A Multicenter Prospective Interventional Trial of Therapeutic Angiogenesis Using Bone Marrow-Derived Mononuclear Cell Implantation for Patients With Critical Limb-Threatening Ischemia Caused by Thromboangiitis Obliterans.

BACKGROUND: Thromboangiitis obliterans (TAO) can lead to the development of critical limb-threatening ischemia (CLTI). Despite conventional treatments, such as smoking cessation or revascularization, young patients (<50 years) still require limb amputation. Therapeutic angiogenesis using bone marrow-derived mononuclear cell (BM-MNC) implantation has been tested and shown to have reasonable efficacy in CLTI. In this multicenter prospective clinical trial, we evaluated the safety and efficacy of BM-MNC implantation in CLTI patients with TAO.Methods and Results: We enrolled 22 CLTI patients with skin perfusion pressure (SPP) <30 mmHg. The primary endpoint of this trial is the recovery of SPP in the treated limb after a 180-day follow-up period. Secondary endpoints include the pain scale score and transcutaneous oxygen pressure (TcPO2). One patient dropped out during follow-up, leaving 21 patients (mean age 48 years, 90.5% male, Fontaine Class IV) for analysis. BM-MNC implantation caused no serious adverse events and increased SPP by 1.5-fold compared with baseline. Surprisingly, this effect was sustained over the longer term at 180 days. Secondary endpoints also supported the efficacy of this novel therapy in relieving pain and increasing TcPO2. Major amputation-free and overall survival probabilities at 3 years among all enrolled patients were high (95.5% and 89.5%, respectively). CONCLUSIONS: BM-MNC implantation showed safety and significant efficacy in CLTI patients with TAO.

Classification and regression tree for estimating predictive markers to detect T790M mutations after acquired resistance to first line EGFR-TKI: HOPE-002.

BACKGROUND AND OBJECTIVE: Osimertinib as first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor (EGFR) mutations remains controversial. Sequential EGFR-tyrosine kinase inhibitor (TKI) might be superior to the first line osimertinib in patients at risk of developing acquired T790M mutations. METHODS: We enrolled consecutive patients with EGFR-mutated (deletion 19 or L858R) advanced NSCLC treated with first-line drugs and evaluated predictive markers using classification and regression tree (CART) for the detection of T790M mutations based on patient backgrounds prior to initial treatment. RESULTS: Patients without acquired T790M mutations had worse outcomes than those with T790M mutations (median OS: 798 days vs. not reached; HR: 2.70; P < 0.001). CART identified three distinct groups based on variables associated with acquired T790M mutations (age, CYF, WBC, liver metastasis, and LDH; AUROC: 0.77). Based on certain variables, CART identified three distinct groups in deletion 19 (albumin, LDH, bone metastasis, pleural effusion, and WBC; AUROC: 0.81) and two distinct groups in L858R (age, CEA, and ALP; AUROC: 0.80). The T790M detection frequencies after TKI resistance of afatinib and first-generation EGFR-TKIs were similar (35.3% vs. 37.4%, P = 0.933). Afatinib demonstrated longer PFS (398 vs. 279 days; HR: 0.67; P = 0.004) and OS (1053 vs. 956 days; HR: 0.68; P = 0.051) than first-generation EGFR-TKIs. CONCLUSION: Identification of patients at risk of acquiring T790M mutations after EGFR-TKI failure may aid in choice of first-line EGFR-TKI. Furthermore, afatinib may be the more effective 1st-line EGFR-TKI treatment for patients at risk of developing T790M as initial EGFR-TKI resistance.

Regulatory issues and the potential use of Bayesian approaches for early drug approval systems in Japan.

Bayesian methods quantify and interpret the therapeutic effects of investigational drugs based on probability statements of the posterior distribution. However, the basic principle underlying the use of Bayesian methods in registration trials for new drug applications in Japan has not been adequately discussed. Motivated by the two drug approval systems for early approval recently enacted in Japan, we present our perspectives on the application of the Bayesian approach in registration trials in Japan. These are based on discussions among academic, industry, and regulatory experts at invited workshops. Based on the aforementioned early approval systems, we discuss putative common regulatory issues related to the use of the Bayesian approach and introduce instances of clinical trials in which the Bayesian approach is expected to be used. This article provides a well-defined premise for the discussion between industry and regulatory agencies on the use of Bayesian approaches for early drug approval in Japan.

