Cell death is closely linked to many diseases including cancer, neurodegenerative diseases, autoimmune diseases, and metabolic disorders. Increased adipocyte death has been reported during the development of obesity. Adipocyte death may be caused by excessive stress during obesity-related adipose tissue remodeling. Adipose tissue macrophages are key players in obesity-related inflammation and systemic insulin resistance. Accumulating evidence suggests that adipocyte death is involved in immune cell function and initiates inflammation through an interaction with macrophages; however, the precise mechanisms remain largely unknown. This review focuses on the contribution of dead cells (particularly dead adipocytes in adipose tissue) to the pathophysiological conditions associated with obesity. J. Med. Invest. 64: 193-196, August, 2017

New applications of approved clinically used drugs are being discovered. Drug repositioning is a proposed strategy for developing these drugs as therapeutic agents for different diseases. Currently, approximately 2000 drugs are used in Japan. However, the compound targets and pathways involved in the pharmacological actions of 70-80% of these drugs have not been adequately clarified. Pharmacological examination of approved drugs is an important task in drug repositioning and vital for improving drug development efficiency. This review reports that angiotensin II type 1 receptor blockers show receptor-independent effects against reactive oxygen species generation in renal cells. Additionally, nitrosonifedipine has an antioxidative effect and protects endothelial cells against oxidative stress, and pioglitazone has multiple effects that improve dysfunctions in vascular control regulated by adrenergic and calcitonin gene-related peptide-containing nerves in animal models of diabetes. These data suggest that some approved drugs could be useful for treating cardiorenal diseases. Since cardiorenal diseases are likely to have chronic pathological conditions and require chronic drug administration, highly safe drugs are needed. Compared to newly developed drugs, drug repositioning of approved drugs with safety information is considered a particularly useful technique for searching new treatments for cardiorenal diseases. J. Med. Invest. 64: 197-201, August, 2017

Recent studies reveal that hypogonadism with low serum androgen levels is associated with advanced cancer and induction of most cancer-related symptoms. We designed an ARTFORM study to evaluate the efficacy of androgen replacement therapy in male advanced cancer patients. The ARTFORM study is an investigator-initiated, randomised controlled trial comparing intramuscle injection of testosterone enanthate with non-administration in male advanced cancer patients with non-curative locally advanced or metastatic lesions. Serum total and free testosterone levels are measured and patients with low testosterone level are randomised. The primary endpoint is the difference in validated health-related quality of life questionnaires at week 12. Trial registration of the ARTFORM study is assigned to University hospital Medical Information Network, Center identifier UMIN 000010939. J. Med. Invest. 64: 202-204, August, 2017

Objective Pheochromocytoma and paraganglioma (PPGLs) are rare neuroendocrine tumors derived from the adrenal medulla or extra-adrenal paraganglioma from extra-adrenal chromaffin tissue. Although malignant PPGLs has miserable prognosis, the treatment strategy remains to be established. An internal radiation therapy using [¹³¹I]meta-iodobenzylguanidine (¹³¹I-mIBG) called MIBG therapy has been attempted as one of the systemic treatment of malignant PPGLs. The aim of this study is therefore to evaluate the safety and the efficacy of MIBG therapy for refractory PPGLs. Methods Patients with refractory PPGLs will be enrolled in this study. The total number of patients for registration is 20. The patients receive a fixed dose of 7,400 MBq of ¹³¹I-mIBG. Adverse events are surveyed during 20 weeks after ¹³¹I-mIBG injection and all severe adverse events will be documented and reported in detail in accordance with the Common Terminology Criteria for Adverse Events (CTCAE). Examination and imaging diagnosis are performed in 12 weeks after ¹³¹I-mIBG injection for the evaluation of therapeutic effect in accordance with the Response Evaluation in Solid Tumours (RECIST). Conclusion The current study is the first multi-institutional prospective study of MIBG therapy and thereby will play a significant role in improving the patients' prognosis of refractory PPGLs. J. Med. Invest. 64: 205-209, August, 2017

