Mantel-Haenszel Log-rank Test Research Articles

Pre-treatment of hyponatremia as a biomarker for poor immune prognosis in advanced or metastatic gastric cancer: A retrospective case analysis

ABSTRACT Hyponatremia, a prevalent electrolyte imbalance among tumor patients, has often been overlooked regarding its prognostic significance for immunotherapy. In this study, we delved into the prognostic ramifications of hyponatremia in advanced gastric cancer (AGC) patients undergoing immunotherapy. Enrolling AGC patients diagnosed between December 2014 and May 2021, we extracted pertinent data from electronic medical records, with a median follow-up of 35.8 months. Kaplan–Meier curves illuminated patients’ progression-free survival (PFS) and overall survival (OS), while survival disparities were tested using the Mantel–Haenszel log rank test. COX and logistic regressions were employed to scrutinize the correlation between serum sodium levels and prognosis in 268 AGC patients, both at baseline and during treatment. Notably, patients with hyponatremia exhibited shorter PFS (4.7 vs 2.1 months, p = .001*) and OS (12.5 vs 3.9 months, p < .001*). Serum sodium emerged as an independent prognostic factor for both PFS (HR = 1.773; 95% CI 1.067–2.945; p = .001*) and OS (HR = 1.773; 95% CI 1.067–2.945; p = .003*). Subgroup analysis revealed that AGC patients with hyponatremia derived no benefit from immunotherapy in terms of PFS and OS. Strikingly, a decrease in serum sodium during immunotherapy was associated with early relapse and mortality. Based on these findings, we hypothesize that hyponatremia portends poor prognostic outcomes in AGC patients treated with immunotherapy and may serve as a valuable prognostic biomarker. However, further large-scale prospective studies are warranted to validate these observations.

Appendiceal adenocarcinoma is associated with better prognosis than cecal adenocarcinoma: a population-based comparative survival study

ObjectiveAlthough appendiceal cancer remains a rare gastrointestinal malignancy compared with colorectal cancer, incidence rates of appendiceal cancer have increased in the last two decades. Appendiceal and cecal adenocarcinomas have distinct...

D-Dimer as a Sensitive Biomarker of Survival Rate in Patients with COVID-19.

The global case fatality rate of coronavirus disease 2019 is 2.16% as announced by the World Health Organization. In Indonesia, according to the Ministry of Health, the number is even higher, reaching a 2.8% case fatality rate. D-dimer levels were found to affect coronavirus disease 2019 patient's survival in several studies. The study aimed to determine whether the amount of D-dimer predicted survival in coronavirus disease 2019 patients. This research was performed in a retrospective cohort design and used survival analysis. From March 1, 2020, to August 31, 2020, the samples were collected from polymerase chain reaction-confirmed coronavirus disease 2019 patients at Mohammad Hoesin General Hospital in Palembang, South Sumatera, Indonesia. We used electronic medical records to obtain demographic (age and gender), coexisting condition, laboratory (coagulation and hematologic test), and outcome (non-survivors or survivors) data. The chi-square and Mann-Whitney tests were used to evaluate the results. The Kaplan-Meier method and the Mantel-Haenszel log-rank test were used to examine D-dimer levels and patient outcomes. Youden index was calculated to determine the optimal cut-off value of D-dimer. There were 52 non-survivors and 235 survivors among the 287 patients who met the inclusion criterion. Non-survivors had D-dimer levels of more than 1.49 mg/L in 82.69%of cases. Males had lower cut-off compared to females (>1.49 mg/L vs. >2.2 mg/L). The researchers discovered a highly significant correlation between D-dimer levels and coronavirus disease 2019 mortality (P=.001). The c-index analysis showed that D-dimer (0.79, 95% CI: 0.73-0.83) ability for mortality prediction was the second-best compared with other laboratory markers. D-dimer can be used as a predictor of coronavirus disease 2019 in-hospital mortality for early identification of coagulopathy.

S209 Appendiceal Adenocarcinomas Are Associated With Better Prognosis Than Cecal Adenocarcinomas: A Population-Based Comparative Survival Study

