Anaplastic Lymphoma Kinase Gene Research Articles

Lung adenocarcinoma with brain metastasis detected dual fusion of LOC399815-ALK and ALK-EML4 in combined treatment of Alectinib and CyberKnife: A case report.

The anaplastic lymphoma kinase (ALK) gene fusion occurs in approximately 3% to 7% of nonsmall cell lung cancer (NSCLC), in which occurs approximately 23% to 31% of brain metastasis patients in poor prognosis. ALK tyrosine kinase inhibitors have shown efficacy in treating ALK-positive (ALK+) NSCLC. More than 90 distinct subtypes of ALK fusions have been identified through sequencing technique and would lead to significant differences in clinical efficacy, it is necessary to guide clinical treatment effectively by gene detection. A 56-year-old nonsmoking female admitted to hospital due to cough, expectoration, and chest pain. Chest computed tomography revealed a space-occupying lesion in the upper left lobe (5.0 cm × 2.4 cm × 2.9 cm), multiple enlarged lymph nodes in mediastinum 3A and 5 (largest size 1.5 cm × 1.4 cm), and evidence of thoracic vertebral metastasis, brain magnetic resonance imaging also showed brain metastasis. Lung adenocarcinoma with brain metastasis. The patient initially received conventional first-line chemotherapy, which led to a deteriorated condition. Blood-base liquid biopsy by next-generation sequencing resulted in double ALK fusions, in which with a neo-partner of lncRNA (LOC399815-ALK). Following subsequent treatment with Alectinib and stereotactic radiotherapy (CyberKnife) was subsequently employed to manage the brain metastatic lesions, resulting in a substantial decreased in both the number and size of tumor lesions. The patient's response to therapy efficacy resulted in a substantial decreased in both the number and size of tumor lesions that assessed comprehensively evaluated through computed tomography imaging and ctDNA sequencing. Patient's condition has been under control for over 29 months. Liquid biopsy may reveal the rare fusion forms of ALK, precisely guiding personalized treatment, and providing a reference method for longitudinal monitoring and efficacy evaluation of ALK-tyrosine kinase inhibitors in NSCLC patients.

Immunohistochemical expression of anaplastic lymphoma kinase in neuroblastoma and its relations with some clinical and histopathological features.

Anaplastic lymphoma kinase (ALK) mutations have been identified as a prominent cause of some familial and sporadic neuroblastoma (NB). ALK expression in NB and its relationship with clinical and histopathological features remains controversial. This study investigated ALK expression and its potential relations with these features in NB. Ninety cases of NB at the Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Viet Nam from 01/01/2018 to 12/31/2021, were immunohistochemically stained with ALK (D5F3) antibody. The ALK expression and its relations with some clinical and histopathological features were investigated. The rate of ALK expression in NB was 91.1%. High ALK expression (over 50% of tumor cells were positive with moderate-strong intensity) accounted for 65.6%, and low ALK expression accounted for 34.4%. All the MYCN-amplified NB patients had ALK immunohistochemistry positivity, most cases had high ALK protein expression. The undifferentiated subtype of NB had a lower ALK-positive rate than the poorly differentiated and differentiated subtype. The percentages of ALK positivity were significantly higher in more differentiated histological types of NB (p = .024). There was no relation between ALK expression and: age group, sex, primary tumor location, tumor stage, MYCN status, clinical risk, Mitotic-Karyorrhectic Index, prognostic group, necrosis, and calcification. ALK was highly expressed in NB. ALK expression was not related to several clinical and histopathological features. More studies are needed to elucidate the association between ALK expression and ALK gene status and to investigate disease progression, especially the oncogenesis of ALK-positive NB.

Molecular analysis of genetic mutations in non-small cell lung cancer in Morocco.

