Landscape of driver mutations and their clinical effects on Down syndrome-related myeloid neoplasms.

ABSTRACT: Transient abnormal myelopoiesis (TAM) is a common complication in newborns with Down syndrome (DS). It commonly progresses to myeloid leukemia (ML-DS) after spontaneous regression. In contrast to the favorable prognosis of primary ML-DS, patients with refractory/relapsed ML-DS have poor outcomes. However, the molecular basis for refractoriness and relapse and the full spectrum of driver mutations in ML-DS remain largely unknown. We conducted a genomic profiling study of 143 TAM, 204 ML-DS, and 34 non-DS acute megakaryoblastic leukemia cases, including 39 ML-DS cases analyzed by exome sequencing. Sixteen novel mutational targets were identified in ML-DS samples. Of these, inactivations of IRX1 (16.2%) and ZBTB7A (13.2%) were commonly implicated in the upregulation of the MYC pathway and were potential targets for ML-DS treatment with bromodomain-containing protein 4 inhibitors. Partial tandem duplications of RUNX1 on chromosome 21 were also found, specifically in ML-DS samples (13.7%), presenting its essential role in DS leukemia progression. Finally, in 177 patients with ML-DS treated following the same ML-DS protocol (the Japanese Pediatric Leukemia and Lymphoma Study Group acute myeloid leukemia -D05/D11), CDKN2A, TP53, ZBTB7A, and JAK2 alterations were associated with a poor prognosis. Patients with CDKN2A deletions (n = 7) or TP53 mutations (n = 4) had substantially lower 3-year event-free survival (28.6% vs 90.5%; P < .001; 25.0% vs 89.5%; P < .001) than those without these mutations. These findings considerably change the mutational landscape of ML-DS, provide new insights into the mechanisms of progression from TAM to ML-DS, and help identify new therapeutic targets and strategies for ML-DS.

Multicenter Registry of Common Femoral Artery Disease Treated With Endovascular Revascularization Using Interwoven Nitinol Stents: An Observational Retrospective Study.

PURPOSE: Surgical thromboendarterectomy has been the gold standard treatment for common femoral artery (CFA) disease. However, endovascular therapy (EVT) is conducted in certain patients with CFA lesions because of multiple comorbidities. The interwoven nitinol stent (IWS) has been developed to prevent stent fracture. Thus, this study aimed to evaluate the feasibility of EVT using IWS for CFA lesions in clinical practice. MATERIALS AND METHODS: This retrospective multicenter registry analyzed patients who had symptomatic lower-extremity artery disease due to CFA lesions and underwent EVT using IWS between 2019 and 2021. The primary endpoint was restenosis 2 years after EVT. RESULTS: This study enrolled a total of 177 patients with 196 CFA lesions. The 2-year estimate of freedom from restenosis was 88.0%. The 2-year freedom rates from the target-lesion revascularization, major amputation, and all-cause death were 92.9%, 99.0%, and 75.2%, respectively. The clinical features significantly associated with restenosis risk were the reference vessel diameter (RVD, per 1.0 mm, hazard ratio [HR], 0.24 [0.08-0.70]; p=0.009), external iliac artery (EIA) involvement (HR=4.03 [1.56-10.4]; p=0.004), superficial femoral artery (SFA) involvement (HR=3.05 [1.00-9.25]; p=0.049), body mass index (BMI; per 1.0, HR=0.85 [0.73-0.99]; p=0.032), occlusion of deep femoral arteries (DFAs) at baseline (HR=7.89 [2.04-30.5]; p=0.003), and chronic limb-threatening ischemia (CLTI, HR=2.63 [1.02-6.78]; p=0.045). Their significant association was also confirmed by the random survival forest analysis. During a median follow-up of 12.0 months, guiding sheaths were inserted via CFAs implanted IWSs in 73 cases (37.2%), and no patients had cannulation-related complications, such as failed hemostasis, fracture of IWS, and stent occlusion. CONCLUSIONS: Endovascular therapy using IWS in CFA lesions showed acceptable 2-year patency rates at 88.0% and might preserve the arterial access via the ipsilateral CFAs. Small RVD, involving EIA and SFA lesions, emaciation, occluded DFA, and CLTI are associated with poor 2-year patency rates following EVT, thus, IWS implantation in CFA lesions may be an option for patients unsuitable for surgical revascularization. CLINICAL IMPACT: This retrospective multicenter registry enrolled 177 patients with 199 CFA lesions treated with EVT using interwoven nitinol stents, because surgical thromboendarterectomy was difficult due to their multiple comorbidities. The 2-year estimate of freedom from restenosis was acceptable at 88.0%. The 2-year freedom rate from major amputation was also high at 99.0%. Moreover, during a median follow-up of 12.0 months, guiding sheaths were inserted via CFAs implanted IWSs in 73 cases, and no patients had cannulation-related complications such as failed hemostasis, fracture of IWS, and stent occlusion.

