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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.

On April 18, 2024, the Food and Drug Administration approved alectinib as an adjuvant treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) after tumor resection. This approval was grounded in the outcomes of the ALINA trial, which demonstrated that alectinib significantly enhances disease-free survival compared to traditional platinum-based chemotherapy in the adjuvant setting. The ALINA trial is notable not just for advancing ALK tyrosine kinase inhibitors (TKIs) into the adjuvant setting but also for its innovative approach of comparing them to adjuvant chemotherapy, distinguishing it from other landmark trials.

Background: While targeted therapies have transformed the treatment landscape of oncogene-addicted non-small cell lung cancer (NSCLC), the influence of sex on treatment outcomes remains insufficiently understood. Objectives: This systematic review aimed to investigate the impact of sex on clinical outcomes in patients with NSCLC harboring driver fusions treated with targeted therapies enrolled in clinical trials. Data sources and methods: A comprehensive literature search was conducted using PubMed, Embase, and relevant conference abstracts to identify phase III randomized and early clinical trials that reported sex-specific data, including progression-free survival (PFS), overall survival (OS), overall response rate, and adverse events (AEs), in patients with fusion-positive NSCLC treated with tyrosine kinase inhibitors (TKIs). Results: This review involved 10 studies reporting PFS data and 3 studies with OS data, focusing on first-line treatments for ALK fusion (9 studies) and RET fusion-positive (1 study) NSCLC. Pooled analysis of hazard ratios (HRs) for PFS and OS in ALK inhibitors trials revealed no significant differences in survival outcomes based on sex. Additionally, none of the studies provided data on sex-based differences in response rates or toxicities, highlighting a significant knowledge gap regarding the impact of sex on secondary outcomes in targeted therapy. Conclusion: This review found no significant sex-related differences in survival outcomes among patients treated with ALK inhibitors. However, the lack of data on sex-specific response and toxicity emphasizes the need for future research to better understand the role of sex in modulating treatment outcomes and treatment decisions with TKIs. Plain language summary: Understanding sex differences in lung cancer treatment outcomes with targeted therapies Why was this review conducted? Lung cancer treatments have advanced significantly with the use of targeted therapies, which are designed to attack specific cancer mutations. However, it is not clear whether a patient's sex influences how well these treatments work. This review looks at whether men and women respond differently to certain targeted treatments for non-small cell lung cancer (NSCLC) to help doctors make better treatment decisions. What did the researchers do? The research team reviewed studies that included both men and women with lung cancer caused by specific genetic changes (called fusion-positive NSCLC). These patients were treated with medications known as tyrosine kinase inhibitors (TKIs), which target cancer-related proteins. The studies were analyzed to see if there were any differences in progression-free survival and overall survival between men and women. What did the researchers find? The review included ten studies looking at how long patients lived without their cancer getting worse and three studies looking at overall survival. These studies focused on patients with two specific genetic changes in their cancer: ALK and RET fusions. The researchers found no major differences between men and women in terms of survival. However, they noted that none of the studies provided information about differences in side effects or how well the cancer responded to treatment between men and women. This is a gap in the research that needs to be addressed. What do the findings mean? This review suggests that, so far, there is no evidence that men and women with NSCLC respond differently to targeted therapies when it comes to survival. However, the lack of data on other important outcomes, like side effects, means that more research is needed to fully understand if sex plays a role in how well these treatments work. [ABSTRACT FROM AUTHOR]

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Anaplastic large cell lymphoma with primary presentation in, and disease limited to, the central nervous system (primary CNS ALCL) is a rare and aggressive lymphoma found in a sensitive anatomic site. We report the clinical and pathologic characteristics of 17 primary CNS ALCL cases that are newly reported from six academic medical centers. We are investigating the characteristics of these cases, alongside their commonalities and differences from systemic ALCL arising at conventional anatomic sites. Clinical, pathologic, and outcome data were extracted by medical record review. The median patient age was 32 years with a male-to-female ratio of 2.4:1. Cases presented with either localized or multifocal central nervous system (CNS) disease without coinciding systemic disease. Histologically, the common pattern prevailed, and loss of pan-T-cell markers was frequent. There was a similar proportion of anaplastic lymphoma kinase (ALK) positivity in primary CNS ALCL (12/17, 71%) compared to that reported in systemic ALCL (70–80%). Our data indicate a 5-year overall survival (OS) rate of 65% and a 5-year progression-free survival (PFS) rate of 48%. Five patient deaths occurred in this study of which all were in the ALK-negative group, and all were patients over 40 years old. ALK-positive patients were significantly younger than ALK-negative patients, and survival analyses showed that both ALK-positive and younger age (≤ 40 years) were favorable prognostic factors. This is the largest series of primary CNS ALCL reported to date, which demonstrates a high proportion of ALK-positive cases and favorable outcomes for both younger and ALK-positive patients despite the involvement of a sensitive anatomic site. [ABSTRACT FROM AUTHOR]

