• Biomolecules & Therapeutics
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• 제30권5호
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• pp.418-426
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• 2022

Chimeric antigen receptor T (CAR-T) cell therapy is one of the promising anticancer treatments. It shows a high overall response rate with complete response to blood cancer. However, there is a limitation to solid tumor treatment. Additionally, this currently approved therapy exhibits side effects such as cytokine release syndrome and neurotoxicity. Alternatively, bispecific antibody is an innovative therapeutic tool that simultaneously engages specific immune cells to disease-related target cells. Since programmed death ligand 1 (PD-L1) is an immune checkpoint molecule highly expressed in some cancer cells, in the current study, we generated αCD3xαPD-L1 bispecific antibody (BiTE) which can engage T cells to PD-L1⁺ cancer cells. We observed that the BiTE-bound OT-1 T cells effectively killed cancer cells in vitro and in vivo. They substantially increased the recruitment of effector memory CD8⁺ T cells having CD8⁺CD44⁺CD62L^low phenotype in tumor. Interestingly, we also observed that BiTE-bound polyclonal T cells showed highly efficacious tumor killing activity in vivo in comparison with the direct intravenous treatment of bispecific antibody, suggesting that PD-L1-directed migration and engagement of activated T cells might increase cancer cell killing. Additionally, BiTE-bound CAR-T cells which targets human Her-2/neu exhibited enhanced killing effect on Her-2-expressing cancer cells in vivo, suggesting that this could be a novel therapeutic regimen. Collectively, our results suggested that engaging activated T cells with cancer cells using αCD3xαPD-L1 BiTE could be an innovative next generation anticancer therapy which exerts simultaneous inhibitory functions on PD-L1 as well as increasing the infiltration of activated T cells having effector memory phenotype in tumor site.

• Asian Pacific Journal of Cancer Prevention
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• 제13권8호
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• pp.4119-4123
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• 2012

Background: Neoadjuvant systemic chemotherapy is the accepted approach for women with locally advanced breast cancer. Anthracycline- and taxane-based regimens have been extensively studied in clinical trials and consequently are widely used. In this study aimed to research the complete response (pCR) rates in different regimens for neoadjuvant setting and determine associated clinical and biological factors. Methods: This study included 63 patients diagnosed with breast carcinoma among 95 patients that had been treated with neoadjuvant chemotherapy between 2007 and 2010. TNM staging system was used for staging. The histologic response to neoadjuvant chemotherapy was characterized as a pCR when there was no evidence of residual invasive tumor in the breast or axillary lymph nodes. Biologic subclassification using estrogen receptor (ER), progesterone receptor (PR), HER2 were performed. Luminal A was defined as ER+, PR+, HER2-; Luminal B tumor was defined as ER+, PR-, HER2-; ER+, PR-, HER2+; ER-, PR+, HER2-; ER+, PR+, HER2+; HER2 like tumor ER-, PR+, HER2+; and triple negative tumor ER, PR, HER2 negative. Results: Patients median age was 54.14 (min-max: 30-75). Thirty-two patients (50.8%) were premenapousal and 31 (49.2%) were postmenapousal. Staging was performed postoperatively based on the pathology report and appropriated imaging modalities The TNM (tumor, lymph node, metastasis) system was used for clinical and pathological staging. Fifty-seven (90.5%) were invasive ductal carcinomas, 6 (9.5%) were other subtypes. Thirty nine (61.9%) were grade II and 24 (38.1%) were grade III. Seven (11.1%) patients were stage II and 56 (88.9) patients were stage III. The patients were classified for ER, PR receptor and HER2 positivity. Seventeen patients had complete response to chemotherapy. Forty patients (63.5%) were treated with dose dense regimen (cyclophosphamide 600 mg/m2 and doxorubicine 60 mg/m every two weeks than paclitaxel 175 mg/m2 every two weeks with filgrastim support) 40 patients (48%) were treated anthracycline and taxane containing regimens. Thirteen patients (76%) from 17 patients with pCR were treated with the dose dense regimen but without statistical significance (p=0.06). pCR was higher in HER2(-), ER(-), grade III, premenopausal patients. Conclusion: pCR rate was higher in the group that treated with dose dense regimen, which should thus be the selected regimen in neoadjuvant setting. Some other factors can predict pCR in Turkish patients, like grade, menopausal status, triple negativity, percentage of ER positivity, and HER2 expression.

