Suppression of TNF-α activity by immobilization rescues Mkx expression and attenuates tendon ossification in a mouse Achilles tenotomy model.

Traumatic heterotopic ossification is a condition in which extraskeletal bone formation occurs in soft tissues after injury. It most commonly occurs in patients who had major orthopedic surgery and in those with severe extremity injuries. The lesion causes local pain and can impair motor function of the affected limb, but there is currently no established prophylaxis or treatment for this condition. In this study, we show that immobilization at an early stage of the inflammatory response after injury can attenuate ossification formation in a murine Achilles tenotomy model. Gene expression analysis revealed a decrease in the expression of Tnf and an increase in the expression of Mkx, which encodes one of the master regulators of tendon differentiation, Mohawk. Notably, we found that TNF-α suppressed the expression of Mkx transcripts and accelerated the osteogenic differentiation of tendon-derived mesenchymal stem cells (MSCs), suggesting that TNF-α acts as a negative regulator of Mkx transcription. Consistent with these findings, pharmaceutical inhibition of TNF-α increased the expression of Mkx transcripts and suppressed bone formation in this mouse model. These findings reveal the previously unrecognized involvement of TNF-α in regulating tendon MSC fate through suppression of Mkx expression and suggest that TNF-α is a potential target for preventing traumatic heterotopic ossification.

Thioredoxin promotes the regeneration and binding of elastic fibre and basement membrane.

OBJECTIVE: Thioredoxin (TRX), a ubiquitous protein with strong antioxidant activity, decreases in the skin with age. A decrease in TRX is expected to induce cellular senescence, chronic inflammation, and degeneration and loss of extracellular matrix (ECM), such as collagen and elastin within the skin. In this study, we investigated the effects of TRX addition to excised skin or skin models to understand the role of TRX on cells and ECM within the skin. METHODS: To evaluate its effect on skin cells, we cultured a three-dimensional (3D) skin model in a medium containing TRX. The mRNA expression levels of proteins related to elastic and collagen fibres and the basement membrane were determined. Furthermore, 3D imaging and computational analysis were performed to evaluate the effect of TRX on the elastic fibres and extending COL VII structures in excised human skin after coculturing with TRX for 1, 4, 5 and 6 days. RESULTS: Thioredoxin application to a 3D skin model upregulated elastin, COLI and COLVII mRNA expression. Applying TRX to the excised skin increased the number of linear elastic fibres. This effect of TRX demonstrated a daily increment in a dose-dependent manner. Thioredoxin extended the fibrous structure of COL VII into the dermis, expanding its colocalization region with elastic fibres. These structural effects were confirmed using 3D imaging and computational methods. CONCLUSION: Thioredoxin elongates elastic fibres from the dermis to the basement membrane and extends the COL VII structure from the basement membrane to the dermis in excised human skin. These findings suggest the potential of TRX to protect the skin against age-related alterations such as wrinkles and sagging.

OBJECTIF: Thioredoxin (TRX), une protéine ubiquitaire dotée d'une forte activité antioxydante, diminue dans la peau avec l'âge. Une diminution de la TRX est susceptible d'induire la sénescence cellulaire, l'inflammation chronique, et la dégénérescence ainsi que la perte de la matrice extracellulaire (ECM), telle que le collagène et l'élastine de la peau. Dans cette étude, nous avons examiné les effets de l'ajout de TRX à la peau prélevée ou aux modèles de peau afin de comprendre le rôle de TRX sur les cellules et la matrice extracellulaire (ECM) de la peau. MÉTHODES: Pour évaluer son effet sur les cellules cutanées, nous avons cultivé un modèle de peau tridimensionnel (3D) dans un milieu contenant du TRX. Les niveaux d'expression de l'ARNm des protéines liées aux fibres élastiques et de collagène ainsi que de la membrane basale ont été déterminés. De plus, une imagerie 3D et une analyse informatique ont été réalisées pour évaluer l'effet de la TRX sur les fibres élastiques et les structures de COL VII étendues dans la peau humaine prélevée après une coculture avec la TRX pendant 1, 4, 5 et 6 jours. RÉSULTATS: L'application de la Thioredoxin à un modèle de peau en 3D a régulé à la hausse l'expression de l'élastine, du COLI et du COLVII au niveau de l'ARNm. L'application de TRX à la peau excisée a augmenté le nombre de fibres élastiques linéaires. Cet effet du TRX a montré une augmentation quotidienne de manière dose­dépendante. Le Thioredoxin a étendu la structure fibreuse du COL VII dans le derme, élargissant ainsi sa région de colocalisation avec les fibres élastiques. Ces effets structuraux ont été confirmés à l'aide d'imagerie 3D et de méthodes computationnelles. CONCLUSIONS: La Thioredoxin allonge les fibres élastiques du derme à la membrane basale et étend la structure de COL VII de la membrane basale au derme dans la peau humaine excisée. Ces résultats suggèrent le potentiel de la TRX pour protéger la peau contre les altérations liées à l'âge telles que les rides et le relâchement cutané.

