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Background/Purpose: Stereotactic ablative radiotherapy (SABR) is the treatment of choice for medically inoperable, early-stage non-small cell lung cancer (ES-NSCLC). The influence of oncogenic driver alterations and comorbidities are not well known. Here we present treatment outcomes based on clinicopathologic features and molecular profiles. Methods: We retrospectively analyzed patients treated with SABR for inoperable ES-NSCLC. Molecular features of oncogenic driver alterations included EGFR, ALK, and ROS1. Comorbidities were assessed using the age-adjusted Charlson Comorbidity Index (ACCI). Survival was calculated using the Kaplan–Meier method. The Cox regression model was performed for univariate and multivariate analyses of prognostic factors. Competing risk analysis was used to evaluate the cumulative incidence of disease progression. Results: From 2008 to 2020, 100 patients (median age: 82 years) were enrolled. The majority of patients were male (64%), ever-smokers (60%), and had adenocarcinoma (65%). With a median follow-up of 21.5 months, the median overall survival (OS) and real-world progression-free survival were 37.7 and 25.1 months, respectively. The competing-risk-adjusted 3-year cumulative incidences of local, regional, and disseminated failure were 8.2%, 14.5%, and 31.2%, respectively. An ACCI ≥7 was independently associated with inferior OS (hazard ratio [HR] 2.45, p = 0.03). Tumor size ≥4 cm (HR 4.16, p

Immune thrombocytopenic purpura (ITP) is characterized by thrombocytopenia and bleeding diathesis. Pancreatitis is a very rare complication but may be fatal. We analyzed data of newly diagnosed ITP patients, excluding those with a history of splenectomy, unknown sex or date of birth, or preexisting pancreatitis at the time of ITP diagnosis, and compared these with selected age-, gender-, and index-year-matched controls, using the Taiwan National Health Insurance Research Database from 1996 to 2013. The study enrolled 100,177 ITP patients and 100,177 controls. We found that pancreatitis risk was higher in secondary ITP patients, regardless of age group, gender, baseline Charlson comorbidity index (CCI) score, history of biliary stone, hyperlipidemia, or alcoholism, than in the control population. Primary ITP patients with CCI score 1 and without biliary tract stone history also showed a higher pancreatitis risk than the controls. The incidence rate and cumulative incidence of pancreatitis were increased in primary, secondary, and unspecified ITP cases. These phenomena may be related to the presence of autoantibodies against glycoprotein IIb/IIIa, or to IgG4, microparticle obstruction, or sclerosis. We noted a direct association between ITP and the development of pancreatitis in Taiwan population.

Background Stereotactic radiosurgery (SRS), a validated treatment for brain tumors, requires accurate tumor contouring. This manual segmentation process is time-consuming and prone to substantial inter-practitioner variability. Artificial intelligence (AI) with deep neural networks have increasingly been proposed for use in lesion detection and segmentation but have seldom been validated in a clinical setting. Methods We conducted a randomized, cross-modal, multi-reader, multispecialty, multi-case study to evaluate the impact of AI assistance on brain tumor SRS. A state-of-the-art auto-contouring algorithm built on multi-modality imaging and ensemble neural networks was integrated into the clinical workflow. Nine medical professionals contoured the same case series in two reader modes (assisted or unassisted) with a memory washout period of 6 weeks between each section. The case series consisted of 10 algorithm-unseen cases, including five cases of brain metastases, three of meningiomas, and two of acoustic neuromas. Among the nine readers, three experienced experts determined the ground truths of tumor contours. Results With the AI assistance, the inter-reader agreement significantly increased (Dice similarity coefficient [DSC] from 0.86 to 0.90, P < 0.001). Algorithm-assisted physicians demonstrated a higher sensitivity for lesion detection than unassisted physicians (91.3% vs 82.6%, P = .030). AI assistance improved contouring accuracy, with an average increase in DSC of 0.028, especially for physicians with less SRS experience (average DSC from 0.847 to 0.865, P = .002). In addition, AI assistance improved efficiency with a median of 30.8% time-saving. Less-experienced clinicians gained prominent improvement on contouring accuracy but less benefit in reduction of working hours. By contrast, SRS specialists had a relatively minor advantage in DSC, but greater time-saving with the aid of AI. Conclusions Deep learning neural networks can be optimally utilized to improve accuracy and efficiency for the clinical workflow in brain tumor SRS.

PURPOSE/OBJECTIVE(S) Apolipoprotein E (APOE) polymorphism is a well-known risk associated with Alzheimer's disease. Its role in neurocognition decline after whole brain radiotherapy (WBRT) for brain metastases is not well-investigated. The present secondary analysis of a prospective blinded randomized controlled phase II trial aimed to evaluate the impact of APOE genotypes upon neurocognitive outcomes after WBRT with or without hippocampal avoidance. MATERIALS/METHODS Adult patients with brain metastases were stratified by prior radiosurgery and randomized to hippocampal avoidant conformal WBRT versus conformal WBRT without hippocampal avoidance to 30 Gy in 10 fractions from March 2015 to November 2018. Memantine was not used during or after WBRT. Standardized neurocognitive test battery (Hopkins Verbal Learning Test-Revised [HVLT-R], Trail Making Test), was performed at baseline, 1, 2, 4, 6, and every 3 months up to two years by trained independent health professionals. Both clinical trial participants and examiners were blinded to the treatment group assignment. APOE alleles were determined by the genome-wide genotyping. The association between APOE genotypes and neurocognitive outcomes was analyzed by general linear model. The role of APOE genotypes on the effect of hippocampal avoidance during WBRT was also evaluated. Factorial ANOVA was used to assess the independent factors associated with neurocognitive outcomes. RESULTS Among 65 analyzable patients, APOE genotyping was available for 64.6% (n = 42) of patients. The most frequent APOE allele was e3 homozygote (e3/e3, n = 24), followed by e2 carrier (e2/e3, n = 11) and e4 carrier (e4/e3, n = 7). No differences in baseline characteristics and cognitions between patients of different APOE genotypes. At 6-month, patients carrying APOE e2 and e4 allele had the best and worst preservation in HVLT-R total recall (mean difference, e2: +3.18 versus e4: -3.20, P = 0.008), and delayed recall (mean difference, e2 carrier: +0.46 versus e4 carrier: -2.40, P = 0.03), respectively. The effect of preservation in 6-month memory score is the strongest in the APOE e2 carriers followed by the APOE e3 homozygotes, and the least in the APEO e4 carriers in order (P = 0.028). Only patients of APOE e3 homozygotes showed improved preservation in late memory score by hippocampal avoidant WBRT at 6-month (mean difference, hippocampal avoidant: +3.67 versus conformal: -3.18, P = 0.037) and beyond. APOE genotyping was independent of age and hippocampal avoidance to be associated with the preservation of 6-month HVLT-R total recall (P = 0.042), and HVLT-R delayed recall (P = 0.032). CONCLUSION The APOE genotype is associated with the risk of memory decline after WBRT. Specifically, APOE e2 carriers exhibited better while e4 carriers showed worse perpetuation in verbal memory function after WBRT. APOE e3 homozygotes but not APOE e2 or e4 carriers benefit late memory preservation by hippocampal avoidant WBRT for brain metastases.

