Dysregulation of Amphiregulin stimulates the pathogenesis of cystic lymphangioma.

Along with blood vessels, lymphatic vessels play an important role in the circulation of body fluid and recruitment of immune cells. Postnatal lymphangiogenesis commonly occurs from preexisting lymphatic vessels by sprouting, which is induced by lymphangiogenic factors such as vascular endothelial growth factor C (VEGF-C). However, the key signals and cell types that stimulate pathological lymphangiogenesis, such as human cystic lymphangioma, are less well known. Here, we found that mouse dermal fibroblasts that infiltrate to sponges subcutaneously implanted express VEGF-D and sushi, Von Willebrand factor type A, EGF, and pentraxin domain containing 1 (SVEP1) in response to PDGFRß signal. In vitro, Pdgfrb knockout (ß-KO) fibroblasts had reduced expression of VEGF-D and SVEP1 and overproduced Amphiregulin. Dysregulation of these three factors was involved in the cyst-like and uneven distribution of lymphatic vessels observed in the ß-KO mice. Similarly, in human cystic lymphangioma, which is one of the intractable diseases and mostly occurs in childhood, fibroblasts surrounding cystic lymphatics highly expressed Amphiregulin. Moreover, fibroblast-derived Amphiregulin could induce the expression of Amphiregulin in lymphatic endothelial cells. The dual source of Amphiregulin activated EGFR expressed on the lymphatic endothelial cells. This exacerbation cascade induced proliferation of lymphatic endothelial cells to form cystic lymphangioma. Ultimately, excessive Amphiregulin produced by fibroblasts surrounding lymphatics and by lymphatic endothelial cells per se results in pathogenesis of cystic lymphangioma and will be a fascinating therapeutic target of cystic lymphangioma.

PDGF receptor signal mediates the contribution of Nestin-positive cell lineage to subcutaneous fat development.

The beiging of white adipose tissue (WAT) is expected to improve systemic metabolic conditions; however, the regulation and developmental origin of this process remain insufficiently understood. In the present study, the implication of platelet-derived growth factor receptor alpha (PDGFRα) was examined in the beiging of inguinal WAT (ingWAT) of neonatal mice. Using in vivo Nestin expressing cell (Nestin+) lineage tracing and deletion mouse models, we found that, in the mice with Pdgfra gene inactivation in Nestin+ lineage (N-PRα-KO mice), the growth of inguinal WAT (ingWAT) was suppressed during neonatal periods as compared with control wild-type mice. In the ingWAT of N-PRα-KO mice, the beige adipocytes appeared earlier that were accompanied by the increased expressions of both adipogenic and beiging markers compared to control wild-type mice. In the perivascular adipocyte progenitor cell (APC) niche of ingWAT, many PDGFRα+ cells of Nestin+ lineage were recruited in Pdgfra-preserving control mice, but were largely decreased in N-PRα-KO mice. This PDGFRα+ cell depletion was replenished by PDGFRα+ cells of non-Nestin+ lineage, unexpectedly resulting in an increase of total PDGFRα+ cell number in APC niche of N-PRα-KO mice over that of control mice. These represented a potent homeostatic control of PDGFRα+ cells between Nestin+ and non-Nestin+ lineages that was accompanied by the active adipogenesis and beiging as well as small WAT depot. This highly plastic nature of PDGFRα+ cells in APC niche may contribute to the WAT remodeling for the therapeutic purpose against metabolic diseases.

Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice.

