A thermally driven rotaxane-catenane interconversion with a dynamic bis(hindered amino) disulfide.

We have developed a versatile and simple synthetic method to produce a [3]catenane. Heating a rotaxane with bis(hindered amino) disulfide groups at both ends spontaneously and selectively produces the [3]catenane. The successful polymerization of the obtained [3]catenane provides a platform for the synthesis of various interlocking polymers.

Resting zone of the growth plate houses a unique class of skeletal stem cells.

Skeletal stem cells regulate bone growth and homeostasis by generating diverse cell types, including chondrocytes, osteoblasts and marrow stromal cells. The emerging concept postulates that there exists a distinct type of skeletal stem cell that is closely associated with the growth plate1-4, which is a type of cartilaginous tissue that has critical roles in bone elongation5. The resting zone maintains the growth plate by expressing parathyroid hormone-related protein (PTHrP), which interacts with Indian hedgehog (Ihh) that is released from the hypertrophic zone6-10, and provides a source of other chondrocytes11. However, the identity of skeletal stem cells and how they are maintained in the growth plate are unknown. Here we show, in a mouse model, that skeletal stem cells are formed among PTHrP-positive chondrocytes within the resting zone of the postnatal growth plate. PTHrP-positive chondrocytes expressed a panel of markers for skeletal stem and progenitor cells, and uniquely possessed the properties of skeletal stem cells in cultured conditions. Cell-lineage analysis revealed that PTHrP-positive chondrocytes in the resting zone continued to form columnar chondrocytes in the long term; these chondrocytes underwent hypertrophy, and became osteoblasts and marrow stromal cells beneath the growth plate. Transit-amplifying chondrocytes in the proliferating zone-which was concertedly maintained by a forward signal from undifferentiated cells (PTHrP) and a reverse signal from hypertrophic cells (Ihh)-provided instructive cues to maintain the cell fates of PTHrP-positive chondrocytes in the resting zone. Our findings unravel a type of somatic stem cell that is initially unipotent and acquires multipotency at the post-mitotic stage, underscoring the malleable nature of the skeletal cell lineage. This system provides a model in which functionally dedicated stem cells and their niches are specified postnatally, and maintained throughout tissue growth by a tight feedback regulation system.

Comparison between the 0- and 30-s balloon dilation time in percutaneous transluminal angioplasty for restenosed arteriovenous fistula among hemodialysis patients: a multicenter, prospective, randomized trial (CARP study).

BACKGROUND: This study aims to compare patency rates of the 0- and 30-s (sec) balloon dilation time in hemodialysis (HD) patients with restenosis after percutaneous transluminal angioplasty (PTA). METHODS: The patients who underwent PTA within 6 months for failed arteriovenous fistula at the forearm were randomly assigned the 0-s or 30-s dilation time group. Effect of dilation time on the 3- and 6-month patency rates after PTA was examined. RESULTS: Fifty patients were enrolled in this study. The 3-month patency rate in the 30-s dilation group was better than that in the 0-s dilation group (P = 0.0050), while the 6-month patency rates did not show a significant difference between the two groups (P = 0.28). Cox's proportional hazard model revealed that 30-s of inflation time (hazard ratio 0.027; P = 0.0072), diameter of the proximal (hazard ratio 0.32; P = 0.031), and dilation pressure (hazard ratio 0.63; P = 0.014) were associated with better 3-month patency. Dilation pressure between previous and present PTA did not differ in the 0-s (P = 0.15) and 30-s dilation groups (P = 0.16). The 6-month patency rate of the present PTA in the 30-s dilation group was higher than that of the previous PTA (P = 0.015). The visual analog scale did not differ between the two groups (P = 0.51). CONCLUSION: The presenting data suggest that 30-s dilation potentially results in a better 3-month patency rate than 0-s dilation in HD patients with restenosis after PTA.

Functional preservation benefits of minimal surgery for extramammary Paget's disease.

