Pathological assessment of the lymph node biopsies for lymphadenopathy in rheumatoid arthritis.

Objectives: To assess the incidence of reactive lymph node hyperplasia (RLH) and the diagnostic characteristics that can help differentiate it from lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA).Methods: Data on patient characteristic from 32 consecutive RA patients with lymphadenopathy at a single medical center over a 6-year period were collected and analyzed to determine whether any of these characteristics can differentiated RLH from LPD.Results: LPD including methotrexate (MTX) - associated LPD (MTX-LPD) and RLH were diagnosed in 19 and 10 patients, respectively. Conclusive diagnosis was not reached in the remaining three cases and they were regarded as grey-zone cases. Age, levels of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R), as well as maximum standardized uptake value (SUVmax), were significantly higher in LPD than in RLH patients. The diagnosis cut-off values for these parameters were 66 year, 169 U/L, 899 U/mL and 8.18, respectively, based on the receiver operating characteristics curve analysis for both RLH and LPD.Conclusions: About one-third of patients with RA who presented with lymphadenopathy had reactive lymph node enlargement. Older age and higher levels of LDH, sIL-2R, and SUVmax are more associated with LPD than should be considered when deciding to perform a biopsy.

[A Case of Autopsy of Sarcomatoid Carcinoma of the Penis with Metastasis to the Right Ventricle of the Heart].

A 75-year-old man with a history of early gastric cancer, phimosis and bronchial asthma experienced pain and palpated a mass in the penis in March 2015. After 2 months, he noticed bleeding from the tumor and visited our hospital. Pelvic computed tomography and magnetic resonance imaging revealed a pelvic tumor, bilateral lymphadenopathy, and para-aortic lymphadenopathy. After partial penis excision and left inguinal lymph node biopsy, the pathological result was penile squamous cell carcinoma sarcomatoid type, stage IV. As controlling bleeding from the left inguinal lymph node metastasis was difficult, radiotherapy and appropriate debridement were performed. However, the size of the metastasis increased, and the general condition of the patient gradually worsened, the patient died two months after the operation. On pathological autopsy, metastasis to the right ventricle was observed in addition to the left inguinal lymph node metastasis. Herein, we present the first autopsy report of metastatic squamous cell carcinoma sarcomatoid type in Japan, along witha literature review.

[A Case of Long-Term Survival in Gastric Cancer with Multiple Liver Metastases Successfully Treated by Conversion Surgery after S-1 plus Cisplatin Combination Therapy].

A 49-year-old man was diagnosed with advanced gastric cancer, with a chief complaint of epigastric discomfort. Computed tomography revealed multiple liver metastases. S-1 plus cisplatin therapy was administered as first-line chemotherapy, and after 4courses, the liver metastases markedly reduced. Total gastrectomy with D2 lymphadenectomy and a needle biopsy of segment 2 of the liver were performed. Histopathological examination revealed no viable cancer cells in the resected stomach, lymph nodes, or liver tissue. The primary tumor was defined as Grade 3 by histopathological examination. Adjuvant chemotherapy with S-1 was administered for 1 year. The patient is alive without recurrence more than 6 years after surgery.

Effect of Recent Antirheumatic Drug on Features of Rheumatoid Arthritis-Associated Lymphoproliferative Disorders.

OBJECTIVE: In this study, we examine how advancements in novel antirheumatic drugs affect the clinicopathologic features of lymphoproliferative disorder (LPD) in patients with rheumatoid arthritis (RA). METHODS: In this multicenter study across 53 hospitals in Japan, we characterized patients with RA who developed LPDs and visited the hospitals between January 1999 and March 2021. The statistical tools used included Fisher's exact test, the Mann-Whitney U-test, the log-rank test, logistic regression analysis, and Cox proportional hazards models. RESULTS: Overall, 752 patients with RA-associated LPD (RA-LPD) and 770 with sporadic LPD were included in the study. We observed significant differences in the clinicopathologic features between patients with RA-LPD and those with sporadic LPD. Histopathological analysis revealed a high frequency of LPD-associated immunosuppressive conditions. Furthermore, patients with RA-LPD were evaluated based on the antirheumatic drugs administered. The methotrexate (MTX) plus tacrolimus and MTX plus tumor necrosis factor inhibitor (TNFi) groups had different affected site frequencies and histologic subtypes than the MTX-only group. Moreover, MTX and TNFi may synergistically affect susceptibility to Epstein-Barr virus infection. In case of antirheumatic drugs administered after LPD onset, tocilizumab (TCZ)-only therapy was associated with lower frequency of regrowth after spontaneous regression than other regimens. CONCLUSION: Antirheumatic drugs administered before LPD onset may influence the clinicopathologic features of RA-LPD, with patterns changing over time. Furthermore, TCZ-only regimens are recommended after LPD onset.