• Asian Pacific Journal of Cancer Prevention
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• 제14권9호
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• pp.5237-5242
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• 2013

Background: Inflammation is a critical component of tumor progression. Many cancers arise from sites of infection, chronic irritation, and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an essential participant in the neoplastic process, promoting proliferation, survival and migration. Platelets can release some growth factors such as platelet-derived growth factor, platelet factor 4, and thrombospondin. Such factors have been shown to promote hematogenous tumour spread, tumor cell adhesion and invasion, and angiogenesis and to play an important role in tumor progression. In this study, we aimed to investigate effects of the pretreatment neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) on survival and response to chemoradiotherapy in patients with non-small-cell lung cancer (NSCLC). Materials and Methods: Ninety-four patients with non-metastatic NSCLC were included and separated into two groups according to median valuse of NLR and PLR (low:<3.44 or high:${\geq}3.44$ and low:<194 or high${\geq}194$, respectively). Results: Pretreatment high NLR and PLR were associated with significantly shorter disease-free and overall survival rates. Multivariate analysis revealed that the overall survival rates were significantly linked with PLR (OR: 1.87, CI: 1.20-2.91, p: 0.006) and response to chemoradiotherapy (OR: 1.80, CI: 1.14-2.81, p: 0.012) and the disease-free survival rates were significantly associated with NLR (OR: 1.81, CI: 1.16-2.82, p: 0.009) and response to chemoradiotherapy (OR: 2.30, CI: 1.45-3.66, p: 0.001). There was no significant difference between patients with high and low NLR in terms of response to chemoradiotherapy. Similarly, there was no significant influence of the PLR. Conclusions: Pretreatment NLR and PLR measurements can provide important prognostic results in patients with NSCLC and assessment of the two parameters together appears to better predict the prognosis in patients with NSCLC. The effect of inflammation, indicators of NLR and PLR, on survival seems independent of the response to chemoradiotherapy.

• Radiation Oncology Journal
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• 제13권3호
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• pp.233-241
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• 1995

Purpose : To analyse clinical outcome and prognostic factors according to treatment modality, this paper report our experience of retrospective study of patients with esophageal cancer Materials and Methods : One hundred and ten patients with primary esophageal cancer who were treated in Presbyterian Medical Center from May 1985 to December 1992. We analysed these patients retrospectively with median follow up time of 28 months, one hundred and four patients($95{\%}$) were followed up from 15 to 69 months. In methods, twenty-eight patients were treated with median radiation dose irradiated 54.3Gy only. Fifty-six patients were treated with combined chemoradiotherapy. Sixteen cases of these patients were treated with concurrent chemoradiation and the other patients(forty cases) were treated sequential chemoradiotherapy. In concurrent chemoradiotherapy group, patients received 5-FU continuous IV infusion for 4 days. Cisplatin IV bolus. and concurrent esophageal irradiation to 30 Gy. After that patients received 5-FU continuous IV, Cisplatin bolus injection and Mitomycin-C bolus IV, Bleomycin continuous IV, and irradiation to 20 Gy. In sequential chemoradiotherapy group, the chemotherapy consisted of 5-FU 1,000mg/$m^2$ administered as a continuous 24 hour intravenous infusion during five days and Cisplatin 80-100mg/$m^2$ bolus injected, or Bleomycin, Vinblastine, Cisplatin, Methotrexate were used of 1 or 2 cycles. After preoperative concurrentm chemoradiation twenty-six patients underwent radical esophagectomy. Results : Ninety-three patients could be examined for response assessment, By treatment modality, response rates were $85.1{\%}$ for radiation alone group and $86.3{\%}$ for combined chemoradiation group. But in operation group, after one cycle of concurrent chemoradiation treatment, response rate was $61.9{\%}$. The pathologic complete response were $15.4{\%}$ in operation group. Overall median survival was II months and actuarial 5-year survival rate was $8{\%}$. The median survival interval was 6 months for radiation alone group, 11 months for combined chemoradiation group and 19 months for operation group. And also median survival was 19 months for complete responder group that 8 months for noncomplete responder group. In univariative analysis, statistically significant prognostic factors were tumor size, clinical stage, tumor response, and operation. In multivariative analysis, significantly better survival was associated with clinical stage, tumor response, radiation dose, and operation. Conclusion : Compared with radiotherapy alone, combined multimodality may improve the median survival in patients with localized carcinoma of the esophagus and toxicity is acceptable.

