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Cooperativity is essential for the proper functioning of numerous proteins by allosteric interactions. Hemoglobin from Scapharca inaequivalvis (HbI) is a homodimeric protein that can serve as a minimal unit for studying cooperativity. We investigated the structural changes in HbI after carbon monoxide dissociation using time-resolved resonance Raman spectroscopy and observed structural rearrangements in the Fe–proximal histidine bond, the position of the heme in the pocket, and the hydrogen bonds between heme and interfacial water upon ligand dissociation. Some of the spectral changes were different from those observed for human adult hemoglobin due to differences in subunit assembly and quaternary changes. The structural rearrangements were similar for the singly and doubly dissociated species but occurred at different rates. The rates of the observed rearrangements indicated that they occurred synchronously with subunit rotation and are influenced by intersubunit coupling, which underlies the positive cooperativity of HbI. [ABSTRACT FROM AUTHOR]

Neuroblastoma is the most common extracranial solid tumor of childhood. While MYCN and mutant anaplastic lymphoma kinase (ALKF1174L) cooperate in tumorigenesis, how ALK contributes to tumor formation remains unclear. Here, we used a human stem cell-based model of neuroblastoma. Mis-expression of ALKF1174L and MYCN resulted in shorter latency compared to MYCN alone. MYCN tumors resembled adrenergic, while ALK/MYCN tumors resembled mesenchymal, neuroblastoma. Transcriptomic analysis revealed enrichment in focal adhesion signaling, particularly the extracellular matrix genes POSTN and FN1 in ALK/MYCN tumors. Patients with ALK-mutant tumors similarly demonstrated elevated levels of POSTN and FN1. Knockdown of POSTN, but not FN1, delayed adhesion and suppressed proliferation of ALK/MYCN tumors. Furthermore, loss of POSTN reduced ALK-dependent activation of WNT signaling. Reciprocally, inhibition of the WNT pathway reduced expression of POSTN and growth of ALK/MYCN tumor cells. Thus, ALK drives neuroblastoma in part through a feedforward loop between POSTN and WNT signaling.

We present the case of a 34‐year‐old Japanese man with anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer and brain metastases. After central nervous system (CNS) disease progression with alecintib and brigatinib, treatment with lorlatinib resulted in a good intracranial response. In this case, we investigated brain penetration ratio of brigatinib using cerebrospinal fluid and paired serum samples, and the ratio was 0.012. Further, we investigated resistance mechanisms via next‐generation sequencing (NGS) using lung biopsy at lung cancer diagnosis and brain biopsy sample at progressive disease of brigatinib. No apparent resistance mechanism of known ALK resistance, such as ALK mutations, amplifications, epithelial‐mesenchymal transition (EMT) and bypass pathway activation were detected. Taken together, we speculate that the low CNS penetration rate of brigatinib confers CNS progression. Further studies are warranted to reveal the resistance mechanism and propose a treatment strategy for CNS progression in ALK‐positive patients. [ABSTRACT FROM AUTHOR]

Lorlatinib is a brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) inhibitor indicated for ALK -positive metastatic non-small cell lung cancer (NSCLC). In a global phase II study, patients who experience disease progression despite prior treatment with ALK tyrosine kinase inhibitors (TKIs) was assessed. Herein, we report real-world clinical outcomes of lorlatinib-treated patients with ALK -positive advanced NSCLC who were heavily pretreated and progressed on first- and second-generation ALK-TKIs, in a Taiwanese population under the lorlatinib expanded access program (EAP). This multicenter observational study examined the effectiveness and safety of ALK -positive advanced NSCLC patients that progressed from previous second-generation ALK-TKI therapy and received lorlatinib treatment subsequently. Patients who received lorlatinib treatment under EAP between Jul 2017 and Sep 2019 were eligible. Patients were followed for at least one year from the first lorlatinib treatment until study completion. Sixty-three patients were eligible for safety analysis (male: 46.0 %; median age: 52.8 [27.5–78.3] years; brain metastases: 81.0 %). Fifty-four patients with more than one-month lorlatinib treatment were included in the effectiveness analysis. Prior to lorlatinib treatment, 10 patients (18.5 %) received one ALK-TKI, 27 (50.0 %) received two ALK-TKIs, and 17 (31.5 %) received three or more ALK-TKIs. The overall median rwPFS was 9.2 months (95 % confidence interval: 5.3–21.1). The best overall response rate (n = 51) was 13.7 %, with a disease control rate of 80.4 %. Lorlatinib exhibits substantial activity and tolerability when used clinically in a later-line setting in a Taiwanese population with ALK -positive advanced NSCLC. [ABSTRACT FROM AUTHOR]

Background Genomic fusions are potent oncogenic drivers across cancer types and many are targetable. We demonstrate the clinical performance of DNA-based comprehensive genomic profiling (CGP) for detecting targetable fusions. Materials and Methods We analyzed targetable fusion genes in >450 000 tissue specimens profiled using DNA CGP (FoundationOne CDx, FoundationOne). Using a de-identified nationwide (US-based) non–small cell lung cancer (NSCLC) clinico-genomic database, we assessed outcomes in patients with nonsquamous NSCLC (NonSqNSCLC) who received matched therapy based on a fusion identified using DNA CGP. Lastly, we modeled the added value of RNA CGP for fusion detection in NonSqNSCLC. Results We observed a broad diversity of fusion partners detected with DNA CGP in conjunction with targetable fusion genes (ALK , BRAF , FGFR2 , FGFR3 , NTRK1/2/3 , RET , and ROS1). In NonSqNSCLC with oncogenic ALK , NTRK , RET , and ROS1 fusions detected by DNA CGP, patients treated with a matched tyrosine kinase inhibitor had better real-world progression-free survival than those receiving alternative treatment regimens and benefit was observed regardless of the results of orthogonal fusion testing. An estimated 1.3% of patients with NonSqNSCLC were predicted to have an oncogenic driver fusion identified by RNA, but not DNA CGP, according to a model that accounts for multiple real-world factors. Conclusion A well-designed DNA CGP assay is capable of robust fusion detection and these fusion calls are reliable for informing clinical decision-making. While DNA CGP detects most driver fusions, the clinical impact of fusion detection is substantial for individual patients and exhaustive efforts, inclusive of additional RNA-based testing, should be considered when an oncogenic driver is not clearly identified. [ABSTRACT FROM AUTHOR]

Approximately 5% of non-small cell lung cancer (NSCLC), exhibits anaplastic lymphoma kinase (ALK) rearrangements. EML4-ALK fusions account for over 90% of ALK rearrangements in NSCLC. The advent of treatment targeting ALK has significantly improved survival rates in patients with advanced ALK-positive NSCLC. However, the emergence of resistance mechanisms and the subsequent progression disease inevitably occurs. The tumor immune microenvironment (TIME) plays a pivotal role in lung cancer, influencing disease development, patient's outcomes, and response to treatments. The aim of this review is to provide a comprehensive characterization of the TIME in ALK rearranged NSCLC and its intrinsic plasticity under treatment pressure. Recognizing the fundamental role of the TIME in cancer progression has shifted the paradigm from a tumor cell-centric perspective to the understanding of a complex tumor ecosystem. Understanding the intricate dynamics of the TIME, its influence on treatment response, and the potential of immunotherapy in patients with ALK-positive NSCLC are currently among the primary research objectives in this patient population. [ABSTRACT FROM AUTHOR]

Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard first- and second-line treatment for advanced ALK+ non-small cell lung cancer (NSCLC). We evaluated outcomes in patients with ALK+ NSCLC receiving third-line ALK TKI versus non-ALK-directed therapy. Methods: Flatiron Health OncoEMR data were extracted for patients with ALK+ NSCLC initiating first-line ALK TKI between January 2015 and March 2022 followed by second-line ALK TKI and third-line ALK TKI (group A) or non-TKI therapy (group B). Time-to-treatment discontinuation (TTD) and overall survival (OS) were analyzed using multivariate modelling. Results: Among patients receiving third-line ALK TKI (A, n = 85) or non-TKI therapy (B, n = 43), most received first-line crizotinib (A/B: 64%/60%) and second-line alectinib (36%/30%), ceritinib (24%/19%), or lorlatinib (15%/30%). Common third-line treatments were lorlatinib/alectinib (41%/33%) in A and immunotherapy, chemotherapy, or chemotherapy + immunotherapy (30%/28%/21%) in B. Group A versus B had longer TTD of first-line treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.41–0.93; p = 0.020) and second-line treatment (HR 0.50, 95% CI 0.33–0.75; p < 0.001) and longer OS from start of first-line treatment (HR 0.32, 95% CI 0.19–0.54; p < 0.001) and second-line treatment (HR 0.40, 95% CI 0.24–0.66; p < 0.001). For third-line treatment, median TTD (A/B) was 6.2/2.4 months (HR 0.61, 95% CI 0.37–1.00; p = 0.049) and OS was 17.6/6.5 months (HR 0.57, 95% CI 0.33–0.98; p = 0.042). Conclusions: Patients receiving third-line non-ALK-directed therapy had suboptimal outcomes on prior TKIs. Patients with longer duration of prior ALK TKI treatment appeared to benefit from third-line ALK TKIs. [ABSTRACT FROM AUTHOR]

There is still much progress to be made in understanding the underlying mechanisms of brain metastasis development and its optimal therapy in non–small cell lung cancer (NSCLC); it is very important to expand research in this area because brain metastasis strongly affects patients' quality of life and overall survival. This editorial reviews the available data in the context of a recent meta‐analysis of the pivotal IMpower130, IMpower131, and IMpower150 studies, which explores metastatic epidermal growth factor receptor and anaplastic lymphoma kinase wild‐type NSCLC to determine potential preventative factors and risk factors for the development of brain metastasis, specifically the question of whether immunotherapy (the anti–programmed death ligand 1 antibody, atezolizumab in particular) plays a role in preventing brain metastasis. [ABSTRACT FROM AUTHOR]

Background: It is reported that treatment with anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) induces hypogonadism both in male patients with ALK‐positive cancer and in murine models. Methods: In this study, three groups, including an experimental group of male patients with ALK‐positive, advanced non–small cell lung cancer (ANSCLC) who were receiving alectinib (cohort A), a control group of female patients with ALK‐positive ANSCLC who were receiving alectinib (cohort B), and a control group of male patients with ALK‐negative ANSCLC (cohort C), prospectively underwent a full hormone assessment for androgen deficiency at 8 weeks after the start of treatment and in case of reported suspected symptoms. Patients with major sexual dysfunctions were referred to an endocrinologist. Results: Ninety‐five patients were consecutively enrolled onto the study. Among sixty‐eight male patients, both median total testosterone levels (2.93 vs. 4.92 ng/ml; p =.0001) and free testosterone levels (0.11 vs. 0.17 pg/ml; p =.0002) were significantly lower in ALK‐positive ANSCLC patients in cohort A compared with ALK‐negative patients in cohort C; conversely, median FSH (10.32 vs. 17.52 mUI/ml; p =.0059) and LH levels (4.72 vs. 7.49 mUI/ml; p =.0131) were significantly higher in cohort C compared to cohort A. Median inhibin B levels were higher in ALK‐positive male patients (74.3 vs. 44.24 pg/ml; p =.0038), but all patients had inhibin B values within the normal range. The percentage of male patients who had positive scores on the Androgen Deficiency in Aging Males (ADAM) questionnaire was 62% in cohort A and 26.8% in cohort C, including eight patients who reported at least one major symptom and were referred to Andrology Unit. No significant differences in the endocrine assessment were reported between cohorts A and B. Conclusions: Symptoms of androgen deficiency should be tracked in male patients with ALK‐positive ANSCLC who are receiving alectinib, and testosterone replacement should be considered, as appropriate. Male patients with ALK‐positive advanced non–small cell lung cancer treated with first‐line alectinib had lower median total testosterone (p =.0001) and free testosterone (p =.0002) levels compared with male patients who had ALK‐negative disease and were receiving other anticancer treatments. Symptoms of hypogonadism were more frequent in ALK‐positive patients compared with ALK‐negative patients (62% vs 26.8% rates of positive score at ADAM questionnaire, respectively), suggesting the need for hormone assessment and referral to an andrologist, as appropriate. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to explore the abilities of atezolizumab plus chemotherapy in preventing brain metastases (BMs) among metastatic non–small cell lung cancer (NSCLC) without initial BMs, as well as the risk factors of BMs. Methods: Individual patient data from three trials involving first‐line atezolizumab for metastatic NSCLC (IMpower130, IMpower131, and IMpower150) were pooled. Among patients without baseline BMs and without epidermal growth factor receptor (EGFR) and/or anaplastic lymphoma kinase (ALK) mutations, those receiving atezolizumab + chemotherapy ± bevacizumab were classified as the atezolizumab plus chemotherapy group and those receiving placebo + chemotherapy ± bevacizumab were classified as the chemotherapy group. The cumulative incidences of BM (CI‐BMs) between the two groups were compared. Other factors associated with the CI‐BM were analyzed by Cox regression analyses. Results: With a median follow‐up of 17.6 months (range, 0.03–33.64 months), 74 (3.1%) of the 2380 enrolled patients developed BMs, including 50 (3.1%) and 24 (3.0%) in the atezolizumab plus chemotherapy group (n = 1589) and the chemotherapy group (n = 791), respectively. The CI‐BMs at 6, 12, and 24 months were 1.7%, 2.8%, and 3.3%, respectively. After taking competing risk events into account, there was no significant difference in the CI‐BMs between the two groups (p =.888). Nevertheless, the use of bevacizumab and the histology of nonsquamous NSCLC were found to be independently associated with the risk of BMs. Conclusions: In patients with metastatic EGFR/ALK wild‐type NSCLC without baseline BMs, adding atezolizumab in the first‐line treatment might not reduce the CI‐BM. However, the administration of bevacizumab may reduce the risk of BMs. In patients with metastatic EGFR/ALK wild‐type non–small cell lung cancer without baseline brain metastases (BMs), adding atezolizumab in the first‐line treatment could not reduce the cumulative incidence of BM. However, administration of bevacizumab may reduce the risk of BMs. [ABSTRACT FROM AUTHOR]

The current understanding of inflammatory myofibroblastic tumours (IMTs) of the gynaecological tract has recently been enhanced by their increased recognition. This increase is largely due to greater accessibility to RNA‐based molecular assays used to identify their defining ALK rearrangements. This review summarises the clinical characteristics, morphological spectrum, immunohistochemical profile and molecular underpinnings of uterine IMT. Additionally, this review discusses practical diagnostic considerations including overlap between uterine IMT and smooth muscle tumours as well as pregnancy‐associated uterine IMT. Finally, we highlight recent literature demonstrating the potential for aggressive behaviour in uterine IMT, including a novel risk stratification model for identifying high‐risk IMT. [ABSTRACT FROM AUTHOR]

Lung cancer remains the leading cause of mortality worldwide. Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer with a generally poor prognosis. In recent years, advances in targeted therapy and sequencing technology have brought significant improvement in the therapeutic outcomes of patients with advanced NSCLC. Targeted inhibitors directed against specific mutated or rearranged oncogenes, such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and receptor tyrosine kinase ROS proto-oncogene 1(ROS1) among others, exhibit promising anti-tumor activity. Unfortunately, some patients develop acquired resistance and disease progression soon after initial remission. Despite the continuous development of new drugs and strategies to overcome drug resistance, it is still a major challenge in the treatment of NSCLC. The landscape of targeted therapy for NSCLC is evolving rapidly in response to the pace of scientific research. This study aimed to provide a comprehensive review of tumor target antigens and agents related to targeted therapy in NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: The use of neoadjuvant anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) has not been extensively explored. The current case report highlights the notable pathological complete response (pCR) achieved following neoadjuvant brigatinib therapy in a patient with stage IIIA ALK-positive non-small cell lung cancer (NSCLC). Case presentation: A 32-year-old male presented with incidental lung lesions, ultimately diagnosed as clinical stage T3N1M0, IIIA NSCLC with an ALK gene rearrangement. Following a multidisciplinary discussion, the patient opted for neoadjuvant brigatinib therapy, which significantly reduced the tumor size. Subsequently, surgery with curative intent was performed, revealing pCR with no residual tumor cells. The patient remained disease-free during a 13-month follow-up period. Conclusion: This case report provides compelling evidence of pCR following brigatinib therapy in ALK-positive NSCLC, suggesting that surgery after neoadjuvant therapy with brigatinib may offer a safe and effective approach for patients with ALK-positive NSCLC. [ABSTRACT FROM AUTHOR]

