EGFR ligands synergistically increase IL-17A-induced expression of psoriasis signature genes in human keratinocytes via IκBζ and Bcl3.

Various epidermal growth factor receptor (EGFR) ligands are highly expressed in the epidermis of psoriasis lesions, and abnormal EGFR activation appears to be involved in the pathogenesis of psoriasis. However, how EGFR signaling contributes to the development of psoriasis is unclear. Interleukin (IL)-17A, a critical effector of the IL-23/IL-17A pathway, increases the expression of psoriasis signature genes in keratinocytes and plays an essential role in the pathogenesis of psoriasis by inducing IκBζ, a critical transcriptional regulator in psoriasis. In this study, we stimulated primary human keratinocytes with IL-17A and various EGFR ligands to investigate whether EGFR ligands regulate the expression of psoriasis signature genes. In cultured normal human keratinocytes and a living skin equivalent, EGFR ligands did not induce psoriasis-related gene expression, but significantly enhanced the IL-17A-mediated induction of various psoriasis signature genes, including antimicrobial peptides, cytokines, and chemokines. This was dependent on an EGFR activation-mediated synergistic increase in IL-17A-induced IκBζ expression and was partially mediated by the EGFR-dependent upregulation of Bcl3. Therefore, EGFR ligands can act as synergistic agents of IL-17A signaling by stimulating the epidermal production of psoriasis signature genes in psoriasis lesions. This study reveals a potential mechanism by which EGFR signaling contributes to the pathogenesis of psoriasis.

Is frequent measurement of tumor markers beneficial for postoperative surveillance of colorectal cancer?

PURPOSE: To determine whether frequent measurement of tumor markers triggers early detection of colorectal cancer recurrence. METHODS: Of 1,651 consecutive patients undergoing colorectal cancer surgery between 2010 and 2016, 1,050 were included. CEA and CA 19-9 were considered to be postoperative tumor markers and were measured every 3 months for 3 years, and then every 6 months for 2 years. Sensitivity analysis of elevated CEA and CA19-9 levels and multivariate analysis of factors associated with elevated CEA and CA19-9 levels were performed. The proportion of triggers for detecting recurrence was determined. RESULTS: The median follow-up period was 5.3 years. After applying the exclusion criteria, 1,050 patients were analyzed, 176 (16.8%) of whom were found to have recurrence. After excluding patients with persistently elevated CEA and CA19-9 levels before and after surgery from the 176 patients, 71 (43.6%) of 163 patients had elevated CEA levels and 35 (20.2%) of 173 patients had elevated CA19-9 levels. Sensitivity/positive predictive values for elevated CEA and CA19-9 levels at recurrence were 43.6%/32.3% and 20.2%/32.4%, respectively. Lymph node metastasis was a factor associated with both elevated CEA and CA19-9 levels at recurrence. Of the 176 patients, computed tomography triggered the detection of recurrence in 137 (78%) and elevated tumor marker levels in 13 (7%); the diagnostic lead interval in the latter 13 patients was 1.7 months. CONCLUSION: Tumor marker measurements in surveillance after radical colorectal cancer resection contribute little to early detection, and frequent measurements are unnecessary for stage I patients with low risk of recurrence.

[Transoral Robot-Assisted Surgery for Pituitary Gland].

Robotic surgery has been introduced into various surgical fields and is expected to be useful in neurosurgery. Robotic surgery is a technology used to safely and reliably perform minimally invasive surgeries. There are three main types of robotic surgery in neurosurgery: 1)Aids to improve the performance and efficiency of stereotactic surgery; 2)Leader-follower types, such as Da Vinci and hinotori, which enable operations under endoscopy, surgical maneuvers in deep-seated lesions, and operations in areas that are difficult to reach with tools; and 3)Aids to assist the surgeon. Many neurosurgical procedures have shifted from microscopy to endoscopy. One such case is pituitary lesions, where transsphenoidal sinus surgery is currently performed. Originally, Hardy's surgery using microscopy was performed, whereas now endoscopic surgery is mainstream, with the possibility of robotic surgery being used in the near future. This report describes the history of the development of robots, including neurosurgery, the advantages and disadvantages of robotic surgery, and the DaVinci Xi approach to the pituitary gland.

