Language：English   Publisher：Eclinicalmedicine  

Background: Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma for which prognosis is typically poor without a timely diagnosis. To explore the safety and efficacy of standard chemotherapy combined with central nervous system (CNS)-directed therapy, we conducted a multicentre, single-arm, phase 2 trial in untreated IVLBCL patients without CNS involvement at diagnosis (PRIMEUR-IVL). In the primary analysis, the PRIMEUR-IVL study demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence (3%) of secondary CNS involvement (sCNSi). Methods: We present a prespecified final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and cumulative incidence of sCNSi. Participants were enrolled between June 2011 and July 2016, and the data cutoff date for the final analysis was 16 November 2021. The trial was registered in the UMIN Clinical Trial Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165). Findings: With a median follow-up of 7.1 years (interquartile range 5.6–8.7), 5-year PFS in all 37 eligible patients was 68% (95% confidence interval [CI] 50%–80%) and OS was 78% (95% CI 61%–89%). No additional sCNSi was observed after the primary analysis. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). Eight deaths occurred during the observation period after enrolment, due to primary disease (n = 6), sepsis (n = 1) and unknown sudden death (n = 1). Interpretation: Long-term follow-up data demonstrated durable response for PFS and OS, and low cumulative incidence of sCNSi, indicating the efficacy of standard chemotherapy combined with CNS-directed therapy for untreated IVLBCL patients. Funding: This study received financial support from the Japan Agency for Medical Research and Development, Center for Supporting Hematology-Oncology Studies, and National Cancer Center.

DOI： 10.1016/j.eclinm.2025.103078

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Language：English   Publisher：Cancer Science  

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma that is characterized by the proliferation of lymphoma cells in the lumina of small vessels. Recent progress uncovering the genetic characteristics associated with MYD88/CD79B mutations has stimulated interest in the use of drugs targeting B-cell receptor signaling, including Bruton's tyrosine kinase. However, difficulties in culturing ex vivo IVLBCL cells has hampered research on the development of novel therapies. In the present study, we demonstrated the establishment of an ex vivo culture system of IVLBCL cells obtained from patient-derived xenograft (PDX) models. The spheroid culture enabled us to culture IVLBCL PDX cells for more than 10 days and to explore the efficacy of drug treatments acting on these cells. We found that carfilzomib and ibrutinib were effective for treating IVLBCL in ex vivo experiments and conducted in vivo analyses to assess the efficacy of these drugs. Although the efficacy of carfilzomib was difficult to confirm due to its toxicity in our models, ibrutinib showed comparable efficacy to a standard combination of chemotherapy drugs. Together, our data provide a new culture method for IVLBCL PDX cells and a rationale for translating ibrutinib to clinical use in IVLBCL patients.

DOI： 10.1111/cas.16310

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Language：English   Publisher：Japanese Society for Magnetic Resonance in Medicine  

<p>Purpose: To investigate the predictive performance of radiomic features extracted from breast MRI for upgrade of ductal carcinoma <i>in situ</i> (DCIS) to invasive carcinoma.</p><p>Methods: This retrospective study included 71 women with DCIS lesions diagnosed preoperatively by biopsy. All women underwent breast dynamic contrast-enhanced (DCE) MRI of the breast, which included pre-contrast and five post-contrast phases continuously with a time resolution of 60s. Lesion segmentation was performed manually, and 144 radiomic features of the lesions were extracted from T2-weighted images (T2WI), pre-contrast T1-weighted images (T1WI), and post-contrast 1st, 2nd, and 5th phase subtraction images on DCE-MRI. Qualitative features of mammography, ultrasound, and MRI were also assessed. Clinicopathological features were evaluated using medical records. The least absolute shrinkage and selection operator (LASSO) algorithm was applied for features selection and model building. The predictive performance of postoperative upgrade to invasive carcinoma was assessed using the area under the receiver operating characteristic curve.</p><p>Results: Surgical specimens revealed 13 lesions (18.3%) that were upgraded to invasive carcinoma. Among clinicopathological and qualitative features, age was the only significant predictive variable. No significant radiomic features were observed on T2WI and post-contrast 2nd phase subtraction images on DCE-MRI. The area under the curves (AUCs) of the LASSO radiomics model integrated with age were 0.915 for pre-contrast T1WI, 0.862 for post-contrast 1st phase subtraction images, and 0.833 for post-contrast 5th phase subtraction images. The AUCs of the 200-times bootstrap internal validations were 0.885, 0.832, and 0.775.</p><p>Conclusion: A radiomics approach using breast MRI may be a promising method for predicting the postoperative upgrade of DCIS. The present study showed that the radiomic features extracted from pre-contrast T1WI and post-contrast subtraction images in the very early phase of DCE-MRI were more predictable.</p>