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. Methods: We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. Results: A functional assay identified that transforming growth factor-β1 (TGF-β1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-β1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. Conclusions: These findings provide compelling evidence for the involvement of TGF-β1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-β1 may be used alone or combined with hOM-MSCs therapy for treating PD. [ABSTRACT FROM AUTHOR]

Simple Summary: The tyrosine kinase inhibitor alectinib is currently the first-line treatment for advanced ALK-positive non-small cell lung cancer. The aim of this commentary is to highlight data from clinical trials, case reports, and case series evaluating alectinib in patients with early-stage ALK-positive non-small cell lung cancer in the adjuvant and perioperative setting. The results of the commentary suggest that alectinib could be the new adjuvant option for stage IB-IIIA ALK-positive NSCLC based on the phase III ALINA trial and, in the near future, the results of the phase II ALNEO and NAUTIKA1 trials, evaluating alectinib in the neoadjuvant/perioperative setting, which could further modify the current therapeutic strategy. Background: Targeted therapies changed the treatment of advanced oncogene-addicted non-small cell lung cancer and could also improve outcomes in resectable disease. Results: The ALINA trial evaluated the clinical benefit of adjuvant alectinib compared with standard chemotherapy and met the primary endpoint with a significant increase in disease-free survival at 2 years among anaplastic lymphoma kinase positive patients with stage IB-IIIA disease; two phase II trials (ALNEO and NAUTIKA1) are currently evaluating perioperative treatment with alectinib, and the results of the case reports published to date are encouraging. Conclusion: In resectable anaplastic lymphoma kinase-positive lung cancer, adjuvant alectinib represents the new standard of care and could soon be used in perioperative treatment. [ABSTRACT FROM AUTHOR]

Purpose: There is a lack of real‐world data in Asian populations for brigatinib, a next‐generation anaplastic lymphoma kinase (ALK) inhibitor for patients with non‐small cell lung cancer (NSCLC). This study analysed real‐world outcomes and dosing patterns for brigatinib in patients with crizotinib‐refractory ALK+ NSCLC in South Korea. Methods: This retrospective, non‐interventional, cohort study used South Korean Health Insurance and Review Assessment claims data for adults with ALK+ NSCLC who initiated brigatinib between 19 April 2019 and 31 March 2021 after receiving prior crizotinib. Patients' characteristics, time to discontinuation (TTD), time to dose reduction, overall survival (OS) and treatment adherence were assessed. Results: The study included 174 patients (56.9% male; 27.0% with a history of brain metastases). Median duration of prior crizotinib was 17 (range 0.3–48) months. Median follow‐up after brigatinib initiation was 18 (range 0–34) months. Overall, 88.5% of patients received full‐dose brigatinib (180 mg/day) and 93.1% of patients were adherent (proportion of days covered ≥0.8). The median TTD was 24.9 months (95% CI 15.2–not reached). The probability of continuing treatment was 63.2% at 1 year and 51.5% at 2 years. The probability of continuing at full or peak dose was 79.7% at 1 year and 75.6% at 2 years. Median OS was not reached. The 2‐year OS rate was 68.7%. Conclusions: In this first nationwide retrospective study using national insurance claim data, brigatinib demonstrated real‐world clinical benefit as second‐line treatment after prior crizotinib in ALK+ NSCLC patients in South Korea. [ABSTRACT FROM AUTHOR]

Background: Targeted therapy is now the standard of care in driver–oncogene-positive non-small cell lung cancer (NSCLC). Its initial clinical effects are remarkable. However, almost all patients experience treatment resistance to targeted therapy. Hence, chemotherapy is considered a subsequent treatment option. In patients with driver–oncogene-negative NSCLC, combined immune checkpoint inhibitors (ICIs) and chemotherapy as the first-line therapy has been found to be beneficial. However, the efficacy of ICI plus chemotherapy against driver–oncogene-positive NSCLC other than epidermal growth factor receptor mutation and anaplastic lymphoma kinase fusion is unclear. Methods: Using the hospital medical records, we retrospectively reviewed advanced or recurrent NSCLC patients who were treated with chemotherapy with or without ICIs at Aichi Cancer Center Hospital between January 2014 and January 2023. Patients with druggable rare mutations such as KRAS-G12C, MET exon 14 skipping, HER2 20 insertion, BRAF-V600E mutations, and ROS1 and RET rearrangements were analyzed. Results: In total, 61 patients were included in this analysis. ICI plus chemotherapy was administered in 36 patients (the ICI-chemo group) and chemotherapy in 25 patients (the chemo group). The median progression-free survival (PFS) rates were 14.0 months in the ICI-chemo group and 4.8 months in the chemo group (hazard ratio [HR] = 0.54, 95% confidence interval [CI] = 0.28–1.01). The median overall survival rates were 31.3 and 21.7 months in the ICI-chemo and chemo groups, respectively (HR = 0.70, 95% CI = 0.33–1.50). Multivariate Cox regression analysis of PFS revealed that HER2 exon 20 insertion mutation was significantly associated with a poorer PFS (HR: 2.39, 95% CI: 1.19–4.77, P = 0.014). Further, ICI-chemo treatment was significantly associated with a better PFS (HR: 0.48, 95% CI: 0.25–0.91, P = 0.025). Conclusion: ICI plus chemotherapy improves treatment efficacy in rare driver–oncogene-positive NSCLC. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present study was to assess the clinical outcomes and prognostic factors of lung adenocarcinoma patients with brain metastases (BMs) after intracranial local therapy. Patients and Methods: A total of 83 lung adenocarcinoma patients with BMs who underwent craniotomy combined with radiotherapy or intracranial radiotherapy alone were retrospectively analyzed. The intracranial tumor response was determined according to the Response Assessment in Neuro-Oncology of Brain Metastases (RANO-BM) criteria. The median overall survival (OS), intracranial progression-free survival (iPFS), and related prognostic factors were analyzed with the Kaplan‒Meier estimator method and Cox proportional hazards regression model. Results: Among 83 patients, 20 patients received craniotomy combined with radiotherapy, and 63 patients received intracranial radiotherapy alone. Following intracranial local therapy, 11 patients (13.3%) achieved complete response (CR); among them, 8 patients underwent neurosurgical resection. In addition, 32 patients (38.55%) achieved partial response (PR), 32 patients (38.55%) experienced stable disease (SD), and 8 (9.6%) experienced progressive disease (PD). The median follow-up period was 25.4 months (range 0.8– 49.6 months). The median follow-up time for the iPFS was 16.2 months (range 0.6– 41.2 months). The median OS, iPFS were 28.2 months and 24.7 months. Epidermal growth factor receptor (EGFR) / anaplastic lymphoma kinase (ALK) mutations (HR 3.216, 95% confidence interval (CI) 1.269– 8.150, p = 0.014) and iPFS (HR 0.881, 95% CI 0.836– 0.929, p < 0.001) were found to be beneficial factors for OS. An intracranial-tumor CR was associated with a longer iPFS (PR: HR 0.052, 95% CI 0.009– 0.297, p = 0.001; SD: HR 0.081, 95% CI 0.025– 0.259, p < 0.001; PD: HR 0.216, 95% CI 0.077– 0.606, p = 0.004). Conclusion: Prolonged iPFS was associated with better OS in lung adenocarcinoma patients with BMs following intracranial local therapy, and mutations of EGFR / ALK or an intracranial-tumor CR are independent prognostic factors for prolonged survival. [ABSTRACT FROM AUTHOR]

This document discusses a court case in Ukraine regarding the deadline for submitting an application for supplementary protection of rights in inventions. The court determines that the patent holder should not be deprived of the opportunity to exercise the right to supplementary protection. The court upholds the claim and orders the implementation of supplementary protection for the patent. The ruling sets a precedent for protecting individual rights and investor confidence in the legal system. [Extracted from the article]