As extramammary Paget's disease (EMPD) sometimes invades and metastasizes from the skin to the mucosa, radical surgical resection of these lesions is often difficult. The purpose of this study was to analyse the association between surgical margins and survival as well as the benefit of functional preservation over complete resection, in patients with EMPD. We retrospectively analysed 230 patients diagnosed with EMPD between 1969 and 2020. Patient and treatment characteristics were recorded. Since our centre is a specialized hospital and almost all patients were referred from other hospitals, we reviewed their referral letters. Prognostic factors and survival time were also analysed. Among 230 patients, 78 (33.9%) had positive margins. The presence of margin positive lesions increased the local recurrence rate but was not significantly correlated with survival. Of all the patients who had received a thorough explanation about the surgical procedure in the referring hospital, 43.8% were scheduled for surgeries that would result in functional impairment, and all of them had function-preserving surgeries at our hospital with a 10-year survival rate of 100%. Our result suggest that less invasive surgery preserves anogenital and urethral function may be an acceptable option for EMPD treatment.

The effects of weight bearing after ACL reconstruction on joint contracture in rats.

PURPOSE: Joint contractures after anterior cruciate ligament (ACL) reconstruction are a serious problem. Given the uncertain effects of weight bearing after ACL reconstruction on contractures, this study was conducted to examine such effects. MATERIALS AND METHODS: To control the amount of weight bearing, ACL-reconstructed rats were reared with either untreated (small weight bearing; weight bearing during locomotion was 54% of pre-surgery at minimum), hindlimb unloading (non-weight bearing), or sustained morphine administration (large weight bearing; weight bearing during locomotion was maintained at 80% or more of pre-surgery) conditions. Untreated rats were used as controls. Knee extension range of motions (ROMs) before (includes myogenic and arthrogenic factors) and after myotomy (includes arthrogenic factor only) and fibrotic reactions in the joint capsule were assessed 7 and 14 days post-surgery. RESULTS: ACL reconstruction significantly reduced ROMs both before and after myotomy and induced fibrosis in the joint capsule accompanying upregulation of fibrosis-related genes (i.e., type I and III collagens and transforming growth factor-ß1) at both time points. Morphine administration increased the ROM before myotomy, but not after myotomy 7 days post-surgery. Unloading after ACL reconstruction improved ROMs both before and after myotomy at both time points. In addition, unloading after ACL reconstruction attenuated fibrotic reactions in the joint capsule. CONCLUSIONS: Our results suggest that morphine administration improves myogenic contractures in parallel with an increase in the amount of weight bearing. Unloading after ACL reconstruction is effective in reducing both myogenic and arthrogenic contractures.

Comparison of survival rates between incident hemodialysis patients and peritoneal dialysis patients: a 5-year prospective cohort study with propensity score matching.

BACKGROUND: The effect of dialytic modality at the start of renal replacement therapy on prognosis is controversial. METHODS: This multicenter, prospective cohort study included patients undergoing incident hemodialysis (HD) (n = 646) and peritoneal dialysis (PD) (n = 72). We excluded patients who lacked complete data for 3 months. One-to-one propensity score (PS) matching was performed before between-group comparison of survival rates (Kaplan-Meier method and log-rank test) and identification of factors affecting prognosis (Cox proportional-hazards regression analysis). RESULTS: We enrolled 621 and 71 patients undergoing HD and PD, respectively (overall mean ± standard deviation age: 74 ± 13 years); 20% had cardiovascular disease (CVD). The median follow-up period was 41 (interquartile range 24-66) months. Following PS matching, we analyzed 65 patients undergoing HD and PD each. The 5-year overall survival rates did not differ between the groups (P = 0.97). The PD group exhibited a better CVD-related survival rate (P = 0.03). PD yielded adjusted hazard ratios for all-cause and CVD-related mortality of 0.99 (95% confidence interval [CI] 0.49-1.99, P = 0.97) and 3.92 (95% CI 1.05-14.7, P = 0.04), respectively. Age (P < 0.001) and the use of a central venous catheter (CVC) at dialytic initiation (P = 0.02) were independent risks for all-cause mortality; whereas, only the use of a CVC (P = 0.01) was an independent risk for CVD-related mortality. CONCLUSION: Although no differences were observed in overall survival, CVD-related survival may be better with dialytic initiation with PD than with HD.

Clinical significance of local control of primary tumour in definitive radiotherapy for scalp angiosarcomas.

