Hypoxia-directed and activated theranostic agent: Imaging and treatment of solid tumor

Kumar, R.,Kim, E.J.,Han, J.,Lee, H.,Shin, W.S.,Kim, H.M.,Bhuniya, S.,Kim, J.S.,Hong, K.S. IPC Science and Technology Press 2016 Biomaterials Vol.104 No.-

<P>Hypoxia, a distinguished feature of various solid tumors, has been considered as a key marker for tumor progression. Inadequate vasculature and high interstitial pressures result in relatively poor drug delivery to these tumors. Herein, we developed an antitumor theranostic agent, 4, which is activated in hypoxic conditions and can be used for the diagnosis and treatment of solid tumors. Compound 4, bearing biotin, a tumor-targeting unit, and SN38, an anticancer drug, proved to be an effective theranostic agent for solid tumors. SN38 plays a dual role: as an anticancer drug for therapy and as a fluorophore for diagnosis, thus avoids an extra fluorophore and limits cytotoxicity. Compound 4, activated in the hypoxic environment, showed high therapeutic activity in A549 and HeLa cells and spheroids. In vivo imaging of solid tumors confirmed the tumor-specific localization, deep tissue penetration and activation of compound 4, as well as the production of a strong anticancer effect through the inhibition of tumor growth in a xenograft mouse model validating it as a promising strategy for the treatment of solid tumors. (C) 2016 Elsevier Ltd. All rights reserved.</P>

Improving drug delivery to solid tumors: Priming the tumor microenvironment

Khawar, I.A.,Kim, J.H.,Kuh, H.J. Elsevier Science Publishers 2015 Journal of controlled release Vol.201 No.-

Malignant transformation and growth of the tumor mass tend to induce changes in the surrounding microenvironment. Abnormality of the tumor microenvironment provides a driving force leading not only to tumor progression, including invasion and metastasis, but also to acquisition of drug resistance, including pharmacokinetic (drug delivery-related) and pharmacodynamic (sensitivity-related) resistance. Drug delivery systems exploiting the enhanced permeability and retention (EPR) effect and active targeting moieties were expected to be able to cope with delivery-related drug resistance. However, recent evidence supports a considerable barrier role of tumors via various mechanisms, which results in imperfect or inefficient EPR and/or targeting effect. The components of the tumor microenvironment such as abnormal tumor vascular system, deregulated composition of the extracellular matrix, and interstitial hypertension (elevated interstitial fluid pressure) collectively or cooperatively hinder the drug distribution, which is prerequisite to the efficacy of nanoparticles and small-molecule drugs used in cancer medicine. Hence, the abnormal tumor microenvironment has recently been suggested to be a promising target for the improvement of drug delivery to improve therapeutic efficacy. Strategies to modulate the abnormal tumor microenvironment, referred to here as ''solid tumor priming'' (vascular normalization and/or solid stress alleviation leading to improvement in blood perfusion and convective molecular movement), have shown promising results in the enhancement of drug delivery and anticancer efficacy. These strategies may provide a novel avenue for the development of new chemotherapeutics and combination chemotherapeutic regimens as well as reassessment of previously ineffective agents.

NK cells encapsulated in micro/macropore-forming hydrogels via 3D bioprinting for tumor immunotherapy

김다홍,Seona Jo,Dongjin Lee,Seok‑Min Kim,Ji Min Seok,여선주,이준희,JaeJong Lee,Kangwon Lee,Tae‑Don Kim,박수아 한국생체재료학회 2023 생체재료학회지 Vol.27 No.00