Simple Summary: This study is an analytic review of the data on the two most used ALK TKIs, alectinib and lorlatinib, used as the first treatment for ALK-positive NSCLC. These drugs have shown promise in separate studies, but there has not been a direct comparison until now. We analyzed data from two major clinical trials that compared these drugs to crizotinib. We found that lorlatinib may be more effective in delaying the progression of the disease compared to alectinib, especially in controlling brain metastases. Although both drugs have side effects, and an alert has been created for the peculiar toxicities of lorlatinib, more people had to stop taking alectinib due to side effects compared to lorlatinib. Overall, the data suggest that lorlatinib might be a better option for patients with this type of lung cancer, but more research is needed to confirm these findings. This information could help clinicians make better treatment decisions for patients with ALK-positive NSCLC. Various next-generation ALK TKIs are available as first-line options for ALK-positive NSCLC, with alectinib and lorlatinib being commonly preferred. However, no direct comparison between them has been conducted, making it impossible to pick a winner. We performed an analytic, 'non-comparative' assessment of the two phase 3 pivotal clinical trials showing superiority of alectinib (ALEX) and lorlatinib (CROWN) in comparison to crizotinib. Overall, the two studies were very similar in the study design and patient characteristics, with the exception of the selection and evaluation of brain metastases. PFS hazard ratios numerically favored lorlatinib, both according to the investigator and to BICR. Notably, the 3-year PFS rate was numerically higher with lorlatinib (64%) than with alectinib (46.4%). Despite similar response rates and overall intracranial response, the rate of complete intracranial response was higher with lorlatinib, with a cumulative incidence risk of CNS disease progression at 12 months of 9.4% with alectinib and 2.8% with lorlatinib. The peculiar toxicities of lorlatinib were related to lipidic profile alterations, peripheral oedema and cognitive effects, with no impact on cardiovascular risk nor impairment in quality of life versus crizotinib. Furthermore, the rate of permanent treatment discontinuation due to adverse events was numerically higher with alectinib (26%) than with lorlatinib (7%). In conclusion, despite the immature OS data for both drugs, the efficacy of lorlatinib appears higher than alectinib while maintaining a manageable toxicity profile. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) fusions account for 5–7% of non-small cell lung cancer (NSCLC) patients, the therapeutic approaches for which have significantly evolved in the last few years. However, the response to target therapies remains heterogeneous, partially due to the many different ALK fusion variants reported to date. Rare fusion variants have also been discovered, but their role in influencing responses to ALK inhibitors (ALKis) remains poorly elucidated. Laboratory investigation at both the tissue and protein levels, and a molecular profile by next-generation sequencing (NGS) were performed on a lung biopsy sample from one patient with poorly differentiated adenocarcinoma. An in silico prediction model using ColabFold software v1.5.5 was used to model and predict the entire structure of the chimeric aberrant ALK protein. Here, we report a case of a former smoker, a 60-year-old man, diagnosed with NSCLC and undergoing ALK translocation. He received first-, second- and third-generation ALK protein inhibitors (ALKis), showing a clinical benefit for about 4 years. IHC analysis and the molecular examination of the tissue biopsy indicated a positive staining for ALK and a novel ALK gene fusion variant, involving the sperm antigen with calponin homology and coiled-coil domain 1-like (SPECC1L) gene with an unreported breakpoint in exon 7. The novel SPECCL1::ALK fusion was identified using Anchored Multiplex PCR (AMP)-NGS technology and was predicted to retain the Pkinase_Tyr domain at the carboxy-terminal region of the resulting chimeric protein. To the best of our knowledge, this is the first case of an ALK-positive NSCLC patient carrying the SPECC1L exon 7 fusion breakpoint and one of the few reports about clinical outcomes related to SPECC1L::ALK fusion. The in silico hypothesized biological role of this newly identified fusion variant corroborates the observed clinical response to multiple ALKis. The molecular findings also reinforce the utility of AMP-based NGS technology as a valuable tool for the identification of rare chromosomal events that may be related to the variability of patient outcomes to different ALKis treatments. [ABSTRACT FROM AUTHOR]

Olanzapine is an atypical antipsychotic drug and a potent muscarinic M3 receptor (M3R) antagonist. Olanzapine has been reported to cause metabolic disorders, including dyslipidemia. Anaplastic lymphoma kinase (Alk), a tyrosine kinase receptor well known in the pathogenesis of cancer, has been recently identified as a key gene in the regulation of thinness via the regulation of adipose tissue lipolysis. This project aimed to investigate whether Olanzapine could modulate the hepatic Alk pathway and lipid metabolism via M3R. Female rats were treated with Olanzapine and/or Cevimeline (an M3R agonist) for 9 weeks. Lipid metabolism and hepatic Alk signaling were analyzed. Nine weeks' treatment of Olanzapine caused metabolic disturbance including increased body mass index (BMI), fat mass accumulation, and abnormal lipid metabolism. Olanzapine treatment also led to an upregulation of Chrm3, Alk, and its regulator Ptprz1, and a downregulation of Lmo4, a transcriptional repressor of Alk in the liver. Moreover, there were positive correlations between Alk and Chrm3, Alk and Ptprz1, and a negative correlation between Alk and Lmo4. However, cotreatment with Cevimeline significantly reversed the lipid metabolic disturbance and adipose tissue accumulation, as well as the upregulation of the hepatic Alk signaling caused by Olanzapine. This study demonstrates evidence that Olanzapine may cause metabolic disturbance by modulating hepatic Alk signaling via M3R, which provides novel insight for modulating the hepatic Alk signaling and potential interventions for targeting metabolic disorders. [ABSTRACT FROM AUTHOR]

Introduction: Post-ovulatory aging is a time-dependent deterioration of ovulated oocytes and a major limiting factor reducing the fitness of offspring. This process may lead to the activation of cell death pathways like apoptosis in oocytes. Methodology: We evaluated oocyte membrane integrity, egg developmental competency, and mRNA abundance of apoptosis-related genes by RT-qPCR. Oocytes from zebrafish Danio rerio were retained in vivo at 28.5°C for 24 h post-ovulation (HPO). Viability was assessed using trypan blue (TB) staining. The consequences of in vivo oocyte aging on the developmental competence of progeny were determined by the embryo survival at 24 h post fertilization, hatching, and larval malformation rates. Results: The fertilization, oocyte viability, and hatching rates were 91, 97, and 65% at 0 HPO and dropped to 62, 90, and 22% at 4 HPO, respectively. The fertilizing ability was reduced to 2% at 8 HPO, while 72% of oocytes had still intact plasma membranes. Among the apoptotic genes bcl-2 (b-cell lymphoma 2), bada (bcl2- associated agonist of cell death a), cathepsin D, cathepsin Z, caspase 6a, caspase 7, caspase 8, caspase 9, apaf1, tp53 (tumor protein p53), cdk1 (cyclin-dependent kinase 1) studied, mRNA abundance of anti-apoptotic bcl-2 decreased and proapoptotic cathepsin D increased at 24 HPO. Furthermore, tp53 and cdk1 mRNA transcripts decreased at 24 HPO compared to 0 HPO. Discussion: Thus, TB staining did not detect the loss of oocyte competency if caused by aging. TB staining, however, could be used as a simple and rapid method to evaluate the quality of zebrafish oocytes before fertilization. Taken together, our results indicate the activation of cell death pathways in the advanced stages of oocyte aging in zebrafish. [ABSTRACT FROM AUTHOR]

