Utility of cerebrospinal fluid liquid biopsy in distinguishing CNS lymphoma from cerebrospinal infectious/demyelinating diseases.

BACKGROUND: Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) analyses. To determine whether detection of genetic mutations enables differentiation between these diseases and the early detection of CNSL, we performed mutational analysis using CSF liquid biopsy technique. METHODS: In this study, we extracted cell-free DNA from the CSF (CSF-cfDNA) of CNSL (N = 10), CNS infectious disease (N = 10), and demyelinating disease (N = 10) patients, and performed quantitative mutational analysis by droplet-digital PCR. Conventional analyses were also performed using peripheral blood and CSF to confirm the characteristics of each disease. RESULTS: Blood hemoglobin and albumin levels were significantly lower in CNSL than CNS infectious and demyelinating diseases, CSF cell counts were significantly higher in infectious diseases than CNSL and demyelinating diseases, and CSF-cfDNA concentrations were significantly higher in infectious diseases than CNSL and demyelinating diseases. Mutation analysis using CSF-cfDNA detected MYD88L265P and CD79Y196 mutations in 60% of CNSLs each, with either mutation detected in 80% of cases. Mutual existence of both mutations was identified in 40% of cases. These mutations were not detected in either infectious or demyelinating diseases, and the sensitivity and specificity of detecting either MYD88/CD79B mutations in CNSL were 80% and 100%, respectively. In the four cases biopsied, the median time from collecting CSF with the detected mutations to definitive diagnosis by conventional methods was 22.5 days (range, 18-93 days). CONCLUSIONS: These results suggest that mutation analysis using CSF-cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform.

Follicular lymphoma suggested to transform into EBV-negative plasmablastic lymphoma.

Follicular lymphoma (FL) is an indolent lymphoma that often transforms into a high-grade lymphoma, mostly diffuse large B-cell lymphoma. A case of FL suggested to transform into plasmablastic lymphoma is presented. A 59-year-old man was admitted to our hospital because of right lower abdominal pain and vomiting. Computed tomography showed a mass in the ileocecum. Colonoscopy showed a mass with an ulcer in the ascending colon, and surgery was performed. Immunohistochemical staining of the biopsied mass showed infiltrated lymphocytes that were positive for CD38, CD45, CD138, and λ chain, and negative for CD4, CD5, CD8, CD10, CD20, CD56, and κ chain. Flow cytometric analysis of the ascites showed similar results. FISH analyses performed using lymph node biopsy specimens, ascite fluid and pleural effusion fluid identified the presence of an IGH/BCL2 translocation. FL was suggested to transform into PBL. Although the patient received three courses of R-CHOP chemotherapy and salvage chemotherapy, the patient died because of lymphoma progression less than 6 months after the diagnosis of PBL. Transformation of FL to PBL is highly unusual. The lack of a standard treatment for PBL results in the poor outcome of this entity. Novel therapeutic approaches are needed.

Alpha-glucosidase inhibitor use is associated with decreased colorectal neoplasia risk in patients with type 2 diabetes mellitus receiving colonoscopy: a retrospective study.

PURPOSE: The purpose of this study was to clarify the factors that influence the incidence of colorectal neoplasia in patients with type 2 diabetes mellitus (DM). STUDY DESIGN AND SETTING: Among a total of 1176 patients who underwent total colonoscopy at our hospital, we retrospectively analyzed 168 patients with type 2 DM. Univariate and multivariate logistic regression analyses were then performed to identify the risk factors associated with colorectal neoplasia. RESULTS: A multivariate analysis of these patients demonstrated that male gender (odds ratio [OR] = 4.04, 95% confidence interval [CI] = 1.67-10.37, p = 0.002), taking statins (OR = 4.59, 95% CI = 1.69-13.43, p = 0.003), taking alpha glucosidase inhibitor (α-GI) (OR = 0.35, 95% CI = 0.13-0.87, p = 0.023) and taking low-dose aspirin (LDA) (OR = 0.32, 95% CI = 0.10-0.95, p = 0.040) were independent factors associated with an increased (male gender and statins) or decreased (α-GI and LDA) risk of colorectal neoplasia. CONCLUSIONS: While male gender and taking statins are risk factors, taking α-GI as well as LDA may reduce the risk of colorectal neoplasia in patients with type2 DM.