INTRODUCTION: Scalp angiosarcoma is a rare and aggressive cancer. Definitive radiotherapy is a treatment option for localised scalp angiosarcoma patients. Although definitive surgical resection reportedly prolongs overall survival (OS), whether initial local treatment effect affects OS when definitive radiotherapy is administered is unclear. Therefore, this study analysed whether local recurrence within 6 months of irradiation correlates with OS and cancer-specific survival (CSS). Furthermore, how local control affects patients' quality of life was investigated. MATERIALS AND METHODS: Thirty-one localised scalp angiosarcoma patients who had received definitive radiotherapy at our institution between October 2010 and July 2021 were analysed retrospectively. The most commonly used dose fractionation was 70 Gy in 35 fractions (83.9%). Local recurrence within 6 months of radiotherapy and other clinical factors were examined in univariate and subsequent multivariate analyses for correlation with OS and CSS. RESULTS: The median follow-up period was 16 months (range, 6-45 months). Local recurrence was detected in 16 patients (51.6%), 12 of whom had recurrence within 6 months. In multivariate analyses, the presence of local recurrence within 6 months of radiotherapy was significantly associated with OS and CSS (p = 0.003, 0.0001, respectively). Ten of the 16 patients with local recurrence had severe symptoms such as bleeding, pain, difficulty opening the eye and malodour. CONCLUSIONS: The initial local treatment effect was significantly associated with OS and CSS after definitive radiotherapy. Furthermore, local recurrence after radiotherapy resulted in a variety of symptoms, including bleeding and pain, which reduced the patient's quality of life.

A Novel Multi-Observation System to Study the Effects of Anterior Ocular Inflammation in Zinn's Zonule Using One Specimen.

Zinn's zonule is a fragile and thin tissue, and little is known about its pathogenesis. The aim of this study was to develop an experimental setup for a comprehensive analysis of Zinn's zonule. Rats were divided into two groups: a control group (n = 4) and an alkali injury group (n = 4). Seven days after injury, the eyes were enucleated, the anterior eye was dissected and embedded in gelatin, and macroscopic observations were made. The gelatin specimens were then embedded in paraffin and observed in detail by low-vacuum scanning electron microscopy, immunofluorescence, and quantitative reverse transcription polymerase chain reaction (RT-qPCR). The results show qualitative changes in Zinn's zonules in both macroscopic and microscopic observations. In addition, macrophage infiltration and increased matrix metalloproteinase 2 (MMP2) expression were observed in the injured group, consistent with the RT-qPCR results. The experimental system in this study allowed us to capture the morphological and molecular biological changes of Zinn's zonule and to gain insight into its pathogenesis. In conclusion, this study presents a new experimental setup for the comprehensive analysis of the rat Zinn's zonule. The results suggest that this system can be used in the future to study and analyze a variety of paraffin-embedded tissues and specimens.

Relationships of hyperchloremia with hypertension and proteinuria in patients with chronic kidney disease.

BACKGROUND: A few previous clinical studies have shown that chloride (Cl) contributes to the progression and development of hypertension or proteinuria. Therefore, we aimed to determine whether hyperchloremia is associated with hypertension or proteinuria in patients with chronic kidney disease (CKD) and to define the relationships between the reduction in serum Cl concentration associated with CKD treatment and improvements in hypertension and/or proteinuria. METHODS: We performed a retrospective observational study of new or referred patients with CKD who had hyperchloremia, moderate proteinuria, renal dysfunction, and hypertension. Patients taking medication for metabolic acidosis or with a history of dialysis were excluded. The participants' systolic and diastolic blood pressure (BP), serum sodium (Na) and Cl concentrations, and urinary protein (UP) concentration were measured at baseline and after 1 month of CKD treatment. RESULTS: Fifty-one patients with CKD were included in the study. Their serum Cl concentration independently correlated with sBP and UP at baseline (P = 0.022 and P = 0.033, respectively). After 1 month's CKD treatment, their serum Na and Cl concentrations, sBP, and UP were significantly lower. The change in sBP during the month (ΔsBP) correlated with the change in serum Cl (ΔCl) (P = 0.012) but not with the change in serum Na. Multivariate analysis showed that ΔsBP was independently associated with ΔCl (P = 0.029). CONCLUSIONS: Hyperchloremia is an independent predictor of hypertension and proteinuria for patients with CKD.

