Rebound Growth Research Articles

CTNI-09. TYPE II RAF INHIBITOR TOVORAFENIB IN RELAPSED/REFRACTORY (R/R) PEDIATRIC LOW-GRADE GLIOMA (PLGG): RESULTS FROM PATIENTS ON A DRUG HOLIDAY (DH) IN THE PHASE 2 FIREFLY-1 TRIAL

Abstract BACKGROUND Tovorafenib, a selective, CNS-penetrant, type II RAF inhibitor, received US FDA accelerated approval for r/r BRAF-altered pLGG. Results from the ongoing FIREFLY-1 (NCT04775485) phase 2 study (Kilburn LK, et al. Nat Med. 2023) in this population showed clinically meaningful tumor responses and a manageable safety profile. METHODS Patients in FIREFLY-1 treated for ≥26 cycles (~24 months) who entered a DH period were routinely assessed every 3 cycles; once-weekly tovorafenib 420 mg/m2 (not to exceed 600 mg) could be restarted if there was radiographic and/or clinical evidence of new disease progression. RESULTS As of the April 19, 2024 data cutoff, 26 patients (BRAF fusion: 22; BRAF V600E mutation: 4) (33.8%) of 77 patients in arm 1 (pLGG registrational) had completed 2 years of treatment and started a DH. No patients on a DH withdrew. Twenty-four patients (92.3%) remain on a DH, of which 22 were evaluable for response (duration range: 0.6-10.9 months); duration of response off-treatment ranged from 0.0-8.5 months. (Ranges exclude 2 non-evaluable patients treated beyond radiographic progression who remained on treatment in first 26 cycles due to ongoing clinical benefit; both remain on DH without clinical progression.) Two patients had tumor progression while on a DH and restarted treatment; 1 patient with a BRAF V600E mutation progressed (≥25% in tumor size) after 1 month (rebound growth per O’Hare P., et al. Neuro-Oncol. 2024: ≥25% increase [per RANO-LGG] w/in 6 months of stopping treatment) and has been on retreatment for 4 months; 1 patient with a BRAF fusion progressed after 9 months and has been on retreatment for 3 months. Treatment-related adverse events of any grade experienced by patients on retreatment were alopecia and rash (1 each). Independent radiographic analysis for response during retreatment is ongoing. CONCLUSIONS Tovorafenib provided durable tumor responses off-treatment in patients with r/r pLGG on a DH in FIREFLY-1.

Efficacy and safety of atenolol versus propranolol for treatment of infantile haemangioma: A narrative review.

Infantile haemangiomas (IH) remain the most common benign vascular tumours in childhood. While most IH can be managed conservatively, a proportion of these lesions can cause disfigurement, ulceration or functional impairment, requiring prompt intervention. Propranolol, a lipophilic non-selective beta blocker, has been regarded as first-line therapy, following a serendipitous discovery of its use for IH in 2008. While efficacious, it has been associated with adverse effects such as hypoglycaemia, bronchospasm, sleep disturbances and agitation in infant trials. Hence, atenolol, a hydrophilic beta-1 selective blocker, has demonstrated similar efficacy and potentially greater tolerability, being less likely to cause sleep disturbances given its inability to cross the blood brain barrier, and a decrease in bronchial reactivity. The purpose of this review is to explore and critique the current knowledge on the efficacy and safety of propranolol against atenolol in children with IH. A total of seven studies comparing the two beta-blockers were identified in our search. Atenolol appeared to be as efficacious as propranolol and was associated with fewer central nervous system and bronchial-related adverse events. Further research exploring the optimal dosing for atenolol, particularly for ulcerated or syndromic IH, as well as incidence and management of rebound growth would be beneficial.

Time to heal: inhibiting fibrosis prevents glioblastoma recurrence

New findings by Walson et al. demonstrate that therapy-induced inflammation and fibrosis potentiate glioblastoma recurrence. Post-treatment fibrotic niches shielded surviving tumor cells from immune surveillance, supported their persistence in a dormant state, and enabled rebound growth. Timely inhibition of inflammation and scarring attenuated recurrence, encouraging the use of new combinatorial approaches in glioblastoma therapy.

Future perspective of targeted treatments in pediatric low-grade glioma (pLGG): the evolution of standard-of-care and challenges of a new era.

