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

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

Anaplastic lymphoma kinase (ALK; also known as ALK tyrosine kinase receptor) inhibitors (ALKi) are effective in treating lung cancer patients with chromosomal rearrangement of ALK. However, continuous treatment with ALKis invariably leads to acquired resistance in cancer cells. In this study, we propose an efficient strategy to suppress ALKi resistance through a meta‐analysis of transcriptome data from various cell models of acquired resistance to ALKis. We systematically identified gene signatures that consistently showed altered expression during the development of resistance and conducted computational drug screening using these signatures. We identified emetine as a promising candidate compound to inhibit the growth of ALKi‐resistant cells. We demonstrated that emetine exhibited effectiveness in inhibiting the growth of ALKi‐resistant cells, and further interpreted its impact on the resistant signatures through drug‐induced RNA‐sequencing data. Our transcriptome‐guided systematic approach paves the way for efficient drug discovery to overcome acquired resistance to cancer therapy. [ABSTRACT FROM AUTHOR]

Hemolytic anemia is a rare and unique complication of alectinib, not observed with other anaplastic lymphoma kinase (ALK) inhibitors. Here, we present a case of an ALK fusion‐positive non‐small‐cell lung cancer (NSCLC) patient who developed liver failure due to diffuse liver metastasis at initial diagnosis. Treatment was initiated with low‐dose alectinib, but the patient developed severe hemolytic anemia. Switching to lorlatinib allowed for the continuation of ALK inhibitor therapy and successful tumor reduction. ALK inhibitors are crucial for ALK fusion‐positive NSCLC patients. Managing severe side effects by switching medications is essential to maintain effective therapy. In this case, lorlatinib effectively controlled the tumor and improved the patient's liver function and performance status. This case highlights the importance of adapting treatment strategies to manage adverse effects while ensuring the continued use of ALK inhibitors for optimal patient outcomes. [ABSTRACT FROM AUTHOR]

Background: Inhibitors of the anaplastic lymphoma kinase (ALK) gene mutation are first-line treatments in patients with ALK-positive lung cancer. The FDA label warns of the risk of interstitial lung disease (ILD) in patients receiving ALK TKIs. However, ILD associated with ALK TKIs is not fully understood. The aim of this study was to characterize the features of ALK TKI-related ILD and to explore risk factors for ALK TKI-related ILD. Methods: FDA's Adverse Event Reporting System (FAERS) reports from 2011 Q1 to 2023 Q2 were extracted and combined. Standardized MedDRA queries (SMQs) were used to search for AEs at the preferred term (PT) level. Four algorithms were employed to quantify the signals of ILD associated with ALK TKIs. The risk of ILD was further analyzed using logistic regression. Results: A total of 20,064 reports of ALK TKIs and 640 (3.2%) reports of ILD AEs were extracted. Significant disproportionality was detected in all five ALK TKIs. Interstitial lung disease and pneumonitis were the most common lung toxicities induced by ALK TKIs. Results of further analyses revealed a different spectrum of lung toxicity among the various TKIs. The median time to onset of ILD related to ALK TKIs was 53 days (Q1:12, Q3:209), and more than 70% of AEs occurred within the first 2 months. Logistic regression analysis and risk prediction model both showed that different ALK TKIs and their combination with PPIs, amlodipine, and magnesium oxide were independent risk factors for ILD (p <0.05). Conclusion: ALK TKIs have different safety profiles regarding lung toxicity, which normally occurs within the first 2 months. Administration in combination with PPIs, amlodipine, and magnesium oxide significantly increases the risk of ILD. These results provide risk prediction for ILD related to ALK TKIs and support pharmacovigilance to promote safe prescribing in oncology. [ABSTRACT FROM AUTHOR]

Background: Alectinib has demonstrated promising disease-free survival (DFS) benefit for early-stage non-small cell lung cancer (NSCLC) patients with ALK rearrangement positive in phase 3 ALINA trial. However, real-world evidence for the efficacy and safety of alectinib in early-stage ALK-positive NSCLC is limited. Materials and methods: We retrospectively reviewed 68 patients with stage IB-IIIB ALK-positive NSCLC who underwent complete pulmonary resections from April 2010 to July 2023 at a single institution. 38 (55.9%) enrolled patients had N2 lymph node metastasis, and 17 (24.9%) patients had multi-station N2 metastasis. Patients were stratified into two groups according to the adjuvant treatment regimen, with 19 patients in the alectinib group and 49 patients in the chemotherapy group. There were no significant differences in clinicopathological characteristics between the two groups. After curative resection surgery, patients in alectinib group received oral alectinib at a dose of 600 mg twice daily and patients in chemotherapy group received platinum-based doublet chemotherapy regimen every 3 weeks for 4 cycles. The primary endpoint was 3-year DFS. The Kaplan-Meier method was used to estimate DFS and overall survival (OS). Safety analyses were conducted by comparing the incidence of adverse events between the two groups. Results: At the last follow-up date (January 22th, 2024), A total of 1 (5.3%) and 28 (57.1%) DFS events were observed in alectinib group and chemotherapy group respectively. The 3-year DFS showed significant improvement in the alectinib group compared with chemotherapy group (91.7% vs 60.7%, P=0.051). In the IIIAN2 subgroup, the 3-year DFS rate in the alectinib group reached a satisfactory 87.5%. In both groups, the majority of AEs were graded as level 1 or 2, No grade 3-4 AEs were observed in alectinib group. Conclusion: Alectinib, as adjuvant therapy, demonstrated favorable efficacy and manageable safety in patients with completely resected ALK-positive stage I B-IIIB non-small cell lung cancer. A limitation of this study is the small sample size, and a larger-scale real-world sample study is needed to further evaluate the efficacy and safety of alectinib as adjuvant therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the role of three specific proteins—FGF8, ALK, and EML4—in predicting the prognosis of patients with esophageal squamous cell carcinoma (ESCC), a common type of esophageal cancer. The aim of the study was to assess whether the presence and levels of these proteins could indicate which patients are at a higher risk of poor survival following surgery. By analyzing tissue samples from 122 patients, who underwent surgical removal of their cancer, the study discovered that an increase in FGF8 protein levels is associated with a reduced chance of survival. Additionally, the study found a significant correlation between FGF8 and alterations in the ALK and EML4 proteins. These results suggest that FGF8 could serve as a valuable marker for predicting patient outcomes and might also become a target for future therapies aimed at improving survival rates in ESCC patients. FGF8, ALK, and EML4 have been identified as promising biomarkers in a number of malignancies. The aim of this study was to examine the prognostic role of FGF8, ALK, and EML4 in esophageal squamous cell carcinoma (ESCC). Methods: Consecutive patients with ESCC who underwent upfront resection were included in this study. ALK and EML4 gene status was evaluated by fluorescence in situ hybridization (FISH) using a triple-color break-apart single-fusion probe and a probe against 2p11. FGF8, ALK, and EML4 protein expression was determined by immunohistochemistry. Results: A total of 122 patients were included in this study. Multivariate analysis revealed that FGF8 overexpression is an independent negative prognostic factor for patients' overall survival (OS) (p = 0.04). Furthermore, a significant correlation between the expression of FGF8, and ALK (p = 0.04) and EML4 (p = 0.01) alteration was found. Conclusions: FGF8 overexpression is an adverse independent prognostic factor in patients with upfront resected ESCC. Furthermore, FGF8 expression significantly correlates with ALK and EML4 amplification and may therefore qualify as a future therapeutic target. [ABSTRACT FROM AUTHOR]

