Development of Magnetocardiograph without Magnetically Shielded Room Using High-Detectivity TMR Sensors.

A magnetocardiograph that enables the clear observation of heart magnetic field mappings without magnetically shielded rooms at room temperatures has been successfully manufactured. Compared to widespread electrocardiographs, magnetocardiographs commonly have a higher spatial resolution, which is expected to lead to early diagnoses of ischemic heart disease and high diagnostic accuracy of ventricular arrhythmia, which involves the risk of sudden death. However, as the conventional superconducting quantum interference device (SQUID) magnetocardiographs require large magnetically shielded rooms and huge running costs to cool the SQUID sensors, magnetocardiography is still unfamiliar technology. Here, in order to achieve the heart field detectivity of 1.0 pT without magnetically shielded rooms and enough magnetocardiography accuracy, we aimed to improve the detectivity of tunneling magnetoresistance (TMR) sensors and to decrease the environmental and sensor noises with a mathematical algorithm. The magnetic detectivity of the TMR sensors was confirmed to be 14.1 pTrms on average in the frequency band between 0.2 and 100 Hz in uncooled states, thanks to the original multilayer structure and the innovative pattern of free layers. By constructing a sensor array using 288 TMR sensors and applying the mathematical magnetic shield technology of signal space separation (SSS), we confirmed that SSS reduces the environmental magnetic noise by -73 dB, which overtakes the general triple magnetically shielded rooms. Moreover, applying digital processing that combined the signal average of heart magnetic fields for one minute and the projection operation, we succeeded in reducing the sensor noise by about -23 dB. The heart magnetic field resolution measured on a subject in a laboratory in an office building was 0.99 pTrms and obtained magnetocardiograms and current arrow maps as clear as the SQUID magnetocardiograph does in the QRS and ST segments. Upon utilizing its superior spatial resolution, this magnetocardiograph has the potential to be an important tool for the early diagnosis of ischemic heart disease and the risk management of sudden death triggered by ventricular arrhythmia.

CD8 T Cells Show Protection against Highly Pathogenic Simian Immunodeficiency Virus (SIV) after Vaccination with SIV Gene-Expressing BCG Prime and Vaccinia Virus/Sendai Virus Vector Boosts.

Toward development of a dual vaccine for human immunodeficiency virus type 1 (HIV-1) and tuberculosis infections, we developed a urease-deficient bacillus Calmette-Guérin (BCG) strain Tokyo172 (BCGΔurease) to enhance its immunogenicity. BCGΔurease expressing a simian immunodeficiency virus (SIV) Gag induced BCG antigen-specific CD4+ and CD8+ T cells more efficiently and more Gag-specific CD8+ T cells. We evaluated its protective efficacy against SIV infection in cynomolgus monkeys of Asian origin, shown to be as susceptible to infection with SIVmac251 as Indian rhesus macaques. Priming with recombinant BCG (rBCG) expressing SIV genes was followed by a boost with SIV gene-expressing LC16m8Δ vaccinia virus and a second boost with SIV Env-expressing Sendai virus. Eight weeks after the second boost, monkeys were repeatedly challenged with a low dose of SIVmac251 intrarectally. Two animals out of 6 vaccinees were protected, whereas all 7 control animals were infected without any early viral controls. In one vaccinated animal, which had the most potent CD8+ T cells in an in vitro suppression activity (ISA) assay of SIVmac239 replication, plasma viremia was undetectable throughout the follow-up period. Protection was confirmed by the lack of anamnestic antibody responses and detectable cell-associated provirus in various organs. Another monkey with a high ISA acquired a small amount of SIV, but it later became suppressed below the detection limit. Moreover, the ISA score correlated with SIV acquisition. On the other hand, any parameter relating anti-Env antibody was not correlated with the protection.IMPORTANCE Because both AIDS and tuberculosis are serious health threats in middle/low-income countries, development of a dual vaccine against them would be highly beneficial. To approach the goal, here we first assessed a urease-deficient bacillus Calmette-Guérin (BCG) for improvement of immunogenicity against both Mycobacterium tuberculosis and SIV. Second, we demonstrated the usefulness of Asian-origin cynomolgus monkeys for development of a preclinical AIDS vaccine by direct comparison with Indian rhesus macaques as the only validated hosts that identically mirror the outcomes of clinical trials, since the availability of Indian rhesus macaques is limited in countries other than the United States. Finally, we report the protective effect of a vaccination regimen comprising BCG, the highly attenuated vaccinia virus LC16m8Δ strain, and nontransmissible Sendai virus as safe vectors expressing SIV genes using repeated mucosal challenge with highly pathogenic SIVmac251. Identification of CD8+ T cells as a protective immunity suggests a future direction of AIDS vaccine development.

Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS.

Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copynumber aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCLEBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.

The Impact of Postoperative Renal Function Recovery after Laparoscopic and Robot-Assisted Partial Nephrectomy in Patients with Renal Cell Carcinoma.

Background and objectives: This study aimed to evaluate the association between warm ischemic time (WIT) and postoperative renal function using Trifecta achievement in patients with renal cell carcinoma (RCC) who underwent robotic (RAPN) or laparoscopic partial nephrectomy (LPN). Materials and Methods: We conducted a retrospective multicenter cohort study of patients with RCC who underwent RAPN (RAPN group) or LPN (LPN group) at three institutions in Japan between March 2012 and October 2021. The primary endpoints were the rate of trifecta achievement in both surgical techniques and the association between WIT and recovery of postoperative renal function surgical outcomes. Results: The rate of trifecta achievement was significantly lower in patients with LPN than in those with RAPN (p < 0.001). WIT ≥ 25 min were 18 patients (18%) in the RAPN group and 89 (52.7%) in the LPN group. The postoperative estimated glomerular filtration rate (eGFR) was almost the same. However, 13 patients (7.7%) had a decreased in eGFR ≥ 15% at 3 months after LPN compared with the preoperative eGFR. Conclusions: The rate of trifecta achievement in the RAPN group was significantly higher than that in the LPN group. However, eGFR was identified as relatively better preserved after PN in both groups.

Conditional Ror1 knockout reveals crucial involvement in lung adenocarcinoma development and identifies novel HIF-1α regulator.

We previously reported that ROR1 is a crucial downstream gene for the TTF-1/NKX2-1 lineage-survival oncogene in lung adenocarcinoma, while others have found altered expression of ROR1 in multiple cancer types. Accumulated evidence therefore indicates ROR1 as an attractive molecular target, though it has yet to be determined whether targeting Ror1 can inhibit tumor development and growth in vivo. To this end, genetically engineered mice carrying homozygously floxed Ror1 alleles and an SP-C promoter-driven human mutant EGFR transgene were generated. Ror1 ablation resulted in marked retardation of tumor development and progression in association with reduced malignant characteristics and significantly better survival. Interestingly, gene set enrichment analysis identified a hypoxia-induced gene set (HALLMARK_HYPOXIA) as most significantly downregulated by Ror1 ablation in vivo, which led to findings showing that ROR1 knockdown diminished HIF-1α expression under normoxia and clearly hampered HIF-1α induction in response to hypoxia in human lung adenocarcinoma cell lines. The present results directly demonstrate the importance of Ror1 for in vivo development and progression of lung adenocarcinoma, and also identify Ror1 as a novel regulator of Hif-1α. Thus, a future study aimed at the development of a novel therapeutic targeting ROR1 for treatment of solid tumors such as seen in lung cancer, which are frequently accompanied with a hypoxic tumor microenvironment, is warranted.

Expression of programmed cell death ligand-1 by immune cells in the microenvironment is a favorable prognostic factor for primary diffuse large B-cell lymphoma of the central nervous system.

Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (PCNS-DLBCL) is rare. Thirty-nine patients consecutively diagnosed as having PCNS-DLBCL were analyzed to highlight the prognostic value of the expression of programmed cell death ligand-1 (PD-L1) by neoplastic cells and immune cells in the microenvironment. They were positive for CD20 in all (100%), CD5 in two (5%), CD10 in nine (23%), BCL-2 in 27 (69%), BCL-6 in 34 (87%), and MUM-1 in 37 (95%). Only one case was positive for neoplastic PD-L1, with an unexpectedly long clinical course of 92 months. The remaining 38 cases were further divided into three groups based on the percentage of PD-L1+ cells among microenvironmental immune cells. Cutoffs of < 5%, 5-40%, and ≥ 40% successfully stratified mean prognoses with three-year overall survival (OS) of 21%, 63%, and 100% (P = 0.009), respectively. Progression-free survival (PFS) and OS were different between the groups with and without methotrexate (MTX)-containing chemotherapy (P = 0.007 and P < 0.001, respectively). Multivariate analysis identified three independent adverse factors of OS: PD-L1 negativity (< 5%) on microenvironmental immune cells (P = 0.027), deep structure involvement (P = 0.034), and performance status (PS) 2-4 (P = 0.009). The study showed that PD-L1 expression on immune cells in the microenvironment was associated with prognosis among patients with PCNS-DLBCL.

[A Case of Pyonephrosis Due to Urethral Stent Forgotten for 4 Years].

A 53-year-old woman had left pyonephrosis and bladder stone. A double-J ureteral stent was placed for left ureterostenosis and she was lost to followup. Five years later, she had back pain. Computed tomography revealed left hydronephrosis, pyonephrosis and bladder stone. After drainage by percutaneous nephrostomy and antibiotic treatment, left nephroureterectomy was performed. She has been free from recurrence of infection for 3 months after the surgery.

[A Case of Mucinous Adenocarcinoma Extending to Bladder Neck and Prostate].

A 56-year-old man visited a clinic with the chief complaint of frequent micturition and residual sensation of urine. He was referred to our hospital for close examination. Cystoscopy showed a tumor protruding toward the bladder neck from the prostate with stones and debris on the surface. Magnetic resonance imaging showed an encapsulated tumor of iso-intensity in the prostate in T2-weighed images. Prostate specific antigen was 0.88 mg/dl. Transurethral resection of prostate was performed under the diagnosis of benign prostate hyperplasia. During the operation, a solid tumor with mucus deposit was observed. Intraoperative rapid pathological diagnosis was mucinous adenocarcinoma. A radical cystectomy was performed. Pathologically, mucinous adenocarcinoma was distributed in the bladder neck, the prostate and surrounding tissue, but the prostatic urethra was intact. The surgery was assessed to be curative. Neither neoadjuvant nor adjuvant chemotherapy was performed, since the effectiveness of chemotherapy for mucinous adenocarcinoma arising from urothelial epithelium has not been established.

CERS6 required for cell migration and metastasis in lung cancer.

Sphingolipids constitute a class of bio-reactive molecules that transmit signals and exhibit a variety of physical properties in various cell types, though their functions in cancer pathogenesis have yet to be elucidated. Analyses of gene expression profiles of clinical specimens and a panel of cell lines revealed that the ceramide synthase gene CERS6 was overexpressed in non-small-cell lung cancer (NSCLC) tissues, while elevated expression was shown to be associated with poor prognosis and lymph node metastasis. NSCLC profile and in vitro luciferase analysis results suggested that CERS6 overexpression is promoted, at least in part, by reduced miR-101 expression. Under a reduced CERS6 expression condition, the ceramide profile became altered, which was determined to be associated with decreased cell migration and invasion activities in vitro. Furthermore, CERS6 knockdown suppressed RAC1-positive lamellipodia/ruffling formation and attenuated lung metastasis efficiency in mice, while forced expression of CERS6 resulted in an opposite phenotype in examined cell lines. Based on these findings, we consider that ceramide synthesis by CERS6 has important roles in lung cancer migration and metastasis.

PD-L1 expression on tumor or stromal cells of nodal cytotoxic T-cell lymphoma: A clinicopathological study of 50 cases.

