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

Non-small cell lung cancer is a very heterogeneous group of diseases. When choosing an effective patient management strategy, an oncologist focuses on the stage of the disease, the morphological form of the tumor, as well as its molecular genetic markers. Most of the targeted mutations in lung cancer today are in adenocarcinoma. The standard for detecting this type of cancer in 2022 is the determination of mutations in the EGFR genes (18-21 exons) and BRAF (V600E), translocations of the ALK and ROS1 genes, and determination of PD-L1 status regardless of gender, age, and history of smoking. Often, lung cancer is detected in the advanced stages, but the detection of ALK gene translocation can give the patient a high chance of a longer life expectancy and long-term control of the disease. In this article, on the example of a clinical case of a patient with ALK-positive lung adenocarcinoma, a multidisciplinary approach to the management of cancer patients, long-term control of the disease with the use of the second-generation targeted medication alectinib, as well as treatment options for disease progression are demonstrated.

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

Introduction. Lorlatinib is a third generation ALK tyrosine kinase inhibitor. Back in 2018, the drug underwent accelerated FDA approval and was recommended for the treatment of patients with ALK-positive non-small cell lung cancer after progression on crizotinib and another ALK inhibitor. For a long time, the use of the drug in Russia was possible only in clinical trials or expanded access program. However, now this drug is becoming available in our country.Purpose. To analyze the overall and intracranial response during lorlatinib therapy, as well as the tolerability of lorlatinib therapy in patients with ALK-positive non-small cell lung cancer who previously received crizotinib and one or more lines of cytostatic therapy.Materials and methods. The study included 39 patients aged 28 to 76 years, diagnosed with non-small cell lung cancer. In 36 cases, a translocation in the ALK gene was detected, in three, a ROS1 translocation. All patients received targeted therapy with crizotinib and one or more lines of chemotherapy before starting lorlatinib therapy. All patients received 100 mg lorlatinib therapy until disease progression or intolerable toxicity.Results. During the observation period for the moment of September 2021, an objective response was achieved in 28 patients (71.7%), in 10 patients (25.6%) – stabilization of the disease, in one patient (2.6%) – progression. The median duration of the drug was just over 40 months. The drug intake was characterized by a predictable and manageable toxicity profile.Conclusions. These data indicate a high direct efficacy of lorlatinib in patients with ALK/ROS1 translocations. The data obtained do not contradict the results obtained in the course of clinical trials. The drug lorlatinib has currently received registration in Russia for the treatment of non-small cell lung cancer in cases of the development of progression while taking secondgeneration ALK inhibitors or several lines of therapy with ALK inhibitors.

Background: Second and third-generation ALK inhibitors (ALKIs) have been recently approved for ALK-translocated lung cancer treatment, improving - and expanding - the first-line scenario. Methods: In this systematic review and metanalysis, we investigated the efficacy and safety of next-generation ALKIs in untreated advanced ALK-translocated lung cancer patients, searching for randomized phase III controlled trials through databases (PubMed, EMBASE, and the Cochrane Library). Inclusion and exclusion of studies, quality assessment, data extraction, and synthesis were independently accomplished by two reviewers, with discrepancies adjudicated by a third reviewer. Stata (StataCorp., v.16) software was used for the metanalysis. Results: In total, seven randomized controlled trials met our inclusion criteria. Comparing the results of next-generation ALKIs and control therapy (crizotinib or chemotherapy), next-generation ALKIs significantly improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), any lesion (aCNSRR) and measurable lesions of central nervous system response rate (mCNSRR). Safety results were similar between the experimental and control groups. Conclusion: Our analysis confirmed that next-generation ALKIs are the preferred first-line treatment option for ALK-translocated lung cancer. They are superior to crizotinib or chemotherapy in several clinical endpoints, including OS, PFS, ORR and CNS disease control, without increased toxicity. In the absence of head-to-head data, the choice between these molecules should be guided by physician experience and preference, drug-specific safety profile and schedule. [ABSTRACT FROM AUTHOR]