We administered a questionnaire to 5^th grade medical students to examine the effect of community-based clinical practice on their attitudes to remote area medicine and their course after the graduation. Data from 192 students were obtained. The intensity of students' attitudes was estimated by using visual analogue scale. The intensities of the interest and a sense of fulfillment in remote area medicine were significantly increased after the practice. A significantly lower level of the intensity to become a generalist than that to become a specialist was seen in the students with low intensity in a sense of fulfillment. The percentages of the students who answered that they can work for 5 years or more in remote area were significantly lower in students with low intensity of a sense of fulfillment than in those with high intensity. A significantly higher percentage in students who worked at a familiar prefecture to them after the graduation was seen in female than in male. This study shows that the community-based practice is meaningful in increasing motivation which desire to work in remote area medicine, and that the motivation may affect their course after the graduation. J. Med. Invest. 64: 210-216, August, 2017

Amyloidosis is often overlooked because its clinical manifestations can mimic those of more-common diseases. It is important to get a precise diagnosis as early as possible for the prevention of further organ damages. Amyloidosis is a disorder caused by deposition of insoluble abnormal amyloid. The kidney is a frequent site of amyloid deposition. The amyloid fibrils have a characteristic appearance and generate birefringence under polarized light when stained with the Congo red dye. Classification of amyloidosis is based on the precursor protein that forms the amyloid fibrils and the distribution of amyloid deposits as either systemic or localized. Involvement of amyloid fibrils in kidneys mainly occurs as amyloid light-chain (AL) or amyloid A (AA) amyloidosis. The potassium permanganate method with Congo red staining was once used widely to discriminate AL and AA amyloidoses, but this method has a problem of false positive results. We found that extracellular and cytoplasmic glomerular 4', 6-diamidino-2-phenylindole (DAPI)-positive areas were clearly consistent with amyloid deposition in AL amyloidosis. In contrast, the overlapping staining was not seen in AA amyloidosis. Therefore, we propose that DAPI staining readily distinguishes AL renal amyloidosis from AA renal amyloidosis as a simple and reproducible histochemical method. J. Med. Invest. 64: 217-221, August, 2017

Serum transthyretin (TTR), also known as prealbumin, is a reliable nutritional indicator and an independent prognostic factor for maintenance hemodialysis patients. However, we recently reported that serum TTR levels did not affect protein-energy wasting (PEW). In this study, we investigated factors affecting serum TTR levels in 60 maintenance hemodialysis patients. The patients were divided into High-TTR and Low-TTR groups according to the median serum TTR level. Albumin levels were significantly higher and C-reactive protein (CRP) levels were significantly lower in the High-TTR group than in the Low-TTR group. Although body fat mass was significantly higher in the High-TTR group than in the Low-TTR group, no significant difference in body fat ratio were observed. These findings suggest that body fat mass is related to serum TTR levels, apart from factors such as albumin and CRP levels, which showed correlations with serum TTR levels. Because body fat mass is related to better survival in maintenance hemodialysis patients, it may contribute to the prognostic value of serum TTR levels. In addition, in such patients, it may be important to evaluate body fat mass rather than body fat ratio and to maintain the minimum necessary body fat mass. J. Med. Invest. 64: 222-227, August, 2017

Whether the near-infrared spectroscopy (NIRS) technology correctly detects the changes in oxygenation related to ischemia and reperfusion of organs and tissues other than brain remains unclear. The present study examined how different tissue oxygenation parameters derived from NIRS reflect the changes in the forearm blood flow (FBF) according to the brief ischemia and the subsequent reperfusion, and whether values of these parameters move in parallel with the medial and lateral sides of FBF. Thirteen volunteers underwent the prospective observational study. The tissue oxygenation index (TOI), regional saturation of oxygen (rSO₂), skin tissue oxygenation (StO₂), and FBF values were evaluated in the forearm. Medial rSO₂ values at 1 to 3 minutes after the termination of brief ischemia were higher than lateral rSO₂ and respective TOI values. FBF and StO₂ values quickly increased according to the cessation of brief ischemia, whereas the medial and lateral values did not differ during and after the brief ischemia. TOI and StO₂, but not rSO₂, reflected changes in FBF of both medial and lateral sides simultaneously in response to the reperfusion after brief ischemia. The muscle tissue oxygenation during reperfusion favors the use of TOI and StO₂, but not rSO₂, as the surrogate parameter. J. Med. Invest. 64: 228-232, August, 2017