The vagus nerve plays an essential role in homeostasis and inflammation. Clinically, peptic ulcer patients without helicobacter pylori (HP) infection may provide a population for studying the effect of vagal hyperactivity. There were interests in the association of gastrointestinal disease and urogenital disorders. Herein, we try to investigate subsequent risk of benign prostatic hyperplasia (BPH) in non-HP infected peptic ulcer patients. We identified 17,672 peptic ulcer admission male patients newly diagnosed in 1998–2007 from Taiwan Health Insurance Database, and 17,672 male comparison without peptic ulcer, frequency matched by age, and index-year. We assessed subsequent incidence of BPH in each cohort by the end of 2013, and then compared the risk of developing BPH between individuals with and without peptic ulcer. In addition, peptic ulcer patients underwent surgery were also examined. There were 2954 peptic ulcer patients and 2291 comparisons noted with the occurrence of BPH (25.35 and 16.70 per 1000 person-years, respectively). Compared to comparisons, peptic ulcer patients had a 1.45- and 1.26-fold BPH risk in multivariable Cox model and Fine and Gray model (95% CI 1.37–1.54 and 1.19–1.34). In age-stratified analysis, the highest risk of BPH was in 45–59 years (interaction p

Whether a strategy of postoperative non-sedation produces better outcomes compared with sedation in patients after head and neck reconstruction remains controversial. Therefore, we retrospectively investigated outcomes in 150 of these patients in our institution. Patients with head and neck cancer that received free anterolateral thigh flap were studied retrospectively, and were categorized in terms of their postoperative care into “sedation” and “non-sedation” groups. The related parameters of each patient were collected for analysis. Overall, 150 patients were included (sedation protocol (N = 56) and non-sedation strategy (N = 94)). No significant differences were observed between groups in patient demographics or postoperative outcomes. Significantly shorter durations of mean and median intensive care unit (ICU) length of stay, mechanical ventilation, hospitalization, and operative time were observed in the non-sedation group than in the sedation group. Among all patients, the sedation and flap reopen were the common variables related to prolonged ICU stay, mechanical ventilator duration, and hospitalization. The current study suggested the strategy of postoperative non-sedation is associated with a significant decrease in the duration of mechanical ventilation, ICU length of stay, hospitalization. Regardless of hospital stay, there were no differences in postoperative outcome between 2 groups.

Background: Limited studies have discussed the association between facial fractures and subsequent migraines. In this study, we examined this association and the effect of facial fracture and surgery on the development of migraines. Methods: We selected 5034 patients with facial fractures and a matched cohort of 20,136 patients without facial fractures or facial-associated surgery with a history of migraine from the National Health Insurance database. Risk factors included age, gender, occupation (white-collar, blue-collar, and others), and comorbidities. Patients were frequency matched by age, gender, and index year. The incidence of migraine and the association between migraine development and facial surgery were identified by facial fracture location stratification. Results: The incidence of migraines in the facial fracture cohort was 1.37-fold higher when compared with the comparison cohort (6.47 vs. 4.73 per 1000 person-years). There was a 1.31-fold risk of migraines in the adjusted hazard model and a 1.30-fold risk of migraines in the subdistribution hazard model (95% confidence interval [CI], 1.12-1.52 and 1.12-1.51, respectively). Malar/maxillary and nasal fractures showed 1.48- and 1.29-fold risks of migraines in the adjusted hazard model and subdistribution hazard model (95% CI, 1.16-1.89 and 1.05-1.59, respectively). There were no significant differences in migraine occurrence among patients who underwent surgery. Conclusions: Our findings indicated that malar/maxillary and nasal fractures were associated with a subsequent risk of migraines. There were no significant differences in migraine occurrence among patients who underwent surgery. Because of the retrospective nature of this study, further studies are warranted.

In end-stage renal disease (ESRD) patients receiving dialysis, anemia is common and related to a higher mortality rate. Erythropoietin (EPO) resistance and iron refractory anemia require red blood cell transfusions. Myelodysplastic syndrome (MDS) is a disease with hematopoietic dysplasia. There are limited reports regarding ESRD patients with MDS. We aim to assess whether, for ESRD patients, undergoing dialysis is a predictive factor of MDS by analyzing data from the Taiwan National Health Insurance Research Database. We enrolled 74,712 patients with chronic renal failure (ESRD) who underwent dialysis and matched 74,712 control patients. In our study, we noticed that compared with the non-ESRD controls, in ESRD patients, undergoing dialysis (subdistribution hazard ratio [sHR] = 1.60, 1.16–2.19) and age (sHR = 1.03, 1.02–1.04) had positive predictive value for MDS occurrence. Moreover, more units of red blood cell transfusion (higher than 4 units per month) was also associated with a higher incidence of MDS. The MDS cumulative incidence increased with the duration of dialysis in ESRD patients. These effects may be related to exposure to certain cytokines, including interleukin-1, tumor necrosis factor-α, and tumor growth factor-β. In conclusion, we report the novel finding that ESRD patients undergoing dialysis have an increased risk of MDS.

BackgroundHippocampal avoidance whole-brain radiotherapy (HA-WBRT) shows potential for neurocognitive preservation. This study aimed to evaluate whether HA-WBRT or conformal WBRT is better for preserving neurocognitive function.MethodsThis single-blinded randomized phase II trial enrolled patients with brain metastases and randomly assigned to receive HA-WBRT or conformal WBRT. Primary end point is the decline of Hopkins Verbal Learning Test–Revised (HVLT-R) Delayed Recall at 4 months after treatment. Neurocognitive function tests were analyzed with a mixed effect model. Brain progression free survival (BPFS) and overall survival (OS) were estimated using the Kaplan–Meier method.ResultsPatients were enrolled from March 2015 to December 2018 with a median follow-up of 12.4 months. A total of 70 patients were randomized. No differences in baseline neurocognitive function existed between the two arms. There were no differences in any neurocognitive assessments at four months. At six months, patients receiving HA-WBRT showed favorable perpetuation of HVLT-R total recall (mean difference = 2.60, p = 0.079) and significantly better preservation of the HVLT-R recognition-discrimination index (mean difference = 1.78, p = 0.019) and memory score (mean difference = 4.38, p = 0.020) compared with patients undergoing conformal WBRT. There were no differences in TMT part A, part B, or the COWA test between the two arms at any time point. There were no differences in BPFS or OS between arms as well.ConclusionsPatients receiving HA-WBRT without Memantine showed better preservation in late verbal memory, but not in verbal fluency or executive function.

Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze BDH2mRNA expression in the bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients with normal BM. Elevated BDH2mRNA expression in BM is observed in MDS patients (n = 187 vs. 43, normal BM, P = 0.009), and this is related to ferritin levels. Patients with higher BDH2 expression show a greater risk of leukemia progression (15.25% vs. 3.77%, lower expression, P = 0.017) and shorter leukemia-free-survival (medium LFS, 9 years vs. 7 years, P = 0.024), as do patients with a ferritin level &ge, 350 ng/mL. Additionally, we investigate the mechanisms related to the prognostic ability of BDH2 by using BDH2-KD THP1. The cell cycle analysis, surface markers, and special stain studies indicate that BDH2-KD induces differentiation and decreases the growth rate of THP1 cells, which is associated with the retardation of the cell cycle. Moreover, many genes, including genes related to mitochondrial catabolism, oncogenes, tumor suppressor genes, and genes related to cell differentiation and proliferation influence BDH2-KD THP1 cells. Herein, we demonstrate that BDH2 is involved in cell cycle arrest and the inhibition of differentiation in malignant cells. Furthermore, the high BDH2 expression in MDS patients could be suggestive of a poor prognostic factor. This study provides a foundation for further research on the roles of BDH2 and iron metabolism in the pathogenesis of MDS.

Purpose The impact of epidermal growth factor receptor (EGFR) mutations on radiotherapy for brain metastases (BM) is undetermined. We evaluated the effects of EGFR mutation status on responses and outcomes in non-small cell lung cancer (NSCLC) patients with BM, treated with upfront or salvage stereotactic radiosurgery (SRS). Methods and materials From 2008 to 2015, 147 eligible NSCLC patients with 300 lesions were retrospectively analyzed. Patterns of tyrosine kinase inhibitor (TKI) therapy were recorded. Radiographic response was assessed. Brain progression-free survival (BPFS) and overall survival were calculated and outcome prognostic factors were evaluated. Results Median follow-up time was 13.5 months. Of the EGFR-genotyped patients, 79 (65%) were EGFR mutants, and 42 (35%) were wild type. Presence of EGFR mutations was associated with higher radiographic complete response rates (CRR). Median time to develop new BM after SRS was significantly longer for mutant-EGFR patients (17 versus 10.5 months, p = 0.02), predominantly for those with adjuvant TKI therapy (26.3 versus 15 months, p = 0.01). EGFR mutations independently predicted better BPFS (HR = 0.55, p = 0.048) in multivariate analysis. Conclusions In patients with NSCLC treated with SRS for BM, the presence of EGFR mutations is associated with a higher CRR, longer time for distant brain control, and better BPFS. The combination of SRS and TKI in selective patient group can be an effective treatment choice for BM with favorable brain control and little neurotoxicity.

PURPOSE/OBJECTIVE(S) This phase II blinded randomized trial investigated the neurocognitive outcomes of conformal whole brain radiotherapy (WBRT) with or without hippocampal avoidance for patients with brain metastases. Patients received hippocampal-avoidant WBRT had better preservation in late verbal memory measured by the Hopkins Verbal Learning Test-Revised. Here, we presented the patient-reported health-related quality of life (HRQOL) and functional outcomes. MATERIALS/METHODS Adult patients with brain metastases were randomized to receive hippocampal-avoidant conformal WBRT (HA-cWBRT) versus conformal WBRT without hippocampal avoidance (cWBRT) to 30 Gy in 10 fractions. Memantine was not used during or after WBRT. HRQOL was a secondary end point in the trial. HRQOL was assessed at baseline, 2, 4, 6, and every 3 months up to two years with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and Brain Cancer Module. The following six primary HRQOL function scales were considered: global health status; physical, cognitive, role, social, and emotional functioning. A ≥ 10-point difference from baseline is considered of clinical relevance. HRQOL results were compared at baseline and over time with mixed effects models adjusted for treatment arm, time, and interaction. Pearson correlation between function scales was performed. Statistical significance required P < 0.05. RESULTS From March 2015 to November 2018, 70 patients were randomized and 65 patients (HA-cWBRT group, n = 33; cWBRT group, n = 32) completed protocol treatment. Compliance was 100% at baseline, 56.9% at 6 months, and dropped to 29.2% at 12 months. Thus, only the first year was analyzed. There were no differences in the six primary HRQOL function scales between the two arms at baseline. Patients in the cWBRT arm reported better HRQOL scores in cognitive functioning (P = 0.02), emotional functioning (P = 0.01), and social functioning (P = 0.04), as well as a favorable score in global health status (P = 0.07) than did patients who received HA-cWBRT. There were no differences in physical and role function scales between the two arms over time. The differences were statistically significant and clinically relevant mostly during the early follow-up period (for cognitive functioning at 2 & 4 months, emotional functioning at 2, 9 & 12 months, social functioning at 2 & 4 months, and global health status at 4 months). Correlation analysis showed that cognitive and emotional function scales were highly related (r value = 0.67 at 2 months, 0.85 at 4 months, and 0.68 at 6 months, respectively, all P < 0.001) CONCLUSION: In contract to the objective standardized neurocognitive test, patients received hippocampal-avoidant WBRT for brain metastases reported worse HRQOL in cognitive, emotional and social functioning over time. There as a strong correlation between cognitive and emotional functioning. Further investigation on the emotional outcomes after WBRT is warrant.