Protocol for an interventional study to reduce postpartum weight retention in obese mothers using the internet of things and a mobile application: a randomized controlled trial (SpringMom).

BACKGROUND: Obese pregnant women are known to experience poorer pregnancy outcomes and are at higher risk of postnatal arteriosclerosis. Hence, weight control during and after pregnancy is important for reducing these risks. The objective of our planned randomized controlled trial is to evaluate whether the rate of change in body weight in obese women before pregnancy to 12 months postpartum would be lower with the use of an intervention consisting of Internet of Things (IoT) devices and mobile applications during pregnancy to 1 year postpartum compared to a non-intervention group. METHODS: Women will be recruited during outpatient maternity checkups at four perinatal care institutions in Japan. We will recruit women at less than 30 weeks of gestation with a pre-pregnancy body mass index ≥ 25 kg/m2. The women will be randomly assigned to an intervention or non-intervention group. The intervention will involve using data (weight, body composition, activity, sleep) measured with IoT devices (weight and body composition monitor, activity, and sleep tracker), meal records, and photographs acquired using a mobile application to automatically generate advice, alongside the use of a mobile application to provide articles and videos related to obesity and pregnancy. The primary outcome will be the ratio of change in body weight (%) from pre-pregnancy to 12 months postpartum compared to before pregnancy. DISCUSSION: This study will examine whether behavioral changes occurring during pregnancy, a period that provides a good opportunity to reexamine one's habits, lead to lifestyle improvements during the busy postpartum period. We aim to determine whether a lifestyle intervention that is initiated during pregnancy can suppress weight gain during pregnancy and encourage weight loss after delivery. TRIAL REGISTRATION: UMIN: UMIN (University hospital Medical Information Network) 000,041,460. Resisted on 18th August 2020. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000047278.

Congenital malformation and hemoglobin A1c in the first trimester among Japanese women with pregestational diabetes.

AIM: To investigate the incidence of major congenital malformations in Japanese women with pregestational diabetes, and to determine the cutoff value of hemoglobin A1c (HbA1c) in the first trimester associated with congenital malformations. METHODS: This retrospective cohort study included singleton pregnancies in Japanese women with pregestational diabetes, including type 1 and type 2 diabetes, and specific types of diabetes due to other causes. The primary outcome was the incidence of major congenital malformations. The secondary outcome was the incidence of all congenital malformations. The cutoff value of HbA1c for congenital malformations was calculated using receiver operating characteristic curve analysis. The adjusted odds ratios (aOR) of major congenital malformations were calculated using multiple logistic regression analyses. RESULTS: This study enrolled 292 patients, including 132 (45.2%) with type 1 diabetes, 156 (53.4%) with type 2 diabetes, and 4 (1.4%) with other specific types. The incidence rates of major congenital malformations and all congenital malformations were 7.2% (21/292) and 12.7% (37/292), respectively. The cutoff value of HbA1c in the first trimester for major malformations and for all congenital malformations was 6.5%. HbA1c ≥ 6.5% was significantly associated with major malformations (aOR 3.5; 95% confidence interval: 1.2-12.6; p = 0.018). CONCLUSION: The incidence of major congenital malformations significantly increased in pregnant Japanese women with HbA1c values of 6.5% or higher. The recommended HbA1c value during the first trimester used in other countries can be applied to pregnant Japanese women.

Prediction models for the viability of pulmonary metastatic lesions after chemotherapy in nonseminomatous germ cell tumors.

