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Mastocytosis is a rare disease with a low incidence in Asia-Pacific populations. CD30 and CD123 may have potential prognostic and therapeutic value, but the results are inconsistent. Because racial disparities may exist, we aim to evaluate the expressions of CD30 and CD123 in a series of mastocytosis cases in Taiwan. Twelve patients with systemic and 7 with cutaneous forms of mastocytosis were studied. The expressions of CD30 and CD123 were correlated with the clinical features of the patients. Eighty-three percent (10/12) of patients with systemic mastocytosis (SM) had an associated hematological neoplasm. Four of the SM patients had both "B" and "C" findings, and they had a median survival time of 0.9 months. CD30 expression was positive in 50% (6/12) of SM cases and 100% (6/6) of cutaneous mastocytosis cases. CD123 was expressed focally or weakly in only 2 SM-associated hematological neoplasm cases. The distribution of mastocytosis subtypes and the expression of CD30 and CD123 in Taiwan differed from those reported in North America and Europe. However, mastocytosis, especially indolent forms, is easily overlooked as its heterogeneous and nonspecific clinical manifestations. A high index of suspicion and improved diagnostic methods can be helpful.

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of hyperinflammatory statuses that are difficult to diagnose and can be life-threatening. Bone marrow (BM) hemophagocytosis is one of the diagnostic criteria according to HLH 2004 diagnostic criteria and HS score. Limited studies have focused on the prognostic factors of BM hemophagocytosis and its association with hematologic malignancies. We aimed to analyze the clinical significance of BM hemophagocytosis. Patients with BM hemophagocytosis, either by cytology or pathology, were enrolled at Taipei Veterans General Hospital from January 2002 to July 2021. Relevant clinical and laboratory data were extracted from medical records. Of 119 patients with BM hemophagocytosis, 57 were diagnosed with hematologic malignancies. The median age of the patients was 58, ranging from 21 to 90. Splenomegaly (adjusted odds ratio [aOR] 2.96; 95% confidence interval [CI] 1.13-7.79) was a risk factor for hematologic malignancies, while autoimmune disease (aOR 0.07; 95% CI 0.01-0.39) and increased D-dimer (aOR 0.25; 95% CI 0.07-0.92) were protective factors. Risk factors for mortality in patients with BM hemophagocytosis were hematologic malignancies (adjusted hazard ratio [aHR] 2.34; 95% CI 1.24-4.44), Eastern Cooperative Oncology Group score ≥3 (aHR 2.42; 95% CI 1.20-4.89) and thrombocytopenia (aHR 3.09; 95% CI 1.04-9.16). In conclusion, among patients with BM hemophagocytosis, splenomegaly was a predictor of hematologic malignancies. Patients with hematologic malignancies, poor performance status, or thrombocytopenia had a higher mortality risk. Further validation studies are warranted.

Background Although various prognostic models for primary central nervous system lymphoma (PCNSL) have been developed, there is no consensus regarding the optimal prognostic index. We aimed to evaluate potential prognostic factors and construct a novel predictive model for PCNSL patients. Methods We enrolled newly diagnosed PCNSL patients between 2003 and 2015. The primary endpoint was progression‐free survival (PFS), and the secondary endpoint was overall survival (OS). The prognostic factors identified using multivariate Cox proportional hazards models were used to develop a predictive model. We subsequently validated the prognostic model in an independent cohort. We also evaluated the validity of the existing scores: the International Extranodal Lymphoma Study Group (IELSG), the Nottingham/Barcelona (NB), and the Memorial Sloan‐Kettering Cancer Center models (MSKCC). Results We identified 101 patients with newly diagnosed PCNSL at our center. Multivariate analysis showed that age ≥80, deep brain lesions, and ECOG ≥2 were independent risk factors of PFS. Assigning one point for each factor, we constructed a novel prognostic model, the Taipei Score, with four distinct risk groups (0‐3 points). The performances of the Taipei Score in discriminating both PFS and OS in the training cohort were significant, and the score was validated in the external validation cohort. The IELSG, NB and MSKCC models had insufficient discriminative ability for either PFS or OS in both cohorts. Conclusion The Taipei Score is a simple model that discriminates PFS and OS for PCNSL patients. The score may offer disease risk stratification and facilitate clinical decision‐making., Age, performance status, and deep brain lesions were associated with primary central nervous system lymphoma (PCNSL) survival. The Taipei Score could offer disease risk stratification for PCNSL.

Plasmablastic myeloma (PBM) is a blastic morphologic variant of plasma cell myeloma with less favorable prognosis than those with non-blastic morphology. PBM is rare, without clear-cut definition and detailed clinicopathologic features in the literature. PBM may mimic plasmablastic lymphoma (PBL) as they share nearly identical morphology and immunophenotype. Using the criteria of ≥ 30% plasmablasts in tissue sections, we retrospectively recruited PBM cases and analyzed their clinical, imaging, and pathologic findings, with emphasis on extramedullary involvement. We performed immunohistochemistry, in situ hybridization for Epstein-Barr virus (EBER), and fluorescence in situ hybridization (FISH) for lymphoma- and myeloma-associated genetic alterations. Of the 25 recruited cases, 15 (60%) had extramedullary involvement, which occurred as initial presentation in nine cases. The most common extramedullary sites were soft tissue and/or skin (10/15, 67%), followed by pleural effusion, the lungs, and lymph nodes. Immunohistochemically, tumor cells expressed MYC (74%; 17/23), CD56 (56%; 14/25), and cyclin D1 (16%; 4/25), while CD117 was all negative (n = 25). Of the 20 cases stained with p53, four (20%) cases were diffusely positive, and the remaining 16 cases showed a heterogeneous pattern. EBER was negative in all 24 cases examined. Of the 13 cases examined with FISH, the genetic aberrations identified included del(13q14)(92%; 12/13), gain of chromosome 1q (90%; 9/10), loss of chromosome 1p (60%; 6/10), IGH-FGFR3 reciprocal translocation (23%; 3/13), rearranged MYC (15%; 2/13), and rearranged CCND1 (8%; 1/13), while there were no cases with TP53 deletion (n = 10) or rearrangement of BCL2 (n = 13) or BCL6 (n = 13). The prognosis was dismal regardless of the presence or absence of extramedullary involvement. In conclusion, PBM in Taiwan frequently presented as extramedullary and extranodal lesions, particularly in soft tissue and/or skin, mimicking PBL. FISH for targeted genetic alterations such as del(13q14), gain of chromosome 1q, loss of chromosome 1p, and IGH-FGFR3 might be helpful for the differential diagnoses. Larger studies are warranted to investigate the genetic alterations between PBM and PBL.

