Diabetic kidney disease is the main cause of end-stage kidney disease. However, the clinical manifestations of diabetic kidney disease are diverse. Therefore, the clinical classification of diabetic kidney disease is clinically important and valuable. In Japan, two clinical staging systems divided by the estimated glomerular filtration rate (eGFR) and albuminuria can be used for diabetic kidney disease: the chronic kidney disease (CKD) risk classification and the Japanese classification of diabetic nephropathy. The Japanese classification of diabetic nephropathy and the CKD risk classification are similar; however, these two classification systems show different frequencies of outcomes. For example, the frequency of the kidney outcomes in stage 4 of the Japanese classification of diabetic nephropathy was found to be higher than that in the red stage of the CKD risk classification (composite kidney events: stage 4=32.0/100 person-years, red =14.5/100 person-years). However, there were no marked differences in the speed or rate of decline in the kidney function (speed: stage 4=6.8 mL/min/1.73 m²/year, red =5.8 mL/min/1.73 m²/year; rate: stage 4=38.8%/year, red =34.3%/year) or in the pathological changes between the two classifications. These data indicate that each stage of these clinical classification systems has characteristic clinical and pathological features. Therefore, it is important to understand each characteristic feature and use each classification system appropriately.

Objective To clarify the underlying diseases, clinical manifestations, and treatment strategies for Amyloid A (AA) amyloidosis (AAA) in Japanese patients.

Methods We conducted a survey on Japanese patients with AAA treated between January 1, 2012, and December 31, 2014.

Results A total of 199 patients with AAA were included in the present study. The underlying diseases of AAA were rheumatoid arthritis (60.3%), uncharacterized inflammatory disorders (11.1%), neoplasms (7.0%), other rheumatic diseases (6.5%), inflammatory bowel diseases (4.5%), chronic infection (4.5%), Castleman's disease (4.0%), and autoinflammatory diseases (2.0%). The clinical manifestations at the diagnosis of AAA were moderate to severe renal dysfunction (46.2%), moderate to severe proteinuria (30.7%), intractable diarrhea (32.2%), melena (4.5%), paralytic ileus (3.5%), heart failure (11.6%), cardiac conduction disturbances (10.1%), arrhythmia (5.5%), and hypothyroidism (11.6%). Diagnostic biopsies were performed most frequently in the gastrointestinal tract (66.3%), followed by the kidneys (22.1%), heart (5.5%), abdominal fat (4.0%), and others (3.0%). Biologics were used to treat 97 patients with AAA (48.7%). Tocilizumab (TCZ) was administered to 66 patients, with 95.5% showing good responses. Anti-TNF agents were administered to 27 patients, with 74.1% showing good responses. The treatment effects of TCZ were significantly superior to those of anti-TNF agents (p<0.007).

Conclusion The most common underlying diseases of AAA were rheumatic diseases. Uncharacterized inflammatory disorders and neoplasms were also frequently observed in patients with AAA. Renal and gastrointestinal manifestations were common and important for the diagnosis of AAA, with cardiac manifestations also being of significance. Biologics, particularly TCZ, were effective therapeutic modalities.

Objective High adherence to medications and accurate handling of inhaler devices are important for asthma management. However, few reports to date have simultaneously evaluated adherence and handling errors. We therefore investigated the adherence to inhaled corticosteroid (ICS) and inhaler handling errors in the same patients in cooperation with pharmacists.

Methods Data were derived from a survey of physicians and pharmacists treating asthma patients who visited participating hospitals and pharmacies from July 2012 to January 2013. The patients were evaluated for asthma control using the Asthma Control Test (ACT) and for inhaler handling errors using checklists. ICS adherence was evaluated based on pharmaceutical records.