High-throughput next-generation sequencing is a powerful tool to identify the genotypic landscapes of somatic variants and therapeutic targets in various cancers including gastric cancer, forming the basis for personalized medicine in the clinical setting. Although the advent of many computational algorithms leads to higher accuracy in somatic variant calling, no standard method exists due to the limitations of each method. Here, we constructed a new pipeline. We combined two different somatic variant callers with different algorithms, Strelka and VarScan 2, and evaluated performance using whole exome sequencing data obtained from 19 Japanese cases with gastric cancer (GC); then, we characterized these tumors based on identified driver molecular alterations. More single nucleotide variants (SNVs) and small insertions/deletions were detected by Strelka and VarScan 2, respectively. SNVs detected by both tools showed higher accuracy for estimating somatic variants compared with those detected by only one of the two tools and accurately showed the mutation signature and mutations of driver genes reported for GC. Our combinatorial pipeline may have an advantage in detection of somatic mutations in GC and may be useful for further genomic characterization of Japanese patients with GC to improve the efficacy of GC treatments. J. Med. Invest. 64: 233-240, August, 2017

Background: Serum appearance of anti-p53 antibody (p53Ab) has been reported as an indicator for progressive potential of human tumor tumors including breast cancer. But its significance in breast cancer has not been discussed fully. Methods: Relationship between serum appearance of p53Abs and representative data accounting for progressive potential in breast cancer, nuclear grade (NG), triple negative cancer, and the cumulative score based on these two data (TGS) was investigated among 129 women with invasive ductal carcinoma (IDC) of the breast, who had been treated with surgical resection. Results: There was a significant correlation between appearance of p53Abs and recurrence of the tumors (P = 0.035). Significant correlation of serum appearance of p53Abs with negative expression of ER (P = 0.011), the proportion of TNBC (P = 0.013), NG (P = 0.017), and TGS (P = 0.0005). Conclusions: Preoperative serum appearance of p53Abs can be correlated with pathological nuclear grade, incidence of triple negative breast cancer, and TGS. These results might demonstrate more powerful significance of serum appearance of p53Abs as an indicator of progressive potential in IDC of the breast. J. Med. Invest. 64: 241-244, August, 2017

Although single-incision laparoscopic cholecystectomy is now widely performed in patients with cholecystitis, some cases require an additional port to complete the procedure. In this study, we focused on risk factor of additional port in this surgery. We performed single-incision cholecystectomy in 75 patients with acute cholecystitis or after cholecystitis between 2010 and 2014 at Gunma University Hospital. Surgical indications followed the TG13 guidelines. Our standard procedure for single-incision cholecystectomy routinely uses two needlescopic devices. We used logistic regression analysis to identify the risk factors associated with use of an additional full-size port (5 or 10 mm). Surgical outcome was acceptable without biliary injury. Nine patients (12.0%) required an additional port, and one patient (1.3%) required conversion to open cholecystectomy because of severe adhesions around the cystic duct and common bile duct. In multivariate analysis, high C-reactive protein (CRP) values (>7.0 mg/dl) during cholecystitis attacks were significantly correlated with the need for an additional port (P = 0.009), with a sensitivity of 55.6%, specificity of 98.5%, and accuracy of 93.3%. This study indicated that the severe inflammation indicated by high CRP values during cholecystitis attacks predicts the need for an additional port. J. Med. Invest. 64: 245-249, August, 2017

Although vascular endothelial growth factor receptor (VEGF-R)-targeted antiangiogenic agents are important treatment for a number of human malignancies, there is accumulating evidence that the therapies may promote disease progression, such as invasion and metastasis. How tumors become to promote their evasiveness remains fully uncertain. One of possible mechanisms for the adaptation may be a direct effect of VEGF-R inhibitors on tumor cells expressing VEGF-R. To elucidate a direct effect of VEGF-R-targeting drug (sunitinib), we established a human colorectal cancer cell model adapted to sunitinib. The sunitinib-conditioned cells showed a significant increase in cellular motility and migration activities, compared to the vehicle-treated control cells. Consistent with the phenotype, the sunitinib-conditioned cells decreased the expression levels of E-cadherin (an epithelial marker), while significantly increased the levels of Slug and Zeb1 (mesenchymal markers). Expression profiles of VEGF-R in the sunitinib-conditioned cells showed that only neuropilin-1 (NRP1) expression was significantly increased among all VEGF-R tested. Blockade of NRP1 using its antagonist clearly repressed the migration activation in sunitinib-conditioned cells, but not in the control cells. These results suggest that inhibition of VEGF-R on colorectal cancer cells can drive the epithelial-mesenchymal transition, leading to activation of cell motility in an NRP1-dependent manner. J. Med. Invest. 64: 250-254, August, 2017