• Korean Journal of Radiology
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• 제21권7호
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• pp.812-828
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• 2020

Objective: To provide an evidence-based guide for the MRI interpretation of complete tumor response after neoadjuvant chemoradiation therapy (CRT) for rectal cancer using visual assessment on T2-weighted imaging (T2) and diffusion-weighted imaging (DWI). Materials and Methods: PubMed MEDLINE, EMBASE, and Cochrane Library were searched on November 28, 2019 to identify articles on the following issues: 1) sensitivity and specificity of T2 or DWI for diagnosing pathologic complete response (pCR) and the criteria for MRI diagnosis; 2) MRI alone vs. MRI combined with other test(s) in sensitivity and specificity for pCR; and 3) tests to select patients for the watch-and-wait management. Eligible articles were selected according to meticulous criteria and were synthesized. Results: Of 1615 article candidates, 55 eligible articles (for all three issues combined) were identified. Combined T2 and DWI performed better than T2 alone, with a meta-analytic summary sensitivity of 0.62 (95% confidence interval [CI], 0.43-0.77; I² = 80.60) and summary specificity of 0.89 (95% CI, 0.80-0.94; I² = 92.61) for diagnosing pCR. The criteria for the complete response on T2 in most studies had the commonality of remarkable tumor decrease to the absence of mass-like or nodular intermediate signal, although somewhat varied, as follows: (near) normalization of the wall; regular, thin, hypointense scar in the luminal side with (near) normal-appearance or homogeneous intermediate signal in the underlying wall; and hypointense thickening of the wall. The criteria on DWI were the absence of a hyperintense signal at high b-value (≥ 800 sec/mm²) in most studies. The specific algorithm to combine T2 and DWI was obscure in half of the studies. MRI combined with endoscopy was the most utilized means to select patients for the watch-and-wait management despite a lack of strong evidence to guide and support a multi-test approach. Conclusion: This systematic review and meta-analysis provide an evidence-based practical guide for MRI assessment of complete tumor response after CRT for rectal cancer.

• Radiation Oncology Journal
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• 제33권4호
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• pp.265-275
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• 2015

Despite the increasing use of stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS) in recent years, the biological base of these high-dose hypo-fractionated radiotherapy modalities has been elusive. Given that most human tumors contain radioresistant hypoxic tumor cells, the radiobiological principles for the conventional multiple-fractionated radiotherapy cannot account for the high efficacy of SBRT and SRS. Recent emerging evidence strongly indicates that SBRT and SRS not only directly kill tumor cells, but also destroy the tumor vascular beds, thereby deteriorating intratumor microenvironment leading to indirect tumor cell death. Furthermore, indications are that the massive release of tumor antigens from the tumor cells directly and indirectly killed by SBRT and SRS stimulate anti-tumor immunity, thereby suppressing recurrence and metastatic tumor growth. The reoxygenation, repair, repopulation, and redistribution, which are important components in the response of tumors to conventional fractionated radiotherapy, play relatively little role in SBRT and SRS. The linear-quadratic model, which accounts for only direct cell death has been suggested to overestimate the cell death by high dose per fraction irradiation. However, the model may in some clinical cases incidentally do not overestimate total cell death because high-dose irradiation causes additional cell death through indirect mechanisms. For the improvement of the efficacy of SBRT and SRS, further investigation is warranted to gain detailed insights into the mechanisms underlying the SBRT and SRS.