Blood-brain barrier (BBB) dysfunction underlies the pathogenesis of many neurological diseases. Platelet-derived growth factor receptor-alpha (PDGFRα) induces hemorrhagic transformation (HT) downstream of tissue plasminogen activator in thrombolytic therapy of acute stroke. Thus, PDGFs are attractive therapeutic targets for BBB dysfunction. In the present study, we examined the role of PDGF signaling in the process of tissue remodeling after middle cerebral arterial occlusion (MCAO) in mice. Firstly, we found that imatinib increased lesion size after permanent MCAO in wild-type mice. Moreover, imatinib-induced HT only when administrated in the subacute phase of MCAO, but not in the acute phase. Secondly, we generated genetically mutated mice (C-KO mice) that showed decreased expression of perivascular PDGFRα. Additionally, transient MCAO experiments were performed in these mice. We found that the ischemic lesion size was not affected; however, the recruitment of PDGFRα/type I collagen-expressing perivascular cells was significantly downregulated, and HT and IgG leakage was augmented only in the subacute phase of stroke in C-KO mice. In both experiments, we found that the expression of tight junction proteins and PDGFRß-expressing pericyte coverage was not significantly affected in imatinib-treated mice and in C-KO mice. The specific implication of PDGFRα signaling was suggestive of protective effects against BBB dysfunction during the subacute phase of stroke. Vascular TGF-ß1 expression was downregulated in both imatinib-treated and C-KO mice, along with sustained levels of MMP9. Therefore, PDGFRα effects may be mediated by TGF-ß1 which exerts potent protective effects in the BBB.

Different PDGF Receptor Dimers Drive Distinct Migration Modes of the Mouse Skin Fibroblast.

BACKGROUND/AIMS: The migration of mesenchymal cells is a fundamental cellular process that has been implicated in many pathophysiological conditions and is induced by chemoattractants such as platelet-derived growth factors (PDGFs). However, the regulatory mechanisms shaping this migration remain to be elucidated. METHODS: Here, we prepared mouse skin fibroblasts inactivated for different PDGF receptor genes and systematically measured their chemotactic responses within a gradient of different chemoattractants. RESULTS: We found that PDGFRαß and PDGFRßß dimers were strong inducers of random and directionally-persistent migration, respectively, that was sustained for up to 24 h. MAPK and PI3K were necessary to mediate random and directional migration, respectively. Directional migration was accompanied by abundant ventral stress fiber formation and consistent cell shape with less frequent formation of branch-like processes. CONCLUSION: This is the first systematic study that characterized the chemotaxis mediated by three-different types of PDGFR dimers in mesenchymal cell migration. Our data demonstrate that PDGFR dimer formation is the critical step to determine the specific mode of fibroblast chemotaxis, while the accompanying cytoskeletal remodeling might contribute to migration persistence.

Glioma-Derived Platelet-Derived Growth Factor-BB Recruits Oligodendrocyte Progenitor Cells via Platelet-Derived Growth Factor Receptor-α and Remodels Cancer Stroma.

Glioma is an aggressive and incurable disease, and is frequently accompanied by augmented platelet-derived growth factor (PDGF) signaling. Overexpression of PDGF-B ligand characterizes a specific subclass of glioblastoma multiforme, but the significance of the ligand remains to be elucidated. For this end, we implanted a glioma-cell line transfected with PDGF-BB-overexpressing vector (GL261-PDGF-BB) or control vector (GL261-vector) into wild-type mouse brain, and examined the effect of glioma-derived PDGF on the tumor microenvironment. The volume of GL261-PDGF-BB rapidly increased compared with GL261-vector. Recruitment of many PDGF receptor (PDGFR)-α and Olig2-positive oligodendrocyte precursor cells and frequent hemorrhages were observed in GL261-PDGF-BB but not in GL261-vector. We then implanted GL261-PDGF-BB into the mouse brain with and without Pdgfra gene inactivation, corresponding to PDGFRα-knockout (KO) and Flox mice, respectively. The recruitment of oligodendrocyte precursor cells was largely suppressed in PDGFRα-KO than in Flox, whereas the volume of GL261-PDGF-BB was comparable between the two genotypes. Frequent hemorrhage and increased IgG-leakage were associated with aberrant vascular structures within the area where many recruited oligodendrocyte precursor cells accumulated in Flox. In contrast, these vascular phenotypes were largely normalized in PDGFRα-KO. Increased matrix metalloproteinase-9 in recruited oligodendrocyte precursor cells and decreased claudin-5 in vasculature may underlie the vascular abnormality. Glioma-derived PDGF-B signal induces cancer stroma characteristically seen in high-grade glioma, and should be therapeutically targeted to improve cancer microenvironment.

PDGFR-ß Plays a Key Role in the Ectopic Migration of Neuroblasts in Cerebral Stroke.