Background Patients face a serious threat if a solid tumor leaves behind partial residuals or cannot be completely removed after surgical resection. Immunotherapy has attracted attention as a method to prevent this condition. However, the conventional immunotherapy method targeting solid tumors, that is, intravenous injection, has limitations in homing in on the tumor and in vivo expansion and has not shown effective clinical results. Method To overcome these limitations, NK cells (Natural killer cells) were encapsulated in micro/macroporeforming hydrogels using 3D bioprinting to target solid tumors. Sodium alginate and gelatin were used to prepare micro-macroporous hydrogels. The gelatin contained in the alginate hydrogel was removed because of the thermal sensitivity of the gelatin, which can generate interconnected micropores where the gelatin was released. Therefore, macropores can be formed through bioprinting and micropores can be formed using thermally sensitive gelatin to make macroporous hydrogels. Results It was confirmed that intentionally formed micropores could help NK cells to aggregate easily, which enhances cell viability, lysis activity, and cytokine release. Macropores can be formed using 3D bioprinting, which enables NK cells to receive the essential elements. We also characterized the functionality of NK 92 and zEGFR-CAR-NK cells in the pore-forming hydrogel. The antitumor effects on leukemia and solid tumors were investigated using an in vitro model. Conclusion We demonstrated that the hydrogel encapsulating NK cells created an appropriate micro–macro environment for clinical applications of NK cell therapy for both leukemia and solid tumors via 3D bioprinting. 3D bioprinting makes macro-scale clinical applications possible, and the automatic process shows potential for development as an off-the-shelf immunotherapy product. This immunotherapy system could provide a clinical option for preventing tumor relapse and metastasis after tumor resection.

태아 복부 고형 종양 (solid tumor)의 영상 진단

김의혁 ( Kim Ui Hyeog ),안은희 ( An Eun Hui ),임종철 ( Im Jong Cheol ),노진래 ( No Jin Lae ),조재성 ( Jo Jae Seong ),박용원 ( Park Yong Won ),김명준 ( Kim Myeong Jun ) 대한산부인과학회 2004 Obstetrics & Gynecology Science Vol.47 No.5

Objective : Ultrasonography is screening modality of choice and plays an important role in prenatal diagnosis of various diseases and neoplasm of fetus. Recently, Magnetic Resonance Imaging was used as a diagnosis tool to fetal disease. We would like to evaluate efficacy of ultrasonography and magnetic resonance imaging for the diagnosis of fetal abdominal solid tumor. Methods : Among 2,055 cases of abnormal ultrasonography findings detected by prenatal ultrasonography from January 1996 and June 2002, a comparison between the diagnosis made by prenatal ultrasonography, fetal magnetic resonance imaging (MRI), postnatal radiological studies and histopathologic studies was made in four cases with fetal abdominal solid tumor. Results : The first case was diagnosed as adrenal tumor or hepatic tumor by US, hemangioedothelioma of liver by fetal MRI, and confirmed as hemangioedothelioma postnatally. The second case showed concordance with mesoblastic nephroma among the diagnosis made by US, fetal MRI, and postnatal histopathologic studies. The third case was diagnosed as extrathoracic pulmonary sequestration by US and MRI, and the same diagnosis was made by postnatal histopathologic studies. The fourth case was suspected as kidney tumor by US and was diagnosed as adrenal as adrenal neuroblastoma postoperatively. Conclusion : Fetal solid tumor is not a common disorder, but the location, size and orgin of tumor plays important role in the prognosis of neonatal period; additional workup by fetal MRI would improve the diagnosis of such tumors.

Differentiation of Solid Pancreatic Tumors by Using Dynamic Contrast-Enhanced MRI

