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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]

Therapeutic strategies for early-stage non-small cell lung cancer (NSCLC) are advancing, with immune checkpoint inhibitors (ICIs) and targeted therapies making their way into neoadjuvant and adjuvant settings. With recent advances, there was a need for multidisciplinary lung cancer healthcare providers from across Ontario to convene and review recent data from practical and implementation standpoints. The focus was on the following questions: (1) To what extent do patient (e.g., history of smoking) and disease (e.g., histology, tumor burden, nodal involvement) characteristics influence treatment approaches? (2) What are the surgical considerations in early-stage NSCLC? (3) What is the role of radiation therapy in the context of recent evidence? (4) What is the impact of biomarker testing on treatment planning? Ongoing challenges, treatment gaps, outstanding questions, and controversies with the data were assessed through a pre-meeting survey, interactive cases, and polling questions. By reviewing practice patterns across Ontario cancer centers in the context of evolving clinical data, Health Canada indications, and provincial (Cancer Care Ontario [CCO]) funding approvals, physicians treating lung cancer voiced their opinions on how new approaches should be integrated into provincial treatment algorithms. This report summarizes the forum outcomes, including pre-meeting survey and polling question results, as well as agreements on treatment approaches based on specific patient scenarios.

Abstract 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.

Simple Summary: Chimeric transcripts frequently function as oncogenic drivers and represent potential targets for tumor-specific therapies. Routine methods for detecting these transcripts include (i) approaches that can detect a limited number of pre-defined targets, such as immunohistochemistry, fluorescence in situ hybridization, and reverse transcription–quantitative polymerase chain reaction, and (ii) approaches that can simultaneously detect multiple fusions, such as NanoString assays and NGS targeted panels. Whole transcriptome sequencing enables the analysis of a wide range of cancer biomarkers, including dysregulated genes, molecular pathways, and both known and novel cancer driver fusion transcripts. However, this method is not commonly employed for fusion discovery due to inadequate coverage at the fusion breakpoint. To address this limitation, we have developed a novel bioinformatics approach that enables the highly accurate prediction of clinically significant ALK fusions from RNA sequencing data. This extends the functionality of whole transcriptome NGS and improves its cost-effectiveness. Background: In clinical practice, various methods are used to identify ALK gene rearrangements in tumor samples, ranging from "classic" techniques, such as IHC, FISH, and RT-qPCR, to more advanced highly multiplexed approaches, such as NanoString technology and NGS panels. Each of these methods has its own advantages and disadvantages, but they share the drawback of detecting only a restricted (although sometimes quite extensive) set of preselected biomarkers. At the same time, whole transcriptome sequencing (WTS, RNAseq) can, in principle, be used to detect gene fusions while simultaneously analyzing an incomparably wide range of tumor characteristics. However, WTS is not widely used in practice due to purely analytical limitations and the high complexity of bioinformatic analysis, which requires considerable expertise. In particular, methods to detect gene fusions in RNAseq data rely on the identification of chimeric reads. However, the typically low number of true fusion reads in RNAseq limits its sensitivity. In a previous study, we observed asymmetry in the RNAseq exon coverage of the 3′ partners of some fusion transcripts. In this study, we conducted a comprehensive evaluation of the accuracy of ALK fusion detection through an analysis of differences in the coverage of its tyrosine kinase exons. Methods: A total of 906 human cancer biosamples were subjected to analysis using experimental RNAseq data, with the objective of determining the extent of asymmetry in ALK coverage. A total of 50 samples were analyzed, comprising 13 samples with predicted ALK fusions and 37 samples without predicted ALK fusions. These samples were assessed by targeted sequencing with two NGS panels that were specifically designed to detect fusion transcripts (the TruSight RNA Fusion Panel and the OncoFu Elite panel). Results: ALK fusions were confirmed in 11 out of the 13 predicted cases, with an overall accuracy of 96% (sensitivity 100%, specificity 94.9%). Two discordant cases exhibited low ALK coverage depth, which could be addressed algorithmically to enhance the accuracy of the results. It was also important to consider read strand specificity due to the presence of antisense transcripts involving parts of ALK. In a limited patient sample undergoing ALK-targeted therapy, the algorithm successfully predicted treatment efficacy. Conclusions: RNAseq exon coverage analysis can effectively detect ALK rearrangements. [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]

Therapeutic strategies for early-stage non-small cell lung cancer (NSCLC) are advancing, with immune checkpoint inhibitors (ICIs) and targeted therapies making their way into neoadjuvant and adjuvant settings. With recent advances, there was a need for multidisciplinary lung cancer healthcare providers from across Ontario to convene and review recent data from practical and implementation standpoints. The focus was on the following questions: (1) To what extent do patient (e.g., history of smoking) and disease (e.g., histology, tumor burden, nodal involvement) characteristics influence treatment approaches? (2) What are the surgical considerations in early-stage NSCLC? (3) What is the role of radiation therapy in the context of recent evidence? (4) What is the impact of biomarker testing on treatment planning? Ongoing challenges, treatment gaps, outstanding questions, and controversies with the data were assessed through a pre-meeting survey, interactive cases, and polling questions. By reviewing practice patterns across Ontario cancer centers in the context of evolving clinical data, Health Canada indications, and provincial (Cancer Care Ontario [CCO]) funding approvals, physicians treating lung cancer voiced their opinions on how new approaches should be integrated into provincial treatment algorithms. This report summarizes the forum outcomes, including pre-meeting survey and polling question results, as well as agreements on treatment approaches based on specific patient scenarios. [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]

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

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

Objective: The Epidermal Growth Factor Receptor (EGFR) is mutated in 15% of lung adenocarcinomas. Eight percent of instances with altered Anaplastic Lymphoma Kinase (ALK) are caused by lung adenocarcinomas. For tumours of Non-Small Cell Lung Cancer (NSCLC) that are EGFR mutant and ALK translocation positive, Tyrosine Kinase Inhibitor therapy (TKI therapy) has changed treatment and produced a remarkable preventive effect. Unfortunately, TKI resistance always appears to spread. To overcome the resistance, numerous innovative and promising medicines are being studied. Results: First-line, recognized opposition, and adjuvant treatment is being investigated for NSCLC with EGFR mutation and ALK positivity, along with the therapeutic implications of recent national meetings and beginning research. Conclusion: There is a signi icant therapeutic advantage to including EGFR TKIs in EGFR mutant NSCLC First Line (FL) therapy. In phase II and III studies, several possible third-generation EGFR TKIs are being examined in the context of acquired resistance. The medicine is better than chemotherapy as an FL treatment for NSCLC with ALK positivity. For NSCLC with established resistance and an ALK-positive test result, cetinib is approved and effective. More study is needed to develop new medications that can combat acquired resistance to TKIs. [ABSTRACT FROM AUTHOR]

T-cell lymphoma is an extremely rare form of malignancy in the female genital tract. Most of the reported cases of lymphoma are B-cell lymphomas. A few cases of primary T-cell lymphomas involving the vagina or the vulva have been reported. We are reporting the first case of anaplastic large cell lymphoma (ALCL) presenting as a uterine cervical mass. The patient is a 24-year-old female who presented to the emergency room with a history of menorrhagia, night sweats and 40-pound weight loss. The diagnosis of ALCL was confirmed through immunohistochemical studies with strong CD30 and ALK expression. Fluorescent hybridization showed a rearrangement of the anaplastic lymphoma kinase (ALK) gene. Since ALCL may have a variable expression of T-cell antigens, the diagnosis may easily be missed when CD45 and/or CD3 is negative, and screening epithelial stains for carcinoma (e.g., p63 and EMA) are positive. CD30 must be performed to raise the consideration of ALCL when reniform nuclei are observed. [ABSTRACT FROM AUTHOR]