Aims‘HER2-low’ breast cancer is an emerging issue as the clinical trials for anti-HER2 antibody–drug conjugates (trastuzumab deruxtecan) are making progress. A reliable method to identify HER2-low cancers is needed. This study aimed to evaluate immunohistochemistry (IHC) and in situ hybridisation (ISH) in detecting HER2-low status.MethodsWe evaluated the HER2 ISH data grouped by the IHC consensus in proficiency tests (PTs), and compared the HER2 ISH results between HER2 IHC scored 0 (IHC-0) and IHC scored 1+ (IHC-1+) tumours from in-house tissue microarrays (TMAs). Since benign/normal glands have HER2 expression and ideally should not be affected by targeted therapy, we evaluated HER2 ISH results in peritumoural benign glands of 52 breast cancers as reference values.ResultsNone of the 565 tissue cores in PTs achieved an 80% participant agreement of IHC-1+. In PTs and in-house TMAs, HER2 signals of the IHC-1+cores (median: 2.6 and 2.0, respectively) were significantly higher than those of IHC-0 cores (median: 2.0 and 1.7, respectively). But the ranges of HER2 signals had a considerable overlap between IHC-1+and IHC-0 cores. The HER2 signals and HER2:CEP17 ratios of peritumoural benign glands exhibited normal distributions, and their upper bounds of the 95% reference intervals were 2.10 and 1.30, respectively.ConclusionsCurrent HER2 testing algorithms are unsatisfactory in detecting HER2-low cases. Using ISH to detect tumour with HER2 signals and HER2:CEP17 ratio higher than the upper bound of the benign glands can be an alternative method.

Background: Overall survival of patients with primary CNS lymphoma (PCNSL) has improved since the introduction of immunochemotherapy. However, up to 10-15% of PCNSL patients still die shortly after diagnosis. In the present study, we aimed to investigate the risk factors of early mortality (death within 60 days after diagnosis) in patients with PCNSL. Methods: We included newly diagnosed PCNSL patients in a tertiary medical center in Taiwan between January 1, 2002 and May 31, 2018. Clinical risk factors were collected and compared between PCNSL patients who had and did not have early mortality. Results: A total of 133 consecutive patients with PCNSL were included in this study. Approximately 9.8% of the PCNSL patients had early mortality. In multivariate analysis, age ≥ 80 (adjusted hazard ratio [HR] 3.34, 95% confidence interval [CI] 1.01-11.04, p = 0.048) and involvement of the basal ganglia (adjusted HR 4.85, 95% CI 1.47-15.95, p = 0.009) were identified as independent risk factors of early mortality. Use of MTX-based chemotherapy served as an independent protective factor for early mortality (adjusted HR 0.19, 95% CI 0.05-0.67, p = 0.010). Infection and tumor-associated mass effect contributed most to early mortality. Conclusion: Early mortality is not uncommon in patients with PCNSL. Identification of patients with higher risk may help clinicians with initiating appropriate surveillance and management.

This paper reviews project cases to explore the role of schools in improving environmental biodiversity. In the past two decades, numerous projects have been implemented in Taiwan to promote environmental sustainability in schools. This process must be continued, and environmental education must be enacted concurrently to cultivate green concepts in people. Three projects are reviewed to describe local-based users’ participatory processes for achieving environmental transformation and sustaining environmental concept cultivation. In addition, connecting individual school grounds can build a solid foundation for preparing a diverse biological environment.

The blast percentage in bone marrow (BM) can be evaluated through biopsy and aspiration, which is essential for diagnosing myeloid neoplasms especially for dividing myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML). However, methods for integrating the results of biopsy and smear have yet to be developed, particularly for cases in which the results fall on both sides of the cut-off value (10% or 20%). We studied 188 cases of MDS/AML initially diagnosed during 2011-2015 by using concomitant BM biopsy and aspiration and used different methods to compare the estimated blast percentages. A linear relationship was noted between the blast percentages estimated through biopsy and smear (R2=0.765). When the blast percentage was classified into four relevant clinical categories (

Primary bone marrow lymphoma (PBML) represents non‐Hodgkin lymphoma (NHL) that primarily arises in the bone marrow (BM) without lymphadenopathy. This condition has various definitions and can be masked by prolonged fever, leading to delayed diagnosis. We aimed to identify clinical features and risk indicators of PBML. We enrolled 269 adults with fever of unknown origin (FUO) who underwent a BM study for potential PBML. Thirty patients were diagnosed with PBML (26 and 4 patients in the training and validation cohort, respectively), and 20 patients (67%) showed initial manifestation of hemophagocytic lymphohistiocytosis (HLH). Among PBML patients in the training cohort, their median overall survival is short (8 days), with pneumonia being the most common direct cause of early mortality, followed by life‐threatening HLH. Despite extremely poor prognoses, some B‐cell PBML patients who survived 30 days after BM studies achieved long‐term survival with rituximab‐based treatment. To assist general practitioners in early PBML diagnosis when approaching adults with naïve FUO, we identified several risk indicators, including elevated serum alkaline‐phosphate levels, lowered serum immunoglobulin‐G levels, cytopenia in ≥2 lineages, and peripheral blood leukoerythroblastosis. Our recently published scoring system, which can predict hematological BM disease in FUO adults, showed excellent ability in recognizing PBML early, with high sensitivity and specificity. We conclude that PBML is a specific “clinical” phenotype of NHL; moreover, we have identified diagnostic clues for early identification of FUO adults with underlying PBML, which should be considered a hematological emergency once suspected in any adult with FUO.