Alectinib, a second-generation anaplastic lymphoma kinase (ALK) inhibitor, has been shown to be effective for patients with ALK-positive non-small cell lung cancer (NSCLC). However, alectinib resistance is a serious problem worldwide. To the best of our knowledge, little information is available on its molecular mechanisms using the Gene Expression Omnibus (GEO) database. In this study, the differentially expressed genes (DEGs) were selected from the gene expression profile GSE73167 between parental and alectinib-resistant human lung adenocarcinoma (LUAD) cell samples. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) annotation enrichment analyses were conducted using Database for Annotation, Visualization and Integrated Discovery (DAVID). The construction of protein–protein interaction (PPI) network was performed to visualize DEGs. The hub genes were extracted based on the analysis of the PPI network using plug-in cytoHubba of Cytoscape software. The functional roles of the key genes were investigated using Gene Expression Profiling Interactive Analysis (GEPIA), University of Alabama at Birmingham Cancer (UALCAN), Gene Set Enrichment Analysis (GSEA), and Tumor Immune Estimation Resource (TIMER) analysis. The networks of kinase, miRNA, and transcription-factor targets of SFTPD were explored using LinkedOmics. The drug sensitivity analysis of SFTPD was analyzed using the RNAactDrug database. Results showed a total of 144 DEGs were identified. Five hub genes were extracted, including mucin 5B (MUC5B), surfactant protein D (SFTPD), deleted in malignant brain tumors 1 (DMBT1), surfactant protein A2 (SFTPA2), and trefoil factor 3 (TFF3). The survival analysis using GEPIA displayed that low expression of SFTPD had a significantly negative effect on the prognosis of patients with LUAD. GSEA revealed that low expression of SFTPD was positively correlated with the pathways associated with drug resistance, such as DNA replication, cell cycle, drug metabolism, and DNA damage repair, including mismatch repair (MMR), base excision repair (BER), homologous recombination (HR), and nucleotide excision repair (NER). The SFTPD expression was negatively correlated with the drug sensitivity of alectinib according to RNAactDrug database. The expression of SFTPD was further validated in parental H3122 cells and alectinib-resistant H3122 cells by quantitative reverse transcription PCR (RT-qPCR). In conclusion, our study found that the five hub genes, especially low expression of SFTPD, are closely related to alectinib resistance in patients with LUAD. [ABSTRACT FROM AUTHOR]

Background: Over the past decade, progress in the diagnosis and treatment of Non-Small Cell Lung Cancer (NSCLC) has led to the identification of many targeted mutations. This has enhanced PFS and OS in both advanced and early-stage NSCLC. The current standard of care for stage III NSCLC varies, and it may combine chemotherapy with either immunotherapy or radiotherapy. This study evaluated the role of induction targeted therapies in patients with driver mutations and inoperable NSCLC. Methods: This is a single-center, retrospective study assessing the efficacy of targeted therapy in resectable stage III NSCLC patients who are EGFR or ALK -positive, using patient records, PET-CT, brain MRI staging, and mediastinal lymph node evaluation. Results: Between January 2020 and February 2024, we identified four patients with either EML4-ALK fusions (2/4) or EGFR mutations (2/4) who underwent treatment with brigatinib or osimertinib before surgery. All patients experienced clinical benefits. Of the two patients with ALK fusion, one responded almost completely, while the other exhibited a notable partial response. Among the patients with EGFR mutations, one had a complete response and the other displayed a significant partial response. All four patients subsequently underwent lobectomy surgical resection. Conclusions: This case series highlights the potential of targeted therapies for resectable NSCLC in the neoadjuvant setting. Further research is required to confirm their benefits, assess their safety and efficacy, and determine optimal timing and sequencing. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) is a well-known oncogene involved in various malignancies such as anaplastic large cell lymphoma, lung cancer and neuroblastoma. Several substrates for fused ALK have been identified and their biological functions have been described. However, the lack of a comprehensive identification of ALK substrates limits our understanding of the biological roles of receptor ALK. Thus, this study aimed to identify novel ALK substrates and characterize their biological functions. We screened the interactors of the kinase domain of receptor ALK using proximity-dependent biotin identification and identified 43 interactors. We narrowed down the candidates by evaluating whether these interactors were downstream of ALK in a neuroblastoma cell line, NB-1. Amongst these, we identified amyloid beta precursor protein-binding family B member 1 (APBB1) as an ALK downstream molecule involved in NB-1 cell viability. Finally, we assessed the kinase-substrate relationship between ALK and APBB1 and found that ALK phosphorylated multiple tyrosine residues in APBB1 both in-cell and in-tube assays, with tyrosine 269 as a major target. In conclusion, we successfully identified a new substrate for receptor ALK. Our results may help further elucidate the molecular mechanism of ALK downstream signalling in neuroblastoma. [ABSTRACT FROM AUTHOR]

Aims: The majority of dermatofibrosarcoma protuberans (DFSP) harbour PDGFB or PDGFD rearrangements. We encountered ALK expression/rearrangement in a PDGFB/D‐negative CD34‐positive spindle cell neoplasm with features similar to DFSP, prompting evaluation of ALK‐rearrangements in DFSP and plaque‐like CD34‐positive dermal fibroma (P‐LDF). Methods and Results: We searched the archives of academic institutions for cases previously coded as DFSP and P‐LDF. NGS‐naïve or PDGFB‐negative DFSP were screened for ALK (clone D5F3) expression by immunohistochemistry. NGS or ALK FISH was performed on ALK‐positive cases. Methylome profiling studies were performed and compared with conventional DFSP. One case of "DFSP" and two "P‐LDF" with ALK expression were identified from the archives, while four cases were detected prospectively. These seven cases (6F:1M; 8 months to 76 years) arose in the dermis of the arm (two), scalp, eyelid, thigh, abdomen, and shoulder and ranged from 0.4 to 4.2 cm. Tumours were composed of spindled cells and displayed a storiform growth pattern. Cytologic atypia was absent, and mitotic figures were scarce (0–2/10 HPFs, high power fields). The lesional cells were diffusely positive for CD34 and ALK and negative for S100 protein. By NGS (n = 5), ALK fusion partners included DCTN1 (2), PLEKHH2, and CLIP2 in DFSP‐like cases and FLNA in P‐LDF‐like lesions. ALK FISH was positive in one (of two) cases previously labelled P‐LDF. Methylome profiling of two (of three) ALK‐rearranged DFSP‐like tumours showed clustering with conventional DFSP in the UMAP dimension reduction plot. To date, no tumour has recurred (n = 2; 26, 27 months). Conclusion: We describe a cohort of novel ALK‐rearranged tumours with morphologic features similar to DFSP. [ABSTRACT FROM AUTHOR]

