinoma of the lungs. He developed fatigue, redness on the front of his neck, muscle weakness, and difficulty in swallowing after receiving the third course of nivolumab. Physical and neurological examinations showed proximal limb muscle weakness, periorbital erythema, and erythema of the front of his neck as well as fingers. Laboratory investigations revealed elevated serum CK and aldolase levels, and he was diagnosed with dermatomyositis. We initiated steroid pulse therapy and intravenous immunoglobulin therapy; however, he died of advanced lung cancer. Immune checkpoint inhibitor-induced neuromuscular disease is increasingly being observed in clinical practice. We report a rare case of dermatomyositis with squamous cell carcinoma of the lungs secondary to nivolumab treatment.

Topics: Aged; Antineoplastic Agents, Immunological; Autoantibodies; Carcinoma, Squamous Cell; Dermatomyositis; Fatal Outcome; Humans; Immune Checkpoint Inhibitors; Immunoglobulins, Intravenous; Immunotherapy; Lung Neoplasms; Male; Methylprednisolone; Nivolumab; Pulse Therapy, Drug; Tacrolimus; Transcription Factors

Topics: Administration, Topical; Adrenal Cortex Hormones; Aged; Antimalarials; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Clofazimine; Diabetic Retinopathy; Drug Therapy, Combination; Ear; Humans; Leprostatic Agents; Lupus Erythematosus, Discoid; Lymph Node Excision; Male; Middle Aged; Neoplasm Staging; Skin Neoplasms; Tacrolimus; Treatment Outcome

Skin lesions are very common among organ transplant recipients (OTR), particularly infections and tumors, because of the immunosuppressive state these patients are put in.. 177 OTR were examined. Skin lesions were categorized into neoplastic, infectious, and inflammatory diseases.. The mean age of OTR was 52 years, the mean age at transplantation was 42.7 years, and kidney was the most common organ transplanted (72%). Skin lesions were found in 147 patients (83%). Cutaneous infections were seen in 106 patients (60%). Warts (30%) had the larger incidence and were associated with azathioprine (P = 0.026), cyclosporine (P = 0.006), and tacrolimus (P = 0.009). Superficial mycoses occurred in 16% of OTR, mostly onychomycosis, which was associated with tacrolimus (P = 0.040). Actinic keratosis (AK) occurred in 31% of patients and cutaneous tumors in 56%. Squamous cell carcinoma (SCC) was the most common tumor type affecting 36% of OTR (n = 64), with invasive SCC predominating over in situ SCC, whereas basal cell carcinoma (BCC) accounted for 17%. Both SCC and BCC were more numerous in patients' skin type I (P < 0.05). SCC was more frequent (36%) in combined kidney and liver recipients (P = 0.004), and BCC was associated with cyclosporine (P = 0.047). Inflammatory complications (acne, alopecia, hypertrichosis, and gingival overgrowth) were observed in 17.5% of patients.. Organ transplant recipients must be regularly evaluated by dermatologists, who should be alert to the onset of infections and skin (pre)malignant diseases in these patients.

Topics: Adolescent; Adult; Aged; Azathioprine; Brazil; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Child; Cyclosporine; Dermatomycoses; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Keratosis, Actinic; Male; Middle Aged; Organ Transplantation; Risk Factors; Skin Diseases, Infectious; Skin Neoplasms; Tacrolimus; Warts; Young Adult

A case of primary cutaneous post liver transplant lymphoproliferative disorder (PTLD) mimicking squamous cell carcinoma-in-situ is presented.. Lesions mimicking SCC-in-situ were confirmed to be PTLD on histopathology and immunohistochemistry. Immunosuppression was gradually reduced and the lesions were successfully treated with 50 gray (Gy) in 25 fractions of radiotherapy.. There was no recurrence of lesions at 3 months follow-up.. Radiotherapy is an effective form of cutaneous directed treatment for localized PTLD.

Topics: Aged; Antibiotics, Antineoplastic; B-Lymphocytes; Carcinoma, Squamous Cell; Follow-Up Studies; Gamma Rays; Humans; Immunohistochemistry; Liver Cirrhosis, Biliary; Liver Transplantation; Lymphoproliferative Disorders; Male; Mycophenolic Acid; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Topics: Aged; Antineoplastic Agents; Bone Marrow Transplantation; Carcinoma, Squamous Cell; Combined Modality Therapy; Conjunctival Neoplasms; Cryotherapy; Graft vs Host Disease; Humans; Immunosuppressive Agents; Interferon alpha-2; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Tacrolimus; Transplantation, Homologous

Oral lichen planus is a chronic inflammatory mucocutaneous disease. Topical use of steroids and other immuno-modulating therapies have been tried for this intractable condition. Nowadays, tacrolimus ointment is used more commonly as a choice for treatment. However, a number of discussions have taken place after tacrolimus was reported to be carcinogenic. This report describes a patient who applied tacrolimus ointment to the lower lip after being diagnosed with oral lichen planus in 2008, and whose lesion developed squamous cell carcinoma in 2010. Since the relationship between tacrolimus and cancer development has been reported in only a few cases, including this case report, the clinician must be careful selecting tacrolimus as a second-line treatment for oral lichen planus.