Results Adherence among participants (n=290) was 33.3% (mean), and the percentage of inhaler handling errors was 20.0% (mean). Total inhalation times in the high-adherence group were fewer than those in the low-adherence group. In a comparison by device, adherence to pressurized metered dose inhalers was significantly lower than that to Diskus^® inhalers, presumably attributable to the total number of inhalations per day. Adherence, handling errors, and total number of inhalations per day were significantly different between the asthma-controlled group and the uncontrolled group. A multivariate analysis showed that adherence and handling errors were independent factors contributing to asthma control.

Conclusion Our data indicated that both adherence to ICS and device handling errors contributed to asthma control in this population.

Objective The autonomic functions of hereditary transthyretin (ATTRm) amyloidosis, traditionally referred to as familial amyloid polyneuropathy, have primarily been investigated in patients with Val30Met mutations, and information regarding non-Val30Met patients is scarce. The aim of this study was to systematically investigate the cardiac and peripheral vasomotor autonomic functions in non-Val30Met patients.

Methods The coefficient of variation of R-R intervals (CVR-R), responses to the Valsalva manoeuvre, head-up tilt test results, noradrenaline infusion test results, and the (123) I-metaiodobenzylguanidine (MIBG) uptake on myocardial scintigraphy were assessed in five patients. The predominant manifestations were neuropathy in three patients (Val94Gly, Val71Ala, and Pro24Ser), cardiomyopathy in one (Thr60Ala), and oculoleptomeningeal involvement in one (Tyr114Cys).

Results Although one patient with predominant cardiomyopathy did not manifest orthostatic hypotension during the head-up tilt test, the CVR-R, responses to the Valsalva manoeuvre, and myocardial MIBG uptake indicated the presence of cardiac sympathetic and parasympathetic dysfunction in all patients. The total peripheral resistance at 60° tilt did not increase from the baseline values in any of the examined patients. An infusion of low-dose noradrenaline induced an increase in the systolic blood pressure, except in one patient with mild neuropathy.

Conclusion Cardiac and peripheral vasomotor autonomic dysfunctions were prevalent in non-Val30Met patients, irrespective of their phenotype, suggesting a common pathology of autonomic involvement. However, the vasoconstrictor function was preserved, even in a patient with advanced neuropathy.

Primary retroperitoneal serous adenocarcinoma (PRSA) is a rare malignancy of which only seven cases have been reported in the literature. The clinical features and outcomes of PRSA are not well understood. We herein report a case of PRSA with liver metastasis in a 74-year-old woman who was treated with surgical excision. The tumor cells were positive for estrogen receptor, Wilms tumor 1, PAX8, p53, and cytokeratin AE1/AE3. The final diagnosis was PRSA and liver metastasis. The pathological features of PRSA resemble those of ovarian serous carcinoma, which suggests that a combination of surgical excision with adjuvant chemotherapy may be the best option.

Neurilemmomas are benign tumors arising from the sheaths of peripheral nerves. They appear rarely in the abdominal cavity. We herein report an 80-year-old man with a multilocular cystic neurilemmoma mimicking a liver lesion. Preoperative images showed a lesion in the porta hepatis. Although a preoperative diagnosis was difficult, surgery was undertaken because of the possibility of malignancy. Histologically, the tumor consisted of spindle-shaped cells with positivity for S-100 protein. The final diagnosis was a neurilemmoma. Porta hepatic neurilemmomas are rare. When we encounter a multilocular cystic lesion of the liver, neurilemmoma should be considered in the differential diagnosis.

Two cases with severe pectus excavatum and symptomatic atrial fibrillation (AF) underwent radiofrequency catheter ablation (RFCA). Their chest X-ray and computed tomography (CT) findings revealed lateral displacement and clockwise rotation of their hearts, and severe right atrial and mild right ventricular compression against the sternum, but no left atrium compression against the spinal column. The procedure was therefore carefully performed under guidance with CT, intra-cardiac echography, atriography, and a three-dimensions mapping system. Finally, the AF was successfully treated by RFCA without any complications. These findings underscore the importance of understanding cases of abnormal anatomy and carefully designing a strategy before performing any procedure.

Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A and is classified into two types: classical and variant. The classical type exhibits classic manifestations, but the variant type does not and is therefore difficult to identify sometimes. A 73-year-old woman with a first episode of heart failure was admitted to our hospital. Her left ventricular wall motion was mildly reduced without hypertrophy. Urine sediment revealed mulberry cells, leading to the diagnosis of Fabry disease. In cases without typical clinical findings, urinary mulberry cells may help diagnose Fabry disease.

Vasospastic angina (VSA) has been recognized as a cause of ventricular fibrillation (VF) degenerating into sudden cardiac death. We experienced a case of VSA with hyperthyroidism in which VF was provoked with an augmented J-wave amplitude in the inferior leads. The patient underwent insertion of an implantable cardioverter-defibrillator for the secondary prevention of VF in addition to taking Ca-channel antagonists. He has shown no recurrence of fatal arrhythmia or anginal attack for a follow-up period of one year.

Syndrome of inappropriate antidiuretic hormone (SIADH) secretion is the most common cause of hypotonic hyponatremia in hospitalized patients. An elderly man with severe symptomatic hyponatremia (109 mEq/L) was diagnosed with SIADH that was likely secondary to large cutaneous herpes zoster (HZ) infection. Hypertonic saline and tolvaptan improved the patient's sodium levels and clinical condition. A one month after discharge, tolvaptan was withdrawn, due to inadequate prescription criteria, after which hyponatremia relapsed several times and was properly treated; eventually fever and sopor occurred and the patient died. SIADH secondary to HZ may induce life-threatening and long-lasting hyponatremia, which requires a prompt diagnosis and treatment.

A 69-year-old Japanese man with a history of suprasellar surgery and irradiation developed bradykinesia and mild fatigue without muscle weakness, myalgia, pyramidal or extrapyramidal signs, parkinsonian symptoms, or ataxia. An endocrinological work-up revealed anterior hypopituitarism associated with secondary adrenal insufficiency. Higher brain function tests indicated an impaired frontal lobe function. The patient's bradykinesia, fatigue, and frontal lobe dysfunction improved within 2 weeks after the initiation of corticosteroid replacement therapy. To our knowledge, this is the first reported case of adrenal insufficiency manifesting as non-parkinsonian bradykinesia. Physicians should consider reversible non-parkinsonian bradykinesia associated with frontal lobe dysfunction as an unusual manifestation of adrenal insufficiency.

The delayed diagnosis of insulinoma remains a clinical issue. One of the main causes of such a delay is hypoglycemia unawareness. A 53-year-old woman fell unconscious during postprandial exercises. Flash glucose monitoring (FGM) systems revealed glucose profiles with fasting hypoglycemia, which facilitated the clinical diagnosis of insulinoma even though she was unaware of her hypoglycemia. The preoperative comparison of the blood glucose values provided by FGM with those obtained from capillary blood were consistent. Thus, FGM may have potential utility in revealing the presence of insulinoma-induced hypoglycemia.

A 27-year-old woman with a history of gestational diabetes mellitus (GDM) developed type 1 diabetes mellitus (T1D) in the early postpartum period. Women with a history of GDM are at an increased risk of developing T1D, which is rarer than type 2 diabetes mellitus. A postpartum follow-up 75-g oral glucose tolerance test and the measurement of glutamic acid decarboxylase autoantibodies aided in the early detection of T1D in this patient. Careful attention should be paid to women with a history of GDM who exhibit clinical features suggestive of future development of T1D.

There have been few reports on the accuracy of the diagnosis of small-cell carcinoma based on a cytological examination of malignant pleural effusion, so whether or not such a diagnosis is possible using this approach alone remains unclear. We herein report a 76-year-old Japanese man in whom small-cell carcinoma was diagnosed cytopathologically from pleural effusion and squamous cell carcinoma was diagnosed histopathologically from a transbronchial biopsy. Tumor shrinkage was achieved by treatment with docetaxel, but the efficacy of carboplatin plus etoposide was inadequate. If small-cell carcinoma is detected on the basis of pleural fluid cytopathology alone, it is extremely important to perform a histopathological examination to rule out the possibility of other malignancies.

