Refinement of Surgery for Postaxial Polysyndactyly of the Toes: Esthetic Outcome in Japanese Feet.

PURPOSE: Treatment for polysyndactyly of the toes aims at cosmetic improvement but the lateroplantar rotation of the new fifth toe remains challenging. This study evaluated our novel surgical procedure for postaxial polysyndactyly of the toes. MATERIALS AND METHODS: Patients with postaxial polysyndactyly involving the fourth, fifth, and sixth toes treated in 2007 to 2017 with a minimum follow-up duration of 1 year were retrospectively investigated. Our aims of surgery for this condition were to avoid excessive lateroplantar rotation of the new fifth toe by using a proximally elongated plantar "shark-fin flap" and to make the tip of this toe appear to be naturally pointing inward by using the dog-ear component of the flap on the tip of the toe. The excess skin of the shark-fin flap was grafted onto the lateral surface of the fourth toe. Lateroplantar rotation of the fifth toe in these patients was compared with that in photographs of the feet of 96 normal 4-year-old children. RESULTS: A total of 11 feet in 10 patients (6 male, 4 female; mean age 1.3 years) were analyzed. Syndactyly between the fourth and fifth toes was complete in 3 feet, incomplete at the level of the distal interphalangeal joint of the fifth toe in 5, and incomplete at the level of the proximal interphalangeal joint of the fifth toe in 3. Lateroplantar rotation of the fifth toe, evaluated by the mean angle between 2 intersecting lines extending from the proximal nail fold of the third and fifth toes, was 25 ± 10° in normal feet and 0 ± 12° in operated feet with polysyndactyly. The absolute left-right difference in this angle was 7 ± 5° in normal children and 22 ± 12° in patients with polysyndactyly. Valgus deformity of the new fifth toe improved in all patients during a mean postoperative follow-up of 3.8 years. CONCLUSIONS: Using our procedure, no excessive lateroplantar rotation has been observed when the tip of the fifth toe is inclined inward using a dog-ear flap component. This procedure could be useful in patients in whom the cosmetic outcome is a priority.

Identification of a novel RNA transcript TISPL upregulated by stressors that stimulate ATF4.

Cells sense, respond, and adapt to environmental conditions that cause stress. In a previous study using HeLa cells, we isolated reporter cells responding to the endoplasmic reticulum (ER) stress inducers, thapsigargin and tunicamycin, using a highly sensitive promoter trap vector system. Splinkerette PCR and 5' rapid amplification of cDNA ends (5' RACE) identified a novel transcript that is upregulated by ER stress. Its endogenous expression increased approximately 10-fold in response to thapsigargin and tunicamycin within 1 h, but was down-regulated after 4 h. Because the transcript starts from an intron of a long noncoding RNA known as LINC-PINT, we designated the newly identified transcript TISPL (transcript induced by stressors from LINC-PINTlocus). TISPL was also expressed under several other stress conditions. It was particularly increased > 10-fold upon glucose starvation and 7-fold by arsenite exposure. Furthermore, in silico analyses, including a ChIP-atlas search, revealed that there is an ATF4-binding region with a c/ebp-Atf response element (CARE) downstream of the transcription start site of TISPL. Based on these results, we hypothesized that TISPL may be induced by the phospho-eIF2α and ATF4- axis of the integrated stress response pathway, which is known to be activated by the stress conditions listed above. As expected, knockout of ATF4 abolished the stress-induced upregulation of TISPL. Our results indicate that TISPL may be a useful biomarker for detecting stress conditions that activate ATF4. Our highly sensitive trap vector system proved beneficial in discovering new biomarkers.

Fluoroscopy- and Endoscopy-Guided Transoral Sclerotherapy Using Foamed Polidocanol for Oropharyngolaryngeal Venous Malformations in a Hybrid Operation Room: A Case Series.

