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Background: Due to its indolent biology and high estrogen receptor positivity of mucinous breast cancer, vast majority of locally advanced mucinous breast cancer (LABC) are treated with first-line endocrine therapy. Case Presentation: A 50-year-old woman was referred to our hospital for the treatment of her huge breast tumor. Computed tomography showed an oval solid tumor, 17 cm in size, and lymph node swelling in both the axilla and parasternum. Pathological study of the core needle biopsy specimen showed the tumor to be luminal mucinous carcinoma. After the failure of endocrine therapy aiming for tumor regression, the patient received sequential chemotherapy to get favorable local control, leading to marked tumor shrinkage. Axillar and parasternal lymph nodes, however, remained unchanged in size. The patient further underwent mastectomy and regional lymph node dissection including removal of the still enlarged parasternal lymph nodes followed by covering of the large skin defect with the latissimus dorsi musculocutaneous (LDMC) flap using a spindle skin island, 15 × 8 cm in size. Postoperative pathological study showed sparse cancer cell remnants with abundant mucus in both the primary tumor and the dissected lymph nodes. The patient has been well without any recurrences on endocrine therapy for 21 months. Conclusion: Breast oncologists should note that multidisciplinary treatment including preoperative chemotherapy and skin defect covering using LDMC flap can give favorable local control even to breast cancer patients with LABC.

Background Advances in pediatric oncology have occurred for some cancers; however, new therapies for sarcoma have been inadequate. Cellular immunotherapy using chimeric antigen receptor (CAR) T cells has shown dramatic benefits in leukemia, lymphoma, and multiple myeloma but has been far less successful in pediatric solid tumors such as rhabdomyosarcoma (RMS) and osteosarcoma (OS). Balancing issues of “on-target, off-tumor toxicity”, investigators have identified B7-H3 as a broadly expressed tumor antigen with otherwise restricted expression on normal tissues. We hypothesized that rapid homing via a chemokine receptor and CAR engagement through B7-H3 would enhance CAR T cell efficacy in solid tumors.Methods We generated B7-H3 CAR T cells that also express the Interleukin-8 (IL-8) receptor, CXCR2. Cytokine production, flow cytometry, Seahorse assays and RNA sequencing were used to compare the B7-H3 CXCR2 (BC2) CAR T cells with B7-H3 CAR T cells. We developed an IL-8 overexpressing human RMS mouse model to test homing and cytotoxicity in vivo.Results We demonstrate that IL-8 is expressed by RMS and OS and expression significantly increases after radiation. Overexpression of an IL-8 receptor, CXCR2, on B7-H3 CAR T cells enhances homing into IL-8 expressing tumors, augments T cell metabolism and leads to significant tumor regression.Conclusion These findings warrant further investigation into the use of BC2 CAR T cells as a treatment for patients with RMS, OS and other B7-H3-expressing, IL-8 producing solid tumors.

Ewing sarcoma is the second most common bone cancer in children, and while patients who present with metastatic disease at the time of diagnosis have a dismal prognosis. Ewing sarcoma tumors are driven by the fusion gene EWS/Fli1, and while these tumors are genetically homogenous, the transcriptional heterogeneity can lead to a variety of cellular processes including metastasis. In this study, we demonstrate that in Ewing sarcoma cells, the canonical Wnt/β-Catenin signaling pathway is heterogeneously activated in vitro and in vivo, correlating with hypoxia and EWS/Fli1 activity. Ewing sarcoma cells predominantly express β-Catenin on the cell membrane bound to CDH11, which can respond to exogenous Wnt ligands leading to the immediate activation of Wnt/β-Catenin signaling within a tumor. Knockdown of CDH11 leads to delayed and decreased response to exogenous Wnt ligand stimulation, and ultimately decreased metastatic propensity. Our findings strongly indicate that CDH11 is a key component of regulating Wnt//β-Catenin signaling heterogeneity within Ewing sarcoma tumors, and is a promising molecular target to alter Wnt//β-Catenin signaling in Ewing sarcoma patients.

