Glutamine-derived aspartate is required for eIF5A hypusination-mediated translation of HIF-1α to induce the polarization of tumor-associated macrophages.

Tumor-associated macrophages (TAMs) are vital contributors to the growth, metastasis, and therapeutic resistance of various cancers, including hepatocellular carcinoma (HCC). However, the exact phenotype of TAMs and the mechanisms underlying their modulation for therapeutic purposes have not been determined. Here, we present compelling evidence that glutamine-derived aspartate in TAMs stimulates spermidine production through the polyamine synthesis pathway, thereby increasing the translation efficiency of HIF-1α via eIF5A hypusination. Consequently, augmented translation of HIF-1α drives TAMs to undergo an increase glycolysis and acquire a metabolic phenotype distinct from that of M2 macrophages. Finally, eIF5A levels in tumor stromal lesions were greater than those in nontumor stromal lesions. Additionally, a higher degree of tumor stromal eIF5A hypusination was significantly associated with a more advanced tumor stage. Taken together, these data highlight the potential of inhibiting hypusinated eIF5A by targeting glutamine metabolism in TAMs, thereby opening a promising avenue for the development of novel therapeutic approaches for HCC.

Benign Intranodal Thyroid Tissue Similar to Nodal Metastasis of Thyroid Papillary Carcinoma: A Rare Case Report.

In patients with thyroid nodules, if the cervical lymph nodes gradually enlarge, a histological confirmation is required to rule out malignancy. Here is a case of benign intranodal thyroid tissue with cystic changes resembling lymph node metastasis of a papillary thyroid carcinoma. A 47-year-old man received ethanol sclerotherapy because of repeated enlargement of the thyroid gland 2 years prior to presentation. Subsequently, the patient underwent abscess removal from the deep neck and partial lobectomy of the attached left thyroid gland. Two months before the visit, extensive cervical lymphadenopathy was detected on ultrasonography (US) and computed tomography (CT). Total thyroidectomy and cervical lymph node dissection were performed to differentiate between metastatic papillary carcinoma of the thyroid gland and benign thyroid inclusions. Microscopic examination revealed multiple variable-sized nodules of benign thyroid follicles with cystic changes in both thyroid glands and bilateral cervical lymph nodes. An occult papillary microcarcinoma strongly positive for HBME-1 was also observed in the left thyroid lobe. However, the benign intranodal thyroid tissue was negative in both the real-time PCR-based BRAF V600E mutation test and HBME-1 immunohistochemical stain. Similarly, benign intranodal thyroid tissue can be enlarged by multiple cystic changes in a large number of lymph nodes along the neck node chain. For the differentiation of metastatic thyroid papillary carcinoma, real-time PCR-based BRAF V600E mutation test and HBME-1 immunohistochemical staining in addition to histological examination are helpful.

Mixed ganglioneuroma and cortical adenoma in adrenal gland: A case report.

RATIONALE: Adrenal mixed corticomedullary tumors (MCMTs) are single tumor masses composed of an intimately admixed population of both adrenal cortical cells and medullary components. Most medullary tumor components are pheochromocytomas; however, MCMTs composed of ganglioneuroma and adrenal cortical adenoma are extremely rare. The current case is a rare case of adrenal MCMT composed of ganglioneuroma and adrenal cortical adenoma with primary aldosteronism. PATIENT CONCERNS: A 49-year-old male was admitted because of hypokalemia and an adrenal mass. He was diagnosed with hypertension in his 20s and was taking blood pressure medications. DIAGNOSIS: Plasma aldosterone concentration 376.5 pg/dL (normal 37.8~233.0 pg/mL) and potassium 2.8 mmol/L (normal 3.4~4.9 mmol/L) were detected. The aldosterone-to-renin ratio [the ratio of plasma aldosterone concentration (ng/dL) to PRA (ng/mL/hour)] was 38. The saline loading test showed that serum aldosterone (49.4 ng/dL) was not suppressed, compared with the basal level (28.4 ng/dL). The adrenal venous sampling test showed that the aldosterone level markedly increased to 1521.2 pg/mL. Abdominal computed tomography revealed an enlarged relatively well-circumscribed multinodular mass (35 × 13 × 30 mm) in the right adrenal gland. INTERVENTIONS: Laparoscopic right adrenalectomy was performed under the clinical diagnosis of a functioning adrenal cortical adenoma. OUTCOMES: After laparoscopic right adrenalectomy, the serum aldosterone and renin levels returned to normal. The patient maintained a normal aldosterone level without recurrence for 16 months. LESSONS: Adrenal MCMTs of the ganglioneuroma and cortical adenomas in the ipsilateral adrenal gland are extremely rare. Adrenal MCMTs exhibit benign clinical behavior, with no metastasis or death due to the tumor. With the development of diagnostic imaging technology, it is possible to identify mixed tumors. However, surgical resection of adrenal gland is a common treatment and a final diagnosis should be made based on the pathological results after surgery. Because this is to rule out the occurrence of rare malignant tumors and confirm the pattern of mixed tumors.