Inhibitors of programmed cell-death 1 (PD-1) and programmed cell-death ligand 1 (PD-L1) have revolutionized cancer therapy. Nodal cytotoxic T-cell lymphoma (CTL) is characterized by a poorer prognosis compared to nodal non-CTLs. Here we investigated PD-L1 expression in 50 nodal CTL patients, with and without EBV association (25 of each). We identified seven patients (14%) with neoplastic PD-L1 (nPD-L1) expression on tumor cells, including three males and four females, with a median age of 66 years. One of the seven cases was TCRαß type, three were TCRγδ type and three were TCR-silent type. Six of the seven cases exhibited a lethal clinical course despite multi-agent chemotherapy, of whom four patients died within one year of diagnosis. Morphological findings were uniform, with six cases showing centroblastoid appearance. Among nPD-L1+ cases, two of three examined had structural variations of PD-L1 disrupting 3'-UTR region. Notably, all of the TCRγδ-type nodal CTL cases showed nPD-L1 or miPD-L1 positivity (3 and 10 cases, respectively). TCRγδ-type cases comprised 42% of nPD-L1+ cases (P = 0.043 vs. PD-L1- ), and 35% of miPD-L1+ cases (P = 0.037 vs. PD-L1- ). The results indicate that PD-L1+ nodal CTL cases, especially of the TCRγδ type, are potential candidates for anti-PD-1/PD-L1 therapies.

Negative reactions of BRAF mutation-specific immunohistochemistry to non-V600E mutations of BRAF.

BRAF mutations are rare driver mutations in non-small cell lung cancer (NSCLC), accounting for 1%-2% of the driver mutations, and the mutation spectrum has a wide range in contrast to other tumors. While V600E is a dominant mutation in melanoma, more than half of the mutations in NSCLCs are non-V600E. However, treatment with dabrafenib plus trametinib targets the BRAF V600E mutation exclusively. Therefore, distinguishing between V600E and non-V600E mutations is crucial for biomarker testing in NSCLC in order to determine treatment of choice. Immunohistochemistry (IHC) using the BRAF V600E mutation-specific antibody is clinically used in melanoma patients, but little is known about its application in NSCLC, particularly with regard to the assay performance for non-V600E mutations. In the present study, we examined 117 tumors with BRAF mutations, including 30 with non-V600E mutations, using BRAF mutation-specific IHC. None of the tumors with non-V600E mutations, including two compound mutations, showed a positive reaction. Furthermore, all V600E mutations were positive except for one case with combined BRAF V600E and K601_W604 deletion. Our findings confirmed that the BRAF V600E mutation-specific IHC is specific without any cross-reactions to non-V600E mutations, suggesting that this assay can be a useful screening tool in clinical practice.

Age-related EBV-associated B-cell lymphoproliferative disorders and other EBV + lymphoproliferative diseases: New insights into immune escape and immunodeficiency through staining with anti-PD-L1 antibody clone SP142.

Epstein-Barr virus (EBV) is prevalent among healthy individuals, and is implicated in numerous reactive and neoplastic processes in the immune system. The authors originally identified a series of senile or age-related EBV-associated B-cell lymphoproliferative disorders (LPD) bearing a resemblance to immunodeficiency-associated ones. These LPDs may be associated with immune senescence and are now incorporated into the revised 4th edition of 2017 WHO lymphoma classification as EBV-positive (EBV+) diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS). These EBV+ B-cells often have a Hodgkin/Reed-Sternberg (HRS)-like appearance and are shared beyond the diagnostic categories of mature B-cell neoplasms, mature T-cell neoplasms, classic Hodgkin lymphoma, and immunodeficiency-associated LPD. In addition, peculiar new diseases, such as EBV+ mucocutaneous ulcer and EBV+ DLBCL affecting the young, were recognized. On the other hand, lymphoma classification is now evolving in accord with deeper understanding of the biology of programmed death ligand 1 (PD-L1). Assessing PD-L1 positivity by staining with the anti-PD-L1 monoclonal antibody SP142 provides new insight by discriminating between immune evasion and senescence or immunodeficiency. The aim of the present review is to briefly summarize the diagnostic use of immunostaining with SP142 in malignant lymphomas and/or LPDs that feature tumor and nonmalignant large B-cells harboring EBV.

