Scientific validation of clinical visual scales and Antera 3D™ consistency with derived measurements in the assessment of infantile haemangioma after laser therapy.

BACKGROUND: Laser therapy is a treatment for infantile haemangiomas. The efficacy of laser therapy for red lesions is determined by visual evaluation; however, this assessment is inaccurate and lacks objectivity. OBJECTIVE: To scientifically validate the consistency between pre- and post-treatment visual assessment grades for infantile haemangioma treated with pulsed dye laser (PDL) and the values calculated from images obtained with Antera 3D™. METHODS: This study involved 81 cases of infantile haemangiomas treated with PDL alone from 2012 to 2015 and with Antera 3D™ images of the lesions. Using images obtained before treatment and 4-6 weeks after the last treatment, the lesions were rated using a visual four-step scale. Ratings were categorised as Poor/Fair/Good/Excellent by the degree of improvement in the red colour tone. The red colour ratio was calculated using the haemoglobin distribution in the lesion and surrounding skin, and the improvement difference and improvement rate were then obtained. The correlation between the improvement difference and improvement rate, and visual evaluation was statistically analysed. RESULTS: No serious adverse effects were observed, with an average of 4.3 treatments per patient; 60.1% of the patients achieved Good/Excellent results. There were statistically significant differences in the post-treatment red colour ratio and improvement ratio in each category after visual evaluation classification. The improvement rate and the four visual grades were statistically correlated. CONCLUSION: This study confirmed the scientific validity of visual evaluation and the evaluation criteria calculated from Antera 3D™. This method could objectively determine treatment effectiveness.

A Comprehensive Study of the Immunophenotype and its Clinicopathologic Significance in Adult T-Cell Leukemia/Lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell tumor caused by human T-lymphotropic virus type 1 (HTLV-1). The typical ATLL immunophenotypes are described in the 2017 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (positive: CD2, CD3, CD5, CD4, and CD25; negative: CD7, CD8, and cytotoxic markers; and partially positive: CD30, CCR4, and FOXP3). However, limited studies are available on the expression of these markers, and their mutual relationship remains unknown. Furthermore, the expression status of novel markers associated with T-cell lymphomas, including Th1 markers (T-bet and CXCR3), Th2 markers (GATA3 and CCR4), T follicular helper markers (BCL6, PD1, and ICOS), and T-cell receptor (TCR) markers, and their clinicopathologic significance is unclear. In this study, we performed >20 immunohistochemical stains in 117 ATLL cases to determine the comprehensive immunophenotypic profile of ATLL, which were compared on the basis of clinicopathologic factors, including morphologic variants (pleomorphic vs anaplastic), biopsy locations, treatments, Shimoyama classification-based clinical subtype, and overall survival. CD3+/CD4+/CD25+/CCR4+ was considered a typical immunophenotype of ATLL, but approximately 20% of cases did not conform to this pattern. Simultaneously, the following new findings were obtained: (1) most cases were negative for TCR-ß and TCR-δ (104 cases, 88.9%), indicating the usefulness of negative conversion of TCR expression to provide differentiation from other T-cell tumors; (2) the positivity of CD30 and CD15 and the negativity of FOXP3 and CD3 were significantly associated with anaplastic morphology; and (3) atypical cases, such as T follicular helper marker-positive (12 cases, 10.3%) and cytotoxic molecule-positive cases (3 cases, 2.6%), were identified. No single markers could predict the overall survival among patients with acute/lymphoma subtypes of ATLL. The results of this study illustrate the diversity of ATLL phenotypes. In T-cell tumors occurring in HTLV-1 carriers, the possibility of ATLL should not be eliminated even when the tumor exhibits an atypical phenotype, and the confirmation of HTLV-1 in the tissue is recommended.

Fatal acquired coagulation factor V deficiency after hepatectomy for advanced hepatocellular carcinoma as a possible immune checkpoint inhibitor-related adverse event: a case report.