Non-small cell lung cancer (NSCLC) is a significant global health issue with diverse molecular profiles affecting treatment responses. Yet, NSCLC's molecular epidemiology in Morocco is largely unexplored. This study focuses on NSCLC genetic mutations, specifically in adenocarcinoma, among Moroccan patients to contribute to understanding NSCLC in this population. Ninety-four patients diagnosed with lung adenocarcinoma were analyzed. Formalin-fixed paraffin-embedded tissue samples were processed, and deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) was extracted using standardized protocols. Mutations were detected using the AmoyDx Pan Lung Cancer Polymerase Chain Reaction (PCR) Panel kit, and their frequencies were assessed through statistical analysis. Epidermal Growth Factor Receptor (EGFR) mutations were detected in 22.34% of patients, predominantly exon 19 deletions (66.66%) and exon 21 L858R mutations (23.80%). Anaplastic lymphoma kinase (ALK) gene fusion was observed in 3.19% of patients, and KRAS mutations in 1.06%. No mutations were found in other tested genes. A slightly higher mutation rate was noted in females (54.16%) compared to males (45.84%). The study reveals a distinct mutation profile in Moroccan NSCLC patients, with a notable prevalence of EGFR mutations, albeit lower than in some Asian populations. The significance of EGFR mutations in treatment response aligns with global findings, highlighting the importance of understanding regional molecular variations for personalized therapy. Despite limitations in sample size and clinical data, this study sheds light on the genetic landscape of NSCLC in Morocco. The observed mutation rates, particularly in EGFR, underscore the potential for targeted therapies in Moroccan NSCLC patients, emphasizing the need for further research to refine treatment strategies tailored to this population.

An Anaplastic Lymphoma Kinase-positive Inflammatory Myofibroblastic Tumor with Rapidly Acquired Resistance to First-line Anaplastic Lymphoma Kinase Inhibitor: A Case and Literature Review

Abstract Inflammatory myofibroblastic tumors (IMTs) are soft-tissue neoplasms with rare metastatic potential. Approximately half of IMTs are positive for an anaplastic lymphoma kinase (ALK) gene rearrangement which causes aberrant expression. Early phase clinical trials have demonstrated the efficacy of ALK inhibitors in the treatment of IMTs. However, there is no definite conclusion on which ALK inhibitor performs best, and data regarding subsequent therapy after first-line ALK inhibitor failure are scarce. Here, we report a case of ALK+ metastatic IMT that demonstrated a dramatic response to first-line alectinib but resulted in rapidly acquired resistance. Repeated biopsy and next-generation sequencing (NGS) showed ALK:c.3604G>A; p.(Gly1202Arg), which is a common mechanism of drug resistance in ALK fusion-positive non-small cell lung cancer. We also report subsequent treatment choices and responses in this patient and perform a literature review regarding similar cases as this rare tumor.

Inflammatory myofibroblastic tumor from molecular diagnostics to current treatment.

Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm with intermediate malignancy characterized by a propensity for recurrence but a low metastatic rate. Diagnostic challenges arise from the diverse pathological presentation, variable symptomatology, and lack of different imaging features. However, IMT is identified by the fusion of the anaplastic lymphoma kinase (ALK) gene, which is present in approximately 70% of cases, with various fusion partners, including ran-binding protein 2 (RANBP2), which allows confirmation of the diagnosis. While surgery is the preferred approach for localized tumors, the optimal long-term treatment for advanced or metastatic disease is difficult to define. Targeted therapies are crucial for achieving sustained response to treatment within the context of genetic alteration in IMT. Crizotinib, an ALK tyrosine kinase inhibitor (TKI), was officially approved by the US Food and Drug Administration (FDA) in 2020 to treat IMT with ALK rearrangement. However, most patients face resistance and disease progression, requiring consideration of sequential treatments. Combining radiotherapy with targeted therapy appears to be beneficial in this indication. Early promising results have also been achieved with immunotherapy, indicating potential for combined therapy approaches. However, defined recommendations are still lacking. This review analyzes the available research on IMT, including genetic disorders and their impact on the course of the disease, data on the latest targeted therapy regimens and the possibility of developing immunotherapy in this indication, as well as summarizing general knowledge about prognostic and predictive factors, also in terms of resistance to systemic therapy.

