Use Of Everolimus Research Articles

LGG-03. LONG-TERM FOLLOW UP OF TARGETED THERAPY IN PEDIATRIC LOW-GRADE GLIOMAS: THE DANA-FARBER/BOSTON CHILDREN’S EXPERIENCE

BackgroundPediatric low grade gliomas (pLGGs) are the most common central nervous system (CNS) tumor in children and characterized by alterations in the MAPK pathway. Standard of care is not well defined, and treatment has evolved over the last decade to include molecular targeted therapies. The impact of targeted agents on the natural history of pLGGs remains unknown. We present a retrospective review of patients receiving targeted agents integrated with molecular profiling. MethodsWe performed an IRB-approved, retrospective chart review of pLGGs treated with off-label use of dabrafenib, vemurafenib, everolimus, and trametinib at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center from 2010 to 2020. ResultsForty-nine patients were identified (dabrafenib n=9, everolimus n=27, trametinib n=10, and vemurafenib n=3). All patients receiving BRAF inhibitors harbored BRAF V600E mutation. Targeted agent was used as first-line therapy for 25% of patients, while for 31% of patients, targeted agent was second-line therapy. The median time from diagnosis to targeted therapy initiation was 4.76 years (0.10 – 23.77), median duration of targeted therapy was 0.79 years (0.01 – 4.87), median time to subsequent therapy post first-line targeted therapy was 0.2 years (0.01 – 3.33), and overall median follow-up for the entire cohort was 3.09 years (0.36 – 11.87). The 1-year, 3-year, and 5-year EFS from targeted therapy initiation was 58.0%, 32.2%, and 26.9%, respectively. Survival analyses by molecular subgroup and agent were performed. Reasons for cessation of targeted therapy included toxicities, progression, and/or planned end of therapy. ConclusionsFurther efforts are ongoing to perform volumetric analysis of growth rates before, during, and after treatment. While targeted molecular therapies show great promise, it will be critical to understand how these agents alter the natural history of pLGGs, particularly in the context of genomic profiling.

Use of everolimus for cardiac rhabdomyomas in a very-low-birthweight infant.

Use of everolimus for cardiac rhabdomyomas in a very-low-birthweight infant.

Covid-19 infection in patients with a history of everolimus use.

e18744 Background: The COVID-19 infection, declared as a pandemic by WHO in March 2020, continues its effects all over the world. Cancer patients also get COVID infection and in some patients this infection is mortal. In our study, we examined the course of COVID-19 infection in patients who actively or in the past used Everolimus. Methods: Patients who used everolimus actively or in the past were examined in our study. Patients who survive after the first cases seen in Turkey March 11, 2020 ; were evaluated in terms of whether they had COVID-19. Demographic characteristics and primary malignancies of the patients were examined. Patients who had COVID-19 infection and died were identified. Results: Our study consists of 50 patients in total. 14 (28%) of the patients were male and 36 (72%) were female. The average age of the patients is 56.72 (28-82), the average age of the male patients is 52.8 (28-80) and the average age of the female patients is 57.58 (36-82). 17 of the patients were treated for breast cancer, 11 for neuroendocrine tumor, 7 for tuberous sclerosis, 5 for renal cell carcinoma, 4 for thymic carcinoma, 2 for thymoma, 2 for ovarian ca, 2 for perivascular ecrine tumor. While it is the most common breast cancer in women (47.2% of female patients), neuroendocrine tumor is the most common in male patients (35.7% of male patients). While 13 patients were actively using everolimus (26%), 37 patients (74%) had discontinued everolimus treatment for 1 year or more.5 of our patients were diagnosed with COVID-19 infection (10% of all patients). 2 of these five patients are actively using everolimus. Of those diagnosed with COVID-19, 3 are women and 2 are men.The average age of the patients is 50.08 (43-66). While 3 patients had mild illness (60%), 2 patients (40%) died. One of the deceased patients is female and one is male. The female patient had a history of using everolimus for breast cancer, while the male patient died at the age of 52 while actively using everolimus for thymoma. Conclusions: Everolimus is a MTOR inhibitor used in many malignancy treatments. In our study, we found that 10% of our patients had COVID infection and 2 of our patients died due to COVID-19. In the group that discontinued everolimus treatment for a year or more, 1 patient died due to COVID-19, and 1 patient in the group still receiving everolimus treatment. Studies with larger patient populations are needed to determine whether everolimus carries an additional risk of COVID-19 infection.