Introduction: The incidence of appendiceal cancer in the U.S. has increased over the past two decades despite stable rates of appendectomies. Although the appendix is embryologically derived from the cecum, appendiceal adenocarcinomas have distinct molecular profiles from those of cecal adenocarcinomas. However, treatment protocols are the same and differences in survival outcomes between these malignancies have not been compared extensively. To this end, we conducted a comparative survival analysis of appendiceal and cecal adenocarcinomas. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified individuals ≥30 years of age with appendiceal or cecal adenocarcinomas from 1975 to 2016. Demographic and clinical data, including sex, age at diagnosis, year of diagnosis, race, ethnicity, marital status, tumor histology, tumor stage, tumor grade, chemotherapy, surgery, and survival in months, was extracted using SEER*Stat software. Relative hazard ratios for death in the five-year period following diagnosis were calculated using multivariate Cox regression analysis, adjusted for other covariates. Survival was compared by Mantel-Haenszel Log-Rank test, and survival curves were generated using the Kaplan-Meier method. The p-value level of significance was set at < 0.05 for a two-tailed test. Data was analyzed using SAS 9.4 software and R. Results: We identified 16,738 appendiceal and 87,047 cecal adenocarcinomas. Male sex, age >60, earlier year of diagnosis, black race, and non-Hispanic ethnicity were independently associated with higher mortality rates (Table). Those who were divorced, separated, never married, or widowed had worse survivorship compared to married individuals. Non-mucinous histology and advanced stage and grade were associated with worse prognosis, while surgery and chemotherapy were associated with improved survival. Multivariate Cox regression analysis demonstrated significantly lower mortality in appendiceal adenocarcinomas (HR 0.61; p< 0.0001). The five-year cancer-specific and overall survival curves for appendiceal and cecal cancers are shown in Figure. Conclusion: In this first large comparative survival study of appendiceal and colon cancers, appendiceal adenocarcinomas were associated with improved survival compared to that of cecal adenocarcinomas. Further investigation of prognostic factors and molecular mechanisms of appendiceal cancers is needed to establish standardized treatment guidelines.Figure 1.: Cecal and appendiceal adenocarcinomas - cancer-specific and overall survival experience by site Table 1. - Demographic and clinical factors associated with five-year mortality following diagnosis of appendiceal or cecal adenocarcinoma using multivariate Cox regression analysis Parameter P-value Hazard Ratio 95% Confidence Interval Sex Male 1 Female < 0.0001 0.89 0.87-0.91 Age >60 1 ≤60 < 0.0001 0.78 0.76-0.80 Year of Diagnosis 2005-2016 1 1991-2005 < 0.0001 1.56 1.49-1.63 1975-1990 < 0.0001 1.25 1.22-1.29 Race White 1 Asian/Pacific Islander 0.0003 0.91 0.87-0.96 Black < 0.0001 1.13 1.10-1.17 Ethnicity Non-Hispanic 1 Hispanic 0.003 0.94 0.90-0.98 Marital status Married 1 Divorced < 0.0001 1.14 1.10-1.19 Separated 0.02 1.11 1.02-1.21 Never married < 0.0001 1.15 1.12-1.19 Widowed < 0.0001 1.21 1.18-1.24 Histology Non-mucinous 1 Mucinous < 0.0001 0.89 0.86-0.91 Stage Local 1 Regional < 0.0001 3.60 3.43-3.77 Distant < 0.0001 17.61 16.79-18.47 Grade I: Well differentiated 1 II: Moderately differentiated < 0.0001 1.32 1.26-1.37 III: Poorly differentiated < 0.0001 1.99 1.90-2.08 IV: Undifferentiated; anaplastic < 0.0001 2.11 1.96-2.28 Surgery Surgical excision 1 Biopsy only < 0.0001 3.55 3.38-3.74 No surgery or biopsy < 0.0001 5.39 4.87-5.97 Chemotherapy Chemotherapy 1 No chemotherapy < 0.0001 1.06 1.03-1.08 Site Cecum 1 Appendix < 0.0001 0.64 0.61-0.67

Circadian Factors Impact Survival From Brain Metastases for Patients Treated With Whole Brain Radiation

There are established links between circadian clock dysregulation, and cancer risk. Numerous reports of increased risk for breast cancer in night shift workers led the World Health Organization to classify circadian disruption as a probable carcinogen. Additionally, the circadian clock has been known to influence the body's response to medications and most recently, a handful of studies demonstrate a link between radiation toxicity and time of day the patient received radiation. Prior studies investigating the temporal association of radiotherapy outcomes have yielded overall conflicting data and contemporary evaluations of this effect are sparse. To determine if chronotherapy should be considered to modulate radiation outcomes, we sought to evaluate if the time of day when radiation treatment was delivered affected outcomes for patients with brain metastases.Retrospective data was collected for all consecutive patients between 2010 and 2020 with a diagnosis of brain metastases who were treated with whole brain radiotherapy. Patients were eligible to be included if ≥80% of their total dose was delivered either before or after 12:00 noon as documented by treatment times in the electronic medical record and if outcome data was available. Data on sex, age, performance status, control of primary disease, extracranial metastases, radiation dose, race, BMI, and zip code were collected. Radiation was delivered as whole-brain radiation to a median dose of 3000 cGY. Analysis of survival was performed using Mantel-Haenszel hazard ratio and log-rank test to compare Kaplan-Meier curves between groups.Complete data were available for 84 patients. The majority of patients had a primary diagnosis of breast or lung cancer (93%) and a small minority had a melanoma, thyroid, or unknown primary. 43 (51%) patients were excluded who did not receive ≥80% of their cumulative radiation either before or after noon, leaving n = 41 patients included for analysis. Demographic data were comparable between groups and overall: 56% female, 44% male; 56% ≥65 years, 44% younger. Distributions for BMI, extracranial metastasis, control of primary disease, and performance status were also similar between groups. Results showed a strong trend toward improved survival in the group that received ≥80% treatment in the afternoon (P = 0.057, HR 0.28-1.02).Treatment time of day impacted survival from brain metastases in our patient population treated with whole brain radiation. Potential explanations for these results include the influence of multiple circadian pathways on tissue and tumor sensitivity through melatonin signaling and other mechanisms, warranting further exploration. Future investigations into entraining circadian rhythms via time of day treatments, light therapy or pharmaceutical interventions to alter radiation outcomes and toxicity should be considered.

