A case of crystalglobulin-induced nephropathy wherein M protein was identified by mass spectrometry and immunoglobulin G subclass staining.

Crystalglobulin-induced nephropathy is a rare disease that causes the deposition of crystallized monoclonal immunoglobulins into the glomerular capillary and arteriole spaces. Here, we report the case of a patient who presented with skin ulcers, urinary protein, and renal dysfunction. The patient underwent renal and skin biopsies, and the biopsy tissue samples were subjected to mass spectrometry. The patient was diagnosed with crystalglobulin-induced nephropathy. A literature review suggested that pathological examinations using electron microscopy, mass spectrometry, and immunofluorescent staining of paraffin-embedded biopsy samples treated with pronase may be useful for the diagnosis of this condition.

Node-by-node diagnosis for multiple ipsilateral nodules by segmental adrenal venous sampling in primary aldosteronism.

OBJECTIVES: In patients with primary aldosteronism (PA), multiple adrenocortical nodules may be present on the surgical side. The aim of this study was to clarify the pathological diagnosis and the node-by-node diagnostic capability of segmental adrenal venous sampling (sAVS). DESIGN: Retrospective study. PATIENTS: A total of 162 patients who underwent adrenalectomy following sAVS were studied. MEASUREMENTS: Multiple nodules on the surgical side were extracted while referring to contrast-enhanced computed tomography images. We also performed a detailed histopathological analysis of the resected specimens from patients undergoing sAVS, which included immunohistochemistry for CYP11B2. RESULTS: In 11 (6.8%) patients, two to three nodules were detected on the surgical side. All patients were diagnosed by sAVS with at least one aldosterone-producing adenoma (APA) for localized aldosterone elevation in tributaries. Seven patients showed a lateralization index value of ≥4 after ACTH stimulation. Histopathologically and clinically, two patients had two or three CYP11B2-positive APAs, and the other nine patients both APAs and non-APAs. The positive predictive value of the most suspected APA, that is, the drainer that showed the highest aldosterone level by sAVS, was 11/11 (100%, 95% confidence interval [CI]: 71.5%-100%), while that for the second and third suspected APA was 3/7 (42.9%, 95% CI: 9.9%-81.6%), and they were significantly different (p = .01). Further, the positive predictive value of non-APA was 4/4 (100%, 95% CI: 39.8%-100%). CONCLUSIONS: The sAVS could correctly diagnose the aldosterone production in multiple ipsilateral adrenal nodules.

Inflammatory Myopathy Associated with Anti-mitochondrial Antibody-negative Primary Biliary Cholangitis Diagnosed by a Liver Biopsy.

Anti-mitochondrial antibody (AMA)-associated myopathies represent a homogeneous disease entity with severe arrhythmia and slowly progressive proximal muscle weakness with lordotic posture, irrespective of the presence of primary biliary cholangitis (PBC). We herein report a case of myositis associated with PBC without AMAs. A 48-year-old woman presented with clinical features very similar to AMA-associated myositis, despite negative AMAs. PBC, ascertained by a liver biopsy performed based on mildly elevated liver enzymes, and the efficacy of steroid therapy on muscle weakness confirmed the diagnosis of immune-mediated myositis. When AMAs are negative, a liver biopsy is indispensable for diagnosing treatable PBC-associated myositis.

A case of matrix-producing carcinoma of the breast treated with preoperative chemotherapy.

