[Dynamics of mandibular density during therapy with zolendronic acid]. / Dinamika plotnosti nizhnei chelyusti v protsesse terapii zolendronovoi kislotoi.

THE AIM OF THE STUDY: Was to investigate the dynamics of mandibular density in cancer patients during therapy with zolendronic acid. MATERIALS AND METHODS: The study comprised 14 patients who received zolendronic acid at a dosage of 4 mg once every 28 days for bone metastases. In all 14 patients, measurements of mandibular density values on CT scans were performed over time. RESULTS: Using multiple linear regression analysis, a model was developed to predict the effect of the number of zolendronic acid injections «X1¼ on the dynamics of mandibular density «Y¼. The resulting formula for predicting mandibular density is Y = 5.9 X1 + 49 HU. CONCLUSION: The model has limitations due to the study design but still can be used by oncologists and dentists to assess mandibular density in patients taking zolendronic acid.

Efficacy and safety of minodronate in the treatment of postmenopausal osteoporosis with low back pain: a single-centre, randomized and open-label controlled trial.

BACKGROUND: Low back pain is one of the most common symptoms of osteoporosis. The pain can seriously affect patients' mood and quality of life; it can also further aggravate bone loss, causing a serious social burden. Minodronate is an oral bisphosphonate that needs to be administered daily. It significantly reduces levels of bone turnover markers (BTMs) and rapidly improves symptoms of low back pain in patients with osteoporosis. Osteoporosis requires long-term treatment, and daily dosing reduces patient compliance. Minodronate has a better safety profile than other bisphosphonates. The objective of the trial is to explore the efficacy and safety of minodronate in the treatment of low back pain in postmenopausal osteoporosis patients. METHODS: This is a single-centre, randomized, open-label controlled trial with a 24-week duration. Seventy-two eligible patients will be randomly divided into 4 groups. Subjects will be randomized at a 1:1 ratio to receive either minodronate (1 mg/day) or alendronate (10 mg/day) every day; senior women (≥ 75 years old) and older women (< 75 years old) will be at a ratio of 1:2. The primary outcome is the time required for the visual analogue scale (VAS) score to decline by ≥ 10 from baseline. The secondary outcome is the changes in VAS scores from baseline, the frequency and dosage of rescue medication, BTMs, bone mineral density (BMD), and variations in upper gastrointestinal (GI) symptom scores from baseline (including heartburn, pain, and bloating). DISCUSSION: This study will provide objective evidence for the efficiency and safety of minodronate. Furthermore, it will be helpful to evaluate the quantitative relationship between BTMs and BMD in patients with osteoporosis under different ages. TRIAL REGISTRATION: This study protocol has been registered with ClinicalTrials.gov ID NCT05645289 ( https://clinicaltrials.gov/search?term=NCT05645289 ) on December 8, 2022. The registry name is Peking University Third Hospital. This study protocol was reviewed and approved by the Peking University Third Hospital Medical Science Research Ethics Committee (M2022465, 2022.08.09, V2.0). The results will be published in scientific peer-reviewed journals. TRIAL STATUS: The protocol was registered at ClinicalTrials.gov (registration number: NCT05645289). Recruitment has started in January 2023 and is still ongoing.

BRAF and MEK inhibitor targeted therapy in papillary craniopharyngiomas: a cohort study.

