Feasibility and impact of extra-vascular ultrasound-guided endovascular treatment for infrapopliteal artery occlusive disease.

PURPOSE: This study aimed to examine the feasibility and impact of extra-vascular ultrasound (EVUS)-guided intervention for infrapopliteal (IP) artery occlusive disease. MATERIALS AND METHODS: A retrospective analysis was performed using data collected from patients who underwent endovascular treatment (EVT) for IP artery occlusive disease between January 2018 and December 2020 at our institution. A total of 63 consecutive de novoocclusive lesions were compared according to the recanalization method utilized. Propensity score matching analysis was performed to compare the clinical outcomes of the methods utilized. The prognostic value was analyzed based on the technical success rate, distal puncture rate, radiation exposure, amount of contrast media, postprocedural skin perfusion pressure (SPP), and procedural complication rate. RESULTS: Eighteen matched pairs of patients were analyzed using propensity score-matched analysis. Radiation exposure was significantly lower in the EVUS-guided group than in the angio-guided group, with 135 and 287 mGy (p = 0.04) exposure on average, respectively. There were no significant differences between the two groups in terms of technical success rate, distal puncture rate, the amount of contrast media, postprocedural SPP, and procedural complication rate. CONCLUSION: EVUS-guided EVT for IP occlusive disease achieved a feasible technical success rate and significantly reduced radiation exposure.

Management system of home transfusion in Japan: A nationwide survey in 2019.

BACKGROUND AND OBJECTIVES: In Japan, there are various opinions on the pros and cons of home transfusion because of safety concerns. We hence aimed to elucidate the safety and availability of home transfusion in Japan, which has not been clarified to date. MATERIALS AND METHODS: Clinics throughout Japan that provide home care and have experience in performing blood transfusions were surveyed. The analysis period was February to December 2019. Basic information about the clinics, their collaboration system with core hospitals, storage method of red blood cells (RBCs) and the system for the management of patient information regarding transfusion reactions were investigated. RESULTS: Detailed information was obtained regarding the implementation of home transfusions by 51 clinics. The proportion of home care clinics performing home transfusions was 17.6%, and they were more frequently performed in urban regions. Approximately half of the clinics collaborated with a core hospital for emergency responses to transfusion reactions. At 84% of the clinics, RBC units were stored in refrigerators that were not exclusively allocated to blood storage. Nurses and family members were involved as patient attendants in 83% and 77% of the home transfusions, respectively. No serious transfusion reactions were reported among the 150 patients in 2019, nor the 623 patients up to 2018. CONCLUSION: From data on its availability and safety, home transfusions are considered to be in the developing phase in Japan. Increased cooperation between hospitals and clinics is crucial towards improving the home transfusion system in Japan in the future.

Home transfusions are implemented using diverse approaches in Japan.

BACKGROUND AND OBJECTIVES: Japan's ageing society has increased the need for home healthcare, including home transfusions. We hence aimed to elucidate the purpose and utilization of home transfusions in Japan, which has not been clarified to date. MATERIALS AND METHODS: Clinics throughout Japan that provide home care and have experience in performing blood transfusions were surveyed. The study period was February to December 2019, and information of patients receiving home red blood cell transfusions, including patient background, pre-transfusion laboratory data and the purpose of the transfusions, was collected. RESULTS: Haematological malignancies and solid tumours accounted for 70% of the patients' underlying diseases, with the former being significantly more common in urban areas. Regarding the purpose of the home transfusions, haematologists focused on symptom improvement, whereas gastroenterology surgeons focused on life support. Furthermore, maintenance of life was more likely to be the aim in the group of patients with the lowest level of activities of daily living. The main items that were significantly associated with a low haemoglobin level before transfusion included age ≥90 years and a gastroenterologist being the physician in charge. CONCLUSION: Home transfusions were found to be performed in a restrictive and diverse manner in Japan. Life support is the second most common purpose of home transfusion in Japan, and optimizing effective home transfusion remains a challenge.