Hyperglycemia induces nonconcordant regulation of renal mitochondrial respiratory complexes, increases oxidative stress, and causes diabetic nephropathy. Hypertension is a complication associated with diabetes and involves glomerular hyperfiltration, the effects of which on mitochondrial respiratory complexes are not well understood. To investigate the effect of glomerular hyperfiltration on renal mitochondrial respiratory complexes, we used the 5/6 nephrectomized BKS. Cg-Dock7^m+/+Lepr^db/J, Dock7^m+/+Lepr^db mice (db/m-5/6Nx mice) as a model for glomerular hyperfiltration. The BKS. Cg-Dock7^m+/+Lepr^db/J, +Lepr^db/+Lepr^db mice (db/db mice), a model for type 2 diabetes, was used as the positive control. We investigated the activities and protein levels of the mitochondrial complex, and the mitochondrial DNA and adenosine triphosphate content in the kidneys of these models. Blood chemistry and renal histopathological examination were performed for characterization of the disease. Both models showed expansion of the mesangial matrix of the glomeruli, which is indicative of glomerular hyperfiltration. The activities of complexes I and IV and the protein levels of complexes I and III were nonconcordant in db/m-5/6Nx mice. In conclusion, we demonstrated that nonconcordant regulation of mitochondrial complexes in db/m-5/6Nx mice involved with glomerular hyperfiltration. The progression and/or severity of nephropathy might be affected through a synergistic effect of mitochondrial dysfunction in hyperglycemia and glomerular hyperfiltration. J. Med. Invest. 64: 255-261, August, 2017

Recently, inhibition of tumor angiogenesis has become an important anti-cancer therapy. Tumor angiogenesis is regulated by multiple signaling pathways, including VEGF and VEGF receptor (VEGF-R), FGF and FGF receptor (FGF-R), and PDGF and PDGF receptor (PDGF-R) pathways. Thus, the antiangiogenic agents, such as regorafenib, simultaneously target those receptors on vascular endothelial cells. In addition to endothelial cells, cancer cells express the three receptors, suggesting that the antiangiogenic inhibitors affect tumor cells. In fact, we previously demonstrated that regorafenib directly acted on human colorectal cancer cells and accelerated their apoptosis resistance and migration capability. Thus, we here elucidated how regorafenib induced the malignant phenotypes in colorectal cancer cells. To identify the responsible receptor among the regorafenib-targeting proangiogenic receptors, we examined the effects of a potent selective inhibitor for VEGF-R, FGF-R or PDGF-R on apoptosis resistance and migration capability. We clarified that blockade of VEGF-R, but not FGF-R and PDGF-R, induced the malignant phenotypes. We confirmed that blocking of VEGF ligands derived from colorectal cancer cells also induced the phenotypes. These results suggest that regorafenib progressed the malignancy via prevention of autocrine and paracrine VEGF signaling in colorectal cancer cells. J. Med. Invest. 64: 262-265, August, 2017

Background/Aims Our previous study showed that time in therapeutic range (TTR) control of warfarin therapy was negatively affected in non-valvular atrial fibrillation (NVAF) patients with heart failure. This study assesses the effect of intervention by hospital pharmacists on TTR control in Japanese NVAF patients with heart failure. Method This retrospective cohort study included NVAF patients with heart failure admitted and discharged from the cardiovascular internal medicine ward between March 2011 and July 2013. Participants were classified into two groups according to the instructions by hospital pharmacists and physicians (Intervention group) and by physicians only (Usual care group). The primary outcome was TTR. Secondary outcomes were major bleeding and minor bleeding. Results In total, 57 participants (35 males, 22 females; mean age: 69.7 years) were classified into the Intervention (n = 25) and Usual care (n = 32) groups. TTR within-therapeutic range was significantly higher and within sub-therapeutic range was significantly lower in the Intervention than the Usual care group. Major bleeding and minor bleeding were not significantly different between the two groups. Conclusion The intervention of hospital pharmacists with anticoagulation therapy can lead to proper use of warfarin, which can be useful when physicians prescribe warfarin. J. Med. Invest. 64: 266-271, August, 2017