AIMS Aggressive natural killer (NK)-cell leukaemia (ANKCL) and extranodal NK/T-cell lymphoma (ENKTCL) with secondary bone marrow involvement are rare bone marrow NK/T-cell neoplasms and share similar features. This study aimed to distinguish these two entities. METHODS AND RESULTS We studied bone marrow NK/T-cell neoplasms by classifying them into those with no extramedullary mass (group 1, eight cases) and those with extramedullary mass (group 2, 13 cases). The two groups showed similar clinical presentations and pathological features. Fever and cytopenia were the most common clinical presentations in both groups. The neoplastic cells varied from small and relatively monotonous cells to large pleomorphic cells. In six cases (two in group 1, and four in group 2), the neoplastic infiltrate was inconspicuous, consisting of ≤10% of marrow cells in the interstitium, which were hardly identified by haematoxylin and eosin staining alone. Nearly all patients rapidly died, regardless of the neoplastic infiltrate volume. All of the group 1 patients fulfilled the World Health Organisation 2017 diagnostic criteria of ANKCL, and their survival was significantly worse than that of the group 2 patients (P = 0.035). In addition, there was a significant association between being in group 1 and chromosome 7 abnormalities. Chromosome 6q deletion, which is commonly reported in ENKTCL, was seen in two of our group 2 patients, and was not observed in any of our group 1 patients. CONCLUSION ANKCL with no extramedullary mass should be distinguished from ENKTCL with bone marrow involvement, as the former shows distinct outcomes and genetic features.

Introduction Myeloid-derived suppressive cells (MDSCs) represent a collection of myeloid-lineage immature cells owning immunosuppressive ability to facilitate tumor growth and can be phenotyped into two major groups: monocytic MDSC (M-MDSC) and granulocytic MDSC (G-MDSC). Earlier studies demonstrated the association between M-MDSC and prognosis in lymphoma patients. Triggering Receptors Expressed on Myeloid cells 2 (TREM-2) is a transmembrane glycoprotein and well-known to polarize macrophage to M2-like phenotype presenting anti-inflammation properties. Given that both the macrophage and M-MDSC belong to monocytic lineage, we wondered if TREM-2 was also expressed on M-MDSC cell surface and tried to elucidate the clinical impact of surface TREM-2 on M-MDSC derived from patients with newly-diagnosed and treatment-naïve non-Hodgkin lymphoma (NHL). Methods This was a prospective observational study conducted in a tertiary medical center (Taipei Veterans General Hospital) in Taiwan. Adult patients with newly-diagnosed and treatment-naïve NHL were eligible for enrollment from May 15, 2019 to February 28, 2021. Patients with HIV infection or other concurrent malignancies were excluded. The Mann-Whitney U test was used for quantitative data, the Kaplan-Meier estimate and log-rank test for survival data, and Cox regression models for hazard ratios (HRs). Human M-MDSC (defined as CD14 + CD11b + CD33 + HLA-DR - CD15 - cells, Figure A) was obtained from freshly isolated PBMC before initiating any treatment, including steroid. To increase inter-experiment reproducibility, the peripheral blood (PB) from the principal investigator (Hao-yuan Wang) was utilized as an internal control (Healthy Control), and every patient's blood sample was paired to the Healthy Control at the same performance of flow cytometric analysis to calculate the normalized MFI change of TREM-2 as the following: (Patient's TREM2 MFI - Healthy Control's TREM2 MFI) / (Healthy Control's TREM2 MFI) x100 % Results One hundred and one adults with newly-diagnosed and treatment-naïve NHL were prospectively enrolled, with median age of 70 years, DLBCL as the most common pathological subtype (64.4%), 8.9% of patients as the T-cell lymphoma, 18.8% of patients being indolent subtypes, 52.5% of patients having stage IV, 36.6% of patients showing high-risk IPI score, and the median percentage of M-MDSC among peripheral-blood CD45 + cells indicating 0.45%. After a medium follow-up of 14.5 months, we confirmed that patients with higher percentage (>0.82%) of M-MDSC among peripheral-blood CD45 + cells had significantly worse overall survival (non-reach v.s. non-reach, P =0.011) when comparing to those with lower percentage (≦0.82%) of M-MDSC in PB. With regard to the expression of TREM-2 on M-MDSC cell surface, M-MDSC from patients with aggressive lymphoma showed significantly higher normalized MFI change of surface TREM-2 when comparing to M-MDSC from patients with indolent lymphoma (Figure B); the normalized MFI change of surface TREM-2 on M-MDSC derived from patients with higher IPI scores is also significantly higher than those from patients with lower IPI scores (Figure C). Furthermore, patients whose M-MDSCs showed higher normalized MFI change of TREM-2 had significantly worse progression-free and overall survival than those with lower normalized MFI change of surface TREM-2 (Figure D & E). To validate the clinical significance of TREM-2 on M-MDSC cell surface in adults with newly-diagnosed and treatment-naïve NHL, seven factors (age > 70 years, male gender, T-cell subtype, aggressive subtype, high-risk IPI score, percentage of M-MDSC among CD45 + cells in PB >0.82%, and normalized change of surface TREM-2 on M-MDSC >0%) were initially verified by univariate analysis and subsequently put into multivariate analysis if qualified, as shown by Table 1. At last, age (>70 years) and normalized change of TREM-2 on M-MDSC cell surface (>0%) were independent predictors of poor PFS and OS. Conclusion: For adults with newly-diagnosed and treatment-naïve NHL, patients with higher percentage of M-MDSC in PB is associated with worse prognosis; more importantly, high expression of TREM-2 on M-MDSC cell surface is an independent predictor for worse progression and overall survival. The functional role of TREM-2 on M-MDSC warranted further investigation for validating its possibility as an immunotherapeutic novel target. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) is delayed by most physicians. This study aimed to identify early parameters and suitable scoring systems for the risk of HLH. Clinical and laboratory data collected ≤3 days after admission were defined as early parameters and used to calculate the number of HLH-2004 criteria met and bone marrow (BM) score. Between January 2006 and February 2016, 233 immunocompetent adults with naive fever of unknown origin who underwent a BM study were enrolled to mimic patients at risk of HLH and randomly assigned into the developmental or validation cohort. Hemophagocytic lymphohistiocytosis was finally diagnosed in 47 patients, with non-Hodgkin lymphoma as the major etiology (51.1%). Upon admission, four-fifths of patients who developed subsequent HLH fulfilled ≤3 of 8 HLH-2004 criteria, and 6 early parameters were independent predictors of HLH: anemia (hemoglobin 2 × upper normal limit), hyperferritinemia (ferritin > 1000 ng/mL), and splenomegaly. Compared with the HLH criteria met upon admission, the BM score was an independent predictor (odds ratio = 1.621; 95% confidence interval, 1.355-1.940) with excellent discrimination (area under the receiver operating characteristic curve = 0.920; 95% confidence interval, 0.883-0.958). The sensitivity and specificity for a BM score cutoff of 10 points were 95% and 75%, respectively. When approaching immunocompetent adults with a continuously high fever, the BM score at initial admission assists with early identification of patients at risk of HLH.