Development of an ultralow-latency communication system using shared internet access: promoting the implementation of telemedicine.

Telemedicine is becoming increasingly important to address the shortage of gastrointestinal surgeons and disparities in domestic and international treatment outcomes for patients with colorectal cancer. The development of a low-latency communication system using existing communication infrastructure (shared internet access: SIA) is necessary to promote the use of telemedicine. The aim of this study was to develop a low-latency communication system using SIA. We conducted an experiment between Sapporo and Tokyo using an ultralow-latency communication system for remote medical education (TELEPRO®). The latency was measured using 2000 annotations from a monitor in Sapporo, which confirmed a median latency of 27.5 ms. A low-latency communication system based on SIA with latency lower than the maximum allowable latency for telemedicine was developed successfully.

Effect of proximal optimization technique on coronary bifurcation stent failure: Insights from the multicenter randomized PROPOT trial.

OBJECTIVE: We investigated the effect of proximal optimization technique (POT) on coronary bifurcation stent failure (BSF) in cross-over stenting by comparing with the kissing balloon technique (KBT) in a multicenter randomized PROPOT trial. BACKGROUND: POT is recommended due to increased certainty for optimal stent expansion and side branch (SB) wiring. METHODS: We randomized 120 patients treated with crossover stenting into the POT group, which was followed by SB dilation (SBD), and the KBT group. Finally, 52 and 57 patients were analyzed by optical coherence tomography before SBD and at the final procedure, respectively. Composite BSF was defined as a maximal malapposition distance of >400 µm, or malapposed and SB-jailed strut rates of >5.95% and >21.4%, respectively. RESULTS: Composite BSF before SBD in the POT and KBT groups was observed in 29% and 26% of patients, respectively. In the POT group, differences in stent volumetric index between the proximal and distal bifurcation (odds ratio [OR] 60.35, 95% confidential interval [CI] 0.13-0.93, p = 0.036) and between the proximal bifurcation and bifurcation core (OR: 3.68, 95% CI: 1.01-13.40, p = 0.048) were identified as independent risk factors. Composite BSF at final in 27% and 32%, and unplanned additional procedures in 38% and 25% were observed, respectively. Composite BSF before SBD was a risk factor for the former (OR: 6.33, 95% CI: 1.10-36.50, p = 0.039) and the latter (OR: 6.43, 95% CI: 1.25-33.10, p = 0.026) in the POT group. CONCLUSION: POT did not result in a favorable trend in BSF. Insufficient expansion of the bifurcation core after POT was associated with BSF.

Isolated Bone Recurrence of Medulloblastoma With MYCN Amplification and TP53 Loss: A Case Report.

Extraneural recurrence of a medulloblastoma is rare with dismal prognosis. A 9-year-old girl with medulloblastoma was treated with gross total resection followed by a combination of chemotherapy and radiotherapy. Fourteen months after treatment completion, she developed multifocal bone metastases. Despite chemotherapy combined with irradiation, she died 18 months after recurrence due to progressive disease. Fluorescence in situ hybridization on formalin-fixed paraffin-embedded tissue sections revealed MYCN amplification and TP53 loss, consistent with the genetic alterations of a rapidly progressive subgroup of recurrent medulloblastomas. In clinical practice, dismal biologic features can be determined using fluorescence in situ hybridization in defective materials.

Accuracy of patient setup positioning using surface-guided radiotherapy with deformable registration in cases of surface deformation.