Approximately 3–5% of non-small cell lung cancers (NSCLC) harbor ALK fusion genes and may be responsive to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors. There are only a few reports on cell lines with EML4-ALK variant 3 (v3) and tumoroids that can be subject to long-term culture (> 3 months). In this study, we established tumoroids (PDT-LUAD#119) from a patient with lung cancer harboring EML4-ALK that could be cultured for 12 months. Whole-exome sequencing and RNA sequencing analyses revealed TP53 mutations and an EML4-ALK v3 mutation. PDT-LUAD#119 lung tumoroids were sensitive to the ALK tyrosine kinase inhibitors (ALK TKIs) crizotinib, alectinib, entrectinib, and lorlatinib, similar to NCI-H3122 cells harboring EML4-ALK variant 1 (v1). Unexpectedly, clear squamous cell carcinoma and solid adenocarcinoma were observed in xenografts from PDT-LUAD#119 lung tumoroids, indicating adenosquamous carcinoma. Immunostaining revealed that the squamous cell carcinoma was ALK positive, suggesting a squamous transformation of the adenocarcinoma. Besides providing a novel cancer model to support basic research on ALK-positive lung cancer, PDT-LUAD#119 lung tumoroids will help elucidate the pathogenesis of adenosquamous carcinoma. [ABSTRACT FROM AUTHOR]

TK-ALCL1, a novel anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) cell line, was established from the primary tumor site of a 59-year-old Japanese male patient. The immune profile of TK-ALCL1 corresponds to that seen typically in primary ALCL cells, i.e., positive for ALK, CD30, EMA, and CD4, but negative for CD2, CD3, CD5, CD8a, and EBV-related antigens. The rearrangement of the T cell receptor-gamma locus shows that TK-ALCL1 is clonally derived from T-lineage lymphoid cells. FISH and RT-PCR analysis revealed that TK-ALCL1 has the nucleophosmin (NPM)-ALK fusion transcript, which is typical for ALK+ ALCL cell lines. When TK-ALCL1 was subcutaneously inoculated into 6-week-old BALB/c Rag2−/−/Jak3−/− (BRJ) mice, it formed tumor masses within 4–6 weeks. Morphological, immunohistochemical, and molecular genetic investigations confirmed that the xenograft and the original ALCL tumor were identical. The ALK inhibitors Alectinib and Lorlatinib suppressed proliferation in a dose-dependent manner. Thus, TK-ALCL1 provides a useful in vitro and in vivo model for investigation of the biology of ALK+ ALCL and of novel therapeutic approaches targeting ALK. [ABSTRACT FROM AUTHOR]

Background: Lorlatinib displays marked systemic and intracranial efficacy against anaplastic lymphoma kinase (ALK) positive non-small cell lung cancer (NSCLC). We aimed to establish the safety profile of lorlatinib based on the Food and Drug Administration Adverse Event Reporting System (FAERS). Methods: Reports from the FAERS between 2019 and 2023 were collected to conduct the disproportionality analysis. Reporting odds ratio (ROR) was employed to detect the potential adverse events (AEs) related to lorlatinib. The clinical characteristics, age and gender differences, time to onset of AEs were also investigated. Results: A total of 2,941 AE reports were found to be associated with lorlatinib among the 8,818,870 AE reports obtained from the FAERS database. 167 lorlatinib-related AE signals were identified. The frequently reported AEs including hypercholesterolemia, oedema, and cognitive disorder were in line with those observed in clinical trials and drug instruction. However, AEs such as interstitial lung disease and AV block indicated in the drug label require further evaluation. More attention should be paid to the new potential unexpected AEs including pulmonary arterial hypertension and radiation necrosis. Furthermore, we examined the specific high-risk AEs of different ages and genders. In addition, majority of AEs occurred within the first 2 months after lorlatinib initiation with a median onset time of 51 days. Conclusion: Our study provides valuable insight into the post-marketing safety profile of lorlatinib, which can potentially benefit the rational and safe administration of lorlatinib in the clinic. Further prospective studies are needed to validate the associations between lorlatinib and the identified AEs. [ABSTRACT FROM AUTHOR]

Aminoacyl-tRNA synthetases (aaRSs) play a central role in the translation of genetic code, serving as attractive drug targets. Within this family, the lysyl-tRNA synthetase (LysRS) constitutes a promising antimalarial target. ASP3026, an anaplastic lymphoma kinase (ALK) inhibitor was recently identified as a novel Plasmodium falciparum LysRS (PfLysRS) inhibitor. Here, based on cocrystal structures and biochemical experiments, we developed a series of ASP3026 analogues to improve the selectivity and potency of LysRS inhibition. The leading compound 36 showed a dissociation constant of 15.9 nM with PfLysRS. The inhibitory efficacy on PfLysRS and parasites has been enhanced. Covalent attachment of l-lysine to compound 36 resulted in compound 36K3, which exhibited further increased inhibitory activity against PfLysRS but significantly decreased activity against ALK. However, its inhibitory activity against parasites did not improve, suggesting potential future optimization directions. This study presents a new example of derivatization of kinase inhibitors repurposed to inhibit aaRS. Using a combination of biochemical and structural approaches, the authors demonstrate that derivatization of kinase inhibitors can yield new repurposed anti-malarial drugs that specifically target Plasmodium falciparum Lysine-tRNA synthetase. [ABSTRACT FROM AUTHOR]

Anaplastic thyroid cancer (ATC) is one of the deadliest human cancers and represents <2% of thyroid carcinomas. A therapeutic target for ATC is represented by anaplastic lymphoma kinase (ALK) rearrangements, involved in tumor growth. Crizotinib is an oral small-molecule tyrosine kinase inhibitor of the ALK, MET, and ROS1 kinases, approved in ALK-positive non-small cell lung cancer. Until now, the effect of crizotinib in "primary human ATC cells" (pATCs) with transforming striatin (STRN)–ALK fusion has not been reported in the literature. In this study, we aimed to obtain pATCs with STRN–ALK in vitro and evaluate the in vitro antineoplastic action of crizotinib. Thyroid surgical samples were obtained from 12 ATC patients and 6 controls (who had undergone parathyroidectomy). A total of 10/12 pATC cultures were obtained, 2 of which with transforming STRN–ALK fusion (17%). Crizotinib inhibited proliferation, migration, and invasion and increased apoptosis in 3/10 pATC cultures (2 of which with/1 without STRN–ALK), particularly in those with STRN–ALK. Moreover, crizotinib significantly inhibited the proliferation of AF cells (a continuous cell line obtained from primary ATC cells). In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN–ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Identifying ALK fusions in advanced non-small-cell lung carcinoma (aNSCLC) is mandatory for targeted therapy. Current methods use ALK IHC, ALK FISH, or NGS, but face challenges due to low fusion frequency, possible tissue exhaustion, and test limitations. We compared RNA NGS with ALK IHC and ALK FISH in 1246 NSCLC cases, finding RNA NGS faster and equally effective. This suggests the need to replace systematic ALK IHC with RNA NGS reflex testing for more efficient assessments of ALK status. The identification of ALK fusions in advanced non-small-cell lung carcinoma (aNSCLC) is mandatory for targeted therapy. The current diagnostic approach employs an algorithm using ALK immunohistochemistry (IHC) screening, followed by confirmation through ALK FISH and/or next-generation sequencing (NGS). Challenges arise due to the infrequency of ALK fusions (3–7% of aNSCLC), the suboptimal specificity of ALK IHC and ALK FISH, and the growing molecular demands placed on small tissue samples, leading to interpretative, tissue availability, and time-related issues. This study investigates the effectiveness of RNA NGS as a reflex test for identifying ALK fusions in NSCLC, with the goal of replacing ALK IHC in the systematic screening process. The evaluation included 1246 NSCLC cases using paired techniques: ALK IHC, ALK FISH, and ALK NGS. ALK IHC identified 51 positive cases (4%), while RNA NGS detected ALK alterations in 59 cases (4.8%). Of the 59 ALK-positive cases identified via NGS, 53 (89.8%) were confirmed to be positive. This included 51 cases detected via both FISH and IHC, and 2 cases detected only via FISH, as they were completely negative according to IHC. The combined reporting time for ALK IHC and ALK FISH averaged 13 days, whereas ALK IHC and RNA NGS reports were obtained in an average of 4 days. These results emphasize the advantage of replacing systematic ALK IHC screening with RNA NGS reflex testing for a more comprehensive and accurate assessment of ALK status. [ABSTRACT FROM AUTHOR]

