A novel treatment strategy targeting cellular pathways with natural products to alleviate sarcopenia.

Sarcopenia is a condition marked by a significant reduction in muscle mass and strength, primarily due to the aging process, which critically impacts muscle protein dynamics, metabolic functions, and overall physical functionality. This condition leads to increased body fat and reduced daily activity, contributing to severe health issues and a lower quality of life among the elderly. Recognized in the ICD-10-CM only in 2016, sarcopenia lacks definitive treatment options despite its growing prevalence and substantial social and economic implications. Given the aging global population, addressing sarcopenia has become increasingly relevant and necessary. The primary causes include aging, cachexia, diabetes, and nutritional deficiencies, leading to imbalances in protein synthesis and degradation, mitochondrial dysfunction, and hormonal changes. Exercise remains the most effective intervention, but it is often impractical for individuals with limited mobility, and pharmacological options such as anabolic steroids and myostatin inhibitors are not FDA-approved and are still under investigation. This review is crucial as it examines the potential of natural products as a novel treatment strategy for sarcopenia, targeting multiple mechanisms involved in its pathogenesis. By exploring natural products' multi-targeted effects, this study aims to provide innovative and practical solutions for sarcopenia management. Therefore, this review indicates significant improvements in muscle mass and function with the use of specific natural compounds, suggesting promising alternatives for those unable to engage in regular physical activity.

Bleb characteristics assessed by ultrasound biomicroscopy correlate with intraocular pressure after Ahmed glaucoma valve surgery in dogs.

OBJECTIVE: To assess the characteristics of blebs formed after Ahmed glaucoma valve (AGV) surgery in dogs using ultrasound biomicroscopy (UBM) and to analyze their correlation with postoperative intraocular pressure (IOP). ANIMALS: 16 eyes (13 dogs) were diagnosed with primary angle-closure glaucoma and were followed up after AGV surgery from June 2021 to September 2023. METHODS: In this prospective study, UBM examinations were performed to assess bleb characteristics, including bleb wall thickness and reflectivity. IOP at the time of UBM imaging and the duration from AGV surgery to UBM imaging were recorded. Histological examination of an enucleated eye removed due to uncontrolled IOP leading to blindness was also conducted. RESULTS: A significant correlation was observed between IOP and relative reflectivity (Pearson r = 0.60; P = .01), and a negative correlation was observed between bleb wall thickness and relative reflectivity (Pearson r = -0.72; P = .002). No significant correlation was observed between the duration from AGV surgery to UBM imaging and either bleb wall thickness or relative reflectivity, respectively. Histological examination of the enucleated eye revealed collagen-rich fibrous encapsulation of the bleb wall, including myofibroblasts that exhibited positive α-smooth muscle actin immunostaining. CLINICAL RELEVANCE: In dogs that underwent AGV surgery, less dense, thick-walled blebs on UBM tended to maintain IOP within the normal range. However, denser, thinner-walled blebs showed IOP levels above the normal range despite the use of antiglaucoma medications. UBM is a useful tool for evaluating bleb characteristics and their influence on IOP regulation after AGV surgery in dogs.

Long-term clinical outcomes after high and low ligations with lymph node dissection around the root of the inferior mesenteric artery in patients with rectal cancer.

