Primary anaplastic lymphoma kinase-positive large B-cell lymphoma of the left bulbar conjunctiva: A case report

BACKGROUND Anaplastic lymphoma kinase(ALK)-positive large B-cell lymphoma(LBCL)is an aggressive and rare variant of diffuse LBCL.Herein,we report an uncommon case of stage IE extranodal ALK-positive LBCL initially originating in the bulbar con-junctiva.CASE SUMMARY A 63-year-old woman presented with a mass in the left bulbar conjunctiva that had persisted for six months,accompanied by swelling and pain that had per-sisted for 3 d.Eye examination revealed an 8 mm slightly elevated pink mass in the lower conjunctival sac of the left eye.Microscopically,the tumor was com-posed of large immunoblastic and plasmablastic large lymphoid cells with scattered anaplastic or multinucleated large cells.Immunophenotypically,the neoplastic cells were positive for ALK,CD10,CD138,Kappa,MUM1,BOB.1,OCT-2,CD4,CD45,EMA,CD79a,CD38,and AE1/AE3,and negative for CD20,PAX5,Lambda,BCL6,CD30 and all other T-cell antigens.The results of gene rearrangement tests showed monoclonal IGH/IGK/IGL and TCRD rearran-gements.Fluorescence in situ hybridization studies did not reveal any BCL2,BCL6 or MYC rearrangements.Furthermore,Epstein-Barr virus was not detected by in situ hybridization in the lesions.Based on the histopathological and imaging examinations,the neoplasm was classified as stage IE ALK-positive LBCL.No further treatments were administered.At the 6,15,and 21 mo postoperative follow-up visits,the patient was in good condition,without obvious discomfort.This case represents the first example of primary extranodal ALK-positive LBCL presenting as a bulbar conjunctival mass,which is extremely rare and shares morphological and immunohistochemical features with a variety of other neo-plasms that can result in misdiagnosis.CONCLUSION Awareness of the condition presented in this case report is necessary for early and accurate diagnosis and appropriate treatment.

Pathological complete response to neoadjuvant alectinib in unresectable anaplastic lymphoma kinase positive non-small cell lung cancer:A case report

BACKGROUND The development of anaplastic lymphoma kinase(ALK)-tyrosine kinase inhibitors(TKIs)has remarkably improved the prognosis of patients with ALK-positive advanced non-small cell lung cancer(NSCLC).Alectinib,the second-generation ALK-TKI,has been approved as first-line treatment for advanced or metastatic NSCLC patients with ALK rearrangement.Neoadjuvant therapy can achieve tumor downstaging and eradicate occult lesions in patients with potentially resectable disease.Whether neoadjuvant alectinib can be a conversion therapy in ALK-positive advanced NSCLC patients remains unclear.CASE SUMMARY A 41-year-old man was pathologically diagnosed with locally advanced ALKpositive stage IIIB NSCLC.Alectinib was prescribed to induce tumor downstaging and facilitate the subsequent surgical resection.The tumor was successfully downstaged and pathological complete response was achieved.Left upper lobectomy with mediastinal lymphadenectomy was performed after tumor downstaging.The patient has continued to receive alectinib as adjuvant therapy during postoperative follow-up with a recurrence-free survival of 29 mo as of writing this report.CONCLUSION This case sheds light on the feasibility and safety of alectinib as a neoadjuvant treatment for stage IIIB NSCLC patients with ALK rearrangement.Its efficacy needs to be validated in prospective clinical trials.