Unravelling the Enigma of Inflammatory Myofibroblastic Tumours: A Cross-sectional Study from a Regional Cancer Centre, Karnataka, India

Introduction: Inflammatory Myofibroblastic Tumour (IMT) is an unusual neoplasm with intermediate malignant potential, which rarely metastasises. IMT occurs in various anatomical sites, and the initial descriptions were primarily centered on its manifestation in the lungs. Although the age range is broad, IMT is most common in the first three decades of life, with a slight female predominance. Recent data and Anaplastic Lymphoma Kinase (ALK) gene aberrations confirm a neoplastic process for these lesions. Aim: To study the clinicopathological features of IMTs in a regional cancer centre in South India. Materials and Methods: A cross-sectional study included 17 cases of IMT over six years, from May 2014 to May 2020, at Memorial Kidwai Memorial Institute of Oncology (KMIO), Bengaluru, Karnataka, India. The clinicopathologic and immunophenotypic features were analysed on needle biopsies and resected specimens. Correlation between the expression of ALK-1 and histological patterns, mimickers, metastasis, and prognosis were described. Results were analysed using Microsoft Excel 2019 and Medcalc calculator. Results: Seventeen cases of IMTs were included in this study, out of which two were in the lung, and the rest were extrapulmonary. Sixteen cases were unifocal on presentation; however, one IMT of extremity showed evidence of secondaries on bone scan. The mean age at presentation was 33.47 years, and the maleto-female ratio was 1:1.12. Among the seventeen cases, sites are as follows: one each in the retroperitoneum, liver, soft-tissue (extremity), two each in the breast, lung, female genital tract, urinary bladder, and three each in the head and neck region (maxilla, trachea, and alveolus) and mesentery. Microscopically, IMTs showed various histological patterns. Immunostaining for ALK-1 was positive in seven out of seventeen cases, and the rest were diagnosed by excluding closer mimickers. Conclusion: The present study provides crucial insights into the clinicopathological features of IMTs. Immunohistochemistry (IHC) is an essential diagnostic tool that helps accurately differentiate IMT from its mimickers by identifying ALK protein expression. This distinction is essential for guiding targeted therapy in recurrent or metastatic cases.

Advances in the Management of Neuroblastoma.

Neuroblastoma is a malignant tumor of neuroblasts, immature nerve cells found in several areas of the body. It usually affects children under age of 5. As usual, the tumor has ability to grow rapidly and to expand vastly which ultimately leads to death. Mostly, management decisions can be drawn by the prediction of the stage of the disease as well as age at the time of its diagnosis. There are four main stages of neuroblastoma, and treatment is according to the low and high risk of the disease. Several cytotoxic agents along with other therapies (antibody therapy, gene therapy, and even immunological therapies, antiangiogenic therapy, etc.) are used. Immunotherapy also has an important treatment option used nowadays for neuroblastoma. The discovery of major neuroblastoma-predisposition gene anaplastic lymphoma kinase cause somatic transformation or gene strengthening in diagnosed neuroblastoma. Promising new antiangiogenic strategies have also been introduced for the treatment of neuroblastoma with multiple mylomas. To manage numerous myelomas and cancers, including neuroblastoma, bone marrow transplantation and peripheral blood stem cell transplantation may be used.

First case report of a novel KIF13A-ALK fusion in a lung adenocarcinoma patient and response to alectinib with a 4-year follow-up.