Introduction: Anaplastic lymphoma kinase (ALK) has been to be involved in the uptake and regulation of dopamine 2 receptor (D2R), a G protein-coupled receptor expressed in various brain regions. Therefore, it is crucial to understand the relationship between ALK inhibitors and seizures is an important issue. This study investigated the relationship between ALK inhibitors and seizures. Methods: This study investigated the relationship between ALK inhibitors and seizures through a disproportionality analysis using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The target drugs were the ALK inhibitors crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib. The seizures covered were defined high-level group term (HLGT): "Seizures (incl. subtype)" including high-level term (HLT): "seizures and seizure disorders NEC." This study used the information component (IC), a signal score, as a Bayesian statistical method for disproportionality analysis. The signal detection criteria used in this study were the same as those reported previously: a lower limit of 95% credible interval (CrI) for IC >0. Results: The signal scores of '"seizures and seizure disorders not elsewhere classified (NEC)" "for each ALK inhibitor were crizotinib (IC: −0.00052, 95% CrI: −0.38–0.27), ceritinib (IC: 1.18, 95% CrI: 0.68–1.54), alectinib (IC: 0.68, 95% CrI: 0.19–1.02), brigatinib (IC: 1.04, 95% CrI: 0.32–1.54), and lorlatinib (IC: 0.82, 95% CrI: 0.11–1.32). On the other hand, "generalized tonic-clonic seizures," "partial simple seizures NEC," "absence seizures," and "partial complex seizures" had no or few reported cases, and no signal was detected. Conclusion: To our knowledge, this is the first report to evaluate the relationship between ALK inhibitors and seizures using post-marketing surveillance data. These results suggest that ceritinib, alectinib, brigatinib, and lorlatinib, which are highly brain-migrating drugs, are associated with seizures. [ABSTRACT FROM AUTHOR]

Inflammatory myofibroblastic tumors (IMTs) represent rare neoplasms, particularly infrequent in the pediatric skull. We present a novel case of a newborn male with a 5 cm right temporal mass and discuss current diagnostic and treatment options for IMTs. A multidisciplinary effort to surgically remove the lesion was successful, and the patient's skull defect healed without neurological deficits. The etiology of IMTs remains elusive, with proposed associations with chromosomal mutations in the anaplastic lymphoma kinase (ALK) gene. Surgical excision remains the primary treatment for IMTs. Promising pharmacological treatments, like Crizotinib, warrant further research into understanding potential alternatives in IMT management. [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]

Purpose: Envonalkib (TQ-B3139) is a novel, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used to treat ALK-positive non-small cell lung cancer. This phase I mass balance study investigated the pharmacokinetics, metabolism, and excretion of 14C-radiolabeled envonalkib in healthy Chinese male subjects. Methods: A single oral dose of 600 mg (150 µCi) [14C]envonalkib was administered to healthy male subjects under fasted state. Samples of blood, urine and feces were collected for quantitative determination of total radioactivity and unchanged envonalkib, and the metabolites identification. Results: After dosing, the median Tmax of radioactivity was 4 h and the mean t1/2 was 65.2 h in plasma. The exposure of total radioactivity was much higher than that of unchanged envonalkib in plasma. The mean total recovery of the radiolabeled dose was 93.93% over 504 h post-dose, with 15.23% in urine and 78.71% in feces. Envonalkib underwent extensive metabolism and a total of 15 metabolites were identified in plasma, urine, and feces. Unchanged envonalkib and its major metabolite M315 were the main components in plasma, accounting for 20.37% and 33.33% of total plasma radioactivity. In urine, O-dealkylation metabolite M315 was the major component accounted for 7.98% of dose. In feces, 16.01% of dose was excreted as cysteine conjugate M434-1. Envonalkib was well tolerated and there were no serious adverse events observed in the study. Conclusion: Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces. [ABSTRACT FROM AUTHOR]

Soft tissue sarcomas are rare cancers and most cases are metastatic at the time of diagnosis. Although the chances of survival are good with surgical treatment in the early stages, systemic treatment in the advanced stages is only associated with a survival duration of ~12 months. Alterations in the anaplastic lymphoma kinase (ALK) gene are becoming increasingly recognized as pan-cancer indicators in solid tumors. However, little is known regarding the molecular spectrum of ALK-positive histiocytosis. Molecular treatments, including ALK inhibitors, are potential treatment options. The present case report describes an aggressive ALK-positive soft tissue sarcoma with intracardiac metastases and severe leukocytosis responding to ALK inhibitors. The patient initially responded to crizotinib but required alectinib due to central nervous system progression. The patient has shown a near-complete response and remained stable for 2 years; however, there has been recent lymph node progression. [ABSTRACT FROM AUTHOR]

Until the early 2000s, advanced or metastatic non–small cell lung cancer (NSCLC) was treated as a single disease with all histologic subtypes treated alike with standard chemotherapy agents. Over the past two decades, the treatment paradigms for advanced NSCLC have changed dramatically with the discovery of multiple targeted therapies that are now approved for the treatment of NSCLC tumors with specific oncogene drivers or molecular alterations. Molecular testing has become integrated and critical for the clinical management of advanced NSCLC. The discovery and success of these targeted therapies have reshaped the classification of NSCLC on the basis of molecular classification and enabled a personalized approach in thoracic oncology. In this review, we discuss recent developments in the molecular profiling of NSCLC, and approved and emerging targeted therapies for the treatment of NSCLC. In this review, we discuss recent developments in the molecular profiling of non–small cell lung cancer (NSCLC), and approved and emerging targeted therapies for the treatment of NSCLC. [ABSTRACT FROM AUTHOR]

Introduction: CEP-37440 was synthesized and supplied by the research and development division of Teva Branded Pharmaceutical Products (West Chester, PA, United States). CEP-37440 represents a newly developed compound that exhibits selectivity inhibition of Focal Adhesion Kinase and Anaplastic Lymphoma Kinase FAK/ALK receptors, demonstrating novel characteristics as an orally active inhibitor. The simultaneous inhibition of ALK and FAK can effectively address resistance and enhance the therapeutic efficacy against tumors through a synergistic mechanism. Methods: The objective of this research was to create an LC-MS/MS method that is precise, efficient, environmentally friendly, and possesses a high level of sensitivity for the quantification of CEP-37440 in human liver microsomes (HLMs). The aforementioned approach was subsequently employed to evaluate the metabolic stability of CEP-37440 in HLMs in an in vitro setting. The validation procedures for the LC-MS/MS analytical method in the HLMs were performed following the bio-analytical method validation guidelines set out by the US-FDA. The AGREE program was utilized to assess the ecological impacts of the current LC-MS/MS methodology. Results and Discussion: The calibration curve linearity was seen in the range of 1–3000 ng/mL. The inter-day accuracy (% RE) exhibited a range of −2.33% to 3.22%, whilst the intra-day accuracy demonstrated a range of −4.33% to 1.39%. The inter-day precision (% RSD) exhibited a range of 0.38% to 3.60%, whilst the intra-day precision demonstrated a range of 0.16% to 6.28%. The determination of the in vitro half-life (t1/2) and moderate intrinsic clearance (Clint) of CEP-37440 yielded values of 23.24 min and 34.74 mL/min/kg, respectively. The current manuscript is considered the first analytical study for CEP-37440 quantification with the application to metabolic stability assessment. These results suggest that CEP-37440 can be categorized as a pharmaceutical agent with a moderate extraction ratio. Consequently, it is postulated that the administration of CEP-37440 to patients may not lead to the accrual of dosages within the human organs. According to in silico P450 metabolic and DEREK software, minor structural alterations to the ethanolamine moiety or substitution of the group in drug design have the potential to enhance the metabolic stability and safety profile of novel derivatives in comparison to CEP-37440. [ABSTRACT FROM AUTHOR]