Sarcoidosis mimicking metastases in an echinoderm microtubuleassociated protein-like 4 anaplastic lymphoma kinase positive nonsmall-lung cancer patient:A case report

BACKGROUND Rearrangements of the anaplastic lymphoma kinase(ALK)gene(ALK-positive)represent an oncogenic driver in approximately 3%-5%of non-small-lung cancer(NSCLC)patients.Sarcoidosis is a multisystem disease,and its reported incidence in Asia is 1 or less per 100000 people per year.The co-occurrence of sarcoidosis and ALK-positive NSCLC is rare,and ALK-positive lung cancer is likely to spread quickly.Therefore,the co-occurrence of sarcoidosis is more easily misdiagnosed as metastatic lung cancer by radiological examination.CASE SUMMARY A 50-year-old man had a nodule in the left superior lobe,many small nodules in left superior and right lungs,and enlarged bilateral hilar,mediastinal,and right supraclavicular lymph nodes.Computed tomography-guided pulmonary biopsy of the nodule in the left superior lobe revealed echinoderm microtubuleassociated protein-like 4 gene-ALK positive NSCLC with concomitant noncaseating granuloma.This patient was treated with crizotinib.Thirty days later,a chest computed tomography scan revealed a dramatic decrease in the size of the left superior lobe nodule;however,the lesions in the right lung progressed.The right supraclavicular lymph nodes showed granulomas,and no tumor cells were identified in the specimens. The angiotensin-converting enzyme level was high.After 1 wk of methylprednisolone treatment, a significant response of all lesionswas revealed. Following radical resection of the lung cancer, noncaseatinggranulomas were observed in both lung tissues and lymph nodes, which resultedin a diagnosis of echinoderm microtubule-associated protein-like 4-ALK positiveNSCLC accompanied with sarcoidosis.CONCLUSIONOur experience illustrates that pathological evidence is needed to confirmmetastatic disease, especially when some suspected metastatic lesions arenegative for malignancy.

Clinicopathologic characteristics and therapeutic responses of Chinese patients with non-small cell lung cancer who harbor an anaplastic lymphoma kinase rearrangement

Introduction: The rearrangement of the anaplastic lymphoma kinase(ALK) gene accounts for approximately 1%–6% of lung adenocarcinoma cases and deines a molecular subgroup of tumors characterized by clinical sensitivity to ALK inhibitors such as crizotinib. This study aimed to identify the relationship between ALK rearrangement and the clinico?pathologic characteristics of non?small cell lung cancer(NSCLC) and to analyze the therapeutic responses of crizotinib and conventional chemotherapy to ALK rearrangement in NSCLC patients.Methods: A total of 487 lung cancer patients who underwent testing for ALK rearrangement in our department were included in this study. ALK rearrangement was examined by using fluorescence in situ hybridization(FISH) assay.Results: Among the 487 patients, 44(9.0%) were diagnosed with ALK rearrangement by using FISH assay. In 123 patients with adenocarcinoma who were non?smokers and of a young age(≤58 years old), the frequency of ALK rearrangement was 20.3%(25/123). Short overall survival(OS) was associated with non?adenocarcinoma tumor type(P = 0.006), poorly diferentiated tumors(P al growth factor rece= 0.001), advanced?stage tumors(P < 0.001), smoking history(P ptor(EGFR)(P = 0.008), and wild?type epidermrter time to cancer p= 0.008). Moreover, patients with poorly diferentiated and advanced?stage tumors had a shorogression compared with those with well diferentiated(P = 0.023) and early?stage tumors(P = 0.001), respectively.Conclusions: ALK?rearranged NSCLC tends to occur in younger individuals who are either non?smokers or light smokers with adenocarcinoma. Patients with ALK rearrangement might beneit from ALK inhibitor therapy.