Background: Matrix-producing carcinoma (MPC) is a rare tumor accounting for 0.1% of all breast cancers. Although MPC is usually triple-negative breast cancer, there have been few reports of preoperative chemotherapy for MPC that is considered chemotherapy-resistant. Herein, we report a case of MPC that was successfully treated with preoperative chemotherapy. Case Description: The patient was a 47-year-old woman diagnosed with right multiple breast cancer, clinical stage IIA. One of the tumors was identified as MPC and the other was invasive ductal carcinoma. The maximum tumor diameter of MPC was 3.8-cm. On immunohistochemistry, the tumor cells of MPC tested negative for estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2). The Ki67 index was 90%. Preoperative chemotherapy was performed. EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2) was administered every 3 weeks for a total of 4 courses, followed by 12 courses of weekly paclitaxel (80 mg/m2). Then, she underwent right skin-sparing mastectomy, sentinel lymph node biopsy, and deep inferior epigastric perforator flap reconstruction. There was no metastasis to the sentinel lymph nodes. Postoperative pathological results showed that the residual tumor of the MPC measured only 0.1 cm. On the other hand, the residual tumor of the invasive ductal carcinoma was 0.7 cm. Endocrine therapy with oral tamoxifen was initiated for the invasive ductal carcinoma. Three years after surgery, no recurrence was observed. It has been reported that prognosis was correlated with residual cancer after preoperative chemotherapy. In addition, preoperative chemotherapy is of high clinical significance for the selection of postoperative treatment. Conclusions: Although our case of MPC was successfully treated with preoperative chemotherapy, the standard of care for MPC remains uncertain. Development of a new targeted therapy for MPC is warranted.

Characteristics of aldosterone-producing adenomas in patients without plasma renin activity suppression.

Primary aldosteronism (PA) usually accompanies suppressed plasma renin activity (PRA) through a negative feedback mechanism. While some cases of PA with unsuppressed PRA were reported, there have been no studies about the characteristics of PA with unsuppressed PRA; thus, these characteristics were examined herein. Nine patients with unsuppressed PRA and 86 patients with suppressed PRA were examined. All patients underwent segmental adrenal venous sampling (sAVS) and adrenalectomy, and were pathologically confirmed to have cytochrome P450 11B2 (CYP11B2)-positive aldosterone-producing adenoma according to international histopathology consensus criteria. Unsuppressed and suppressed PRA were defined as PRA levels of > 1.0 and ≤ 1.0 ng/mL/hr, respectively, in multiple blood samples obtained in the resting position. The unsuppressed PRA group had higher morning cortisol levels (12.6 [8.5, 13.5] vs. 8.5 [7.1, 11.0] µg/dL, P = 0.03) and higher cortisol levels after a 1 mg dexamethasone suppression test (DST) (2.2 [1.6, 2.5] vs. 1.3 [1.0, 1.9] µ g/dL, P = 0.004) than the suppressed PRA group. The unsuppressed PRA group also showed higher aldosterone levels on the non-surgical side during sAVS (P = 0.02 before adrenocorticotropic hormone (ACTH) stimulation, P = 0.002 after ACTH stimulation), a higher intensity of CYP17 expression in the resected adrenal gland (P = 0.02), and a lower clinical complete success rate 1 year after surgery (P = 0.04) compared with those in the suppressed PRA group. These findings suggest that PA should not be ruled out by unsuppressed PRA among patients with hypertension, particularly when their cortisol levels remain unsuppressed in the 1 mg DST. Meanwhile, it should be acknowledged that patients with unsuppressed PRA have higher aldosterone levels on the non-surgical side, and a lower likelihood of postoperative complete clinical success is to be expected.

Hereditary pheochromocytoma/paraganglioma syndrome with a novel mutation in the succinate dehydrogenase subunit B gene in a Japanese family: two case reports.