최승준,김형식,박현진 한국물리학회 2014 THE JOURNAL OF THE KOREAN PHYSICAL SOCIETY Vol.64 No.2

Distinguishing among different solid pancreatic tumor types, pancreatic ductal adenocarcinomas,neuroendocrine tumors (NETs), and solid pseudopapillary tumors (SPTs) is important, as the treatmentoptions are vastly different. This study compared characteristics of solid pancreatic tumorsby using dynamic contrast enhanced magnetic resonance imaging (MRI). Fifty patients underwentMR imaging of pancreatic masses with a histopathology that was later confirmed as an adenocarcinoma(n = 27), a NET (n = 16), and a SPT (n = 7). For qualitative analysis, two reviewersevaluated the morphologic features of the tumors: locations, margins, shapes, contained products,pancreatic ductal dilatation, and grade of signal intensity (SI). For the quantitative analysis, allphases of the MR images were co-registered using proprietary image registration software; thus, aregion of interest (ROI) defined on one phase could be re-applied in other phases. The followingfour ratios were considered: tumor-to-uninvolved pancreas SI ratio, percent SI change, tumor-touninvolvedpancreas enhancement index, and arterial-to-delayed washout rate. The areas under thereceiver operating characteristic (ROC) curves were assessed for the four ratios. Adenocarcinomashad ill-defined margins, irregular shapes, and ductal dilatation compared with NETs and SPTs (P< 0.001). The tumor-to-uninvolved pancreas ratio on all dynamic phases was significantly higherfor NETs than for both adenocarcinomas and SPTs (P < 0.05). Percentage SI changes of pancreatictumors on the pancreatic and the portal venous phases were significantly higher for NETsthan for both adenocarcinomas and SPTs (P < 0.05). A significant difference between NETs andadenocarcinomas was also found with respect to the tumor-to-uninvolved pancreas enhancementindex and arterial-to-delayed washout rate. The percentage SI changes in the pancreatic phase andthe arterial-to-delayed washout rate best distinguished between adenocarcinomas and NETs withthe area under the ROC curve being 0.87. The percentage SI changes in the pancreatic and theportal venous phases best distinguished between NETs and SPTs with area under the ROC curve0.87. In summary, contrast-enhanced MRI can be useful in differentiating solid pancreatic tumorsin qualitative and quantitative analyses

Tandem High-Dose Chemotherapy Increases the Risk of Secondary Malignant Neoplasm in Pediatric Solid Tumors

임하나,임민주,서은섭,조희원,주희영,유건희,조성윤,김종원,임도훈,성기웅,이지원 대한암학회 2024 Cancer Research and Treatment Vol.56 No.2

Purpose This study aimed to investigate the incidence and risk factors for secondary malignant neoplasms (SMN) in pediatric solid tumors, focusing on the effects of tandem high-dose chemotherapy (HDCT).Materials and Methods Patients (aged < 19 years) diagnosed with or treated for pediatric solid tumors between 1994 and 2014 were retrospectively analyzed. The cumulative incidence of SMN was estimated using competing risk methods by considering death as a competing risk.Results A total of 1,435 patients (413 with brain tumors and 1,022 with extracranial solid tumors) were enrolled. Seventy-one patients developed 74 SMNs, with a 10-year and 20-year cumulative incidence of 2.680±0.002% and 10.193±0.024%, respectively. The types of SMN included carcinoma in 28 (37.8%), sarcoma in 24 (32.4%), and hematologic malignancy in 15 (20.3%) cases. Osteosarcoma and thyroid carcinoma were the most frequently diagnosed tumors. Multivariate analysis showed that radiotherapy (RT) > 2, 340 cGy, and tandem HDCT were significant risk factors for SMN development. The SMN types varied according to the primary tumor type; carcinoma was the most frequent SMN in brain tumors and neuroblastoma, whereas hematologic malignancy and sarcomas developed more frequently in patients with sarcoma and retinoblastoma, respectively.Conclusion The cumulative incidence of SMN in pediatric patients with solid tumors was considerably high, especially in patients who underwent tandem HDCT or in those who received RT > 2,340 cGy. Therefore, the treatment intensity should be optimized based on individual risk assessment and the long-term follow-up of pediatric cancer survivors.