Topics: Administration, Topical; Biopsy; Candidiasis, Oral; Carcinoma, Squamous Cell; Diagnosis, Differential; Diagnostic Errors; Humans; Immunosuppressive Agents; Lichen Planus, Oral; Male; Middle Aged; Mouth Neoplasms; Surgical Flaps; Tacrolimus

Organ transplant recipients (OTRs) have a substantially elevated risk of squamous cell skin carcinoma (SCSC), largely attributed to immunosuppressive medications used to prevent graft rejection, although data to support the role of newer drugs in SCSC risk are sparse. We investigated the association between immunosuppressive medications and SCSC risk among cardiac and renal transplant recipients in the SCOT cohort study. Incident cases were ascertained through medical record review after self-report of skin biopsy (n = 170). Controls without SCSC (n = 324) were matched to cases on sex, age, race, transplant year, hospital, donor type, organ transplanted, and time between transplantation and interview. Conditional logistic regression was used to evaluate the association between specific medications and SCSC. Users of the antimetabolite azathioprine were more than twice as likely to develop SCSC (odds ratio [OR] = 2.67, 95% confidence interval [CI] 1.23-5.76). In contrast, the newer antimetabolite preparations (i.e., mycophenolic acid [MPA]) were associated with lower SCSC risk (OR = 0.45, 95% CI 0.29-0.69). This inverse association between MPA and SCSC persisted among OTRs with no history of azathioprine use, even after adjustment for simultaneous use of the calcineurin inhibitor tacrolimus (OR = 0.52, 95% CI 0.32-0.84). Our data suggest that the increased risk of SCSC historically associated with azathioprine is not seen in OTRs prescribed newer regimens, including MPA and tacrolimus.

Topics: Antibiotics, Antineoplastic; Carcinoma, Squamous Cell; Case-Control Studies; Cohort Studies; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Prognosis; Risk Factors; Skin Neoplasms; Tacrolimus; Washington

This study aims to investigate how immunosuppression influences the protein expression of antiapoptotic members of the Bcl-2 family-namely, Bcl-xL and Mcl-1-in nonmelanoma skin cancer (NMSC) and the peritumoral epidermis of renal transplant recipients.. NMSC and peritumoral epidermis protein expression of Bcl-xL and Mcl-1 were assessed by immunohistochemistry in renal transplant recipients receiving tacrolimus or sirolimus and the general population not receiving immunosuppression.. NMSC from renal transplant recipients compared with patients not receiving immunosuppressant medications had a reduced Bcl-xL expression intensity (P = .042). Mcl-1 expression intensity in NMSC was decreased in tacrolimus-treated patients compared with sirolimus-treated patients and the nonimmunosuppressed population (P = .024). Bcl-xL expression intensity was increased in peritumoral epidermis compared with NMSC (P = .002).. It was shown for the first time that Bcl-xL and Mcl-1 expression are widespread in the peritumoral epidermis and NMSC of renal transplant recipients. Importantly in NMSC, Bcl-xL expression was reduced with immunosuppression exposure, and Mcl-1 expression was reduced in tacrolimus-treated compared with sirolimus-treated patients.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; bcl-X Protein; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Female; Humans; Immunohistochemistry; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mitosis; Myeloid Cell Leukemia Sequence 1 Protein; Sirolimus; Skin Neoplasms; Tacrolimus; Transplant Recipients

Topics: Administration, Topical; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Dermatologic Agents; Humans; Lip Neoplasms; Male; Middle Aged; Tacrolimus

Topics: Antineoplastic Agents; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Risk Factors; Sirolimus; Skin Neoplasms; Tacrolimus; Treatment Outcome

To evaluate disease dynamics, treatment results, and frequency of malignant transformation. Ten-year single center retrospective study. The study included 171 patients, 28-99 years old. Follow-up was 1-16 years. 49.5% exhibited changes in clinical presentation, with 19% yearly increase of probability for type shift. Index of extent (number of oral locations) showed a mean 40% decrease and 94.1% reported improvement. There were significant differences between treated and untreated patients (P=0.012). Patients with or without systemic diseases had identical treatment requirements for oral lesions. The prevalence of SCC was 5.8%. Oral lichen planus constantly changes presentation and extent of involvement. The effect of systemic diseases was insignificant in the present study. There is a clear value for treatment to reduce the extent of lesions. The results indicate that all clinical forms of the disease need to be equally followed since the clinical presentation typically changes over time, while malignant transformation can occur in all forms.