A 53-year-old man with advanced lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) exon 19 deletion received erlotinib. After 12 months of disease control with erlotinib monotherapy, leptomeningeal metastases (LM) occurred. A cerebrospinal fluid examination demonstrated a pre-existing EGFR exon 19 deletion. Bevacizumab was combined with erlotinib, and the LM improved. After six months of combination therapy, however, the LM was exacerbated. A re-examination of the cerebrospinal fluid revealed a T790M mutation and exon 19 deletion. Osimertinib was administered, and the LM improved. The combination of bevacizumab and erlotinib was effective for erlotinib-resistant LM and resulted in the expression of a newly acquired T790M mutation, which enabled successful treatment with osimertinib.

Squamous cell carcinoma (SCC) transformation has been identified as a mechanism of resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), gefitinib or erlotinib, in EGFR-mutated lung cancer. However, whether second- or third-generation TKIs can overcome resistance due to SCC transformation remains unclear. We herein report an EGFR-mutated lung adenocarcinoma undergoing transformation into SCC that exhibited a durable response to afatinib, which is a second-generation irreversible EGFR-TKI. We suggest that afatinib can be considered as a treatment option for EGFR-mutated tumor undergoing SCC transformation, particularly in the absence of a T790M mutation.

Hereditary hemochromatosis and β-thalassemia can both result in the inappropriately low production of the hormone hepcidin, which leads to an increase in intestinal absorption and excessive iron deposition in the parenchymal cells. To the best of our knowledge, there have been no reports on the coexistence of the two disorders in China. We herein report a case in a Chinese who presented with late-onset hepatic cirrhosis with hereditary hemochromatosis and β-thalassemia. We analyzed the pedigree of the two disorders and the iron status in his family members. Our case supports that a heterozygous H63D mutation can interact with β-thalassemia, leading to late-onset hemochromatosis.

Myoclonus epilepsy associated with ragged-red fibers (MERRF) is traditionally characterized by myoclonus, generalized epilepsy and ragged-red fibers. We herein report a 42-year-old man who complained of falling after starting running, symptoms resembling those of paroxysmal kinesigenic dyskinesia. He showed only slight muscle weakness of the right quadriceps femoris. Muscle pathology and a genetic analysis identified him as having MERRF with a 8344A>G mtDNA mutation. We diagnosed his symptoms as having been caused by slight quadriceps femoris muscle weakness and exercise intolerance. This case suggests that mitochondrial myopathy should be considered in cases with strong muscle symptoms for muscle weakness.

We herein report the case of a patient who developed peripheral neuropathy of the bilateral lower legs that later became complicated with isolated oculomotor nerve disorder and was finally diagnosed as systemic lupus erythematosus (SLE). Based on the findings for oculomotor nerve paralysis and contrast-enhanced magnetic resonance imaging findings for the oculomotor nerve in the prepontine cistern, the isolated oculomotor nerve disorder was considered to be a manifestation of peripheral neuropathy. This oculomotor nerve disorder may contribute to the diagnosis of SLE and can be effectively treated with steroid pulse therapy. Reports of SLE manifesting as isolated oculomotor nerve paralysis are rare.

Progressive encephalomyelitis with rigidity and myoclonus (PERM) is an autoimmune disorder involving the brainstem and spinal cord and is sometimes associated with thymoma. We encountered a 75-year-old woman with typical PERM features, glycine receptor antibody, and thymoma. Her neurologic symptoms improved after thymectomy, but she unexpectedly developed anasarca with massive pleural effusions and hypoalbuminemia and finally succumbed to death. The autopsy showed edema and mononuclear infiltration in the pleura but no neuropathological findings typical of PERM. Effective treatment of PERM can reverse the neuropathological signs of encephalomyelitis. The autoimmune nature of anasarca is possible but not proven.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease with marked variety in its clinical manifestations. While characteristic neuroimaging and skin biopsy findings are important clues to the diagnosis, autopsy studies are still important for confirming the exact disease features. We herein report the case of a patient who received an antemortem diagnosis of familial NIID with dementia-dominant phenotype that was later confirmed by an autopsy. Our report is the first to document a case of autopsy-confirmed NIID involving both cognitive impairment and sensorimotor neuropathy.

