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.

A case of pancreatic endocrine carcinoma with a different clinical diagnosis before chemotherapy and pathological autopsy.

We encountered a case of pancreatic neuroendocrine carcinoma (pNEC) diagnosed via pathological autopsy that was initially diagnosed clinically as G3 pancreatic neuroendocrine tumor (G3 pNET) and discussed the differences between these entities in the literature. A 76-year-old man was admitted to our department because of jaundice. Computed tomography revealed multiple round nodules in both lung fields, suggesting metastasis, and a mass lesion was detected in the head of the pancreas with poor contrast in the arterial phase and slight contrast enhancement in the equilibrium phase. Biopsy of the lungs and pancreas led to a diagnosis of multiple pulmonary metastases of G3 pNET. Because the lesions were unresectable, chemotherapy was administered. Treatment was started with everolimus for 5 weeks. However, the patient experienced severe loss of appetite and malaise, and the lung lesions progressed, prompting treatment discontinuation. Subsequently, the patient's disease progressed rapidly, and he died 99 days after the start of chemotherapy. We performed a pathological autopsy with the consent of the family because of the rapid tumor growth. A pathological autopsy revealed a final diagnosis of pNEC, which differed from the clinical diagnosis.

Concomitant Nephrotic Syndrome with Diffuse Large B-cell Lymphoma: A Case Report.

Membranous nephropathy (MN) is a common glomerular disease that is characterized by diffuse thickening of the glomerular basement membrane, and a common cause of nephrotic syndrome (NS). MN is often accompanied with malignant disease; The solid tumors are commonly associated with MN, whereas hematological malignancies are rarely found in patients with MN. A 68-year-old man with a history of diabetes mellitus visited a hospital with a chief complaint of general fatigue. He was previously not diagnosed with any complications of diabetes. Computed tomography revealed a pancreatic tumor, and the pathological findings of the biopsied tumor revealed the tumor was diffuse large B-cell lymphoma (DLBCL). Concurrently, he developed severe proteinuria, hypoalbuminemia, systemic edema and hyperlipidemia, consistent with the diagnosis of NS. The biopsied renal specimen revealed minute spike lesions of glomerular basement membrane, and abnormal lymphocytes infiltrated in the kidney interstitially. Anti-glomerular basement membrane antibody, proteinase-3-/myeloperoxidase antineutrophil cytoplasmic antibody and hepatitis B antigenemia, are absent in the patient. Serum anti-phospholipase A2 receptor (PLA2R) antibody (marker for primary MN) was not detected. A diagnosis of secondary MN induced by DLBCL was made. He received rituximab containing chemotherapy for DLBCL, resulting in amelioration of both DLBCL and MN. We report the rare case of a patient co-existing NS and DLBCL. DLBCL might be pathogenesis of NS; the findings are supported by the presence of MN, an underlying malignancy (DLBCL), and the lack of anti-PLA2R antibodies. Although further investigation is warranted, our case suggests that DLBCL is a possible cause of secondary MN.

[Rupture of Tuberculous Infective Abdominal Aortic Aneurysm after Intravesical Bacillus Calmette-Guérin Instillation Therapy].

The patient was a 74-year-old male who had undergone intravesical Bacillus Calmette-Guérin(BCG) instillation therapy for bladder cancer. He visited our hospital with chief complaints of fever and abdominal pain. Abdominal aortic aneurysmal rupture and iliopsoas muscle abscess were confirmed by computed tomography( CT). We performed semi-emergency surgery, including replacement of the abdominal aorta with a synthetic graft, iliopsoas abscess debridement, and omentopexy. A rifampicin-bonded synthetic graft was used because of the possibility of tuberculous involvement after BCG instillation therapy. Examination of the tissues collected during surgery were positive for tuberculosis deoxyribonucleic acid (DNA) in a polymerase chain reaction (PCR), and showed multiple giant cell granulomas with caseous necrosis, which both strongly suggested involvement of tuberculosis. Therefore, 4 types of antituberculous drugs were administered for 40 days. This case shows that an infective aneurysm should be suspected when fever and abdominal pain develop after intravesical BCG instillation therapy.