Topics: Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Clobetasol; Dexamethasone; Female; Humans; Lichen Planus, Oral; Male; Middle Aged; Mouth Neoplasms; Precancerous Conditions; Prednisone; Prevalence; Retrospective Studies; Tacrolimus; Tretinoin; Triamcinolone

Cancer after heart transplant is recognized as a leading cause of morbidity and mortality. A man's clinical course after receiving a heart transplant is described, with emphasis on important clinical considerations in the care of heart transplant recipients.

Topics: Azathioprine; Carcinoma, Squamous Cell; Drug Therapy, Combination; Fatal Outcome; Glucocorticoids; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Neoplasms; Male; Mediastinal Neoplasms; Middle Aged; Mycophenolic Acid; Neoplasm Recurrence, Local; Pleural Neoplasms; Prednisone; Sirolimus; Skin Neoplasms; Tacrolimus

Oral lichen planus (OLP) is a chronic mucosal disorder of unclear etiology. The mainstay of therapy is topical use of steroids but other immuno-modulating therapies have also been tried. One such example is topical application of tacrolimus. Tacrolimus was in 2000 approved for treatment of atopic dermatitis, but in 2005 a boxed warning was included because of a potential risk of cancer development and for lack of long-term studies of the safety of the drug. The present study describes a patient who in 2003 was diagnosed with OLP and where treatment has included an intermittent use of tacrolimus. Five years after diagnosis, the patient developed a squamous cell carcinoma in the region where tacrolimus had been applied. The possible relationship between the use of tacrolimus and cancer development and rationale to include tacrolimus in OLP treatment is discussed.

Topics: Administration, Buccal; Carcinoma, Squamous Cell; Clobetasol; Follow-Up Studies; Glucocorticoids; Humans; Immunosuppressive Agents; Lichen Planus, Oral; Male; Middle Aged; Mouth Neoplasms; Tacrolimus; Triamcinolone Acetonide

Hailey-Hailey disease (HHD) is a rare, autosomal dominant intraepidermal blistering disorder characterized by recurrent vesicles and erosions affecting mostly the intertriginous areas. We report a case of HHD affecting exclusively the vulva from which an invasive squamous cell carcinoma developed after tacrolimus therapy.

Topics: Adult; Carcinoma, Squamous Cell; Female; Humans; Immunosuppressive Agents; Lymph Node Excision; Pemphigus, Benign Familial; Tacrolimus; Vulvar Diseases; Vulvar Neoplasms

Non-melanoma skin cancers (NMSCs) are the most common malignancies after solid organ transplantation. Their incidence increases with time after transplantation. Calcineurin-inhibitors (CNIs) and azathioprine are known as skin neoplasia-initiating and -enhancing immunosuppressants. In contrast, increasing clinical experience suggests a relevant antiproliferative effect of mammalian target of rapamycin inhibitors, also named proliferation signal inhibitors (PSIs). We report the case of a cardiac allograft recipient with an impressive and consolidated reduction of recurrent NMSC, observed after conversion from CNI-therapy to a PSI-based protocol.

Topics: Calcineurin Inhibitors; Carcinoma, Squamous Cell; Cell Proliferation; Drug Therapy, Combination; Everolimus; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Neoplasm Recurrence, Local; Photochemotherapy; Signal Transduction; Sirolimus; Skin Neoplasms; Tacrolimus; Time Factors; TOR Serine-Threonine Kinases; Transplantation, Homologous; Treatment Outcome

Recent studies have demonstrated that cancer stem cells play an important role in the pathobiology of head and neck squamous cell carcinomas (HNSCC). However, little is known about functional interactions between head and neck cancer stem-like cells (CSC) and surrounding stromal cells. Here, we used aldehyde dehydrogenase activity and CD44 expression to sort putative stem cells from primary human HNSCC. Implantation of 1,000 CSC (ALDH+CD44+Lin-) led to tumors in 13 (out of 15) mice, whereas 10,000 noncancer stem cells (ALDH-CD44-Lin-) resulted in 2 tumors in 15 mice. These data demonstrated that ALDH and CD44 select a subpopulation of cells that are highly tumorigenic. The ability to self-renew was confirmed by the observation that ALDH+CD44+Lin- cells sorted from human HNSCC formed more spheroids (orospheres) in 3-D agarose matrices or ultra-low attachment plates than controls and were serially passaged in vivo. We observed that approximately 80% of the CSC were located in close proximity (within 100-μm radius) of blood vessels in human tumors, suggesting the existence of perivascular niches in HNSCC. In vitro studies demonstrated that endothelial cell-secreted factors promoted self-renewal of CSC, as demonstrated by the upregulation of Bmi-1 expression and the increase in the number of orospheres as compared with controls. Notably, selective ablation of tumor-associated endothelial cells stably transduced with a caspase-based artificial death switch (iCaspase-9) caused a marked reduction in the fraction of CSC in xenograft tumors. Collectively, these findings indicate that endothelial cell-initiated signaling can enhance the survival and self-renewal of head and neck CSC.

