Identification of Potential Genomic Alterations Using Pan-Cancer Cell-Free DNA Next-Generation Sequencing in Patients With Gastric Cancer

Background@#Molecular cancer profiling may lead to appropriate trials for molecularly targeted therapies. Cell-free DNA (cfDNA) is a promising diagnostic and/or prognostic biomarker in gastric cancer (GC). We characterized somatic genomic alterations in cfDNA of patients with GC. @*Methods@#Medical records and cfDNA data of 81 patients diagnosed as having GC were reviewed. Forty-nine and 32 patients were tested using the Oncomine Pan-Cancer CellFree Assay on the Ion Torrent platform and AlphaLiquid 100 kit on the Illumina platform, respectively. @*Results@#Tier I or II alterations were detected in 64.2% (52/81) of patients. Biomarkers for potential targeted therapy were detected in 55.6% of patients (45/81), and clinical trials are underway. ERBB2 amplification is actionable and was detected in 4.9% of patients (4/81). Among biomarkers showing potential for possible targeted therapy, TP53 mutation (38.3%, 35 variants in 31 patients, 31/81) and FGFR2 amplification (6.2%, 5/81) were detected the most. @*Conclusions@#Next-generation sequencing of cfDNA is a promising technique for the molecular profiling of GC. Evidence suggests that cfDNA analysis can provide accurate and reliable information on somatic genomic alterations in patients with GC, potentially replacing tissue biopsy as a diagnostic and prognostic tool. Through cfDNA analysis for molecular profiling, it may be possible to translate the molecular classification into therapeutic targets and predictive biomarkers, leading to personalized treatment options for patients with GC in the future.

Reaching New Heights: A Comprehensive Study of Hand Transplantations in Korea after Institutionalization of Hand Transplantation Law

Purpose@#With the revision of the Organ and Transplantation Act in 2018, the hand has become legal as an area of transplantable organs in Korea. In January 2021, the first hand allotransplantation since legalization was successfully performed, and we have performed a total of three successful hand transplantation since then. By comparing and incorporating our experiences, this study aimed to provide a comprehensive reconstructive solution for hand amputation in Korea. @*Materials and Methods@#Recipients were selected through a structured preoperative evaluation, and hand transplantations were performed at the distal forearm level. Postoperatively, patients were treated with three-drug immunosuppressive regimen, and functional outcomes were monitored. @*Results@#The hand transplantations were performed without intraoperative complications. All patients had partial skin necrosis and underwent additional surgical procedures in 2 months after transplantation. After additional operations, no further severe complications were observed. Also, patients developed acute rejection within 3 months of surgery, but all resolved within 2 weeks after steroid pulse therapy. Motor and sensory function improved dramatically, and patients were very satisfied with the appearance and function of their transplanted hands. @*Conclusion@#Hand transplantation is a viable reconstructive option, and patients have shown positive functional and psychological outcomes. Although this study has limitations, such as the small number of patients and short follow-up period, we should focus on continued recovery of hand function, and be careful not to develop side effects from immunosuppressive drugs. Through the present study, we will continue to strive for a bright future regarding hand transplantation in Korea.

ERRATUM: Comparison of Surgery Plus Chemotherapy and Palliative Chemotherapy Alone for Advanced Gastric Cancer with Krukenberg Tumor / Journal of the Korean Cancer Association, 대한암학회지

In this article, a grant number error was found in the Acknowledgments section.

Prognostic Factor Analysis of Overall Survival in Gastric Cancer from Two Phase III Studies of Second-line Ramucirumab (REGARD and RAINBOW) Using Pooled Patient Data

