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Hiroshi Kobayashi,1 Miho Sekiguchi,1 Koji Otani,1 Rei Ono,2 Takuya Nikaido,1 Kazuyuki Watanabe,1 Kinshi Kato,1 Yoshihiro Kobayashi,1 Shoji Yabuki,1 Shin-ichi Konno,1 Yoshihiro Matsumoto1 1Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan; 2Department of Physical Activity Research, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Settsu, JapanCorrespondence: Hiroshi Kobayashi, Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Tokyo, 960-1295, Japan, Tel +8124-547-1276, Fax +8124-548-5505, Email hiroshik@fmu.ac.jpPurpose: Insomnia has been reported to coexist with various musculoskeletal disorders. Although lumbar spinal stenosis (LSS) is the most frequently operated on spinal disease, the causal relationship between LSS and development of sleep disorders remains unclear due to lack of longitudinal studies. This study aimed to determine whether LSS was a risk factor for developing new sleep disorders, primarily insomnia, using a prospective cohort of community residents.Patients and Methods: This study was a prospective cohort study. Participants aged ≥ 65 years from the “Locomotive Syndrome and Health Outcomes in Aizu Cohort Study (LOHAS)” conducted in 2008 formed our study population. LSS was diagnosed using the self-administered, self-reported history questionnaire, a validated diagnostic support tool for LSS. Sleep disorder was investigated using a questionnaire during the 2-year follow-up. The impact of LSS on sleep disorder onset was analyzed after adjusting for potential confounders, such as age, sex, obesity, hypertension, diabetes, depression, and smoking habits, using propensity score matching.Results: Of the 489 participants who were followed up for two years, 38 (7.8%) had newly developed a sleep disorder in 2010. After adjusting for confounding factors, a comparison of 133 participants each in the control and LSS groups showed significantly higher frequency of new-onset sleep disorders (19 [14.3%] in the LSS group versus 6 [4.5%] in the control group).Conclusion: LSS was found to be an independent risk factor for sleep disorders.Keywords: lumbar spinal stenosis, sleep disorder, insomnia, cohort study, musculoskeletal disorder, locomotive syndrome

Background and purposeDelayed leukoencephalopathy is a rare complication that occurs after endovascular coiling of cerebral aneurysms. We aimed to describe a clinical picture of delayed leukoencephalopathy and explore potential associations with procedural characteristics.Materials and methodsWe considered endovascular coiling procedures for cerebral aneurysms performed between January 2006 and December 2017 in our institution with follow-up MRIs. We used logistic regression models to estimate the ORs of delayed leukoencephalopathy for each procedural characteristic.ResultsWe reviewed 1754 endovascular coiling procedures of 1594 aneurysms. Sixteen of 1722 (0.9%) procedures demonstrated delayed leukoencephalopathy on follow-up FLAIR MR imaging examinations after a median period of 71.5 days (interquartile range, 30-101 days) in the form of high-signal changes in the white matter at locations remote from the coil mass. Seven patients had headaches or hemiparesis, and 9 patients were asymptomatic. All imaging-associated changes improved subsequently. We found indications suggesting an association between delayed leukoencephalopathy and the number of microcatheters used per procedure (P = .009), along with indications suggesting that these procedures required larger median volumes of contrast medium (225 versus 175 mL, OR = 5.5, P = .008) as well as a longer median fluoroscopy duration (123.6 versus 99.3 minutes, OR = 3.0, P = .06). Our data did not suggest that delayed leukoencephalopathy was associated with the number of coils (P = .57), microguidewires (P = .35), and guiding systems (P = .57).ConclusionsDelayed leukoencephalopathy after coiling of cerebral aneurysms may have multiple etiologies such as foreign body emboli, contrast-induced encephalopathy, or hypersensitivity reaction to foreign bodies.