Angioleiomyoma mimicking a swollen bursa on first metatarsophalangeal joint accompanying with hallux valgus deformity.

We present a case of a patient who underwent a modified scarf osteotomy and tumour excision based on a preoperative diagnosis of hallux valgus deformity and accompanying bursitis. Subsequent histopathological examination revealed that the tumour was an angioleiomyoma. While tumours around the first metatarsophalangeal (MTP) joint are typically associated with gouty nodules, infections, or swollen bursa (bursitis) in patients with hallux valgus deformity, the occurrence of soft tissue tumours in this area is rare. Moreover, angioleiomyoma is an even rarer form of soft tissue tumour and is seldom suspected prior to resection. To our knowledge, there have been no reports of angioleiomyoma arising in the first MTP joint. However, it is important to consider the possibility of an atypical tumour in cases where soft tissue masses are present, even in patients with hallux valgus deformity, and to perform at least imaging tests such as ultrasound and magnetic resonance imaging before surgery. This prospect should always be kept in mind.

Early Resection of the Tibialis Anterior Tendon for Tendon Exposure After Total Ankle Arthroplasty to Prevent Deep Infection: A Report of Three Cases in Patients With Rheumatoid Arthritis.

Exposure of the tibialis anterior (TA) tendon with wound dehiscence after total ankle arthroplasty (TAA) with the anterior approach is a problematic complication, especially in rheumatoid arthritis (RA) patients. Once the TA tendon is exposed, the duration of wound healing is prolonged, and it could be a risk factor for deep infection. Thus, early resection of the TA tendon was evaluated for tendon exposure with wound dehiscence after TAA in RA patients. In this case report, three rheumatoid ankles that showed wound dehiscence with exposure of the TA tendon after TAA with the anterior approach are presented. Early resection of the TA tendon and debridement under local anesthesia were performed within two days after wound dehiscence. In all cases, wound healing was completed within two weeks after the treatment. Drop foot was not seen in any patients, and there was no difference between the pre and postoperative (1 year after TAA) range of dorsiflexion. Muscle strength for ankle dorsiflexion was also maintained. In conclusion, early resection of the TA tendon appears to be a useful option for undesirable tendon exposure with wound dehiscence to prevent deep infection and prolonged wound healing after total ankle arthroplasty in RA patients.

[Waldenström macroglobulinemia complicated with chylothorax].

An 81-year-old male had been diagnosed with Waldenström macroglobulinemia (WM) eight years previously and had thus been administered appropriate treatment. Left chylothorax later developed at 3 years and 8 months after the initial diagnosis. He was hospitalized with severe anemia, general fatigue, and appetite loss one year prior to this presentation and died due to a severe fungal infection. Autopsy revealed the presence of 1,300 ml chylothorax and infiltration of lymphoplasmacytic lymphoma (LPL) cells throughout his entire body. LPL cells were found to have invaded the excitation conducting system in the heart. In an evaluation of a resected lung tissue specimen of pneumothorax, subpleural infiltrated lymphoid cells were observed to show immunohistochemical positivity for IgM and bcl-2. Although these lymphoid cells were initially considered to be non-neoplastic lymphocytes, they were later determined to be LPL cells, which thus induced dilatation and proliferation of the lymph vessels. Chylothorax complications in patients with WM are rare events and only six such cases have so far been reported. The present case is considered to be an instructive one in which autopsy suggested the invasion of LPL cells to be involved in the development of arrhythmia, pneumothorax, and chylothorax before death.

[Lung cancer incidentally detected at the treatment of pneumothorax ; report of two cases].