Abstract Background Few reports of inflammatory myofibroblastic tumor (IMT) of the breast have been published worldwide. Furthermore, primary anaplastic lymphoma kinase (ALK)-positive IMT of the breast is extremely rare. To date, only six patients with ALK-positive IMT have been reported in the literature. Case presentation A 52-year-old woman underwent a medical examination, and a left breast mass was detected. She did not feel a mass in her chest. Mammography showed a focal asymmetric density at the lower outer portion of the left breast. Breast ultrasonography showed a 1.2-cm hypoechoic lesion with relatively clear boundaries and poor blood flow. Magnetic resonance imaging and computed tomography revealed a solitary heterogeneous mass in the left breast. Pathologic examination revealed a fibrosing lesion with proliferation of fibroblastic cells arranged in a storiform pattern and admixed inflammatory cells. Immunohistochemical examination showed that the tumor cells were positive for ALK. Under the preoperative diagnosis of IMT, we performed partial mastectomy with adequate margins. The postoperative diagnosis was pathologically confirmed as IMT. Immunohistochemical staining also showed overexpression of ALK-1 in the tumor. The patient had a good clinical course for 24 months postoperatively, without recurrence or metastasis. Conclusions IMT of the breast shows nonspecific imaging findings, making preoperative diagnosis difficult. Nevertheless, IMT has the characteristics of low-grade neoplasms with recurrence, invasion, and metastatic potential. Our report emphasizes the importance of determining a treatment plan as soon as possible based on an accurate diagnosis to improve the prognosis of this disease.

Simple Summary: Anaplastic Lymphoma Kinase (ALK) is a protein linked to cancer growth. A review of scientific studies was conducted to understand ALK's role in certain brain tumors, particularly those not originating from glial cells (supportive cells in the brain) and located in the lower back part of the brain. From an initial pool of 992 studies, 16 were found to be relevant. These studies focused on 55 cases of tumors displaying ALK presence or ALK alterations, including medulloblastoma, lymphoma, histiocytosis, and other rare tumors. Studies mainly used tissue analysis and genetic testing to study ALK. Findings suggest that examining ALK can help in diagnosing and predicting the outcome of some of these brain tumors, especially medulloblastoma. Interestingly, many cases of brain histiocytosis (a rare condition) with ALK changes were found in this area. These findings point to the potential benefits of targeting ALK in treating certain brain tumors, a promising area for future research. Anaplastic Lymphoma Kinase (ALK) has been implicated in several human cancers. This review aims at mapping the available literature on the involvement of ALK in non-glial tumors localized in the posterior cranial fossa and at identifying diagnostic, prognostic, and therapeutic considerations. Following the PRISMA-ScR guidelines, studies were included if they investigated ALK's role in primary CNS, non-glial tumors located in the posterior cranial fossa. A total of 210 manuscripts were selected for full-text review and 16 finally met the inclusion criteria. The review included 55 cases of primary, intracranial neoplasms with ALK genetic alterations and/or protein expression, located in the posterior fossa, comprising of medulloblastoma, anaplastic large-cell lymphoma, histiocytosis, inflammatory myofibroblastic tumors, and intracranial myxoid mesenchymal tumors. ALK pathology was investigated via immunohistochemistry or genetic analysis. Several studies provided evidence for potential diagnostic and prognostic value for ALK assessment as well as therapeutic efficacy in its targeting. The available findings on ALK in posterior fossa tumors are limited. Nevertheless, previous findings suggest that ALK assessment is of diagnostic and prognostic value in medulloblastoma (WNT-activated). Interestingly, a substantial proportion of ALK-positive/altered CNS histiocytoses thus far identified have been localized in the posterior fossa. The therapeutic potential of ALK inhibition in histiocytosis warrants further investigation. [ABSTRACT FROM AUTHOR]

A 23-year-old female with a history of idiopathic epilepsy was found to have a right chest cavity shadow in a school health checkup 5 years before. CT revealed a thin-walled cavity lesion in the right middle lobe containing a ball-like mass, showing air crescent sign. After falling due to a seizure, she was transported by ambulance and admitted. CT revealed diffuse ground-glass opacities throughout the right lung field. Bronchoscopy revealed bloody bronchial alveolar lavage fluid. Due to the tumor hemorrhage, an elective simple right middle lobe resection was performed without complications. The initial immunohistochemical staining was negative for ALK using ALK1 clone; however, subsequent staining of ALK by D5F3 and 5A4 clone was positive. Immunostaining findings led to a diagnosis of inflammatory myofibroblastic tumor. The patient remains under regular observation and has experienced no recurrence over the 6-year postoperative period. This case contains two different points: the first is that a cavity lesion of inflammatory myofibroblastic tumor may cause traumatic bleeding and should be treated with caution; the second is that attention should be paid to differences in stainability among clones when diagnosing inflammatory myofibroblastic tumor.

Objective: The study sought to determine clinical characteristics and histologic subtypes of a cohort of lung cancer patients in a tertiary facility. Design: Retrospective review of the medical records of histology-confirmed lung cancer cases at the respiratory clinic over a 3-year period. Setting: Respiratory Clinic, Korle-Bu Teaching Hospital, Accra, Ghana. Participants: All adult patients with histologically diagnosed lung cancer were enrolled. Main outcome measures: Lung cancer histological types. Results: The proportion of lung cancer cases was 12.4%. The majority were women (57.8%) and the mean age at diagnosis was 55.8±16.0 years. The patients were predominantly non-smokers (61%). Common symptoms were chronic cough and chest pain. More than two-thirds of the cases presented in clinical stages III and IV with the predominant histological subtype being adenocarcinoma in smokers and non-smokers. Genetic testing for epidermal growth factor receptor (EGFR) and Anaplastic Lymphoma kinase (ALK) mutations were largely absent. Conclusions: The majority of lung cancer patients presented late with advanced disease. Adenocarcinoma was the predominant histological subtype in a predominantly non-smoking population, with an increased prevalence among women less than 60 years. This should encourage testing for genetic mutations to improve patient survival. [ABSTRACT FROM AUTHOR]