Junichi Handa, Koji Otani, Takuya Nikaido, Shin-ichi Kikuchi ,† Shin-ichi Konno Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan†Shin-ichi Kikuchi passed away on February 22th, 2022Correspondence: Junichi Handa, Tel +81-24-547-1276, Fax +81-24-548-5505, Email hanhan@fmu.ac.jpPurpose: Nocturnal leg cramps are considered to be a symptom of lumbar spinal stenosis (LSS). However, the relationship between LSS and nocturnal leg cramps in the general population remains unclear. The purpose of this study was to investigate the prevalence and characteristics of nocturnal leg cramps in LSS in the community.Patients and Methods: 328 voluntary participants were enrolled in this study. The presence of LSS was assessed by a validated and self-administered diagnostic support tool. The presence of nocturnal leg cramps and neurological findings were evaluated by one experienced spine surgeon. To investigate the relationship between leg cramps and anatomical factors, the participants underwent an MRI scan, and the dural sac cross-sectional area (DCSA) at each lumbar intervertebral disc level was measured.Results: A total of 214 participants (65.2%) had nocturnal leg cramps, and 94 of 328 participants (28.7%) showed typical LSS symptoms. In the typical LSS symptom group, 31 participants (33.0%) had nocturnal leg cramps. In the atypical LSS symptom group, 83 participants (35.5%) had nocturnal leg cramps. There was no statistically significant difference in the prevalence of nocturnal leg cramps between the two groups. The narrowest DCSA (< 25 mm2 and 25– 49.4mm2) was statistically related to the presence of nocturnal leg cramp. Statistically significant differences in sensory disturbance and motor weakness were not observed between the subjects with and those without nocturnal leg cramps. Moreover, impaired PTR was statistically related to the presence of nocturnal leg cramp.Conclusion: The prevalence of nocturnal leg cramps did not differ with or without typical LSS symptoms in the community. The degree of dural tube compression that is determined by DCSA had a direct effect on the presence of nocturnal leg cramps. Neurological impairment, such as PTR abnormalities, was associated with the presence of nocturnal leg cramps.Keywords: nocturnal leg cramps, lumbar spinal stenosis, general population, magnetic resonance imaging, sensory disturbance, motor weakness

Hiroshi Kobayashi, Koji Otani, Takuya Nikaido, Kazuyuki Watanabe, Kinshi Kato, Junichi Handa, Shoji Yabuki, Shin-Ichi Konno Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, JapanCorrespondence: Hiroshi Kobayashi 1-Hikarigaoka, Fukushima, 960-1295, JapanTel +8124-547-1276Fax +81 24-548-5505Email hiroshik@fmu.ac.jpPurpose: Early diagnosis of degenerative cervical spondylosis (DCM) is desirable because late treatment can lead to irreversible sequelae. No screening method has yet been established. Grip strength is commonly used in primary care settings to evaluate disease activity and diagnose sarcopenia. This single-center, cross-sectional study aimed to determine the diagnostic accuracy of grip strength for cervical myelopathy (DCM) and cutoff values for primary care DCM screening using area under the curve (AUC) and sensitivity values.Patients and Methods: The DCM group comprised 249 consecutive participants (165 males, 84 females; mean age, 65.1 years) with DCM who had undergone surgery at the affiliated hospital. The control group comprised 735 (280 males, 455 females; mean age, 65.8 years) participants undertaking a local government health checkup. Stratifying by age and sex, receiver operating characteristic (ROC) analyses were constructed for each group using minimum grip strength values for both hands. Based on ROC analysis, cut-off values were established so that the screening sensitivity would be 90% for either sex or age group, respectively.Results: According to age group and sex (males/females [M/F]), AUC values for a diagnosis of DCM in M/F were as follows: 40– 59 years, 0.92/0.87; 60– 69 years, 0.94/0.89; 70– 79 years, 0.89/0.91; and 80– 89 years, 0.97/0.97. Calculated M/F cutoff values were 41/24.5, 27/16, 27/15, and 20/10 kg, which were similar to cutoff scores for sarcopenia in M/F patients aged 60– 69 and 70– 79 years. M/F sensitivities in each age groups were 0.94/0.91, 0.92/0.90, 0.95/0.96, and 0.92/0.93. M/F specificities were 0.62/0.59, 0.84/0.83, 0.61/0.71, and 0.83/0.88.Conclusion: Grip strength had moderate-to-high diagnostic accuracy for DCM between participants in the control and DCM groups. We developed easily applicable cutoff values for primary care DCM screening with ≥ 90% sensitivity. In patients with sarcopenia, DCM should be differentially diagnosed in primary care.Keywords: degenerative cervical myelopathy, cervical spondylotic myelopathy, ossification of posterior longitudinal ligament, cervical disc herniation, primary care, early detection, sarcopenia