We report 2 cases of lung cancer incidentally detected following pneumothorax. Case 1:A 40-year-old man complaining of dyspnea was admitted with right pneumothorax. Chest computed tomography (CT) after chest drainage showed a cavitary nodule with pleural indentations in the right lower lobe. It was indicated at surgery that pneumothorax was caused by perforation of the tumor into the pleural cavity. Right lower lobectomy was performed because the pathological diagnosis of the nodule was a large cell carcinoma. The final histopathological diagnosis was stage II A (pT2aN1M0). The patient died of recurrence 14 months after surgery. Case 2:A 47-year-old man who admitted with right pneumothorax was found to have a nodule with pleural indentations closely a bulla at the apex of the right lung by chest CT after chest drainage. Pneumothorax was indicated to be caused by rupture of the bulla at surgery. Right upper lobectomy was performed because the pathological diagnosis of the nodule was a squamous carcinoma. The final histopathological diagnosis was stage I A (pT1bN0M0). The patient is alive at 2 years after the operation without recurrence. Lung cancer detected following pneumothorax which was caused by perforation of the tumor is generally considered to have poor prognosis. Whereas, prognosis of lung cancer incidentally detected following pneumothorax depends on its staging.

[Mediastinal goiter; report of a case].

A 76-year-old female was admitted to our hospital because of an abnormal shadow on chest computed tomography (CT) which showed the tumor extending from left lower end of the thyroid to the aortic window along the left side of the trachea, indicating the retrosternal goiter. Serum thyroid stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) were within normal ranges. The tumor was resected through cervical collar incision and median sternotomy. The pathological diagnosis was an adenomatous goiter. The patient was discharged without complications.

Usefulness of electron microscopy in the diagnosis of wild-type transthyretin cardiac amyloidosis.

Wild-type transthyretin cardiac amyloidosis (ATTRwt) has been recognized as an important cause of heart failure with preserved ejection fraction; thus, its accurate diagnosis is crucial. Herein, we describe the case of a 76-year-old man who presented with dyspnea and palpitation. On observing the laboratory evaluations and clinical course, we suspected cardiac amyloidosis. However, optical microscopic analysis by Congo-red and direct fast scarlet staining revealed no amyloid deposits in the biopsy samples. Therefore, a more thorough investigation was pursued by examining the myocardial tissue under electron microscopy. We could recognize amyloid deposits between the myocardial fibers using electron microscopy. We submitted all the pathological specimens to a specialized facility for genetic testing to ensure the accurate diagnosis of the amyloidosis disease type. As a result, a biopsy sample from the minor salivary gland was stained with the Congo red stain. Anti-transthyretin antibody detected using immunohistochemical analysis of amyloidosis supported the presence of transthyretin form of amyloid proteins. Genetic testing revealed the absence of TTR gene mutations. The final diagnosis was ATTRwt. We believe that this case suggests the usefulness of electron microscopy in the diagnosis of ATTRwt and other related disorders. Further study is warranted to validate our findings.

Modulation of TNFR 1-triggered two opposing signals for inflammation and apoptosis via RIPK 1 disruption by geldanamycin in rheumatoid arthritis.

OBJECTIVES: To evaluate the ability of geldanamycin to modulate two opposing TNFα/TNFR1-triggered signals for inflammation and cell death. METHODS: The effects of geldanamycin on TNFα-induced proinflammatory cytokine production, apoptosis, NF-κB activation, caspase activation, and necroptosis in a human rheumatoid synovial cell line (MH7A) were evaluated via ELISA/qPCR, flow cytometry, dual-luciferase reporter assay, and western blotting assay, respectively. In addition, therapeutic effects on murine collagen-induced arthritis (CIA) were also evaluated. RESULTS: Geldanamycin disrupted RIPK1 in MH7A, thereby inhibiting TNFα-induced proinflammatory cytokine production and enhancing apoptosis. TNFα-induced NF-κB and MLKL activation was inhibited, whereas caspase 8 activation was enhanced. Recombinant RIPK1 restored the geldanamycin-mediated inhibition of TNFα-induced NF-κB activation. In addition, GM showed more clinical effectiveness than a conventional biologic TNF inhibitor, etanercept, in murine CIA and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA. CONCLUSIONS: GM disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway, while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line. Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF inhibitor. Key Points • Geldanamycin (GM) disrupts RIPK1 and selectively inhibits the TNFR1-triggered NF-κB activation signaling pathway while enhancing the apoptosis signaling pathway upon TNFα stimulation, thereby redressing the balance between these two opposing signals in a human rheumatoid synovial cell line, MH7A. • GM showed more clinical effectiveness than a conventional biologic TNF-inhibitor, etanercept, in murine collagen-induced arthritis (CIA), and significantly attenuated synovial hyperplasia, a histopathological hallmark of RA. • Therapeutic targeting RIPK1 may be a novel concept which involves TNF inhibitor acting as a TNFR1-signal modulator and have great potential for a more fundamental, effective, and safer TNF-inhibitor.

