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Purpose We aimed to investigate manifestations and patterns of care for patients with brain metastasis (BM) from breast cancer (BC) and compared their overall survival (OS) from 2005 through 2014 in Korea.Materials and Methods We retrospectively reviewed 600 BC patients with BM diagnosed between 2005 and 2014. The median follow-up duration was 12.5 months. We categorized the patients into three groups according to the year when BM was initially diagnosed (group I [2005-2008], 98 patients; group II [2009-2011], 200 patients; and group III [2012-2014], 302 patients).Results Over time, the median age at BM diagnosis increased by 2.2 years (group I, 49.0 years; group II, 48.3 years; and group III, 51.2 years; p=0.008). The percentage of patients with extracranial metastasis was 73.5%, 83.5%, and 86.4% for group I, II, and III, respectively (p=0.011). The time interval between BC and BM was prolonged in patients with stage III primary BC (median, 2.4 to 3 years; p=0.029). As an initial brain-directed treatment, whole-brain radiotherapy alone decreased from 80.0% in 2005 to 41.1% in 2014. Meanwhile, stereotactic radiosurgery or fractionated stereotactic radiotherapy alone increased from 13.3% to 34.7% during the same period (p=0.005). The median OS for group I, II, and III was 15.6, 17.9, and 15.0 months, respectively, with no statistical significance.Conclusion The manifestations of BM from BC and the pattern of care have changed from 2005 to 2014 in Korea. However, the OS has remained relatively unchanged over the 10 years.

Background: We analyzed the treatment outcome of breast cancer patients with brain metastases (BM) in Korea to identify the prognostic factors and the role of whole brain radiation therapy (WBRT). Methods: Seven hundred thirty patients of breast cancer with BM treated at 17 institutions in Korea from 2000 to 2014 were analyzed. The median follow-up duration was 12 months. The analysis consisted of three cohorts: in cohort A, a total of 730 patients were included; in cohort B, 538 patients with available follow-up imaging after initial brain-directed treatment; and in cohort C, 54 patients receiving salvage WBRT due to recurrent BM after initial Stereotactic radiosurgery or WBRT. Overall survival (OS) was calculated from BM diagnosis in cohort A or from the last day of salvage WBRT in cohort C. Results: Median OS of cohort A was 15 months. In multivariate analysis, histologic grade 3, extracranial metastasis, number of BM >4, hormone receptor (HR) or HER2 negativity, and shorter time interval to diagnosis of BM were associated with inferior OS. Among 538 patients in cohort B, 201 showed subsequent development of new BM at a median of 11 months after stereotactic radiosurgery or WBRT for the management of initial BM (at 1 year, HR+/HER2- 51.9%, HER2+ 44.0%, and TNBC 69.6%, respectively; p=0.008). Upfront WBRT reduced subsequent development of new BM, which showed the significant difference among molecular subtypes (HR+/HER2-, 42% reduction at 1 year, p4, and involvement of both tentoria increased subsequent development of new BM. Anti-HER2 therapy for HER2+ patients and upfront WBRT significantly reduced risk of new BM. In cohort C, upfront WBRT prolonged the salvage WBRT-free duration (median 6.9 vs. 8.7 months, p=0.058). Median OS was 6.8 months after salvage WBRT. Longer interval to salvage WBRT, controlled primary tumor, high dose of salvage WBRT (BED10 >37.5 Gy), and systemic treatment after salvage WBRT showed better OS. Uncontrolled extracranial systemic disease and salvage WBRT due to local progression without distant intracranial failure showed worse OS. Conclusions: The rates of new BM showed the significant differences among molecular subtypes. Upfront WBRT decreased subsequent development of new BM and this effect was dependent on the molecular subtype as well. Anti-HER2 therapy for HER2+ patients significantly decreased the subsequent development of new BM. On salvage WBRT setting, the patients having high dose of salvage WBRT, stable extracranial systemic disease and subsequent systemic therapy showed better OS. Citation Format: Jae Sik Kim, Kyubo Kim, Wonguen Jung, Kyung Hwan Shin, Seock-Ah Im, Hee-Jun Kim, Yong Bae Kim, Jee Suk Chang, Jee Hyun Kim, Doo Ho Choi, Yeon Hee Park, Dae Yong Kim, Tae Hyun Kim, Byung Ock Choi, Sea-Won Lee, Suzy Kim, Jeanny Kwon, Ki Mun Kang, Woong-Ki Chung, Kyung Su Kim, Won Sup Yoon, Jin Hee Kim, Jihye Cha, Yoon Kyeong Oh, In Ah Kim. Multicenter study for brain metastasis from breast cancer in Korea: The significance of molecular subtype (KROG 1612) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-01.