Novel Route for Enhancing Piezoelectricity of Ferroelectric Films: Controlling Nontrivial Polarization States in Pb(Zr, Ti)O3 Monodomain Superlattice Structure.

Artificial superlattice films made of Pb(Zr0.4Ti0.6)O3 and Pb(Zr0.6Ti0.4)O3 were investigated for their polarization states and piezoelectric properties theoretically and experimentally in this study. The developed theory predicts nontrivial polarization along neither [001] nor [111] directions in (111)-epitaxial monodomain superlattice films with uniform compressive strain. Such films were achieved via pulsed laser deposition. When the layer thickness is reduced to 3 nm, d33 becomes 128 ± 3.8 pm/V at 100 kV/cm and 71.3 ± 2.83 pm/V at 600 kV/cm, comparable to that of (111)-oriented Pb(Zr0.4Ti0.6)O3 or Pb(Zr0.6Ti0.4)O3 bulks and clearly exceeding that of the typical clamped films. The measurement agrees with the theoretical analysis, which reveals that the enhanced piezoelectricity is due to rotation of the nontrivial polarization. Furthermore, the theoretical study predicts an even larger d33 exceeding 300 pm/V for specific parameters in superlattice films with uniform tensile strain, which is promising for applications of microelectromechanical systems.

Elastin microfibril interface-located protein 1 in fibroblasts is regulated by amphiregulin and interleukin-1α produced by keratinocytes.

OBJECTIVE: The structure of elastic fibres changes with ageing. Elastin microfibril interface-located protein 1 (EMILIN-1) is known to contribute to structural changes in elastic fibres. EMILIN-1 is one of the components of elastic fibres and also colocalizes with oxytalan fibres near the epidermis. Therefore, EMILIN-1 may be affected by epidermal-dermal interactions. The purpose of this study is to identify the key factors involved in epidermal-dermal interactions during the structural degeneration of elastic fibres. METHODS: Keratinocytes and fibroblasts were co-cultured, and changes in elastic fibre-related proteins were evaluated. Additionally, cytokine arrays were used to identify the factors involved in epidermal-dermal interactions. RESULTS: EMILIN-1 expression in fibroblasts was increased in the presence of keratinocytes, and its expression decreased when keratinocytes were stressed. Amphiregulin (AREG) and interleukin-1α (IL-1α) were identified as the keratinocyte-derived cytokines that influence the production of EMILIN-1, which is secreted by the fibroblasts. EMILIN-1 expression was promoted by AREG and decreased by IL-1α via an increase in cathepsin K (a catabolic enzyme). AREG and IL-1α were associated with changes in EMILIN-1 levels in fibroblasts. CONCLUSION: The findings suggest that the suppression of IL-1α expression and promotion of AREG expression in the epidermis could be a new approach that prevents the wrinkles and sagging caused by the structural changes in elastic fibres.