Keisuke Noto,1 Akihito Suzuki,1 Toshinori Shirata,1 Yoshihiko Matsumoto,1 Nana Takahashi,1 Kaoru Goto,2 Koichi Otani1 1Department of Psychiatry, Yamagata University School of Medicine, Yamagata 990-9585, Japan; 2Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585, JapanCorrespondence: Toshinori Shirata Email white_gregory000@yahoo.co.jpPurpose: Attachment research shows that attachment experiences with parents in childhood influence the characterization of personality traits. Meanwhile, it is known that mu-opioid receptor function is involved in human attachment. Furthermore, a few studies suggest that the A118G polymorphism of the mu-opioid receptor gene (OPRM1) is associated with altered mu-opioid receptor function. Thus, we examined if the OPRM1 polymorphism moderates the sensitivity to parental behaviors and thereby contributes to the characterization of personality traits.Materials and Methods: Participants were 725 healthy Japanese. Parenting practices of their parents were evaluated by the Parental Bonding Instrument (PBI) with the care and protection subscales. Personality was evaluated using the Temperament and Character Inventory (TCI). The OPRM1 A118G polymorphism was detected by a PCR method.Results: Multiple regression analyses revealed significant effects of the interaction between the OPRM1 genotype and maternal protection on scores of the self-directedness and cooperativeness dimensions, while significant main effects of the OPRM1 genotype on scores of the TCI were not found. Further analyses showed that there were significant negative correlations between maternal protection scores and the two dimensional scores in the A/A and A/G genotypes with higher correlation coefficients in the former, but not in the G/G genotype.Conclusion: The present study suggests that the OPRM1 polymorphism contributes to the characterization of personality traits by moderating the sensitivity to parental behaviors, especially maternal protection.Keywords: OPRM1, attachment, personality, PBI, TCI, gene–environment interaction

Toshinori Shirata,1 Akihito Suzuki,1 Yoshihiko Matsumoto,1 Keisuke Noto,1 Kaoru Goto,2 Koichi Otani1 1Department of Psychiatry, Yamagata University School of Medicine, Yamagata 990-9585, Japan; 2Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata 990-9585, JapanCorrespondence: Toshinori Shirata Email white_gregory000@yahoo.co.jpPurpose: It is suggested that increased methylation of the brain-derived neurotrophic factor (BDNF) gene is involved in the pathogenesis of depression, while sociotropy and autonomy are proposed as personality vulnerability factors in cognitive model of depression. We examined the interrelation between BDNF gene methylation and sociotropy or autonomy, with taking into account the previously reported deleterious effect of parental overprotection on sociotropy. Materials and Methods: The participants consisted of 90 healthy Japanese volunteers. Methylation levels of the BDNF gene in peripheral blood were quantified by bisulfite pyrosequencing. Sociotropy and autonomy were assessed by the Sociotropy-Autonomy Scale, and perceived parental protection was evaluated by the Parental Bonding Instrument.Results: In Pearson’s correlation analysis, there was a positive correlation between methylation levels of the BDNF gene and sociotropy scores (p< 0.05) but not autonomy scores, and a positive correlation between maternal protection scores and sociotropy scores (p< 0.05). In structural equation modeling, two models were proposed; the first one is that hypermethylation of the BDNF gene and maternal overprotection independently contribute to high sociotropy, and the second one is that maternal overprotection contributes to high sociotropy which then leads to hypermethylation of the BDNF gene.Conclusion: The present study suggests an interrelation between increased BDNF gene methylation and high sociotropy.Keywords: autonomy, BDNF gene, methylation, parental protection, sociotropy