This article analyzes approaches of the treatment of ALK-positive non-small cell lung cancer (NSCLC). Despite the relatively small percentage of patients with ALK-gene rearrangements, identification of this mutation is very important. The most effective treatment for patients with ALK translocation is the use of ALK inhibitors, which significantly improve survival rates compared to standard chemotherapy. Crisotinib was the first drug approved for the treatment of advanced ALK-positive NSCLC. However, the soon emerging resistance during crizotinib therapy and the inevitable progression of the disease led to the development and introduction into clinical practice of new ALK inhibitors, such as ceritinib and alectinib, the latter of which is currently the best choice for the first-line treatment of metastatic ALK-positive NSCLC. Brigatinib and lorlatinib are drugs that are expected to be registered in the Russian Federation as soon as possible. Lorlatinib, a third generation of ALK and ROS1-kinase inhibitor, allows achieving a high rate of intracranial disease control, and is also effective against acquired resistance mutations during therapy with crizotinib and other ALK inhibitors. The toxicity profiles of each ALK inhibitor are extensively studied and controlled. The wider application of molecular genetic testing and the accumulation of data on resistance mutations will make it possible to correct selection of the next line of treatment. It also became possible to use a combined regimen of immunochemotherapy as the next line of treatment in case of progression against the background of targeted therapy. The available information allows

BackgroundSecond and third-generation ALK inhibitors (ALKIs) have been recently approved for ALK-translocated lung cancer treatment, improving - and expanding - the first-line scenario.MethodsIn this systematic review and metanalysis, we investigated the efficacy and safety of next-generation ALKIs in untreated advanced ALK-translocated lung cancer patients, searching for randomized phase III controlled trials through databases (PubMed, EMBASE, and the Cochrane Library). Inclusion and exclusion of studies, quality assessment, data extraction, and synthesis were independently accomplished by two reviewers, with discrepancies adjudicated by a third reviewer. Stata (StataCorp., v.16) software was used for the metanalysis.ResultsIn total, seven randomized controlled trials met our inclusion criteria. Comparing the results of next-generation ALKIs and control therapy (crizotinib or chemotherapy), next-generation ALKIs significantly improved progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR), any lesion (aCNSRR) and measurable lesions of central nervous system response rate (mCNSRR). Safety results were similar between the experimental and control groups.ConclusionOur analysis confirmed that next-generation ALKIs are the preferred first-line treatment option for ALK-translocated lung cancer. They are superior to crizotinib or chemotherapy in several clinical endpoints, including OS, PFS, ORR and CNS disease control, without increased toxicity. In the absence of head-to-head data, the choice between these molecules should be guided by physician experience and preference, drug-specific safety profile and schedule.

Lung cancer holds a leading position in the cancer mortality pattern worldwide. The emergence of knowledge about driver mutations heralded a new era in the targeted therapy for lung carcinomas. ALK translocation is identified in 5–7% of non-small cell lung cancer cases. ALK-positive lung adenocarcinomas are associated with specific clinical features, including no or light smoking history and younger age. Alectinib is a novel ALK inhibitor that has been granted a breakthrough therapy status by the FDA to accelerate approval as a second-line therapy after progression during crizotinib therapy.Here, the case of a patient with metastatic ALK-positive lung adenocarcinoma treated with alectinib has been discussed. Molecular genetic testing for driver mutations makes it possible to personalize approaches to anticancer drug therapy. At the same time, the custom-compounded targeted therapy is more often accompanied by significant objective responses and moderate symptoms of toxicity, which is relevant for patients in critical condition. The experience in using alectinib demonstrates the possibility of its long-term administration with high efficiency and a controlled safety profile.

Introduction. Translocations of ALK receptor tyrosine kinase occur in approximately 5–9 % of lung adenocarcinomas. The use of ALK inhibitors usually results in the reduction of tumor size. Nevertheless, the extent and duration of response can vary significantly. The aim of the study is to summarize the available information on the predictive role of various types of ALK translocations in response to ALK inhibitors. Material and methods. The review presents the data from relevant laboratory and clinical studies published in PubMed database, as well as the authors’ own results. Results. A number of experiments on cell cultures have demonstrated that the structure of ALK fusion affects the properties of the resulting chimeric protein, in particular its stability and sensitivity to crisotinib action. The few available clinical trials, evaluating the effect of ALK inhibitors depending on the type of translocation, showed heterogeneous results. While some of them detected associations between the so-called «short» variants of EML4-ALK rearrangements and worse survival when using crisotinib in comparison with the EML4-ALK type 1 variant, the others failed to confirm these observations. The study of 64 Russian patients receiving ALK inhibitors also did not support the effect of different ALK translocation variants on progression-free survival or objective response rate. Conclusions. There is a diversity of reported associations, with none of them characterized by sufficient reproducibility. Current evidences do not support the predictive role of ALK variants.