Prognostic value of the metabolic score obtained via [18F]FDG PET/CT and a new prognostic staging system for gastric cancer.

We developed and validated a new staging system that includes metabolic information from pretreatment [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) for predicting disease-specific survival (DSS) in gastric cancer (GC) patients. Overall, 731 GC patients undergoing preoperative [18F]FDG PET/CT were enrolled and divided into the training (n = 543) and validation (n = 188) cohorts. A metabolic score (MS) was developed by combining the maximum standardized uptake value (SUVmax) of the primary tumor (T_SUVmax) and metastatic lymph node (N_SUVmax). A new staging system incorporating the MS and tumor-node-metastasis (TNM) stage was developed using conditional inference tree analysis. The MS was stratified as follows: score 1 (T_SUVmax ≤ 4.5 and N_SUVmax ≤ 1.9), score 2 (T_SUVmax > 4.5 and N_SUVmax ≤ 1.9), score 3 (T_SUVmax ≤ 4.5 and N_SUVmax > 1.9), and score 4 (T_SUVmax > 4.5 and N_SUVmax > 1.9) in the training cohort. The new staging system yielded five risk categories: category I (TNM I, II and MS 1), category II (TNM I, II and MS 2), category III (TNM I, II and MS ≥ 3), category IV (TNM III, IV and MS ≤ 3), and category V (TNM III, IV and MS 4) in the training cohort. DSS differed significantly between both staging systems; the new staging system showed better prognostic performance in both training and validation cohorts. The MS was an independent prognostic factor for DSS, and discriminatory power of the new staging system for DSS was better than that of the conventional TNM staging system alone.

A tissue attached to self-expandable metal stents for biliary stricture could be useful to find malignancy.

Biliary strictures can have several benign or malignant causes. We attempted to determine the usefulness of establishing a diagnosis using self-expandable metal stents (SEMS) in a prospective series of patients with suspected malignant biliary obstruction. Data of patients who underwent SEMS removal from August 2016 to December 2019 were collected. During this period, 55 patients underwent endobiliary biopsy and SEMS insertion and removal. Fifty-five consecutive patients (mean age, 69 years; range 53-90 years) were enrolled, and of these, 37 were male and 18 were female. A final diagnosis was established using biopsy specimens in 37 cases (67.3%) and surgical specimens in 6 cases (10.9%), with 12 cases (21.8%) diagnosed on radiological follow-up. The final diagnoses included malignancy in 34 cases (61.8%) and benign stricture in 21 cases (38.2%). Endobiliary biopsy had a sensitivity and specificity of 44.1% and 95.2%, whereas SEMS cytology had a sensitivity and specificity of 52.9% and 100%, respectively. Combining endobiliary biopsy and/or SEMS cytology yielded a sensitivity and specificity of 73.5% and 95.2%, respectively. (1) The use of biopsy results alone as a diagnostic tool yielded an area under the receiver operating characteristic curve (AUC) of 0.70 (0.60-0.79). (2) The addition of SEMS to the biopsy results yielded an AUC of 0.86 (0.78-0.94). (3) The addition of CA 19-9 levels to the biopsy results yielded an AUC of 0.81 (0.71-0.94). (4) Combining the endobiliary biopsy results, SEMS tissues, and CA 19-9 levels yielded the best diagnostic accuracy, with an AUC of 0.90 (0.83-0.98). Detection of biliary obstruction using the combination strategy was better than the diagnostic results based on biopsy alone according to recent 3-year data. Our study suggested that SEMS removal could help establish a diagnosis of suspected malignant biliary obstruction.

Structural changes in the retina after implantation of subretinal three-dimensional implants in mini pigs.