We previously constructed a nomogram for predicting the risk of arm lymphedema following contemporary breast cancer treatment. This nomogram should be validated in patients with different background characteristics before use. Therefore, we aimed to externally validate the nomogram in a large multi-institutional cohort.Overall, 8835 patients who underwent breast cancer surgery during 2007-2017 were identified. Data of variables in the nomogram and arm lymphedema were collected. The nomogram was validated externally using C-index and integrated area under the curve (iAUC) with 1000 bootstrap samples and by calibration plots.Overall, 1377 patients (15.6%) developed lymphedema. The median time from surgery to lymphedema development was 11.4 months. Lymphedema rates at 2, 3, and 5 years were 11.2%, 13.1%, and 15.6%, respectively. Patients with lymphedema had significantly higher body mass index (median, 24.1 kg/mThis nomogram, which was developed using factors related to multimodal breast cancer treatment and was validated in a large multi-institutional cohort, can well predict the risk of breast cancer-related lymphedema.

To identify the risk factors leading to new brain metastases (BM) following brain-directed treatment for initial BM resulting from breast cancer (BC). In this multi-institutional study, 538 BC patients with available follow-up imaging after brain-directed treatment for initial BM were analyzed. Tumor molecular subtypes were classified as follows: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−, n = 136), HER2-positive (HER2+, n = 253), or triple-negative BC (TNBC, n = 149). In 37.4% of patients, new BM emerged at a median of 10.5 months after brain-directed treatment for initial BM. The 1-year actuarial rate of new BM for HR+/HER2−, HER2+, and TNBC were 51.9%, 44.0%, and 69.6%, respectively (p = 0.008). Initial whole-brain radiotherapy (WBRT) reduced new BM rates (22.5% reduction at 1 year, p 4) (p

To identify the risk factors leading to new brain metastases (BM) following brain-directed treatment for initial BM resulting from breast cancer (BC).In this multi-institutional study, 538 BC patients with available follow-up imaging after brain-directed treatment for initial BM were analyzed. Tumor molecular subtypes were classified as follows: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-, n = 136), HER2-positive (HER2+, n = 253), or triple-negative BC (TNBC, n = 149).In 37.4% of patients, new BM emerged at a median of 10.5 months after brain-directed treatment for initial BM. The 1-year actuarial rate of new BM for HR+/HER2-, HER2+, and TNBC were 51.9%, 44.0%, and 69.6%, respectively (p = 0.008). Initial whole-brain radiotherapy (WBRT) reduced new BM rates (22.5% reduction at 1 year, p 0.001) according to molecular subtype (HR+/HER2-, 42% reduction at 1 year, p 0.001; HER2+, 18.5%, p = 0.004; TNBC, 16.9%, p = 0.071). Multivariate analysis revealed an increased risk of new BM for the following factors: shorter intervals between primary BC diagnoses and BM (p = 0.031); TNBC (relative to HR+/HER2-) (p = 0.016); presence of extracranial metastases (p = 0.019); number of BM (4) (p 0.001); and BM in both tentorial regions (p = 0.045). Anti-HER2 therapy in HER2+ patients (p = 0.013) and initial use of WBRT (p 0.001) significantly lowered new BM development.Tumor molecular subtypes were associated with both rates of new BM development and the effectiveness of initial WBRT. Anti-HER2 therapy in HER2+ patients significantly lowered new BM occurrence.

