scholarly journals Use of sirolimus in the treatment of lymphangioleiomyomatosis: favorable responses in patients with different extrapulmonary manifestations

2015 ◽  
Vol 41 (3) ◽  
pp. 275-280 ◽  
Author(s):  
Carolina Salim Gonçalves Freitas ◽  
Bruno Guedes Baldi ◽  
Mariana Sponholz Araújo ◽  
Glaucia Itamaro Heiden ◽  
Ronaldo Adib Kairalla ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Case Series ◽  
Mtor Inhibitors ◽  
Optimal Dose ◽  
Metastatic Potential ◽  
Low Grade ◽  
Renal Angiomyolipoma ◽  
Duration Of Treatment ◽  
Abdominal Lymph Node ◽  
Significant Regression

OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare disease that is currently considered a low-grade neoplasm with metastatic potential and variable progression. Mammalian target of rapamycin (mTOR) inhibitors, such as sirolimus and everolimus, have recently become a treatment option for LAM patients, especially those with extrapulmonary manifestations. The objective of the present study was to describe a case series of four patients with LAM in Brazil who showed significant improvement, particularly in their extrapulmonary manifestations, after treatment with sirolimus (at 1-4 mg/day). METHODS: We describe four cases of LAM patients with different extrapulmonary manifestations who were treated with sirolimus. RESULTS: After treatment with sirolimus for 12 months, one patient presented resolution of severe chylothorax; one had a significant reduction in renal angiomyolipoma volume; and one showed significant regression of retroperitoneal lymphangioleiomyomas and abdominal lymph node enlargement. After treatment with sirolimus for 6 months, the remaining patient had a significant reduction in the volume of a massive retroperitoneal lymphangioleiomyoma. CONCLUSIONS: Our findings confirm that mTOR inhibitors are beneficial for patients with LAM, especially those with extrapulmonary manifestations, such as renal angiomyolipoma, lymphangioleiomyomas, and chylous effusions. However, certain aspects, such as the optimal dose, duration of treatment, and long-term adverse effects, have yet to be sufficiently clarified for mTOR inhibitors to be incorporated into LAM management protocols.

scholarly journals LGG-18. EVEROLIMUS TREATMENT IN PEDIATRIC PATIENTS AFFECTED BY LOW-GRADE GLIOMAS (pLGG) NON-TSC, BRAF v600-WT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii369-iii369
Author(s):  
Antonella Cacchione ◽  
Evelina Miele ◽  
Maria Chiara Lodi ◽  
Andrea Carai ◽  
Giovanna Stefania Colafati ◽  
...  
Keyword(s):  
Adverse Event ◽  
Disease Progression ◽  
Mapk Pathway ◽  
Brain Mri ◽  
Mammalian Target Of Rapamycin ◽  
Low Grade ◽  
Duration Of Treatment ◽  
Tumor Biopsy ◽  
Low Grade Gliomas ◽  
Personalized Approach

Abstract BACKGROUND MAPK pathway is the hallmark of pediatric low grade gliomas (pLGGs); hyperactivation of mTOR (mammalian target of rapamycin) might be a suitable biomarker for therapeutic response. We investigated the feasibility of Everolimus, mTOR inhibitor, in patients affected by pLGGs. METHODS Patients 1 to 18 years old, diagnosed with pLGG, with a positive tumor biopsy for mTOR/phospho-mTOR and radiological and / or clinical disease progression, treated at Bambino Gesù Children’s Hospital in Rome were evaluated. Tumor DNA methylation analysis was performed in 10 cases. Exclusion criteria included: Tuberous Sclerosis patients, Sub Ependymal Giant Astrocytoma. Everolimus was administered orally at a dose of 2.5 mg or 5 mg daily based on body weight. Patients were evaluated with brain MRI every 4, 8 and 12 months after treatment start and every six months thereafter. RESULTS 16 patients were enrolled from September 2014 and 2019. The median age was 7.5 years old. All patients had at least one adverse event. Events rated as severe (grade 3/4) were reported in 6 patients. Stomatitis was the most frequent adverse event. One patient discontinued treatment due to grade 4 toxicity (ulcerative stomatitis and fatigue). The median duration of treatment was 21 months (4–57 months). Brain MRI evaluations have showed disease stability in 11 patients, partial response in 2 patients and disease progression in 3 patients. CONCLUSIONS Everolimus has proven to be well tolerated and effective treatment in terms of disease stability in patients with pLGGs. It’s also an excellent example of chemo-free personalized approach.