The prevalence of Anaplastic Lymphoma Kinase gene (ALK) fusion is about 5% among patients with lung adenocarcinoma, underscoring the importance of pinpointing distinct fusion variants for optimizing treatment approaches. This is the first reported case of a 74-year-old female with stage IV lung adenocarcinoma, featuring a novel Kinesin Family Member 13A (KIF13A)-ALK fusion, identified via next-generation sequencing (NGS) and confirmed with fluorescence in situ hybridization (FISH). Initially undergoing chemotherapy and then crizotinib, she achieved a partial response (PR) before progressing with multiple bone metastases. However, subsequent treatment with alectinib as a third-line option yielded positive results. A stable disease state persisted for an impressive 31months of progression-free survival (PFS), accompanied by minimal toxicity symptoms. Up until now, a remarkable near 4-year span of overall survival (OS) has been consistently observed and monitored. This report of a KIF13A-ALK fusion case benefit significantly from alectinib with extensive follow-up. The case diversifies the array of ALK fusion partners and holds clinical relevance in refining therapeutic choices for KIF13A-ALK fusion-associated lung cancer.

Renal Inflammatory Myofibroblastic Tumor in an Infant: Case Report with Review of Literature

AbstractInflammatory myofibroblastic tumor (IMT) is an intermediate-grade neoplasm of myofibroblastic lineage occurring due to a cytogenetic clonal abnormality of chromosome 2p23. Pediatric renal IMTs are rare and infant renal IMTs are almost anecdotal. We herein report a 1-year-old female child who presented with a firm mass in the right lumbar region. Biopsy, and later, surgical resection revealed a tumor composed of spindle cells with intermixed plasma cells. On immunohistochemistry (IHC), the lesional cells were positive for smooth muscle actin and anaplastic lymphoma kinase (ALK). A diagnosis of IMT was made based on morphology and IHC. Diagnosis of renal IMTs become challenging especially in a tiny biopsy wherein clear cell sarcoma of kidney, Wilms tumor with predominant mesenchymal component, congenital mesoblastic nephroma, and metanephric stromal tumor are the differential diagnoses in this age group. Renal IMTs generally have better prognosis as compared to extrarenal IMTs. Approximately, 50 to 60% of these tumors harbor ALK gene rearrangement as demonstrated by positivity for ALK IHC. ALK inhibitors like crizotinib or ceritinib can be given for advanced metastatic tumors.

Case report: ALK-positive histiocytosis presented as bilateral synchronous breast masses with long-term remission on crizotinib

ALK-positive histiocytosis (APH) is a rare type of histiocytic neoplasm with characteristic ALK (Anaplastic Lymphoma Kinase) gene translocation and fusion, with only 27 reported cases in the literature. In this study, we report the first case of synchronous bilateral breast involvement of ALK-positive histiocytosis on initial presentation in a 46-year-old Hispanic woman. APH was diagnosed by the confirmation of clonal histiocyte proliferation with ALK overexpression on IHC and the presence of KIF5B-ALK gene fusion from her breast and lung biopsies. The patient in our study is currently under complete and long-term remission with crizotinib treatment (an ALK inhibitor). This report expands on the clinical manifestation of APH, emphasizes the importance of ALK detection in histiocytic diseases, and provides the efficacy and long-term prognosis of the ALK inhibitor therapy for APH.