Primary bone anaplastic lymphoma kinase positive anaplastic largecell lymphoma: A case report and review of the literature

BACKGROUND Primary bone lymphoma(PBL)is an uncommon extranodal disease that represents approximately 1%-3%of lymphomas.Anaplastic lymphoma kinase(ALK)positive anaplastic large-cell lymphoma(ALCL)is an extremely rare type of PBL.The aim of this report is describe the symptoms,diagnosis,and treatment of primary bone ALK-positive ALCL.CASE SUMMARY A 66-year-old man presented to our hospital with neck and shoulder pain and intermittent fever that lasted for 1 mo.After extensive evaluation,positron emission tomography-computed tomography(CT)examination showed multiple osteolytic bone lesions without other sites lesions.CT-guided biopsy of the T10 vertebral body was performed,and the pathology results showed that neoplastic cells were positive for ALK-1,CD30,and CD3.A diagnosis of primary bone ALK positive ALCL was ultimately made.The patient was in partial response after four cycle soft cyclophosphamide,doxorubicin,vincristine,and prednisone chemotherapy,and we planned to repeat the biopsy and radiological examination after completion of the fifth cycle of therapy.CONCLUSION Primary bone ALK positive ALCL is a rare disease and physicians should keep in mind that ALCL can present with isolated osseous involvement without nodal involvement,and lymphoma should be considered in the differential diagnosis of primary bone lesions.

Acute leukemic phase of anaplastic lymphoma kinase-anaplastic large cell lymphoma: A case report and review of the literature

BACKGROUND Anaplastic large cell lymphoma(ALCL)is a rare and heterogeneous malignant tumor,which is classi
ed as anaplastic lymphoma kinase(ALK)positive ALCL and ALK-ALCL.Many patients are diagnosed with ALCL at the stage of bone marrow involvement.However,ALCL patients with clinical manifestations consistent with acute leukemia are relatively rare.CASE SUMMARY In this report,the patient did not receive appropriate diagnosis and treatment despite a two-year history of lymph node enlargement.Hereafter,she was admitted for B symptoms and was diagnosed as ALK-ALCL by lymph node biopsy.Then,the disease progressed to leukemia without any treatment after 2 mo.The proportion of lymphoma cells in bone marrow was as high as 96%,and the proportion of peripheral blood was 84%.She also had clinical manifestations similar to acute leukemia.After completion of chemotherapy,she developed granulocytopenia and fever and died from septicemia.CONCLUSION ALCL with leukemic presentation is a late manifestation of lymphoma with low chemotherapy tolerance and poor prognosis.

Coexistence of anaplastic lymphoma kinase rearrangement in lung adenocarcinoma harbouring epidermal growth factor receptor mutation:A single-center study

BACKGROUND Accumulating evidences confirm that epidermal growth factor receptor(EGFR)mutation and anaplastic lymphoma kinase(ALK)rearrangement have coexisted in lung adenocarcinoma(LUAD).However,Its biological mechanism,clinicopathological features,and optimization of targeted drugs have not yet been completely elucidated.AIM To explore the clinical profile of LUAD patients with co-mutations of EGFR and ALK genes,with hopes of scientifically guiding similar patients towards selected,targeted drugs.METHODS Two hundred and thirty-seven LUAD patients were enrolled.EGFR mutations were detected by the amplification refractory mutation system-peptide nucleic acid technique,while the expression of ALK rearrangement was screened by the 5′/3′imbalance strategy for reverse transcription followed by quantitative polymerase chain reaction analysis.The clinicopathological features of these patients were analysed retrospectively,and the follow-up data were collected.RESULTS There were six cases with co-mutations of EGFR and ALK genes,which were more common in women,non-smoking and stage IV LUAD patients with bone metastasis,hence a positive rate of 2.53%(6/237).EGFR-tyrosine kinase inhibitors(EGFR-TKIs)were their preferred drugs for targeted therapy in these patients,with progression-free survival ranging from two months to six months.CONCLUSION In Gannan region,the positive rate of co-mutations of EGFR and ALK genes in LUAD patients is relatively high,and the co-mutations are more common in women,non-smoking and stage IV patients with bone metastasis.These patients prefer EGFR-TKIs as their preferred targeted drugs,but the therapeutic effect is not good.EGFR/ALK dual-TKIs may be more effective targeted drugs,which needs further study.