Introduction. Sufficient experience has been gained with the use of target drugs in patients with ALK-positive non-small cell lung cancer (NSCLC) over the past years. The multikinase inhibitor crizotinib was the first drug approved for use. The drug passed the accelerated registration in the United States, showing an indisputable advantage over standard chemotherapy both in untreated patients and patients, who had previously received cytostatic therapy. Brain metastasis is the manifestation of acquired resistance to crizotinib in almost half of patients, which requires local monitoring and/or prescription of the nextgeneration ALK inhibitors – ceritinib or alectinib. Experience has proven that it is sequential targeted therapy with the nextgeneration ALK inhibitors with a wider spectrum of anti-tumour activity and penetrating the blood-brain barrier that significantly improves the overall survival of these patients after disease progression on crizotinib. It appears then that the second generation drugs – ceritinib and particularly alectinib – show more impressive results when they are prescribed in the firstline therapy and have now replaced crisotinib in the clinical guidelines. Crizotinib has long remained the only target drug to treat ALK-positive patients in the Russian Federation. Material and methods. In our work, we analysed the crizotinib therapy outcomes in 104 patients with translocation in the ALK gene. The drug was prescribed in a standard dose of 250 mg orally twice per day. Treatment continued until disease progression or intolerable toxicity. Results. The objective response was 56.8%. The median time to progression was 13 months; the median overall survival was 46 months. Conclusion. The obtained data are consistent with previously published data and confirm the effectiveness of the drug in comparison with the previously available universal standard – combination chemotherapy.

Anaplastic lymphoma kinase (ALK) translocation is a rare genetic disorder that underlies lung cancer development. As a rule, these are young people, people with no or little smoking experience in whom the diagnosis is made at a late stage of the disease, when there are distant metastases; the liver and brain are often affected.The right choice of treatment policy in patients with ALK-positive non-small cell lung cancer can significantly improve survival rates. And molecularly targeted therapy with ALK inhibitors is effective even in these cases.Crizotinib (Xalkori). is the first ALK inhibitor that has been proven its antitumor activity. However, despite the initial pronounced antitumor effect, most patients develop drug resistance after 1–2 years of administration to krizotinib. In this case, the prescription of the second-generation drugs alectinib (Alecensa) and ceritinib (Zykadia) allows half of the patients to achieve a long objective response. Nevertheless today, alectinib in first-line demonstrates the best long-term results: the median progression-free survival is more than 34 months, 4-year overall survival rate is 64.5%. The drug has been shown a high activity in patients with brain metastases. Alektinib therapy not only has an advantage in terms of survival over Crizotinib, but also has an acceptable safety profile. This opens up new perspectives in the treatment of ALK-positive patients.

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Based on the high incidence of thromboembolic events (TEs) observed in lung adenocarcinomas with ALK translocations and taking into account the biological proximity of ROS1 and ALK , we conducted a retrospective analysis of patients with advanced lung carcinoma carrying rearrangements in ROS1 from 23 centres in Spain and one centre in Portugal. The main objective of the study was to analyse the incidence of TE in this population, looking for predictive risk factors, and its impact on overall survival. A total of 58 patients were included. The incidence of TEs throughout the disease was 46.6% (n = 27) with a median follow-up of 19 months (range: 1–78 months) and a median overall survival of 52 months in the total population and 50 months for the patients presenting TEs, with a hazards ratio of 1.12 (95% confidence interval: 0.47–2.65) p = 0.78. The majority of the events were venous (n = 24; 89%) and occurred in the ambulatory setting (n = 18; 67%). Almost half of the patients (n = 13; 48%) presented the TE in the peri-diagnostic period. The high incidence of thrombosis, especially during the cancer diagnosis process, requires special attention from a clinician. Despite the limitations of such a small descriptive study, its results are in accordance with previously reported data. It would be important to design prospective studies of antithrombotic prophylaxis in this population because of their possible impact in reducing the risk of TEs. • Patients with ROS1 NSCLC have an incidence of thromboembolic events of 46.6%. • Most of the thromboembolic events occurred during the diagnostic process of cancer. • Despite high incidence of thromboembolic events, it had no impact in overall survival. • Low albumin is associated with higher risk of thromboembolic events in this cohort. [ABSTRACT FROM AUTHOR]

