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Pharmacological Research Sep 2023Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterised by abnormal cell proliferation and differentiation that affects multiple organs and can... (Review)
Review
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterised by abnormal cell proliferation and differentiation that affects multiple organs and can lead to the growth of hamartomas. Tuberous sclerosis complex is caused by the disinhibition of the protein mTOR (mammalian target of rapamycin). In the past, various therapeutic approaches, even if only symptomatic, have been attempted to improve the clinical effects of this disease. While all of these therapeutic strategies are useful and are still used and indicated, they are symptomatic therapies based on the individual symptoms of the disease and therefore not fully effective in modifying long-term outcomes. A new therapeutic approach is the introduction of allosteric inhibitors of mTORC1, which allow restoration of metabolic homeostasis in mutant cells, potentially eliminating most of the clinical manifestations associated with Tuberous sclerosis complex. Everolimus, a mammalian target of the rapamycin inhibitor, is able to reduce hamartomas, correcting the specific molecular defect that causes Tuberous sclerosis complex. In this review, we report the findings from the literature on the use of everolimus as an effective and safe drug in the treatment of TSC manifestations affecting various organs, from the central nervous system to the heart.
Topics: Humans; Everolimus; Tuberous Sclerosis; Sirolimus; Mechanistic Target of Rapamycin Complex 1
PubMed: 37549757
DOI: 10.1016/j.phrs.2023.106884 -
Journal of Kidney Cancer and VHL 2023Renal leiomyomas are rare benign mesenchymal tumors of kidney that affect adults of second to sixth decade. They can present as small asymptomatic multifocal lesions...
Renal leiomyomas are rare benign mesenchymal tumors of kidney that affect adults of second to sixth decade. They can present as small asymptomatic multifocal lesions that are identified only in autopsy, or as large solitary lesions that cause pain and abdominal distention. Histomorphologically it appears exactly like its counterpart in other soft tissues. Differentiating renal leiomyoma from the lipid-poor angiomyolipoma is difficult by morphology, hence immunohistochemical studies are recommended. The case described is that of a female patient aged 74 years with a small solitary lesion in right kidney, who presented with history of pain and abdominal distention. She underwent wedge resection, histopathologically and immunohistochemically diagnosed as renal leiomyoma.
PubMed: 37398509
DOI: 10.15586/jkcvhl.v10i2.264 -
Nature Communications Jan 2024Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions in...
Tuberous Sclerosis Complex (TSC) is caused by TSC1 or TSC2 mutations, leading to hyperactivation of mechanistic target of rapamycin complex 1 (mTORC1) and lesions in multiple organs including lung (lymphangioleiomyomatosis) and kidney (angiomyolipoma and renal cell carcinoma). Previously, we found that TFEB is constitutively active in TSC. Here, we generated two mouse models of TSC in which kidney pathology is the primary phenotype. Knockout of TFEB rescues kidney pathology and overall survival, indicating that TFEB is the primary driver of renal disease in TSC. Importantly, increased mTORC1 activity in the TSC2 knockout kidneys is normalized by TFEB knockout. In TSC2-deficient cells, Rheb knockdown or Rapamycin treatment paradoxically increases TFEB phosphorylation at the mTORC1-sites and relocalizes TFEB from nucleus to cytoplasm. In mice, Rapamycin treatment normalizes lysosomal gene expression, similar to TFEB knockout, suggesting that Rapamycin's benefit in TSC is TFEB-dependent. These results change the view of the mechanisms of mTORC1 hyperactivation in TSC and may lead to therapeutic avenues.
Topics: Animals; Mice; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice, Knockout; Sirolimus; Tuberous Sclerosis
PubMed: 38195686
DOI: 10.1038/s41467-023-44229-4 -
Orphanet Journal of Rare Diseases Dec 2023The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms... (Clinical Trial)
Clinical Trial
BACKGROUND
The randomised double-blinded placebo-controlled EXIST-1-3 studies have showed everolimus effective with adverse effects reported as acceptable in treatment of symptoms in patients with tuberous sclerosis complex (TSC), although evidence of outcomes in clinical practice remains limited. This study aimed to investigate, in clinical practice, the effectiveness and safety of everolimus for epilepsy, renal angiomyolipoma (rAML), and subependymal giant cell astrocytoma (SEGA) in patients with TSC.
RESULTS
The study included 64 patients with TSC (median age: 19, range 0.9-54 years) receiving everolimus treatment (Norway: n = 35; Denmark: n = 29). Among 45 patients with epilepsy, 14 (31%) were responders experiencing ≥ 50% reduction in seizure frequency in the last 3 months of treatment compared with the last 3 months before treatment. Nineteen (42%) patients changed their anti-seizure medications (ASMs). Responders were more common among patients < 18 years (46%) than among patients ≥ 18 years (14%, p = 0.03). In 29 patients with rAML, everolimus reduced (≥ 30% decrease) and stabilized (< 20% increase, ≤ 30% decrease) longest diameter of rAML in 38% and 59%, respectively, after a mean treatment duration of 37 months. SEGA volume was reduced in three patients by 71%, 43%, and 48% after 39, 34, and 82 months. Adverse effects were reported in 61 of 64 patients (95%) after a median treatment duration of 31 months (range 0-106), with oral ulceration/stomatitis (63%) and upper respiratory tract infections (38%) being the most common. The most common laboratory abnormalities were increased cholesterol (41%), anaemia (30%), and leucopoenia (25%). Grade 3-4 adverse effects were reported in 36% of cases, and life-threatening conditions were reported in two patients. Nine patients discontinued everolimus treatment.