While surgery, when possible, remains the mainstay of pediatric low-grade glioma (pLGG) management, adjuvant therapy has significantly evolved over time. Radiation therapy was commonly used in the late 1990s for tumors that could not be resected or recurred. This resulted in significant late morbidity in this population and mortality related to secondary malignancies and chronic health conditions. Chemotherapy became the mainstay of adjuvant therapy but children still experienced late morbidity secondary to exposure to multiple lines of treatment over time. Targeted therapies emerged after the identification of frequent genetic alterations in the mitogen activated protein kinase (MAPK) pathway including KIAA1549-BRAF fusions and BRAF-V600 mutations and the near universal upregulation of the MAPK pathway in these tumors. Both BRAF and MEK inhibitors have shown efficacy in the treatment of pLGG and have led to prolonged stability in some cases. Multiple phase III clinical trials are now comparing targeted therapy to standard-of-care chemotherapy regimens setting the stage for targeted therapy to replace chemotherapy as the first-line treatment in some cases. Targeted therapy, however, is not without its challenges. There are clear examples of resistance and mechanisms of resistance have not been fully elucidated. There is also no clear duration for these therapies and rebound growth is a well-known phenomenon especially in BRAF-V600 mutant tumors. Targeted therapies are also fairly recent developments and long-term toxicities and functional outcomes are still being monitored. Very young and adolescent/young adult LGGs also carry molecular features that may not be addressed by inhibition of the MAPK pathway. Adjuvant therapy for pLGG has evolved from radiation for all unresectable or residual tumors to molecularly driven targeted therapies with improved quality of life, late effects, and less off-target toxicities. While there is still much to learn in regard to newer targeted therapies for pLGG, the era of targeted therapies for pediatric LGG is upon us.

LGG-09. REBOUND GROWTH AFTER MAPKI WITHDRAWAL INVOLVES RAPID MAPK REACTIVATION AND CYTOKINE-MEDIATED MICROGLIA RECRUITMENT IN PEDIATRIC LOW-GRADE GLIOMA MODEL

Abstract Patients with pediatric low-grade gliomas (pLGG), the most common primary brain tumor in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge. Four patient-derived pLGG models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset of the rebound model encompassing different MAPKi withdrawal timepoints was generated using RNA sequencing and LC-MS/MS based phospho-/proteomics to investigate possible driving mechanisms of rebound growth. Following in vitro validation, putative rebound driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model. Of the tested models, BT-40 (BRAFV600E, CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal, characterized by faster cell regrowth after MAPKi withdrawal compared to standard-of-care chemotherapy. Using this model, we observed MAPK pathway reactivation within hours after withdrawal, associated with a transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels. Additionally, we observed increased expression and secretion of cytokines (in particular CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal (at least until 24 h). While increased cytokine expression did not affect response to MAPKi or rebound growth upon withdrawal in an autocrine manner, increased attraction of microglia cells mediated by these cytokines was observed. MAPK pathway reactivation during rebound growth and increased expression of CX3CL1 and CXCL10 induced by MAPKi treatment could further be confirmed in vivo. Taken together, these data indicate a rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound driving mechanism. Furthermore, increased microglia recruitment during MAPKi treatment and withdrawal, mediated by cytokines, may play a role in response to MAPKi treatment and rebound growth upon withdrawal, warranting further evaluation.

NFS-30. ADJUVANT MEK INHIBITION TO PREVENT REBOUND GROWTH FOLLOWING PARTIAL RESECTION OF PLEXIFORM NEUROFIBROMAS

Abstract BACKGROUND Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that occur in patients with neurofibromatosis type I. These tumors can cause significant morbidity leading to functional impairment, pain, and disfigurement. Management of PNs is challenging. Complete surgical resection is often not possible due to tumor growth along vital structures, and rebound growth is frequently experienced following subtotal resection (STR) of PNs. The mitogen-activated protein kinase (MAPK) pathway has been implicated in the growth of PNs, and the use of MAPK enzyme (MEK1/2) inhibitors has been shown to be an effective therapy in the treatment of PNs. Herein, we described our institutional experience using a short course of adjuvant MEK1/2 inhibitors in the treatment of pediatric patients with PNs following STR to prevent rebound growth. METHODS A single-institution retrospective record review of pediatric patients who underwent STR of their PN. RESULTS A total of 35 patients with 39 separate PNs had STR of their PNs. Fourteen PNs were treated with resection alone and 25 PNs were treated with a six-month course of adjuvant MEK1/2 inhibitors following STR. The number of patients requiring additional treatment with surgical resection or medical therapy was 11 of 14 patients (79%) in the resection only group and 6 of 25 patients (24%) in the adjuvant MEK1/2 inhibitor group. The mean time to additional treatment for the resection only group was 22 months, and the mean follow-up time for patients receiving adjuvant MEK1/2 inhibition was 29 months. Skin rash was the most common adverse effect seen with adjuvant MEK1/2 inhibition, and one patient experienced a dose-limiting thrombus. CONCLUSIONS A short course of MEK1/2 inhibitors following STR of PNs is effective in the short-term in preventing rebound growth when compared to STR alone. Treatment is well tolerated and should be considered as adjuvant therapy in pediatric patients.