This article discusses the case of a patient with non-small cell lung cancer (NSCLC) who had a rare EGFR S645C mutation. The patient was initially treated with immunochemotherapy but experienced disease progression. They were then treated with afatinib, an EGFR tyrosine kinase inhibitor (TKI), which resulted in a decrease in tumor size and improvement in symptoms. However, the patient eventually developed resistance to afatinib and passed away. The article highlights the importance of comprehensive genomic profiling using next-generation sequencing (NGS) to identify rare mutations and guide treatment decisions for patients with NSCLC. [Extracted from the article]

PURPOSE: Genomic alterations have been identified in patients with breast cancer brain metastases (BCBMs), but large structural rearrangements have not been extensively studied. MATERIALS AND METHODS: We analyzed the genomic profiles of 822 BCBMs and compared them with 11,988 local, breast-biopsied breast cancers (BCs) and 15,516 non-CNS metastases (Non-CNS M) derived from formalin-fixed paraffin-embedded material using targeted capture sequencing. RESULTS: Nine genes with structural rearrangements were more prevalent within BCBMs as compared with local BCs and Non-CNS M (adjusted- P <.05) and displayed a prevalence of >0.5%. The most common rearrangements within BCBMs involves cyclin-dependent kinase 12 (CDK12 ; 3.53%) as compared with the local BC (0.86%; adjusted- P = 7.1 × 10–8) and Non-CNS M specimens (0.68%; adjusted- P = 3.7 × 10–10). CDK12 rearrangements had a significantly higher frequency within human epidermal growth factor receptor 2 (HER2)–positive BCBMs (14.59%) compared with HER2-positive BCs (7.80%; P = 4.6 × 10–3) and HER2-positive Non-CNS M (7.87%; P = 4.8 × 10–3). CONCLUSION: The most common structural rearrangements involve CDK12 with the higher prevalence in HER2-positive BCBMs. These data support more detailed investigation of the role and importance of CDK12 rearrangements in BCBMs. CDK12 the most common gene rearranged in breast cancer brain mets, with the highest prevalence in HER2+ disease. [ABSTRACT FROM AUTHOR]

Lung cancer is the malignant tumor with the highest incidence and mortality rate worldwide. For lung adenocarcinoma, identifying specific gene mutations, fusions, and giving corresponding targeted drugs can greatly improve the survival time of the patients. Among them, anaplastic lymphoma kinase (ALK) fusion occurs in 3%-7% of non-small cell lung cancer (NSCLC). In clinical practice, a variety of detection methods can be used to determine the ALK fusion status, but false negative test results are possible. This paper retrospectively analyzed the diagnosis and treatment of a patient with lung adenocarcinoma, judged the ALK fusion status by various detection methods. Among them, immunohistochemistry (IHC)(Ventana D5F3), RNA based next-generation sequencing (RNA-based NGS) confirmed positive echinoderm microtubule associated protein like 4 (EML4)-ALK fusion, while DNA-based NGS was negative. This paper analyzed the detection methods of ALK fusion, in order to clarify which detection method is the most accurate and simple to choose in different clinical cases and guide the subsequent treatment. [ABSTRACT FROM AUTHOR]

Lysophosphatidic acid (LPA) is a well-documented pro-oncogenic factor in different cancers, but relatively little is known on its biological activity in neuroblastoma. The LPA effects and the participation of the tyrosine kinase receptor anaplastic lymphoma kinase (ALK) in LPA mitogenic signaling were studied in human neuroblastoma cell lines. We used light microscopy and [3H]-thymidine incorporation to determine cell proliferation, Western blot to study intracellular signaling, and pharmacological and molecular tools to examine the role of ALK. We found that LPA stimulated the growth of human neuroblastoma cells, as indicated by the enhanced cell number, clonogenic activity, and DNA synthesis. These effects were curtailed by the selective ALK inhibitors NPV-TAE684 and alectinib. In a panel of human neuroblastoma cell lines harboring different ALK genomic status, the ALK inhibitors suppressed LPA-induced phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2), which are major regulators of cell proliferation. ALK depletion by siRNA treatment attenuated LPA-induced ERK1/2 activation. LPA enhanced ALK phosphorylation and potentiated ALK activation by the ALK ligand FAM150B. LPA enhanced the inhibitory phosphorylation of the tumor suppressor FoxO3a, and this response was impaired by the ALK inhibitors. These results indicate that LPA stimulates mitogenesis of human neuroblastoma cells through a crosstalk with ALK. [ABSTRACT FROM AUTHOR]

Anaplastic large cell lymphoma (ALCL) and inflammatory myofibroblastic tumor (IMT) are rare cancers observed predominantly in children and young adults. ALCL accounts for 10–15% of all pediatric non-Hodgkin lymphomas and is commonly diagnosed at an advanced stage of disease. In children, 84–91% of cases of ALCL harbor an anaplastic lymphoma kinase (ALK) gene translocation. IMT is a rare mesenchymal neoplasm that also tends to occur in children and adolescents. Approximately 50–70% of IMT cases involve rearrangements in the ALK gene. A combination of chemotherapeutic drugs is typically used for children with ALK-positive ALCL, and the only known curative therapy for ALK-positive IMT is complete surgical resection. Crizotinib, a first-generation ALK inhibitor, was approved in the USA in 2021 for pediatric patients and young adults with relapsed or refractory ALK-positive ALCL; however, its safety and efficacy have not been established in older adults. In 2022, crizotinib was approved for adult and pediatric patients with unresectable, recurrent, or refractory ALK-positive IMT. This podcast provides an overview of ALK-positive ALCL and IMT. We discuss the current treatment landscape, the role of ALK tyrosine kinase inhibitors, and areas of future research. [ABSTRACT FROM AUTHOR]

Background: Non‐small‐cell lung cancer (NSCLC) is the primary cause of brain metastases (BM). This study aimed to investigate differences in clinical and magnetic resonance imaging (MRI) features of BM between anaplastic lymphoma kinase (ALK) gene fusion (ALK+) and ALK wild‐type (ALK‐) NSCLC, and to preliminarily assess the efficacy of radiotherapy for treating BM. Methods: A retrospective analysis included 101 epidermal growth factor receptor (EGFR)‐ NSCLC patients with BM: 41 with ALK gene fusion and 60 being ALK‐. The brain MRI and clinical features were compared between different ALK status using the multivariate analysis, and a nomogram was constructed to predict ALK gene fusion. Fifty‐six patients who did not undergo cerebral surgery and had complete pre‐ and post‐ treatment data were further divided based on whether they received radiotherapy. Log‐rank test was used to compare the short‐term effect of treatment between the two groups under different genotypes. Results: ALK+ BM exhibited decreased peritumoral brain edema size, lower peritumoral brain edema index (PBEI), and a more homogeneous contrast enhancement pattern compared to ALK‐ BM. Age (OR = 1.04; 95%CI: 1.02–1.06), time to BM (OR = 1.50; 95% CI: 1.04–2.14), PBEI (OR = 1.26; 95% CI: 0.97–1.62), smoking status (smoking index >400 vs. non‐smoking status: OR = 1.42; 95% CI: 0.99–2.04) and contrast enhancement pattern (OR = 1.89; 95% CI: 1.28–2.78) were associated with ALK gene fusion. A nomogram based on these variables demonstrated acceptable predictive efficiency (AUC = 0.844). In the ALK+ group, patients who received radiotherapy did not show increased disease control rate (DCR) or progression‐free survival (PFS). In contrast, in the ALK‐ group, those who received radiotherapy had improved objective response rate (ORR), DCR, and PFS compared to those who were only treated with systemic therapy. Conclusions: The clinical and MRI features of BM can indicate the status of ALK in NSCLC. In the ALK‐ group, patients who received radiotherapy showed higher ORR, DCR, and PFS compared to those who did not. [ABSTRACT FROM AUTHOR]