First-line treatment option for patients with ALK-positive metastatic NSCLC

Non-small cell lung cancer (NSCLC) that occupies a leading place in the pattern of cancer incidence and mortality is a highly heterogeneous group of diseases. The presence of a wide spectrum of NSCLC driver mutations has led to a fundamentally different understanding of the treatment strategy for this cohort of patients and a significant improvement in long-term oncological outcomes, even in the metastatic process. Chromosomal rearrangements involving the anaplastic lymphoma kinase (ALK) gene loci on chromosome 2 are found in approximately 3–5% of patients with metastatic NSCLC (mNSCLC) and in most cases are associated not only with a number of specific clinical features, but also with high sensitivity to targeted therapy with tyrosine kinase inhibitors (TKI). Crizotinib was the first approved ALK inhibitor, but although most patients achieved response within the first two years after start of the treatment, disease progression occurred often due to intracranial injury. The development of second-(ceritinib, alectinib), brigatinib and third-generation (lorlatinib) drugs has led to a statistically significant improvement in progression-free survival (PFS) rates, as well as control over intracranial manifestations of the disease and a change in the initial treatment strategy for these patients. In addition, new-generations of TKIs were developed to solve the problem of acquired resistance, as well as to achieve the best outcomes in the presence of such unfavourable factors as the presence of a TP53 mutation and/or ALK inhibitor low-sensitive translocation variants of the intracellular kinase domain of EML4 (echinoderm microtubule‐associated protein‐like 4)‐ALK (anaplastic lymphoma kinase) protein. Thus, advances in the therapeutic options for ALK-positive mNSCLC has completely changed the course of the disease, resulting in a significant increase in overall survival (OS) rates not only with the sequential use of different generation TKIs, but also with the choice of the most effective first-line option. In this article, we present an analysis of data on the efficacy and toxicity of lorlatinib, a third-generation TKI, in the first-line treatment for ALK+ mNSCLC.

The Prognosis of Advanced Non-Small Cell Lung Cancer Patients with Precision-Targeted Therapy Guided by NGS Testing or Routine Testing.

We aim to observe the potential survival benefits of driver gene-guided targeted therapy in advanced non-small cell lung cancer (NSCLC) patients compared to non-targeted therapy. Additionally, the study aims to assess whether Next-generation sequencing technology (NGS)-guided targeted therapy can provide survival advantages for advanced NSCLC patients compared to conventional Epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) gene detection. Clinical data, genetic testing results, and treatment information of 1663 advanced lung cancer patients diagnosed by pathology from January 2013 to June 2019 in Jiangsu University Affiliated Lianyungang Hospital were collected. Propensity score matching survival analysis was used to evaluate the differences in overall survival(OS) between groups. In the unadjusted survival curve, targeted therapy patients had significantly longer median OS than non-targeted therapy patients (28.3 months vs 15.4 months, Hazard ratio (HR) = 0.5426, 95% confidence interval (CI) 0.4768-0.6176, P < 0.0001); the conclusion was the same after propensity score matching analysis, with targeted therapy group patients having significantly prolonged OS median (27.5 months vs 14.8 months, HR = 0.5572, 95% CI 0.4796-0.6474, P < 0.0001). In the unadjusted survival curve, the NGS group had a significantly prolonged median OS compared to the conventional gene detection group (23.4 months vs 21.2 months, HR = 1.243, 95% CI = 1.017-1.519, P = 0.0495). However, after propensity score matching analysis, no statistically significant difference existed in the median OS between the two patient groups (23.1 months vs 21.5 months, HR = 1.288, 95% CI = 0.9557-1.735, P = 0.0926). Further analysis demonstrated no advantage in the five-, three-, and two-year survival rates of the NGS group compared to conventional gene detection group patients. However, the one-year survival rate of the NGS group was significantly increased (83.2% vs 68.1%, HR = 0.4890, 95% CI = 0.3170-0.7544, P = 0.0015). Driver gene-guided targeted precision therapy significantly prolonged the median OS of advanced NSCLC patients compared to non-targeted therapy. NGS detection did not improve the median OS of advanced NSCLC patients compared to conventional EGFR/ALK gene detection but increased the one-year survival rate of patients.

Oligometastasis: Expansion of Curative Treatments in the Field of Oncology.