Diagnostic utility of programmed cell death ligand 1 (clone SP142) in mediastinal composite lymphoma: A report of two cases.

Composite lymphoma is a well-known diagnostic entity exhibiting the synchronous occurrence of two or more distinct types of lymphomas in the same specimen. Here we report two patients, a 14-year-old female (Case 1) and a 45-year-old male (Case 2), with mediastinal composite lymphoma, comprising nodular sclerosis classic Hodgkin lymphoma (NSCHL) and primary mediastinal large B-cell lymphoma (PMBL). Both patients had a mediastinal mass, and manifested two different histologic components in the same biopsy, one characteristic of NSCHL and the other PMBL. The NSCHL areas included Hodgkin and Reed-Sternberg (HRS) cells with typical immunophenotypic features (CD30-positive and CD20-negative), whereas the sheets of large tumor cells characteristic of PMBL were strongly and uniformly CD20-positive. Interestingly, although both cases showed neoplastic PD-L1 (nPD-L1) positivity on the HRS cells of NSCHL, they differed regarding nPD-L1 expression on the PMBL tumor cells. In Case 1, the nPD-L1-negative PMBL component was anatomically situated outside the NSCHL lesion. On the other hand, in Case 2, the nPD-L1-positive PMBL component was characterized by transitional or continuous areas with the NSCHL component. These findings suggested that nPD-L1 expression may define two subtypes of PMBL that are more similar to or distinct from classic Hodgkin lymphoma.

Syncytial variant of classic Hodgkin lymphoma: Four cases diagnosed with the aid of CD274/programmed cell death ligand 1 immunohistochemistry.

Although several reports have highlighted neoplastic PD-L1 (nPD-L1) expression in classic Hodgkin lymphoma (CHL), some have addressed associations between its expression and detailed histopathologic features. Here we describe four cases of syncytial variant of CHL (SV-CHL), with and without Epstein-Barr virus (EBV) association, and highlight the diagnostic utility of PD-L1 (clone SP142) immunohistochemistry. The patients were a 61-year-old male, 45-year-old male, 85-year-old female, and 89-year-old female. All presented with cervical or axillary lymphadenopathy, which on biopsy had the established histopathologic features of SV-CHL with a biphasic pattern of cohesive sheets of large tumor cells and typically scattered distribution of Hodgkin and Reed-Stenberg (HRS) cells. These tumor cells showed identical immunophenotypic findings for CD15, CD30, Fascin, PAX5, OCT2, BOB1 and EBV harboring, regardless of location. The exception was absent or decreased expression of nPD-L1 from tumor cells in the confluent sheets, contrasting with HRS cell positivity in typical areas of CHL. These findings offer the first suggestion of possible downregulation of nPD-L1 expression in association with the histopathologic progression of CHL. The results may be relevant for recognizing 'confluent' sheets in the diagnostic workup for SV-CHL.

The updated JSPGHAN guidelines for the management of Helicobacter pylori infection in childhood.

The Japan Pediatric Helicobacter pylori Study Group published the first guidelines on childhood H. pylori infection in 1997. They were later revised by the Japanese Society for Pediatric Gastroenterology, Hepatology and Nutrition (JSPGHAN). The H. pylori eradication rates, when employing triple therapy with amoxicillin and clarithromycin, currently recommended as the first-line therapy of H. pylori infection in Japan, have substantially decreased, creating an important clinical problem worldwide. In Japanese adults, the "test-and-treat" strategy for H. pylori infection is under consideration as an approach for gastric cancer prevention. However, the combined North American and European pediatric guidelines have rejected such a strategy for asymptomatic children. As risk for gastric cancer development is high in Japan, determining whether the "test-and-treat" strategy can be recommended in children has become an urgent matter. Accordingly, the JSPGHAN has produced a second revision of the H. pylori guidelines, which includes discussion about the issues mentioned above. They consist of 19 clinical questions and 34 statements. An H. pylori culture from gastric biopsies is recommended, not only as a diagnostic test for active infection but for antimicrobial susceptibility testing to optimize eradication therapy. Based upon antimicrobial susceptibility testing of H. pylori strains (especially involving clarithromycin), an eradication regimen including use of the antibiotics to which H. pylori is susceptible is recommended as the first-line therapy against H. pylori-associated diseases. The guidelines recommend against a "test-and-treat" strategy for H. pylori infection for asymptomatic children to protect against the development of gastric cancer because there has been no evidence supporting this strategy.