OBJECTIVE: Targeted therapy (TT) with BRAF/MEK inhibitors has emerged as a potential treatment in papillary craniopharyngiomas (PCPs). However, standardized data on large cohorts are lacking. Our study aimed to assess real-life efficacy and safety of BRAF/MEK inhibition in patients with PCPs. DESIGN: Retrospective French multicenter study involving BRAF V600E-mutated PCP patients, treated with BRAF/MEK inhibitor combination dabrafenib and trametinib, from April 2019 to July 2023. METHODS: Objective response and clinical and safety outcomes were assessed after 3 months and at the last available follow-up during TT. RESULTS: Sixteen patients (8 females, mean age 50.5 ± 15.75 years), receiving either neoadjuvant therapy (NEO) for non-resectable tumors (n = 6), post-surgical adjuvant therapy (ADJ; n = 8), or palliative therapy (PAL) following failure of multimodal treatment (n = 2), were included.At the last follow-up (mean 7.6 ± 5.3 months), 12 patients showed subtotal response, 3 exhibited partial response, and 1 maintained stable disease. Mean volume reduction was 88.9 ± 4.4%, 73.3 ± 23.4%, and 91.8 ± 4.3% in the NEO, ADJ, and PAL groups, respectively.Targeted therapy resolved headaches in 5/5 patients and visual impairment in 6/9; 2/3 patients had improved neurological symptoms, 1/4 presented weight loss, and 2/14 recovered endocrine function.Targeted therapy was well-tolerated in 62.5% of cases; adverse events led to treatment discontinuation in 5 patients and definitive discontinuation in 3 cases. CONCLUSIONS: In this study, 94% of patients showed partial response or better to TT. Adverse events were acceptable. Further research is needed to establish standardized protocols; however, these results advocate for a NEO approach in invasive PCPs.

Local therapy with combination TLR agonists stimulates systemic anti-tumor immunity and sensitizes tumors to immune checkpoint blockade.

Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel.

MET alterations as resistance mechanisms of dabrafenib-trametinib in BRAF p.V600E mutated non-small cell lung cancer patient.

The combination of BRAF and MEK inhibitors demonstrated significant clinical benefit in patients with BRAF-mutant non-small cell lung cancer (NSCLC). However, the molecular mechanisms of acquired resistance to BRAF and MEK inhibition in NSCLC are still unknown. Herein, we report a case of a 76-year-old man with a history of smoking who was diagnosed with BRAF V600E-mutant lung adenocarcinoma (PD-L1 > 50%) and subsequently candidate to first-line therapy with pembrolizumab. After 18 months since the start of immunotherapy, computed tomography scan showed disease progression and a second-line therapy with dabrafenib and trametinib was initiated. Seven months later, due to a suspect disease progression, a left supraclavicular lymphadenectomy was performed and next-generation sequencing analysis revealed the appearance of MET exon 14 skipping mutation, while fluorescence in situ hybridization analysis showed MET amplification. The patient is still on BRAF and MEK inhibitor treatment. Our case highlights the relevance of performing tumor tissue rebiopsy at the time of progression during treatment with BRAF/MEK inhibition with the aim of identifying putative mechanisms of resistance.

Diffusive delivery of plasmid DNA using zwitterionic carboxyalkyl poly(1-vinylimidazole) into skeletal muscle in vivo.

Zwitterionic carboxyalkyl poly(1-vinylimidazole) (CA-PVIm) polymers with imidazolium cations and carboxylate anions have been synthesized as a carrier for the in vivo delivery of plasmid DNA (pDNA) to skeletal muscle. From differential scanning calorimetry measurements, resulting CA-PVIm had intermediate water in hydration water as a biocompatible polymer. Notably, when the pDNA and resulting CA-PVIm were mixed, slight retarded bands of the pDNA were observed in agarose gel electrophoresis, suggesting the polyion complex (PIC) formation between the pDNA and CA-PVIm despite zwitterionic polymers. Resulting PICs maintained the higher-order structure of the pDNA. Using resulting pDNA PICs, the highest pDNA expression by intramuscular injection was achieved in the PIC with 7 mol% carboxymethylated PVIm, that is, CA1(7)-PVIm, observed in a widespread area by in vivo imaging system. These results suggest that the CA1(7)-PVIm/pDNA PIC is effective for the diffusive delivery of the pDNA into skeletal muscle for the treatment of serious muscle diseases.

Clinical Pharmacy Initiatives Contribute to the Excellent Efficacy of the Dabrafenib/Trametinib Combination for Iodine-Refractory Thyroid Carcinoma: A Case Report.