A Multi-institutional, Retrospective Analysis of Patients with Metastatic Renal Cell Carcinoma to Bone Treated with Combination Ipilimumab and Nivolumab.

Bone metastases (BM) in renal cell carcinoma (RCC) patients are associated with poor outcomes. There are limited published data on outcomes in these patients with immunotherapy agents. We present a multi-institutional, retrospective analysis of metastatic RCC patients with BM treated with ipilimumab and nivolumab (I + N). Patient, tumor, and treatment-related variables were retrospectively collected from electronic medical records of patients with a histologically confirmed diagnosis of RCC and at least one radiographically confirmed BM prior to initiation of I + N. Best objective response was assessed by clinical chart review, imaging reports, and treating physician evaluation; progression-free survival (PFS) and overall survival (OS) were recorded as of 31 December 2020. Descriptive statistics were used to summarize patient characteristics and BM-related variables. Kaplan-Meier method and Mantel-Haenszel log-rank test were used to compare survival among groups. Cox regression univariable and multivariable models were used to correlate patient- and treatment-related variables to outcomes. Eighty patients with RCC and BM treated with I + N were identified. Patients were predominantly male and Caucasian presenting primarily with IMDC intermediate or poor-risk clear-cell RCC. Best response to I + N was progressive disease (46%), stable disease (28%), partial response (21%), and not evaluable (5%). Median PFS was 6.1 months (95% CI 3.8-8.9 months) with the majority of patients (65%) discontinuing I + N due to disease progression. Median OS was 25.6 months (95% CI 14.9-NA) with median follow-up of 25.2 months. A multivariable regression model for PFS showed several variables to be significantly associated with worse PFS including female gender [p = 0.02; hazard ratio (HR) 2.16; 95% CI 1.14-4.12], metastases to other sites (p = 0.006; HR 2.12; 95% CI 1.24-3.62) and presence of BM to ribs (p = 0.0007; HR 2.61; 95% CI 1.50-4.52). A multivariable Cox model of OS showed no prior radiation therapy to BM (p = 0.02; HR 2.17; 95% CI 1.13-4.17) and presence of liver metastases (p = 0.0006; HR 3.19; 95% CI 1.65-6.19) to be significantly associated with worse OS. RCC patients with ≥ 1 BM who received I + N therapy had a relatively low response rate, PFS, and OS. Strategies to improve outcomes in this subset of patients are needed.

Clinical Outcomes of Metastatic Renal Carcinoma Following Disease Progression to Programmed Death (PD)-1 or PD-L1 Inhibitors (IO): A Meet-URO Group Real World Study (Meet-Uro 7).

The aim of our study was to collect data about of the outcome of metastatic renal cell carcinoma patients who progressed after immune checkpoint inhibitors in order to enhance data about efficacy and safety of treatment beyond immune-oncology (IO). A total of 162 eligible patients, progressing to IO, were enrolled from 16 Italian referral centers adhering to the Meet-Uro association. Baseline characteristics, outcome data and toxicities were retrospectively collected. Descriptive analysis was made using median values and ranges. Kaplan-Meier method and Mantel-Haenszel log-rank test were performed to compare differences between groups. A total of 111 patients (68.5%) were treated after IO progression. In all, 51 patients (31.5%) did not receive further treatment for clinical deterioration. Median IO progression free survival (PFS) was 4 months (95% confidence interval [CI]: 3.1-4.8). IO-PFS tends to be longer in patients reporting adverse events (AE) of any grade (5.03 [95% CI: 3.8-6.1] vs. 2.99 [95% CI: 2.4-3.5] months P=0.004). Subsequent therapies included cabozantinib (n=79, 48%), everolimus (n=11, 6.7%), and others (n=21, 12.9%).Median PFS post-IO was 6.5 months (95% CI: 5.1-7.8). Cabozantinib showed longer PFS compared with everolimus (7.6 mo [95% CI: 5.2-10.1] vs. 3.2 mo [95% CI: 1.8-4.5]) (hazard ratio: 0.2; 95% CI: 0.1026-0.7968) and other drugs (4.3 mo [95% CI: 1.3-7.4]) (hazard ratio: 0.6; 95% CI: 0.35-1.23). All grade AE were reported in 83 patients (74%) and G3 to G4 AE in 39 patients (35%). Target therapies post-IO showed median overall survival of 14.7 months (95% CI: 0.3-21.4). In our real world experience after progression to IO, vascular endotelial groth factor-tyrosine kinase inhibitors, given to patients, proved to be active and safe choices. Cabozantinib was associated with a better outcome in terms of median PFS.

