Efficacy of edoxaban for the treatment of gynecological cancer-associated venous thromboembolism: analysis of Japanese real-world data

ObjectiveDirect oral anticoagulants (DOACs) are increasingly being used for the treatment of cancer-associated venous thromboembolism (CAT). However, there is limited evidence of the efficacy of DOACs for the treatment of gynecological CAT. Thus, this study aimed to investigate the efficacy and safety of edoxaban for the treatment of gynecological CAT using Japanese real-world data.MethodsWe reviewed the medical records of patients with 371 gynecological cancer who received edoxaban or vitamin K antagonist (VKA) between January 2011 and December 2018.ResultsAltogether, 211 and 160 patients were treated with edoxaban and VKA, respectively. Fourteen patients (6.8%) in the edoxaban group and 22 (13.8%) in the VKA group showed recurrence of venous thromboembolism (VTE). Cumulative VTE recurrence was not significantly different between the 2 groups (p=0.340). Adverse events occurred in 15 (7.1%) and 11 (6.9%) patients in the edoxaban and VKA groups, respectively (p=0.697). Subgroup analysis of the edoxaban and VKA groups according to different tumor types, including ovarian, endometrial, and cervical cancer, showed equivalent outcomes in terms of VTE recurrence and adverse events. Patients without pulmonary embolism (PE) were mostly omitted from initial unfractionated heparin (UFH) therapy prior to administration of edoxaban. However, this did not increase the recurrence of VTE.ConclusionThis study confirmed that edoxaban is effective and safe for the treatment of gynecological CAT. This finding was consistent for different types of gynecological cancer. Additionally, initial UFH therapy prior to the administration of edoxaban may be unnecessary for patients without PE.     

Prognosis Prediction Using Magnetic Resonance Spectroscopy and Oligoclonal Bands in Central Nervous System Methotrexate-associated Lymphoproliferative Disorder

Central nervous system methotrexate-associated lymphoproliferative disorder (CNS-MTX-LPD) is rare, but its spontaneous regression has been observed in some patients after withdrawal of agents. We herein report three cases of primary CNS-MTX-LPD that received oral MTX for rheumatoid arthritis. Epstein-Barr virus and oligoclonal bands (OCBs) were positive, while proton magnetic resonance spectroscopy (¹H-MRS) showed an elevated lipid peak and slightly elevated choline/N-acetylaspartate ratio in common. After MTX withdrawal, brain lesions showed spontaneous regression in all cases. Our patient''s ¹H-MRS findings and OCBs may reflect a non-monoclonal lymphoproliferative histology as benign-type lesions in CNS-MTX-LPD.     

Identifying the Optimal Arm Priming Exercise Intensity to Improve Maximal Leg Sprint Cycling Performance

Priming exercises improve subsequent motor performance; however, their effectiveness may depend on the workload and involved body areas. The present study aimed to estimate the effects of leg and arm priming exercises performed at different intensities on maximal sprint cycling performance. Fourteen competitive male speed-skaters visited a lab eight times, where they underwent a body composition measurement, two V̇O_2max measurements (leg and arm ergometers), and five sprint cycling sessions after different priming exercise conditions. The five priming exercise conditions included 10-minute rest (Control); 10-minute arm ergometer exercise at 20% V̇O_2max (Arm 20%); 10-minute arm ergometer exercise at 70% V̇O_2max (Arm 70%); 1-min maximal arm ergometer exercise at 140% V̇O_2max (Arm 140%); and 10-min leg ergometer exercise at 70% V̇O_2max (Leg 70%). Power outputs of 60-s maximal sprint cycling, blood lactate concentration, heart rate, muscle and skin surface temperature, and rating of perceived exertion were compared between the priming conditions at different measurement points. Our results showed that the Leg 70% was the optimal priming exercise among our experimental conditions. Priming exercise with the Arm 70% also tended to improve subsequent motor performance, while Arm 20% and Arm 140% did not. Mild elevation in blood lactate concentration by arm priming exercise may improve the performance of high-intensity exercise. Key points

• Maximal sprint cycling performance was comparable between the Arm 70% condition and the Leg 70% condition
• A mild elevation in BLC by arm priming exercise may improve the performance of high-intensity exercise
• Low (i.e., Arm 20%) and high (i.e., Arm 140%) workloads did not provide any performance benefits

Key words: Exercise, arm, heart rate, lactic acid     

Pembrolizumab-related Immune Thrombocytopenia in a Patient with Lung Adenocarcinoma Treated by Radiotherapy: Potential Immune-related Adverse Event Elicited by Radiation Therapy

The effect of radiotherapy during immunotherapy on immune-related adverse events (irAEs) is not fully understood. We herein report a 74-year-old woman diagnosed with lung adenocarcinoma with programmed death ligand 1 expression ≥50% and treated with pembrolizumab. She developed fatal immune thrombocytopenia associated with pembrolizumab immediately following radiotherapy. A flow cytometry analysis of peripheral blood detected an increased expression of programmed death-1 (PD-1) and Ki-67 in CD4^＋ and CD8^＋ T cells after radiotherapy, compared with pre-irradiation measurements. This case suggests that radiotherapy may evoke irAEs during treatment with anti-PD-1 antibodies, which physicians should consider when using radiotherapy in patients treated with these drugs.     