The retinal structural changes after subretinal implantation of three-dimensional (3D) microelectrodes were investigated in a mini pig. Three types of electrode were implanted into the subretinal spaces of nine mini pigs: 75-µm-high 3D electrodes on a 200-µm-thick right-angled polydimethylsiloxane (PDMS) substrate (group 1); a 140-µm-thick sloped PDMS substrate without electrodes (group 2); and a 140-µm-thick sloped PDMS substrate with 20-µm-high 3D electrodes (group 3). One mini pig was used as a control. Spectral domain-optical coherence tomography (SD-OCT) images were obtained at baseline and 2, 6, and 12 weeks post-surgery. Retinal specimens were immunostained using a tissue-clearing method 3 months post-implantation. The 75-µm-high 3D electrodes progressively penetrated the inner nuclear layer (INL) and touched the inner plexiform layer (IPL) 2 weeks post-surgery. At 6 weeks post-operatively, the electrodes were in contact with the nerve-fiber layer, accompanied by a severe fibrous reaction. In the other groups, the implants remained in place without subretinal migration. Immunostaining showed that retinal ganglion and bipolar cells were preserved without fibrosis over the retinal implants in groups 2 and 3 during the 12-week implantation period. In summary, SD-OCT and immunohistology results showed differences in the extent of reactions, such as fibrosis over the implants and penetration of the electrodes into the inner retinal layer depending on different types of electrodes. A sloped substrate performed better than a right-angled substrate in terms of retinal preservation over the implanted electrodes. The 20-µm-high electrodes showed better structural compatibility than the 75-µm-high 3D electrodes. There was no significant difference between the results of sloped implants without electrodes and 20-µm-high 3D electrodes, indicating that the latter had no adverse effects on retinal tissue.

Primary Clear Cell Carcinoma of the Pancreas: A Rare Case Report.

Most pancreatic carcinoma is ductal adenocarcinoma. Primary pancreatic clear cell carcinomas composed almost entirely of clear tumor cells are very rare. We present a case of a 72-year-old man with a pancreatic mass, which was detected on abdominal computed tomography (CT). He had no symptoms and no abnormal findings on physical examination; however, he had a history of hepatitis B, hepatitis C, and hepatocellular carcinoma. He had received anti-viral treatment and radiofrequency ablation twice until 2 years prior. One year prior, follow-up contrast-enhanced abdominal CT revealed a newly developed pancreatic mass. Laparoscopic radical antegrade modular pancreato-splenectomy was performed. An ill-defined white-to-tan firm solid mass was observed in the pancreas, approximately 4.3 cm in diameter. The tumor cells showed >95% clear cell features, with a large round to oval nuclei and abundant clear cytoplasms, and well-defined cell membranes. Immunohistochemical staining revealed that the tumor cells were positive for cytokeratin 7, cytokeratin 19, HNF-1ß, MUC-1, and p53. We excluded the possibility of metastatic clear renal cell carcinoma, neuroendocrine carcinoma, perivascular epithelioid cell tumor, malignant melanoma, and sarcoma because of the negativity for vimentin, chromogranin, synaptophysin, and HMB45. Consequently, he was diagnosed as having primary clear cell carcinoma of the pancreas and was treated with postoperative radiotherapy. Two months later, abdominal CT was suspicious for local recurrence at the resection margin. Additional adjuvant FOLFIRINOX chemotherapy was carried out 12 times. The patient is still alive after his third radiofrequency ablation for the newly-developed hepatic mass. Immunohistochemical staining for MUC-1 and HNF-1ß, as well as histologic feature is very helpful for the diagnosis of primary pancreatic clear cell carcinoma with imaging methods for metastasis exclusion.

A Case of Hepatic Immunoglobulin G4-Related Disease Presenting as an Inflammatory Pseudotumor and Sclerosing Cholangitis.

An inflammatory pseudotumor is a benign disease characterized by tumor-like lesions consisting of inflammatory cells including plasma cells and fibrous tissue. Recently, some inflammatory pseudotumor cases proved to be a form of Immunoglobulin G4-related disease (IgG4-RD). This novel clinical entity, recognized as a fibroinflammatory condition, is characterized by lymphoplasmacytic infiltration with a predominance of IgG4-positive plasma cells, storiform fibrosis, and often elevated serum IgG4 concentrations. We report a case of IgG4-RD in the form of an inflammatory pseudotumor in the liver with combined sclerosing cholangitis. We recommend that for diagnosing IgG4-RD accurately, it is important to obtain adequate tissue samples and follow-up the lesion in clinical practice.