Topics: Aldehyde Dehydrogenase; Animals; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cells, Cultured; Endothelial Cells; Head and Neck Neoplasms; Humans; Hyaluronan Receptors; Immunohistochemistry; Isoenzymes; Mice; Mice, SCID; Microscopy, Confocal; Neoplasms, Experimental; Neoplastic Stem Cells; Neovascularization, Pathologic; Signal Transduction; Tacrolimus; Transplantation, Heterologous

Pimecrolimus and tacrolimus are topical calcineurin inhibitors developed specifically for the treatment of atopic eczema. Experience with long-term use of topical calcineurin inhibitors is limited and the risk of rare but serious adverse events remains a concern. We have previously demonstrated the absence of carcinogenic effect of tacrolimus alone and in combination with simulated solar radiation (SSR) on hairless mice. The aim of this study is to determine whether pimecrolimus accelerates photocarcinogenesis in combination with SSR or pimecrolimus and tacrolimus accelerate photocarcinogenesis in combination with UVA. We used 11 groups of 25 hairless female C3.Cg/TifBomTac immunocompetent mice (n = 275). Pimecrolimus cream or tacrolimus ointment was applied on their dorsal skin three times weekly followed by SSR (2, 4, or 6 standard erythema doses, SED) or UVA (25 J/cm(2)) 3-4 h later. This was done up to 365 days in the SSR-treated groups and up to 500 days in the UVA-treated groups. Pimecrolimus did not accelerate the time for development of the first, second or third tumor in any of the groups. Median time to the first tumor was 240 days for the control-2SED group compared with pimecrolimus-2SED group (233 days), control-4SED group (156 days) compared with pimecrolimus-4SED group (163 days) and control-6SED group (162 days) compared with pimecrolimus-6SED group (170 days). Only one mouse in each of the three UVA groups developed a tumor. We conclude that pimecrolimus in combination with SSR and both pimecrolimus and tacrolimus in combination with UVA do not accelerate photocarcinogenesis in hairless mice.

Topics: Administration, Topical; Animals; Carcinoma, Squamous Cell; Disease Models, Animal; Disease Progression; Female; Immunosuppressive Agents; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Skin; Skin Neoplasms; Skin Pigmentation; Tacrolimus; Ultraviolet Rays

Traditional immunosuppressive regimens make laryngeal transplantation in cancer patients prohibitive because of the increased risk of recurrence. Everolimus, a recently developed immunosuppressant, has demonstrated significant antitumor properties. The purpose of this study was to examine the effects of everolimus alone and in combination with other immunosuppressants on tumor growth in a combined laryngeal transplantation and tumor model.. Animal, prospective, randomized, controlled, and blinded.. One million squamous cell carcinoma cells (SCC-158) were injected intravenously into a total of 40 rats 1 day before laryngeal transplantation. Rats were divided into four groups differing by immunosuppressive regimens. Lung surface metastases were counted 21 days after inoculation, and numerical transplantation rejection scores were recorded. A separate experiment for comparison was performed with no transplant on 24 rats, but with the same immunosuppressive treatment groups.. The median number of lung surface metastases were: a) control (i.e., no immunosuppression): 85; b) everolimus 1.0 mg/kg: 25; c) tacrolimus 1.2 mg/kg: 1650; d) everolimus 1.0 mg/kg + tacrolimus 0.05 mg/kg: 1300. Rats receiving everolimus alone showed a statistically significant decrease in pulmonary surface metastases compared with the other groups. Transplanted rats had no difference in their outcomes when compared with non-transplanted rats.. Everolimus significantly decreases SCC-158 growth in our combined transplantation and tumor model compared with controls and other immunosuppressants.

Topics: Administration, Oral; Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Graft Survival; Immunosuppressive Agents; Laryngeal Neoplasms; Laryngectomy; Larynx; Lung Neoplasms; Male; Neoplasm Recurrence, Local; Neoplasm Transplantation; Rats; Rats, Inbred F344; Sirolimus; Tacrolimus

Malignancies are a serious long-term complication among liver transplant recipients, with an overall incidence of 4.5%-15%. Posttransplantation lymphoproliferative disease (PTLD) is one of the leading causes of late death. Its development is related to complex interactions between immunosuppressive drugs and environmental agents. The aim of this study was to analyze risk factors for PTLD and survival after orthotopic liver transplantation (OLT) compared with solid tumors.. We undertook a retrospective review of the clinical histories of adult patients who underwent OLT between July 1986 and February 2001, and who had been followed until 2005. This study comprised 528 adult recipients who survived more than 2 months after OLT. We excluded pediatric, partial-organ, and multiorgan recipients.. No differences were observed concerning gender, viral etiology of hepatitis, calcineurin inhibitor regimen, or steroid maintenance period. Treated acute rejection episodes accounted for 53.3% of patients who developed PTLD compared with 47.3% in the control group (P = .787). Patients with solid tumors were older at the time of diagnosis than those with PTLD (57.5 +/- 8.13 years vs 48.8 +/- 13.9; P = .002). The overall mortality rate for PTLD was 55.5%, which did not differ significantly from solid tumors.. PTLD develops in younger patients after OLT. Various immunosuppressive regimens do not seem to influence the incidence of PTLD or other solid tumors.