The neuroprotective agents and induction of endogenous neurogenesis remain to be the urgent issues to be established for the care of cerebral stroke. Platelet-derived growth factor receptor beta (PDGFR-ß) is mainly expressed in neural stem/progenitor cells (NSPCs), neurons and vascular pericytes of the brain; however, the role in pathological neurogenesis remains elusive. To this end, we examined the role of PDGFR-ß in the migration and proliferation of NSPCs after stroke. A transient middle cerebral-arterial occlusion (MCAO) was introduced into the mice with conditional Pdgfrb-gene inactivation, including N-PRß-KO mice where the Pdgfrb-gene was mostly inactivated in the brain except that in vascular pericytes, and E-PRß-KO mice with tamoxifen-induced systemic Pdgfrb-gene inactivation. The migration of the DCX(+) neuroblasts from the subventricular zone toward the ischemic core was highly increased in N-PRß-KO, but not in E-PRß-KO as compared to Pdgfrb-gene preserving control mice. We showed that CXCL12, a potent chemoattractant for CXCR4-expressing NSPCs, was upregulated in the ischemic lesion of N-PRß-KO mice. Furthermore, integrin α3 intrinsically expressed in NSPCs that critically mediates extracellular matrix-dependent migration, was upregulated in N-PRß-KO after MCAO. NSPCs isolated from N-PRß-KO rapidly migrated on the surface coated with collagen type IV or fibronectin that are abundant in vascular niche and ischemic core. PDGFR-ß was suggested to be critically involved in pathological neurogenesis through the regulation of lesion-derived chemoattractant as well as intrinsic signal of NSPCs, and we believe that a coordinated regulation of these molecular events may be able to improve neurogenesis in injured brain for further functional recovery.

Pathogenetic significance and possibility as a therapeutic target of platelet derived growth factor.

Platelet-derived growth factor (PDGF) is one of the major mitogens and chemoattractants for mesenchymal and glial cells. Nowadays, the expression of PDGFs are recognized widely in our body, and emerging data indicate the relevance of PDGFs in the homeostatic control of systemic connective tissue as well as parenchymal cells such as neurons. Aberrant PDGF signal is primarily tumorigenic, and also regulates tumor microenvironments. The roles of the PDGF signal in tumorigenesis are diverse depending on the type of cancer, and anti-PDGF therapy needs to be carefully designed based on the information of each tumor cell type and the surrounding microenvironment. PDGFs and receptors (PDGFRs) are abundant in neurons and glial cells, and are neuroprotective through the regulation of neurovascular unit. PDGF signal is functionally correlated with neurotransmission, and can be pathogenetically correlated with psychosomatic neurological diseases. Growing genetic information has been unraveling novel connective tissue diseases and vascular abnormalities in which aberrant PDGF signaling is etiologically correlated. Novel therapeutic approaches targeting PDGF signal are beginning to emerge in various diseases.

Successful multimodal treatment of intraoral salivary duct carcinoma in a patient with multiple lymph node metastases: a case report.

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary gland malignancy that is associated with an aggressive clinical behavior and poor prognosis. Herein, we report on a long surviving case of SDC of the minor salivary gland with multiple lymph node metastases (LNMs). CASE PRESENTATION: An 83-year-old woman presented with a history of lymphadenopathy in the right side of the neck and recent onset and rapid growth of a mass in the right buccal region. Clinical examinations and biopsy findings were suggestive of a salivary gland malignant tumor with regional LNMs. The patient was treated with neoadjuvant chemotherapy. Tumor excision and ipsilateral radical neck dissection were performed, followed by adjuvant chemoradiotherapy. Postoperative histological examination revealed a tumor with irregular nests of atypical ductal epithelial cells, a cribriform growth pattern, and comedo-like central necrosis that lead to a final diagnosis of SDC. LNMs were observed in six lymph nodes of the right side of the neck. The patient underwent postoperative chemotherapy using single-agent cisplatin that was administered concurrently with radiotherapy (total, 65 Gy). There was no evidence of local recurrence or distant metastasis for >6 years. CONCLUSIONS: Although available data on treatment modalities for SDC remain limited, multimodal therapy may contribute to improved clinical outcomes in patients with advanced intraoral SDC.

Significance of Extracellular Vesicles: Pathobiological Roles in Disease.

