EBV-associated lymphoproliferative disease post-CAR-T cell therapy.

Epstein-Barr virus (EBV)-associated lymphoproliferative diseases (EBV-LPDs) are common complications that occur after solid organ transplantation or allogeneic hematopoietic stem-cell transplantation (HSCT). However, their occurrence and treatment post-chimeric antigen receptor-modified T (CAR-T) cell therapy has not been reported. Two patients had been diagnosed with EBV-positive aggressive B-cell lymphoma and experienced relapses after multiple lines of treatment. After receiving CAR-T cell therapy in tandem with autologous HSCT, the patients achieved complete remission. However, with a median time of 38.5 months after CAR-T cell therapy, B-cell-derived EBV-LPDs were diagnosed, and they were relieved through the administration of immune checkpoint inhibitor or B-cell-depleting agents. Collectively, our report suggests that EBV-LPDs may represent a long-term adverse event after CAR-T cell therapy, especially in patients who previously had EBV-positive disorders, and they can be resolved by immune normalization strategy or B-cell depleting therapy.

Case report: Differential diagnosis of highly amplified anti-CD5 CAR T cells and relapsed lymphoma cells in a patient with refractory ALK positive anaplastic large cell lymphoma.

Background: Anaplastic Large Cell Lymphoma (ALCL) is one of the most common subtypes of T-cell lymphoma. Among these, refractory and relapsed (r/r) ALK positive ALCL lacks effective therapies. The chimeric antigen receptor-modified T (CAR-T) cell therapy holds great promise as a therapeutic strategy for this disease. However, it is not known yet whether anti-CD5 CAR-T cells are sufficient for the definitive treatment of relapsed ALK+ ALCL, nor the role of accurate laboratory-based diagnoses during CAR-T treatment. Case presentation: The adolescent patient received autologous T cells containing sequences encoding VH domains specific to CD5. Following the infusion, there was an increase in both the copy number and proportion of CAR-T cells in peripheral blood. IL-6 and ferritin levels in the patient exhibited significant fluctuations, with increases of 13 and 70 folds respectively, compared to baseline after the treatment. Additionally, adverse effects were observed, including grade 4 rash, grade 1 headache, nausea, and neck-pain. Surprisingly, a relapsed disease phenotype was identified based on the results of PET/CT and histopathological analysis of the inguinal lymph node biopsy. After conducting a thorough diagnostic assessment, which included flow cytometry, next-generation sequencing (NGS), examination of immune-related gene rearrangements, and analysis of the immune repertoire of T-cell receptors (TCR), we conclusively determined that the hyperplastic T cells identified in the lymph node were the result of an expansion of CAR-T cells. Ultimately, the patient has attained complete remission (CR) and has sustained a disease-free survival state for 815 days as of the cutoff date on August 30, 2023. Conclusion: Taken together, the results demonstrate that anti-CD5 CAR-T cells can induce a clinical response in r/r ALK+ ALCL patient. Furthermore, this case underscores the importance of utilizing advanced technologies with high sensitivity and accuracy for biological detection in clinical laboratory diagnosis and prognosis in CAR-T cell treatment. Trial registration number: NCT04767308.

ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming.

Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we explored whether FGFR1 acted a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL) and the molecular mechanisms underlying T-ALL cell resistance to FGFR1 inhibitors. We showed that FGFR1 was significantly upregulated in human T-ALL and inversely correlated with the prognosis of patients. Knockdown of FGFR1 suppressed T-ALL growth and progression both in vitro and in vivo. However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage. Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2α pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. Targeting FGFR1 and mTOR exhibited synergistically anti-leukemic efficacy. These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL therapy.

Exome sequencing analysis of gastric primary myeloid sarcoma with monocytic differentiation with altered immunophenotype after chemotherapy: case report.