Evolution of overall survival and receipt of new therapies by subtype among 20 446 metastatic breast cancer patients in the 2008-2017 ESME cohort

BackgroundTreatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008.Patients and methodsWe evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2−; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD).ResultsThe median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2– MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2– and TNBC cohorts, respectively, whatever YOD.ConclusionOS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed.

Diabetes in Individuals With Tuberous Sclerosis Complex Treated With mTOR Inhibitors

BackgroundTuberous sclerosis complex (TSC) is a genetic disorder that is manifested in multiple body systems. A mammalian target of rapamycin (mTOR) inhibitor (mTORi), either everolimus or sirolimus, is now routinely prescribed for multiple clinical manifestations of TSC, including subependymal giant cell astrocytoma and epilepsy. These medications are generally well tolerated. Side effects previously identified in well-designed clinical trials tend to be mild and readily manageable. Regulatory approvals for the treatment of TSC have expanded the use of everolimus and sirolimus clinically, enlarging clinician experience and enabling identification of potential treatment-related effects that are rarer than could be identified or recognized in previous clinical trials. MethodsThe medical records of clinical patients from our TSC center who were treated with an mTORi and later developed diabetes mellitus (DM) were analyzed and compared with those who were not treated with an mTORi. Eight individuals received detailed analysis, including laboratory results, concomitant medications, and body mass indices. ResultsAmong the 1576 individuals with TSC, 4% taking an mTORi developed diabetes compared with 0.6% of those not on mTORi, showing a significant interaction between DM and mTORi (chi-square = 18.1, P < 0.001). Details of eight patients who developed DM were presented. ConclusionsThe long-term use of mTORi agents in TSC may contribute to a risk of diabetes. Early detection can be critical in management. Additional studies are need to further investigate a causal relationship, but clinicians should be aware of this possible association when initiating and monitoring ongoing treatment.

Safety and efficacy of everolimus (EVE) plus exemestane (EXE) in postmenopausal women with locally advanced or metastatic breast cancer: final results from EVEREXES.

This study was conducted to collect clinical safety, tolerability, and efficacy data with the use of everolimus (EVE) combined with exemestane (EXE) in patients with advanced breast cancer (ABC). The EVEREXES trial initiated in 2012, provided early access to the first dual blockade treatment with EVE + EXE in patients with HR+, HER2 - ABC in Asia and other emerging growth countries. Postmenopausal women with HR+, HER2 - ABC who had documented recurrence or progression, following a nonsteroidal aromatase inhibitor therapy, were treated with EVE (10mg/day) + EXE (25mg/day) orally. A total of 235 patients received ≥ 1 dose of study medication. At the end of the study, all patients ceased the treatment. Disease progression (66.0%) was the primary reason of discontinuation. The most common AEs (≥ 20%) were stomatitis, decreased appetite, hyperglycemia, rash, aspartate aminotransferase increased, anemia, alanine aminotransferase increased, cough, and fatigue. No new safety concerns were identified in the current study. Median progression-free survival (PFS) in the Asian subset was similar to that of the overall population (9.3months in both groups). Confirmed overall response rate (ORR) was achieved for 19.6% of the patients. Efficacy of EVE + EXE across subgroups (prior CT, line of treatment, and presence of visceral metastases) was maintained. The safety and efficacy results from EVEREXES trial are consistent to data previously reported in BOLERO-2. These results support that EVE + EXE could be a viable treatment option for the postmenopausal women with HR+, HER2 - ABC in Asian region.

Long-term Efficacy and Safety of Everolimus Versus Mycophenolate in Kidney Transplant Recipients Receiving Tacrolimus.