The Catalyst™ HD (C-RAD Positioning AB, Uppsala, Sweden) is surface-guided radiotherapy (SGRT) equipment that adopts a deformable model. The challenge in applying the SGRT system is accurately correcting the setup error using a deformable model when the body of the patient is deformed. This study evaluated the effect of breast deformation on the accuracy of the setup correction of the SGRT system. Physical breast phantoms were used to investigate the relationship between the mean deviation setup error obtained from the SGRT system and the breast deformation. Physical breast phantoms were used to simulate extension and shrinkage deformation (-30 to 30 mm) by changing breast pieces. Three-dimensional (3D) Slicer software was used to evaluate the deformation. The maximum deformations in X, Y, and Z directions were obtained as the differences between the original and deformed breasts. We collected the mean deviation setup error from the SGRT system by replacing the original breast part with the deformed breast part. The mean absolute difference of lateral, longitudinal, vertical, pitch, roll, and yaw, between the rigid and deformable registrations was 2.4 ± 1.7 mm, 1.3 ± 1.2 mm, 6.4 ± 5.2 mm, 2.5° ± 2.5°, 2.2° ± 2.4°, and 1.0° ± 1.0°, respectively. Deformation in the Y direction had the best correlation with the mean deviation translation error (R = 0.949) and rotation error (R = 0.832). As the magnitude of breast deformation increased, both mean deviation setup errors increased, and there was greater error in translation than in rotation. Large deformation of the breast surface affects the setup correction. Deformation in the Y direction most affects translation and rotation errors.

Changes in carnitine levels through induction chemotherapy in head and neck cancer patients as a potential cause of therapy-related malaise.

BACKGROUND: Carnitine is related to malaise, and cisplatin is associated with decreased carnitine. The purpose of this study was to elucidate the effects of one course of induction chemotherapy (IC) for head and neck cancer on blood carnitine levels, focusing on free carnitine (FC). METHODS: This single-center prospective study investigated 20 patients diagnosed with primary head and neck cancer who underwent IC with cisplatin, docetaxel, and 5-fluorouracil. FC, acylcarnitine (AC), and total carnitine (TC) levels were measured before starting therapy and on Days 7 and 21 after starting IC. In addition, malaise was evaluated before and after therapy using a visual analog scale (VAS). RESULTS: All subjects were men and the most common primary cancer site was the hypopharynx (9 patients). FC levels before starting therapy and on Days 7 and 21 were 47.7 ± 2.2 µM/mL, 56.7 ± 2.2 µM/mL, and 41.1 ± 1.9 µM/mL, respectively. Compared with the baseline before starting therapy, FC had significantly decreased on Day 21 (p = 0.007). AC levels before starting therapy and on Days 7 and 21 were 12.5 ± 1.2 µM/mL, 13.6 ± 1.4 µM/mL, and 10.7 ± 0.7 µM/mL, respectively. TC levels before starting therapy and on Days 7 and 21 were 60.2 ± 2.5 µM/mL, 70.2 ± 3.3 µM/mL, and 51.7 ± 2.3 µM/mL, respectively. No significant differences in AC, TC or VAS were seen before the start of therapy and on Day 21. CONCLUSIONS: After IC, a latent decrease in FC occurred without any absolute deficiency or subjective malaise.

Comparison of ultrasound-guided versus angiography-guided endovascular treatment for femoropopliteal artery occlusive disease.

PURPOSE: This study aimed to compare the efficacy of ultrasound-guided and angiography-guided intraluminal approach for femoropopliteal (FP) artery occlusive disease. METHODS: A retrospective analysis was performed using the data collected regarding patients that underwent endovascular treatment (EVT) for FP artery occlusive disease between January 2010 and April 2018 at two centers. A total of 221 consecutive de novo lesions were analyzed according to the method of recanalization. Propensity score-matched analysis was performed to compare the clinical outcomes of recanalization methods for FP occlusive lesions. The prognostic value was analyzed based on the number of guidewires, wire cross time, distal puncture rate, radiation exposure, the amount of contrast media, primary patency, and clinically driven-target lesion revascularization (CD-TLR) at 1 year. RESULTS: A total of 44 matched pairs of patients were analyzed after propensity score-matched analysis. The number of guidewires, distal puncture rate, wire passage time, radiation exposure, and the amount of contrast media were significantly lower in the ultrasound-guide group, with 3.4 vs. 4.7, 9.1% vs. 54.5%, 47 min vs. 83 min, 207 mGy vs. 821 mGy, 66 ml vs. 109 ml, respectively (p < .01), but there were no significant differences between the two groups in terms of primary patency and CD-TLR. CONCLUSIONS: The ultrasound-guided EVT for FP occlusive disease significantly reduced the number of guidewires, wire cross time, the rate of distal puncture, radiation exposure, and the amount of contrast media used.