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a rare form of cytotoxic T-cell lymphoma. It is believed that SPTL in patients without hemophagocytic syndrome (HPS) follows an indolent course; in contrast, SPTL in patients with HPS has been associated with unfavorable survival. To provide more clinical data on SPTL in Asian populations and to identify optimal therapeutic strategies for SPTL, we assessed the clinicopathological features and long-term follow-up data of 10 Taiwanese SPTL patients diagnosed at a single center. Our study demonstrates a group of patients with high incidence of HPS (50%), rather aggressive courses, and early progression. A total of eight patients underwent hematopoietic stem cell transplant (HSCT), including one autologous HSCT and seven allogeneic HSCT. Seven of eight patients receiving HSCT achieved durable remission and maintained in remission for over 30 months (range 30–132 months). There was no difference in 3-year survival of patients with HPS (80%) compared with patients without HPS (80%). Of long-term survivors in the HPS group, three of four received HSCT (autologous HSCT, n = 1; allogeneic HSCT, n = 2). Our study indicated that HSCT is a curative option for eligible SPTL patients with HPS.

A 2-year-old Asian girl presented to our facility for the evaluation of thrombocytopenia. She was treated with intravenous immunoglobulin under the impression of immune thrombocytopenia. However, her body temperature spiked and progressive pancytopenia, hepatosplenomegaly, abnormal liver function, coagulopathy, and pulmonary infiltration developed. The final diagnosis was systemic Epstein-Barr virus (EBV)-positive T-cell lymphoma of childhood with hemophagocytic syndrome. This type of cancer is extremely rare but occurs more commonly in Asians. Its prognosis is generally poor, and a treatment strategy is yet to be established. Double staining for EBV-encoded RNA and CD3 or CD8 is crucial for diagnosis. This type of lymphoma must be diagnosed differentially from acute EBV-associated hemophagocytic lymphohistiocytosis, which is considered nonmalignant. This case report highlights the importance of awareness of this type of rare cancer, a comprehensive diagnostic approach, and close communication between primary care physicians and pathologists.

The relationship between human cytomegalovirus (HCMV) and glioblastoma (GBM) has been debated for more than a decade. We investigated the presence of HCMV genes, RNA and protein in GBMs and their relationships with tumor progression. Results of quantitative PCR for HCMV UL73, nested PCR for HCMV UL144, in situ hybridization (ISH) for RNA transcript, and immunohistochemistry (IHC) for protein expression and their relationship to the prognosis of 116 patients with GBM were evaluated. Nine (7.8%) cases revealed a low concentration of HCMV UL73, and only 2 of the 9 (1.7%) cases showed consistent positivity on repeat PCR testing. HCMV UL144, ISH and IHC assays were all negative. The HCMV UL73 positive cases did not show significant difference in the clinicopathological characters including age, gender, Karnofsky performance status, extent of resection, bevacizumab treatment, isocitrate dehydrogenase 1 mutation, O6-methylguanine-DNA-methyltranferase status and Ki67 labeling index, and did not reveal prognostic significance. As only one HCMV gene was detected at low concentration in 7.8% of GBMs and there was no evidence of transcription, protein expression or prognostic impact, we cannot conclude a relationship between HCMV and GBM in Taiwanese patients.

The aim of this study was to investigate clinical characteristics, outcome, and factors associated with response to systemic administration of steroids in patients with ocular adnexal immunoglobulin G4 (IgG4)-related disease. This was a retrospective evaluation of 11 patients with histopathologically verified ocular adnexal IgG4-related diseases at a medical center in Taiwan between January 2006 and December 2012. Clinical features and outcome, including serial change of serum IgG4 and clinical factors related to response to steroids systemically were evaluated. Seven men and four women, mean age 54.5 years and mean follow-up of 33.5 months, were evaluated. Elevated serum IgG4 levels (>135 mg/dl) were observed in ten patients (91 %). Lacrimal gland involvement was noted in eight (72.7 %), followed by orbit, extraocular muscles, and eyelids. Seven patients (63.6 %) had bilateral ocular lesions and eight (72.7 %) had extraorbital involvement. Eight of ten patients who underwent systemic steroid treatment responded well in the early phase. Recurrence developed in five patients (45 %), requiring repeat steroid therapy and adjunctive treatment. Median serum levels of IgG4 reduced from 540 to 101 mg/dl in ten patients after systemic corticosteroid administration. Patients with lower serum IgG4 and IgG4:IgG ratio at diagnosis were associated with poor response (p = 0.037). Ocular adnexal IgG4-related disease predominantly involved the lacrimal glands bilaterally and was usually associated with high serum IgG4 levels and multiple organ involvement. Most patients responded well to steroid therapy, which was accompanied by a marked decrease in serum IgG4.

The treatment of multiple myeloma (MM) has made greatly advances over the last decade, nearly doubling the overall survival time after the use of novel agents such as thalidomide, lenalidomide and bortezomib. However, the improvement of overall survival has occasionally led to clinical scenarios that were rarely recognized before, for example, light chain escape and extramedullary plasmacytoma (EMP). Here we report an MM patient who relapsed and manifested simultaneously with both a light chain escape and a disseminated pattern of EMP after several different modes of treatment, including conventional chemotherapy, autologous peripheral blood stem cell (PBSC) transplantation, and novel agents. The result was disappointing in this case, which taught us several important things: First, intact immunoglobulin may not be a reliable marker in the surveillance of pretreated multiple myeloma. Various tests for renal function, skeletal condition, and serum free light chain should also be carried out for a comprehensive evaluation. Second, EMP remains a tremendous challenge to the clinician, especially when refractory to current novel agents. Further researches are required to clarify the optimal treatment of such a condition in order to help more patients.

