• Journal of Gastric Cancer
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• v.23 no.3
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• pp.476-486
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• 2023

Purpose: The optimal tumor mutational burden (TMB) value for predicting treatment response to programmed cell death-1 (PD-1) checkpoint inhibitors in advanced gastric cancer (AGC) remains unclear. We aimed to investigate the optimal TMB cutoff value that could predict the efficacy of PD-1 checkpoint inhibitors in AGC. Materials and Methods: Patients with AGC who received pembrolizumab or nivolumab between October 1, 2020, and July 27, 2021, at Samsung Medical Center in Korea were retrospectively analyzed. The TMB levels were measured using a next-generation sequencing assay. Based on receiver operating characteristic curve analysis, the TMB cutoff value was determined. Results: A total 53 patients were analyzed. The TMB cutoff value for predicting the overall response rate (ORR) to PD-1 checkpoint inhibitors was defined as 13.31 mutations per megabase (mt/Mb) with 56% sensitivity and 95% specificity. Based on this definition, 7 (13.2%) patients were TMB-high (TMB-H). The ORR differed between the TMB-low (TMB-L) and TMB-H (8.7% vs. 71.4%, P=0.001). The progression-free survival and overall survival (OS) for 53 patients were 1.93 (95% confidence interval [CI], 1.600-2.268) and 4.26 months (95% CI, 2.992-5.532). The median OS was longer in the TMB-H (20.8 months; 95% CI, 2.292-39.281) than in the TMB-L (3.31 months; 95% CI, 1.604-5.019; P=0.049). Conclusions: The TMB cutoff value for predicting treatment response in AGC patients who received PD-1 checkpoint inhibitor monotherapy as salvage treatment was 13.31 mt/Mb. When applying the programmed death ligand-1 status to TMB-H, patients who would benefit from PD-1 checkpoint inhibitors can be selected.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.12
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• pp.7651-7656
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• 2013

Background: Breast cancer is the most common malignancy among women in both developed and developing countries. The burden is increasing in low-income and middle-income countries (LMCs) and threatens the public health of such societies. Introduction of expensive monoclonal antibodies to cancer treatment regimens poses a real challenge in the health systems of LMCs. Despite controversy of cost-effectiveness of bevacizumab in breast cancer, some studies indicate gain of patients from this drug. The present study aimed to propose a priority setting model for administration of anti-angiogenic agents in breast cancer via assessment of tumor angiogenesis by the microvessel density (MVD) method and associations with clinicopathological characteristics (including simultaneous mutations of TP53 and HER-2 genes). Materials and Methods: Age, axillary lymph nodes status, tumor size, stage and grade, estrogen and progesterone receptors status, HER-2/neu status (by immunohistochemistry and FISH test), TP53 mutation, Ki-67 (for proliferation assay) and CD34 (for angiogenesis assay) were assessed in 111 breast cancer patients. The molecular subtype of each tumor was also determined and correlations of simultaneous mutations of HER-2 and p53 genes with angiogenesis and other clinicopathological characteristics were evaluated. Results: There were significant associations between simultaneous mutations of HER-2 and p53 genes and all other parameters except tumor size. The degree of angiogenesis in the ERBB2 subtype was greater than the others. Younger patients showed a higher angiogenesis rate rather those older than 50 years. Conclusions: Our results demonstrated that patients with simultaneous mutations of HER-2 and p53 genes, those with ERBB2 molecular subtype and also younger women (often triple negative) seem more eligible for obtaining anti-angiogenic agents. These results suggest a model for priority setting of patients with breast cancer for treatment with anti-angiogenic drugs in LMCs.