The short-term efficacy and safety of everolimus in combination with tacrolimus have been described in several clinical trials. Yet, detailed long-term data comparing the use of everolimus or mycophenolate in kidney transplant recipients receiving tacrolimus are lacking. This is a 5-y follow-up post hoc analysis of a prospective trial including 288 patients who were randomized to receive a single 3-mg/kg dose of rabbit antithymocyte globulin, tacrolimus, everolimus (EVR), and prednisone (rabbit antithymocyte globulin/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (basiliximab/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (basiliximab/mycophenolate, n = 101). There were no differences in the incidence of treatment failure (31.8% versus 40.2% versus 34.7%, P = 0.468), de novo donor-specific HLA antibodies (6.5% versus 11.7% versus 4.0%, P = 0.185), patient (92.9% versus 94.1% versus 92.1%, P = 0.854), and death-censored graft (87.1% versus 90.2% versus 85.1%, P = 0.498) survivals. Using a sensitive analysis, the trajectories of estimated glomerular filtration rate were comparable in the intention-to-treat (P = 0.145) and per protocol (P = 0.354) populations. There were no differences in study drug discontinuation rate (22.4% versus 30.4% versus 17.8%, P = 0.103). In summary, this analysis in a cohort of de novo low/moderate immunologic risk kidney transplant recipients suggests that the use of a single 3 mg/kg rabbit antithymocyte globulin dose followed by EVR combined with reduced tacrolimus concentrations was associated with similar efficacy and renal function compared with the standard of care immunosuppressive regimen.

Patterns and predictors of oral anticancer agent utilization in diverse metastatic renal cell carcinoma patients.

279 Background: Availability of targeted oral anti-cancer agents (OAA) has transformed care delivery for metastatic renal cell carcinoma (RCC) patients. Our objective was to identify patterns and predictors of OAA use within the 12 months after metastatic RCC was detected to understand the extent of real-world adoption of these treatment advances. Methods: We used a novel, North Carolina, registry-linked multi-payer claims data resource to examine patterns of use of sorafenib, sunitinib, pazopanib, everolimus, axitinib, cabozantinib, and levantinib in a cohort of metastatic RCC patients diagnosed over 10 years (2006-2015, with claims through 2016). Patients were required to have 12 months of pre- and post-metastatic-index-date continuous enrollment. Log-Poisson models estimated unadjusted and adjusted risk ratios (RRs) and 95% confidence limits (CLs) for associations between patient characteristics and OAA use. In sensitivity analyses, we used a competing risk framework to estimate adjusted risk differences (RD) in OAA use. Results: Our population-based study of 713 patients demonstrated relatively low (37%) OAA use at any time during the 12 months post-metastatic-index date among publicly and privately insured patients, with shifting patterns of use consistent with regulatory approvals over time. Lower OAA use was observed among patients who were older, frailer, and with greater comorbidity burden. Other patient-level characteristics, such as sex, race, rurality and type of insurance were not significant predictors of OAA use. Conclusions: These data underscore the importance of distinguishing clinically appropriate from potentially poor-quality care and warrant additional studies to understand in more depth the system, provider and patient level drivers of these patterns.

Early use of everolimus improved renal function after adult deceased donor liver transplantation.

BackgroundTacrolimus (TAC) is a main therapy for liver transplantation (LT) patients, but it has side effects such as chronic nephrotoxicity that progressively aggravate renal function. The purpose of this study was to retrospectively compare the renal function between a TAC group and a combination of everolimus and reduced TAC (EVR-TAC) group after deceased donor liver transplantation (DDLT).MethodsThe study comprised 131 patients who underwent DDLT between January 2013 and April 2018 at our institution. They received TAC or EVR-TAC after DDLT. Everolimus (EVR) was introduced between 1 and 6 months after DDLT.ResultsThirty-six of 131 patients (27.5%) received EVR-TAC. The incidence of chronic kidney disease (CKD; estimated glomerular filtration rate, <60 mL/1.73 m2) in the EVR-TAC group was higher than in the TAC group (25% vs. 8.4%; P=0.019). Increasing serum creatinine (n=23, 63.9%) was the most common cause for adding EVR to treatment of the posttransplant patients. There were no statistical differences in acute rejection and CKD between the two groups. The TAC trough level was significantly lower in the EVR-TAC group than in the TAC group, and the renal function of the EVR-TAC group was worse than that of the TAC group until 1 year after DDLT. However, the renal function of the EVR-TAC group improved and became similar to that of TAC group at 3 years posttransplant.ConclusionsThe present study suggests that EVR should be introduced as soon as possible after DDLT to reduce exposure to high doses of TAC to improve the renal function.

