Selective Inhibition of PI3K Isoforms in Brain Tumors Suppresses Tumor Growth by Increasing Radiosensitivity

Purpose@#Glioblastoma (GBM) is a malignant brain tumor with poor prognosis. Radioresistance is a major challenge in the treatment of brain tumors. The development of several types of tumors, including GBM, involves the phosphoinositide 3-kinase (PI3K)/ protein kinase B (AKT) signaling pathway. Upon activation, this pathway induces radioresistance. In this study, we investigated whether additional use of selective inhibitors of PI3K isoforms would enhance radiosensitivity in GBM. @*Materials and Methods@#We evaluated whether radiation combined with PI3K isoform selective inhibitors can suppress radioresistance in GBM. Glioma 261 expressing luciferase (GL261-luc) and LN229 were used to confirm the effect of combination of radiation and PI3K isoform inhibitors in vitro. Cell viability was confirmed by clonogenic assay, and inhibition of PI3K/AKT signaling activation was observed by Western blot. To confirm radiosensitivity, the expression of phospho-γ-H2AX was observed by immunofluorescence. In addition, to identify the effect of a combination of radiation and PI3K-α isoform inhibitor in vivo, an intracranial mouse model was established by implanting GL261-luc. Tumor growth was observed by IVIS imaging, and survival was analyzed using Kaplan–Meier survival curves. @*Results@#Suppression of the PI3K/AKT signaling pathway increased radiosensitivity, and PI3K-α inhibition had similar effects on PI3K-pan inhibition in vitro. The combination of radiotherapy and PI3K-α isoform inhibitor suppressed tumor growth and extended survival in vivo. @*Conclusion@#This study verified that PI3K-α isoform inhibition improves radiosensitivity, resulting in tumor growth suppression and extended survival in GBM mice.

Comprehensive Molecular Characterization of Soft Tissue Sarcoma for Prediction of Pazopanib-Based Treatment Response / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Even though pazopanib, a multitargeted tyrosine kinase inhibitor, has been approved for refractory soft tissue sarcoma (STS), little is known about the molecular determinants of the response to pazopanib. We performed integrative molecular characterization to identify potential predictors of pazopanib efficacy. @*Materials and Methods@#We obtained fresh pre-treatment tumor tissue from 35 patients with advanced STS receiving pazopanib-based treatment. Among those, 18 (51.4%) received pazopanib monotherapy, and the remaining 17 (48.6%) received pazopanib in combination with durvalumab, programmed death-ligand 1 blockade. Whole-exome and transcriptome sequencing were performed for each tumor and patient germline DNA. @*Results@#Of the 35 patients receiving pazopanib-based treatment, nine achieved a partial response (PR), resulting in an objective response rate (ORR) of 27.3%, and the median progression-free survival (PFS) was 6.0 months. Patients with CDK4 amplification (copy ratio tumor to normal > 2) exhibited shorter PFS (3.7 vs. 7.9 months, p=2.09×10–4) and a poorer response (ORR; 0% vs. 33.3%) compared to those without a gene amplification (copy ratio ≤ 2). Moreover, non-responders demonstrated transcriptional activation of CDK4 via DNA amplification, resulting in cell cycle activation. In the durvalumab combination cohort, seven of the 17 patients (41.2%) achieved a PR, and gene expression analysis revealed that durvalumab responders exhibited high immune/stromal cell infiltration, mainly comprising natural killer cells, compared to non-responders as well as increased expression of CD19, a B-cell marker. @*Conclusion@#Despite the limitation of heterogeneity in the study population and treatment, we identified possible molecular predictors of pazopanib efficacy that can be employed in future clinical trials aimed at evaluating therapeutic strategies.

Landscape of Actionable Genetic Alterations Profiled from 1,071 Tumor Samples in Korean Cancer Patients / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: With the emergence of next-generation sequencing (NGS) technology, profiling a wide range of genomic alterations has become a possibility resulting in improved implementation of targeted cancer therapy. In Asian populations, the prevalence and spectrum of clinically actionable genetic alterations has not yet been determined because of a lack of studies examining high-throughput cancer genomic data. MATERIALS AND METHODS: To address this issue, 1,071 tumor samples were collected from five major cancer institutes in Korea and analyzed using targeted NGS at a centralized laboratory. Samples were either fresh frozen or formalin-fixed, paraffin embedded (FFPE) and the quality and yield of extracted genomic DNA was assessed. In order to estimate the effect of sample condition on the quality of sequencing results, tissue preparation method, specimen type (resected or biopsied) and tissue storage time were compared. RESULTS: We detected 7,360 non-synonymous point mutations, 1,164 small insertions and deletions, 3,173 copy number alterations, and 462 structural variants. Fifty-four percent of tumors had one or more clinically relevant genetic mutation. The distribution of actionable variants was variable among different genes. Fresh frozen tissues, surgically resected specimens, and recently obtained specimens generated superior sequencing results over FFPE tissues, biopsied specimens, and tissues with long storage duration. CONCLUSION: In order to overcome, challenges involved in bringing NGS testing into routine clinical use, a centralized laboratory model was designed that could improve the NGS workflows, provide appropriate turnaround times and control costs with goal of enabling precision medicine.