PURPOSE: To identify baseline prognostic factors for survival in patients with disease progression, during or after chemotherapy for the treatment of advanced gastric or gastroesophageal junction (GEJ) cancer. MATERIALS AND METHODS: We pooled data from patients randomized between 2009 and 2012 in 2 phase III, global double-blind studies of ramucirumab for the treatment of advanced gastric or GEJ adenocarcinoma following disease progression on first-line platinum- and/or fluoropyrimidine-containing therapy (REGARD and RAINBOW). Forty-one key baseline clinical and laboratory factors common in both studies were examined. Model building started with covariate screening using univariate Cox models (significance level=0.05). A stepwise multivariable Cox model identified the final prognostic factors (entry+exit significance level=0.01). Cox models were stratified by treatment and geographic region. The process was repeated to identify baseline prognostic quality of life (QoL) parameters. RESULTS: Of 1,020 randomized patients, 953 (93%) patients without any missing covariates were included in the analysis. We identified 12 independent prognostic factors of poor survival: 1) peritoneal metastases; 2) Eastern Cooperative Oncology Group (ECOG) performance score 1; 3) the presence of a primary tumor; 4) time to progression since prior therapy <6 months; 5) poor/unknown tumor differentiation; abnormally low blood levels of 6) albumin, 7) sodium, and/or 8) lymphocytes; and abnormally high blood levels of 9) neutrophils, 10) aspartate aminotransferase (AST), 11) alkaline phosphatase (ALP), and/or 12) lactate dehydrogenase (LDH). Factors were used to devise a 4-tier prognostic index (median overall survival [OS] by risk [months]: high=3.4, moderate=6.4, medium=9.9, and low=14.5; Harrell's C-index=0.66; 95% confidence interval [CI], 0.64–0.68). Addition of QoL to the model identified patient-reported appetite loss as an independent prognostic factor. CONCLUSIONS: The identified prognostic factors and the reported prognostic index may help clinical decision-making, patient stratification, and planning of future clinical studies.

Three Types of Cancer in a Patient with Neurofibromatosis Type I: Gastrointestinal Stromal Tumor, Breast and Ampulla of Vater Cancer / 대한내과학회지

Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder with a prevalence of approximately 1 in 3,500 live births. NF-1 predisposes to various benign and malignant neoplasms. Neurological malignancies are most frequent, but the risks of non-nervous system tumors, such as of the esophagus, stomach, colon, liver, biliary tract, pancreas, lung, melanoma, thyroid gland, female breast and ovaries, are also increased. Malignant tumors are the most common cause of death in patients with NF-1. Cases with double primary tumors have been reported, but cases involving three or more primary cancers are rarely reported. Therefore, we present the case of a NF-1 patient diagnosed with gastrointestinal stromal tumor, breast cancer and ampulla of Vater cancer.

Overexpression of Endoplasmic Reticulum Oxidoreductin 1-α (ERO1L) Is Associated with Poor Prognosis of Gastric Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Gastric cancer is the second leading cause of cancer-related death worldwide. Although surgery is the standard curative treatment for gastric cancer, relapse occurs in a large number of patients, except in the case of early diagnosed gastric cancer. Following previous studies that identified endoplasmic reticulum oxidoreductin 1-α (ERO1L) as a potential marker for gastric cancer, we investigated the functional role of ERO1L in gastric cancer. MATERIALS AND METHODS: For validation of microarray data, the mRNA expression level of ERO1L was measured by quantitative real-time reverse transcription polymerase chain reaction in 56 independent stage III gastric cancer patients. Immunohistochemical staining was performed to examine the protein expression level of ERO1L in 231 gastric cancer patients. Correlation between gene expression and cancer prognosis was evaluated. RESULTS: Patients with high ERO1L expression had poorer survival than those with low expression (p < 0.01). Functional assays demonstrated that ERO1L knockdown inhibited cell proliferation, migration, invasion, and chemoresistance. In addition, involvement of inactivation of Akt and JNK signaling in molecular mechanisms of ERO1L inhibition was demonstrated. CONCLUSION: High expression of ERO1L is associated with poor prognosis of patients with gastric cancer. These results indicate that ERO1L expression may be a clinically promising therapeutic target for prevention of gastric cancer.