CONCLUSIONS
Seizure reduction in this study sample was consistent with results from EXIST, but might be lower than expected, given that changes in concomitant ASMs are part of clinical practice. Seizure reduction was associated with younger age. As with EXIST, everolimus reduced or stabilised rAML size in most patients. SEGA volume was reduced in all three patients. Close follow-up is needed for this group, especially for children and patients who may not be able to report adverse effects.
Topics: Adolescent; Adult; Child; Child, Preschool; Humans; Infant; Middle Aged; Young Adult; Angiomyolipoma; Antineoplastic Agents; Astrocytoma; Epilepsy; Everolimus; Kidney Neoplasms; Seizures; Tuberous Sclerosis
PubMed: 38042867
DOI: 10.1186/s13023-023-02982-1 -
BMC Pediatrics Jun 2023To investigate the complete clinical spectrum of individuals with paediatric tuberous sclerosis complex in southern Sweden and explore changes over time. (Observational Study)
Observational Study
AIM
To investigate the complete clinical spectrum of individuals with paediatric tuberous sclerosis complex in southern Sweden and explore changes over time.
METHODS
In this retrospective observational study, 52 individuals aged up to 18 years at the study start were followed-up at regional hospitals and centres for habilitation from 2000 to 2020.
RESULTS
Cardiac rhabdomyoma was detected prenatally/neonatally in 69.2% of the subjects born during the latest ten years of the study period. Epilepsy was diagnosed in 82.7% of subjects, and 10 (19%) were treated with everolimus, mainly (80%) for a neurological indication. Renal cysts were detected in 53%, angiomyolipomas in 47%, astrocytic hamartomas in 28% of the individuals. There was a paucity of standardized follow-up of cardiac, renal, and ophthalmological manifestations and no structured transition to adult care.
CONCLUSION
Our in-depth analysis shows a clear shift towards an earlier diagnosis of tuberous sclerosis complex in the latter part of the study period, where more than 60% of cases showed evidence of this condition already in utero due to the presence of a cardiac rhabdomyoma. This allows for preventive treatment of epilepsy with vigabatrin and early intervention with everolimus for potential mitigation of other symptoms of tuberous sclerosis complex.
Topics: Adult; Child; Humans; Aged; Tuberous Sclerosis; Everolimus; Rhabdomyoma; Sweden; Early Intervention, Educational; Heart Neoplasms
PubMed: 37386496
DOI: 10.1186/s12887-023-04137-4 -
Journal of Surgical Case Reports Oct 2023Perivascular epithelioid cell neoplasm (PEComa) is a rare type of tumor, and hepatic PEComa is even rarer. Its preoperative diagnosis is difficult, given the absence of...
Perivascular epithelioid cell neoplasm (PEComa) is a rare type of tumor, and hepatic PEComa is even rarer. Its preoperative diagnosis is difficult, given the absence of specific clinical manifestations, often constituting an accidental finding, and the lack of a gold standard for identification using imaging studies. Instead, the diagnosis of hepatic PEComa is based on morphological and immunohistochemical features. We describe a case of an asymptomatic hepatic PEComa, angiomyolipoma type, which appeared in a middle-aged woman with chronic liver disease, during her follow-up and screening. Given the patient's context, human immunodeficiency virus-positive with chronic hepatitis C, and the similarities between the two tumors, the hepatic lesion was interpreted as hepatocellular carcinoma. The patient underwent surgical excision of the tumor, and the positive immunohistochemical staining for human melanoma black 45 and Melan A made the definitive diagnosis. In the absence of aggressiveness tumor markers, surveillance was decided. We also provide a literature review of these tumors.
PubMed: 37846416
DOI: 10.1093/jscr/rjad556 -
Oncology Letters Sep 2023Epithelioid angiomyolipoma (EAML) of the kidney is an uncommon neoplasm with malignant potential. It can occur sporadically or be associated with tuberous sclerosis....
Epithelioid angiomyolipoma (EAML) of the kidney is an uncommon neoplasm with malignant potential. It can occur sporadically or be associated with tuberous sclerosis. EAML is a monotypic variant of angiomyolipoma (AML), which is classified as neoplasm of the perivascular epithelioid cell or perivascular epithelioid cell tumor. Due to its epithelioid nature and paucity of fat components, unlike classic AML, which has abundant adipose tissue with characteristic features on CT scans, it is difficult to distinguish EAML from renal cell carcinoma and fat-poor AML on CT or MRI preoperatively, which may lead to misdiagnosis and unnecessary nephrectomy. The present report describes two cases of renal EAML, which were successfully treated by laparoscopic surgery. Preoperative diagnosis had not been achieved until surgery was performed and histological analysis was accomplished. No local recurrence or distal metastasis was observed during follow-up. Although the differential diagnosis was challenging preoperatively, a diagnosis of EAML should be considered and surgical excision was the preferred treatment strategy for the patients with localized tumors.
PubMed: 37600337
DOI: 10.3892/ol.2023.13995