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Update on systemic therapies of metastatic renal cell carcinoma.

PURPOSE: Recent advances in understanding the molecular biology of advanced and metastatic renal cell carcinoma (RCC) have led to the develo … iate-risk patients according to Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, whereas temsirolimus is recommended for the poor-risk group. The combination of bevacizumab and INF-alpha can be regarded as an alternative to sunitinib. After cytokine failure, patients should be recommended to sorafenib. Everolimus must be considered after first-line …

[Treatment of locally advanced renal tumors].

INTRODUCTION: Locally advanced renal tumors show a high progression rate after surgery. Surgical treatment of renal tumors has some unique characteristics related to involvement of the adrenal gland, vena cava, or regional lymph nodes. OBJECTIVE: To review the current treatment of locally advanced renal tumors. MATERIALS AND METHODS: A review is made of both the different drugs used and the different therapeutic possibilities in these tumors. RESULTS: Systemic treatment with angiogenesis inhibitors may improve the natural history of these patients. Systemic treatment may be administered bef

LKB1 and AMP-activated protein kinase control of mTOR signalling and growth.

The AMP-activated serine/threonine protein kinase (AMPK) is a sensor of cellular energy status found in all eukaryotes that is activated under conditions of low intracellular ATP following stresses such as nutrient deprivation or hypoxia. In the past 5 years, work from a large number of laboratories has revealed that one of the major downstream signalling pathways regulated by AMPK is the mammalian target-of-rapamycin [mammalian target of rapamycin (mTOR) pathway]. Interestingly, like AMPK, the mTOR serine/threonine kinase plays key roles not only in growth control and cell proliferation but a

The TSC-mTOR pathway mediates translational activation of TOP mRNAs by insulin largely in a raptor- or rictor-independent manner.

The stimulatory effect of insulin on protein synthesis is due to its ability to activate various translation factors. We now show that insulin can increase protein synthesis capacity also by translational activation of TOP mRNAs encoding various components of the translation machinery. This translational activation involves the tuberous sclerosis complex (TSC), as the knockout of TSC1 or TSC2 rescues TOP mRNAs from translational repression in mitotically arrested cells. Similar results were obtained upon overexpression of Rheb, an immediate TSC1-TSC2 target. The role of mTOR, a downstream effe

Pulmonary lymphangioleiomyomatosis (LAM): progress and current challenges.

Lymphangioleiomyomatosis (LAM), a rare lung disease, is characterized by the progressive proliferation, migration, and differentiation of smooth muscle (SM)-like LAM cells, which lead to the cystic destruction of the lung parenchyma, obstruction of airways and lymphatics, and loss of pulmonary function. LAM is a disease predominantly affecting women and is exacerbated by pregnancy; only a lung transplant can save the life of a patient. It has been discovered that in LAM, somatic or genetic mutations of tumor suppressor genes tuberous sclerosis complex 1 (TSC1) or TSC2 occur and the TSC1/TSC2 p

mTORC1 signaling can regulate growth factor activation of p44/42 mitogen-activated protein kinases through protein phosphatase 2A.

The mTORC1 complex (mammalian target of rapamycin (mTOR)-raptor) is modulated by mitogen-activated protein (p44/42 MAP) kinases (p44/42) through phosphorylation and inactivation of the tuberous sclerosis complex. However, a role for mTORC1 signaling in modulating activation of p44/42 has not been reported. We show that in two cancer cell lines regulation of the p44/42 MAPKs is mTORC1-dependent. In Rh1 cells rapamycin inhibited insulin-like growth factor-I (IGF-I)-stimulated phosphorylation of Thr(202) but not Tyr(204) and suppressed activation of p44/42 kinase activity. Down-regulation of rapt

Mechanism by which mammalian target of rapamycin inhibitors sensitize multiple myeloma cells to dexamethasone-induced apoptosis.

Mammalian target of rapamycin (mTOR) inhibitors curtail cap-dependent translation. However, they can also induce post-translational modifications of proteins. We assessed both effects to understand the mechanism by which mTOR inhibitors like rapamycin sensitize multiple myeloma cells to dexamethasone-induced apoptosis. Sensitization was achieved in multiple myeloma cells irrespective of their PTEN or p53 status, enhanced by activation of AKT, and associated with stimulation of both intrinsic and extrinsic pathways of apoptosis. The sensitizing effect was not due to post-translational modificat

The Management of Hematopoietic Stem Cell Transplant in People with HIV.