Background: Few reports of inflammatory myofibroblastic tumor (IMT) of the breast have been published worldwide. Furthermore, primary anaplastic lymphoma kinase (ALK)-positive IMT of the breast is extremely rare. To date, only six patients with ALK-positive IMT have been reported in the literature. Case presentation: A 52-year-old woman underwent a medical examination, and a left breast mass was detected. She did not feel a mass in her chest. Mammography showed a focal asymmetric density at the lower outer portion of the left breast. Breast ultrasonography showed a 1.2-cm hypoechoic lesion with relatively clear boundaries and poor blood flow. Magnetic resonance imaging and computed tomography revealed a solitary heterogeneous mass in the left breast. Pathologic examination revealed a fibrosing lesion with proliferation of fibroblastic cells arranged in a storiform pattern and admixed inflammatory cells. Immunohistochemical examination showed that the tumor cells were positive for ALK. Under the preoperative diagnosis of IMT, we performed partial mastectomy with adequate margins. The postoperative diagnosis was pathologically confirmed as IMT. Immunohistochemical staining also showed overexpression of ALK-1 in the tumor. The patient had a good clinical course for 24 months postoperatively, without recurrence or metastasis. Conclusions: IMT of the breast shows nonspecific imaging findings, making preoperative diagnosis difficult. Nevertheless, IMT has the characteristics of low-grade neoplasms with recurrence, invasion, and metastatic potential. Our report emphasizes the importance of determining a treatment plan as soon as possible based on an accurate diagnosis to improve the prognosis of this disease. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) inhibitors have demonstrated robust clinical activity in patients with ALK-rearranged lung cancers. The echinoderm microtubule-associated protein-like (EML)-ALK translocation was first discovered in 2007 and 4 years later, crizotinib, a first-generation ALK inhibitor was approved. Since then, subsequent generations of ALK inhibitors have demonstrated superior efficacy and better CNS activity compared to crizotinib. Alectinib and brigatinib, both second-generation ALK inhibitors have been compared directly to crizotinib in the first-line setting and has demonstrated improved progression free survival (PFS) and intracranial response. Ceritinib, another second-generation ALK inhibitor has been shown to be superior to chemotherapy in ALK-rearranged disease with good CNS activity. Initial responses to ALK inhibitors are not always durable and resistance can occur as on-target or off-target alterations. Lorlatinib, a third-generation ALK inhibitor, has demonstrated activity in the treatment naïve setting and in resistance to crizotinib and second-generation ALK inhibitors. Lorlatinib has also shown improved PFS in patients harboring EML4-ALK variant 3, which is associated with the development of ALK resistance mutations, specifically G1202R. Another new ALK inhibitor, ensartinib, has demonstrated efficacy in the first-line setting and in alectinib refractory disease. Additional studies are underway examining mechanisms of resistance and best treatment options post resistance.

This report describes an extremely rare case of a primary inflammatory myofibroblastic tumor of the trachea. The patient underwent surgical resection by a transtracheal approach and reconstruction with esophageal tracheoplasty. This case report highlights the rarity of such tumors and a minimally invasive and safe surgical technique for tumors around the central neck structures. [ABSTRACT FROM AUTHOR]

Introduction There is scarce data regarding the incidence of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in the molecular subtypes of non-small cell lung cancer (NSCLC). We aimed to investigate the association between Anaplastic Lymphoma Kinase (ALK) -positive NSCLC and thromboembolic events. Methods A retrospective population-based cohort study of the Clalit Health Services database, included patients with NSCLC diagnosed between 2012 and 2019. Patients exposed to ALK-tyrosine-kinase inhibitors (TKIs) were defined as ALK -positive. The outcome was VTE (at any site) or ATE (stroke or myocardial infarction) 6 months prior to the diagnosis of cancer, until 5 years post-diagnosis. The cumulative incidence of VTE and ATE and hazard-ratios (HR) with 95% CIs were calculated (at 6- 12- 24 and 60-months), using death as a competing risk. Cox proportional hazards multivariate regression was performed, with the Fine and Gray correction for competing risks. Results The study included 4762 patients, of which 155 (3.2%) were ALK -positive. The overall 5-year VTE incidence was 15.7% (95% CI, 14.7-16.6%). ALK -positive patients had a higher VTE risk compared to ALK -negative patients (HR 1.87 [95% CI, 1.31-2.68]) and a 12-month VTE incidence of 17.7% (13.9-22.7%) compared to 9.9% (9.1-10.9%) in ALK -negative patients. The overall 5-year ATE incidence was 7.6% [6.8-8.6%]. ALK positivity was not associated with ATE incidence (HR 1.24 [0.62-2.47]). Conclusions In this study, we observed a higher VTE risk, but not ATE risk, in patients with ALK- rearranged NSCLC relative to those without ALK rearrangement. Prospective studies are warranted to evaluate thromboprophylaxis in ALK -positive NSCLC. [ABSTRACT FROM AUTHOR]

Keywords: anaplastic lymphoma kinase (ALK); brigatinib; ceritinib; crizotinib; photosensitivity EN anaplastic lymphoma kinase (ALK) brigatinib ceritinib crizotinib photosensitivity 285 290 6 05/11/23 20230501 NES 230501 To the Editor, The U.S. Food and Drug Administration (FDA) has approved five anaplastic lymphoma kinase (ALK) inhibitors (i.e., crizotinib, ceritinib, alectinib, brigatinib, lorlatinib) since 2011 to treat ALK-positive, metastatic non-small cell lung cancer. 6 e Patient concomitant medications were not considered to be contributing confounders as photosensitivity improved/resolved upon interruption of ALK inhibitor and worsened/recurred upon resumption of ALK inhibitor (positive rechallenge), while other drug(s) labeled for photosensitivity were continued throughout clinical course. [Extracted from the article]

Background: This study compares the safety and efficacy of first‐line treatments for anaplastic lymphoma kinase (ALK)‐mutated non–small cell lung cancer (NSCLC). Methods: A comprehensive literature search was conducted in PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Abstracts related to lung cancer presented at important international conferences were also reviewed. Randomized clinical trials that qualified the inclusion criteria were subjected to Bayesian network meta‐analysis and systematically reviewed. Results: The authors included a total of nine studies including 2441 patients and seven first‐line treatments (ensartinib, brigatinib, crizotinib, lorlatinib, alectinib, ceritinib, and pemetrexed‐based chemotherapy). Overall, lorlatinib appeared to confer the best progression‐free survival (PFS) (probability of being the best [Prbest], 90%; surface under the cumulative ranking curve [SUCRA], 98%), and the same conclusion was obtained on paired comparisons (lorlatinib vs. ceritinib [hazard ratio (HR), 0.31; 95% confidence interval (CI), 0.20–0.47); lorlatinib vs. chemotherapy [HR, 0.17; 95% CI, 0.12–0.23]; crizotinib vs. lorlatinib [HR, 3.6; 95% CI, 2.4–5.2]; and brigatinib vs. lorlatinib [HR, 1.7; 95% CI, 1.0–2.8]). Alectinib conferred the best overall survival (OS) and safety profile. In the Asian population, ensartinib conferred the best PFS (Prbest 50%, SUCRA 87%), and for patients with brain metastases at baseline, lorlatinib showed the best PFS (Prbest 70%, SUCRA 93%). Conclusions: For first‐line treatment of patients with ALK‐positive NSCLC, lorlatinib was associated with the best PFS and objective response rate, but poorer safety profile, whereas alectinib demonstrated the best OS and safety profile. In Asians, ensartinib conferred the best PFS benefit, and in the brain baseline metastasis population, lorlatinib conferred the best PFS benefit. Plain Language Summary: Among the many molecularly targeted drugs currently used to treat anaplastic lymphoma kinase mutation‐positive non–small cell lung cancer, lorlatinib may be one of the most effective targeted drugs.Lung cancer has long been at the top of cancer rankings in terms of incidence and mortality.Today, the treatment of lung cancer has moved into the era of precision therapy.In this article, we use a statistical approach to compare the efficacy and safety of targeted drugs that have been used in the first‐line treatment of anaplastic lymphoma kinase mutations to improve the reference for clinicians to make treatment decisions in the real world. Lorlatinib showed the best progression‐free survival benefit not only in anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer patients, but it also showed promising clinical benefit in ALK‐positive patients with brain metastases. [ABSTRACT FROM AUTHOR]