PURPOSE: This study aimed to evaluate the long-term clinical outcomes based on the ligation level of the inferior mesenteric artery (IMA) in patients with rectal cancer. METHODS: This was a retrospective analysis of a prospectively collected database that included all patients who underwent elective low anterior resection for rectal cancer between January 2013 and December 2019. The clinical outcomes included oncological outcomes, postoperative complications, and functional outcomes. The oncological outcomes included overall survival (OS) and relapse-free survival (RFS). The functional outcomes, including defecatory and urogenital functions, were analyzed using the Fecal Incontinence Severity Index, International Prostate Symptom Score, and International Index of Erectile Function questionnaires. RESULTS: In total, 545 patients were included in the analysis. Of these, 244 patients underwent high ligation (HL), whereas 301 underwent low ligation (LL). The tumor size was larger in the HL group than in the LL group. The number of harvested lymph nodes (LNs) was higher in the HL group than in the LL group. There were no significant differences in complication rates and recurrence patterns between the groups. There were no significant differences in 5-year RFS and OS between the groups. Cox regression analysis revealed that the ligation level (HL vs. LL) was not a significant risk factor for oncological outcomes. Regarding functional outcomes, the LL group showed a significant recovery in defecatory function 1 year postoperatively compared with the HL group. CONCLUSION: LL with LNs dissection around the root of the IMA might not affect the oncologic outcomes comparing to HL; however, it has minimal benefit for defecatory function.

Direct Repair of Symptomatic Lumbar Spondylolysis Using Rod-Screw-Cable System.

OBJECTIVE: To assess the efficacy of a new direct lysis repair technique using internal fixation with rod, screws, and Songer cable in symptomatic lumbar spondylolysis. METHODS: Between December 2015 and January 2020, patients who were diagnosed with symptomatic lumbar spondylolysis and surgically treated with a rod-screw-cable system were recruited. Pedicle screwing by the Magerl technique was performed in all included patients, followed by direct lysis repair with bone allograft and demineralized bone matrix by stabilizing the posterior lamina and spinous process using a rod-screw-cable system. Clinical outcome was measured using the visual analog scale and Oswestry disability index preoperatively and 6 weeks, 3 months, 6 months, 1 year, and 2 years postoperatively. RESULTS: Sixteen patients were included in this study-11 men and 5 women (mean age: 47 years; range, 26-67 years). The lytic defects were at L4 and L5 in 6 and 10 patients, respectively. The mean follow-up period was 41 months (24-62 months). The visual analog scale values were 7.3, 6.1, 4.3, 3.3, 2.1, and 1.9 preoperatively and 6 weeks, 3 months, 6 months, 1 year, and 2 years postoperatively, respectively. The Oswestry disability index values were 59.8%, 55.4%, 41.7%, 32.4%, 21.1%, and 16.9% for the same periods, respectively. No patient had an increase in the slip after surgery. There were no significant complications such as implant failure. CONCLUSIONS: Our technique provides rigid intra-segmental repair of spondylolysis without intersegmental motion interference, even if the patient is older or has disc degeneration.

Capillary gingival hemangioma in a cat.

A 12-year-old spayed female American short-haired cat presented with a palatal gingival mass located between the right maxillary third incisor and the canine teeth. The mass was dark red and had a narrow attachment to the gingival margin of the canine tooth. The mass was completely removed by marginal excision and the histopathological diagnosis was a capillary hemangioma. The mass did not relapse until 1 year later; however, the tooth was extracted because of cervical resorption of the right maxillary canine immediately adjacent to the mass resection site. This report presents a rare case of the gingival hemangioma in a cat and the possibility of a causal relationship between the occurrence of external cervical tooth resorption and hemangioma resection.

Combined inhibition of Bcl-2 family members and YAP induces synthetic lethality in metastatic gastric cancer with RASA1 and NF2 deficiency.