Resistance, rebound, and recurrence regrowth patterns in pediatric low-grade glioma treated by MAPK inhibition: A modified Delphi approach to build international consensus-based definitions-International Pediatric Low-Grade Glioma Coalition.

Pediatric low-grade glioma (pLGG) is the most common childhood brain tumor group. The natural history, when curative resection is not possible, is one of a chronic disease with periods of tumor stability and episodes of tumor progression. While there is a high overall survival rate, many patients experience significant and potentially lifelong morbidities. The majority of pLGGs have an underlying activation of the RAS/MAPK pathway due to mutational events, leading to the use of molecularly targeted therapies in clinical trials, with recent regulatory approval for the combination of BRAF and MEK inhibition for BRAFV600E mutated pLGG. Despite encouraging activity, tumor regrowth can occur during therapy due to drug resistance, off treatment as tumor recurrence, or as reported in some patients as a rapid rebound growth within 3 months of discontinuing targeted therapy. Definitions of these patterns of regrowth have not been well described in pLGG. For this reason, the International Pediatric Low-Grade Glioma Coalition, a global group of physicians and scientists, formed the Resistance, Rebound, and Recurrence (R3) working group to study resistance, rebound, and recurrence. A modified Delphi approach was undertaken to produce consensus-based definitions and recommendations for regrowth patterns in pLGG with specific reference to targeted therapies.

Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines

IntroductionPatients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge.MethodsFour patient-derived pediatric glioma models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal. A multi-omics dataset (RNA sequencing and LC-MS/MS based phospho-/proteomics) was generated to investigate possible rebound-driving mechanisms. Following in vitro validation, putative rebound-driving mechanisms were validated in vivo using the BT-40 orthotopic xenograft model.ResultsOf the tested models, only a BRAFV600E-driven model (BT-40, with additional CDKN2A/Bdel) showed rebound growth upon MAPKi withdrawal. Using this model, we identified a rapid reactivation of the MAPK pathway upon MAPKi withdrawal in vitro, also confirmed in vivo. Furthermore, transient overactivation of key MAPK molecules at transcriptional (e.g. FOS) and phosphorylation (e.g. pMEK) levels, was observed in vitro. Additionally, we detected increased expression and secretion of cytokines (CCL2, CX3CL1, CXCL10 and CCL7) upon MAPKi treatment, maintained during early withdrawal. While increased cytokine expression did not have tumor cell intrinsic effects, presence of these cytokines in conditioned media led to increased attraction of microglia cells in vitro.ConclusionTaken together, these data indicate rapid MAPK reactivation upon MAPKi withdrawal as a tumor cell intrinsic rebound-driving mechanism. Furthermore, increased secretion of microglia-recruiting cytokines may play a role in treatment response and rebound growth upon withdrawal, warranting further evaluation.

P11.16.B THE MAYO CLINIC MULTIDISCIPLINARY NF2 CLINIC EXPERIENCE OF BEVACIZUMAB IN NEUROFIBROMATOSIS TYPE 2-RELATED SCHWANNOMATOSIS PATIENTS WITH VESTIBULAR SCHWANNOMAS