Hematopoietic stem cell transplant (HSCT) is now recognized as a standard treatment option for people with HIV (PWH) who develop high-risk hematologic malignancies. However, the involved polypharmacy can lead to complications from drug interactions and toxicities, affecting the efficacy and safety of chemotherapy and antiretroviral therapy (ART). Managing these patients requires a personalized approach, including the careful selection of ART based on previous therapies and potential interactions, alongside risk assessment for infections. This discussion will address the history of HSCT in PWH

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… These include calcineurin inhibitors (tacrolimus or cyclosporine), mTOR inhibitors (sirolimus), antimetabolites (mycophenolate), and/or corticosteroids such as prednisone. … Calcineurin inhibitors like tacrolimus and cyclosporine and mTOR inhibitors such as sirolimus are substrates of CYP3A4 and P-gp [ 53 , 54 , 55 , 56 ]. …

Cardiovascular Considerations in Patients Undergoing Hematopoietic Cell Transplantation.

Opinion statementCardiac dysfunction is a serious adverse effect of cancer therapies that can interfere with quality of life and impact long-term survival in patients with cancer. Hematopoietic cell transplantation is a potentially curative therapy for many advanced hematologic malignancies and bone marrow failure syndromes, however is associated with several short- and long-term adverse effects, including importantly, cardiovascular toxicities. The goal of this review article is to describe the cardiovascular events that may develop before, during, and after hematopoietic cell transplantation

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… GVHD prevention standards include steroids, calcineurin inhibitors (tacrolimus/cyclosporine), sirolimus, and methotrexate or mycophenolate. … Sirolimus may elevate hypertriglyceridemia and hyperlipidemia risk, while mycophenolate mofetil (MMF) and corticosteroids have been linked to hyperlipidemia [ 42 ]. …

Intestinal/Multivisceral Transplantation

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… Sirolimus-induced pneumonitis is reported in at least 2 % of liver transplant recipients and should be suspected in patients who develop respiratory symptoms while receiving sirolimus [ 68 ]. … In rapid and persistent deterioration of the kidney function, sirolimus, a macrolide with potent immunosuppressive properties, can be used as maintenance therapy instead of tacrolimus. However, in intestinal organ transplants experience with sirolimus is limited. …

The choice of new treatments in autoimmune hemolytic anemia: how to pick from the basket?

Autoimmune hemolytic anemia (AIHA) is defined by increased erythrocyte turnover mediated by autoimmune mechanisms. While corticosteroids remain first-line therapy in most cases of warm-antibody AIHA, cold agglutinin disease is treated by targeting the underlying clonal B-cell proliferation or the classical complement activation pathway. Several new established or investigational drugs and treatment regimens have appeared during the last 1-2 decades, resulting in an improvement of therapy options but also raising challenges on how to select the best treatment in individual patients. In severe w

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… Sirolimus Sirolimus, an immunosuppressive ingredient of Streptomyces hygroscopicus , has been found to prevent graft rejection following organ transplantations ( 127 ). … Sirolimus for the treatment of multi-resistant autoimmune haemolytic anaemia in children. Br J Haematol (2014) 167(4):571–4. doi: 10.1111/bjh.13010 129. Jasinski S, Weinblatt ME, Glasser CL. …

Case Report: First occurrence of smoldering multiple myeloma in activated phosphoinositide 3-Kinase δ syndrome.

Activated phosphoinositide 3-kinase δ syndrome (APDS) is a newly described inborn error of immunity. Heterozygous mutations in the PI3Kδ catalytic subunit p110δ (PIK3CD) or regulatory subunit p85α (PIK3R1) lead to APDS1 and APDS2, respectively. Clinical manifestations include lymphoproliferation, recurrent respiratory tract infections, herpesvirus infections, enteropathy, elevated IgM, autoimmunity, and increased susceptibility to tumors, particularly lymphoma. Smoldering multiple myeloma (SMM), an asymptomatic clonal plasma cell disorder considered a pre-malignant entity, may progress to symp

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… The patient was advised to consider sirolimus, immunoglobulin replacement, or allogeneic HSCT, but she declined due to financial constraints and opted for prophylactic antibiotics and antivirals (trimethoprim-sulfamethoxazole and valacyclovir). … At the time of diagnosis (2022), only sirolimus, immunoglobulin replacement, and HSCT were available, all of which the patient declined. …

Transplant oncology and anti-cancer immunosuppressants.

