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.

Inflammatory myofibroblastic tumor of the adrenal gland: A case report.

Inflammatory Myofibroblastic Tumor (IMT) occurring in the adrenal gland is extremely rare, and pathologic examination is the gold standard for confirming the diagnosis. We report a case of IMT of adrenal origin in a patient whose diagnosis was confirmed by pathological examination after surgical resection of the tumor. Although previous studies have reported an overall favorable prognosis for IMT, regular and long-term follow-up is necessary.

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.

Population modeling analyses of crizotinib in pediatric patients with ALK-positive advanced cancers.

BACKGROUND: Alterations in the ALK (anaplastic lymphoma kinase) gene play a critical role in pathogenesis of anaplastic large cell lymphoma (ALCL). Crizotinib is a small molecule competitive inhibitor of ALK, ROS1, and MET kinases and was approved for pediatric patients with ALK-positive relapsed or refractory, systemic ALCL, and ALK-positive unresectable, recurrent, or refractory inflammatory myofibroblastic tumors (IMT). PROCEDURE: Crizotinib data from pediatric patients with relapsed or refractory solid tumors, IMT, or ALCL were included in the analyses. All patients received crizotinib orally at doses ranging from 100 to 365 mg/m2 twice daily (BID). PopPK analyses were conducted to characterize crizotinib disposition in pediatric patients. Exposure-response (ER) safety and antitumor analyses were conducted to characterize relationships between crizotinib dose or exposure with safety and antitumor activity endpoints of interest. RESULTS: The population pharmacokinetic (popPK), ER safety, and ER antitumor analysis included 98, 110, and 36 pediatric patients, respectively. A one-compartment pharmacokinetic model with allometric scaling, first-order elimination, and first-order absorption with lag time adequately described the data. Natural log-transformed model-predicted crizotinib AUCss (steady-state area under the concentration-time curve) demonstrated a significant, positive relationship with Grade ≥3 NEUTROPENIA and Any Grade VISION DISORDER. Crizotinib dose demonstrated a positive relationship with objective response rate. CONCLUSIONS: No significant differences in PK were identified across a wide range of ages or across tumor types, suggesting body surface area (BSA)-based dosing adequately adjusted for differences in patient size to achieve similar systemic crizotinib exposures across young children and adolescent pediatric patients. None of the myelosuppressive events except Grade ≥3 NEUTROPENIA had significant relationships identified with crizotinib dose or exposure, suggesting crizotinib is a tolerable treatment with less hematological toxicity than traditional chemotherapy regimens for pediatric patients with ALK-mutated cancers. Results from the presented analyses support the pediatric dosing recommendations in the product label.

Inflammatory Myofibroblastic Tumor After Receiving Treatment for Non-small Cell Carcinoma.

Inflammatory pseudotumor encompasses a spectrum of both neoplastic and non-neoplastic conditions characterized by a histological pattern featuring a proliferation of cytologically bland spindle cells, accompanied by a prominent chronic inflammatory infiltrate. Within this spectrum, inflammatory myofibroblastic tumor (IMT) has emerged as a distinct entity over the past two decades, marked by unique clinical, pathological, and molecular characteristics. Typically affecting the visceral soft tissues of children and adolescents, IMT exhibits a propensity for local recurrence while posing a minimal risk of distant metastasis. They are extremely rare in adults, constituting less than 1% of adult lung tumors. Our patient, a 63-year-old female, has an intricate medical background, encompassing chronic obstructive pulmonary disease (COPD), a previous history of smoking (35 pack-years, quit a year before admission), coronary artery disease, non-obstructive hypertrophic cardiomyopathy, and obstructive sleep apnea. Presenting with a diagnostic dilemma, she recently received treatment for non-small cell carcinoma with radiation therapy, which has evolved into a swiftly advancing case of IMT.

Advances in uterine inflammatory myofibroblastic tumours: Diagnostic challenges and risk stratification.

