The emerging role of myeloid-derived suppressor cells in radiotherapy

Radiotherapy (RT) has been used for decades as one of the main treatment modalities for cancer patients. The therapeutic effect of RT has been primarily ascribed to DNA damage leading to tumor cell death. Besides direct tumoricidal effect, RT affects antitumor responses through immune-mediated mechanism, which provides a rationale for combining RT and immunotherapy for cancer treatment. Thus far, for the combined treatment with RT, numerous studies have focused on the immune checkpoint inhibitors and have shown promising results. However, treatment resistance is still common, and one of the main resistance mechanisms is thought to be due to the immunosuppressive tumor microenvironment where myeloid-derived suppressor cells (MDSCs) play a crucial role. MDSCs are immature myeloid cells with a strong immunosuppressive activity. MDSC frequency is correlated with tumor progression, recurrence, negative clinical outcome, and reduced efficacy of immunotherapy. Therefore, increasing efforts to target MDSCs have been made to overcome the resistance in cancer treatments. In this review, we focus on the role of MDSCs in RT and highlight growing evidence for targeting MDSCs in combination with RT to improve cancer treatment.

Definitive radiotherapy with or without chemotherapy for clinical stage T4N0-1 non-small cell lung cancer

PURPOSE: To determine failure patterns and survival outcomes of T4N0-1 non-small cell lung cancer (NSCLC) treated with definitive radiotherapy. MATERIALS AND METHODS: Ninety-five patients with T4N0-1 NSCLC who received definitive radiotherapy with or without chemotherapy from May 2003 to October 2014 were retrospectively reviewed. The standard radiotherapy scheme was 66 Gy in 30 fractions. The main concurrent chemotherapy regimen was 50 mg/m2 weekly paclitaxel combined with 20 mg/m2 cisplatin or AUC 2 carboplatin. The primary outcome was overall survival (OS). Secondary outcomes were failure patterns and toxicities. RESULTS: The median age was 64 years (range, 34 to 90 years). Eighty-eight percent of patients (n = 84) had an Eastern Cooperative Oncology Group performance status of 0-1, and 42% (n = 40) experienced pretreatment weight loss. Sixty percent of patients (n = 57) had no metastatic regional lymph nodes. The median radiation dose was EQD2 67.1 Gy (range, 56.9 to 83.3 Gy). Seventy-one patients (75%) were treated with concurrent chemotherapy; of these, 13 were also administered neoadjuvant chemotherapy. At a median follow-up of 21 months (range, 1 to 102 months), 3-year OS was 44%. The 3-year cumulative incidences of local recurrence and distant recurrence were 48.8% and 36.3%, respectively. Pretreatment weight loss and combined chemotherapy were significant factors for OS. Acute esophagitis over grade 3 occurred in three patients and grade 3 chronic esophagitis occurred in one patient. There was no grade 3-4 radiation pneumonitis. CONCLUSION: Definitive radiotherapy for T4N0-1 NSCLC results in favorable survival with acceptable toxicity rates. Local recurrence is the major recurrence pattern. Intensity modulated radiotherapy and radio-sensitizing agents would be needed to improve local tumor control.

Down-Regulation of Survivin by Nemadipine-A Sensitizes Cancer Cells to TRAIL-Induced Apoptosis

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor family of cytokines. TRAIL selectively induces apoptotic cell death in various tumors and cancer cells, but it has little or no toxicity in normal cells. Agonism of TRAIL receptors has been considered to be a valuable cancer-therapeutic strategy. However, more than 85% of primary tumors are resistant to TRAIL, emphasizing the importance of investigating how to overcome TRAIL resistance. In this report, we have found that nemadipine-A, a cell-permeable L-type calcium channel inhibitor, sensitizes TRAIL-resistant cancer cells to this ligand. Combination treatments using TRAIL with nemadipine-A synergistically induced both the caspase cascade and apoptotic cell death, which were blocked by a pan caspase inhibitor (zVAD) but not by autophagy or a necrosis inhibitor. We further found that nemadipine-A, either alone or in combination with TRAIL, notably reduced the expression of survivin, an inhibitor of the apoptosis protein (IAP) family of proteins. Depletion of survivin by small RNA interference (siRNA) resulted in increased cell death and caspase activation by TRAIL treatment. These results suggest that nemadipine-A potentiates TRAIL-induced apoptosis by down-regulation of survivin expression in TRAIL resistant cells. Thus, combination of TRAIL with nemadipine-A may serve a new therapeutic scheme for the treatment of TRAIL resistant cancer cells, suggesting that a detailed study of this combination would be useful.

