Noninvasive Monitoring of Mantle Cell Lymphoma by Immunoglobulin Gene Next-Generation Sequencing in a Phase 2 Study of Sequential Chemoradioimmunotherapy Followed by Autologous Stem-Cell Rescue.

BACKGROUND: Minimal residual disease (MRD) monitoring has been used to identify early molecular relapse and predict clinical relapse in mantle cell lymphoma (MCL). Few published data exist in MCL on the performance of next-generation sequencing-based assay of immunoglobulin gene rearrangements for MRD assessment. PATIENTS AND METHODS: In a prospective clinical trial (NCT01484093) with intensive induction chemotherapy and autologous stem-cell transplantation, posttreatment peripheral blood samples were collected from 16 MCL patients and analyzed with an earlier version of the Adaptive Biotechnologies MRD assay. RESULTS: Of the 7 patients whose disease remained in remission, the MRD test remained negative in 5 (71%). Of the 9 patients who experienced relapse, the MRD test was positive at least 3 months before relapse in 6 patients (67%) and positive at the time of relapse in 1 patient (11%). All patients with at least 2 positive MRD tests experienced relapse. CONCLUSION: The next-generation sequencing-based MRD assay identified early molecular relapse, and we observed more sensitivity in the cellular (circulating leukocytes) versus acellular (plasma cell-free DNA) compartment. This observation may be due to availability of tumor target or a limitation of the assay.

Effect of the duration of hospice and palliative care on the quality of dying and death in patients with terminal cancer: A nationwide multicentre study.

Early referral to hospice and palliative care (HPC) has significant benefits, but little is known about the appropriate time for referral. The purpose of this study of terminal cancer patients was to identify the most appropriate time for referral to HPC. Cross-sectional correlation study design was used. Participants were the bereaved relatives, who were the adult primary caregivers of the 1,829 terminal cancer patients who died 2-6 months previously in nationwide centres that provide HPC in Korea. A post-bereavement survey (Good Death Inventory, GDI) of family caregivers was used to assess patients' quality of dying and death. Relative to patients who were in HPC for 3-7 days and HPC for 8-21 days, those in HPC for 22-84 days had significantly higher quality of dying. Propensity score matched comparison between the group hospitalised for 22-84 days (n = 65) and the group hospitalised for 85 days or longer (n = 65) showed no significant differences in all the items on quality of dying and death. Our results suggest that terminal cancer patients who stay in HPC at least for 22 days have improved quality of dying and death.

Prognostic value of sequencing-based minimal residual disease detection in patients with multiple myeloma who underwent autologous stem-cell transplantation.

BACKGROUND: Most patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Therefore, new technologies to assess deeper response are required. PATIENTS AND METHODS: We retrospectively analyzed 125 patients with MM who underwent high-dose melphalan plus autologous stem-cell transplantation (ASCT) to detect MRD in autograft/bone marrow (BM) cells using a next-generation sequencing (NGS)-based method and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). RESULTS: NGS-based method was applicable to 90% and this method had at least one to two logs greater sensitivity compared to ASO-PCR. MRD negative by NGS [MRDNGS(-)] (defined as <10-6) in post-ASCT BM cases (n = 26) showed a significantly better progression-free survival (PFS) (96% at 4 years, P < 0.001) and overall survival (OS) (100% at 4 years, P =0.04) than MRDNGS(+) in post-ASCT BM cases (n = 25). When restricting the analysis to the 39 complete response cases, patients who were MRDNGS(-) (n = 24) showed a significantly better PFS than those that were MRDNGS(+) (n = 15) (P =0.02). Moreover, MRDNGS(-) in post-ASCT BM cases (n = 12) showed significantly a better PFS than MRDNGS(+) cases (n = 7) where MRD was not detected by ASO-PCR (P = 0.001). Patients whose autografts were negative by NGS-based MRD assessment (<10-7) (n = 19) had 92% PFS and 100% OS at 4 years post-ASCT. Conversely, the NGS-based MRD positive patients who received post-ASCT treatment using novel agents (n = 49) had a significantly better PFS (P = 0.001) and tended to have a better OS (P= 0.214) than those that were untreated (n = 33). CONCLUSIONS: Low level MRD detected by NGS-based platform but not ASO-PCR has significant prognostic value when assessing either the autograft product or BM cells post-ASCT.

Pulmonary nodule size evaluation with chest tomosynthesis and CT: a phantom study.

OBJECTIVE: We compared digital tomosynthesis (TOMO) and chest CT in terms of assessing the sizes of nodules located in zones where evaluation by simple radiography is limited. METHODS: A total of 48 images comprising phantom nodules of four sizes in six different locations were used. Nodule size measurement errors for measurements using TOMO and CT images compared with the actual size from each observer were calculated. The inter- and intraobserver repeatability of the measured values and the agreement between the two techniques were assessed using the method described by Bland and Altman. RESULTS: The mean measurement errors for all of the nodules and four observers were -0.84 mm [standard deviation (SD), 0.60 mm] on TOMO and -0.18 mm (SD, 0.71 mm) on CT images. The mean measurement errors for the different observers ranged from -1.11 to -0.55 mm for TOMO and from -0.39 to 0.08 mm for CT. Assessing the agreement between nodule size measurements using TOMO and CT resulted in mean measurement errors of -0.65 mm, with a 95% limit of agreement of -2.53 to 1.22 mm for comparison of TOMO with CT. CONCLUSION: Our results suggest that nodule sizes obtained using TOMO and chest CT are comparable, even for nodules located in areas where the size measurement is limited on simple radiography. ADVANCES IN KNOWLEDGE: TOMO and CT can be used interchangeably, even for nodules located in a blind area on simple radiography.

