Phase II Trial of Combined Durvalumab Plus Tremelimumab with Proton Therapy for Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#This phase II study investigated whether durvalumab/tremelimumab with proton therapy improves the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) in heavily treated recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) patients. @*Materials and Methods@#Patients who previously received more than one chemotherapy, including at least one platinum-based regimen, and who had at least two measurable lesions were enrolled. Patients received 1,500 mg durvalumab intravenously combined with 75 mg tremelimumab intravenously every 4 weeks for four cycles followed by 1,500 mg durvalumab every 4 weeks. After one cycle of the durvalumab/tremelimumab treatment, proton therapy was given with a total dose of 25 Gy in 5 Gy daily fractions to one of the measurable lesions. We also assessed the ORR in the target lesion outside the radiation field to evaluate the abscopal effect. @*Results@#Thirty-one patients were enrolled between March 2018 and July 2020. With 8.6 months of follow-up, the ORR was 22.6% (7/31), including one complete response and six partial responses. The median OS was 8.4 months (95% confidence interval [CI], 2.5 to 14.3) and the median PFS was 2.4 months (95% CI, 0.6 to 4.2). Among the 23 evaluable patients who completed proton therapy, the ORR was 30.4% (7/23). The median OS was 11.1 months (95% CI, 6.5 to 15.8), and the median PFS was 3.7 months (95% CI, 1.6 to 5.7). Grade 3 or higher adverse events were observed in six patients (19.4%) as follows: anemia (n=1), constipation (n=1), electrolyte imbalances (n=2), hyperglycemia (n=1), and pneumonia (n=1). @*Conclusion@#The combination of durvalumab/tremelimuab with proton therapy was tolerated well and had encouraging anti-tumor efficacy in non-irradiated tumor lesions of heavily treated HNSCC patients.

Subclinical Hypothyroidism Affects the Long-Term Outcomes of Patients Who Undergo Coronary Artery Bypass Grafting Surgery but Not Heart Valve Surgery

Background@#The aim of this study was to determine the associations between subclinical hypothyroidism (SCH) and long-term cardiovascular outcomes after coronary artery bypass grafting (CABG) or heart valve surgery (HVS). @*Methods@#We retrospectively reviewed and compared all-cause mortality, cardiovascular mortality, and cardiovascular events in 461 patients who underwent CABG and 104 patients who underwent HVS. @*Results@#During a mean±standard deviation follow-up duration of 7.6±3.8 years, there were 187 all-cause deaths, 97 cardiovascular deaths, 127 major adverse cardiovascular events (MACE), 11 myocardial infarctions, one unstable angina, 70 strokes, 30 hospitalizations due to heart failure, 101 atrial fibrillation, and 33 coronary revascularizations. The incidence of all-cause mortality after CABG was significantly higher in patients with SCH (n=36, 55.4%) than in euthyroid patients (n=120, 30.3%), with a hazard ratio of 1.70 (95% confidence interval, 1.10 to 2.63; P=0.018) after adjustment for age, sex, current smoking status, body mass index, underlying diseases, left ventricular dysfunction, and emergency operation. Interestingly, low total triiodothyronine (T3) levels in euthyroid patients who underwent CABG were significantly associated with increased risks of all-cause mortality, cardiovascular mortality, and MACE, but those associations were not observed in HVS patients. Both free thyroxine and thyroid-stimulating hormone levels in euthyroid patients were not related with any cardiovascular outcomes in either the CABG or HVS group. @*Conclusion@#SCH or low total T3 might be associated with a poor prognosis after CABG, but not after HVS, implying that preoperative thyroid hormonal status may be important in ischemic heart disease patients.

Low Predictive Value of FRAX Adjusted by Trabecular Bone Score for Osteoporotic Fractures in Korean Women: A Community-Based Cohort Study