The current understanding of inflammatory myofibroblastic tumours (IMTs) of the gynaecological tract has recently been enhanced by their increased recognition. This increase is largely due to greater accessibility to RNA-based molecular assays used to identify their defining ALK rearrangements. This review summarises the clinical characteristics, morphological spectrum, immunohistochemical profile and molecular underpinnings of uterine IMT. Additionally, this review discusses practical diagnostic considerations including overlap between uterine IMT and smooth muscle tumours as well as pregnancy-associated uterine IMT. Finally, we highlight recent literature demonstrating the potential for aggressive behaviour in uterine IMT, including a novel risk stratification model for identifying high-risk IMT.

Reclassification of a spindle cell sarcoma after identification of a TFG-ROS1 fusion: A case demonstrating the clinical benefit of next-generation sequencing in sarcoma.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal soft tissue sarcomas that often present diagnostic challenges due to their wide and varied morphology. A subset of IMTs have fusions involving ALK or ROS1. The role of next-generation sequencing (NGS) for classification of unselected sarcomas remains controversial. METHODS AND RESULTS: We report a case of a metastatic sarcoma in a 34-year-old female originally diagnosed as an unclassified spindle cell sarcoma with myofibroblastic differentiation and later reclassified as IMT after NGS revealed a TFG-ROS1 rearrangement. Histologically, the neoplasm had spindle cell morphology with a lobulated to focally infiltrative growth pattern with scant inflammatory cell infiltrate. Immunohistochemistry demonstrated focal desmin and variable smooth muscle actin staining but was negative for SOX10, S100, and CD34. Fluorescence in situ hybridization was negative for USP6 or ALK gene rearrangements. NGS revealed a TFG-ROS1 rearrangement and the patient was treated with crizotinib with clinical benefit. CONCLUSIONS: We discuss the role of NGS as well as its potential benefit in patients with unresectable, ALK-negative metastatic disease. Considering this case and previous literature, we support the use of NGS for patients requiring systemic treatment.

Inflammatory Myofibroblastic Tumor of the Esophagus and Stomach Successfully Treated With ALK Inhibitor in a Pediatric Patient: A Case Report and Concise Review of Literature.

An inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm of borderline malignant potential. Nearly half of all IMTs have rearrangement of anaplastic lymphoma kinase (ALK) locus on chromosome 2p23 which can be treated with targeted therapy. Herein, we describe an unusual presentation of IMT involving an anatomical region rarely implicated in this disease process. A 15-year-old male patient came to the ER with dysphagia and coffee ground emesis. On esophagogastroscopy, a nodular luminal obstructing 30 × 50 mm mass in the lower esophagus was found, which was continuous with a large, partially circumferential gastric mass extending from the mid-body to the proximal antrum. Biopsies from esophageal and gastric masses revealed submucosal lesions composed of cytologically bland spindle and epithelioid cells, intermingled with inflammatory infiltrate, for which several immunohistochemical (IHC) stains were performed. The molecular study demonstrated ATIC::ALK fusion. Based on morphological, IHC, and molecular study findings, the diagnosis of ALK-positive IMT was rendered. Because surgical excision was deemed infeasible, the patient was started on ALK-inhibiting therapy with crizotinib. The patient responded well with no evidence of residual or recurrent disease on follow-up imaging or surveillance esophagogastroduodenoscopy. Crizotinib was ultimately discontinued after 10 months of therapy, and the patient continues to undergo surveillance imaging for monitoring of disease burden.

Evaluation of Myo-Intimal Media Thickness and Atheromatous Plaques in People Living with HIV from the Archiprevaleat Cohort vs. HIV-Negative Subjects.

BACKGROUND: Antiretroviral therapy has allowed a clear improvement in prognosis for HIV patients, but metabolic problems, such as dyslipidemia, remain. This can lead to the development of atheromatous plaques. Our study aims to evaluate whether HIV-positive (HIV+) patients show higher myo-intimal media thickness (IMT) and atheromatous plaques compared to HIV-negative (HIV-) patients. METHODS: To evaluate the association between HIV infection in experienced patients and vascular pathology, we performed a cross-sectional study, observing 1006 patients, 380 HIV+ enrolled in the Archiprevaleat cohort, and 626 HIV- as a control group. All patients underwent a Doppler scan of the supra-aortic vessels. We compared the prevalence of IMT > 1.0 mm and plaques in the two groups. RESULTS: Patients in the HIV+ group were younger than those in the HIV- group, with a lower prevalence of hypertension and diabetes and higher dyslipidemia. The prevalence of plaques in strata of age was higher in the HIV+ group than in the HIV- group and was associated with the length of ART exposure. CONCLUSIONS: Our cross-sectional, retrospective study shows that HIV+ experienced patients are at greater risk of IMT and atheromatous plaques compared to HIV-. The risk is associated with being HIV+ and with the length of ART exposure. This finding may be useful in preventing cardiovascular risk.