Over the past decade, many studies have been conducted on extracellular vesicles (EVs) in the fields of basic and clinical research. EVs are small sized membranous vesicles generated from many type of cells upon activation by environmental stresses such as heat, hypoxia, and irradiation. EVs theoretically consist of microparticles/microvesicles, exosomes, and apoptotic bodies by different productive mechanisms. Clinically, EVs are observed in the blood stream of patients suffering from acute and chronic inflammation evoked by various diseases, and number of EVs in blood flow is often dependent on the inflammatory status and severity of the diseases. To date, it has been reported that small molecules such as RNAs and proteins are encapsulated in EVs; however, the functions of EVs are still unclear in the biological, pathological, and clinical aspects. In this review, we summarize and discuss the biogenesis-based classification, expected function, and pathobiological activities of EVs.

Review of small cell carcinoma of the kidney with focus on clinical and pathobiological aspects.

Small cell carcinoma (SmCC) of the kidney is extremely rare. In this article, we present a review of SmCC of the kidney with the focus on clinical and pathobiological aspects. Macroscopically, this tumor often shows a bulky mass extensively replacing the renal parenchyma with vascular invasion and metastasis to lymph nodes. Histologically, the tumor is composed of small cells with scant cytoplasm, round to oval nuclei, finely granular chromatin and inconspicuous nucleoli. Rosette or tubular formation may be present. Immunohistochemically, neoplastic cells show variable positivity for neuron-specific enolase, chromogranin A, synaptophysin, CD57 (Leu7) and CD56. A dot-like staining pattern for cytokeratin may also be observed. An electron microscopic examination may identify electron-dense neurosecretory granules in the cytoplasm. As a therapeutic option, nephrectomy and systemic chemotherapy should be considered. However, despite multimodal therapy, most patients have a dismal outcome and die of widely metastatic disease within one to two years. As there are limited genetic data on SmCC of the kidney, a large series studying this will be needed in the future.

A case of BRCA1-mutated giant pancreatic acinar cell carcinoma successfully treated with modified FOLFIRINOX therapy and radical resection.

Pancreatic acinar cell carcinoma (PACC) is a rare type of pancreatic cancer; further, its pathogenesis and treatment strategies remain unclear. We report the case of a 70-year-old man who presented with a chief complaint of abdominal distention. Computed tomography scans revealed a large lobulated mass (tumor diameter: 150 mm) in the pancreatic body tail, which was diagnosed as a PACC through endoscopic ultrasonography fine needle aspiration. The other imaging modalities did not reveal distant metastases, and the tumor was classified as resectable. Neoadjuvant chemotherapy was planned after staging laparoscopy ruled out microscopic distant metastasis. First-line chemotherapy with gemcitabine + nab-paclitaxel failed due to tumor growth and worsening abdominal distention. Evaluation using the BRACAnalysis® device indicated that the patient was positive for BRCA1 mutation. Second-line modified FOLFIRINOX (mFFX) resulted in a marked decrease in elastase 1 levels; moreover, a partial antitumor response was observed, which prompted radical resection. After distal pancreatectomy, the patient has survived for 3.5 years without recurrence. BRCA-mutated pancreatic cancer is more likely to respond to mFFX, including platinum, and BRCA mutations have been reported to be highly prevalent in PACC. It is important to evaluate the presence of BRCA mutations in patients with PACC prior to treatment.

Thoracoscopic enucleation of an esophageal glomus tumor in the prone position: a case report and literature review.