A pilot study to assess the safety and usefulness of combined transurethral endoscopic mucosal resection and en-bloc resection for non-muscle invasive bladder cancer.

BACKGROUND: Transurethral resection (TUR) is the standard operation used for non-muscle invasive bladder cancer (NMIBC). Although most solid tumors are principally removed via single block resection without incising the mass, disruption of the lesion is unavoidable in traditional TUR. Furthermore, pathological diagnosis is often difficult due to heat-related denaturation of tissues in TUR. Although transurethral en-bloc resection is useful for judging tumor invasion, it is associated with a prolonged operative duration. We attempted to show the safety and usefulness of combined endoscopic mucosal resection (EMR) and en-bloc resection in NMIBC patients. METHODS: We investigated 39 patients with clinical NMIBC who were treated using our original EMR + en-bloc resection technique, which involved removal of the tumor mass that protruded from the mucosa, using a polypectomy snare similar to that used for EMR. The residual lesion was removed using en-bloc resection. The operative period, duration of hospitalization, and recurrence rates were compared with those of conventional TUR (n = 31). RESULTS: The mean (standard deviation, range) time interval for EMR and total operative duration were 1.6 (1.1, 1-5) min and 18.3 (10.5, 3-48) min, respectively. The total operative duration was comparable to that of TUR (17.3 min, p = 0.691). The mean duration of catheterization in the EMR + en-bloc resection group (4.2 days) was also similar to that in the TUR group (3.7 days; p = 0.285). No severe complications were observed with EMR + en-bloc resection. The pathologists were able to determine tumor invasiveness with considerable certainty in all specimens obtained via the EMR + en-bloc procedure than via TUR, and the difference in the ease of diagnosis was statistically significant (p = 0.016). Recurrence rates were comparable (p = 0.662) between the EMR + en-bloc (15.4%) and TUR groups (19.4%). CONCLUSIONS: Our results demonstrated that the EMR + en-bloc resection technique is feasible, safe, and useful for treating patients with NMIBC. Furthermore, this technique helps provide a more accurate pathological diagnosis.

Paraneoplastic Sarcoidosis in Multiple Myeloma.

Sarcoidosis predominantly affects the lungs, intrathoracic lymph nodes, and eyes; it less frequently affects the musculoskeletal system. We herein report a case of paraneoplastic sarcoidosis in a patient presenting with multiple myeloma. The patient developed ocular sarcoidosis and showed an increased 18F-fluorodeoxyglucose uptake in the mediastinal lymph nodes and vertebral column. A lymph node specimen showed the histological features of sarcoidosis, while an examination of the vertebral tumor revealed myeloma. Although the simultaneous occurrence of sarcoidosis and myeloma is extremely rare, our case indicates the importance of exculing any underlying malignancies before establishing a diagnosis of skeletal sarcoidosis when bone lesions are observed at unusual sites.

Trochlear nerve schwannoma with intratumoral hemorrhage presenting with persistent hiccups: a case report.

Trochlear nerve schwannoma without neurofibromatosis is extremely rare. To our knowledge, only 31 surgical cases have been reported to date, and only 2 cases of trochlear nerve schwannoma with intratumoral hemorrhage have been reported. None of those cases presented with persistent hiccups. We report the case of a 44-year-old man with trochlear nerve schwannoma associated with intratumoral hemorrhage who presented with a 10-day history of persistent hiccups. Computed tomography and magnetic resonance imaging revealed a solid tumor with a 3-cm diameter and intratumoral hemorrhage in the left petroclival region that compressed the midbrain and pons. Subtotal removal of the tumor was performed via the zygomatic transpetrosal approach. Intraoperative findings revealed a tumor arising from the trochlear nerve. The histologic diagnosis was schwannoma of Antoni type A cells with intratumoral hemorrhage. Although the patient's left trochlear nerve palsy worsened temporarily, his postoperative course was uneventful. We present this rare case and discuss the mechanism underlying the patient's persistent hiccups.