CFAP58 is involved in the sperm head shaping and flagellogenesis of cattle and mice.

CFAP58 is a testis-enriched gene that plays an important role in the sperm flagellogenesis of humans and mice. However, the effect of CFAP58 on bull semen quality and the underlying molecular mechanisms involved in spermatogenesis remain unknown. Here, we identified two single-nucleotide polymorphisms (rs110610797, A>G and rs133760846, G>T) and one indel (g.-1811_ g.-1810 ins147bp) in the promoter of CFAP58 that were significantly associated with semen quality of bulls, including sperm deformity rate and ejaculate volume. Moreover, by generating gene knockout mice, we found for the first time that the loss of Cfap58 not only causes severe defects in the sperm tail, but also affects the manchette structure, resulting in abnormal sperm head shaping. Cfap58 deficiency causes an increase in spermatozoa apoptosis. Further experiments confirmed that CFAP58 interacts with IFT88 and CCDC42. Moreover, it may be a transported cargo protein that plays a role in stabilizing other cargo proteins, such as CCDC42, in the intra-manchette transport/intra-flagellar transport pathway. Collectively, our findings reveal that CFAP58 is required for spermatogenesis and provide genetic markers for evaluating semen quality in cattle.

Small-Incision new generation implantable miniature telescope surgical technique and patient outcomes.

BACKGROUND: Various ocular implants were suggested as a means of enhancing vision in patients with advanced age related macular degeneration. Recently, a new generation of implantable telescopes has been released. The purpose of this study is to report the surgical technique of implantation along with patient outcomes. METHODS: This work focuses on the surgical technique. Crucial surgical steps are carefully reported along with discussion on main drawbacks and limitations. RESULTS: This approach uses a preloaded delivery system with improved features and requires a smaller incision. First patient outcomes are also reported. CONCLUSIONS: Surgical steps to implant this preloaded intraocular telescope are easier than previous versions, however this remains a complex procedure. Initial patient functional outcomes look promising.

Inflammatory Myofibroblastic Tumor With Rapid Recurrence and Distant Metastasis: Report of a Rare Case.

Inflammatory myofibroblastic tumors (IMTs) are rare spindle cell tumors clinically, morphologically, and genetically heterogeneous, mimicking many other reactive and neoplastic lesions and creating great diagnostic problems. Although it is generally characterized by oncogene-derived proliferation of myofibroblasts in a background of polyclonal inflammatory cell infiltrates, morphological variations do occur requiring immunohistochemistry and molecular genetics to confirm the diagnosis. It encompasses a wide age range, and locations, mostly said to be of intermediate grade having a low risk of recurrence and metastasis. However, its biological behavior and course are variable and unpredictable. Here, we report a case of thoracic IMT in a 32-year-old adult female presenting with a history of fever, cough, and chest pain associated with neutrophilic leukocytosis. Radiological investigations revealed a large mass in the thoracic region with possibilities of hydatid cyst and neurogenic tumor. Initial core needle biopsy specimen and subsequent local resection specimen revealed the diagnosis of IMT on histopathology and immunohistochemistry, having conventional morphology with expression of Anaplastic lymphoma kinase (ALK) protein. The patient developed rapid local recurrence and was started with first-generation ALK inhibitor Crizotinib. After a brief period of response, she developed vertebral and brain metastasis within a short span of time and was switched to a third-generation ALK inhibitor, Lorlatinib. The patient is on regular follow-up, has stable disease, and maintains a good quality of life after two years of diagnosis.

The Role of Corticosteroids and Immunomodulatory Therapy in the Management of Infectious Uveitis.