Oligometastasis is defined as the presence of several limited metastatic lesions and is generally limited to three or fewer than five metastatic lesions. Previously, the treatment of metastatic cancer aimed to alleviate symptoms rather than cure them; however, the use of immunotherapy or targeted therapy has greatly improved patient life expectancy. Additionally, the effectiveness and safety of local treatment have recently been proven for oligometastatic cancers and have significantly improved patient survival and decreased recurrence rates. A few metastatic studies on lung cancer have demonstrated the usefulness of combining radiation therapy and immunotherapy. Recently, local and targeted therapy combinations have shown promising results in treating non-small cell lung cancer, predominantly caused by the epidermal growth factor receptor and anaplastic lymphoma kinase gene mutations, suggesting the potential of these new treatment strategies. It is well known that oligometastasis has better clinical results than polymetastasis; however, research on the biological profile of oligometastasis is still lacking. Studies using circulating tumor DNA and circulating tumor cells are at the initial stages of providing a better understanding of oligometastatic cancers, and the biological characteristics of these cancers may be revealed based on more diverse studies. With the development of these treatments, the prognosis for patients with oligometastatic cancers is steadily improving, and if the biological profile is revealed, customized treatment may be provided.

Diagnosis and Treatment of Advanced ALK Rearrangement-Positive Non-Small-Cell Lung Cancer in Portugal: Results of a National Questionnaire.

Rearrangements in the anaplastic lymphoma kinase (ALK) gene define a molecular subgroup of non-small-cell lung carcinoma (NSCLC) that should be treated with ALK-targeting tyrosine kinase inhibitors (TKIs). This study aimed to portray the Portuguese reality about the diagnosis and treatment of stage IV ALK-positive NSCLC. Institutions that treat lung cancer in Portugal were invited to participate in an anonymous electronic questionnaire. A total of 22/35 geographically dispersed institutions responded. A descriptive statistical analysis of the results was performed. Reflex molecular testing was done in 54.6% of the institutions. Next-generation sequencing (NGS) was the preferred diagnostic method (90.9%). Typically, physicians obtained molecular study results within 14-21days. Alectinib was the most commonly used first-line treatment. For patients with brain metastases, 86.4% of the physicians preferred alectinib and 13.6% preferred first-line brigatinib. In the case of asymptomatic oligoprogression in the central nervous system, 85.7% of physicians performed local treatment and kept the patient on a TKI; if symptomatic, 66.7% gave local treatment and stayed with the TKI, while 28.6% gave local treatment and altered the TKI. For patients with symptomatic systemic progression, 47.6% and 38.1% of physicians prescribed lorlatinib after initial treatment with alectinib or brigatinib, respectively. After progression on lorlatinib, 42.9% of respondents chose chemotherapy and 57.1% requested detection of resistance mutations. NGS is widely used for the molecular characterization of ALK-positive NSCLC in Portugal. The country has access to up-to-date therapy. Overall, national clinical practice follows international recommendations for the diagnosis and treatment of ALK-positive NSCLC.

A NSCLC patient with novel ALK fusion responded to crizotinib therapy after alectinib-induced interstitial lung disease.

A 54-year-old, non-smoking woman was diagnosed as stage ⅣB adenocarcinoma with widespread bone metastasis (cT4N2M1c) in our hospital. Immunohistochemistry (Ventana D5F3 antibody) result showed the presence of ALK rearrangement; and next-generation sequencing assay (NGS) indicated EML4-ALK fusion (E6:A20) with concurrent CCDC148-ALK (C1:A20), PKDCC-ALK (Pintergenic:A20)and VIT-ALK (V15:A20) fusions. After 32 weeks of alectinib treatment, the patient complained cough and exertional chest distress but had no sign of infection. Computed tomography (CT) showed bilateral diffuse ground glass opacities, suggesting a diagnosis of alectinib-related interstitial lung disease (ILD). Following corticosteroid treatment and discontinuation of alectinib, clinical presentations and CT scan gradually improved, but the primary lung lesions enlarged in the regular follow-up. The administration of a first-generation ALK inhibitor crizotinib was then initiated and the disease was stable for 25 months without recurrence of ILD.

Alk-rearranged lung adenocarcinoma: From molecular genetics to therapeutic targeting.