BACKGROUND: Pheochromocytoma and paraganglioma caused by succinate dehydrogenase gene mutations is called hereditary pheochromocytoma/paraganglioma syndrome. In particular, succinate dehydrogenase subunit B mutations are important because they are strongly associated with the malignant behavior of pheochromocytoma and paraganglioma . This is a case report of a family of hereditary pheochromocytoma/paraganglioma syndrome carrying a novel mutation in succinate dehydrogenase subunit B. CASE PRESENTATION: A 19-year-old Japanese woman, whose father died of metastatic paraganglioma, was diagnosed with abdominal paraganglioma, and underwent total resection. Succinate dehydrogenase subunit B genetic testing detected a splice-site mutation, c.424-2delA, in her germline and paraganglioma tissue. Afterwards, the same succinate dehydrogenase subunit B mutation was detected in her father's paraganglioma tissues. In silico analysis predicted the mutation as "disease causing." She is under close follow-up, and no recurrence or metastasis has been observed for 4 years since surgery. CONCLUSIONS: We detected a novel succinate dehydrogenase subunit B mutation, c.424-2delA, in a Japanese family afflicted with hereditary pheochromocytoma/paraganglioma syndrome and found the mutation to be responsible for hereditary pheochromocytoma/paraganglioma syndrome. This case emphasizes the importance of performing genetic testing for patients with pheochromocytoma and paraganglioma suspected of harboring the succinate dehydrogenase subunit B mutation (that is, metastatic, extra-adrenal, multiple, early onset, and family history of pheochromocytoma and paraganglioma) and offer surveillance screening to mutation carriers.

A case of PR3-ANCA-positive anti-GBM disease associated with intrarenal arteritis and thrombotic microangiopathy.

Coexistence of anti-glomerular basement membrane (anti-GBM) disease with anti-neutrophil cytoplasmic antibody (ANCA) is occasionally reported and termed "double positive" disease. Interestingly, the majority of "double positive" ANCA is myeloperoxidase (MPO)-ANCA, and some of the MPO-ANCA-positive cases reveal intrarenal arteritis indicating an ANCA-associated renal lesion. In contrast, proteinase 3 (PR3)-ANCA-positive "double positive" disease had rarely been reported, and as far as we know, none of the cases showed intrarenal arteritis. Herein, we report a case of PR3-ANCA-positive "double positive" anti-GBM disease presenting with pulmonary-renal syndrome and hemolytic uremic syndrome. The kidney biopsy showed crescentic glomerulonephritis, intrarenal arteritis, and thrombotic microangiopathy. This case newly describes PR3-ANCA-associated intrarenal arteritis in "double positive" anti-GBM disease.

Angiosarcoma of the gallbladder with hemobilia: a case report.

A 61-year-old woman presented to our hospital with epigastric pain. She underwent abdominal contrast-enhanced computed tomography, which showed signal enhancement in the gallbladder fundus. As biliary obstruction was suspected, endoscopic nasobiliary drainage was performed, which revealed hemobilia. Based on this finding, gallbladder tumor was suspected, and open cholecystectomy was performed. Immunohistological staining of the resected tissue was positive for factor VIII that led to the diagnosis of gallbladder angiosarcoma. Hepatectomy and biliary reconstruction were performed for disease control; however, the patient died due to multiple liver metastases 4 months after the surgery.

LAPAROSCOPIC RADICAL NEPHRECTOMY FOR LARGE RENAL CELL CARCINOMA: RETROSPECTIVE ANALYSIS OF SAFETY AND ONCOLOGICAL OUTCOME.

(Objectives) To evaluate the safety and oncologic efficacy of laparoscopic radical nephrectomy (LRN) for renal cell carcinoma (RCC) >7 cm, we retrospectively reviewed the clinical outcome and long-term cancer control of patients who underwent LRN in comparison to open radical nephrectomy (ORN). (Patients and methods) The clinical records of 79 patients with RCC >7 cm, who underwent radical nephrectomy (37 LRN; 42 ORN) between 1993 and 2014, were reviewed. (Results) The 2 groups (LRN and ORN) were comparable regarding age, body mass index and mean tumor size (86.5 mm vs. 94.6 mm).The operative time was significantly longer in the LRN group than ORN group (204 min vs. 168 min; p<0.05) and blood loss was significantly lower in the LRN group than in the ORN group (144 ml vs. 930 ml; p<0.05).No statistically significant difference was found in complication rate (10.8% vs. 23.8%) and the 2-year recurrence-free survival rate (85.6% vs. 83.8%). (Conclusion) Despite the longer operative time, LRN for large RCC was associated with lower blood loss. This study provides evidence of the safety and efficacy of LRN for large RCC.