Topics: Adult; Carcinoma, Squamous Cell; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Liver Transplantation; Lymphoproliferative Disorders; Male; Retrospective Studies; Risk Factors; Skin Neoplasms; Survival Analysis; Survivors; Tacrolimus

Numerous studies have demonstrated the utility of topical tacrolimus ointment in atopic dermatitis. However, there is a concern that local immunosuppression by calcineurin inhibitors may enhance dermal photocarcinogenesis and carcinogenesis. Therefore, we investigated the influence of topical tacrolimus ointment on squamous cell carcinoma formation in hairless female C3.Cg/TifBomTac immunocompetent mice exposed to solar simulated radiation (SSR). In a first experiment, mice (n = 200) had tacrolimus applied on their dorsal skin three times weekly followed by SSR (2, 4 or 6 standard erythema doses, SED) 3-4 h later. Tacrolimus did not reduce the time to tumor development and in the group receiving 4 SED it even had a protective effect (156 days vs 170 days, P = 0.008). In a second experiment, mice (n = 50) were irradiated with 6 SED three times weekly for 3 months and subsequently treated five times weekly with topical tacrolimus to mimic the use of tacrolimus on sun-damaged skin. The median time to the first skin tumor was 234 days in SSR + tacrolimus group compared with 227 days in the only SSR-irradiated group (P = 0.160). In a third experiment, mice (n = 25) had tacrolimus applied on their dorsal skin every day for 1 month, thereafter the group was irradiated with 4 SED three times weekly. The median time to the first skin tumor was 142 days in tacrolimus + SSR group compared with 156 days in the only SSR-irradiated group from experiment 1 (P = 0.363). We conclude that tacrolimus ointment does not accelerate photocarcinogenesis or induce any dermal carcinogenicity in hairless mice.

Topics: Administration, Topical; Animals; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Immunosuppressive Agents; Mice; Mice, Hairless; Neoplasms, Radiation-Induced; Skin; Skin Neoplasms; Skin Pigmentation; Tacrolimus; Ultraviolet Rays

Erythroplasia of Queyrat of the glans penis developed in a 79-year-old uncircumcised man on a background of biopsy proven Zoon's plasma cell balanitis affecting the same site on the glans. The Zoon's plasma cell balanitis had been treated with topical pimecrolimus for 1 month prior to the development of clinically evident erythroplasia of Queyrat. He was subsequently treated with topical 5-fluorouracil 5% for 2 weeks, which resulted in clinical clearance. He has since been circumcised.

Topics: Aged; Balanitis; Carcinoma in Situ; Carcinoma, Squamous Cell; Circumcision, Male; Erythroplasia; Humans; Immunosuppressive Agents; Male; Penile Neoplasms; Penis; Plasma Cells; Tacrolimus

Squamous cell carcinoma (SCC) has a recognized association with lichen sclerosus (LS) of the vulva. Several recent reports have indicated the usefulness of the new macrolide immunosuppressant agents pimecrolimus and tacrolimus in the treatment of LS, emphasizing the advantage over topical corticosteroids of lack of atophogenicity. Despite this there may be risks involved that could outweigh this benefit. The potential of these medications to potentiate the risk of SCC in LS in the short and long-term is unknown. Once lichen sclerosus is well controlled, there is often no need for ongoing use of superpotent corticosteroids, and there may be no reason to use immunosuppressants when moderate-strength corticosteroids provide adequate control.. A 73-year-old woman with a 10-year history of hypertrophic LS and genital psoriasis presented with intractable superimposed inflammatory vulvitis. She was treated with topical pimecrolimus 1% cream on the assumption that she was either allergic to or intolerant of topical corticosteroids. One month after commencing therapy, she suddenly developed a rapidly growing vulvar tumor. This was excised and proved to be a well-differentiated squamous cell carcinoma.. It may be safest to restrict the use of topical immunosuppressives to patients with LS who are unable to use topical corticosteroids because of the risk of potentiating SCC.