Safety and effectiveness of everolimus in maintenance kidney transplant patients in the real-world setting: results from a 2-year post-marketing surveillance study in Japan

BackgroundData on real-world use of everolimus (EVR) in Japanese maintenance kidney transplant (KTx) patients are limited. This post-marketing surveillance study was conducted to assess the safety and effectiveness of EVR, and identify factors affecting renal impairment.MethodsAdult maintenance KTx patients were enrolled within 14 days of initiating EVR. Patient medical data were collected using electronic data capture case report forms at 6 months, 1, and 2 years after initiating EVR, or at discontinuation.ResultsAll patients receiving EVR in Japan during the surveillance period were enrolled (N = 263). Mean time from transplantation to EVR initiation was 75.7 months. Decreased renal function (31.56%) was the primary reason for initiating EVR. In combination with EVR, the mean daily dose of tacrolimus and cyclosporine could be reduced to ~ 79 and ~ 64%, by 2 years, respectively. Incidences of serious adverse events and adverse drug reactions were 15.97 and 49.43%, respectively. Two-year graft survival rate was 95.82% and low in patients with baseline estimated glomerular filtration rate (eGFR; modification of diet in renal disease) < 30 mL/min/1.73 m2 (69.57%; P < 0.0001) and urinary protein/creatinine ratio (UPCR) ≥ 0.55 g/gCr (84.21%; P = 0.0206). Throughout the survey, mean eGFR values were stable (> 55 mL/min/1.73 m2). Renal impairment was influenced by patient and donor age, eGFR, and UPCR at baseline.ConclusionsNo new safety concerns for the use of EVR in adult maintenance KTx patients were identified. Early EVR initiation may be considered in these patients before renal function deterioration occurs.

Malignancies and Pediatric Liver Transplantation: Promising Management with the mTOR-inhibitor Everolimus

Some malignancies such as hepatoblastoma may be an indication for liver transplantation (LT) or some, for example, post-transplant lymphoproliferative disease (PTLD) may develop after successful LT. An immunosuppressive therapy after LT can promote the recurrence of the primary malignancy. The mammalian target-of-rapamycin inhibitors (mTORi) are immunosuppressive agents with anti-tumor properties. We examined the impact of everolimus (EVL) together with calcineurin inhibitors on allograft outcome and patient survival in pediatric LT (PLT) with various tumors. This retrospective study included eleven liver-transplanted pediatric patients who received EVL after LT. The reason for adding an mTOR inhibitor was the neoplastic disease, either leading to LT (n = 7) or PTLD that developed after LT under immunosuppression (n = 3). The median age at the start of therapy was four years (range: seven months- 18 years); the median follow-up was 3 (range: 1 – 5) years). The primary endpoints were recurrence or metastasis of the primary tumor, uncontrolled PTLD, or death. Graft function and potential side effects were documented. Both patient survival and graft survival rates for the observation period were 100%. No patient developed recurrence or reported metastatic disease of the primary tumor. Liver function test results remained normal during the study period in 8 out of 11 patients. Three patients developed elevated liver enzymes that resolved over time. All the patients received EVL either as monotherapy (n = 2) or in combination with cyclosporine A (n = 7) or tacrolimus (n = 2). Typical side effects documented were recurrent infections (n = 8), stomatitis (n = 5), and cytopenia (n = 2), and medication was temporarily interrupted in one patient. Although the patient cohort was small, our results support the use of EVL in patients with tumor occurrence in the context of pediatric LT. No cases of recurrence or metastases were reported during the follow-up period after LT; sufficient immunosuppression was maintained. The side effect profile appeared acceptable. A longer follow-up in more number of patients is necessary to confirm these preliminary data.