scholarly journals Promises of targeted therapy for low grade gliomas in children

2019 ◽  
Vol 6 (2) ◽  
pp. 28-41
Author(s):  
E. F. Valiakhmetova ◽  
L. A. Yasko ◽  
L. I. Papusha ◽  
A. E. Druy ◽  
A. I. Karachunsky
Keyword(s):  
Targeted Therapy ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Inhibitors ◽  
Molecular Pathogenesis ◽  
New Drugs ◽  
Mitogen Activated Protein Kinase ◽  
System Control ◽  
Low Grade ◽  
Low Grade Gliomas ◽  
Mitogen Activated Protein

Low grade gliomas are the most common brain tumors in children. Total resection for operable lesion helps to achieve local and system control. Nevertheless, for inaccessible tumors are required more effective treatment both to overcome the refractory course of the disease, and to mi nimize toxicity with conventional adjuvant chemotherapy and various types of radiation therapy. In recent years, there has been an accelerated understanding of the molecular pathogenesis of some tumors in children, including low grade gliomas. Given the fact that the basis of the molecular pathogenesis of the low grade gliomas is the activation of signaling pathways MARK (mitogen activated protein kinase) and mTOR (mammalian target of rapamycin), the most promising targeted agents are BRAF, MEK and mTOR inhibitors. Nevertheless, a number of other agents have been studied to find promising targeted therapy for this tumors type. This article summarizes the latest literature evaluating new drugs in low grade glioma.

scholarly journals Trends in Percutaneous Thermal Ablation Therapies in the Treatment of T1a Renal Cell Carcinomas Rather than Partial Nephrectomy/Radical Nephrectomy

2019 ◽  
Vol 36 (03) ◽  
pp. 183-193 ◽  
Author(s):  
Sepideh Shakeri ◽  
Steven S. Raman
Keyword(s):  
Renal Cell ◽  
Thermal Ablation ◽  
Meta Analysis ◽  
Case Series ◽  
Metastatic Potential ◽  
Surgical Approaches ◽  
Low Grade ◽  
Long Term Follow Up

AbstractWith the increased incidence of stage T1a renal cell carcinoma (RCC) has come the recognition that these lesions tend to be low grade and slow growing, with low probability of metastasis not necessarily requiring surgery. As alternatives to surgery, both active surveillance and ablation have been advocated for the management of selected patients with stage T1a renal cancers due to slow rate of tumor growth and low metastatic potential based on recent epidemiological studies. Thermal ablation also has consistently reported favorable complication and renal preservation rates compared with surgical approaches. However, most studies are single-center case series and meta-analysis of these series and comparative prospective series with long-term follow-up are lacking. The purpose of this article is to review the principal thermal ablation modalities and oncological outcomes for the treatment of stage T1 RCCs with long-term follow-up.

Therapeutic targeting of mTOR in tuberous sclerosis

2009 ◽  
Vol 37 (1) ◽  
pp. 259-264 ◽  
Author(s):  
Julian R. Sampson
Keyword(s):  
Tuberous Sclerosis ◽  
Anticancer Agents ◽  
Mammalian Target Of Rapamycin ◽  
Case Series ◽  
Mtor Inhibitors ◽  
Clinical Settings ◽  
Protein Activity ◽  
Variable Feature ◽  
Drug Eluting ◽  
Mtor Complex 1