Detailed clinicopathological characteristics and possible lymphomagenesis of type II intestinal enteropathy-associated T-cell lymphoma in Japan.

Twenty-six Japanese cases of type II enteropathy-associated T-cell lymphoma (EATL) were examined. Multiple tumors throughout the small intestine were found in 15 patients (58%) and duodenal and colonic mucosal lesions in 8 and 6 cases, respectively. Histologically, intramucosal tumor spread and a zone of neoplastic intraepithelial lymphocytes (IELs) neighboring the main transmural tumors were detected in 20 (91%) and 17 (77%) of the 22 cases examined, respectively. Inside and outside the IEL zone, some degree of enteropathy with many reactive small IELs and villous atrophy was detected in 11 cases (50%). Immunohistologically, many CD56/CD8-positive small IELs were found in the enteropathic lesions of 4 (36%) and 7 (64%) of these 11 cases. Lymphoma cells expressed tyrosine kinase receptor c-Met, serial phosphorylated (p)-mitogen-activated protein kinase/extracellular signal-regulated kinase, c-Myc, and Bcl2 in 18 (78%), 21 (91%), 11 (42%), and 19 (73%) of the total cases, respectively. By fluorescence in situ hybridization, chromosomal loci 7q31 (c-Met) and 8q24 (c-Myc) were amplified in 11 (65%) and 12 (71%) of the 17 cases analyzed. Gain of 7q31 and c-Met expression were significantly (P < .01) higher than in peripheral CD8-positive T-cell or CD56-positive natural killer-cell lymphomas. Enteropathy was seen near the IEL zone in type II EATL, and activation of the c-Met, mitogen-activated protein kinase/extracellular signal-regulated kinase-mitogen-activated protein kinase pathway, and c-Myc-Bcl2-mediated cell survival may play important roles in lymphomagenesis, converting enteropathy to type II EATL. Seven cases in the early clinical stages I and II-1 showed significantly (P < .01) better prognoses than did those in the advanced stages. Early detection of the mucosal lesions and tumors may improve patient prognosis.

[A case of internal carotid artery stenosis with discontinuance of carotid endarterectomy due to the tight adhesions around the internal carotid artery].

A 73-year-old female visited her local doctor after repeatedly experiencing temporary weakness in her left upper and lower extremities. The patient underwent a cervical magnetic resonance imaging (MRI) scan and was diagnosed with right internal carotid artery stenosis. Despite administration of antiplatelet drugs, her symptoms continued, and she was referred to our department for medical treatment. Her medical history revealed hypertension, hyperlipidemia, and cholesteatoma. We diagnosed symptomatic internal carotid artery stenosis and performed carotid endarterectomy (CEA). However, tight adhesions between the carotid artery and surrounding tissue made separation difficult, and surgery had to be discontinued. Some of the extracted adherent tissue consisted of hyalinized fibrous tissue that had the appearance of soft tissue which had organized because of inflammation. Although there have been no reports of cholesteatoma directly causing adhesion around the internal carotid artery, it has been reported to have led to abscess formation in the parapharyngeal space adjacent to the carotid space. Because the boundaries of the parapharyngeal space and carotid space are anatomically incomplete, inflammation often affects the area between them. As far as we know, this report, which also includes a discussion of the literature, is the first to indicate that cholesteatoma causes strong adhesions around the carotid artery.

[A case of Mycobacterium intracellulare pulmonary infection with vertebral osteomyelitis].