Abstract BACKGROUND Neurofibromatosis type 2-related schwannomatosis (NF2) is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS) as well as other nervous system tumors. Management decisions for NF2-related VS are typically predicated on tumor size, associated symptoms, patient age, and comorbidities. Observation, surgical resection, and stereotactic radiosurgery can be viable options. In patients with VS associated with NF2, vascular endothelial growth factor A (VEGF-A) inhibitor, bevacizumab, is a systemic treatment option. In this single institution study, we review our clinical experience in patients with NF2 who received bevacizumab for VS and evaluate the effect of bevacizumab treatment on VS growth and symptom progression. MATERIAL AND METHODS This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Three-dimensional volumetric data for VS were measured using manual segmentation with Visage PACS software under the direct supervision of a board-certified neuroradiologist. RESULTS Out of 76 patients with NF2 evaluated in the past 3 years, we identified 19 that received treatment with bevacizumab. Median age of NF2 diagnosis was 19 years (range 0.5-61) with a median NF2 phenotype severity score of 2 (range 1-3). Thirteen of these patients have discontinued bevacizumab, accounting for a median duration of 12.2 months (range 3.3-88 months) of bevacizumab treatment. Bevacizumab was discontinued due to hypertension (n=5), proteinuria and renal dysfunction (n=3), tumor progression (n=2), fatigue or other intolerance (n=2), or non-compliance (n=1). The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March 2023 (range 3.7-48.3 months). Fifteen patients had brain MRI data available to evaluate VS change during bevacizumab treatment, with partial response observed in 5 patients, stable disease in 8, and progression in 2. Ten of the 13 patients who stopped bevacizumab had MRI data to evaluate VS change following treatment termination. Within 6 months of bevacizumab discontinuation, 6 patients had rebound growth of their VS between 21-95% from their previous tumor volume, while 4 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management. CONCLUSION Our single institution experience confirms that bevacizumab can slow progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.

Isolating factors for the prediction of rebound after guided growth with tension band plating for the valgus deformity of the knee.

The conditions leading to growth rebound after hemiepiphysiodesis are still poorly understood. This article analyzes the radiographical outcomes after guided growth with tension band plating, using plates in idiopathic genu valgum patients and attempts to generate a predictive model of growth rebound. Patients with idiopathic genu valgum deformity who received tension band plating were selected for evaluation. We only analyzed coronal plane deformities. Only patients with a long-standing X-ray before tension band plating surgery, a long-standing X-ray at tension band plating removal, and a long-standing X-ray at the latest follow-up after tension band plating removal were considered for this study. The change of mechanical axis deviation between the tension band plating removal and the last follow-up was evaluated for rebound, and ordinal logistic regression was performed to determine the relevant variables for predictive modeling rebound growth. Overall, 100 patients (189 legs) were analyzed. The mean mechanical axis deviation at tension band plating removal was 8.4 mm in varus direction, and the mean mechanical axis deviation at the last follow-up was -3.4 mm (p ≤ 0.001). However, 111 legs (59%) showed rebound growth, 57 (30%) stayed stable, and 21 (11%) showed a continuous correction. Six significant factors significantly influencing rebound were isolated which are clinically relevant: sex, age, baseline mechanical axis deviation, mechanical lateral distal femoral angle, and mechanical medial proximal tibial angle, and mechanical axis deviation correction rate. Mechanical axis deviation correction rate had the highest odds ratios. The machine learning classification model for predicting rebound growth built from the study data showed a misclassification rate of 39%. There was a high rate of rebound growth in this cohort, especially for patients at a young age at implantation. The highest risk factors for rebound growth were male sex, and high correction rates, such as found during peak growth spurt. The proposed classification model needs more data to improve its predictive power before it can be used in clinics. Level III.

TIMOLOL IN CAPILLARY HEMANGIOMA IN INFANT

Background: The purpose of this study was to evaluate the effect of topical timolol in the management of periocular capillary hemangioma. Objective: Efficacy of Timolol in Capillary Hemangioma Methods: A prospective study was performed in 48 consecutive patients with periocularhemangioma. 24 patients underwent topical timolol and Next 24 patientreceived lubricating eye drops topical as a control group.The size of the lesion was measured serially every week during the first month, every 2 weeks for the second month, and then monthly for another 4 months. Therefractive statusand degree of ptosis if present were measured before and at the end of the study. Results: There was reduction in the size of hemangioma, astigmatic error, and degree of ptosisin both the groups. The difference in outcome between two groups was statistically significant. Rebound growth occurred in 22.22% of the group Using timolol and 37.51% of the control group. No adverse effects were reported during or after topical timolol. Conclusion: Topical timolol may have good efficacy fortreatment of infantile periocular hemangioma.

Long-term outcomes of sirolimus treatment for kaposiform hemangioendothelioma: Continuing successes and ongoing challenges.