Purpose: To evaluate the role of curative radiotherapy alone in the treatment of uterine cervical carcinomas, by a retrospective analysis with respects to survival and pelvic control, and to find any risk factors of failure Materials and Methods: Between Jan. 1990 and Dec. 1995, a total of 187 patients, diagnosed with uterine cervical carcinomas in FIGO stages greater than IA, were treated by curative radiotherapy alone with no chemotherapy. The ages of the patients ranged from 26 to 80 years, with a median of 60 years. The number of patients diagnosed with squamous cell carcinomas were 183 (97.9%). The number of patients with FIGO stage IB1, IB2, IIA, IIB, IIIA, IIIB and IVA were 61 (32.6%), 7 (3.7%), 43 (23.0%), 62 (33.3%), 3 (1.6%), 7 (3.7%) and 4 (2.1%), respectively. External radiotherapy was performed with 6 MV or 10 MV X-rays, with a dose range of 19.8 Gy- 50.4 Gy (median; 30.6), to whole pelvis. Intracavitary radiation (ICR) was then performed using a high-dose rate remote controlled afterloader with radioisotopes of Co-60 and Cs-137. The fraction size of the ICR was 5 Gy twice a week, and was delivered up to total doses of 10 Gy- 55 Gy (median; 40). After the ICR, additional pelvic external radiotherapy with midline shielding width of 4 cm was performed with the dose range of 0-30.6 Gy (median; 19.8), and the resultant total doses of A points ranged between 49.8 Gy and 86.0 Gy (median; 70.6). Results: The five-year overall survival rates of FIGO IB1, IB2, IIA, IIB, III and IVA were 88.3%, 83.3%, 86.1%, 65.2%, 60.0% and 50.0%, respectively (p=0.005). The pelvic control rates of each stage were 90.1%, 85.7%, 86.1%, 69.4%, 68.6% and 50.0%, respectively (p=0.03). From the multivariate analysis, the radiation response and tumor diameter were found to be significant factors affecting the overall survival. The significant factors influencing pelvic control were the radiation response and pre-treatment hemoglobin level. Conclusion: The radiation response and tumor diameter were significant factors affecting survival, so patients with tumor diameters greater than 4 cm should be considered for a combined modality, such as concurrent chemoradiotherapy.

This study investigated radioresistance mechanisms in the doxorubicin-resistant acute myelogenous leukemia (AML)-2/DX100. AML-2/DX100 also showed resistance to radiation. AML-2/DX100 characterized by down-regulated catalase expression was supersensitive to exogenous hydrogen peroxide whereas they increased defense mechanisms against endogenous reactive oxygen species (ROS) as compared with AML-2/WT. In AML-2/WT, radiation increased Bax expression and its translocation to mitochondria but had little effect on translocation of Bcl-2 and consequently induced the release of cytochrome c from the mitochondria with the subsequent caspase-3 activation. On the contrary, in AML-2/DX100, radiation neither increased Bax expression nor its translocation to mitochondria while it increased Bcl-2 translocation to mitochondria. A specific p38 MAPK inhibitor SB203580 increased radioresistance in AML-2/WT but little in AML-2/DX100. It inhibited radiation-induced Bax translocation in AML-2/WT but not in AML-2/DX100, indicating that p38 MAPK is working after irradiation in AML-2/WT but not in AML-2/DX100. Electrophoretic mobility shift assay and Western blot analysis revealed that NF-kappaB in AML-2/DX100 was more activated with degradation of cytosolic IkappaBalpha than was that of AML-2/WT. cDNA microarray showed that Bfl-1/A1 and granzyme H in AML-2/DX100 were highly up-regulated (6.21-fold) and down-regulated (6.49-fold), respectively, as compared with each of AML-2/WT, which were confirmed by RT-PCR assay. Taken together, these results indicate that radioresistance mechanisms of AML-2/DX100 could be related to alterations in ROS-scavenging activity, in mitochondrial translocation of Bax and Bcl-2, and in expression of pro-apoptotic (granzyme H) and anti-apoptotic (Bfl-1/A1) genes. It has been shown that balance of p38 MAPK and NF-kappaB signals is a determinant in radiosensitivity of AML-2/WT and AML-2/DX100.