BACKGROUND: Myeloid Sarcoma with monocytic differentiation is rare and quite likely is missed by surgical pathologists. However it is frequently misdiagnosed because of its non-specific imaging and histological pattern. CASE PRESENTATION: We report the case of a 64-year-old woman with gastric primary myeloid sarcoma with monocytic differentiatio. Upper endoscopy revealed a neoplastic growth at the junction of the lesser curvature and gastric antrum. Except for a slightly increased peripheral monocyte count, no abnormalities were found on hematological and bone-marrow examination. Gastroscopic biopsy showed poorly differentiated atypical large cells with visible nucleoli and nuclear fission. Immunohistochemistry showed positive CD34, CD4, CD43, and CD56 expression, and weakly positive lysozyme expression. Immune markers for poorly differentiated adenocarcinoma, malignant melanoma, and lymphohematopoietic-system tumors were negative. The final diagnosis was myeloid sarcoma with monocytic differentiation. Chemotherapy did not shrink the tumor, so, radical surgery was performed. Although the tumor morphology did not change postoperatively, the immunophenotype did. CD68 and lysozyme expression (tumor tissue markers) changed from negative and weakly positive to strongly positive, AE1/3 expression (epithelial marker) changed from negative to positive, and CD34, CD4, CD43, and CD56 expression (common in naive hematopoietic cell-derived tumors) was greatly attenuated. Exome sequencing revealed missense mutations in FLT3 and PTPRB, which are associated with myeloid sarcoma, and in TP53, CD44, CD19, LTK, NOTCH2, and CNTN2, which are associated with lymphohematopoietic tumors and poorly differentiated cancers. CONCLUSION: We diagnosed myeloid sarcoma with monocytic differentiation after excluding poorly differentiated adenocarcinoma, common lymphohematopoietic-system tumors, epithelioid sarcoma, and malignant melanoma. We identified that the immunophenotypic of patient had alterations after chemotherapy, and FLT3 gene mutations. We hope that the above results will improve our understanding of this rare tumor.

[Goblet cell adenocarcinoma in the digestive system: a clinicopathological analysis of 22 cases].

Objective: To investigate the clinical features, morphological characteristics, immunophenotype, and differential diagnosis of goblet cell adenocarcinoma (GCA) in the digestive system. Methods: The clinicopathological data, morphological characteristics, immunophenotypes of 22 cases of GCA in the digestive system diagnosed from January 2010 to January 2021 were collected. Meanwhile, 25 cases of neuroendocrine neoplasm (NEN) and 24 cases of adenocarcinoma were used as controls. Relevant literature was also reviewed. Results: There were 16 males and 6 females, aged from 36 to 79 years with an average of 56 years. The anatomical sites of the 22 GCA were mostly appendix (17 cases) and occasionally extra-appendix (5 cases), including 3 cases in stomach, 1 case in duodenum and 1 case in anal. All 17 cases of appendiceal GCA were pure GCA. Among the 5 cases of extra-appendiceal GCA, One case of gastric GCA was pure, two cases of gastric GCA with NEN or adenocarcinoma, duodenal GCA with NEN and adenocarcinoma, anal GCA with NEN.Low-grade GCAs were composed of goblet, Paneth and neuroendocrine cells, which were arranged in intestinal crypt tubular or cluster structures and distributed in the wall of digestive system. The tubular and cluster structures lacked adhesion. Goblet cells were columnar, located in the base, with clear cytoplasm, small nuclei, inconspicuous atypia, and uncommon mitoses. Extracellular mucus and signet-ring cells with nuclear variations could be seen in some cases. Nerve fiber bundle invasion and tumor thrombus in vessels were often present. High-grade GCAs lacked tubular and cluster structures, and their histological structures were more complex. Tumor cells expressed mixed neuroendocrine and glandular epithelial markers. Similar to the expression patterns of synaptophysin and chromogranin A, CD200 and INSM1 were also dot-like or patch-positive in GCA. Conclusions: GCA is an infrequent tumor of the digestive system and shows the bi-directional differentiation characteristics of neuroendocrine and glandular epithelium. Accurate diagnosis and staging are related to its prognosis.

Inhibition of acylglycerol kinase sensitizes DLBCL to venetoclax via upregulation of FOXO1-mediated BCL-2 expression.

