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The early progression of disease (POD) of Hodgkin lymphoma (HL) leads to a poor prognosis. To identify risk factors for early POD, this retrospective two-center cohort analysis was conducted.Medical records of HL patients between 1998 and 2020 from two referral centers were reviewed.Two-hundred and sixty-nine patients were analyzed. The distribution of early vs. advanced stages was 51.1 vs. 48.9%, respectively. The 5-year progression free survival (PFS) was 63%, and the overall survival (OS) was 87% with a median follow-up of 52.0 months. The complete remission (CR) rate was 85.7%. Disease progression or relapsed disease occurred in 33.9% (n = 85) of patients while 17.0% of this cohort had early POD within 12 months of induction therapy. Patients with early POD had a worse median OS than those without (p 0.001). Failure to achieve post-induction CR and high international prognostic score (IPS, 3-7) were independent risk factors for early POD. Compared with chemotherapy alone, consolidative radiotherapy after induction chemotherapy was associated with a lower risk of early POD (21.3% vs. 6.2%, p = 0.006).High IPS was an independent risk factor for early POD, which was less observed in those with consolidative radiotherapy.

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma often with extranodal involvement at diagnosis, and yet how this feature correlates with survival awaits elucidation. To address this issue, a correlative analysis between clinical features of 127 MCL patients and their overall survival (OS) was conducted. In this cohort, the median age at MCL diagnosis was 62 years and 81% were males. Eighty-four percent of patients were Ann Arbor stage 4, and 15% were blastoid variants. In patients with gastrointestinal MCL, approximately 40% had gastric involvement. In treatment, CHOP-based induction chemotherapy was given to 61.1% of patients. One-third of patients undertook autologous stem cell transplant (SCT), and 4.7% had allogeneic SCT. The median OS was 82 months and well-stratified in MIPI risk groups. In the multivariate analysis for OS, blastoid variants and gastric involvement were both independent risk factors whereas auto-SCT had a protective effect. Overall, this study corroborated with the current understandings and international therapeutic standards for MCL. Auto-SCT associated with a better OS while allo-SCT remained an option for blastoid variants and those who failed Auto-SCT. Interestingly, patients with gastric involvement tended to have worse survival, a finding that spawns more studies to investigate the mechanism.

Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive, rare lymphoma of natural killer (NK) cell origin with poor clinical outcomes. Here we used phenotypic and molecular profiling, including epigenetic analyses, to investigate how ENKTL ontogeny relates to normal NK-cell development. We demonstrate that neoplastic NK cells are stably, but reversibly, arrested at earlier stages of NK-cell maturation. Genes downregulated in the most epigenetic immature tumors were associated with polycomb silencing along with genomic gain and overexpression of EZH2. ENKTL cells exhibited genome-wide DNA hypermethylation. Tumor-specific DNA methylation gains were associated with polycomb-marked regions, involving extensive gene silencing and loss of transcription factor binding. To investigate therapeutic targeting, we treated novel patient-derived xenograft (PDX) models of ENKTL with the DNA hypomethylating agent, 5-azacytidine. Treatment led to reexpression of NK-cell developmental genes, phenotypic NK-cell differentiation, and prolongation of survival. These studies lay the foundation for epigenetic-directed therapy in ENKTL. Significance: Through epigenetic and transcriptomic analyses of ENKTL, a rare, aggressive malignancy, along with normal NK-cell developmental intermediates, we identified that extreme DNA hypermethylation targets genes required for NK-cell development. Disrupting this epigenetic blockade in novel PDX models led to ENKTL differentiation and improved survival. This article is highlighted in the In This Issue feature, p. 85