Alectinib: a novel second generation anaplastic lymphoma kinase(ALK) inhibitor for overcoming clinically-acquired resistance

The development of inhibitors for the tyrosine anaplastic lymphoma kinase(ALK) has advanced rapidly, driven by biology and medicinal chemistry. The first generation ALK inhibitor crizotinib was granted US FDA approval with only four years of preclinical and clinical testing. Although this drug offers significant clinical benefit to the ALK-positive patients, resistance has been developed through a variety of mechanisms. In addition to ceritinib, alectinib is another second-generation ALK inhibitor launched in 2014 in Japan. This drug has a unique chemical structure bearing a 5H-benzo[b]carbazol-11(6H)-one structural scaffold with an IC_(50) value of 1.9 nmol/L, and is highly potent against ALK bearing the gatekeeper mutation L1196 M with an IC_(50) of 1.56 nmol/L. In the clinic, alectinib is highly efficacious in treatment of ALK-positive non-small cell lung cancer(NSCLC), and retains potency to combat crizotinib-resistant ALK mutations L1196 M, F1174 L, R1275 Q and C1156 Y.

Association of an anaplastic lymphoma kinase pathway signature with cell de-differentiation, neoadjuvant chemotherapy response, and recurrence risk in breast cancer

Background:Aberrant activation of anaplastic lymphoma kinase(ALK)signaling has been found to be involved in the tumorigenesis of multiple types of cancer.The aim of this study was to determine the role of this pathway in the pathogenesis of breast cancer.Methods:An ALK pathway signature that we generated previously was used to compute the ALK pathway activity in 6381 breast cancer samples from 42 microarray datasets,and the associations between ALK pathway signature score and clinical variables were examined using logistic regression and survival analyses.Results:Our results indicated that high ALK pathway activity was a significant risk factor for hormone receptor-negative,high-grade breast cancer in the 42 datasets.ALK pathway activity was positively associated with pathological complete response(pCR)in 15 datasets annotated with patient’s neoadjuvant chemotherapy response information(overall odds ratio=1.67,P<0.01),and this association was more significant in HER2-negative and grade 1&2 tumors than in HER2-positive and grade 3 tumors.ALK pathway activity was also positively associated with recurrence risk in breast cancer patients from 30 datasets annotated with survival information(overall hazard ratio=1.21,P<0.01),particularly in patients with age>50 years old,with positive lymph nodes,or with residual disease after neoadjuvant chemotherapy.Conclusions:ALK may be involved in breast cancer tumorigenesis,and ALK pathway signature score may serve as a prognostic biomarker for breast cancer.

The Role of Anaplastic Lymphoma Kinase Receptor in Neuroblastoma

Neuroblastoma(NB),a frequently occurring pediatric disease,is derived from the neural crest cells in the sympathetic ganglia and adrenal medulla.Notably,it is a heterogeneous tumor consisting of many affection factors,such as the diagnosis time within the first year and the diversity of the histology and genetic features.Despite improved outcomes in NB patients,it remains a difficult clinical problem and requires new therapeutic targets and methods.The somatic acquired activation point mutations in the receptor tyrosine kinase anaplastic lymphoma kinase(ALK)represent potential targets for treating NB.Herein,we review the underlying mechanisms of ALK in NB development,the latest available strategies to block ALK constitutive activity to treat NB,and discuss the current clinical challenges of resistance to these therapies and the strategies to overcome them.

Inflammatory myofibroblastic tumor from molecular diagnostics to current treatment

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

Rapidly progressing primary pulmonary lymphoma masquerading as lung infectious disease:A case report and review of the literature

