Browsing by Author "Yang, Kai-Lin"

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Comparing the Effectiveness of Combined External Beam Radiation and Hyperthermia Versus External Beam Radiation Alone in Treating Patients With Painful Bony Metastases: A Phase 3 Prospective, Randomized, Controlled Trial
(2018-01-01)
Chi, Mau-Shin
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Yang, Kai-Lin
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Chang, Yue-Cune
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Ko, Hui-Ling
;
Lin, Yi-Hsien
Purpose: To compare the response, duration of pain relief, and time to achieve complete pain relief after radiation therapy (RT) with or without hyperthermia (HT) in patients with painful bony metastases. Methods and Materials: Cancer patients with bony metastases and pain score >= 4 on the Brief Pain Inventory (BPI) were randomized to RT of 30 Gy in 10 fractions combined with HT (RT + HT) versus RT alone. Hyperthermia was performed by the Thermotron RF-8, with maintenance of the target temperature for 40 minutes per treatment within 2 hours after RT, twice weekly for 2 weeks. Patients were stratified by lesion number (solitary or multiple), BPI score (4-6 vs 7-10), and primary site. The primary endpoint was complete response (CR) (BPI = 0 with no increase of analgesics) within 3 months after treatment. This study was registered with ClinicalTrials.gov. Results: The study was terminated early after an interim analysis of 57 patients, 3 years after the first enrollment (November 2013 to November 2016): 29 patients in the RT + HT group and 28 patients in the RT-alone group. The CR rate at 3 months after treatment was 37.9% in the RT + HT group versus 7.1% in the RT-alone group (P=.006). The accumulated CR rate within 3 months after treatment was 58.6% in the RT + HT group versus 32.1% in the RT-alone group (P=.045). Median time to pain progression was 55 days in patients with CR (n=9) in the RT-alone group, whereas the endpoint was not reached during the 24-week follow-up in the RT + HT group (P<.01). Conclusions: The addition of HT to RT significantly increases the pain control rate and extends response duration compared with RT alone for painful bony metastases. (C) 2017 Elsevier Inc. All rights reserved.
Double autophagy modulators reduce 2-deoxyglucose uptake in sarcoma patients
(2015-10-06)
Chi, Mau-Shin
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Lee, Cheng-Yen
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Huang, Su-Chen
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Yang, Kai-Lin
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Ko, Hui-Ling
Rationale: According to the metabolic symbiosis model, cancer stromal fibroblasts could be hijacked by surrounding cancer cells into a state of autophagy with aerobic glycolysis to help provide recycled nutrients. The purpose of this study was to investigate whether combined treatment with the autophagy inhibitor: hydroxychloroquine (HCQ) and the autophagy inducer: sirolimus (rapamycin, Rapa) would reduce glucose utilization in sarcoma patients. Methods: Ten sarcoma patients who failed first-line treatment were enrolled in this study. They were treated with 1 mg of Rapa and 200 mg of HCQ twice daily for two weeks. The standardized uptake values (SUV) from pretreatment and posttreatment [F-18]-fluorodeoxyglucose positron emission tomography (FDG PET) scans were reviewed, and changes from the baseline SUVmax were evaluated. Results: Based on FDG PET response criteria, six patients had a partial response; three had stable disease, and one had progressive disease. Nevertheless, none of them showed a reduction in tumor volume. The mean SUVmax reduction in the 34 lesions evaluated was -19.6% (95% CI = -30.1% to -9.1%), while the mean volume change was +16.4% (95% CI = +5.8% to + 27%). Only grade 1 toxicities were observed. Elevated serum levels of lactate dehydrogenase were detected after treatment in most metabolic responders. Conclusions: The results of reduced SUVmax without tumor volume reduction after two weeks of Rapa and HCQ treatment may indicate that non-proliferative glycolysis occurred mainly in the cancer associated fibroblast compartment, and decreased glycolytic activity was evident from Rapa + HCQ double autophagy modulator treatment.
Modulated electro-hyperthermia-enhanced liposomal drug uptake by cancer cells
(2019-01-01)
Tsang, Yuk-Wah
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Chi, Kwan-Hwa
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Huang, Cheng-Chung
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Chi, Mau-Shin
;
Chiang, Hsin-Chien
Purpose: Modulated electro-hyperthermia (mEHT) stands to be a significant technological advancement in the hyperthermia field, utilizing autofocusing electromagnetic power on the cell membrane to create massive apoptosis. Since mEHT possesses the unique ability to excite cell membranes, we hypothesized that mEHT could enhance the uptake of liposomal drugs by enhancing phagocytic activity. Materials and methods: Water bath control and mEHT were used to compare the enhancement of liposome-encapsulated doxorubicin (Lipodox (R)) uptake by cancer cells. Cancer cells were made visible by doxorubicin fluorescence to investigate drug uptake. Viable cell yield was determined via the Trypan Blue exclusion method. Various substrates were used to investigate the mechanism of drug-uptake enhancement. The murine colon carcinoma model, CT26, was used to confirm the tissue infiltration of Lipodox (R) and its therapeutic effect. Results: mEHT treatment showed a significant enhancement of Lipodox (R) uptake of doxorubicin fluorescence compared with 37 degrees C or 42 degrees C water bath treatment. Tumor tissue sections also confirmed that mEHT treatment achieved the highest doxorubicin concentration in vivo (1.44 +/- 0.32 mu g/g in mEHT group and 0.79 +/- 0.32 mu g/g in 42 degrees C water bath). Wortmannin was used to inhibit the macropinocytosis effect and 70 kDa dextran-FITC served as uptake substance. The uptake of dextran-FITC by cancer cells significantly increased after mEHT treatment whereas such enhancement was significantly inhibited by wortmannin. Conclusion: The result showed mEHT-induced particle-uptake through macropinocytosis. mEHT-enhanced uptake of Lipodox (R) may amplify the therapeutic effect of liposomal drugs. This novel finding warrants further clinical investigation.