OBJECTIF: La structure des fibres élastiques change avec le vieillissement. La protéine située à l'interface des microfibrilles d'élastine 1 (EMILIN-1) est connue pour sa contribution aux changements structurels des fibres élastiques. EMILIN-1 est l'un des composants des fibres élastiques et colocalise également avec les fibres oxytalanes à proximité de l'épiderme. Par conséquent, EMILIN-1 peut être affectée par des interactions épidermiques-dermiques. Cette étude a objectif d'identifier les facteurs clés impliqués dans les interactions épidermiques-dermiques au cours de la dégénérescence structurelle des fibres élastiques. MÉTHODES: Co-cultiver les kératinocytes et les fibroblastes, et évaluer les changements dans les protéines liées aux fibres élastiques. De plus, identifier les facteurs impliqués dans les interactions épidermique-dermique des puces à l'aide des cytokines. RÉSULTATS: L'expression de l'EMILIN-1 dans les fibroblastes était augmentée en présence des kératinocytes, et son expression a diminué lorsque les kératinocytes ont été stressés. L'amphiréguline (AREG) et l'interleukine-1α (IL-1α) étaient identifiées comme les cytokines dérivées des kératinocytes qui influencent la production d'EMILIN-1, qui est sécrétée par les fibroblastes. L'expression d'EMILIN-1 était favorisée par l'AREG et diminuée par l'IL-1α via une augmentation de la cathepsine K (une enzyme catabolique). L'AREG et l'IL-1α étaient liés aux changements du niveau d'EMILIN-1 dans les fibroblastes. CONCLUSION: Les résultats montrent que la suppression de l'expression de l'IL-1α et la promotion de l'expression de l'AREG dans l'épiderme pourraient être une nouvelle approche qui prévient les rides et l'affaissement dus aux changements structurels des fibres élastiques.

Investigation of stratum corneum cell morphology and content using novel machine-learning image analysis.

BACKGROUND: The morphology and content of stratum corneum (SC) cells provide information on the physiological condition of the skin. Although the morphological and biochemical properties of the SC are known, no method is available to fully access and interpret this information. This study aimed to develop a method to comprehensively decode the physiological information of the skin, based on the SC. Therefore, we established a novel image analysis technique based on artificial intelligence (AI) and multivariate analysis to predict skin conditions. MATERIALS AND METHODS: SC samples were collected from participants, imaged, and annotated. Nine biomarkers were measured in the samples using enzyme-linked immunosorbent assay. The data were then used to teach machine-learning models to recognize individual SC cell regions and estimate the levels of the nine biomarkers from the images. Skin physiological indicators (e.g., skin barrier function, facial analysis, and questionnaires) were measured or obtained from the participants. Multivariate analysis, including biomarker levels ​​and structural parameters of the SC as variables, was used to estimate these physiological indicators. RESULTS: We established two machine-learning models. The accuracy of recognition was assessed according to the average intersection over union (0.613), precision (0.953), recall (0.640), and F-value (0.766). The predicted biomarker levels significantly correlated with the measured levels. Skin physiological indicators and questionnaire answers were predicted with strong correlations and correct answer rates. CONCLUSION: Various physiological skin conditions can be predicted from images of the SC using AI models and multivariate analysis. Our method is expected to be useful for dermatological treatment optimization.

Eribulin mesylate induces bone mass loss by promoting osteoclastic bone resorption in mice.

Over the past few decades, the clinical outcomes of patients with cancer have significantly improved mostly owing to the development of effective chemotherapeutic treatments. However, chronic health conditions such as bone mass loss and risk of fragility fractures caused by chemotherapy have also emerged as crucial issues in patients treated for cancer. In this study, we aimed to understand the effect of eribulin mesylate (ERI), a microtubule-targeting agent currently used to treat metastatic breast cancer and certain subtypes of advanced sarcomas, on bone metabolism in mice. The administration of ERI reduced bone mass in mice, mainly by promoting osteoclast activity. Gene expression analysis of skeletal tissues revealed no change in the expression levels of the transcripts for RANK ligand, one of the master regulators of osteoclastogenesis; however, the transcript levels of osteoprotegerin, which neutralizes RANK ligand, were significantly reduced in ERI-treated mice compared with those in vehicle-treated controls, indicating a relative increase in RANK ligand availability after ERI treatment. In line with the increased bone resorption in ERI-treated mice, we found that zoledronate administration effectively suppressed bone loss in these mice. These results reveal a previously unrecognized effect of ERI on bone metabolism and suggest the application of bisphosphonates for patients with cancer undergoing treatment with ERI.

Long Hanging Structure of Collagen VII Connects the Elastic Fibers and the Basement Membrane in Young Skin Tissue.