Predictive factors of periodontal regeneration outcomes using rhFGF-2: A case-control study.

OBJECTIVE: This study aimed to investigate the factors influencing the clinical outcomes of regenerative therapy using recombinant human fibroblast growth factor-2 (rhFGF-2). BACKGROUND: rhFGF-2 promotes periodontal regeneration, and identifying the factors influencing this regeneration is important for optimizing the effectiveness of rhFGF-2. METHODS AND MATERIALS: This study used a hospital information-integrated database to identify patients who underwent periodontal regenerative therapy with rhFGF-2. Factors included age, smoking status, diabetes mellitus (DM), periodontal inflamed surface area (PISA) at the initial visit, whether the most posterior tooth was involved or not, and preoperative radiological bone defect angle. Periodontal regenerative therapy outcomes were defined as good if radiographic bone fill ≥35% or periodontal pocket closure at 9-15 months after surgery. Bone fill rate (%) and periodontal pocket depth (mm) were also used as outcome measures. Factors were evaluated by simple regression analysis, and then the association between factors and the outcomes was determined by multivariate analysis. RESULTS: PISA and age at the first visit did not significantly influence the success or failure of bone fill rate byrhFGF-2. However, DM, radiographic bone defect angle, and the most posterior tooth significantly influenced the regenerative effect (success/failure in bone fill) of rhFGF-2. The most posterior tooth was significantly associated with bone fill rate by rhFGF-2. Examination of the association between pocket closure and factors shows that the most posterior tooth significantly influenced. The most posterior tooth and preoperative PPD were significantly associated with pocket reduction depth. For the most posterior tooth, a significantly higher bone regeneration rate (p < .05) was observed with a combination of autologous bone graft and rhFGF-2 than with rhFGF-2 alone, and the effect was significant in multivariate analysis. CONCLUSIONS: The radiographic bone defect angle, the involvement of most posterior teeth, and the presence of DM influenced the effectiveness of rhFGF-2 in periodontal regeneration. However, PISA values and age at the initial visit had no significant effect.

Periodontal tissue regeneration with cementogenesis after application of brain-derived neurotrophic factor in 3-wall inflamed intra-bony defect.

OBJECTIVE: The purpose of this study is to investigate regenerative process by immunohistochemical analysis and evaluate periodontal tissue regeneration following a topical application of BDNF to inflamed 3-wall intra-bony defects. BACKGROUND: Brain-derived neurotrophic factor (BDNF) plays a role in the survival and differentiation of central and peripheral neurons. BDNF can regulate the functions of non-neural cells, osteoblasts, periodontal ligament cells, endothelial cells, as well as neural cells. Our previous study showed that a topical application of BDNF enhances periodontal tissue regeneration in experimental periodontal defects of dog and that BDNF stimulates the expression of bone (cementum)-related proteins and proliferation of human periodontal ligament cells. METHODS: Six weeks after extraction of mandibular first and third premolars, 3-wall intra-bony defects were created in mandibular second and fourth premolars of beagle dogs. Impression material was placed in all of the artificial defects to induce inflammation. Two weeks after the first operation, BDNF (25 and 50 µg/mL) immersed into atelocollagen sponge was applied to the defects. As a control, only atelocollagen sponge immersed in saline was applied. Two and four weeks after the BDNF application, morphometric analysis was performed. Localizations of osteopontin (OPN) and proliferating cell nuclear antigen (PCNA)-positive cells were evaluated by immunohistochemical analysis. RESULTS: Two weeks after application of BDNF, periodontal tissue was partially regenerated. Immunohistochemical analyses revealed that cells on the denuded root surface were positive with OPN and PCNA. PCNA-positive cells were also detected in the soft connective tissue of regenerating periodontal tissue. Four weeks after application of BDNF, the periodontal defects were regenerated with cementum, periodontal ligament, and alveolar bone. Along the root surface, abundant OPN-positive cells were observed. Morphometric analyses revealed that percentage of new cementum length and percentage of new bone area of experimental groups were higher than control group and dose-dependently increased. CONCLUSION: These findings suggest that BDNF could induce cementum regeneration in early regenerative phase by stimulating proliferation of periodontal ligament cells and differentiation into periodontal tissue cells, resulting in enhancement of periodontal tissue regeneration in inflamed 3-wall intra-bony defects.