• Radiation Oncology Journal
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• v.35 no.2
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• pp.172-179
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• 2017

Purpose: To evaluate the outcomes of stereotactic body radiation therapy (SBRT) for patients with liver oligo-recurrence and oligo-progression from various primary tumors. Materials and Methods: Between 2002 and 2013, 72 patients with liver oligo-recurrence (oligo-metastasis with a controlled primary tumor) and oligo-progression (contradictory progression of a few sites of disease despite an overall tumor burden response to therapy) underwent SBRT. Of these, 9 and 8 patients with uncontrollable distant metastases and patients immediate loss to follow-up, respectively, were excluded. The total planning target volume was used to select the SBRT dose (median, 48 Gy; range, 30 to 60 Gy, 3-4 fractions). Toxicity was evaluated using the Common Toxicity Criteria for Adverse Events v4.0. Results: We evaluated 55 patients (77 lesions) treated with SBRT for liver metastases. All patients had controlled primary lesions, and 28 patients had stable lesions at another site (oligo-progression). The most common primary site was the colon (36 patients), followed by the stomach (6 patients) and other sites (13 patients). The 2-year local control and progression-free survival rates were 68% and 22%, respectively. The 2- and 5-year overall survival rates were 56% and 20%, respectively. The most common adverse events were grade 1-2 fatigue, nausea, and vomiting; no grade ${\geq}3$ toxicities were observed. Univariate analysis revealed that oligo-progression associated with poor survival. Conclusion: SBRT for liver oligo-recurrence and oligo-progression appears safe, with similar local control rates. For liver oligo-progression, criteria are needed to select patients in whom improved overall survival can be expected through SBRT.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.4
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• pp.1105-1109
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• 2012

Breast cancer is the second most common cancer in women in India and the disease burden is increasing annually. The lack of awareness initiatives, structured screening, and affordable treatment facilities continue to result in poor survival. We present a breast cancer survival scenario, in urban population in India, where standardised care is distributed equitably and free of charge through an employees' healthcare scheme. We studied 99 patients who were treated at our hospital during the period 2005 to 2010 and our follow-up rates were 95.95%. Patients received evidence-based standardised care in line with the tertiary cancer centre in Mumbai. One-, three- and five-year survival rates were calculated using Kaplan-Meier method. Socio-demographic, reproductive and tumor factors, relevant to survival, were analysed. Mortality hazard ratios (HR) were calculated using Cox proportional hazard method. Survival in this series was compared to that in registries across India and discrepancies were discussed. Patients mean age was 56 years, mean tumor size was 3.2 cms, 85% of the tumors belonged to T1 and T2 stages, and 45% of the patients belonged to the composite stages I and IIA. Overall 5-year survival was 74.9%. Patients who presented with large-sized tumors (HR 3.06; 95% CI 0.4-9.0), higher composite stage (HR 1.91; 0.55-6.58) and undergone mastectomy (HR 2.94; 0.63-13.62) had a higher risk of mortality than women who had higher levels of education (HR 0.25; 0.05-1.16), although none of these results reached the significant statistical level. We observed 25% better survival compared to other Indian populations. Our results are comparable to those from the European Union and North America, owing to early presentation, equitable access to standardised free healthcare and complete follow-up ensured under the scheme. This emphasises that equitable and affordable delivery of standardised healthcare can translate into early presentation and better survival in India.

• Advances in pediatric surgery
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• v.8 no.2
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• pp.101-106
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• 2002

The antiangiogenic effects of novel agent KJ3, Betulinic acid, and Fumagillin on the neovascularization were studied by examining ultrastructural alterations in the vasculature of synthetic gelform and mouse neuroblastoma C1300. Small pieces of gelform with 0.4% agar were introduced subcutaneously (s.c.) in 7 week old male CH3/HeJ mice. After the $LD_{50}s$ were determined by FACS analysis, a third of $LD_{50}$ of three drugs were injected either locally or intraperitoneally every other day for 14 days. A/J mice were inoculated s.c. with the C1300 neuroblastoma cell line, then either saline or three drugs were injected in the same manner. The antiangiogenic effects of three drugs were studied by measuring the histologic changes in tumors, and immunostaining for CD34, VIII/vWF, CD105, and thymidine phosphorylase. In the drug treated groups, the number of vessels in gelform experiments and C1300 neuroblastoma experiments were lower than the corresponding values in the control. The histologic findings were significantly different in drug treated groups on day 7, but these were not significant on day 14. These results imply that antiangiogenic agents were effective when the tumor burden is minimal.