BACKGROUND: Targetable molecular drivers of gastric cancer (GC) metastasis remain largely unidentified, leading to limited targeted therapy options for advanced GC. We aimed to identify molecular drivers for metastasis and devise corresponding therapeutic strategies. METHODS: We performed an unbiased in vivo genome-wide CRISPR/Cas9 knockout (KO) screening in peritoneal dissemination using genetically engineered GC mouse models. Candidate genes were validated through in vivo transplantation assays using KO cells. We analyzed target expression patterns in GC clinical samples using immunohistochemistry. The functional contributions of target genes were studied through knockdown, KO, and overexpression approaches in tumorsphere and organoid assays. Small chemical inhibitors against Bcl-2 members and YAP were tested in vitro and in vivo. RESULTS: We identified Nf2 and Rasa1 as metastasis-suppressing genes through the screening. Clinically, RASA1 mutations along with low NF2 expression define a distinct molecular subtype of metastatic GC exhibiting aggressive traits. NF2 and RASA1 deficiency increased in vivo metastasis and in vitro tumorsphere formation by synergistically amplifying Wnt and YAP signaling in cancer stem cells (CSCs). NF2 deficiency enhanced Bcl-2-mediated Wnt signaling, conferring resistance to YAP inhibition in CSCs. This resistance was counteracted via synthetic lethality achieved by simultaneous inhibition of YAP and Bcl-2. RASA1 deficiency amplified the Wnt pathway via Bcl-xL, contributing to cancer stemness. RASA1 mutation created vulnerability to Bcl-xL inhibition, but the additional NF2 deletion conferred resistance to Bcl-xL inhibition due to YAP activation. The combined inhibition of Bcl-xL and YAP synergistically suppressed cancer stemness and in vivo metastasis in RASA1 and NF2 co-deficiency. CONCLUSION: Our research unveils the intricate interplay between YAP and Bcl-2 family members, which can lead to synthetic lethality, offering a potential strategy to overcome drug resistance. Importantly, our findings support a personalized medicine approach where combined therapy targeting YAP and Bcl-2, tailored to NF2 and RASA1 status, could effectively manage metastatic GC.

Development of Reproducible and Scalable Culture Conditions for In Vitro Maintenance of Pig Embryonic Stem Cells Using the Sandoz Inbred Swiss Mouse Thioguanine-Resistant Ouabain-Resistant Cell Line as a Feeder Layer.

Feeder cells play a crucial role in maintaining the pluripotency of embryonic stem cells (ESCs) by secreting various extrinsic regulators, such as extracellular matrix (ECM) proteins and growth factors. Although primary mouse embryonic fibroblasts (MEFs) are the most widely used feeder cell type for the culture of ESCs, they have inevitable disadvantages such as batch-to-batch variation and labor-intensive isolation processes. Here, we revealed that the Sandoz inbred Swiss Mouse (SIM) thioguanine-resistant ouabain-resistant (STO) cell line, an immortalized cell line established from mouse SIM embryonic fibroblasts, can be used as a feeder layer for in vitro culture of authentic pig ESCs instead of primary MEFs. First, the expression of genes encoding ECM proteins and growth factors was analyzed to compare their secretory functions as feeder cells. Quantitative real-time polymerase chain reaction (qPCR) showed that the gene expression of these pluripotency-associated factors was downregulated in STO cells compared to primary MEFs of similar density. Therefore, subsequent optimization of the culture conditions was attempted using higher STO cell densities. Notably, pig ESCs cultured on STO cell density of 3 × (187,500 cells/cm2) exhibited the most similar pluripotent state to pig ESCs cultured on primary MEF density of 1 × (62,500 cells/cm2), as determined by alkaline phosphatase staining, qPCR, and immunocytochemistry. In addition, pig ESCs cultured on STO cell density of 3 × formed complex teratoma containing multiple types of tissues derived from all three germ layers. Our culture conditions using optimal STO cell density can be applied to fields requiring reproducible and scalable production of pig ESCs, such as preclinical research and cellular agriculture.

Common Regulators of Lipid Metabolism and Bone Marrow Adiposity in Postmenopausal Women.

A variety of metabolic disorders are associated with a decrease in estradiol (E2) during natural or surgical menopause. Postmenopausal women are prone to excessive fat accumulation in skeletal muscle and adipose tissue due to the loss of E2 via abnormalities in lipid metabolism and serum lipid levels. In skeletal muscle and adipose tissue, genes related to energy metabolism and fatty acid oxidation, such as those encoding peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) and estrogen-related receptor alpha (ERRα), are downregulated, leading to increased fat synthesis and lipid metabolite accumulation. The same genes regulate lipid metabolism abnormalities in the bone marrow. In this review, abnormalities in lipid metabolism caused by E2 deficiency were investigated, with a focus on genes able to simultaneously regulate not only skeletal muscle and adipose tissue but also bone metabolism (e.g., genes encoding PGC-1α and ERRα). In addition, the mechanisms through which mesenchymal stem cells lead to adipocyte differentiation in the bone marrow as well as metabolic processes related to bone marrow adiposity, bone loss, and osteoporosis were evaluated, focusing on the loss of E2 and lipid metabolic alterations. The work reviewed here suggests that genes underlying lipid metabolism and bone marrow adiposity are candidate therapeutic targets for bone loss and osteoporosis in postmenopausal women.