Aging leads to substantial structural changes in the skin. Elastic fibers maintain skin structure, but their degeneration and loss of function with age result in wrinkle formation and loss of skin elasticity. Oxytalan fiber, a type of elastic fiber, extends close to the dermal-epidermal junction (DEJ) from the back of the dermis. Oxytalan fibers are abundant in the papillary layer and contribute to skin elasticity and texture. However, to accurately understand the mechanisms of skin elasticity, the interaction between elastic fibers and DEJ should be elucidated. Here, we investigated elastic fibers and DEJ and their structural alterations with aging. Several basement membrane proteins [collagen (COL) IV, COLVII, and laminin 332], fibrous tropoelastin, and fibrillin-1 in excised human skin tissue were observed using three-dimensional imaging. Age-related alterations in COLVII, elastic fibers, and fibrillin-1 were evaluated. We found that COLVII forms long hanging structures and is co-localized with fibrous tropoelastin in young skin but not aged skin. Fibrillin-1-rich regions were observed at the tips of elastin fibers in young skin tissue, but rarely in aged skin. This co-localization of elastic fiber and COLVII may maintain skin structure, thereby preventing wrinkling and sagging. COLVII is a potential therapeutic target for skin wrinkling.

Exponential increase of the gestational-age-specific incidence of preeclampsia onset (COPE study): a multicenter retrospective cohort study in women with maternal check-ups at <20 weeks of gestation in Japan.

According to the 2004 Japanese definition, early-onset (EO) preeclampsia (PE) is defined as PE occurring at <32 weeks of gestation. This was based on the presence of "dual peaks" (30-31 and 34-35 weeks) in the prevalence of severe forms of hypertension. In contrast, the international definition adopted a cutoff of 34 weeks based on the consensus. Our aim was to investigate whether there were "dual peaks" in the gestational-age-specific incidence or prevalence of PE onset in pregnant women who underwent maternal check-ups at <20 weeks of gestation in a multicenter retrospective cohort study. Diagnoses of PE and superimposed preeclampsia (SPE) were based on the new Japanese definition. A total of 26,567 pregnant women with singleton pregnancy were investigated. The best fitting equations for the distribution of the onset of gestational-age-specific incidence (hazard) rates of PE/SPE, PE, and PE with severe hypertension (a systolic blood pressure ≥160 and/or a diastolic blood pressure ≥110 mmHg) were investigated using the curve estimation function in SPSS. PE/SPE occurred in 1.83% of the patients. EO-PE/SPE with onset at <32 and <34 weeks of gestation and preterm PE/SPE occurred in 0.38, 0.56, and 1.07% of the patients, respectively. Gestational-age-specific incidence rates of PE/SPE, PE, and PE with severe hypertension showed exponential increases, with very high R2 values (0.975, 0.976, and 0.964, respectively). There were no "dual peaks" in the prevalence rates of women with SPE/PE, PE, and PE with severe hypertension. In conclusion, the absence of "dual peaks" refutes the previous rationale of EO-PE being defined as PE at <32 weeks of gestation. Further studies to determine an appropriate definition of EO-PE/SPE are needed.

Trehangelins ameliorate inflammation-induced skin senescence by suppressing the epidermal YAP-CCN1 axis.

Trehangelins (THG) are newly identified trehalose compounds derived from broth cultures of an endophytic actinomycete, Polymorphospora rubra. THG are known to suppress Cellular Communication Network factor 1 (CCN1), which regulates collagen homeostasis in the dermis. Although the physical properties of THG suggest a high penetration of the stratum corneum, the effect of THG on the epidermis has not been reported. Here we describe a possible mechanism involved in skin aging focusing on the effect of THG on epidermal CCN1. This study shows that: (1) THG suppress epidermal CCN1 expression by inhibiting the translocation of Yes-Associated Protein (YAP) to nuclei. (2) Epidermal CCN1, localized at the basement membrane, regulates the balance between the growth and differentiation of keratinocytes. (3) Keratinocytes secrete more CCN1 than fibroblasts, which leads to disruption of the basement membrane and extracellular matrix components. (4) The secretion of CCN1 from keratinocytes is increased by ultraviolet B exposure, especially in aged keratinocytes, and deteriorates the elastic fiber structures in the underlying dermis. (5) Topical application of THG ameliorates the structure of the basement membrane in ex vivo human skin explants. Taken together, THG might be a promising treatment for aged skin by suppressing the aberrant YAP-CCN1 axis.