Usefulness of three-dimensional computed tomography venography differentiating calvarium subperiosteal hematoma crossing the suture lines due to hair pulling from subgaleal hematoma: case report and review of the literature.

This case showed a 13-year-old boy presented with calvarium subperiosteal hematoma crossing the suture lines caused by hair pulling, and 3D-CTV can differentiate calvarium subperiosteal hematoma crossing the suture lines from subgaleal hematoma. He was treated successfully.

Evaluating diploic vein blood flow using time-resolved whole-head computed tomography angiography and determining the positional relationship between typical craniotomy approaches and diploic veins in patients with meningioma.

BACKGROUND: Diploic veins may act as collateral venous pathways in cases of meningioma with venous sinus invasion. Diploic vein blood flow should be preoperatively evaluated to consider preserving the veins. In this study, we evaluated the use of time-resolved whole-head computed tomography angiography (4D-CTA)-which is less patient-intensive than digital subtraction angiography (DSA)-for assessing diploic vein blood flow and the positional relationship between typical craniotomy approaches and diploic veins. METHODS: We retrospectively examined 231 patients who underwent surgery for intracranial meningioma. We performed contrast-enhanced magnetic resonance imaging (MRI) to evaluate diploic vein pathways and compared the visualization rates of diploic vein blood flow assessed using 4D-CTA and DSA. Subsequently, we evaluated the rates of the diploic veins transected during craniotomy by comparing the pre- and postoperative contrast-enhanced MRI. RESULTS: The diagnostic performance of 4D-CTA was assessed in 45 patients. Of the 320 diploic veins identified in these patients, blood flow in 70 (21.9%) diploic veins was identified by 4D-CTA and DSA, and both results were consistent. To assess the transection rates of the diploic veins, 150 patients were included. A trend towards a high transection rate of the diploic vein in the basal interhemispheric, frontotemporal, orbitozygomatic, combined transpetrosal, and convexity craniotomy approaches was observed. CONCLUSIONS: In patients with meningiomas, both 4D-CTA and DSA are useful in evaluating diploic vein blood flow. In meningiomas with venous sinus invasion, determining the extent of craniotomy after understanding the pathways and blood flow of diploic veins is recommended.

The necessity of intensive surveillance colonoscopy for patients with a remaining right colon after resection of colorectal cancer: a retrospective cohort study.

PURPOSE: To clarify how often postoperative surveillance colonoscopy should be undertaken based on the risk factors for the development of metachronous cancer (MC) and advanced adenoma (AA) after surgery for colorectal cancer. METHODS: We collected data of consecutive patients who underwent curative resection for primary colorectal cancer between 2005 and 2012, with preoperative colonoscopy and surveillance colonoscopy at 1 year after surgery (406 patients, mean age: 69 years, 59% male). The detection rates of AA (with villous features, > 10 mm or high-grade dysplasia) and MC by surveillance colonoscopy were the primary outcomes. RESULTS: At 5 years, colonoscopy was performed as postoperative surveillance an average of 3.2 times. AA and MC were detected in 57 (14.0%) and 18 patients (4.4%), respectively. Both lesions were more common in the right colon (n = 43) than in the left colon (n = 28). The detection rate did not differ to a statistically significant extent according to the number of colonoscopies performed for surveillance (p = 0.21). However, after left-sided colectomy, both types of lesions were more commonly detected in those who received ≥ 3 colonoscopies than in those with one or two colonoscopies (p = 0.04). CONCLUSION: A remaining right colon after left-sided colectomy was associated with a higher risk of developing AA and MC. Physicians should consider performing surveillance colonoscopy more frequently if the right colon remains after surgery.

Primary central nervous system lymphomas with massive intratumoral hemorrhage: Clinical, radiological, pathological, and molecular features of six cases.