OBJECTIVES: To analyze predictors associated with viable cells in pulmonary residual lesions after chemotherapy for metastatic testicular nonseminomatous germ cell tumors and to develop models to prioritize pulmonary resection. METHODS: Between 2008 and 2017, 40 patients underwent pulmonary metastasectomy after chemotherapy for nonseminomatous germ cell tumors. We evaluated these patients, and 326 pulmonary residual lesions were confirmed using computed tomography and pathological evaluations. Relationships with outcomes were analyzed using logistic regression analyses. Risk prediction models were developed, and predictive probabilities for the risk of viable cells were estimated. RESULTS: Histological examinations showed that 73 (22%) pulmonary residual lesions contained viable cells: teratomas, 46 (14%); and cancer cells, 37 (11%). Multivariate analyses showed that the predictors associated with cancer cells in the residual lesions were elevated tumor marker levels, multiregimen chemotherapy, increased tumor size 6 months before surgery and the histological composition of the primary lesion, including yolk sac tumors. Additional predictors associated with teratomas were aspect ratio and histological composition of the primary lesion, including teratomas. CONCLUSIONS: Intratumoral heterogeneity contributes to nonseminomatous germ cell tumor chemoresistance, and primary lesion site yolk sac tumors and teratomas are associated with greater risks of viable cells. Increased residual lesion size during chemotherapy could also be a predictor. Our simple model can predict the presence of viable cells in residual lesions after chemotherapy, and it might assist in decision-making and prioritizing pulmonary residual lesion resection.

A Bayesian basket trial design that borrows information across strata based on the similarity between the posterior distributions of the response probability.

Basket trials simultaneously evaluate the effect of one or more drugs on a defined biomarker, genetic alteration, or molecular target in a variety of disease subtypes, often called strata. A conventional approach for analyzing such trials is an independent analysis of each of the strata. This analysis is inefficient as it lacks the power to detect the effect of drugs in each stratum. To address these issues, various designs for basket trials have been proposed, centering on designs using Bayesian hierarchical models. In this article, we propose a novel Bayesian basket trial design that incorporates predictive sample size determination, early termination for inefficacy and efficacy, and the borrowing of information across strata. The borrowing of information is based on the similarity between the posterior distributions of the response probability. In general, Bayesian hierarchical models have many distributional assumptions along with multiple parameters. By contrast, our method has prior distributions for response probability and two parameters for similarity of distributions. The proposed design is easier to implement and less computationally demanding than other Bayesian basket designs. Through a simulation with various scenarios, our proposed design is compared with other designs including one that does not borrow information and one that uses a Bayesian hierarchical model.

Changing profile of eating disorders between 1963 and 2004 in a Japanese sample.

OBJECTIVE: The purpose of this study was to investigate possible changes in the demographic and clinical characteristics of Japanese patients with eating disorders using a consecutive series of patients who presented at Kyoto University Hospital between 1963 and 2004. We also studied cultural factors related to eating disorders over time. METHOD: We completed a retrospective review of a cohort of patients using a checklist based on the DSM-5 diagnostic criteria. Patients seen from 1963 to 1974 (Period I, n = 26), 1975 to 1984 (Period II, n = 97), 1985 to 1994 (Period III, n = 540), and 1995 to 2004 (Period IV, n = 700) were compared. RESULTS: In this study, patients with restrictive eating appeared in the early 1960s. Patients with binge eating and purging behaviors appeared in the mid-1970s and thereafter increased over time. The number of patients with anorexia nervosa and bulimia nervosa dramatically increased in Period III. The proportion of patients with binge eating increased, while the proportion of patients with restrictive eating decreased over time. All patients with anorexia nervosa in the 1960s had fat phobia and disturbed body image, but none of them reported dieting for slimness. DISCUSSION: The prevalence and clinical characteristics of patients with eating disorders significantly changed across the four time periods. In terms of cultural factors, present findings suggest that factors beyond industrialization, modernization and westernization may be necessary for the development of eating disorders, and these factors may change with the times.

The impact of DSM-5 on the diagnosis and severity indicator of eating disorders in a treatment-seeking sample.