Anaplastic Lymphoma Kinase (ALK) is a potent oncogenic driver of lung adenocarcinoma (LUAD). ALK is constitutively activated by gene fusion events between the ALK and other gene fusion partners in about 2-3% of LUADs, characterized by few other gene alterations. ALK-fusions are a druggable target through potent pharmacological inhibitors of tyrosine kinase activity. Thus, several ALK-TKIs (Tyrosine Kinase Inhibitors) of first-, second- and third-generation have been developed that improved the outcomes of ALK-rearranged LUADs when used as first- or second-line agents. However, resistance mechanisms greatly limit the durability of the therapeutic effects elicited by these TKIs. The molecular mechanisms responsible for these resistance mechanisms have been in part elucidated, but overcoming acquired resistance to ALK-derived therapy remains a great challenge. Some new therapeutic strategies under investigation aim to induce long-term remission in ALK-fusion positive LUADs.

Unveiling the Molecular Mechanisms Behind the Devastating Impact of the ALK Protein on Pediatric Cancers: Insights into Deleterious SNPs through In Silico Predictions, Molecular Docking, and Dynamics Studies

Abstract Introduction Pediatric cancers present significant challenges in terms of diagnosis and treatment, and the anaplastic lymphoma kinase (ALK) protein has emerged as a crucial molecular target in these malignancies. ALK, a receptor tyrosine kinase, plays a vital role in normal cellular processes, but genetic alterations and aberrant activation of the ALK gene have been implicated in various pediatric cancer types. While genetic alterations have been well studied, the precise molecular mechanisms underlying the pathogenicity of the ALK protein in pediatric cancers remain poorly understood. Objective In this study, the primary objective is to uncover the molecular mechanisms associated with the effects of deleterious single-nucleotide polymorphisms (SNPs) on the structure and functionality of the ALK protein. Material and Methods Several known point mutations of the ALK protein were taken for the in silico predictions such as PolyPhen-2, SIFT, PANTHER, PredictSNP, etc., residue conservation analysis using Consurf server, molecular docking (AutoDock), and molecular dynamics simulation studies (GROMACS). Results The computation predictions found that the studied variants are deleterious in different tools. The residue conservation analysis reveals all the variants are located in highly conserved regions. The molecular docking study of wild-type and mutant structures with the crizotinib drug molecule found the variants were modulating the binding cavity and had a strong impact on the binding affinity. The binding energy of the wild-type is –5.896 kcal/mol, whereas the mutants have –9.988 kcal/mol. The specific amino acid Ala1200 of wild-type was found to interact with crizotinib, and Asp1203 residue was found to interact predominantly in the mutant structures. Conclusion The simulation study differentiates the variants in terms of structural stability and residue fluctuation. Among the studied variants, R1275Q, F1245V, and F1174L had strong deleterious effects, structural changes, and pathogenicity based on the in silico predictions. By elucidating the functional consequences of deleterious mutations within the ALK gene, this research may uncover novel therapeutic targets and personalized medicine approaches for the management of pediatric cancers. Ultimately, gaining insights into the molecular mechanisms of the ALK protein's role in driving response and resistance will contribute to improving patient outcomes and advancing our understanding of this complex disease.

ALK-Rearranged Epithelioid Mesenchymal Neoplasm: Expanding the Spectrum of Tyrosine Kinase–Altered Mesenchymal Tumors