BRAFV600E is the most prevalent mutation in thyroid cancer and correlates with poor prognosis and therapy resistance. Although selective inhibitors of BRAFV600E have been developed, more advanced tumors such as anaplastic thyroid carcinomas show a poor response in clinical trials. Therefore, the study of alternative survival mechanisms is needed. Since metabolic changes have been related to malignant progression, in this work we explore metabolic dependencies of thyroid tumor cells to exploit them therapeutically. Our results show that respiration of thyroid carcinoma cells is highly dependent on fatty acid oxidation and, in turn, fatty acid mitochondrial availability is regulated through macroautophagy/autophagy. Furthermore, we show that both lysosomal inhibition and the knockout of the essential autophagy gene, ATG7, lead to enhanced lipolysis; although this effect is not essential for survival of thyroid carcinoma cells. We also demonstrate that following inhibition of either autophagy or fatty acid oxidation, thyroid tumor cells compensate oxidative phosphorylation deficiency with an increase in glycolysis. In contrast to lipolysis induction, upon autophagy inhibition, glycolytic boost in autophagy-deficient cells is essential for survival and, importantly, correlates with a higher sensitivity to the BRAFV600E selective inhibitor, vemurafenib. In agreement, downregulation of the glycolytic pathway results in enhanced mitochondrial respiration and vemurafenib resistance. Our work provides new insights into the role of autophagy in thyroid cancer metabolism and supports mitochondrial targeting in combination with vemurafenib to eliminate BRAFV600E-positive thyroid carcinoma cells. Abbreviations: AMP: adenosine monophosphate; ATC: anaplastic thyroid carcinoma; ATG: autophagy related; ATP: adenosine triphosphate; BRAF: B-Raf proto-oncogene, serine/threonine kinase; Cas9: CRISPR-associated protein; CREB: cAMP responsive element binding protein; CRISPR: clustered regularly interspaced short palindromic repeats; 2DG: 2-deoxyglucose; FA: fatty acid; FAO: fatty acid oxidation; FASN: fatty acid synthase; FCCP: trifluoromethoxy carbonyl cyanide phenylhydrazone; LAMP1: lysosomal associated membrane protein 1; LIPE/HSL: lipase E, hormone sensitive type; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; OCR: oxygen consumption rate; OXPHOS: oxidative phosphorylation; PRKA/PKA: protein kinase cAMP-activated; PTC: papillary thyroid carcinoma; SREBF1/SREBP1: sterol regulatory element binding transcription factor 1. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) gene fusions are rare in papillary thyroid carcinoma (PTC) but may serve as a therapeutic target. This study aims to evaluate the preoperative cytologic findings and clinicopathologic features of a series of eight ALK-rearranged PTCs from our pathology archives and consultations. All cases were confirmed by ALK D5F3 immunohistochemistry and six with additional targeted RNA-based next-generation sequencing (NGS). The original fine-needle aspiration (FNA) cytology diagnosis included the Bethesda System (TBS) category II in three (37.5%), TBS III in two (25%), TBS V in two (25%), and TBS VI in one (12.5%). Six cases had available FNA cytology and were reviewed. The cytologic features showed microfollicular architecture as well as limited or reduced nuclear elongation and chromatin alterations in all six. Nuclear grooves and pseudoinclusions were absent in two cases, rarely or focally noted in three, and frequently found in one. Two cases initially diagnosed as TBS II, showing microfollicular architecture without well-developed nuclear features, were revised to TBS III (with architectural atypia only). For histologic correlations, four were infiltrative follicular variant PTCs, three as classic subtype PTC with predominant follicular growth, and one as solid/trabecular subtype PTC. All eight cases demonstrated reduced PTC nuclear features with respect to nuclear elongation and chromatin alterations compared to those typically identified in "BRAF-like" PTCs. The NGS testing revealed EML4::ALK fusion in three, STRN::ALK fusion in two, and ITSN2::ALK fusion in one. In conclusion, although ALK-rearranged PTCs have been associated with neutral gene expression profile from a BRAF-RAS scoring perspective, the "RAS-like" nuclear features were more commonly identified in this series, resulting in frequent indeterminate diagnosis of preoperative FNA. [ABSTRACT FROM AUTHOR]

The anaplastic lymphoma kinase (ALK, CD247) is a potential target for antibody-based therapy. However, no antibody-based therapeutics targeting ALK have entered clinical trials, necessitating the development of novel antibodies with unique therapeutic merits. Single-domain antibodies (sdAb) bear therapeutic advantages compared to the full-length antibody including deeper tumor penetration, cost-effective production and fast washout from normal tissues. In this study, we identified a human immunoglobulin heavy chain variable domain (VH domain) (VH20) from an in-house phage library. VH20 exhibits good developability and high specificity with no off-target binding to ~6000 human membrane proteins. VH20 efficiently bound to the glycine-rich region of ALK with an EC50 of 0.4 nM and a KD of 6.54 nM. Both VH20-based bispecific T cell engager (TCE) and chimeric antigen receptor T cells (CAR Ts) exhibited potent cytolytic activity to ALK-expressing tumor cells in an ALK-dependent manner. VH20 CAR Ts specifically secreted proinflammatory cytokines including IL-2, TNFα and IFNγ after incubation with ALK-positive cells. To our knowledge, this is the first reported human single-domain antibody against ALK. Our in vitro characterization data indicate that VH20 could be a promising ALK-targeting sdAb with potential applications in ALK-expressing tumors, including neuroblastoma (NBL) and non-small cell lung cancer. [ABSTRACT FROM AUTHOR]

The emergence of anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancer (NSCLC) has revolutionized targeted therapy. This dynamic landscape, featuring novel ALK inhibitors and combination therapies, necessitates a profound understanding of resistance mechanisms for effective treatment strategies. Recognizing two primary categories – on-target and off-target resistance – underscores the need for comprehensive assessment. This review delves into the intricacies of resistance to ALK inhibitors, exploring complexities in identification and management. Molecular testing, pivotal for early detection and accurate diagnosis, forms the foundation for patient stratification and resistance management. The literature search methodology involved comprehensive exploration of Pubmed and Embase. The multifaceted perspective encompasses new therapeutic horizons, ongoing clinical trials, and their clinical implications post the recent approval of lorlatinib. Our expert opinion encapsulates the critical importance of understanding resistance mechanisms in the context of ALK inhibitors for shaping successful treatment approaches. With a focus on molecular testing and comprehensive assessment, this review contributes valuable insights to the evolving landscape of NSCLC therapy. [ABSTRACT FROM AUTHOR]

Cure of cancer is a sensitive and multidimensional concept that is challenging to define, difficult to assert at the individual patient level, and often surrounded by controversy. The notion of cure in non‐small cell lung cancer (NSCLC) has changed and continues to evolve with improvements in diagnosis and treatment. Targeted and immune therapies have recently entered the treatment landscape of stage I–III NSCLC. While some initial pivotal trials of such agents failed to improve survival, recently approved epidermal growth factor receptor (EGFR) inhibitors (in EGFR‐mutated NSCLC) and immune checkpoint inhibitors have shown delays in disease recurrence or progression and unprecedented survival gains compared to previous standards of care. Additional data is now emerging supporting the benefit of treatment strategies based on alternation‐matched targeting (anaplastic lymphoma kinase [ALK] inhibition in ALK‐altered disease) and immune checkpoint inhibition in stage I–III NSCLC. Similar to previous developments in the treatment of early and locally advanced NSCLC, it is expected that statistically significant and clinically meaningful trial‐level benefits will translate into real‐world benefits, including improvements in cure measures. Parallel advances in molecular testing (e.g., circulating tumor DNA analyses) are also allowing for a deeper and more comprehensive characterization of disease status and treatment response. Given the impact that curative‐intent treatments have on survival, it is critical that various stakeholders, including clinicians and patients, are aware of new opportunities to pursue cure in stage I–III NSCLC. [ABSTRACT FROM AUTHOR]

Foetal lung interstitial tumour (FLIT) is a rare and presumably benign lung tumour found in neonates. Only 21 cases of FLIT have been reported, with molecular data available for only two cases. This study reports a novel fusion called STRN::ALK, expanding the spectrum of ALK rearrangement in FLIT. The study describes the case of a premature male neonate with an intrathoracic tumour, diagnosed antenatally and confirmed as FLIT through histological examination. The study also discusses the potential therapeutic implications of ALK fusion in FLIT and recommends close follow-up due to the limited number of cases reported. [Extracted from the article]

An aggressive subtype of inflammatory myofibroblastic tumor, epithelioid inflammatory myofibroblastic sarcoma occurs primarily inside the abdominal cavity, followed by a pulmonary localization. Most harbor anaplastic lymphoma kinase (ALK) gene rearrangements, with RANBP2 and RRBP1 among the well-documented fusion partners. We report the second case of primary epithelioid inflammatory myofibroblastic sarcoma of the brain, with a well-known EML4::ALK fusion. The case is notable for its intra-axial presentation that clinico-radiologically mimicked glioma.