A 76-year-old female patient presented with an iodine-refractory papillary thyroid carcinoma (PTC), diagnosed eight years earlier, with several lymph node recurrences requiring successive surgeries. Fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) imaging revealed a new unresectable loco-regional recurrence. The patient was diagnosed with a somatic BRAF V600E mutation. Therefore, dabrafenib and trametinib combination therapy was introduced and closely monitored by a dedicated multidisciplinary team, involving pharmaceutical consultations. As early as six weeks after treatment initiation, the patient reported multiple adverse events (AEs) to the clinical pharmacy team, who provided advice on resolving AEs or improving tolerance. Close interprofessional collaboration among healthcare workers involved in the care pathway allowed for the identification of the most opportune times for temporary suspension of treatment (four suspensions over seven months) or dose reduction (two reductions over 3.5 months). This resulted in a total treatment duration (one year) longer than the average times reported in the literature. The patient showed a rapid and excellent response to treatment immediately after initiation, culminating in a complete metabolic response assessed by [18F]FDG PET/CT imaging at nine months. Twenty-five months after treatment discontinuation, the disease remained controlled. Overall, dabrafenib and trametinib combination could offer excellent outcomes in selected patients with refractory BRAF-mutated PTC, with additional clinical pharmacy initiatives allowing for the optimized management of AEs and prolonged treatment periods.

TPGS nanoparticles co-loaded with ABT-737 and R848 for breast cancer therapy.

The development of new effective drugs to treat breast cancer remains a huge challenge. ABT-737 can inhibit Bcl-2 proteins to promote apoptosis. Resiquimod (R848) is a TLR7/8 agonist that is effective in modulating the immunosuppressive microenvironment. In this study, a codelivery system (TPGS/ABT+R848 NPs) based on D-α-tocopheryl poly (ethylene glycol) 1000 succinate as a potential drug delivery vector to codelivery ABT-737 and R848 was investigated. The size of TPGS/ABT+R848 NPs was 102.5 nm, the drug loading of ABT-737 and R848 was 30.6 % and 12.5 %, and the entrapment efficiency was 84.2 % and 23.7 %, respectively. The nanoparticles showed no significant change in particle size over 14 days. R848 and ABT-737 were released in co-loaded nanoparticles in sequential order. In vitro anti-tumor experiments, the IC50 value of TPGS/ABT+R848 NPs was 0.30 µg·mL-1, 34 times lower than that of free ABT-737. Animal experiments also verified that TPGS/ABT+R848 NPs could enhance the anti-tumor activity, and the tumor weight inhibition rate was 75.3 %. This study demonstrated that TPGS NPs loaded with ABT-737 and R848 have superior combination tumor therapeutic effects, and the co-loaded preparation is conducive to anti-tumor efficacy. The TPGS/ABT+R848 NPs could be a promising platform against breast cancer.

Dual-Targeted Zeolitic Imidazolate Frameworks Drug Delivery System Reversing Cisplatin Resistance to Treat Resistant Ovarian Cancer.

Objective: Ovarian cancer cells are prone to acquire tolerance to chemotherapeutic agents, which seriously affects clinical outcomes. The development of novel strategies to enhance the targeting of chemotherapeutic agents to overcome drug resistance and minimize side effects is significant for improving the clinical outcomes of ovarian cancer patients. Methods: We employed folic acid (FA)-modified ZIF-90 nanomaterials (FA-ZIF-90) to deliver the chemotherapeutic drug, cisplatin (DDP), via dual targeting to improve its targeting to circumvent cisplatin resistance in ovarian cancer cells, especially by targeting mitochondria. FA-ZIF-90/DDP could rapidly release DDP in response to dual stimulation of acidity and ATP in tumor cells. Results: FA-ZIF-90/DDP showed good blood compatibility. It was efficiently taken up by human ovarian cancer cisplatin-resistant cells A2780/DDP and aggregated in the mitochondrial region. FA-ZIF-90/DDP significantly inhibited the mitochondrial activity and metastatic ability of A2780/DDP cells. In addition, it effectively induced apoptosis in A2780/DDP cells and overcame cisplatin resistance. In vivo experiments showed that FA-ZIF-90/DDP increased the accumulation of DDP in tumor tissues and significantly inhibited tumor growth. Conclusion: FA-modified ZIF-90 nanocarriers can improve the tumor targeting and anti-tumor effects of chemotherapeutic drugs, reduce toxic side effects, and are expected to be a novel therapeutic strategy to reverse drug resistance in ovarian cancer.