Highlights • The role of thoracic control for lung cancer has become increasingly important with improvements in lung cancer treatment and patient survival. Thoracic re-irradiation became feasible with the advance and adaptation of radiation technology. • Our study retrospectively collected data related to clinicopathological features and treatment outcomes of 50 patients who had two courses of thoracic RT in at least 50% overlapping fields. A promissing local control with median time to local progression of 18 months and a median overall survival of 25.1 months were found. • We also found that subsequent chemotherapy with taxanes- or gemcitabine-based regimen following thoracic re-irradiation was significantly related to lethal lung events. • These results helped prove the feasibility of re-irradiation with conventionally fractionated RT and increase awareness regarding underestimated lung toxicity resulting from subsequent chemotherapy following thoracic re-irradiation., Background and purpose Thoracic re-irradiation may be an alternative treatment for lung cancer patients who develop intrathoracic locoregional recurrence without systemic progression. This study aimed to retrospectively assess locoregional control, clinical outcomes, and toxicities in lung cancer patients who received thoracic re-irradiation. Materials and methods We retrospectively reviewed 50 lung cancer patients who received thoracic re-irradiation using conventional photon radiotherapy (RT) and stereotactic body radiotherapy (SBRT) between 2009 and 2017. The correlations of clinicopathologic factors, treatment factors, and dosimetric factors of RT with time to local progression (TTLP), progression-free survival (PFS), and overall survival (OS) after starting thoracic re-irradiation were calculated using log-rank tests and Cox regression models. Results The median re-irradiation dose in equivalent dose in 2-Gy fractions was 51.1 Gy, and the mean re-irradiation planning target volume was 201.58 ml. The median mean lung dose (MLD) was 4.18 Gy, and the total lung volumes receiving a dose of 5 Gy (lung V5) and of 20 Gy (V20) were 19.8% and 5.85%, respectively. The TTLP, PFS, and OS were 18.0, 5.9, and 25.1 months, respectively. Lung V5 (p

Rationale: Lymphoma with an initial manifestation of ascites and peritoneal invasion is rare. Patient concerns: A 65-year-old woman presented to the emergency department with a 3-week history of abdominal distention, anorexia, and night sweating, and a 2-week history of melena. She was a silent hepatitis B virus carrier. Abdominal ultrasound showed massive ascites without cirrhosis. Abdominal computed tomography revealed ascites, infiltrative peritoneal lesions with omental cake appearance, and lymphadenopathies. Diagnosis: We performed paracentesis and the ascites cytology was obtained. The patient also underwent esophagogastroduodenoscopy, which showed ulcerative tumors in the stomach. Both ascites cytology and pathology of the gastric tumors confirmed the diagnosis of B-cell lymphoma. Interventions: This patient received 7 cycles of chemotherapy. Outcomes: Follow-up imaging studies revealed partial remission of lymphoma, but an enlargement of residual tumors in omentum and mesentery, which resulted in intractable ascites and rapid deterioration of performance status. Despite a change of regimen of chemotherapy, this patient expired 10 months after diagnosis. Lessons: Lymphoma should be one of the differential diagnoses in patients with intractable ascites not attributable to other comorbidities.

Background: Most Aristolochiaceae plants are prohibited due to aristolochic acid nephropathy (AAN), except Xixin ( Asarum spp. ). Xixin contains trace amounts of aristolochic acid (AA) and is widely used in Traditional Chinese Medicine. Methylglyoxal and D-lactate are regarded as biomarkers for nephrotoxicity. Thus, this study aimed to evaluate tubulointerstitial injury and interstitial renal fibrosis by determining urinary methylglyoxal and D-lactate after withdrawal of low-dose AA in a chronic mouse model. Methods: C3H/He mice in the AA group ( n =24/group) were given ad libitum access to distilled water containing 3 µg/mL AA (0.5 mg/kg/day) for 56 days and drinking water from days 57 to 84. The severity of tubulointerstitial injury and fibrosis were evaluated using the tubulointerstitial histological score (TIHS) and Masson’s trichrome staining. Urinary and serum methylglyoxal were determined by high-performance liquid chromatography (HPLC); urinary D-lactate were determined by column-switching HPLC. Results: After AA withdrawal, serum methylglyoxal in the AA group increased from day 56 (429.4±48.3 μg/L) to 84 (600.2±99.9 μg/L), and peaked on day 70 (878.3±171.8 μg/L; p Conclusions: Methylglyoxal is induced after AA-induced tubulointerstitial injury, thus methylglyoxal excretion and metabolism may be a detoxification and repair strategy. A low cumulative AA dose is the key factor that limits tubulointerstitial injury and repair. Thus, AA-containing herbs, especially Xixin, should be used at low doses for short durations (less than one month).

Gene mutation and pathogenesis bacteria are highly associated with colorectal cancer (CRC) development and progression. Autophagy is a self-clearance pathway to degrade abnormal proteins and infected bacteria in cells. Autophagy plays a dual role in cancer development. Among the autophagy-related (ATG) proteins, ATG5 is the key component required for the core machinery of autophagy. However, the role of ATG5 in CRC malignancy remains unclear. Herein, we found that a high ATG5 protein level was correlated with poor overall survival (OS) and disease-free survival (DFS) of 118 patients with CRC. After stratification with demographic and clinicopathologic factors, a high ATG5 protein level was significantly correlated with unfavorable overall survival in female and elder (&gt, 60 year) CRC patients and tumor tissues with poor differentiation, late T stages (III + IV), whereas the ATG5 protein level was positively associated with the overall survival in CRC patients without lymph node invasion and radiation therapy. In contrast, a high ATG5 protein level was significantly associated with worse DFS in CRC patients with early stage of AJCC and no radiation therapy. In addition, colorectal cancer cells stably harboring small interfering RNA (siRNA) against ATG5 diminished the tumorsphere formation and sensitized cancer cells to chemotherapeutic agents. Taken together, our results suggest that ATG5 might be a prognostic biomarker for CRC and a potential therapeutic target for CRC patients.

Treatment strategies for nasal extranodal NK/T-cell lymphoma (ENKTL), including sequential chemotherapy followed by radiotherapy (SCRT), concurrent chemoradiotherapy (CCRT), or radiotherapy alone (RT), remain varied. The purpose of this study was to assess the treatment outcome, the toxicity, and the potential prognostic factors for patients with early-stage nasal ENKTL treated using definitive RT (minimum of 50 Gy) with or without chemotherapy. From 1998 to 2014, 37 patients were included in the study. Eight patients were treated with RT alone, 1 with CCRT, and 28 with SCRT. Local regional control (LRC), progression-free survival (PFS), and overall survival (OS) were calculated using the Kaplan–Meier method. RT resulted in an overall response rate of 91.2%, with a complete response rate of 78.4%. After a median follow-up time of 36.8 months, the 3-year LRC, PFS and OS were 87.4%, 64.0% and 76.3%, respectively. Acute severe toxicity (Grade 3) of mucositis was observed in 6 (16.2%) of the 37 patients. In univariate analyses, extensive disease (Stage I/II with local invasiveness) and the presence of B symptoms were significantly associated with a poor PFS, whereas extensive disease was significantly associated with a poor OS. Multivariate analysis identified the presence of extensive disease as an independent predictor of PFS (P

We present a rare case of intracardiac myeloid sarcoma (MS) of acute myeloid leukemia (AML) and who responds completely well to low-dose radiotherapy. This 19-year-old young man initially presented with AML and received standard chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, he developed intracardiac isolated MS relapse with the presentation of exertional dyspnea and superior vena cava (SVC) syndrome 3 years later. He then received radiotherapy with 24 Gy at a 12 daily fractions using forward “field in field” intensity modulated radiotherapy technique. He dramatically had improved clinical symptoms, and complete remission was achieved one month after completing radiotherapy. Our result is in line with anecdotal case reports showed that radiotherapy with 15 Gy in 10 fractions or with 24 Gy in 12 fractions resulted in good response and less toxicity of 2 cases of MS with cardiac involvement. These results indicate that a modest radiotherapy dose, 24 Gy, achieves good local control of MS with cardiac involvement.