A 78-year-old woman seen in June 2005 for chest abnormal shadows after 3 months of steroid therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies was found in chest computed tomography (CT) revealed bronchiectasis and small nodules in the right middle lobe and left lingula. Sputum cultures were positive for Mycobacterium intracellulare. Based on a diagnosis of pulmonary nontuberculous mycobacteriosis, the woman underwent antimycobacterial therapy with clarithromycin, rifampicin, and ethambutol hydrochloride for 10 months. She was then admitted in June 2009 with right chest pain. Chest CT showed consolidation shadows with bronchiectasis in the right middle lobe and the left lingula and left pleural effusion. Magnetic resonance imaging (MRI) showed that Th7-Th8 vertebral bodies had collapsed. A vertebral body specimen obtained by CT-guided biopsy was positive for M. intracellulare. Based on a diagnosis of vertebral osteomyelitis due to M. intracellulare, she underwent antimycobacterial therapy with clarithromycin (800 mg), rifampicin (450 mg), ethambutol hydrochloride (750 mg), and streptomycin (750 mg). After 4 weeks of antimycobacterial therapy, she underwent radical debridement and decompression surgery with anterior and posterior spinal fusion. Four weeks postoperatively, streptomycin was discontinued. We continued clarithromycin, rifampicin, and ethambutol hydrochloride for 18 months, and no recurrence was detected. Although vertebral osteomyelitis due to nontuberculous mycobacteria is rare, clinicians should consider the combination of nontuberculous mycobacteriosis and vertebral osteomyelitis in cases such at these.

TRPA1 underlies a sensing mechanism for O2.

Oxygen (O(2)) is a prerequisite for cellular respiration in aerobic organisms but also elicits toxicity. To understand how animals cope with the ambivalent physiological nature of O(2), it is critical to elucidate the molecular mechanisms responsible for O(2) sensing. Here our systematic evaluation of transient receptor potential (TRP) cation channels using reactive disulfides with different redox potentials reveals the capability of TRPA1 to sense O(2). O(2) sensing is based upon disparate processes: whereas prolyl hydroxylases (PHDs) exert O(2)-dependent inhibition on TRPA1 activity in normoxia, direct O(2) action overrides the inhibition via the prominent sensitivity of TRPA1 to cysteine-mediated oxidation in hyperoxia. Unexpectedly, TRPA1 is activated through relief from the same PHD-mediated inhibition in hypoxia. In mice, disruption of the Trpa1 gene abolishes hyperoxia- and hypoxia-induced cationic currents in vagal and sensory neurons and thereby impedes enhancement of in vivo vagal discharges induced by hyperoxia and hypoxia. The results suggest a new O(2)-sensing mechanism mediated by TRPA1.

A case of Serratia granuloma in the soft tissue around the left kidney: a role of PTHrP in the formation of Serratia granuloma.

Serratia marcescens is an ubiquitous, saprophytic gram-negative bacillus that is associated with infections such as bacteremia, pneumonia and osteomyelitis. However, it has not been known to form granulomas. A 72-year-old man with a history of tricuspidal insufficiency, mitral insufficiency and ureterolithiasis presented with lumbago on the left side. He was admitted to our hospital, where abscess formation in the subcapsular space and perirenal fat space of the left kidney, and left renal calculi were identified by computed tomography of the abdomen. As infection and/or a tumor were suspected, nephrectomy was performed. The histopathological findings in the resected kidney indicated severe infiltration by inflammatory cells with lymphoid follicles in the interstitium, and the proliferation of mesangial cells and matrix in glomerulus. Furthermore, giant cell granulomas were observed in the soft tissue around the kidney. As an aerobic culture of the abscess from the granulomas only produced Serratia marcescens, these granulomas were diagnosed as Serratia marcescens granulomas. In addition, expressions of PTHrP and PTH/PTHrP-receptor were observed in the giant cells in Serratia granuloma, which suggested that PTHrP might be involved in giant cell formation in Serratia granuloma by autocrine and/or paracrine mechanisms.

Expression patterns of angiopoietin-1, -2, and tie-2 receptor in ulcerative colitis support involvement of the angiopoietin/tie pathway in the progression of ulcerative colitis.