Validation of Global Limb Anatomical Staging System (GLASS) in patients with hemodialysis and Chronic Limb-Threatening Ischemia after endovascular treatment.

Recently, Society for Vascular Surgery guideline recommends evaluating anatomic pattern with use of Global Limb Anatomic Staging System (GLASS) in Chronic Limb-Threatening Ischemia (CLTI) patients. The aim of this study is to validate GLASS stage into CLTI patients on hemodialysis (HD) and investigate the impact of GLASS stage to wound healing and amputation-free survival (AFS). Between April 2009 and March 2018, we performed EVT for 154 limbs in CLTI patients on HD. GLASS was defined as femoropopliteal (FP) and infrapopliteal (IP) segments separately graded (0-4), then combined into three GLASS stages for the limb (I-III). We divided them into three GLASS stages with using this system. We compared the clinical outcomes between three groups (GLASS I, GLASS II, and GLASS III). Patient characteristics were almost similar between the three groups. Lesion characteristics was more complex and the rate of success was lower in GLASS III. Cox regression multivariate analysis revealed that diabetes mellitus (HR 2.4, 95% CI 1.37-4.01, p < 0.01) and WIfI high (HR 2.3, 95% CI 1.04-6.01, p = 0.04) were the predictors of non-wound healing, whereas age (HR 1.6, 95% CI 1.09-2.29, p = 0.01), WIfI clinical stage 4 (HR 2.4, 95% CI 1.30-4.36, p < 0.01), and non-ambulatory status (HR 2.0, 95% CI 1.17-3.29, p = 0.01) were the predictors of AFS. GLASS stage in CLTI patient on HD could not predict wound healing, and AFS in this study.

Predicting the efficacy of chemoradiotherapy for locally advanced human papilloma virus-related oropharyngeal squamous cell carcinoma using one course of TPF chemotherapy.

PURPOSE: The standard induction chemotherapy for head and neck cancer is TPF [cisplatin (CDDP), docetaxel (DOC), and 5-fluorouracil (5-FU)]. We assessed whether one course of TPF could predict the efficacy of chemoradiotherapy for human papilloma virus (HPV)-related oropharyngeal squamous cell carcinoma. METHODS: We retrospectively reviewed 51 patients with stage III-IV HPV-related oropharyngeal squamous cell carcinoma who received one course of TPF with CDDP 60 mg/m2, DOC 60 mg/m2, and 5-FU 600 mg/m2. We recommended chemoradiotherapy for patients with complete or partial response (CR/PR), and surgery for those with stable or progressive disease (SD/PD). The endpoints were TPF-related adverse events and efficacy, chemoradiotherapy efficacy, and 2-year survival. RESULTS: Neutropenia was the most common grade ≥ 3 adverse event (88%). No grade 5 adverse events occurred. TPF achieved CR in 4% of patients (2/51), PR in 73% (37/51), SD in 20% (10/51), and PD in 4% (2/51). Concurrent cetuximab and radiotherapy (bio-radiotherapy, BRT) were administered to 61% of patients (31/51), concurrent CDDP and radiotherapy (CDDP-RT) to 16% (8/51), RT alone to 2% (1/51), and surgery was performed for 22% (11/51). CR was achieved in 85% of the chemoradiotherapy group, and the rate tended to increase with TPF efficacy. CR was achieved in 84% (26/31) of patients receiving BRT, 88% (7/8) receiving CDDP-RT, and 100% (1/1) receiving RT. The 2-year survival rates were 92% overall, and 97% and 79% in the chemoradiotherapy and surgery groups, respectively. CONCLUSIONS: When facing difficulty in deciding between chemoradiotherapy and surgery, one course of TPF may be an effective option.