Elastin microfibril interface-located protein 1 and its catabolic enzyme, cathepsin K, regulate the age-related structure of elastic fibers in the skin.

INTRODUCTION: The elastic fiber structure becomes shorter, thicker, and curved with age. Nonetheless, the proteins and catabolic enzymes influencing the maintenance of and change in the three-dimensional (3D) structure of elastic fibers remain unknown. This study aimed to identify the proteins involved in the maintenance and degeneration of elastic fiber structures. METHODS: We performed a combined 3D structural analysis using tissue decolorization technology and mRNA abundance and comprehensive protein expression of tissue-derived cells. The relationship between the proteins was evaluated. RESULTS: Elastin microfibril interface-located protein 1 (EMILIN-1) and cathepsin K (CTSK) were implicated in structural changes in elastic fibers with aging. EMILIN-1 and CTSK levels were highly correlated and changed with age. CTSK was identified as the degrading enzyme of EMILIN-1. CTSK fragmented the otherwise linearly existing dermal elastic fiber structure, with more evident changes in oxytalan fibers. EMILIN-1 expression in fibroblasts was increased by co-culturing with keratinocytes. Furthermore, CTSK expression was increased by UV stress in keratinocytes, resulting in decreased EMILIN-1 expression. CONCLUSION: Using our new assessment strategy, we observed that EMILIN-1 and CTSK are highly linked to changes in the elastic fiber structure with aging. These results indicate that suppressing CTSK expression and increasing EMILIN-1 expression might be an effective approach to prevent elastic fiber morphological changes that lead to wrinkles and sagging. Furthermore, EMILIN-1 in the dermis increases due to interaction with the epidermis, which could provide a new target for the therapeutic care of elastic fibers (including preservation of oxytalan fibers) in epidermis-dermis interaction.

Split-dose low-volume polyethylene glycol is non-inferior but less preferred compared with same-day bowel preparation for afternoon colonoscopy.

Currently, the same-day polyethylene glycol-electrolyte lavage solution (PEG-ELS) regimen is particularly recommended for afternoon colonoscopy as an alternative to the split-dose regimen in western countries. However, in Japan, the split-dose regimen has never been used as a standard colonoscopy preparation regimen. The aim of this study was to compare the efficacy and tolerability of split-dose PEG containing ascorbic acid (ASC) with same-day single dose PEG-ASC in Japan.This was a single-blinded, non-inferiority, two-center, randomized, controlled study. In-hospital patients were randomized to the same-day regimen or the split regimen using a web-based registry system. The same-day group was instructed to take 5 mL of sodium picosulfate in the evening, and on the day of the colonoscopy, they took 1.5 L of PEG-ASC. The split group was instructed to take 1 L of PEG-ASC before the day of colonoscopy, followed by another 1 L of PEG-ASC on the day of colonoscopy. Bowel cleansing was evaluated by the Boston Bowel Preparation Scale.A total of 153 patients were randomized to either the same-day group (n=78, males 60.0%, mean age 62.7 years) or the split group (n=75, 61.3%, 61.9 years). The rates of successful bowel cleansing were 83.3% in the same-day group vs. 92.0% (83.4%-97.0%) in the split group, P=0.10). No serious adverse events occurred in the study population. However, more patients in the same-day group were willing to repeat the same preparation regimen (P<0.001). The split-dose regimen was not inferior to the same-day regimen with respect to the efficacy of bowel preparation, but the patients preferred the same-day regimen.

A Novel In Vitro Assay Using Human iPSC-Derived Sensory Neurons to Evaluate the Effects of External Chemicals on Neuronal Morphology: Possible Implications in the Prediction of Abnormal Skin Sensation.