BACKGROUND Primary anaplastic large cell lymphoma of the lung represents a diagnostic challenge due to diverse manifestations and non-specific radiological findings,particularly in cases that lack extra-pulmonary manifestations and lung biopsy.CASE SUMMARY A 40-year-old woman presented with a 6-d history of fever,dry coughing,and dyspnea.Her white blood cell count was 20100/mm3 with 90%neutrophils.PaO2 was 60 mmHg and SaO2 was 90%when breathing ambient air.Chest computed tomography(CT)identified a solid nodule,15 mm in diameter,with a poorly defined boundary in the upper right lung,and several smaller solid nodules throughout both lungs.Pulmonary artery CT and subsequent bedside X-ray showed diffuse patchy shadows throughout both lungs.Repeated cultures of blood samples and alveolar lavage failed to identify any pathogen.Due to the mismatch between clinical and imaging features,we conducted a bone marrow biopsy,and the results showed proliferation along all three lineages but no atypical or malignant cells.The patient received empirical antibacterial,antiviral,and antifungal treatments,as well as corticosteroids.The patient’s condition deteriorated rapidly despite treatment.The patient died 6 d after hospitalization due to respiratory failure.Post-mortem lung biopsy failed to show inflammation but identified widespread infiltration of alveolar septum by anaplastic lymphoma kinase(ALK)-positive anaplastic cells.CONCLUSION ALK-positive anaplastic large cell lymphoma could present as a primary pulmonary disease without extra-pulmonary manifestations.

Hepatic inflammatory myofibroblastic tumor: A case report

BACKGROUND Hepatic inflammatory myofibroblastic tumor(HIMT)is a rare type of hepatic tumor.It is always misdiagnosed and mistreated because it is primarily found with no obvious specific manifestation,and its imaging findings are diverse.CASE SUMMARY Here,we report a case of HIMT that was initially diagnosed as liver malignancy but was confirmed as HIMT by histopathology after hepatectomy.Mostly,HIMTs are infiltrated with plasma cells and stain positively for anaplastic lymphoma kinase on immunohistochemistry as well as for some other kinases.CONCLUSION HIMT can be treated with single nonsteroidal anti-inflammatory drugs and without surgery when it is diagnosed accurately.Because the etiology of HIMT is unknown and the diagnosis is difficult,the pathogenesis and clinical process need to be further studied.

Detection of ALK translocation in non-small cell lung carcinoma(NSCLC) and its clinicopathological significance using the Ventana immunohistochemical staining method: a single-center large-scale investigation of 1,504 Chinese Han patients

Objective： The novel fully automated immunohistochemistry （IHC） assay-Ventana anaplastic lymphoma kinase （ALK）-DSF3 for screening ALK rearrangements has been approved by China＇s Food and Drug Administration in 2013, our previous study disclosed a highly specificity and sensitivity nearly 100%, and its efficacy needs to be evaluated in a large cohort of primary lung adenocarcinoma patients, and to compare clinicopathological features with ALK （＋） and ALK （-） lung adenocarcinoma.Methods： A total of 1,504 consecutive surgical lung adenocareinoma eases of Chinese Han population were collected and re-diagnosed according to the 2011 multidisciplinary classification of lung adenocarcinoma. Fully automated Ventana ALK-D5F3 IHC staining with a binary scoring was adopted to evaluate staining and correlated with dinieopathologieal characters, including age, sex, differentiation degree, histological subtype, lymph node metastasis, and clinical staging. ALK （＋） patients were followed-up, and targeted therapy of ALKinhibitors was adopted and observed in patients with stage IV according to the NCCN guideline.Results： ALK positive adenocarcinomas were identified in 6.6% of the surgically resected 1,504 NSCLCs, and significantly younger than the negative group （P〈0.05）.Mucinous adenocarcinoma （28.2%） was determined to be predominant in ALK （＋） cases, followed by the solid type （11.7%）, specific type （6.8%）, papillary type （5.6%）, acinar type （5.5%）, and lepidic type （3.1%）, and the differences were statistically significant （χ2=42.01 1, P〈0.05）. ALK （＋） adenocarcinoma with lymph node metastasis （10.8%） were significantly higher than that without lymph node metastasis （4.5%） （g2=19.809, P〈0.05）; and ALK （＋） in phase Ⅳ （20%） was significantly higher than phaseⅢ （12.9%）, phase Ⅱ （4.2%）, phase Ⅰ （4.5%）, and phase 0 （0） （g2=36.068, P〈0.05）. Multivariate logistic regression disclosed that patient age, AJCC staging, and histological mucinous subtype were correlated with ALK positive staining （OR=0.959, 1.578, 5.036, respectively）. Sixty eight patients had followed-up results, five patients out of which primarily diagnosed or progressed into Stage IV benefited well from targeted therapy with Crizotinib.Conclusions： The ALK fusion protein was seen in 6.6% Chinese NSCLC patients, and mosdy seen in younger, clinically higher staging, mueinous and solid predominant adenoearcinoma. Clinical trials in patients of Stage Ⅳ eonfirmed that ALK-DSF3 Ventana IHC is serviceable in screening ALK-positive candidates for molecular targeted therapy.