Early diagnosis of prodromal dementia with Lewy bodies using clinical history of probable REM sleep behaviour disorder and cardiac 123 I-MIBG scintigraphy in memory clinics.

BACKGROUND: Rapid eye movement sleep behaviour disorder (RBD) is associated with reduced cardiac 123 I-metaiodobenzylguanidine (MIBG) uptake and often precedes the onset of Lewy body (LB) disorders. We investigated the role of cardiac 123 I-MIBG scintigraphy in relation to probable RBD for the clinical diagnosis of prodromal dementia with Lewy bodies (DLB) in memory clinics. METHODS: We reviewed clinical profiles of 60 consecutive patients who underwent cardiac 123 I-MIBG scintigraphy in our memory clinics. The diagnostic threshold of 2.20 was used as the cut-off for the heart-to-mediastinum ratio at the delayed phase. RESULTS: Cardiac 123 I-MIBG abnormality was identified in 28 patients at baseline; six were cognitively unimpaired, six had mild cognitive impairment (MCI)-LB, and 16 had probable DLB based on the National Institute on Aging and Alzheimer's Association Research Framework. Although the number of core features increased in accordance with the progression of three cognitive categories, there were no differences in the prevalence of probable RBD and the cardiac MIBG scintigraphy indices among them. During the observation period, two cognitively unimpaired patients with probable RBD progressed to MCI-LB, and three MCI-LB patients with probable RBD developed DLB. The prevalence of final diagnosis of probable MCI-LB or DLB was significantly higher in these patients (85%) than the remaining 32 patients without (9%). Of 25 patients with probable RBD, 22 (88%) had a cardiac 123 I-MIBG abnormality regardless of cognitive conditions. Only one patient consulted a sleep centre for the abnormal sleep behaviour before visiting our memory clinics. Regarding the gender differences, male predominance was not identified and sleep-related injury more frequently occurred in men (7/12, 58%) than in women (1/10, 10%). CONCLUSIONS: Proactive detection of probable RBD plus cardiac 123 I-MIBG abnormality provides the opportunity for an early diagnosis of prodromal DLB in memory clinics. This approach warrants further follow-up studies with polysomnographic and pathological verification.

Midterm Clinical Impacts of Biodegradable Polymer Everolimus-Eluting Stents Compared with Durable Polymer Everolimus-Eluting Stents: A 3-Year Propensity-Matched Study.

OBJECTIVES: Our aim was to evaluate the safety and efficacy of biodegradable polymer everolimus-eluting stents (BP-EES) compared with durable polymer everolimus-eluting stents (DP-EES) in midterm. BACKGROUND: There are few data about midterm clinical outcomes of BP-EES compared with DP-EES. METHODS AND RESULTS: Between January 2016 and December 2017, 395 consecutive patients were treated with BP-EES and 391 consecutive patients were treated with DP-EES in Nagoya Heart Center. The primary endpoint was a 3-year cumulative incidence of target lesion failure (TLF) defined as cardiac death, target vessel myocardial infarction (MI), and clinical indicated target lesion revascularization (TLR). Moreover, clinical indicated target vessel revascularization (TVR) and definite stent thrombosis (ST) were also evaluated as the secondary endpoints. After propensity score matching, 327 patients were selected in each group. At 3 years, the cumulative incidence of TLF was 4.5% in the BP-EES group versus 6.5% in DP-EES (adjusted HR 0.67 (95% CI 0.33-1.30), log-rank P=0.23). Regarding the individual components of the TLF at 3 years, the cumulative incidence of target vessel MI was significantly lower in BP-EES than in DP-EES (0% versus 1.9%: adjusted HR 0.83 (95% CI 0.71-0.97), log-rank P=0.01), but there was no difference between BP-EES and DP-EES in the incidence of cardiac death and clinically indicated TLR. The cumulative 3-year incidence of definite ST was significantly lower in BP-EES than in DP-EES (0% versus 1.6%, log-rank P=0.02). CONCLUSIONS: There were no significant differences of TLF between BP-EES and DP-EES within 3 years. In this study, BP-EES seems to prevent definite ST and be safer than DP-EES in midterm.