A Case Report on Tacrolimus Induced TTP and Early Use of Everlimus as Immunosuppressant in Pediatric Living Donor Liver Transplant

Objective: In this case report ,we describe our experience with Tacrolimus induced TTP in pediatric LDLT and early use of Everolimus as immuosupression. Method: Eight year old male child with DCLD due to cholesterol ester storage disorder Underwent LDLT .POD5 there was raised in bilirubin and thrombocytopenia(2.2 lakh to 20,000 /uL) ,elevated LDH (1660U/L ) and PS showed schistocytes (5-6%) F/S/O TTP .Patient developed seizures .MRI brain showed F/S/O PRESS. Tacrolimus was withheld .Patient was started on Retuximab therapy and he underwent 5 cycles of plasmapheresis. Gradually LFT's and Blood pictures normalized and patient was discharged on POD20. Thirteen year old male child presenting with cryptogenic cirrhosis underwent LDLT. POD 10 he developed seizures and hematuria. NCCT brain showed water shed area with infarcts. POD16 patient had elevated bilirubin , Thrombocytopenia ,PS showed Schistocytes .Patient underwent 3 cycles of plamapheresis.LDH and Schistocytes levels reduced .However we lost the child to sepsis on POD 30. Results: Diagnostic criteria for TTP include Severe thrombocytopenia30 X 10 9/L, Elevated LDH, Microangiopathic Hemolytic anemia,Schistocytes on the blood smear. Clinical presentation includes Brain 60% stroke, Heart ischemia 25%, Mesenteric ischemia 35% and Hematuria. Treatment includes plasmaphersis, steroids and Rituximab. Organ transplantation associated TTP is not the result of an immune-mediated ADAMTS13 deficiency and has the Worst prognosis. Conclusion: Very few cases of post LDLT with TTP has been mentioned in literature review. To best of our knowledge this is the only case in which Everolimus has been used as immunosuppressant early post op period in TTP.

Administration of Nivolumab in Metastatic Renal Cell Cancer Following Treatment With mTOR Inhibitors.

Immunotherapy with checkpoint inhibitors is currently considered a cornerstone of metastatic renal clear cell cancer (mRCC) therapy. Despite the general improvement in the survival of patients with mRCC, there are some clinical situations that have not been specifically evaluated in clinical trials, such as the use of everolimus before nivolumab. We performed a retrospective analysis evaluating the efficacy of nivolumab in the real-world setting, including a subset of patients with previous mTOR inhibitor therapy. From a total of 56 patients, 25 were pre-treated with everolimus before receiving nivolumab. The overall progression-free survival (PFS), overall survival (OS), and objective response rate were 10.3, 21.3 months, and 34%, respectively. There were no statistically significant differences in patients who were or were not pre-treated with everolimus. mRCC patients should be treated with checkpoint inhibitors and prior use of mTOR inhibitors should not be a definitive exclusion criterium.

Tuberous sclerosis complex: analysis of areas of involvement, treatment progress and translation to routine clinical practice in a cohort of paediatric patients