PURPOSE: The index review aims to provide an update on the role of corticosteroids and steroid-sparing immunomodulatory therapy (IMT) in managing patients with infectious uveitis. METHOD: Narrative literature review. RESULTS: Corticosteroids and immunomodulatory therapy (IMT) focus on the host defense system instead of the pathogen, adjusting exaggerated inflammatory reactions to reduce potential harm to ocular tissues. Systemic or local corticosteroids are primarily selected as adjunctive medication for infectious uveitis. Concomitant corticosteroids have also been used in cases of paradoxical worsening in ocular tuberculosis and immune recovery uveitis in cytomegalovirus (CMV) retinitis. While there is no well-established evidence to support the use of IMT in infectious uveitis, it is occasionally used in clinical settings to treat persistent inflammation following resolution of infection such as cases of ocular tuberculosis and ocular syphilis where an insufficient response is observed with corticosteroids. CONCLUSION: There is no consensus on the position of immunomodulatory therapy in the management of infectious uveitis with different etiologies. The index review provides an overview of available adjunctive corticosteroids and IMT options to assist clinicians in managing such disease entities more efficiently.

Cytohistological findings and diagnostic challenges in rare pediatric pulmonary mesenchymal malignancies: A report of two cases.

Pulmonary mesenchymal tumors are uncommon neoplasms and the data available on their clinical, cytohistomorphological, immunohistochemical, and molecular findings are limited, leading to difficulty in timely diagnosis and management. Case 1: A 12-year-old boy presented with a right endobronchial mass. Imprint smears from endobronchial biopsy revealed moderately pleomorphic spindle cell tumor arranged in fascicles and perivascular pattern with attached myxoid material showing occasional mitotic activity suggesting a cytological diagnosis of sarcoma. Biopsy also displayed similar morphology. Extensive immunohistochemistry (IHC) showed diffuse SMA, focal AE1/AE3, and diffuse ALK positivity along with a MIB/Ki67 index of 30%-40% leading to the diagnosis of inflammatory myofibroblastic tumor (IMT; Sarcoma grade). Case 2: A 8-year-old boy presented with a huge left-sided mass replacing the entire lung parenchyma and eroding adjoining ribs. Pleural fluid cytology revealed vague clusters of PAS-positive diastase-sensitive small atypical cells with associated inflammatory cells in the hemorrhagic background, suggesting a diagnosis of malignant small round blue cell tumor. Trucut biopsy from the mass showed spindled to round cells showing diffuse positivity with CD99 and BCL-2. Molecular studies with reverse transcription-PCR (RT-PCR) for SYT-SSX and EWS-FLI1 were negative for synovial sarcoma and Ewing's sarcoma, respectively. Given the clinical setting, PAS positivity, IHC, and molecular studies, the diagnosis of tumors of uncertain differentiation with the possibility of Ewing's sarcoma family of tumors (ESFT) with a translocation between EWS1 and other ETS-family members (ERG, FEV, ETV1, E1AF, etc.) was suggested.

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.

Gastric and cardiac inflammatory myofibroblastic tumor: an extremely rare case.

BACKGROUND: Inflammatory myofibroblastic tumor (IMT) is a unique, rarely metastatic tumor composed of myofibroblasts and fibrous spindle cells with inflammatory cell infiltration that can affect any organ in the human body. By reviewing the relevant literature on PubMed, we found that this is the first case report of IMT with both gastric and cardiac involvement. CASE PRESENTATION: A 57-year-old male patient was admitted to the hospital with complaints of malaise, poor appetite, and epigastric pain with black stools. We found a mass in the patient's stomach and left atrium by contrast-enhanced computed tomography, 18 F-fluorodeoxyglucose positron emission tomography/computed tomography, and other tests. The patient underwent laparoscopic Billroth II subtotal gastrectomy and Braun's gastrointestinal reconstruction under general anesthesia. On the 46th day following stomach surgery, the cardiac tumor was removed under general anesthesia. The patient has treated with doxorubicin 70 mg of D1 chemotherapy two months after cardiac surgery. Postoperative pathological immunohistochemistry of the mass confirmed the diagnosis of an IMT. His review three months after the cardiac surgery suggested the progression of the left atrial mass, but he declined further treatment and finally died one month after the review. CONCLUSIONS: As a unique class of tumors that rarely metastasize, IMTs have an unknown etiology and pathogenesis, and distant metastasis is primarily observed in patients with negative activin receptor-like kinase (ALK) expression. The preferred treatment for IMT is complete surgical resection, and the effectiveness of adjuvant therapy for patients with distant metastases is still being determined. The clinical presentation of IMT lacks specificity and is often related to the location of tumor growth, which poses a diagnostic challenge. Pathological immunohistochemistry is the only way to confirm the diagnosis at present. Our case report reminds clinicians that a category of ALK-negative IMT with a tendency toward distant metastasis should not be ignored.