• Newer generation tyrosine kinase inhibitors (TKIs) have demonstrated high CNS objective response rates, opening the door to new multidisciplinary treatment strategies for brain metastases. • For extensive brain metastases presentations, TKIs can downstage the burden of CNS disease allowing for the avoidance of whole-brain radiotherapy (WBRT) and the conversion of some patients into candidates for stereotactic radiosurgery (SRS). • CNS downstaging is an emerging multidisciplinary paradigm with the potential to offer encouraging CNS control outcomes and reduced treatment-related toxicity by avoiding upfront WBRT administration. For extensive brain metastases (BrM) presentations arising from oncogene-addicted lung cancer, tyrosine kinase inhibitors (TKIs) with high response rates in the central nervous system (CNS) could potentially downstage the CNS disease burden, allowing for the avoidance of upfront whole-brain radiotherapy (WBRT) and the conversion of some patients into candidates for focal stereotactic radiosurgery (SRS). We describe the outcomes of patients with ALK, EGFR, and ROS1-driven NSCLC with extensive BrM presentations (defined as > 10 BrMs or leptomeningeal disease) treated with upfront newer generation CNS-active TKIs alone, including osimertinib, alectinib, brigatinib, lorlatinib, and entrectinib, from 2012 to 2021 at our institution. All BrMs were contoured at study entry, best CNS response (nadir), and first CNS progression. Twelve patients met criteria including 6 with ALK, 3 with EGFR, and 3 with ROS1-driven NSCLC. The median number and volume of BrMs at presentation were 49 and 19.6 cm3, respectively. Eleven patients (91.7 %) achieved a CNS response by modified-RECIST criteria to upfront TKI (10 partial responses, 1 complete response, 1 stable disease) with nadir observed at a median of 5.1 months. At nadir, the median number and volume of BrMs were 5 (median 91.7 % reduction per-patient) and 0.3 cm3 (median 96.5 % reduction per-patient), respectively. Eleven patients (91.6 %) developed subsequent CNS progression (7 local failures, 3 local + distant, 1 distant) at a median of 17.9 months. At CNS progression, the median number and volume of BrMs were 7 and 0.7 cm3, respectively. Seven patients (58.3 %) received salvage SRS and no patients received salvage WBRT. The median overall survival from initiation of TKI for the extensive BrM presentation was 43.2 months. In this initial case series, we describe CNS downstaging as a promising multidisciplinary treatment paradigm involving the upfront administration CNS-active systemic therapy and close MRI surveillance for extensive BrMs as a strategy to avoid upfront WBRT and to convert some patients into SRS candidates. [ABSTRACT FROM AUTHOR]

Abstract Background Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations. Methods KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic–pharmacodynamic correlations and the mechanism of actions driving drug combination synergy. Results In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449. Conclusions Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK + NSCLC refractory to earlier-generation ALK inhibitors. Trial registration Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019).

Superficial anaplastic lymphoma kinase (ALK)-rearranged myxoid spindle cell neoplasms are a recently identified subtype of cutaneous soft tissue tumors, distinct for their co-expression of CD34 and S100 and characterized by ALK gene rearrangements. Although 72 cases have been reported primarily as isolated case reports, this tumor subtype has yet to be included in the WHO classification of soft tissue tumors, underscoring the need for further study. In this study, we diagnosed two additional cases, both arising in the dermis and subcutaneous tissue. These tumors exhibited characteristic pathological features, including linear or concentric whorl patterns, prominent myxoid and collagenized stroma, mild cellular atypia, and rare mitotic activity. The presence of infiltrative margins and the potential for recurrence after surgery suggest at least locally aggressive clinical behavior. Immunohistochemically, the tumors diffusely expressed S100 and CD34, with strong ALK-D5F3 positivity, confirmed by ALK gene rearrangement. These findings further expand the clinical and pathological spectrum of ALK -rearranged neoplasms and highlight the need for continued research on their biological behavior and classification. • Anaplastic Lymphoma Kinase-rearranged spindle cell tumors represent a unique entity. • This study presents two cases of this entity with detailed analysis. • Histology reveals myxoid, low-grade spindle cells arranged in whorls and cords. • Both cases show diffuse expression of S100, CD34, and the ALK-D5F3 marker. • Comprehensive review for this entity, offering diagnostic and differential insights. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) takes the first place in the structure of overall oncology in males. More than 1.8 million of new cases of lung cancer (LC) are registered each year worldwide. LC is the leading cause of cancer death in both developing and developed countries, and the 5 years survival rate is as low as 19 %. Many factors explain such unsatisfactory outcomes, including the LC diagnosis at an advanced stage, when the currently available treatments can rarely provide cure. Non-small cell lung cancer (NSCLC) with chromosomal rearrangement of anaplastic lymphoma kinase (ALK) is sensitive to targeted therapy with tyrosine kinase inhibitors (TKIs). Tumor cells containing ALK fusion are sensitive to TKIs – targeted drugs that have significantly improved the results of treatment of patients with ALK-positive NSCLC, half of whom survive more than 6.8 years after diagnosis. The number of patients with ALK-positive NSCLC varies, so ALK rearrangements are detected in about 3–7 % of lung adenocarcinomas, which accounts for up to 60.000 new cases of the disease annually worldwide. ALK-positive NSCLC is observed almost exclusively in adenocarcinomas associated with persons of younger age, male and never smoked or smoked a little. Patients with ALK-positive stage I–III NSCLC are shown treatment similar to patients with wild-type NSCLC, including surgery, radiation therapy, chemotherapy or multimodal treatment, depending on the stage of the tumor process. Numerous ALK TKIs have been developed in recent years, including alectinib, which is the current preferred first-line agent for patients who haven’t received therapy. The study of the mechanisms of resistance has led to the development of next-generation ALK inhibitors that better penetrate the central nervous system, actively affecting brain metastases. This review highlights the current state and prospects for the development of ALK-positive NSCLC therapy.

Abstract Background Programmed death ligand-1 (PD-L1), anaplastic lymphoma kinase (ALK), and c-ros oncogene1 (ROS1) expression may influence the prognosis of non-small cell lung carcinoma (NSCLC). We aimed to investigate the prognostic and predictive significance of PD-1/PD-L1 along with c-ros ROS1 and ALK in NSCLC patients. Methods Immunohistochemistry used to identify ALK, ROS1, PD-1, and PD-L1 proteins expression as well as ROS1 rearrangement via fluorescence in situ hybridization, in 70 NSCLC patients. Results were related to clinicopathological feature, survival, and treatment response. Results Expression of ROS1, ALK, PD-1, and PD-L1 and ROS1-rearrangement were detected in 18.57%, 54.29%, 84.29%, 87.14%, and 15.71% of the cases, respectively. No association was found between ROS1, PD-1, and PD-L1 and any clinicopathological features, survival, or treatment outcome. ALK expression significantly associated with stage-IV and left-sided tumors. Epidermal growth factor receptor (EGFR) mutation and ALK-positive patients had significantly reduced progression-free survival than patients with wild type EGFR [HR: 1.99, 95% CI: 1.37–2.93, p