Hemophagocytic lymphohistiocytosis induced by dabrafenib-trametinib in a patient with metastatic melanoma: a case report and pharmacovigilance analysis.

Hemophagocytic lymphohistiocytosis (HLH) has been reported rarely with BRAF/MEK inhibitor combinations, including dabrafenib/trametinib. Postmarketing pharmacovigilance analyses evaluating outcomes associated with dabrafenib/trametinib-induced HLH are also lacking. Herein, we report a case of dabrafenib/trametinib-induced HLH in a patient with metastatic melanoma. Recovery of HLH-related symptoms was observed following drug discontinuation, supportive care, and corticosteroids. We also conducted a pharmacovigilance analysis of the USA Food and Drug Administration Adverse Event Reporting System (FAERS) to describe postmarketing cases of HLH with dabrafenib/trametinib exposure. There were 50 reports of HLH with dabrafenib/trametinib in FAERS. Most cases occurred in the setting of melanoma ( n  = 39; 78%) and most were reported in Europe ( n  = 39; 74%). Hospitalization was the most common outcome ( n  = 39; 78%) of this adverse event per FAERS. HLH is a rare complication of dabrafenib/trametinib, and clinicians should be aware and monitor for signs of this potentially serious and life-threatening adverse event.

Resiquimod-loaded cationic liposomes cure mice with peritoneal carcinomatosis and induce specific anti-tumor immunity.

Peritoneal carcinomatosis (PC) is characterized by a high recurrence rate and mortality following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC), primarily due to incomplete cancer elimination. To enhance the standard of care for PC, we developed two cationic liposomal formulations aimed at localizing a toll-like receptor agonist, resiquimod (R848), in the peritoneal cavity to activate the immune system locally to specifically eradicate residual tumor cells. These formulations effectively extended R848 retention in the peritoneum by >10-fold, resulting in up to a 2-fold increase in interferon α (IFN-α) induction in the peritoneal fluid, without increasing the plasma levels. In a CT26 colon cancer model with peritoneal metastases, these liposomal R848 formulations, when combined with oxaliplatin (OXA)-an agent used in HIPEC that induces immunogenic cell death-increased tumor infiltration of effector immune cells, including DCs, CD4, and CD8 T cells. This led to the complete elimination of PC in 60-70% of the mice, while the control mice reached humane endpoints by 30 days. The cured mice developed specific antitumor immunity, as re-challenging them with the same tumor cells did not result in tumor establishment. However, inoculation with a different tumor line led to tumor development. Additionally, exposing CT26 tumor antigens to the splenocytes isolated from the cured mice induced the expansion of CD4 and CD8 T cells and the release of IFN-γ, demonstrating long-term immune memory to the specific tumor. The anti-tumor efficacy of these liposomal R848 formulations was mediated via CD8 T cells with different levels of involvement of CD4 and B cells, and the combination with an anti-PD-1 antibody achieved a cure rate of 90%.

Targeting tumor-associated macrophages with mannosylated nanotherapeutics delivering TLR7/8 agonist enhances cancer immunotherapy.

