Role of reactive oxygen species in regulating 27-hydroxycholesterol-induced apoptosis of hematopoietic progenitor cells and myeloid cell lines.

Oxysterols are oxygenated derivatives of cholesterol that contain an additional hydroxy, epoxide, or ketone group in the sterol nucleus and/or a hydroxyl group in the side chain of the cholesterol molecule. 27-Hydroxycholesterol (27HC) is a side-chain oxysterol that is oxygenated at the 27th carbon atom of cholesterol. The oxysterol (27HC) is produced via oxidation by sterol 27-hydroxylase (CYP27A1) and metabolized via oxysterol 7a-hydroxylase (CYP7B1) for bile acid synthesis in the liver. A previous study has demonstrated that treatment with the alternative Estrogen receptor alpha (ERα) ligand 27HC induces ERα-dependent hematopoietic stem cell (HSC) mobilization. In addition, Cyp27a1-deficient mice demonstrate significantly reduced 27HC levels and HSC mobilization. Here, we report that exogenous 27HC treatment leads to a substantial reduction in the hematopoietic stem and progenitor cell (HSPC) population owing to significantly increased reactive oxygen species (ROS) levels and apoptosis in the bone marrow (BM). However, 27HC does not influence the population of mature hematopoietic cells in the BM. Furthermore, exogenous 27HC treatment suppresses cell growth and promotes ROS production and apoptosis in leukemic cells. Moreover, acute myeloid leukemia (AML) patients with high CYP7B1 expression (expected to have inhibition of 27HC) had significantly shorter survival than those with low CYP7B1 expression (expected to have an elevation of 27HC). Single-cell RNA-sequencing (scRNA seq) analysis revealed that the expression of CYP7B1 was significantly increased in AML patients. Thus, our study suggests that 27HC may serve as a potent agent for regulating pools of HSPCs and may have an application as a novel therapeutic target for hematological malignancies. Collectively, pharmacological inhibition of CYP7B1 (expected to have an elevation of 27HC) would potentially have fewer long-term hematological side effects, particularly when used in combination with chemotherapy or radiation for the treatment of leukemia patients.

Oxime derivative TFOBO promotes cell death by modulating reactive oxygen species and regulating NADPH oxidase activity in myeloid leukemia.

Several derivatives derived from the oxime structure have been reported as potential anticancer agents in various cancers. Here, we first tested a novel oxime-containing derivative of 2-((2,4,5-trifluorobenzyl)oxy)benzaldehyde oxime (TFOBO) to evaluate its anticancer effect in myeloid leukemic cells. Compared to (2-((2,4,5-trifluorobenzyl)oxy)phenyl)methanol (TFOPM), the oxime derivative TFOBO suppresses leukemic cell growth by significantly increasing reactive oxygen species (ROS) levels and cell death. Leukemic cells treated with TFOBO displayed apoptotic cell death, as indicated by nuclear condensation, DNA fragmentation, and annexin V staining. TFOBO increases Bax/Bcl2 levels, caspase9, and caspase3/7 activity and decreases mitochondrial membrane potential. ROS production was reduced by N-acetyl-L-cysteine, a ROS scavenger, diphenyleneiodonium chloride, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, after exogenous TFOBO treatment. ROS inhibitors protect leukemic cells from TFOBO-induced cell death. Thus, our study findings suggest that TFOBO promotes apoptosis by modulating ROS and regulating NADPH oxidase activity. Collectively, the oxime-containing derivative TFOBO is a novel therapeutic drug for myeloid leukemia.

The Pattern of Care for Brain Metastasis from Breast Cancer over the Past 10 Years in Korea: A Multicenter Retrospective Study (KROG 16-12).

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.

An inhibitor of programmed death ligand 1 enhances natural killer cell-mediated immunity against malignant melanoma cells.

Since ionizing radiation has showed the dramatic effect to kill the cancer cells through direct DNA damage as well as triggering anti-cancer immune responses including induction of NKG2D ligands, it has used for long time to treat many cancer patients. However, it has been known that radiotherapy might promote the remnant cancer cells to escape immune system and metastasis. One of the suggested ways of immune evasion is induction of a ligand for programmed death-1 (PD-L1) in head and neck cancer, bladder cancer and lung cancer cells which engages the receptor, programmed death-1 (PD-1) in immune cells. PD-1/PD-L1 axis transduces the inhibitory signal and suppresses the adaptive immunity. However, their role in innate immunity remains poorly understood. Therefore, we investigated whether ionizing radiation could change the expression of PD-L1 in malignant melanoma cells and the receptor, programmed death-1 (PD-1), in NK-92 cells. Surface PD-L1 levels on melanoma cells were increased by ionizing radiation in a dose-independent manner but the level of PD-L1 was not changed significantly in NK-92 cells. Radiation-induced PD-L1 suppressed the activity of the NK-92 cells against melanoma cells despite of upregulation of NKG2D ligands. Furthermore, activated NK cells had high level of PD-1 and could not kill PD-L1+ melanoma cells effectively. When we used PD-L1 inhibitor or silenced PD-L1 gene, inhibited PD-1/PD-L1 axis reversed the activity of the suppressed NK cells. Through these results, we supposed that PD-1/PD-L1 blockade could enhance the immune responses of NK cells against melanoma cells after radiotherapy and might overcome the PD-L1 mediated radioresistance of cancer cells.