Simple Summary: Patients with Anaplastic lymphoma kinase (ALK)-positive lung cancer after progression of ALK-tyrosine kinase inhibitor have limited treatment options. This study shows clinical efficacy of the combination of alectinib and bevacizumab with acceptable toxicity in patients with ALK-positive lung cancer after ALK-TKI failure. Anaplastic lymphoma kinase (ALK)-positive lung cancer is a rare cancer that occurs in approximately 5% of non-small-cell lung cancer (NSCLCs) patients. Despite the excellent efficacy of ALK-tyrosine kinase inhibitor in ALK-positive NSCLCs, most patients experience resistance. We conducted a phase II study to investigate the combination of alectinib with bevacizumab in ALK-positive NSCLC patients after failure of alectinib. In this study, ALK-positive nonsquamous NSCLC patients previously treated with alectinib received bevacizumab 15 mg/kg on day 1 every 3 weeks and alectinib 600 mg/day until disease progression. The primary endpoints were progression-free survival (PFS) and the safety of alectinib and bevacizumab. The secondary endpoints included overall survival (OS) and correlation of circulating tumor DNA and plasma proteins with PFS. Of the 12 patients treated, the median PFS was 3.1 months (95% CI 1.2–16.1), and the median OS was 24.1 months (95% CI 8.3-not estimable). The EML4-ALK fusion gene in circulating tumor DNA was significantly correlated with shorter PFS (1.2 months vs. 11.4 months, HR 5.2, p = 0.0153). Two patients experienced grade 3 adverse events; however, none of the patients required dose reduction. Although the primary endpoint was not met, alectinib combined with bevacizumab showed clinical efficacy in ALK-positive patients. [ABSTRACT FROM AUTHOR]

Background: The tumor immune microenvironment of anaplastic lymphoma kinase (ALK)-rearranged lung adenocarcinoma (LUAD) stratified by ALK fusion variants is poorly pictured. Hence, in this study, we aim to explore the immune heterogeneity of ALK + LUAD across different ALK fusion variants and further investigate their significance on clinical prognosis., Methods: A retrospective analysis was conducted on ALK + LUAD patients (N=68). DNA and RNA-based next-generation sequencing (NGS) was performed to clarify the specific ALK fusion variants. Clinical and pathological characteristics were compared between long and short ALK variants. To research the immune heterogeneity, multi-fluorescence was carried out to explore the differences in immune properties, such as tumor-infiltrating lymphocyte (TIL) number, TIL subset, and tertiary lymphoid structures (TLS) development, between long and short ALK variants. Furthermore, the prognostic value of these characteristics was analyzed. Finally, the expression of lymphocyte-activation gene-3 (LAG3), one novel immune therapy target, was assessed across ALK + LUAD., Results: LUAD patients with short ALK fusion variant-driven tumors exhibited higher American Joint Committee on Cancer (AJCC) stage as well as larger tumor size than those with long ALK fusion variant-driven tumors. Compared to long ALK fusion variants, there were more TILs, especially natural killer (NK) cells, within short ALK variants. However, fewer TLS were established in cancers harboring short ALK variants than those with long ALK variants. In advanced-stage LUAD patients with ALK fusion, short ALK variants, hot immune status, and high-level NK cells were identified to be adverse prognostic factors, while high-level B cells, as well as the development of TLS, served as positive prognostic factors. As for LAG3 expression, LAG3 + immune cells were more enriched in short ALK variants than in long ALK variants., Conclusions: LUAD patients with short ALK fusion variant-driven tumors exhibited worse prognosis than those with long ALK fusion variant-driven tumors. The tumor immune microenvironments are heterogeneous across different ALK fusion variants with short variants characterized by higher levels of TIL, especially NK cells, but by less TLS development than long variants ALK + LUAD, which disfavor disease outcomes., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-682/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Simple Summary: In recent years, prognosis of non-small cell lung cancer (NSCLC) patients significantly improved thanks to the introduction of tyrosine kinase inhibitors (TKIs) in clinical practice. ALK-rearranged NSCLC patients benefit from treatment with ALK inhibitors (ALK-i), which have shown a greater efficacy and a better intracranial activity than chemotherapy. Comparative studies between next-generation ALK-i are still lacking and clinicians are looking for reliable tools to determine which drug suits best for each patient. The aim of this review is to deepen the role of clinical and pathological characteristics influencing patients' prognosis during treatment with ALK-i and to provide an overview of molecular mechanisms of ALK-i resistance. In this setting, liquid biopsy may play an important role in predicting tumor response and monitoring resistance mutations. We will summarize ongoing trials developing new ALK-i or combinations between ALK-i and other agents, which may represent future scenarios in the field of NSCLC research. During the last decade, the identification of oncogenic driver mutations and the introduction of tyrosine kinase inhibitors (TKIs) in daily clinical practice have substantially revamped the therapeutic approach of oncogene-addicted, non-small cell lung cancer (NSCLC). Rearrangements in the anaplastic lymphoma kinase (ALK) gene are detected in around 3–5% of all NSCLC patients. Following the promising results of Crizotinib, a first-generation ALK inhibitor (ALK-i), other second-generation and more recently third-generation TKIs have been developed and are currently a landmark in NSCLC treatment, leading to a significant improvement in patients prognosis. As clinical trials have already demonstrated high efficacy of each ALK-i, both in terms of systemic and intracranial disease control, comparative studies between second and third generation ALK-i are still lacking, and primary or secondary ALK-i resistance inevitably limit their efficacy. Resistance to ALK-i can be due to ALK-dependent or ALK-independent mechanisms, including the activation of bypass signaling pathways and histological transformation: these findings may play an important role in the future to select patients' subsequent therapy. This review aims to provide an overview of underlying molecular alterations of ALK-i resistance and point out promising role of liquid biopsy in predicting tumor response and monitoring resistance mutations. The purpose of this review is also to summarize current approval for ALK-rearranged NSCLC patients, to help clinicians in making decisions on therapeutic sequence, and to deepen the role of clinicopathological and genomic characteristics influencing patients' prognosis during treatment with ALK-i. [ABSTRACT FROM AUTHOR]

Abstract Background The prognostic significance of ALK rearrangement is still contradictory. Here, we aimed to investigate the clinical characteristics and outcomes of lung adenocarcinoma patients with ALK rearrangement, and analyze whether these patients benefited from targeted therapy. Methods This was a retrospective cohort study of 80 ALK‐rearranged lung adenocarcinoma patients who had undergone radical surgery and another 3031 ALK mutation‐negative patients were retrospectively reviewed for inclusion in this case‐controlled analyses. Overall survival (OS) was evaluated using the Kaplan‐–Meier method. Univariate analysis (UVA) and multivariate analysis (MVA) by the Cox proportional hazards regression identified risk factors that predicted OS. Results Compared to ALK‐negative patients, the ALK rearranged patients were younger, with more non‐smokers, more females, a larger primary tumor was demonstrated, and were a higher pathological stage. In particular, the risk of lymph node metastasis was higher. For patients with surgically‐resected tumors, the prognosis was better for ALK rearranged patients (HR = 0.503; 95% CI: 0.259–0.974, p = 0.041). In addition, for stage II–III patients, targeted therapy was an independent prognostic factor of better OS (HR = 0.159; 95% CI: 0.032–0.801, p = 0.026). Conclusions ALK rearranged lung adenocarcinoma patients who have undergone radical surgery have distinct clinical features. Patients with ALK rearrangement may have a favorable prognosis, and stage II–III patients may benefit from targeted treatment.