BACKGROUND: Atezolizumab plus bevacizumab therapy was recently introduced as the first line for unresectable advanced hepatocellular carcinoma (HCC), but immune-related adverse events (IrAEs) due to atezolizumab are a great concern. Here, we report the case of a patient who developed fatal acquired coagulation factor deficiency after hepatectomy for HCC, treated with atezolizumab and bevacizumab before surgery. CASE PRESENTATION: A 70-year-old man received right trisegmentectomy of the liver with hepaticojejunostomy for advanced HCC with bile duct invasion, after atezolizumab and bevacizumab therapy. The patient suffered the sudden onset of severe multiple coagulation factor deficiency (II, V, VII, VIII, IX, X, XI and XII) immediately following reoperation for anastomotic leakage of hepaticojejunostomy, 7 days after hepatectomy. The coagulation factor deficiency did not reverse even with intensive treatment, and the patient died of uncontrollable bleeding 32 days after hepatectomy. An IrAE due to atezolizumab was suspected because the patient had developed the possible IrAE of enthesitis of the right gastrocnemius muscle before surgery, and specific inhibitors against factor V and anti-factor V autoantibodies were detected, leading to an ultimate diagnosis of autoimmune FV/5 deficiency (AiF5D). CONCLUSION: Severe acquired coagulopathy should be recognized as a possible life-threatening IrAE when using atezolizumab and bevacizumab for HCC.

Clinically amyopathic dermatomyositis manifested after the allogeneic haematopoietic stem cell transplantation: Case presentation and literature review.

Clinically amyopathic dermatomyositis (CADM) lacks muscle symptoms, associated with rapidly progressive interstitial lung disease. Anti-melanoma differentiation-associated gene 5 (MDA-5) antibody has been identified as a disease-labelling autoantibody. We report two cases of CADM manifested after the allogeneic haematopoietic stem cell transplantation (allo-HSCT)-Case 1: a 56-year-old man with acute leukaemia received the allo-HSCT and Case 2: a 45-year-old female patient with lymphoma received the allo-HSCT. She received donor lymphocyte infusion because of a post-transplant relapse. After allo-HSCT or donor lymphocyte infusion, Gottron papules emerged, and both patients were diagnosed as CADM based on dermatological findings coupled with the positivity of anti-MDA-5 antibody, accompanied by interstitial shadows consistent with ILD on chest computed tomography. Case 2 was initially diagnosed as a kind of chronic graft versus host disease. Their symptoms were improved by the combination of immunosuppressive agents with a concomitant decrease in anti-MDA-5 antibody levels. For Case 2, rituximab was subsequently started for relapse of lymphoma, resulting in a substantial decrease in the level of anti-MDA-5 antibody and improvement in rash and ILD. Our cases raise a possibility that CADM emerges after the HSCT, highlighting the importance of early diagnosis to avoid fated progression into ILD.

Impact of anti-diabetic sodium-glucose cotransporter 2 inhibitors on tumor growth of intractable hematological malignancy in humans.

Under the dysfunction of mitochondria, cancer cells preferentially utilize both glycolytic and pentose phosphate pathways rather than electron transport chains to desperately generate adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH), classically recognized as the Warburg effect. Based on this background, the present study tested the hypothesis that anti-diabetic sodium-glucose cotransporter 2 (SGLT2) inhibitors would exert a tumor-suppressive impact on intractable human hematological malignancies via the modulation of glucose metabolism within cells and cell cycles. The level of mRNA for SGLT2 was remarkably elevated in leukemic cells from patients with adult T-cell leukemia (ATL), one of the most intractable blood cancers in humans, and as well as in two kinds of ATL cell lines (MT-1 and MT-2). Two kinds of SGLT2 inhibitors, Luseogliflozin and Tofogliflozin substantially suppressed the proliferation of MT-1 and MT-2 cells in both adherent and anchorage-independent culture conditions. Such a suppressive effect on tumor cell growth was reproduced by Luseogliflozin in leukemic cells in peripheral blood from patients with ATL. In MT-2 cells, both of SGLT2 inhibitors considerably attenuated glucose uptake, intracellular ATP levels, and NADPH production, resultantly enhancing cell cycle arrest at the G0/G1 phase. From the standpoint of metabolic oncology, the present study suggests that SGLT2 inhibitors would be a promising adjunctive option for the treatment of the most intractable human hematological malignancies like ATL.