Comparison of initial and sequential salvage brain-directed treatment in patients with 1-4 vs. 5-10 brain metastases from breast cancer (KROG 16-12).

PURPOSE: We aimed to compare the initial and salvage brain-directed treatment and overall survival (OS) between patients with 1-4 brain metastases (BMs) and those with 5-10 from breast cancer (BC). We also organized a decision tree to select the initial whole-brain radiotherapy (WBRT) for these patients. METHODS: Between 2008 and 2014, 471 patients were diagnosed with 1-10 BMs. They were divided into two groups based on the number of BM: 1-4 BMs (n = 337) and 5-10 BMs (n = 134). Median follow-up duration was 14.0 months. RESULTS: Stereotactic radiosurgery (SRS)/fractionated stereotactic radiotherapy (FSRT) was the most common treatment modality (n = 120, 36%) in the 1-4 BMs group. In contrast, 80% (n = 107) of patients with 5-10 BMs were treated with WBRT. The median OS of the entire cohort, 1-4 BMs, and 5-10 BMs was 18.0, 20.9, and 13.9 months, respectively. In the multivariate analysis, the number of BM and WBRT were not associated with OS, whereas triple-negative BC and extracranial metastasis decreased OS. Physicians determined the initial WBRT based on four variables in the following order: number and location of BM, primary tumor control, and performance status. Salvage brain-directed treatment (n = 184), mainly SRS/FSRT (n = 109, 59%), prolonged OS by a median of 14.3 months. CONCLUSION: The initial brain-directed treatment differed notably according to the number of BM, which was chosen based on four clinical factors. In patients with ≤ 10 BMs, the number of BM and WBRT did not affect OS. The major salvage brain-directed treatment modality was SRS/FSRT and increased OS.

Primary well differentiated hepatic liposarcoma in a meerkat (Suricata suricatta).

A 9-year-old female meerkat (Suricata suricatta) succumbed to progressive abdominal distension, anorexia, and depression. Necropsy revealed an extensively distended abdomen with ascites and markedly enlarged liver. The liver had multiple yellowish masses and displaced the thoracic cavity and abdominal organs. There was no evidence of metastatic lesions based on the gross and microscopic findings. Histologically, the liver mass was composed of locally invasive well-differentiated neoplastic adipocytes with Oil Red O-positive lipid vacuoles. Immunohistochemistry revealed positive immunoreactivity to vimentin, S-100 and negative to pancytokeratin, desmin, smooth muscle actin (SMA), ionized calcium-binding adapter molecule 1 (IBA-1). Thus, the primary well differentiated hepatic liposarcoma was diagnosed based on gross, histological and immunohistochemistry results.

One-Week versus Two-Week Chemoradiotherapy Followed by Curative Surgery in Rectal Cancer: Long-Term Comparative Pooled Analysis of Two Prospective Multicenter Phase II Trials.