Adverse events and outcomes in dogs with appendicular osteosarcoma treated with limb amputation and a single subcutaneous infusion of carboplatin.

To evaluate adverse events and outcomes in dogs with appendicular osteosarcoma treated with limb amputation followed by a single SC infusion of carboplatin. 45 client-owned dogs with appendicular osteosarcoma treated with limb amputation and SC infusion of carboplatin between January 1, 2006, and January 15, 2017. Medical records were reviewed, and data collected included signalment, tumor location, treatment, results of clinicopathologic analyses and diagnostic imaging, adverse effects of chemotherapy, metastasis-free interval, survival time, and communications with owners and referring veterinarians. Findings were evaluated with the Kaplan-Meier survival analysis and Mantel-Haenszel log-rank test. 45 dogs were identified that met the inclusion criteria (12 of the 45 dogs had been reported in a previous case series). No dogs had pulmonary metastases detectable by CT or radiography before treatment. All dogs completed the protocol as planned. Median survival time (MST) was 196 days; metastasis-free interval was 197 days. Three of the 45 (7%) dogs required hospitalization for gastrointestinal signs related to chemotherapy. There were no chemotherapy-related deaths. Results indicated that although treatment with SC infusion of carboplatin was well tolerated, the MST for dogs in the present study was similar to reported MSTs in dogs with appendicular osteosarcoma treated with limb amputation alone and was in the lower range of historically reported survival times for dogs receiving IV adjunctive chemotherapy. Therefore, we could not recommend this protocol of SC infusion of carboplatin but recommended that protocols with IV administration of carboplatin be used instead.

Polymorphous low-grade adenocarcinoma: A Danish national study

To present a national series of polymorphous low-grade adenocarcinoma (PLGA) patients, including survival rates and an analysis of prognostic factors. By merging three Danish nationwide registries, 73 patients diagnosed with PLGA from 1990 to 2005 were identified. Histological slides were reviewed and data concerning demographics, tumour site, clinical stage, treatment profiles and follow-up were retrieved. Survival estimates and prognostic factors were evaluated by comparing Kaplan-Meier plots using the Mantel-Haenszel log-rank test. Of the 73 patients, 47 (64%) were female. Median age was 58years. The most common location was the palate (73%). Median latency was five months. Recurrence was seen in 13% of patients. Overall survival (OS), disease-specific survival (DSS) and recurrence-free survival (RFS) rates after 10years were 73%, 99% and 83%, respectively. Univariate analyses suggested that free resection margins significantly improve RFS. PLGA usually has an excellent survival outcome even in cases of advanced stage disease and locoregional recurrence. Primary choice of treatment should be complete surgical excision. Although there is no convincing evidence for the efficacy of adjuvant radiotherapy, it should still be considered, particularly in cases of involved resection margins and advanced stage disease. Late recurrences are common and respond well to salvage therapy.

Conditional Survival of Patients Treated With First-Line Chemotherapy for Metastatic Urothelial Cancer

BackgroundMeasures of prognosis for cancer patients are typically evaluated at the time of diagnosis. However, this study assessed the changes in 2-year CS rates after first-line chemotherapy for metastatic UC. Patients and MethodsConditional overall survival and CPFS probability were estimated using the Kaplan–Meier method. Adjusted survival functions were stratified according to age groups (< 70 years vs. ≥ 70 years), sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS; ECOG PS ≤ 2 vs. ECOG PS > 2), pretreatment Hb levels (< 12 mg/dL vs. ≥ 12 mg/dL) and pretreatment NLR (< 3 vs. ≥ 3). Pairs of CS curves were compared using the Mantel–Haenszel log-rank test. ResultsTwo hundred ninety-eight patients were included in this analysis, 233 were male, and their median age was 69 years. First-line median overall survival and progression-free survival were 10.7 months (95% confidence interval [CI], 9.6-12.6) and 6.0 months (95% CI, 5.5-7.1), respectively. CPFS and COS showed an increasing trend in the population considered (b = 0.35; P < .001 and b = 0.79; P < .001, respectively). A significant increase in terms of COS and CPFS trends was identified in patients with age < 70 years (P = .02 and P = .005, respectively) and pretreatment NLR ≤ 3 (P = .05 and P < .001, respectively). Patients with Hb levels < 12 g/dL showed a significantly poorer 2-year COS. ConclusionThe conditional probability of survival at 2 years from the start of first-line chemotherapy for advanced UC changes over time according to clinical characteristics.