Tuberous sclerosis complex (TSC) displays great phenotypic variability. Increasingly early diagnosis, including prenatal identification, entails the need for the paediatrician and neuropaediatrician to establish early suspicion and identification of factors that may influence prognosis and treatment. To determine the clinical criteria for early diagnosis, initial complementary tests, actions and treatments to prevent different comorbidities, so as to improve the prognosis of these patients. Descriptive, retrospective study of = 18-year-olds with a definitive diagnosis of TSC in a tertiary hospital from 1998 to 2019. We collected variables referring to epidemiological data, multisystem involvement, complementary tests and genetics. Ninety-four patients were analysed. The main diagnostic reasons were epilepsy and rhabdomyomas. The frequency of occurrence of clinical criteria was determined, and neuropathological findings were the main findings, followed by cutaneous stigmata, rhabdomyomas and renal lesions. Statistical relationships were found between clinical, radiological and genetic aspects, the influence of preventive activities on the occurrence of epilepsy and the relevance of everolimus use were tested. Rhabdomyomas and skin stigmata in patients and parents are major diagnostic signs in infants. Tubers and subependymal nodules are statistically associated with the development of epilepsy. Early epileptic spasms, refractory to treatment in the first months, increase the risk of cognitive deficits and autism spectrum disorder. Epileptic abnormalities need to be closely monitored in the first year of life. Everolimus is an alternative treatment for several comorbidities, but its early use (< 3 years) requires further study.

Upfront treatment with mTOR inhibitor everolimus in pediatric low-grade gliomas: A single-center experience.

Pediatric low-grade gliomas (pLGGs) are the most frequent brain tumor in children. Adjuvant treatment, consisting in chemotherapy and radiotherapy, is often necessary if a complete surgical resection cannot be obtained. Traditional treatment approaches result in a significant long-term morbidity, with a detrimental impact on quality of life. Dysregulation of the mitogen-activated protein kinase (MAPK) pathway is the molecular hallmark of pLGGs and hyperactivation of the downstream mammalian target of rapamycin (mTOR) pathway is frequently observed. We report clinical and radiological results of front-line treatment with everolimus in 10 consecutive patients diagnosed with m-TOR positive pLGGs at the Bambino Gesù Children's Hospital in Rome, Italy. Median duration of treatment was 19 months (range from 13-60). Brain magnetic resonance imaging showed stable disease in 7 patients, partial response in 1 and disease progression in 2. Therapy-related adverse events were always reversible after dose reduction or temporary treatment interruption. To the best of our knowledge, this is the first report of everolimus treatment for chemo- and radiotherapy-naïve children with pLGG. Our results provide preliminary support, despite low sample size, for the use of everolimus as target therapy in pLGG showing lack of progression with a manageable toxicity profile.

CTNI-52. PHASE II STUDY OF EVEROLIMUS (AFINITOR®) FOR CHILDREN WITH RECURRENT OR PROGRESSIVE EPENDYMOMA

Abstract Preclinical studies suggested that the mTOR signaling pathway could be a potential therapeutic target in childhood ependymomas. As a result, a phase II clinical trial (ClinicalTrials.gov identifier: NCT02155920) of single-agent everolimus was performed to test the hypothesis that inhibition of the mTOR pathway would result in tumor responses for children with recurrent and/or progressive ependymoma. Eleven patients [sex: 4 females (36.4%); median age: 8 years (range: 2 – 15 years); race: 9 white and 2 other; prior therapies: median 6 (range: 3 – 9)] were enrolled on the study. The primary tumor location for 10 participants was the posterior fossa; the primary location of the remaining tumor was the cervical spine. All patients were treated with oral everolimus 4.5 mg/m2/day (each cycle = 28 days) that was titrated to achieve serum trough levels of 5 – 15 ng/mL. Overall, everolimus was well tolerated; adverse events were grade 1 – 2 and consistent with its previously established safety profile in children. No objective tumor responses were observed. All patients discontinued therapy due to tumor progression after a median of 2 cycles of therapy (1 cycle = 2; 2 cycles = 6; 3, 4, and 8 cycles = 1 each). This study does not support the use of everolimus for children with recurrent or progressive ependymoma.