Background@#The value of the Fracture Risk Assessment Tool (FRAX) and the trabecular bone score (TBS) for assessing osteoporotic fracture risk has not been fully elucidated in Koreans. We conducted this study to clarify the predictive value of FRAX adjusted by TBS for osteoporotic fractures in Korean women. @*Methods@#After screening 7,192 eligible subjects from the Ansung cohort, 1,165 women aged 45 to 76 years with available bone mineral density (BMD) and TBS data were enrolled in this study. We assessed their clinical risk factors for osteoporotic fractures and evaluated the predictive value of FRAX with or without BMD and TBS. @*Results@#During the mean follow-up period of 7.5 years, 99 (8.5%) women suffered major osteoporotic fractures (MOFs) and 28 (2.4%) experienced hip fractures. FRAX without BMD, BMD-adjusted FRAX, and TBS-adjusted FRAX were significantly associated with the risk of MOFs (hazard ratio [HR] per percent increase, 1.08; 95% confidence interval [CI], 1.03 to 1.14; HR, 1.09; 95% CI, 1.03 to 1.15; and HR, 1.07; 95% CI, 1.02 to 1.13, respectively). However, BMD-adjusted FRAX and TBS-adjusted FRAX did not predict MOFs better than FRAX without BMD based on the Harrell’s C statistic. FRAX probabilities showed limited value for predicting hip fractures. The cut-off values of FRAX without BMD, FRAX with BMD, and FRAX with BMD adjusted by TBS for predicting MOFs were 7.2%, 5.0%, and 6.7%, respectively. @*Conclusion@#FRAX with BMD and TBS adjustment did not show better predictive value for osteoporotic fractures in this study than FRAX without adjustment. Moreover, the cut-off values of FRAX probabilities for treatment might be lower in Korean women than in other countries.

Digital Therapeutics: Emerging New Therapy for Neurologic Deficits after Stroke / 대한뇌졸중학회지

Digital therapeutics is an evidence-based intervention using high-quality software, with the sole purpose of treatment. As many healthcare systems are encountering high demands of quality outcomes, the need for digital therapeutics is gradually increasing in the clinical field. We conducted review of the implications of digital therapeutics in the treatment of neurological deficits for stroke patients. The implications of digital therapeutics have been discussed in four domains: cognition, speech and aphasia, motor, and vision. It was evident that different forms of digital therapeutics such as online platforms, virtual reality trainings, and iPad applications have been investigated in many trials to test its feasibility in clinical use. Although digital therapeutics may deliver high-quality solutions to healthcare services, the medicalization of digital therapeutics is accompanied with many limitations. Clinically validated digital therapeutics should be developed to prove its efficacy in stroke rehabilitation.

Cancer Immunotherapy Related Endocrine Adverse Effects

Cancer immunotherapy has emerged as a promising therapy for a wide variety of tumors. Immune checkpoint inhibitors including anti cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1) monoclonal antibodies have proven to be especially effective in various advanced cancers. However, cancer the immunotherapy disturbs the immune system and may also cause immune related side effects (IRAE) distinguished from cytotoxic chemotherapy toxicity. Among them, endocrine IRAE has been reported with a higher incidence than other organ IRAE. We focus on the most relevant and new aspects related to endocrine IRAE due to cancer immunotherapy in this review.

A Case of Aggravation of Thyroid Goiter after Treatment with PD-1 Inhibitor for Breast Cancer in Patients with Underlying Hashimoto's Thyroiditis

Anti-programmed cell death-1 (PD-1) humanized monoclonal antibody inhibits PD-1 activity by binding to the PD-1 receptor on T-cells and blocking PD-1 ligands and induces immune tolerance of cancer cells. It has been widely used for various kinds of cancer treatment. However, many immune-related adverse events (irAEs) have been reported because it modulates our immune system. In this case study, we reported a case of 42-year-old woman with Hashimoto's thyroiditis who showed rapid aggravation of thyroid goiter and acute hyperventilation syndrome after treatment with PD-1 inhibitor as a neoadjuvant chemotherapy for breast cancer.

Secular Trends for Diagnostic Motives and Environmental Risk Factors in Thyroid Cancer Using Questionnaire Survey

BACKGROUND AND OBJECTIVES: We analyzed the clinicopathologic differences of thyroid cancer by diagnosis periods, diagnostic motives, residence history and clinical risk factors in thyroid cancer patients. MATERIALS AND METHODS: Total 1599 thyroid cancer patients who answered the questionnaires about family history of thyroid cancer, residence history including duration of residence and location were enrolled from two hospitals, Seoul National University Hospital and National Cancer Center in Korea. Demographics and environmental information were collected via questionnaires and clinical data were reviewed via electronic medical records. RESULTS: More thyroid cancer has been diagnosed in 2011 to 2013 by screening test without specific symptom than before 1990. The size of cancer at diagnosis was significantly smaller and multifocal tumor was more frequently found in 2011 to 2013 than before 1990 as well. The tumors of obese or overweight patients tended to harbor extrathyroidal extension and lymph node metastasis than normal weight subjects with statistical significance. However, there were no differences in clinicopathologic characteristics according to residence and smoking history. CONCLUSION: In this study, there were some different clinicopathologic characteristics according to the diagnosis era, diagnostic motives, family history of thyroid cancer and body mass index.