Autocrine regulation of mesenchymal progenitor cell fates orchestrates tooth eruption.

Formation of functional skeletal tissues requires highly organized steps of mesenchymal progenitor cell differentiation. The dental follicle (DF) surrounding the developing tooth harbors mesenchymal progenitor cells for various differentiated cells constituting the tooth root-bone interface and coordinates tooth eruption in a manner dependent on signaling by parathyroid hormone-related peptide (PTHrP) and the PTH/PTHrP receptor (PPR). However, the identity of mesenchymal progenitor cells in the DF and how they are regulated by PTHrP-PPR signaling remain unknown. Here, we show that the PTHrP-PPR autocrine signal maintains physiological cell fates of DF mesenchymal progenitor cells to establish the functional periodontal attachment apparatus and orchestrates tooth eruption. A single-cell RNA-seq analysis revealed cellular heterogeneity of PTHrP+ cells, wherein PTHrP+ DF subpopulations abundantly express PPR. Cell lineage analysis using tamoxifen-inducible PTHrP-creER mice revealed that PTHrP+ DF cells differentiate into cementoblasts on the acellular cementum, periodontal ligament cells, and alveolar cryptal bone osteoblasts during tooth root formation. PPR deficiency induced a cell fate shift of PTHrP+ DF mesenchymal progenitor cells to nonphysiological cementoblast-like cells precociously forming the cellular cementum on the root surface associated with up-regulation of Mef2c and matrix proteins, resulting in loss of the proper periodontal attachment apparatus and primary failure of tooth eruption, closely resembling human genetic conditions caused by PPR mutations. These findings reveal a unique mechanism whereby proper cell fates of mesenchymal progenitor cells are tightly maintained by an autocrine system mediated by PTHrP-PPR signaling to achieve functional formation of skeletal tissues.

Role of Zinc and Copper in Erythropoiesis in Patients on Hemodialysis.

Plasma zinc concentrations are decreased in patients on hemodialysis; zinc supplementation increases hemoglobin levels and reduces erythropoietin-stimulating agent treatments. However, inappropriate zinc supplementation causes copper deficiency. This review discusses the roles of zinc and copper throughout erythropoiesis; it also describes erythropoiesis-stimulating nutritional therapy that avoids copper deficiency, while providing safe zinc supplementation. In early erythropoiesis, erythropoietin regulates erythrocyte precursor proliferation and survival via zinc finger transcription factors. Mature blood cell formation and functional activation are regulated by zinc-mediated hormones, vitamins, and growth peptides. Zinc antagonizes the uptake of divalent cations (e.g., iron and copper) in erythrocyte precursors. Copper is required for iron transfer from cells to blood, ensuring dietary iron absorption and systemic iron distribution. In patients with copper deficiency, copper supplementation is initially performed, followed by zinc supplementation to manage hypozincemia. Serum zinc and copper measurements are needed at 2- to 3-month intervals during zinc supplementation to prevent copper deficiency.

Left DLPFC activity is associated with plasma kynurenine levels and can predict treatment response to escitalopram in major depressive disorder.

AIM: To establish treatment response biomarkers that reflect the pathophysiology of depression, it is important to use an integrated set of features. This study aimed to determine the relationship between regional brain activity at rest and blood metabolites related to treatment response to escitalopram to identify the characteristics of depression that respond to treatment. METHODS: Blood metabolite levels and resting-state brain activity were measured in patients with moderate to severe depression (n = 65) before and after 6-8 weeks of treatment with escitalopram, and these were compared between Responders and Nonresponders to treatment. We then examined the relationship between blood metabolites and brain activity related to treatment responsiveness in patients and healthy controls (n = 36). RESULTS: Thirty-two patients (49.2%) showed a clinical response (>50% reduction in the Hamilton Rating Scale for Depression score) and were classified as Responders, and the remaining 33 patients were classified as Nonresponders. The pretreatment fractional amplitude of low-frequency fluctuation (fALFF) value of the left dorsolateral prefrontal cortex (DLPFC) and plasma kynurenine levels were lower in Responders, and the rate of increase of both after treatment was correlated with an improvement in symptoms. Moreover, the fALFF value of the left DLPFC was significantly correlated with plasma kynurenine levels in pretreatment patients with depression and healthy controls. CONCLUSION: Decreased resting-state regional activity of the left DLPFC and decreased plasma kynurenine levels may predict treatment response to escitalopram, suggesting that it may be involved in the pathophysiology of major depressive disorder in response to escitalopram treatment.