Treatment with sirolimus, an inhibitor of the mammalian target of rapamycin pathway, has improved the prognosis of patients with kaposiform hemangioendothelioma (KHE). However, the efficacy, durability and tolerability of long-term sirolimus treatment in patients with KHE have not been well elucidated. We performed efficacy and safety assessments based on more than 4.5 years of follow-up in patients receiving sirolimus therapy for KHE. One hundred sixty-seven patients were analyzed, including 102 (61.1%) patients with the Kasabach-Merritt phenomenon (KMP). Follow-up was conducted after a median of 56.0months. A total of 154 (92.2%) patients had a durable response to sirolimus treatment. No difference in durable response was found between patients without KMP and patients with KMP (95.4% vs 90.2%; difference, 5.2%; 95% confidence interval [CI], -4.0% to 13.1%). Rebound growth occurred in 17.3% of patients upon sirolimus discontinuation. Early treatment discontinuation (odds ratio [OR]: 3.103; 95% CI: 1.529-6.299; P=.002) and mixed lesion type (OR: 2.271; 95% CI: 0.901-5.727; P=.047) were associated with tumor rebound growth. No KHE-related deaths occurred in this cohort. At the last follow-up, approximately 17.4% of patients had active disease and/or changes in body structures to a variable extent. Serious adverse events occurred most commonly during the first year of sirolimus therapy. Follow-up of almost 4.5 years demonstrated that the efficacy of sirolimus persisted over time and that long-term treatment with sirolimus was not associated with unacceptable cumulative toxicities. However, nonresponse, tumor relapse and long-term sequelae remained challenges despite intensified and prolonged sirolimus therapy.

Withdrawal of bevacizumab is associated with rebound growth of vestibular schwannomas in neurofibromatosis type 2-related schwannomatosis patients.

Neurofibromatosis type 2 (NF2)-related schwannomatosis is an autosomal dominant tumor-predisposition syndrome characterized by bilateral vestibular schwannomas (VS). In patients with VS associated with NF2, vascular endothelial growth factor A inhibitor, bevacizumab, is a systemic treatment option. The aim of this study is to retrospectively evaluate NF2 patient responses to bevacizumab on VS growth and symptom progression. This is a retrospective analysis of patients seen at the Mayo Clinic Rochester Multidisciplinary NF2 Clinic. Out of 76 patients with NF2 evaluated between 2020 and 2022, we identified 19 that received treatment with bevacizumab. Thirteen of these patients discontinued bevacizumab after median treatment duration of 12.2 months. The remaining 6 patients are currently receiving bevacizumab treatment for a median duration of 9.4 months as of March, 2023. Fifteen patients had evaluable brain MRI data, which demonstrated partial responses in 5 patients, stable disease in 8, and progression in 2. Within 6 months of bevacizumab discontinuation, 5 patients had rebound growth of their VS greater than 20% from their previous tumor volume, while 3 did not. Three patients with rebound growth went on to have surgery or irradiation for VS management. Our single-institution experience confirms prior studies that bevacizumab can control progression of VS and symptoms associated with VS growth. However, we note that there is the potential for rapid VS growth following bevacizumab discontinuation, for which we propose heightened surveillance imaging and symptom monitoring for at least 6 months upon stopping anti-VEGF therapy.

The growth rebound effect: A theoretical–empirical investigation into the relation between rebound effects and economic growth

Rebound effects may challenge the concept that green growth can reconcile economic growth and reductions in energy consumption. This article investigates the interdependence between the rebound phenomenon and growth and introduces the ‘growth rebound effect’ (GRE) following a three-track strategy. First, we assess whether individual rebound mechanisms are associated with economic growth. Rebound mechanisms at all economic levels (micro, meso and macro) contribute to economic growth. 14 out of 22 rebound mechanisms lead to economic growth. Second, we analyse the perspective of macroeconomic approaches. While all approaches argue for the existence of a GRE, its size differs. The historical approach and the exergy approach predict a large GRE while the cost-share theorem approach predicts a small GRE. The difference lies in the former two arguing for energy efficiency impacting economic growth via a third variable. Third, we conduct an econometric estimation of the GRE using a unique bottom-up index of energy efficiency and a dynamic panel data model. Our estimation of a GRE between 20% and 47% depicts a lower bound estimate — the true GRE is probably larger. Considerably reducing energy consumption may require policies beyond green growth.