Very late (more than 10 years) relapse of plasma cell myeloma after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is rare. The most common relapse pattern in such cases involves the bone marrow. Here, we report the case of a 51-year-old woman whose myeloma relapsed 15 years after allo-HSCT. She retained full donor chimerism, and the myeloma presented as soft tissue in the colonic wall. According to our review of the literature, this case presents the longest time to relapse after allo-HSCT. Patients with myeloma who undergo allo-HSCT should continue to receive regular follow-up even after 15 years.

The genetic or functional inactivation of the p53 pathway plays an important role with regards to disease progression from the chronic phase (CP) to blast phase (BP) and imatinib treatment response in chronic myeloid leukemia (CML). Two functional single nucleotide polymorphisms (SNPs), p53 R72P and MDM2 SNP309, are associated with alternation of p53 activity, however the association regarding CML susceptibility and BP transformation under imatinib treatment is unclear. The MDM2 SNP309 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing from 116 CML patients, including 104 in the CP at diagnosis, and 162 healthy Taiwanese controls. The p53 R72P polymorphism was examined in all CML patients. The SNP309 G/G genotype was associated with an increased risk of CML susceptibility (OR: 1.82, 95% CI: 1.03-3.22, P = 0.037), and an earlier age of disease onset (log-rank P = 0.005) compared with the T/T + T/G genotypes. Higher MDM2 mRNA expression was found in G/G genotype compared with T/T (P = 0.034) and T/T + T/G (P = 0.056) genotypes. No associations were found between the p53 R72P genotypes and clinical parameters and survival outcomes. Among 62 CP patients receiving imatinib as first-line therapy, the G/G genotype was associated with a shorter blast-free survival (log-rank P = 0.048) and more clonal evolution compared with the T/T + T/G genotypes. In patients with advanced diseases at diagnosis, the G/G genotype was associated with a poor overall survival (log-rank P = 0.006). Closely monitoring CML patients harboring the G/G genotype and further large-scale studies are warranted.

Super scan pattern on technetium-99m methyldiphosphonate (Tc-99m MDP) bone scintigraphy is a special condition of extremely high bone uptake relative to soft tissue with absent or faint renal radioactivity visualization, which is usually seen in diffuse bone metastases or discrete endocrine entities. Here, two cases with super bone scan are presented. One was a young man diagnosed with gastric cancer. The other was a middle-aged woman with a history of breast cancer with recent recurrence. Both cases had 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) diagnosis simultaneously. Based on imaging of 18F-FDG PET/CT, diffusely incremental 18F-FDG avidity in spine/pelvis on PET and subtle erosion of cortical bone on CT were seen. The cytological results of bone marrow biopsy showed evidence of malignant metastasis. However, there were several focal discrepant findings between the 18F-FDG PET/CT and Tc-99m MDP bone scan. According to integration of both imaging findings and the result of bone marrow biopsy, we believe that the disseminated malignant spread in bone marrow is a primitive alternation in the super bone scan and that it is also as a result of neoplasm-related endocrine factors.

Circadian clock genes use transcriptional-translational feedback loops to control circadian rhythms. Recent studies have demonstrated that expression of some circadian clock genes displays daily oscillation in peripheral tissues including peripheral blood and bone marrow. Circadian rhythms regulate various functions of human body, and the disruption of circadian rhythm has been associated with cancer development and tumor progression. However, the direct links between aberrant circadian clock gene expression and human disorders remain largely unknown. In this study, comparisons were made between the expression profiles of 9 circadian clock genes from peripheral blood mononuclear cells (PBMCs) and polymorphonuclear cells (PMNs) from 18 healthy volunteers. Peripheral blood (PB) total leukocytes from 54 healthy volunteers and 95 patients with chronic myeloid leukemia (CML) were also investigated. Similar expression profiles of all 9 circadian clock genes were observed in PBMCs and PMNs of healthy individuals. In PB total leukocytes of healthy individuals, the daily pattern of PER1, PER2, PER3, CRY1, CRY2, and CKIε expression level peaked at 0800 h, and BMAL1 peaked at 2000 h. Daily pattern expression of these 7 genes was disrupted in newly diagnosed pre—imatinib mesylate—treated and blast crisis—phase patients with CML. Partial daily pattern gene expression recoveries were observed in patients with CML with complete cytogenetic response and major molecular response. The expression of CLOCK and TIM did not show a time-dependent variation among the healthy and patients with CML. These results indicate a possible association of the disrupted daily patterns of circadian clock gene expression with the pathogenesis of CML.

The Philadelphia (Ph) chromosome and/or Breakpoint cluster region-Abelson leukemia virus oncogene transcript are unique markers for chronic myeloid leukemia (CML). However, CML demonstrates heterogeneous presentations and outcomes. We analyzed the cytogenetic and molecular results of CML patients to evaluate their correlation with clinical presentations and outcome. A total of 84 newly diagnosed CML patients were enrolled in the study. Patients were treated according to disease status. Bone marrow samples were obtained to perform cytogenetic and molecular studies. Clinical presentations, treatment courses, and survival were reviewed retrospectively. Among 84 patients, 72 had chronic phase and 12 had accelerated phase CML. Cytogenetic study showed 69 (82.1%) with the classic Ph chromosome, 6 (7.2%) with a variant Ph chromosome, and 9 (10.7%) with additional chromosome abnormalities. Fifty-four (64.3%) cases harbored b3a2 transcripts, 29 (34.5%) had b2a2 transcript, and 1 had e19a2 transcript. There was no difference in clinical presentations between different cytogenetic and molecular groups; however, additional chromosome abnormalities were significantly associated with the accelerated phase. Imatinib therapy was an effective treatment, as measured by cytogenetic response, when administered as first- and second-line therapy in chronic phase patients. Survival analysis showed that old age, additional chromosome abnormalities, high Sokal score, and no cytogenetic response in second-line therapy had a significant poor impact (p

