sirolimus and Retroperitoneal-Neoplasms

To improve the diagnosis and treatment of pulmonary lymphangiomyomatosis, clinical data for the first successfully treated case of pulmonary and retroperitoneal lymphangiomyomatosis in our hospital has been comprehensively analyzed, and the relevant literature has been reviewed. A 45-year-old Han Chinese woman initially presented six months ago with increasing shortness of breath on exertion and was admitted to our hospital after four days of chest pain. Admission examination revealed chylothorax, interstitial lung disease, and enlarged retroperitoneal lymph nodes. The patient was finally diagnosed with pulmonary and retroperitoneal lymphangiomyomatosis based on laparotomy examination and biopsy of the retroperitoneal lymph nodes. After six months of rapamycin treatment, the symptoms - lung function, arterial blood gas, and imaging of the patient- were improved significantly. Pulmonary lymphangiomyomatosis clinically manifests as progressive dyspnea, recurrent pneumothorax, and chylothorax, and can be diagnosed by its characteristic features in high-resolution computed tomographic images or pathological examination. The successful treatment of pulmonary lymphangiomyomatosis with rapamycin brings new hope to those afflicted with this disease.

Topics: Female; Humans; Lung Neoplasms; Lymphangioleiomyomatosis; Middle Aged; Retroperitoneal Neoplasms; Sirolimus

Lymphangioleiomyomatosis (LAM) is a rare, progressive, diffuse cystic lung disease predominantly affecting women of child bearing age. Recently treatment with sirolimus was shown to stabilize lung function decline and improve quality of life in patients with LAM. We treated three premenopausal women suffering from LAM manifesting as diffuse cystic lung disease, chylous effusions, and lymphangioleioyomas with sirolimus (1-3 mg a day; sirolimus trough levels 2.9-8.5 ng/ml). All three patients had a remarkable response to sirolimus, with resolution of effusions, improvement in lung function and shrinking of abdominal lymphangioleiomyomas. Our case series further complements the literature in that sirolimus is a safe and effective treatment for LAM and its lymphatic manifestations.

Topics: Adult; Antineoplastic Agents; Biomarkers, Tumor; Biopsy; Female; Humans; Immunohistochemistry; Lung Neoplasms; Lymphangioleiomyomatosis; Respiratory Function Tests; Retroperitoneal Neoplasms; Sirolimus; Tomography, X-Ray Computed; Treatment Outcome

Topics: Adult; Antibiotics, Antineoplastic; Female; Forced Expiratory Volume; Humans; Lung Neoplasms; Lymphangioleiomyomatosis; Lymphangiomyoma; Respiratory Function Tests; Retroperitoneal Neoplasms; Sirolimus; Tomography, X-Ray Computed

Topics: Female; Forced Expiratory Volume; Humans; Lung Neoplasms; Lymphangioleiomyomatosis; Middle Aged; Remission Induction; Retroperitoneal Neoplasms; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Tumor Burden; Vital Capacity

A young woman received a diagnosis of abdominal, sporadic lymphangioleiomyomatosis (LAM) and multiple abdominal lymphangioleiomyomas and was referred for recurrent chylous ascites responding only to a fat-free diet. On admission, pulmonary function test (PFT) results showed a moderate reduction in the transfer factor for carbon monoxide with normal exercise performance. The serum vascular endothelial growth factor D (VEGF-D) level was 2,209 pg/mL. DNA sequences, amplified at loci kg8, D16S3395, D16S3024, D16S521, and D16S291 on chromosome 16p13.3, showed a loss of heterozygosity (LOH) only for kg8. Fat-free total parenteral nutrition in association with sirolimus (2 mg po daily) was initiated. Serum sirolimus levels were maintained at concentrations between 5 and 15 ng/mL. After 1 month, reintroduction of a low-fat oral feeding was achieved without recurrence of ascites. PFT results were stable. Interestingly, clinical improvement was associated with a reduction in the VEGF-D serum level (1,558 pg/mL). LOH at the kg8 biomarker in blood LAM cells was no longer detected.