Tuberous sclerosis: a review of the past, present, and future

Tuberous sclerosis complex (TSC) is an autosomal dominant, multisystem disorder that is characterized by cellular and tissue dysplasia in several organs. With the advent of genetic and molecular techniques, mutations in the TSC1 or TSC2 genes were discovered to be responsible for mTOR overactivation, which is the underlying mechanism of pathogenesis. TSC is a highly heterogenous clinical entity with variable presentations and severity of disease. The brain, heart, skin, eyes, kidneys, and lungs are commonly involved in this syndrome, with neurologic symptoms comprising a significant source of morbidity and mortality. In 2012, the diagnostic criteria for TSC were revised by the International Tuberous Sclerosis Complex Consensus panel, and genetic testing was incorporated into the guidelines. Early detection of cardiac rhabdomyomas or TSC-associated skin lesions can suggest the diagnosis and underlie the importance of clinical vigilance. Animal studies have demonstrated the benefit of using mTOR inhibitors for various symptoms of TSC, and they have been successfully translated into clinical trials with significant improvement in symptom burden. Subependymal giant cell astrocytomas, renal angiomyolipomas, and epilepsy are the three FDA-approved indications in relation to TSC for the use of everolimus, which is a first generation mTOR inhibitor. Rapamycin has been FDA approved for lymphangioleiomyomatosis. Other TSC symptoms that could potentially benefit from this class of medication are currently under investigation. TSC constitutes a unique combination of protean physical symptoms and neurobehavioral abnormalities. TSC associated neuropsychiatric disorders (TAND), including intellectual disability, mood disorders, and autism spectrum disorder, represent significant challenges but remain underdiagnosed and undertreated. The TAND checklist is a useful tool for routine use in the clinical evaluation of TSC patients. A multidisciplinary treatment plan, based on the specific problems and needs of individuals, is the key to management of this genetic condition. Ongoing research studies have been providing promising leads for developing novel mechanistic strategies to address the pathophysiology of TSC.

Time to Conversion to an Everolimus-Based Regimen: Renal Outcomes in Liver Transplant Recipients From the EVEROLIVER Registry.

Longterm use of a calcineurin inhibitor (CNI)-based regimen is one of the major reasons for chronic renal failure in liver transplantation recipients (LTRs). The Everolimus Liver registry (EVEROLIVER) evaluated renal function in LTRs who were converted to everolimus (EVR). This observational registry included all LTRs receiving EVR across 9 centers from France. Data are being collected in an electronic database over 10 years (12 visits/patient) to evaluate efficacy, renal function (estimated glomerular filtration rate [eGFR]), and safety of EVR use in clinical practice, and the current analysis is reporting up to 60months of findings. Until September 2017, 1045 patients received EVR after a mean time of 3.6±5.1years. CNI withdrawal was feasible in 57.7% of patients as of month 60. Mean eGFR improved in patients with baseline eGFR <60mL/minute/1.73m2 and was maintained in those with baseline eGFR ≥60mL/minute/1.73m2 . Among patients with chronic kidney disease (CKD; baseline eGFR <60mL/minute/1.73m2 ), 55% converted to EVR within 3 months (early conversion) and 39.4% converted between 4 and 12months after transplantation (mid-conversion) experienced improvement in eGFR (≥60mL/minute/1.73m2 ) at month 36. Only 20.9% and 17.4% among those converted beyond 12months (late conversion) experienced improvement respectively at month 36 and 60. A logistic regression analysis in patients with CKD stage ≥3 demonstrated that late conversion, age, and female sex were associated with nonimprovement of eGFR (≥60mL/minute/1.73m2 ). Data from this real-life use of EVR indicate that renal function was maintained from the preconversion period until month 36 even in patients with advanced CKD. However, early rather than late conversion appears to be a safe approach to preserve longterm renal function in LTRs.

N6-methyladenosine-dependent pri-miR-17-92 maturation suppresses PTEN/TMEM127 and promotes sensitivity to everolimus in gastric cancer

N6-methyladenosine (m6A) is the most common epigenetic RNA modification with essential roles in cancer progression. However, roles of m6A and its regulator METTL3 on non-coding RNA in gastric cancer are unknown. In this study, we found elevated levels of m6A and METTL3 in gastric cancer. Increased METTL3 expression indicated poor outcomes of patients and high malignancy in vitro and in vivo. Mechanically, m6A facilitated processing of pri-miR-17-92 into the miR-17-92 cluster through an m6A/DGCR8-dependent mechanism. The m6A modification that mediated this process occurred on the A879 locus of pri-miR-17-92. The miR-17-92 cluster activated the AKT/mTOR pathway by targeting PTEN or TMEM127. Compared with those with low levels of METTL3, METTL3-high tumors showed preferred sensitivity to an mTOR inhibitor, everolimus. These results reveal a perspective on epigenetic regulations of non-coding RNA in gastric cancer progression and provide a theoretical rationale for use of everolimus in the treatment of m6A/METTL3-high gastric cancer.