[A Case of Squamous Cell Carcinoma of the Renal Pelvis that Disseminated to the Nephrostomy Tract after Percutaneous Nephrolithotripsy].

A 50-year-old man was diagnosed with right staghorn calculus. Urine cytology showed atypical cells, and he was followed for suspicion of urothelial carcinoma. However, there was no evidence of tumor six months later, and percutaneous nephrolithotripsy (PNL) was performed for right staghorn calculus. Eight months later, renal pelvic squamous cell carcinoma extending to the abdominal wall through the nephrostomy tract was identified. After neoadjuvant chemotherapy, radical nephroureterectomy and enbloc resection of the nephrostomy tract tumor was performed. The renal pelvic squamous cell carcinoma did not recur. However he died of small cell lung cancer 3 years postoperatively. Planning of treatment strategy was difficult in the present case. Even though PNL was performed after sufficient follow up and examination, renal pelvic cancer could not be diagnosed and extended to the PNL tract. Fortunately, radical en-bloc resection was possible. We herein, report a case of renal pelvic squamous cell carcinoma after PNL.

Helicobacter pylori (HP) infection alone, but not HP-induced atrophic gastritis, increases the risk of gastric lymphoma: a case-control study in Japan.

Infection with Helicobacter pylori (H. pylori) is associated with an increased risk of gastric malignant lymphoma. The chronic inflammation of gastric mucosa by H. pylori infection induces lymphomagenesis. Although this chronic mucosal inflammation also results in atrophic gastritis, evidence supporting the possible significance of atrophic gastritis in gastric lymphomagenesis is scarce. Here, to evaluate the association between gastric mucosal atrophy and the risk of gastric lymphoma, we conducted a matched case-control study at Aichi Cancer Center focusing on the attribution of H. pylori infection status and pepsinogen (PG) serum levels. In total, 86 patients with gastric lymphoma (including 49 cases of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) and 24 cases of diffuse large B cell lymphoma (DLBCL)) and 1720 non-cancer controls were included. Odds ratios (ORs) and 95% confidence intervals (CIs) were assessed by conditional logistic regression analysis with adjustment for potential confounders. Results failed to show a statistically significant association between atrophic gastritis and the risk of gastric lymphoma. The adjusted ORs of positive atrophic gastritis relative to negative for overall gastric lymphoma, MALT lymphoma, DLBCL, and other lymphomas were 0.77 (95% CI 0.45-1.33), 0.65 (0.30-1.39), 1.03 (0.38-2.79), and 0.84 (0.22-3.29), respectively. In contrast, a positive association between overall gastric lymphoma and H. pylori infection was observed (OR = 2.14, 95% CI 1.30-3.54). A consistent association was observed for MALT lymphoma, DLBCL, and other lymphomas with ORs of 1.96 (1.00-3.86), 1.92 (0.74-4.95), and 5.80 (1.12-30.12), respectively. These findings suggest that H. pylori infection triggers gastric lymphoma but that epithelial changes due to atrophic gastritis do not inherently affect the development of gastric lymphoma.

Decrease of bone mineral density in Japanese patients with non-metastatic prostate cancer treated with androgen deprivation therapy.