The active stage of ulcerative colitis (UC) involves transmigration of polymorphonuclear (PMN) cells to colonic epithelia. The angiopoietin (Ang) pathway plays a role as the regulator of PMN transmigration. To clarify the role of the Ang/Tie pathway in the activation of UC, especially in cypt abscess formation, 67 tissue samples were obtained from patients with UC and ten controls without UC for immunohistochemical analysis for the expression of Ang-1, -2, or Tie-2. The epithelia of crypt abscess was strongly positive for Ang-1 and -2 for all 57 samples derived from patients with active UC, though the colorectal epithelium without crypt abscess showed minimal expression of Ang-1, -2, and Tie-2. Numerous transepithelial migrating PMN cells in crypt abscesses also expressed Tie-2. The specimens of UC patients in remission showed significantly less immunoreactivity for Ang-1, -2, or Tie-2. These findings suggest that the Ang/Tie pathway may play a role in the progression of UC.

Expression of angiopoietin-1, 2 and 4 and Tie-1 and 2 in gastrointestinal stromal tumor, leiomyoma and schwannoma.

AIM: To investigate the role of angiopoietin (Ang) -1, -2 and -4 and its receptors, Tie-1 and -2, in the growth and differentiation of gastrointestinal stromal tumors (GISTs). METHODS: Thirty GISTs, seventeen leiomyomas and six schwannomas were examined by immunohistochemistry in this study. RESULTS: Ang-1, -2 and -4 proteins were expressed in the cytoplasm of tumor cells, and Tie-1 and -2 were expressed both in the cytoplasm and on the membrane of all tumors. Immunohistochemical staining revealed that 66.7% of GISTs (20 of 30), 76.5% of leiomyomas (13 of 17) and 83.3% of schwannomas (5 of 6) were positive for Ang-1. 83.3% of GISTs (25 of 30), 82.4% of leiomyomas (14 of 17) and 100% of schwannomas (6 of 6) were positive for Ang-2. 36.7% of GISTs (11 of 30), 58.8% of leiomyomas (10 of 17) and 83.3% of schwannomas (5 of 6) were positive for Ang-4. 60.0% of GISTs (18 of 30), 82.4% of leiomyomas and 100% of schwannomas (6 of 6) were positive for Tie-1. 10.0% of GISTs (3 of 30), 94.1% of leiomyomas (16 of 17) and 33.3% of schwannomas (2 of 6) were positive for Tie-2. Tie-2 expression was statistically different between GISTs and leiomyomas (P < 0.001). However, there was no correlation between expression of angiopoietin pathway components and clinical risk categories. CONCLUSION: Our results suggest that the angiopoietin pathway plays an important role in the differentiation of GISTs, leiomyomas and schwannomas.

[Case report of acute death on the 7th day due to exposure to the vapor of the insecticide chlorfenapyr].

We present the case of a 55-year-old male agricultural worker who complained of severe general fatigue and hyperperspiration after exposure to an insecticide vapor. He worked in a tea plantation and used chlorfenapyr, a broad spectrum for harmful insects, without any protective mask or clothes. After one day of insecticide spray work, he gradually began to complain of general fatigue, hyperperspiration, nausea and vomiting. At first, he was diagnosed as being dehydrated and was treated with fluid replacement therapy. Although he received this conservative therapy, there was no effect on the above mentioned symptoms. On the 7th day of the onset of his symptoms, his consciousness level deteriorated rapidly and body temperature exceeded 40 degrees C. No cerebral vascular disease or meningitis was observed. Finally, he died despite intensive care. The findings of the clinical course and laboratory data suggest a clinical diagnosis of acute pesticide poisoning due to exposure to chlorfenapyr vapor. We suggest that agricultural workers should use this insecticide with caution and sufficient protective gear.

Expression of vascular endothelial growth factor and its receptors VEGFR-1 and 2 in gastrointestinal stromal tumors, leiomyomas and schwannomas.