• 대한한의학방제학회지
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• 제5권1호
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• pp.147-168
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• 1997

Tish study was carried out to evaluate the possible therapeutic or antitumoral effects of Takrisodokyeum extract against tumor, and immunomodulatory effect. Some kinds of tumor were induced by the typical application of 3-methylcholanthrene (MCA) or by the implantation(s.c) of malignant tumor cells such as leukemia cells(3LL cells) or sarcoma cells(S-I80 and Fas II cells). Treatment of the Takrisodokyeum water-extract(daily 1mg mouse, i.p.) was continued for 7 days prior to tumor induction and after that the treatment was lasted for 15 days. Against squamous cell carcinoma induced by MCA, Takrisodokyeum decreased not only the frequency of tumor production but also the number and the weight of tumors per tumor bearing mice (TBM). Takrisodokyeum also significantly suppressed the development of 3LLcell and S-180 cell by frequency and their size, and some developed tumors were regressed by the continuous treatment of Takrisodokyeum extract into TBM. However, when tumor was induced by FsaII cell-implantation, the growth of implanted cells in mice was delayed by the water extract of Takrisodokyeum until day 7 and then rapid growth ensued. In vitro, treatment of Takrisodokyeum extract had no effect on the growth of some kind of cell lines such as FsaII, A-131 strain but significantly inhibited the proliferation of 3LL, S-180 cells. Takrisodokyeum also stimulated the migrative ability of leucocyte, the MIF and IL 2-production of T lymphocytes, but not IL 6 production of B cells. Takrisodokyeum enhanced Arthus reaction and DTH to sheep erythrocytes, and NK cells activities. These results demonstrated that Takrisodokyeum extract different results according to the type of tumor cells. And these results also suggested that antitumor effect of Takrisodokyeum might be chiefly due to nonspecific enhancement of NK cell activities and cell-mediated immune responses.

• IMMUNE NETWORK
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• 제3권3호
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• pp.188-200
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• 2003

Background: Immunization of dendritic cells (DCs) pulsed with tumor antigen can activate tumor-specific cytotoxic T lymphocytes (CTL) that are responsible for protection and regression. In this study, we examined whether the uptake of necrotic tumor cells could modulate DC phenotypes and whether the immunization of necrotic tumor cell-loaded DCs could elicit efficient tumor specific immune responses followed by a regression of established tumor burdens. Methods: We prepared necrotic tumor cell-pulsed DCs for the therapeutic vaccination and investigated their phenotypic characteristics, the immune responses induced by these DCs, and therapeutic vaccine efficacy against colon carcinoma in vivo. Several parameters including phagocytosis of tumor cells, surface antigen expression, chemokine receptor expression, IL-12 production, and NK as well as CTL activation were assessed to characterize the immune response. Results: DCs derived from mouse bone marrow efficiently phagocytosed necrotic tumor cells and after the uptake, they produced remarkably increased levels of IL-12. A decreased CCR1 and increased CCR7 expression on DCs was also observed after the tumor uptake, suggesting that antigen uptake could induce DC maturation. Furthermore, co-culturing of DCs with NK cells in vitro enhanced IL-12 production in DCs and IFN-${\gamma}$ production in NK cells, which was significantly dependent on IL-12 production and cell-to-cell contact. Immunization of necrotic tumor cell-loaded DCs induced cytotoxic T lymphocytes as well as NK activation, and protected mice against subsequent tumor challenge. In addition, intratumoral or contra-lateral immunization of these DCs not only inhibited the growth of established tumors, but also eradicated tumors in more than 60% of tumor-bearing mice. Conclusion: Our data indicate that production of IL-12, chemokine receptor expression and NK as well as CTL activation may serve as major parameters in assessing the effect of tumor cell-pulsed DC vaccine. Therefore, DCs loaded with necrotic tumor cells offer a rational strategy to treat tumors and eventually lead to prolonged survival.

• Radiation Oncology Journal
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• 제26권4호
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• pp.213-221
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• 2008