Background: Screening for anaplastic lymphoma kinase (ALK) rearranged non‐small cell lung cancer (NSCLC) is crucial for identifying patients eligible for targeted therapy. The FDA‐approved ALK (D5F3) immunohistochemistry (IHC) assay, used with the OptiView Amplification Kit, demonstrates excellent sensitivity and specificity in detecting these patients. However, the clinical significance of resulting focal positivity remains unclear, and ALK (D5F3) expression unrelated to ALK fusion is observed in some cases of neuroendocrine differentiation. This study aims to validate these findings with molecular testing and contribute to the accurate interpretation of ALK (D5F3) IHC results. Methods: A total of 1619 patients diagnosed with NSCLC and neuroendocrine carcinoma were evaluated using ALK (D5F3) IHC. For cases with strong but focal expression and those with diffuse strong positivity in neuroendocrine differentiation, ALK fluorescence in situ hybridization (FISH) and/or next‐generation sequencing (NGS) tests were performed. Results: Seven out of 1109 adenocarcinomas (0.6%) and six out of 289 squamous cell carcinomas (2.1%) exhibited strong focal ALK (D5F3) expression. Nine out of 209 neuroendocrine carcinomas (4.3%) showed homogeneously strong ALK (D5F3) expression. All these cases, including adenocarcinoma with neuroendocrine differentiation and combined small cell carcinoma, were negative for ALK fusions by FISH and/or NGS. Conclusion: This study demonstrates that strong but focal ALK (D5F3) immunostaining and strong expression in neuroendocrine differentiation may not indicate ALK fusion. By considering these findings, we can improve the accuracy of patient selection for targeted therapy by minimizing false‐positive interpretations of ALK (D5F3) staining. [ABSTRACT FROM AUTHOR]

Echinoderm microtubule-associated protein 4 (EML4) - anaplastic lymphoma kinase (ALK) fusion gene detection is of great significance in personalized tumor treatment. With the development of EML4-ALK fusion variants detection, it is necessary to establish traceability to ensure the consistency and comparability of its detection results in clinical practice. The establishment of traceability relies on SI traceable reference materials (RMs) and potential reference measurement procedures (RMPs). In this study, a potential RMP for the quantitative detection of V1 and V3 fusion mutations and the reference type (ALK-ref, including wild type, V1 and V3 mutant type) based on reverse transcription dPCR (RT-dPCR) and EML4-ALK fusion gene RMs were established. The proposed potential RMP has high specificity, good inter-laboratory reproducibility (CV < 7.3%) and good linear relationship (0.92 < slope < 1.06, R2 ≧ 0.99). The limit of detection (LoD) of V1, V3, and ALK-ref are 2 copies/reaction, 2 copies/reaction, and 1 copy/reaction, respectively. Interlaboratory studies using the EML4-ALK RMs and potential RMP showed that participating laboratories can produce consistent copy concentrations of fusion variant and ALK-ref as well as the ratio of EML4-ALK/ALK-ref. The established potential RMP with high specificity and accuracy can be used to characterize the EML4-ALK RMs, and the potential RMP and RM are useful to establish the traceability of EML4-ALK fusion measurement to improve the comparability and consistency in clinical tests. [ABSTRACT FROM AUTHOR]

Background: There has been significant improvement in treating metastatic non–small-cell lung cancer (mNSCLC) over the past 2 decades. The aim of this study is to describe the use of tyrosine kinase inhibitors (TKIs) in Qatar. This study focuses on the objective response rate (ORR) and reported adverse drug events (ADEs) of TKIs used for the management of patients with mNSCLC. Methods: This is a descriptive retrospective cohort study. All non–small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations who received TKIs between 2015 and 2019 in Qatar were included. The TKIs used during this period include EGFR inhibitors such as afatinib, erlotinib, gefitinib, and osimertinib and ALK inhibitors such as alectinib and crizotinib. The response on each TKI was identified by reporting the ORR (as the sum of the complete response [CR] and the partial response [PR]), in addition stable disease (SD) and disease progression (DP) were reported. While ADEs were reported using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE). Results: A total of 63 patients were included, of which 36 cases (57.1%) expressed EGFR mutation, and 27 patients (42.9%) expressed ALK rearrangement. The ORR in EGFR inhibitors was as follows: osimertinib 40%, gefitinib 33%, afatinib 22%, and erlotinib 18%. However, the response to the ALK-targeted therapy was 43% with alectinib and 40% with crizotinib. A total of 112 ADEs were reported. They were distributed as 63.4% (71 of 112) with the anti-EGFR and 36.6% (41 of 112) ADEs with the ALK inhibitors. In the anti-EGFR group, the most common types of ADEs were dermatological toxicity 30%, whereas, in the anti-ALK group, gastrointestinal toxicity was the most common (29%). Conclusions: The EGFR-targeted and ALK-targeted therapies appear to have acceptable clinical response rate and safety profile in our population. Close and frequent monitoring of adverse events is advised to ensure a good quality of life and prevent serious complications. [ABSTRACT FROM AUTHOR]

ABSTRACT 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]

Background: Inhibitors of the anaplastic lymphoma kinase (ALK) gene mutation are first-line treatments in patients with ALK-positive lung cancer. The FDA label warns of the risk of interstitial lung disease (ILD) in patients receiving ALK TKIs. However, ILD associated with ALK TKIs is not fully understood. The aim of this study was to characterize the features of ALK TKI-related ILD and to explore risk factors for ALK TKI-related ILD. Methods: FDA's Adverse Event Reporting System (FAERS) reports from 2011 Q1 to 2023 Q2 were extracted and combined. Standardized MedDRA queries (SMQs) were used to search for AEs at the preferred term (PT) level. Four algorithms were employed to quantify the signals of ILD associated with ALK TKIs. The risk of ILD was further analyzed using logistic regression. Results: A total of 20,064 reports of ALK TKIs and 640 (3.2%) reports of ILD AEs were extracted. Significant disproportionality was detected in all five ALK TKIs. Interstitial lung disease and pneumonitis were the most common lung toxicities induced by ALK TKIs. Results of further analyses revealed a different spectrum of lung toxicity among the various TKIs. The median time to onset of ILD related to ALK TKIs was 53 days (Q1:12, Q3:209), and more than 70% of AEs occurred within the first 2 months. Logistic regression analysis and risk prediction model both showed that different ALK TKIs and their combination with PPIs, amlodipine, and magnesium oxide were independent risk factors for ILD (p<0.05). Conclusion: ALK TKIs have different safety profiles regarding lung toxicity, which normally occurs within the first 2 months. Administration in combination with PPIs, amlodipine, and magnesium oxide significantly increases the risk of ILD. These results provide risk prediction for ILD related to ALK TKIs and support pharmacovigilance to promote safe prescribing in oncology. [ABSTRACT FROM AUTHOR]