Introduction Anaplastic lymphoma kinase ( ALK ) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK -rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants. Methods Among 96 ALK -rearrangement patients treated with crizotinib, 60 patients were identified with tumor specimens that could be evaluated by next-generation sequencing (NGS). We retrospectively evaluated the efficacy of crizotinib in different ALK variants. Results The median Progression-free survival (PFS) of the 96 ALK -rearrangement patients was 14.17 months. Among the 60 patients with NGS results, the most frequent variants were variant 3a/b (33.33%), variant 1 (23.33%) and variant 2 (15.00%). The percentage of rare EML4 - ALK variants and non EML4 - ALK variants were 10.00% and 18.33%. Survival analysis showed that patients with variant 2 appeared to have longer PFS than others (P = .021); also, patients with TP53 mutation seemed to have an unfavorable PFS than those with TP53 wild-type with a borderline p value (P = .068). After adjusting for other baseline characteristics, EML4 - ALK variant 2 was identified as an important factor for a better PFS of crizotinib. We also found that patients with variant 3a/b had shorter duration of response to crizotinib; however, no significant difference of PFS was observed between the PFS of variant3a/b and non-v3 EML4 - ALK variants. Conclusions Our results indicate prolonged PFS in patients with EML4 - ALK variant 2. [ABSTRACT FROM AUTHOR]

Patients with brain metastases (BM) are a population of high clinical need for new therapeutic approaches due to, as yet, very impaired survival prognosis. However, only few clinical trials have specifically addressed this prognostically highly heterogeneous patient population. New developments in the treatment of BM patients aim to reduce the side effects of local therapies, for example, by redefining the indications for stereotactic radiosurgery and whole-brain radiotherapy (WBRT) or introducing new applications like hippocampal sparing WBRT. Furthermore, systemic therapies become a more important treatment approach in patients harboring targetable mutations, as recent BM-specific endpoints in several phase III trials have shown promising intracranial efficacy. In addition, immune-checkpoint inhibitors show promising intracranial efficacy, particularly in patients with melanoma and non-small lung cancer BM. Here, we provide a review on the recent new developments in the local and systemic therapy approaches in BM patients. [ABSTRACT FROM AUTHOR]

Background: Monitoring response and resistance to kinase inhibitors is essential to precision cancer medicine, and is usually investigated by molecular profiling of a tissue biopsy obtained at progression. However, tumor heterogeneity and tissue sampling bias limit the effectiveness of this strategy. In addition, tissue biopsies are not always feasible and are associated with risks due to the invasiveness of the procedure. To overcome these limitations, blood-based liquid biopsy analysis has proven effective to non-invasively follow tumor clonal evolution. Patients and methods: We exploited urine cell-free, trans-renal DNA (tr-DNA) and matched plasma circulating tumor DNA (ctDNA) to monitor a metastatic colorectal cancer patient carrying a CAD-ALK translocation during treatment with an ALK inhibitor. Results: Using a custom next generation sequencing panel we identified the genomic CAD-ALK rearrangement and a TP53 mutation in plasma ctDNA. Sensitive assays were developed to detect both alterations in urine tr-DNA. The dynamics of the CAD-ALK rearrangement in plasma and urine were concordant and paralleled the patient's clinical course. Detection of the CADALK gene fusion in urine tr-DNA anticipated radiological confirmation of disease progression. Analysis of plasma ctDNA identified ALK kinase mutations that emerged during treatment with the ALK inhibitor entrectinib. Conclusion: We find that urine-based genetic testing allows tracing of tumor-specific oncogenic rearrangements. This strategy could be effectively applied to non-invasively monitor tumor evolution during therapy. The same approach could be exploited to monitor minimal residual disease after surgery with curative intent in patients whose tumors carry gene fusions. The latter could be implemented without the need of patient hospitalization since urine tr-DNA can be self-collected, is stable over time and can be shipped at specified time-points to central labs for testing. [ABSTRACT FROM AUTHOR]