Comparison of intensity-modulated radiotherapy with the 5-field technique,helical tomotherapy and volumetric modulated arc therapy for localized prostate cancer

The outcomes of three methods of intensity-modulated radiation therapy (IMRT) for localized prostate cancer were evaluated. Between 2010 and 2018, 308 D’Amico intermediate- or high-risk patients were treated with 2.2 Gy daily fractions to a total dose of 74.8 Gy in combination with hormonal therapy. Overall, 165 patients were treated with 5-field IMRT using a sliding window technique, 66 were then treated with helical tomotherapy and 77 were treated with volumetric modulated arc therapy (VMAT). The median age of patients was 71 years. The median follow-up period was 75 months. Five-year overall survival (OS) and biochemical or clinical failure-free survival (FFS) rates were 95.5 and 91.6% in the 5-field IMRT group, 95.1 and 90.3% in the tomotherapy group and 93.0 and 88.6% in the VMAT group, respectively, with no significant differences among the three groups. The 5-year cumulative incidence of late grade ≥2 genitourinary and gastrointestinal toxicities were 7.3 and 6.2%, respectively, for all patients. Late grade ≥2 gastrointestinal toxicities were less frequent in patients undergoing VMAT (0%) than in patients undergoing 5-field IMRT (7.3%) and those undergoing tomotherapy (11%) (P = 0.025), and this finding appeared to be correlated with the better rectal DVH parameters in patients undergoing VMAT. Other toxicities did not differ significantly among the three groups, although bladder dose-volume parameters were slightly worse in the tomotherapy group than in the other groups. Despite differences in the IMRT delivery methods, X-ray energies and daily registration methods, all modalities may be used as IMRT for localized prostate cancer.     

Study on removal effects of filling materials and broken files from root canals using pulsed Nd:YAG laser

OBJECTIVES: The aims of this study were to investigate the capability of removing the filling materials or broken files from root canals with pulsed Nd:YAG laser irradiation at three parameters, and to evaluate the temperature rises on root surfaces and morphological changes of root canal walls in vitro. SUMMARY BACKGROUND DATA: There has been no report on removing the filling materials and broken instruments from root canals with laser irradiation. MATERIALS AND METHODS: Thirty-six extracted human incisors were divided into two groups of 18 each. Eighteen root canals were shaped and obturated with gutta-percha and root canal sealer. In another 18 specimens, 3-mm long fractures of files were performed intentionally during root canal preparation. A pulsed Nd:YAG laser irradiation was performed repeatedly at three parameters of 1, 2, and 3 W to remove the filling materials or file fragments. Temperature rises on root surfaces during laser irradiation were measured by thermography, and the remaining of obturated materials and morphological changes of root canal walls were evaluated by stereoscopy and scanning electron microscopy. RESULTS: In more than 70% of the teeth, the obturated materials were completely removed by laser, and in more than 55% of the teeth, the broken files were successfully removed. Temperature rises ranging from 17 degrees C to 27 degrees C were measured from 6 to 11 repeated times. CONCLUSION: These results demonstrated that a pulsed Nd:YAG laser irradiation has the capability of removing the obturated materials in root canals and is useful for removing the broken files in same if the counter-measure reducing the temperature rise is performed.     

Label‐free multiphoton excitation imaging as a promising diagnostic tool for breast cancer

Histopathological diagnosis is the ultimate method of attaining the final diagnosis; however, the observation range is limited to the two‐dimensional plane, and it requires thin slicing of the tissue, which limits diagnostic information. To seek solutions for these problems, we proposed a novel imaging‐based histopathological examination. We used the multiphoton excitation microscopy (MPM) technique to establish a method for visualizing unfixed/unstained human breast tissues. Under near‐infrared ray excitation, fresh human breast tissues emitted fluorescent signals with three major peaks, which enabled visualizing the breast tissue morphology without any fixation or dye staining. Our study using human breast tissue samples from 32 patients indicated that experienced pathologists can estimate normal or cancerous lesions using only these MPM images with a kappa coefficient of 1.0. Moreover, we developed an image classification algorithm with artificial intelligence that enabled us to automatically define cancer cells in small areas with a high sensitivity of ≥0.942. Taken together, label‐free MPM imaging is a promising method for the real‐time automatic diagnosis of breast cancer.     