Gemcitabine Combined with Capecitabine Compared to Gemcitabine with or without Erlotinib as First-Line Chemotherapy in Patients with Advanced Pancreatic Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study is to retrospectively compare the efficacy and tolerability between three regimens for first-line chemotherapy-gemcitabine plus capecitabine (GEM-X), gemcitabine plus erlotinib (GEM-T), and gemcitabine monotherapy (GEM)-in patients with advanced pancreatic cancer. MATERIALS AND METHODS: There was a total of 127 patients who underwent chemotherapy for pancreatic cancer between January 2007 and November 2011 at our institution. Patients were treated with either GEM (gemcitabine 1,000 mg/m2 on days 1, 8, and 15 every 4 weeks), GEM-T (gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks and erlotinib 100 mg daily), or GEM-X (gemcitabine 1,000 mg/m2 on days 1 and 8 every 3 weeks and capecitabine 850 mg/m2 twice daily for 2 weeks followed by 1 week's rest) as the first-line treatment. Progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and toxicity were evaluated. RESULTS: The patient population was divided into groups depending on their first-line treatment: GEM (n=47), GEM-T (n=44), and GEM-X (n=36). GEM-X significantly improved ORR (21.2% vs. 12.7% and 15.9%), PFS (8.9 vs. 5.2 and 3.9 months; p < 0.001), and OS (12.1 vs. 10.4 and 9.9 months; p = 0.03) compared to GEM and GEM-T, respectively. There were higher incidences of some non-hematologic adverse events with GEM-X and GEM-T compared to GEM, but most were grade 1 or 2. CONCLUSION: GEM-X presented better clinical efficacy and acceptable tolerability than GEM-T and GEM in advanced pancreatic cancers. It is worthy to further investigate which agent has a clinical advantage as a combination drug with gemcitabine in pancreatic cancer and to explore the predictive markers leading to personalize anti-cancer treatment.

Treatment of a Patient with Kaposi's Sarcoma Arising during Hemodialysis with the Multikinase Inhibitor Pazopanib / 대한내과학회지

Kaposi's sarcoma (KS) is an unusual multifocal neoplastic angioproliferative disorder. We herein report a case of classic KS that occurred in a patient receiving hemodialysis for 7 years. The patient had a history of chronic renal failure due to glomerulonephritis for 20 years. Multiple reddened violaceous patches, plaques, and nodules were found on the right knee. Biopsy revealed positivity for human herpesvirus 8 (KS-associated herpesvirus) consistent with KS. Pazopanib, a multitarget tyrosine kinase inhibitor, is an effective agent for treatment of advanced soft tissue sarcoma. The patient received pazopanib for 6 months investigate its effects on KS. The skin lesions and painful symptoms showed improvement. Further studies are required to determine the mechanism underlying the anticancer action of pazopanib and the pathogenesis of KS.

Comparison of Surgery Plus Chemotherapy and Palliative Chemotherapy Alone for Advanced Gastric Cancer with Krukenberg Tumor / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: This study was conducted to validate the survival benefit of metastasectomy plus chemotherapy over chemotherapy alone for treatment of Krukenberg tumors from gastric cancer and to identify prognostic factors for survival. MATERIALS AND METHODS: Clinical data from 216 patients with Krukenberg tumors from gastric cancer were collected. Patients were divided into two arms according to treatment modality: arm A, metastasectomy plus chemotherapy and arm B, chemotherapy alone. RESULTS: Overall survival (OS) was significantly increased in arm A relative to arm B for patients initially diagnosed with stage IV gastric cancer (18.0 months vs. 8.0 months; p < 0.001) and those with recurrent Krukenberg tumors (19.0 months vs. 9.0 months; p=0.002), respectively. Metastasectomy (hazard ratio [HR], 0.458; 95% confidence interval [CI], 0.287 to 0.732; p=0.001), signet-ring cell pathology (HR, 1.583; 95% CI, 1.057 to 2.371; p=0.026), and peritoneal carcinomatosis (HR, 3.081; 95% CI, 1.610 to 5.895; p=0.001) were significant prognostic factors for survival. CONCLUSION: Metastasectomy plus chemotherapy offers superior OS when compared to palliative chemotherapy alone in gastric cancer with Krukenberg tumor. Prolonged survival applies to all patients, regardless of gastric cancer stage. Metastasectomy, signet-ring cell pathology, and peritoneal carcinomatosis were prognostic factors for survival. Future prospective randomized trials are needed to confirm the optimal treatment strategy for Krukenberg tumors from gastric cancer.