Failure in the regulation of mTOR (mammalian target of rapamycin) appears to be critical to the pathogenesis of the inherited disorder tuberous sclerosis and the related lung disease LAM (lymphangioleiomyomatosis). Both diseases are caused by mutations of TSC1 or TSC2 (TSC is tuberous sclerosis complex) that impair GAP (GTPase-activating protein) activity of the TSC1–TSC2 complex for Rheb, leading to inappropriate activity of signalling downstream of mTORC1 (mTOR complex 1). mTOR inhibitors are already used in a variety of clinical settings including as immunosuppressants, anticancer agents and antiproliferative agents in drug-eluting coronary artery stents. They also represent candidate therapies directed to the underlying molecular pathology in tuberous sclerosis and LAM. Phase I/II clinical trials of the mTORC1 inhibitor rapamycin have demonstrated reduction in size of tuberous-sclerosis- and LAM-associated renal tumours (angiomyolipomas) and some evidence for reversible improvement in lung function in patients with LAM. A case series of tuberous-sclerosis-associated brain tumours were also reported to shrink during rapamycin therapy. An important, although variable, feature of the tuberous sclerosis phenotype is learning difficulty. Recent studies in mouse models carrying heterozygous Tsc2 mutations demonstrated improvement in memory and learning deficits following treatment with rapamycin. These promising pre-clinical and early human trials are being followed by larger-scale randomized control trials of mTOR inhibitors for treatment of renal, lung and brain manifestations of TSC1- and TSC2-associated disease.

scholarly journals A200 VEDOLIZUMAB IS AN EFFECTIVE TREATMENT OPTION FOR NON INFLAMMATORY BOWEL DISEASE RELATED ENTEROPATHY

2021 ◽  
Vol 4 (Supplement_1) ◽  
pp. 224-225
Author(s):  
H Akhtar ◽  
T Nguyen ◽  
V Jairath
Keyword(s):  
Clinical Response ◽  
Case Series ◽  
Duration Of Treatment ◽  
Effective Treatment Option ◽  
Histologic Response ◽  
Funding Agencies ◽  
Full Text Review ◽  
Language Restriction ◽  
Inflammatory Bowel ◽  
Cell Adhesion Molecule 1

Abstract Background Vedolizumab is an α4β7 integrin antagonist which inhibits intestinal T-cell translocation by blocking integrin interactions with mucosal vascular addressin cell adhesion molecule 1, reducing lymphocyte mediated inflammation. Its gut selective mode of action and safety profile have lead to reports of off-label use of vedolizumab for non-IBD related inflammatory intestinal disorders. Aims We conducted a literature review to assess clinical, endoscopic and histologic improvement in patients treated with Vedolizumab for non-IBD enteropathies refractory to conventional therapy. Methods EMBASE, Medline, Clinicaltrials.gov and Cochrane CENTRAL were searched on September 12, 2019 for case studies, case series and cohort studies without language restriction yielding 356 studies with 164 duplicates, 74 non-applicable studies, leaving 118 studies. After full text review, 98 studies were excluded, leaving 20 included studies. Results 65% of patients (51/79) achieved clinical response. 40.5% (15/37) of patients experienced endoscopic improvement and 33% (17/51) of patients experienced histologic improvement. The duration of treatment varied from patients receiving only induction doses to up to 70 months for maintenance therapy. There were four reported cases of withdrawal due to adverse events from Vedolizumab. Conclusions In a treatment refractory population, over 60% of patients reported to have a clinical response and one-third endoscopic/histologic response, indicating that Vedolizumab is a viable option for patients with refractory non-IBD enteropathy. Funding Agencies None

scholarly journals Impact of Pathological Stratification on the Clinical Outcomes of Advanced Well-Differentiated/Dedifferentiated Liposarcoma Treated with Trabectedin

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1453
Author(s):  
Chiara Fabbroni ◽  
Giovanni Fucà ◽  
Francesca Ligorio ◽  
Elena Fumagalli ◽  
Marta Barisella ◽  
...  
Keyword(s):  
Clinical Outcomes ◽  
Proportional Hazards ◽  
Case Series ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Low Grade ◽  
High Grade ◽  
Retrospective Case ◽  
Well Differentiated ◽  
The Impact