Correlative volume-imaging using combined array tomography and FIB-SEM tomography with beam deceleration for 3D architecture visualization in tissue.

Focused ion beamed (FIB) SEM has a higher spatial resolution than other volume-imaging methods owing to the use of ion beams. However, in this method, it is challenging to analyse entire biological structures buried deep in the resin block. We developed a novel volume-imaging method by combining array tomography and FIB-SEM tomography and investigated the chondrocyte ultrastructure. Our method imparts certainty in determining the analysis area such that cracks or areas with poor staining within the block are avoided. The chondrocyte surface showed fine dendritic processes that were thinner than ultrathin sections. Upon combination with immunostaining, this method holds promise for analysing mesoscopic architectures.

Application of Neck Lift Technique for Corrections of Concave Deformity and Scar Contracture After Tracheal Fenestration.

ABSTRACT: Following a tracheostomy or tracheal fenestration procedure, neck concave deformity, and contracture after spontaneous closure are common problems. Since the neck is an exposed part of the body, its concave deformity can cause cosmetic problems and functional problems such as difficulty in neck extension and swallowing due to contracture. We report the case of a 63-year-old man who underwent tracheal fenestration for worsening respiratory status due to sepsis after aspiration pneumonia. After spontaneous closure of the tracheal fenestration, the patient developed a deformity of the neck, impaired neck extension, and dysphagia due to contracture. In this case, the submental sagging skin was used as a subcutaneous pedicle flap to correct the problem, and the result was both functionally and cosmetically satisfactory. We found that the submandibular skin could be used as a random pattern flap for reconstruction of the lower half of the neck. Therefore, this procedure can be an effective method for reconstruction around the tracheal stoma in the future.

Indication for management of oropharyngocutaneous fistulas after head and neck reconstruction using a "stick-shaped platysma flap" technique.

The main strength of the stick-shaped platysma flap technique is it provides adequate tissue volume, while being comparatively simple to perform. It is a highly efficient and straightforward method to close intractable fistulas with minimal morbidity.

The Positivity of Phosphorylated STAT3 Is a Novel Marker for Favorable Prognosis in Germinal Center B-Cell Type of Diffuse Large B-Cell Lymphoma.

On the basis of immunohistochemistry, diffuse large B-cell lymphoma (DLBCL) is categorized as a germinal center B-cell (GCB) or non-GCB subtype. Recent integrated genomic analyses have highlighted the importance of the JAK-STAT3 pathway in the molecular pathogenesis of DLBCL. However, its relevance to clinical outcomes remains controversial. Therefore, we evaluated the extent of the nuclear expression of phosphorylated STAT3 (pSTAT3), a surrogate marker of signal transducer and activator of transcription 3 (STAT3) activation, by immunohistochemistry. We also analyzed the potential relationship between pSTAT3 positivity (defined as ≥40% positive neoplastic cells) and clinicopathologic characteristics in 294 patients with DLBCL. pSTAT3 was detected in 122 patients (42%), with a higher rate in the non-GCB subtype than in the GCB subtype (57% vs. 28%, P<0.001). Factors potentially activating STAT3, MYD88L265P, and Epstein-Barr virus-encoded small RNA were identified in the pSTAT3-positive non-GCB subtype, whereas the pSTAT3-positive GCB subtype often showed STAT3 mutations and lacked EZH2 mutations and the rearrangements of BCL2 and MYC. Multivariate analyses revealed that the pSTAT3-positive GCB subtype showed a favorable prognosis (HR: 0.17; 95% confidence interval, 0.04-0.7; P=0.014). These findings suggest that pSTAT3 positivity may have a unique impact on the clinicopathologic characteristics of DLBCL, making it a promising novel marker for the favorable prognosis of patients with the GCB subtype.