Topics: Administration, Topical; Aged; Carcinoma, Squamous Cell; Female; Humans; Immunosuppressive Agents; Risk Factors; Tacrolimus; Vulvar Lichen Sclerosus; Vulvar Neoplasms

Topics: Calcineurin Inhibitors; Carcinoma, Squamous Cell; Female; Humans; Immunosuppressive Agents; Lichen Sclerosus et Atrophicus; Male; Tacrolimus

Topics: Administration, Topical; Carcinoma, Squamous Cell; Circumcision, Male; Humans; Immunosuppressive Agents; Lichen Sclerosus et Atrophicus; Male; Male Urogenital Diseases; Penile Neoplasms; Tacrolimus

Immunosuppressive therapies allow long-term patient and transplant survival, but are associated with increased development of UV-induced skin cancers, particularly squamous cell carcinomas. The mechanisms by which CsA, MMF, tacrolimus (TAC) or sirolimus (SRL), alone or in dual combinations, influence tumor development and progression are not completely understood. In the current study, chronically UV-exposed mice treated with SRL alone or in combination with CsA or TAC developed more tumors than mice treated with vehicle or other immunosuppressants, but the tumors were significantly smaller and less advanced. Mice treated with CsA or TAC developed significantly larger tumors than vehicle-treated mice, and a larger percentage in the CsA group were malignant. The addition of MMF to CsA, but not to TAC, significantly reduced tumor size. Immunosuppressant effects on UVB-induced inflammation and tumor angiogenesis may explain these findings. CsA enhanced both UVB-induced inflammation and tumor blood vessel density, while MMF reduced inflammation. Addition of MMF to CsA reduced tumor size and vascularity. SRL did not affect inflammation, but significantly reduced tumor vascularity. Thus the choice of immunosuppressants has important implications for tumor number, size and progression, likely due to the influence of immunosuppressants on UVB-induced inflammation and angiogenesis.

Topics: Animals; Blood Vessels; Carcinoma, Squamous Cell; Cyclosporine; Disease Models, Animal; Drug Therapy, Combination; Female; Immunosuppressive Agents; Inflammation; Mice; Mice, Hairless; Mycophenolic Acid; Neoplasms, Radiation-Induced; Neovascularization, Pathologic; Sirolimus; Skin Neoplasms; Tacrolimus; Ultraviolet Rays

Since tacrolimus ointment was approved by the U.S. Food and Drug Administration (FDA) as a promising treatment for atopic dermatitis, it has been approved in more than 30 additional countries, including numerous European Union member nations. Moreover, in the current clinical routine the use of this drug is no longer restricted to the approved indication, but has been extended to a wide variety of inflammatory skin diseases including some with the potential of malignant transformation. So far, the side-effects reported from the topical use of tacrolimus have been relatively minor (e.g. burning, pruritus, erythema). Recently, however, the FDA reviewed the safety of topical tacrolimus, which resulted in a warning that the use of calcineurin inhibitors may be associated with an increased risk of cancer.. Oral lichen planus (OLP) was diagnosed in a 56-year-old women in February 1999. After several ineffective local and systemic therapeutic measures an off-label treatment of this recalcitrant condition using Tacrolimus 0.1% ointment was initiated in May 2002. After a few weeks of treatment most of the lesions ameliorated, with the exception of the plaques on the sides of the tongue. Nevertheless, the patient became free of symptoms which, however, reoccurred once tacrolimus was weaned, as a consequence treatment was maintained. In April 2005, the plaques on the left side of the tongue appeared increasingly compact and a biopsy specimen confirmed the suspected diagnosis of an oral squamous cell carcinoma.. The suspected causal relationship between topical use of tacrolimus and the development of a squamous cell carcinoma prompted us to test the notion that the carcinogenicity of tacrolimus may go beyond mere immune suppression. To this end, tacrolimus has been shown to have an impact on cancer signalling pathways such as the MAPK and the p53 pathway. In the given case, we were able to demonstrate that these pathways had also been altered subsequent to tacrolimus therapy.

Topics: Administration, Topical; Calcineurin Inhibitors; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Enzyme Activation; Female; Guanine Nucleotide Exchange Factors; Humans; Immunosuppressive Agents; Lichen Planus, Oral; Middle Aged; Mitogen-Activated Protein Kinase 3; Tacrolimus; Tongue Neoplasms; Ubiquitin-Protein Ligases

The aim of this study was to determine the oral status of renal transplant recipients receiving cyclosporin A (CsA) or tacrolimus (FK-506) as immunosuppressant.. A total of 88 renal transplant recipients receiving CsA (63 men and 25 women, mean age 51.4 years) and 67 receiving FK-506 (57 men and 10 women, mean age 33.5 years) were included in the study. Donor type, histocompatibility, cold ischemia time and prior delayed graft function were similar between the two groups. Demographics and pharmacological data were recorded for all subjects.. The results demonstrated that CsA caused a greater number of oral diseases. A greater number of gingival overgrowth was present in patients treated with CsA. However, the combined use with calcium channel blockers increased the gingival overgrowth number. The occurrence of candida in saliva was observed in 80 renal recipients treated with CsA and 20 treated with FK-506. The presence of squamous oral carcinoma (n = 3) and herpes simplex (n = 10) was observed in patients treated with CsA. These alterations were not observed in renal recipients treated with FK-506.. Renal recipients constitute a high-risk group for oral diseases, as they are immunocompromised. However, the FK-506 regime appears to ameliorate this effect, compared with CsA. Adequate pre- and post-transplant oral health care is recommended for these subjects, irrespective of the time interval for which the drug is administered.