Directing Human Embryonic Stem Cells towards Functional Endothelial Cells Easily and without Purification

Hemangioblasts or blood islands only arise in early development thereby the sources to obtain these bi-potential cells are limited. While previous studies have isolated both lineages in vitro through the hemangioblast, derivation efficiency was rather low due to cellular damage attributed by enzyme usage and fluorescent activated cell sorting (FACS). This study focused on avoiding the use of damaging factors in the derivation of endothelial cells (ECs). Single cell H9-human embryonic stem cells (hESCs) were obtained by using a mild dissociation protocol then human embryoid body (hEB) formation was performed under hemangioblast differentiation conditions. The hEBs were subjected to a two-stage cytokine treatment procedure. Subsequent culture of the adhesive cells in day 4 hEBs gave arise to a seemingly pure population of ECs. The hESC-derived ECs were characterized by identifying signature endothelial gene and protein markers as well as testing for in vitro functionality. Furthermore, in vivo functionality was also confirmed by transplanting the cells in hindlimb ischemic murine models. We demonstrate that the genetic change required for EC derivation precedes blast colony formation. Furthermore, cell damage was prevented by abating enzyme usage and FACS, resulting in a high yield of ECs upon adhesion. Under this method, confluent cultures of ECs were obtainable 4 days after hEB formation which is significantly faster than previous protocols.

Thyroid nodules with Bethesda System IV Cytology: Can Ultrasonography Differentiate Malignancy from Benign?

PURPOSE: The purpose of this study is to identify clinical and imaging parameters that can be used in differentiation of benign versus malignancy of preoperative FNA diagnosis of Bethesda system IV nodules. MATERIALS AND METHODS: We analyzed clinical, ultrasonographic, and CT findings of 28 thyroid nodules with Bethesda system IV cytology on FNA, which were proven as follicular or Hurthle cell neoplasms on surgical pathology. RESULTS: No statistically significant differences according to age, sex, and ultrasonographic parameters, including echogenicity, margin, calcification, shape, cystic component, and degree of vascularity and enhancement on CT were observed between benign and malignant follicular neoplasms. Only the lesion size was significantly different (p<0.05). CONCLUSION: The size of follicular neoplasm is predictive of malignancy. If a thyroid nodule with the Bethesda IV cytology is larger than 24.5 mm, there will be a greater probability of malignancy.

Polysomnographic Characteristics and Prescription Status of Restless Legs Syndrome Patients in Naturalistic Setting / 수면정신생리

OBJECTIVES: The aim of this study is to evaluate the polysomnographic characteristics and prescription status of restless legs syndrome (RLS) patients in naturalistic setting. METHODS: We reviewed medical record of the patients over 18 years olds who (i) satisfied the clinical RLS diagnostic criteria and (ii) had the polysomnography and got treatment related thereto. As a baseline, we evaluated the four diagnostic criteria of the International Restless Legs Syndrome Study Group (IRLSSG) and the International Restless Legs Scale (IRLS) of the subjects. Then the polysomnography and the suggested immobilization test (SIT) were conducted and, after one month of pharmacotherapy using dopamine agonist, the IRLS was evaluated again. RESULTS: A total of 211 subjects participated in this analysis and 94 (44.5%) of them were male and the other 117 (55.5%) were female and the average age of the 211 subjects was 46.9+/-14.2. Out of such 211 subjects, 136 subjects (64.5%) also had the obstructive sleep apnea (OSA), and 53 subjects (25.1%) also had the periodic limb movement disorder (PLMD). 185 subjects (87.7%) out of the 211 subjects had some other sleep disorders except RLS. The results of the polysomnography were as follows : 78.0% of sleep efficiency, 86.8 min of wake after sleep onset, and 3.4% of N3. More specifically, 12.4/h of the average apnea hypopnea index, 14.8/h of the periodic limb movement during sleep (PLMS), 41.2/h of the periodic limb movement during wake during SIT and 21.6/h of total arousal index during sleep. Out of the total subjects, 149 (70.6%) of them took the ropinirole and 47 (22.3%) of them took the pramipexole, and the average dosage of ropinirole was 0.9mg(dosage range 0.125-5 mg) while the average dosage of pramipexole was 0.5 mg (dosage range 0.125-4 mg). The dosage of the ropinirole showed a significant positive correlation with the age (r=0.25, p=0.002) and also with the IRLS (r=0.23, p=0.038). The IRLS at the baseline was 24.9 while the same was decreased down to 13.4 after one month. CONCLUSIONS: Analyzing the result of this study, a majority of clinical RLS subjects demonstrated comorbidity with some other sleep disorder such as the OSA or PLMD. 25.1% of the subjects showed a PLMD, which was less than in previous researches and the average PLMS was not very high as 14.8/h. The dosage of dopamine agonist taken was often a bit more than the amount recommended in Korea. A prospective research using a large scale controlled subjects will be necessary with respect to this topic.