BACKGROUND: Glomus tumors (GT) generally occur in the skin. However, esophageal GT, an extremely rare condition, has no established standardized treatment guidelines. Herein, we report the case of an esophageal GT successfully removed by thoracoscopic enucleation in the prone position using intra-esophageal balloon compression. CASE PRESENTATION: A 45-year-old man underwent an annual endoscopic examination and was found to have a submucosal tumor in the lower esophagus. Endoscopic ultrasound (EUS) revealed a hyperechoic mass originating from the muscular layer. Contrast-enhanced computed tomography identified a 2 cm mass lesion with high contrast enhancement in the right side of the lower esophagus. Pathologic findings of EUS-guided fine needle aspiration biopsy (EUS-FNA) revealed round to spindle shaped atypical cells without mitotic activity. Immunohistochemically, the tumor was positive for alpha-smooth muscle actin, but negative for CD34, desmin, keratin 18, S-100 protein, melan A, c-kit, and STAT6. He was diagnosed with an esophageal GT and a thoracoscopic approach to tumor resection was planned. Under general anesthesia, a Sengstaken-Blakemore (SB) tube was inserted into the esophagus. The patient was placed in the prone position and a right thoracoscopic approach was achieved. The esophagus around the tumor was mobilized and the SB tube balloon inflated to compress the tumor toward the thoracic cavity. The muscle layer was divided and the tumor was successfully enucleated without mucosal penetration. Oral intake was initiated on postoperative day (POD) 3 and the patient discharged on POD 9. No surgical complications or tumor metastasis were observed during the 1-year postoperative follow-up. CONCLUSIONS: As malignancy criteria for esophageal GT are not yet established, the least invasive procedure for complete resection should be selected on a case-by-case basis. Thoracoscopic enucleation in the prone position using intra-esophageal balloon compression is useful to treat esophageal GT on the right side of the esophagus.

Chromophobe renal cell carcinoma, oncocytic variant: a proposal of a new variant giving a critical diagnostic pitfall in diagnosing renal oncocytic tumors.

In chromophobe renal cell carcinoma (RCC), two forms of typical and eosinophilic variants have been reported to date. We have previously reported a new variant of chromophobe RCC, namely an oncocytic variant. However, little is known on the histological features of this variant. In this article, we report such five cases. Macroscopically, the tumor was well demarcated, but unencapsulated. The cut surface of the tumor showed brown in color, but neither hemorrhage nor necrosis was seen. Microscopically, the tumor consisted of predominant tubular configuration with or without various proportion of solid-sheet pattern. In one tumor, tumor cells microscopically invaded branches of renal vein. In addition, the constituting cells were characterized by the oncocytic cytoplasm, trivial to minimal variation in tumor size, indistinct to slightly distinct cell border, centrally located round nuclei and the absence of perinuclear halo. These characteristics entirely resembled renal oncocytoma. However, neoplastic cells immunohistochemically showed the diffuse and strong labeling for cytokeratin 7 and mitochondrial antigen in all cases. In addition, in fluorescence in situ hybridization (FISH) study the loss of more than four chromosomes among chromosomes 7, 10, 13, 17 and 21 was confirmed in all tumors and the diagnosis of chromophobe RCC was rendered. In conclusion, we propose a new variant, namely an oncocytic variant, of chromophobe RCC morphologically resembling renal oncocytoma and biologically showing characteristics of chromophobe RCC, and this recognition is practically crucial in the differential diagnosis from renal oncocytoma.

Liver metastasis affects progression pattern during immune checkpoint inhibitors monotherapy in gastric cancer.

Introduction: The efficacy of immune checkpoint inhibitors (ICIs) is heterogeneous at each metastatic site, and tumor progression pattern is associated with survival; however, it remains unclear in gastric cancer (GC). Therefore, we aimed to clarify the progression pattern in response to ICIs in patients with GC, and we analyzed its mechanism focusing on the intratumoral immune cells. Methods: Patients who received ICIs were retrospectively classified into non-systemic and systemic progression groups based on their radiological assessments. Moreover, the best percentage change in target lesions from each organ was compared. Results: Among 148 patients, the non-systemic progression group showed a significant improvement in overall survival (OS) compared with the systemic progression group (median, 5.6 months vs. 3.3 months; HR, 0.53; 95%CI, 0.32-0.89; p = 0.012). Poor performance status (HR, 1.73, 95%CI, 1.00-2.87) and systemic progression (HR, 3.09, 95%CI, 1.95-4.82) were associated with OS. Of all metastatic sites, the liver showed the poorest percentage change, and liver metastasis (OR, 2.99, 95%CI, 1.04-8.58) was associated with systemic progression. Hence, intratumoral CD8+ T-cell density was lower in patients with liver metastasis than in those without liver metastasis after ICIs, although the density of CD4+ T-cells (Th1, Th17, and Treg) and CD163+ cells (TAM) were not significantly different. Conclusion: The new progression pattern was associated with OS in GC. Liver metastasis may be a predictive factor of systemic progression during ICIs by regulating intratumoral CD8+ T-cells.