Tumor-associated macrophages (TAMs) constitute 50-80% of stromal cells in most solid tumors with high mortality and poor prognosis. Tumor-infiltrating dendritic cells (TIDCs) and TAMs are key components mediating immune responses within the tumor microenvironment (TME). Considering their refractory properties, simultaneous remodeling of TAMs and TIDCs is a potential strategy of boosting tumor immunity and restoring immunosurveillance. In this study, mannose-decorated poly(lactic-co-glycolic acid) nanoparticles loading with R848 (Man-pD-PLGA-NP@R848) were prepared to dually target TAMs and TIDCs for efficient tumor immunotherapy. The three-dimensional (3D) cell culture model can simulate tumor growth as influenced by the TME and its 3D structural arrangement. Consequently, cancer spheroids enriched with tumor-associated macrophages (TAMs) were fabricated to assess the therapeutic effectiveness of Man-pD-PLGA-NP@R848. In the TME, Man-pD-PLGA-NP@R848 targeted both TAMs and TIDCs in a mannose receptor-mediated manner. Subsequently, Man-pD-PLGA-NP@R848 released R848 to activate Toll-like receptors 7 and 8, following dual-reprograming of TIDCs and TAMs. Man-pD-PLGA-NP@R848 could uniquely reprogram TAMs into antitumoral phenotypes, decrease angiogenesis, reprogram the immunosuppressive TME from "cold tumor" into "hot tumor", with high CD4+ and CD8+ T cell infiltration, and consequently hinder tumor development in B16F10 tumor-bearing mice. Therefore, dual-reprograming of TIDCs and TAMs with the Man-pD-PLGA-NP@R848 is a promising cancer immunotherapy strategy.

Biomimetic ZIF-8 Nanoparticles: A Novel Approach for Biomimetic Drug Delivery Systems.

Metal-organic frameworks (MOFs) are porous materials resulting from the coordination of metal clusters or ions with organic ligands, merging macromolecular and coordination chemistry features. Among these, zeolitic imidazolate framework-8 (ZIF-8) stands out as a widely utilized MOF known for its robust stability in aqueous environments owing to the robust interaction between its constituent zinc ions (Zn2+) and 2-methylimidazole (2-MIM). ZIF-8 readily decomposes under acidic conditions, serving as a promising candidate for pH-responsive drug delivery systems. Moreover, biomimetic materials typically possess good biocompatibility, reducing immune reactions. By mimicking natural structures or surface features within the body, they enhance the targeting of nanoparticles, prolong their circulation time, and increase their bioavailability in vivo. This review explores the latest advancements in biomimetic ZIF-8 nanoparticles for drug delivery, elucidating the primary obstacles and future prospects in utilizing ZIF-8 for drug delivery applications.

MARRIAGE: A Randomized Trial of Moxonidine Versus Ramipril or in Combination With Ramipril in Overweight Patients With Hypertension and Impaired Fasting Glucose or Diabetes Mellitus. Impact on Blood Pressure, Heart Rate and Metabolic Parameters.

BACKGROUND: Moxonidine, an imidazoline I1 receptor agonist, is an effective antihypertensive drug that was shown to improve insulin sensitivity. RAAS-blockers are recommended as first-line therapy in patients with diabetes, alone or in combination with a calcium-channel antagonist or a diuretic. AIMS: This study compared the effects of moxonidine and ramipril on blood pressure (BP) and glucose metabolism in overweight patients with mild-to-moderate hypertension and impaired fasting glucose or type 2 diabetes. METHODS: Treatment-naïve patients for hypertension and dysglycemia were randomized to 12 weeks of double-blind moxonidine 0.4 mg or ramipril 5 mg once-daily treatment. At 12 weeks, for a further 12 weeks non-responders received combination of mox/ram, while responders continued blinded treatment. RESULTS: Moxonidine and ramipril were equivalent in lowering SiDBP and SiSBP at the end of the first 12 weeks. The responder rate was approximately 50% in both groups, with a mean SiDBP and SiSBP decrease of 10 and 15 mm Hg in the responders, respectively. The normalization rate (SiDBP < 85 mm Hg) was non significantly different between treatments groups. Moxonidine reduced heart rate (HR) (average -3.5 bpm, p = 0.017) during monotherapy, and when added to ramipril. HbA1c decreased significantly at Week 12 in both groups. Neither drug affected glucose or insulin response to the oral glucose tolerance test. In non-responders, moxonidine/ramipril combination further reduced BP without compromising metabolic parameters. CONCLUSION: Moxonidine 0.4 mg and ramipril 5 mg were equally effective on BP lowering and were well tolerated and mostly metabolically neutral either as monotherapies or in combination. HR was lowered on moxonidine treatment.