Epidemiological study of depression among patients with Hansen Disease at the national sorokdo hospital / 나학회지

OBJECTIVE: Geriatric depression is a disease, that possibly can cause serious problems, in case it is not detected and treated. As the mean age of patients on Sorok Island increases, possibility of depression along with dementia rises, but up to date prevalence of this disease in this population has not been studied. This study identifies dementia and depression in patients on Sorok Island via a questionnaire survey, to incorporate the results in future treatment. METHOD: Two hundred thirty-six Sorok Island residents (142 male, 94 female) were enrolled in this survey including Geriatric depression scale (GDS), Korean modified Mini Mental Status Exam (k-mMMSE), and Global Deterioration Scale (GDS). RESULTS: Suspicious group of depression was found in 25% and Certain group of depression in 17%, which adds up to a high overall prevalence of 42%. There was no gender difference in Suspicious group of depression, but Certain group of depression was significantly more prevalent in women compared to men. Suspicious group of depression detected with k-mMMSE and GDS showed a prevalence of 30% and 35%, respectively, and prevalence was higher in women. Comparing depression group to non-depression group, a significantly higher prevalence of depression group was detected in patients with symptoms of dementia. CONCLUSION: The results, compared to prevalence studies in other populations, showed a higher prevalence of depression and dementia in patients on Sorok Island. This may be due to the relatively higher mean age or due to a realtively lower functional level of the patients. Possiblity of dementia accompanied by depression is high, and in geriatric patients, the denial of depression or misinterpretation of it as somatic disorders is common. Thus, implication of these results in treatment may yield an improvement of future outcome.

A Clinical study of Intrauterine Fetal Death / 대한산부인과학회잡지

OBJECTIVE: The purpose of this study was to evaluate intrauterine fetal death and elucidate the etiology of intrauterine fetal death. METHODS: This is a clinical study of 74 cases of intrauterine fetal death (IUFD) among 5,523 deliveries at Soonchunhyang University Hospital during Jan. 1998 to Apr. 2003. RESULTS: The overall incidence of IUFD was 1.34%. And the age distribution of mother with IUFD was between 19 to 44 year old and was highest in the 25 to 29 year old age group (39.1%). The parity of mothers with IUFD was the highest in nulliparous group (78.3%) and there was a decreased tendency with high parity. There were 47 cases (63.5%) with previous history of abortion and 2 cases (2.7%) with previous history of IUFD. The highest incidence rate of IUFD was shown at 20-24 weeks of gestation (48.6%) and in the fetus weighted less than 1,000 gm (59.5%), and the sex ratio of male versus female fetus was 1:1.07. The modes of delivery were labor induction (54.1%), laparotomy (18.9%), spontaneous labor (27.0%). The indication for laparotomy was placental abruption, placenta previa, previous cesarean section state. The etiology factors of IUFD were unexplained causes (55.4%), cord complication (12.2%), placental abruption (9.4%), placenta previa (9.4%) in order. CONCLUSION: The causes of IUFD were unexplained, cord complication, placental abruption in order. So, the proper antenatal care should be taken of fetuses on the basis of risk factors of antepartum and intrapartum.

Postnatal outcome of Prenatally detected Fetal Hydronephrosis / 대한주산의학회잡지

OBJECTIVE: To help prenatal counselling in fetal hydronephrosis by demonstrating the postnatal investigation, treatment and outcome of infants with hydronephrosis prenatally diagnosed. METHODS: Between January 2000 and December 2001, we studied 20 infants who presented with fetal hydronephrosis confirmed by postnatal ultrasonography. In the postnatal follow-up period, the infants were followed with sequential ultrasonography and urinalysis. (99m)Tc-DTPA scan, intravenous pyelography and voiding cystourethrography were performed in selected cases. An anteroposterior renal pelvic diameter >7 mm after 30 weeks of pregnancy was defined as fetal hydronephrosis. Follow-up ranged from 6 to 18 months (mean, 12). RESULTS: Unilateral hydronephrosis was diagnosed in 13 infants and bilateral in 7. A male predilection was found (4:1) and the left kidney was more commonly involved. If there was no resolution, ultrasonographic follow-up was done until 18 months. As a results, hydronephrosis resolved in 11, who were all in the unilateral hydronephrosis group. The range of the fetal renal pelvis on prenatal ultrasonography was 7~13 mm in the resolution group. Pyeloplasty was performed in two unilateral hydronephrosis infants. CONCLUSION: When the fetal renal pelvis was below 14 mm at least on prenatal ultrasonography, it didn't progress. Fetal hydronephrosis below 14 mm may be safely observed, and surgical correction was performed only a few infants. So, we suppose that this outcome must be considered enough in prenatal counsellings and that the work-up for more many people is needed, because of the small number of the patients whose renal pelvic diameter is above 14 mm in this study.