ALK gene expression status in pleural effusion predicts tumor responsiveness to crizotinib in Chinese patients with lung adenocarcinoma

Objective： The relationship between anaplastic lymphoma kinase（ALK） expression in malignant pleural effusion（MPE） samples detected only by Ventana immunohistochemistry（IHC） ALK（D5F3） and the efficacy of ALKtyrosine kinase inhibitor therapy is uncertain.Methods： Ventana anti-ALK（D5F3） rabbit monoclonal primary antibody testing was performed on 313 cell blocks of MPE samples from Chinese patients with advanced lung adenocarcinoma, and fluorescence in situ hybridization（FISH） was used to verify the ALK gene status in Ventana IHC ALK（D5F3）-positive samples. The follow-up clinical data on patients who received crizotinib treatment were recorded.Results： Of the 313 MPE samples, 27（8.6%） were confirmed as ALK expression-positive, and the Ventana IHC ALK（D5F3）-positive rate was 17.3%（27/156） in wild-type epidermal growth factor receptor（EGFR） MPE samples. Twenty-three of the 27 IHC ALK（D5F3）-positive samples were positive by FISH. Of the 11 Ventana IHC ALK（D5F3）-positive patients who received crizotinib therapy, 2 patients had complete response（CR）, 5 had partial response（PR） and 3 had stable disease（SD）.Conclusions： The ALK gene expression status detected by the Ventana IHC ALK（D5F3） platform in MPE samples may predict tumor responsiveness to crizotinib in Chinese patients with advanced lung adenocarcinoma.

Primary tracheobronchial anaplastic large cell lymphoma in an 8-year-old child presenting with asthma-like symptoms

Primary tracheobronchial anaplastic large cell lymphoma （ALCL） is very rare.In spite of its rarity,tracheobronchial tumor can cause life-threatening airway obstruction because of its growing site and biological characteristics.Here we represented the clinical and pathological features of a patient with ALCL in the respiratory tract.

China National Medical Products Administration approval summary:anlotinib for the treatment of advanced non-small cell lung cancer after two lines of chemotherapy

Background:On May 8,2018,the China National Medical Products Administration(NMPA)approved anlotinib,an orally administered anti-angiogenesis inhibitor,for the treatment of patients with advanced non-small cell lung can-cer(NSCLC)who have progressed after treatment with two or more lines of prior systemic chemotherapy.Main body of the abstract:China NMPA reviewed and inspected a regional double-blinded,placebo-controlled,Phase III trial comparing the overall survival(OS)of NSCLC patients between the anlotinib and placebo arms.A total of 437 patients were randomized(2:1)to receive either anlotinib(n=294)or placebo(n=143)once daily on a 2-week on and 1-week off schedule.Patients with epidermal growth factor receptor(EGFR)or activating anaplastic lymphoma kinase(ALK)genomic tumor aberrations should have disease progression on NMPA-approved therapy.Anlotinib is the first NMPA-approved drug for patients with advanced NSCLC who have progressed on at least two lines of prior systemic chemotherapies in China.The approval was based on a statistically and clinically significant improvement in median OS with anlotinib(9.46 months)compared with placebo[6.37 months;hazard ratio(HR])=0.70,95%confidence interval(CI)=0.55-0.89;two-sided log-rank P=0.002].The confirmed objective response rate(ORR)was 9.2%in the anlotinib arm and 0.7%in the placebo arm.The median duration of response(DoR)was 4.83 months,with a 95%CI of 3.31-6.97 months.The toxicity profile of anlotinib was consistent with that of known anti-angiogenesis inhibitors.Common adverse drug reactions(ADRs)in anlotinib-treated patients included hypertension(67.4%),hand-foot syndrome(43.9%),hemoptysis(14.0%),thyroid stimulating hormone(TSH)elevation(46.6%),and corrected QT interval(QTc)prolongation(26.2%).Short conclusion:Anlotinib demonstrated a clinically significant OS prolongation as a novel therapeutic option for advanced or metastatic NSCLC following at least two lines of chemotherapy.