Omental cake is a term to describe peritoneal thickening caused by different processes. Metastatic malignancy is the most common cause. Plasma cell leukemia is a rare hematological malignancy involving plasma cells and differ from multiple myeloma in its aggressiveness, initial presentation, and dismal prognosis. Herein, we reported a case of primary plasma cell leukemia initially presented with diffuse omental cake and ascites and subsequent systemic capillary leak syndrome.

Nasopharyngeal (NP) lymphoma is a rare primary malignancy of the head and neck and represents a minority of malignancies originating from the nasopharynx. For this reason, there are limited data regarding epidemiologic and treatment outcomes. This is a retrospective review of patients diagnosed with NP lymphoma from 1995 to 2017 at a tertiary medical center. The patients&rsquo, demographic data, clinical presentations, treatment modalities, Epstein&ndash, Barr virus (EBV)-encoded small RNA (EBER) staining, and outcomes were investigated. We considered a total of 35 patients, including 20 males and 15 females, diagnosed with NP lymphoma. The age ranged from 17 to 88 years (mean = 59.6). The common presentations were nasal obstruction, epistaxis, and neck mass. In our study, the most common pathological diagnosis of NP lymphoma was diffuse large B cell lymphoma (DLBCL) (n = 17), followed by NK/T cell lymphoma (NKTCL) (n = 9). Other pathologic diagnoses included extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALToma), small lymphocytic lymphoma, mantle cell lymphoma. There were 13 cases showing EBER positivity, including 7 cases of NKTCL, 5 cases of DLBCL, and 1 case of post-transplant lymphoproliferative disorder (PTLD). Most patients received chemotherapy alone, while some patients received both chemotherapy and radiotherapy. Seven patients had local recurrence, and fewer than half of the patients (n = 16) were alive at the time of the study (mean follow-up duration: 54.4 months). The five-year overall survival was 50.4%. NP lymphoma is very rare, and the most common pathologic type is DLBCL. EBER positivity is found in both NKTCL and DLBCL. Identifying more effective therapeutic agents is extremely important to improve patients&rsquo, survival.

Aims To identify an easily obtainable non-neoplastic tissue that can be used as control material for monitoring optimal Ki-67 immunohistochemical staining. Methods and results Various tissues, including tonsil (60), uterine cervix (31), breast skin (26), oesophagus (15), stomach (15), small intestine (15) and colon (16), were studied in the search for ideal control tissue. Tonsil surface epithelium is superior to other tissues because it displayed an easily recognized Ki-67 staining pattern including high positive (parabasal layer), low positive (intermediate layer) and negative (basal and superficial layers) zones. Moderate to weak staining of the majority of the intermediate cells could serve as a threshold for positive staining. Of the variables potentially affecting staining results that were tested, the pretreatment solution for antigen retrieval had the greatest impact, of which pH 9 EDTA was far better than pH 6 citrate solution. Conclusions Tonsil surface epithelium is a useful control for monitoring Ki-67 staining. Achieving optimal staining results could minimize variations in Ki-67 index due to differences in the staining methods used by different laboratories.

BACKGROUND: Long-term outcomes are favorable for patients with polycythemia vera (PV) and for patients with essential thrombocythemia (ET). However, hemorrhage is a significant cause of morbidity and mortality in those patients. METHODS: We retrospectively recruited 247 patients who had received a diagnosis of PV (n = 101) or ET (n = 146) during the period 2001-2010. RESULTS: After a median follow-up period of 36.2 months, the cumulative incidence of hemorrhage was 39.6% in patients with PV (6.2% per person-year) and 29.7% in patients with ET (5.9% person-years). Episodes of major bleeding occurred in 9.9% of patients with PV and in 14.4% of patients with ET. Overall survival was significantly shorter among patients with hemorrhage than among those without said complication (P < 0.001 for overall patients; P = 0.002 for patients with PV; P = 0.026 for patients with ET). In the univariate analysis, age ≥ 60 yr (OR: 4.77, P = 0.046) and WBC ≥ 16 × 10(9) /L (OR: 4.15, P = 0.010) were predictors of hemorrhage in patients with PV, and age ≥ 60 yr (OR: 3.25, P = 0.040), WBC ≥ 16 × 10(9) /L (OR: 2.89, P = 0.024), albumin

The diagnosis of hemophagocytic lymphohistiocytosis (HLH) is delayed by most physicians. This study aimed to identify early parameters and suitable scoring systems for the risk of HLH. Clinical and laboratory data collected ≤3 days after admission were defined as early parameters and used to calculate the number of HLH-2004 criteria met and bone marrow (BM) score. Between January 2006 and February 2016, 233 immunocompetent adults with naïve fever of unknown origin who underwent a BM study were enrolled to mimic patients at risk of HLH and randomly assigned into the developmental or validation cohort. Hemophagocytic lymphohistiocytosis was finally diagnosed in 47 patients, with non-Hodgkin lymphoma as the major etiology (51.1%). Upon admission, four-fifths of patients who developed subsequent HLH fulfilled ≤3 of 8 HLH-2004 criteria, and 6 early parameters were independent predictors of HLH: anemia (hemoglobin 10 g/dL), thrombocytopenia (platelet count 100 × 10