Three-dimensional structure analysis of melanocytes and keratinocytes in senile lentigo.

Senile lentigo or age spots are hyperpigmented macules of skin that commonly develop following long-term exposure to ultraviolet radiation. This condition is caused by accumulation of large numbers of melanosomes (melanin granules) produced by melanocytes within neighboring keratinocytes. However, there is still no consensus regarding the melanosome transfer mechanism in senile lentigo. To date, most pathohistological studies of skin have been two-dimensional and do not provide detailed data on the complex interactions of the melanocyte-keratinocyte network involved in melanosome transfer. We performed a three-dimensional reconstruction of the epidermal microstructure in senile lentigo using three different microscopic modalities to visualize the topological melanocyte-keratinocyte relationship and melanosome distribution. Confocal laser microscopy images showed that melanocyte dendritic processes are more frequently branched and elongated in senile lentigo skin than in normal skin. Serial transmission electron micrographs showed that dendritic processes extend into intercellular spaces between keratinocytes. Focused ion beam-scanning electron micrographs showed that dendritic processes in senile lentigo encircle adjacent keratinocytes and accumulate large numbers of melanosomes. Moreover, melanosomes transferred to keratinocytes are present not only in the supranuclear area but throughout the perinuclear area except on the basal side. The use of these different microscopic methods helped to elucidate the three-dimensional morphology and topology of melanocytes and keratinocytes in senile lentigo. We show that the localization of melanosomes in dendritic processes to the region encircling recipient keratinocytes contributes to efficient melanosome transfer in senile lentigo.

Successful Treatment of Full Thickness Frontal Skull Bone Defect With Dermal Fat Grafting and Artificial Bone Grafts.

Rigid reconstruction for frontal bone defects not only improves function, but also approximates more normal appearance. However, in cases involving dural scar contractures, a concave deformation remains when rigid reconstruction is performed without compensating for dead space created by swelling of the brain. This study involved 4 cases in which a 2-stage reconstruction procedure was used to first eliminate dead space by grafting dermal fat, and subsequently carry out rigid reconstruction to achieve a natural forehead configuration. This method is advantageous and considered to be effective in allowing dead space to be easily filled with minimal invasiveness for concave deformations of the dura mater with bone defects. Furthermore, the risk of artificial bone exposure is reduced by adding the dermal component of dermal fat, which is grafted to thinned frontal skin.

Surgical Management of Deep Brain Stimulator Infection without Electrode Removal: Report of Two Cases.

Objective Stimulation of the subthalamic nucleus by implanted electrodes (deep brain stimulation [DBS]) is performed to suppress symptoms of Parkinson's disease. However, postoperative wound dehiscence and infection can require removal of the implanted electrode leads. This report describes treatment of intractable unilateral wound infection in two patients without removing the DBS device. Methods First, components of the DBS system were removed except for the electrode lead and thorough debridement of the infected wound was conducted. Second, the edges of the bone defect left by removal of DBS components were smoothed to eliminate dead space. Subsequently, the electrode lead was covered by using a pericranial-frontalis-muscle flap or a bi-pedicled-scalp flap with good blood supply. Closed intrawound continuous negative pressure and irrigation treatment was conducted for 1 week after the surgery, and then the drain was removed. Results We treated two patients with wound infection after implantation of DBS electrodes. Case 1 developed a cutaneous fistula and Case 2 had wound dehiscence. After treatment by the method described above, complete wound healing was achieved in both patients. Conclusion DBS is always associated with a risk of infection or exposure of components and treatment can be very difficult. We successfully managed intractable wound infection while leaving the electrode lead in situ, so that it was subsequently possible to continue DBS for Parkinson's disease.

Analysis of Scars and Keloids by Focused Ion Beam/Scanning Electron Microscopy: Distinguishing Between Hypertrophic Scars and Keloids.