Topics: Adult; Antibiotics, Antineoplastic; Chylous Ascites; Diet, Fat-Restricted; Female; Humans; Loss of Heterozygosity; Lung Neoplasms; Lymphangioleiomyomatosis; Magnetic Resonance Imaging; Neoplastic Cells, Circulating; Parenteral Nutrition, Total; Pulmonary Diffusing Capacity; Respiratory Function Tests; Retroperitoneal Neoplasms; Sequence Analysis, DNA; Sirolimus; Tomography, X-Ray Computed; Vascular Endothelial Growth Factor D

With this study we aimed to research the effects of immunosuppressive drugs, their cumulative doses, and viral infections on development of malign tumors in patients who have undergone treatment for 5 years.. We examined 100 patients who underwent renal transplantation from 2004 to 2009. Patients had mycophenolate mofetil and steroid in addition to cyclosporine, sirolimus, or tacrolimus as immunosuppressive treatment. For malignancy screening, physical examination, radiologic and endoscopic screening were done, and immunosuppressive drugs and their cumulative doses, age, sex, body mass index (BMI), dialysis history, and viral infection history were investigated.. The mean age of patients was 42.03 ± 11.30 years. There were 1 colon cancer patient, 1 retroperitoneal liposarcoma, 1 renal oncocytoma, 3 Kaposi sarcoma patients treated with cyclosporine; in those treated with Tac there were 1 basal cell carcinoma, 1 Kaposi sarcoma, 2 thyroid carcinoma, 1 breast carcinoma, 1 bladder carcinoma, 1 renal cell carcinoma, and 1 colon carcinoma patients. The mean age of patients having carcinoma was statistically significant compared with those without cancer (P < .01). The prednisolone cumulative dose was significantly higher in carcinoma patients than in patients without carcinoma (P < .01).. The use of long-term chronic immunosuppressive therapy may increase the development of cancer. The risk of carcinoma increases with increasing drug dose and time period of the immunosuppressive drug. There was not a negative effect on cancer prevalence in patients with cyclosporine or tacrolimus. But the cumulative dose of steroids significantly increased malignancy occurence.

Topics: Adult; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Cyclosporine; Early Detection of Cancer; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Retroperitoneal Neoplasms; Sarcoma, Kaposi; Sirolimus; Steroids; Tacrolimus; Thyroid Neoplasms; Time Factors; Urologic Neoplasms

Lymphangioleiomyomatosis (LAM) is a rare progressive disease affecting women of childbearing age. The disease is characterised by an abnormal proliferation of immature smooth muscle cells predominantly in the lung. It gradually leads to respiratory failure, and it frequently result in death. Extrapulmonary LAM typically presents with abdominal mass, abdominal pain and chylous ascites. In the case reports we describe two cases of premenopausal females with extrapulmonary LAM. In both cases they occur in pelvic location in the obturator fossa and around the external iliac artery. After surgical procedures patients were primary treated with progesterone. Sirolimus was second-line drugs.

Topics: Adult; Antineoplastic Agents; Female; Humans; Lymphangioleiomyomatosis; Progesterone; Retroperitoneal Neoplasms; Sirolimus