Survival outcomes of breast cancer patients with brain metastases: A multicenter retrospective study in Korea (KROG 16-12).

PURPOSE: This study evaluated the influence of prognostic factors and whole brain radiotherapy (WBRT) on overall survival (OS) of breast cancer (BC) patients with brain metastases (BM). METHODS AND MATERIALS: Medical records of 730 BC patients diagnosed with BM from 2000 to 2014 at 17 institutions were retrospectively reviewed. OS was calculated from BM diagnosis. Median follow-up duration was 11.9 months (range, 0.1-126.2). RESULTS: Median OS was 15.0 months (95% CI: 14.0-16.9). Patients with different BC-specific graded prognostic assessment (GPA) scores showed significant differences (p < 0.001) in OS. In multivariate analysis, histologic grade 3 (p = 0.014), presence of extracranial metastasis (p < 0.001), the number of BM (>4; p = 0.002), hormone receptor negativity (p = 0.005), HER2-negativity (p = 0.003), and shorter time interval (<30 months) between BC and BM diagnosis (p = 0.007) were associated with inferior OS. By summing the ß-coefficients of variables that were prognostic in multivariate analyses, we developed a prognostic model that stratified patients into low-risk (≤0.673) and high-risk (>0.673) subgroups; the high-risk subgroup had poorer median OS (10.1 months, 95% CI: 7.9-11.9 vs. 21.9 months, 95% CI: 19.5-27.1, p < 0.001). Univariate and multivariate analyses of propensity score-matched patients diagnosed with BM ≥ 30 months after BC diagnosis (n = 389, "late BM") revealed that WBRT-treated patients showed superior OS compared to non-WBRT-treated patients (p = 0.070 and 0.030, respectively). CONCLUSION: Our prognostic model identified high-risk BC patients with BM who might benefit from increased surveillance; if validated, our model could guide treatment selection for such patients. Patients with late BM might benefit from WBRT as initial local treatment.

A Study on the Diagnostic Elements of Cold-Heat Pattern Identification by Korean Medicine Doctors: Association with Objective and Subjective Body Temperature.

Although the Cold-Heat Pattern is the most important diagnostic factor in Traditional Korean Medicine (TKM), its relationship to body temperature and subjective temperature has not been clearly revealed. In this study, based on clinical data from 551 patients, we classified patients treated with herbal medicines into a Cold-prescription group (CG) and a Heat-prescription group (HG), and we compared the ordinary symptoms between the two groups. Subjective body temperature was higher in the HG than in the CG (OR = 1.68, p < 0.01) and digestive ability was better in the HG than in the CG (expert's questionnaire, OR = 1.91, p < 0.001). However, objectively measured body temperature did not show any significant difference between the HG and CG in both gender groups (p = 0.383 and 0.181 for males and females, resp.). Our study suggests that the subjective body temperature and digestive ability may be the principal diagnostic elements of Cold-Heat Pattern identification by Korean Medicine Doctors. These findings may contribute to the investigation of an objective method to measure the Cold-Heat Pattern.

Maximum Standardized Uptake Value of Pelvic Lymph Nodes in [18F]-Fluorodeoxyglucose Positron Emission Tomography Is a Prognostic Factor for Para-Aortic Lymph Node Recurrence in Pelvic Node-Positive Cervical Cancer Treated With Definitive Chemoradiotherapy.