In vitro and in vivo detection of tunneling nanotubes in normal and pathological osteoclastogenesis involving osteoclast fusion.

Osteoclasts are multinucleated cells formed through specific recognition and fusion of mononuclear osteoclast precursors derived from hematopoietic stem cells. Detailed cellular events concerning cell fusion in osteoclast differentiation remain ambiguous. Tunneling nanotubes (TNTs), actin-based membrane structures, play an important role in intercellular communication between cells. We have previously reported the presence of TNTs in the fusion process of osteoclastogenesis. Here we analyzed morphological details of TNTs using scanning electron microscopy. The osteoclast precursor cell line RAW-D was stimulated to form osteoclast-like cells, and morphological details in the appearance of TNTs were extensively analyzed. Osteoclast-like cells could be classified into three types; early osteoclast precursors, late osteoclast precursors, and multinucleated osteoclast-like cells based on the morphological characteristics. TNTs were frequently observed among these three types of cells. TNTs could be classified into thin, medium, and thick TNTs based on the diameter and length. The shapes of TNTs were dynamically changed from thin to thick. Among them, medium TNTs were often observed between two remote cells, in which side branches attached to the culture substrates and beaded bulge-like structures were often observed. Cell-cell interaction through TNTs contributed to cell migration and rapid transport of information between cells. TNTs were shown to be involved in cell-cell fusion between osteoclast precursors and multinucleated osteoclast-like cells, in which movement of membrane vesicles and nuclei was observed. Formation of TNTs was also confirmed in primary cultures of osteoclasts. Furthermore, we have successfully detected TNTs formed between osteoclasts observed in the bone destruction sites of arthritic rats. Thus, formation of TNTs may be important for the differentiation of osteoclasts both in vitro and in vivo. TNTs could be one target cellular structure for the regulation of osteoclast differentiation and function in bone diseases.

Clonal dynamics of circulating tumor DNA during immune checkpoint blockade therapy for melanoma.

Assessment of treatment efficacy of immune checkpoint inhibitors in melanoma patients is difficult as the response to these therapies varies among patients or lesions. The clonal evolution of cancer during immune checkpoint blockade therapy could cause treatment resistance. We investigated the potential of liquid biopsy in monitoring the mutational profiles of metastatic melanoma during immunotherapy. Plasma samples collected from 21 Japanese metastatic melanoma patients before immune checkpoint blockade therapy were subjected to whole-exome sequencing (WES). Furthermore, 14 Japanese patients with melanoma were enrolled for longitudinal analysis of circulating tumor DNA (ctDNA). Plasma samples were collected prospectively before and during therapy and sequenced. WES of the pretreatment plasma from Japanese melanoma patients showed detectable ctDNA levels with wide ranges of variant allele frequencies within a sample, suggesting clonal and subclonal mutations in ctDNA. In targeted sequencing using longitudinal samples, ctDNA levels correlated with increased tumor size, while ctDNA content immediately decreased after a surge in a patient exhibiting pseudo-progression, suggesting the potential of ctDNA analysis in discriminating between pseudo- and true progression. Mutant ctDNA levels showed different patterns within the clinical course of specific patients, suggesting that these mutations were derived from different tumor clones with distinct therapeutic responses. During further investigation, WES of plasma samples from 1 patient showed marked differences in the mutational profiles of ctDNA, including expansive tumor evolution during an acute exacerbation. Immunotherapy may induce characteristic clonal evolutions of tumors; longitudinal analysis of ctDNA has the potential of determining these tumor evolution patterns and therapeutic responses.

A review of the AJCC melanoma staging system in the TNM classification (eighth edition).

In the eighth edition of the American Joint Committee on Cancer Staging Manual, several modifications were made for melanoma. These modifications were aimed at improving the prognosis prediction accuracy of the staging system. The main modifications are as follows: the cutoff value of the T1 category has been changed, and there are new classifications of stage IIID and of M1d (metastasis of the central nervous system). These changes will allow for more accurate stratification of melanoma prognosis. However, it is necessary to validate the new modifications through future clinical research.