Putative Abscopal Effect in Three Patients Treated by Combined Radiotherapy and Modulated Electrohyperthermia
(2020-03-10)
Chi, Mau-Shin
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Mehta, Minesh P.
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Yang, Kai-Lin
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Lai, Hung-Chih
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Lin, Ying-Chu
Purpose: True abscopal responses from radiation therapy are extremely rare; the combination of immune checkpoint inhibitors with radiation therapy has led to more reports of the abscopal effect, but even in this setting, the genuine magnitude remains unknown and is still considered generally uncommon. We report the occurrence of what appears to be putative, durable abscopal tumor responses with associated auto-immune systemic reactions resulting from the combination of local radiotherapy (RT) and modulated electrohyperthermia (mEHT). Materials and Methods: Data from advanced cancer patients treated palliatively with RT and mEHT between January and December 2017 were collected as part of a post-marketing safety monitoring program of mEHT therapy. We specified a minimum RT dose of 30 Gy and at least four mEHT treatments for reporting toxicities, which was the primary aim of the larger study. Results: Thirty-three patients treated with RT and mEHT, both applied to the same lesion, were included. The median RT dose was 45.5 Gy in 20 fractions (fxs) and the median number of mEHT treatments was 12 (range, 4-20). Most patients had subsequent systemic therapy after one course of RT and mEHT. Three patients (9.1%) developed autoimmune toxicities. Case number 1 received RT and mEHT only; case number 2 had two cycles of concurrent low dose chemotherapy during RT; and case number 3 received concurrent immune checkpoint inhibitors. None of the three patients received any further systemic treatment due to obvious treatment-related autoimmune reactions which occurred rapidly after RT; one had autoimmune hepatitis, one had dermatitis herpetiformis and the third developed severe myasthenia gravis. Interestingly, what we surmise to be long-lasting abscopal responses outside the irradiated area, were noted in all three patients. Conclusion: RT combined with mEHT could putatively result in enhancing immune responsiveness. These preliminary observational findings lead to the generation of a hypothesis that this combination induces both an in-situ, tumor-specific immune reaction and an anti-self-autoimmune reaction, in at least a small proportion of patients, and of those who experience the auto-immune response, tumor response is a concomitant finding. Mechanisms underlying this phenomenon need to be investigated further.
Relationship between Energy Dosage and Apoptotic Cell Death by Modulated Electro-Hyperthermia
(2020-06-02)
Kao, Patrick Hung-Ju
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Chen, Chia-Hung
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Tsang, Yuk-Wah
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Lin, Chen-Si
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Chiang, Hsin-Chien
Modulated electro-hyperthermia (mEHT) is a form of mild hyperthermia (HT) used for cancer treatment. The principle utility of HT is the ability not only to increase cell temperature, but also to increase blood flow and associated pO(2) to the microenvironment. While investigational evidence has shown the unique ability of mEHT to elicit apoptosis in cancer cells, in vivo and in vitro, the same trait has not been observed with conventional HT. There is dissension as to what allows mEHT to elicit apoptosis despite heating to only mild temperatures, with the predominant opinion in favor of increased temperature at a cellular level as the driving force. For this study, we hypothesized that in addition to temperature, the amount of electrical energy delivered is a major factor in induction of apoptosis by mEHT. To evaluate the impact of electrical energy on apoptosis, we divided generally practiced mEHT treatment into 3 phases: Phase I (treatment start to 10min. mark): escalation from 25 degrees C to 37 degrees C Phase II (10min. mark to 15min. mark): escalation from 37 degrees C to 42 degrees C Phase III (15min. mark to 45min. mark): maintenance at 42 degrees C Combinations of mEHT at 18W power, mEHT at 7.5W power, water bath, and incubator were applied to each of the three phases. Power output was recorded per second and calculated as average power per second. Total number of corresponding Joules emitted per each experiment was also recorded. The biological effect of apoptotic cell death was assayed by annexin-V assay. In group where mEHT was applied for all three phases, apoptosis rate was measured at 31.18 +/- 1.47%. In group where mEHT was only applied in Phases II and III, apoptosis rate dropped to 20.2 +/- 2.1%. Where mEHT was only applied in Phase III, apoptosis was 6.4 +/- 1.7%. Interestingly, when mEHT was applied in Phases I and II, whether Phase III was conducted in either water bath at 42 degrees C or incubator at 37 degrees C, resulted in nearly identical apoptosis rates, 26 +/- 4.4% and 25.9 +/- 3.1%, respectively. These results showed that accumulation of mEHT at high-powered setting (18W/sec) during temperature escalation (Phase I and Phase II), significantly increased apoptosis of tested cancer cells. The data also showed that whereas apoptosis rate was significantly increased during temperature escalation by higher power (18W/sec), apoptosis was limited during temperature maintenance with lower power (7.5W/sec). This presents that neither maintenance of 42 degrees C nor accumulation of Joules by mEHT has immediate correlating effect on apoptosis rate. These findings may offer a basis for direction of clinical application of mEHT treatment.