The purpose of this study was to investigate the adaptive mechanisms of hydrogen peroxide-supersensitive AML cells against the reactive oxygen species (ROS). Their scavenging capacity against ROS was determined using a fluorometric probe in the doxorubicin-resistant AML-2/DX100 cell characterized by the down-regulation of catalase. AML-2/DX100 cells had more scavenging capacity against endogenous pro-oxidants than did the parental cells AML-2/WT, suggesting that an anti-oxidant adaptation against ROS occurred. cDNA microarrays for 8000 human genes revealed that among 21 anti-oxidant genes, each four gene was up- and down-regulated more than 1.5-fold in AML-2/DX100 compared with AML-2/WT. The mRNA expression of glutathione S-transferase Pi, peroxiredoxin 2, thioredoxin 2, and glutaredoxin was elevated whereas that of peroxiredoxin 3, metallothionein-1F, superoxide dismutase 2, and thioredoxin reductase 1 was depressed. The result indicates that the down-regulation of certain anti-oxidant mechanisms can be compensated for by the up- and down-regulation of the other anti-oxidant mechanisms.

We report a unique case of skeletal metastasis with prominent soft tissue extension from a colon cancer in a 44-year-old male patient. Four years after the diagnosis of colon cancer, plain radiographic examinations revealed a prominent soft tissue mass associated with cortical destruction of the right femur. Palliative radiotherapy of the right femur was performed. After completing radiotherapy, massive remineralization was seen in the soft tissue component. With the assistance of pre- and post-radiotherapy computerized tomography images, obtained in the process of planning the radiotherapy, we reached the conclusion that in our case the pre-radiotherapy finding was an extreme case of eccentric expansion of the bony cortex due to the outgrowth of bony metastasis. Retrospectively, the initial prominent soft tissue mass associated with the cortical destruction seems to have been a protruding bone metastasis, extending from the medial aspect of the right femur. This peculiar feature with remineralization after radiotherapy should help explain the phenomenon of atypical bony metastasis from a radiological perspective.

The purpose of this study was to determine the effect of irradiation on the healing process and the effect on the contact surface of Medpor and bone. Eighteen dogs were studied. The animals were divided into three groups. Six non-irradiated dogs served as controls (Group 1). Twelve dogs irradiated on the left femur, before and after implantation of Medpor, were studied. The dogs were euthanized 4 and 8 weeks after Medpor was implanted in presurgical irradiation subgroup animals (Group 2) and after the completion of irradiation in post-surgical irradiation subgroup animals (Group 3). Light microscopic and scanning electron microscopic examinations were performed. The appearance of osteoblasts and bone matrix formation were remarkably late and manifest slight reactions in post-surgical irradiation group compared to the control group presenting the osteoblasts at 4 weeks, and those osteoblasts were not visible in presurgical irradiation group in both the 4-week and 8-week observation. We concluded that the bone remodeling was delayed in the irradiated bone, especially in the presurgical group.

Purposes : The objectives of this prospective clinical trial were to determine whether pentoxifylline improves the radiation response and survival in patients with non-small cell lung cancer. Materials and methods : From July 1993 through October 1994, 64 patients with histologically confirmed Stage I, II and III non-small cell lung cancer were randomly divided into pentoxifylline (Pento)+Radiotherapy (RT) group and RT alone group. Out of the 64 patients, only 47 patients who had measurable tumors on chest X-ray views were analyzed and divided into Pento+RT group ( n =27) and RT alone group ( n =20). Total tumor dose of 65–70 Gy was delivered as conventional fractionated radiation schedules. Pento was given to the patients 3×400 mg/day with a daily dose of 1200 mg during RT. Results : Complete response (CR), partial response (PR), and stable in Pento+RT group were three (11%), 13 (48%), and 11 (41%), respectively, as compared with corresponding values of three (15%), 13 (65%), and four (20%) in the RT alone group. The median time to relapse in the Pento+RT group was 11 months which was 2 months longer than for the RT alone group ( P >0.05). All the patients in both groups showed lower than or equal to grade 2 dysphagia, odynophagia, pulmonary fibrosis, and pneumonitis. The median survival was 18 months in the Pento+RT group and 7 months in the RT alone group. The 1-year survival rate was 60% in the Pento+RT group and 35% in the RT alone group, the 2-year survival rate was 18% in the Pento+RT group and 12% in the RT alone group. But these differences were not statistically significant ( P >0.05). Conclusion : We concluded that Pento is a modestly effective radiation response modifier and provide benefit in the treatment of non-small cell lung cancer.