Background: Despite of the paradigm change on the treatments of acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) by venetoclax, it has been less successful in the treatment of diffuse large B-cell lymphoma (DLBCL). Here, we explored whether acylglycerol kinase regulates the sensitivity of DLBCLs to venetoclax and its mechanism in both cell lines and preclinical animal models. Methods: The expression of AGK and sensitivity to venetoclax of seven DLBCL cell lines were determined. Upon knockdown and overexpression of AGK by lentivirus in DLBCL cells, the venetoclax-induced apoptosis and PTEN-FOXO1-BCL-2 signaling axis were evaluated in vitro. The efficacy of venetoclax and PTEN-FOXO1-BCL-2 signaling axis were evaluated in immunodeficient NCG mice that were implanted with control or shAGK stably transduced SU-DHL4 cells. The expressions of AGK, BCL-2 and FOXO1 were evaluated in tumor tissues of DLBCL patients. Results: AGK expression was inversely correlated with sensitivity of DLBCL to venetoclax. Inhibition of AGK rendered the DLBCL cells more sensitive to venetoclax. Mechanistically, AGK phosphorylated and inactivated PTEN, which led to AKT activation and reduced FOXO1 nuclear translocation. Inhibition of AGK also led to enhanced efficacy of venetoclax for suppression of DLBCL tumor growth in vivo, which was dependent on FOXO1. In human DLBCL tumor tissues, the expression of AGK inversely correlated with BCL-2 expression, as well as the amounts of nuclear FOXO1. Conclusions: Our data demonstrated that AGK regulates venetoclax response in DLBCL via PTEN-FOXO1-BCL-2 signaling axis. Targeting AGK may enhance the efficacy of venetoclax for the treatment of DLBCL patients.

A novel diagnostic approach for the classification of small B-cell lymphoid neoplasms based on the NanoString platform.

Small B-cell lymphoid neoplasms (SBCLNs) are a heterogeneous group of diseases characterized by malignant clonal proliferation of mature B-cells. However, the classification of SBCLNs remains a challenge, especially in cases where histopathological analysis is unavailable or those with atypical laboratory findings or equivocal pathologic data. In this study, gene expression profiling of 1039 samples from 27 gene expression omnibus (GEO) datasets was first investigated to select highly and differentially expressed genes among SBCLNs. Samples from 57 SBCLN cases and 102 nonmalignant control samples were used to train a classifier using the NanoString platform. The classifier was built by employing a cascade binary classification method based on the random forest algorithm with 35 refined gene signatures. Cases were successively classified as chronic lymphocytic leukemia/small lymphocytic lymphoma, conventional mantle cell lymphoma, follicular lymphoma, leukemic non-nodal mantle cell lymphoma, marginal zone lymphoma, lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia, and other undetermined. The classifier algorithm was then validated using an independent cohort of 197 patients with SBCLNs. Under the distribution of our validation cohort, the overall sensitivity and specificity of proposed algorithm model were >95%, respectively, for all the cases with tumor cell content greater than 0.72. Combined with additional genetic aberrations including IGH-BCL2 translocation, MYD88 L265P mutation, and BRAF V600E mutation, the optimal sensitivity and specificity were respectively found at 0.88 and 0.98. In conclusion, the established algorithm demonstrated to be an effective and valuable ancillary diagnostic approach for the sub-classification and pathologic investigation of SBCLN in daily practice.

Clinicopathologic Features of COVID-19: A Case Report and Value of Forensic Autopsy in Studying SARS-CoV-2 Infection.

ABSTRACT: As of August 23, 2020, the 2019 novel coronavirus disease (COVID-19) has infected more than 23,518,340 people and caused more than 810,492 deaths worldwide including 4,717 deaths in China. We present a case of a 53-year-old woman who was admitted to the hospital because of dry coughs and high fever on January 26, 2020, in Wuhan, China. She was not tested for SARS-CoV-2 RNA until on hospital day 11 (illness day 21) because of a significant shortage of test kits at the local hospital. Then, her test was positive for COVID-19 on hospital day 20. Despite intensive medical treatments, she developed respiratory failure with secondary bacterial infection and expired on hospital day 23 (3 days after she was tested positive for SARS-CoV-2 RNA). A systemic autopsy examination, including immunohistochemistry and ultrastructural studies, demonstrates that SARS-CoV-2 can infect multiple organs with profound adverse effect on the immune system, and the lung pathology is characterized by diffuse alveolar damage. Extrapulmonary SARS-CoV-2 RNA was detected in several organs postmortem. The detailed pathological features are described. In addition, this report highlights the value of forensic autopsy in studying SARS-CoV-2 infection and the importance of clinicopathological correlation in better understanding the pathogenesis of COVID-19.