Junichi Yoshida, Tetsuya Kikuchi, Takako Ueno, Akiko Mataga, Ikuyo Asano, Kazuhiro Otani, Tetsuro Tamura, Masao Tanaka Division of Infection Control, Shimonoseki City Hospital, Shimonoseki, JapanCorrespondence: Junichi YoshidaDivision of Infection Control, Shimonoseki City Hospital, 1-13-1, Shimonoseki 750-8520, JapanTel +81 83 231 4111Fax +81 83 224 3838Email yoshidaj@uicalumni.orgPurpose: To reduce Clostridioides difficile infection (CDI), we implemented interprofessional antimicrobial, infection control, and diagnostic stewardship (ipAS) conducted by physicians/pharmacists, infection control nurses, and medical technologists, respectively. As a numerical indicator for ipAS, we used antimicrobial use density (AUD) in an 8-year study to validate its efficacy in CDI reduction.Patients and methods: This was an observational study. CDI was defined as stool samples or C. difficile isolates containing toxin A and/or B from a patient with diarrhea occurring three or more times per day. From 2011–2018 at a 10-ward single site the subjects were in-patients with CDI, and the following data were collected: AUDs for 23 antibiotics, and antimicrobial test results. By 2015, we had established ipAS, consisting of culture submission before the administration of broad-spectrum antimicrobials, the promotion of point-of-care testing for diagnosis-based antimicrobials, perioperative prophylactic antibiotics, intervention at positive diagnosis of blood culture, team round for diarrhea, and inspection on contact precautions and disinfection in CDI cases. The study outcomes included annual numbers of CDI patients and blood culture sets. We compared annual AUDs between former (2011–14) and latter (2015–18) periods using Kruskal–Wallis tests and examined the correlation between AUDs and CDI numbers.Results: Of a total 50,970 patients, 1,750 patients underwent C. difficile toxin tests, of whom 171 patients (9.8%) were positive for CDI. Between the former and latter periods, AUDs for flomoxef (11.96 to 2.71 by medians), panipenem/betamipron (0.30 to 0.00), and clindamycin (3.87 to 2.19) significantly decreased (P

Koji Otani, Shin-ichi Kikuchi, Takuya Nikaido, Shin-ichi Konno Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan Background: The North American Spine Society states that lumbar spinal stenosis (LSS) is a clinical syndrome, and there is insufficient evidence to make a recommendation for or against a correlation between clinical symptoms or function and the presence of anatomic narrowing of the spinal canal on MRI. The main purpose of this study was to assess the influence of the magnitude of dural tube compression on MRI on LSS symptoms at the cross-sectional and 1-year follow-up. Methods: This was a prospective cohort study of 459 participants who were assessed for LSS using a questionnaire and conventional MRI of the lumbar spine. After 1 year, 335 subjects (follow-up rate 73.0%) were assessed for LSS using the same questionnaire. The time course of the clinical subjective symptoms of LSS and the relationship between the said symptoms of LSS and magnitude of dural tube compression on MRI were analyzed in a cross-sectional and longitudinal fashion. Results: 1) The dural sac cross-sectional area (DCSA) decreased with age. 2) Severe dural tube compression had a strong influence on the presence of symptomatic LSS; however, 40%–70% of participants with severe dural tube compression did not show clinical symptoms of LSS. 3) At the 1-year follow-up, >50% of the LSS-positive participants in the initial year were reclassified as LSS negative, and 10% of the LSS-negative participants were reclassified as LSS positive. 4) The magnitude of the DCSA on MRI did not directly affect the presence of LSS at the 1-year follow-up. Conclusion: LSS symptoms were changeable. Anatomical dural tube compression on MRI did not predict the presence of clinical LSS symptoms at the 1-year follow-up. Keywords: lumbar spinal stenosis, epidemiology, natural history, quality of life, prognostic factors, comorbidities, cross-sectional area, MRI