Background: Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations.Methods: KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic-pharmacodynamic correlations and the mechanism of actions driving drug combination synergy.Results: In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449.Conclusions: Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK+ NSCLC refractory to earlier-generation ALK inhibitors.Trial Registration: Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019). [ABSTRACT FROM AUTHOR]

ALK positive histiocytosis is a relatively new histiocytic proliferation disease with a characteristic gene translocation involving fusion of the ALK gene with different partners, mostly KIF5B. We report a case of ALK-positive histiocytosis with literature review. A 27-year-old male patient presented mainly with progressive lower limb weakness. Imaging studies showed an intradural extramedullary enhancing lesion at the L3 level. A 1.5 cm mass was excised from the sensory nerve root in the filum terminale at the level of L3. Histologic examination showed infiltration of the nerve by numerous histiocytes with moderate to abundant eosinophilic to clear-foamy and variably-vacuolated cytoplasm with irregular-to-smooth contoured nuclei. The histiocytes were positive for CD68 and ALK1 and negative for S100 and CD1a. KIF5B-ALK fusion was detected by real time-polymerase chain reaction. The patient is asymptomatic nine months after surgical excision. This is the first reported localized case occurring in the nerve root of an adult patient, thus expanding the clinical manifestations of this disease. An integrated histological, immunohistochemical and molecular approach is recommended for diagnosis. We recommend performing ALK1 immunohistochemical stain on all histiocytosis cases to increase awareness and detection of this newly described entity.

Background: Programmed death ligand-1 (PD-L1), anaplastic lymphoma kinase (ALK), and c-ros oncogene1 (ROS1) expression may influence the prognosis of non-small cell lung carcinoma (NSCLC). We aimed to investigate the prognostic and predictive significance of PD-1/PD-L1 along with c-ros ROS1 and ALK in NSCLC patients. Methods: Immunohistochemistry used to identify ALK, ROS1, PD-1, and PD-L1 proteins expression as well as ROS1 rearrangement via fluorescence in situ hybridization, in 70 NSCLC patients. Results were related to clinicopathological feature, survival, and treatment response. Results: Expression of ROS1, ALK, PD-1, and PD-L1 and ROS1-rearrangement were detected in 18.57%, 54.29%, 84.29%, 87.14%, and 15.71% of the cases, respectively. No association was found between ROS1, PD-1, and PD-L1 and any clinicopathological features, survival, or treatment outcome. ALK expression significantly associated with stage-IV and left-sided tumors. Epidermal growth factor receptor (EGFR) mutation and ALK-positive patients had significantly reduced progression-free survival than patients with wild type EGFR [HR: 1.99, 95% CI: 1.37–2.93, p < 0.001] and negative-ALK expression [HR: 1.46, 95% CI: 1.03–2.07, p = 0.03]. In multivariate analysis, lymph node metastasis, EGFR-mutations, and ALK were independent predictors of NSCLC. PD-L1 expression was significantly correlated with PD-1 but not with ROS1, ALK, or EGFR-mutation. Conclusion: Positive ALK expression and EGFR-mutations are independent adverse predictors of NSCLC. Overexpression of PD-1/PD-L1 is not a significant prognostic marker in NSCLC patients receiving chemotherapy, making them susceptible to immunotherapy. Since PD-1/PD-L1 expression is independent to oncogenic driver mutations, future studies into specific immune checkpoint inhibitors combined with targeted therapies for individualized treatment of NSCLC is warranted. Positive ALK expression and EGFR mutations are independent risk factors for NSCLC. Overexpression of PD-1/PD-L1 is not a significant prognostic factor in patients with NSCLC who are receiving chemotherapy, making them immunotherapy susceptible. Given that PD-1/PD-L1 expression is not dependent on oncogenic driver mutations, additional research into specific immune checkpoint inhibitors in combination with targeted therapies for the treatment of NSCLC on an individual basis is warranted. [ABSTRACT FROM AUTHOR]

Abstract Background Spontaneous pneumothorax occurs more often in younger, slim, and shallow-chested men. Although less common, differential diagnoses for secondary pneumothorax in children are asthma, emphysematous blebs, catamenial pneumothorax, and others. We report a patient who presented with pneumothorax and was found to have an inflammatory myofibroblastic tumor (IMT)-like lesion, and present a review of the related literature. Case presentation A 14-year-old girl visited her physician for chest pain that developed while exercising. Although chest drainage was performed, the symptoms associated with a collapsed lung did not improve, and she was referred to our hospital. Computed tomography revealed the presence of a 19 × 17-mm cyst with a thick wall in the apex of the right lung. She was tested for infectious diseases, namely tuberculosis, but the results were not definitive. Catamenial pneumothorax was also suspected because she was menstruating when she presented to our hospital. As a therapeutic diagnosis, we performed a thoracoscopic partial resection of the right upper lobe of the lung. Three small openings were identified inside the cyst, suggesting connection with the bronchiole. The lesion was pathologically diagnosed as an IMT-like lesion. Considering the progress so far, we considered that the final diagnosis to be an IMT. The patient was discharged on postoperative day 3, and we have followed her for the past 6 months with no local recurrence or metastasis. Conclusions IMT is not uncommon in children. Therefore, this lesion should be considered as a possible diagnosis if children and young adults develop spontaneous pneumothorax.