Endovascular Therapy with Interwoven Nitinol Stent Placement after Predilation for Heavily Calcified Femoropopliteal Artery Disease: Results of the BURDOCK Study.

PURPOSE: To investigate the 1-year and 2-year clinical outcomes of interwoven stent (IWS) implantation for symptomatic femoropopliteal arterial disease with calcification. MATERIAL AND METHODS: This prospective multicenter study evaluated 308 limbs (63% with the peripheral arterial calcium scoring system 3 and 4 severe calcification and 87% with ≥180° calcification on intravascular ultrasound) of 299 patients (diabetes in 66.9%, chronic renal failure in 52.8%, and dialysis in 49.2%) who underwent IWS (Supera; Abbott, Abbott Park, Illinois) implantation after sufficient predilation (residual stenosis < 30%) for calcified femoropopliteal lesions. The primary outcome measure was primary patency (freedom from restenosis) at 1 and 2 years, whereas the secondary outcome measure included freedom from clinically driven target lesion revascularization (CD-TLR). Clinical parameters associated with loss of patency were explored. RESULTS: Kaplan-Meier analysis showed that primary patency was 88.2% (95% confidence interval [CI], 84.5%-92.1%) at 1 year and 80.8% (95% CI, 76.1%-85.8%) at 2 years. The CD-TLR-free rate was 96.5% and 94.8% at 1 and 2 years, respectively. The characteristics associated with loss of patency were restenotic lesion with and without stent implantation (adjusted hazard ratio, 1.96 and 2.40; P = .047 and .041, respectively), chronic total occlusion (adjusted hazard ratio, 1.88; P = .022), and popliteal involvement (adjusted hazard ratio, 2.60; P = .002). CONCLUSIONS: The implantation of IWS after sufficient predilation for calcified femoropopliteal atherosclerotic disease demonstrated clinically acceptable primary patency.

Regulation of osteogenesis in bone marrow-derived mesenchymal stem cells via histone deacetylase 1 and 2 co-cultured with human gingival fibroblasts and periodontal ligament cells.

OBJECTIVE: This study aimed to determine the regulatory mechanism of bone marrow-derived mesenchymal stem cell (BM-MSC) differentiation mediated by humoral factors derived from human periodontal ligament (HPL) cells and human gingival fibroblasts (HGFs). We analyzed histone deacetylase (HDAC) expression and activity involved in BM-MSC differentiation and determined their regulatory effects in co-cultures of BM-MSCs with HPL cells or HGFs. BACKGROUND: BM-MSCs can differentiate into various cell types and can, thus, be used in periodontal regenerative therapy. However, the mechanism underlying their differentiation remains unclear. Transplanted BM-MSCs are affected by periodontal cells via direct contact or secretion of humoral factors. Therefore, their activity is regulated by humoral factors derived from HPL cells or HGFs. METHODS: BM-MSCs were indirectly co-cultured with HPL cells or HGFs under osteogenic or growth conditions and then analyzed for osteogenesis, HDAC1 and HDAC2 expression and activity, and histone H3 acetylation. BM-MSCs were treated with trichostatin A, or their HDAC1 or HDAC2 expression was silenced or overexpressed during osteogenesis. Subsequently, they were evaluated for osteogenesis or the effects of HDAC activity. RESULTS: BM-MSCs co-cultured with HPL cells or HGFs showed suppressed osteogenesis, HDAC1 and HDAC2 expression, and HDAC phosphorylation; however, histone H3 acetylation was enhanced. Trichostatin A treatment remarkably suppressed osteogenesis, decreasing HDAC expression and enhancing histone H3 acetylation. HDAC1 and HDAC2 silencing negatively regulated osteogenesis in BM-MSCs to the same extent as that achieved by indirect co-culture with HPL cells or HGFs. Conversely, their overexpression positively regulated osteogenesis in BM-MSCs. CONCLUSION: The suppressive effects of HPL cells and HGFs on BM-MSC osteogenesis were regulated by HDAC expression and histone H3 acetylation to a greater extent than that mediated by HDAC activity. Therefore, regulation of HDAC expression has prospects in clinical applications for effective periodontal regeneration, mainly, bone regeneration.