Introduction Brain metastases in EGFR / ALK -driven NSCLC frequently pose treatment dilemmas. Tyrosine kinase inhibitors (TKIs) can control extracranial disease, but radiotherapy is often required for intracranial control. We aimed to evaluate the impact of first-line whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRS) or TKI alone on outcomes of patients with brain metastases from EGFR / ALK -driven NSCLC. Methods This single center retrospective review included 184 patients with brain metastases from EGFR / ALK -driven NSCLC, and analyzed effect of treatment choice on time to intracranial progression (TTIP) and overall survival (OS). Results First-line treatment for brain metastases consisted of WBRT in 120 patients, SRS in 37 and TKI alone in 27. WBRT-treated patients had more brain metastases, and more baseline symptoms. Median TTIP was longer in the WBRT group at 50.5 months than SRS or TKI groups at 12 and 15 months ( p = 0.0038). No significant difference was seen in median OS: 21.6 months in the WBRT group, 23.9 months in the SRS group and 22.6 months in the TKI group ( p = 0.67). In multivariable analysis, age > 65 years (HR 2.2, p = 0.0014), greater number of brain metastases (HR 2.48, p = 0.0002) and greater number of extracranial metastatic sites (2 vs 0–1 HR = 2.05, p = 0.014 and 3+ vs 0–1 HR = 2.95, p = 0.0001 were associated with shorter OS. No independent effect was seen from first-line CNS treatment choice. Conclusions First-line WBRT for brain metastases from EGFR / ALK -driven NSCLC was associated with longer TTIP than SRS or TKI alone, with no difference in OS. These results could support deferral of WBRT until intracranial progression in selected patients who are closely monitored. [ABSTRACT FROM AUTHOR]

Background: Anaplastic lymphoma kinase (ALK) inhibition using crizotinib has become the standard of care in advanced ALK-rearranged non-small cell lung cancer (NSCLC), but the treatment outcomes and duration of response vary widely. Echinoderm microtubule-associated protein-like 4 (EML4)-ALK is the most common translocation, and the fusion variants show different sensitivity to crizotinib in vitro. However, there are only limited data on the specific EML4-ALK variants and clinical responses of patients to various ALK inhibitors. Patients and methods: By multiplex reverse-transcriptase PCR, which detects 12 variants of known EML4-ALK rearrangements, we retrospectively determined ALK fusion variants in 54 advanced ALK rearrangement-positive NSCLCs. We subdivided the patients into two groups (variants 1/2/others and variants 3a/b) by protein stability and evaluated correlations of the variant status with clinical responses to crizotinib, alectinib, or ceritinib. Moreover, we established the EML4-ALK variantexpressing system and analyzed patterns of sensitivity of the variants to ALK inhibitors. Results: Of the 54 tumors analyzed, EML4-ALK variants 3a/b (44.4%) was the most common type, followed by variants 1 (33.3%) and 2 (11.1%). The 2-year progression-free survival (PFS) rate was 76.0% [95% confidence interval (CI) 56.8-100] in group EML4-ALK variants 1/2/others versus 26.4% (95% CI 10.5-66.6) in group variants 3a/b (P=0.034) among crizotinibtreated patients. Meanwhile, the 2-year PFS rate was 69.0% (95% CI 49.9-95.4) in group variants 1/2/others versus 32.7% (95% CI 15.6-68.4) in group variants 3a/b (P=0.108) among all crizotinib-, alectinib-, and ceritinib-treated patients. Variant 3a- or 5aharboring cells were resistant to ALK inhibitors with>10-fold higher half maximal inhibitory concentration in vitro. Conclusion: Our findings show that group EML4-ALK variants 3a/b may be a major source of ALK inhibitor resistance in the clinic. The variant-specific genotype of the EML4-ALK fusion allows for more precise stratification of patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Various mechanisms of resistance to ALK inhibitors in ALK rearranged adenocarcinomas are reported including secondary gatekeeper mutations, bypass signaling or ALK amplifications as the commonest ones. We report a new mechanism of resistance with transformation of adenocarcinoma into small cell lung cancer. A 53-year-old non-smoker woman, experienced cancer progression after two lines of ALK inhibitors. A new biopsy showed a small cell lung cancer. FISH revealed persistent ALK rearrangement with an atypical pattern and complete loss of the 5′ region of the ALK gene. [ABSTRACT FROM AUTHOR]

