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.

Pediatric skull inflammatory myofibroblastic tumor: a rare case report and literature review.

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

Establishment and characterization of TK-ALCL1: a novel NPM-ALK-positive anaplastic large-cell lymphoma cell line.

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.

Executive summary of the American Radium Society appropriate use criteria for brain metastases in epidermal growth factor receptor mutated-mutated and ALK-fusion non-small cell lung cancer.

The American Radium Society (ARS) Central Nervous System (CNS) committee reviewed literature on epidermal growth factor receptor mutated (EGFRm) and ALK-fusion (ALK+) tyrosine kinase inhibitors (TKIs) for the treatment of brain metastases (BrMs) from non-small cell lung cancers (NSCLC) to generate appropriate use guidelines addressing use of TKIs in conjunction with or in lieu of radiotherapy (RT). The panel developed three key questions to guide systematic review: can radiotherapy be deferred in patients receiving EGFR or ALK TKIs at (1) diagnosis or (2) recurrence? Should TKI be administered concurrently with RT (3)? Two literature searches were performed (May 2019 and December 2023). The panel developed 8 model cases and voted on treatment options using a 9-point scale, with 1-3, 4-6 and 7-9 corresponding to usually not appropriate, may be appropriate, and usually appropriate (respectively), per the UCLA/RAND Appropriateness Method. Consensus was achieved in only 4 treatment scenarios, all consistent with existing ARS-AUC guidelines for multiple BrM. The panel did not reach consensus that RT can be appropriately deferred in patients with BrM receiving CNS penetrant ALK or EGFR TKIs, though median scores indicated deferral may be appropriate under most circumstances. Whole brain RT with concurrent TKI generated broad disagreement except in cases with 2-4 BrM, where it was considered usually not appropriate. We identified no definitive studies dictating optimal sequencing of TKIs and RT for EGFRm and ALK+ BrM. Until such studies are completed, the committee hopes these cases guide decision- making in this complex clinical space.

Anaplastic Lymphoma Kinase (ALK)-Negative Anaplastic Large Cell Non-Hodgkin Lymphoma as a Rare Differential Diagnosis of Lung Cancer: A Case Report.

Anaplastic large cell lymphomas (ALCL) are a group of sporadic malignancies that generally have an aggressive clinical course, especially the subtype of anaplastic lymphoma kinase (ALK)-negative ALCL. The appropriate diagnostic study modalities must be chosen to make an accurate diagnosis and promptly initiate specific treatment. We present the clinical case of a 72-year-old male patient with dyspnea on small efforts accompanied by diaphoresis and a weight loss of 10 kg in two months. Physical examination revealed adenopathy in the cervical region and bilateral pleural effusion. The pleural and lung biopsies revealed poorly differentiated metastatic adenocarcinomas. A multidisciplinary analysis was carried out; the typical clinical-radiographic presentation of adenocarcinoma was ruled out with immunohistochemistry, thus determining a diagnosis of ALK-negative anaplastic large cell non-Hodgkin's lymphoma. This case represented a diagnostic and therapeutic challenge since it is a rare entity with a poor prognosis, and there are only a few studies about the choice of appropriate chemotherapy in these patients.

Symptomatic androgen deficiency and sexual dysfunctions in male patients receiving alectinib for ALK-positive advanced nonsmall cell lung cancer.

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 nonsmall 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.

Inflammatory myofibroblastic tumor of the genitourinary tract: a narrative review.