Introduction: Aberrant expression of anaplastic lymphoma kinase (ALK) is found in 3%–7% of patients with non-small cell lung cancer (NSCLC). Alectinib is a tyrosine kinase inhibitor used as first-line treatment targeting ALK-positive tumors. We herein report two cases of appendicitis highlighting it as a rare, possible adverse event of treatment with alectinib. Case presentation: The first case is a 60-year-old woman with a previous history of stage 1 lobular breast cancer and early-stage lung cancer treated with segmentectomy, subsequently presenting with ALK-positive advanced NSCLC. Treatment with alectinib resulted in partial response, but she developed gastrointestinal symptoms that were assessed with computed tomography (CT) of the abdomen revealing right lower quadrant stranding without appendiceal visualization. Her symptoms continued despite an antibiotic course with re-imaging concerning for acute appendicitis, which was successfully treated with appendectomy and amoxicillin–clavulanic acid. The second case is a previously healthy 58-year-old man with advanced ALK-positive NSCLC who was started on first-line treatment with alectinib and subsequently diagnosed with asymptomatic acute appendicitis on re-staging CT abdomen. Signs on CT resolved with amoxicillin–clavulanic acid. Definitive treatment was conducted with a delayed elective appendectomy. Both patients remained on alectinib over the courses of appendicitis without interruption. Conclusion: While appendicitis has not been previously described as an adverse effect of alectinib, its incidence in two patients at our center within several months following the administration of alectinib raises its suspicion as a possible adverse effect. [ABSTRACT FROM AUTHOR]

Objective: Uterine inflammatory myofibroblastic tumor (UIMT) is a rare tumor of the female reproductive tract with uncertain malignant potential. Previous case series reports have limited our understanding of its diagnosis and treatment. Therefore, we conducted a retrospective analysis of patient files at West China Second University Hospital, Sichuan University to contribute valuable clinical insights to future treatment strategies for this disease. Method: We comprehensively reviewed patient files of individuals diagnosed with UIMT from January 1st, 2013 to May 1st, 2023. Results: We included twenty-seven cases of uterine inflammatory myofibroblastic tumor in our study. Of these, 51.85% (14 cases) were diagnosed with abnormal uterine bleeding, 2 cases had dysmenorrhea, and 12 were unexpectedly diagnosed with suspected uterine fibroids. Ten cases performed total hysterectomy, and 17 cases underwent lesion resection. The positive rate of anaplastic lymphoma kinase (ALK) immunohistochemistry reached 96.3%. After a median of 8 months follow-up time, all patients were disease-free and had survived. Conclusion: Uterine inflammatory myofibroblastic tumor is easily misdiagnosed, making its diagnosis challenging. Histological features, immunohistochemical results, and molecular confirmation using fluorescence in situ hybridization (FISH) or Next-generation sequencing should be used to confirm the diagnosis. Positive ALK immunohistochemistry, ALK rearrangement, ALK fusion are helpful in diagnosis and ALK inhibitor therapy. Total hysterectomy is often performed for women who do not require fertility, while lesion resection and close follow-up may be considered for those who require fertility preservation. [ABSTRACT FROM AUTHOR]

Purpose: The risk stratification of pediatric anaplastic large cell lymphoma (ALCL) has not been standardized. In this study, new risk factors were included to establish a new risk stratification system for ALCL, and its feasibility in clinical practice was explored. Materials and Methods: On the basis of the non-Hodgkin's lymphoma Berlin–Frankfurt–Munster 95 (NHL-BFM-95) protocol, patients with minimal disseminated disease (MDD), high-risk tumor site (multiple bone, skin, liver, and lung involvement), and small cell/lymphohistiocytic (SC/LH) pathological subtype were enrolled in risk stratification. Patients were treated with a modified NHL-BFM-95 protocol combined with an anaplastic lymphoma kinase inhibitor or vinblastine (VBL). Results: A total of 136 patients were enrolled in this study. The median age was 8.8 years. The 3-year event-free survival (EFS) and overall survival of the entire cohort were 77.7% (95% confidence interval [CI], 69.0% to 83.9%) and 92.3% (95% CI, 86.1% to 95.8%), respectively. The 3-year EFS rates of low-risk group (R1), intermediate-risk group (R2), and high-risk group (R3) patients were 100%, 89.5% (95% CI, 76.5% to 95.5%), and 67.9% (95% CI, 55.4% to 77.6%), respectively. The prognosis of patients with MDD (+), stage IV cancer, SC/LH lymphoma, and high-risk sites was poor, and the 3-year EFS rates were 45.3% (95% CI, 68.6% to 19.0%), 65.7% (95% CI, 47.6% to 78.9%), 55.7% (95% CI, 26.2% to 77.5%), and 70.7% (95% CI, 48.6% to 84.6%), respectively. At the end of follow-up, one of the five patients who received maintenance therapy with VBL relapsed, and seven patients receiving anaplastic lymphoma kinase inhibitor maintenance therapy did not experience relapse. Conclusion: This study has confirmed the poor prognostic of MDD (+), high-risk site and SC/LH, but patients with SC/LH lymphoma and MDD (+) at diagnosis still need to receive better treatment (ClinicalTrials.gov number, NCT03971305). [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)-rearranged mesenchymal neoplasms (non-inflammatory myofibroblastic tumor and non-epithelioid fibrous histiocytoma) have been recently described which tend to occur in the superficial and deep soft tissues. Occurrence as a primary sinonasal neoplasm has not been reported thus far. Herein, we describe the first case of sinonasal ALK-rearranged mesenchymal tumor that harbored remarkable epithelioid and spindle cell morphology. The tumor affected a 40-year-old man who presented with flu-like symptoms and was thought to have influenza A. However, computed tomography demonstrated a nasal polypoid lesion causing curvature of the nasal septum. Histological examination revealed a heterogeneous tumor composed of round to epithelioid cells with foci of spindle cells. The tumor cells exhibited moderate pleomorphism and mitotic activity. By immunohistochemistry, they showed diffuse staining of CD34, S100, ALK (D5F3) and CD30. Fluorescence in situ hybridization analysis demonstrated ALK rearrangement. Subsequent next-generation sequencing (RNA-seq) identified a rare PLEKHH2exon6::ALKexon20 fusion. This study further demonstrates the importance of molecular profiling in identifying kinase fusion-positive soft tissue tumors, particularly for those that arise at unusual sites and display atypical cytomorphology. [ABSTRACT FROM AUTHOR]

Lung cancer is the leading cause of cancer-related morbidity and mortality. The median survival time for patients with advanced non-small-cell lung cancer before the era of molecular-based personalized treatment was 7.9 months. The discovery of predictive factors and the introduction of molecular diagnostics into daily practice made a breakthrough, enabling several years of survival in patients with advanced disease. The discovery of rearrangements in the ALK gene and ALK tyrosine kinase inhibitors has resulted in a dramatic improvement in the prognosis of patients with this subtype of cancer. Currently, three generations of ALK inhibitors differing in activity, toxicity and degree of penetration into the central nervous system are available in clinical practice. The current state of knowledge on ALK inhibitors used in clinical practice is summarised in this research paper. Methods of diagnosis of abnormalities in ALK have been shown, and the review of research that contributed to the development of the next generation of ALK inhibitors has been presented. [ABSTRACT FROM AUTHOR]