Background Multigene assays are recommended for hormone receptor-positive invasive breast carcinoma to determine the risk of recurrence, but they are highly expensive. We investigated the prognostic values of immunohistochemistry (IHC)-based prognostic models as an alternative to multigene assays. Methods The risk categories estimated by the IHC-based prognostic models were correlated to those estimated by the multigene assays in 71 cases and the follow-up results in 642 consecutive cases of HER2− luminal-type early breast cancer. Cut-off values of IHC-based models were adjusted based on survival outcome to reveal maximum Harrell C index or based on the maximum positive likelihood ratio correlated to multigene assay. Results All investigated IHC-based models could predict the risk of distant recurrence, but their cut-off values required adjustment. Using distant recurrence-free survival (DRFS) to refine the cut-off values could improve the prognostic values. Adjusting the cut-off values using the results of multigene assays, the positive predictive values of an estimate of low risk or low recurrence score (≤ 21) were higher than 90%. On average, 23% of cases got different results of risk assessment after adjustment. Although cut-off values adjusted by multigene assay were not identical to those refined by survival, the adjusted values (17.1 and 23.8) and the refined values (17.5 and 24.5) of the best model (Magee Eq. 1) were close. Among all the evaluated models, Magee equation 2 was the only one without Ki67, and its prognostic values were the lowest. Using 20% as cut-off for Ki67 as suggested by St. Gallen consensus, we could confidently define luminal A cancer. Conclusion It is necessary to adjust the cut-off values of IHC-based prognostic models to fit the purpose. If the estimated risk is clearly high or low, it may be reasonable to omit multigene assays when cost is a consideration.

Background: Reversal of renal impairment (RI) in patients with multiple myeloma (MM) has been evaluated using the estimated glomerular filtration rate (eGFRMDRD) formula developed by the Modification of Diet in Renal Disease study group. However, the prognostic impact of eGFRMDRD at diagnosis of MM is not well studied, particularly its use in conjunction with the International Staging System (ISS). Methods: Newly diagnosed patients with MM were enrolled between 1996 and 2007. Data on clinical features, laboratory tests, and overall survival were compared in terms of corresponding eGFRMDRD. Results: A total of 387 patients with MM (median age, 71 yr) were enrolled. At diagnosis, 56% had ISS stage III disease; the median values of serum creatinine (SCr) and eGFRMDRD were 1.4 mg/dL and 38.2 mL/min/1.73 m2, respectively. Thirty-four percent of patients had SCr of ≥2.0 mg/dL, and 81.2% had chronic kidney disease stages 3–5 (CKD 3–5). Higher CKD stages were significantly more common in men, older patients (≥65 yr), and those with Durie–Salmon and ISS stage III, light-chain diseases, anemia, thrombocytopenia, hypercalcemia, elevated serum β2 microglobulin, or lactate dehydrogenase. In the Cox regression model, CKD 4–5 or CKD 5 alone was independently associated with poor survival. A diagnosis of CKD 5 was shown to be useful in identifying the subgroup of ISS-III patients at high risk – those with a median overall survival of 7.2 months. Conclusions: Our study demonstrates the prognostic impact of eGFRMDRD in patients with MM and CKD 5 as the ISS-independent surrogate predictor of poorest prognosis.

We report 67 patients with acute erythroid leukemia (erythroleukemia) based on the World Health Organization (WHO) 2008 classification. Reviewing the clinicopathologic features, cytogenetics and outcomes, the characteristics of erythroleukemia resembled myelodysplastic syndromes (MDS). Patients with poor performance status, advanced anemia and poor-risk cytogenetics had significantly inferior outcomes. The International Prognostic Scoring System (IPSS) for MDS is useful to differentiate the prognosis of erythroleukemia.

The Wnt/beta-catenin signaling is important for controlling self-renewal of hematopoietic stem cells and its constitutive activation has recently been documented in a significant proportion of acute myeloid leukemia (AML) cases. Topoisomerase IIalpha (Topo IIalpha) is a marker of cell proliferation and a crucial target for anthracycline cytotoxicity, the mainstay of management employed in AML. We retrospectively investigated the prognostic roles of beta-catenin and topo IIalpha in a cohort of 59 patients with newly diagnosed AML by immunohistochemistry. Aberrant beta-catenin expression was demonstrated in 13 patients (22%), and it was more likely to occur in those with unfavorable karyotypes. Advanced age and poor performance status adversely influenced the achievement of complete remission, while neither aberrant beta-catenin expression nor enhanced topo IIalpha activity did. On multivariate survival analysis, four factors independently predicted a shortened overall survival: aberrant beta-catenin expression, high topo IIalpha activity, poor-risk cytogenetics, and presence of at least one comorbidity factor. Our results suggest that both beta-catenin and topo IIalpha independently predicted an adverse prognosis and might serve as new markers for risk stratification in AML patients.

Anemia is one of the characteristics of idiopathic myelofibrosis (IMF), and malignant thymoma is usually associated with various hematologic disorders, including anemia, pancytopenia, and hypogammaglobulinemia. However, the relationship between IMF and malignant thymoma has not been published before. Here, we report a 48-year-old woman who was initially diagnosed of IMF with severe anemia and transfusion dependent. Five years later, malignant thymoma was found when she was examined for chronic cough. After performing extended thymectomy, her anemia dramatically recovered to normal and sustained for 2 years till last follow-up. Her splenomegaly and myelofibrosis were also improved. We hypothesized that her malignant thymoma induced the progression of IMF, especially in anemia.

Cytogenetics represents the most valuable predictor for a poor outcome in patients with acute myeloid leukemia (AML), but it encompasses a heterogeneous patient population who might have diverse pathogenesis and clinical courses. In particular, the significance of complex chromosome aberrations within this cohort has seldom been addressed before. We analyzed 48 AML patients with adverse-risk cytogenetics in this study. The complex karyotype (three or more numerical/structural cytogenetic changes; 29 patients) was found to occur more frequently among the elderly than a noncomplex adverse karyotype (19 patients; median age, 71 vs. 48; P = 0.005). The patients' performance status was the sole independent factor determining the complete remission rate among patients receiving standard induction chemotherapy. On survival analysis, two factors independently predicted a longer overall survival: noncomplex karyotypes [vs. complex karyotypes, hazard ratio (HR) 0.434, 95% confidence interval (CI) 0.189–0.994, P = 0.048] and achievement of complete remission [(CR) vs. CR not reached, HR 0.170, 95% CI 0.051–0.572, P = 0.004)]. In conclusion, among AML patients with adverse cytogenetics, complex chromosomal aberrations occurred more frequently among the elderly and predicted a poor outcome. These patients should be considered as a unique entity and be separated from those with a noncomplex adverse cytogenetic change. Exploring the underlying mechanisms of leukemogenesis could improve the therapeutic outcome for this group of patients.