Leptomeningeal carcinomatosis (LMC) is a devastating complication of advanced cancers, such as lung cancer and breast cancer, which is usually indicative of a poor prognosis. The current treatments for LMC include palliative care, with others aiming to prolong survival and relieve neurological symptoms. Traditional treatments for LMC include radiotherapy, systemic chemotherapy, and intrathecal injection. Furthermore, the application of molecularly targeted agents, such as antiepidermal growth factor receptor (anti‐EGFR), antihuman epidermal growth factor receptor 2 (anti‐HER2), and anti‐PD‐1 monoclonal antibody, have prolonged the survival of LMC patients. Targeted therapy with tyrosine kinase inhibitors has also been proven to be an effective treatment. Tyrosine kinases can be overactive or expressed at high levels in some cancer cells; therefore, the use of tyrosine kinase inhibitors may prevent the activation of tumor‐related pathways, preventing cancer cell growth. The EGFR family are cell surface receptors directly related to tumor occurrence with tyrosine kinase activity; it is the most widely used target for tyrosine kinase inhibitors in the treatment of LMC. In this review, we introduced the clinical manifestation and diagnostic criteria of LMC, clarified the treatment mechanism of tyrosine kinase inhibitors for LMC with mutations in EGFR, HER2, or anaplastic lymphoma kinase, reviewed the current application of various generation tyrosine kinase inhibitors in patients with LMC, and discussed new clinical trials and the future directions of tyrosine kinase inhibitor therapy. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK)‐positive histiocytosis has emerged as a clinically relevant diagnosis featuring a wide span of clinical presentations, which are unified by the presence of ALK‐positive histiocytes on histopathology and molecular drivers involving the ALK kinase gene. This report presents an adult case of multisystem ALK‐positive histiocytosis with xanthogranuloma‐like features on histopathology that was responsive to ALK inhibition, and includes a review of ALK‐positive histiocytoses with cutaneous involvement reported in the literature. A 56‐year‐old male developed a widespread eruption of red‐brown papules on the face, trunk, and upper extremities. Histopathological evaluation revealed a well‐circumscribed, nodular dermal infiltrate of epithelioid histiocytes with Touton giant cells, rare bizarre multinucleated cells, and focal emperipolesis. The lesional cells were positive for CD68 and ALK1 immunohistochemical stains, and negative for CD1a. Next‐generation sequencing identified a DCTN1::ALK fusion. On imaging, he was found to have bone, lung, soft tissue, and salivary gland involvement. ALK inhibition was initiated with alectinib, resulting in rapid improvement of cutaneous lesions and eventual complete resolution of abnormal imaging findings, which was sustained at 24 months of follow‐up. This case adds to the spectrum of ALK‐positive histiocytoses and further demonstrates the positive response with targeted therapy. [ABSTRACT FROM AUTHOR]

ALK is related to poor survival in neuroblastoma patients. We investigated the prognostic relevance of ALK mRNA expression and the relationship with ALK immunohistochemical expression, histological subtype and ALK aberrations. Whole transcriptome sequencing data were available from 54 patients. Overall survival (OS) and event-free survival (EFS) were estimated with Kaplan–Meier’s methodology. ALK protein expression was analyzed by immunohistochemistry. ALK aberrations were detected using whole exome sequencing, single nucleotide polymorphism array, next generation sequencing and/or fluorescence in situ hybridization. OS was 74.8% and EFS was 60%. ALK mRNA expression was not associated with OS (HR 1.127, 95% CI (0.812–1.854), p = 0.331) and adjusted EFS (HR 1.134, 95% CI (0.783–1.644), p = 0.505), but was associated with histological subtype (OR 1.914, 95% CI (1.083–3.382), p = 0.025) and ALK protein expression (negative versus weak: OR 2.829, 95% CI (1.290–6.204), p = 0.009) (negative versus moderate/strong: OR 2.934, 95% CI (0.889–9.679), p = 0.077). ALK mutated tumors had significantly higher ALK mRNA expression than non-mutated tumors (p < 0.001). MYCN-amplified neuroblastomas have higher MYCN mRNA expression (p ≤ 0.001), but not ALK mRNA expression (p = 0.553). ALK mRNA expression is higher in ALK mutated neuroblastomas and is associated with poorer differentiation degree and higher protein expression. ALK mRNA expression is not significantly associated with OS and EFS.

Zhaohui Liao Arter,1,2 Misako Nagasaka1– 3 1Division of Hematology/Oncology, University of California Irvine School of Medicine, Orange, CA, USA; 2Chao Family Comprehensive Cancer Center, Orange, CA, USA; 3Division of Neurology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, JapanCorrespondence: Misako Nagasaka, Division of Hematology/Oncology, University of California Irvine School of Medicine, Orange, CA, USA, Email nagasakm@hs.uci.eduAbstract: On April 18, 2024, the Food and Drug Administration approved alectinib as an adjuvant treatment for patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) after tumor resection. This approval was grounded in the outcomes of the ALINA trial, which demonstrated that alectinib significantly enhances disease-free survival compared to traditional platinum-based chemotherapy in the adjuvant setting. The ALINA trial is notable not just for advancing ALK tyrosine kinase inhibitors (TKIs) into the adjuvant setting but also for its innovative approach of comparing them to adjuvant chemotherapy, distinguishing it from other landmark trials.Keywords: ALK, NSCLC, adjuvant therapy, targeted therapy

Abstract 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.

Background: 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). Methods: 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. Results: 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 %. Conclusion: Lorlatinib exhibits substantial activity and tolerability when used clinically in a later-line setting in a Taiwanese population with ALK-positive advanced NSCLC.