Primary central nervous system lymphomas (PCNSLs) rarely exhibit intratumoral hemorrhage. The differential diagnosis of hemorrhagic neoplasms of the central nervous system (CNS) currently includes metastatic carcinomas, melanomas, choriocarcinomas, oligodendrogliomas, and glioblastomas. Here we present the clinical, radiological, pathological, and molecular genetic features of six cases of PCNSL associated with intratumoral hemorrhage. The median age of patients was 75 years, with male predominance. While conventional PCNSLs were associated with low cerebral blood volume (CBV), perfusion magnetic resonance imaging (MRI) revealed elevated CBV in three cases, consistent with vascular proliferation. All six cases were diagnosed pathologically as having diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell-like (non-GCB) phenotype; marked histiocytic infiltrates and abundant non-neoplastic T-cells were observed in most cases. Expression of vascular endothelial growth factor and CD105 in the lymphoma cells and the small vessels, respectively, suggested angiogenesis within the neoplasms. Neoplastic cells were immunohistochemically negative for programmed cell death ligand 1 (PD-L1), while immune cells in the microenvironment were positive for PD-L1. Mutations in the MYD88 gene (MYD88) (L265P) and the CD79B gene (CD79B) were detected in five and one case, respectively. As therapeutic modalities used for PCNSLs differ from those that target conventional hemorrhagic neoplasms, full tissue diagnoses of all hemorrhagic CNS tumors are clearly warranted.

Objective and quantitative evaluation of angiographic vascularity in meningioma: parameters of dynamic susceptibility contrast-perfusion-weighted imaging as clinical indicators of preoperative embolization.

Digital subtraction angiography (DSA) assesses the necessity of preoperative embolization in meningioma cases but entails complication risks. Previous studies evaluating meningiomas' angiographic vascularity using perfusion-weighted imaging (PWI) have performed subjective visual assessments, not managing to assess the need for preoperative embolization. We objectively assessed the angiographic stain of meningiomas and examined the usefulness of two parameters of dynamic susceptibility contrast (DSC)-PWI, normalized cerebral blood volume (nCBV) and cerebral blood flow (nCBF), in predicting vascularity and the necessity of preoperative embolization. We retrospectively examined 52 patients who underwent surgery for primary meningioma and preoperative DSA and DSC-PWI. We calculated the normalized luminance (nLum) of the tumor stain in DSA. In 29 meningioma cases with a single feeding artery, we determined the DSC-PWI parameter that correlated with meningioma angiographic vascularity and predicted the necessity of preoperative embolization. We also compared vascularity between meningiomas with single and multiple feeding arteries and between convexity and skull-base meningiomas. nCBF (cut off: 3.66, P = 0.03, area under the curve [AUC] = 0.80) alone could predict the necessity of preoperative embolization and was more significantly correlated with the nLum than nCBV (P = 0.08, AUC = 0.73). Vascularity did not differ between meningiomas with single and multiple feeding arteries; skull-base meningiomas were more vascularized than convexity meningiomas (P = 0.0027). Our objective, quantitative assessments revealed nCBF as the most suitable parameter for evaluating meningioma vascularity. Tumor vascularity assessment using nCBF values and CBF images may aid predicting the necessity of preoperative DSA.

Intraoperative real-time near-infrared optical imaging for the identification of metastatic brain tumors via microscope and exoscope.