소아 고위험 고형종양에서의 자가 조혈모세포이식 후 Interleukin-2 치료

신미용,안강모,성기웅,구홍회 대한조혈모세포이식학회 1999 대한조혈모세포이식학회지 Vol.4 No.2

연구배경: 최근 고용량 화학요법과 자가 조혈모세포이식으로 소아 고위험 고형종양의 치료 성적이 향상되었음에도 불구하고 이식 후 미세잔존종양에 의한 재발이 여전히 문제가 되고 있다. 이에 미세잔존종양을 제거하여 재발을 줄이기 위한 방법으로 rIL-2를 이용한 면역요법이 시도되고 있다. 본 연구에서는 소아 고위험 고형종양에서 고용량 화학요법 및 자가 조혈모세포 이식 후에 rIL-2를 이요한 면역요법을 시행하고 면역학적 변화와 부작용을 평가하고자 하였다. 방법: 5명의 신경모세포종, 1명의 원시신경외배엽성종양, 1명의 재발된 clear cell sarcoma 환아 등 7명의 진행된 고위험 고형종양 환아를 대상으로 하였다. 이 중 6명은 조혈모세포이식 후 6개월 (40일-9개월)후 에 rIL-2를 투여하였으며, 1명은 통상적인 치료를 종결한 후 rIL-2를 투여하였다. 유도요법(d0: 2×10^(6) U/m²/day, d1-d4: 4×10^(6) U/m²/day, 5일간 연속정맥주사)을 72시간 간격으로 2회 시행한 후 유도요법이 끝난 2주 후부터 4주마다 유지요법(2×10^(6) U/m²/day, 4회 이후 : 3×10^(6) U/m²/day; 5일간 피하주사)을 시행하였다. 3명의 신경모세포종 환아는 13-cis-retinoic acid를 병용하였다. 면역학적 변화를 평가하기 위해 림프구아형분석과 혈액검사를 시행하고 부작용을 기록하였다. 결과: NK 세포 수는 유도요법이 끝난 후 현저히 증가하였고(5.3-14.4배), 유지요법 중에서도 대부분 치료전 기저치 보다는 높게 유지되었다. T세포 수와 총 림프구수, T4 세포수, T8 세포수, T4/T8 ratio도 비슷한 양상의 변화를 보였다. 유도요법 중 발열(7명), 피로o식욕부진(7명), 구토(2명), 경한 capillary leak syndrome (1명), 혈소판감소(6명), 빈혈(4명), 경한 간효소치의 상승(4명),경한 혈액응고시간의 연장(3명) 등이 관찰되었으나 rIL-2 투여가 끝난 후 바로 소실되거나 회복되었다. 유지요법 중에는 발열과 피로(7명), 혈소판 감소(2명)외에 다른 부작용은 없었다. 결론: 고위험 고형종양에서 조혈모세포이식 후에 rIL-2는 심각한 부작용 없이 비교적 쉽게 사용할 수 있었고, 면역학적을 NK 세포와 T 세포 수의 증가를 유도하여 미세잔존종양에 의한 재발을 방지하는데 효과가 있을 것으로 기대된다. Background: Although high- dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) has improved the outcome of high-risk solid tumors in children, but in some patients tumor relapse after HDCT and ASCT is due to minimal residual disease (MRD). To reduce tumor recurrence due to growth of MRD, immunotherapy with recombinant human Interleukin-2 (rIL-2) was introduced. The purpose of this study was to evaluate the immunologic changes and side effects of r-IL-2 therapy after HDCT and ASCT in children with high-risk solid tumor. Methods: Seven patients with high-risk solid tumor(5 neuroblastomas, 1 promotive neuroecto-dermal tumor, 1 recurred clear cell sarcoma) were enrolled in this study. Six patients received rIL-2,since 6 months (40 days-9 months) after HDCT and ASCT, and 1 patients received rIL-2 after completion of conventional treatments. After 2 courses of induction treatment (d0: 2×10^(6) U/m²/day, d1-d4: 4×10^(6) U/m²/day, CIV) with 72 hours interval, maintenance treatment (1st-3trd; 2×10^(6) U/m²/day, 4for 5 days, 4th-; 3×10^(6) U/m²/day for 5 days, SC) was done every 4 weeks. In 3 patients with neuroblastoma, 13-cis-retionoic acid was used simultaneously. Blood tests including enumeration of lymphocyte subpopulation were done to evaluate immunologic and hematologic change, and various side effects were recorded. Results: The number of natural killer(NK) cells increased 5.3 to 14.4 fold after 2 courses of induction treatment, and maintained at higher level during maintenance treatment than before treatment. The number of total lymphocyte and T cell, T4 cell, T8 cell, and T4/T8 ratio changed in similar pattern. Fever (7), fatigue (7), anorexia (7), vomiting (2), local erythema of injection site (3), rash (2), mild capillary leak syndrome (1), thrombocytopenia (6), mild anemia (4), mild elevation of liver enzyme (4) and mild prolongation of coagulation time (3) were observed during induction, but disappeared or recovered soon after completion of induction treatment. There was no significant side effects other than fever (7), fatigue (7), and thromocytopenia (2) during maintenance treatment. Conclusion: This study demonstrated the feasibility of rIL-2 therapy after HDCT and ASCT in children with high-risk solid tumor without significant side effects. we expect that rIL-2 therapy has effects to control and remove MRD, and therefore prevent tumor recurrence.