Background and Objective: Inflammatory myofibroblastic tumor (IMT) is a rare entity that is described in several organ systems. This comprehensive review aims to identify IMTs occurring at various genitourinary (GU) organ sites and describe patterns of clinical management in adult and pediatric patients. Methods: A comprehensive search of PubMed and Web of Science was conducted according to the Preferred Reporting Items for Systematic Review and meta-analyses statement. Two reviewers performed independent initial screening of abstracts. Eligible articles underwent full review and data extraction. The clinical features, diagnostic tests, treatment, and outcomes at each GU organ site were analyzed individually and summarized into a comprehensive review. Key Content and Findings: Of the 270 articles identified, 112 met inclusion criteria. Articles primarily consisted of case reports or small series describing a total of 167 cases, of which 30 (18%) occurred in children. Most patients (96%) were symptomatic at presentation. The most frequently involved sites included bladder (106 cases) and kidney (n=33) followed by epididymis (n=6), urachus (n=6), ureter (n=5), prostate (n=4), testis (n=4), and spermatic cord (n=3). Complete surgical excision of the mass including partial or total removal of involved organs provided excellent outcomes. Incomplete excision was associated with early local recurrence and progression. Late recurrence or metastatic transformation was rarely noted (<2%). Conclusions: IMTs exhibit locally invasive, symptomatic and progressive phenotypes that affect all urologic organs in adults and children. Clinical features and imaging results are similar to those noted with urologic cancers. These tumors require complete surgical excision since incomplete resection increases the risk of symptomatic recurrence.

Prognostic factors of resectable anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) patients: a retrospective analysis based on a single center.

Background: Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) exhibited a higher propensity for lymph node metastasis (LNM). This study aimed to investigate risk factors of occult lymph node metastasis (OLNM) and recurrence in resectable ALK-rearranged NSCLC patients. Methods: This retrospective analysis included patients with ALK-rearranged NSCLC receiving lung resections at Shanghai Pulmonary Hospital from June 2016 to August 2021. Logistic regression analysis was used to ascertain predictors of OLNM, and Cox regression analysis to identify risk factors of recurrence. Results: A total of 603 resectable ALK-rearranged NSCLC patients were included. The mean age was 55 years old. There were 171 patients (28.4%) pathologically confirmed to have LNM, 51.5% of which were occult. Logistic regression analysis identified clinical tumor size and computed tomography (CT) density as independent factors for OLNM. Cox regression analysis showed that pleural invasion and pathological tumor size were independent prognosticators for recurrence in pathologically nodal negative patients. Among pathologically nodal positive patients, adjuvant ALK-tyrosine kinase inhibitors (TKI) showed a similar recurrence-free survival (RFS) to chemotherapy (hazard ratio, 0.454; 95% confidence interval, 0.111-1.864). Conclusions: Assessing the potential risk of OLNM is required for ALK-rearranged NSCLC patients with large tumors characterized by high CT densities. Patients with large pathological tumor size or pleural infiltration should be closely monitored despite being pathologically nodal negative. Additionally, adjuvant ALK-TKI may present a comparable RFS to chemotherapy in pathologically nodal positive patients.

Anaplastic large cell lymphoma presenting as a mass in the uterine cervix: a case report.

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.

Anaplastic Lymphoma Kinase (ALK) in Posterior Cranial Fossa Tumors: A Scoping Review of Diagnostic, Prognostic, and Therapeutic Perspectives.

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.

Anaplastic lymphoma kinase-positive anaplastic large-cell lymphoma with primary bone involvement: a case report.

Background: Lymphomas originating in bone but not involving visceral or regional lymph nodes are diagnosed as primary bone lymphoma (PBL). Few case reports of anaplastic large-cell lymphoma (ALCL) originating in bone have been reported. The purpose of this report is to describe the difficulty in diagnosing and complete treatment process of this rare type of bone lymphoma. Case Description: We describe a case of anaplastic lymphoma kinase positive (ALK+) ALCL patient with primary multiple bone lesions. The patient was initially in the local hospital due to lumbosacral pain and was diagnosed with multiple myeloma. However, after receiving two cycles of bortezomib, lenalidomide and dexamethasone (VRD) chemotherapy, the patient's pain increased. After discussion with the patient and his family, the patient finally agreed to accept the biopsy of the T10 and L2 vertebral bodies and diagnosed as ALK+ ALCL stage IV with primary bone involvement. After receiving multiple cycles of chemotherapy, local bone radiotherapy and denosumab treatment, the patient's bone pain and osteolytic lesions were improved. Regular follow-up shows that the patient's bone pain has been controlled and he is generally in good condition. Conclusions: ALK+ ALCL originating primarily in the bone may be easily misdiagnosed and hence require appropriate evaluation in the upfront setting. In consideration of the lack of relevant experience due to the rarity of the disease, choosing a suitable treatment regimen requires comprehensive consideration. In the next clinical work, we must observe relevant cases to summarize the treatment experience better.