Abstract The advent of dose intensified interval compressed therapy has improved event-free survival for patients with localized Ewing sarcoma (EwS) to 78% at 5 years. However, nearly a quarter of patients with localized tumors and 60–80% of patients with metastatic tumors suffer relapse and die of disease. In addition, those who survive are often left with debilitating late effects. Clinical features aside from stage have proven inadequate to meaningfully classify patients for risk-stratified therapy. Therefore, there is a critical need to develop approaches to risk stratify patients with EwS based on molecular features. Over the past decade, new technology has enabled the study of multiple molecular biomarkers in EwS. Preliminary evidence requiring validation supports copy number changes, and loss of function mutations in tumor suppressor genes as biomarkers of outcome in EwS. Initial studies of circulating tumor DNA demonstrated that diagnostic ctDNA burden and ctDNA clearance during induction are also associated with outcome. In addition, fusion partner should be a pre-requisite for enrollment on EwS clinical trials, and the fusion type and structure require further study to determine prognostic impact. These emerging biomarkers represent a new horizon in our understanding of disease risk and will enable future efforts to develop risk-adapted treatment.

Abstract Background Oncofertility is a developing field of increasing importance, particularly in pediatric oncology, where most patients are likely to survive long‐term and have not yet had the opportunity to have children. Aims We performed a quality improvement initiative to increase our rates of fertility preservation counseling and referral through the implementation of a pediatric oncofertility team, and we report outcomes 7 years following implementation of our initiative. Methods and results We compare our baseline oncofertility survey to 44 post‐intervention survey respondents and electronic medical record documentation for 149 patients treated in 2019. Ninety‐five percent of post‐intervention survey respondents recalled fertility counseling (baseline 70%, p = .004) and 89.3% were appropriately referred for fertility preservation (baseline 50%, p = .017). Counseling was documented in 60.4% of charts; 81% of patients analyzed by chart review were appropriately referred for fertility preservation. Fertility preservation outcomes differed by sex assigned at birth. Conclusion Creation of an oncofertility team produced improvements in fertility counseling and fertility preservation referral across an extended period of time.

Abstract Background Hand osteoarthritis (OA) has a wide spectrum of clinical presentations and physical function is one of the core domains where patients suffer. The Functional Index for Hand Osteoarthritis (FIHOA) is a leading assessment tool for hand OA-related functional impairment. Our objective was to make a Japanese version of FIHOA (J-FIHOA) and validate it among Japanese hand OA patients. Methods Forward and backward translation processes were completed to create a culturally adapted J-FIHOA. A prospective, observational multicenter study was undertaken for the validation process. Seventeen collaborating hospitals recruited Japanese hand OA patients who met the American College of Rheumatology criteria. A medical record review and responses to the following patient-rated questionnaires were collected: J-FIHOA, Hand20, Health Assessment Questionnaire (HAQ), numerical rating scale for pain (NRS pain) and Short Form 36 Health Survey (SF-36). We explored the structure of J-FIHOA using factor analysis. Cronbach’s alpha coefficients and item-total correlations were calculated. Correlations between J-FIHOA and other questionnaires were evaluated for construct validity. Participants in clinically stable conditions repeated J-FIHOA at a one- to two-week interval to assess test-retest reliability. To evaluate responsiveness, symptomatic patients who started new pharmacological treatments had a 1-month follow-up visit and completed the questionnaires twice. Effect size (ES) and standardized response mean (SRM) were calculated with pre- and post-treatment data sets. We assessed responsiveness, comparing ES and SRM of J-FIHOA with other questionnaires (construct approach). Results A total of 210 patients participated. J-FIHOA had unidimensional structure. Cronbach’s alphas (0.914 among females and 0.929 among males) and item-total correlations (range, 0.508 to 0.881) revealed high internal consistency. Hand20, which measures upper extremity disability, was strongly correlated with J-FIHOA (r = 0.82) while the mental and role-social components of SF-36 showed no correlations (r = − 0.24 and − 0.26, respectively). Intraclass correlation coefficient for test-retest reliability was 0.83 and satisfactory. J-FIHOA showed the highest ES and SRM (− 0.68 and − 0.62, respectively) among all questionnaires, except for NRS pain. Conclusions Our results showed J-FIHOA had good measurement properties to assess physical function in Japanese hand OA patients both for ambulatory follow-up in clinical practice, and clinical research and therapeutic trials.