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.

Intensive exercise therapy for restenosis after superficial femoral artery stenting: the REASON randomized clinical trial.

Endovascular treatment (EVT) is the main treatment for peripheral artery disease (PAD). Despite advances in device development, the restenosis rate remains high in patients with femoropopliteal lesions (FP). This study aimed to evaluate the effectiveness of exercise training in reducing the 1-year in-stent restenosis rate of bare metal nitinol stents for FPs. This prospective, randomized, open-label, multicenter study was conducted from January 2017 to March 2019. We randomized 44 patients who had claudication with de novo stenosis or occlusion of the FP into an intensive exercise group (n = 22) and non-intensive exercise group (n = 22). Non-intensive exercise was defined as walking for less than 30 min per session, fewer than three times a week. We assessed exercise tolerance using an activity meter at 1, 3, 6, and 12 months, and physiotherapists ensured maintenance of exercise quality every month. The primary endpoint was instant restenosis defined as a peak systolic velocity ratio > 2.5 on duplex ultrasound imaging. Kaplan-Meier analysis was used to evaluate the data. There were no significant differences in background characteristics between the groups. Six patients dropped out of the study within 1 year. In terms of the primary endpoint, intensive exercise significantly improved the patency rate of bare nitinol stents at 12 months. The 1-year freedom from in-stent restenosis rates were 81.3% in the intensive exercise group and 47.6% in the non-intensive exercise group (p = 0.043). No cases of stent fracture were observed in the intensive exercise group. Intensive exercise is safe and reduces in-stent restenosis in FP lesions after endovascular therapy for PAD. Clinical trial registration: University Hospital Medical Information Network Clinical Trials Registry (No. UMIN 000025259).

Involvement of Rac1 in macrophage activation by brain-derived neurotrophic factor.

Brain-derived neurotrophic factor (BDNF) enhances periodontal tissue regeneration. Tissue regeneration is characterized by inflammation, which directs the quality of tissue repair. This study aimed to investigate the effect of BDNF on the phagocytic activity of RAW264.7 cells. In addition, we studied the effect of BDNF on guanosine triphosphatase (GTP)-RAS-related C3 botulinus toxin substrate (Rac)1 and phospho-Rac1 levels in RAW264.7 cells. Rac1 inhibitor inhibited BDNF-induced phagocytosis of latex-beads. In addition, BDNF enhanced Porphyromonas gingivalis (Pg) phagocytosis by RAW264.7 cells as well as latex-beads. We demonstrated for the first time that BDNF enhances phagocytic activity of RAW264.7 cells through Rac1 activation. The present study proposes that BDNF may reduce inflammatory stimuli during BDNF-induced periodontal tissue regeneration through enhanced phagocytic activity of macrophages.

Association of Multiple Gene Polymorphisms Including Homozygous NUDT15 R139C With Thiopurine Intolerance During the Treatment of Acute Lymphoblastic Leukemia.

Although thiopurine is a crucial drug for treating acute lymphoblastic leukemia, individual variations in intolerance are observed due to gene polymorphisms. A 3-year-old boy with B-cell precursor acute lymphoblastic leukemia who was administered thiopurine developed mucositis, sepsis, and hemophagocytic lymphohistiocytosis due to prolonged hematologic toxicity, chronic disseminated candidiasis, and infective endocarditis that triggered multiple brain infarctions. The patient was found to harbor 3 gene polymorphisms associated with thiopurine intolerance including homozygous NUDT15 R139C, heterozygous ITPA C94A, and homozygous MTHFR C677T and heterozygous RFC1 G80A. Thus, the combined effect of intolerance via multiple gene polymorphisms should be considered in case of unexpected adverse reactions.