Toshinori Shirata,1 Akihito Suzuki,1 Yoshihiko Matsumoto,1 Nana Takahashi,1 Keisuke Noto,1 Kaoru Goto,2 Koichi Otani1 1Department of Psychiatry, Yamagata University School of Medicine, Yamagata, Japan; 2Department of Anatomy and Cell Biology, Yamagata University School of Medicine, Yamagata, Japan Background: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that has an important function in neuroplasticity and neuronal development. It is suggested that increased methylation of the BDNF gene resulting in decreased BDNF activity is associated with depression. Meanwhile, neuroticism is a well-known risk factor for developing depression. In the present study, the relationship between methylation of the BDNF gene and personality traits including neuroticism was examined. Subjects and methods: The subjects were 98 healthy Japanese. Methylation levels of the BDNF gene were determined by the bisulfite-pyrosequencing method. Personality traits including neuroticism were assessed by the NEO Personality Inventory-Revised. Results: There was a positive correlation between neuroticism scores and methylation levels of the BDNF gene. The subjects with higher neuroticism scores had higher levels of BDNF gene methylation compared with those with lower neuroticism scores. Meanwhile, other personality traits were not associated with BDNF gene methylation. Conclusion: The present study suggests that high neuroticism is related to increased methylation of the BDNF gene. Keywords: BDNF, depression, epigenetics, methylation, neuroticism

Koichi Otani, Akihito Suzuki, Yoshihiko Matsumoto, Toshinori Shirata Department of Psychiatry, Yamagata University School of Medicine, Yamagata, Japan Objective: The cognitive model of depression posits two distinctive personality vulnerabilities termed sociotropy and autonomy, each of which is composed of a cluster of maladaptive self-schemas. It is postulated that negative core beliefs about self underlie maladaptive self-schemas as a whole, whereas those about others may be implicated in the autonomous self-schemas. Therefore, the present study examined the relations of sociotropy and autonomy with core beliefs about self and others.Methods: The sample of this study consisted of 321 healthy Japanese volunteers. Sociotropy and autonomy were evaluated by the corresponding subscales of the Sociotropy–Autonomy Scale. Core beliefs about self and others were assessed by the negative-self, positive-self, negative-other and positive-other subscales of the Brief Core Schema Scales.Results: In the forced multiple regression analysis, sociotropy scores were correlated with negative-self scores (β = 0.389, P < 0.001). Meanwhile, autonomy scores were correlated with positive-self scores (β = 0.199, P < 0.01) and negative-other scores (β = 0.191, P < 0.01).Conclusion: The present study suggests marked differences in core beliefs about self and others between sociotropy and autonomy, further contrasting the two personality vulnerabilities to depression. Keywords: sociotropy, autonomy, core belief, self, other, personality, cognitive vulnerability

Koji Otani, Shin-Ichi Kikuchi, Shoji Yabuki, Akira Onda, Takuya Nikaido, Kazuyuki Watanabe, Shin-Ichi Konno Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan Purpose: Lumbar spinal stenosis (LSS) is a common condition in the aging population. However, limited information exists on discrepancies between LSS symptoms and imaging findings and/or prognostic factors of LSS, as well as the relationship between changes in LSS symptoms and quality of life (QoL) during the natural course of LSS. The purpose of the current study was to clarify any changes in clinically diagnosed LSS at a one-year follow-up, and identify its prognostic factors, using a community-dwelling cohort.Participants and methods: In this study, the presence of LSS, its associated comorbidities, and the status of QoL pertaining to general health and low-back pain were assessed in 1,080 community-dwelling volunteers. The same assessment was carried out a year after the initial survey. Clinically diagnosis as LSS (LSS-positive) was determined by a validated diagnostic support tool in the form of a self-administered, self-reported history questionnaire. QoL was assessed using the 36-Item Short Form Health Survey and the Roland–Morris Disability Questionnaire.Results: Among subjects who were LSS-positive in the initial assessment, 54% were clinically diagnosed as negative for LSS (LSS-negative) after the one-year period, whereas 10% of those who were initially diagnosed as LSS-negative changed to LSS-positive during the same period. With the improvement or deterioration of LSS-positive/negative status, low-back pain-related QoL and some components of the 36-Item Short Form Health Survey similarly improved or deteriorated. Decisive prognostic factors of LSS-positive status were not determined at the one-year follow-up.Conclusion: Approximately half of the subjects who had initially been diagnosed as LSS-positive converted to LSS-negative after one year. Prognostic factors of LSS-positive diagnosis after one-year follow-up were not detected. Keywords: epidemiology, natural history, quality of life, prognostic factors, comorbidities