Neuronal morphological changes in the epidermis are considered to be one of causes of abnormal skin sensations in dry skin-based skin diseases. The present study aimed to develop an in vitro model optimised for human skin to test the external factors that lead to its exacerbation. Human-induced pluripotent stem cell-derived sensory neurons (hiPSC-SNs) were used as a model of human sensory neurons. The effects of chemical substances on these neurons were evaluated by observing the elongation of nerve fibers, incidence of blebs (bead-like swellings), and the expression of nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2). The nerve fiber length increased upon exposure to two common cosmetic preservatives-methylparaben and phenoxyethanol-but not to benzo[a]pyrene, an air pollutant at the estimated concentrations in the epidermis. Furthermore, the incidence of blebs increased upon exposure to benzo[a]pyrene. However, there was a decrease in the expression of NMNAT2 in nerve fibers, suggesting degenerative changes. No such degeneration was found after methylparaben or phenoxyethanol at the estimated concentrations in the epidermis. These findings suggest that methylparaben and phenoxyethanol promote nerve elongation in hiPSC-SNs, whereas benzo[a]pyrene induces nerve degeneration. Such alterations may be at least partly involved in the onset and progression of sensitive skin.

Clinical significance of neutrophil gelatinase-associated lipocalin and galectin-7 in tape-stripped stratum corneum of acne vulgaris.

The usefulness of stratum corneum neutrophil gelatinase-associated lipocalin and stratum corneum galectin-7 as biomarkers of acne vulgaris was studied. A comparison of neutrophil gelatinase-associated lipocalin levels on the cheeks of patients with acne vulgaris at the start of the study and at the time of symptom improvement showed a significant decrease. On the other hand, the galectin-7 levels at the time of symptom improvement were significantly higher than those at the start of the study. Therefore, because the inflammation in the epidermis and hair follicles was reduced after therapy, as a result of the solution of the inflammatory eruptions caused by acne vulgaris, the neutrophil gelatinase-associated lipocalin level also showed a significant decrease after therapy. These results suggest that stratum corneum neutrophil gelatinase-associated lipocalin may be useful as an objective biomarker of changes in acne vulgaris symptoms.

Prognostic factors for salvage endoscopic resection for esophageal squamous cell carcinoma after chemoradiotherapy or radiotherapy alone.

BACKGROUND AND STUDY AIMS: Endoscopic resection is one treatment option for residual or locally recurrent esophageal cancer after definitive chemoradiotherapy or radiotherapy alone. However, little is known about the clinical benefit of salvage endoscopic resection for these lesions. Therefore, the effectiveness and prognostic factors of salvage endoscopic resection were investigated. PATIENTS AND METHODS: A total of 37 patients with esophageal squamous cell carcinoma (SCC) who underwent salvage endoscopic resection after definitive chemoradiotherapy or radiotherapy alone were reviewed. The method of salvage endoscopic resection was endoscopic mucosal resection using a cap (EMR-C), strip biopsy, or endoscopic submucosal dissection. The effectiveness and prognostic factors of salvage endoscopic resection were retrospectively analyzed. RESULTS: A total of 37 patients with 49 lesions underwent salvage endoscopic resection. Baseline clinical stages were I in 23 patients, II in 3 patients, III in 9 patients, and IV in 2 patients. The number of locoregional recurrences and residual lesions were 35 and 14, respectively. The curative en bloc resection rate was 53.1 % (26/49). The total incidence of complications was 18.9 % (7/37); all were successfully managed conservatively. The 3-year and 5-year overall survival rates were 72.9 % and 53.3 %, respectively, with a median follow-up period of 54 months. Baseline clinical T1 - 2 and N0 were significant factors for good prognosis in terms of overall survival on univariate analysis. CONCLUSIONS: Salvage endoscopic resection, especially EMR-C, is a safe and feasible procedure to control residual or recurrent superficial esophageal SCC after definitive chemoradiotherapy or radiotherapy alone. The present results showed that baseline clinical T1 - 2 and N0 before chemoradiotherapy or radiotherapy were significant prognostic factors.

Sarcoid-like reaction mimicking vaginal cancer recurrence.

A sarcoid-like reaction is a development of non-caseating granuloma in patients with underlying malignancy and represents a false positive finding on positron emission tomography/computed tomography (PET/CT). A sarcoid-like reaction is a benign condition; therefore, differentiating a sarcoid-like reaction from cancer recurrence is necessary. Only uterine and ovarian cancer related cases have been reported in the gynecological field and to the best of our knowledge, this is the first case of a sarcoid-like reaction in vaginal cancer. A 59-year-old vaginal cancer patient received concurrent chemoradiotherapy and achieved complete remission. Recurrence of vaginal cancer was suspected because of the elevation of serum squamous cell carcinoma antigen level. PET/CT revealed abnormal uptake at the bilateral mediastinal and hilar lymph nodes. A non-caseating granuloma was detected from the biopsy of the swollen lymph nodes. No evidence of cancer recurrence was observed. A sarcoid-like reaction should be considered when evaluating PET/CT in cancer patients to prevent unnecessary treatments.