Cucurbit[7]uril-based host-guest complexes for improving bioavailability and reducing side effects of piroxicam.

Piroxicam (PX) is a nonsteroidal anti-inflammatory drug (NSAID) commonly associated with gastrointestinal (GI) injuries, including dyspepsia, heartburn, inflammation, bleeding, ulceration, and life-threatening perforation. The ß-cyclodextrin (ß-CD)-based PX formulation (PX@CD) has been shown to reduce gastric side effects by improving PX's solubility and dissolution rates. However, the solubility of PX can only be increased to a limited extent by ß-CD, due to the low binding constant between PX and ß-CD (∼100 M-1). As a result, adverse reactions such as epigastric pain and pyrosis are still commonly reported. Cucurbit[7]uril (CB[7]) is a synthetic macrocyclic host compound that binds strongly to various drugs. In this study, we demonstrated that CB[7] forms complexes with PX in the gastric acid environment with a binding constant approximately 70 times higher than that between ß-CD and PX. The PX@CB[7] inclusion complexes exhibited rapid dissolution rates in the gastric environment. In addition, PX@CB[7] showed significantly higher oral bioavailability and maximum concentration (Cmax) compared to PX and PX@CD (1:2.5), resulting in improved anti-inflammatory effects in both mouse and rat models. Moreover, PX@CB[7] (1:2.5) had the least adhesion to the gastric mucosa and caused the mildest gastric side effects in rat models when compared to PX, PX@CD (1:2.5), and PX@CB[7] (1:1). Lastly, CB[7] demonstrated good oral biocompatibility in a subacute toxicity evaluation study. These findings indicate that CB[7] could be used as an excipient to improve treatment effectiveness and decrease adverse reactions in orally administered formulations with a favorable safety profile.

Five-year analysis of neoadjuvant dabrafenib and trametinib for stage III melanoma.

BACKGROUND: Neoadjuvant dabrafenib plus trametinib has a high pathological response rate and impressive short-term survival in patients with resectable stage III melanoma. We report 5-year outcomes from the phase II NeoCombi trial. PATIENTS AND METHODS: NeoCombi (NCT01972347) was a single-arm, open-label, single-centre, phase II trial. Eligible patients were adults (aged ≥18 years) with histologically confirmed, resectable, RECIST-measurable, American Joint Committee on Cancer seventh edition clinical stage IIIB-C BRAF V600E/K-mutant melanoma and Eastern Cooperative Oncology Group performance status ≤1. Patients received 52 weeks of treatment with dabrafenib 150 mg (orally twice per day) plus trametinib 2 mg (orally once per day), with complete resection of the pre-therapy tumour bed at week 12. RESULTS: Between 20 August 2014 and 19 April 2017, 35 patients were enrolled. At data cut-off (17 August 2021), the median follow-up was 60 months [95% confidence interval (CI) 56-72 months]. Overall, 21 of 35 (60%) patients recurred, including 12 (57%) with first recurrence in locoregional sites (followed by later distant recurrence in 6) and 9 (43%) with first recurrence in distant sites, including 3 in the brain. Most recurrences occurred within 2 years, with no recurrences beyond 3 years. At 5 years, recurrence-free survival (RFS) was 40% (95% CI 27% to 60%), distant metastasis-free survival (DMFS) was 57% (95% CI 42% to 76%), and overall survival was 80% (95% CI 67% to 94%). Five-year survival outcomes were stratified by pathological response: RFS was 53% with pathological complete response (pCR) versus 28% with non-pCR (P = 0.087), DMFS was 59% versus 55% (P = 0.647), and overall survival was 88% versus 71% (P = 0.205), respectively. CONCLUSIONS: Neoadjuvant dabrafenib plus trametinib has high pathological response rates in clinical stage III melanoma, but low rates of RFS, similar to those achieved with adjuvant targeted therapy alone. Patients with a pCR to dabrafenib plus trametinib still had a high risk of recurrence, unlike that seen with immunotherapy where recurrences are rare.