Koichi Otani, Akihito Suzuki, Yoshihiko Matsumoto, Toshinori Shirata Department of Psychiatry, Yamagata University School of Medicine, Yamagata, Japan Objective: Cognitive theory assumes a pivotal role of negative core beliefs about the self in dysfunctional attitudes predisposing to depression. Meanwhile, the role of positive core beliefs about the self in cognitive vulnerability to depression is unknown. Therefore, we examined the relationship of negative and positive core beliefs about the self with dysfunctional attitudes in three aspects of life.Methods: The subjects were 311 Japanese volunteers. Core beliefs of negative-self and positive-self were evaluated by the corresponding subscales of the Brief Core Schema Scales. Dysfunctional attitudes in the areas of achievement, dependency and self-control were measured by the corresponding subscales of the 24-item Dysfunctional Attitude Scale.Results: The negative-self subscale was correlated with the achievement, dependency and self-control subscales. The positive-self subscale was correlated with the achievement and self-control subscales.Conclusion: The present study suggests that negative core beliefs about the self underlie all types of dysfunctional attitudes, while positive core beliefs about the self have some connections with dysfunctional attitudes related to achievement and self-control. Keywords: negative-self, achievement, dependency, self-control, depression

Nana Takahashi, Akihito Suzuki, Yoshihiko Matsumoto, Toshinori Shirata, Koichi Otani Department of Psychiatry, Yamagata University School of Medicine, Yamagata, Japan Objective: Depressed patients are prone to perceive that they were exposed to affectionless control by parents. Meanwhile, high neuroticism is a well-established risk factor for developing depression. Therefore, this study examined whether perceived parental affectionless control is associated with high neuroticism.Methods: The subjects were 664 healthy Japanese volunteers. Perceived parental care and protection were assessed by the Parental Bonding Instrument. Parental rearing was categorized into either optimal parenting (high care/low protection) or three dysfunctional parenting styles including affectionless control (low care/high protection). Neuroticism was evaluated by the NEO Personality Inventory-Revised.Results: The subjects with paternal affectionless control had higher neuroticism scores than those with paternal optimal parenting. Similar tendency was observed in maternal rearing. Neuroticism scores increased in a stepwise manner with respect to the increase in the number of parents with affectionless control.Conclusion: The present study shows that perceived parental affectionless control is associated with high neuroticism, suggesting that this parental style increases neuroticism in recipients. Keywords: parenting, attachment, personality, vulnerability, depression, PBI, NEO PI-R

Hiroki Karata,1 Tomonori Tanaka,1 Ryoko Egashira,2 Kazuhiro Tabata,1 Kyoko Otani,3 Ryuji Hayashi,4 Takashi Hori,5 Junya Fukuoka1 1Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; 2Department of Radiology, Faculty of Medicine, Saga University, Saga, Japan; 3Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan; 4Department of Internal Medicine, University of Toyama, Faculty of Medicine, Toyama, Japan; 5Laboratory of Pathology, Toyama University Hospital, Toyama, Japan Abstract: We report an educational autopsy case of combined pulmonary fibrosis and emphysema. Radiological patterns of the upper lung were considered as mostly emphysema, but pathological observation revealed significant interstitial fibrosis of usual interstitial pneumonia as a major pathology. The patient eventually developed acute exacerbation of background interstitial pneumonia. Careful radiological and pathological correlation of the current case indicates that regions with distal acinar emphysema on computed tomography image may possess histologically marked dense fibrosis of lethal interstitial pneumonia. Keywords: interstitial pneumonia, CPFE, AEF, smoking, CT