Angiosarcoma Presenting with a Wide Range of Histopathological Features and Differentiation: A Case Report / 대한피부과학회지

No abstract available.

Age-Related Changes in Sulfur Amino Acid Metabolism in Male C57BL/6 Mice

Alterations in sulfur amino acid metabolism are associated with an increased risk of a number of common late-life diseases, which raises the possibility that metabolism of sulfur amino acids may change with age. The present study was conducted to understand the age-related changes in hepatic metabolism of sulfur amino acids in 2-, 6-, 18- and 30-month-old male C57BL/6 mice. For this purpose, metabolite profiling of sulfur amino acids from methionine to taurine or glutathione (GSH) was performed. The levels of sulfur amino acids and their metabolites were not significantly different among 2-, 6- and 18-month-old mice, except for plasma GSH and hepatic homocysteine. Plasma total GSH and hepatic total homocysteine levels were significantly higher in 2-month-old mice than those in the other age groups. In contrast, 30-month-old mice exhibited increased hepatic methionine and cysteine, compared with all other groups, but decreased hepatic S-adenosylmethionine (SAM), S-adenosylhomocysteine and homocysteine, relative to 2-month-old mice. No differences in hepatic reduced GSH, GSH disulfide, or taurine were observed. The hepatic changes in homocysteine and cysteine may be attributed to upregulation of cystathionine β-synthase and down-regulation of γ-glutamylcysteine ligase in the aged mice. The elevation of hepatic cysteine levels may be involved in the maintenance of hepatic GSH levels. The opposite changes of methionine and SAM suggest that the regulatory role of SAM in hepatic sulfur amino acid metabolism may be impaired in 30-month-old mice.

Recurrent Indeterminate Dendritic Cell Tumor of the Skin

Indeterminate dendritic cell tumor (IDCT) is a dendritic cell tumor that displays histologic features similar to those of Langerhans cells. The origin of the indeterminate cells may represent precursors of Langerhans cells or skin dendritic cells. IDCT is extremely rare, and tumor progression and predictive factors are not well known. Here, we report a case of a 61-year-old man who presented with a papule on his back and was finally diagnosed with IDCT based on histology and immunohistochemistry. The tumor recurred three months after surgical excision.

Outcomes of Treatment for Malignant Peripheral Nerve Sheath Tumors: Different Clinical Features Associated with Neurofibromatosis Type 1 / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Malignant peripheral nerve sheath tumors (MPNSTs) are a rare subtype of sarcoma that occur spontaneously or in association with neurofibromatosis type 1 (NF-1). This study aimed to clinically differentiate these types of MPNSTs. MATERIALS AND METHODS: The study reviewed 95 patients diagnosed with and treated for MPNST at Yonsei University Health System, Seoul, Korea over a 27-year period. The clinical characteristics, prognostic factors, and treatment outcomes of sporadic MPNST (sMPNST) and NF-1 associated MPNST (NF-MPNST) cases were compared. RESULTS: Patients with NF-MPNST had a significantly lower median age (32 years vs. 45 years for sMPNST, p=0.012), significantly larger median tumor size (8.2 cm vs. 5.0 cm for sMPNST, p < 0.001), and significantly larger numbers of imaging studies and surgeries (p=0.004 and p < 0.001, respectively). The 10-year overall survival (OS) rate of the patients with MPNST was 52±6%. Among the patients with localized MPNST, patients with NF-MPNST had a significantly lower 10-year OS rate (45±11% vs. 60±8% for sMPNST, p=0.046). Univariate analysis revealed the resection margin, pathology grade, and metastasis to be significant factors affecting the OS (p=0.001, p=0.020, and p < 0.001, respectively). Multivariate analysis of the patients with localized MPNST identified R2 resection and G1 as significant prognostic factors for OS. CONCLUSION: NF-MPNST has different clinical features from sMPNST and requires more careful management. Further study will be needed to develop specific management plans for NF-MPNST.