• The Korean Journal of Pain
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• v.36 no.1
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• pp.72-83
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• 2023

Background: Globally, spinal cord injury (SCI) results in a big burden, including 90% suffering permanent disability, and 60%-69% experiencing neuropathic pain. The main causes are oxidative stress, inflammation, and degeneration. The efficacy of the stem cell secretome is promising, but the role of human neural stem cell (HNSC)-secretome in neuropathic pain is unclear. This study evaluated how the mechanism of HNSC-secretome improves neuropathic pain and locomotor function in SCI rat models through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities. Methods: A proper experimental study investigated 15 Rattus norvegicus divided into normal, control, and treatment groups (30 µL HNSC-secretome, intrathecal in the level of T10, three days post-traumatic SCI). Twenty-eight days post-injury, specimens were collected, and matrix metalloproteinase (MMP)-9, F2-Isoprostanes, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, and brain derived neurotrophic factor (BDNF) were analyzed. Locomotor recovery was evaluated via Basso, Beattie, and Bresnahan scores. Neuropathic pain was evaluated using the Rat Grimace Scale. Results: The HNSC-secretome could improve locomotor recovery and neuropathic pain, decrease F2-Isoprostane (antioxidant), decrease MMP-9 and TNF-α (anti-inflammatory), as well as modulate TGF-β and BDNF (neurotrophic factor). Moreover, HNSC-secretomes maintain the extracellular matrix of SCI by reducing the matrix degradation effect of MMP-9 and increasing the collagen formation effect of TGF-β as a resistor of glial scar formation. Conclusions: The present study demonstrated the mechanism of HNSC-secretome in improving neuropathic pain and locomotor function in SCI through antioxidant, anti-inflammatory, anti-matrix degradation, and neurotrophic activities.

• Korean Journal of Radiology
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• v.22 no.9
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• pp.1481-1489
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• 2021

Objective: To construct a CT-based Fagotti scoring system by analyzing the correlations between laparoscopic findings and CT features in patients with advanced ovarian cancer. Materials and Methods: This retrospective cohort study included patients diagnosed with stage III/IV ovarian cancer who underwent diagnostic laparoscopy and debulking surgery between January 2010 and June 2018. Two radiologists independently reviewed preoperative CT scans and assessed ten CT features known as predictors of suboptimal cytoreduction. Correlation analysis between ten CT features and seven laparoscopic parameters based on the Fagotti scoring system was performed using Spearman's correlation. Variable selection and model construction were performed by logistic regression with the least absolute shrinkage and selection operator method using a predictive index value (PIV) ≥ 8 as an indicator of suboptimal cytoreduction. The final CT-based scoring system was internally validated using 5-fold cross-validation. Results: A total of 157 patients (median age, 56 years; range, 27-79 years) were evaluated. Among 120 (76.4%) patients with a PIV ≥ 8, 105 patients received neoadjuvant chemotherapy followed by interval debulking surgery, and the optimal cytoreduction rate was 90.5% (95 of 105). Among 37 (23.6%) patients with PIV < 8, 29 patients underwent primary debulking surgery, and the optimal cytoreduction rate was 93.1% (27 of 29). CT features showing significant correlations with PIV ≥ 8 were mesenteric involvement, gastro-transverse mesocolon-splenic space involvement, diaphragmatic involvement, and para-aortic lymphadenopathy. The area under the receiver operating curve of the final model for prediction of PIV ≥ 8 was 0.72 (95% confidence interval: 0.62-0.82). Conclusion: Central tumor burden and upper abdominal spread features on preoperative CT were identified as distinct predictive factors for high PIV on diagnostic laparoscopy. The CT-based PIV prediction model might be useful for patient stratification before cytoreduction surgery for advanced ovarian cancer.