Musculocontractural Ehlers–Danlos syndrome (mcEDS) is a subtype of EDS caused by defective dermatan sulfate biosynthesis, characterized by multiple malformations (craniofacial features, ocular and visceral malformations) and progressive cutaneous, skeletal, vascular, and visceral fragility-related manifestations. Repeated dislocations and deformities of the joints due to joint relaxation are observed, causing serious damage to the musculoskeletal system of the whole body; however, the motor function of the upper limbs and the morphology of the bone joints have not been systematically investigated. In this study, we present a detailed and comprehensive report on upper limb lesions of 13 patients with a mean age at the first visit of 21 years. Twelve patients (92.3%) had a history of dislocation. Eleven patients (84.6%) had shoulder dislocations, and two patients (15.4%) had elbow dislocations. Four patients (30.8%) had elbow osteoarthritis, and three patients (23.1%) had distal radioulnar joint (DRUJ) osteoarthritis. The phalanges and metacarpals are thin, and the ratio of medullary cavity of the metacarpal bone decreases with age. As bone and joint deformity progresses, patients with mcEDS should be recommended to receive regular follow-up, including radiology. The present findings suggest an important role for dermatan sulfate in the maintenance of the skeletal system.

Purpose We aimed to evaluate the extent of collagenase clostridium histolyticum (CCH) diffusion in Dupuytren’s contracture (DC) for tissues outside of the contracture cord using Magnetic Resonance Imaging (MRI) immediately after CCH injection. Methods: 10 male patients aged 57–79 with DC of the metacarpophalangeal (MCP) joints were examined. Extension deficits were 10–60°(mean, 34.3) and 0–60°(mean, 26.6) in the MCP and proximal interphalangeal (PIP) joints, respectively. CCH injection was performed according to the standard method. MRI was performed within 15 min of CCH injection. Results: In all 10 cases, the extended area of high-intensity signal change outside of the cord was observed on short-T1 inversion recovery images (STIRs). Continuity from the insertion site was observed in the area of signal change involving the flexor tendon and neurovascular bundle. The signal change area spanned distally and proximally beyond the injection level. The signal change area expanded along the tendon sheath but no signal changes were observed inside the flexor tendon, suggesting the tendon sheath serves as a protective barrier from the CCH solution. After 1 week of injection, the mean decrease in contracture was 32.5°(94.7%) for the MCP joint and 19.8°(74.4%) for the PIP joint. In nine out of 10 cases, the extension deficit was within five degrees of full extension in the affected finger. There was no neurovascular injury or tendon rupture at 3 months of observation. Conclusions: MRI indicated the possible leakage of the drug outside of the cord during the early phase after administration, suggesting that CCH could persistently affect healthy tissues until CCH inactivates its enzyme process.

For many pediatric sarcoma patients, multi-modal therapy including chemotherapy, radiation, and surgery is sufficient to cure their disease. However, event-free and overall survival rates for patients with more advanced disease are grim, necessitating the development of novel therapeutic approaches. Within many pediatric sarcomas, the normal immune response, including recognition and destruction of cancer cells, is lost due to the highly immune suppressive tumor microenvironment (TME). In this setting, tumor cells evade immune detection and capitalize on the immune suppressed microenvironment, leading to unchecked proliferation and metastasis. Recent preclinical and clinical approaches are aimed at understanding this immune suppressive microenvironment and employing cancer immunotherapy in an attempt to overcome this, by renewing the ability of the immune system to recognize and destroy cancer cells. While there are several factors that drive the attenuation of immune responses in the sarcoma TME, one of the most remarkable are tumor associated macrophage (TAMs). TAMs suppress immune cytolytic function, promote tumor growth and metastases, and are generally associated with a poor prognosis in most pediatric sarcoma subtypes. In this review, we summarize the mechanisms underlying TAM-facilitated immune evasion and tumorigenesis and discuss the potential therapeutic application of TAM-focused drugs in the treatment of pediatric sarcomas.