Background. We previously showed that grading can prognosticate the outcome of retroperitoneal liposarcoma (LPS). In the present study, we aimed to explore the impact of pathological stratification using grading on the clinical outcomes of patients with advanced well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) treated with trabectedin. Patients: We included patients with advanced WDLPS and DDLPS treated with trabectedin at the Fondazione IRCCS Istituto Nazionale dei Tumori between April 2003 and November 2019. Tumors were categorized in WDLPS, low-grade DDLPS, and high-grade DDLPS according to the 2020 WHO classification. Patients were divided in two cohorts: Low-grade (WDLPS/low-grade DDLPS) and high-grade (high-grade DDLPS). Results: A total of 49 patients were included: 17 (35%) in the low-grade cohort and 32 (65%) in the high-grade cohort. Response rate was 47% in the low-grade cohort versus 9.4% in the high-grade cohort (logistic regression p = 0.006). Median progression-free survival (PFS) was 13.7 months in the low-grade cohort and 3.2 months in the high-grade cohort. Grading was confirmed as an independent predictor of PFS in the Cox proportional-hazards regression multivariable model (adjusted hazard ratio low-grade vs. high-grade: 0.45, 95% confidence interval: 0.22–0.94; adjusted p = 0.035). Conclusions: In this retrospective case series, sensitivity to trabectedin was higher in WDLPS/low-grade DDLPS than in high-grade DDLPS. If confirmed in larger series, grading could represent an effective tool to personalize the treatment with trabectedin in patients with advanced LPS.

scholarly journals The Gerbode defect: a case series

2021 ◽  
Vol 5 (2) ◽  
Author(s):  
Nicholas Sunderland ◽  
Ahmed El-Medany ◽  
Justin Temporal ◽  
Laura Pannell ◽  
Gemina Doolub ◽  
...  
Keyword(s):  
Infective Endocarditis ◽  
Aortic Valve ◽  
Case Series ◽  
Decompensated Heart Failure ◽  
Left Ventricular ◽  
Cardiac Complications ◽  
Low Grade ◽  
Care Needs ◽  
Intravenous Antibiotics ◽  
Gerbode Defect

Abstract Background  The Gerbode defect is a rare abnormal communication between the left ventricle (LV) and right atrium (RA). The lesion is either congenital or acquired. Acquired defects are largely iatrogenic or infective in origin. We present two cases of acquired Gerbode defects with similar clinical presentations but very different outcomes. Case summaries Patient 1 A 64-year-old male presented with features of decompensated cardiac failure and a low-grade temperature. Dehiscence of a recently implanted bioprosthetic aortic valve and high-velocity LV to RA jet (Gerbode defect) was found on echocardiography. Blood cultures grew Staphylococcus warneri and the diagnosis of infective endocarditis was established. The patient was treated with intravenous antibiotics and the aortic valve and Gerbode defect were successfully surgically repaired. Patient 2 An 81-year-old male presented after being found on the floor at home. On admission, he was clinically septic with evidence of decompensated heart failure. No clear infective focus was initially found. Transthoracic echocardiography revealed severe left ventricular impairment, with a normal bioprosthetic aortic valve. He was treated with intravenous antibiotics, but later deteriorated with evidence of embolic phenomena. Repeat echocardiography revealed a complex infective aortic root lesion with bioprosthetic valve dehiscence and flow demonstrated from the LV to RA. Unfortunately, the patient succumbed to the infection and cardiac complications. Discussion  The Gerbode defect is a rare but important complication of infective endocarditis and valve surgery. Care needs to be taken to assess for Gerbode defect shunts on echocardiogram, especially in the context of previous cardiac surgery.

scholarly journals Mammalian target of rapamycin signaling activation patterns in neuroendocrine tumors of the lung