Rituximab causes hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-seronegative patients with CD20-positive B-cell non-Hodgkin lymphoma (CD20 NHL), especially for those seropositive to the antibody of core antigen (anti-HBc). Clinical hepatitis usually develops after reverse seroconversion of HBsAg (HBV-RS), indicated by the reappearance of HBsAg in serum. Because of the relatively high prevalence of anti-HBc seropositivity in unvaccinated HBsAg-seronegative adults in an HBV hyperendemic area, we aimed to investigate additional factors influencing the development of rituximab-associated HBV-RS.Between January 2000 and December 2010, unvaccinated HBsAg-seronegative adults with CD20 NHL who had received rituximab-containing therapy but not anti-HBV agents were enrolled. Patients with and without HBV-RS were compared in terms of clinical factors and treatments including the number of cycles of rituximab therapy, and transplantation. Competing risk regression was used to identify the factors associated with HBV-RS.For the 482 patients enrolled, the serological status of anti-HBc was available in 75.9%, with a seropositivity rate of 86.6%. At the last follow-up, a total of 33 (6.85%) patients had HBV-RS, with 95.8% anti-HBc seropositive, 78.9% anti-HBs seropositive, and none anti-HCV seropositive. HBV-RS patients have received more cycles (≥6) and prolonged durations of rituximab therapy, and hematopoietic stem cell transplantation. The overall survival was not different between patients with and those without HBV-RS. At the time of HBV-RS, a total of 25 (78.1%) patients had hepatitis flare, especially when HBV-RS appeared during/after induction therapy (100%, 10 of 10). Three (9.1%) patients had fulminant hepatitis, resulting in death in 1 (3%) patient. A higher rituximab cycle intensity was associated with a higher rate of hepatitis flare at the time of HBV-RS. When death in the absence of HBV-RS was considered as the competing risk, the univariate and multivariate regression analyses showed that several factors were independently associated with the development of HBV-RS, including anti-HCV seronegativity, histological subtype of posttransplant lymphoproliferative disorders, ≥6 cycles of rituximab therapy, and succeeding hematopoietic stem cell transplantation.The findings of our study identify additional factors influencing the development of rituximab-associated HBV-RS in HBsAg-seronegative adults with CD20 NHL.

MIB-1 labeling index has been used as a complementary method to differentiate better and worse prognostic groups of astrocytic tumors. However, its reproducibility has been doubted because of the interlaboratory and interobserver variability. We studied the interobserver reproducibility of four manual counting methods of MIB-1 labeling index, including direct counting, area fraction, line intersection with a graticule, and line intersection without a graticule to estimate the total number of the cells. Using line intersection estimate, either with or without a graticule, yielded a worse result. Those MIB-1 labeling indices of astrocytomas were overlapping with those of anaplastic astrocytomas and glioblastomas. Besides, the intraclass correlation coefficient was smaller, and the coefficient of variation was greater than that attained when using a graticule and counting the total number of cells either directly or by area-fraction estimate. The level of interobserver agreement using an MIB-1 labeling index cutoff value of 11.0 was moderate to substantial when applying the line-intersection estimate, and it was almost perfect when applying the direct counting or the area-fraction estimate. The interobserver reproducibility and agreement of MIB-1 labeling index in astrocytic tumors were different depending on the counting methods. Direct counting with a graticule yielded the best result. Before establishing reference standards for staining and counting, the reproducibility of MIB-1 labeling index should be verified.

Although there are criteria for interpretation of the staining results for Her-2/neu in the DAKO HercepTest, the determination of staining intensity and percentage of complete membrane staining is subjective. We studied 46 cases of invasive breast carcinoma to evaluate interobserver reproducibility among 5 pathologists. Complete agreement was achieved in 22 (48%) of 46 cases. Generalized kappa values indicated substantial agreement (0.80). Discrepancies between negative (0, 1+) and positive (2+, 3+) results occurred in 2 cases (kappa = 0.96). One was because of a tangential cut of the basal part of the tumor that mimicked complete membranous staining, and the other was a borderline case that revealed focal (5%-15%) complete membranous staining. Distinguishing weakly (2+) from strongly (3+) positive results showed agreement in only 13 (59%) of 22 positive cases (kappa = 0.38). If more than 50% of tumor cells revealing strong complete membrane staining were regarded as strongly positive, agreement would be improved (kappa = 0.78). While there was a high percentage (70%-80%) of negative cases during routine evaluation, the good interobserver agreement and high negative predictive value made immunohistochemical analysis an effective screening test to exclude negative cases.

Background Primary mediastinal large B-cell lymphoma (PMBCL) is a rare malignancy that has been reported in young individuals, especially young women. Patients with PMBCL commonly receive rituximab induction. This single-institution study was designed to analyze the clinical benefits of rituximab induction and its impact on postinduction treatments (PITs), especially radiotherapy. Methods The benefits of rituximab induction were evaluated by complete response (CR), early treatment failure, relapse, and overall survival (OS) rates. The impact of the induction therapy on the adoption of PIT was evaluated by the proportion of patients who had received at the last follow up any PIT modality [i.e., radiotherapy or hematopoietic stem cell transplantation (HSCT)], radiotherapy alone, HSCT alone, or both modalities. Results Between 1999 and 2012, 48 PMBCL patients (29 men, 60%) were identified; they had a median age of 31 years. Twenty-eight patients received rituximab induction; of these, 23 (82%) patients also underwent fludeoxyglucose-positron emission tomography (FDG-PET) evaluation. Rituximab induction was significantly associated with higher rates of CR and OS, and lower rates of early treatment failure and relapse. Regarding PIT, patients with rituximab induction were more likely to receive radiotherapy alone [with rituximab induction (25%) vs. without rituximab induction (5%)], and patients with FDG-PET evaluation were similarly more likely to receive radiotherapy alone [with FDG-PET evaluation (28.6%) vs. without FDG-PET evaluation (0%)]. In multivariate analysis, age older than 60 years [hazard ratio (HR), 16.697; 95% confidence interval (CI), 1.106–252.022; p = 0.042] and rituximab induction (HR, 0.089; 95% CI, 0.012–0.653; p = 0.017) were significantly associated with OS. Conclusion Rituximab improved the CR and OS rates of patients with PMBCL, but these improvements may be attributable to the increased use of radiotherapy (which may have also resulted from FDG-PET evaluation).