Skeletal myogenic differentiation of human periodontal ligament stromal cells isolated from orthodontically extracted premolars / 대한치과교정학회지

OBJECTIVE: To investigate the stem cell-like characteristics of human periodontal ligament (PDL) stromal cells outgrown from orthodontically extracted premolars and to evaluate the potential for myogenic differentiation. METHODS: PDL stromal cells were obtained from extracted premolars by using the outgrowth method. Cell morphological features, self-replication capability, and the presence of cell-surface markers, along with osteogenic, adipogenic, and chondrogenic differentiation, were confirmed. In addition, myogenic differentiation was induced by the use of 5-aza-2'-deoxycytidine (5-Aza) for DNA demethylation. RESULTS: PDL stromal cells showed growth patterns and morphological features similar to those of fibroblasts. In contrast, the proliferation rates of premolar PDL stromal cells were similar to those of bone marrow and adipogenic stem cells. PDL stromal cells expressed surface markers of human mesenchymal stem cells (i.e., CD90 and CD105), but not those of hematopoietic stem cells (i.e., CD31 and CD34). PDL stromal cells were differentiated into osteogenic, adipogenic, and chondrogenic lineages. Myotube structures were induced in PDL stromal cells after 5-Aza pretreatment, but not in the absence of 5-Aza pretreatment. CONCLUSIONS: PDL stromal cells isolated from extracted premolars can potentially be a good source of postnatal stem cells for oromaxillofacial regeneration in bone and muscle.

Diffusion-Weighted MR Imaging before and after Contrast Enhancement with Superparamagnetic Iron Oxide for Assessment of Hepatic Metastasis

PURPOSE: The purpose of our study was to validate diffusion-weighted MRI (DWI) before and after superparamagnetic iron oxide (SPIO) injection for assessment of hepatic metastases. MATERIALS AND METHODS: Eighty-six hepatic metastases (size range, 0.3-4.7 cm; mean, 1.5 cm) verified pathologically or by follow-up imaging studies in 22 consecutive patients (17 men and 5 women; 44-83 years; mean age, 60 years) during a 13-month period were enrolled. Hepatic MRI, including DWI (b-factors=50, 400, 800 s/mm2) with breath-holding technique of single-shot spin-echo echo-planar imaging (TR/TE=1000/69 ms, average=2) before and after SPIO administration, were retrospectively reviewed by two independent radiologists with a 5-point scale confidence score for each hepatic lesion on pre-contrast DWI (pre-DWI), SPIO-enhanced DWI (SPIO-DWI), and SPIO-enhanced T2*-weighted imaging (SPIO-T2*wI). RESULTS: For all lesions, SPIO-T2*wI showed significantly higher confidence score in the diagnosis of hepatic metastases than pre-contrast or SPIO-DWI regardless of the size of b-factors (p0.05). Pre-DWI using b-factor=50 sec/mm2 was also comparable with SPIO-T2*wI by observer 1 (p=0.060). CONCLUSION: Pre-DWI has a limited value for the assessment of hepatic metastases, however, the repetition of DWI after SPIO injection using small b-factors could complement SPIO-T2*wI, especially for subcentimeter lesions.