Background: Rearrangement in anaplastic lymphoma kinase ( ALK ) occurs in 4-7% of non-small cell lung cancer (NSCLC) cases. Despite improved survival with tyrosine kinase inhibitors (TKIs), treatment resistance remains challenging. This retrospective study analyzed advanced ALK-positive NSCLC patients, focusing on clinical aspects, treatments, resistance, and outcomes., Methods: Patients diagnosed between January 2009 and December 2021 who received at least one ALK-TKI line at the Karolinska University Hospital, were included. We evaluated crizotinib or 2 nd generation ALK-TKI effectiveness in first-line treatment and lorlatinib in subsequent lines. Overall survival (OS) was defined as from the date of advanced lung cancer diagnosis until the date of last follow-up (April 22, 2022) or the date of death from any cause. Progression-free survival (PFS), from the date of starting ALK-TKI until the date of progression, death, or last follow-up. Resistance mechanisms were assessed through re-biopsies utilizing next-generation sequencing (NGS)., Results: Out of 160 eligible patients, 10 were excluded. Median follow-up was 54.0 months from diagnosis and 45.0 months from initial ALK-TKI treatment. Crizotinib showed a median PFS of 8.0 months and a median OS of 35.0 months. Second generation ALK-TKIs demonstrated a median PFS of 52.0 months [OS was not reached (NR)]. Overall, the median OS was 65.0 months. Poor prognostic factors included male sex, thromboembolism, crizotinib treatment, and chronic obstructive pulmonary disease (COPD)/asthma. Rebiopsies in 18 cases revealed secondary ALK mutations in 8 patients, correlating with a shorter median PFS in subsequent ALK-TKI treatment (1.0 vs. 7.0 months)., Conclusions: This comprehensive study, spanning over a decade, provides crucial insights into the clinical characteristics, treatment patterns, and resistance mechanisms of advanced ALK-positive NSCLC, where median OS exceeds 5 years. Re-biopsies during treatment are essential for advancing our understanding of resistance mechanisms and the tumor dynamics evolving during ALK-TKI therapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-396/coif). G.T. reports honoraria from MSD, Roche AB for lectures and reports paid participation at ELCC 2023 from Roche AB. K.V. is supported for salary and other project related costs by the indicated private funding bodies or region grants Stockholm Cancer Society (contract No. 221383), Stockholm County Council (contract Nos. 909121, 750032, and FoUI-966345), and Erling Persson Family Foundation. R.L. reports grant from the Swedish Cancer Society (No. CAN2021/1469), the Stockholm Cancer Society (No. 221212), the Stockholm County Council (contract Nos. FoUI-966345, 909121, and 750032), the Erling Persson Family Foundation, and the Swedish Foundation for Strategic Research (No. SIP21-0106). S.E. reports grants from the Swedish Cancer Society (grant No. CAN2023/2919), the King Gustaf V Jubilee Fund (grant No. 204053), the Sjöberg Foundation (No. 2022-2024), and the Stockholm County Council (No. 987911). The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Background and Objective: The standard first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor ( EGFR ) mutations or anaplastic lymphoma kinase ( ALK ) fusions is targeted therapy using tyrosine kinase inhibitors (TKIs). However, data are still lacking on the use of TKIs as a neoadjuvant or induction approach. Therefore, this narrative review aims to summarize the current knowledge on resectable EGFR -mutant and ALK -fused NSCLC regarding available perioperative treatment regimens and off-label neoadjuvant use of targeted therapy., Methods: The relevant literature was identified by using PubMed and ClinicalTrials.gov (last search phase June 2024) and was restricted to English language. Peer-reviewed manuscripts but also conference abstracts that did not undergo peer-review were included., Key Content and Findings: Patients with EGFR -mutations and ALK -fusions have typically been excluded from available phase III perioperative immunotherapy trials due to lower efficacy and higher toxicity of immunotherapy in those patients. In the adjuvant setting, recent evidence from the phase III ALINA and ADAURA trials demonstrated efficacy and safety of targeted therapy in resected ALK -fused and EGFR -mutant NSCLC. However, to date there is no approval for the use of TKIs as neoadjuvant or induction therapy in those patients. We have therefore identified a number of case series and phase II trials using targeted therapy in resectable EGFR -mutant and ALK -fused NSCLC., Conclusions: Current evidence suggests that targeted therapies might be effective in patients with resectable EGFR -mutant and ALK -positive NSCLC, but ongoing trials will need to provide further evidence on the safety and efficacy of perioperative TKI therapy., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-359/coif). M.K. received support for attending meetings and/or travel as well as research grants from Deutsche Forschungsgemeinschaft (DFG), Pierre Fabre, Amgen, AstraZeneca, Daiichi Sankyo, Janssen-Cilag, Novartis, Roche Pharma, Takeda Pharma. G.L. received grants or contracts from Roche, Gilead, Janssen, Bayer, Celgene, Novartis, AstraZeneca, MorphoSys; received consulting fees from Roche, Gilead, Janssen, Bayer, Celgene, Novartis, AstraZeneca, Takeda, BMS, NanoString, AbbVie, Incyte, MorphoSys, Genmab, Karyopharm, Constellation, ADC, Miltenyi, PentixaPharm, Sobi, Immagene, Genase,Hexal/Sandoz, Lilly, BeiGene, MSD GmbH, Pierre Fabre Pharma GmbH; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Janssen, Bayer, Celgene, Takeda, BMS, AbbVie, Incyte, MorphoSys, Sobi, Hexal/Sandoz; payment for expert testimony from Roche; support for attending meetings and/or travel from Janssen, AbbVie, BMS, and Roche; participated on a Data Safety Monitoring Board or Advisory Board from Roche, Gilead, Janssen, Bayer, Celgene, Novartis, AstraZeneca, Takeda, BMS, NanoString, AbbVie, Incyte, MorphoSys, Genmab, Karyopharm, Constellation, ADC, Miltenyi, PentixaPharm, Sobi, BMS Safety Monitoring Board; the author is the president of German Lymphoma Alliance and also in the board of directors GLA. A.B. received honoraria or travel grants not related to this manuscript from Bayer, BMS, Takeda, Onkowissen TV, MSD, Boehringer, AstraZeneca, Sanofi, Pfizer, Streamedup, Lilly, Art Tempi, Amgen, RG GmbH, Roche, Novartis, Digimed Verlag, Janssen, DGHO Juniorakademie, Ärztekammer, Pius Hospital Onsabrück, St. Johannes Hospital DO, WTZ, Daiichi, FOMF, Knappschaft-krankenhaus Bochum; participated on a Data Safety Monitoring Board or Advisory Board from Bayer, BMS, Takeda, Onkowissen TV, MSD, Boehringer, AstraZeneca, Sanofi, Pfizer, Streamedup, Lilly, Art Tempi, Amgen, RG GmbH, Roche, Novartis, Digimed Verlag, Janssen, Daiichi. G.E. received honoraria or travel grants not related to this manuscript from BMS, MSD, Pfizer, Bayer, AstraZeneca, Boehringer, Roche, Merck, Takeda, Novocure, Pierre Fabre, Janssen-Cilag, Lilly, Servier, Roche, Celgene, Actelion, CLS Behring, Fresenius, AOP Health, AMGEN, Daiichi-Sankyo. The other authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

• This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. • NBEA-ALK (N5:A20) has never been reported previously. • Alectinib could be a viable therapeutic option for NSCLC patients with double-ALK fusion. • Initial NGS detection is crucial to follow-up treatment while liquid biopsy can dynamically monitor clinical curative effect. The echinoderm microtubule-associated protein-like 4 gene (EML4) and anaplastic lymphoma kinase gene (ALK) fusion is the most common ALK rearrangements in non-small cell lung cancer (NSCLC). Herein, we firstly report that coexistence of a novel Neurobeachin (NBEA)-ALK, EML4-ALK double-fusion is sensitive to alectinib. Hematoxylin-eosin staining (HE), fluorescent in situ hybridization (FISH), and next-generation sequencing (NGS) was performed on the biopsy sample. The patient responded to alectinib as a second-line treatment and achieved stable disease for 11 months, without significant symptoms of toxicity. Significantly, the liquid biopsy also validated clinical benefit, with the disappearance of NBEA-ALK and EML4-ALK fusion variants. We also provided a comprehensive review of all 50 ALK fusion genes in NSCLC. This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. Alectinib may be a viable therapeutic option for NSCLC patients with double-ALK fusion, and liquid biopsy could dynamically monitor clinical curative effect. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance.