Prospective observational study of the efficacy of nivolumab in Japanese patients with advanced melanoma (CREATIVE study).

BACKGROUND: Nivolumab, the anti-programmed cell death protein 1 antibody, has been approved for advanced melanoma, mainly based on evidence from Western countries. The profile of melanoma differs between Caucasian and Asian patients. This study was performed to obtain post-marketing data of nivolumab in Japanese patients with advanced melanoma. METHODS: This prospective, observational study involved patients with unresectable or metastatic melanoma treated with nivolumab at dosages of 2 mg/kg every 3 weeks or 3 mg/kg every 2 weeks. The primary endpoints were objective response rate and overall survival. The secondary endpoints were progression-free survival and the objective response rate according to immune-related Response Evaluation Criteria in Solid Tumours. RESULT: Among 124 patients analysed, mucosal melanoma was the most common subtype, followed by acral lentiginous, nodular, superficial spreading and lentigo maligna melanoma. Response Evaluation Criteria in Solid Tumours evaluation showed an objective response rate of 17.7%. The median survival time was 15.93 months, and the 1-year overall survival rate was 66%. Outcomes were not significantly different among melanoma subtypes. Better overall survival and/or progression-free survival but not objective response rate were associated with performance status 0, lower levels of lactate dehydrogenase, C-reactive protein and neutrophil-to-lymphocyte ratio. Patients with immune-related adverse events showed a better objective response rate, 3-month landmark overall survival and progression-free survival than patients without immune-related adverse events. CONCLUSION: The objective response rate and median survival time in Japanese patients treated with nivolumab were lower in daily practice than the >30% and >30 months, respectively, seen in global phase III trials. The occurrence of immune-related adverse events may be a predictor for survival and response to treatment with nivolumab.

RB1 gene mutations are a distinct predictive factor in Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma that tends to show local recurrence and metastasis. Typically, MCC is polyomavirus (MCPyV)-associated and cytokeratin 20 (CK20) positive. However, little is known about this tumor and its origins. Here, we aimed to determine the developmental origins of MCC and to identify prognostic clinicopathologic factors. Initial examinations revealed that CK20 and MCPyV expression (CK20+, MCPyV+ (60%); CK20+, MCPyV- (10%); CK20-, and MCPyV- (30%)) did not affect overall survival. With RB1 gene sequencing of FFPE specimens, which covered an entire exon, all RB1 mutation-positive cases showed positive regional lymph node and/or distant metastases (8/8 cases, 100%), whereas the frequency of the metastasis was statistically significantly lower in RB1 mutation-negative cases, (10/16 cases, 62%, P = 0.033). The results were also confirmed with immunohistochemistry, and either RB1 alterations, entire exon sequencing, or immunohistochemistry was associated with the metastasis (P = 0.007). RB1 alterations may be used to access the aggressive clinical course of MCC.

Impact of the changes in the completion lymph node dissection criteria and approval of adjuvant therapies on the real-world outcomes of Japanese stage III melanoma patients.

BACKGROUND: Completion lymph node dissection (CLND) has long been the standard treatment for stage III melanomas identified as metastasis on the sentinel node (SN-positive). Two major changes occurred in 2017 and 2018, the change in the CLND criteria for SN-positive patients and the approval of several adjuvant therapies could revolutionize such management approach. However, their effects have not been fully investigated on the real-world outcomes of stage III melanoma patients. Therefore, we investigated the impact of these changes on the prognosis of Japanese stage III melanoma patients. METHODS: Totally, 119 stage III, SN-positive melanoma patients were included. They were categorized into those diagnosed as SN-positive between January 2015 and June 2017 (pre-June 2017 group) and between July 2017 and December 2019 (post-July 2017 group). Recurrence-free survival (RFS), overall survival, and prognostic factors were analyzed. RESULTS: The frequency of patients who received CLND was significantly higher in the pre-June 2017 group (p = 0.001), and those who received adjuvant therapy were significantly higher in the post-July 2017 group (p < 0.001). The 2-year RFS was 50.1% and 68.5% in the pre-June and post-July 2017 groups, respectively (p = 0.049). Cox proportional hazards model analysis for RFS showed that adjuvant therapies reduce the risk of recurrence (hazard ratio 0.37; 95% confidence interval 0.14-0.99; p = 0.047). CONCLUSION: Changes in the CLND criteria in SN-positive patients and the approval of adjuvant therapies for stage III melanomas have significantly impacted Japanese melanoma medicine. Adjuvant therapy tended to prolong patient's RFS while omitting immediate CLND had no significant negative influence on it.