Multiple primary lung cancer (MPLC) refers to patients with two or more primary lesions of lung cancer. It can be divided into synchronous MPLC (sMPLC) and metachronous MPLC (mMPLC) based on the timing of occurrence. In recent years, the detection rate of MPLC has gradually increased. However, considerable controversy exists in distinguishing MPLC from intrapulmonary metastasis (IM), especially when the histopathological types are identical. Given the significant differences in treatment strategies and prognosis in clinical practice currently, accurate diagnosis of MPLC is crucial for personalized precision therapy. Molecular genetics and sequencing technologies offer effective strategies for assessing the clonal origin of tumors. There have been reports of coexisting mutations in the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) fusion genes in non-small cell lung cancer, but case of EGFR mutation following an ALK mutation has not been mentioned. This article accurately diagnoses and retrospectively analyzes the clinical data of a case of ALK mutant adenocarcinoma in a male patient who developed an EGFR mutation with multiple metastases four years after surgery, and reviews the relevant literature. This paper aims to deepen the understanding of mMPLC and provide clinical references for the diagnosis and treatment of such patients.

The mortality rate linked to non-small cell lung cancer (NSCLC) has notably decreased in recent years, primarily due to refined diagnostic techniques. This retrospective study aims to offer new insights into the frequency of EGFR gene mutations in Romanian NSCLC patients, examining potential associations or exclusions with ALK rearrangements and elevated PD-L1 expression level and seeks to contribute crucial insights into molecular marker alterations associated with NSCLC, advancing our understanding of targeted therapy prospects for oncology patients diagnosed with NSCLC in Romania.

ALK‐positive histiocytosis is a rare histiocytic disease characterized by ALK positivity. It was first described in 2008 as a systemic disease in infants. The disease often shows positivity for CD68 and CD163 on immunohistochemistry, and genomic analysis frequently reveals KIF5B::ALK fusions. ALK‐positive histiocytosis typically follows an indolent course and has a promising prognosis, with conventional treatments usually being effective. Here, we report a rare case of ALK‐positive histiocytosis with exclusive involvement of the central nervous system in a 33‐year‐old Asian adult woman. Although cranial MRI suggested a meningioma, immunohistochemical workup showed that the ALK‐positive tumor cells expressed macrophage/histiocyte markers such as CD163 and CD68. Additionally, second‐generation sequencing revealed a KIF5B::ALK fusion. Our case highlights the importance of the differential diagnosis in adult central nervous system tumors, emphasizing the combination of morphology, immunophenotype, and molecular approach with ALK status evaluation to confirm a diagnosis of ALK‐positive histiocytosis. This case also expands the clinicopathologic spectrum of ALK‐positive histiocytosis. [ABSTRACT FROM AUTHOR]

Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase within the insulin receptor superfamily. Alterations in ALK, such as rearrangements, mutations, or amplifications, have been detected in various tumours, including lymphoma, neuroblastoma, and non-small cell lung cancer. In this study, we outline a computational workflow designed to uncover new inhibitors of ALK. This process starts with a ligand-based exploration of the pharmacophoric space using 13 diverse sets of ALK inhibitors. Subsequently, quantitative structure-activity relationship (QSAR) modelling is employed in combination with a genetic function algorithm to identify the optimal combination of pharmacophores and molecular descriptors capable of elucidating variations in anti-ALK bioactivities within a compiled list of inhibitors. The successful QSAR model revealed three pharmacophores, two of which share three similar features, prompting their merger into a single pharmacophore model. The merged pharmacophore was used as a 3D search query to mine the National Cancer Institute (NCI) database for novel anti-ALK leads. Subsequent in vitro bioassay of the top 40 hits identified two compounds with low micromolar IC50 values. Remarkably, one of the identified leads possesses a novel chemotype compared to known ALK inhibitors. [ABSTRACT FROM AUTHOR]

The EML4-ALK oncogene is a fusion of the EML4 and ALK genes and is found in approximately 5– 6% of the cases of non-small cell lung cancer (NSCLC). Herein, we present a unique case of lung adenocarcinoma with metastases to the bilateral ovaries harboring a rare EML4-ALK fusion gene variant in a 52-year-old patient. The patient had initially received a diagnosis of ovarian cancer, then had undergone neo-adjuvant chemotherapy followed by a surgical resection. Despite two cycles of adjuvant chemotherapy consisting of carboplatin and gemcitabine, CT revealed that the pleural effusion had increased from it before chemotherapy, and the shortness of breath worsened. Molecular profiling revealed an EML4-ALK rearrangement containing ALK -EML4 and ALK -NPR2 fusion genes. The diagnosis was changed to primary lung adenocarcinoma with metastases to the bilateral ovaries based on a pathological reevaluation. Treatment with alectinib, a second-generation ALK-tyrosine kinase inhibitor, led to a partial response of 18 months' duration, and the shortness of breath improved. No adverse events related to the alectinib therapy occurred. To assess the unique structure of the fusion genes, RNA sequencing was performed. An intronic sequence from both ALK and EML4 was found between ALK and EML4 exon, possibly because of an unusual insertion of a gene fragment derived from NRP2, indicated by the panel sequencing results. Variations in the drug response among EML4-ALK fusion variants highlight the importance of understanding their molecular structure. Further investigation is warranted to refine fusion gene detection methods and assess the therapeutic implications of rare fusion variants. [ABSTRACT FROM AUTHOR]