2010 ◽  
Vol 17 (4) ◽  
pp. 977-987 ◽  
Author(s):  
Luisella Righi ◽  
Marco Volante ◽  
Ida Rapa ◽  
Veronica Tavaglione ◽  
Frediano Inzani ◽  
...  
Keyword(s):  
Neuroendocrine Tumors ◽  
Mammalian Target Of Rapamycin ◽  
Mtor Pathway ◽  
Differential Sensitivity ◽  
Initiation Factor ◽  
Target Of Rapamycin ◽  
Low Grade ◽  
Mtor Inhibition ◽  
Signaling Activation ◽  
Activation Status

Among alternative therapeutic strategies in clinically aggressive neuroendocrine tumors (NETs) of the lung, promising results have been obtained in experimental clinical trials with mammalian target of rapamycin (mTOR) inhibitors, though in the absence of a proven mTOR signaling activation status. This study analyzed the expression of phosphorylated mTOR (p-mTOR) and its major targets, the ribosomal p70S6-kinase (S6K) and the eukaryotic initiation factor 4E-binding protein 1 (4EBP1) in a large series of 218 surgically resected, malignant lung NETs, including 24 metastasizing typical carcinoids, 73 atypical carcinoids, 60 large cell neuroendocrine carcinomas (LCNECs), and 61 small cell carcinomas (SCLCs). By immunohistochemistry, low-to-intermediate-grade tumors as compared with high-grade tumors showed higher levels of p-mTOR and phosphorylated S6K (p-S6K) (P<0.001), at variance with phosphorylated 4EBP1 (p-4EBP1), which was mainly expressed in LCNECs and SCLCs (P<0.001). The activated status of mTOR pathway was proved by the strong correlation of p-mTOR with p-S6K and somatostatin receptor(s). Western blot analysis of NET tumor samples confirmed such findings, and differential sensitivity to mTOR inhibition according to mTOR pathway activation characteristics was determined in two lung carcinoid cell lines in vitro. None of the investigated molecules had an impact on survival. However, in low-grade tumors, low p-mTOR expression correlated with lymph node metastases (P=0.016), recurrent disease, and survival (P=0.005). In conclusion, these data demonstrate a differential mTOR activation status in the spectrum of pulmonary NETs, possibly suggesting that mTOR pathway profiling might play a predictive role in candidate patients for mTOR-targeted therapies.

scholarly journals Long-term follow-up after colorectal endoscopic submucosal dissection in 182 cases

2021 ◽  
Vol 09 (02) ◽  
pp. E258-E262
Author(s):  
Christian Suchy ◽  
Moritz Berger ◽  
Ingo Steinbrück ◽  
Tsuneo Oyama ◽  
Naohisa Yahagi ◽  
...  
Keyword(s):  
Case Series ◽  
En Bloc Resection ◽  
Bloc Resection ◽  
Published Data ◽  
Low Grade ◽  
Recurrence Rates ◽  
En Bloc ◽  
Long Term Follow Up

Abstract Background and study aims We previously reported a case series of our first 182 colorectal endoscopic submucosal dissections (ESDs). In the initial series, 155 ESDs had been technically feasible, with 137 en bloc resections and 97 en bloc resections with free margins (R0). Here, we present long-term follow-up data, with particular emphasis on cases where either en bloc resection was not achieved or en bloc resection resulted in positive margins (R1). Patients and methods Between September 2012 and October 2015, we performed 182 consecutive ESD procedures in 178 patients (median size 41.0 ± 17.4 mm; localization rectum vs. proximal rectum 63 vs. 119). Data on follow-up were obtained from our endoscopy database and from referring physicians. Results Of the initial cohort, 11 patients underwent surgery; follow-up data were available for 141 of the remaining 171 cases (82,5 %) with a median follow-up of 2.43 years (range 0.15–6.53). Recurrent adenoma was observed in 8 patients (n = 2 after margin positive en bloc ESD; n = 6 after fragmented resection). Recurrence rates were lower after en bloc resection, irrespective of involved margins (1.8 vs. 18,2 %; P < 0.01). All recurrences were low-grade adenomas and could be managed endoscopically. Conclusions The rate of recurrence is low after en bloc ESD, in particular if a one-piece resection can be achieved. Recurrence after fragmented resection is comparable to published data on piecemeal mucosal resection.

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