Tumor VEGF expression correlates with tumor stage and identifies prognostically different groups in patients with clear cell renal cell carcinoma

ObjectivesVascular endothelial growth factor (VEGF) is a potent inducer of tumor angiogenesis and represents the key element in the pathogenesis of clear cell renal cell carcinoma (ccRCC). The aim of this study was to investigate the use of tumor VEGF expression as a parameter to identify tumor stage and prognostically different patient groups. Methods and materialsWe retrospectively collected clinical data of 137 patients treated with partial or radical nephrectomy at our institutions for organ-confined, locally advanced, and metastatic ccRCCs between 1984 and 2013. Tumor cell VEGF immunohistochemical expression was compared with pathological and clinical features including age, sex, tumor stage, and Fuhrman grade. Comparison of VEGF expression levels between tumor stages was performed via Kruskal-Wallis nonparametric test. Survival analysis was conducted via Kaplan-Meier product-limit method, and Mantel-Haenszel log-rank test was employed to compare survival among groups. ResultsMedian age at diagnosis was 61 years (range: 33–85y). Tumor stage was pT1N0M0 in 67 patients (49%), pT2N0M0 in 5 (4%), and pT3N0M0 in 25 (18%), while 40 patients (29%) had metastatic tumors at diagnosis. Fuhrman nuclear grade was G1 in 22 patients (16%), G2 in 60 (44%), G3 in 33 (24%), G4 in 13 patients (9%), and unknown in 9 patients. Tumor VEGF was differentially expressed among different stages (P<0.001) and in low (G1–2) and high (G3–4) Fuhrman grade tumors (P<0.001). No significant differences were found when stratifying by sex (P = 0.06) or age (P = 0.29). Median overall survival (OS) from partial or radical nephrectomy was 161 months (range: 1–366). We observed a significantly longer OS in patients with low (<25%) vs. high (>25%) VEGF expression levels (median OS 206 vs. 65mo, P<0.001). ConclusionsOur data show that tumor cell VEGF expression is significantly associated with tumor stage and Fuhrman grade and is able to predict patient outcome, suggesting a potential use of this parameter in identifying prognostically different patients with ccRCC.

Total Atrial Conduction Time Assessed by Tissue Doppler Imaging (PA‐TDI Interval) to Predict Early Recurrence of Persistent Atrial Fibrillation After Successful Electrical Cardioversion

The aim of this study was to investigate whether total atrial conduction time (TACT) assessed via tissue Doppler imaging (PA-TDI interval) can identify patients with early recurrent atrial fibrillation (ERAF) after successful direct-current electrical cardioversion (CV) of persistent atrial fibrillation (persPAF). A total of 54 patients without antiarrhythmic drug medication (mean ± SD: 66 ± 10.4 years; 33% women) with persPAF and successful CV were enrolled between May 2012 and May 2013. TACT was measured 6 hours after successful CV in the left atrium by tissue Doppler imaging (PA-TDI interval). ERAF was determined via Holter-electrocardiogram over a period of 7 days after CV. Receiver opearting characteristic analysis was used to determine an optimal cutoff value of PA-TDI interval for prognosis of ERAF. Based on this result, recurrence-free survival was assessed with Mantel-Haenszel's log-rank test. ERAF occurred in 23 patients (43%). PA-TDI interval was longer in patients with ERAF compared to those who maintained sinus rhythm (mean ± SD: 163.5 ± 11.1 vs 132.3 ± 11.2 milliseconds; P < 0.00001). At the cutoff value of 152 milliseconds, PA-TDI interval sensitivity and specificity related to ERAF were 87% and 100%, respectively. Measuring PA-TDI interval may help to predict ERAF after successful CV in patients with persAF.