OBJECTIVE: To examine the impact of the DSM-5 on the diagnoses and severity indicators of eating disorders, we conducted a comparative study on the classification of eating disorders including subtypes of anorexia nervosa (AN) between the DSM-IV and DSM-5 criteria. In addition, we studied the association of the DSM-5 severity criteria and clinical variables. METHOD: Participants were 304 outpatients, aged 16-45 years, with eating disorders, diagnosed using semi-structured clinical interviews and the eating disorder examination questionnaire (EDE-Q). The severity of AN, bulimia nervosa (BN), and binge-eating disorder (BED) was rated from mild to extreme using the DSM-5 severity criteria. RESULTS: The DSM-5 remarkably reduced the number of diagnoses in the residual category from 37.5% to 9.2% and effectively differentiated the diagnostic groups in eating disorder psychopathology. Unexpectedly, however, the scores of all the EDE-Q subscales significantly decreased as severity ratings increased in the DSM-5 AN. Furthermore, while the AN binge-eating/purging group reported significantly lower severity ratings than the AN restricting group, the former displayed more severe eating disorder psychopathology than the latter. In the BN and BED groups, the level of eating concern increased as severity ratings increased, but the severity groups did not differ on other eating pathology variables. DISCUSSION: The DSM-5 effectively reduced the reliance on residual categories and differentiated the diagnostic groups in eating disorder psychopathology. However, our findings show limited support for the DSM-5 severity specifiers for eating disorders. It is necessary to test additional clinical or functional variables for severity specifiers across eating disorders.

D-Dimer Trends Predict Recurrent Stroke in Patients with Cancer-Related Hypercoagulability.

INTRODUCTION: In patients with cancer-associated hypercoagulability (CAH)-related stroke, D-dimer trends after anticoagulant therapy may offer a biomarker of treatment efficacy. The purpose of this study was to clarify the association between D-dimer trends and recurrent stroke after anticoagulant therapy in patients with CAH-related stroke. METHODS: We performed retrospective cohort study of consecutive patients with CAH-related stroke at two stroke centers from 2011 to 2020. The ratio of posttreatment to pretreatment D-dimer levels (post/pre ratio) was used as an indicator of D-dimer trends after anticoagulant therapy. Fine-Gray models were used to evaluate the association between post/pre ratio and recurrent stroke. RESULTS: Among 360 acute ischemic stroke patients with active cancer, 73 patients with CAH-related stroke were included in this study. Recurrent stroke occurred in 13 patients (18%) during a median follow-up time of 28 days (interquartile range, 11-65 days). Multivariate analysis revealed that high post/pre ratio was independently associated with recurrent stroke (per 0.1 increase: hazard ratio 2.20, 95% confidence interval 1.61-3.01, p = 0.012). CONCLUSION: D-dimer levels after anticoagulant therapy were associated with recurrent stroke in CAH-related stroke patients. Patients with neutral trends in high D-dimer levels after anticoagulant therapy were at high risk of recurrent stroke.

Particle beam therapy versus photon radiotherapy for extrahepatic biliary cancer-systemic review and meta-analysis.

Particle beam therapy (PT) is a potentially promising approach to the treatment of extrahepatic biliary cancer (EBC) because of its unique dose distribution using the Bragg peak. However, the superiority of PT to photon radiotherapy (XT) remains unclear. Therefore, we conducted a systematic review and meta-analysis to compare PT and XT for the treatment of EBC. The primary endpoint was overall survival (OS), which was pooled using a random-effects model. Nine articles comprising a total of 1558 patients (seven XT articles, n = 1488 patients; two PT articles, n = 70 patients) were screened. In addition, we compared the outcomes of XT and PT with the outcomes available from a prospective data registry (proton-net). The 1-year OS probability rates were 55, 65 and 72% for the XT group, PT group and PT registry, respectively. The 2-year OS probability rates were 26, 38 and 38% for the XT group, PT group and PT registry, respectively. The 3-year OS probability rates were 12, 35 and 18% for the XT group, PT group and PT registry, respectively. Although the difference between the 1-year OS rates of the XT group and PT registry was statistically significant, no other significant superiority was observed among these groups. In conclusion, the efficacy of PT was not superior to that of XT during this meta-analysis.