NFB-14. Post-operative use of MEK inhibitors to prevent rebound growth following partial resection of plexiform neurofibromas

Abstract BACKGROUND: Plexiform neurofibromas (PNs) can cause significant morbidity leading to functional impairment, pain, and disfigurement. Management of PNs is challenging. Complete surgical resection is often not possible due to tumor growth along vital structures, and rebound growth is frequently experienced with partially resected PNs. The mitogen-activated protein kinase pathway has been implicated in the growth of PNs, and MEK1/2 inhibitors have been shown to be an effective treatment of PNs. OBJECTIVE: To describe our institutional experience using post-operative MEK1/2 inhibitors in the treatment of pediatric patients with PNs following subtotal resection (STR). METHODS: A single-institution retrospective record review. RESULTS: A total of 35 patients had STR of their PN. Fourteen patients underwent resection alone, ten patients received adjuvant mechanistic target of rapamycin (mTOR) inhibitors and eleven patients received adjuvant MEK1/2 inhibitors. The mean follow-up time was 5.1 years, but relatively shorter for patients receiving adjuvant MEK1/2 inhibitors. Mean time from resection to start of adjuvant therapy and mean duration of adjuvant therapy for patients in the mTOR inhibitor group was 3.3 weeks and 3.9 months, respectively, and for patients in the MEK1/2 inhibitor group was 3.1 weeks and 8.5 months, respectively. The number of patients in each group requiring additional treatment with surgical resection or medical therapy, was 11 of 14 patients (78.6%) in the resection only group, 7 of 10 patients (70%) in the adjuvant mTOR inhibitor group and 3 of 11 patients (27.3%) in the adjuvant MEK1/2 inhibitor group. CONCLUSIONS: A short course of MEK1/2 inhibitors following subtotal resection of PNs is effective in the short term in preventing rebound growth when compared to STR alone or adjuvant mTOR inhibitors. Treatment is well tolerated and should be considered as adjuvant therapy in pediatric patients. Long-term follow-up is necessary to judge the effectiveness of this approach.

LGG-17. Preventing recurrence: targeting molecular mechanisms driving tumor growth rebound after MAPKi withdrawal in pediatric low-grade glioma

Pediatric low-grade gliomas, a diverse group of WHO grade 1 and 2 glial or glioneural tumors, comprise the most common category of primary brain tumors in children. The majority of these tumors are driven by alterations in the MAPK pathway, making them in principle susceptible to MAPKi therapy. While patients often benefit from MAPKi during treatment, tumor rebound may occur once treatment is stopped, constituting a significant clinical challenge. BT-40, patient-derived cells with molecular features of pleomorphic xanthoastrocytoma (BRAFV600E, CDKN2Adel), were used to model the rebound growth in vitro, based on viable cell counts in response to treatment and withdrawal of the clinically relevant BRAFV600E specific inhibitor dabrafenib. Standard-of-care chemotherapy (vincristine and carboplatin) was used as a reference. MAPK pathway reactivation upon withdrawal was assessed by WB and qPCR analysis. Based on the observed cell-regrowth and MAPK-reactivation pattern, key-timepoints during withdrawal were identified, which are currently being further analyzed through RNAseq and phospho-/proteomics. BT-40 cells started to proliferate again two days after dabrafenib withdrawal, and earliest five days after chemotherapy withdrawal. MAPK pathway activity, based on Mek and Erk phosphorylation, reached baseline levels three hours after dabrafenib withdrawal, this was associated with 2.5-fold increased c-Fos gene expression two hours after withdrawal. The earlier cell regrowth after dabrafenib withdrawal compared to chemotherapy withdrawal matches clinical observations, making the model suitable to study the rebound. The observed MAPK overactivation suggests the growth rebound might not only be caused by a fast reactivation of the pathway but also by other mechanisms, e.g. accumulation of upstream activators due to loss of negative feedback or parallel pathways. To investigate this, key-timepoints during treatment withdrawal will be analyzed using a multi-omics approach. Based on these findings, possible rebound-driving mechanisms will be identified and further validated using BT-40 and additional PXA models in vitro and in vivo.