PURPOSE: The optimal short-course chemotherapeutic regimen for rectal cancer has not been clearly defined until now. KROG 10-01 and KROG 11-02 prospective trials investigated the efficacy and safety of 1- and 2-week chemoradiotherapy (CRT), respectively. Materials and Methods: Patients eligible for KROG 10-01 and KROG 11-02 involved those with clinical T3-4N0-2M0 rectal cancers. They received preoperative CRT and total mesorectal excision. Patients in KROG 10-01 received radiation of 25 Gy in 5 fractions during 1 week with 5-fluorouracil/leucovorin. Patients in KROG 11-02 received radiation of 33 Gy in 10 fractions for 2 weeks with oral capecitabine. RESULTS: A total of 150 patients consisting of 70 patients from KROG 10-01 and 80 patients from KROG 11-02 were collectively analyzed. With a median follow-up time of 89.2 months, the 5-year overall survival rate was 86.5% in 1-week CRT and 85.3% in 2-week CRT (p=0.841). The 5-year recurrence-free survival rate was 83.5% in 1-week CRT and 77.1% in 2-week CRT (p=0.448). One patient (1.4%) in 1-week CRT and 11 patients (13.8%) in 2-week CRT exhibited pathologic complete regression (ypT0N0M0) after radiotherapy (p=0.006). One-week CRT had significantly higher acute hematologic (12.8% vs. 3.8%, p=0.040) and nonhematologic (38.6% vs. 16.3%, p=0.002) toxicity than 2-week CRT. CONCLUSION: Both 1- and 2-week schedules of CRT showed favorable survival outcomes after 7 years of follow-up. But, 2-week course achieved more increased tumor response and decreased acute toxicity than 1-week course.

Splenic epidermoid cyst in a dog.

Splenic epithelial cysts are rare in humans and have not been reported in animals, to our knowledge. During a routine medical examination of a 12-y-old castrated male Maltese dog, a splenic mass was found and subsequently removed via splenectomy. Histologically, a well-defined multilocular cyst in the spleen was lined mostly by simple cuboidal, multifocally by stratified cuboidal, or occasionally by stratified squamous epithelium. Immunohistochemically, the lining cells were positive for cytokeratin and negative for vimentin, CD31, and Wilms tumor protein 1. The case was diagnosed as a primary splenic epidermoid cyst.

TXNIP Suppresses the Osteochondrogenic Switch of Vascular Smooth Muscle Cells in Atherosclerosis.

BACKGROUND: The osteochondrogenic switch of vascular smooth muscle cells (VSMCs) is a pivotal cellular process in atherosclerotic calcification. However, the exact molecular mechanism of the osteochondrogenic transition of VSMCs remains to be elucidated. Here, we explore the regulatory role of TXNIP (thioredoxin-interacting protein) in the phenotypical transitioning of VSMCs toward osteochondrogenic cells responsible for atherosclerotic calcification. METHODS: The atherosclerotic phenotypes of Txnip-/- mice were analyzed in combination with single-cell RNA-sequencing. The atherosclerotic phenotypes of Tagln-Cre; Txnipflox/flox mice (smooth muscle cell-specific Txnip ablation model), and the mice transplanted with the bone marrow of Txnip-/- mice were analyzed. Public single-cell RNA-sequencing dataset (GSE159677) was reanalyzed to define the gene expression of TXNIP in human calcified atherosclerotic plaques. The effect of TXNIP suppression on the osteochondrogenic phenotypic changes in primary aortic VSMCs was analyzed. RESULTS: Atherosclerotic lesions of Txnip-/- mice presented significantly increased calcification and deposition of collagen content. Subsequent single-cell RNA-sequencing analysis identified the modulated VSMC and osteochondrogenic clusters, which were VSMC-derived populations. The osteochondrogenic cluster was markedly expanded in Txnip-/- mice. The pathway analysis of the VSMC-derived cells revealed enrichment of bone- and cartilage-formation-related pathways and bone morphogenetic protein signaling in Txnip-/- mice. Reanalyzing public single-cell RNA-sequencing dataset revealed that TXNIP was downregulated in the modulated VSMC and osteochondrogenic clusters of human calcified atherosclerotic lesions. Tagln-Cre; Txnipflox/flox mice recapitulated the calcification and collagen-rich atherosclerotic phenotypes of Txnip-/- mice, whereas the hematopoietic deficiency of TXNIP did not affect the lesion phenotype. Suppression of TXNIP in cultured VSMCs accelerates osteodifferentiation and upregulates bone morphogenetic protein signaling. Treatment with the bone morphogenetic protein signaling inhibitor K02288 abrogated the effect of TXNIP suppression on osteodifferentiation. CONCLUSIONS: Our results suggest that TXNIP is a novel regulator of atherosclerotic calcification by suppressing bone morphogenetic protein signaling to inhibit the transition of VSMCs toward an osteochondrogenic phenotype.