[Case of 55-year-old female with primary central nervous system lymphoma, presenting with brain and eye lesions and long-term relapsing/remitting course].

We report the case of a 55-year-old immunocompetent female with primary central nervous system lymphoma (PCNSL). Seven years previously, the patient presented with left facial dysesthesia, and a right thalamus lesion was revealed by brain MRI. Both her dysesthesia and the lesion disappeared spontaneously in six months. One year previously, she noted motor disturbance of the right limbs, and brain MRI revealed lesions in the bilateral basal ganglia and the left internal capsule which gradually increased in size. She was admitted to our hospital owing to the brain MRI findings of a white matter lesion in the left occipital lobe and bilateral optic neuritis. Previously, she had experienced two episodes of steroid-responsive uveitis in her left eye. An inflammatory disease such as multiple sclerosis was initially suspected because of the relapsing/remitting clinical course with a long time interval. Treatment with corticosteroids improved her clinical symptoms and decreased the size of the lesions, but the brain lesions and bilateral optic neuritis recurred within one month. At that time, the ß2 microglobulin level in the cerebrospinal fluid was high and the left occipital lobe lesions showed increased 18F-fluoro-deoxyglucose uptake in positron emission tomography and decreased Cho/NAA ratio in 1H-MR spectroscopy. These findings suggested PCNSL. A brain biopsy confirmed the presence of diffuse large B cell lymphoma. Both uveitis and optic neuritis were considered to be caused by intraocular lymphoma associated with PCNSL. Although patients with PCNSL may experience temporary spontaneous remission, our present case suggests that the time interval from remission to relapse can be much longer than generally expected. We suggest that it is necessary to consider PCNSL and perform a brain biopsy on patients presenting with atypical clinical manifestations of an inflammatory disease, even in cases with a long clinical course.

Variability in measuring the Ki-67 labeling index in patients with breast cancer.

BACKGROUND: Luminal-type breast cancer is divided into types A and B, depending on the Ki-67 labeling index (LI). However, the area at which Ki-67 is measured and the choice of specimen greatly affects the results. The aim of the present study was to evaluate the Ki-67 LI variability using different measurement methods and specimens. We also evaluated how the chemotherapy indication changed for luminal-type breast cancer using the different measurements. MATERIALS AND METHODS: The Ki-67 levels in 87 patients with breast cancer were assessed, and the Ki-67 LI was calculated. Five measurement sites were randomly selected, including the most densely labeled areas (hot spots) in both core needle biopsy (CNB) and surgical specimens. RESULTS: The intraclass correlation coefficient of the CNB and surgical specimens was 0.91 and 0.95, respectively. If the hot spot was used, the correlation coefficient (CC) between the CNB and surgical specimens was 0.635. If the average score was used, the CC was 0.730. If the average score was used, the CNB specimens indicated that 49 patients had a high Ki-67 LI, and 48 patients had a high Ki-67 LI using surgical specimens. If the hot spot was used, 60 patients using the CNB specimens and 58 patients using the surgical specimens had a high Ki-67 LI. If the average score was used, 17 patients were identified as being in different groups, and if the hot spot was used, 16 patients were identified as being in different groups, depending on the specimens that were used. CONCLUSION: The results differed according to the method and specimen type that was used.

Association between factors associated with colorectal cancer and rectal aberrant crypt foci in humans.