Myostatin, a member of the transforming growth factor‐β (TGF‐β) superfamily, is expressed in developing and adult skeletal muscle and negatively regulates skeletal muscle growth. Recently, myostatin has been found to be expressed in tendons and increases tendon fibroblast proliferation and the expression of tenocyte markers. C2C12 is a mouse myoblast cell line, which has the ability to transdifferentiate into osteoblast and adipocyte lineages. We hypothesized that myostatin is capable of inducing tenogenic differentiation of C2C12 cells. We found that the expression of scleraxis, a tendon progenitor cell marker, is much higher in C2C12 than in the multipotent mouse mesenchymal fibroblast cell line C3H10T1/2. In comparison with other growth factors, myostatin significantly up‐regulated the expression of the tenogenic marker in C2C12 cells under serum‐free culture conditions. Immunohistochemistry showed that myostatin inhibited myotube formation and promoted the formation of spindle‐shaped cells expressing tenomodulin. We examined signaling pathways essential for tenogenic differentiation to clarify the mechanism of myostatin‐induced differentiation of C2C12 into tenocytes. The expression of tenomodulin was significantly suppressed by treatment with the ALK inhibitor SB341542, in contrast to p38MAPK (SB203580) and MEK1 (PD98059) inhibitors. RNAi silencing of Smad3 significantly suppressed myostatin‐induced tenomodulin expression. These results indicate that myostatin has a potential role in the induction of tenogenic differentiation of C2C12 cells, which have tendon progenitor cell characteristics, through activation of Smad3‐mediated signaling.

The purpose of this study was to investigate the role of lubricin on the gliding resistance of intrasynovial tendons by comparing lubricin knockout, heterozygous, and wild type mice. A total of thirty-six deep digital flexor (DDF) tendons in the third digits of each hind paw from eighteen adult mice were used, including six lubricin knockout mice (Prg4 -/-), six heterozygous mice (Prg4 +/-), and six wild type mice (Prg4 +/+). The tendon gliding resistance was measured using a custom-made device. Tendon structural changes were evaluated by scanning electron and light microscopy. The gliding resistance of intrasynovial tendons from lubricin knockout mice was significantly higher than the gliding resistance of either wild type or heterozygous mice. The surface of the lubricin knockout tendons appeared to be rougher, compared to the wild type and heterozygous tendons. Synovial hyperplasia was found in the lubricin knockout mice. Cartilage-like tissue was found in the tendon and pulley of the lubricin knockout mice. Our findings confirm the importance of lubricin in intrasynovial tendon lubrication. This knockout model may be useful in determining the effect of lubricin on tendon healing and the response to injury.

The implantation of bone marrow cells (BMCs) into ischemic heart after myocardial infarction can induce angiogenesis and improve heart function. We compared the advantages of delivering BMCs intramyocardially and intravenously. An acute myocardial infarction model was created by the ligation of left anterior descending artery in female Dark Agouti rats. The rats were then randomly divided into four treatment groups: one given an intramyocardial injection of phosphate-buffered saline (PBS group), one given an intravenous injection of 2 × 107 BMCs from male rats (IV group), one given an intramyocardial injection with total of 2 × 107 BMCs from male rats at four points in the infarction area (IM group), and one given an intravenous injection of 10-fold the number of BMCs from male rats (10xIV group). Quantitative analysis of the SRY gene by real-time PCR showed that the survival of BMCs in the infarcted area was significantly higher in the IM group than in the IV and 10xIV groups, 3 days after treatment (p < 0.05), but not thereafter. However, the blood flow in the infarcted myocardium was significantly better in the IM and 10xIV groups than in the PBS and IV groups 14 days after treatment (p < 0.05). Echocardiography showed that the LVEF continued to decrease in the PBS and IV groups, but was stable after 3 days in the IM and 10xIV groups. By 14 days after treatment, the LVEF was significantly higher in the IM and 10xIV groups than in the PBS and IV groups (p < 0.01). Our results showed that BMCs were more effective delivered intramyocardially than intravenously for inducing angiogenesis and repairing injured myocardium.