DOI： 10.2463/mrms.mp.2023-0168

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Language：English   Publisher：The Editorial Committee of Annals of Thoracic and Cardiovascular Surgery  

<p>Primary pulmonary sarcoma is a rare disease and is much less common than lung cancer among tumors arising from pulmonary cysts. We report the case of a female patient who showed multifocal cysts in the left S9–10. Follow-up computed tomography (CT) revealed that the cyst tended to regress, but the solid component of the cyst wall continued to thicken, growing to a 10-cm-diameter tumor. Thoracoscopic left lower lobectomy was performed to diagnose and treat the cystic lung lesions. For the pathology of the pulmonary cystic lesion, it was marked by solid tumors composed of proliferative atypical spindle cells, with some trapped bronchial tissue. Based on the imaging and pathological findings, the diagnosis was primary pulmonary sarcoma arising from the pulmonary cyst. The present case highlights that, even when a pulmonary cyst appears to shrink, careful follow-up and timely surgical consideration are warranted if cyst wall thickening is observed.</p>

DOI： 10.5761/atcs.cr.25-00097

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Language：English   Publisher：International Journal of Hematology  

Patient-derived xenograft (PDX) mouse models are useful for deepening our understanding of the biology of malignant lymphoma; however, factors associated with the success of the PDX lymphoma model are largely unknown. We retrospectively analyzed the characteristics of 66 xenotransplantations from 65 patients. In all, 43 (65%) specimens were obtained from patients aged > 60 years, and 42 (64%) specimens were obtained at diagnosis. Specimens were obtained from patients with the following diseases: diffuse large B-cell lymphoma (n = 30), intravascular large B-cell lymphoma (n = 12), follicular lymphoma (n = 8), peripheral T-cell lymphoma (n = 7), mantle cell lymphoma (n = 2), and other (n = 7). The specimens were sourced mainly from bone marrow (n = 31, 47%) and extranodal tumors (n = 13, 20%). Engraftment was successful in 33/66 (50%) xenotransplantations. The median age of patients who provided successful specimens was significantly higher than that for unsuccessful specimens (p = 0.013). Specimens with a high proportion of tumor cells in the graft and those obtained from patients with relapsed/refractory disease showed higher tendencies toward successful engraftment. Taken together, these data suggest that tumor cells with a highly malignant potential might have a high likelihood of engraftment.

DOI： 10.1007/s12185-023-03604-z

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Language：English   Publisher：Journal of Spine Surgery  

Solitary fibrous tumors (SFTs) and hemangiopericytomas (HPCs) have been classified as one entity by the World Health Organization in 2016 due to gene fusion between NAB2 and STAT6. In the Central Nervous System (CNS), a hypocellular, collagenized tumor with a classic SFT phenotype is considered grade I, whereas more densely cellular tumors mostly corresponding to the HPC phenotype are classified as grade II or III (anaplastic) depending in mitotic count (<5 vs. >5 mitoses per 10 high-power fields). Herein, we report two cases of targeted SFT/HPC in which pathological differences and WHO grading affect clinical features. A 75-year-old woman presented with headache and had an intradural extramedullary tumor at the C1 to C2 level. The tumor was well-circumscribed and attached only to the dura mater. It was totally removed and diagnosed SFT/HPC grade I. In contrast, a 68-year-old woman presented with numbness in the right upper limb and had an intradural extramedullary tumor at the medulla to C3 levels The tumor was irregularly marginated and strongly adherent to the spinal cord and involved the vertebral artery. It was sub totally removed and diagnosed SFT/HPC grade II. To the best of our knowledge, there are only 12 cases of SFT/HPC at the craniocervical junction, including the present two cases, of which four that were adherent to the spinal cord or involved the vertebral artery were grade II or III. Although the location of the tumor was almost the same, there were significant differences in the intraoperative findings according to the WHO grading.