OBJECTIVES: This study aimed to identify prognostic factors for para-aortic lymph node (PALN) recurrence and their effect on survival outcomes in patients with pelvic node-positive squamous cell carcinoma (SCC) of the cervix treated with definitive concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: Of the 116 patients with biopsy-proven SCC of the uterine cervix who underwent primary CCRT from 2007 to 2012, 48 patients with pelvic LN metastasis detected by [F]-fluorodeoxyglucose positron emission tomography (FDG PET) were retrospectively analyzed. Patients with evidence of para-aortic lymphadenopathy were excluded. The whole pelvis was the standard irradiation field for all patients. The associations of age, stage, serum SCC antigen (SCC-Ag) level, maximum standardized uptake value (SUVmax), hemoglobin level, overall treatment time, adjuvant chemotherapy, and pelvic LN status with PALN recurrence and survival outcomes were evaluated. RESULTS: At a median follow-up of 34.0 months (range, 8-73 months), 10 (20.8%) patients had developed PALN recurrences. The relationship between pelvic LN FDG uptake and PALN recurrence was evaluated by the cutoff value (SUVmax = 3.85) determined by receiver operating characteristic curve analysis. The independent risk factors for PALN recurrence were FDG-avid pelvic LN (SUVPLN) greater than 3.85 (hazard ratio, 13.12; P = 0.025) and posttreatment SCC-Ag level greater than 2.0 (ng/mL) (hazard ratio, 20.69; P = 0.019). Patients with an SUVPLN greater than 3.85 were found to have significantly worse 5-year distant metastasis-free (51.0% vs 79.0%, P = 0.016) and progression-free survival (38.7% vs 67.3%, P = 0.011) than those with an SUVPLN less than or equal to 3.85. CONCLUSIONS: SUVPLN is a statistically significant prognostic factor of PALN recurrence and survival after definitive CCRT for pelvic node-positive SCC of the uterine cervix.

Enchondroma of the Foot.

The present study is a review of 20 patients with enchondroma of the foot treated from January 2005 to March 2012. All patients were examined clinically, followed by an evaluation of their enchondroma of the foot radiographically and an assessment of the outcome of their surgical intervention. The patients' sex and age, enchondroma location, findings from imaging studies such as plain radiography, computed tomography, and magnetic resonance imaging, clinical findings, operative findings, and treatment outcomes were recorded. The average postoperative follow-up period was 24 months. Eighty percent of the tumors were located in the proximal phalanx and 14 (70%) patients presented with pathologic fracture. The plain radiographs and computed tomography findings revealed 13 (65%) cases of internal calcification and 11 (55%) with endosteal scalloping. A periosteal reaction was seen only in 4 (20%) cases. Magnetic resonance imaging of 11 (55%) patients showed low T1-weighted and high T2-weighted signal intensity in all cases. Internal septa and nodules with low T2-weighted signal intensity were observed in 9 (82%) out of 11 cases, and adjacent soft tissue edema was noted in 9 (82%). All patients underwent curettage of the tumor and bone grafting as their surgical treatment. No recurrence or postoperative complications were observed during the 24-month follow-up period. Enchondroma of the foot most frequently involves the proximal phalangeal bone and is often associated with pathologic fracture. The unique clinical signs and characteristic radiographic images are easily recognized, making this a relatively easy diagnosis. With appropriate treatment, a good surgical outcome can be expected.

Analysis of the prognostic factors for distant metastasis after induction chemotherapy followed by concurrent chemoradiotherapy for head and neck cancer.

PURPOSE: The aim of this study is to identify the prognostic factors of distant metastasis (DM) after induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) for locoregionally advanced head and neck cancer (HNC). MATERIALS AND METHODS: A total of 321 patients with HNC who underwent IC followed by CRT treated between January 2005 and December 2010 were analyzed retrospectively. IC consisted of three courses of docetaxel (70 mg/m(2)) and cisplatin (75 mg/m(2)) every three weeks, followed by radiotherapy of 66-70 Gy/2 Gy per fraction/5 fractions per week concurrent with weekly cisplatin (40 mg/m(2)). Tumor/nodal stage, primary site, tumor differentiation, lower neck node involvement (level IV, VB, and supraclavicular regions), number of concurrent chemotherapy cycles, overall duration of radiotherapy, and response to IC were assessed as potential prognostic factors influencing DM and survival outcome. RESULTS: The five-year loco-regional recurrence and DM rates were 23.6% and 18.2%. N stage, overall duration of radiotherapy, lower neck node involvement, and response to IC were significant factors for DM. With a median follow-up period of 52 months (range, 4 to 83 months), the 5-year progression-free, DM-free, and overall survival rates were 41.2%, 50.7%, and 55.1%, respectively. Lower neck node involvement (p=0.008) and poor response to IC (p < 0.001) showed an association with significantly inferior DM-free survival. CONCLUSION: Even with the addition of IC, the DM rate and survival outcome were poor when metastatic lower neck lymph nodes were present or when patients failed to respond after receiving IC.

Three-dimensional conformal radiotherapy for portal vein tumor thrombosis alone in advanced hepatocellular carcinoma.