A Comparison of the effect of Synthetic Hormone Replacement therapy on Bone Mineral Density and Biochemical markers of Bone metabolism / 대한산부인과학회잡지

OBJECTIVE: To determine the effect of hormone replacement therapy on bone mineral density and biochemical marker of bone metabolism in postmenopausal women receiving hormone replacement therapy. METHOD: We have treated two groups of menopausal women for 4 years; Group 1 received Conjugated Equine Estrogen 0.625 mg (Premarin(R)); Group 2 received Cyclic combined therapy, estrogen and progestin, (Premarin(R) 0.625 mg per day, Provera(R) 10mg per day for 12days), Group 1 was hysterectomized women, received Conjugated Equine Estrogen 0.625 mg per day. We compared the change of bone marker, osteocalcin and bone mineral density during therapy. RESULT: The data demonstrated a beneficial effect in bone marker, osteocalcin decreased in two groups from the baseline values. And hormone replacement therapy shows the beneficial effect in bone mineral densities. Spine BMD increased in two groups by 3.67%, 3.04% after 4years. Femur BMD increased in two groups by 5.34%, 5.25% from the initial value after 4 years. CONCLUSION: Our study results suggest that single estrogen therapy and cyclic combined therapy have benificial effect on increased BMD and decreased bone marker, osteocalcin. Their effects were not signigicantly different between two groups.

A clinical study on benign and malignant ovarian tumor in postmenopausal women / 대한산부인과학회잡지

OBJECTIVE: This study was performed to compare the clinical characteristics of benign and malignant tumor in postmenopausal woman. METHODS: We reviewed the chart of 91 postmenopausal women over 50 years of age, operated and confirmed by postoperative histopathologic study at Department of Obstetrics and Gynecology, Soonchunhyang Chunan Hospital, from January 1st 1995 to December 31th 1998. RESULTS: Benign ovarian tumor was found in 85.7% (78 cases) and malignant ovarian tumor was found in 14.3% (13 cases). Age distribution of malignant ovarian tumors showed the highest frequency in the age group 61-65 years compared to benign ovarian tumor. In the larger than 10 cm in tumor size, there were 7 benign (58.3%) and 5 malignant (41.7%) lesion. There was no evidence of malignant tumor according to the parity. In malignant lesion, stage I was seen in 15.4%, stage II in 30.7%, stage III in 7.7%, stage IV in 23.0% and unexplored in 23.0%. Tumor marker of CA 125 in malignant lesion was increased in 69.2%. As the subjective symptoms of benign lesions, no symptom was noticed in 38.4%, but in malignant lesions, lower abdominal pain was noticed in 38.4% as the most common. Bilaterality in benign lesions was noted in 29.4% and the same in malignant lesions was 15.3%. CONCLUSIONS: Considering the above results, as the tumor size increases, the risk of malignancy increases.

Induction of apoptosis in human leukemia cells by 3-deazaadenosine is mediated by caspase-3-like activity

3-Deazaadenosine (DZA), one of the potent inhibitors of S-adenosylhomocysteine hydrolase, is known to possess several biological properties including an induction of apoptosis. To evaluate a possibility that DZA may be utilized for the treatment of human leukemia, we studied molecular events of cell death induced by DZA in human leukemia HL-60 and U-937 cells. DZA induced a specific cleavage of poly ADP-ribose polymerase (PARP) and an activation of the cysteine protease caspase-3/CPP32 which is known to cleave PARP. DZA-mediated nuclear DNA-fragmentation was completely blocked in the presence of a universal inhibitor of caspases (z-VAD-fmk) or the specific inhibitor of caspase-3 (z-DEVD-fmk) unlike of cycloheximide (CHX). DNA fragmentation was preceded by the lowering of c-myc mRNA in the DZA treated cells. In addition, DZA-induced apoptosis was blocked by pretreatment with adenosine transporter inhibitors such as nitrobenzylthioinosine (NBTI) and dipyridamole (DPD). Taken together, these results demonstrate that DZA-induced apoptosis initiated through an active transport of DZA into human leukemia cells, is dependent on the caspase-3-like activity without de novo synthesis of proteins and possibly involves c-myc down-regulation.