A 45-year-old woman presented with marked edema of both lower extremities over 6 weeks for a nephrological work-up; she had gained 8 kg of body weight. Voiding was asymptomatic and she had a stable diuresis. The patient took oestrogens for contraception over 10 years. Blood pressure was normotensive. Serum-creatinine was 0.8 mg/dl; a slight microalbuminuria was noted. Left and right ventricular systolic function were normal. DIAGNOSTIC FINDINGS, TREATMENT AND CLINICAL COURSE: Computed tomography of the abdomen revealed a hemodynamically relevant obstruction of the venous blood flow or the lymphatic vessels as cause for the edema of both legs. Masses of lymphangioleiomyomas located around the v. cava inferior were documented. Biopsy of the masses proved a massive proliferation of smooth muscle cells and epitheloid cells with an immunohistochemically typical staining. Furthermore, CT revealed multiple pulmonary cysts in both lungs, results which are pathognomic for lymphangioleiomyomatosis (LAM). In our patient, the structural impairment of the lungs was not substantiated clinically, i. e. she had only slight dyspnoe during exertion. By mild diuretic treatment with HCT and fluid control, a moderate regression of the edema was achieved. At present, the mTOR inhibitor rapamycin as antiproliferative treatment is considered to reduce the retroperitoneal LAM-related masses on an individual basis.. LAM is a rare genetically determined progressive disease occurring frequently in women in childbearing age. LAM is characterized by a proliferation of smooth muscle cells, lymphangioma, renal angiomyolipoma, pulmonary cysts and progressive destruction of lung parenchyma. Refractory edema can result from an obstruction of the venous blood and lymphatic flow by lymphangioma masses located paracaval, which was the impressive and first clinical feature of LAM in our case report.

Topics: Antibiotics, Antineoplastic; Biopsy; Diuretics; Drinking; Female; Humans; Hydrochlorothiazide; Lung Neoplasms; Lymphangioleiomyomatosis; Lymphedema; Magnetic Resonance Imaging; Middle Aged; Retroperitoneal Neoplasms; Sirolimus; Tomography, X-Ray Computed; Vena Cava, Inferior

Perivascular epithelioid cell tumors (PEComas) are a group of rare mesenchymal tumors that typically show both melanocytic and smooth muscle cell features. Some types of PEComa are seen at high frequency in tuberous sclerosis complex (TSC). The TSC1 and TSC2 genes are commonly mutated in both TSC-associated and sporadic PEComas, and mTOR signaling pathway activation is also common in these tumors. Preliminary reports have indicated that the mTOR inhibitors sirolimus and related drugs have activity in some patients with non-TSC-associated PEComa. Here, we report on the use of these medications in the treatment of five consecutive patients with extrarenal nonpulmonary PEComas seen at one institution. Three complete responses, one partial response and one case of progression were seen. Molecular studies identified TSC2 aberrations in four of these patients, and TFE3 translocation was excluded in the resistant case. A review of all published cases as well as those reported here indicates that partial or complete response was seen in 6 of 11 PEComas, with 5 of 6 having a complete response. These findings highlight the consistent though incomplete activity of mTOR inhibitors in the treatment of PEComas.

Topics: Adrenal Gland Neoplasms; Adult; Aged; Antibiotics, Antineoplastic; Everolimus; Female; Humans; Immunoenzyme Techniques; Immunosuppressive Agents; In Situ Hybridization, Fluorescence; Loss of Heterozygosity; Male; Middle Aged; Mutation; Perivascular Epithelioid Cell Neoplasms; Prognosis; Remission Induction; Retroperitoneal Neoplasms; Review Literature as Topic; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins

Perivascular epithelioid cell tumor (PEComa) is an extremely rare neoplasm that appears to arise most commonly at visceral (especially gastrointestinal and uterine), retroperitoneal, and abdominopelvic sites. Malignant PEComas exist but are very rare. These tumors represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. Metastatic PEComa is a rare form of sarcoma for which no effective therapy has been described previously and that has a uniformly fatal outcome. Although there is no known effective therapy, the molecular pathophysiology of aberrant mTOR signaling provides a scientific rationale to target this pathway therapeutically. The difficulty in determining optimal therapy, owing to the sparse literature available, led us to present this case. On this basis, we report a case of metastatic retroperitoneal PEComa treated with an oral mTOR inhibitor, with everolimus achieving significant clinical response.