Gender Differences in Hepatocellular Carcinoma in the United States

Purpose: Hepatocellular carcinoma is the sixth most common cancer in the world. Hepatocellular carcinoma is more common in men as compared to women. Higher incidence of hepatocellular carcinoma in men may be due to differences in hormonal characteristics. Previous studies of gender differences in hepatocellular carcinoma were done in single institutions and outside the United States. The primary objective of our study is to compare stage-specific survival of men and women with hepatocellular carcinoma in the United States. Methods: We studied a retrospective cohort of hepatocellular carcinoma patients in National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. Seventeen registries are currently enrolled in SEER database and cover approximately 28% of U.S. population. SEER database has information about demographic characteristics of patients, presenting features and survival of patients with hepatocellular carcinoma. We included all patients aged 65 years or older with hepatocellular carcinoma in SEER database from 1973-2009. Patients with unknown stage were excluded from the study. The survival curves were compared using the Mantel-Haenszel log-rank test. A multivariate Cox-proportional hazards regression model was used to compare survival between men and women after adjusting for variables that are statistically significant different between those groups in univariate analysis. We performed statistical analysis using SPSS software (version 19.0). Results: We included 10,497 adult patients age greater than 65 years with hepatocellular carcinoma in SEER database from1973-2009. We excluded 2,962 patients who did not have documented staging. There were predominantly men 7,194 (68.5%). Mean age (SD) of women was 76 (6.8) years compared to men 74 (6.2) years (P<0.001). A higher proportion of men were Caucasian compared to women (68% vs. 65%, respectively). The median survival of women and men for localized, regional and distant stage of disease in years was 1.33 vs.1.33, 0.33 vs. 0.41, 0.17 vs. 0.17, respectively. Univariate survival analysis showed women and men had similar stage-specific survival (P = 0.24). Women had similar survival time compared to men even after adjusting for age, stage of the disease, and race in multi-variate analysis (hazard ratio (95%CI) 1.01 (0.96-1.04). Conclusion: Hepatocellular carcinoma is more common in men but stage-specific survival was similar in women and men even after adjusting for differences in age, stage and race.

Acute Megakaryoblastic Leukemia (AMKL) in Children without Down Syndrome.

Abstract 482 Background:Acute megakaryoblastic leukemia (AMKL) in children without Down syndrome represents approximately 10% of pediatric acute myeloid leukemia (AML). Published reports regarding prognosis of non-Down syndrome children with AMKL vary; hence, some groups treat these patients as high-risk while others as standard-risk. As a result, the optimal treatment strategy, including the role of hematopoeitic stem cell transplant (HSCT), remains unclear. Methods:We reviewed the treatment and outcomes of patients with AMKL treated on two pediatric AML protocols. Pediatric Oncology Group (POG) 9421 (1995-99) included two cycles of induction chemotherapy with randomization to standard or high-dose DAT (daunorubicin, cytarabine, 6-thioguanine) followed by HSCT for children in remission with matched sibling donors or three cycles of consolidation chemotherapy with or without cyclosporine for those without suitable donors. St. Jude protocol AML02 (2002-2008) randomized patients during induction to receive high- or low-dose cytarabine with daunorubicin and etoposide (ADE). Patients without complete remission (CR) received gemtuzumab ozogamicin (GO) with induction 2 chemotherapy (ADE). After induction, AMKL patients with availabel donor proceeded to HSCT while those without donors received three cycles of consolidation chemotherapy including mitoxantrone and cytarabine. Comparisons of event-free survival (EFS) and overall survival (OS) were performed by Mantel-Haenszel log-rank test. Independent effect of HSCT on EFS or OS were analyzed by Cox proportional hazard model, with HSCT as time-dependent variable. Results:The 49 patients with AMKL treated on POG 9421 had a median age at diagnosis of 1.8 years (range 0.13-16.2 years), and a median leukocyte count of 13.5 × 109/L (range 0.3-98.4). The patient with the t(1;22) translocation remains in CR. 39 patients had CR after induction, 5 partial response and 4 no response with no difference between standard- and high-dose DAT. The 5-year EFS for all AMKL patients was 34.7% ± 7.5%. Of the 39 patients in CR, 6 underwent matched sibling HSCT, of whom 4 remain in CR, and the other 33 patients received consolidation chemotherapy, of whom 15 remain in continuous remission. The 5-year OS for patients undergoing HSCT was 66.7% ± 19.3% compared to 36.1% ± 8.4% for those receiving consolidation chemotherapy (p = 0.2). The 26 patients with AMKL treated on SJCRH AML02 had a median age at diagnosis of 1.2 years (range 0.21-11.2 years), and a median leukocyte count of 11.8 × 109/L (range 2.3-72.9). All 5 patients with the t(1;22) translocation achieved CR after one induction cycle, with negative minimal residual disease, and remain in CR after treatment with chemotherapy only. The 3-year EFS was 35.9% ± 12.9% for the other AMKL patients, significantly lower than the 61.5% ± 4.8% for non-AMKL patients (p = 0.026). The 3-years OS estimates are 100% for patients with t(1;22), 48% ± 14.1% for other AMKL patients, and 71.8% ± 4.4% for non-AMKL patients (p = 0.03). Of the 21 patients without t(1;22), 14 received HSCT with 7 survivors (3-year EFS 46.3 ± 17%) while 7 received chemotherapy with only one long-term survivor (3-year EFS 14.3 ± 9.4%) (p=0.55). Conclusions:AMKL patients with the t(1;22) translocation have excellent treatment outcome with chemotherapy alone. In contrast, AMKL patients without t(1;22) fared poorly, especially when they were treated with only chemotherapy. Additional studies of larger number of patients are needed to determine if they would benefit from HSCT. Disclosures:No relevant conflicts of interest to declare.