A 47-Year-Old Man with Advanced Distal Pancreatic Carcinoma and an Initial Partial Response to Chemotherapy Requiring Celiac Axis Reconstruction of the Common Hepatic Artery and Left Gastric Artery.

BACKGROUND Distal pancreatectomy with en bloc celiac artery resection (DP-CAR) is a curative surgical method for locally advanced pancreatic body cancer; however, arterial reconstruction remains controversial in this procedure. This report presents the case of a 47-year-old man with advanced distal pancreatic carcinoma and initial partial response to chemotherapy who required celiac axis reconstruction of the common hepatic artery and left gastric artery. CASE REPORT A 47-year-old man had loss of appetite. He had a 40-mm hypovascular tumor extending from the pancreatic body to the tail, invading around the celiac artery, common hepatic artery, left gastric artery, and splenic artery. We initiated chemotherapy concurrent with chemo-radiotherapy with S-1 administration. After chemo-radiotherapy, computed tomography (CT) showed tumor shrinkage, indicating partial response, but soft tissue CT density surrounding the celiac axis arteries persisted. We conducted conversion surgery. When the common hepatic artery was clamped during surgery, the intrahepatic arterial blood flow reduced; thus, we reconstructed the middle hepatic artery to the common hepatic artery. The left gastric artery was also reconstructed using the second jejunal artery to prevent ischemic gastropathy. Histopathologic examination showed no tumor cells in the specimen; thus, R0 resection was achieved. CONCLUSIONS Arterial reconstruction can be an option for R0 resection in DP-CAR when hepatic arterial blood flow is reduced due to an intraoperative common hepatic artery clamping test.

Hypothalamic orexin prevents non-alcoholic steatohepatitis and hepatocellular carcinoma in obesity.

Non-alcoholic steatohepatitis (NASH) occasionally occurs under obesity; however, factors modulating the natural history of fatty liver disease remain unknown. Since hypothalamic orexin that regulates physical activity and autonomic balance prevents obesity, we investigate its role in NASH development. Male orexin-deficient mice fed a high-fat diet (HFD) show severe obesity and progression of NASH with fibrosis in the liver. Hepatic fibrosis also develops in ovariectomized orexin-deficient females fed an HFD but not ovariectomized wild-type controls. Moreover, long-term HFD feeding causes hepatocellular carcinoma (HCC) in orexin-deficient mice. Intracerebroventricular injection of orexin A or pharmacogenetic activation of orexin neurons acutely activates hepatic mTOR-sXbp1 pathway to prevent endoplasmic reticulum (ER) stress, a NASH-causing factor. Daily supplementation of orexin A attenuates hepatic ER stress and inflammation in orexin-deficient mice fed an HFD, and autonomic ganglionic blocker suppresses the orexin actions. These results suggest that hypothalamic orexin is an essential factor for preventing NASH and associated HCC under obesity.

Roles of PDGF receptor-beta in the structure and function of postnatal kidney glomerulus.

BACKGROUND: Mesangial cell functions are critically regulated by platelet-derived growth factor receptor (PDGFR)-ß signals. In contrast to the well-established role of PDGFR-ß in the development of kidney glomerulus, its role in adult kidney glomerulus remains controversial. METHODS: We deleted the PDGFR-ß gene postnatally using the Cre-loxP system and analysed the long-term effects of PDGFR-ß inhibition on glomerular changes associated with ageing and subtotal nephrectomy. RESULTS: Mice depleted of PDGFR-ß (Deletant) survived without showing apparent abnormalities. In glomerulus of Deletant, mesangial PDGFR-ß expression was decreased. The glomerular cell numbers were low, and the ageing-associated increment of mesangial matrix area was suppressed in Deletant as compared with control mice with conserved PDGFR-ß expression (Floxed) at 48 weeks of age. At 2 weeks after subtotal nephrectomy, albuminuria and the elevation of blood urea nitrogen were aggravated in Deletant. At this time, Deletant showed specific glomerular changes that included many hypertrophic podocytes and collapsed capillaries. At 12 weeks after subtotal nephrectomy, the kidney function in Deletant restored to the level of Floxed; however, the Deletant glomeruli showed dilated capillaries, decreased cell number and reduced mesangial matrix area with less extended mesangial cell processes as compared with Floxed. CONCLUSIONS: The long-term inhibition of mesangial PDGFR-ß prevented age-related mesangial expansion. On the other hand, the kidney glomeruli with decreased PDGFR-ß showed increased vulnerability to the acute nephron loss, and showed mesangial insufficiency in the following adaptive process.