ALK is related to poor survival in neuroblastoma patients. We investigated the prognostic relevance of ALK mRNA expression and the relationship with ALK immunohistochemical expression, histological subtype and ALK aberrations. Whole transcriptome sequencing data were available from 54 patients. Overall survival (OS) and event-free survival (EFS) were estimated with Kaplan–Meier's methodology. ALK protein expression was analyzed by immunohistochemistry. ALK aberrations were detected using whole exome sequencing, single nucleotide polymorphism array, next generation sequencing and/or fluorescence in situ hybridization. OS was 74.8% and EFS was 60%. ALK mRNA expression was not associated with OS (HR 1.127, 95% CI (0.812–1.854), p = 0.331) and adjusted EFS (HR 1.134, 95% CI (0.783–1.644), p = 0.505), but was associated with histological subtype (OR 1.914, 95% CI (1.083–3.382), p = 0.025) and ALK protein expression (negative versus weak: OR 2.829, 95% CI (1.290–6.204), p = 0.009) (negative versus moderate/strong: OR 2.934, 95% CI (0.889–9.679), p = 0.077). ALK mutated tumors had significantly higher ALK mRNA expression than non-mutated tumors (p < 0.001). MYCN-amplified neuroblastomas have higher MYCN mRNA expression (p ≤ 0.001), but not ALK mRNA expression (p = 0.553). ALK mRNA expression is higher in ALK mutated neuroblastomas and is associated with poorer differentiation degree and higher protein expression. ALK mRNA expression is not significantly associated with OS and EFS. [ABSTRACT FROM AUTHOR]

Leading from a two-case series, including two patients receiving a diagnosis of epidermotropic T-cell lymphoma, featuring a mycosis fungoides (MF)-like clinical pattern and ALK expression and molecular alteration, we performed a critical appraisal of ALK+ primary cutaneous T-cell lymphomas (pcTCL). Considering our patients and the literature, 32 cases were retrieved, 7 of which featured an MF-like clinical picture over a 4-to-20-year period. MF-like cases show distinctive histology, comprising a predominantly epidermotropic infiltration of small-to-large, atypical-to-pleomorphic, with few anaplastic cells, negligible-to-intense CD30-expression, and a CD4+/cytotoxic granule+ phenotype. These features should prompt a search for ALK expression captured by the ALK D5F3 clone. Bona fide ALK+ pcTCL is very rare, and existent data suggest the presence of a broader pattern of disease, including instances mimicking MF and/or primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. The major challenges in dealing with this subset include prodromal phases, misinterpreted as inflammatory dermatosis or parapsoriasis/early phase MF both clinically and histologically, while recognition of its ALK-driven biology is hampered both by the unusual clinic-pathologic pattern of the disease, which stands apart from the classical (i.e., nodal) picture of ALK+ anaplastic large cell lymphoma and by the low sensitivity of ALK1 clone. Data on its optimal management are far from being conclusive: An MF-like approach is currently chosen, but depending on CD30 and, most notably, ALK expression, a targeted therapy could be envisaged in advanced stages, as clinical response to ALK inhibition was documented in one patient. [ABSTRACT FROM AUTHOR]

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]

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]

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]

FUS::CREM fusion is a distinct primary driver in rare neoplasms of the head and neck and other anatomic sites. Herein, we describe the clinicopathological, imaging, and molecular features of a malignant epithelioid mesenchymal neoplasm harboring FUS::CREM fusion, arising in the tongue of a 46-year-old male. Clinically, the patient presented with a left upper neck mass. Imaging revealed a 4.0 cm mass at the left base of tongue. Histologically, the tumor consisted of sheets of loosely cohesive, small round to ovoid cells with moderate cytoplasm, small nuclei with coarse chromatin, frequent nuclear pseudoinclusions, and dense peripheral lymphoplasmacytic and histiocytic infiltrates. Malignant features, including tumor necrosis, perineural invasion, and increased mitotic activity were observed; however, lymphovascular invasion was absent with no evidence metastatic disease in the examined lymph nodes. A comprehensive panel of immunohistochemical stains showed positivity for synaptophysin and ALK, with negative results for all other markers. RNA-based next-generation sequencing using anchored multiplex polymerase chain reaction (PCR) was performed and detected FUS::CREM fusion gene. The patient was treated by excision and postsurgical chemoradiation with no evidence of recurrence after four months. Additional cases supported by comprehensive clinical data collected over an extended period are necessary to precisely characterize epithelioid mesenchymal neoplasms harboring FUS::CREM fusion in the head and neck. [ABSTRACT FROM AUTHOR]

Simple Summary: This systematic review and meta-analysis aimed to evaluate the neurocognitive adverse events (NAEs) related to lorlatinib in patients with ALK/ROS1-positive non-small cell lung cancer (NSCLC). A random-effects model was used for the meta-analysis and the proportions were pooled with 95% confidence intervals (CIs). In our pooled analysis, cognitive and mood effects were the most important NAEs, with 14% and 11% overall rates, respectively. Speech changes and psychotic effects had an overall frequency of 7% and 5%, respectively. In a subanalysis, mood effects were significantly more frequent in clinical trials than in real-world studies. Therefore, this study showed that lorlatinib-related NAEs are emerging important toxicities in clinical practice. Hence, increasing awareness about NAEs is paramount to improving their recognition and reporting, and thus enhancing patients' quality of life. Lorlatinib has been FDA-approved as a systemic therapy for ALK/ROS1-positive non-small cell lung cancer (NSCLC) patients. However, it has been associated with an increased frequency of neurocognitive adverse events (NAEs). Therefore, we conducted a systematic review and meta-analysis to assess the NAEs related to lorlatinib therapy in NSCLC patients. PubMed, Scopus, the Cochrane Library, and prominent conference proceedings were searched for eligible studies of lorlatinib in NSCLC patients. NAEs included cognitive, mood, speech, and psychotic effects. A total of 1147 patients from 12 studies were included; 62% had brain metastases. A pooled analysis of NAEs showed frequencies of cognitive effects of 14.57% (95% CI, 8.37 to 24.14, I2 = 84%), mood effects of 11.17% (95% CI, 5.93 to 20.07, I2 = 84%), speech effects of 7.24% (95% CI, 3.39 to 15.20, I2 = 72%), and psychotic effects of 4.97% (95% CI, 3.27 to 7.49, I2 = 21%). Clinical trials reported a significantly higher frequency of mood effects than was indicated by real-world data. These results highlight the importance of educating patients and healthcare professionals about lorlatinib-related NAEs for early detection and management to improve NSCLC patients' quality of life. [ABSTRACT FROM AUTHOR]