Bond failure of gingivally offset mandibular premolar brackets: A randomized controlled clinical trial

The purpose of this randomized controlled clinical trial was to examine the clinical bond failure rate of gingivally offset mandibular premolar brackets and compare it with that of standard mandibular premolar brackets. Eighty-three patients were enrolled in this trial. A total of 240 brackets--120 standard and 120 offset--were bonded in a split-mouth design. Ten standard brackets and 1 offset bracket debonded during the trial period. Survival times were analyzed by using the Kaplan-Meier nonparametric test, and comparisons between bracket types were made with the Mantel-Haenszel log rank test. These tests showed that the failure rate between the bracket types was statistically significant (P <0.0058). Gingivally offset mandibular premolar brackets have a lower bond failure rate than standard mandibular premolar brackets.

Amelioration of Coxsackievirus B3-Mediated Myocarditis by Inhibition of Tissue Inhibitors of Matrix Metalloproteinase-1

Coxsackievirus B3 (CVB3) is a major cause of acute myocarditis, a serious condition that is refractory to treatment. Myocardial damage results in tissue remodeling that, if too extensive, may contribute to disease. Remodeling is achieved by extracellular proteolysis mediated by the matrix metalloproteinases (MMPs), and MMP activity is counterbalanced by tissue inhibitors of MMPs (TIMPs). We show herein that TIMP-1 expression is induced in the myocardium by CVB3 infection. Surprisingly, TIMP-1 knockout mice exhibited a profound attenuation of myocarditis, with increased survival. The amelioration of disease in TIMP-1 knockout mice was not attributable to either an altered T-cell response to the virus or to reduced viral replication. These data led us to propose a novel function for TIMP-1: its highly localized up-regulation might arrest the MMP-dependent migration of inflammatory cells at sites of infection, thereby anatomically focusing the adaptive immune response. The benefits of TIMP-1 blockade in treating viral myocarditis were confirmed by administering, to wild-type animals, TIMP-1-specific siRNA or polyclonal antisera, both of which diminished CVB3-induced myocarditis. These unexpected findings indicate that increased TIMP-1 expression exacerbates, rather than ameliorates, CVB3-induced myocarditis and, thus, that TIMP-1 may represent a target for the treatment of virus-induced heart disease.

Preformed metal crowns for carious primary molars

Background There is a high level of untreated dental decay in primary teeth in Scotland. Despite evidence for the efficacy of preformed metal crowns (PMCs) for the restoration of primary molars, few are placed in general practice, possibly due to the interventive nature of the clinical procedure. There is, however, a novel way of placing PMCs involving no local anaesthesia, no caries removal and no preparation of the tooth: the Hall technique. Aim To investigate the survival of carious primary teeth treated with PMCs placed using a novel, simplified method — the Hall technique. Setting General dental practice, in Scotland. Methods A retrospective analysis of practice records from one general practitioner, from 1988 to 2001. The majority of the 978 PMCs fitted on 259 children, using the Hall technique, were placed when there was clinical evidence of approximal caries into dentine. The Kaplan-Meier approach was used to analyse survival times and the Mantel-Haenszel Log rank test for comparison between tooth types. Results For all tooth types, the probability of surviving three years without being extracted or the PMC being lost, was 73.4% (95% confidence interval 70.1% to 76.4%), and for five years was 67.6% (95% confidence interval 63.3% to 71.5%). The probability of surviving without extraction alone for three years was 86.0% (95% confidence interval 83.2% to 88.4%), and for five years was 80.5% (95% confidence interval 76.5% to 83.9%). Conclusion Hall technique restorations placed on primary molars with decay clinically into dentine, by a single operator in general dental practice, have a similar success rate to some other, more conventional, restorative techniques. The technique requires further evaluation through a prospective randomised control clinical trial before its use could be generally recommended.

A novel technique using preformed metal crowns for managing carious primary molars in general practice — A retrospective analysis

There is a high level of untreated dental decay in primary teeth in Scotland. Despite evidence for the efficacy of preformed metal crowns (PMCs) for the restoration of primary molars, few are placed in general practice, possibly due to the interventive nature of the clinical procedure. There is, however, a novel way of placing PMCs involving no local anaesthesia, no caries removal and no preparation of the tooth: the Hall technique. To investigate the survival of carious primary teeth treated with PMCs placed using a novel, simplified method - the Hall technique. General dental practice, in Scotland. A retrospective analysis of practice records from one general practitioner, from 1988 to 2001. The majority of the 978 PMCs fitted on 259 children, using the Hall technique, were placed when there was clinical evidence of approximal caries into dentine. The Kaplan-Meier approach was used to analyse survival times and the Mantel-Haenszel Log rank test for comparison between tooth types. For all tooth types, the probability of surviving three years without being extracted or the PMC being lost, was 73.4% (95% confidence interval 70.1% to 76.4%), and for five years was 67.6% (95% confidence interval 63.3% to 71.5%). The probability of surviving without extraction alone for three years was 86.0% (95% confidence interval 83.2% to 88.4%), and for five years was 80.5% (95% confidence interval 76.5% to 83.9%). Hall technique restorations placed on primary molars with decay clinically into dentine, by a single operator in general dental practice, have a similar success rate to some other, more conventional, restorative techniques. The technique requires further evaluation through a prospective randomised control clinical trial before its use could be generally recommended.