The efficacy of recombinant human soluble thrombomodulin for obstetric disseminated intravascular coagulation: a retrospective study.

INTRODUCTION: Recombinant human soluble thrombomodulin (rhTM) is a novel anti-coagulant agent that regulates the imbalanced coagulation system by reducing the excessive activation of thrombin. rhTM potentially reduces the morbidity and mortality in patients with sepsis-induced disseminated intravascular coagulation (DIC). However, the efficacy of rhTM in obstetric DIC has not yet been established. We performed this study to examine whether the administration of rhTM was a potentially effective treatment for DIC induced by one or more underlying obstetric disorders. METHODS: This is a single-center, retrospective cohort study conducted between January 2007 and February 2015 using the records of the Department of Obstetrics at the Perinatal Medical Center of TOYOTA Memorial Hospital, Aichi, Japan. The eligibility criteria were known or suspected obstetric DIC documented on the basis of clinical and laboratory data and association with one or more major underlying obstetric disorders. Baseline imbalance between patients with and without treatment of rhTM was adjusted using an inverse probability of treatment weighting using propensity scores composed of the following independent variables: severe postpartum hemorrhage, placental abruption, and preeclampsia/eclampsia, including hemolysis, elevated liver enzymes, and low platelet syndrome, initial platelet counts, D-dimer levels, fibrinogen levels, and prothrombin time-international normalized ratio (PT-INR). We evaluated laboratory changes and clinical outcomes in the early phase of obstetric DIC. RESULTS: In total, 66 of 4627 patients admitted to our department during the study period fulfilled the required criteria; of these, 37 and 29 patients were included in the rhTM and control group, respectively. After adjustment, treatment with rhTM was associated with significant improvements in platelet counts, D-dimer levels, fibrinogen levels, and PT-INR compared with the control group. The platelet concentrate transfusion volume was significantly lower in the rhTM treatment group (3.02 vs 6.03 units, P = 0.016). None of the adjusted group differences were statistically significant for all types of organ damage and failure. CONCLUSION: rhTM administration was associated with clinical and laboratory improvement in patients with DIC caused by underlying obstetric conditions. Further clinical research is needed to clarify the optimal application of rhTM in each of the causative obstetric disorders.

Successful endoscopic stent placement as a bridge to surgery for colonic obstruction induced by bevacizumab-based chemotherapy.

The use of a self-expandable metallic stent (SEMS) as a bridge to surgery (BTS) for obstructive colorectal cancer is known to be effective. However, whether the use of a SEMS as a BTS for obstruction induced by effective chemotherapy (CTx) is useful is unknown. We present the case of a 54-year-old female patient with colorectal cancer who underwent SEMS placement as a BTS for colorectal obstruction induced by bevacizumab-based CTx. The patient was diagnosed as having transverse colon cancer with multiple liver metastases invading the inferior vena cava. Bevacizumab-based CTx was started; however, although it was effective, colonic obstruction occurred at the primary site after 31 months. A SEMS was placed as a BTS, and surgical resection of the primary lesion was performed after cessation of bevacizumab. However, the liver metastases remained unresectable. CTx was restarted after surgery, and 48-month survival was achieved. This case shows that SEMS placement as a BTS for colorectal obstruction induced by a good response to bevacizumab-based CTx was safe and beneficial. With the development of CTx and molecular-targeted agents, the frequency of colorectal obstruction associated with effective CTx is expected to increase. SEMS placement as a BTS might be one of the treatment options.

Clinical characteristics of adenosquamous carcinoma of the pancreas: a matched case-control study.