Prediction of the Technical Success of Endovascular Therapy in Patients with Critical Limb Threatening Ischaemia Using the Global Limb Anatomical Staging System.

OBJECTIVE: This study aimed to determine the clinical impact of the Global Limb Anatomical Staging System (GLASS) and develop a model to determine the grade of difficulty for target artery path (TAP) using GLASS stage. METHODS: This was a single centre retrospective study. Endovascular treatment (EVT) was performed for 400 lesions in 257 patients with critical limb threatening ischaemia (CLTI) between April 2009 and March 2018. All lesions were divided into three groups (GLASS Ⅰ, Ⅱ, and Ⅲ), which were compared in terms of patient characteristics, lesion characteristics, technical success, and procedural complications. All observations were then randomly assigned to the derivation set or validation set at a ratio of 2:1 (derivation set: 166 patients; validation set: 91 patients). Predictors of technical success for TAP were identified by multivariable analysis. Each predictor was assigned a score based on its regression coefficient, and the total score was calculated. This value was used to categorise all lesions into the following four groups: low (score 0), intermediate (score 1), difficult (score 2), and very difficult (score ≥ 3). RESULTS: No significant differences in patient characteristics were observed between the three GLASS groups. In GLASS Ⅲ group, anatomic/limb severity and procedural complications were observed frequently, and the technical success rate was lower than that in the other groups. Through multivariable analysis, absence of pedal modifier (P)0 or P1, GLASS Ⅲ, total occlusion, and severe calcification predicted technical failure. The four groups stratified according to GLASS score demonstrated stepwise and highly reproducible difference in the probability of technical success for TAP. The area under the receiver operating characteristic (ROC) curve was 0.95 in the development group and 0.93 in the validation sample. CONCLUSION: In GLASS Ⅲ, anatomic/limb severity was more complex and procedural complications were more frequent. The GLASS scoring system reliably predicts the technical success of de novo TAP in patients with CLTI.

The Impact of Femoropopliteal Artery Calcium Score after Endovascular Treatment.

BACKGROUND: The coronary artery calcium score is a widely known independent predictor of cardiac events. Tibial artery calcification had been reported as an amputation risk, but the femoropopliteal artery calcium score is rarely known. METHODS: A retrospective analysis was performed using the data collected from the patients who underwent endovascular treatment for the femoropopliteal artery between January 2010 and December 2017. The femoropopliteal artery calcium scores on preprocedural computed tomography were calculated according to the Agatston definition. The mean value of total of femoropopliteal artery calcium scores was used to divide the scores into two groups. The prognostic value of the calcium score was analyzed based on primary patency, clinically driven target lesion revascularization, major amputation, and all-cause death. RESULTS: In total, 132 consecutive limbs that underwent successful endovascular intervention were analyzed in this study; 44 and 88 limbs were assigned to the high and low calcium score groups, respectively. There were no significant differences between the two groups in terms of patient and lesion characteristics, except for chronic kidney disease (7% vs. 25%, P < 0.01), hemodialysis (80% vs. 25%, P < 0.01), and coronary artery disease (73% vs. 53%, P = 0.03). Compared with the low calcium score group, the high calcium score group had a significantly higher rate of loss of primary patency and clinically driven target lesion revascularization at one year, based on the Kaplan-Meier curve (55% vs. 81%, 44% vs. 8%, both P < 0.01). There were no significant differences between the two groups in terms of major amputation and death. Multivariate analysis revealed that hemodialysis [hazard ratio (HR): 1.9; 95% confidence interval (CI): 1.01-5.28; P = 0.04] runoff grade 0 (HR: 2.9; 95% CI: 1.02-10.9; P = 0.04), lesion length > 200 mm (HR: 3.9; 95% CI: 1.1-13.7; P = 0.03), and calcium score per 100 increase (HR: 1.05; 95% CI: 1.02-1.08; P < 0.01) were predictors of clinically driven target lesion revascularization. As per receiver operating characteristic analysis, the best cutoff value of target lesion calcium score for target lesion revascularization was 206. CONCLUSIONS: A high femoropopliteal artery calcium score might increase loss of patency and the risk for clinically driven target lesion revascularization.