Objectives The Janus kinase 2 mutation, JAK2 (V617F) , and megakaryocytic mutations, MPL (W515L/K) , have been identified and correlated with a subtype of essential thrombocythemia (ET) patients. We investigated the frequency of mutations in ET patients and analyzed the relationship with their clinical features. Methods Fifty-three ET patients were enrolled in the study. The amplification refractory mutation system was applied for the mutation survey of the JAK2 V617F , while the polymerase chain reaction with sequencing was used for the mutation survey of MPL W515L/K . Results Thirty-five (66%) patients harboring the JAK2 V617F mutation, including 3 homozygous and 32 heterozygous changes, but no MPL W515L/K mutation, were found. During follow-up, 17 (32.1%) patients suffered from documented thrombotic events, with 15 having JAK2 V617F mutations. Statistical analysis showed that patients with the JAK2 mutation had significantly higher leukocytes, hemoglobin level, and thrombotic event ( p = 0.043, p = 0.001, and p = 0.029, respectively). Thrombotic events were also significantly correlated with leukocytosis and older age. Conclusions The JAK2 V617F mutation was noted in a certain population of ET patients and correlated with leukocytosis, high hemoglobin level, and thrombosis. Therefore, detection of the JAK2 V617F mutation can affect not only the diagnosis, but also the management of ET patients.

Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments. Although the treatments have improved, the major problem in MM is resistance to therapy. Clonal evolution of MM cells and bone marrow microenvironment changes contribute to drug resistance. Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction. Here, we review the pathogenesis of MM cells and bone marrow microenvironment and highlight possible drug resistance mechanisms. We also review a potential molecular targeting treatment and immunotherapy for patients with refractory or relapse MM.

Hemophagocytic syndrome is a rare complication of acute Q fever. We reported the case of 26-year-old man with fever, chills, severe headache, non-productive cough and progressive thrombocytopenia. Bone marrow aspirate revealed hemophagocytosis. We discussed the differences among the three previous reported cases and the possible mechanisms of hemophagocytic syndrome.

Iron is an important regulator of cell growth, apoptosis and enzymatic functions. Many cancers, including soft tissue sarcoma, mesothelioma, renal cell carcinoma, colorectal cancer, gastric cancer, lung cancer, hepatocellular carcinoma, and endometriosis have been associated with iron overload. Iron metabolism is also affected in leukemia, and iron chelators can inhibit proliferation of leukemia cells. Lipocalin 2 (LCN2) is an iron transporter that plays important roles in cellular metabolism, growth and differentiation, and host immune response. Siderophores are small iron-binding molecules that facilitate microbial and mammalian cells iron transport. Type 2 Hydroxy Butyrate Dehydrogenase (BDH2), a member of the short-chain dehydrogenase family, is a rate-limiting factor in the biogenesis of the mammalian siderophores. In our previous studies, we reported that LCN2 is a good prognostic marker in patients with Cytogenetically Normal Acute Myeloid Leukemia (CN-AML), and BDH2 predicts poor prognosis in CN-AML patients. Expression levels of both LCN2 and BDH2 genes are independent from other well-known gene alterations and clinical characteristics of CN-AML patients. They may - (pass through does not make sense) induce or inhibit apoptosis during Reactive Oxygen Species (ROS) challenges. We have also demonstrated that higher BDH2 expressions are associated with a greater chance of leukemic transformation in Myelodysplasia Syndrome (MDS) patients. Since the level of BDH2 expression directly correlates with the serum ferritin concentration in MDS patients, iron metabolism may have important roles in tumor transformation. In this review, we summarize evidence of how iron metabolism and iron transporters influence the prognosis of leukemia.

Several molecular markers, such as NPM1, FLT3 and CEBPA, have been incorporated into both the World Health Organization and European LeukemiaNet classifications as routine assessments for the diagnosis and evaluation of prognostic significance in acute myeloid leukemia (AML). Lipocalin 2 (LCN2) is related to cancer development and is believed to be associated with the outcome of cytogenetically normal (CN)-AML. In the present study, we analyzed the prognostic effects and interactions of LCN2 expression (by molecular analysis, quantitative real-time polymerase chain reaction [qRT-PCR]) with neucleophosmin 1, fms-related tyrosine kinase 3 (FLT3) and CCAAT/enhancer-binding protein alpha mutations in 85 patients with CN-AML receiving intensive induction chemotherapy. Our results indicate that patients with higher LCN2 mRNA expression in the bone marrow (LCN2high), especially in combination with wild type FLT3-ITD, had better prognoses. FLT3-ITD compensated LCN2-overexpression-enhanced oxidative stress-induced apoptosis in cell line studies. In conclusion, LCN2high was associated with better prognosis, and FLT3 status had an adjuvant effect on overall survival.

Acute kidney injury (AKI) is a significant complication after hematopoietic stem cell transplantation (HSCT) and frequently limits treatment success. Patients suffering complications with AKI often have high mortality. This investigation analyzed the outcomes of patients receiving allogeneic HSCT and identified the association between prognosis and RIFLE (risk of renal failure, injury to kidney, failure of kidney function, loss of kidney function and end-stage renal disease) classification. This study reviewed the medical records of 101 patients receiving allogeneic HSCT during an 8-year period at a specialized hematology ward in a university hospital in Taiwan. Demographic, clinical and laboratory variables were retrospectively gathered as predicators. Overall 6-month mortality was 36.6% (37/101). Mortality progressively and significantly increased (x 2 for trend, P , 0.001) based on RIFLE classification severity. Multiple variable Cox regres- sion analysis identified maximum RIFLE score on day 7 to 14 post- HSCT, occurrence of hepatic veno-occlusive disease and respiratory failure during admission as independent risk factors for 6-month mortality. Using the area under the receiver operating characteristic curve, the RIFLE classification on day 7 to 14 post-HSCT has the best discriminative power (area under the receiver operating characteristic curve: 0.696 6 0.057, P , 0.001) compared with day 0 to 7, 14 to 30 and 30 to 60 post-HSCT. Cumulative survival rates at 6-month follow- up differed significantly (P , 0.05) among non-AKI, RIFLE-R versus RIFLE-I and RIFLE-F. Hepatic veno-occlusive disease, respiratory fail- ure and severity of maximum RIFLE score on day 7 to 14 post-HSCT were independent predictors for 6-month mortality. RIFLE classifica- tion on day 7 to 14 post-HSCT can improve the accuracy of 6-month mortality in patients who received allogeneic HSCT. Key Indexing Terms: Acute kidney injury; RIFLE classification