• Tuberculosis and Respiratory Diseases
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• v.50 no.2
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• pp.171-181
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• 2001

Background : Angiogenesis is an essential process for the growth and metastatic ability of solid tumors. One of the key factors known to be capable of stimulating tumor angiogenesis is the vascular endothelial growth factor (VEGF). The serum VEGF concentration has been shown to be a useful parameter related to the clinical features and prognosis of lung cancer and has been recently applied to a the malignant pleural effusion showing a correlation with the biochemical parameters. The VEGF has been shown to play a role in the inflammatory diseases, but rarely in the tuberculosis (TB). The serum and pleural fluid VEGF levels were measured in patients with lung cancer and TB. Their relationship with the clinical and laboratory parameters and repeated measurement 3 months after various anticancer treatments were evaluated to assess the utility of the VEGF as a tumor marker. Methods : Using a sandwich enzyme-linked immunosorbent assay, the VEGF conoentration was measured in both sera and pleural effusions collected from a total of 85 patients with lung cancer, 13 patients with TB and 20 healthy individuals. Results : The serum VEGF levels in patients with lung cancer ($619.9{\pm}722.8pg/ml$) were significantly higher than those of healthy controls ($215.9{\pm}191.1pg/ml$), However, there was no significant difference between the VEGF levels in the lung cancer and TB patients. The serum VEGF levels were higher in large cell and undifferentiated carcinoma than in squamous cell carcinoma and adenocarcinoma. The serum VEGF levels of lung cancer patients revealed no significant relationship with the various clinical parameters. The VEGF concentrations in the malignant effusion ($2,228.1{\pm}2,103.0pg/ml$) were significantly higher than those in the TB effusion ($897.6{\pm}978.8pg/ml$). In the malignant pleural effusion, the VEGF levels revealed significant correlation with the number of red blood cells (r=0.75), the lactate dehydrogenase (LDH)(r=0.70), and glucose concentration (r=-0.55) in the pleural fluid. Conclusion : The serum VEGF levels were higher in the lung cancer patients. The VEGF levels were more elevated in the malignant pleural effusion than in the tuberculous effusion. In addition, the VEGF levels in the pleural fluid were several times higher than the matched serum values suggesting a local activation and possible etiologic role of VEGF in the formation of malignant effusions. The pleural VEGF levels showed a significant correlation with the numbers of red blood cells, LDH and glucose concentrations in the pleural fluid, which may represent the tumor burden.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.4
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• pp.2201-2205
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• 2013

Colorectal cancer (CRC) is one of the most common cancers in many parts of the world. Its development is a multi-step process involving three distinct stages, initiation that alters the molecular message of a normal cell, followed by promotion and progression that ultimately generates a phenotypically altered transformed malignant cell. Reports have suggested an association of the phosphoinositide-3-kinase (PI3K)/Akt pathway with colon tumorigenesis. Activation of Akt signaling and impaired expression of phosphatase and tensin homolog (PTEN) (a negative regulator of Akt) has been reported in 60-70% of human colon cancers and inhibitors of PI3K/Akt signaling have been suggested as potential therapeutic agents. Around 80% of human colon tumors possess mutations in the APC gene and half of the remainder feature ${\beta}$-catenin gene mutations which affect downstream signaling of the PI3K/Akt pathway. In recent years, there has been a great focus in targeting these signaling pathways, with natural and synthetic drugs reducing the tumor burden in different experiment models. In this review we survey the role of PI3K/Akt/mTOR and Wnt signaling in CRC.

• Journal of Korean Traditional Oncology
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• v.20 no.1
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• pp.11-21
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• 2015

Objectives : The cancer incidence and cancer burden is increasing. In addition, the use of botanical agents in cancer care is increasing. This article aims to review a research strategy for botanical agents. Methods : The clinical studies of anticancer botanical agents and the papers about clinical research methodology of botanical agents were reviewed. Results : In phase I study, safety confirmation, optimal dose determination and drug interaction study are important. Most botanical agents have low toxicity and some have non-monotone dose response. Therefore, dose-response curve must be evaluated separately from the dose-toxicity curve to determine optimal dose. Although anticancer botanical agents can't shrink tumor size rapidly, they do extend survival. So, in phase II study, response should be evaluated by the survival. Conclusions : Clinical research of botanical agents in cancer is different from traditional methods and strategies. Considering the characteristics of botanical agents and experimental mechanism is necessary in conducting botanical based clinical trials.