To examine the association of maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) with anthropometry in the offspring of mothers with gestational diabetes mellitus (GDM).We performed a retrospective cohort study in 1263 GDM mother-child pairs. General linear models and Logistic regression models were used to assess the single and joint associations of maternal pre-pregnancy BMI  and GWG  with anthropometry and overweight status in the offspring from birth to 1-5 years old.Maternal pre-pregnancy BMI and GWG were positively associated with birth weight for gestational age Z score and birth weight for length for gestational age Z score at birth, and weight for age Z score, length/height for age Z score, and weight for length/height Z score at of 1-5 years old offspring. Maternal pre-pregnancy overweight, obesity, and excessive GWG were associated with increased risks of large for gestational age  and macrosomia  at birth and childhood overweight at 1-5 years old .Offspring born to GDM mothers with pre-pregnancy overweight/obesity or excessive GWG were associated with increased risks of large for gestational age and macrosomia at birth, and childhood overweight at 1-5 years old, compared with those born to GDM mothers with pre-pregnancy normal weight and adequate GWG. Obesity has progressed in a few decades from a public health footnote in developed countries to a top-priority international issue, affecting all socioeconomic classes and age groups including children younger than 5 years old , 2. The Maternal pre-pregnancy overweight and obesity have also increased nowadays , 8. MoreTianjin is the fourth largest city in Northern China. All pregnant women who live in six urban districts have participated in the universal screening for GDM since 1999  by usingTianjin Gestational Diabetes Mellitus Prevention Program from August 2009 to July 2011. Finally, 1263 GDM women and their children had completed the baseline survey for the TGDMPP from August 2009 to July 2011 (participation rate 27%) . In. In2), oth percentile. Macrosomia was defined as birth weight ≥4000 grams. At baseline (1–5 years of offspring age), z scores for weight for age, height for age, weight for length and BMI for age, and childhood overweight were calculated based on the standards for the WHO growth reference [th percentiles for age and gender using the WHO BMI growth reference (≥1.035 Z score) [Z scores for birth weight for gestational age and birth weight for length for gestational age were calculated using our own study population means and standard deviations  in 2009–2011 . A largeeference . ChildreZ score) .The general characteristics of both GDM mothers and offspring according to different categories of maternal pre-pregnancy BMI and GWG were compared using one-way ANOVA and chi-square test. General Linear Models were used to compare the differences in Z scores for birth weight for gestational age and birth weight for length for gestational age, Z scores for weight for age, height for age, weight for height and BMI for age at baseline survey, and changes in Z scores for weight for age and weight for height from birth to baseline (1–5 years of offspring age) according to different categories of maternal pre-pregnancy BMI and GWG. Logistic regression was used to estimate the odd ratios (ORs) and 95% confidence intervals (95% CIs) of large for gestational age and macrosomia at birth, and childhood overweight at baseline survey with maternal pre-pregnancy BMI and GWG categories. We set up two models: Model 1, adjusted for variables with significant differences according to maternal pre-pregnancy BMI and gestational weight gain categories, including maternal age, family history of diabetes, education, income, gestational diabetes treatment during pregnancy, gestational weeks of birth, and infant feeding; Model 2, adjusted for variables in Model 1 and also for variables at birth, including birth weight for gestational age Z-score or birth weight for length for gestational age Z score. All statistical analyses were performed with SAS for Windows, version 9.3 .Maternal and offspring’s general characteristics were presented in Maternal pre-pregnancy BMI and GWG were positively associated with birth weight for gestational age Z score  and birtMaternal pre-pregnancy BMI and GWG were positively associated with weight for age Z score, length/height for age Z score , and weiWhen maternal pre-pregnancy BMI and GWG were examined as continuous variables, ORs (95% CIs) of large for gestational age, macrosomia and childhood overweight were 1.14 (1.09–1.19), 1.17 (1.12–1.22) and 1.07 (1.03–1.19) with pre-pregnancy BMI, and 1.09 (1.07–1.12), 1.09 (1.06–1.12) and 1.03 (1.01–1.06) with GWG, respectively.The subgroup analyses of associations of large for gestational age, macrosomia and childhood overweight risks with pre-pregnancy obesity and excessive GWG were presented in 2) and non-excessive GWG, pre-pregnancy overweight (BMI ≥24 kg/m2) and non-excessive GWG, pre-pregnancy normal weight and excessive GWG, as well as