Background: The prognostic significance of ALK rearrangement is still contradictory. Here, we aimed to investigate the clinical characteristics and outcomes of lung adenocarcinoma patients with ALK rearrangement, and analyze whether these patients benefited from targeted therapy. Methods: This was a retrospective cohort study of 80 ALK‐rearranged lung adenocarcinoma patients who had undergone radical surgery and another 3031 ALK mutation‐negative patients were retrospectively reviewed for inclusion in this case‐controlled analyses. Overall survival (OS) was evaluated using the Kaplan‐–Meier method. Univariate analysis (UVA) and multivariate analysis (MVA) by the Cox proportional hazards regression identified risk factors that predicted OS. Results: Compared to ALK‐negative patients, the ALK rearranged patients were younger, with more non‐smokers, more females, a larger primary tumor was demonstrated, and were a higher pathological stage. In particular, the risk of lymph node metastasis was higher. For patients with surgically‐resected tumors, the prognosis was better for ALK rearranged patients (HR = 0.503; 95% CI: 0.259–0.974, p = 0.041). In addition, for stage II–III patients, targeted therapy was an independent prognostic factor of better OS (HR = 0.159; 95% CI: 0.032–0.801, p = 0.026). Conclusions: ALK rearranged lung adenocarcinoma patients who have undergone radical surgery have distinct clinical features. Patients with ALK rearrangement may have a favorable prognosis, and stage II–III patients may benefit from targeted treatment. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) is a validated molecular target for non-small-cell lung cancer (NSCLC). The use of tyrosine kinase inhibitors (TKIs) has led to significantly improved survival benefits. However, the clinical benefits of targeting ALK using TKIs are limited due to the emergence of drug resistance. The landscape of resistance mechanisms and treatment decisions has become increasingly complex. Therefore, continued research into new drugs and combinatorial therapies is required to improve outcomes in NSCLC. In this review, we explore the resistance mechanisms of ALK TKIs in advanced NSCLC in order to provide a theoretical basis and research ideas for solving the problem of ALK drug resistance. [ABSTRACT FROM AUTHOR]

ALK positive histiocytosis is a relatively new histiocytic proliferation disease with a characteristic gene translocation involving fusion of the ALK gene with different partners, mostly KIF5B. We report a case of ALK-positive histiocytosis with literature review. A 27-year-old male patient presented mainly with progressive lower limb weakness. Imaging studies showed an intradural extramedullary enhancing lesion at the L3 level. A 1.5 cm mass was excised from the sensory nerve root in the filum terminale at the level of L3. Histologic examination showed infiltration of the nerve by numerous histiocytes with moderate to abundant eosinophilic to clear-foamy and variably-vacuolated cytoplasm with irregular-to-smooth contoured nuclei. The histiocytes were positive for CD68 and ALK1 and negative for S100 and CD1a. KIF5B-ALK fusion was detected by real time-polymerase chain reaction. The patient is asymptomatic nine months after surgical excision. This is the first reported localized case occurring in the nerve root of an adult patient, thus expanding the clinical manifestations of this disease. An integrated histological, immunohistochemical and molecular approach is recommended for diagnosis. We recommend performing ALK1 immunohistochemical stain on all histiocytosis cases to increase awareness and detection of this newly described entity. [ABSTRACT FROM AUTHOR]

Abstract Background Primary pulmonary lymphoepithelioma‐like carcinoma (PLELC) is a rare and unique subtype of lung cancer. However, the prevalence of driver alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, and the response of tyrosine kinase inhibitor (TKIs) in PLELC has not been thoroughly investigated. Method We retrospectively reviewed the genetic profiles and treatment course of 330 PLELC patients at the Guangdong Lung Cancer Institute (GLCI) from 1st January, 2008 to 30th December, 2018. We searched and analyzed related literature published in PubMed and Web of Science from 1st January, 2000 and 31th August, 2019 based on their mention of “driver mutations” and “the response of TKIs to mutant PLELC”. Results Genetic alterations of EGFR/ALK were tested in 203 patients (203/330, 61.5%). Five patients (5/175, 2.9%) had EGFR mutation and three patients (3/140, 2.1%) had ALK alteration. From the total of 15 articles identified from electronic searches, 1071 PLELC cases mentioned the driver mutations. EGFR mutation and ALK rearrangement were detected in 15 patients and one patient, respectively. In total, there were four EGFR/ALK mutant PLELC patients who received targeted therapy as palliative treatment at the GLCI and in the literature. However, there was disease progression in all cases one month after use of TKIs. Conclusion The mutation rates of EGFR and ALK were low in PLELC. EGFR and ALK TKIs showed limited response in EGFR/ALK mutant PLELC. Further studies are needed to explore other molecular targets to optimize the therapeutic strategy for PLELC.

Abstract Objective To investigate the 18F-FDG PET/CT imaging manifestations for anaplastic large cell lymphoma (ALCL), a rare subtype of T/NK cell lymphoma. Methods Fifty patients with ALCL, including 32 anaplastic lymphoma kinase (ALK)-positive patients and 18 ALK-negative patients, were enrolled. The positive detection, maximal standardized uptake value (SUVmax), and distribution of nodal and extranodal involvement were recorded and analysed. Fifty patients with diffuse large B cell lymphoma (DLBCL) were collected as a control group. Results ALCL lesions were demonstrated to be 18F-FDG-avid tumours with a mean SUVmax of 19.4 ± 12.6. Most (76%) ALCL patients presented with stage III-IV disease, and nodal and extranodal involvement occurred in 74.0 and 72.0% of the patients, respectively. ALCL and DLBCL showed many similarities in tumour stage, 18F-FDG uptake and tumour involvement (P > 0.05), although the preferred extranodal organs of involvement (bone and the gastrointestinal tract, respectively) were different (P

Inflammatory myofibroblastic tumors (IMT) of the urachus is a rare neoplastic condition characterized by proliferation of spindle cell, likely derived from myofibroblasts or fibroblasts, with acute and chronic inflammatory infiltrate. Urachal IMT present with abdominal/pelvic pain and urinary symptoms. These often manifest as abdominal mass involving adjacent structures. We describe a case of young female with urachal IMT that was excised with a wide margin to ensure complete removal of all adjacent affected tissue using robotic-assisted laparoscopic approach. Immunohistochemical evidence of ALK and ALK gene rearrangement were confirmed in this tumor which are diagnostic of IMT.

Background: A previous network meta-analysis (NMA) compared the efficacy of anaplastic lymphoma kinase (ALK) inhibitors in ALK -positive non-small cell lung cancer (NSCLC). The phase III INSPIRE study of iruplinalkib was published recently. The present study aimed to add the results related to iruplinalkib to the NMA., Methods: A systematic literature search was performed in PubMed, Embase, Cochrane Library, Google, and Baidu. Randomized controlled trials (RCTs) reporting the independent review committee-assessed progression-free survival (PFS), objective response rate (ORR), or disease control rate (DCR) results of Asian patients with ALK inhibitor-naïve advanced ALK -positive NSCLC were eligible for inclusion in the NMA. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Bayesian fixed-effect models were used for the direct and indirect pairwise comparisons. This study was registered with PROSPERO (CRD42024555299)., Results: Eight studies, involving 1,477 Asian patients and seven treatments (crizotinib, alectinib, brigatinib, ensartinib, envonalkib, iruplinalkib, and lorlatinib), were included in the NMA. In terms of the overall risks of bias, all of the studies had "some concerns". All the next-generation ALK inhibitors were statistically superior to crizotinib in terms of PFS. Iruplinalkib had the best surface under the cumulative ranking curve (74.0%), followed by brigatinib (69.1%) and ensartinib (63.7%). Most of the pairwise comparisons did not reveal significant differences in the ORR and DCR. In terms of both the ORR and DCR, alectinib ranked first, followed by lorlatinib., Conclusions: Next-generation ALK inhibitors had better efficacy than crizotinib in the treatment of Asian patients with ALK inhibitor-naïve advanced ALK -positive NSCLC. Iruplinalkib may have more favorable PFS benefit than other ALK inhibitors for Asians., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-604/coif). The authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)