Crizotinib, as the first‐generation of anaplastic lymphoma kinase (ALK) inhibitor, effectively improves the survival time of ALK‐positive non‐small cell lung cancer (NSCLC) patients. However, its efficacy is severely limited by drug resistance caused by secondary mutations. G1202R and L1196M are classical mutation sites located in ALK kinase domain. They may hinder the binding of ALK inhibitors to the target kinase domain, resulting in drug resistance in patients. However, the exact mechanism of drug resistance mediated by these mutations remains unclear. In this study, we aimed to evaluate how G1202R and L1196M mutations mediate crizotinib resistance. To explore the resistance mechanism, we constructed EML4‐ALK G1202R and L1196M mutant cell lines with A549 cells. The results showed that the mutant cells exhibited significant epithelial–mesenchymal transition (EMT) and metastasis compared to control (A549‐vector) or wild type (A549‐EML4‐ALK) cells. Subsequently, it was found that the occurrence of EMT was correlated to the high expression of murine double minute 2 (MDM2) protein and the activation of mitogen‐activated protein kinase (MEK)/extracellular signal‐regulated kinase (ERK) pathway in mutant cells. Down‐regulation of MDM2 inhibited the activation of MEK/ERK pathway, thus reversed the EMT process and markedly increased the inhibitory effect of crizotinib on the growth of mutant cells. Collectively, resistance of ALK‐positive NSCLC cells to crizotinib is induced by G1202R and L1196M mutations through activation of the MDM2/MEK/ERK signalling axis, promoting EMT process and metastasis. These findings suggest that the combination of MDM2 inhibitors and crizotinib could be a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

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

Background: Adenocarcinoma with positive echinoderm microtubuleassociated protein-like 4 gene and anaplastic lymphoma kinase (EML4-ALK) gene fusion accounts for 3-7% of lung cancer cases and can be targeted with ALK tyrosine kinase inhibitors (TKIs). Second-generation TKIs are the standard of care for targeted populations, especially those with central nervous system (CNS) metastasis. However, most patients eventually experience disease progression because of drug resistance caused by multiple mechanisms, predominantly secondary mutations. Case description: We present a female advanced non-small cell lung cancer (NSCLC) case with positive EML4-ALK gene fusion, in which disease progression occurred in only 3 months after first-line treatment with alectinib. Two secondary mutations were detected by next-generation sequencing; one was V1180L located in exon 23, and the other was E803Q located in exon 14, which was a novel mutation that had never been reported. Ensartinib and ceritinib were administered as second-line and third-line treatments. However, the response to these TKIs was poor, and her overall survival was only 7 months. Conclusion: The secondary mutation E803Q located in exon 14 seems resistant to most second-generation ALK-TKIs. If there is an opportunity, the efficacy of the third-generation ALK-TKI loratinib should be tested. [ABSTRACT FROM AUTHOR]

Pulmonary mucoepidermoid carcinoma (PMEC) is a rare tumor with limited clinical data available due to its low incidence. So far, there are no universal treatment guidelines for this malignant tumor. We present here the case of a 59-year-old female never smoker who was initially referred to our hospital with cough and hemoptysis and was eventually diagnosed with PMEC. Based on further genetic testing, echinoderm microtubule-associated protein-like-4-anaplastic lymphoma kinase (EML4-ALK) fusion variants E20:A20 (V2) was found. The patient was treated with lorlatinib as the first-line treatment. This case is the first to describe the effectiveness of lorlatinib in treating an advanced high-grade PMEC with EML4-ALK fusion V2 mutation patient. [ABSTRACT FROM AUTHOR]

Epithelioid inflammatory myofibroblastic sarcoma (EIMS) is an extremely rare and aggressive form of inflammatory myofibroblastic tumor. Clinically, it has a high risk of relapse and peripheral organ infiltration, and it responds poorly to conventional chemotherapy. Anaplastic lymphoma kinase (ALK) inhibitors are currently the most effective targeted therapy for EIMS. This report discusses a typical case of abdominal EIMS in a 43-year-old woman. The tumors recurred rapidly within one month after surgery. Alectinib was promptly administered upon diagnosis. However, the patient developed a severe allergic reaction to the medication. After a comprehensive assessment and symptomatic treatment, her condition stabilized, leading to a favorable prognosis. This study summarizes cases of abdominal EIMS, highlights the successful use of Alectinib for treatment, and discusses the management of medication-related complications. [ABSTRACT FROM AUTHOR]

Background: Distant metastases from lung cancer are commonly found in the brain, bone, and liver. Metastases to the breast from non-mammary malignancies are extremely rare, and their clinical presentations remain unclear. Case presentation: We herein report a case of bilateral breast metastases from anaplastic lymphoma kinase-positive advanced lung cancer in a 51-year-old Japanese male patient. During the course of systemic treatment for advanced lung cancer, computed tomography revealed bilateral breast enlargement without contrast enhancement, a finding consistent with gynecomastia. While other metastatic lesions responded to chemotherapy, both breast masses grew vertically like nodules. The breast masses were immunohistochemically diagnosed as metastases from lung cancer and were removed surgically. Simultaneous bilateral breast metastases from malignancies of other organs, like ones in this case, have rarely been described. Conclusions: It is important to keep in mind that breast metastases from nonmammary malignancies are a possible explanation for unusual breast findings in a patient with a history of malignancies. [ABSTRACT FROM AUTHOR]

Objective: To discuss the effects of 5-aza-2'-deoxycytidine (5-Aza-CdR) on autophagy and apoptosis of the TPC-1 cells in subcutaneous xenograft tumor tissue of the nude mice, and to clarify its mechanism. Methods: Sixteen female BALB/c nude mice were inoculated with human papillary thyroid carcinoma (PTC) TPC-1 cells in the right axilla to establish the xenograft tumor model. After tumor formation, the mice were randomly divided into control group and experiment group (n=8). The nude mice in control group were given an intraperitoneal injection of saline, while the nude mice in experiment group were given the intraperitoneal injection of 5-Aza-CdR, administered once every other day for four weeks. The growth status of xenograft tumor of the mice in both groups was observed, and the mice were sacrificed after the final administration and the tumor weights of the nude mice in two groups were detected. HE staining was used to observe the pathomorphology of xenograft tumor tissue of the nude mice in both groups; immunohistochemistry was used to detect the expression levels of microtubule-associated protein light chain 3 (LC3), B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) in xenograft tumor tissue of the nude mice in two groups; real-time fluorescence quantitative PCR (RT-qPCR) and Western blotting methods were used to detect the expression levels of LC3, Beclin-1, Bcl-2, Bax, mitogenactivated protein kinase kinase (MEK), extracellular signal-regulated kinase 1 (ERK1), extracellular signal-regulated kinase 2 (ERK2), phosphorylated EPK1 (p-ERK1), and phosphorylated EPK2 (p-ERK2) mRNA and proteins in xenograft tumor tissue of the nude mice in two groups. Results: Compared with control group, the tumor volume and weight of the nude mice in experiment group were significantly decreased (P<0. 01). The number of cancer cells of the nude mice in control group was high, and the cells were densely arranged, with irregular shapes, clear nuclear staining, large overlapping nuclei, and lobulation, showing significant pathological mitotic figures consistent with PTC pathological characteristics. The number of cancer cells of the nude mice in experiment group showed a significant decresing trend, and the cells were sparse arrangement, nuclear shrinkage, and less distinct nuclei, with a significant increase in connective tissue. Compared with control group, the expression levels of LC3B and Beclin-1 mRNA and proteins in xenograft tumor tissue of the nude mice in experiment group were significantly increased (P<0. 05) and the ratio of and Bax/Bcl-2 was increased (P<0. 05 or P<0. 01), while the expression levels of MEK, ERK1/2, and p-ERK1/2 mRNA and proteins were significantly decreased (P<0. 05 or P<0. 01). Conclusion: 5-Aza-CdR can inhibit the growth of TPC-1 cells in subcutaneous xenograft tumor tissue of the nude mice, induce the autophagy, and promote the apoptosis of the tumor cells. The mechanism may be related to the inhibition of the mitogen-activated protein kinase (MAPK) /MEK/ extracellular signal-regulated kinase (ERK) signaling pathways. [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]