Topics: Angiomyolipoma; Antineoplastic Agents; Everolimus; Female; Humans; Lung Neoplasms; Middle Aged; Neoplasm Recurrence, Local; Radiography, Abdominal; Retroperitoneal Neoplasms; Signal Transduction; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases

Topics: Anti-Inflammatory Agents; Antibiotics, Antineoplastic; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Disseminated Intravascular Coagulation; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Substitution; Female; Follow-Up Studies; Hemangioendothelioma; Humans; Infant; Infant, Newborn; Kasabach-Merritt Syndrome; Platelet Count; Prednisolone; Retroperitoneal Neoplasms; Sarcoma, Kaposi; Sirolimus; Skin Neoplasms; TOR Serine-Threonine Kinases; Vincristine

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Biopsy; Female; Humans; Lymphangioleiomyomatosis; Middle Aged; Protein Kinase Inhibitors; Retroperitoneal Neoplasms; Sirolimus; Tomography, X-Ray Computed; TOR Serine-Threonine Kinases; Treatment Outcome

Topics: Antineoplastic Combined Chemotherapy Protocols; Boronic Acids; Bortezomib; Chemotherapy, Adjuvant; Clinical Trials, Phase I as Topic; Disease Progression; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Intracellular Signaling Peptides and Proteins; Middle Aged; Perivascular Epithelioid Cell Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrazines; Retroperitoneal Neoplasms; Sirolimus; Topotecan; TOR Serine-Threonine Kinases; Treatment Failure

Resistance to angiogenesis inhibition can occur through the upregulation of alternative mediators of neovascularization. We used a combination of angiogenesis inhibitors with different mechanisms of action, interferon-beta (IFN-beta) and rapamycin, to target multiple angiogenic pathways to treat neuroblastoma xenografts.. Subcutaneous and retroperitoneal neuroblastoma xenografts (NB-1691 and SK-N-AS) were used. Continuous delivery of IFN-beta was achieved with adeno-associated virus vector-mediated, liver-targeted gene transfer. Rapamycin was delivered intraperitoneally (5 mg/kg per day). After 2 weeks of treatment, tumor size was measured, and tumor vasculature was evaluated with intravital microscopy and immunohistochemistry.. Rapamycin and IFN-beta, alone and in combination, had little effect on tumor cell viability in vitro. In vivo, combination therapy led to fewer intratumoral vessels (69% of control), and the remaining vessels had an altered phenotype, being covered with significantly more pericytes (13x control). Final tumor size was significantly less than controls in all tumor models, with combination therapy having a greater antitumor effect than either monotherapy.. The combination of IFN-beta and rapamycin altered the vasculature of neuroblastoma xenografts and resulted in significant tumor inhibition. The use of combinations of antiangiogenic agents should be further evaluated for the treatment of neuroblastoma and other solid tumors.

Topics: Actins; Animals; Antibiotics, Antineoplastic; Antigens, CD34; Cluster Analysis; Humans; Immunohistochemistry; Immunologic Factors; Injections, Intraperitoneal; Interferon-beta; Male; Mice; Mice, SCID; Neoplasms, Experimental; Neovascularization, Pathologic; Neuroblastoma; Retroperitoneal Neoplasms; Sirolimus; Transplantation, Heterologous; Tumor Cells, Cultured

Pulmonary lymphangioleiomyomatosis (PLAM) is an indication for lung transplantation (LTx). Angiomyolipomas occur in approximately 50% to 60% of patients with PLAM. We describe a patient presenting with hemoptysis post-LTx for PLAM. Computed tomography (CT) scan demonstrated no pulmonary abnormality, but identified a retroperitoneal mass confirmed as angiomyolipoma by CT-guided core biopsy. Based on experimental work that rapamycin may inhibit angiomyolipoma cells, we commenced the patient on low-dose rapamycin. She had no adverse reactions and follow-up CT scan after 7 months demonstrated almost complete resolution of the tumor. This suggests a role for rapamycin in routine post-LTx immunosuppression for PLAM.

Topics: Adult; Angiomyolipoma; Antibiotics, Antineoplastic; Biopsy; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Lung Transplantation; Lymphangioleiomyomatosis; Neoplasms, Second Primary; Postoperative Period; Retroperitoneal Neoplasms; Sirolimus; Surgery, Computer-Assisted; Tomography, X-Ray Computed