Organ transplantation is a life-saving intervention that enhances the quality of life for patients with end-stage organ failure. However, long-term immunosuppressive therapy is required to prevent allogeneic graft rejection, which inadvertently elevates the risk of post-transplant malignancies, especially for liver transplant recipients with a prior history of liver cancer. In response, the emerging field of transplant oncology integrates principles from oncology and immunology to improve outcomes for patients at high risk of tumor occurrence or recurrence following transplantation. Therefore,

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… Sirolimus and Everolimus While in transplantation, rapamycin binds to FKBP12 and inhibits mTOR, which blocks T-cell and B-cell activation and proliferation by preventing the response to IL-2 ( 23 ). … Sirolimus-based immunosuppression in liver transplantation for hepatocellular carcinoma: a meta-analysis. Liver Transpl. (2012) 18:62–9. doi: 10.1002/lt.22441 26. Zimmermann T, Schemmer P, Berghauser KH, Mylo M, Buhr J, Padberg WM. …

Targeted therapy in the treatment of malignant gliomas.

Malignant gliomas are invasive tumors with the potential to progress through current available therapies. These tumors are characterized by a number of abnormalities in molecular signaling that play roles in tumorigenesis, spread, and survival. These pathways are being actively investigated in both the pre-clinical and clinical settings as potential targets in the treatment of malignant gliomas. We will review many of the therapies that target the cancer cell, including the epidermal growth factor receptor, mammalian target of rapamycin, histone deacetylase, and farnesyl transferase. In additi

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… as a single agent and two trials evaluating sirolimus in combination with erlotinib. … Temsirolimus, an ester analogue of sirolimus, was evaluated as a single agent in a phase II trial of recurrent GBM. …

Exploring the genetic alterations of Gorham-Stout disease.

The "vanishing bone disease" or Gorham-Stout disease (GSD) is a very rare disorder characterized by massive lymphatic and angiomatous proliferation accompanied by progressive osteolysis, without the deposition of new bone matrix. Because of its rare and complex clinical features, diagnosis is challenging and its etiopathogenesis is not completely known; the genetic basis of GSD has been hypothesized and different mutations have been reported in patients. Our review aims to describe all these genetic alterations found in GSD patients and their association with clinical features. The identificat

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… More recently, the repurposing of oncogenic treatments, such as Sirolimus or Alectinib, has become more frequent and will be further described in this review. … GATA2 In a very short case report, Oguz and colleagues investigated the genomic signature of a pediatric female diagnosed with GSD and presenting cardiac tamponade, who was successfully treated with Sirolimus ( 71 ). …

Assessment of kidney transplant suitability for patients with prior cancers: is it time for a rethink?

Kidney transplant recipients have up to a 100-fold greater risk of incident cancer compared with the age/sex-matched general population, attributed largely to chronic immunosuppression. In patients with a prior history of treated cancers, the type, stage and the potential for cancer recurrence post-transplant of prior cancers are important factors when determining transplant suitability. Consequently, one of the predicaments facing transplant clinicians is to determine whether patients with prior cancers are eligible for transplantation, balancing between the accelerated risk of death on dialy

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… Randomized controlled trial of sirolimus for renal transplant recipients at high risk for nonmelanoma skin cancer . … Inhibition of mTOR by sirolimus induces remission of post‐transplant lymphoproliferative disorders . …

Treosulfan-Based Conditioning Regimen Prior to Allogeneic Stem Cell Transplantation: Long-Term Results From a Phase 2 Clinical Trial.