PURPOSE: We sought to evaluate the clinical outcomes of 3-dimensional conformal radiation therapy (3D-CRT) for portal vein tumor thrombosis (PVTT) alone in patients with advanced hepatocellular carcinoma. MATERIALS AND METHODS: We retrospectively analyzed data on 46 patients who received 3D-CRT for PVTT alone between June 2002 and December 2011. Response was evaluated following the Response Evaluation Criteria in Solid Tumors. Prognostic factors and 1-year survival rates were compared between responders and non-responders. RESULTS: Thirty-seven patients (80.4%) had category B Child-Pugh scores. The Eastern Cooperative Oncology Group performance status score was 2 in 20 patients. Thirty patients (65.2%) had main or bilateral PVTT. The median irradiation dose was 50 Gy (range, 35 to 60 Gy) and the daily median dose was 2 Gy (range, 2.0 to 2.5 Gy). PVTT response was classified as complete response in 3 patients (6.5%), partial response in 12 (26.1%), stable disease in 19 (41.3%), and progressive disease in 12 (26.1%). There were 2 cases of grade 3 toxicities during or 3 months after radiotherapy. Twelve patients in the responder group (15 patients) received at least 50 Gy irradiation, but about 84% of patients in the non-responder group received less than 50 Gy. The 1-year survival rate was 66.8% in responders and 27.4% in non-responders constituting a statistically significant difference (p = 0.008). CONCLUSION: Conformal radiotherapy for PVTT alone could be chosen as a palliative treatment modality in patients with unfavorable conditions (liver, patient, or tumor factors). However, more than 50 Gy of radiation may be required.

Color distribution differences in the tongue in sleep disorder.

Introduction. According to traditional East Asian medicine (TEAM) theory, the tongue represents conditions of qi and blood. In the present study, the relationship between the tongue and the qi and blood in conditions with no apparent disease was investigated. Methods. A total of 454 elderly people with no apparent disease were recruited. Two Korean oriental medicine doctors classified subjects into a normal group (n = 402) and a sleep disorder group (n = 52). Three to five weeks after the experiment, 153 subjects were rerecruited for a second experiment. Two-dimensional color histograms, whose seven variables represent the color distribution in Commission Internationale de l'Éclairage 1976 (L∗, a∗, b∗) color space, were produced from tongue images. Results. The color of the tongue body in the sleep disorder group appeared paler than that in the normal group, and the tongue coating in the normal group was less widely distributed compared with that in the sleep disorder group. The differences in tongue color between the normal at first experiment and sleep disorder at second experiment conditions were similar to the differences between the normal and the sleep disorder groups. Conclusions. The tongue states in the sleep disorder group indicate a qi and blood deficiency according to TEAM theory.

Patellar dislocation with genu valgum treated by DFO.

Congenital habitual patellar dislocation is a rare condition of the knee where the patella dislocates during flexion and relocates during extension. The congenital form is permanent, irreducible, and presents at birth. It is characterized by a short quadriceps and a major patellofemoral dysplasia and short height. This article presents a rare case of a 27-year-old woman with recurring bilateral habitual dislocation of the patella after a failed previous proximal and distal realignment procedure. Clinical examinations of both knees revealed genu valgus knees and lateral joint pain that recurred after several previous operations. Radiographs of both knees showed patellar dislocation and genu valgum associated with patellofemoral dysplasia and osteoarthritis of the lateral compartment. Long-leg standing radiographs showed an anatomic tibiofemoral angle of right 13° and left 6° valgus and a mechanical tibiofemoral angle of right 8° and left 2° valgus and weight-bearing line of 65% on the right and 48% on the left. The authors performed a distal femoral closing wedging osteotomy to correct the valgus deformity, and then percutaneous lateral release and medial reefing were performed to stabilize the patellas of both knees simultaneously.

Short-course palliative radiotherapy for uterine cervical cancer.

PURPOSE: The purpose of this retrospective study was to evaluate the efficacy and feasibility of short-course hypofractionated radiotherapy (RT) for the palliation of uterine cervical cancer. MATERIALS AND METHODS: Seventeen patients with cancer of the uterine cervix, who underwent palliative hypofractionated 3-dimensional conformal radiotherapy between January 2002 and June 2012, were retrospectively analyzed. RT was delivered to symptomatic lesions (both the primary mass and/or metastatic regional lymph nodes). The total dose was 20 to 25 Gy (median, 25 Gy) in 5 Gy daily fractions. RESULTS: The median follow-up duration was 12.2 months (range, 4 to 24 months). The median survival time was 7.8 months (range, 4 to 24 months). Vaginal bleeding was the most common presenting symptom followed by pelvic pain (9 patients). The overall response rates were 93.8% and 66.7% for vaginal bleeding control and pelvic pain, respectively. Nine patients did not have any acute side effects and 7 patients showed minor gastrointestinal toxicity. Only 1 patient had grade 3 diarrhea 1 week after completion of treatment, which was successfully treated conservatively. Late complications occurred in 4 patients; however, none of these were of grade 3 or higher severity. CONCLUSION: Short-course hypofractionated RT was effective and well tolerated as palliative treatment for uterine cervical cancer.