Standard versus low-dose nab-paclitaxel in previously treated patients with advanced non-small cell lung cancer: A randomized phase II trial (JMTO LC14-01).

BACKGROUND: Nab-paclitaxel (nab-PTX) has better transfer to tumor tissue than cremophor-based paclitaxel. It suggests that the optimum dose of nab-PTX might be lower than the dose and schedule that is widely used. We designed a randomized phase II trial to examine the clinical utility and safety of nab-PTX in patients with previously treated advanced non-small cell lung cancer (NSCLC). METHODS: Patients were randomly allocated (1:1) to receive nab-PTX monotherapy at 100 mg/m2 (group A) or 70 mg/m2 (group B). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Finally, 81 patients were randomized. Similar results were observed in both groups for PFS (3.75 vs. 3.71 months), OS (13.50 vs. 16.13 months), or ORR (20.5% vs. 23.1%). The incidences of grade 3 or worse AEs were 57.5% in group A and 41.5% in group B. The proportion of serious side effects was 10.0% in group A and 4.9% in group B. CONCLUSION: Both standard dose and low dose of nab-PTX monotherapy are active for previously treated NSCLC patients with better safety profile. Therefore, nab-PTX 70 mg/m2 dose and schedule in the trial would be a reasonable option.

Comprehensive analysis of Japanese nationwide cohort data of particle beam therapy for pulmonary, liver and lymph node oligometastases: particle beam therapy versus high-precision X-ray radiotherapy.

Japanese national oncological experts convened to evaluate the efficacy and safety of particle beam therapy (PT) for pulmonary, liver and lymph node oligometastases (P-OM, L-OM and LN-OM, respectively) and to conduct a statistically comparative analysis of the local control (LC) rate and overall survival (OS) rate of PT versus those of X-ray stereotactic body radiotherapy (X-SBRT) and X-ray intensity-modulated radiotherapy (X-IMRT). They conducted [1] an analysis of the efficacy and safety of metastasis-directed therapy with PT for P-OM, L-OM and LN-OM using a Japanese nationwide multi-institutional cohort study data set; [2] a systematic review of X-ray high-precision radiotherapy (i.e. X-SBRT/X-IMRT) and PT for P-OM, L-OM and LN-OM; and [3] a statistical comparison between LC and OS of the cohort data set in PT and that of the extracted historical data set in X-SBRT/X-IMRT from the preceding systematic review. Safety was evaluated as the incidence of grade ≥ 3 adverse events, while statistical comparisons of LC and OS were conducted by estimating the incidence rate ratios (IRR) for local progression and mortality, respectively. This study demonstrated that PT provided durable LC (3-year LC rate: 72.8-83.2%) with acceptable OS (3-year OS rate: 38.5-68.1%) and risk of severe toxicity incidence of 0.8-3.5% in radical metastasis-directed therapy for P-OM, L-OM and LN-OM. Compared to LC with X-SBRT or X-IMRT, LC with PT was potentially superior for P-OM; superior for L-OM; and equivalent for LN-OM. In particular, this study demonstrated that PT may be a new treatment option for L-OM tumors measuring > 5 cm.

The influence of venous system patterns on DIEP flap viability for breast reconstruction.

A deep inferior epigastric artery perforator (DIEP) flap has unique variations in the anatomy of the vascular supply, and this idea has been adapted to the venous system. Venous system patterns, including connections between the superficial and deep inferior epigastric vein (SDC) or connections of the superficial inferior epigastric vein across the midline-crossing linking veins (MCLV), have gradually become recognized as a cause of fat necrosis and induration due to venous congestion. Therefore, it is important to select patients who are appropriate for transplantation by evaluating blood flow in the flap based on these patterns. The subjects were 52 consecutive patients who underwent DIEP flap breast reconstruction. Relationships of fat necrosis and induration of a transplanted flap and venous system patterns (presence of SDC on the contralateral side: cSDC or MCLV, direction and diameter of perforator vein) in the flap were investigated. Logistic regression and univariate and multivariate analyses were used to identify predictors of fat necrosis and induration of the flap. Fat necrosis and induration were detected in 17.4 and 34.8% of cases, respectively. These incidences were significantly linked to the absence of cSDC and MCLV patterns in the flap. Patients without a cSDC or MCLV pattern had harder fat tissue in Zone II, especially in the distal portion. These results suggest that the absence of a cSDC or MCLV pattern causes complications such as fat necrosis and induration in a transplanted flap. If neither pattern is detected before surgery, improvement of venous drainage is recommended.