A Study of the Validity of and Cut-Off Scores for the Korean Version of Asperger Syndrome Diagnostic Scale

OBJECTIVES: This study examined the reliability and validity of the Korean version of Asperger Syndrome Diagnostic Scale (K-ASDS), to calculate the cut-off score in the diagnosis of Asperger syndrome. Further, we examined classification error rate when applying cut-off scores. METHODS: One hundred sixty-seven children participated in this study, including 46 with Asperger syndrome, 26 with PDD or PDD NOS, 43 with ADHD, and 52 normal children. RESULTS: An ANCOVA demonstrated no significant differences in the K-ASDS total score between the Asperger and the PDD & PDD NOS groups. However, these groups did show significantly higher scores than the ADHD and normal groups. Among the five subscales on the K-ASDS, the Asperger group obtained significantly higher scores on the language and cognition subscales than the PDD & PDD NOS groups. Two scales were found to be useful in distinguishing the Asperger group from the PDD & PDD NOS group through a discriminant analysis. According to an analysis of ROC curve, the cut-off score on the K-ASDS for the diagnosis of PDD including Asperger syndrome was 121. CONCLUSION: We discussed that K-ASDS has pretty limit.

Spontaneous Remission of Nephrotic Syndrome in IgA Nephropathy / 대한신장학회지

Although a moderate degree of proteinuria is common in patients with IgA nephropathy (IgAN), nephrotic syndrome combined with IgAN is rare. It has been reported that approximately 5% of all patients with IgAN are complicated by minimal change disease and these patients respond well to corticosteroid therapy. However, spontaneous remission is uncommon in heavy proteinuric patients with IgAN. Recently, we experienced two cases of spontaneous remission of nephrotic syndrome combined with IgAN without use of corticosteroid. In these patients, heavy proteinuria disappeared in 1 month after the onset and no recurrence occurred during follow-up. With such limited number of cases, factors associated with spontaneous remission in these patients could not be explored. Further study with a larger number of patients is required and careful attention should be paid to these complicated cases.

BioSubroutine: an Open Web Server for Bioinformatics Algorithms and Subroutines

We present BioSubroutine, an open depository server that automatically categorizes various subroutines frequently used in bioinformatics research. We processed a large bioinformatics subroutine library called Bio.pl that was the first Bioperl subroutine library built in 1995. Over 1000 subroutines were processed automatically and an HTML interface has been created. BioSubroutine can accept new subroutines and algorithms from any such subroutine library, as well as provide interactive user forms. The subroutines are stored in an SQL database for quick searching and accessing. BioSubroutine is an open access project under the BioLicense license scheme.

3 DFT Magnetic Resonance Dacryocystography in the Evaluation of Epiphora

PURPOSE: To evaluate the feasibility of 3-dimensional Fourier transformation magnetic resonancedacryocystography (3DFT MR DCG: MR DCG) and its diagnostic efficacy in patients with epiphora. MATERIALS AND METHODS: Three normal volunteers and ten patients complaining of epiphora were studied by MR DCG using 3DFT CISSand 3DFT FLASH techniques. In normal volunteers, MR DCG was obtained by instillation of diluted Gd-DTPA solutionsof different concentrations (Gd-DTPA : saline=1:100, 1:50, 1:25) using various instillation methods. In patientswith epiphora, MR DCG was compared with conventional D C G . RESULTS: In normal volunteers, the best image wasobtained with the continuous instillation method during MR scanning. In all normal volunteers, MR DCG demonstratedthe entire course of the nasolacrimal duct (NLD). In patients with epiphora, however, there were five cases inwhich MR DCG failed to visualize the NLD, as well as five cases of occlusion and two of stenosis at the level ofthe proximal NLD. These findings corresponded with conventional DCG findings as four cases of occlusion at thelevel of the common canaliculi, one case of lacrimal sac, five cases of occlusion and two cases of stenosis at thelevel of the proximal NLD. There was no significant difference between MR DCG findings using 3DFT CISS and 3DFTFLASH MR techniques. CONCLUSION: MR DCG can detect the correct level of obstruction and differentiate betweenocclusion and stenosis of the NLD in patients with obstruction of the lacrimal drainage system. It may be a usefuldiagnostic method for investigating complicated cases in which conventional DCG is not possible due topost-surgical or traumatic obstruction.