Neurolymphomatosis is a rare form of extranodal malignant lymphoma defined as the infiltration of malignant lymphocytes into the central or peripheral nerve. We herein report a case of neurolymphomatosis in the cauda equina diagnosed by an open surgical biopsy. He presented with muscle weakness, atrophy, numbness and hypoesthesia in the bilateral lower extremities with the accumulation of ¹⁸fluoro-2-deoxyglucose (FDG) in the bilateral cauda equina. Cerebrospinal fluid cytology (three times) and flow cytometry (two times) and biopsies of the left sural nerve, bone marrow, paranasal sinus and left testis were all negative for malignancy, so finally we performed a surgical open biopsy of the cauda equina by laminectomy and diagnosed him with diffuse large B-cell lymphoma in the cauda equina. He was successfully treated with the disappearance of the FDG accumulation for a long time. The present case suggested that an early open biopsy of the cauda equina may be considered for cases of suspected neurolymphomatosis in the cauda equina for a good outcome.

A 64-year-old woman with lymphoma-associated demyelinating neuropathy was treated by 6 cycles of R-CHOP with intravenous immunoglobulin in the first 2 cycles. We noted substantial improvement in the findings of a nerve conduction study (NCS) after the first cycle, followed by more protracted improvement during the second to sixth cycles. The improvement of the neurological symptoms paralleled the findings of the NCS. Our case provides important information for understanding the etiology and optimization of treatments for lymphoma-associated demyelinating neuropathy.

A 56-year-old Japanese woman with muscle weakness, increased creatine kinase and aldolase levels, and characteristic cutaneous lesions was diagnosed with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 antibody)-positive dermatomyositis. She also had interstitial lung disease (ILD). After corticosteroid and tacrolimus combination therapy was started, bicytopenia and elevated serum ferritin and transaminase emerged. Because the bone marrow tissues were hypoplastic with hemophagocytes, she was diagnosed with concomitant autoimmune-associated hemophagocytic syndrome (HPS). Intravenous cyclophosphamide pulse therapy and plasmapheresis were performed. The laboratory findings indicated improved abnormalities, and the ILD did not progress. Anti-MDA5 antibody-positive dermatomyositis can be complicated by HPS.

A 70-year-old man with prior Raynaud's phenomena developed hypertension and renal insufficiency. Raynaud's phenomena, finger skin thickening, interstitial lung disease, and positive anticentromere antibody findings indicated systemic sclerosis (SSc). Based on the presence of SSc, severe hypertension with rapidly progressive renal failure, and proliferative and obliterative arteriolar vasculopathy, scleroderma renal crisis (SRC) was diagnosed. Despite good blood pressure control with antihypertensive drugs, hemodialysis was initiated and could not be withdrawn owing to unimproved renal dysfunction. Although SRC in anticentromere antibody-positive limited cutaneous SSc is extremely rare, some patients may develop SRC, and their renal prognosis may be poor.

Scedosporium apiospermum is an opportunistic fungus that can cause various types of infections, including localized infections and life-threatening disseminated infections, particularly in immunocompromised patients. Treatment is especially challenging due to its multidrug resistance. We herein report the case of a 73-year-old woman who was non-immunocompromised but developed S. apiospermum lung infection and a pulmonary tumorlet. To our knowledge, this is the first report of the coexistence of pulmonary S. apiospermum infection and tumorlet. The lung lesion was successfully treated by surgical excision without any antifungal agents, and no recurrence of the tumorlet or S. apiospermum infection has occurred.