A Raman algorithm to estimate human age from protein structural variations in autopsy skin samples: a protein biological clock.

The recent increase of the number of unidentified cadavers has become a serious problem throughout the world. As a simple and objective method for age estimation, we attempted to utilize Raman spectrometry for forensic identification. Raman spectroscopy is an optical-based vibrational spectroscopic technique that provides detailed information regarding a sample's molecular composition and structures. Building upon our previous proof-of-concept study, we measured the Raman spectra of abdominal skin samples from 132 autopsy cases and the protein-folding intensity ratio, RPF, defined as the ratio between the Raman signals from a random coil an α-helix. There was a strong negative correlation between age and RPF with a Pearson correlation coefficient of r = 0.878. Four models, based on linear (RPF), squared (RPF2), sex, and RPF by sex interaction terms, were examined. The results of cross validation suggested that the second model including linear and squared terms was the best model with the lowest root mean squared error (11.3 years of age) and the highest coefficient of determination (0.743). Our results indicate that the there was a high correlation between the age and RPF and the Raman biological clock of protein folding can be used as a simple and objective forensic age estimation method for unidentified cadavers.

Effect of Empagliflozin as an Add-On Therapy on Decongestion and Renal Function in Patients With Diabetes Hospitalized for Acute Decompensated Heart Failure: A Prospective Randomized Controlled Study.

BACKGROUND: Empagliflozin reduces the risk of hospitalization for heart failure in patients with type 2 diabetes and cardiovascular disease. We sought to elucidate the effect of empagliflozin as an add-on therapy on decongestion and renal function in patients with type 2 diabetes admitted for acute decompensated heart failure. METHODS: The study was terminated early due to COVID-19 pandemic. We enrolled 59 consecutive patients with type 2 diabetes admitted for acute decompensated heart failure. Patients were randomly assigned to receive either empagliflozin add-on (n=30) or conventional glucose-lowering therapy (n=29). We performed laboratory tests at baseline and 1, 2, 3, and 7 days after randomization. Percent change in plasma volume between admission and subsequent time points was calculated using the Strauss formula. RESULTS: There were no significant baseline differences in left ventricular ejection fraction and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide), hematocrit, or serum creatinine levels between the 2 groups. Seven days after randomization, NT-proBNP level was significantly lower in the empagliflozin group than in the conventional group (P=0.040), and hemoconcentration (≥3% absolute increase in hematocrit) was more frequently observed in the empagliflozin group than in the conventional group (P=0.020). The decrease in percent change in plasma volume between baseline and subsequent time points was significantly larger in the empagliflozin group than in the conventional group 7 days after randomization (P=0.017). The incidence of worsening renal function (an increase in serum creatinine ≥0.3 mg/dL) did not significantly differ between the 2 groups. CONCLUSIONS: In this exploratory analysis, empagliflozin achieved effective decongestion without an increased risk of worsening renal function as an add-on therapy in patients with type 2 diabetes with acute decompensated heart failure. Registration: URL: https://www.umin.ac.jp/ctr/index.htm; Unique identifier: UMIN000026315.

Factors associated with chronic pain following breast reconstruction in Japanese women.