People treated with anaplastic lymphoma kinase (ALK) inhibitors, especially lorlatinib, have had problems with their central nervous system (CNS). According to a real-world pharmacovigilance study, the most frequent psychiatric symptoms were mood disorders, psychotic disorders, anxiety, agitation, and irritability. Still, it is not clear how ALK tyrosine kinase inhibitors (ALK-TKIs) might cause psychiatric adverse effects. However, ALK seems involved in the endocytosis of dopamine D2 receptors in response to long-term dopamine stimulation. Here, we report three cases of patients treated with ALK inhibitors in a single Italian Centre who developed psychiatric disorders. [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]

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]

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Introduction: Despite receiving alectinib therapy, patients with ALK-positive NSCLC remain at risk of central nervous system (CNS) progression. Our retrospective study aimed to identify baseline clinical and molecular factors associated with the risk of CNS progression in this patient subset. Methods: We analyzed the clinical, molecular, and imaging data of 318 patients with ALK-positive advanced NSCLC who received alectinib as first-line (1L-alectinib) or second-line (2L-alectinib) therapy at baseline (1L, n = 183; 2L, n = 135) and at disease progression (1L, n = 80; 2L, n = 76). Results: The incidence rates of CNS progression were 23.7% after 1L-alectinib treatment and 31.6% after 2L-alectinib treatment. Compared with patients who received 1L-alectinib, CNS progression was similar in patients who received 2L-alectinib (p > 0.05). Oligoprogression was detected in 55.0% (44 of 80) of patients who progressed after first-line alectinib, with the remaining 45.0% (36 of 80) having nonoligoprogression. Univariate and multivariate analyses and stepwise regression analyses consistently identified a higher likelihood of CNS progression among (1) patients who received 2L-alectinib than 1L-alectinib, (2) patients with non-3a/b variant ALK fusion than those with echinoderm microtubule-associated protein-like 4–ALK variant 3a/b, and (3) patients with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of 50% or higher than PD-L1 TPS of less than 50%. Conclusions: Our study provided real-world evidence that patients who harbored PD-L1 TPS of 50% or higher were more likely to experience CNS progression during alectinib therapy. The association between CNS progression and breakpoint variants warrants further investigation. Our findings suggest that close monitoring and prompt intervention are crucial in prolonging the quality of life of this patient subset.

Introduction: The role of maintenance durvalumab after definitive concurrent chemoradiotherapy (CCRT) in unresectable locally advanced NSCLC with EGFR mutation or ALK translocation remains unclear. We compared the effectiveness of durvalumab maintenance therapy in groups with EGFR and ALK wild-type versus those with EGFR or ALK mutations. Methods: In this retrospective multicenter observational study, patients with locally advanced NSCLC without progression after CCRT followed by maintenance durvalumab and available molecular test results (EGFR and ALK) were eligible. The primary objective was to compare progression-free survival (PFS) between EGFR and ALK wild-type and EGFR or ALK mutant NSCLC. Secondary objectives include overall survival according to EGFR or ALK mutation and programmed death-ligand 1 (PD-L1) expression. Results: Among 339 patients, 279 had wild-type EGFR/ALK, 41 had EGFR mutations and 19 had ALK translocations. The median age was 68 years with 276 male individuals (81.4%) and 63 female individuals (18.6%), 165 (49.3%) had adenocarcinoma, 149 (44.5%) had squamous cell carcinoma, and 21 (6.3%) had other histologic types, 120 (35.4%) had stage IIIA, 168 (49.6%) stage IIIB, and 51 (15.0%) had stage IIIC. Most of the patients (n = 288, 85%) achieved partial response to CCRT, two (0.6%) had a complete response, and 49 patients (14.4%) had stable disease. Excluding four patients with unknown PD-L1 tumor proportion score (TPS), 16 (4.8%) had a PD-L1 TPS of 0, 168 (50.1%) had 1 to 49, and 151 (45.1%) had 50 or higher. The median PFS was 21.4 months (95% confidence interval [CI]: 17.3–25.3) for the EGFR/ALK wild-type group and 21.0 months (95% CI: 15.7–not available [NA]) for the EGFR or ALK mutant group with no difference (p = 0.74). Significant differences occurred in PFS on the basis of PD-L1 expression with values of 13.6 (95% CI: 10.5–NA), 18.7 (95% CI: 15.1–26.9), and 24.7 (95% CI: 20.7–NA) months for TPS of 0, 1–49, and 50 or higher, respectively (p = 0.02). Conclusions: Durvalumab maintenance therapy after definitive CCRT in unresectable locally advanced NSCLC patients with EGFR or ALK mutation demonstrates comparable clinical outcomes to those with wild-type EGFR/ALK when PD-L1 expression is present.

Anaplastic lymphoma kinase (ALK) is an attractive therapeutic target for the treatment of anaplastic large cell lymphoma (ALCL). We identified novel deuterated 2,4-diarylamino pyrimidine compounds as potent ALK inhibitors. The compound 9 (AMX6001) showed better in vitro activity against ALK and NPM-ALK kinase and significantly inhibited proliferation of Karpas299 and SU-DHL-1 cell lines. In vivo efficacy of compound 9 was better than reference standard ceritinib in ALCL Karpas299 mice models. Daily oral treatment of compound 9 (25 mg/kg) induced tumor suppression TGI up to 95.8 % in ALCL models.