The association between bone mineral density and periodontitis in Korean adults (KNHANES 2008-2010).

OBJECTIVES: This study investigated the association between bone mineral density (BMD) and periodontitis in a representative sample of Korean adults. MATERIAL AND METHODS: Of 36 188 individuals who participated in the Korea National Health and Nutrition Examination Survey in 2008, 2009, and 2010, 9977 participants aged ≥40 years were included in this cross-sectional study. The associations of BMD of lumbar spine, total femur, and femoral neck with periodontitis were investigated using logistic regression analysis. Additionally, dose-response relationships with BMD divided into quintiles and the association between osteoporosis and periodontitis were investigated. RESULTS: With the set of Community Periodontal Index (CPI) ≥ 3 as a dependent variable, logistic regression analysis revealed that a decrease of BMD was significantly associated with higher odds of periodontitis [range of adjusted odds ratios (AORs); 1.15-1.20, P < 0.001 for all BMD sites]. Similarly, these associations were also found in the CPI 4 model. With regard to dose-response relations, the lower the BMD quintile, the higher the AORs appeared with statistical significance in the CPI ≥ 3 model. (P for trend < 0.001) Participants with osteoporosis had 2.26 and 1.91 times higher odds for CPI ≥ 3 and CPI 4, respectively, than those with normal BMD, indicating a significant association between the two diseases. CONCLUSIONS: Our results suggest that BMD is significantly associated with periodontitis.

Timeliness of MMR vaccination and barriers to vaccination in preschool children.

The documented vaccine coverage rate of measles-mumps-rubella (MMR) vaccination is almost 99% in Korea, but measles cases are constantly being reported. This study evaluated the vaccine coverage, timeliness, and barriers to immunization of measles vaccination in preschool children in Korea. We assessed 452 children aged 15-23 months and 300 children aged 4-6 years in September 2007. Questionnaires were administered in order to estimate measles vaccination rate, its timeliness and barriers to vaccine uptake. Being unaware of the necessity for vaccination and its schedule, child being sick during the recommended vaccination period, and recommended vaccination period not being over were significant preventive factors to timely vaccination (P < 0·05). Children with working mothers, single parents, those not being cared for by their parents, and those younger among siblings were at a higher risk of not being vaccinated on time. In order to increase timely vaccination, accurate information should be delivered and a systematic approach should be targeted to high-risk groups.

Effect of postnatal catch-up growth on blood pressure in children at 3 years of age.

Size at birth and early postnatal growth rates appear to be important determinants of cardiovascular diseases. We examined whether intrauterine growth restriction or the subsequent catch-up postnatal weight gain leads to higher blood pressure in early life to confirm that size at birth and early postnatal growth rates appear to be important determinants of blood pressure changes in early life. Of 407 children born between December 2001 and November 2002 in hospital based-birth cohorts, 102 were followed up at 3 years of age (24.2%) at Ewha Womans University Hospital in Seoul, Korea. At 3 years of age, those who had a low birth weight still belonged in the lower-weight group than the others. The subjects' systolic blood pressure was correlated with their current weight (r=0.41) and weight gain (r=0.39), but not with their birth weight. Those with a higher current weight and higher weight gain based on birth weight (conditional weight gain) had the highest blood pressure. Systolic blood pressure increased by 0.2 mm Hg for every 100-g increase in weight at 3 years and, independently, by 1.5 mm Hg for every 100-unit increase in conditional weight gain. This study suggests that birth weight is not directly associated with blood pressure, but accelerated growth, which occurs mostly in those born with a low birth weight, seems to affect blood pressure in early life.

Increased expression of Galphaq protein in the heart of streptozotocin-induced diabetic rats.

Heart disease is one of the major cause of death in diabetic patients, but the pathogenesis of diabetic cardio-myopathy remains unclear. In this experiment, to assess the significance of G protein signaling pathways in the pathogenesis of diabetic cardiomyopathy, we analyzed the expression of G proteins and the activities of second messenger dependent protein kinases: cAMP-dependent protein kinase (PKA), DAG-mediated protein kinase C (PKC), and calmodulin dependent protein kinase II (CaM kinase II) in the streptozotocin induced diabetic rat heart. The expression of Galphaq was increased by slightly over 10% (P<0.05) in diabetic rat heart, while Galphas, Galphai, and Gbeta remained unchanged. The PKA activity in the heart did not change significantly but increased by 27% (P<0.01) in the liver. Insulin treatment did not restore the increased activity in the liver. Total PKC activity in the heart was increased by 56% (P<0.01), and insulin treatment did not restore such increase. The CaM kinase II activity in the heart remained at the same level but was slightly increased in the liver (14% increase, P<0.05). These findings of increased expression of Galphaq in the streptozotocin-diabetic rat heart that are reflected by the increased level of PKC activity and insensitivity to insulin demonstrate that alteration of Galphaq may underlie, at least partly, the cardiac dysfunction that is associated with diabetes.