Background: Treatment of oropharyngolaryngeal venous malformations (VMs) remains challenging. This study evaluated the effectiveness and safety of fluoroscopy- and endoscopy-guided transoral sclerotherapy for oropharyngolaryngeal VMs in a hybrid operation room (OR). Methods: Patients with oropharyngolaryngeal VMs who underwent transoral sclerotherapy in a hybrid OR were enrolled. Results: Fourteen patients (six females, eight males; median age of 26 years; range, 4-71 years) were analyzed. The symptoms observed were breathing difficulties (n = 3), snoring (n = 2), sleep apnea (n = 1), and swallowing difficulties (n = 1). Lesions were extensive in the face and neck (n = 9) and limited in the oropharyngolarynx (n = 5). A permanent tracheostomy was performed on two patients, while a temporary tracheostomy was performed on five patients. The treated regions were the soft palate (n = 8), pharynx (n = 7), base of the tongue (n = 4), and epiglottis (n = 1). The median number of sclerotherapy sessions was 2.5 (range, 1-9). The median follow-up duration was 81 months (range, 6-141). Treatment outcomes were graded as excellent (n = 2), good (n = 7), or fair (n = 5). The post-treatment complication was bleeding (n = 1), resulting in an urgent tracheostomy. Conclusions: Fluoroscopy- and endoscopy-guided transoral sclerotherapy in a hybrid OR can be effective and safe for oropharyngolaryngeal VMs.

Lymphatic drainage patterns of malignant skin tumors in the head and neck region: a single-center retrospective study.

BACKGROUND: This study aimed to clarify the relationship between primary site and lymphatic drainage pattern for malignant skin tumors in the head and neck region. Malignant melanoma and squamous cell carcinoma in the head and neck region are known to have poor prognosis because of lymph node metastasis. Nevertheless, numerous aspects of lymphatic drainage patterns remain elusive. METHODS: We statistically analyzed data of 47 patients with malignant skin tumors in the head and neck region. Information was collected on the patients' clinical characteristics, primary tumor site, and lymphatic drainage patterns. RESULTS: The parotid lymph nodes drained the greatest amount of lymph from skin tumors of the head and neck. Important lymphatic drainage pathways were the superficial cervical nodes for primary tumors in the buccal/nasal region, level IA and level IB nodes for primary tumors in the lip region, the occipital nodes, posterior auricular nodes, and level VA nodes in the parietal/occipital region, and the preauricular nodes in the auricular region. CONCLUSION: These findings have considerable significance in terms of understanding lymphatic drainage patterns for malignant skin tumors in the head and neck and may be useful for clinical decision-making and when planning treatment. Further research and clinical applications are expected to contribute to an improved prognosis in patients with cutaneous head and neck malignancies.

The Prospective Natural History Study of Patients with Intractable Venous Malformation and Klippel-Trenaunay Syndrome to Guide Designing a Proof-of-Concept Clinical Trial for Novel Therapeutic Intervention.

Background: The natural history of venous malformation (VM) and Klippel-Trenaunay Syndrome (KTS) has not been quantitatively studied. To obtain benchmarks to guide designing clinical trials to assess safety and efficacy of novel drug candidates, the clinical course of the patients was followed for 6 months. Methods and Results: This is a multicenter prospective observational study evaluating the change rate in lesion volume from baseline with magnetic resonance images, as the primary endpoint. In addition, disease severities, performance status (PS), pain visual analog scale (VAS) score, quality of life (QoL), infections, and coagulation markers were also evaluated. Thirty-four patients (VM = 17, KTS = 17, 1-53 of age; median 15.9 years) with measurable lesion volume were analyzed. There was no statistically significant difference in the lesion volume between baseline and day 180, and the mean change rate (standard deviation) was 1.06 (0.28). There were no baseline characteristics that affected the change in lesion volume over 6 months. However, there were patients who showed more than 20% volume change and it was suggested that the lesion volume was largely impacted by local infection. There were no statistically significant changes in pain VAS score, severity, PS, QoL score, D-dimer, and platelet count over 6 months within all patients analyzed. Conclusion: The results showed the representative natural course of VM and KTS for a 6-month period with objective change of lesion volume and other factors, suggesting that it is scientifically reasonable to conduct a Phase 2 proof-of-concept study without a placebo arm, using the results of this study as the control. Clinical Trial Registration: NCT04285723, NCT04589650.