OBJECTIVE: As chemotherapy and radiotherapy have developed, the role of a neurosurgeon in the treatment of metastatic brain tumors is gradually changing. Real-time intraoperative visualization of brain tumors by near-infrared spectroscopy (NIRS) is feasible. The authors aimed to perform real-time intraoperative visualization of the metastatic tumor in brain surgery using second-window indocyanine green (SWIG) with microscope and exoscope systems. METHODS: Ten patients with intraparenchymal brain metastatic tumors were administered 5 mg/kg indocyanine green (ICG) 1 day before the surgery. In some patients, a microscope was used to help identify the metastases, whereas in the others, an exoscope was used. RESULTS: NIRS with the exoscope and microscope revealed the tumor location from the brain surface and the tumor itself in all 10 patients. The NIR signal could be detected though the normal brain parenchyma up to 20 mm. While the mean signal-to-background ratio (SBR) from the brain surface was 1.82 ± 1.30, it was 3.35 ± 1.76 from the tumor. The SBR of the tumor (p = 0.030) and the ratio of Gd-enhanced T1 tumor signal to normal brain (T1BR) (p = 0.0040) were significantly correlated with the tumor diameter. The SBR of the tumor was also correlated with the T1BR (p = 0.0020). The tumor was completely removed in 9 of the 10 patients, as confirmed by postoperative Gd-enhanced MRI. This was concomitant with the absence of NIR fluorescence at the end of surgery. CONCLUSIONS: SWIG reveals the metastatic tumor location from the brain surface with both the microscope and exoscope systems. The Gd-enhanced T1 tumor signal may predict the NIR signal of the metastatic tumor, thus facilitating tumor resection.

Diploic veins as collateral venous pathways in patients with dural venous sinus invasion by meningiomas.

BACKGROUND: Although it is known that diploic veins frequently communicate with the dural venous sinuses, the role of diploic veins in patients with venous sinus invasion from meningiomas remains unknown. METHODS: We retrospectively examined the medical records of 159 patients who underwent their first craniotomies for intracranial meningiomas. Contrast-enhanced magnetic resonance imaging was used to evaluate diploic vein routes, and digital subtraction angiography (DSA) was used to evaluate diploic vein blood flow. When high blood flow was visualized concurrently with the venous sinuses, the veins were classified as of the "early type." Diploic vein routes were classified into five routes. RESULTS: DSA was performed in 110 patients, with 14 showing superior sagittal sinus (SSS) invasion (SSS group) and 23 showing non-SSS venous sinus invasion (non-SSS group). The proportion of early type diploic veins was significantly higher in the SSS group (27.1%) than in other patients (patients without venous sinus invasion, 2.1%; non-SSS, 4.3%) (p < 0.01). In patients not in the SSS group, diploic veins were sacrificed during craniotomy in 76 patients, including four patients with veins of the early type. No patients demonstrated new neurological deficits postoperatively. In the SSS group, diploic veins were sacrificed in all patients, and early type diploic veins were cut in five patients. Two of these five patients showed postoperative neurological deficits. CONCLUSIONS: In the SSS group, diploic veins may function as collateral venous pathways, and attention is recommended for their interruption. In patients without SSS invasion, diploic veins, even of the early type, can be sacrificed.

A new technique to avoid unintentional adhesion while deploying ProGrip mesh and its utility in the laparoscopic repair of obturator hernia.

The ProGrip™ laparoscopic self-fixating mesh provides advantages such as low cost and reduced pain following tack-free fixation in laparoscopic hernia repair through a transabdominal preperitoneal approach. Obturator hernia repair needs adequate fixation around the hernial orifice without the use of tacking, and ProGrip™ mesh provides options for secure fixation. However, it is often difficult to adequately adjust the mesh placement to cover the obturator hernia orifice with a ProGrip™ mesh, due to adhesion of the grips to the surrounding tissues. We introduce our technique to avoid unintentional adhesion during ProGrip mesh repair and discuss its utility in the treatment of obturator hernias. We repaired seven obturator hernia lesions in five patients using this technique without any complications. The biggest advantage of our technique is that the position of the mesh can be adjusted after it is expanded, unless the sheet is completely removed, allowing the surgeons to fix the mesh without any unintended adhesion to surrounding tissue.

[A Case of Pulmonary Metastasis from Hilar Cholangiocarcinoma Treated by Stereotactic Body Radiotherapy].