Cisplatin-induced acute kidney injury (AKI) is a major concern among clinicians in prescribing cisplatin-based chemotherapy. This study evaluated and compared the ability of urinary biomarkers, including urinary neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, and the urinary albumin to creatinine ratio (ACR) to predict cisplatin-induced AKI. Thirty-three cancer patients receiving cisplatin-based chemotherapy were prospectively studied, including 10 (30%) who developed AKI (the study group). Changes of urinary biomarkers were compared at 4 hours, 8 hours, and 12 hours, and 1 day, 2 days, 3 days, and 4 days after cisplatin intravenous infusions (75mg/m2) versus the baseline. There was a significant increase in urinary NGAL levels from 12 hours to 4 days (p

Cytomegalovirus (CMV) infection and disease are important concerns after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The similarity of hepatitis B virus (HBV) and CMV with regards to their chronic viral persistence and potential reactivation at the time of impaired cellular immunity has raised clinicians’ interest in the occurrence and association between them among patients receiving allo-HSCT; however, only limited data have been obtained from a high seroprevalence region of both CMV and HBV. We monitored 117 adult allo-HSCT patients with both CMV polymerase chain reaction and pp65 antigenemia assay weekly until day 100. In 91.8% of our cases, donors and recipients were both CMV seropositive, and 13.7% of the patients were positive for HBV surface antigen. The incidences of CMV infection and disease were 45.3% and 6.8%, respectively. Grade II–IV acute graft-versus-host disease and anti-thymocyte globulin-containing conditioning regimen were associated with an increased risk of CMV infection in a multivariate analysis (hazard ratio 3.02, 95% CI 1.68–5.42, p < 0.001 and hazard ratio 5.29, 95% CI 2.57–10.8, p < 0.001). No survival disadvantage was found in patients who developed CMV infection (p = 0.699) and CMV disease (p = 0.093). No clinically significant HBV reactivation was found, and the underlying HBV infection in donors or recipients before allo-HSCT did not increase the risk of CMV infection and CMV disease and did not influence survival after allo-HSCT.

Despite efforts to improve iron supplements for iron deficiency anemia, there is no consensus on products that balance efficacy, safety and tolerability, and cost. Ferrous products are effective, but they are associated with more gastrointestinal side effects than ferric products. Ferric products tend to have lower absorption. We present results from a 12-week study that randomized 72 people with uncomplicated iron deficiency anemia to receive a ferrous iron supplement (Ferall, a combination of ferrous fumarate with ascorbic acid, folic acid, and cyanocobalamin) or a ferric iron polysaccharide complex (Niferex, ferro-glycine sulfate) plus ascorbic acid. The ferrous product was significantly more effective, the primary and secondary endpoints including changes in levels of hemoglobin and serum ferritin. There was a slightly higher frequency of gastrointestinal side effects in patients taking the ferrous product, but both supplements were well tolerated. No participant withdrew from the study because of side effects. We concluded that the ferrous product is safe and effective for use in uncomplicated iron deficiency anemia. The lack of direct comparison between single-agent ferrous fumarate and the combination ferrous product limited interpretation of results in terms of possible effects due to other components, such as ascorbic acid.

Hypertrophic osteoarthropathy (HOA) is characterized by clubbed fingers and periosteal new bone formation. Etiologically, it can be divided into primary and secondary HOA, but its pathogenesis is uncertain. We report a 42-year-old male patient who suffered from painful clubbing fingers and toes. Serial examinations revealed periosteal new bone formation in the four limb long bones and a solid mass lesion in the right upper lung field. Pathologic examination of the resected mass lesion showed squamous cell carcinoma. After surgery and chemotherapy, the severity of clubbed fingers decreased and joint pain improved. Follow-up bone scan also suggested regression of the uptake of radioactivity in the four limb bones. We concluded that the HOA in this case was probably caused by lung cancer.

Objective: Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells. In MDS patients, leukemia progression is associated with iron overload. Hydroxybutyrate dehydrogenase type 2 (BDH2) catalyzes the production of 2,5-dihydroxybenzoic acid (DHBA), an iron-binding component. Methods: The bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients (stage I-III) with normal BM were analyzed. BDH2mRNA expressions from BM and BDH2-KD THP1 were analyzed using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). Cell cycle and cell maturation were determined by flowcytometry and surface markers in RNA interference–mediated-knockdown of BDH2 (BDH2-KD) THP1, an acute leukemia cell line. Immunohistochemistry was performed to detect BDH2 protein expression in the bone marrow. Results: Elevated BDH2mRNA expression was observed in bone marrow in MDS patients (P=0.009) and was related to ferritin levels (P=0.049). The higher BDH2 expression (15%) group showed a greater risk for leukemia progression than the lower expression group (3.18%) (P=0.017). Leukemia-free-survival was longer in patients with low BDH2mRNA expression (P=0.028) and patients with ferritin level Conclusions: We identified new molecular mechanisms of BDH2. BDH2 is involved in cell cycle arrest and inhibition of differentiation in malignant cells. Further, high BDH2 expression in MDS patients suggest that it could act as a poor prognostic factor. Disclosures No relevant conflicts of interest to declare.