Association between increased serum GP88 (progranulin) concentrations and prognosis in patients with malignant lymphomas.

BACKGROUND: GP88 (progranulin; PGRN) is a secreted 88kDa glycosylated protein, with important functions, including inflammation and tumorigenesis. We assessed the significance of GP88 expression in survival outcomes of patients with malignant lymphoma (ML). METHODS: Serum samples from 254 previously untreated ML patients were examined to measure GP88 concentrations using a sandwich human GP88 ELISA kit. Immunohistochemical analyses were performed to examine GP88 tumor tissue expression. RESULTS: The median serum GP88 concentration of ML patients was 91.3ng/ml, and was significantly higher than that of the control group (median, 57.7ng/ml) (p<0.0001). Association between GP88 serum concentrations and overall survival (OS) was examined in patients with diffuse large B cell lymphoma (DLBCL) who had been stratified based on their serum GP88 concentrations. Kaplan Meier survival analysis showed that patients with serum GP88 concentrations of ≤116 and >116ng/ml, had 5-y OS rates of 70% and 50%, respectively (p=0.02). The immunohistochemical analyses of GP88 tumor expression revealed that DLBCL patients had lymphoma cells that were positive for GP88. CONCLUSIONS: High serum GP88 concentrations are associated with poor prognosis in patients with DLBCL.

A salvage chemotherapy of R-P-IMVP16/CBDCA consisting of rituximab, methylprednisolone, ifosfamide, methotrexate, etoposide, and carboplatin for patients with diffuse large B cell lymphoma who had previously received R-CHOP therapy as first-line chemotherapy.

We have reported the efficacy of the salvage chemotherapy P-IMVP16/CBDCA for patients with diffuse large B cell lymphoma (DLBCL) who had previously received CHOP before the availability of rituximab (R). Here, we confirmed the efficacy of R combined with P-IMVP16/CBDCA as a salvage chemotherapy for patients with DLBCL, who had previously received R-CHOP. We retrospectively analysed 59 patients with relapse or refractory DLBCL (38 male patients and 21 female patients) presenting between June 2004 and June 2013. The patients received R 375 mg/m2 on day 1, methylprednisolone 1000 mg/body for 3 days (from day 3 to day 5), ifosfamide 1000 mg/m2 for 5 days (from day 3 to day 7), methotrexate 30 mg/m2 on day 5 and day 12, etoposide 80 mg/m2 for 3 days (from day 3 to day 5), and carboplatin 300 mg/m2 on day 3 every 21 days. Patients aged 70 years or older were given 75% of the standard dose. The overall response rate (complete response + partial response) was 64.4%. The 2-year overall survival rate was 55.3%. The 2-year progression free survival rate was 34.7%. The 2-year overall survival rate was 61.5% for the relapse patients, and 15.6% for the refractory patients (p < 0.0001). One patient died because of sepsis related to the treatment regimen. Non-hematological adverse effects were mild and tolerable. The R-P-IMVP-16/CBDCA regimen displayed a significant activity in relapsed DLBCL, with acceptable toxicity, and should be considered a candidate for salvage chemotherapy. Copyright © 2016 John Wiley & Sons, Ltd.

Serum concentrations of l-kynurenine predict clinical outcomes of patients with peripheral T-cell lymphoma, not otherwise specified.

Indoleamine 2,3-dioxygenase exerts intense immunomodulatory effects due to enzymatic activities that catalyze the breakdown of the essential amino acid l-tryptophan. The activity of indoleamine 2,3-dioxygenase can be estimated by measuring serum l-kynurenine concentrations. Here, we aimed to determine the role of l-kynurenine as a prognostic factor for peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in a retrospective analysis of data derived from 31 consecutive patients between June 2000 and March 2013 who were histologically diagnosed with PTCL-NOS according to the World Health Organization classification and treated with 6-8 cycles of cyclophosphamide, doxorubicin or pirarubicin, vincristine, and prednisolone. l-kynurenine concentrations in serum samples collected at admission were measured using high-performance liquid chromatography. The median serum concentration of l-kynurenine was 3.28 (range 0.92-8.16) µM. The l-kynurenine cutoff was set at 3.07 µM using receiver operating characteristics curves. The complete remission rates of patients with l-kynurenine <3.07 and ≥3.07 µM were 69% and 51%, respectively. The 5-year overall survival (OS) rates for patients with l-kynurenine <3.07 and ≥3.07 µM were 80.2% and 23.4%, respectively (p < 0.001). More advanced age, poor performance status, elevated lactate dehydrogenase, an unfavorable International Prognostic Index, and a poor prognostic index for T-cell lymphoma were significantly worse factors for OS. Multivariate analyses revealed only l-kynurenine as an independent prognostic factor for OS. In conclusion, serum concentrations of l-kynurenine might comprise a novel prognostic factor with which to determine the outcomes of treatment for PTCL-NOS. Copyright © 2016 John Wiley & Sons, Ltd.