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

Crizotinib (CRZ), one of anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), has emerged as a frontline treatment for ALK-positive (ALK+) lung adenocarcinoma. However, the overexpression of P-glycoprotein (P-gp, a mitochondrial adenosine triphosphate (ATP)-dependent protein) in lung adenocarcinoma lesions causes multidrug resistance (MDR) and limits the efficacy of CRZ treatment. Herein, a mitochondria-targeting nanosystem, zeolitic imidazolate framework-90@indocyanine green (ZIF-90@ICG), was fabricated to intervene in mitochondria and overcome drug resistance. Due to the zinc ion (Zn2+) interference of ZIF-90 and the photodynamic therapy (PDT) of ICG, this nanosystem is well suited for damaging mitochondrial functions, thus downregulating the intracellular ATP level and inhibiting P-gp expression. In addition, systematic bioinformatics analysis revealed the upregulation of CD44 in CRZ-resistant cells. Therefore, hyaluronic acid (HA, a critical target ligand of CD44) was further modified on the surface of ZIF-90@ICG for active targeting. Overall, this ZIF-90@ICG nanosystem synergistically increased the intracellular accumulation of CRZ and reversed CRZ resistance to enhance its anticancer effect, which provides guidance for nanomedicine design to accurately target tumours and induce mitochondrial damage and represents a viable regimen for improving the prognosis of patients with ALK-TKIs resistance. The original aim of our research was to combat multidrug resistance (MDR) in highly aggressive and lethal lymphoma kinase-positive (ALK+) lung adenocarcinoma. For this purpose, a cascade-targeted system was designed to overcome MDR, integrating lung adenocarcinoma-targeted hyaluronic acid (HA), mitochondrion-targeted zeolitic imidazolate framework-90 (ZIF-90), the clinically approved drug crizotinib (CRZ), and the fluorescence imaging agent/photosensitizer indocyanine green (ICG). Moreover, using a "two birds with one stone" strategy, ion interference and oxidative stress induced by ZIF-90 and photodynamic therapy (PDT), respectively, disrupt mitochondrial homeostasis, thus downregulating adenosine triphosphate (ATP) levels, inhibiting MDR-relevant P-glycoprotein (P-gp) expression and suppressing tumour metastasis. Overall, this research represents an attempt to implement the concept of MDR reversal and realize the trade-offs between MDR and therapeutic effectiveness. [Display omitted] [ABSTRACT FROM AUTHOR]

The discovery of epinephrine (adrenaline) and its subsequent implications in medicine owes significant contributions to Cybulski across different centuries, who, in 1894, was pivotal in identifying the adrenal medulla's role in blood pressure regulation and naming the active substance "nadnerczyna", known today as adrenaline. His work demonstrated the adrenal glands' critical function in the body's regulatory mechanisms beyond the nervous system. Cybulski's groundbreaking research laid foundational knowledge for future endocrinological studies and pharmaceutical advancements. In the late 20th century, Andruszkiewicz collaborated with Silverman at Northwestern University to develop pregabalin, the active ingredient in Lyrica. Their innovative synthesis of gamma-aminobutyric acid derivatives led to a significant advancement in treating epilepsy, neuropathic pain, and fibromyalgia. Andruszkiewicz's expertise in organic chemistry and enzymology was crucial in this collaborative effort, resulting in the successful development and commercialization of Lyrica. Additionally, Mroczkowski's leadership at Pfizer contributed to the development of crizotinib, a notable anaplastic lymphoma kinase and proto-oncogene 1 tyrosine-protein kinase inhibitor used to treat specific types of non-small cell lung cancer. Her work exemplifies the continuing influence of Polish researchers in pioneering drug discovery and advancing therapeutic treatments over the past three centuries. These contributions highlight Poland's significant role in global pharmaceutical innovations and medical research. [ABSTRACT FROM AUTHOR]

Abstract Background Screening for anaplastic lymphoma kinase (ALK) rearranged non‐small cell lung cancer (NSCLC) is crucial for identifying patients eligible for targeted therapy. The FDA‐approved ALK (D5F3) immunohistochemistry (IHC) assay, used with the OptiView Amplification Kit, demonstrates excellent sensitivity and specificity in detecting these patients. However, the clinical significance of resulting focal positivity remains unclear, and ALK (D5F3) expression unrelated to ALK fusion is observed in some cases of neuroendocrine differentiation. This study aims to validate these findings with molecular testing and contribute to the accurate interpretation of ALK (D5F3) IHC results. Methods A total of 1619 patients diagnosed with NSCLC and neuroendocrine carcinoma were evaluated using ALK (D5F3) IHC. For cases with strong but focal expression and those with diffuse strong positivity in neuroendocrine differentiation, ALK fluorescence in situ hybridization (FISH) and/or next‐generation sequencing (NGS) tests were performed. Results Seven out of 1109 adenocarcinomas (0.6%) and six out of 289 squamous cell carcinomas (2.1%) exhibited strong focal ALK (D5F3) expression. Nine out of 209 neuroendocrine carcinomas (4.3%) showed homogeneously strong ALK (D5F3) expression. All these cases, including adenocarcinoma with neuroendocrine differentiation and combined small cell carcinoma, were negative for ALK fusions by FISH and/or NGS. Conclusion This study demonstrates that strong but focal ALK (D5F3) immunostaining and strong expression in neuroendocrine differentiation may not indicate ALK fusion. By considering these findings, we can improve the accuracy of patient selection for targeted therapy by minimizing false‐positive interpretations of ALK (D5F3) staining.

Abstract Background Anaplastic lymphoma kinase (ALK) test in advanced non‐small cell lung cancer (NSCLC) can help physicians provide target therapies for patients harboring ALK gene rearrangement. This study aimed to investigate the real‐world test patterns and positive rates of ALK gene rearrangements in advanced NSCLC. Methods In this real‐world study (ChiCTR2000030266), patients with advanced NSCLC who underwent an ALK rearrangement test in 30 medical centers in China between October 1, 2018 and December 31, 2019 were retrospectively analyzed. Interpretation training was conducted before the study was initiated. Quality controls were performed at participating centers using immunohistochemistry (IHC)‐VENTANA‐D5F3. The positive ALK gene rearrangement rate and consistency rate were calculated. The associated clinicopathological characteristics of ALK gene rearrangement were investigated as well. Results The overall ALK gene rearrangement rate was 6.7% in 23,689 patients with advanced NSCLC and 8.2% in 17,436 patients with advanced lung adenocarcinoma. The quality control analysis of IHC‐VENTANA‐D5F3 revealed an intra‐hospital consistency rate of 98.2% (879/895) and an inter‐hospital consistency rate of 99.2% (646/651). IHC‐VENTANA‐D5F3 was used in 53.6%, real‐time polymerase chain reaction (RT‐PCR) in 25.4%, next‐generation sequencing (NGS) in 18.3%, and fluorescence in‐situ hybridization (FISH) in 15.9% in the adenocarcinoma subgroup. For specimens tested with multiple methods, the consistency rates confirmed by IHC‐VENTANA‐D5F3 were 98.0% (822/839) for FISH, 98.7% (1,222/1,238) for NGS, and 91.3% (146/160) for RT‐PCR. The overall ALK gene rearrangement rates were higher in females, patients of ≤ 35 years old, never smokers, tumor cellularity of > 50, and metastatic specimens used for testing in the total NSCLC population and adenocarcinoma subgroup (all P < 0.05). Conclusions This study highlights the real‐world variability and challenges of ALK test in advanced NSCLC, demonstrating a predominant use of IHC‐VENTANA‐D5F3 with high consistency and distinct clinicopathological features in ALK‐positive patients. These findings underscore the need for a consensus on optimal test practices and support the development of refined ALK test strategies to enhance diagnostic accuracy and therapeutic decision‐making in NSCLC.