pre-pregnancy overweight and excessive GWG  compared with those born to mothers with pre-pregnancy normal weight and adequate GWG, after adjusted for birth size.Our study also assessed the joint association of maternal pre-pregnancy BMI and GWG with the risks of offspring overweight at birth and 1–5 years old at baseline survey. We found that offspring born to GDM mothers with pre-pregnancy overweight/obesity and excessive GWG presented the highest risk of macrosomia and large for gestational age at birth and overweight at 1–5 years old compared with those born to GDM mothers with pre-pregnancy normal weight and adequate GWG. Another important observation was that the associations of maternal excessive GWG with macrosomia and large for gestational overweight of their offspring at birth were similar to that of maternal pre-pregnancy overweight/obesity, but the effects of maternal excessive GWG on their offspring’s overweight status at 1–5 years old were smaller than that of maternal pre-pregnancy overweight/obesity. This finding was confirmed in the subgroup analyses that the association of childhood overweight with maternal pre-pregnancy obesity tended to be larger among older children, while the association of childhood overweight with maternal excessive GWG tended to be smaller among older children. Previous studies suggested that among the general population, maternal pre-pregnancy overweight was a risk factor for both early onset overweight (persisted throughout childhood) and late onset overweight (after age 8) of their offspring, while maternal excessive GWG was only associated with the early onset overweight of their offspring . AlthougIn the present study, GDM women with pre-pregnancy obesity had a lower mean value of GWG. Since it has been suggested that pre-pregnancy obese women may benefit from low GWG , the IOMThere are several mechanisms that maternal pre-pregnancy overweight/obesity and excessive GWG might confer the risk of overweight/obesity of their offspring, including the child’s inheritance of genes susceptible to overweight/obesity , the intOur study has several strengths, including use of GWG category instead of net weight gain, a large number of GDM mother-child pairs, and adjustment for multiple prenatal and perinatal factors in analyses. However, there were several limitations. First, the study was a retrospective cohort which might produce recall bias. Second, the participation rate was only 27%. Although there were no differences in age, 2-h glucose, fasting glucose, and the prevalence of IGT and diabetes at 26–30 weeks’ gestation (based on OGTT) between those returned and those not returned, whether there was a difference between the postpartum outcomes cannot be verified. Third, even though our analyses adjusted for an extensive set of confounding factors, residual confounding due to the measurement error in the assessment of confounding factors, unmeasured factors such as genetic and environmental factors of GDM mothers and their children, cannot be excluded.In summary, we found that offspring born to GDM mothers with pre-pregnancy overweight/obesity or excessive GWG had increased risks of large for gestational age and macrosomia at birth, and childhood overweight at 1–5 years old, compared with those born to GDM mothers with pre-pregnancy normal weight and adequate GWG.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


To evaluate the effects of nurse-led multifactorial care to prevent disability in community-living older people.In a cluster randomized trail, 11 practices  were randomized to the intervention group, and 13 practices  were randomized to the control group. Participants aged ≥ 70 years were at increased risk of functional decline based on a score ≥ 2 points on the Identification of Seniors at Risk- Primary Care, ISAR-PC. Participants in the intervention group received a systematic comprehensive geriatric assessment, and individually tailored multifactorial interventions coordinated by a trained community-care registered nurse (CCRN) with multiple follow-up home visits. The primary outcome was the participant’s disability as measured by the modified Katz activities of daily living (ADL) index score (range 0–15) at one year follow-up. Secondary outcomes were health-related quality of life, hospitalization, and mortality.At baseline, the median age was 82.7 years (IQR 77.0–87.1), the median modified Katz-ADL index score was 2 (IQR 1–5) points in the intervention group and 3 (IQR 1–5) points in the control group. The follow-up rate was 76.8% (n = 1753) after one year and was similar in both trial groups. The adjusted intervention effect on disability was -0.07 . No intervention effects were found for the secondary outcomes.We found no evidence that a one-year individualized multifactorial intervention program with nurse-led care coordination was better than the current primary care in community-living older people at increased risk of functional decline in The Netherlands.NTR2653Netherlands Trial Register  The need to prevent disability and functional decline in later life is increasingly urgent with the ageing of society, the increase of multimorbidity and growing strain on limited resources. DisabiliIt has been suggested that a proactive, integrated care provision for community-dwelling older people is needed to address complex care needs, enable independent living and improve quality of life.