CHOP or THP-COP regimens in the treatment of newly diagnosed peripheral T-cell lymphoma, not otherwise specified: a comparison of doxorubicin and pirarubicin.

The CHOP regimen consisting of cyclophosphamide, doxorubicin (DOX), vincristine and prednisolone has been the most used regimen for peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Pirarubicin [tetrahydropyranyladriamycin (THP)], a derivative of DOX, is an anthracycline with reportedly less cardiotoxicity than DOX. Here, we confirmed the efficacy of THP-COP using THP instead of DOX in the treatment of PTCL-NOS. The study protocol employed a retrospective, consecutive entry design. We retrospectively analysed 56 patients with PTCL-NOS who had received THP-COP or CHOP. These regimens were performed every 21 days. Twenty-nine patients received THP-COP, and 27 received CHOP. There were no significant differences in known prognostic factors, including in the International Prognostic Index (IPI) and the prognostic index for T-cell lymphoma (PIT), between the two groups. Complete remission rates in patients with THP-COP and CHOP were 52% in both groups; the 3-year overall survival (OS) rates were 67% and 52% (p = 0.074), and the 3-year progression-free survival (PFS) rates were 51% and 29% (p = 0.070), respectively. In patients with low IPI (low or low-intermediate), THP-COP had significantly better 3-year OS (100% vs. 64%; p < 0.001) and 3-year PFS (75% vs. 33%; p < 0.05) than CHOP. Similar differences between THP-COP and CHOP were observed in patients with a low PIT (groups 1 or 2). Our study showed that THP-COP produced results equivalent to CHOP regarding efficacy and safety in patients with PTCL-NOS. In patients with low IPI or PIT, THP-COP resulted in significantly better prognosis. Copyright © 2015 John Wiley & Sons, Ltd.

A refractory duodenal ulcer with a biliary-duodenal fistula following the administration of bevacizumab.

A 65-year-old woman with recurrent breast cancer was repeatedly treated with bevacizumab, an anti-VEGF antibody. In addition, she was also frequently prescribed a nonsteroidal anti-inflammatory drug for abdominal pain. Melena was revealed 2 months after the final treatment with bevacizumab, and an endoscopic study revealed a duodenal ulcer (DU) that was resistant to anti-ulcer therapy. A cholangiography identified a biliary-duodenal fistula with bile juice leaking from the ulcer base. Therefore, a biliary stent was placed into the common bile duct for 3 months until the DU healed. This is the first case of a refractory DU with a biliary-duodenal fistula in a patient treated with bevacizumab.

Development of a Novel Scoring System for Predicting the Risk of Colorectal Neoplasia: A Retrospective Study.

OBJECTIVE: The purpose of this study was to develop a novel scoring system to screen subjects who have a high risk for colorectal neoplasia. STUDY DESIGN AND SETTING: We retrospectively analyzed 1061 subjects undergoing total colonoscopy (TCS) for the first time at Gihoku Kosei Hospital. The characteristics and habits of the subjects were analyzed using a multivariate logistic regression analysis. The risk score was established according to each odds ratio of the individual risk factors, and the correlations between the sum of the risk scores and the prevalence of colorectal neoplasia for each individual were evaluated. RESULTS: Age 45-59 (risk score: 2 points) and ≥60 (3 points), male gender (1 point), and habitual alcohol consumption ≥21g daily (1 point) were extracted as the significant risk factors for colorectal neoplasia. When the risk groups were determined by summing up these risk scores, the prevalence rates of colorectal neoplasia were 8.8% for the low risk group (0-2 points), 30.5% for the low-moderate risk group (3 points), 39.1% for the high-moderate risk group (4 points), and 57.6% for the high risk group (5 points). In comparison with the low risk group, the odds ratio of the low-moderate risk, the high-moderate risk, and the high risk groups were 4.6, 6.7, and 14.1 folds, respectively. CONCLUSION: Our scoring system, which linearly correlates with the prevalence rate of colorectal neoplasia, may be an effective tool for screening the subjects who have a high risk for colorectal neoplasia. These subjects, therefore, should be recommended to undergo TCS.