DOI： 10.21037/jss-21-83

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Language：English   Publisher：Oncogene  

The tumor microenvironment is deeply involved in the process of tumor growth and development. In this study, we focused on cancer-associated fibroblasts (CAFs) and their derived exosomes on the lymphoma microenvironment to uncover their clinical significance. CAFs were established from primary lymphoma samples, and exosomes secreted from CAFs were obtained by standard procedures. We then investigated the roles of CAFs and their derived exosomes in the survival and drug resistance of lymphoma cells. CAFs supported the survival of lymphoma cells through increased glycolysis, and the extent differed among CAFs. Exosomes were identified as a major component of the extracellular vesicles from CAFs, and they also supported the survival of lymphoma cells. The suppression of RAB27B, which is involved in the secretion of exosomes, using a specific siRNA resulted in reduced exosome secretion and decreased survival of lymphoma cells. Moreover, anti-pyrimidine drug resistance was induced in the presence of exosomes through the suppression of the pyrimidine transporter, equilibrative nucleoside transporter 2 (ENT2), and the suppression of ENT2 was significant in in vivo experiments and clinical samples. RNA sequencing analysis of miRNAs in exosomes identified miR-4717-5p as one of the most abundant miRNAs in the exosome, which suppressed the expression of ENT2 and induced anti-pyrimidine drug resistance in vitro. Our results suggest that exosomes including miR-4717-5p secreted from CAFs play a pivotal role in the lymphoma microenvironment, indicating that they are a promising therapeutic target.

DOI： 10.1038/s41388-021-01829-y

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Language：English   Publisher：American Journal of Surgical Pathology  

On the basis of immunohistochemistry, diffuse large B-cell lymphoma (DLBCL) is categorized as a germinal center B-cell (GCB) or non-GCB subtype. Recent integrated genomic analyses have highlighted the importance of the JAK-STAT3 pathway in the molecular pathogenesis of DLBCL. However, its relevance to clinical outcomes remains controversial. Therefore, we evaluated the extent of the nuclear expression of phosphorylated STAT3 (pSTAT3), a surrogate marker of signal transducer and activator of transcription 3 (STAT3) activation, by immunohistochemistry. We also analyzed the potential relationship between pSTAT3 positivity (defined as ≥ 40% positive neoplastic cells) and clinicopathologic characteristics in 294 patients with DLBCL. pSTAT3 was detected in 122 patients (42%), with a higher rate in the non-GCB subtype than in the GCB subtype (57% vs. 28%, P < 0.001). Factors potentially activating STAT3, MYD88^L265P, and Epstein-Barr virus-encoded small RNA were identified in the pSTAT3-positive non-GCB subtype, whereas the pSTAT3-positive GCB subtype often showed STAT3 mutations and lacked EZH2 mutations and the rearrangements of BCL2 and MYC. Multivariate analyses revealed that the pSTAT3-positive GCB subtype showed a favorable prognosis (HR: 0.17; 95% confidence interval, 0.04-0.7; P = 0.014). These findings suggest that pSTAT3 positivity may have a unique impact on the clinicopathologic characteristics of DLBCL, making it a promising novel marker for the favorable prognosis of patients with the GCB subtype.

DOI： 10.1097/PAS.0000000000001691

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Language：English   Publisher：Blood  

Key Points: • Genetic alterations in immune checkpoint–related genes are frequent in IVLBCL. • Plasma cfDNA is an alternative tumor DNA source of IVLBCL to detect genetic alterations by comprehensive analyses.