Diffusion kurtosis imaging: correlation analysis of quantitative model parameters with molecular features in advanced lung adenocarcinoma

Background:Due to development of magnetic resonance-based functional imaging, it is easier to detect micro-structural alterations of tumor tissues. The aim of this study was to conduct a preliminary evaluation of the correlation of non-Gaussian diffusion kurtosis imaging (DKI) parameters with expression of molecular markers (epidermal growth factor receptor [ EGFR];anaplastic lymphoma kinase [ ALK];Ki-67 protein) in patients with advanced lung adenocarcinoma, using routine diffusion-weighted imaging as the reference standard. Methods::Data from patients with primary lung adenocarcinoma diagnosed at Cancer Hospital, Chinese Academy of Medical Sciences (CHCAMS) from 2016 to 2019 were collected for retrospective analysis. The pathologic and magnetic resonance imaging data of 96 patients who met the inclusion criteria were included in this study. Specifically, the Kapp and Dapp parameters measured from the DKI model;apparent diffusion coefficient (ADC) value from the diffusion-weighted imaging model;and the EGFR, ALK, and Ki-67 biomarkers detected by immunohistochemistry and/or molecular biology techniques after biopsy or surgery were evaluated. The relations between quantitative parameters (ADC, Kapp, Dapp) and pathologic outcomes ( EGFR, ALK, and Ki-67 expression) were analyzed by Spearman correlation test. Results:Of the 96 lung adenocarcinoma lesions (from 96 patients), the number of EGFR- and ALK-positive and high Ki-67 expressing lesions were 53, 12, and 83, respectively. The Kapp values were significantly higher among patients with EGFR-positive mutations (0.81 ± 0.12 vs. 0.66 ± 0.10, t = 6.41, P < 0.001), ALK rearrangement-negative (0.76 ± 0.12 vs. 0.60 ± 0.15, t = 4.09, P < 0.001), and high Ki-67 proliferative index (PI) (0.76 ± 0.12 vs. 0.58 ± 0.13, t = 4.88, P < 0.001). The Dapp values were significantly lower among patients with high Ki-67 PI (3.19 ± 0.69 μm 2/ms vs. 4.20 ± 0.83 μm 2/ms, t = 4.80, P < 0.001) and EGFR-positive mutations (3.11 ± 0.73 μm 2/ms vs. 3.59 ± 0.77 μm ^2/ms, t = 3.12, P = 0.002). The differences in mean Dapp (3.73 ± 1.26 μm^ 2/ms vs. 3.26 ± 0.68 μm 2/ms, t = 1.96, P = 0.053) or ADC values ([1.34 ± 0.81] × 10^ -3 mm ^2/s vs. [1.33 ± 0.41] × 10 ^-3 mm ^2/s, t = 0.07, P = 0.941) between the groups with or without ALK rearrangements were not statistically significant. The ADC values were significantly lower among patients with EGFR-positive mutation ([1.19 ± 0.37] × 10 ^-3 mm^ 2/s vs. [1.50 ± 0.53] × 10 ^-3 mm ^2/s, t = 3.38, P = 0.001) and high Ki-67 PI ([1.28 ± 0.39] × 10 -3 mm 2/s vs. [1.67 ± 0.77] × 10^ -3 mm^ 2/s, t = 2.88, P = 0.005). Kapp was strongly positively correlated with EGFR mutations ( r = 0.844, P = 0.008), strongly positively correlated with Ki-67 PI ( r = 0.882, P = 0.001), and strongly negatively correlated with ALK rearrangements ( r = -0.772, P = 0.001). Dapp was moderately correlated with EGFR mutations ( r = -0.650, P = 0.024) or Ki-67 PI ( r = -0.734, P = 0.012). ADC was moderately correlated with Ki-67 PI ( r = -0.679, P = 0.033). Conclusions:The Kapp value of DKI parameters was strongly correlated with different expression of EGFR, ALK, and Ki-67 in advanced lung adenocarcinoma. The results potentially indicate a surrogate measure of the status of different molecular markers assessed by non-invasive imaging tools.