Intrahepatic Bile Duct Injury as a Hepatic Immune-Related Adverse Event after Immune-Checkpoint Inhibitor Treatment.

The increased use of immune-checkpoint inhibitors to treat various types of cancer has increased the incidence of immune-related adverse events (irAEs). Hepatic irAEs are frequent and can lead to serious conditions. Among the various types of hepatic irAEs reported to date, bile duct injury has been shown refractory to steroid treatment. This study describes 2 patients with hepatic irAEs manifesting as intrahepatic bile duct injury. Immunostaining with antibodies to both CD8 and cytokeratin-7 was useful for the diagnosis, and both patients were refractory to steroid treatment. Prompt diagnosis and active immunosuppressive therapies are required in such cases.

Neuroprotective effects of PDGF against oxidative stress and the signaling pathway involved.

The neuroprotective effects of platelet-derived growth factor (PDGF) and the major signaling pathways involved in these were examined using primary cultured mouse cortical neurons subjected to H(2)O(2)-induced oxidative stress. The specific function of the PDGF beta-receptor (PDGFR-beta) was examined by the selective deletion of the corresponding gene using the Cre-loxP system in vitro. In wild-type neurons, PDGF-BB enhanced the survival of these neurons and suppressed H(2)O(2)-induced caspase-3 activation. The prosurvival effect of PDGF-AA was less than that of PDGF-BB. PDGF-BB highly activated Akt, extracellular signal-regulated kinase (ERK), c-jun amino-terminal kinase (JNK) and p38. PDGF-AA activated these molecules at lesser extent than PDGF-BB. In particular, PDGF-AA induced activation of Akt was at very low level. The neuroprotective effects of PDGF-BB were antagonized by inhibitors of phosphatidylinositol 3-kinase (PI3-K), mitogen-activated protein kinase kinase (MEK), JNK and p38. The PDGFR-beta-depleted neurons showed increased vulnerability to oxidative stress, and less responsiveness to PDGF-BB-induced cytoprotection and signal activation, in which Akt activation was most strongly suppressed. After all, these results demonstrated the neuroprotective effects of PDGF and the signaling pathways involved against oxidative stress. The effects of PDGF-BB were more potent than those of PDGF-AA. This might be due to the activation and additive effects of two PDGFRs after PDGF-BB stimulation. Furthermore, the PI3-K/Akt pathway that was deduced to be preferentially activated by PDGFR-beta may explain the potent effects of PDGF-BB.

Clinicopathological Features of Thyroid-Like Low-Grade Nasopharyngeal Papillary Adenocarcinoma: A Case Report and Review of the Literature.

Thyroid-like low-grade nasopharyngeal papillary adenocarcinoma (TL-LGNPPA) is an extremely rare neoplasm of the nasopharynx. Accordingly, its clinical and pathological characteristics are not well-known. We report a case of TL-LGNPPA and review the relevant literature on TL-LGNPPA. A 38-year-old Japanese woman presented with a history of nasal obstruction that had persisted for 1 month after symptoms of a common cold (e.g., low-grade fever, sore throat, and fatigue). A pedunculated tumor of ~20 mm in diameter was found on the posterior edge of the nasal septum. The tumor was endoscopically resected. Based on careful histopathological and immunohistochemical examinations, it was diagnosed as TL-LGNPPA. At 5 years after surgery, the patient remained disease-free. TL-LGNPPA has a very good prognosis, and complete resection with a sufficient safety margin is recommended as the first-line treatment. The morphological characteristics and immunohistochemical findings, especially TTF-1 positivity and thyroglobulin negativity, are important for the diagnosis.