Objectives Anaplastic Lymphoma Kinase (ALK) gene rearrangements have been described in 3–5% of lung adenocarcinomas (ADC) and their identification is essential to select patients for treatment with ALK tyrosine kinase inhibitors. For several years, fluorescent in situ hybridization (FISH) has been considered as the only validated diagnostic assay. Currently, alternative methods are commercially available as diagnostic tests. Material and methods A series of 217 ADC comprising 196 consecutive resected tumors and 21 ALK FISH-positive cases from an independent series of 702 ADC were investigated. All specimens were screened by IHC (ALK-D5F3-CDx-Ventana), FISH (Vysis ALK Break-Apart-Abbott) and RT-PCR (ALK RGQ RT-PCR-Qiagen). Results were compared and discordant cases subjected to Next Generation Sequencing. Results Thirty-nine of 217 samples were positive by the ALK RGQ RT-PCR assay, using a threshold cycle (Ct) cut-off ≤35.9, as recommended. Of these positive samples, 14 were negative by IHC and 12 by FISH. ALK RGQ RT-PCR/FISH discordant cases were analyzed by the NGS assay with results concordant with FISH data. In order to obtain the maximum level of agreement between FISH and ALK RGQ RT-PCR data, we introduced a new scoring algorithm based on the ΔCt value. A ΔCt cut-off level ≤3.5 was used in a pilot series. Then the algorithm was tested on a completely independent validation series. By using the new scoring algorithm and FISH as reference standard, the sensitivity and the specificity of the ALK RGQ RT-PCR(ΔCt) assay were 100% and 100%, respectively. Conclusions Our results suggest that the ALK RGQ RT-PCR test could be useful in clinical practice as a complementary assay in multi-test diagnostic algorithms or even, if our data will be confirmed in independent studies, as a standalone or screening test for the selection of patients to be treated with ALK inhibitors. [ABSTRACT FROM AUTHOR]

Objective As the diagnosis of non-small cell lung cancer ( NSCLC) is based on cytology in around 70% of cases, it is important to use the same material for molecular analyses. Fluorescence in situ hybridization ( FISH) is the only approved test for the detection of the translocation and inversion of anaplastic lymphoma kinase ( ALK), but the optimal procedures for the fixation or staining of the sample before FISH evaluation have not been established. We investigated whether ALK gene status determined by FISH in a prospectively enrolled case series of patients was affected by fixation and staining. Methods One hundred and fifteen cytological samples were obtained by transbronchial needle aspiration (TBNA) or endobronchial ultrasound (EBUS)-TBNA from 109 patients with NSCLC. All samples were evaluated for epidermal growth factor receptor ( EGFR) mutation by pyrosequencing and for ALK rearrangement by FISH. Specimens for ALK determination had been fixed with Cytofix® and/or Carnoy's solution or 10% formalin (cell blocks) and variously stained. Results Sixteen (14%) of the 115 samples were mutated for EGFR and 99 (86%) showed wild-type EGFR status. Of these 115 samples, 79 (69%) were negative for echinoderm microtubule-associated protein like 4 ( EML4) - ALK translocation, nine (8%) were positive and 27 (23%) were unevaluable. In particular, 19 (26%) of the 72 Papanicolaou-stained smears fixed with Cytofix were unevaluable because of inadequate samples or cell overlapping; neither of the two May-Grünwald-Giemsa-stained samples were evaluable. Ten of 17 smears used for rapid on-site evaluation ( ROSE) and immediately post-fixed in Carnoy's solution or 80% alcohol were evaluable. Conclusions In this series, smears were unevaluable as a result of inadequate samples, cell overlapping or lack of fixation performed immediately after FNA. [ABSTRACT FROM AUTHOR]

Purpose: To present a case of uveal metastases in a patient with anaplastic lymphoma kinase (ALK)--positive non--small-cell lung cancer and the response to systemic ALK inhibitors. Methods: A retrospective case report. A 75-year-old nonsmoker who has ALK-positive left upper bronchus adenocarcinoma-developed uveal metastases during his course of treatment. Results: Initially, the patient's disseminated malignancy showed a significant response to crizotinib. However, because the bone metastases started progressing again and he developed bilateral ocular metastases, he was switched to ceritinib. After initiation of ceritinib therapy, the uveal melanomas have shown a significant decrease in thickness and no new lesions have developed. Conclusion: ALK inhibitors are an effective first-line treatment in patients with ALKpositive uveal metastases secondary to ALK-positive non--small-cell lung cancer. Despite the fact that crizotinib, a first-generation ALK inhibitor, is initially effective in dealing with non--small-cell lung cancer and its metastases, resistance to it seems to develop on a regular basis. A second-generation ALK inhibitor, such as ceritinib, is also effective in overcoming this resistance in treating those with ALK-positive uveal metastases. [ABSTRACT FROM AUTHOR]