Comparison of amide proton transfer imaging and magnetization transfer imaging in revealing glioma grades and proliferative activities: a histogram analysis.

PURPOSE: Comprehensive understanding glioma metabolic characters is of great help for patient management. We aimed to compare amide proton transfer imaging (APTw) and magnetization transfer imaging (MT) in predicting glioma malignancy and reflecting tumor proliferation. METHODS: Thirty low-grade gliomas (LGGs) and 39 high-grade gliomas (HGGs) were prospectively included, of which 58 samples Ki-67 levels were quantified. Anatomical MRI, APTw, and MT were scanned, and magnetization transfer ratio (MTR) and asymmetric magnetic transfer ratio at 3.5 ppm (MTRasym(3.5ppm)) were calculated. ROIs were semi-automatically drawn with ImageJ, from which histogram features, including 5th, 25th, 50th, mean, 70th, 90th, and 95th percentiles were extracted. The independent t test was used to test differences in LGGs and HGGs, and correlations between histogram features and tumor grades, Ki-67 were revealed by Spearman's rank or Pearson's correlation analysis. RESULTS: The maximum correlation coefficient (R) values of APTw were 0.526 (p < 0.001) with tumor grades and 0.397 (p < 0.001) with Ki-67 at 90th percentiles, while only 5th and 25th percentiles of MT significantly correlated with tumor grades. Moreover, APTw features were significantly different in LGGs and HGGs, except 5th percentile. The most significantly different feature was 95th percentile, providing the excellent AUC of 0.808. However, the best feature in MTR was 5th percentiles with AUC of 0.703. Combing 5th and 95th of APTw achieved highest AUC Of 0.837. CONCLUSIONS: Both APTw and MT provide quantitative information for tumor metabolite imaging. However, APTw supplys more specific information in reflecting glioma biological behaviors than MT, and well differentiates glioma malignancy.

The clinicopathological and molecular features of sinusoidal large B-cell lymphoma.

We report 17 cases of sinusoidal large B-cell lymphoma (SLBCL). Clinical, morphologic, immunophenotypic, and molecular features were detected and analyzed. All cases showed an obvious sinusoidal growth pattern, usually associated with residual atrophic lymphoid tissue. All tumors contained large pleomorphic lymphoid cells and one or more prominent nucleoli, with abundant amphophilic cytoplasms; 15/17 cases showed anaplastic morphologic features. The patient age ranged from 43 to 80 years (median 57 years), and 7 males and 10 females were included. Eleven of 15 (73.3%) patients had Ann Arbor stage III or IV disease, and 10/15 (66.6%) patients had an International Prognostic Index (IPI) score ≥3. Immunophenotypically, 16/17 (94.1%) cases displayed a nongerminal center B-cell (non-GCB) immunophenotype. Furthermore, 16/17 (94.1%) cases were positive for CD30, and p53 was expressed in 10/16 (62.5%) cases. In total, 12/14 (85.7%) cases expressed BCL2 and MYC simultaneously (double expression), and 11/14 (78.6%) cases showed PD-L1 positivity (6/11 had a PD-L1 tumor proportion score ≥50%). Cytogenetically, concurrent MYC and BCL2 and/or BCL6 abnormalities (break-apart or extra copy) were detected in 10/15 cases, and 7/13 (53.8%) cases harbored a PD-L1/L2 amplification. TP53 mutation was found in 7/13 (53.8%) cases by Sanger sequencing. Whole-exome and large-panel sequencing results revealed high mutation frequencies of TP53 (4/7), MYD88 (3/7), KMT2D (3/7), CREBBP (3/7), and PIM1 (3/7). Among the 13 patients with SLBCL treated with aggressive chemotherapy regimens, the median overall survival (OS) was 18 months, and the 2-year OS rate was 34.6%. The OS of patients with SLBCL was markedly worse than that of 35 control group patients with common diffuse large B-cell lymphoma (DLBCL) without sinusoidal features (P < 0.001). SLBCL may represent a specific type of DLBCL that has characteristic pathologic features. The cancer is aggressive in most clinical cases, and outcomes are poor. SLBCL and anaplastic DLBCL (A-DLBCL) have many overlapping clinicopathological and molecular features.

Deficiency of Tfh Cells and Germinal Center in Deceased COVID-19 Patients.