DOI： 10.1182/blood.2020007245

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Language：English   Publisher：Respirology Case Reports  

A 75-year-old man was diagnosed with advanced follicular lymphoma because of enlarged cervical lymph nodes. He received chemotherapy and was in complete remission for four years. However, after four years, he developed diffuse lymphadenopathy in the abdominal and iliac area suspected to be recurrent follicular lymphoma. At the time, he was asymptomatic and did not have any accompanying lung lesions. Due to his asymptomatic state, careful monitoring was chosen. Later, he developed diffuse granular shadow in the lung fields. A definite diagnosis was difficult to achieve without histological findings. Therefore, transbronchial lung biopsy of the lesions was performed. The pathology and immunohistochemistry of the lesions revealed recurrent follicular lymphoma. Although the frequency of recurrent follicular lymphoma presenting with diffuse granular shadow is uncommon, recurrent malignant lymphoma should be considered as a differential diagnosis in case with a history of malignant lymphoma.

DOI： 10.1002/rcr2.710

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Language：English   Publisher：Japanese Society of Lymphoma Research  

<p>The programmed cell death 1 (PD1)/PD1 ligand (PD-L1) axis plays an important role in tumor cell escape from immune control and has been most extensively investigated for therapeutic purposes. However, PD-L1 immunohistochemistry is still not used widely for diagnosis. We review the diagnostic utility of PD-L1 (by clone SP142) immunohistochemistry in large-cell lymphomas, mainly consisting of classic Hodgkin lymphoma (CHL) and diffuse large B-cell lymphoma (DLBCL). Neoplastic PD-L1 (nPD-L1) expression on Hodgkin and Reed-Sternberg cells is well-established among prototypic CHL. Of note, EBV+ CHL often poses a challenge for differential diagnosis from peripheral T-cell lymphoma with EBV+ non-malignant large B-cells; their distinction is based on the lack of PD-L1 expression on large B-cells in the latter. The nPD-L1 expression further provides a good diagnostic consensus for CHL with primary extranodal disease conceivably characterized by a combined pathogenesis of immune escape of tumor cells and immunodeficiency. Compared with CHL, the nPD-L1 expression rate is much lower in DLBCL, highlighting some specific subgroups of intravascular large B-cell lymphoma, primary mediastinal large B-cell lymphoma, and EBV+ DLBCL. They consist of nPD-L1-positive and -negative subgroups, but their clinicopathological significance remains to be elucidated. Microenvironmental PD-L1 positivity on immune cells may be associated with a favorable prognosis in extranodal DLBCL. PD-L1 (by SP142) immunohistochemistry has helped us to understand the immune biology of lymphoid neoplasms possibly related by immune escape and/or immunodeficiency. However, knowledge of these issues remains limited and should be clarified for diagnostic consensus in the future.</p>

DOI： 10.3960/jslrt.21003

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Language：English   Publisher：Japanese Society of Lymphoma Research  

<p>Neoplastic programmed cell death ligand 1 (PD-L1) expression, activated by <i>PD-L1</i> gene alterations, is strongly associated with classic Hodgkin lymphoma (CHL). This association enabled a diagnostic consensus for lymphocyte-depleted CHL (LD-CHL), a previously enigmatic disease. We describe two patients with LD-CHL and primary extranodal disease. One patient was a 92-year-old female (Case #1) with a large mass that involved the uterus combined with swollen lymph nodes in the pelvic cavity. The second patient was a 76-year-old female (Case #2) with human T-cell leukemia virus type 1 (HTLV-1) who initially exhibited massive bone marrow involvement without peripheral lymphadenopathies. Biopsies of these tumors from the cervix uteri and bone marrow, respectively, revealed lesions rich in Hodgkin and Reed-Sternberg (H-RS) cells and diminished populations of other cell populations. Immunohistochemistry demonstrated that these H-RS cells expressed CD30, BOB1, and fascin, but not CD15, CD20, PAX5, or OCT2. They also expressed PD-L1, which led to our preferred diagnosis of LD-CHL in both patients. Epstein-Barr virus was associated with LD-CHL in Case #1, but not in Case #2. Both patients were deemed too frail for treatment. They died of disease at 1 (Case #1) and 15 months (Case #2) after the diagnosis. These findings highlight the abnormal biological behavior of this immune-escape-related lymphoid neoplasm in patients with immunodeficiency due to immune senescence and HTLV1 infection.</p>