목 적: 직장암에 수술 전 항암화학요법과 방사선치료를 동시에 병용시행한 후 완치절제술 후 병리학적 완전관해율과 종양 병기 하향률에 영향을 주는 예측인자를 후향적으로 분석하여 환자에 따른 맞춤치료의 가능성을 알기 위하여 본 연구를 시도하였다. 대상 및 방법: 2000년 5월부터 2008년 3월까지 국소적으로 진행된 직장암으로 진단받고 원격전이가 없는 환자 39명을 대상으로 수술 전 항암화학요법과 골반강에 방사선치료 50.4 Gy ($45{\sim}59.4\;Gy$)를 시행한 후 완치적 수술후 절제된 조직을 병리학적으로 관찰하여 완전관해율과 종양 및 림프절의 병기하향률을 측정하였다. 항암화학요법은 39명 중 38명은 방사선치료 1주와 5주에 각각 1주간 5-fluorouracil과 leucovorin을 연속적으로 정맥 주입하였으며 1명은 방사선치료기간 중 하루에 2회 capecitabine를 복용하였다. 결 과: 병리학적 완전관해를 보인 환자는 39명 중 12명(31%), 종양-병기하향을 보인 환자는 24명(63%)이었으며 임상적으로 림프절이 양성인 환자 28명 중 12명은(43%) 병리학적으로 하향되었으며 2명은 임상적으로 림프절이 음성이었으나 병리학적으로 양성을 보였다. 단변량분석에 의하면 종양의 둘레범위가 직장의 50% 미만(p=0.031), 종양의 길이가 5 cm 미만(p=0.004), 치료 후 CEA 수치가 3.0 mg/mL 이하(p=0.015)인 환자에서 병리학적 완전관해율이 높았다. 또한 선암(p=0.045), 방사선량이 50 Gy 이상(p=0.021)인 환자에서 병기-하향률이 높았고, 방사선 치료 기간이 42일 이하인(p=0.018)환자에서 림프절-병기하향률이 높았다. 다변량분석에 의하면 종양의 둘레범위가 50% 미만(HR 0.150; p=0.028), 종양의 길이가 5 cm 미만인(HR 0.084; p=0.005) 환자에서 통계학적으로 유의하게 병리학적 완전관해율이 높았으며, 방사선량이 50 Gy 이상 높은 경우(HR 0.115; p=0.025) 종양-병기하향률이 높았고 방사선치료 기간이 42일 이하인(HR 0.028; p=0.010) 경우 림프절-병기하향률이 높았다. 병리학적 완전관해에 영향을 주는 예측인자는 종양의 둘레범위와 종양의 길이이었으며, 종양-병리하향에 영향을 주는 예측인자는 방사선량, 림프절-병기하향에 영향을 주는 예측인자는 방사선치료 기간이었다. 이러한 예측인자를 파악함으로써 환자의 치료결과를 예측할 수 있으며 위험인자가 있는 환자에 좀 더 적극적인 치료계획을 설정하는 데 도움이 될 것으로 생각한다.

• Korean Journal of Radiology
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• 제22권10호
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• pp.1658-1670
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• 2021

Objective: To assess the two-year treatment outcomes of chemoembolization with drug-eluting embolics (DEE) for nodular hepatocellular carcinoma (HCC). Materials and Methods: This study was a prospective, multicenter, registry-based, single-arm trial conducted at five university hospitals in Korea. Patients were recruited between May 2011 and April 2013, with a target population of 200. A DC Bead loaded with doxorubicin was used as the DEE agent. Patients were followed up for two years. Per-patient and per-lesion tumor response analysis, per-patient overall survival (OS) and progression-free survival (PFS) analysis, and per-lesion tumor control analysis were performed. Results: The final study population included 152 patients, with 207 target lesions for the per-lesion analysis. At one-month, six-month, one-year, and two-year per-patient assessments, complete response (CR) rates were 40.1%, 43.0%, 33.3%, and 19.6%, respectively. The objective response (OR) rates were 91.4%, 55.4%, 35.1%, and 19.6%, respectively. The cumulative two-year OS rate was 79.7%. The cumulative two-year PFS rate was 22.4% and the median survival was 9.3 months. In multivariable analysis, the Child-Pugh score (p = 0.019) was an independent predictor of OS, and tumor multiplicity (p < 0.001), tumor size (p = 0.020), and Child-Pugh score (p = 0.006) were independent predictors of PFS. In per-lesion analysis, one-month, six-month, one-year and two-year CR rates were 57.5%, 58.5%, 45.2%, and 33.3%, respectively, and the OR rates were 84.1%, 65.2%, 46.6%, and 33.3%, respectively. The cumulative two-year per-lesion tumor control rate was 36.2%, and the median time was 14.1 months. The Child-Pugh score (p < 0.001) was the only independent predictor of tumor control. Serious adverse events were reported in 11 patients (7.2%). Conclusion: DEE chemoembolization for nodular HCCs in the Korean population showed acceptable survival, tumor response, and safety profiles after a two-year follow-up. Good liver function (Child-Pugh score A5) was a key predictor of per-patient OS, PFS, and per-lesion tumor control.