To develop effective non-human primate models for coping with numerous HIV-1/AIDS studies, rhesus macaque-tropic HIV-1 (HIV-1rmt) clones with a variety of biological properties are required. Such clones, if available, are powerful tools to experimentally elucidate HIV-1 replication and pathogenicity in host individuals, and also to develop anti-HIV-1 drugs/vaccines. However, only limited numbers of HIV-1rmt clones have been currently reported. In the present study, we generated new HIV-1rmt clones carrying various CCR5-tropic env (envelope) genes by standard recombinant DNA and intracellular homologous recombination techniques. Resultant virus clones contain the env sequences derived from an AIDS-inducible laboratory or two clinically isolated viral strains. We further constructed their variant clones bearing N160K, S304G, or G310R mutation in Env that potentially can change the viruses to better grow. Newly generated clones were analyzed for their virological properties such as Env expression, single-cycle infectivity, and multi-cycle replication ability. Out of a number of new clones examined, two were found to grow better in macaque cells than the previously constructed clone used for comparison. Our study described here constitutes the initial and essential step towards obtaining CCR5-tropic HIV-1rmt clones useful for various basic and clinical research projects on infected individuals. J. Med. Invest. 64: 272-279, August, 2017

To accurately and rapidly screen for higher brain dysfunction, we developed a screening test named the “higher brain dysfunction screening test” (HIBRID-ST). Previous studies have reported a decrease in higher brain function with age. However, whether HIBRID-ST can detect a decrease in higher brain function in healthy persons remains unclear. We aimed to assess the usefulness of HIBRID-ST for evaluating higher brain function in healthy persons. We recruited 60 persons without physiological abnormalities and divided them into six equal groups based on their age (20s-70s). HIBRID-ST addresses orientation, short-term memory, word recall, situational awareness, visual short-term memory, and graphic replication and includes the Trail Making and Kana-hiroi tests. There was a significant negative correlation between the participants' age and their total HIBRID-ST score (ρ = -0.68, p < 0.01). The total HIBRID-ST score of participants in their 70s was significantly lower than that of participants in their 20s-60s; the total HIBRID-ST score of participants in their 60s was significantly lower than that of participants in their 20s-50s. Our findings show that HIBRID-ST accurately detects an age-related decline in higher brain function. Further studies are needed to examine the usefulness of HIBRID-ST in patients with higher brain dysfunction. J. Med. Invest. 64: 280-285, August, 2017

A 78-year-old female was referred to our hospital with a diagnosis of type A acute aortic dissection. There was a history of thrombosed aortic dissection six months prior and conservative management has been performed. Enhanced computed tomography showed type A acute aortic dissection with patent false lumen limited to the ascending aorta and ileus of the small intestine. Emergency hemiarch replacement was performed under mild hypothermic circulatory arrest and selective antegrade cerebral perfusion. Due to preoperative paralytic ileus, oral intake was initiated postoperative day four. Postoperative computed tomography revealed improvement of paralytic ileus. J. Med. Invest. 64: 286-287, August, 2017

A 77-year-old Japanese female underwent laparoscopic ileocecal resection and lymph node dissection for cecal cancer by a previous doctor. Two years and 9 months after previous operation, contrast-enhanced computed tomography and magnetic resonance imaging with gadolinium ethoxybenzyl-L-diethylenetriamine pentaacetic acid revealed an intraperitoneal tumor at the right subphrenic fossa. 18F-fluorodeoxyglucose position emission tomography showed fluorodeoxyglucose accumulation in the tumor, and we suspected the tumor to be solitary distant peritoneal metastasis of the previous cecal cancer to the right diaphragm. We performed partial diaphragmectomy and direct closure, and pathological examination revealed moderately differentiated tubular adenocarcinoma resembling the previous cecal cancer, which seemed to be disseminated metastasis in the pathological features. Based on the intraoperative findings, we assumed the tumor to be solitary distant peritoneal metastasis caused by procedures during the previous laparoscopic operation. The present report suggests the importance of paying close attention to procedures during laparoscopic colorectal resection to prevent peritoneal seeding. J. Med. Invest. 64: 288-290, August, 2017

Percutaneous endoscopic surgery for the lumbar spine has become established in the last decade. It requires only an 8 mm skin incision, causes minimal damage to the paravertebral muscles, and can be performed under local anesthesia. With the advent of improved equipment, in particular the high-speed surgical drill, the indications for percutaneous endoscopic surgery have expanded to include lumbar spinal canal stenosis. Transforaminal percutaneous endoscopic discectomy has been used to treat intervertebral stenosis. However, it has been reported that adjacent level disc degeneration and foraminal stenosis can occur following intervertebral segmental fusion. When this adjacent level pathology becomes symptomatic, additional fusion surgery is often needed. We performed minimally invasive percutaneous full endoscopic lumbar foraminoplasty in an awake and aware 50-year-old woman under local anesthesia. The procedure was successful with no complications. Her radiculopathy, including muscle weakness and leg pain due to impingement of the exiting nerve, improved after the surgery. J. Med. Invest. 64: 291-295, August, 2017