We report a case of pulmonary metastasis from hilar cholangiocarcinoma successfully treated by stereotactic body radiotherapy. The patient was a 70-year-old woman who underwent extended left hemi-hepatectomy with bile duct reconstruction for hilar cholangiocarcinoma at the age of 67. Pathological diagnosis indicated a well-differentiated adenocarcinoma. We followed up the patient without adjuvant chemotherapy. Nineteen months after the initial resection, a solitary pulmonary metastasis was detected in the right upper lobe. The patient received gemcitabine plus cisplatin(GC)therapy. After 4 courses of GC therapy, the size of the pulmonary metastasis was unchanged. Therefore, we performed a thoracoscopic wedge resection. Pathological diagnosis indicated that the pulmonary metastasis originated from the cholangiocarcinoma. Fifteen months after the pulmonary resection, another solitary pulmonary metastasis was detected in the left lower lobe. As the patient refused further chemotherapy, we performed stereotactic body radiotherapy(SBRT)(50 Gy/4 Fr). An adverse event of Grade 1 radiation pneumonitis was observed. The metastasis disappeared after SBRT. Twenty-eight months after SBRT and 70 months after the initial surgery, the patient is alive without recurrence.

Laparoscopic Distal Pancreatectomy for Left-Sided Pancreatic Cancer Using the "Caudo-Dorsal Artery First Approach".

BACKGROUND: Pancreatic cancer (PC) has serious malignant potential, thus requiring complete resection and adequate regional lymphadenectomy with tumor-free margins.1,2 A standard laparoscopic distal pancreatectomy (LDP) procedure for PC is not yet established due to lack of supportive evidence.3-6 METHODS: In our hospital, we first administered neoadjuvant chemoradiotherapy for resectable PC. Considering the benefits offered by a laparoscopic magnified caudo-dorsal view, we devised and standardized an LDP procedure for PC, which we employed in five patients with left-sided resectable tumors. First, the retroperitoneum was incised between the proximal jejunum and the inferior mesenteric vein with the transverse colon pushed up ventrally and cranially and with the proximal jejunum moved to the right. Then, the left renal vein (LRV) could be easily identified at this site. The retroperitoneal tissue was dissected along the LRV, and the origin of the superior mesenteric artery (SMA) also was identified just above the LRV easily. The left adrenal gland was removed to secure the dorsal margin, if needed. The retroperitoneal dissection was continued along the major anatomical landmarks, including the LRV, the left renal artery, the left kidney, and the crus of the diaphragm beside the origin of the SMA. Using the same operative field, lymphadenectomy around the SMA was performed before dividing the pancreas. We could safely and easily expose the left aspect of the SMA after dissecting the ligament of Treitz. The dissection around the SMA was performed toward the side of the arterial root that had already been exposed above the LRV. Thus, the most important difficult steps of LDP for PC, such as retroperitoneal dissection and lymphadenectomy around the SMA, were safely performed early in the operation with a good laparoscopic view. RESULTS: The median operative time was 341 (range 288-354) minutes, and median blood loss was 150 (range 50-150) ml. An intraoperative transfusion was not required for any patient. Severe postoperative complications or mortality were absent. An R0 resection was achieved in all patients. CONCLUSIONS: LDP using the "caudo-dorsal artery first approach" is safe and useful for performing a minimally invasive, curative resection for left-sided PC.

Clostridioides difficile-related toxic megacolon after Cryptococcus neoformans cellulitis: A complex of two rare infections in an immunocompromised host.

A 76-year-old Japanese woman was admitted due to uncontrolled cellulitis of the right lower leg. She had deep vein thrombosis on the right limb. Moreover, she had a long history of rheumatoid arthritis treated with corticosteroids. Skin biopsy and lumbar puncture were performed to diagnose disseminated cryptococcosis. She was administered antifungal agents (liposomal amphotericin B and 5-fluorocytosine). On treatment day 14, debridement was performed, and cryptococcosis was controlled. However, she developed toxic megacolon due to Clostridioides difficile infection (CDI). On day 32, she was transferred to the intensive care unit due to severe acidosis and acute kidney injury secondary to CDI-related toxic megacolon. Vancomycin, metronidazole, and tigecycline were administered for treatment of CDI. After several weeks of intensive care, toxic megacolon was improved, but renal replacement therapy was discontinued according to the patient's will. On day 73, she died of renal failure. We experienced a complex of rare diseases, Cryptococcus neoformans cellulitis and Clostridioides difficile-related toxic megacolon. Both diseases were presumed to be the result of corticosteroid and methotrexate use. Hence, careful monitoring is required when treating immunocompromised hosts to reduce the risk of developing complications.