The COVID-19 pandemic caused by SARS-CoV2 is characterized by a remarkable variation in clinical severity ranging from a mild illness to a fatal multi-organ disease. Understanding the dysregulated human immune responses in the fatal subjects is critical for management of COVID-19 patients and the pandemic. In this study, we examined the immune cell compositions in the lung tissues and hilar lymph nodes using immunohistochemistry on 6 deceased COVID-19 patients and 4 focal organizing pneumonia (FOP) patients who underwent lung surgery and served as controls. We found a dominant presence of macrophages and a general deficiency of T cells and B cells in the lung tissues from deceased COVID-19 patients. In contrast to the FOP patients, Tfh cells and germinal center formation were largely absent in the draining hilar lymph nodes in the deceased COVID-19 patients. This was correlated with reduced IgM and IgG levels compared to convalescent COVID-19 patients. In summary, our data highlight a defect of germinal center structure in deceased COVID-19 patients leading to an impaired humoral immunity. Understanding the mechanisms of this deficiency will be one of the key points for the management of this epidemic.

Epstein-Barr virus-positive inflammatory follicular dendritic cell sarcoma presenting as a solitary colonic mass: two rare cases and a literature review.

AIMS: Follicular dendritic cell (FDC) sarcoma is a rare neoplasm originating from follicular dendritic cells in germinal centres. It is classified as conventional and Epstein-Barr virus (EBV)-positive inflammatory FDC sarcoma according to the 2019 World Health Organization classification of digestive system tumours; the latter is rarer. So in view of the rarity and difficulty in diagnosis, the aim of the manuscript is to share our experience of diagnosing EBV-positive inflammatory FDC sarcoma. METHODS AND RESULTS: Here, we describe the clinicopathological features, gross description, histomorphology, immunophenotype, EBV-encoded mRNA (EBER) in-situ hybridisation, gene rearrangement and clinical follow-up of two patients with EBV-positive inflammatory FDC sarcoma in the colon, and review the relevant literature. The tumours were found in two males, aged 53 and 48 years, respectively, with a tumour diameter between 10 and 45 mm. Both cases occurred in the colon and presented as pedunculated colonic masses. Microscopically, scanty atypical ovoid to spindle neoplastic cells were mixed in a background of florid lymphoplasmacytic infiltration. The nuclei of these atypical cells showed vesicular chromatin and small, distinct nucleoli. Immunohistochemistry demonstrated that the atypical stromal cells were positive for CD21, CD23, CD35, and D2-40. EBER in-situ hybridisation also gave positive results in two cases. There was a mean follow-up of 9 months (range, 7-11 months). CONCLUSION: EBV-positive inflammatory FDC sarcoma is an extremely rare tumour with a distinct morphology and phenotype. Therefore, it is very important to recognise it particularly for correct diagnosis and prevention of misdiagnosis and mistreatment.

Pathological changes in the lungs and lymphatic organs of 12 COVID-19 autopsy cases.

Systematic autopsy and comprehensive pathological analyses of COVID-19 decedents should provide insights into the disease characteristics and facilitate the development of novel therapeutics. In this study, we report the autopsy findings from the lungs and lymphatic organs of 12 COVID-19 decedents-findings that evaluated histopathological changes, immune cell signature and inflammatory factor expression in the lungs, spleen and lymph nodes. Here we show that the major pulmonary alterations included diffuse alveolar damage, interstitial fibrosis and exudative inflammation featured with extensive serous and fibrin exudates, macrophage infiltration and abundant production of inflammatory factors (IL-6, IP-10, TNFα and IL-1ß). The spleen and hilar lymph nodes contained lesions with tissue structure disruption and immune cell dysregulation, including lymphopenia and macrophage accumulation. These findings provide pathological evidence that links injuries of the lungs and lymphatic organs with the fatal systematic respiratory and immune malfunction in critically ill COVID-19 patients.

Amid proton transfer (APT) and magnetization transfer (MT) MRI contrasts provide complimentary assessment of brain tumors similarly to proton magnetic resonance spectroscopy imaging (MRSI).