Efficacy of hyperbaric oxygen after microtia reconstruction using costal cartilage: A retrospective case-control study.

Introduction: Microtia reconstruction with autologous costal cartilage framework grafting is challenging because the three-dimensional structure of the ear is highly complex, and meeting the high aesthetic demands of patients can be difficult. If the skin flap overlying the framework is thinned to achieve a smooth and accentuated outline, a poor blood supply in the thin skin flap may lead to skin necrosis, exposure of the framework, and poor surgical results. Hyperbaric oxygen (HBO2) therapy can promote the healing of complex wounds and flaps. This study sought to determine the effectiveness of HBO2 therapy for the prevention of postoperative complications after framework grafting in microtia reconstruction. Methods: We retrospectively evaluated postoperative complications and compared outcomes in pediatric patients who underwent costal cartilage grafting for microtia reconstruction at our institution between 2011 and 2015, according to whether or not they received postoperative HBO2 therapy. HBO2 therapy was applied once daily for a total of 10 sessions starting on the first postoperative day. Results: During the study period, eight patients received HBO2 therapy after costal cartilage grafting, and 12 did not. There was no significant difference in the incidence of postoperative ulcers. However, the incidence of framework exposure was lower, and the healing time was shorter in patients who received HBO2 therapy than in those who did not. Discussion: HBO2 therapy can be used safely in pediatric patients to reduce postoperative complications and improve the aesthetic outcome of microtia reconstruction. After costal cartilage grafting, HBO2 therapy should be considered as adjuvant therapy.

Intranodal lymphangiography with lipiodol as a diagnostic and therapeutic approach for spontaneous cervical chyle leak.

We present a case of spontaneous cervical chyle leak that showed as left-sided neck swelling. Spontaneous chyle leak is extremely rare. Lymphangiography with lipiodol is useful as a diagnostic and therapeutic approach for chyle leak.

Partially involuting congenital hemangioma with pyogenic granuloma-induced rapid progression following incisional biopsy in infancy: A case report.

We present a case of partially involuting congenital hemangioma (PICH) that showed rapid growth with ulceration after incisional biopsy. PICH does not typically grow after birth. However, if growth occurs due to stimuli like biopsy, it is essential to consider the possibility of pyogenic granuloma complication.

Tyrosine Kinase Inhibitor Profiling Using Multiple Forskolin-Responsive Reporter Cells.

We have developed a highly sensitive promoter trap vector system using transposons to generate reporter cells with high efficiency. Using an EGFP/luciferase reporter cell clone responsive to forskolin, which is thought to activate adenylate cyclase, isolated from human chronic myelogenous leukemia cell line K562, we found several compounds unexpectedly caused reporter responses. These included tyrosine kinase inhibitors such as dasatinib and cerdulatinib, which were seemingly unrelated to the forskolin-reactive pathway. To investigate whether any other clones of forskolin-responsive cells would show the same response, nine additional forskolin-responsive clones, each with a unique integration site, were generated and quantitatively evaluated by luciferase assay. The results showed that each clone represented different response patterns to the reactive compounds. Also, it became clear that each of the reactive compounds could be profiled as a unique pattern by the 10 reporter clones. When other TKIs, mainly bcr-abl inhibitors, were evaluated using a more focused set of five reporter clones, they also showed unique profiling. Among them, dasatinib and bosutinib, and imatinib and bafetinib showed homologous profiling. The tyrosine kinase inhibitors mentioned above are approved as anticancer agents, and the system could be used for similarity evaluation, efficacy prediction, etc., in the development of new anticancer agents.

Targeted next-generation sequencing for detection of PIK3CA mutations in archival tissues from patients with Klippel-Trenaunay syndrome in an Asian population : List the full names and institutional addresses for all authors.