DOI： 10.3960/jslrt.21008

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CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/pin.12946

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DOI： 10.1002/cam4.3104

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DOI： 10.1016/S1470-2045(20)30059-0

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DOI： 10.1111/pin.12891

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DOI： 10.1111/pin.12888

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DOI： 10.1182/blood-2019-126798

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Publisher：学研メディカル秀潤社  

DOI： 10.15105/gz.0000001162

CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/pin.12757

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DOI： 10.1111/pin.12742

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DOI： 10.1111/his.13475

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DOI： 10.1111/pin.12653

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Lymphoma Research  

<p>Intravascular large B-cell lymphoma (IVLBCL) is a rare and clinically distinctive entity characterized by the almost exclusive growth of large cells within the lumen of blood vessels in particular capillaries. Reports of this peculiar disease, do not commonly address the PD-L1 expression on IVLBCL tumor cells. Here, we describe a 51-year-old Japanese woman who presented with rapidly progressive cognitive decline and higher brain dysfunction. CT scan and MRI revealed multiple ischemic foci in the cerebral hemispheres, ground-glass opacity in the lungs, and splenomegaly. Random skin biopsy for IVLBCL diagnosis yielded negative results. The patient experienced a rapidly deteriorating clinical course with no treatment, and died from the disease after 3 months of hospitalization. Post-mortem examination revealed systemic intravascular plugging of lymphoma cells, without mass lesions in the central nervous system or in visceral organs such as the lungs, liver, pituitary gland, ovaries, and uterus. The tumor cells were positive for CD10, CD20, BCL2, BCL6, and MUM1, but not other lineage-specific markers. Notably, the tumor cells showed strong PD-L1 expression. Our case was diagnosed as IVLBCL with neoplastic PD-L1 expression. These findings suggest that PD-L1 is associated with immune evasion of IVLBCL and may play a role in the pathogenesis and peculiar biological behavior of this unique disease. Additionally, PD-L1 may represent a possible therapeutic target for immune check-point inhibitors.</p>

DOI： 10.3960/jslrt.17037

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CiNii Research

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.18632/oncotarget.14393

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Language：Japanese   Publisher：The Japanese Society of Gastroenterological Surgery  

<p>We report a case of granular cell tumor at the hepatic hilum mimicking hilar bile duct carcinoma. The patient was a 38-year-old woman. She was admitted to our hospital for investigation of her liver dysfunction. Enhanced CT and MRI showed a soft mass about 2 cm in diameter at the left hepatic duct with intrahepatic biliary dilatation in the left hepatic lobe. Subsequent imaging with MRCP and ERCP revealed a stricture at the left hepatic duct. Endoscopic biopsy of the stricture revealed atypical cells. Suspicion of cholangiocarcinoma prompted surgery. The patient underwent left hemi-hepatectomy with extrahepatic bile duct excision. The biliary tract was reconstructed with a Roux-en Y choledochojejunostomy. Pathological examination of the specimen revealed a stricture at the left hepatic duct surrounded by a 22-mm mass. The lesion was a benign granular cell tumor. The postoperative course was uneventful, and the patient has been doing well and recurrence free 1 1/2 years after presentation. To the best of our knowledge, this is the first documented case of a granular cell tumor of the hepatic hilum in Japan.</p>

DOI： 10.5833/jjgs.2016.0116

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DOI： 10.1016/j.humpath.2013.05.025

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DOI： 10.1111/j.1440-1789.2011.01203.x

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DOI： 10.1111/j.1440-1827.2009.02390.x

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DOI： 10.1111/j.1365-2559.2008.02997.x

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DOI： 10.1007/s12185-008-0102-7

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DOI： 10.1111/j.1440-1827.2006.02059.x

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DOI： 10.1016/j.humpath.2007.01.013

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DOI： 10.1016/S0167-4838(98)00191-5