A Case of Acardiac Twin / 대한주산의학회잡지

No abstract available.

Intravaginal Misoprostol for the Termination of Second and Third Trimester Pregnancy / 대한주산의학회잡지

OBJECTIVE: The purpose was to evaluate the effect of the intravaginal misoprostol(prostaglandin E1,) for termination after second trimester. METHODS: Thirty pregnant women with intrauterine fetal death and with indications for therapeutic termination of intrauterine pregnancy at least fourteen weeks of gestation were recruited. They were evaluated the mean time from induction to termination, maternal side effects, and total dose of the powdered 100ug misoprostol adminstered in the posterior vaginal fornix every six hours. RESULTS: The mean time from induction to termination was 21.1+/-8.2 hours after administration of the intravaginal misoprostol. Only two patients had not been delivered within 48hours. Vomiting, diarrhea, and fever were not accompanied except nausea. The total dosage of misoprostol was 412.5+/-156.1ug. CONCLUSION: This study shows that intravaginal misoprostol appears to be safe, effective and inexpensive method for the labor induction for termination of pregnancy in the second or third trimester of pregnancy.

The Relationship between Lipid Peroxidation of Red Blood Cell Membrane, and Mean Corpuscular Volume and Liver Enzyme Markers in Alcohol Dependence Patients

OBJECTIVES: Alcohol-induced oxidative stress has been known to injure various tissues or organs. This stress is related with free radicals which are produced as the result of long-term alcohol consumption. Malonyldialdehyde(MDA) is produced by the interaction of free radicals and cell membrane lipids, and indicates the degree of lipid peroxidation indirectly. The purpose of this study was to investigate the relationship between red blood cell(RBC) membrane lipid peroxidation by free radicals, and associated hepatic injuries and hematologic changes. METHODS: Thirty-three subjects diagnosed as alcohol dependence according to DSM-IV diagnostic criteria were evaluated within 72 hours after discontinuing alcohol drinking. Clinical characteristics were evaluated by CAGE questionnaire and Korean Michigan Alcoholism Screening Test(MAST). RBC membrane MDA level was measured as the marker of RBC membrane lipid peroxidation. Aspartate aminotransferase(AST), alanine aminotransferase(ALT) and gamma-glutamyltransferase(GGT) were used as the biochemical markers of liver damage due to alcohol ingestion. The alcohol-induced hematologic change was assessed by mean corpuscular volume(MCV). RESULTS: The results were as follows. Clinical characteristics were not different between two groups having normal and abnormal levels of AST, ALT, GGT or MCV. The levels of MDA were not correlated with the clinical characteristics and serum levels of AST, ALT and GGT. However, there was a significant correlation between the levels of MDA and the value of MCV(p=0.017). CONCLUSIONS: These findings suggest that oxidative stress in alcohol dependence may not be reflected in liver enzyme markers such as AST, ALT and GGT, but may be reflected in MCV.

Active adenosine transporter-mediated adenosine entrance into HL-60 cells leads to the induction of apoptosis through down-regulation of c-Myc

Although adenosine (Ado) is being recently recognized as a potent inducer of apoptosis, molecular mechanism of apoptosis by Ado remains to be elucidated. In this study we observed that c-Myc was rapidly down-regulated in the apoptosis in human promyelocytic leukemia HL-60 cells treated with Ado. To establish the molecular and biochemical mechanisms of apoptosis, we tested the specific effects of several antagonists of Ado receptors or inhibitors of Ado transporter on the induction of apoptosis. Treatment of dipyridamole (DPD), an Ado transport inhibitor, effectively suppressed both c-Myc reduction and DNA fragmentation, suggesting that the induction of apoptosis and down-regulation of c-Myc is mediated by active Ado transporter. It was another evidence supporting the entrance of Ado into cells undergoing apoptosis that Ado cytotoxicity was potentiated by a addition of methylation cycle intermediates. These results suggest that the active Ado transporter-mediated Ado entrance into HL-60 cells leads to the induction of apoptosis through down-regulation of c-Myc.