[Catamenial pneumothorax; report of a case].

A 39-year-old woman was referred to our hospital because of pneumothorax related to menstruation. Chest X-ray showed right pneumothorax. Right thoracoscopy revealed 3 fenestrations on the diaphragm. Partial resection of the diaphragm including these lesions were performed. Intrathoracic minocycline was applied expecting pleural adhesion after surgery. Histopathological examination confirmed the presence of endometriosis on the resected diaphragm.

Effect of interleukin-6 receptor blockage on renal injury in apolipoprotein E-deficient mice.

Hyperlipidemia has been demonstrated to be associated with renal disease, yet the mechanism of renal injury is still poorly understood. Inflammation that occurs with the hyperlipidemia has been considered to play an important role in development of glomerular injury. In the present study, we investigated the role of interleukin-6 (IL-6), a key inflammatory molecule, on renal injury in apolipoprotein E-deficient (ApoE(-/-)) mice with severe hypercholesterolemia. The 6-wk-old mice were fed a high-fat diet and administered weekly rat anti-IL-6 receptor monoclonal antibody (MR16-1), control rat IgG, or saline for a total of 4 wk. We examined histopathological changes in the kidney and urinary excretion of protein and albumin. Saline- and IgG-treated mice showed remarkable proteinuria at 10 wk of age, whereas MR16-1-treated mice exhibited significantly lower levels. Renal histopathology of saline- and IgG-treated mice revealed striking lipid deposits and foam cells in the glomerular tuft, juxtaglomerular area, and arteriolar wall along with range of mesangial cell proliferation and matrix expansion. Notably, the severity of lipid deposits and mesangial cell proliferation were significantly reduced in MR16-1-treated mice. Immunohistochemistry demonstrated that mesangial IL-6 expression was dramatically reduced in MR16-1-treated mice compared with IgG-treated mice. Blocking the IL-6 receptor prevented progression of proteinuria and renal lipid deposit, as well as the mesangial cell proliferation associated with severe hyperlipoproteinemia. These results clearly demonstrate that IL-6 plays an essential role in the pathogenesis of hyperlipidemia-induced glomerular injury in ApoE(-/-) mice and suggests the usefulness of anti-IL-6 receptor antibody in treatments for hyperlipidemia-induced organ damage.

ABO-incompatible adult liver transplantation when the anti-ABO antibody titer is high.

In comparison with ABO-compatible cases, ABO-incompatible liver transplantation has an increased risk of humoral rejection. The risk factors are the recipient's age (> or = 16 years) and elevated titers of anti-donor blood group antibodies. We report a case of adult A-to-O liver transplantation in which the recipient's preoperative IgG titer was 1:8192. Plasmapheresis, splenectomy, rituximab administration, and liver-directed anticoagulation therapy in addition to conventional immunosuppression effectively suppressed the antibody titer, thereby preventing humoral rejection. Preoperative administration of rituximab alone had minimal impact on antibody production, and a substantial amount of plasma cells remained in the spleen. This result is encouraging for high-risk ABO-incompatible liver transplantation and we recommend splenectomy combined with rituximab administration for such cases. Additionally, postoperative modulation of the recipient's immunity to the ABO-incompatible graft was noted, which is necessary for long-term survival of an ABO-mismatched allograft.

[A case of epidermoid cyst in the intrapancreatic accessory spleen mimicking pancreatic malignant tumor].