–10 EarliIn 2008, the Dutch government launched the National Care for the Elderly Programme (NCEP) stimulating innovative healthcare projects focused on older people with multifactorial care needs to promote physical, mental and social health and wellbeing. DesigninThe protocol for this study and CONShttp://www.trialregister.nl)Between December 2010 and May 2014 we conducted a cluster randomized trial with a 1-year intervention and a 2-year follow-up in the north-west of the Netherlands. We invited 95 general practices who had not implemented nurse-led care coordination for community-living older people to participate. Twenty-four general practices were willingly to participate and were randomized. Community-care registered nurses (CCRN) provided the multifactorial intervention program to participants from practices allocated to the intervention group. The control group received no extra care or information besides usual care. The trial was registered at Trial Registration NTR2653.  selected their patients aged 70 years and over from their electronic medical record and excluded those who had a life expectancy of less than three months, suffered from dementia, did not understand Dutch, planned to move or spend a long time abroad, or lived in a nursing home. The selected persons received a self-reporting questionnaire, including a screening instrument: Identification of Seniors At Risk—Primary Care (ISAR-PC) .29] ISA ISA29] IAn independent statistician performed the computerized cluster randomization, stratified on the basis of socio-economic status, number of participants and general practices in both study groups. ParticipThe participants in the intervention group received a systematically administered CGA, an individually tailored care treatment plan (CTP) consisting of multifactorial interventions, and nurse-led care coordination with multiple follow-up visits. The CGA, CTP and follow-up visits were conducted by the same CCRN. In total, 15 experienced CCRNs, employed by one homecare organization, participated in the intervention. All CCRNs followed a formal 10-day training in providing integrated elderly care in the community, prior to the start of the study , health-rThe primary outcome was participants’ change in disability measured with the 15-item modified Katz-ADL index score at one year follow-up. This indThe secondary outcomes were the participants’ change in health-related quality of life (EQ-5D), emotional wellbeing subscale RAND-36), self-perceived quality of life, healthcare utilization, number of falls at all follow-up moments, and all-cause mortality. The EQ5D is a five-dimension scale to estimate preference-based health-related quality of life values. Possible health states were converted in a utility score, using a Dutch general population validation study. Self-per, self-peThe intervention group’s adherence to the protocol was based on 1) the percentage of participants that received both the CGA and their personalized care and treatment plan; 2) the percentage of the CGAs that the CCRN discussed with the GP; and 3) the percentage of participants that received an evaluation of the CTP after one year.The sample size was based on observational data from primary care practices from a prospective cohort study , which wointeraction < 0.05) interaction terms for treatment × time were added, to assess whether the treatment effect, if any, varied over time. Kaplan-Meier curves were used to estimate survival rates and compared using the log-rank test.Analyses were performed according to the intention-to-treat principle. Baseline characteristics of participants were described for the two study groups. Mixed linear and negative binomial regression models with a random intercept for participants were used for continuous  and count data , respectively. An additional random intercept at the GP level did not improve model fit (likelihood-ratio test p = 0.20). Linear mixed regression models employed robust standard errors to account for skewness in the outcome variable. The modeinteraction < 0.05). In the treatment group, we visually explored the mean change on the modified Katz-ADL index between baseline and one year as a function of the number of home visits, the number of interventions, and the variation among the 15 community care nurses in the intervention group.Post-hoc analyses were performed by adding interaction terms for treatment × levels of education (high and intermediate), treatment × socio-economic status (low and intermediate), treatment × levels of age , and treatment × baseline disability (tertiles of the Katz score) to the fully adjusted model  in STATA 13. Missing Eleven practices were randomized to