Sulfatase-2 Regulates Liver Fibrosis through the TGF-ß Signaling Pathway.

Transforming growth factor-ß (TGF-ß) activates hepatic stellate cells (HSCs), which drive liver fibrosis via the production and deposition of extracellular matrix (ECM). We aimed to elucidate the mechanistic role of sulfatase-2 (SULF2) in liver fibrosis. To this end, we induced liver fibrosis in wild-type (WT) and SULF2 knockout (Sulf2-KO) mice (6-8 weeks-old) via bile duct ligation (BDL), intraperitoneal injection of carbon tetrachloride (CCl4) or thioacetamide (TAA). The levels of fibrosis in the liver sections were assessed via Sirius red and Masson's trichrome staining, immunohistochemistry and immunoblotting for α-smooth muscle actin (α-SMA) and hydroxyproline. To evaluate the interaction between TGF-ß and SULF2, we transfected human HSCs with scrambled control shRNA and shRNA constructs targeting SULF2 and measured α-SMA expression following treatment with TGF-ß1 ligand. We show here that knockout of SULF2 significantly decreases collagen content, as well as bands of bridging fibrosis, as demonstrated by Sirius red, Masson's trichrome and α-SMA staining after BDL, CCl4 and TAA injection in Sulf2-KO versus WT mice. In all three models of liver fibrosis, we observed significantly lower levels of hydroxyproline in the Sulf2-KO mice compared to the WT mice. HSCs with reduced levels of SULF2 failed to significantly express α-SMA and collagen type I following treatment with TGF-ß1. Furthermore, SULF2 co-localizes with TGFBR3 and the in vitro knockdown of SULF2 in HSCs decreases the release of TGF-ß1 from TGFBR3. Together, these data suggest that SULF2 regulates liver fibrosis via the TGF-ß signaling pathway. Pharmacologic inhibition of SULF2 may represent a novel therapeutic approach to improve liver fibrosis.

Standardization of the pathologic diagnosis of appendiceal mucinous neoplasms.

Although the understanding of appendiceal mucinous neoplasms (AMNs) and their relationship with disseminated peritoneal mucinous disease have advanced, the diagnosis, classification, and treatment of AMNs are still confusing for pathologists and clinicians. The Gastrointestinal Pathology Study Group of the Korean Society of Pathologists (GPSG-KSP) proposed a multicenter study and held a workshop for the "Standardization of the Pathologic Diagnosis of the Appendiceal Mucinous Neoplasm" to overcome the controversy and potential conflicts. The present article is focused on the diagnostic criteria, terminologies, tumor grading, pathologic staging, biologic behavior, treatment, and prognosis of AMNs and disseminated peritoneal mucinous disease. In addition, GPSG-KSP proposes a checklist of standard data elements of appendiceal epithelial neoplasms to standardize pathologic diagnosis. We hope the present article will provide pathologists with updated knowledge on how to handle and diagnose AMNs and disseminated peritoneal mucinous disease.

An Intrafascicular Neural Interface With Enhanced Interconnection for Recording of Peripheral Nerve Signals.

For implantable devices, Parylene C (hereafter referred to as Parylene) has shown promising properties such as flexibility, biocompatibility, biostability, and good barrier properties. Parylene-based flexible interconnection cable (FIC) was previously developed to connect a flexible penetrating microelectrode array (FPMA) with a recording system. However, Parylene-based FIC was difficult to handle and prone to damage during the implantation surgery because of its low mechanical strength. To improve the mechanical properties of the FIC, we suggest a mechanically enhanced flexible interconnection cable (enhanced FIC) obtained using a combination of Parylene and polyimide. To investigate the long-term stability of the enhanced FIC, Parylene-only FIC, and enhanced FIC were tested and their mechanical properties were compared under an accelerated aging condition. During the course of six months of soaking, the maximum strength of the enhanced FIC remained twice as high as that of the Parylene-only FIC throughout the experiment, although the mechanical strength of both FICs decreased over time. To show the capability of the enhanced FIC in the context of nerve signal recording as a part of a neural interfacing device, it was assembled together with the FPMA and custom-made wireless recording electronics. We demonstrated the feasibility of the enhanced FIC in an in vivo application by recording acute nerve signals from canine sciatic nerves.