Epithelioid inflammatory myofibroblastic sarcoma, a variant of the inflammatory myofibroblastic tumor, is a rare tumor that is not well described in the radiologic literature. We present a case of a 14-year-old male adolescent who presented with fever, fatigue, and weight loss symptoms and was found to have an abdominal mass on contrast enhanced CT. Initial differentials included lymphoma, pheochromocytoma, desmoid, and sarcoma, and pathological evaluation revealed an epithelioid inflammatory myofibroblastic sarcoma. The mass was separate from the surrounding structures of the left upper abdomen with unique radiologic features not previously described in the literature. Prior literature examples of epithelioid inflammatory myofibroblastic sarcoma described a heterogenous, enhancing lobulated mass, and our case was a lobulated, avidly enhancing homogenous mass on CT with surrounding inflammation and avid uptake on PET/CT. In addition to the imaging features, we describe the surgical findings, the pathologic features of the tumor, and the oncologic treatment of this patient. This case highlights the importance of including rare tumors such as epithelioid inflammatory myofibroblastic sarcoma as a potential differential consideration of an avidly enhancing homogenous abdominal mass in an adolescent.

Background: Lung cancer (LC) is one of the most common neoplastic diseases and a leading cause of death in Saudi Arabia. Its incidence in Saudi Arabia has increased by more than 3% within two decades. Our study aimed to describe the epidemiological and genetic landscapes of LC in Al-Madinah city in Saudi Arabia. Methods: A retrospective analysis was conducted on the medical records of 65 patients diagnosed with lung cancer between 2015 and 2021 at a single medical oncology center in Al-Madinah city of Saudi Arabia. Results: The mean patients' age was 59.2 years, with 50 (76.9%) males and 15 (23.1%) females; 37 (57%) smokers, and 28 (43%) non-smokers. The number of cases per year has increased gradually over six years from 2015 (n = 3) to 2020 (n = 13). The most prevalent histopathological diagnosis was non-small cell lung cancer (NSCLC) (n = 58, 89%) followed by small cell lung cancer (SCLC) (n = 5, 7.8%). NSCLC was frequently more common in smokers while squamous cell carcinoma was more frequent in non-smokers. Around 89% (n = 58) of the cases were diagnosed in late stage IV and the most common metastatic sites were to pleura and lymph nodes (n = 32, 49.2%). Program Death Legend-1 (PDL-1) was fairly expressed in 7/10 (70%) patients. Epidermal Growth Factor Receptor (EGFR) was mutated in 5/17 (29%) patients. Other mutations detected include Anaplastic Lymphoma Kinase (ALK) and phosphatidylinositol 3-kinase (PIK3C) mutations in two patients. Conclusions: Our study revealed that lung cancer is a significant burden in Al-Madinah city of Saudi Arabia. If the risk factors are not controlled, the number of cases may increase considerably. Health education about the risk factors and cancer prevention helps in early lung cancer detection. [ABSTRACT FROM AUTHOR]

Aims: Chondromyxoid fibroma (CMF) is a rare, benign bone tumour which arises primarily in young adults and is occasionally diagnostically challenging. Glutamate metabotropic receptor 1 (GRM1) gene encodes a metabotropic glutamate receptor and was recently shown to be up‐regulated in chondromyxoid fibroma through gene fusion and promoter swapping. The aim of this study was to interrogate cases of CMF for the presence of GRM1 gene rearrangements, gene fusions and GRM1 protein overexpression. Methods and results: Selected cases were subjected to testing by fluorescent in‐situ hybridisation (FISH) with a GRM1 break‐apart probe, a targeted RNA sequencing method and immunohistochemical study with an antibody to GRM1 protein. Two cases were subjected to whole transcriptomic sequencing. In 13 of 13 cases, GRM1 protein overexpression was detected by immunohistochemistry using the GRM1 antibody. Of the 12 cases successfully tested by FISH, nine of 12 showed GRM1 rearrangements by break‐apart probe assay. Targeted RNA sequencing analysis did not detect gene fusions in any of the eight cases tested, but there was an increase in GRM1 mRNA expression in all eight cases. Two cases subjected to whole transcriptomic sequencing (WTS) showed elevated GRM1 expression and no gene fusions. Conclusion: GRM1 gene rearrangements can be detected using FISH break‐apart probes in approximately 75% of cases, and immunohistochemical detection of GRM1 protein over‐expression is a sensitive diagnostic method. The gene fusion was not detected by targeted RNA sequencing, due most probably to the complexity of fusion mechanism, and is not yet a reliable method for confirming a diagnosis of CMF in the clinical setting. [ABSTRACT FROM AUTHOR]

Aim: To report the efficacy and safety of ensartinib, an anaplastic lymphoma kinase (ALK) inhibitor, in treating patients with ALK‐positive advanced lung squamous cell carcinoma (LUSC) or lung adenosquamous carcinoma (LASC) in China. Methods: This retrospective study analyzed data for 36 advanced‐stage patients with ALK‐positive LUSC (cohort A) and 13 patients with ALK‐positive LASC (cohort B) between December 16, 2020 and December 16, 2021. All patients received once‐daily ensartinib 225 mg. Outcome analysis included the demographic characteristics, tumor response, progression‐free survival (PFS), and treatment‐related adverse events (TRAE). Results: Among the 49 patients, the majority were under 65 years old (73.5%), non‐smokers (85.7%), had an Eastern Cooperative Oncology Group Performance Status of 0–1 (77.6%), and were at stage IV (71.4%). All patients were included in the efficacy and safety analysis. Seven PFS events were reported in cohort A while no patients experienced PFS events in cohort B. The median PFS was not estimable for both cohorts. In cohort A, the objective response rate (ORR) was 63.9%, and the disease control rate (DCR) was 83.3%. In the cohort B, the ORR was 76.9% and the DCR was 100.0%. Rash was the only TRAE reported in the cohort A (8.3%) and cohort B (23.1%). No patients had grade 3 or higher TRAE. Conclusion: Ensartinib has been tentatively proven favorable efficacy and tolerability in the treatment of patients with ALK‐positive advanced LUSC or LASC in the real‐world. However, confirmatory studies are still needed in larger sample sizes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Inflammatory myofibroblastic tumor (IMT) is an intermediate malignant neoplasm, and approximately 50% of patients are anaplastic lymphoma kinase positive (ALK+). Given this unique trait, ALK tyrosine kinase inhibitors (TKIs), initially developed for ALK+ nonsmall cell lung carcinoma, were expected to be effective. Subsequently, crizotinib, a first-generation ALK-TKI, was approved by the U. S. Food and Drug Administration, and other generations of ALK-TKIs have since been tested for their efficacy. In this study, we report a case of unresectable IMT who showed a partial response to ceritinib, a second-generation ALK-TKI, allowing conversion surgery to be performed. Furthermore, the patient was found to have a rare ALK translocation, sequestosome 1 (5)-ALK (20), detected by next-generation sequencing. In conclusion, this case presents real-world evidence to establish the role of ceritinib as a first-line treatment for ALK+ IMT, which can contribute to further studies on ALK+ IMT.