High serum concentration of L-kynurenine predicts unfavorable outcomes in patients with acute myeloid leukemia.

The immunomodulatory effects of indoleamine 2,3-dioxygenase (IDO) are ascribed to its ability to catalyze the breakdown of the L-tryptophan along the L-kynurenine pathway. Because blasts from patients with acute myeloid leukemia (AML) express IDO, the goal of this study was to investigate the role of L-kynurenine as a prognostic marker for AML. We enrolled 48 AML patients. L-kynurenine concentrations were measured by high-performance liquid chromatography. The median serum L-kynurenine level was 1.67 µM. There was no significant difference in the complete remission rate between patients with L-kynurenine < 2.4 (77%) and ≥ 2.4 µM (75%). However, 3-year overall survival (OS) rates were significantly better in patients with low L-kynurenine levels (76%) than in those with high L-kynurenine levels (11%) (p < 0.0001). Furthermore, in intermediate-risk cytogenetics patients, only L-kynurenine was significantly associated with OS (p < 0.005). Multivariate analyses revealed that L-kynurenine and high leukocyte count were independent prognostic factors.

Elevation of serum interleukins 8, 4, and 1ß levels in patients with gastrointestinal low-grade B-cell lymphoma.

Proinflammatory cytokines that are produced by helper T cells (Th) regulate immune reactions, facilitate class switching of B cells, and prolong the lifespan of B and T cells. Eradication therapy using antibiotics is sometimes effective against gastrointestinal (GI) malignant lymphoma, suggesting that the tumor development or progression is affected by the inflammatory microenvironment. In the present study, serum samples from 148 patients with various subtypes of malignant lymphoma were tested for 11 proinflammatory Th1/Th2 cytokines. In the comparison by subtype or GI lesions, serum interleukin (IL)-8 (P = 6.7E-05), IL-4 (P = 7.5E-05), and IL-1ß (P = 0.0043) levels showed significant differences among subtypes, being particularly elevated in follicular lymphomas (FL) and mucosa-associated lymphoid tissue (MALT) lymphomas. Serum IL-8 levels were elevated in GI-FL and MALT lymphomas, and serum IL-4 and IL-1 ß levels were elevated in MALT lymphomas. These findings show that GI low-grade B-cell lymphoma could develop against the background of an inflammatory microenvironment. Thus, these cytokines may be useful as diagnostic markers and could provide new insights into tumor development.

Sarcopenia is an independent prognostic factor in male patients with diffuse large B-cell lymphoma.

Sarcopenia reportedly predicts poor outcomes in elderly patients with diffuse large B-cell lymphoma (DLBCL). However, because previous studies only involved elderly patients, it is difficult to generalize these results to all patients with DLBCL. We retrospectively analyzed 207 patients with DLBCL who received the R-CHOP or R-THP-COP regimen between June 2004 and May 2014. Sarcopenia was measured by the analysis of CT images at the L3 level before treatment. The surface of muscular tissues was selected according to the CT Hounsfield unit. This value was normalized for stature in order to calculate the L3 skeletal muscle index (L3 SMI, cm(2)/m(2)). Median age at diagnosis in the 121 males and 86 females was 67 years (range, 19-86 years). The sex-specific cutoffs for the L3 SMI were determined by receiver operator curve (ROC) analysis. Sarcopenic patients were older than non-sarcopenic patients, with a median age of 70 and 65 years, respectively (p < 0.001). Other International Prognostic Index factors were not significantly different when comparing sarcopenic and non-sarcopenic patients. With a median follow-up of 50.4 months, the 3-year overall survival (OS) was 70 % in the sarcopenic group and 85 % in the non-sarcopenic group (p = 0.0260). In a subgroup analysis by gender, there was a significant difference in the OS when comparing sarcopenic and non-sarcopenic patients in males but not in females (p = 0.0003, p = 0.4440, respectively). Sarcopenia is an independent prognostic factor in male patients with DLBCL.

Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice.

Indoleamine 2,3-dioxygenase (IDO) catalyzes the rate-limiting step in the metabolism of tryptophan along the kynurenine pathway. In tumors, increased IDO activity inhibits proliferation and induces apoptosis of T cells and natural killer cells. We investigated the therapeutic potential of IDO inhibitor 1-methyl-D-tryptophan (D-1MT) with cyclophosphamide (CY) in a mouse model of lymphoma. To examine the effect of D-1MT, mice were killed on day 28. Serum concentrations of L-kynurenine and L-tryptophan were measured by high-performance liquid chromatography. Regulatory T cells (Tregs) were counted by flow cytometry, and mRNA expressions of IDO1, Foxp3, IFN-γ, and COX-2 were examined by quantitative real-time reverse transcription-polymerase chain reaction. D-1MT+CY combination treatment significantly inhibited tumor growth as compared to either treatment alone. There were no significant differences in the serum L-kynurenine/L-tryptophan ratio or the IDO1 expression level in the tumors among the treatment groups. The expression levels of IFN-γ and COX-2 mRNA in tumor-draining lymph nodes (TDLNs) were found to be significantly up-regulated in the CY and D-1MT+CY groups. The number of Tregs in TDLNs in the D-1MT+CY group was significantly lower than that in CY groups on day 17. These results suggest that D-1MT in combination with CY is an effective treatment for lymphoma in a mouse model.

Cytokeratin-positive fibroblastic reticular cell tumor with follicular dendritic cell features: a case report and review of the literature.

Fibroblastic reticular cell (FRC) neoplasms, which are one of the histiocyte tumor types, are very rare. Here we report a cytokeratin (CK)-positive FRC neoplasm having features of follicular dendritic cells in a 54-year-old woman with right axillary lymph node swelling. The resected lymph node showed multiple nodular aggregations simulating and replacing normal follicles. The tumor cells had a uniform, large and oval to polygonal shape, abundant cytoplasm, and various sizes of nuclei with central eosinophilic nucleoli and coarse nuclear chromatin. They were positive for CK AE1/AE3+CAM5.2, CK7, tenascin C, l-caldesomone, and CD21, weakly positive for S100, and negative for CD1a. Ultrastructurally, the tumor cells had long interdigitating microvillus-like cell processes and oval to elongated vesicular nuclei. In addition, the intercellular spaces contained accumulations of collagen, and some tumor cells had desmosomal-like junctions. These findings suggest that the present case is a CK-positive FRC tumor with follicular dendritic cell features.

Peripheral T-Cell Lymphoma, Not Otherwise Specified and Concurrent Seminoma in Testis.

Concurrent seminoma and malignant lymphoma of the testis is rare. We present a case of concurrent seminoma and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) in a 54-year-old man who complained of painless left testicular enlargement. Radical left orchiectomy was performed. Macroscopically, the tumor (4.0 × 3.0 cm) was creamy, soft, and homogeneous, and microscopic evaluation revealed an alveolar structure of large cells that formed sheets, as well as colonization by other abnormal cells in a 1.0 × 1.0 cm area. The portion of the tumor comprising large abnormal cells was diagnosed as a seminoma, which was positive for c-kit by immunohistochemistry; the other portion was diagnosed as CD3/CD8, TIA, and granzyme B-positive PTCL-NOS. These two portions were clearly differentiated from one another. The patient received CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy and achieved complete response for 50 months. To our knowledge, this is the first reported case of synchronous advanced seminoma and PTCL.

Delayed stenosis of the small intestine after cardiopulmonary arrest.

A man in his 70s experienced cardiopulmonary arrest (CPA) due to acute myocardial infarction. He was resuscitated and treated with a multimodal approach, and he fortunately survived CPA without neurological damage. However, abdominal pain and vomiting occurred 45 days after the CPA. Small intestinal endoscopy showed pinhole-like stenosis of the ileum. Although balloon dilation was performed through the scope, his symptoms did not improve. Partial small bowel resection was eventually performed 139 days after the CPA. Pathological findings revealed ischemic changes in the mucosa at two spots. We speculate that an ischemic event occurred in the small bowel during CPA.