Derivation of Ultrasonic Irradiation Condition to Inhibit the Growth of Microcystis aeruginosa

Objectives : The optimal ultrasonic irradiation conditions were derived through laboratory-scale experiments to evaluate growth inhibition effect of Microcystis aeruginosa (M. aeruginosa), which is the main specie of Cyanobacterial Harmful Algal Blooms (CyanoHABs) in Republic of Korea.Methods : The experiment was conducted by changing ultrasonic frequency, intensity, and initial cell concentration to observe the growth inhibition effect of M. aerginosa. The experiment was performed using shielded acrylic reactor [20 cm (W) × 20 cm (L) × 30 cm (H)]. Experiments were conducted using large volume (7.2 L) of water samples with high concentrations of M. aeruginosa, and the ultrasonic irradiation time was fixed at 3 hours.Results and Discussion : In all experiments, pictorial view of M. aeruginosa samples, chlorophyll-a (Chl-a) and cell number of M. aerginosa were observed. As a result of ultrasonic irradiation on M. aeruginosa, the decrease in both Chl-a concentration and cell number of M. aeruginosa was monitored after sonication compared to the decrease during sonication. In addition, the rebound growth was confirmed after certain period of growth inhibition of M. aeruginosa. The optimal ultrasonic irradiation conditions for the growth inhibition of M. aeruginosa were obtained at the lower frequency and the higher intensity. Whereas algal growth inhibition was observed with high concentration (4.5 × 106 cells mL-1) of M. aeruginosa, algal growth inhibition was not monitored with low concentration (1.1 × 106 cells mL-1) of M. aeruginosa.Conclusion : Through this study, the algal growth inhibition by ultrasonic was effective. Although the growth inhibition effect persisted for a certain period of time, subsequent regrowth was observed. Therefore, periodic ultrasonic irradiation is necessary for long-term growth inhibition of algal in field applications.

Phosphorylation of SHP2 at Tyr62 Enables Acquired Resistance to SHP2 Allosteric Inhibitors in FLT3-ITD-Driven AML.

These findings suggest that combined inhibition of SHP2 and FLT3 effectively treat FLT3-ITD-positive AML, highlighting the need for development of more potent SHP2 inhibitors and combination therapies for clinical applications.

Soft tissue re-growth after different crown lengthening techniques among Indian patients.

Patients often report complaining of fractured or decayed teeth with severe morphological deformities. However, all these clinical scenarios require the same level of care and consideration to rehabilitate form, function and esthetics. Some cases have sufficient clinical crown height while others often require an interdisciplinary approach in the form of orthodontic/surgical extrusion or surgical periodontal options. A common factor delaying treatment is soft tissue regrowth after crown lengthening which delays the impression required for final prosthesis. Therefore, it is of interest to compare the prevalence of soft tissue regrowth a week after different crown lengthening techniques including laser gingivectomy, electrocautery gingivectomy, modified Widman flap and apically repositioned. The parameters assessed included 1-week postoperative soft tissue regrowth after crown lengthening, age of patients and gender. It was observed that laser and electrocautery-assisted gingivectomy had a higher rate of soft tissue regrowth as compared to surgical techniques. It was further noted that laser and electrocautery assisted gingivectomy had a higher frequency of soft tissue rebound growth compared to surgical crown lengthening using modified widman flap and apically repositioned flap, which was statistically insignificant. Patients within the age groups of 26-60 years were found to have a higher tendency of soft tissue regrowth, which was found to be clinically and statistically significant (p<0.05).

Hemiepiphysiodesis for the Correction of Distal Femoral Valgus in Growing Dogs.

The aim of this study was to describe hemiepiphysiodesis for the treatment of distal femoral valgus in immature dogs and to evaluate its effect on the anatomical lateral distal femoral angle (aLDFA). Skeletally immature dogs with distal femoral valgus deformities that had undergone hemiepiphysiodesis between November 2012 and March 2020 at two private veterinary practices were included. Criteria for inclusion in the study were a preoperative aLDFA below the previously published reference range (94 ± 3.3 degrees) and radiographs of the femur taken preoperatively and at growth plate closure. A total of 11 dogs fulfilled the inclusion criteria, and a total of 17 limbs were treated. The mean aLDFA was 82.1 ± 3.2 degrees (range: 76-87 degrees) preoperatively and 93.1 ± 5 degrees (range: 76-99 degrees) at the final re-evaluation. The mean difference between the preoperative and final aLDFA was +11 degrees, which was significant. Undercorrection occurred in 2/17 cases, whereas overcorrection was not recorded. The implants were removed in 12/17 cases, and rebound growth occurred in 3 of these. Hemiepiphysiodesis for the treatment of distal femoral valgus is a technique that allows for increase in aLDFA and should be considered as an early treatment in affected immature dogs. Monitoring for possible overcorrection using serial radiography is important. Implant removal when the desired aLDFA has been achieved is recommended because the incidence of rebound growth is uncommon in dogs.