Detection of MEAF6-PHF1 translocation in an endometrial stromal nodule.

Endometrial stromal nodule (ESN) and low-grade endometrial stromal sarcoma (LG-ESS) are rare uterine tumors known as endometrial stromal tumors (ESTs). In addition to their similarity in morphological features, recent studies have shown that these two tumors share common genetic alterations. In particular, JAZF1-SUZ12 fusion is found with high frequency in both ESN and LG-ESS. In LG-ESS, some minor fusions have also been described, which include rearrangements involving PHF1 and its partner genes, such as JAZF1, EPC1, MEAF6, BRD8, EPC2, and MBTD1. Because of the rarity of ESN, genetic alterations other than JAZF1 fusion have not been investigated in detail. In this study, we performed a next-generation sequencing-based analysis in a case of ESN with peripheral metaplastic bone formation and detected MEAF6-PHF1 fusion, which has been reported in a small subset of uterine LG-ESSs and soft tissue ossifying fibromyxoid tumors. The finding that MEAF6-PHF1 fusion is a background genetic abnormality detected both in ESN and LG-ESS, along with JAZF1-SUZ12, provides further support for the similarity and continuum between these two types of ESTs. Furthermore, the association between metaplastic bone formation and MEAF6-PHF1 fusion may not be limited to soft tissue tumors.

IVUS Assessment of the Crossing Pathway of an Intraluminal Reentry Device Used in the Primary Treatment of Infrainguinal Chronic Total Occlusions.

Purpose: To examine with intravascular ultrasound (IVUS) the crossing pathways of the TruePath reentry device during primary antegrade recanalization of infrainguinal chronic total occlusions (CTOs). Methods: Between July 2017 and September 2018, a prospective multicenter study enrolled 143 consecutive patients (mean age 75±9 years; 101 men) with 146 CTOs treated in an antegrade approach using the TruePath reentry device with IVUS assessment of the crossing pathway in successful cases. Outcome measures were complete success (reentry device reached the distal true lumen), assisted success (reentry device use followed by a conventional guidewire to reach the distal true lumen), reentry device crossing route by IVUS assessment, and procedure- and device-related complications. Regression analyses were employed to identify any relevant associations between baseline patient variables and the outcome measures; results are presented as the odds ratio (ORs) and 95% confidence interval (CI). Results: Complete success was achieved in 82 (56.2%) lesions; any success (complete plus assisted) was documented in 117 (80.1%) lesions. Four (3%) perioperative device-related complications were observed. The crossing route was intraplaque for most of the total crossing distance in both complete success cases (95.3%±13.2%) and any success cases (94.8%±14.4%), with relatively short subintimal (3.6%±10.2% and 4.2%±11.2%, respectively) or intramedial (1.2%±5.8% and 1.0%±5.4%, respectively) crossing. CTO length was a significant risk factor for not achieving complete success (OR 1.74, 95% CI 1.13 to 2.68, p=0.012), and a history of failed revascularization was associated with not achieving any success (OR 6.40, 95% CI 1.28 to 28.9, p=0.038). Conclusion: The intraplaque route was the primary pathway taken by the TruePath reentry device as it crossed infrainguinal CTOs. Crossing rates were acceptable, with few device-related complications. However, a longer CTO length and a failed revascularization history negatively affected the success rate.

Clinical, cytogenetic, and molecular analyses of 17 neonates with transient abnormal myelopoiesis and nonconstitutional trisomy 21.