Endocrine therapies, which inhibit estrogen receptor signaling, are the most common and effective treatments for estrogen receptoralpha-positive breast cancer. However, the utility of these agents is limited by the frequent development of resistance, and the precise mechanisms underlying endocrine therapy resistance remain incompletely understood. Here, we demonstrate that peptidyl-prolyl isomerase Pin1 is an important determinant of resistance to tamoxifen and show that Pin1 increases E2F-4- and Egr-1-driven expression of LC-3 as a result of an increased interaction with and phosphorylation of MEK1/2. In human tamoxifen-resistant breast cancer, our results show a significant correlation between Pin1 overexpression and high levels of LC-3. Promoter activity as well as expression levels of Pin1 were drastically higher in tamoxifen-resistant MCF7 cells than control MCF7 cells, as were levels of LC-3 mRNA and protein, an autophagy marker. Pin1(-/-) mouse embryonic fibroblasts showed lower 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MEK1/2 phosphorylation than Pin1(+/+) mouse embryonic fibroblasts. Silencing of Pin1 expression inhibited TPA-induced MEK1/2 phosphorylation in MCF7 cells. Moreover, PD98059, a specific inhibitor of MEK1/2, and juglone, a potent Pin1 inhibitor, significantly suppressed the TPA-induced expression of E2F-4 as well as Egr-1 transcription factors, which control LC-3 gene expression. Importantly, 4-hydroxy tamoxifen, when used in combination with silencing of Pin1 or LC-3, increased cleaved poly(ADP-ribose) polymerase and DNA fragmentation to inhibit cologenic growth of MCF7 cells. We therefore link the Pin1-MEK pathway and LC-3-mediated tamoxifen resistance and show the therapeutic potential of Pin1 in the treatment of tamoxifen-resistant breast cancer.

†Purpose: The purpose of this study was to evaluate the impact of the use of external radiation therapy (ERT) in terms of survival and compliance in patients with anaplastic thyroid carcinoma. Materials and Methods: The medical records of 17 patients with anaplastic thyroid carcinoma treated with ERT between 1993 and 2002 were retrospectively reviewed. ERT was administered after surgery in 14 patients and after a biopsy in three patients. Among the 14 patients who had undergone surgery, nine underwent a curative resection and five underwent a palliative resection. Six patients had associated well-differentiated thyroid carcinomas and 14 patients were diagnosed with a tumor size exceeding 5 cm. The radiation dose ranged from 6∼ 70 Gy (median dose, 37.5 Gy). Eleven patients completed the planned course of ERT, whereas six patients did not. The follow-up period ranged from 1∼104 months (median, 5 months; mean, 20 months). Results: Five patients started the ERT without the presence of a gross mass and all of the patients completed ERT without a re-growth of tumor. Twelve patients (four patients after a curative resection, five patients after a palliative resection and three patients after a biopsy) started ERT with a gross mass present and only six patients were able to complete the planned course of ERT. Among the six patients who completed ERT, two patients showed a marked regression of the tumor mass, whereas two patients showed slight regression and two patients showed no response. The median surviv al was five months (range, 1∼104 months) and the mean survival was 21 months. The overall survival was 41% at 1-year, 24% at 2-years and 12% at 5-years. Significant prognostic factors included the number of primary tumors present, tumor size, whether surgery was performed and completion of ERT as planned. Long-term survivors showed a tendency of having smaller sized initial tumors and smaller sized pre-ERT tumors than the short-term survivors. Conclusion: This study suggests that patients with a small initial tumor (≤5 cm), which was treated by surgery (curative resection or palliative resection) before ERT, and without rapid re-growth of the mass seen at the surgical site at the beginning of the ERT course, would be the best candidates for postoperative ERT. In contrast, patients with a large initial tumor (＞5 cm) and did not undergo surgery before ERT or that rapid re-growth of the mass was observed at the surgical site are likely to have a short survival time, along with the interruption of ERT. In these cases, the role of ERT is very limited and the omission of ERT could be considered.