Adult-onset immunodeficiency syndrome (AOIS) caused by anti-interferon-γ autoantibodies is an emerging disease. Affected patients present typically with systemic lymphadenopathy, fatigue, and fever. We studied 36 biopsy specimens, 31 lymph nodes, and 5 extranodal sites, of AOIS confirmed by serum autoantibody or QuantiFERON-TB Gold In-Tube assay. We describe the morphologic features and the results of ancillary studies, including special stains, immunohistochemistry, and molecular testing. The overall median age of these patients was 60.5 years (range, 41 to 83 y) with a male-to-female ratio of 20:16. All biopsy specimens showed nontuberculous mycobacterial infection, and most cases showed the following histologic features: capsular thickening with intranodal sclerosing fibrosis, irregularly distributed ill-formed granulomas or histiocytic aggregates with neutrophilic infiltration, interfollicular expansion by a polymorphic infiltrate with some Hodgkin-like cells that commonly effaces most of the nodal architecture and proliferation of high endothelial venules. In situ hybridization analysis for Epstein-Barr virus-encoded RNA showed scattered (

Objectives Distinguishing Kikuchi disease (KD) from lupus lymphadenitis (LL) histologically is nearly impossible. We applied C4d immunohistochemical (IHC) stain to develop diagnostic tools. Methods We retrospectively investigated clinicopathological features and C4d IHC staining in an LL-enriched development cohort (19 LL and 81 KD specimens), proposed risk stratification criteria and trained machine learning models, and validated them in an external cohort (2 LL and 55 KD specimens). Results Clinically, we observed that LL was associated with an older average age (33 vs 25 years; P=0.005), higher proportion of biopsy sites other than the neck [4/19 (21%) vs 1/81 (1%); P=0.004], and higher proportion of generalized lymphadenopathy compared with KD [9/16 (56%) vs 7/31 (23%); P=0.028]. Histologically, LL involved a larger tissue area than KD did (P=0.006). LL specimens exhibited more frequent interfollicular pattern [5/19 (26%) vs 3/81 (4%); P=0.001] and plasma cell infiltrates (P=0.002), and less frequent histiocytic infiltrates in the necrotic area (P=0.030). Xanthomatous infiltrates were noted in 6/19 (32%) LL specimens. Immunohistochemically, C4d endothelial staining in the necrotic area [11/17 (65%) vs 2/62 (3%); P Conclusions Integrating clinicopathological and C4d findings could distinguish LL from KD.

Primary cardiac lymphoma (PCL) is very rare, with the variable clinical manifestations potentially leading to a delayed diagnosis. PCL is usually detected incidentally through image studies, whereas the diagnosis can be confirmed via analysis of pericardial effusion, endomyocardial biopsy tissue, or surgical specimens. Although no standard therapy has been established for PCL, without treatment, the prognosis is grave, with the estimated overall survival being approximately 1 year.We report a difficult diagnosis and complicated case of fulminant PCL, which is the first comprehensively reported case of PCL with secondary hemophagocytosis. A man presented with progressive dyspnea for 3 weeks, and then sudden cardiac death with ventricular fibrillation occurred. After resuscitation, echocardiography revealed a thickened left ventricular wall and severe mitral regurgitation, and computed tomography showed a right atrial mass with diffuse myocardial lesions. PCL was confirmed through a pathological analysis of specimens collected during mitral valvuloplasty, which also implied extensive myocardial involvement. Bone marrow biopsy demonstrated no evidence of lymphoma involvement, but secondary hemophagocytosis was noted. Despite aggressive chemotherapy, the patient died of sepsis with multiorgan failure 26 days after the operation. Keywords: Heart neoplasms, Hemophagocytosis, Death, Sudden, Lymphoma, Cardiac