INTRODUCTION: Reducing toxicities while preserving efficacy in allogeneic stem cell transplant (allo-HCT) remains a particularly challenging problem. Different strategies to enhance the antitumor activity without increasing early and late adverse toxicities of the conditioning regimens have been investigated. METHODS: The aim of "AlloTreo" prospective phase 2 clinical trial was to evaluate the efficacy and safety of a conditioning regimen based on Treosulfan (42 g/m2) and fludarabine (https://clinicaltrials.gov/ct2/show/NCT00598624). We enrolled 108 patients with hematological diseases who re

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… Sirolimus-Based Graft- Versus -Host Disease Prophylaxis Promotes the In Vivo Expansion of Regulatory T Cells and Permits Peripheral Blood Stem Cell Transplantation From Haploidentical Donors . … Post-Transplantation Cyclophosphamide and Sirolimus After Haploidentical Hematopoietic Stem Cell Transplantation Using a Treosulfan-Based Myeloablative Conditioning and Peripheral Blood Stem Cells . …

Use of azathioprine for graft-vs-host disease is the major risk for development of secondary malignancies after haematopoietic stem cell transplantation: a nationwide population-based study.

BackgroundAs more patients are treated by haematopoietic stem cell transplantation (HSCT), development of secondary malignancy (SM) becomes an increasingly common issue in long-term survivors.MethodsWe conducted a nationwide population-based study of the Taiwanese population to analyse patients who received HSCT between January 1997 and December 2010. Standardised incidence ratios (SIRs) were used to compare the risk of SM in HSCT patients and the general population. Multivariate analysis was performed to identify independent predictors of SM.ResultsPatients receiving HSCT had a significantly

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… 427 (38.7%) cGVHD | 751 (49.6%) | 413 (49.4%) | 338 (49.8%) Immunosupressants b Cyclosporin | 1471 (97.1%) | 805 (96.2%) | 666 (98.2%) Tacrolimus | 138 (9.1%) | 76 (9.1%) | 62 (9.1%) Methylprednisolone | 253 (16.7%) | 134 (16.0%) | 119 (17.5%) Mycophenolate | 253 (16.7%) | 145 (17.3%) | 108 (15.9%) Sirolimus … There were trends for cGVHD (HR 2.19, 95% CI 0.91–5.27; P =0.082) and sirolimus use (HR 6.34, 95% CI 0.81–49.29; P =0.078) to be risk factors. …

Beyond the rare: a case of pseudomyogenic hemangioendothelioma treated sequentially with everolimus, denosumab, and pazopanib.

Pseudomyogenic hemangioendothelioma is an ultra-rare vascular sarcoma that most commonly affects young adults, with a male predominance. It is diagnosed using a combination of imaging studies, histopathological examinations, and immunohistochemical staining. Surgical excision is the mainstay of treatment for pseudomyogenic hemangioendothelioma, with the goal of achieving a wide local excision and reducing the risk of recurrence. The role of systemic therapies is not well established because of the rarity of pseudomyogenic hemangioendothelioma, uncertainty regarding its response to currently ap

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… | PD Stable disease in two years of follow-up | Positive for phospho-S6 protein and negative for VEGF expression Danforth et al. ( 31 ) | One patient, 6-year-old | Sirolimus Zoledronic Acid | CR | Brance et al. ( 16 ) | One patient, 25 years old Left femur, tibia, patella, ankle and foot | Pamidronate … therapy in the treatment of pseudomyogenic hemangioendothelioma Pediatr Blood Cancer 2018 65 2 e26781 10.1002/pbc.26781 28843050 31 Danforth OM Tamulonis K Vavra K Oh C Brickman A Ebersole J Effective Use of Sirolimus and Zoledronic Acid for Multiosteotic Pseudomyogenic Hemangioendothelioma of the …

A systematic review of ongoing clinical trials in optic pathway gliomas.

INTRODUCTION: Optic pathway gliomas (OPGs), also known as Visual Pathway Gliomas, are insidious, debilitating tumours. They are most commonly WHO grade 1 pilocytic astrocytomas and frequently occur in patients with neurofibromatosis type 1. The location of OPGs within the optic pathway typically precludes complete resection or optimal radiation dosing, hence outcomes remain poor compared to many other low-grade gliomas. The aim of this systematic review was to formulate a comprehensive list of all current ongoing clinical trials that are specifically looking at clinical care of OPGs in order t

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… Sirolimus/everolimus | First- and second-generation mTOR inhibitors. The mTOR pathway is important in control of cellular growth. … Differentiating the mTOR inhibitors everolimus and sirolimus in the treatment of tuberous sclerosis complex. Neuro-Oncology. 2015;17:1550–1559. doi: 10.1093/neuonc/nov152. 58. Kyi C, Roudko V, Sabado R, et al. …