The aim of this study was to conduct a cross-sectional survey of investigations related to the bone mineral density (BMD) of both non-metastatic prostate cancer (NMPC) patients who have not yet received androgen deprivation therapy (ADT) and patients receiving prolonged ADT in Japan. Japanese male patients with NMPC who received continuous ADT or who were planning to receive ADT were enrolled in this study. Lumbar spine and femoral neck BMD was measured using dual-energy X-ray absorptiometry (DEXA). To assess patient characteristics, we searched medical records and questionnaires to determine whether they had any factors that could possibly affect BMD. A total of 230 patients with a mean age of 76.6 ± 6.4 years were evaluated. Of these, 151 (65.7%) were receiving ADT, and 79 (34.4%) had not yet received ADT. The mean duration of ADT was 37.4 ± 30.7 months. DEXA showed that as the duration of ADT increased, lumbar spine and femoral neck BMD decreased gradually (p = 0.0005 and p = 0.0014, respectively). Stepwise regression analyses revealed that the duration of ADT was a significant variable of both lumbar spine and femoral neck BMD. Moreover, as the duration of ADT increased, the prevalence of osteoporosis increased statistically (p = 0.0002). This study showed that ADT negatively affected lumbar spine and femoral neck BMD. It also showed a progressive increase in the prevalence of osteoporosis in Japanese NMPC patients with ADT.

Anaplastic variant of diffuse large B-cell lymphoma: Reappraisal as a nodal disease with sinusoidal involvement.

Anaplastic variant (av) of diffuse large B-cell lymphoma (DLBCL) is morphologically defined in the 2017 World Health Organization classification, but still an enigmatic disease in its clinicopathologic distinctiveness, posing the differential diagnostic problem from gray zone lymphoma (GZL) and classic Hodgkin lymphoma (cHL). Thirty-one cases previously diagnosed as avDLBCL were reassessed. Of these, 27 (87%) and 4 (13%) were node-based and extranodal diseases, respectively. They were further reclassified into nodal avDLBCL (n = 18), nodal CD30+ DLBCL with T-cell/histiocyte-rich large B-cell lymphoma-like features (CD30+ DLBCL-THRLBCL) (n = 6), GZL with features intermediate between DLBCL and cHL (n = 3) and CD30+ extranodal DLBCL, NOS (n = 4). The nodal avDLBCL cases had a sheet-like proliferation of large cells and/or Hodgkin/Reed-Sternberg (HRS)-like cells in 12 (67%) notably with a sinusoidal pattern in 16 (89%). They showed an expression of CD20 and/or CD79a in all and CD30 in 15 of 18. All of them were negative for PD-L1 on tumor cells, although HRS-like cells showed negativity or partial loss of other B-cell markers to varying degrees. The present study highlighted the distinctiveness of the nodal avDLBCL with sinusoidal pattern, but without neoplastic PD-L1 expression, which provide refined diagnostic criteria for a more precise pathologic and clinical characterization of this disease.

Immune evasion-related extranodal large B-cell lymphoma: A report of six patients with neoplastic PD-L1-positive extranodal diffuse large B-cell lymphoma.

We identified six patients with Epstein-Barr virus (EBV)-negative extranodal diffuse large B-cell lymphoma (DLBCL) and immunohistochemical expression of PD-L1 on their tumor cells by examining 283 DLBCL cases with the PD-L1 SP142 clone between 2015 and 2017. They consisted of two men and four women with a median age of 71 years, and were examined in an autopsy (n = 1) and biopsies from the adrenal gland (n = 2), skin (n = 1), pelvic cavity (n = 1), and kidney (n = 1). All showed a monomorphic population of large transformed B-cells leading to diagnoses of DLBCL with two intravascular large B-cell lymphoma (IVLBCL) and one de novo CD5+ type and were featured by an invariable immunephenotype: CD3-, CD20+, BCL-2+, and MUM1+. In addition, CD5 and CD10 were each detected in one case. All cases expressed PD-L1 on >10% to >90% of tumor cells, which was confirmed with two other PD-L1 antibodies (E1J2J and 28-8). Three untreated patients had a rapid, lethal clinical course within 7 months after diagnosis; while, the remaining three achieved complete remission after treatment and were alive at the last follow-up. We suggest immune evasion-related extranodal large B-cell lymphoma should be recognized beyond the currently identified entities of IVLBCL and de novo CD5+ DLBCL.