BACKGROUND: Histological differentiation between hypertrophic scars (HSs) and keloids has been considered difficult. In this study, we analyzed differences in the 3-dimensional tissue architecture between HSs and keloids using focused ion beam/scanning electron microscopy (FIB/SEM). METHODS: Five specimens each of normal skin, normotrophic scars (NSs), HSs, and keloids were investigated. Three sites in each specimen were observed by FIB/SEM tomography, resulting in an observation of 15 sites per tissue type. We identified fibroblasts and macrophages and assessed the contact ratio and the mode of intercellular contact (planar contact or point contact). The significance of differences among the 4 tissue types was determined by Fisher exact test. RESULTS: In normal skin, contact between fibroblasts and macrophages was observed at all 15 sites, and the mode of contact was always planar. There was contact at 87% of the NS sites (planar: point = 80%: 7%). In HSs, contact was seen at 80% of the sites (planar: point = 20%: 60%). In keloids, contact was found at only 15% of the sites (planar: point = 7.5%: 7.5%). The intercellular contact ratio showed no significant differences among normal skin, NSs, and HSs; however, a significant difference was noted between these tissues and keloids. The intercellular contact mode also showed no significant difference between normal skin and NSs, but a significant difference between these tissues and HSs. CONCLUSIONS: These histopathologic findings suggest that FIB/SEM tomography is useful for distinguishing between HSs and keloids and can provide important knowledge for understanding the pathogenesis of keloids.

Late-Onset Infection of Resorbable Plates After Multiple Facial Fractures.

In recent years, a variety of resorbable plates have been used for craniofacial fractures. The authors report a case of plate infection that occurred more than 1 year after surgery and was difficult to distinguish from a foreign body reaction. A 19-year-old male suffered fractures of the right zygomatic bone, orbital floor, and left maxilla in a motorcycle accident. Reduction was performed using resorbable plates at 7 days after injury. The postoperative course was good. However, the patient presented 396 days after surgery with redness/swelling of the right upper eyelid and right cheek pain. There were no systemic signs of infection such as fever. A foreign body reaction to the plate was suspected. After 1 week, swelling of the patient's upper eyelid was worse, and the remaining resorbable plate was removed via a skin incision. Swelling subsequently extended to the right cheek and upper gingiva, and all plates were removed under general anesthesia on the 418th day after the first operation. The swelling subsided after removal of the plates. Pathological examination revealed neutrophil infiltration and Staphylococcus hominis was detected by bacterial culture, leading to a diagnosis of late-onset plate infection. This coagulase-negative staphylococcus usually causes infection in neonates and immunocompromised individuals. Postoperative complications of resorbable plates include foreign body reaction and infection, which are difficult to differentiate clinically. Removing the foreign body is the principal technique for obvious wound infection. A foreign body reaction with subcutaneous fluid retention is slow to heal. Therefore, early plate removal is also recommended.

Transplant-related complications are impediments to the success of allogeneic hematopoietic stem cell transplantation for adult T cell leukemia patients in non-complete remission.

Outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with adult T cell leukemia/lymphoma (ATL) are not satisfactory, particularly in patients in non-complete remission at transplantation (Pt-non-CR). We conducted a regional retrospective study in the ATL endemic area of Okinawa, Japan. Of 62 ATL patients, 21 received allo-HSCT in CR and 41 in non-CR. The 3-year overall survival (3yOS) rate and median survival time for the whole cohort was 25.6% and 7.7 months, respectively. The 3yOS of Pt-non-CR was significantly lower than that of patients in CR (Pt-CR) (16.8% vs. 43.6%, P = 0.005). Transplant-related mortality (TRM) was significantly higher in Pt-non-CR than in Pt-CR (46.3% vs. 15.7%, P = 0.025), while there was no significant difference in disease-associated mortality (DAM) between Pt-non-CR and Pt-CR. Multivariable analysis for Pt-non-CR revealed that poor performance status (poor-PS) and higher sIL-2R level (high sIL-2R) adversely affected OS. Poor-PS was associated with higher TRM, but not with higher DAM in Pt-non-CR. High sIL-2R did not affect TRM or DAM in Pt-non-CR. Overall, high TRM rates rather than DAM contribute to the poor outcomes of Pt-non-CR, suggesting that not only disease control but also management of transplant-related complications is required for allo-HSCT in ATL patients.