Response to dabrafenib plus trametinib on a rare BRAF mutation (V600_W604 deletion-insertion R) in an advanced non-small cell lung cancer patient.

Although dabrafenib plus trametinib has been approved for BRAF V600E mutation positive advanced non-small cell lung cancer (NSCLC), data on its efficacy against uncommon BRAF mutations are still limited due to their rare frequency. We report a case of 70-year-old woman with BRAF V600_W604 deletion-insertion R-positive stage IVA lung adenocarcinoma, who was successfully treated with dabrafenib plus trametinib. Herein, we discuss the oncogenic role of uncommon BRAF mutations and highlight the importance of performing comprehensive genomic profiling on patients without any targetable gene alterations in companion diagnostics.

Toxicities associated with tyrosine kinase inhibitor maintenance following allogeneic hematopoietic cell transplantation in Philadelphia chromosome-positive acute lymphoblastic leukemia.

Allogeneic hematopoietic cell transplantation (HCT) offers a potential cure in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); nonetheless, relapses are common and the major cause of mortality. One strategy to prevent relapse is tyrosine kinase inhibitor (TKI) maintenance post-HCT, but published clinical experience is primarily with the first-generation TKI imatinib while data with newer generation TKIs are limited. We conducted a retrospective analysis of 185 Ph+ ALL patients who underwent HCT followed by TKI maintenance from 2003 to 2021 at City of Hope. Initially, 50 (27.0%) received imatinib, 118 (63.8%) received a second-generation TKI (2G-TKI), and 17 (9.2%) received ponatinib. A total of 77 patients (41.6%) required a dose reduction of their initial TKI due to toxicity. Sixty-six patients (35.7%) did not complete maintenance due to toxicity; 69 patients (37.3%) discontinued 1 TKI, and 11 (5.9%) discontinued 2 TKIs due to toxicity. Initial imatinib versus 2G-TKI versus ponatinib maintenance was discontinued in 19 (38.0%) versus 68 (57.6%) versus 3 (17.6%) patients due to toxicity (p = .003), respectively. Patients on ponatinib as their initial TKI had a longer duration of TKI maintenance versus 2G-TKI: 576.0 days (range, 72-921) versus 254.5 days (range, 3-2740; p = .02). The most common reasons for initial TKI discontinuation include gastrointestinal (GI) intolerance (15.1%), cytopenia (8.6%), and fluid retention (3.8%). The 5-year overall survival and progression-free survival for the total population were 78% and 71%, respectively. Our findings demonstrate the challenges of delivering post-HCT TKI maintenance in a large real-world cohort as toxicities leading to TKI interruptions, discontinuation, and dose reduction were common.

Ponatinib vs Imatinib in Frontline Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Randomized Clinical Trial.