EVEROLIMUS-INDUCED PULMONARY ALVEOLAR PROTEINOSIS

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Pulmonary alveolar proteinosis (PAP) is a rare respiratory disease characterized by an excessive accumulation of lipoproteinaceous surfactant material in the distal air spaces. This is mostly the result of inadequate clearance of surfactant by alveolar macrophages. Autoimmune etiologies make up ∼90% of adult cases, however there are congenital and secondary etiologies as well (1). We present a unique case of drug induced PAP caused by everolimus use. CASE PRESENTATION: A 44 year old female, history of renal cell carcinoma (RCC) with lung metastasis, presents with 1 week of worsening shortness of breath following a round of chemotherapy and immunotherapy (nivolumab, ipilimumab, everolimus). Associated fever, vomiting and productive cough were also reported. On the scene, EMS reported an oxygen saturation of 81% on room air. In the ED, the patient was placed on BiPAP and started on scheduled breathing treatments, IV fluids and broad spectrum antibiotics. Chest exam revealed diffuse rales. Initial labs showed lactic acidosis without an elevated WBC. ABG showed PaO2 of 103 mmHg on 60% BiPAP. CT chest showed new onset loculated right-sided pleural effusion and extensive left-sided ground glassing, concerning for a crazy pavement appearance. Right-sided thoracentesis was attempted and failed as the fluid could not be aspirated. On Day 2, she was intubated due to worsening respiratory status. Bronchoalveolar lavage (BAL) sample was obtained. BAL cytology was negative for malignant cells or active inflammation, but showed an abundance of amorphous, eosinophilic, periodic acid-Schiff (PAS)-positive material. Bacterial, fungal and viral cultures and respiratory viral PCR were negative. She continued to decline and on day 8, in light of her terminal illness, her family decided to transition to hospice care. Compassionate extubation was done on day 9 and the patient expired shortly after. DISCUSSION: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor, often used in breast, pancreatic and renal carcinoma. Though there have been reports of PAP complicating sirolimus use, no such reports exist for everolimus (2). PAS stains of BAL or lung biopsy samples confirm the diagnosis of PAP. But without a sample, high index of clinical suspicion is needed to differentiate PAP from other pulmonary processes and intervene early. If diagnosed early, stopping the offending agent may be all that is needed. In those with moderate to severe symptoms, whole lung lavage (WLL) is the most accepted intervention. 30-50% of cases only require one lavage, others will require repeat at 6-12-month intervals. Cases refractory to WLL may require trials of GM-CSF inhaled therapy and rituximab but their efficacy has only been shown in autoimmune PAP (3). CONCLUSIONS: We present a case of everolimus induced pulmonary alveolar proteinosis in a patient with metastatic RCC. Diagnosis was confirmed with a PAS-positive BAL sample. Reference #1: Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis. N Engl J Med 2003; 349:2527. Reference #2: Kadikoy H, Paolini M, Achkar K, et al. Pulmonary alveolar proteinosis in a kidney transplant: a rare complication of sirolimus. Nephrol Dial Transplant 2010; 25: 2795–2798 Reference #3: Kumar A, Abdelmalak B, Inoue Y, Culver DA. Pulmonary alveolar proteinosis in adults: pathophysiology and clinical approach. Lancet Respir Med 2018; 6:554. DISCLOSURES: No relevant relationships by Gnananandh Jayaraman, source=Web Response No relevant relationships by Ramesh Babu Kesavan, source=Web Response No relevant relationships by Robert Liu, source=Web Response No relevant relationships by Sivatej Sarva, source=Web Response