BACKGROUND: Klippel-Trenaunay syndrome (KTS) is a rare slow-flow combined vascular malformation with limb hypertrophy. KTS is thought to lie on the PIK3CA-related overgrowth spectrum, but reports are limited. PIK3CA encodes p110α, a catalytic subunit of phosphatidylinositol 3-kinase (PI3K) that plays an essential role in the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway. We aimed to demonstrate the clinical utility of targeted next-generation sequencing (NGS) in identifying PIK3CA mosaicism in archival formalin-fixed paraffin-embedded (FFPE) tissues from patients with KTS. RESULTS: Participants were 9 female and 5 male patients with KTS diagnosed as capillaro-venous malformation (CVM) or capillaro-lymphatico-venous malformation (CLVM). Median age at resection was 14 years (range, 5-57 years). Median archival period before DNA extraction from FFPE tissues was 5.4 years (range, 3-7 years). NGS-based sequencing of PIK3CA achieved an amplicon mean coverage of 119,000x. PIK3CA missense mutations were found in 12 of 14 patients (85.7%; 6/8 CVM and 6/6 CLVM), with 8 patients showing the hotspot variants E542K, E545K, H1047R, and H1047L. The non-hotspot PIK3CA variants C420R, Q546K, and Q546R were identified in 4 patients. Overall, the mean variant allele frequency for identified PIK3CA variants was 6.9% (range, 1.6-17.4%). All patients with geographic capillary malformation, histopathological lymphatic malformation or macrodactyly of the foot had PIK3CA variants. No genotype-phenotype association between hotspot and non-hotspot PIK3CA variants was found. Histologically, the vessels and adipose tissues of the lesions showed phosphorylation of the proteins in the PI3K/AKT/mTOR signaling pathway, including p-AKT, p-mTOR, and p-4EBP1. CONCLUSIONS: The PI3K/AKT/mTOR pathway in mesenchymal tissues was activated in patients with KTS. Amplicon-based targeted NGS could identify low-level mosaicism from low-input DNA extracted from FFPE tissues, potentially providing a diagnostic option for personalized medicine with inhibitors of the PI3K/AKT/mTOR signaling pathway.

Identification of microbial metabolites that accelerate the ubiquitin-dependent degradation of c-Myc.

Myc belongs to a family of proto-oncogenes that encode transcription factors. The overexpression of c-Myc causes many types of cancers. Recently, we established a system for screening c-Myc inhibitors and identified antimycin A by screening the RIKEN NPDepo chemical library. The specific mechanism of promoting tumor cell metastasis by high c-Myc expression remains to be explained. In this study, we screened approximately 5,600 microbial extracts using this system and identified a broth prepared from Streptomyces sp. RK19-A0402 strongly inhibits c-Myc transcriptional activity. After purification of the hit broth, we identified compounds closely related to the aglycone of cytovaricin and had a structure similar to that of oligomycin A. Similar to oligomycin A, the hit compounds inhibited mitochondrial complex V. The mitochondria dysfunction caused by the compounds induced the production of reactive oxygen species (ROS), and the ROS activated GSK3α/ß that phosphorylated c-Myc for ubiquitination. This study provides a successful screening strategy for identifying natural products as potential c-Myc inhibitors as potential anticancer agents.

Identification of antimycin A as a c-Myc degradation accelerator via high-throughput screening.