AbstractA series of novel benzimidazole derivatives were designed and synthesised based on the structures of reported oral available ALK inhibitor and HDAC inhibitor, pracinostat. In enzymatic assays, compound 3b, containing a 2-acyliminobenzimidazole moiety and hydroxamic acid side chain, could inhibit both ALK and HDAC6 (IC50 = 16 nM and 1.03 µM, respectively). Compound 3b also inhibited various ALK mutants known to be involved in crizotinib resistance, including mutant L1196M (IC50, 4.9 nM). Moreover, 3b inhibited the proliferation of several cancer cell lines, including ALK-addicted H2228 cells. To evaluate its potential for treating cancers in vivo, 3b was used in a human A549 xenograft model with BALB/c nude mice. At 20 mg/kg, 3b inhibited tumour growth by 85% yet had a negligible effect on mean body weight. These results suggest a attracting route for the further research and optimisation of dual ALK/HDAC inhibitors.

BackgroundOver the past decade, progress in the diagnosis and treatment of Non-Small Cell Lung Cancer (NSCLC) has led to the identification of many targeted mutations. This has enhanced PFS and OS in both advanced and early-stage NSCLC. The current standard of care for stage III NSCLC varies, and it may combine chemotherapy with either immunotherapy or radiotherapy. This study evaluated the role of induction targeted therapies in patients with driver mutations and inoperable NSCLC.MethodsThis is a single-center, retrospective study assessing the efficacy of targeted therapy in resectable stage III NSCLC patients who are EGFR or ALK-positive, using patient records, PET-CT, brain MRI staging, and mediastinal lymph node evaluation.ResultsBetween January 2020 and February 2024, we identified four patients with either EML4-ALK fusions (2/4) or EGFR mutations (2/4) who underwent treatment with brigatinib or osimertinib before surgery. All patients experienced clinical benefits. Of the two patients with ALK fusion, one responded almost completely, while the other exhibited a notable partial response. Among the patients with EGFR mutations, one had a complete response and the other displayed a significant partial response. All four patients subsequently underwent lobectomy surgical resection.ConclusionsThis case series highlights the potential of targeted therapies for resectable NSCLC in the neoadjuvant setting. Further research is required to confirm their benefits, assess their safety and efficacy, and determine optimal timing and sequencing.

Cancers can develop resistance to treatment with ALK tyrosine kinase inhibitors (ALK‐TKIs) via emergence of a subpopulation of drug‐tolerant persister (DTP) cells that can survive initial drug treatment long enough to acquire genetic aberrations. DTP cells are thus a potential therapeutic target. We generated alectinib‐induced DTP cells from a patient‐derived ALK+ non‐small‐cell lung cancer (NSCLC) cell line and screened 3114 agents in the anticancer compounds library (TargetMol). We identified phospholipid hydroperoxide glutathione peroxidase GPX4 as being involved in promoting the survival of DTP cells. GPX4 was found to be upregulated in DTP cells and to promote cell survival by suppressing reactive oxygen species (ROS) accumulation; GPX4 inhibitors blocked this upregulation and facilitated ROS‐mediated cell death. Activated bypass signals involving epidermal growth factor receptor (EGFR)/receptor tyrosine‐protein kinase erbB‐3 (HER3) were also identified in DTP cells, and co‐treatment with EGFR‐TKI plus ALK‐TKI enhanced ROS levels. Triple combination with an ALK‐TKI plus a bypass pathway inhibitor plus a GPX4 inhibitor suppressed cell growth and induced intracellular ROS accumulation more greatly than did treatment with each agent alone. The combined inhibition of ALK plus inhibition of activated bypass signals plus inhibition of GPX4 may be a potent therapeutic strategy for patients with ALK+ NSCLC to prevent the development of resistance to ALK‐TKIs and lead to tumor eradication. [ABSTRACT FROM AUTHOR]

This ALK-positive anaplastic large cell lymphoma (ALCL) case highlights the importance of considering ALCL in the setting of iatrogenic immunosuppression in hidradenitis suppurativa patients. Diagnosis of ALCL can be challenging in situations with very low viability/cellularity, negative CD3 and/or other T-cell markers, and immunosuppression.

Aim. To determin the clinical and biological features of neuroblastoma in patients over 10 years old. Materials and methods. Patients with a histologically verified diagnosis of neuroblastoma / ganglioneuroblastoma established over the age of 10 years were retrospectively selected. Molecular genetic tests included fluorescence in situ hybridization (FISH), multiplex ligation-dependent amplification (MLPA) and targeted next generation sequencing of tumor-derived DNA. The described cohort included 11 adolescents with histologically verified neuroblastoma / ganglioneuroblastoma with a median age of 160 months (124–173 months) at diagnosis and 1 patient aged 41 years (clinical data is missing). All adolescents were treated according to the neuroblastoma treatment protocol NB-2004. The median follow-up time for patients (n = 11) was 32 months (8–68 months). Results. MYCN gene amplification was detected by FISH in 17 %; deletion of 1p and 11q – in 20 and 22.2 % of cases, respectively. Deletions of 1p and 3p (80 % cases each), 11q (67 % cases), 4p (56 % cases), and gain 17q (62.5 % cases) were frequently detected in tumors (n = 9) by MLPA. ATRX gene aberrations was found in 91.6 % (11 / 12). In the most cases (10 / 11; 90 %), ATRX gene deletions of varying length were detected. Missense substitutions p.V1678F, p.N2125I and nonsense mutation p.S213* were detected in 3 / 11 (27.3 %) patients. Moreover, in 2 patients, oncogenic nucleotide substitutions were identified in combination with ATRX gene deletion entire and monosomy X. Oncogenic genetic variants in components of the RAS-RAF-MEK (BRAF, NRAS, ALK) and p53 (ATM, TP53) pathways were detected in 58 % (7 / 12) of cases. No adverse events were observed when ALK inhibitors were added to first-line therapy in neuroblastomas harboring activating ALK mutations. Conclusion. The clinical aggressiveness of adolescent / adult NB may be explained by the replicative immortalization of cells through alternative lengthening of telomeres, which is highlighted by ATRX aberrations. Special therapeutic recommendations should be elaborated for the treatment of patients in this age group, where special attention should be paid to the use of molecularly targeted therapy.