BACKGROUND Kaposi sarcoma-associated herpesvirus (KSHV) recently has been identified in the bone marrow (BM) dendritic cell of multiple myeloma (MM) patients. However, whether or not KSHV is associated with MM remains controversial because many studies have failed to detect the presence of KSHV DNA sequences in the BM of their MM patients. METHODS We have assayed for KSHV DNA sequences in the BM biopsy samples from 49 patients with MM and from 8 patients with normal BM, using nested polymerase chain reaction and dot blot analysis. The polymerase chain reaction product of KSHV was further determined by single-strand conformation polymorphism and sequence analyses. RESULTS KSHV DNA was detectable in 22 of 49 patients (44.9%) with MM but was not detectable in normal BM cells. Single-strand conformation polymorphism and sequence analyses showed that there were interpatient specific mutations. Sixteen out of 22 KSHV DNA sequences belonged to a previously defined subgroup, and the other 6 remain unclassified and may represent distinct strains of KSHV in Taiwan. CONCLUSIONS Data strongly supported that KSHV infection did exist in the BM of the current study patients with MM. However, the role of KSHV in the pathogenesis of multiple myeloma remains to be determined. Cancer 2001;91:1409–13. © 2001 American Cancer Society.

Subcutaneous panniculitis-like T cell lymphoma is a rare disease, characterized by a typical clinical presentation mimicking panniculitis, and is often associated with systemic symptoms including hemophagocytic syndrome. The pathogenesis and etiology of this disease is not fully understood. Here we report two patients coming from the same family. They lived together. The disease afflicted a boy and his elder sister at different time with an interval period of 11 years. Both of them had hemophagocytic syndrome preceding the full-blown manifestations of the lymphoma. However, severity of the disease and the response to chemotherapy is quite different between the two siblings.

A 60-year-old woman sought treatment for right orbital fullness and intermittent headache. CT revealed an inferior orbital mass along the inferior rectus muscle. Incisional biopsy revealed an adenoid cystic carcinoma. Orbital exenteration followed by concurrent radiotherapy and chemotherapy was performed. The lacrimal gland was uninvolved by tumor microscopically. Although rare, adenoid cystic carcinoma must be considered in the differential diagnosis of an orbital tumor, because the unusual location of an orbital adenoid cystic carcinoma may make its early detection difficult.

Supplemental Digital Content is available in the text, Hepatitis B virus (HBV) reactivation has been noted in HBV surface antigen (HBsAg)-seronegative patients with CD20+ B-cell non-Hodgkin lymphoma (NHL) undergoing rituximab treatment. Clinically, hepatitis flares are usually associated with the reappearance of HBsAg (reverse seroconversion of HBsAg, HBV-RS). It is unclear whether human genetic factors are related to rituximab-associated HBV reactivation. Unvaccinated HBsAg-seronegative adults (n = 104) with CD20+ NHL who had received rituximab-containing therapy without anti-HBV prophylaxis were enrolled. Eighty-nine candidate single nucleotide polymorphisms (SNPs) of 49 human cytokine genes were chosen and were analyzed using the iPLEX technique. Competing risk regression was used to identify the factors associated with HBV-RS. Participants had a median age of 66.1 years and 56.7% were male (n = 59). The anti-HBs and anti-HBc positivity rates were 82.4% and 94.1%, respectively, among patients for whom data were available (approximately 81%). A mean of 7.14 cycles of rituximab therapy were administered, and a total of 14 (13.4%) patients developed HBV-RS. Nine SNPs showed significant differences in frequency between patients with or without HBV-RS: CD40 rs1883832, IL4 rs2243248 and rs2243263, IL13 rs1295686, IL18 rs243908, IL20 rs1518108, and TNFSF13B rs12428930 and rs12583006. Multivariate analysis showed that ≥6 cycles of rituximab therapy, IL18 rs243908, and the IL4 haplotype rs2243248∼rs2243263 were independently associated with HBV-RS. The IL4 haplotype rs2243248∼rs2243263 was significantly associated with HBV-RS regardless of anti-HBs status. Polymorphisms in human cytokine genes impact the risk of rituximab-associated HBV-RS.

Objectives Type 2 diabetes mellitus is present in approximately 10% of patients at diagnosis of multiple myeloma (MM) and is associated with increased risks of adverse events caused by novel antimyeloma agents. However, the impact of type 2 diabetes on the survival of patients with MM has not been studied. Methods We enrolled newly diagnosed patients with MM in Taipei Veterans General Hospital between 1999 and 2007 and identified those with pre-existing diabetes. The impact of pre-existing diabetes on patients with MM was evaluated by comparing clinical features, treatments and adverse reactions related to glycaemic control and overall survival (OS) of patients with and without pre-existing diabetes. Results Of 310 patients with MM, 73% were men and 40 (12.9%) had pre-existing diabetes. Compared with their non-diabetic counterparts, MM patients with pre-existing diabetes had a significantly higher proportion of renal impairment [(RI), serum creatinine ≥2.0 mg/dL] and International Staging System stage III at diagnosis, and a significantly lower proportion of bisphosphonate use and a lower rate of RI reversal (P = 0.087). During the course of the disease, hyperglycaemia and hypoglycaemia of any grade were noted in 23 (67.6%) and 6 (17.6%) of these patients, respectively. Antidiabetic therapy was changed in 10 (29.4%) of 34 evaluable patients. MM patients with pre-existing diabetes had a significantly higher all-cause mortality risk (hazard ratio, 1.509; 95% confidence interval, 1.023–2.225, P = 0.037) compared with their non-diabetic counterparts. Conclusions Our study demonstrated the impact of pre-existing diabetes on clinical features and OS in patients with MM.