We report a rare case of an epidermoid cyst in the intrapancreatic accessory spleen with producing CA19-9. A 42-year-old woman was referred to department of internal medicine of our hospital due to growing cystic lesion at the pancreatic tail. Laboratory tests on admission revealed a high serum CA19-9 (102.0 U/mL). Ultrasound sonography detected a 25-mm monolocular cystic tumor with thick capsule and septum. The capsule and septum was enhanced on computed tomography. Endoscopic examination of upper gastrointestinal tract and colon revealed normal. CA19-9 was elevated up to 147.3 U/mL after 2-month follow-up, and she was referred to department of digestive surgery. We suspected a mucinous cystic neoplasm or endocrine tumor, and distal pancreatectomy was performed. The surgical specimen showed a septate cyst surrounded by brown solid tissue resembling normal spleen. The patient was discharged on postoperative day 11. Histological diagnosis was an epidermoid cyst originated from an intrapancreatic accessory spleen. Immunohistochemical analysis of CA19-9 in the epidermoid cyst showed clear staining of the inner epithelium of the cyst. The serum CA19-9 value was confirmed to decline to normal 1 month after resection.

Recovery from established graft-vs-host disease achieved by bone marrow transplantation from a third-party allogeneic donor.

OBJECTIVE: We investigated whether established graft-vs-host disease (GVHD) could be successfully treated by a second allogeneic bone marrow transplantation (BMT) through elimination of first donor-derived lymphocytes responsible for GVHD. MATERIALS AND METHODS: In a murine GVHD model of BDF1 (H-2(b/d))-->B6C3F1(H-2(b/k)), GVHD mice underwent a second BMT using a graft (1 x 10(7) bone marrow and 3 x 10(7) spleen cells) from a major histocompatibility complex (MHC) antigen haploidentically mismatched (to host and also to first donor) mouse strain, B6B10F1(H-2(b/s)), following low-dose total body irradiation (TBI) 2 to 3 weeks after the first BMT. RESULTS: Results demonstrated that severe GVHD could be successfully and stably treated by a second allogeneic BMT. For successful treatment of GVHD, rapid achievement of full second-donor T-cell chimerism was required. Furthermore, we showed that mice with GVHD could easily accept MHC haploidentically mismatched second-donor hematopoietic cells even after minimal conditioning (2-4 Gy TBI) because they were in a profoundly immunosuppressed state, and that the mice were relatively resistant to new development of GVHD by second-donor grafts. Furthermore, the timing of the second BMT, the intensity of conditioning treatment (GVHD mice are very sensitive), and donor selection were also found to be important for obtaining successful outcomes. Increased regulatory T cells and reduction of interferon-gamma levels may be involved in tolerance induction. CONCLUSIONS: We demonstrated that established GVHD in a murine GVHD model could be successfully treated by a second BMT from a third-party allogeneic donor.

Parathyroid hormone and premature thymus ageing in patients with chronic kidney disease.

Premature immune ageing, including thymic atrophy, is observed in patients with chronic kidney disease (CKD). Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), which are mineral and bone disorder (MBD)-related factors, affect immune cells and possibly cause thymic atrophy. We examined the cross-sectional association between thymic atrophy, evaluated as the number of CD3+CD4+CD45RA+CD31+ cells [recent thymic emigrants (RTE)/µL], and MBD-related factors [(serum PTH, FGF23, and alkaline phosphatase (ALP) level] in 125 patients with non-dialysis dependent CKD. Median estimated glomerular filtration rate (eGFR) was 17 mL/min/1.73 m2. Older age (r = -0.46), male sex (r = -0.34), lower eGFR (r = 0.27), lower serum-corrected calcium (r = 0.27), higher PTH (r = -0.36), and higher ALP level (r = -0.20) were identified as determinants of lower number of RTE. In contrast, serum concentrations of FGF23 and phosphorus were not correlated with RTE. Multivariate non-linear regression analysis indicated a negative association between serum PTH and log-transformed RTE (P = 0.030, P for non-linearity = 0.124). However, the serum levels of FGF23 and ALP were not associated with RTE. In patients with CKD, serum PTH concentrations were related to thymic atrophy which contributes to immune abnormality.