Legal and ethical framework for global health information and biospecimen exchange - an international perspective.

BACKGROUND: The progress of electronic health technologies and biobanks holds enormous promise for efficient research. Evidence shows that studies based on sharing and secondary use of data/samples have the potential to significantly advance medical knowledge. However, sharing of such resources for international collaboration is hampered by the lack of clarity about ethical and legal requirements for transfer of data and samples across international borders. MAIN TEXT: Here, the International Clinical Trial Center Network (ICN) reports the legal and ethical requirements governing data and sample exchange (DSE) across four continents. The most recurring requirement is ethical approval, whereas only in specific conditions approval of national health authorities is required. Informed consent is not required in all sharing situations. However, waiver of informed consent is only allowed in certain countries/regions and under certain circumstances. The current legal and ethical landscape appears to be very complex and under constant evolution. Regulations differ between countries/regions and are often incomplete, leading to uncertainty. CONCLUSION: With this work, ICN illuminates the unmet need for a single international collaborative framework to facilitate DSE. Harmonising requirements for global DSE will reduce inefficiency and waste in research. There are many challenges to realising this ambitious vision, including inconsistent terminology and definitions, and heterogeneous and dynamic legal constraints. Here, we identify areas of agreement and significant difference as a necessary first step towards facilitating international collaboration. We propose the establishment of a working group to continue the comparison across jurisdictions, create a standardised glossary and define a set of basic principles and fundamental requirements for DSE.

Integrated genetic and epigenetic analysis revealed heterogeneity of acute lymphoblastic leukemia in Down syndrome.

Children with Down syndrome (DS) are at a 20-fold increased risk for acute lymphoblastic leukemia (ALL). Compared to children with ALL and no DS (non-DS-ALL), those with DS and ALL (DS-ALL) harbor uncommon genetic alterations, suggesting DS-ALL could have distinct biological features. Recent studies have implicated several genes on chromosome 21 in DS-ALL, but the precise mechanisms predisposing children with DS to ALL remain unknown. Our integrated genetic/epigenetic analysis revealed that DS-ALL was highly heterogeneous with many subtypes. Although each subtype had genetic/epigenetic profiles similar to those found in non-DS-ALL, the subtype distribution differed significantly between groups. The Philadelphia chromosome-like subtype, a high-risk B-cell lineage variant relatively rare among the entire pediatric ALL population, was the most common form in DS-ALL. Hypermethylation of RUNX1 on chromosome 21 was also found in DS-ALL, but not non-DS-ALL. RUNX1 is essential for differentiation of blood cells, especially B cells; thus, hypermethylation of the RUNX1 promoter in B-cell precursors might be associated with increased incidence of B-cell precursor ALL in DS patients.

Development of Dried Emulsion/Mannitol Composite Microparticles through a Unique Spray Nozzle for Efficient Delivery of Hydrophilic Anti-tuberculosis Drug against Alveolar Macrophages.