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

PURPOSE: Patients with metastatic or advanced non–small cell lung cancer (NSCLC) need biomarker testing, including, in most cases, anaplastic lymphoma kinase (ALK), epidermal growth factor receptor (EGFR), and PD-L1, to identify options for targeted therapies and to optimally incorporate immune checkpoint inhibitors into therapeutic regimens. We sought to examine real-world patterns of biomarker testing, quantify interphysician practice variation, and correlate testing with clinical outcomes. METHODS: We extracted real-world data from a nationwide electronic health record–derived deidentified database from 17,165 patients diagnosed with advanced NSCLC between 2018 and 2021 and receiving care in the community setting. We analyzed data using descriptive analyses, fixed- and mixed-effects logistic regression models, and proportional hazard models. RESULTS: Only 67% of all 17,165 patients and 77% of patients with nonsquamous, metastatic NSCLC had ALK, EGFR, and PD-L1 testing within 90 days of diagnosis. Later diagnosis year (2019-2021 compared with 2018) was associated with higher rates of ALK, EGFR, and PD-L1 testing; stage IIIB/C disease (compared with stage IV), squamous histology, and Black or African American race were associated with lower rates. Interphysician variation was substantial with a median odds ratio between physicians (adjusted for patient factors) of 1.78 for ALK, EGFR, and PD-L1 testing. Patients with nonsquamous, metastatic NSCLC had significantly prolonged survival if tested with all three biomarkers (median, 364 days for all three v 180 for none of the three; hazard ratio, 0.67; P <.001). CONCLUSION: Rates of biomarker testing appear suboptimal with substantial interphysician variation. Testing correlates with improved survival, although causality cannot be proven from this study. Additional work is needed to address the underlying causes of suboptimal test ordering. [ABSTRACT FROM AUTHOR]

Ophiuroids, the most diverse group of echinoderms, inhabit a vast array of ecological niches and play vital roles in benthic ecosystems as suspension feeders, scavengers and opportunists. Despite the important ecological roles played by Ophiuroidea, their evolutionary history and phylogenetic relationship is not yet fully understood. In this study, 47 mitochondrial genomes of ophiuroids, including 21 newly sequenced ones, were analyzed. tRNA duplication was firstly discovered in four species and a new start codon was identified for Ophiuroidea. Eighteen phylogenetic trees based on mitochondrial genomes consistently supported two major lineages, Ophintegrida and Euryophiurida. It further confirmed the monophyly of Euryalida and Ophiurida, respectively, as well as families represented by multiple species. Among 18 trees, only the two ML trees based on amino acid sequences using IQtree method supported monophyly of Amphilepidida and Ophiacanthida, consistent with current phylogenetic system of Ophiuroidea. This result highlighted the effect of phylogenetic analysis methods and datasets on tree topology, indicating that amino acid sequence data maybe more suitable for higher taxonomic level phylogenetic analysis of ophiuroids than nucleotide sequences. Four new gene orders of 13 proteincoding genes + two rRNAs and 12 new gene orders of all 37 genes were identified. Mitochondrial gene orders were highly variable in Ophiacanthida, but were extremely conserved in Eurylida. Additionally, both branch lengths and estimated positive selection varied among the four orders, and a positive relationship between branch lengths and mitochondrial gene rearrangement rates was revealed, suggesting distinctly different evolutionary history among the four major clades of Ophiuroidea. Overall, we (1) reconstructed the phylogenetic relationship based on mitochondrial genome, supporting the current phylogenetic system in Ophiuroidea, (2) revealed a high variability in mitochondrial gene rearrangement among the four orders, (3) provided the first evidence to link gene rearrangement and nucleotide substitution in Echinodermata. [ABSTRACT FROM AUTHOR]

Introduction: Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) are at increased risk of central nervous system (CNS) metastasis at initial diagnosis and throughout treatment. In a phase 3 trial, lorlatinib, a third-generation ALK tyrosine kinase inhibitor, significantly improved progression-free survival. In further analysis, lorlatinib revealed superior intracranial efficacy and prolonged time to intracranial progression compared with crizotinib. Case Presentation: Herein, we report a case of ALK-positive NSCLC with leptomeningeal metastasis that was successfully treated with lorlatinib after progression to brigatinib and alectinib. This case demonstrates the potential of lorlatinib in managing leptomeningeal metastasis in ALK-positive NSCLC. Conclusion: The case suggests a paradigm shift in therapeutic approaches for CNS metastasis, including brain and leptomeningeal metastases. [ABSTRACT FROM AUTHOR]

In recent years, significant improvement has been made in the management of non‐small cell lung cancer (NSCLC), primarily driven by advances in targeted therapy and immunotherapy. Research on neoadjuvant targeted therapy has also experienced considerable development, primarily directed towards NSCLC harboring epidermal growth factor receptor or anaplastic lymphoma kinase mutations. Nevertheless, there remains a dearth of studies investigating neoadjuvant targeted therapy in the context of BRAF (V‐Raf murine sarcoma viral oncogene homolog B) V600E mutant NSCLC. Herein, we describe the clinical trajectory of a stage IIIA NSCLC patient who underwent a two‐month course of neoadjuvant targeted therapy comprising BRAF and MEK (mitogen‐activated extracellular signal‐regulated kinase) inhibitors prior to surgical intervention, and subsequent postoperative evaluation unveiled a pathological complete response. The case reported here indicates the efficacy and safety of combining BRAF and MEK inhibitors as neoadjuvant targeted therapy in BRAF V600E‐mutant NSCLC and suggests the potential viability of such a therapeutic modality in improving treatment outcomes in this subset of NSCLC. [ABSTRACT FROM AUTHOR]

Background: Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is a rare malignancy. Many cases of BIA-ALCL are identified based on the presence of late-onset effusion and/or masses. Importantly, the United States Food and Drug Administration noted that in all cases diagnosed in patients with textured implants, the patients either had a history of mixed implantation of smooth and textured devices or no clinical history was supplied for review. In Japan, the first case of BIA-ALCL was reported in 2019, and we encountered the third case in Japan in December 2021. There have been a total of five cases of BIA-ALCL previously reported at Japanese academic conferences (Japan Oncoplastic Breast Surgery Society. http://jopbs.umin.jp/medical/index.html), of which only the first case has been published. Unlike the first case, this patient had clinical features that were highly suggestive of the postoperative chest wall recurrence of breast cancer, with a mass and rash on the skin. Case presentation: The patient was a 45-year-old woman who had undergone breast reconstruction after breast cancer surgery of the right breast 8 years previously. The patient presented with a mass and skin rash inside the inframammary area, and we suspected a damaged silicone breast implant (SBI) or chest wall recurrence. We examined the mass by a core needle biopsy and made a pathological diagnosis of BIA-ALCL. Imaging findings suggested internal thoracic lymph node swelling and lymphoma infiltration beyond the capsule but no metastatic lesions (cStage III). After en bloc resection of the SBI and lymphoma, adjuvant systemic therapy was performed. Conclusion: We encountered the third case of BIA-ALCL in Japan. This was a case with clinically advanced stage of disease; however, the BIA-ALCL was found to be in remission. [ABSTRACT FROM AUTHOR]