We report the case of a 40-year-old woman with pseudoachondroplasia (PSACH), with a heterozygous mutation (c.806A > G, p.Asp269Gly) located in the Type 3 repeats domain of the cartilage oligomeric matrix protein gene, who complained of the unusual symptom of painful locking of the wrist. Her condition was caused by a non-traumatic enlargement of the extensor carpi radialis longus (ECRL) and brevis (ECRB) tendons along with bulbous swelling of the synoviums around them. Surgical treatment resolved these unusual tendon-related symptoms. Repetitive mechanical loading of the wrist in daily activities, including distal intersection tenosynovitis between the extensor pollicis longus tendon and ECRL and ECRB tendons, may have contributed to changes in the structural integrity of the tendons. We should pay more attention to tendon-related symptoms in patients with PSACH. [ABSTRACT FROM AUTHOR]

Efficient one-pot synthesis in water of polyrotaxanes, with native and permethylated α-cyclodextrins (α-CD and PMe α-CD) as the wheel components, is described. The procedure involves initial mixing of α-CDs and an amine-terminated linear polymer, which acts as the axle, by sonication and subsequent addition of an end-capping agent for the axle terminal amino groups. The polyrotaxanes were prepared by mixing the axle and wheel components by sonication for 30 min at room temperature and standing overnight if necessary, followed by treatment with a bulky isocyanate in water at 0 °C for an hour. Both amine-terminated polytetrahydrofuran (ATPT) and poly(ethylene glycol) (ATPEG) afforded the corresponding polyrotaxanes (PRXs) in good yields (27−49%) in the case of a native α-CD wheel. The coverage ratio of the axle component with the wheel component of the PRXs ranged from 85% to 96% when the molecular weight of the axle was Mn1000−1800, while it was 54% when the axle was long (Mn7700). The polyrotaxanes (PMePRXs) with PMe α-CD and ATPT were similarly obtained in high yields. In this case, the yield of the PMePRXs was unusually high (66 and 69%) when a higher molecular weight axle (Mn4100 and 7100, respectively) was used. The formation of a PMePRX from ATPEG axle proceeded with low efficiency. The present work provides the first synthesis of polyrotaxanes with PMe α-CD in solution. [ABSTRACT FROM AUTHOR]

Purpose: To characterize the cone electroretinograms (ERGs) elicited by chromatic stimuli obtained from a newly-developed contact lens electrode with built-in light-emitting diodes (LEDs) emitting different colors. Methods: Cone ERGs were recorded from normal subjects with a contact lens electrode with built-in blue (430 nm), red (644 nm), and white LEDs. These LEDs have a wide range of luminance intensities (3 log units), and can be used as either the background illumination or the stimulus in any combination. The stimulus duration was fixed at 1 ms. For comparison, cone ERGs were recorded with Ganzfeld color flash stimuli using Wratten color filters on a bright white background. Results: With a bright background illumination provided by the white LED (2.0 log cd/m2), the blue LED stimulus elicited an ERG with two positive peaks similar to that recorded with conventional Ganzfeld blue flashes. The peak time of the early b-wave was 24 to 28 ms, and that of the later one was 43 to 48 ms, and these values were identical to the L,M-cone and S-cone b-wave, respectively, elicited by Ganzfeld flashes. The ERGs elicited by the red LED lacked the second peak. Conclusion: These results indicate that the S-cone and L,M-cone ERGs can be recorded simultaneously under the same background with this contact lens electrode. This relatively simple technique can be used to examine the human S-cone system in a routine clinical setting. [ABSTRACT FROM AUTHOR]