c-Myc is a critical regulator of cell proliferation and growth. Elevated levels of c-Myc cause transcriptional amplification, leading to various types of cancers. Small molecules that specifically inhibit c-Myc-dependent regulation are potentially invaluable for anticancer therapy. Because c-Myc does not have enzymatic activity or targetable pockets, researchers have attempted to obtain small molecules that inhibit c-Myc cofactors, activate c-Myc repressors, or target epigenetic modifications to regulate the chromatin of c-Myc-addicted cancer without any clinical success. In this study, we screened for c-Myc inhibitors using a cell-dependent assay system in which the expression of c-Myc and its transcriptional activity can be inferred from monomeric Keima and enhanced GFP fluorescence, respectively. We identified one mitochondrial inhibitor, antimycin A, as a hit compound. The compound enhanced the c-Myc phosphorylation of threonine-58, consequently increasing the proteasome-mediated c-Myc degradation. The mechanistic analysis of antimycin A revealed that it enhanced the degradation of c-Myc protein through the activation of glycogen synthetic kinase 3 by reactive oxygen species (ROS) from damaged mitochondria. Furthermore, we found that the inhibition of cell growth by antimycin A was caused by both ROS-dependent and ROS-independent pathways. Interestingly, ROS-dependent growth inhibition occurred only in the presence of c-Myc, which may reflect the representative features of cancer cells. Consistently, the antimycin A sensitivity of cells was correlated to the endogenous c-Myc levels in various cancer cells. Overall, our study provides an effective strategy for identifying c-Myc inhibitors and proposes a novel concept for utilizing ROS inducers for cancer therapy.

Utility of Color Doppler Ultrasonography in Monitoring of a Free Jejunal Flap.

OBJECTIVES: External color Doppler ultrasonography is reported to be a useful monitoring technique that is simple and noninvasive; however, details of imaging of the transferred free jejunal flap have not been reported. We reviewed our experience using external color Doppler ultrasonography to monitor a transferred free jejunal flap and examined its utility. STUDY DESIGN: Retrospective study. METHODS: Subjects were 43 patients who underwent total pharyngolaryngectomy, reconstruction with a free jejunal flap, and color Doppler ultrasonography before, during, and after surgery between September 2017 and December 2021. RESULTS: During surgery, arterial thrombosis was detected up to 100% with the loss of continuous color signals in the entire circumference. After surgery, the positive predictive value was 100% for each of wiggling movement, dynamic intestinal movement, and continuous color signals in the entire circumference on color Doppler ultrasonography for detecting flap viability. Their negative predictive value was 100%, 7.1%, and 50%, respectively. CONCLUSIONS: During surgery, the continuous color signals in the entire circumference sign were useful with 100% negative predictive value for detecting the arterial thrombosis. After surgery, the wiggling movement sign very was useful with 100% positive and negative predictive values, enabling salvage surgery to be performed soon after detection of flap failure. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:3361-3369, 2023.

Development of a simultaneous and noninvasive measuring method using high-frame rate videography and motion analysis software for the assessment of facial palsy recovery in a rat model.

BACKGROUND: For the development of new therapeutic and reconstructive methods for facial nerve palsy, it is critical to validate them in animal models. This study developed a novel evaluation method using a high-speed camera and motion analysis software for rat facial paralysis models. The validity of the new method was verified using normal rats and rats with facial paralysis. METHODS: The whisker movement was recorded using a high-frame video camera. The video files were processed using motion analysis software, and the angular velocities were measured. The score was calculated as the percentage of movement on the side that had palsy compared with the movement on the normal side. Normal rats were used to examine which of the four indices of angular velocity is appropriate for this evaluation method. Using this method, two types of facial nerve palsy models were compared. Furthermore, the three agents that were predicted to promote axon regeneration from previous studies were evaluated. RESULTS: The two averages of the protraction and retraction movement velocities of the whiskers were considered as the most appropriate indicators for this new method. Compared with the saline group, all agent groups showed significant differences in the improvement of facial palsy recovery. CONCLUSIONS: This method is an evaluation method for the effects of therapeutic intervention for facial nerve paralysis in real time without sacrificing animals.

Therapeutic Potential of the Prolyl Hydroxylase Inhibitor Roxadustat in a Mouse Hindlimb Lymphedema Model.