OBJECTIVES: Using MRSI as comparison, we aimed to explore the difference between amide proton transfer (APT) MRI and conventional semi-solid magnetization transfer ratio (MTR) MRI, and to investigate if molecular APT and structural MTR can provide complimentary information in assessing brain tumors. METHODS: Seventeen brain tumor patients and 17 age- and gender-matched volunteers were included and scanned with anatomical MRI, APT and MT-weighted MRI, and MRSI. Multi-voxel choline (Cho) and N-acetylaspartic acid (NAA) signals were quantified from MRSI and compared with MTR and MTRasym(3.5ppm) contrasts averaged from corresponding voxels. Correlations between contrasts were explored voxel-by-voxel by pooling values from all voxels into Pearson's correlation analysis. Differences in correlation coefficients were tested with the Z-test (set at p<0.05). RESULTS: APT and MT provide good contrast and quantitative parameters in tumor imaging, as do the metabolite (Cho and NAA) maps. MTRasym(3.5ppm) significantly correlated with MTR (R=-0.61, p<0.0001), Cho (R=0.568, p<0.0001) and NAA (R=-0.619, p<0.0001) in tumors, and MTR also significantly correlated with Cho (R=-0.346, p<0.0001) and NAA (R=0.624, p<0.0001). In healthy volunteers, MTRasym(3.5ppm) was non-significantly correlated with MTR (R=-0.049, p=0.239), Cho (R=0.030, p=0.478) and NAA (R=-0.083, p=0.046). Significant correlations were found among MTR with Cho (R=0.199, p<0.0001) and NAA (R=0.263, p<0.0001) in the group of healthy volunteers with lower correlation R values than those in tumor patients. CONCLUSIONS: APT and MT could provide independent and supplementary information for the comprehensive assessment of molecular and structural changes due to brain tumor cancerogenesis. KEY POINTS: • MTR asym(3.5ppm) positively correlated with Cho while negatively with NAA in tumors. • MTR positively correlated with NAA while negatively with Cho in tumors. • Combining APT/MT provides molecular and structural information similarly to MRSI.

Microcystic Stromal Tumor of Testicle: First Case Report and Literature Review.

Microcystic stromal tumor (MCST) is a rare subtype of sex cord-stromal neoplasm. Tumors from all 31 previously reported cases were located in the ovary. Herein, we present a unique case of a right-side testicular tumor in a 33-year-old Chinese male. The tumor is composed of predominantly lobulated cellular nodules separated by hyalinized fibrous stroma and they expressed CD10, ß-catenin (nuclear), and cyclin D1. Molecular analysis identified a point mutation (c.110C>G) in exon 3 of CTNNB1. The histopathological features, immunohistochemistry profiles, and molecular analysis of this tumor were consistent with MCST of the ovary. Therefore, a diagnosis of MCST of the right testicle was determined. To the best of our knowledge, this is the first case of MCST occurring in the testicles. The study may provide new insights to the tumor biology of MCST and a better understanding of this rare entity.

Integrated genomic analysis identifies deregulated JAK/STAT-MYC-biosynthesis axis in aggressive NK-cell leukemia.

Aggressive NK-cell leukemia (ANKL) is a rare form of NK cell neoplasm that is more prevalent among people from Asia and Central and South America. Patients usually die within days to months, even after receiving prompt therapeutic management. Here we performed the first comprehensive study of ANKL by integrating whole genome, transcriptome and targeted sequencing, cytokine array as well as functional assays. Mutations in the JAK-STAT pathway were identified in 48% (14/29) of ANKL patients, while the extracellular STAT3 stimulator IL10 was elevated by an average of 56-fold (P < 0.0001) in the plasma of all patients examined. Additional frequently mutated genes included TP53 (34%), TET2 (28%), CREBBP (21%) and MLL2 (21%). Patient NK leukemia cells showed prominent activation of STAT3 phosphorylation, MYC expression and transcriptional activities in multiple metabolic pathways. Functionally, STAT3 activation and MYC expression were critical for the proliferation and survival of ANKL cells. STAT signaling regulated the MYC transcription program, and both STAT signaling and MYC transcription were required to maintain the activation of nucleotide synthesis and glycolysis. Collectively, the JAK-STAT pathway represents a major target for genomic alterations and IL10 stimulation in ANKL. This newly discovered JAK/STAT-MYC-biosynthesis axis may provide opportunities for the development of novel therapeutic strategies in treating this subtype of leukemia.