Intralymphatic spread is common in solid cancers, but has been rarely studied in lymphomas. Review of 635 extranodal specimens from 475 diffuse large B-cell lymphoma (DLBCL) patients revealed intralymphatic spread in 10 surgical resection specimens from 10 patients including 9 de novo DLBCLs and 1 Richter transformation. The prevalence in de novo DLBCL with extranodal involvements was 1.65%. The most common involved site of intralymphatic spread was the gastrointestinal tract, followed by the female genital tract and breasts. Lymphatic vessels, lined by D2-40-positive endothelial cells, were expanded by lymphoma cells, reminiscent of intravascular lymphoma or tumor emboli. None of the involved lymphatic vessels were located in the mucosa. Patients with intralymphatic spread had a trend of lower overall response rate and a trend of higher progressive disease than those without intralymphatic spread. Compared with patients without intralymphatic spread, those patients with intralymphatic spread had a shorter median overall survival (14.3 vs. 96.2 mo; P=0.004) and a shorter median progression-free survival (11.2 vs. 64.2 mo; P=0.01), respectively. Multivariate analyses showed that intralymphatic spread was an independent poor prognostic factor for overall survival (hazard ratio, 3.029; 95% confidence interval, 1.315-6.978; P=0.009), irrespective of the National Comprehensive Cancer Network-International Prognostic Index, B symptoms, and serum albumin levels. Among patients who underwent surgical resection, intralymphatic spread was still an independent prognostic factor. In conclusion, our study demonstrated extranodal intralymphatic spread in DLBCL. Inspiringly, this rare morphologic finding may serve as a new negative prognostic indicator in DLBCL with extranodal involvements.

Summary FGFR1 translocation may cause myeloid or lymphoid neoplasm but rarely systemic mastocytosis (SM). Conversely, SM is associated with myeloproliferative neoplasm (MPN) but rarely lymphoblastic lymphoma (LBL) or FGFR1 translocation. We report the first case of FGFR1 translocation in a patient with concurrent LBL, MPN, and SM. A 21-year-old male patient presented with diffuse lymphadenopathies and leukocytosis. TdT + /cytoCD3 + /CD79a weakly+ LBL was identified in the lymph node. Bone marrow had MPN, SM, and TdT + /CD79a + /cytoCD3 weakly+ LBL. The cytogenetic study, reverse-transcription polymerase chain reaction, and sequencing revealed t(8;13)(p11;q12) involving FGFR1 and ZMYM2 . Under the hyper–cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen, complete remission of LBL was achieved despite persistent MPN and SM in the bone marrow. This rare case implies FGFR1 translocation in a precursor cell capable of differentiation into mast cells and lymphoblasts, strengthening the relationship between the 2 tumors in the World Health Organization classification: myeloid and lymphoid neoplasms with FGFR1 abnormalities, and SM with an associated hematologic neoplasm.

Splenic marginal zone lymphoma (SMZL) and splenic diffuse large B-cell lymphoma (DLBCL) are the most common types of lymphomas involving the spleen. Geographic variation in hepatitis C virus (HCV) seroprevalence is characteristic of splenic lymphomas. In Italy, HCV seroprevalence was higher in patients with SMZL and splenic DLBCL than in patients with all types of lymphoma. In Japan, HCV seroprevalence was higher in patients with splenic DLBCL than in patients with all types of lymphoma; however, HCV seroprevalence in patients with SMZL was similar to that in patients with all types of lymphoma. In this study, clinicopathological data of 74 splenic lymphoma cases between 1988 and 2011 collected from the Department of Pathology at National Taiwan University Hospital were analyzed. Serology for HCV infection was available for 41 cases. Splenic DLBCL and SMZL accounted for 36% (n = 27) and 42% (n = 31) of splenic lymphomas, respectively. Microscopically, most cases of DLBCL (26/27) presented with circumscribed tumor and most cases of SMZL (28/31) presented with white pulp expansion. HCV seroprevalence in patients with DLBCL and SMZL was 44% and 10%, respectively (7/16 vs. 2/20, p = 0.020). The pattern identified in this study is closer to that in Japan than in Italy. HCV seroprevalence in patients with early-stage (I/II) and late-stage (III/IV) DLBCL was 100% and 10%, respectively (6/6 vs. 1/10, p