Traumatic tumor hemorrhage of inflammatory myofibroblastic tumor of the lung.

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.

Successful application of lorlatinib in a 23-year-old patient with anaplastic lymphoma kinase (ALK)-positive lung cancer and multiple brain metastases.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive lung cancer has a better long-term prognosis with ALK-inhibitor than other lung cancers. However, resistance to ALK-inhibitors and the control of metastases in the central nervous system (CNS) remain to be a challenge in the management of ALK-positive lung cancer. CASE: We present the case of a 23-year-old man who developed multiple brain metastases while receiving alectinib treatment for ALK-positive lung cancer. After 3 months of lorlatinib initiation, brain metastases disappeared, and complete response (CR) was maintained. CONCLUSION: While lorlatinib can be used as first line therapy, this drug may be considered as second line or later option for patients with multiple brain metastases if the patient has already been treated with other ALK-inhibitors since lorlatinib is thought to have good CNS penetration. This treatment option should be verified by further research.

A retrospective comparative cohort study: concurrent versus consolidative immunotherapy with chemoradiotherapy in EGFR- or ALK-negative unresectable stage III non-small cell lung cancer.

Background: The treatment of stage III non-small cell lung cancer (NSCLC) is very challenging because it is a heterogeneous group of diseases. This study was to investigative whether concurrent immunotherapy with chemoradiotherapy was associated with improved outcomes compared to consolidative immunotherapy following chemoradiotherapy in patients with unresectable stage III NSCLC, which may provide evidence-based medical evidence for the treatment of stage III NSCLC. Methods: A total of 78 epidermal growth factor receptor or anaplastic lymphoma kinase (EGFR/ALK) negative patients from the clinical database of the shanghai pulmonary hospital with locally advanced unresectable NSCLC and we evaluated them for baseline clinical factors, follow-up. Patients underwent concurrent immunotherapy with chemoradiotherapy or consolidative immunotherapy after chemoradiotherapy. Patients were classified based on initial site of progression (primary versus non-primary site). The study endpoints were progression-free survival (PFS) and time to death or distant metastasis (TDDM). Cox proportional hazards analysis was used to assess the factors affecting PFS and TDDM. Results: The median follow-up time for both groups was 26 months, and there was no significant difference in baseline clinical characteristics (P>0.05). The patients receiving concurrent immunotherapy (n=36) had a longer PFS than those receiving consolidative immunotherapy (n=42) (median 32.4 vs. 15.5 months; P<0.01). The TDDM was also longer in patients with concurrent immunotherapy than those with consolidative immunotherapy (median 57.3 vs. 31.0 months; P=0.01). Furthermore, in a subset of patients with initial site of progression at a non-primary-site, patients undergoing concurrent immunotherapy had longer PFS than those undergoing consolidative immunotherapy (median 22.7 vs. 11.9 months; P=0.03). Conclusions: Concurrent immunotherapy with chemoradiotherapy may be associated with improved disease progression outcomes as compared to consolidative immunotherapy following chemoradiotherapy.

Adjuvant crizotinib treatment selected by patient-derived organoids in a patient with stage IIIA adenocarcinoma with novel LRRTM4-ALK fusion: a case report.

Background: Over 90 different anaplastic lymphoma kinase (ALK) fusions have been reported, and patients with different ALK fusion partners exhibit different responses to targeted therapy. Patient-derived organoid (PDO), a kind of 3-dimensional culture, is a promising model for drug-sensitivity testing for personalized treatment decision-making. It further has the potential to provide treatment strategy for patients with novel mutations, rare mutations, and concomitant mutations, serving as a supplement to evidence-based medicine. Case Description: We report a case in which a man with stage IIIA adenocarcinoma had pleural effusion 1 month after surgery. A novel leucine-rich repeat transmembrane neuronal protein 4 (LRRTM4)-ALK fusion was unveiled by next-generation sequencing (NGS), and PDOs were used in drug-sensitivity testing to select a proper adjuvant therapy for this patient. We chose crizotinib based on result of the test and drugs' availability in China and helped the patient achieve a more than 3-year-long disease-free survival (DFS). Higher variant allele frequencies (VAFs) of the driver mutation were also found in PDOs and their waste culture medium, indicating that the PDO model could filter out cells with driver genes or stemness and help us to identify the critical cancer cell colony in treatment decision-making. Conclusions: For the first time, we report the case of a LRRTM4-ALK fusion. The patient achieved a more than 3-year long-term DFS under crizotinib treatment, which was selected by an emerging PDO drug-sensitivity test model. We also discovered the enrichment of a low-abundance driver mutation in PDO and its waste culture medium, providing a new direction for future research.