Research over the last decade has determined that the gene rearrangement involving the anaplastic lymphoma kinase (ALK) gene is an oncogenic driver in approximately 5% of patients with non-small cell lung carcinoma (NSCLC). This review describes the discovery of the ALK translocation, development of ALK directed therapy, and acquired resistance to ALK directed therapy with a focus on the clinical data and efficacy of the most recently approved ALK inhibitor, ceritinib. [ABSTRACT FROM AUTHOR]

Brain metastases (BM) are an increasing challenge in the management of patients with advanced cancer. Treatment options for BM are limited and mainly focus on the application of local therapies. Systemic therapies including targeted therapies are only poorly investigated, as patients with BM were frequently excluded from clinical trials. Several targeted therapies have shown promising activity in patients with BM. In the present review we discuss existing and emerging targeted therapies for the most frequent BM primary tumor types. We focus on challenges in the conduction of clinical trials on targeted therapies in BM patients such as patient selection, combination with radiotherapy, the obstacles of the blood-brain barrier and the definition of study end points. [ABSTRACT FROM AUTHOR]

Abstract: The discovery of several molecular alterations that underlie non-small cell lung cancer (NSCLC) pathogenesis has led to the development of targeted therapies. In particular, gefitinib and erlotinib have become the standard of care in patients harboring epidermal growth factor receptor mutations, while crizotinib showed an impressive efficacy in patients with ALK-positive NSCLC. Nevertheless, the occurrence of clinical resistance limits the long term results of these novel agents. The identification of the molecular mechanisms responsible for acquired resistance to targeted therapy is crucial in order to pursue the creation of rational strategies to overcome resistance. In the current review, we will focus on the acquired resistance mechanisms to EGFR-TKIs and crizotinib and the therapeutic strategies currently under study to overcome resistance. [Copyright &y& Elsevier]

Aims To study the ALK translocation in patients with advanced non-small-cell lung carcinomas ( NSCLCs) seen at a European cancer centre, and its association with EGFR mutations, KRAS mutations and MET amplification. Methods and results The study included samples from 86 patients diagnosed with advanced NSCLC. ALK fluorescence in-situ hybridization ( FISH) was performed using the ALK break-apart probe set (Vysis). ALK FISH-positive cases were defined as those with more than 15% break-apart signals or isolated red signals in 50 cells. EGFR and KRAS mutations were determined by direct sequencing. All ALK-positive cases were analysed retrospectively for MET amplification using a FISH assay, and for ALK mutations by sequencing. We found nine (10.5%) ALK-positive cases, all in adenocarcinomas and the majority in female patients (88.9%). Signet ring cells were observed in four (44.4%) of the nine patients. None of the ALK translocated cases showed MET amplifications or EGFR, KRAS and ALK mutations. Conclusions The prevalence of ALK translocation in an unselected population of European patients with advanced NSCLCs was 10%. This alteration was mutually exclusive with EGFR and KRAS mutations, as well as with MET amplification. If multiplexing is considered at the preanalytical phase, lung biopsy specimens are sufficient for performing several predictive assays. [ABSTRACT FROM AUTHOR]