Synopsis on Clinical Practice Guideline of Gastric Cancer in Korea: An Evidence-Based Approach / 대한소화기학회지

Although, gastric cancer is quite common in Korea, the treatment outcome is relatively favorable compared to that of Western countries. However, there is no Korean multidisciplinary guideline for gastric cancer and thus, a guideline adequate for domestic circumstances is required. Experts from related societies developed 22 recommendation statements for the diagnosis (n=9) and treatment (n=13) based on relevant key questions. Evidence levels based on systematic review of literatures were classified as five levels from A to E, and recommendation grades were classified as either strong or weak. The topics of this guideline cover diagnostic modalities (endoscopy, endoscopic ultrasound, radiologic diagnosis), treatment modalities (surgery, therapeutic endoscopy, chemotherapy, radiotherapy) and pathologic evaluation. External review of the guideline was conducted at the finalization phase.

Clinical Practice Guidelines for Gastric Cancer in Korea: An Evidence-Based Approach

Although gastric cancer is quite common in Korea, the treatment outcome is relatively favorable compared to those in western countries. However, there are currently no Korean multidisciplinary guidelines for gastric cancer. Experts from related societies developed guidelines de novo to meet Korean circumstances and requirements, including 23 recommendation statements for diagnosis (n=9) and treatment (n=14) based on relevant key questions. The quality of the evidence was rated according to the GRADE evidence evaluation framework: the evidence levels were based on a systematic review of the literature, and the recommendation grades were classified as either strong or weak. The applicability of the guidelines was considered to meet patients' view and preferences in the context of Korea. The topics of the guidelines cover diagnostic modalities (endoscopy, endoscopic ultrasound, and radiologic diagnosis), treatment modalities (surgery, therapeutic endoscopy, chemotherapy, and radiotherapy), and pathologic evaluation. An external review of the guidelines was conducted during the finalization phase.

Molecular Diagnosis for Personalized Target Therapy in Gastric Cancer

Gastric cancer is the second leading cause of cancer-related deaths worldwide. In advanced and metastatic gastric cancer, the conventional chemotherapy with limited efficacy shows an overall survival period of about 10 months. Patient specific and effective treatments known as personalized cancer therapy is of significant importance. Advances in high-throughput technologies such as microarray and next generation sequencing for genes, protein expression profiles and oncogenic signaling pathways have reinforced the discovery of treatment targets and personalized treatments. However, there are numerous challenges from cancer target discoveries to practical clinical benefits. Although there is a flood of biomarkers and target agents, only a minority of patients are tested and treated accordingly. Numerous molecular target agents have been under investigation for gastric cancer. Currently, targets for gastric cancer include the epidermal growth factor receptor family, mesenchymal-epithelial transition factor axis, and the phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathways. Deeper insights of molecular characteristics for gastric cancer has enabled the molecular classification of gastric cancer, the diagnosis of gastric cancer, the prediction of prognosis, the recognition of gastric cancer driver genes, and the discovery of potential therapeutic targets. Not only have we deeper insights for the molecular diversity of gastric cancer, but we have also prospected both affirmative potentials and hurdles to molecular diagnostics. New paradigm of transdisciplinary team science, which is composed of innovative explorations and clinical investigations of oncologists, geneticists, pathologists, biologists, and bio-informaticians, is mandatory to recognize personalized target therapy.

Design of precise third-line therapy for gastric cancer: target or chemotherpy?

No abstract available.