Chronic pain after breast surgery including breast reconstruction is a major concern for patients. However, the factors associated with chronic pain after breast surgery are uncertain in Japanese population. The aim of this study was to identify patient-specific and medical/surgical factors that predict chronic pain after breast surgery in Japanese patients. The subjects were 189 Japanese women undergoing breast surgery including tissue expander/implant (TE/implant), deep inferior epigastric perforator (DIEP) procedures and mastectomy only. Pain was assessed at one year postoperatively using a validated survey instrument: the Japanese version of the Short-Form McGill Pain Questionnaire (SF-MPQ-JV). A multiple linear regression model was used to examine the relationships of clinical factors with postoperative pain. Surveys were completed by 141 subjects. A younger age (p = .04) and bilateral procedures (p < .05) were both closely associated with the extent of increased postoperative pain at 1 year using the MPQ-Total pain rating. Compared to total mastectomy only, TE/implant procedures showed a significantly lower visual analog scale (VAS) (p = .04) and present pain index (PPI) (p = .03) scores. No factor related to chronic pain was also significantly related to the frequency of pain medication use postoperatively or the effect of social life of the patients. This study identified patients at risk for greater chronic pain after breast surgery. These findings will allow surgeons to improve patient comfort, reduce clinical morbidity and enhance patient satisfaction with their surgical outcome. Abbreviations: BMI: body mass index; CI: confidence interval; DIEP: deep inferior epigastric perforator flap; MPQ: McGill pain questionnaire; PPI: present pain index; SD: standard deviation; SF-MPQ-JV: Japanese version of the short-form McGill pain questionnaire; TE: tissue expander; VAS: visual analog scale.

Objective evaluation of fat tissue induration after breast reconstruction using a deep inferior epigastric perforator (DIEP) flap.

Problems in breast reconstruction with deep inferior epigastric perforator (DIEP) flaps include postoperative fat induration and necrosis. A resulting clinical symptom is palpable indurated tissue, but it is difficult to measure the stiffness of transplanted fat tissues objectively at a deep site. The ability to perform shear-wave elastography (SWE) was recently added to some common ultrasonic echo devices, enabling objective three-dimensional measurements of tissue stiffness. In this study, we measured the stiffness of transplanted DIEP flaps using SWE to examine the effects of measurement sites, flap size and perforator patterns on stiffness. The subjects were 26 patients who showed induration of a transplanted flap on palpation in follow-up observation performed more than 6 months after breast reconstruction with a DIEP flap. The effects of the weight of the transplanted flap, and the diameter, number and location of the perforators on the stiffness of fat tissue were also analyzed. Within each zone, distal regions showed higher values, but in Zone II, significantly higher stiffness was also found in the proximal region. Multivariate regression analysis including all measurement sites, the weight of transplanted flap, and diameter, number and location of perforators showed that the stiffness of fat tissue was significantly higher in subjects with a larger weight flap. For safe reconstruction, it will be useful to examine the stiffness of fat tissue in individual regions of a transplanted flap retrospectively, because the examination results can be used in actual clinical practice.

Efficacy of denosumab for restoring normal bone mineral density in women receiving adjuvant aromatase inhibitors for early breast cancer.

BACKGROUND: Osteoporosis is a major side effect of aromatase inhibitors (AIs), which are greatly effective in the treatment of breast cancer. However, there are no satisfactory measures against osteoporosis. In this multicenter, randomized, comparative study, we evaluate the efficacy of denosumab for preventing loss of bone mineral density (BMD) induced by adjuvant therapy with AI s in breast cancer patients with normal BMD. PATIENTS AND METHODS: The bone loss-suppressing effect of denosumab will be comparatively evaluated in postmenopausal patients scheduled to receive letrozole or anastrozole as a postoperative endocrine therapy for stage I-IIIA hormone-sensitive breast cancer and a control group. Patients will be administered letrozole 2.5 mg or anastrozole 1 mg once a day, and the treatment will be continued for 5 years unless recurrence, secondary cancer, or unacceptable toxicity develops. Patients in the denosumab group will receive a subcutaneous injection of 60 mg of denosumab every 6 months. The primary endpoint is the rate of change in the lumbar spine (L1-L4) BMD, as determined by dual-energy X-ray absorptiometry (DXA), 12 months after the start of the injection. The secondary endpoints were ETHICS AND DISSEMINATION:: The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating faculties. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. TRIAL REGISTRATION: Clinical Trials.gov Identifier: NCT03324932, Japan Registry of Clinical Trial (jRCT): CRB5180001.