Background: Lymphedema is an intractable disease with no curative treatment available. Conservative treatment is the mainstay, and new drug treatment options are strongly needed. The purpose of this study was to investigate the effect of roxadustat, a prolyl-4-hydroxylase inhibitor, on lymphangiogenesis and its therapeutic effect on lymphedema in a radiation-free mouse hindlimb lymphedema model. Methods and Results: Male C57BL/6N mice (8-10 weeks old) were used for the lymphedema model. Mice were randomized to an experimental group receiving roxadustat or a control group. The circumferential ratio of the hindlimbs was evaluated, and lymphatic flow of the hindlimbs was compared by fluorescent lymphography up to 28 days postoperatively. The roxadustat group showed an early improvement in hindlimb circumference and stasis of lymphatic flow. The number and area of lymphatic vessels on postoperative day 7 were significantly larger and smaller, respectively, in the roxadustat group compared with the control group. Skin thickness and macrophage infiltration on postoperative day 7 were significantly reduced in the roxadustat group compared with the control group. The relative mRNA expression of hypoxia-inducible factor-1α (Hif-1α), vascular endothelial growth factor receptor-3 (VEGFR-3), vascular endothelial growth factor-C (VEGF-C), and Prospero homeobox 1 (Prox1) on postoperative day 4 was significantly higher in the roxadustat group compared with the control group. Conclusions: Roxadustat demonstrated a therapeutic effect in a murine model of hindlimb lymphedema through promotion of lymphangiogenesis through the activation of HIF-1α, VEGF-C, VEGFR-3, and Prox1, suggesting the potential of roxadustat as a therapeutic option in lymphedema.

Effectiveness and safety of percutaneous sclerotherapy using absolute ethanol and/or polidocanol for maxillofacial venous malformations involving the masticatory muscles: A case series.

OBJECTIVE: This study evaluated the effectiveness and safety of percutaneous sclerotherapy for maxillofacial venous malformations. STUDY DESIGN: Patients who had venous malformations involving the masticatory muscles and who underwent sclerotherapy were enrolled in this retrospective study. RESULTS: Twenty-four patients (13 female, 11 male; mean age 21 years) were analyzed. Major clinical symptoms were swelling (100%) and intralesional pain (54%). Intramuscular lesions involved the masseter muscle only in 38% of cases, both the masseter and temporalis muscles in 33%, all masticatory muscles in 21%, and the temporalis muscle only in 8%. Extramuscular involvement was observed in 58% of patients. Absolute ethanol and polidocanol were used as sclerosants. The mean number of sclerotherapy sessions per patient was 6.6 (range, 1-32). The mean follow-up duration after the first sclerotherapy session was 64.8 months (range, 6-178). The complications included paralysis of the facial nerve (25%), intraoral ulceration (8%), and hemoglobinuria (8%). The effectiveness of treatment was rated as excellent in 33% of cases, good in 46%, and fair in 21%. Better results were obtained in patients without extramuscular involvement. CONCLUSION: Percutaneous sclerotherapy can be effective and safe for maxillofacial intramuscular venous malformations, especially for localized lesions of the masseter muscle.

Restoration of lymph flow by flap transfer can prevent severe lower extremity lymphedema after inguino-pelvic lymphadenectomy.

PURPOSE: Severe lymphedema is difficult to treat because of the associated extensive scar formation. Therefore, preventing scar formation might alleviate the severity of lymphedema following lymphadenectomy. In this study, we evaluated the usefulness of flap transfer, performed immediately after lymphadenectomy, for preventing scar formation. METHODS: Twenty-three patients with subcutaneous malignancy in a lower extremity, who underwent inguino-pelvic lymphadenectomy, were divided into groups based on whether flap transfer was performed. The severity of lymphedema was categorized according to the ratio of the circumference of the affected extremity to that of the unaffected extremity, as mild (< 20% increase in volume), moderate (20-40%), or severe (> 40%). RESULTS: In the 18 patients who underwent lymphadenectomy without flap transfer, lymphedema was classified as mild in 7, moderate in 7, and severe in 4. In the five patients who underwent lymphadenectomy with flap transfer, lymphedema was classified as mild in 4 and moderate in 1. This difference between the groups did not reach significance. CONCLUSIONS: The findings of this study suggest that flap transfer may help prevent scar formation and contribute to the restoration of lymph flow after lymphadenectomy.