Hematopoietic stem cell transplant (HSCT) recipients have a higher risk of cervical cancer. Papanicolaou (Pap) smear is the standard tool for screening cervical cancer, but there is limited research about the cervical cytology in HSCT recipients. Here, we retrospectively included adult female patients who underwent allogeneic or autologous HSCT at National Taiwan University Hospital during 2009 to 2015 and reviewed their Pap smears before and after HSCT. There were 248 allogeneic and 131 autologous HSCT recipients in our study. In allogeneic HSCT recipients, 38.7% (96 of 248) had pre-HSCT Pap smears and 17.1% (44 of 248) had post-HSCT Pap smears. In the autologous HSCT recipients, 35.1% (46 of 131) had pre-HSCT Pap smears and 13.7% (18 of 131) had post-HSCT Pap smears. Compared with allogeneic HSCT recipients without post-HSCT Pap smears, more recipients with post-HSCT Pap smears received bone marrow-derived stem cells (18.2% versus 4.9% respectively; P = .0077) and had longer overall survival (median overall survival, not reached versus 22.1 months; P .0001). The abnormal rates of post-HSCT Pap smear were 13% (6 of 44) and 11% (2 of 18) in allogeneic and autologous recipients respectively, higher than in the general Taiwanese population (1.22%). Infections were rare in post-HSCT Pap smears. Of note, 11% (5 of 44) of post-HSCT Pap smears from allogeneic recipients showed therapy-related atypia, manifesting as enlarged hyperchromatic nuclei, vacuolated cytoplasm, and occasional tadpole-like cells. These atypical cytological features mimic precancerous lesions, but cervical biopsies and human papilloma virus tests were negative. The atypical cytological features resolved spontaneously in the subsequent follow-up Pap smears. On average, Pap smears with therapy-related atypia were sampled at day +77, significantly earlier than those without therapy-related atypia (P = .016). Therapy-related atypia was more frequent in post-HSCT Pap smears sampled within 100 days after HSCT (before day +100, 4 of 5, 80%, versus after day +100, 1 of 39, 2.56%; P = .0002). The strong temporal relationship suggests these atypical cytological changes resulted from conditioning regimen, most likely busulfan-containing chemotherapy. No therapy-related atypia were observed after total body irradiation or nonbusulfan-containing chemotherapy. In conclusion, therapy-related atypia was common in post-HSCT Pap smears sampled within 100 days after HSCT. Clinical information is critical for correct cytological diagnosis.

Kikuchi-Fujimoto disease (KFD) is a self-limited disease without any need of surgical treatments. Sampling of tissue is the only invasive procedure during the clinical course. However, the standard sampling procedure with accuracy, minimal invasiveness, and esthetic maintenance has not been established yet. In this study, a retrospective review of clinical utility and pathological presentations of the ultrasound-guided core biopsy (USCB) and the open biopsy (OB) in consecutive KFD patients. From 2010 to 2012, 34 consecutive patients were enrolled. USCB was performed in 11 patients, and OB was done in 26 patients. KFD was confirmed in 82% cases by USCB. Similar pathological presentations were found both in the specimens of USCB and OB. In the three patients who had received both USCB and OB, KFD was confirmed by USCB in one case, while two by OB. Sampling errors were found both in USCB and OB. For diagnosing KFD, USCB can serve as the first-line diagnostic tool. OB can be applied only in the failed cases of USCB.