Abstract: Most of the cases of non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage and are treated with platinum-doublet chemotherapy. However, some patients are refractory to this treatment. The aim of this study was to identify the clinical and molecular characteristics of patients with refractory disease. All consecutive patients between 2003 and 2006, who received a platinum-doublet chemotherapy as first-line treatment for stage IIIb-IV NSCLC, were included. Refractory patients were defined as early progressive disease (PD) at the first evaluation of chemotherapy according to WHO criteria. The clinical, histo-pathological, and molecular characteristics (EGFR: exon 19, 20, 21 and KRAS: exon 2 by PCR sequencing; ALK by immunohistochemistry) and survival of refractory patients with initial PD (r-patients) and controlled disease (c-patients) were compared by univariate analyses. Factors that differed between the two groups (p-value <0.25 in univariate analyses) were entered into multivariate analysis. In this study, 178 patients were included. The first tumor assessment was carried out after a median of three cycles (range 1–4). Forty-six (25.8%) patients were refractory. Clinical presentation was similar between r- and c-patients. The sarcomatoid histological subtype was more common in r-patients than c-patients (10.9% vs. 1.5%, respectively; p =0.057). The proportion of EGFR (5.2% vs. 9.6%, p =0.224) and KRAS mutations (11.1% vs. 5.7%, p =0.357), and the expression of ALK (6.3% vs. 2.5%, p =0.327) did not differ significantly between the two groups. In multivariate analysis, sarcomatoid histological subtype was the only factor associated with early PD (OR=7.50; 95%CI: 1.02–55.45; p =0.048). r-Patients had significantly shorter survival than c-patients (median 5 months (IQR 3.2–9.9) vs. 15.4 months (IQR 9.9–22.5), respectively; p <0.0001). In conclusion, patients with early PD under platinum-doublet chemotherapy had shorter survival than c-patients. Sarcomatoid histological subtype was the only independent factor associated with early PD. [Copyright &y& Elsevier]

Abstract: Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations in non-small cell lung cancer (NSCLC) are mutually exclusive. However, several exceptional cases harboring both genetic alterations have been reported. In this study, a total of 444 patients with lung adenocarcinoma were examined for their EGFR and ALK status at Seoul National University Hospital between July 2008 and September 2011. EGFR mutations and ALK translocations were detected in 228 (51.4%) and 34 (7.7%) patients, respectively. Four patients (0.9%) had both genetic alterations and three underwent curative surgery. One patient who received both EGFR tyrosine kinase and ALK inhibitors, separately showed an objective response to the ALK inhibitor alone. Considering our and previous studies, patients harboring both EGFR mutation and ALK translocation showed differential sensitivities to both targeted therapies, suggesting a variable dependence on EGFR and ALK oncogenes. [Copyright &y& Elsevier]

Abstract: Primary adenocarcinoma with signet-ring cell component (Ad-SRCC) of the lung has been well characterized clinicopathologically and histologically, but their genetics has rarely been investigated. A recent report suggesting an association between Ad-SRCC and EML4-ALK fusion prompted us to undertake a histological, immunohistochemical, and molecular analysis of 10 cases of primary Ad-SRCC identified out of 699 lung adenocarcinomas (1.4%). Most of the Ad-SRCCs showed characteristic architectural as well as cytological features including cohesive clustering of signet-ring cells, a solid/acinar growth pattern, and alveolar filling at the tumor periphery. Diffuse co-expression of TTF-1 and p63 was observed in half of the Ad-SRCCs, and this immunoprofile has not been recognized previously. Four Ad-SRCCs (40%) harbored ALK translocations detected by reverse-transcriptase polymerase chain reaction, fluorescence in situ hybridization, and immunohistochemistry. One new EML4-ALK fusion variant was identified. One ALK-rearranged tumor showed focal squamous differentiation. None of the present Ad-SRCCs had EGFR or KRAS mutations, regardless of ALK status. This study successfully utilized tumor histology alone to identify a subset of adenocarcinomas showing a high rate of ALK translocation. The characteristic histology, immunoprofile, frequent ALK translocation, and total lack of EGFR or KRAS mutations, may suggest that Ad-SRCC forms a histologically/molecularly coherent subgroup of adenocarcinoma. [Copyright &y& Elsevier]

In January 2003, a 55-year old, non-smoking woman visited our hospital to undergo treatment for T4N0M0 pulmonary adenocarcinoma of the left lung. Until death in October 2015, she received over 20 lines of treatment including a second line therapy with gefitinib, which showed long response. In March 2014, she noticed the left axillar lymph node swelling. Aspiration cytology of the lymph node revealed the presence of adenocarcinoma harboring EGFR exon 19 deletion (Ex19del) but not T790M. Concomitant ALK translocation of variant 1 was also detected. Crizotinib and alectinib showed marked decrease of serum CEA value from 731.9 to 122.2 and moderate radiologic response. In contrast, both Ex19del and T790M, but not ALK translocation, were detected in the metastasis to the left anterior chest wall. [ABSTRACT FROM AUTHOR]