[A Case of Bladder Urothelial Carcinoma with Hepatic Metastasis Achieving Histologically Complete Response by Multimodal Treatment Including Pembrolizumab].

A 70s man underwent transurethral resection of the bladder tumor(TURBT)at a previous hospital. The pathological diagnosis was urothelial carcinoma pT1. Nine months later, recurrence appeared in the bladder and he underwent repeated TURBT. The pathological diagnosis was also pT1 and he was administered 8 courses of intravesical BCG therapy. Fourteen months after the first operation, computed tomography scans showed new lesions in the liver. Therefore, he was referred to our hospital. Because biopsy from the hepatic lesion confirmed the diagnosis of metastatic urothelial carcinoma, he received 10 courses of gemcitabine plus cisplatin(GC)and radiofrequency ablation. However, daughter nodule and enlargement of the main tumor were revealed on MRI 33 months after the initial TURBT. After 5 courses of pembrolizumab that limited the potential for hepatic metastases, he had no evidence of other metastatic sites and underwent laparoscopic right hepatectomy. There was no viable carcinoma in the pathological specimens of the hepatic lesions. Six months after hepatectomy, the patient has a high quality of life without any recurrence.

N-myristoylation and S-acylation are common modifications of Ca2+ -regulated Arabidopsis kinases and are required for activation of the SLAC1 anion channel.

N-myristoylation and S-acylation promote protein membrane association, allowing regulation of membrane proteins. However, how widespread this targeting mechanism is in plant signaling processes remains unknown. Through bioinformatics analyses, we determined that among plant protein kinase families, the occurrence of motifs indicative for dual lipidation by N-myristoylation and S-acylation is restricted to only five kinase families, including the Ca2+ -regulated CDPK-SnRK and CBL protein families. We demonstrated N-myristoylation of CDPK-SnRKs and CBLs by incorporation of radiolabeled myristic acid. We focused on CPK6 and CBL5 as model cases and examined the impact of dual lipidation on their function by fluorescence microscopy, electrophysiology and functional complementation of Arabidopsis mutants. We found that both lipid modifications were required for proper targeting of CBL5 and CPK6 to the plasma membrane. Moreover, we identified CBL5-CIPK11 complexes as phosphorylating and activating the guard cell anion channel SLAC1. SLAC1 activation by CPK6 or CBL5-CIPK11 was strictly dependent on dual lipid modification, and loss of CPK6 lipid modification prevented functional complementation of cpk3 cpk6 guard cell mutant phenotypes. Our findings establish the general importance of dual lipid modification for Ca2+ signaling processes, and demonstrate their requirement for guard cell anion channel regulation.

Frequency and Characteristics of Occult Hepatitis B Infection Among Hepatocellular Carcinoma Patients in Japan.