A synergistic partnership between IL-33/ST2 and Wnt pathway through Bcl-xL drives gastric cancer stemness and metastasis.

ST2 functions as a receptor for the cytokine IL-33. It has been implicated in carcinogenesis. In this study, we sought to mechanistically determine how ST2 and IL-33 function to support cancer stem cell (CSC) activity and drive gastric cancer (GC) pathogenesis. ST2+ subpopulation spontaneously arose during gastric tumorigenesis. A thorough evaluation of ST2 and IL-33 expression in gastric tumors revealed that they show an overlapping expression pattern, notably in poor differentiated GC and metastasis foci. Moreover, their expression levels are clinically correlated to cancer progression. Using a genetic model of CSC-driven gastric carcinogenesis, ST2+ subpopulation displays increased tumorigenicity, chemoresistance and metastatic potentials through increased survival fitness endowed by an elevated MAPK-regulated Bcl-xL. The IL-33/ST2 axis enhances the self-renewal and survival of GC stem cells and organoids. Importantly, we observed a synergistic cooperation between IL-33/ST2 and the canonical Wnt pathway in transactivating Wnt-dependent transcription and supporting CSC activity, a partnership that was abrogated by inhibiting Bcl-xL. Concordant with this, ST2+ subpopulation was targeted by MEK1/2 and Bcl-xL-specific inhibitors. These findings establish ST2 as a functional CSC marker that fortifies the Wnt signal while availing a novel therapeutic strategy to suppress GC progression by targeting the IL-33/ST2/Bcl-xL signaling axis.

The loss of epithelial Smad4 drives immune evasion via CXCL1 while displaying vulnerability to combinatorial immunotherapy in gastric cancer.

SMAD4 is frequently mutated and inactivated in human gastric cancer (GC). Although the epithelial cell-autonomous functions of Smad4 have been extensively studied, its contribution to tumor immunity is largely undetermined. Here, we report that the loss of Smad4 expression in GC cells endows them with the ability to evade tumor immunity. Unlike their Smad4-proficient counterparts, Smad4-deficient stomach organoids can evade host immunity to form tumors in immunocompetent mice. Smad4-deficient GC cells show expanded CD133+ cancer stem-like cells while suppressing dendritic cell (DC) differentiation and cytotoxic T cells with granulocytic myeloid-derived suppressor cell (G-MDSC) accumulation through a secretome containing CXCL1. Moreover, Smad4 deficiency increases programmed cell death ligand-1 (PD-L1) and decreases 4-1BBL expressions, indicating a change in immunogenicity. Combinatorial immune checkpoint blockade (ICB) of anti-PD-L1 and anti-CTLA-4 or agonistic anti-4-1BB antibodies effectively treats ICB monotherapy-resistant Smad4-deficient allografts, exposing a specific vulnerability. Collectively, these data provide a rational basis for ICB strategies in treating advanced GC with Smad4 deficiency.

Single-cell transcriptomics reveal cellular diversity of aortic valve and the immunomodulation by PPARγ during hyperlipidemia.