소아악성고형종의 진단에 있어서 chimeric transcript의 유용성

최승훈,Choi, Seung-Hoon 대한소아외과학회 1999 소아외과 Vol.5 No.1

Pediatric solid tumors have many histologic similarity. These tumors contained small round cell types, and cause frequent diagnostic problems in pediatric pathology. An important advance in the differentiation of these small round cell tumors has been the identification of consistent chromosomal translocations associated with several types of tumors. Eighteen patients with soft tissue sarcoma were available for review. Seventeen cell lines were also included in this study. The RNA from the specimens were analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). PAX3-FKHR fusion was present in four of five alveolar rhabdomyosarcoma and PAX7-FKHR fusion was detected in one of five alveolar rhabdomyosarcoma. None of the specimens expressed more than one chimeric transcript. EWS-FLI1 or EWS-ERG fusions were detected in all seven Ewings' sarcoma. No specimens showed EWS-WT1 fusion. These results corresponded well to the histopathologic diagnosis. There were no differences in the histologic appearances of tumors with the more frequent PAX3-FKHR or EWS-FLI1 fusions compared with those containing the variant PAX7-FKHR or EWS-ERG fusions. RT-PCR assay for chimeric transcript is a useful tool for rapid and objective diagnosis of pediatric solid tumors. Through these tools, we can approach genetically to the differential diagnosis of undifferentiated small round tumors.

A Spindle Cell Predominant Pancreatic Solid-pseudopapillary Tumor

고재향 연세대학교의과대학 2008 Yonsei medical journal Vol.49 No.4

A hitherto unrecognized variant of solid-pseudopapillary tumor (SPT) of the pancreas is reported. The tumor presented in the pancreatic tail of a 44-year-old female patient. It was a well-defined, solid nodule measuring 25mm in diameter, with homogenous tan gray cut surface. Histologically, the neoplasm was mostly composed of sheets of spindle cells. No cellular atypia and mitosis was identified. The periphery of the tumor showed typical feature of SPT. Immunohistochemically, the tumor cells were positive for vimentin, CD10, CD56, β- catenin, and α1-antichymotrypsin, but negative for cytokeratin, chromogranin, synaptophysin and S-100 protein. Ultrastructurally, the tumor showed a few acinar spaces with microvilli between tumor cells. This case is peculiar in that the tumor did not show gross cystic change and predominantly consists of spindle shaped tumor cells, so may cause difficult diagnostic problem.

Clinical Implication of Surgically treated Abdominoperineal Soild Tumor in the Newborn : A Single-Center Experience

조용훈,Soo-Hong Kim,김해영,Young Mi Han,Na Rae Lee,Mi Hye Bae,Kyung Hee Park,변신연 대한신생아학회 2018 Neonatal medicine Vol.25 No.1

Purpose: Abdominoperineal solid tumors presenting in neonates often require surgical intervention during the neonatal period. Although we report our single-center experience, this study would be meaningful to understand the clinical implications of these neoplasms. Methods: We retrospectively reviewed and analyzed the clinical data and characteristics of 22 patients (≤28 days old) diagnosed with histopathologically confirmed abdominoperineal solid neoplasms (benign or malignant) after surgical resection. Results: The mean gestational age and postnatal age at the time of operation were 38.3±1.8 weeks and 13.5±8.3 days, respectively. Most patients (18/22, 81.8%) were diagnosed during antenatal care visits; however, 4 (18.2%) were identified after birth. The mean tumor size was 6.4×5.3 cm (3.5–17.0 cm), and tumors occurred most frequently within the sacrococcygeal region (8/22, 36.4%). Histopathologically, 14 patients (63.6%) demonstrated benign tumors and 8 (36.4%) demonstrated malignant tumors. Germ cell tumors and hepatoblastomas were the most commonly observed tumors. Fortunately, all patients showed a localized pattern of tumor involvement without distant metastasis. No recurrence or mortality was observed during the follow-up period (mean 66.4±44.2 months). Conclusion: Abdominoperineal solid tumors occurring in neonates show variable clinical patterns during the antenatal and postnatal monitoring/screening periods. We conclude that aggressive and multidisciplinary approaches could achieve good clinical results in these patients.