Abstract Background In the era of second-generation ALK tyrosine kinase inhibitors (ALK-TKIs), there was a paucity of data regarding the progression patterns, resistant mechanisms, and subsequent therapeutic approaches for ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Methods Patients with advanced ALK+ NSCLC were retrospectively selected from our center. Cohort 1 consisted of patients who experienced disease progression after receiving first-line alectinib treatment (n = 20), while Cohort 2 included patients who progressed following sequential treatment with crizotinib and second-generation ALK-TKIs (n = 53). Oligo-progression was defined as the occurrence of disease progression in no more than three lesions. Symptomatic progression was determined when patients developed new symptoms or experienced worsening of pre-existing symptoms during radiological progression. Results The incidence of central nervous system (CNS) progression and symptomatic CNS progression was significantly lower in Cohort 1 compared to patients treated with crizotinib, with rates of 15.0% vs. 56.6% (p = 0.002) and 5.0% vs. 32.1% (p = 0.016), respectively. A total of 60.3% (44/73) patients underwent repeated biopsy and next-generation sequencing subsequent to the second-generation ALK-TKI resistance, with secondary mutation in ALK kinase domain emerging as the predominant mechanism of resistance (56.8%). Local therapy was applied to 50% of oligo-progression cases. Subsequent ALK-TKIs demonstrated significantly prolonged progression-free survival (PFS) (8.6 m vs. 2.7 m, p = 0.021, HR = 0.43, 95%CI: 0.15–0.85) and long-term overall survival (OS) (NA vs. 11.9 m, p = 0.132, HR = 0.50, 95%CI: 0.18–1.25) in patients harboring ALK resistance mutations, compared to those without such mutations. For patients without ALK-resistant mutations following progression on second-generation ALK-TKIs, there was no statistically significant difference in survival outcomes between subsequent chemotherapy or alternative ALK-TKI treatments. Conclusions First-line alectinib demonstrated superior efficacy in protecting the CNS compared to crizotinib. For patients with ALK-resistant mutations following the resistance to second-generation ALK-TKIs, appropriate sensitive ALK-TKI should be administered; for those without such mutations, the selection of chemotherapy or third-generation ALK-TKI should be based on the patient’s overall physical health and personal preferences.

Abstract Breast cancer (BC) is a leading cause of global cancer-related mortality in women, necessitating accurate tumor classification for timely intervention. Molecular and histological factors, including PAM50 classification, estrogen receptor α (ERα), breast cancer type 1 susceptibility protein (BRCA1), progesterone receptor (PR), and HER2 expression, contribute to intricate BC subtyping. In this work, through a combination of bioinformatic and wet lab screenings, followed by classical signal transduction and cell proliferation methods, and employing multiple BC cell lines, we identified enhanced sensitivity of ERα-positive BC cell lines to ALK and MELK inhibitors, inducing ERα degradation and diminishing proliferation in specific BC subtypes. MELK inhibition attenuated ERα transcriptional activity, impeding E2-induced gene expression, and hampering proliferation in MCF-7 cells. Synergies between MELK inhibition with 4OH-tamoxifen (Tam) and ALK inhibition with HER2 inhibitors revealed potential therapeutic avenues for ERα-positive/PR-positive/HER2-negative and ERα-positive/PR-negative/HER2-positive tumors, respectively. Our findings propose MELK as a promising target for ERα-positive/PR-positive/HER2-negative BC and highlight ALK as a potential focus for ERα-positive/PR-negative/HER2-positive BC. The synergistic anti-proliferative effects of MELK with Tam and ALK with HER2 inhibitors underscore kinase inhibitors’ potential for selective treatment in diverse BC subtypes, paving the way for personalized and effective therapeutic strategies in BC management.

Abstract Background Pulmonary inflammatory myofibroblastic tumour (IMT) is a rare condition that usually presents in young individuals and is associated with anaplastic lymphoma kinase (ALK)-translocation. Case presentation We report a case of an 18-year-old Caucasian man with ALK-translocated pulmonary IMT treated with multimodality therapy. The patient presented with breathlessness and was found to have a collapsed left lung. Further investigations revealed an ALK-translocated pulmonary IMT. This is usually treated with an ALK-inhibitor but patient declined after discussing potential side-effects and had repeated rigid bronchoscopic interventions for local disease control. Due to persistent local recurrence, patient received radical external beam radiotherapy (EBRT) with pulse steroids, and one year later started on Ibuprofen, a non-steroidal anti-inflammatory agent (NSAID). Following multimodality treatment, he developed a complete response. He remains treatment-free for the past seven years. Eleven years on from his diagnosis, he remains in remission with a ECOG performance status of zero. Conclusions Achieving long-term local control in pulmonary IMT can be challenging. Multimodality treatment is sometimes needed but the overall outlook remains good.

Anaplastic lymphoma kinase (ALK) positive large B-cell lymphoma (ALK+ LBCL) is an aggressive and rare subtype of B-cell lymphoma. Patients typically present with advanced clinical stage disease and do not respond to conventional chemotherapy; the median overall survival is 1.8 years. The genetic landscape of this entity remains poorly understood. Here we report a unique case of ALK+ LBCL harbouring a rare TFG::ALK fusion. Targeted next-generation sequencing showed no significant single nucleotide variants, insertions/deletions, or other structural variants beyond the TFG::ALK fusion; deep deletions of FOXO1, PRKCA, and the MYB locus were also detected. Our case report draws attention to this rare disease, highlights a need for larger genetic profiling studies, and focuses on the pathogenesis and potential therapeutic targets of this aggressive disease. To our knowledge, this is the first report of a TFG::ALK fusion in ALK+ LBCL.