Perianal Paget disease: a report of 2 cases

Extramammary Paget disease (EMPD) is a rare cutaneous neoplasm. Perianal Paget disease (PPD) is a subset of EMPD manifesting perianal lesions. Two cases of PPD in Severance Hospital are described in this article. A 65-year-old female and 78-year-old male patients visited our institution because of an unhealed perianal skin lesion despite treatment for a long period with topical agents. PPD was diagnosed by skin biopsies in both cases, and the patients underwent surgical treatment. Clinical manifestations, preoperative work-ups, and surgical treatments including different reconstruction methods are described in detail. As only sporadic PPD cases have been reported and no standard treatment has been established, we hope that our experience could contribute to improving the diagnosis and treatment of PPD patients.

Perianal Paget disease: a report of 2 cases

Extramammary Paget disease (EMPD) is a rare cutaneous neoplasm. Perianal Paget disease (PPD) is a subset of EMPD manifesting perianal lesions. Two cases of PPD in Severance Hospital are described in this article. A 65-year-old female and 78-year-old male patients visited our institution because of an unhealed perianal skin lesion despite treatment for a long period with topical agents. PPD was diagnosed by skin biopsies in both cases, and the patients underwent surgical treatment. Clinical manifestations, preoperative work-ups, and surgical treatments including different reconstruction methods are described in detail. As only sporadic PPD cases have been reported and no standard treatment has been established, we hope that our experience could contribute to improving the diagnosis and treatment of PPD patients.

Soft Tissue Roasi-Dorfman Disease with Features of IgG4-Related Disease in a Patient with a History of Acute Myeloid Leukemia

No abstract available.

IgG4-Related Sclerosing Mesenteritis

No abstract available.

Primary Cutaneous Adenoid Cystic Carcinoma Arising in Umbilicus

No abstract available.

Portal venous perfusion steal causing graft dysfunction after orthotopic liver transplantation: serial imaging findings in a successfully treated patient

A 53-year-old male with hepatocellular carcinoma underwent orthotopic liver transplantation. Preoperative computed tomography revealed main portal vein luminal narrowing by flat thrombi and the development of cavernous transformation. On post-transplantation day 1, thrombotic portal venous occlusion occurred, and emergency thrombectomy was performed. Subsequent Doppler ultrasonography and contrast-enhanced ultrasonography confirmed the restoration of normal portal venous flow. The next day, however, decreased portal venous velocity was observed via Doppler ultrasonography, and serum liver enzymes and bilirubin levels remained persistently elevated. Direct portography identified massive perfusion steal through prominent splenorenal collateral veins. Stent insertion and balloon angioplasty of the portal vein were performed, and subsequent Doppler ultrasonography demonstrated normalized portal flow parameters. Afterwards, the serum liver enzymes and bilirubin levels rapidly normalized.

NgR1 Expressed in P19 Embryonal Carcinoma Cells Differentiated by Retinoic Acid Can Activate STAT3

NgR1, a Nogo receptor, is involved in inhibition of neurite outgrowth and axonal regeneration and regulation of synaptic plasticity. P19 embryonal carcinoma cells were induced to differentiate into neuron-like cells using all trans-retinoic acid and the presence and/or function of cellular molecules, such as NgR1, NMDA receptors and STAT3, were examined. Neuronally differentiated P19 cells expressed the mRNA and protein of NgR1, which could stimulate the phosphorylation of STAT3 when activated by Nogo-P4 peptide, an active segment of Nogo-66. During the whole period of differentiation, mRNAs of all of the NMDA receptor subtypes tested (NR1, NR2A-2D) were consistently expressed, which meant that neuronally differentiated P19 cells maintained some characteristics of neurons, especially central nervous system neurons. Our results suggests that neuronally differentiated P19 cells expressing NgR1 may be an efficient and convenient in vitro model for studying the molecular mechanism of cellular events that involve NgR1 and its binding partners, and for screening compounds that activate or inhibit NgR1.

Necrotic lymphoma in a patient with post-transplantation lymphoproliferative disorder: ultrasonography and CT findings with pathologic correlation

Seventeen months after kidney transplantation for the treatment of nephrotic syndrome, a retroperitoneal mass was incidentally detected in a 30-year-old man during routine follow-up. Ultrasonography revealed a mass measuring 5.5 cmx4.3 cm located between the liver and the atrophic right kidney, which showed markedly heterogeneous internal echogenicity. Contrast-enhanced computed tomography displayed a mild degree of enhancement only at the periphery of the mass, while the center lacked perceivable intensification. The patient underwent surgical resection. The final pathological diagnosis was non-Hodgkin lymphoma (diffuse large B-cell lymphoma), and extensive necrosis was observed on microscopic examination. We found that the prominent heterogeneous echogenicity of the mass (an unusual finding of lymphoma) demonstrated on ultrasonography is a result of extensive necrosis, which may sometimes occur in patients with post-transplantation lymphoproliferative disorder.