Management strategies for intracranial progression in ALK-positive non-small cell lung cancer: a real-world cohort study.

PURPOSE: ALK-positive NSCLC patients exhibit a particularly high propensity for the development of brain metastases. Current guidelines suggest transit to next-line therapy (SysTx) or local radiotherapy (RadTx) including whole-brain radiotherapy and radiosurgery. However, the clinical impact of these two strategies remains unclear. METHODS: We conducted a retrospective analysis focusing on patients with stage IV ALK-positive NSCLC who underwent first-line ALK TKI treatment. Patients with intracranial progression may receive two different treatment strategies: SysTx and RadTx. Our objective was to investigate the outcomes associated with these two distinct treatment pathways. RESULTS: A total 20 patients of ALK-positive NSCLC who received first-line ALK TKI therapy and subsequently developed intracranial progression were enrolled. About 55% of patients had brain metastasis initially. Nine patients (45%) were treated with crizotinib at first. Patients treated with crizotinib demonstrated a significantly shorter intracranial PFS1 (crizotinib: 8.27 months vs. others: 27.0 months, p = 0.006). Following intracranial progression, approximately 60% of patients transitioned to the next line of systemic treatment (SysTx), while the remaining 40% opted for local cranial radiotherapy (RadTx). Intriguingly, our analysis revealed no statistically significant difference in intracranial progression-free survival (PFS2) between these two distinct treatment strategies. (SysTx: 20.87 months vs. RadTx: 28.23 months, p = 0.461). CONCLUSION: The intracranial progression-free survival showed no difference between the two strategies suggesting that both local radiotherapy and systemic therapy may be valid options. Individualized strategy, molecular analysis, and multidisciplinary conferences may all play a pivotal role in decision-making.

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

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

Spoilt for choice: different immunosuppressive potential of anaplastic lymphoma kinase inhibitors for non small cell lung cancer.

Introduction: Several anaplastic lymphoma kinase (ALK)-inhibitors (ALKi) have been approved for the treatment of ALK-translocated advanced or metastatic Non Small Cell Lung Cancer (NSCLC), amongst crizotinib and alectinib. This forces physicians to choose the most suitable compound for each individual patient on the basis of the tumor´s genetic profile, but also in regard to toxicities and potential co-treatments. Moreover, targeted therapies might be combined with or followed by immunotherapy, which underlines the importance to gain detailed knowledge about potential immunomodulatory effects of these inhibitors. We here aimed to 1.) determine whether ALKi display an immunosuppressive effect on human dendritic cells (DCs) as important mediators of antigen-specific immunity and to 2.) dissect whether this immunosuppression differs among ALKi. Methods: We investigated the effect of alectinib and crizotinib on human monocyte-derived DCs (moDC) as most powerful antigen-presenting cells. We performed immunophenotyping by flow cytometry, migration, antigen uptake and cytokine assays. Results: Crizotinib-treated DCs showed reduced activation markers, such as CD83, decreased chemokine-guided migration, lower antigen uptake and produced inferior levels of pro-inflammatory cytokines, especially Interleukin-12. In contrast, the immunosuppressive potential of alectinib was significantly less pronounced. This indicates that crizotinib might profoundly dampen anti-tumor immunity, while alectinib had no unfavourable immunosuppressive effects. Conclusions: Our results implicate that current ALKi differ in their capacity to suppress the activation, migration and cytokine production of DCs as essential mediators of T cell immunity. We show that crizotinib, but not alectinib, had immunosuppressive effects on DCs phenotype and reduced DC function, thereby potentially impairing anti-tumor immunity.

Anaplastic lymphoma kinase-positive inflammatory myofibroblastic tumor of the breast: a case report and review of the literature.

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.