Sentinel node restoration by vascularized lymph node transfer in mice.

BACKGROUND: Recent reports have indicated that vascularized lymph node transfer (VLNT) may improve the impaired immunity in lymphedema but there has been no report concerning anti-cancer immunity. In the early tumor immune response, dendritic cells (DCs) participate in tumor recognition and antigen presentation in local lymphatics. Here, we investigated the impact of VLNT on DC dynamics against cancer in mouse models. METHODS: Forty-seven 8-week-old C57BL/6 N male mice were divided into three surgical groups: a VLNT model in which a vascularized inguinal lymph node (LN) flap was transferred into the ipsilateral fossa after a popliteal LN was removed; a LN dissection (LND) model in which the popliteal LN was dissected; and a control model in which a skin incision was made at the popliteal fossa and an ipsilateral inguinal LN was removed. Postoperative lymphatic flows were observed by indocyanine green lymphography and B16-F10-luc2 mouse melanoma were implanted into the ipsilateral footpad. The proportion of DCs in the transplanted nodes was measured by CD11c immunohistochemistry using digital imaging analysis 4 days after cancer implantation. Metastases to the lungs and LNs were quantitatively evaluated by luciferase assay 4 weeks after cancer implantation. RESULTS: After VLNT, lymphatic reconnection was observed in 59.2% of mice. The proportion of DCs was significantly higher in the VLNT group with lymphatic reconnection (8.6% ± 1.0%) than in the naïve LN (4.3% ± 0.4%) (p < .001). The tumor burden of lung metastases was significantly less in the VLNT group with lymphatic reconnection compared with the LND group (p = .049). CONCLUSIONS: Metastasis decreased in mice with reconnected lymphatics after VLNT. A possible explanation was that lymphatic restoration may have contributed to the tumor immune response by allowing DC migration to LNs.

Streptococcal Toxic Shock Syndrome in a Pediatric Patient With Intramuscular Venous Malformation in the Neck.

BACKGROUND: Streptococcal toxic shock syndrome (STSS) is diagnosed based on signs of shock with multiorgan system involvement, a generalized erythematous macular rash, and rapidly progressive and destructive soft tissue infection. CASE REPORT: The patient was a 2-year-old girl with intramuscular venous malformation in the neck in which an infection occurred, developing into STSS. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Group A streptococcal infections are common in children and usually have a mild clinical presentation, but may be life threatening in severe cases. Patients with venous malformations are known to have slow-flow anomalies with venous pooling, which can result in hypoxia and possible immune cell dysfunction. Thus, clinicians should be aware of STSS when a patient with venous malformation has a rapidly progressive infection.

Lonidamine and domperidone inhibit expansion of transformed cell areas by modulating motility of surrounding nontransformed cells.

Cancer cells intrinsically proliferate in an autonomous manner; however, the expansion of cancer cell areas in a tissue is known to be regulated by surrounding nontransformed cells. Whether these nontransformed cells can be targeted to control the spread of cancer cells is not understood. In this study, we established a system to evaluate the cancer-inhibitory activity of surrounding nontransformed cells and screened chemical compounds that could induce this activity. Our findings revealed that lonidamine (LND) and domperidone (DPD) inhibited expansion of oncogenic foci of KRASG12D-expressing transformed cells, whereas they did not inhibit the proliferation of monocultured KRASG12D-expressing cells. Live imaging revealed that LND and DPD suppressed the movement of nontransformed cells away from the attaching cancer cells. Moreover, we determined that LND and DPD promoted stress fiber formation, and the dominant-negative mutant of a small GTPase RhoA relieved the suppression of focus expansion, suggesting that RhoA-mediated stress fiber formation is involved in the inhibition of the movement of nontransformed cells and focus expansion. In conclusion, we suggest that elucidation of the mechanism of action of LND and DPD may lead to the development of a new type of drug that could induce the anticancer activity of surrounding nontransformed cells.