A Case of Adenocarcinomatous Transformation of a Sacrococcygeal Teratoma in an Adult / 대한내과학회지

Sacrococcygeal teratoma (SCT) is an unusual tumor in adults. The incidence of malignant transformation of this tumor increases when its excision is delayed beyond 1 month of age. We report an uncommon case of adenocarcinoma arising within the colonic mucosa of a mature teratoma of the sacrococcyx in a 44-year-old male. The patient received surgical resection for a sacrococcygeal mass in a local hospital and was diagnosed with adenocarcinoma arising from SCT. He was referred to our hospital for further treatment and received chemotherapy as adjuvant treatment. After 4.5 years, the coccygeal mass recurred on follow-up imaging workup, and surgical resection was performed. On pathologic work-up, residual disease at the resection margin was identified microscopically. Pathologic diagnosis was a primary adenocarcinoma arising from the colonic mucosa within a mature teratoma. The patient received adjuvant-chemotherapy and radiotherapy and has been followed up.

A Case of Adenocarcinoma Arising within Intra-Abdominal Bronchogenic Cyst / 대한내과학회지

Gastric foregut duplication cyst is a rare congenital anomaly. There have been very few reports of bronchogenic cysts in the abdominal cavity attached to the stomach. We report a case of a 57-year-old Korean man with an adenocarcinoma arising within a bronchogenic cyst of the stomach. Pathologic findings revealed ciliated columnar epithelium lining the cyst and a solid papillary adenocarcinoma involving the subserosa of the stomach and the skeletal part of the diaphragm. Surgical resection is the treatment of choice for foregut cysts of the stomach, and the possibility of malignancy should be considered in patients with gastric duplication cysts.

A Case of Biliary Sepsis Caused by Hafnia Alvei in a Patient with Cholangiocarcinoma / 대한내과학회지

Hafnia alvei is a Gram-negative rod that is rarely isolated from human specimens and is rarely pathogenic. It has been associated with gastroenteritis, pneumonia, urinary tract infection, bacteremia, and nosocomial wound infection, but extra-intestinal H. alvei infection is very rare. We present a case of biliary sepsis caused by H. alvei. A 42-year-old woman was admitted with abdominal pain and jaundice. She was diagnosed with metastatic cholangiocarcinoma and received conservative treatment. Six days later, hyperbilirubinemia and signs of sepsis developed and H. alvei was isolated from both the bile and blood. Despite treatment with antibiotics the organism was sensitive to (it was documented as susceptible to piperacillin/tazobactam and ciprofloxacin in sensitivity tests), the patient's condition grew worse. The antibiotics were switched to meropenem and the biliary sepsis was resolved.

A Case of Adenocarcinoma Arising within Intra-Abdominal Bronchogenic Cyst / 대한내과학회지

Gastric foregut duplication cyst is a rare congenital anomaly. There have been very few reports of bronchogenic cysts in the abdominal cavity attached to the stomach. We report a case of a 57-year-old Korean man with an adenocarcinoma arising within a bronchogenic cyst of the stomach. Pathologic findings revealed ciliated columnar epithelium lining the cyst and a solid papillary adenocarcinoma involving the subserosa of the stomach and the skeletal part of the diaphragm. Surgical resection is the treatment of choice for foregut cysts of the stomach, and the possibility of malignancy should be considered in patients with gastric duplication cysts.

Treatment Outcome of Patients with Anaplastic Thyroid Cancer: A Single Center Experience

PURPOSE: Anaplastic thyroid cancer is known to have a poor prognosis due to its aggressive and rapid metastasis with median survival of less than 6 months. Multimodal treatment involving surgery and chemoradiotherapy has been used to improve the survival of patients. Here, we retrospectively review of treatment outcome of 13 consecutive patients who were treated at a single center. MATERIALS AND METHODS: We retrospectively reviewed medical records of 13 anaplastic thyroid cancer patients who received multidisciplinary treatment between 2006 and 2010. Kaplan-Meier survival curve was used to analyze progression-free survival and overall survival of patients. RESULTS: The median patient age at diagnosis was 69 years, and six patients had stage IVc diseases. Eight patients received primary surgery followed by radiotherapy or concurrent chemoradiotherapy (CCRT). Five patients received weekly doxorubicin-based definitive CCRT, but only one patient's condition remained stable, while the rest experienced rapid disease progression. The median progression-free survival was 2.8 months (95% CI, 1.2-4.4 months), and the median overall survival was 3.8 months (95% CI, 3.0-4.6 months). CONCLUSION: Patients with anaplastic thyroid cancer showed poor prognosis despite multimodality treatment. Therefore, identification of novel therapeutic targets is warranted to take an effective mode of treatment.