[A Case of Myeloid Sarcoma in the Small Intestine Presenting with Intussusception].

A sixty-something man presented with lower abdominal pain in early Y month 20XX, and was examined at the hospital's internal medicine outpatient clinic. An abdominal CT showed a soft tissue mass around the left hip joint, and multiple enlarged lymph nodes from inside the pelvis to the mesentery of the abdomen. We noted a small-intestinal intussusception in the lower right abdomen, and suspected malignant lymphoma. We did a CT-guided biopsy on the left hip joint soft tissue mass, and performed surgery on the small-intestinal intussusception. During surgery, we noted an approximately 30 cm ileal intussusception located about 60 cm from the terminal ileum, and enlarged lymph nodes in the nearby mesentery. We removed the ileal intussusception. The pathological diagnosis was myeloid sarcoma, and the soft tissue mass in the left hip joint was also diagnosed as myeloid sarcoma. We performed a bone-marrow biopsy at the hematology department, and diagnosed acute myeloid leukemia M2. We then started remission-induction therapy and consolidation therapy, and the patient was diagnosed as in remission in Y+5 month 20XX. We also need to keep in mind myeloid sarcoma in the intestine as a subtype of acute myeloid leukemia, as malignant tumor in the small intestine presenting with intussusception.

A single-arm confirmatory trial of pazopanib in patients with paclitaxel-pretreated primary cutaneous angiosarcoma: Japan Clinical Oncology Group study (JCOG1605, JCOG-PCAS protocol).

BACKGROUND: Paclitaxel is a standard of care for patients with primary cutaneous angiosarcoma of the scalp and face. However, no standard second-line treatment for paclitaxel-resistant patients has ever been established. Since primary cutaneous angiosarcoma expresses a high level of vascular endothelial growth factor receptor, the multitargeted tyrosine kinase inhibitor pazopanib seemed to be the most promising agent, and several retrospective studies have demonstrated its activity against this disease. However, the efficacy and safety of pazopanib in paclitaxel-resistant patients with primary cutaneous angiosarcoma have never been evaluated in a clinical trial. METHODS: In February 2018 the Dermatologic Oncology Group of Japan Clinical Oncology Group started a single-arm confirmatory trial to evaluate the efficacy and safety of pazopanib as a second-line treatment for patients with primary cutaneous angiosarcoma whose disease was resistant to paclitaxel or who were unable to tolerate paclitaxel (JCOG1605, JCOG-PCAS). Patients with primary cutaneous angiosarcoma not associated with lymphedema or radiation, progressing despite first-line paclitaxel monotherapy are included in the study. No prior systemic chemotherapy other than paclitaxel is permitted. Pazopanib is administered orally at an initial dosage of 800 mg once daily. Dose modifications for adverse events are made according to the dose reduction criteria described in the protocol. Treatment is continued until recurrence, disease progression, unacceptable toxic effects, patient refusal, or death. The primary endpoint is progression-free survival, secondary endpoints include overall survival, response rate, disease control rate, adverse events, and serious adverse events. We plan to recruit 30 participants in 5.5 years from 23 Japanese institutions. The follow-up period is set as 1 year after completion of accrual. The study protocol was approved by the Japan Clinical Oncology Group Protocol Review Committee in December 2017. Ethical approval for this study was granted by Ethics Committee of each institute. DISCUSSION: If the primary endpoint is met, pazopanib will be regarded as a standard of care for paclitaxel-resistant patients for whom no standard second-line treatment is established. TRIALS REGISTRATION: Registry number: UMIN000031438 [ http://www.umin.ac.jp/ctr/index.htm ]. Date of Registration: 23/Feb/2018. Date of First Participant Enrollment: 8/Mar/2018.