New Alternative Therapeutic Strategy for Gustilo Type IIIB Open Fractures, Using an Intra-Wound Continuous Negative Pressure Irrigation Treatment System.

The treatment of Gustilo type IIIB and IIIC open fractures remains a challenging problem, because the infection rate is 15-45%. Infection can lead to serious complications such as osteomyelitis or amputation. The intra-wound continuous negative pressure and irrigation treatment (IW-CONPIT) was developed for infected wounds and intractable ulcers, and is very effective in suppressing infection and accelerating wound healing. Here the IW-CONPIT was applied to severe open fractures for the purpose of preventing infection. After thorough debridement and lavage of the wound, bony stabilization is performed by external fixation. Dermal matrix is grafted onto any areas where the bone or tendon is exposed. A sponge containing two tubes is placed over the entire surface of the wound including the dermal matrix. Then it is covered with a film dressing to make the wound completely airtight. A bottle of physiologic saline solution is attached to one tube, and a continuous aspirator is attached to the other. This system maintains negative pressure on the wound surface, which is continuously irrigated. Thirty-five patients were treated with this method. A superficial infection developed in two cases but was resolved by additional debridement and continued application of IW-CONPIT. Complete wound healing was obtained with split thickness skin graft in all cases. There were no complications such as osteomyelitis, delayed bone union or amputation. IW-CONPIT was able to definitively prevent wound infection in Gustilo type ⅢB open fractures. We believe this method will become a standard treatment option for this condition.

Closure of Intractable Enterocutaneous Fistula with a Rectus Abdominis Musculocutaneous Flap.

Large enterocutaneous fistulas of the small intestine are rare and difficult to close, particularly if the fistula is associated with massive leakage of digestive juice and the residual intestinal tract is too short for anastomosis. We present a patient who underwent small bowel resection and secondary anastomosis following massive necrosis of the small intestine due to superior mesenteric artery thrombosis. After resection of an enterocutaneous fistula and reanastomosis, the residual small bowel was only 70 cm long with a persistent fistula. We successfully closed the fistula by employing a hinged rectus abdominis musculocutaneous flap. Here, we report our procedure for treating a large enterocutaneous fistula without performing laparotomy and bowel resection.

Phosphorylated STAT3 expression predicts better prognosis in smoldering type of adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell neoplasm, and is divided into 2 indolent (smoldering and chronic) and 2 aggressive (acute and lymphoma) clinical subtypes. Based on previous integrated molecular analyses suggesting the importance of the JAK-STAT pathway in ATLL, we attempted to clarify the clinicopathological significance of this pathway. Clinical and morphological findings were reviewed in 116 cases with ATLL. The nuclear localizations of phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6 were analyzed by immunohistochemistry. Targeted sequencing was undertaken on the portion of STAT3 encoding the Src homology 2 domain. Expression of pSTAT3 was observed in 43% (50/116) of ATLL cases, whereas pSTAT5 and pSTAT6 were largely undetected. Cases with the lymphoma type showed significantly less frequent pSTAT3 expression (8/45, 18%) than those with the other subtypes (41/66, 62%; P < .001). STAT3 mutations were detected in 36% (10/28) and 19% (12/64) of cases with the smoldering and aggressive types of ATLL, respectively. The correlation between STAT3 mutation and pSTAT3 expression was not significant (P = .07). Both univariate and multivariate analysis revealed that pSTAT3 expression was significantly associated with better overall survival and progression-free survival in the smoldering type of ATLL, whereas STAT3 mutation was not related to a line of clinical outcome. Collectively, our data show that only the lymphoma type showed a low prevalence of tumor cells positive for pSTAT3 expression, and raises the possibility that pSTAT3 expression is a novel biomarker to predict better prognosis in the smoldering type of ATLL.