BACKGROUND: Transient abnormal myelopoiesis (TAM) is a unique myeloproliferative disorder that occurs in neonates with constitutional trisomy 21/Down syndrome (DS). Although TAM also develops in neonates without constitutional trisomy 21, the clinical, cytogenetic, and molecular characteristics of those patients are not fully understood. PROCEDURE: We retrospectively evaluated the clinical and cytogenetic findings and GATA1 mutation status of 17 neonates with TAM and nonconstitutional trisomy 21 tested for GATA1 mutations at our institute, and compared the findings with those of 64 neonates with TAM and constitutional trisomy 21/DS. RESULTS: DS clinical features were observed in five of the 17 (29%) patients. In all patients, both trisomy 21 and GATA1 mutations were detected in diagnostic samples. Over a median follow-up of 33 (range, 0-139) months, early death (< 6 months of age) occurred in four patients (24%). Overall and event-free survivals were not significantly different between the patients with TAM and nonconstitutional trisomy 21 and those with TAM and constitutional trisomy 21/DS (five-year overall survival: 76% ± 10% vs 53% ± 13%, P = 0.40; five-year event-free survival: 55% ± 13% vs 48% ± 12%, P = 0.90). The five-year cumulative incidence of progression to myeloid leukemia of DS was also similar between the groups (21% vs 24%, P = 0.80). CONCLUSIONS: Patients with TAM and nonconstitutional trisomy 21 exhibited similar biology and outcomes to those with TAM and constitutional trisomy 21/DS. The possibility of TAM should be considered even in phenotypically normal neonates with TAM symptoms, for appropriate management.

A Rapid Cytologic Double Staining of Epstein-Barr Virus-encoded Small RNA and Cell Surface Markers for Diagnosis of Epstein-Barr Virus-associated Hemophagocytic Lymphohistiocytosis.

A 3-year-old boy was clinically diagnosed with Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis. We identified EBV-infected CD8-positive T-lymphocytes by cytologic double staining of the peripheral blood for EBV-encoded small RNA and cell surface markers. The patient was subsequently administered immunosuppressive therapy with a reduced dose of etoposide because of previous organ damage. EBV clearance was confirmed by serial quantification of cell-fractionated EBV-DNA, whereas EBV-DNA persisted in the plasma for 18 weeks. Immunochemotherapy with low-dose etoposide combined with serial viral load monitoring is a potential therapeutic option for severe EBV-hemophagocytic lymphohistiocytosis cases with organ damage.

Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations.

X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.

Relationship between periodontal inflammation and calcium channel blockers induced gingival overgrowth-a cross-sectional study in a Japanese population.

OBJECTIVES: Periodontal inflammation is regarded as a risk factor for drug-induced gingival overgrowth (DIGO). In order to elucidate the involvement of periodontal inflammation in DIGO, the periodontal status of subjects who do not develop DIGO despite receiving causative drugs (non-responders) needs to be examined. Therefore, the aim of the present study which was a pilot study was to assess periodontal inflammatory variables in responders (calcium channel blocker induced-GO patients), non-responders, and patients who did not receive causative drugs (non-consumers). MATERIALS AND METHODS: The following parameters were measured: (1) existence of gingival overgrowth, (2) number of teeth, (3) mean periodontal pocket depth (PPD), and (4) percentage of positive sites for bleeding on probing (BOP). The periodontal inflamed surface area (PISA) and periodontal epithelial surface area (PESA) and the PISA/PESA ratio which indicated the degree of periodontal inflammation in each patient were also used to evaluate periodontal inflammation. RESULTS: Thirteen responders, 32 non-responders, and 83 non-consumers were included in the analyses. The mean PPD, percentage of BOP, PESA, and PISA, and the PISA/PESA ratio were significantly higher in responders than in non-responders and non-consumers (p < 0.01). The BOP, PISA, and PISA/PESA ratio were significantly lower in non-responders than in non-consumers (p < 0.05). A positive correlation was found between PPD and age in non-consumers. On the other hand, a negative correlation was noted between PPD and age in non-responders. CONCLUSIONS: Periodontal inflammation may be associated with the initiation of DIGO. CLINICAL RELEVANCE: It could be speculated that periodontal therapy before the administration of calcium channel blockers may prevent the development of gingival overgrowth.

Two siblings with familial neuroblastoma with distinct clinical phenotypes harboring an ALK germline mutation.

The authors report two siblings with familial neuroblastoma with a germline R1275Q mutation of the tyrosine kinase domain of ALK. Whole exome sequencing and copy number variation assay were performed to investigate genetic alterations in the two cases. No common somatic mutations or gene polymorphisms related to the tumorigenesis of neuroblastoma were detected. A distinct pattern involving both segmental chromosomal alteration and MYCN amplification was detected. The diversity of biological behavior of familial neuroblastoma harboring a germline ALK mutation may depend on conventional prognostic factors, such as segmental chromosomal alterations and MYCN amplification, rather than additional acquired mutations.