Studies in large-scale genome sequencing have shown that only 2% of the mammalian genome encodes mRNAs, but the most part is transcribed as long and short non-coding RNAs (ncRNAs). The ncRNAs with gene regulatory functions are starting to be seen as a common feature of mammalian gene regulation. Genomic imprinting is a form of epigenetic regulation and imprinted genes are silenced in a parental-specific manner. Although the exact mechanism how imprinted ncRNA regulates gene expression remains largely unknown, it is general accepted that imprinted ncRNAs binds to chromatin modifying complexes, such as PRC2, TRX, and G9a, and generates specific silencing of genomic loci both in cis and trans. Imprinting is associated with many human diseases or syndromes (e.g. Prader-Willi, Angelman, Beckwith-Wiedemann, Retts, and Silver-Russell syndromes) and various cancers (e.g. breast, prostate, and colorectal cancers), but its role in leukemogenesis remain elusive. In this present study, the expression of a panel of 24 human imprinted ncRNA genes (AMPD3, C15orf2, COPG2, CPA4, GABRB3, H19, IGF2, IMPACT, INPP5F, L3MBTL, NR3251, NR3252, PEG3-AS, PPP1R9A, PRIM2, RASGRF1, RTL1, SFMBT2, SLC22A3, SNURF, TCEB3C, TSPAN32, ZNF215, ZNF264) and a panel of 66 human histone modifying enzymes (HME) genes was investigated in 68 newly-diagnosed acute myeloid leukemia patients with chromosome normal (AML-CN), 115 AML patients with chromosome abnormal (AML-CA), and 85 healthy individuals using real-time quantitative RT-PCR. Altered expression of 9 imprinted ncRNA genes (C15orf2, COPG2, H19, IGF2, IMPACT, PEG3-AS, PRIM2, SLC22A3, ZNF215) and 16 HME genes were observed. In AML-CN, patients’ survival days are correlated with the expression levels of H19 (p < 0.01), IMPACT (p < 0.05), DNMT3L (p < 0.05) and AURORA (p < 0.01). In AML-CA, patients’ survival days are correlated with the expression levels of PGE3-AS (p < 0.01), PRIM2 (p < 0.01), SLC22A3 (p < 0.05), and ZNF215 (p < 0.01). Multiple linear regression analysis further revealed the expression level of H19 and ZNF215 can be used as predictors for 2-year survival for AML-CN patients (p = 0.002) and AML-CA patients (p = 0.040), respectively. Cox proportional hazard model was used to analyze the hazard ratio (HR) for H19 (HR=0.868, 95.0% Confident Interval: 0.797-0.945, p = 0.001) and ZNF215 (HR=0.904, 95.0% Confident Interval: 0.821-0.995, p =0.040). In addition to survival, analysis has also been performed to correlate patients’ clinical parameters and expression levels of these altered genes and to correlate the expression levels between imprinted ncRNA genes and HME genes (results will be presented at the meeting). From our preliminary results, it is reasonable to hypothesize that loss imprinting of imprinted ncRNA is critical for the leukemogenesis of AML and under CN or CA conditions different ncRNAs are activated and affect different imprinted gene expression and thus leading to different clinical outcomes. Based on our findings, we will further perform in vitro functional analysis to elucidate the functions and mechanisms of these imprinted ncRNAs in AML tumorigenesis. Updated results of these analyzes will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Abstract 4613 Circadian rhythms regulate various functions of human body and disruption of circadian rhythm has been associated with cancer development and tumor progression. Circadian clock genes use transcriptional-translational feedback loops to control circadian rhythms. Many transcriptional regulators are histone acetyltransferases (HAT) or histone deacetylases (HDAC). As clock function and integration of inputs rely on transcriptional regulation, it is possible that chromatin is remodeled during circadian cycles and in response to signals that regulate the clock. SIRT1 (sirtuin 1) is a HDAC that has recently been identified as a crucial modulator of the circadian clock machinery. To date, at least 7 SIRT genes (SIRT1–7) have been identified. In our previous report we have demonstrated the daily expression patterns of PER1, PER2, PER3, CRY1, CRY2, and CKIe in peripheral blood (PB) of healthy individuals were abolished in chronic myeloid leukemia (CML) patients and partial recoveries of daily patterns were observed in CML patients with complete cytogenetic response (CCyR) and major molecular response (MMR) post-imatinib treatment [J Biol Rhythms 2011]. In this study we further investigated the expression profiles of the 7 SIRT genes (SIRT1–7) in PB total leukocytes from 49 CML and 22 healthy volunteers. Collection of PB was carried out at four time points: 2000 h, 0200 h, 0800 h, and 1400 h, respectively. In PB total leukocytes of healthy individuals, the daily pattern of SIRT1 (p < 0.01) and SIRT5 (p < 0.05) expression level peaked at 0200 h, and SIRT2 (p < 0.01) peaked at 0800 h. Daily pattern expression of these 3 genes was abolished in newly diagnosed pre-imatinib mesylate treated and blast crisis-phase CML patients. Partial daily patterns of gene expression recoveries were observed in CML patients with CCyR and MMR. In some serial monitored individual patients, the recoveries of oscillations of SIRT1, 2, and 5 genes expression accompanied with the disappearance of BCR-ABL transcripts were also noted. The expression of SIRT3, 6, and 7 did not show a time-dependent variation among the healthy and CML patients. SIRT4 expression was undetectable both in the healthy and CML patients. Updated in vitro study results of the regulation of SIRT1, 2, and 5 genes on circadian clock genes expression will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Abstract 3633 Circadian rhythm is present in human and all eukaryotes with a 24-hour cycle. Circadian genes use transcriptional-translational feedback loops to control circadian rhythms. Therefore, the marked characteristic of circadian systems is the strong daily cycling of clock gene mRNA, clock protein, and clock-controlled gene RNA and protein. Recent studies have demonstrated that expression of some of the circadian genes display daily oscillation in peripheral tissues including liver, eye, lung, heart, spleen, kidney, peripheral blood and bone marrow. Circadian rhythms regulate various functions of human body and disruption of circadian rhythm has been associated with cancer development and tumor progression. In this study the expression profiles of the 9 circadian genes (hPER1, hPER2, hPER3, hCRY1, hCRY2, hCLOCK, hBMAL1, hCK1e and hTIM) in peripheral blood (PB) total leukocytes from 95 chronic myeloid leukemia (CML) and 54 healthy volunteers were investigated. For comparison of circadian gene expression between PB mononuclear cells (PBMCs) and polymorphonuclear cells (PMNLs), another group of 10 healthy volunteers were also investigated. Collection of PB was carried out at four time points: 20:00, 02:00, 08:00, and 14:00, respectively. In healthy individuals, the daily oscillation was shown for hPER1, hPER2, hPER3, and hCRY2 with peak expression levels at 8:00AM, and the expression of the nine genes displayed similar profile both in PBMCs and in PMNs. In contrast, oscillations of these four genes were abolished in newly diagnosed pre-imatinib mesylate treated and blast crisis-phase CML patients and partial recoveries of oscillations were observed in CML patients with complete cytogenetic response and major molecular response. In some serial monitored individual patients, the recoveries of oscillations of circadian gene expression accompanied with the disappearance of BCR-ABL transcripts were also noted. Expression of hCRY1, hCLOCK, hBMAL1, hCK1e and hTIM did not oscillate both in healthy individuals and CML patients. Updated results on more healthy volunteers and serial monitored CML patients will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant inherited cancer syndrome that expresses nonendocrine and endocrine tumors. Here, we describe a 42-year-old man with an initial presentation of low back pain and hypertension. Clinical assessments revealed pheochromocytoma, medullary thyroid carcinoma with bone metastasis, and parathyroid hyperplasia. MEN 2A was diagnosed, and a family history of pheochromocytoma was traced. Surgical resection of the pheochromocytoma of the adrenal gland resulted in a cure of the patient’s hypertension. He received systemic chemotherapy with the “MAID” regimen (mesna, doxorubicin, ifosfamide, and dacarbazine) over three cycles of 3 weeks each, and showed a partial response.