Kei Kohno,1 Hiroto Narimatsu,2 Katsumi Otani,2 Ri Sho,2 Yosuke Shiono,1 Ikuko Suzuki,1 Yuichi Kato,1 Akira Fukao,2 Takeo Kato,1 1Department of Neurology, Hematology, Metabolism, Endocrinology, and Diabetology, Yamagata University School of Medicine, 2Department of Public Health, Yamagata University Graduate School of Medicine, Yamagata, Japan Abstract: “Spatial statistics” is an academic field that deals with the statistical analysis of spatial data, and has been applied to econometrics and various other policy fields. These methods are easily applied by hematologists and oncologists using better and much less expensive software. To encourage physicians to use these methods, this review introduces the methods and demonstrates the analyses using R and FleXScan, which can be freely downloaded from the website, with sample data. It is demonstrated that spatial analysis can be used by physicians to analyze hematological diseases. In addition, applying the technique presented to the investigation of patient prognoses may enable generation of data that are also useful for solving health policy-related problems, such as the optimal distribution of medical resources. Keywords: leukemia, malignant lymphoma, Tango's index, spatial regression model

Radiotherapy (RT) +/- androgen deprivation therapy (ADT) plays a key role in salvage therapy of prostate cancer (PC) recurrent after radical prostatectomy. However, not all patients benefit, and there is an unmet need for biomarkers to distinguish responders from non-responders (defined as those with second biochemical failure after salvage). We hypothesized that somatic mutations in primary PC are correlated with response to salvage RT+ADT. We retrospectively identified 718 consecutive PC patients treated with post-operative RT at a single institution from 1992-2013, of whom 40 were treated with salvage RT+ADT and had formalin-fixed, paraffin-embedded prostatectomy and matched normal tissues available for DNA extraction. The indication for salvage therapy was biochemical failure after an undetectable post-operative PSA in 72%, gross local recurrence in 17%, and persistently elevated PSA after surgery in 11%. Median RT dose was 64.8 Gy, and all patients received concurrent ADT. Whole exome sequencing (WES) was performed to an average depth of 162X (r, 70.7-219). We tested for association between somatic mutations and clinical outcomes using the log-rank test and Cox proportional hazards model. Median age at salvage was 64.5 yrs. High quality WES data was available in 31 patients. With a median follow-up of 122 months (range = 29-248), 16 experienced second biochemical failure after salvage while 15 did not. Median time to second biochemical failure was 82.3 months (range = 1.2-140). Overall tumor mutational burden (TMB) was 3.3 mutations/Mb (range = 1.4-12.9). TMB among those with second biochemical failure was 3.8 vs. 2.8 among those without (p = 0.22). The most common mutations detected in the overall cohort were ALEC (n = 6) and CUX1 (n = 5). The presence of mutations in BRCA2, CASZ1, SYNE1 , and AFDN was significantly correlated with second biochemical failure after salvage RT+ADT (see Table 1). Local failure after salvage occurred in 3 patients and was correlated with AFDN mutation (p = 0.0002). In contrast, none of the patients with mutations in WIZ (n = 4) or FOXA1 (n = 3) , experienced second biochemical failure during follow-up. Using WES analysis, we found that mutations in BRCA2, CASZ1, SYNE1 , and AFDN correlated with second biochemical failure after salvage therapy with RT+ADT. These findings require validation in larger cohorts, but suggest that somatic mutations could potentially serve as predictive biomarkers for post-prostatectomy salvage therapy. [ABSTRACT FROM AUTHOR]