Aberrant crypt foci (ACF) are regarded as potential biomarkers for colorectal cancer (CRC), and have been used as such in recent early-phase chemoprevention trials. However, the associations between the presence of ACF and other factors associated with the development of CRC, such as lifestyle factors, medication use and comorbid medical conditions, remain unknown. Thus, the present retrospective, large, cross-sectional study was conducted to evaluate the potential usefulness of ACF as a surrogate biomarker of CRC. Total colonoscopy was performed and the number of rectal ACF was counted in a total of 902 subjects. A retrospective review of the medical records of the study subjects was performed, and the factors associated with the increased prevalence of ACF was investigated using univariate and multivariate logistic regression analyses. The analysis results identified older age [odds ratio (OR), 9.24; 95% confidence interval (CI), 4.80-17.8; P<0.01], smoking habit (OR, 1.78; 95% CI, 1.20-2.63; P<0.01) and use of insulin (OR, 9.97; 95% CI, 1.28-77.5; P=0.03) as significant independent risk factors associated with the increased prevalence of ACF, regardless of the presence/absence of colon tumors. In addition, it was revealed that the prevalence and number of ACF, and the Ki-67 labeling indices of the colonic epithelial cells were significantly higher in diabetic patients receiving insulin therapy than in those not receiving insulin therapy (P<0.01, P=0.03 and P=0.01, respectively). In conclusion, the potential usefulness of ACF as a surrogate biomarker of CRC was confirmed, although useful data could not be obtained on candidate chemopreventive agents. These results indicated that insulin can enhance colonic epithelial proliferative activity and induce the formation of ACF, thereby possibly triggering CRC development.

Serum p53 antibody in breast cancer.

BACKGROUND: The significance of the measurement of anti-p53 antibodies in serum remains undisclosed. The aim of this study was to assess anti-p53 antibodies in the serum of patients with breast cancer, and correlate these results with various clinicopathologic parameters. METHODS: We analyzed serum anti-p53 antibody levels in 124 patients with breast cancers and 7 patients with benign disease between April 2012 and March 2013, as well as levels of serum carcinoembryonic antigen (CEA) and cancer antigen (CA) 15-3. RESULTS: Twenty-two of 124 patients with breast cancer had an increased concentration of anti-p53 antibodies. By distribution of clinical stage, in stage 0-II the positive ratio of anti-p53 antibodies was significantly higher than that of CEA (p=0.03) and CA15-3 (p=0.01). There was a significant correlation between anti-p53 antibodies and family history (p=0.03). Triple-negative cancer also showed a significant correlation with anti-p53 antibodies (p=0.007). In patients with multiple and/or bilateral breast cancer, the level of anti-p53 was significantly higher than in unilateral breast cancer (62.5% vs 14.7%, p=0.004). CONCLUSION: Measurement of anti-p53 antibodies is useful for the prevention of oversight in the evaluation of multiple and/or bilateral breast cancer.

[A case of small intestinal stage IV gastrointestinal stromal tumor in which long-term disease control was maintained for more than 10 Years through a multidisciplinary team approach].

The prognosis of metastatic or recurrent gastrointestinal stromal tumors (GISTs) accompanied by multiple hepatic metastases and peritoneal dissemination is very poor. We encountered a case of stage IV small intestinal GIST with multiple hepatic metastases and peritoneal dissemination that were observed after resection of the primary lesion. Multidisciplinary treatments were performed over time, including hepatic resection, radiotherapy, imatinib therapy, sunitinib therapy, and transcatheter arterial chemoembolization, and the disease had been brought under control following resection of a primary lesion 14 years ago. The patient was a 49-year-old woman diagnosed with hemorrhagic stool in July 1998, when a computed tomography scan revealed an 8-cm-diameter tumor in her small bowel. Partial resection of her small bowel was performed and the pathological diagnosis was a high-risk GIST showing 15 mitoses per 50 high power fields. Several metastases developed in the S4 and S5 segments of the patient's liver 3 years after resection of the primary lesion, and a central two-segmental resection of the liver was performed. Furthermore, 1 year after this procedure, peritoneal dissemination developed near the pancreas, for which radiotherapy was performed. Four months later, the patient again developed multiple liver metastases and was started on treatment with 400 mg imatinib per day, achieving a partial response(PR). Five years and 6 months after imatinib initiation, resistance emerged in one of the liver metastases. The patient was switched to sunitinib(50 mg per day), but was diagnosed with progressive disease at the end of the second course and the procedure was discontinued. Treatment with 400 mg of imatinib per day was resumed, and transcatheter arterial chemoembolization was performed twice over a 17-month period for the resistant hepatic region and a PR was achieved each time. We were able to maintain a PR in this patient; other metastases indicated the effectiveness of imatinib therapy. Therefore, a multidisciplinary team approach can be effective in achieving long-term disease control in patients with metastatic or recurrent GIST.