AIM: To investigate the role of vascular endothelial growth factor (VEGF) and its receptors VEGFR-1 and 2 in the growth and differentiation of gastrointestinal stromal tumors (GISTs). METHODS: Thirty-three GISTs, 15 leiomyomas and 6 schwannomas were examined by immunohistochemistry in this study. RESULTS: VEGF protein was expressed in the cytoplasm of tumor cells, and VEGFR-1 and 2 were expressed both in the cytoplasm and on the membrane of all tumors. Immunohistochemical staining revealed that 26 GISTs (78.8%), 9 leiomyomas (60.0%) and 3 schwannomas (50.0%) were positive for VEGF; 24 GISTs (72.7%), 12 leiomyomas (80.0%) and 4 schwannomas (66.7%) were positive for VEGFR-1; 30 GISTs (90.9%), 5 leiomyomas (33.3%) and 4 schwannomas (66.7%) were positive for VEGFR-2. VEGFR-2 expression was statistically different between GISTs and leiomyomas (P < 0.0001). However, there was no correlation between the expression of VEGF pathway componenets and the clinical risk categories. CONCLUSION: Our results suggest that the VEGF pathway may play an important role in the differentiation of GISTs, leiomyomas and schwannomas.

Expressions of sonic hedgehog, patched, smoothened and Gli-1 in human intestinal stromal tumors and their correlation with prognosis.

AIM: To investigate the role that the hedgehog (Hh) signaling pathway, which includes sonic hedgehog (Shh), Patched (Ptc), Smoothened (Smo) and Gli-1, plays in human gastrointestinal stromal tumors (GISTs). METHODS: Surgically resected specimens from patients with GISTs, leiomyomas and schwannomas were examined by immunohistochemical staining for aberrant expression of hedgehog signaling components, Shh, Ptc, Smo and Gli-1, respectively. RESULTS: In GISTs, 58.1% (18 of 31), 77.4% (24 of 31), 80.6% (25 of 31) and 58.1% (18 of 31) of the specimens stained positive for Shh, Ptc, Smo and Gli-1, respectively. In leiomyomas, 92.3% (12 of 13), 92.3% (12 of 13), 69.2% (9 of 13) and 92.3% (12 of 13) stained positive for Shh, Ptc, Smo and Gli-1, respectively. In schwannomas, 83.3% (5 of 6), 83.3% (5 of 6), 83.3% (5 of 6) and 100% (6 of 6) stained positive for Shh, Ptc, Smo and Gli-1, respectively. Immunohistochemistry revealed that the expressions of Shh and Gli-1 were significantly higher in leiomyomas than in GISTs (P < 0.05, respectively). Shh expression strongly correlated with the grade of tumor risk category and with tumor size (P < 0.05, respectively). However, the expressions of Ptc and Smo did not correlate with histopathological differentiation. CONCLUSION: These results suggest that the Hh signaling pathway may play an important role in myogenic differentiation and the malignant potential of human intestinal stromal tumors.

Expression of Ets-1 proto-oncoprotein in gastrointestinal stromal tumors, leiomyomas and schwannomas.

AIM: Gastrointestinal stromal tumors (GISTs) are rare. GISTs differ from other mesenchymal tumors of the gastrointestinal tract (e.g. leiomyomas and schwannomas). The purpose of this study was to investigate the role of Ets-1 in the growth and differentiation of GISTs. METHODS: Twenty-eight GISTs, nine leiomyomas and six schwannomas were examined by immunohistochemical staining method for Ets-1 in this study. Specimens were selected from surgical pathology archival tissues at Nagasaki University Hospital. RESULTS: Ets-1 protein was expressed in the cytoplasm of cells in all of these tumors. Immunohistochemical staining revealed that 27 GISTs (96.4%), six leiomyomas (66.7%), and five schwannomas (83.3%) were positive for Ets-1. Ets-1 expression was statistically different between GISTs and leiomyomas (P<0.005). However, there was no correlation between Ets-1 expression and clinical risk categories. CONCLUSION: Ets-1 plays an important role in the growth and differentiation of GISTs, leiomyomas and schwannomas.