Polymorphism in the hypoxia-inducible factor 1α gene may confer susceptibility to androgen-independent prostate cancer

The hypoxia-inducible factor 1α (HIF-1α) plays a major role in cancer progression. The role of this transcription factor in prostate cancer development and its transition to a metastatic and androgen refractory state remains to be elucidated. Previous reports have identified the existence of single nucleotide polymorphisms (SNPs) in the oxygen-dependent degradation domain of the HIF-1α gene in renal cell carcinoma, head and neck squamous cell carcinoma, and androgen-independent prostate cancer (AIPC). Studies in prostate cancer, however, are variable and limited in the number of cases assessed. Herein we further investigate these SNPs, specifically C1772T (which results in an amino acid change from proline 582 to serine) and G1790A (alanine 588 to threonine). The frequency of these polymorphisms was evaluated in a population of individuals with metastatic AIPC and compared to a set of healthy control subjects. The distribution of HIF-1α genotypes for C1772T in 196 AIPC patients was 161 C/C (82.1%), 29 C/T (14.8%), and 6 T/T (3.1%). The genotype distribution in 196 controls was 179 C/C (91.3%), 14 C/T (7.1%), and 3 T/T (1.5%). Our results demonstrate a significant difference in genotype distribution between AIPC patients and control subjects only for the C1772T polymorphism (p = 0.024). The association of the incidence of the polymorphism with overall survival was determined to be not statistically significant (p = 0.93) by the Mantel-Haenszel (log-rank) test. These results suggest that the C1772T polymorphism in HIF-1? may confer susceptibility to AIPC and contribute to the progression or metastasis of this disease.

Cervical squamous intraepithelial lesions of low-grade in HIV-infected women: recurrence, persistence, and progression, in treated and untreated women

Background: Human immunodeficiency virus (HIV)-infected patients are more predisposed than HIV-negative women to develop squamous intraepithelial lesions (SIL) of the uterine cervix, and cervical dysplasia may be of higher grade in HIV-positive women than in HIV-negative subjects, with more extensive and multi-centric involvement of the lower genital tract by human papillomavirus (HPV)-associated lesions. Moreover, recurrence and progression rate of cervical intraepithelial neoplasia (CIN) is particularly higher in immunocompromised women. Design: Retrospective case-control study of HIV-positive women and HIV-negative controls, all affected by low-grade SIL of the uterine cervix, treated by loop excision or followed-up without treatment. Correlation of progression and recurrence of SIL with HIV status and CD4+ count. Patients: From September 1990 to October 1997, 75 HIV-positive low-grade-SIL patients, 47 treated and 28 followed-up without treatment, and 75 HIV-negative low-grade-SIL controls, 45 treated and 30 followed-up. Results: Among treated patients, 17/47 (36.2%) HIV-positive and 5/45 (11.1%) controls had recurrence ( P < 0.0101, O.R. = 4.53, 95% CI = 1.5–13.7), progression of untreated lesion was seen in 15/28 (53.6%) HIV-positive and 7/30 (23%) controls ( P < 0.05, O.R. = 3.79, 95% CI = 1.23–11.69). The risk of recurrence or progression of low-grade SIL linked to HIV seropositivity is about 4–5 times higher in comparison with seronegative counterpart, matched for age, risk factors and lesion size. More significantly, considering the cut-off of 200 CD4+/mm 3 in HIV-positive women, 13/17 cases of recurrence ( P < 0.05, O.R. = 4.88, 95% CI = 1.28–18.58) and 10/15 cases with progression ( P < 0.05, O.R. = 6.67, 95% CI = 1.24–35.73) were immunocompromised (<200 CD4+/mm 3), with a significant higher risk of recurrence or progression linked to immunodeficiency status. Considering time of progression or recurrence, during follow-up, Kaplan–Meier curves shows that HIV-positive status and immunodeficiency are correlated with more rapid evolution of cervical dysplasia and HPV-related lesions: comparison of recurrence in treated patients report P < 0.005 and progression in untreated P < 0.05 (Mantel–Haenszel log-rank test). Conclusions: Immunological status seems to be a determinant factor in prognosis of cervical SIL, HIV-positive women affected by this lesion, even if low-grade, need more aggressive management than the immunocompetent counterpart. Strict cytologic and colposcopic screening is recommended and CD4+ count and HPV-DNA testing may be useful risk indicators. Excisional procedures are preferred, while ablative treatments or wait and see policy may expose to some risk this type of population with poor compliance to follow-up.