Multiple chemical sensitivity (MCS) is a disorder of unknown etiology with no effective treatment. Many clinicians accept that a diagnosis of somatic symptoms disorder (SSD) is an appropriate diagnostic category for MCS. We found that administration of levetiracetam improved recurrent symptoms of MCS in a patient. A 23-year-old female presented with recurrent multiple symptoms of musculoskeletal, airway or mucous membrane, heart/chest-related, gastrointestinal, cognitive, affective, neuromuscular, head-related, and skin-related induced by exposure to diesel or gas engine exhaust, tobacco smoke, insecticide, gasoline, paint or paint thinner, cleaning products, fragrances, tar or asphalt, nail polish or hairspray, and new furnishings. Gastrointestinal, cognitive, and skin-related symptoms were precipitated by some food additives. She suffered partial seizures from the age of 17 years, and was diagnosed with right parietal lobe epilepsy. Administration of levetiracetam (250 mg/day) eliminated her MCS symptoms. Levetiracetam reduces the release of presynaptic neurotransmitter including glutamate by binding to presynaptic vesicle protein. A recent study established the presence of glutamatergic overactivation in somatization disorder, a form of SSD. Our case may indicate that a subset of patients with SSD have glutamatergic overactivation, which levetiracetam can normalize. J. Med. Invest. 64: 296-298, August, 2017

Radical resection of recurrent cholangiocellular carcinoma (CCC) is rare. To date, only two patients have been reported to undergo major hepatectomy twice after pancreatoduodenectomy (PD) for metachronous CCC. This report describes a patient who underwent three metachronous radical resections of CCC with curative intent, consisting of PD followed by two hepatectomies, for cancer of the middle bile duct. A 60 year old male, who had undergone a distal gastrectomy for duodenal ulcer perforation in 23 years ago, underwent PD (Honjo method) for middle bile duct cancer (papillary adenocarcinoma) in 20 years ago at another hospital. In 12 years ago, he was referred to our hospital for further examinations of hepatic tumors and was diagnosed with CCC (S6, solitary, 4 cm). He underwent S6 subsegmentectomy of the liver. Pathological examination revealed a poorly differentiated CCC, considered a second primary cancer. In 6 years ago, subsequent follow up as an outpatient revealed repeated cholangitis, with CT showing a hilar mass caused by obstructive jaundice. He was diagnosed with a hilar cholangioma, and underwent hepatectomy and hepaticojejunostomy, which were safe despite surgical difficulties caused by severe adhesions and re-anastomosis. Pathological examination showed a well-differentiated CCC, considered the third primary cancer. The lung metastasis was revealed in 28 months after the last operation, however he has survived after partial lung resection without further metastasis. J. Med. Invest. 64: 299-304, August, 2017

A 36-year-old male was found two nodules in the right lower lobe of the lung. After the surgical resection, both lesions were diagnosed as invasive adenocarcinomas. One lesion was primarily lepidic growth component with EGFR-L858R mutation, and the other was micropapillary component with ALK translocation accompanying mediastinal lymphnode metastases. While he experienced disease recurrence, the disease was controlled by an ALK inhibitor, given based on the findings of surgical specimens. This is the first case who had two simultaneous lung cancers with EGFR mutation and ALK translocation in each respective lesion, and was successfully treated with ALK inhibitor at the post-surgical recurrence. J. Med. Invest. 64: 305-307, August, 2017

Calcinosis cutis can be classified into four subtypes: dystrophic, metastatic, idiopathic, and iatrogenic. Of these subtypes, dystrophic calcinosis (DC) is the most common, and is most frequently associated with connective tissue disease, particularly dermatomyositis and systemic sclerosis, and less commonly with systemic lupus erythematosus. However, DC associated with rheumatoid arthritis (RA) is extremely rare. In this paper, we present a Japanese woman with RA, who suffered from bilateral leg ulcers secondary to DC. To the best of our knowledge, only two cases of DC associated with RA have been reported to date. Similar to this case, the DC lesions were observed in the extremities, including the buttocks in the other two cases. Although the ulcers on her left leg were gradually epithelialized after one year, they may easily recur due to whitish abnormal underlying tissues, and a large ulcer remains on her right leg. Thus, it is important for physicians to identify DC when encountering non-healing leg ulcers associated with connective tissue diseases. J. Med. Invest. 64: 308-310, August, 2017