Personalized medicine in non-small cell lung cancer: a review from a pharmacogenomics perspective

Non-small cell lung cancer is a prevalent and rapidly-expanding challenge to modern medicine. While generalized medicine with traditional chemotherapy yielded comparatively poor response rates and treatment results, the cornerstone of personalized medicine using genetic profiling to direct treatment has exalted the successes seen in the field and raised the standard for patient treatment in lung and other cancers. Here, we discuss the current state and advances in the field of personalized medicine for lung cancer, reviewing several of the mutation-targeting strategies that are approved for clinical use and how they are guided by patient genetic information. These classes include inhibitors of tyrosine kinase(TKI), anaplastic lymphoma kinase(ALK), and monoclonal antibodies. Selecting from these treatment plans and determining the optimal dosage requires in-depth genetic guidance with consideration towards not only the underlying target genes but also other factors such as individual metabolic capability and presence of resistance-conferring mutations both directly on the target gene and along its cascade(s).Finally, we provide our viewpoints on the future of personalized medicine in lung cancer, including target-based drug combination, mutation-guided drug design and the necessity for data of population genetics, to provide rough guidance on treating patients who are unable to get genetic testing.

Inflammatory Myofibroblastic Tumor of the Liver:A Diagnostic Challenge

Inflammatory myofibroblastic tumor (IMT) is an uncommon myofibroblastic neoplasm that was formerly included within the broad category of inflammatory pseudotumor (IPT).IMT is rarely encountered in the liver.Similar to IMT of other organs,the interchangeable use of the terms IMT and IPT in liver has made the analysis of these lesions difficult.In this review,clinical and pathological features of IMT of the liver are reviewed and the differential diagnosis of IMT is discussed,with emphasis on IPT and the other entities included in this large category.IMT can mimic malignant tumors.There are no known unique diagnostic clinical,laboratory,or radiological features.The definitive diagnosis of IMT depends on careful pathological examination.The histopathological evaluation of hepatic IMT reveals that,the myxoid/vascular pattern is the most frequently observed,followed by,in decreasing frequency,fibrous histiocytomalike pattern and hypocellular fibrous pattern.In IMT of the liver,anaplastic lymphoma kinase (ALK) expression reliably predicts the presence of an ALK gene rearrangement.The diagnosis of hepatic IMT depends on the dominant histopathological pattern,and the management of the disease is still controversial.IMTof the liver is a distinctive neoplasm of intermediate biological potential,and should be distinguished from the variety of lesions that are included under the broad category of IPT.Therefore,to avoid confusion regarding the true incidence and behavior of hepatic IMT,the term IPT should not be used interchangeably with IMT.The rarity of IMT in liver should not minimize its consideration in the differential diagnosis of liver tumors,especially in patients with tumor markers in normal range.