Valvular inflammation triggered by hyperlipidemia has been considered as an important initial process of aortic valve disease; however, cellular and molecular evidence remains unclear. Here, we assess the relationship between plasma lipids and valvular inflammation, and identify association of low-density lipoprotein with increased valvular lipid and macrophage accumulation. Single-cell RNA sequencing analysis reveals the cellular heterogeneity of leukocytes, valvular interstitial cells, and valvular endothelial cells, and their phenotypic changes during hyperlipidemia leading to recruitment of monocyte-derived MHC-IIhi macrophages. Interestingly, we find activated PPARγ pathway in Cd36+ valvular endothelial cells increased in hyperlipidemic mice, and the conservation of PPARγ activation in non-calcified human aortic valves. While the PPARγ inhibition promotes inflammation, PPARγ activation using pioglitazone reduces valvular inflammation in hyperlipidemic mice. These results show that low-density lipoprotein is the main lipoprotein accumulated in the aortic valve during hyperlipidemia, leading to early-stage aortic valve disease, and PPARγ activation protects the aortic valve against inflammation.

Subungual Pigmented Squamous Cell Carcinoma in a Dog.

An 11-year-old spayed female Miniature Schnauzer dog was presented with loss of a claw caused by a nail bed mass. Histopathological evaluation revealed that the mass comprised neoplastic squamous cells with abundant cytoplasmic melanin pigment. Immunohistochemically, the neoplastic cells were positive for cytokeratin and negative for vimentin and ionized calcium-binding adaptor molecule 1, supporting a diagnosis of pigmented squamous cell carcinoma. To our knowledge, this is the first report of subungual pigmented squamous cell carcinoma in animals.

Calcifying aponeurotic fibroma on the paw in a dog.

A 12-year-old, spayed female, Maltese dog with a round and firm mass on the dorsal part of the left rear paw and a cervical mass was brought to the clinic. The paw mass was contiguous to the adjacent tendon; it was composed of neoplastic mesenchymal cells and had scattered foci of calcification with chondroid differentiation microscopically. The neoplastic cells were positive for vimentin and S100, but negative for desmin and smooth muscle actin. Microscopic features and immunohistochemistry results were consistent with calcifying aponeurotic fibroma (CAF). The cervical mass was composed of polygonal cells forming acini with marked anisocytosis and anisokaryosis and diagnosed as thyroid follicular carcinoma. No recurrence or metastasis occurred during follow-up. To the best of our knowledge, this is the first case of canine CAF with features identical to its human counterparts. Key clinical message: This report describes the rare case of calcifying aponeurotic fibroma on the paw in a dog. This is apparently the first case in the veterinary literature with identical clinical and pathological features to the human counterpart.

Fibrome aponévrotique calcifiant sur la patte chez un chien. Une chienne maltaise stérilisée âgée de 12 ans avec une masse ronde et ferme sur la partie dorsale de la patte arrière gauche et une masse cervicale a été amenée à la clinique. La masse de la patte était contiguë au tendon adjacent; il était composé de cellules mésenchymateuses néoplasiques et présentait des foyers de calcification dispersés avec une différenciation chondroïde au microscope. Les cellules néoplasiques étaient positives pour la vimentine et le S100, mais négatives pour la desmine et l'actine des muscles lisses. Les caractéristiques microscopiques et les résultats d'immunohistochimie étaient compatibles avec un fibrome aponévrotique calcifiant (CAF). La masse cervicale était composée de cellules polygonales formant des acini avec une anisocytose et une anisocaryose marquées et diagnostiquée comme un carcinome folliculaire de la thyroïde. Aucune récidive ou métastase n'est survenue au cours du suivi. À notre connaissance, il s'agit du premier cas de CAF canin avec des caractéristiques identiques à ses homologues humains.Message clinique clé :Ce rapport décrit le cas rare de fibrome aponévrotique calcifiant sur la patte chez un chien. C'est apparemment le premier cas dans la littérature vétérinaire avec des caractéristiques cliniques et pathologiques identiques à son homologue humain.(Traduit par Dr Serge Messier).

The Pattern of Care for Brain Metastasis from Breast Cancer over the Past 10 Years in Korea: A Multicenter Retrospective Study (KROG 16-12).