INTRODUCTION AND AIM: Occult hepatitis B virus (HBV) infection (OBI) represents a state without detectable hepatitis B surface antigen, but positive for HBV DNA. The correlation between OBI and hepatocellular carcinoma (HCC) carcinogenesis is controversial. We studied the frequency and characteristics of OBI among HCC patients and metastatic liver cancer patients. MATERIAL AND METHODS: DNA was obtained from tumor and non-tumor tissues from 75 HCC patients (15 chronic hepatitis B (CHB), 39 chronic hepatitis C (CHC), 21 cryptogenic) and 15 metastatic liver cancer patients who underwent liver resection. HBV DNA and covalentlyclosed circular (ccc) DNA were detected using real-time polymerase chain reaction (PCR), and four HBV DNA regions were detected by nested PCR. Clinicopathological factors were compared between patients with and without OBI. RESULTS: HBV DNA was detected in 14 (93.3%) CHB, five (22.7%) cryptogenic and four (10.3%) CHC patients. cccDNA was detected in 12 (80.0%) CHB, three (14.3%) cryptogenic and two (5.1%) CHC patients. All CHB, eight (38.1%) cryptogenic and ten (25.6%) CHC patients tested positive with nested PCR. No metastatic liver cancer patients were positive for any HBV DNA regions. OBI patients had shorter prothrombin times (P = 0.0055), and lower inflammation activity score in non-tumor liver (P = 0.0274). There were no differences in anti-HBV antibodies. CONCLUSIONS: OBI was detected in 38% of cryptogenic and 25.6% of CHC patients. There was no correlation between OBI and anti-HBV antibodies, but fewer patients with OBI had high inflammatory activity, suggesting that factors other than inflammation may be involved in HCC carcinogenesis in patients with OBI.

Leukocytoclastic Vasculitis and Dermal Perivascular Hemophagocytosis Associated With Adalimumab Therapy for Rheumatoid Arthritis.

Tumor necrosis factor (TNF)-α inhibitors target TNF-α to effectively treat autoimmune inflammatory conditions, such as rheumatoid arthritis. However, many cases of cutaneous and systemic vasculitis related to TNF-α inhibitors have been reported in the literature. Here, the authors report the first case of a 61-year-old Japanese woman who developed leukocytoclastic vasculitis with cutaneous perivascular hemophagocytosis, which was related to elevated cytokines and immune complexes after initiating adalimumab for rheumatoid arthritis without evidence of hemophagocytic syndrome and rarely encountered in the skin. The patient was successfully treated by discontinuing adalimumab and initiating corticosteroid therapy, which should be considered as the treatment of choice. We believe that our case confirms and adds to the evidence pertaining to the involvement of TNF-α in dermal perivascular hemophagocytosis, a histologic finding rarely observed in the skin.

Hyaluronan breakdown contributes to immune defense against group A Streptococcus.

Group A Streptococcus (GAS) commonly infects human skin and occasionally causes severe and life-threatening invasive diseases. The hyaluronan (HA) capsule of GAS has been proposed to protect GAS from host defense by mimicking endogenous HA, a large and abundant glycosaminoglycan in the skin. However, HA is degraded during tissue injury, and the functions of short-chain HA that is generated during infection have not been studied. To examine the impact of the molecular mass of HA on GAS infection, we established infection models in vitro and in vivo in which the size of HA was defined by enzymatic digestion or custom synthesis. We discovered that conversion of high molecular mass HA to low molecular mass HA facilitated GAS phagocytosis by macrophages and limited the severity of infection in mice. In contrast, native high molecular mass HA significantly impaired internalization by macrophages and increased GAS survival in murine blood. Thus, our data demonstrate that GAS virulence can be influenced by the size of HA derived from both the bacterium and host and suggest that high molecular mass HA facilitates GAS deep tissue infections, whereas the generation of short-chain HA can be protective.

Review of angiogenesis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a hypervascular tumor, and its vascularity is unique and greatly different from peripheral parenchyma of liver. Afferent and efferent vessels of HCC lesions come to differ as the lesion develops. The characteristic of the flow regulates the common style of metastasis. The portal tract of the HCC lesion is the first site of the intrahepatic metastasis, because cancer cells roll into the portal vein via efferent flow. On microscopic observation, HCC displays marked vascular abnormalities, arteriogenesis and capillarization. Arteriogenesis is defined as the growth of functional collateral arteries covered with smooth muscle cells from pre-existing arteries. Sinusoidal capillarization involves the transformation of fenestrated hepatic sinusoids into continuous capillaries. Several angiogenic factors have been reported, and some of them are studied as prognostic factors or target molecules of chemotherapeutic reagents. However, the mechanism of neovascularization during HCC development is still unclear. This review discusses the characteristics of angiogenesis in HCC and known angiogenic factors of HCC.