Malignant rhabdoid tumor in the renal allograft of an adult transplant recipient: a unique case of a rare tumor.

BACKGROUND: Renal transplant recipients have increased risk for developing malignant diseases because of immunosuppression or donor-to-recipient transmission. Malignant rhabdoid tumor (MRT) is a rare, highly aggressive and lethal tumor primarily affecting the kidney of infants and young children. MRT has not been reported in the renal allograft of an adult recipient after kidney transplantation. CASE PRESENTATION: In this report, a 47-year-old woman who received a kidney transplantation from an infant donor and developed a mass in the transplanted kidney is presented. Pathological examinations revealed a malignant tumor with rhabdoid cells morphologically and the loss of INI1 expression immunohistochemically. The diagnosis of malignant rhabdoid tumor in the transplanted kidney was made. We confirmed that donor-to-recipient malignancy transmission was the cause of MRT in the transplanted kidney by fluorescence in situ hybridization (FISH) and short tandem repeat (STR) analysis. CONCLUSION: To our knowledge, this is the first case of MRT in an adult renal allograft recipient. This report highlights the importance of the criteria for selection of donors to screen possible malignant tumors transmission.

A case report of tracheal inflammatory myofibroblastic tumor in a 34-week pregnant woman misdiagnosed with asthma.

RATIONALE: Inflammatory myofibroblastic tumor (IMT) is an uncommon neoplastic entity with a tendency of local recurrence and a low risk of distant metastasis. Involvement of trachea is extremely rare. PATIENT CONCERNS: A 34-week pregnant woman previously diagnosed with asthma for 2 months was admitted with persistent wheezing and hemoptysis. A computed tomography scan and bronchoscopy revealed a gigantic polyp in the trachea. DIAGNOSES: Tracheal inflammatory myofibroblastic tumor. INTERVENTIONS: The mass was removed with an electrocautery snare and identified histologically as an IMT. Further immunochemical staining showed strong positive staining for smooth muscle actin and platelet-derived growth factor receptor α (PDGFRA), weak positive staining for caldesmon, and negative staining for anaplastic lymphoma kinase (ALK)1, desmin, S-100, and CD34. The tracheal IMT strongly expressed estrogen receptor-α (ER-α), which indicated that the development of this rare IMT might have been associated with hormone fluctuations that occurred during the pregnancy. OUTCOMES: Follow-up and histological analyses revealed no evidence of recurrence and metastasis. LESSONS: This report describes an extremely rare case of a tracheal IMT that presented a diagnostic dilemma for the clinician and the pathologist. Tracheal IMT is a challenge for the clinician in diagnosis due to the nonspecific clinical presentation. Histology and immunohistochemistry are required to reach an accurate diagnosis of IMT.

Chop Deficiency Protects Mice Against Bleomycin-induced Pulmonary Fibrosis by Attenuating M2 Macrophage Production.

C/EBP homologous protein (Chop) has been shown to have altered expression in patients with idiopathic pulmonary fibrosis (IPF), but its exact role in IPF pathoaetiology has not been fully addressed. Studies conducted in patients with IPF and Chop(-/-) mice have dissected the role of Chop and endoplasmic reticulum (ER) stress in pulmonary fibrosis pathogenesis. The effect of Chop deficiency on macrophage polarization and related signalling pathways were investigated to identify the underlying mechanisms. Patients with IPF and mice with bleomycin (BLM)-induced pulmonary fibrosis were affected by the altered Chop expression and ER stress. In particular, Chop deficiency protected mice against BLM-induced lung injury and fibrosis. Loss of Chop significantly attenuated transforming growth factor ß (TGF-ß) production and reduced M2 macrophage infiltration in the lung following BLM induction. Mechanistic studies showed that Chop deficiency repressed the M2 program in macrophages, which then attenuated TGF-ß secretion. Specifically, loss of Chop promoted the expression of suppressors of cytokine signaling 1 and suppressors of cytokine signaling 3, and through which Chop deficiency repressed signal transducer and activator of transcription 6/peroxisome proliferator-activated receptor gamma signaling, the essential pathway for the M2 program in macrophages. Together, our data support the idea that Chop and ER stress are implicated in IPF pathoaetiology, involving at least the induction and differentiation of M2 macrophages.