OBJECTIVES: Adenosquamous carcinoma of the pancreas (ASC) is a variant of pancreatic ductal adenocarcinoma (PDAC), but the prognosis remains unclear. The purpose of this study was to clarify the prognosis of ASC using a matched case-control design. METHODS: We evaluated clinical characteristics of ASC treated between 2001 and 2011 in our institution. As controls, PDAC cases matched with ASC cases for sex, age, pretreatment Eastern Cooperative Oncology Group performance status, location, initial therapy and American Joint Committee on Cancer TNM staging for pancreatic cancer were also evaluated. RESULTS: Of the 914 cases of pancreatic neoplasm, 28 cases (3.06%) of ASC were identified, and 56 cases of PDAC were matched as controls. Median overall survival (OS) was significantly worse for ASC (8.38 months) than for PDAC (15.75 months; hazard ratio [HR], 1.94; 95% confidence interval, 1.07-3.51; P = 0.026). Of the 22 unresected cases, median OS was again significantly worse for ASC (4.67 months) than for PDAC (12.36 months; HR, 2.39; 95% confidence interval, 1.27-4.51; P = 0.007). CONCLUSION: These results demonstrate that ASC is more aggressive than PDAC.

Evaluation of Ki-67 index in EUS-FNA specimens for the assessment of malignancy risk in pancreatic neuroendocrine tumors.

BACKGROUND AND STUDY AIM: Malignancy in pancreatic neuroendocrine tumors (PNETs) is graded by assessing the resected specimens according to the World Health Organization (WHO) 2010 criteria. The feasibility of such grading using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) specimens remains unclear. The aim of this study was to ascertain the optimal method of measuring the Ki-67 index in EUS-FNA specimens, using resected specimens as the criterion standard. PATIENTS AND METHODS: A total of 58 consecutive patients diagnosed with PNETs between March 1998 and May 2011 were included. The study measured intratumoral Ki-67 index heterogeneity, concordance rates of PNET grading by EUS-FNA with grade of the resected tumor, optimal method of measuring the Ki-67 index in EUS-FNA specimens, and survival analysis based on EUS-FNA specimen grading. RESULTS: Intratumoral dispersion of Ki-67 index in resected specimens was 0.033 for Grade 1 and 0.782 for Grade 2 tumors (P<0.001). Concordance rates for WHO classification between EUS-FNA and resected specimens were 74.0% using the mean Ki-67 index in EUS-FNA specimens and 77.8% using the highest Ki-67 index. The concordance rate rose to 90% when EUS-FNA samples with less than 2000 tumor cells were excluded (26% of EUS-FNA cases). The Kaplan-Meier survival curves were significantly stratified by the EUS-FNA grading of PNETs with 5-year survival rates of 100%, 58.3%, and 0%, for Grade 1, Grade 2, and neuroendocrine carcinoma (NEC) tumors, respectively. CONCLUSIONS: Grading of PNETs by the highest Ki-67 index in EUS-FNA specimens with adequate cellularity has a high concordance with grading of resected specimens, and can predict long term patient survival with high accuracy.

Risk of second malignancies in patients with gastric marginal zone lymphomas of mucosa associate lymphoid tissue (MALT).

BACKGROUND: It is controversial whether patients with gastric marginal zone lymphomas of mucosa associated lymphoid tissue (MALT) have higher risk of second malignancies. The aim of this study was to define the risk of second malignancies in these patients. METHODS: We analyzed prospective follow-up data of 146 consecutive patients with gastric MALT lymphoma treated at Aichi Cancer Center Hospital and compared the incidence of second malignancies with that in the general population. We calculated the standardized incidence ratio (SIR), using age- and sex-specific incidence rates from the Aichi Cancer Registry. RESULTS: The median follow-up period was 74 months. A total of 27 tumors occurred in 22 patients (15.1%), including 19 solid tumors. Of these, nine tumors were detected concomitantly with, and 18 tumors following, the diagnosis of gastric MALT lymphoma. Four patients had two second malignancies each. For the entire group, the SIR of an additional malignancy was 3.39 (95% confidence interval [CI] 2.11-4.66). An increased incidence of solid tumors (SIR 2.91 [1.60-4.22]) and hematologic malignancies (SIR 5.54 [1.70-9.38]) were seen. In addition, there was increased risk for development of second malignancies during follow up (SIR 2.26 [1.21-3.30]). Chemotherapy for treatment of MALT was an independent risk factor for second malignancies (age-sex adjusted hazard ratio 3.98 [1.47-10.79]. CONCLUSIONS: Compared with the general population, patients with gastric MALT lymphoma are at increased risk for second malignancies, including gastric cancer.