Identifying, evaluating, and controlling workplace hazards are important functions of safety professionals (SPs). The purpose of this study was to investigate the content and frequency of hazard management dealt by safety professionals in colleges. The authors also explored the effects of organizational factors/individual factors on SPs’ perception of frequency of hazard management. The researchers conducted survey research to achieve the objective of this study. The researchers mailed questionnaires to 200 SPs in colleges after simple random sampling, then received a total of 144 valid responses (response rate = 72%). Exploratory factor analysis indicated that the hazard management scale (HMS) extracted five factors, including physical hazards, biological hazards, social and psychological hazards, ergonomic hazards, and chemical hazards. Moreover, the top 10 hazards that the survey results identified that safety professionals were most likely to deal with (in order of most to least frequent) were: organic solvents, illumination, other chemicals, machinery and equipment, fire and explosion, electricity, noise, specific chemicals, human error, and lifting/carrying. Finally, the results of one-way multivariate analysis of variance (MANOVA) indicated there were four individual factors that impacted the perceived frequency of hazard management which were of statistical and practical significance: job tenure in the college of employment, type of certification, gender, and overall job tenure. SPs within colleges and industries can now discuss plans revolving around these five areas instead of having to deal with all of the separate hazards.

Extramedullary plasmacytoma (EMP) and multiple myeloma (MM) are both plasma cell (PC) tumours that are usually distinguished by clinical manifestations, but not by histopathological examination alone. However, EMP may express B-cell markers, such as CD79a and CD20, and MM may express germinal centre B-cell (GCBC)-associated microRNAs, such as miR-93 and miR-181b. Down-regulation of miR-30a or up-regulation of miR-223 is associated with the transition from GCBCs into PCs or memory B-cells, respectively. We studied B-cell markers and microRNAs to establish criteria that could distinguish EMP from MM.Immunostains for the B-cell markers CD19, CD20, CD79a and PAX5 were performed. Expression levels of microRNAs 30a, 93, 181b and 223 were measured by real-time reverse transcription polymerase chain reactions. 73% of EMPs expressed CD19 whereas MM cases were negative. EMP and MM had similar levels of miR-30a, miR-93, and miR-181b, but EMP lacked expression of miR-223.The presence of CD19 and lack of miR-223 suggested aberrant B-cell differentiation in EMP. Although the underlying mechanism for this differential expression was unclear, a CD19(+) /miR-223(-) phenotype could be used to distinguish EMP from the CD19(-) /miR-223(+) phenotype of MM.

Molecular biomarkers to determine the effectiveness of targeted therapies in cancer treatment have been widely adopted in colorectal cancer (CRC), but those to predict chemotherapy sensitivity remain poorly defined. We tested our hypothesis that KRAS mutation may be a predictor of oxaliplatin sensitivity in CRC. KRAS was knocked-down in KRAS-mutant CRC cells (DLD-1(G13D) and SW480(G12V)) by small interfering RNAs (siRNA) and overexpressed in KRAS-wild-type CRC cells (COLO320DM) by KRAS-mutant vectors to generate paired CRC cells. These paired CRC cells were tested by oxaliplatin, irinotecan and 5FU to determine the change in drug sensitivity by MTT assay and flow cytometry. Reasons for sensitivity alteration were further determined by western blot and real-time quantitative reverse transcriptase polymerase chain reaction (qRT -PCR). In KRAS-wild-type CRC cells (COLO320DM), KRAS overexpression by mutant vectors caused excision repair cross-complementation group 1 (ERCC1) downregulation in protein and mRNA levels, and enhanced oxaliplatin sensitivity. In contrast, in KRAS-mutant CRC cells (DLD-1(G13D) and SW480(G12V)), KRAS knocked-down by KRAS-siRNA led to ERCC1 upregulation and increased oxaliplatin resistance. The sensitivity of irinotecan and 5FU had not changed in the paired CRC cells. To validate ERCC1 as a predictor of sensitivity for oxaliplatin, ERCC1 was knocked-down by siRNA in KRAS-wild-type CRC cells, which restored oxaliplatin sensitivity. In contrast, ERCC1 was overexpressed by ERCC1-expressing vectors in KRAS-mutant CRC cells, and caused oxaliplatin resistance. Overall, our findings suggest that KRAS mutation is a predictor of oxaliplatin sensitivity in colon cancer cells by the mechanism of ERCC1 downregulation.