As alveolar macrophages are attractive targets for the treatment of tuberculosis, effective methods for delivery to alveolar macrophages are under development. We investigated a pulmonary formulation for the efficient delivery of high water-soluble drugs at high concentration targeting alveolar macrophages. In this study, a surfactant-coated high water-soluble drug complex (SDC, a hydrophobic dried emulsion), which can preferably target alveolar macrophages and be expected to deliver drug at a high concentration, was prepared in the first process. OCT313, a high water-soluble sugar derivative with anti-tuberculosis activity was used. Then, a unique two-solution, mixing-type nozzle was used to prepare the SDC nanoparticles in mannitol (MAN) microparticles (SDC/MAN microparticles) because it was difficult to disperse the SDC nanoparticles in aqueous solution. The single micron size of OCT313-SDC/MAN microparticles contained OCT313-SDC nanoparticles (mean particle size of OCT313-SDC nanoparticles, 277.9 nm; drug contents, 1.31 ± 0.041 wt%). We found that the treatment of SDC/MAN microparticles exhibited significantly higher drug accumulation in macrophage cells (Raw264.7 cells, 7.5-fold, at 4 h after treatment) in vitro and in alveolar macrophages in rats (9.1-fold, at 4 h after treatment) in vivo than that of drug alone. These results suggest that the SDC/MAN microparticle formulation prepared by spray drying through a two-solution mixing-type nozzle provides efficient delivery of a water-soluble drug targeting alveolar macrophages and may be useful for tuberculosis treatment.

Neoadjuvant chemotherapy with docetaxel, nedaplatin, and fluorouracil for resectable esophageal cancer: A phase II study.

Cisplatin plus 5-fluorouracil is regarded as standard neoadjuvant chemotherapy for esophageal squamous cell carcinoma (ESCC) in Japan, but the prognosis remains poor. We have previously described how definitive chemoradiotherapy with docetaxel, nedaplatin, and 5-fluorouracil (DNF) led to a very high response rate and promising survival times. We therefore undertook a phase II trial to evaluate the feasibility and efficacy of neoadjuvant DNF. The study included patients with clinical stage Ib-III ESCC. Chemotherapy consisted of i.v. docetaxel (30 mg/m2 ) and nedaplatin (50 mg/m2 ) on days 1 and 8, and a continuous infusion of 5-fluorouracil (400 mg/m2 /day) on days 1-5 and 8-12, every 3 weeks. After three courses of chemotherapy, esophagectomy was carried out. The primary end-point was the completion rate of the protocol treatment. Twenty-eight patients were enrolled (cStage Ib/II/III, 2/3/23) and all received at least two cycles of chemotherapy. Twenty-five patients underwent surgery, all of whom achieved an R0 resection, leading to a completion rate of 89.3%. The overall response rate was 87.0%. A pathological complete response was confirmed in eight (32.0%) cases. Grade 3/4 adverse events included leukopenia (32.1%), neutropenia (39.3%), febrile neutropenia (10.7%), thrombocytopenia (10.7%), and diarrhea (14.3%), but were manageable. Treatment-related deaths and major surgical complications did not occur. Estimated 2-year progression-free and overall survival rates were 70.4% and 77.2%, respectively. Thus, DNF therapy was well tolerated and deemed feasible, with a strong tumor response in a neoadjuvant setting for ESCC. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014305).

Synthesis, photophysical properties, and photodynamic activity of positional isomers of TFPP-glucose conjugates.

The synthesis and characterization of a 'complete set' of positional isomers of tetrakis(perfluorophenyl)porphyrins (TFPP)-glucose conjugates (1OH, 2OH, 3OH, 4OH, and 6OH) are reported herein. The cellular uptake and photocytotoxicity of these conjugates were examined in order to investigate the influence of location of the TFPP moiety on the d-glucose molecule on the biological activity of the conjugates. An In vitro biological evaluation revealed that the certain of these isomers have a greater effect on cellular uptake and cytotoxicity than others. The TFPP-glucose conjugates 1OH, 3OH, and 4OH were found to exert exceptional photocytotoxicity in several types of cancer cells compared to 2OH and 6OH substituted isomers.