The anaplastic lymphoma kinase (ALK) gene encodes a receptor tyrosine kinase, and fusions involving this gene have been reported in a variety of mesenchymal neoplasms. ALK-altered tumors with epithelioid morphology have been described in epithelioid inflammatory myofibroblastic sarcoma and epithelioid fibrous histiocytoma. Herein, we describe the clinicopathologic features of 7 ALK-rearranged mesenchymal tumors with epithelioid morphology occurring predominately in the pediatric population. Tumors occurred in 4 females and 3 males with an age ranging from 1 month to 28 years. Five tumors were superficial and solitary, while 1 presented with multiple peritoneal/omental nodules, and 1 presented as a large mediastinal mass. Morphologically, all tumors comprised epithelioid cells arranged in sheets, anastomosing cords, or small clusters embedded in a myxohyaline stroma. The cells had slightly variably sized ovoid nuclei with moderately prominent nucleoli and abundant eosinophilic cytoplasm. Four cases had sparse mitotic figures without necrosis. The remaining 3 tumors (2 deep and 1 superficial) had more than 10 mitoses per 10 high-power fields as well as foci of necrosis. ALK fusions were identified in all cases. The fusion partners included HMBOX1 (n = 1), VCL (n = 1), PRRC2B (n = 1), MYH10 (n = 1), STRN (n = 1), and EML4 (n = 2). One tumor recurred locally 2 years after initial resection; 1 patient had widely metastatic disease (mediastinal tumor). At the time of last follow-up (n = 6), 4 patients were alive without evidence of disease, 1 died due to complications of therapy (peritoneal tumor), and 1 was alive with disease. Our findings expand the spectrum of ALK-rearranged mesenchymal tumors. Our cases predominately occurred in older children and mainly exhibited epithelioid to round cell morphology, as opposed to spindle cell morphology. We also show that tumors in a deep location with higher-grade features follow a more aggressive clinical course.

Thromboembolism risk in patients diagnosed with EGFR- and ALK-mutant lung adenocarcinoma

In this study, we investigated the incidence of venous thromboembolism (VTE), related risk factors for VTE, and the effect of VTE on overall survival in patients with non-small-cell lung cancer harboring epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene mutations. The study included patients older than 18 years of age who were diagnosed with histologically proven locally advanced or advanced-stage adenocarcinoma and were followed in our center between January 2014 and December 2019. These patients were divided into two groups: one comprising mutation-positive individuals and the other mutation-negative individuals. We examined factors influencing the occurrence of VTE, assessed the incidence of VTE, and compared the differences in overall survival. Univariate Cox regression analysis revealed that the independent predictors of VTE were the number of metastases (Hazard ratio [HR]: 3.784; 95% confidence interval [CI]: 2.198 &amp;ndash; 6.515; P &lt; 0.001) and the presence of EGFR exon 21 mutations (HR: 2.386; 95% CI: 1.276 &amp;ndash; 4.462; P = 0.006). However, in multivariate analysis, only the number of comorbidities was associated with an increased risk for VTE (HR: 3.462; 95% CI: 1.977 &amp;ndash; 6.060; P &lt; 0.001). It is essential to consider the risk of VTE development in patients with EGFR exon 21 mutation-positive lung adenocarcinoma. Physicians should be vigilant in terms of screening, prophylaxis, and follow-up for underlying VTE in these patients.

Rare giant ovarian metastasis arising from a small primary lung adenocarcinoma: a case report.

This intricate case report details an exceptionally rare incidence of ovarian metastasis originating from a primary lung adenocarcinoma (LUAD). The relative rarity of this metastatic pathway in medical literature indicates significant diagnostic challenges. This patient was initially found to have both the ovarian tumor and lung nodule and they were originally considered independent primary tumors, derived from radiological interpretations and biomarker profiling. Nevertheless, subsequent postoperative histopathological and immunohistochemical staining evaluations identified ovarian tumors as invasive adenocarcinoma metastasized from lung. The lung and ovary tumor both showed marked anaplastic lymphoma kinase gene (ALK) protein expression by immunohistochemistry. The molecular pathologic genetic testing for lung tumor also revealed ALK rearrangement positive. The complexity of this case underscores the essentiality of maintaining a high degree of diagnostic vigilance, particularly when confronting synchronous tumors. In addition, immunohistochemical staining plays an important role in diagnosing the ovarian neoplasm's metastatic nature and determining the primary site of metastatic adenocarcinoma. For lung cancer with ovary metastasis patients, the adopting an adaptable treatment approach responsive to evolving diagnostic evidence can improve the accuracy of diagnosis and avoid excessive treatment of patients.