PURPOSE: We aimed to investigate manifestations and patterns of care for patients with brain metastasis (BM) from breast cancer (BC) and compared their overall survival (OS) from 2005 through 2014 in Korea. MATERIALS AND METHODS: We retrospectively reviewed 600 BC patients with BM diagnosed between 2005 and 2014. The median follow-up duration was 12.5 months. We categorized the patients into three groups according to the year when BM was initially diagnosed (group I [2005-2008], 98 patients; group II [2009-2011], 200 patients; and group III [2012-2014], 302 patients). RESULTS: Over time, the median age at BM diagnosis increased by 2.2 years (group I, 49.0 years; group II, 48.3 years; and group III, 51.2 years; p=0.008). The percentage of patients with extracranial metastasis was 73.5%, 83.5%, and 86.4% for group I, II, and III, respectively (p=0.011). The time interval between BC and BM was prolonged in patients with stage III primary BC (median, 2.4 to 3 years; p=0.029). As an initial brain-directed treatment, whole-brain radiotherapy alone decreased from 80.0% in 2005 to 41.1% in 2014. Meanwhile, stereotactic radiosurgery or fractionated stereotactic radiotherapy alone increased from 13.3% to 34.7% during the same period (p=0.005). The median OS for group I, II, and III was 15.6, 17.9, and 15.0 months, respectively, with no statistical significance. CONCLUSION: The manifestations of BM from BC and the pattern of care have changed from 2005 to 2014 in Korea. However, the OS has remained relatively unchanged over the 10 years.

Effect of Elective Internal Mammary Node Irradiation on Disease-Free Survival in Women With Node-Positive Breast Cancer: A Randomized Phase 3 Clinical Trial.

IMPORTANCE: The benefit of internal mammary node irradiation (IMNI) for treatment outcomes in node-positive breast cancer is unknown. OBJECTIVE: To investigate whether the inclusion of IMNI in regional nodal irradiation improves disease-free survival (DFS) in women with node-positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 3 randomized clinical trial was conducted from June 1, 2008, to February 29, 2020, at 13 hospitals in South Korea. Women with pathologically confirmed, node-positive breast cancer after breast-conservation surgery or mastectomy with axillary lymph node dissection were eligible and enrolled between November 19, 2008, and January 14, 2013. Patients with distant metastasis and those who had received neoadjuvant treatment were excluded. Data analyses were performed according to the intention-to-treat principle. INTERVENTIONS: All patients underwent regional nodal irradiation along with breast or chest wall irradiation. They were randomized 1:1 to receive radiotherapy either with IMNI or without IMNI. MAIN OUTCOMES AND MEASURES: The primary end point was the 7-year DFS. Secondary end points included the rates of overall survival, breast cancer-specific survival, and toxic effects. RESULTS: A total of 735 women (mean [SD] age, 49.0 [9.1] years) were included in the analyses, of whom 373 received regional nodal irradiation without IMNI and 362 received regional nodal irradiation with IMNI. Nearly all patients underwent taxane-based adjuvant systemic treatment. The median (IQR) follow-up was 100.4 (89.7-112.1) months. The 7-year DFS rates did not significantly differ between the groups treated without IMNI and with IMNI (81.9% vs 85.3%; hazard ratio [HR], 0.80; 95% CI, 0.57-1.14; log-rank P = .22). However, an ad hoc subgroup analysis showed significantly higher DFS rates with IMNI among patients with mediocentrally located tumors. In this subgroup, the 7-year DFS rates were 81.6% without IMNI vs 91.8% with IMNI (HR, 0.42; 95% CI, 0.22-0.82; log-rank P = .008), and the 7-year breast cancer mortality rates were 10.2% without IMNI vs 4.9% with IMNI (HR, 0.41; 95% CI, 0.17-0.99; log-rank P = .04). No differences were found between the 2 groups in the incidence of adverse effects, including cardiac toxic effects and radiation pneumonitis. CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that including IMNI in regional nodal irradiation did not significantly improve the DFS in patients with node-positive breast cancer. However, patients with medially or centrally located tumors may benefit from the use of IMNI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04803266.