The patient, a 70-year-old Japanese woman diagnosed with parotid gland cancer, underwent wide excision and reconstruction (facial nerve ablation, nerve transposition). At 1 month after the surgery, she was brought to our hospital's pain medicine department because her postoperative pain and cancer-related pain were poorly controlled. She had already been prescribed a tramadol (37.5 mg)/acetaminophen (325 mg) combination tablet (5 tablets/day). However, in addition to the continuous pain in her face and lower limbs, she was troubled by a trigeminal neuralgia-like prominence ache. Because this pain could not be controlled by an increase to eight combination tablets per day, we switched her medication to a tramadol capsule. At 11 months post-surgery, we then switched her medication to an orally disintegrating tramadol tablet to improve medication adherence of the drug. From 14 months post-surgery, the patient also used a sustained-release tramadol preparation, and she was then able to sleep well. Her current regimen is an orally disintegrating sustained-release tablet combination (total 300 mg tramadol) per day, and she achieved sufficient pain relief. Because tramadol is not classified as a medical narcotic drug, it widely available and was shown here to be extremely useful for the treatment of our patient's mixed (mainly cancer) pain. J. Med. Invest. 64: 311-312, August, 2017

A 21-year-old woman who was high-level college softball player presented with a 6-month history of low back pain that had been treated unsuccessfully by medication at local clinics. There was tenderness in the left paravertebral muscle at the lower lumbar level. X-ray and computed tomography revealed congenital scoliosis and an L6 hemivertebra. Short tau inversion recovery magnetic resonance imaging showed a fluid collection at the left L6-S1 facet joint. We performed a diagnostic facet injection, consisting of 1% lidocaine and steroids, that was infiltrated into the left facet joint at L6-S1. Her persistent low back pain disappeared immediately after the facet block. We diagnosed left-sided facet arthritis at L6-S1. Due to her multiple congenital anomalies, excessive loading occurred at the facet joint. Therefore, we opted for conservative management, including mobilization of the thoracic spine and stretching of hamstrings and quadriceps. This case report underscores the importance of accurate diagnosis of low back pain and of the diagnostic utility of short tau inversion recovery magnetic resonance imaging and lumbar facet block in young athletes with chronic spinal pain. J. Med. Invest. 64: 313-316, August, 2017

Background: The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC. Methods/Design: RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design. The primary endpoint is safety. In step 2, alectinib will be administered at the recommended dose (RD) defined by step 1. The primary endpoint is the response rate of RET inhibitor treatment-naïve patients. Conclusion: This is the first study to investigate the safety and preliminary efficacy of alectinib in RET fusion-positive NSCLC patients. If successful, alectinib treatment may lead to substantial and important changes in the management of NSCLC with RET fusion genes. J. Med. Invest. 64: 317-320, August, 2017

The BIM deletion polymorphism is reported to be associated with poor outcomes of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) treated with EGFR-TKIs, including gefitinib. We have shown that a histone deacetylase inhibitor, vorinostat, can epigenetically restore BIM function and apoptosis sensitivity to EGFR-TKIs in EGFR-mutant NSCLC cells with BIM deletion polymorphisms. The purpose of this study is to determine the feasibility of combined treatment of vorinostat with gefitinib in BIM deletion polymorphism positive EGFR-mutant NSCLC patients. BIM deletion polymorphism positive EGFR-mutant NSCLC patients treated with at least one EGFR-TKI and one regimen of chemotherapy are being recruited to this study. Vorinostat (200-400 mg) will be administered orally once daily on days 1-7, and gefitinib 250 mg orally once daily on days 1-14. With a fixed dose of gefitinib, the dose of vorinostat will be escalated following a conventional 3+3 design. The primary endpoint is to define the maximum tolerated dose (MTD) of vorinostat combined with 250 mg of gefitinib. This is the first phase I study of combined therapy with vorinostat and gefitinib for NSCLC patients double selected for an EGFR mutation and BIM deletion polymorphism. J. Med. Invest. 64: 321-325, August, 2017