Topics: Adult; Calcium Channel Blockers; Candida; Carcinoma, Squamous Cell; Cyclosporine; Drug Therapy, Combination; Female; Gingival Overgrowth; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mouth Neoplasms; Saliva; Stomatitis, Herpetic; Tacrolimus

Topics: Balanitis; Carcinoma, Squamous Cell; Humans; Immunosuppressive Agents; Male; Middle Aged; Penile Neoplasms; Tacrolimus

The occurrence of an oesophageal squamous cell carcinoma following liver transplantation is very infrequent. Such an event has been related to a history of alcohol-induced cirrhosis, as in other squamous cell tumours of the oropharynx. We report the case of a 64-year-old male patient diagnosed as having oesophageal squamous cell carcinoma six years after having had a liver transplant due to alcohol-induced cirrhosis. The tumour was treated surgically and consisted of an Ivor-Lewis oesophagectomy. The patient is disease-free 17 months after surgery. A review of the cases reported in the literature indicated treatment with chemotherapy and radiation therapy, and with excision in some cases. Generally, despite aggressive treatment the prognosis is poor.

Topics: Alcoholism; Carcinoma, Squamous Cell; Cardia; Deglutition Disorders; Esophageal Neoplasms; Esophageal Stenosis; Esophagectomy; Humans; Immunocompromised Host; Immunosuppression Therapy; Immunosuppressive Agents; Liver Cirrhosis, Alcoholic; Liver Transplantation; Male; Middle Aged; Neoplasms, Multiple Primary; Postoperative Complications; Remission Induction; Stomach Neoplasms; Tacrolimus

Topics: Administration, Topical; Carcinoma, Squamous Cell; Diagnosis, Differential; Female; Humans; Lichen Sclerosus et Atrophicus; Precancerous Conditions; Risk Assessment; Skin Neoplasms; Tacrolimus; Vulvar Diseases

Immunosuppression used to avoid graft rejection in solid organ transplantation recipients leads to a variety of side-effects, and an increased rate of infections and de novo malignancies. Oral conditions usually associated with immunosuppressive drugs include fungal and viral infection, and lip lesions, but intra-oral carcinoma has not been reported as having a high incidence. This report deals with a male liver transplant recipient receiving FK506 (5 mg/day) and prednisone (20 mg/day) who was diagnosed with a homogeneous leukoplakia on the floor of the mouth 4 months after transplantation, and 4 months later with a squamous cell carcinoma growth at the site of this lesion. The rapid transformation of the lesion suggests that in patients who display oral premalignant conditions, immunosuppression must be considered as an important risk factor for oral cancer.

Topics: Carcinoma, Squamous Cell; Disease Progression; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Leukoplakia, Oral; Liver Transplantation; Male; Middle Aged; Mouth Neoplasms; Prednisone; Tacrolimus

Tacrolimus, produced by the fungus Streptomyces tsukabaensis, is a potent macrolide immunosuppressant widely used in liver and kidney transplantation. Topical tacrolimus has recently been found to be an effective treatment for atopic dermatitis (AD).. Because of the well-known association between T-cell immunosuppression and an increased risk of carcinogenesis, we investigated the effect of topical tacrolimus on skin carcinogenesis in 117 mice.. Approximately 8 cm2 of the shaved dorsal skin of 7-week-old female CD-1 mice was treated with 7,12-dimethylbenz[alpha]anthracene (DMBA) dissolved in acetone, which is in general use as a tumour initiator, or acetone alone, on day 1 of the experiment, followed by promoting treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) with or without tacrolimus, or acetone with or without tacrolimus, for 20 weeks. The mice were divided into six treatment groups: (1) DMBA followed by acetone; (2) DMBA followed by TPA; (3) DMBA followed by acetone + tacrolimus; (4) DMBA followed by TPA + tacrolimus; (5) acetone followed by acetone + tacrolimus; and (6) acetone followed by acetone (control).. The induction of skin tumours was significantly greater in the TPA-treated groups than in the absence of TPA. However, after 14 weeks there was marked synergy between tacrolimus and the DMBA/TPA regimen, with 0.47 +/- 0.13 (mean +/- SD) new tumours per mouse per week in group 4 vs. 0.10 +/- 0.025 in group 2 (P < 0.01), and 0.01 +/- 0.002 in group 3. A significant reduction in the CD4/CD8 ratio was found in axillary and inguinal lymph nodes in tacrolimus-treated mice, supporting the presumption that the immunosuppressive effect of the drug was responsible for its effect in promoting tumorigenesis. The major increase in tumours caused by topical tacrolimus was of papillomas, not squamous cell carcinomas. Papillomas are uncommon in humans, and are benign. However, 8.5% of the tumours found in the experiment were squamous cell carcinomas, and a considerable synergy between topical tacrolimus and conventional carcinogens was observed, raising the spectre of some risk of skin carcinogenesis in AD patients undergoing prolonged treatment with tacrolimus.. Caution and careful surveillance are required with regard to skin lesions in patients treated with tacrolimus for prolonged periods.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Administration, Cutaneous; Animals; Carcinogens; Carcinoma, Squamous Cell; CD4 Lymphocyte Count; Cell Transformation, Neoplastic; Female; Immunosuppressive Agents; Lymph Nodes; Mice; Mice, Inbred Strains; Papilloma; Skin Neoplasms; Tacrolimus