Importance: In newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), disease progression due to acquired resistance to first- or second-generation BCR::ABL1 tyrosine kinase inhibitors is common. Ponatinib inhibits BCR::ABL1 and all single-mutation variants, including T315I. Objective: To compare frontline ponatinib vs imatinib in adults with newly diagnosed Ph+ ALL. Design, Setting, and Participants: Global registrational, phase 3, open-label trial in adults aged 18 years or older with newly diagnosed Ph+ ALL. From January 2019 to May 2022, eligible patients at 77 sites were randomized 2:1 to ponatinib (30 mg/d) or imatinib (600 mg/d) with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after the cycle 20 phase of the trial. The last date of follow-up for this analysis was August 12, 2022. Intervention: Patients received ponatinib, 30 mg/d, or imatinib, 600 mg/d, with reduced-intensity chemotherapy, followed by single-agent ponatinib or imatinib after cycle 20. The ponatinib dose was reduced to 15 mg on achievement of minimal residual disease-(MRD) negative complete remission. Main Outcomes and Measures: The primary end point of this interim analysis was MRD-negative complete remission (≤0.01% BCR::ABL1 [MR4] centrally assessed by reverse transcriptase-quantitative polymerase chain reaction), with complete remission maintained for at least 4 weeks at the end of cycle 3. The key secondary end point was event-free survival. Results: Of 245 patients randomized (median age, 54 years; 133 [54.3%] female), 232 (ponatinib, n = 154; imatinib, n = 78) who had p190 or p210 dominant isoforms verified by the central laboratory were analyzed for the primary end point. The MRD-negative complete remission rate (primary end point) was significantly higher with ponatinib (34.4% [53/154]) vs imatinib (16.7% [13/78]) (risk difference, 0.18 [95% CI, 0.06-0.29]; P = .002). At the data cutoff, event-free survival had not met the prespecified number of events. Median event-free survival was not reached in the ponatinib group and was 29 months in the imatinib group. The most common adverse events were similar between treatment groups. Arterial occlusive events were infrequent and comparable between groups (ponatinib, 2.5%; imatinib, 1.2%). Conclusions and Relevance: Ponatinib demonstrated a superior rate of MRD-negative complete remission at the end of induction vs imatinib when combined with reduced-intensity chemotherapy in adults with newly diagnosed Ph+ ALL. The safety profile of ponatinib was comparable with imatinib. Trial Registration: ClinicalTrials.gov Identifier: NCT03589326.

Activation of SIRT1/Nrf2/HO-1 and Beclin-1/AMPK/mTOR autophagy pathways by eprosartan ameliorates testicular dysfunction induced by testicular torsion in rats.

Testicular torsion carries the ominous prospect of inducing acute scrotal distress and the perilous consequence of testicular atrophy, necessitating immediate surgical intervention to reinstate vital testicular perfusion, notwithstanding the paradoxical detrimental impact of reperfusion. Although no drugs have secured approval for this urgent circumstance, antioxidants emerge as promising candidates. This study aspires to illustrate the influence of eprosartan, an AT1R antagonist, on testicular torsion in rats. Wistar albino rats were meticulously separated into five groups, (n = 6): sham group, eprosartan group, testicular torsion-detorsion (T/D) group, and two groups of T/D treated with two oral doses of eprosartan (30 or 60 mg/kg). Serum testosterone, sperm analysis and histopathological examination were done to evaluate spermatogenesis. Oxidative stress markers were assessed. Bax, BCL-2, SIRT1, Nrf2, HO-1 besides cleaved caspase-3 testicular contents were estimated using ELISA or qRT-PCR. As autophagy markers, SQSTM-1/p62, Beclin-1, mTOR and AMPK were investigated. Our findings highlight that eprosartan effectively improved serum testosterone levels, testicular weight, and sperm count/motility/viability, while mitigating histological irregularities and sperm abnormalities induced by T/D. This recovery in testicular function was underpinned by the activation of the cytoprotective SIRT1/Nrf2/HO-1 axis, which curtailed testicular oxidative stress, indicated by lowering the MDA content and increasing GSH content. In terms of apoptosis, eprosartan effectively countered apoptotic processes by decreasing cleaved caspase-3 content, suppressing Bax and stimulating Bcl-2 gene expression. Simultaneously, it reactivated impaired autophagy by increasing Beclin-1 expression, decreasing the expression of SQSTM-1/p62 and modulate the phosphorylation of AMPK and mTOR proteins. Eprosartan hold promise for managing testicular dysfunction arising from testicular torsion exerting antioxidant, pro-autophagic and anti-apoptotic effect via the activation of SIRT1/Nrf2/HO-1 as well as Beclin-1/AMPK/mTOR pathways.