MRI Findings of Rectal Submucosal Tumors

Rectal submucosal lesions encompass a wide variety of benign and malignant tumors involving the rectum. With optical colonoscopy, any mass-like protrusion covered by normal mucosa, whether the underlying process is intramural or extramural in origin, may be reported as a submucosal lesion. Whereas the assessment of submucosal lesions may be limited with performing optical colonoscopy, cross-sectional imaging such as CT, transrectal ultrasonography and MRI allows the evaluation of perirectal tissues and pelvic organs in addition to the entire thickness of the rectum, and so this is advantageous for the assessment of rectal submucosal tumors. Among these, MRI is the best investigative modality for soft tissue characterization. Therefore, knowledge of the MRI features of rectal submucosal tumors can help achieve accurate preoperative diagnoses and facilitate the appropriate management.

An Autopsy Case of Multiple System Atrophy

Multiple-system atrophy (MSA) is an adult-onset, sporadic, progressive neurodegenerative disease. Clinically, the cardinal features include autonomic failure, parkinsonism, cerebellar ataxia, and pyramidal signs in any combination, of which autonomic failure is an integral component in the diagnosis. Pathologically, MSA is characterized by alpha-synuclein-positive glial cytoplasmic inclusions and neuronal loss, predominantly in the basal ganglia, brainstem, cerebellum, and intermediolateral cell columns of the spinal cord. We report the first case of MSA confirmed by autopsy in Korea.

Multicentric Hepatocellular Carcinomas and Multiple Dysplastic Nodules: Spectrum of Nodular Lesions in Hepatitis B-viral Cirrhotic Liver / 대한소화기학회지

No abstract available.

Achalasia Combined with Esophageal Cancer Treated by Concurrent Chemoradiation Therapy

Achalasia is a rare neurological deficit of the esophagus that produces an impaired relaxation of the lower esophageal sphincter and decreased motility of the esophageal body. Achalasia is generally accepted to be a pre-malignant disorder, since, particularly in the mega-esophagus, chronic irritation by foods and bacterial overgrowth may contribute to the development of dysplasia and carcinoma. We present a case of a 51-year-old man with achalasia combined with esophageal cancer who has had dysphagia symptoms for more than 20 years. Since there was a clinically high possibility of supraclavicular lymph node metastasis, concurrent chemoradiation therapy was scheduled. After the third cycle of chemoradiation therapy, transthoracic esophageolymphadenectomy was performed. Histopathological examination of the main esophagus specimen revealed no residual carcinoma. And the entire regional lymph node areas were free of carcinoma except for one azygos metastatic lymph node. In summary, achalasia is a predisposing factor for esophageal squamous cell carcinoma. Although surveillance endoscopy in achalasia patients is still controversial, periodic screening for cancer development in long-standing achalasia patients might be advisable.

Clinicopathologic Characteristics of Left-Sided Colon Cancers with High Microsatellite Instability

BACKGROUND: High microsatellite instability (MSI-H) colorectal carcinomas (CRCs) with numerous mutations in the microsatellite sequence are characterized by a right-sided preponderance, frequent peritumoral and intratumoral lymphocytic infiltration, and frequent mucin production. However, no study has correlated anatomic site and type of genetic changes with clinicopathologic changes. METHODS: We analyzed the histopathologic features of 135 MSI-H CRCs and compared them to 140 microsatellite stable (MSS) CRCs. Histopathologic changes in MSI-H were further analyzed according to anatomic sites and genetic changes. RESULTS: MSI-H CRCs showed previously reported clinicopathologic findings; a right-sided preponderance, an increased number of mucinous carcinomas, and peritumoral lymphoid reactions (p<0.001 for each variable). Increased serum CEA levels showed an MSS CRC preponderance (p=0.013). We further analyzed the histologic differences between right- and left-sided MSI-H tumors. We found that MSI-H CRCs on both sides had similar clinicopathologic findings, except for higher tumor stage (p=0.048) and less frequent abnormal CEA levels in left-sided MSI-H tumors (p=0.027). We found that not all clinicopathologic features were different between hereditary nonpolyposis colorectal cancers (HNPCCs) and sporadic MSI-H CRCs. CONCLUSIONS: These findings indicate that MSI-H CRCs of the left colon have similar clinicopathologic characteristics as right-sided MSI-H CRCs. We did not find any significant clinicopathological difference between HNPCCs and sporadic MSI-H CRCs.