Radiation-induced angiosarcoma of the parotid gland after postoperative radiotherapy for hypopharyngeal carcinoma

Secondary carcinogenesis within the irradiation range is one of the most severe problems in cancer survivors. A 60-year-old woman developed hypopharyngeal carcinoma, and she received radical surgery and postoperative radiotherapy. Eight years later, brown pigmentation and induration were observed in the left subaural region. Fine-needle aspiration biopsy revealed malignancy and the parotid tumor was diagnosed as recurrence of hypopharyngeal carcinoma. Neoadjuvant chemotherapy followed by radical parotidectomy was performed. The pathological diagnosis was angiosarcoma, which was most likely induced by past irradiation. About two months after surgery, lung metastases were detected. Docetaxel did not affect to lung metastases, but paclitaxel therapy was partially effective. The lung tumors increased in size, and brain metastases developed, resulting in death. Both neoadjuvant chemotherapy and radical surgery played important roles in the local disease control. Administration of newer agents as adjuvant chemotherapeutic agent should also be considered for improving the prognosis.     

The effects of breaking sedentary time with different intensity exercise bouts on energy metabolism: A randomized cross-over controlled trial

Background and aimsBreaking up sedentary periods, particularly with light activity, increases total energy expenditure (EE), and helps provide better glycemic control. However, the effects of activities of various intensities to interrupt prolonged sedentary time are unclear. The purpose of the present study was to examine potential differences in glycemic control and EE from breaking up sedentary time with short exercise bouts of different intensities.Methods and resultsNine overweight/obesity young men underwent whole body indirect calorimetry at 19:00 on day 1 and stayed overnight. After awakening on day 2, they performed short duration jogging every 30 min over 8 h (16-time bouts in total) under 3 different conditions with the same running distance: (1) lactate threshold (LT) for 2 min, (2) 60% LT for 200 s, and (3) onset of blood lactate accumulation (OBLA) for 75 s. The 24-h EE and interstitial glucose concentration (from 8:00 to 19:00 on day 2) was continuously measured throughout the trials. The standard deviation during intervention and indexes of postprandial of the interstitial glucose concentration was significantly lower at LT and OBLA than at 60% LT (p < 0.05). The 24-h EE was not significantly different among conditions, but EE at OBLA during intervention was slightly but significantly higher than at 60% LT and LT.ConclusionBreaking up sedentary time with short-duration jogging at LT and with OBLA intensities may have better glycemic control and increased use of carbohydrate as a fuel, while short-duration a jogging at OBLA intensity may increase EE.Trial registrationUMIN000041361.     

Ontogenic studies on the rat brain capillaries in relation to the human brain tumor vessels

Summary One of the major morphological disparities of brain capillaries between newborn or young and adult rats might be reflected in the aspect of development of the basement membrane. The basement membrane in young animals is clearly evident to be poorly developed up to 15 days of age, and then better developed to possess some similarity to that in adult animals. In addition, it also should be emphasized that slightly distended extracellular space is evident in the nervous tissue of newborn animals.Although in malignant astrocytoma some small blood vessels do not possess any perivascular space around them, others evidently have narrow or relatively wide perivascular spaces where some fibrils of mesodermal origin and fibrocytes can be clearly seen. Also, in some astrocytomas, wide extracellular space is distributed extensively all over the tumor tissue.However, in this context the immaturity of endothelial and glial cells in both young animals and brain tumors should be duly considered.The permeability of the brain capillaries in both young animals and brain tumors has been very well known to be higher than that of the adult brain tissue. However, the higher permeability has another significance, from the morphological point of view, in young animals than it has in brain tumors.

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Zusammenfassung Einer der hervorstechendsten morphologischen Unterschiede zwischen den Hirncapillaren neugeborener und junger oder erwachsener Ratten kommt in der Entwicklung der Basalmembran zum Ausdruck. Bei jungen Tieren bis zu einem Alter von 15 Tagen ist die Basalmembran wenig ausgebildet, mit fortschreitendem Alter der Tiere tritt die Ähnlichkeit mit der Basalmembran von erwachsenen Tieren ausgeprägter in Erscheinung. Außerdem ist zu betonen, daß im Nervengewebe neugeborener Tiere etwas erweiterte extracelluläre Räume zu beobachten sind.Im maligen Astrocytom gibt es kleine Blutgefäße, die keine perivasculären Räume besitzen, andere dagegen haben deutliche engere oder verhältnismäßig weite perivasculäre Räume, in denen mesodermale Fibrillen und Fibrocyten zu finden sind. In manchen Astrocytomen sind im gesamten Tumorgewebe weite extracelluläre Räume vorhanden.Allerdings müßte hier die Unreife der Endothelzellen und der Gliazellen bei jungen Tieren wie auch bei Hirntumoren in Rechnung gestellt werden.Es ist bekannt, daß sowohl bei jungen Tieren wie auch bei Hirntumoren die Permeabilität der Hirncapillaren höher ist als bei erwachsenen Tieren. Vom morphologischen Standpunkt jedoch bestehen in den Voraussetzungen der erhöhten Permeabilität bei jungen Tieren einerseits und bei Hirntumoren andererseits deutliche Unterschiede.

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With 11 Figures in the Text

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This study was made possible by a grant from the Rockfeller Foundation GAMNS 59117.