Interleukin (IL-2) and IL-2Rbeta/gamma have been shown to be expressed in human carcinomas in culture and in situ. Recently, expression of endogenous IL-2 and IL-2R in the cytoplasm was found to be up-regulated in tumour cells undergoing mitosis. This observation suggested that similar to its role in lymphocytes, the IL-2/IL-R pathway is involved in the regulation of carcinoma cell proliferation. Metabolic labelling followed by immunoprecipitation and Western blot results showed that IL-2 in carcinomas was identical to that in human lymphocytes. However, tumour cells did not secrete IL-2 detectable by immunoassays, although membrane-associated IL-2 was detectable on a proportion of these cells cultured in the absence of exogenous IL-2. Antibodies to IL-2 failed to inhibit proliferation of carcinoma cells, but antibodies specific for the ligand-binding site of the IL-2R were growth inhibitory. Growth of tumour cells was also inhibited by the immunosuppressive drugs, cyclosporin A (CsA), FK506 and rapamycin (RPA), known to interfere with the IL-2 pathway in lymphocytes. To further confirm the role of endogenous IL-2 in the growth of carcinomas, tumour cells were incubated with an IL-2-specific antisense oligonucleotide. The treatment was shown to transiently inhibit IL-2 mRNA and IL-2 protein expression as well as proliferation of tumour cells. Tumour cells treated with IL-2-specific antisense oligonucleotide demonstrated increased apoptosis in comparison to untreated or sense oligonucleotide-treated control cells. The data indicate that in human carcinomas, endogenous IL-2 promotes growth and protects tumour cells from apoptosis.

Topics: Antibodies; Apoptosis; Carcinoma, Squamous Cell; Cell Division; Head and Neck Neoplasms; Humans; Interleukin-2; Jurkat Cells; Oligonucleotides, Antisense; Receptors, Interleukin-2; Sirolimus; Stomach Neoplasms; Tacrolimus; Tumor Cells, Cultured

FK506-binding proteins and cyclophilins are intracellular proteins that express peptidylproline cis-trans-isomerase (PPIase) activity. The effects of FK506-binding protein 12 (FKBP12) and the cyclophilins 18 and 23 on autophosphorylation of the epidermal growth factor (EGF) receptor prepared from plasma membranes of the human epidermoid cell line A431 have been investigated. Whereas FKBP12 inhibited EGF receptor tyrosine kinase activity in a concentration-dependent manner, the cyclophilins did not affect autophosphorylation. In contrast to the wild-type enzyme, several variants of FKBP12 with greatly reduced PPIase activity were unable to suppress EGF receptor tyrosine kinase significantly. Pervanadate an inhibitor of protein tyrosine phosphatases, abolished the effect of FKBP12 on EGF receptor autophosphorylation. Finally, FK506 and rapamycin, which are known to block the PPIase activity of FKBP12, induced a significant stimulation of EGF receptor autophosphorylation in intact A431 cells suggesting suppression of EGF receptor autophosphorylation by intracellular FKBP12 in vivo. Taken together the data point to an inhibitory function of FKBP12 in EGF receptor signaling, possibly induced by stimulation of a protein tyrosine phosphatase coupled to the EGF receptor. Both PPIase activity and substrate specificity of FKBP12 seem to be indispensable for this effect.

Topics: Adenosine Triphosphate; Carcinoma, Squamous Cell; Carrier Proteins; Cell Membrane; Cyclosporine; DNA-Binding Proteins; ErbB Receptors; Genetic Variation; Heat-Shock Proteins; Humans; Kinetics; Peptidylprolyl Isomerase; Phosphorylation; Point Mutation; Recombinant Proteins; Tacrolimus; Tacrolimus Binding Proteins; Tumor Cells, Cultured