Enhancing the Functional Performance of Patients with Late-Stage Age-Related Macular Degeneration Implanted with a Miniature Telescope using Rehabilitation Training.

INTRODUCTION: In this work, our aim is to report the functional outcomes of cataract surgery with smaller-incision new-generation miniature telescope (SING IMT) implantation followed by rehabilitation training in patients with central visual loss due to late-stage age-related macular degeneration (AMD). METHODS: This retrospective study included patients who were monocularly implanted with SING IMT and then followed a rehabilitation program based on 6 biweekly sessions focused on visual abilities, reading, writing, visual motor integration and mobility. A total of 11 participants were included in this study. Reading acuity (RA), reading speed (RS), and fixation stability (FS) were assessed biweekly at 6-, 8-, 10-, 12-, 14-, and 16-week follow-up visits after SING IMT implantation and at a final assessment at 24 weeks. Best-corrected distance visual acuity (BCDVA) was also measured at baseline and at the same postoperative timepoints. RESULTS: Mean baseline BCDVA was 12.5 ± 8.6 letter score. Both RA and RS were found to be significantly improved from the first rehabilitation session (6 weeks after surgery) to the last session (24 weeks after surgery). At the end of the rehabilitation program, mean RA was 0.45 ± 0.19 LogMAR and mean RS was 30.9 ± 17.6 words per minute. Moreover, all patients achieved a FS of 15 s or more after the last rehabilitation session. Most patients (55%) achieved an improvement of 15 letters in BCDVA at the end of the study. CONCLUSIONS: This study suggests that rehabilitation training can improve visual functions of patients with late-stage AMD implanted with SING IMT in real-world tasks such as reading skills.

Individualized targeted treatment in a case of a rare TFG::ROS1 fusion positive inflammatory myofibroblastic tumor (IMT).

BACKGROUND: Inflammatory myofibroblastic tumor (IMTs) are rare mesenchymal neoplasms with slow growth. Resection is considered as therapeutic standard, with chemotherapy being insufficiently effective in advanced disease. ALK translocations are present in 50% of cases, ROS1 fusions (YWHAE::ROS1, TFG::ROS1) are extremely rare. Here, we present a case with TFG::ROS1 fusion and highlight the significance of molecular tumor boards (MTBs) in clinical precision oncology for post-last-line therapy. CASE PRESENTATION: A 32-year-old woman presented with IMT diagnosed at age 27 for biopsy and treatment evaluation. Previous treatments included multiple resections and systemic therapy with vinblastine, cyclophosphamide, and methotrexate. A computed tomography scan showed extensive tumor infiltration of the psoas muscles and the posterior abdomen. Next generation sequencing revealed an actionable ROS1 fusion (TFG::ROS1) with breakpoints at exon 4/35 including the kinase domain and activating the RAS-pathway. TFG, the Trk-fused gene, exerts functions such as intracellular trafficking and exhibits high sequence homology between species. Based on single reports about efficacy of ROS1-targeting in ROS1 translocation positive IMTs the patient was started on crizotinib, an ATP-competitive small molecule c-MET, ALK and ROS1-inhibitor. With a follow-up of more than 9 months, the patient continues to show a profound response with major tumor regression, improved quality of life and no evidence for severe adverse events. CONCLUSION: This case underscores the importance of the availability of modern molecular diagnostics and interdisciplinarity in precision oncology to identify rare, disease-defining genotypes that make an otherwise difficult-to-treat disease targetable.