Angiographic Dissection Patterns and Patency Outcomes After Balloon Angioplasty for Superficial Femoral Artery Disease.

PURPOSE: To investigate the angiographic dissection patterns after balloon angioplasty for superficial femoral artery (SFA) lesions, the clinical outcome associated with each dissection pattern, and the predictive factors for severe dissection. METHODS: A retrospective, multicenter analysis examined 621 patients (mean age 72.8±9.5 years; 414 men) with 748 symptomatic de novo SFA lesions treated with endovascular therapy. Vessel dissection after the initial balloon angioplasty procedure was graded into 7 types according to a modified version of the coronary artery classification types A to F. Severe vessel dissection patterns were defined as type C or higher. Nitinol stent implantation was performed in 555 (74.2%) lesions for residual stenosis >30% or flow-limiting dissection; 193 lesions (25.8%) were treated with balloon angioplasty only. To determine the clinical outcomes associated with each dissection pattern and identify predictive factors for severe dissection, 2-year follow-up data for the 193 lesions treated with balloon angioplasty only were analyzed for primary patency and clinically driven target lesion revascularization (TLR). RESULTS: No dissection was found in 16% (120/748) of lesions, and types A and B dissections were seen in 19% (142/748) and 23% (172/748), respectively. Dissection grades above type C were observed in 42% of cases, most frequently type D (180/748, 24%) and less often type C (37/748, 5%), type E (67/748, 9%), and type F (30/748, 4%). The bailout stent implantation rate increased according to dissection severity. At up to 2 years, the severe dissection group (types C-F) showed a significantly lower patency rate (p<0.001) and higher clinically driven TLR (p<0.001) compared to the nonsevere group (no dissection and types A and B dissections). Severe dissection was a significant risk factor for restenosis, which rose progressively from types C to F. Multivariate analysis identified a small reference vessel diameter <5 mm (p=0.001), lesion length >15 cm (p=0.001), and chronic total occlusion (p<0.001) as independent predictors of severe dissection. In subgroup analysis, vessels with a small reference diameter and TASC II C and D lesions had a higher prevalence of severe dissection. CONCLUSION: Severe dissection was found in 42% of cases after PTA. A small vessel diameter and/or TASC II C/D lesions were related to a high incidence of dissection. Severe dissection during procedures employing balloon angioplasty only could affect long-term patency.

Randomized comparison between provisional and routine kissing-balloon technique after main vessel crossover stenting for coronary bifurcation lesions.

We compared the myocardial ischemic burden of provisional and routine final kissing-balloon inflation (FKI) with the 1-stent strategy using a second-generation drug-eluting stent for coronary bifurcation lesions (CBL). There are no established guidelines for side branch (SB) intervention after main vessel stenting. In total, 113 CBL patients were randomized to receive different SB intervention strategies: provisional-FKI group (n = 57; FKI only when SB flow was TIMI <3) and routine-FKI group (n = 56; mandatory FKI with aggressive treatment until SB-residual stenosis <50%). Dipyridamole-stress myocardial perfusion scintigraphy with 99mTc was performed after 8 months. The regional summed-difference score (r-SDS) was calculated according to the coronary territory. The primary endpoint included target vessel ischemia (TVI; r-SDS ≥ 2) at 8 months, whereas the clinical primary endpoint was major adverse cardiovascular events (MACE) at 3 years. The percent (%) myocardial ischemia (100 × SDS/68) was also calculated. At 8 months, TVI was identified in 11 and 4% in the provisional-FKI and routine-FKI groups, respectively (p = 0.226). SB-binary restenosis (48 vs. 4%, p < 0.001) and myocardial ischemia at the SB territory (11 vs. 0%, p = 0.030) were more common in the provisional-FKI group; however, in TVI patients, % myocardial ischemia (4.12 ± 1.23% vs. 3.68 ± 1.04%; p = 0.677) did not significantly differ. Moderate/severe ischemia (>10% myocardial ischemia) was not observed in the target vessel in either group. Long-term cumulative MACE were similar between the groups (9 vs. 14%; p = 0.358). Provisional-FKI according to TIMI-SB flow grade led to similar and acceptable myocardial ischemia, in comparison with routine-FKI, which may contribute to the identical long-term follow-up.