Introduction Inflammatory myofibroblastic tumors are difficult to diagnose because of the lack of specific indicators. We describe a diagnostically challenging case of an inflammatory myofibroblastic tumor primary to the peritoneum. Case presentation The patient was a 25‐year‐old male who presented at our hospital with lower abdominal pain. Computed tomography revealed a mass lesion 80 mm in diameter just above the bladder. This was suspected to be a bleeding tumor of the urachus. Since malignancy could not be ruled out, surgery was planned. This revealed a fragile tumor arising from the peritoneum. Following its removal, the tumor was diagnosed by histopathological analysis as an inflammatory myofibroblastic tumor. Conclusion We describe a case of inflammatory myofibroblastic tumor primary to the peritoneum diagnosed by histopathology. Inflammatory myofibroblastic tumor should be considered in the differential diagnosis of abdominal wall and anterior bladder tumors.

Abstract Background The initial phase II stuty (NCT03215693) demonstrated that ensartinib has shown clinical activity in patients with advanced crizotinib‐refractory, anaplastic lymphoma kinase (ALK)‐positive non‐small cell lung cancer (NSCLC). Herein, we reported the updated data on overall survival (OS) and molecular profiling from the initial phase II study. Methods In this study, 180 patients received 225 mg of ensartinib orally once daily until disease progression, death or withdrawal. OS was estimated by Kaplan‒Meier methods with two‐sided 95% confidence intervals (CIs). Next‐generation sequencing was employed to explore prognostic biomarkers based on plasma samples collected at baseline and after initiating ensartinib. Circulating tumor DNA (ctDNA) was detected to dynamically monitor the genomic alternations during treatment and indicate the existence of molecular residual disease, facilitating improvement of clinical management. Results At the data cut‐off date (August 31, 2022), with a median follow‐up time of 53.2 months, 97 of 180 (53.9%) patients had died. The median OS was 42.8 months (95% CI: 29.3‐53.2 months). A total of 333 plasma samples from 168 patients were included for ctDNA analysis. An inferior OS correlated significantly with baseline ALK or tumor protein 53 (TP53) mutation. In addition, patients with concurrent TP53 mutations had shorter OS than those without concurrent TP53 mutations. High ctDNA levels evaluated by variant allele frequency (VAF) and haploid genome equivalents per milliliter of plasma (hGE/mL) at baseline were associated with poor OS. Additionally, patients with ctDNA clearance at 6 weeks and slow ascent growth had dramatically longer OS than those with ctDNA residual and fast ascent growth, respectively. Furthermore, patients who had a lower tumor burden, as evaluated by the diameter of target lesions, had a longer OS. Multivariate Cox regression analysis further uncovered the independent prognostic values of bone metastases, higher hGE, and elevated ALK mutation abundance at 6 weeks. Conclusion Ensartinib led to a favorable OS in patients with advanced, crizotinib‐resistant, and ALK‐positive NSCLC. Quantification of ctDNA levels also provided valuable prognostic information for risk stratification.

Background: Lung cancer ranks first in both cancer incidence and mortality in China. The emergence of novel treatments for ALK-positive NSCLC led to an improvement in survival and quality of life for patients with advanced ALK mutation-positive non-small cell lung cancer (NSCLC). This study sought to assess the cost-effectiveness of 6 tyrosine kinase inhibitors (TKIs)—crizotinib, alectinib, ceritinib, brigatinib, ensartinib, and lorlatinib—as first-line treatments for ALK-positive NSCLC from the perspective of the Chinese health care system. Methods: A Markov model was developed to estimate the cost-effectiveness of these 6 TKIs. In this model, ALK-positive NSCLC patients were initially simulated to receive 1 of the 6 TKIs as first-line therapy, followed by different TKIs as subsequent treatment and salvage chemotherapy as last-line treatment. Survival data were sourced from the latest published clinical trials. Costs were derived from recent national health insurance negotiations and hospital information systems of selected health care facilities. Utilities for healthy states and adverse events were obtained from the literature. One-way and probabilistic sensitivity analysis as well as scenario analysis was conducted to assess the robustness of the results. Results: Compared to ensartinib, crizotinib, alectinib, ceritinib, brigatinib, and lorlatinib demonstrated incremental quality-adjusted life years (QALYs) of −1.13, 0.39, −0.58, −0.09, and 0.35, respectively. The corresponding incremental costs were $10 677, $33 501, −$6426, $2672, and $24 358. This resulted in ICERs of –$9449/QALY, $85 900/QALY, $11 079/QALY, $29 689/QALY and $69 594/QALY, respectively. Conclusion: Crizotinib was considered to be absolutely dominated by ensartinib. Under a willingness-to-pay threshold of $38 223/QALY, ceritinib and brigatinib were cost-effective compared with ensartinib, while lorlatinib and alectinib were not cost-effective when compared with ensartinib. Overall, brigatinib emerged as the most cost-effective treatment among all the options considered. [ABSTRACT FROM AUTHOR]

Background: Inflammatory myofibroblastic tumors (IMTs) are uncommon neoplasms most prevalent in individuals under 40 years old and predominantly in the lungs. Despite their rarity, multiple anaplastic lymphoma kinase (ALK)-positive IMTs, especially those of various sizes, have not been widely reported. This report describes a case of multiple ALK-positive IMTs in the lungs, aiming to further our understanding of their behavior and management. Case presentation: Herein, we present the case of a 64-year-old woman who presented with an abnormal shadow on chest examination. Chest computed tomography revealed a main tumor in the right middle lobe and multiple irregularly shaped small nodules in both lungs. Thus, thoracoscopic wedge resection of the left lower lobe was performed for diagnosis. Pathological findings indicated smooth muscle proliferation without malignancy. IMT was diagnosed following thoracoscopic right middle lobectomy. Twenty months postoperatively, one residual nodule shrank, but another grew. Conclusions: This is the first report of multiple ALK-positive IMTs in both lungs, highlighting the need for definitive diagnosis and treatment of IMTs based on surgical resection. Although caution is required in patients with lymph node metastases or distant metastases, careful follow-up is acceptable unless there is a tendency for nodules to increase in size on imaging. [ABSTRACT FROM AUTHOR]

The E3 SUMO ligase PIAS2 is expressed at high levels in differentiated papillary thyroid carcinomas but at low levels in anaplastic thyroid carcinomas (ATC), an undifferentiated cancer with high mortality. We show here that depletion of the PIAS2 beta isoform with a transcribed double-stranded RNA–directed RNA interference (PIAS2b-dsRNAi) specifically inhibits growth of ATC cell lines and patient primary cultures in vitro and of orthotopic patient-derived xenografts (oPDX) in vivo. Critically, PIAS2b-dsRNAi does not affect growth of normal or non-anaplastic thyroid tumor cultures (differentiated carcinoma, benign lesions) or cell lines. PIAS2b-dsRNAi also has an anti-cancer effect on other anaplastic human cancers (pancreas, lung, and gastric). Mechanistically, PIAS2b is required for proper mitotic spindle and centrosome assembly, and it is a dosage-sensitive protein in ATC. PIAS2b depletion promotes mitotic catastrophe at prophase. High-throughput proteomics reveals the proteasome (PSMC5) and spindle cytoskeleton (TUBB3) to be direct targets of PIAS2b SUMOylation at mitotic initiation. These results identify PIAS2b-dsRNAi as a promising therapy for ATC and other aggressive anaplastic carcinomas. Anaplastic thyroid cancer (ATC) is a particularly aggressive cancer type with limited effective therapeutic options. Here, the authors identify the SUMO E3 ligase PIAS2 as a potential therapeutic target in ATC and mechanistically investigate its role in mitotic spindle and centrosome assembly. [ABSTRACT FROM AUTHOR]