Prognostic Factors of Second and Third Line Chemotherapy Using 5-FU with Platinum, Irinotecan, and Taxane for Advanced Gastric Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The aims of this study are to find out whether the sequence of chemotherapeutic regimens including second- and third-line taxane and irinotecan influences the survival of patients with unresectable gastric carcinoma and to identify clinical characteristics of patients with improved response. MATERIALS AND METHODS: Fifty gastric carcinoma patients who were treated by third-line sequential chemotherapy between November 2004 and July 2010 were enrolled in this study. Their overall survival (OS) and time to progression (TTP) were set up as primary and secondary end points. For the sequence of chemotherapy regimen, two arms were used. Arm A was defined as 5-fluorouracil (5-FU)+cisplatin (FP) or folinic acid, 5-FU and oxaliplati (FOLFOX), followed by folinic acid, 5-FU and irinotecan (FOLFIRI), and paclitaxel or docetaxel plus 5-FU, with or without epirubicin. Arm B was defined as FP or FOLFOX, followed by paclitaxel or docetaxel plus 5-FU, and FOLFIRI. RESULTS: The median OS of all patients was 16.0 months (95% confidence interval, 13.6 to 18.3 months), which is longer than historical control of patients who did not receive third-line chemotherapy. The sequence of second and third-line regimen, including irinotecan and taxane, did not present significant difference in OS or TTP after failure of 5-FU with platinum chemotherapy. In survival analysis of patients' clinicopathologic characteristics, poor prognosis was shown in patients with poorly differentiated histologic features, elevated serum carcinoembryonic level, and shorter TTP of first line chemotherapy. CONCLUSION: It is possible for patients to respond differently to chemotherapy due to differences in clinical features and underlying gene expression profiles. Development of individualized chemotherapy regimens based on gene expression profiles is warranted.

Antifibrotic effects of magnesium lithospermate B on hepatic stellate cells and thioacetamide-induced cirrhotic rats

Magnesium lithospermate B (MLB) is one of the major active components of Salvia miltiorrhizae. The anti-oxidative effects of Salvia miltiorrhizae have been previously reported. The aim of this study was to investigate the effect of purified MLB on hepatic fibrosis in rats and on the fibrogenic responses in hepatic stellate cells (HSCs). Hepatic fibrosis was induced in rats by intraperitoneal thioacetamide (TAA) injections over a period of 8 or 12 weeks. MLB was orally administered daily by gavage tube. Serum AST and ALT levels in TAA + MLB group were significantly lower than those in TAA only group at week 8. Hepatic fibrosis was significantly attenuated in TAA + MLB group than in TAA only group at week 8 or 12. Activation of HSCs was also decreased in TAA + MLB group as compared to TAA only group. Hepatic mRNA expression of alpha-smooth muscle actin (alpha-SMA), TGF-beta1, and collagen alpha1(I) was significantly decreased in TAA + MLB group as compared to TAA only group. Incubation with HSCs and MLB (> or =100 microM) for up to 48 h showed no cytotoxicity. MLB suppressed PDGF-induced HSC proliferation. MLB inhibited NF-kappaB transcriptional activation and monocyte chemotactic protein 1 (MCP-1) production in HSCs. MLB strongly suppressed H2O2-induced reactive oxygen species (ROS) generation in HSCs, and MLB inhibited type I collagen secretion in HSCs. We concluded that MLB has potent antifibrotic effect in TAA-treated cirrhotic rats, and inhibits fibrogenic responses in HSCs. These data suggest that MLB has potential as a novel therapy for hepatic fibrosis.