IgG4-related tubulointerstitial nephritis and lymphadenopathy after therapy for malignant lymphoma.

We report a middle-aged Japanese man who had a past history of malignant lymphoma with tubulointerstitial nephritis (TIN) presenting a high serum immunoglobulin G4 (IgG4) concentration and bilateral kidney enlargement and swelling of many lymph nodes. Although lymph node biopsy was not evident of a recurrence of lymphoma, kidney biopsy showed prominent infiltration of IgG4-positive plasma cells in a tubulointerstitial lesion but not in glomeruli. We made a diagnosis of IgG4-related TIN and lymphadenopathy; administration of oral prednisolone improved his physical and laboratory parameters. This is the first report of a case of IgG4-related TIN and lymphadenopathy after therapy for malignant lymphoma.

Intralobar pulmonary sequestration supplied by an anomalous aneurysmal artery.

Pulmonary sequestration is a relatively rare condition in which a systemic artery supplies blood to an abnormal lung tissue. Pulmonary sequestration with an aneurysmal systemic artery is extremely rare. We describe the case of a 52-year-old man with intralobar pulmonary sequestration supplied by an aneurysmal systemic artery. Because the nomenclature of pulmonary sequestration is still not clear, we propose that type 1 intralobar pulmonary sequestration be called "systemic arterial supply to the normal lung," as named by many professionals, and for this to be distinguished from pulmonary sequestration.

Active surveillance criteria for prostate cancer: can they be applied to Japanese patients?

Prostate-specific antigen screening has significantly increased the percentage of men who are diagnosed with low-risk prostate cancer. All men undergoing retropubic radical prostatectomy for primary treatment of prostate cancer from April 2004 to September 2010 in our hospital were examined in order to determine whether active surveillance criteria could be applied to Japanese men. From pathological data of prostate biopsies, whether these men met five published criteria for active surveillance (Johns Hopkins Medical Institution, Prostate Cancer Research International: Active Surveillance Study, University of California, San Francisco, Toronto and Kakehi criteria) was evaluated. Men who met any of the criteria had a statistically significant lower extracapsular extension rate and organ-confinement rate. From the view of the possibility of Gleason upgrading and organ-confinement rate, the Johns Hopkins Medical Institution and Prostate Cancer Research International: Active Surveillance Study criteria showed to be appropriate for Japanese patients. However, the present study had limitations of selection bias and a limited number of cases.

[A case of lung cancer with endometrial metastasis].

A 50-year-old woman was admitted because of chest pain and lumbago. A chest X-ray film showed a 4-cm mass in the left lower lung field. Computed tomography scans revealed a nodule with spicule formation in the left lower lobe, and therefore we strongly suspected lung cancer. Fiberoptic bronchoscopy yielded a diagnosis of adenocarcinoma. However, since she had metrorrhagia we performed an endometrial biopsy. Histologically, the endometrium was similar to the lung lesion, with positive staining for thyroid transcription factor-1 (TTF-1), and lung cancer with endometrial metastasis was therefore diagnosed. Although lung cancer with endometrial metastasis is rare, it should be included in the differential diagnosis in patients with gynecological symptoms such as metrorrhagia.