the intervention group and 13 practices were randomized to the control group. Screening with ISAR-PC resulted in 35.2% (1209/3430) of the participants in the intervention group and 33.2% (1074/3238) of the participants in the control group . The medThe prevalence of geriatric conditions identified by the CGA is shown in Eleven practices were randomized to the intervention group and 13 practices were randomized to the control group. In both groups around 35% of the invited persons were at increased risk of functional decline and participated in the study. In both groups the follow-up rates were around 77% and 76% after one and two years respectively.Among all participants, older people 77.0% (934/1209) received a CGA and 76.6% (926/1209) received a CTP . During One year after the start, the mean modified Katz-ADL index score had increased in both groups, indicating an increase in disability. The effect of the intervention after one year, adjusted for baseline modified Katz-ADL score, age, sex, SES and level of education, was -0.07  -0.22 to 0.07) .At each follow-up moment, we found neither clinically nor statistically significant intervention effects for health-related quality of life (EQ5D), emotional wellbeing, self-perceived quality of life, or number of hospitalizations or falls . At six No interactions were found between treatment group and level of education, level of socio-economic status, baseline level of disability or baseline level of age in the post-hoc analyses . FurtherIn this cluster randomized trial, we found no evidence that a one-year individualized multifactorial intervention program with nurse-led care coordination was better than current primary care in community-living older people at increased risk of functional decline in The Netherlands. Additionally, the intervention was not more effective than current primary care for all other outcomes assessed.A major strength of the study is that, given that we avoided major bias, it robustly excluded clinically relevant effects of the intervention on the primary outcome. Specifically, the 95% confidence interval around the mean difference between the two treatment groups  excluded the predefined functional decline of -0.5 points by a wide margin. Thus, although the study was not designed as a non-inferiority trial, we found evidence of no effect. The sensitivity analyses accounting for missing data confirmed the robustness of the main analyses. To prevent bias in the outcome assessment, outcome assessors and participants were blinded using a postponed informed consent procedure. Another strength is the patient-centered approach comprising recognition and prioritization of identified problems for care and treatment. Addressing problems that older persons consider important may increase adherence to the intervention and facilitate implementation. Other strengths of the study include the active involvement of older people in the design and evaluation of the study, the high participation rate, the high adherence rate to the structured study protocol, and the evidence-based toolkit.The study also has some limitations. First, the CCRNs and the GPs could not be blinded for the purpose of the study because they were part of the intervention. Second, despite computerized randomization the study showed some imbalance in baseline disability and SES. To overcome this, we adjusted the analyses for SES and baseline value of the outcome measure. Third, in the intervention group 23% of the participants declined to take part in the CGA. Although we collected reasons for non-participation/declining . These nTwo recent meta-analyses on multifactorial interventions,, 41 and Recent studies in the United Kingdom, Canada, and The Netherlands found neutral effects of multifactorial preventive interventions to prevent disability or functional decline,, 20, 21 There are several possible explanations why we did not find an effect of a one-year nurse-led multifactorial intervention. First, the intervention lasted one year and measured its potential effects over a two-year period, which may have been too short to see effects emerge. Targeting a pre-frail population, which focuses on the prevention of future incidents, such as disability or mortality, a longer intervention and follow-up period has demonstrated beneficial effects.–47 FurthSecond, insufficient contrast between the study groups could explain the lack of effect that was observed. The majority of the participants in the control group contacted their GP on a regular basis and received home care nursing . The NetThird, although the modified Katz-ADL index is able to validly and reliably measure unfavourable health outcomes, more insFourth, the intensity of the intervention may have been too low to see effects emerge. However, we found no “dose-response” effects by the number of home visits and interventions in the CTP.Fifth, although many geriatric conditions were identified in the CGA, only one condition per participant was recognized as a problem and only one intervention was initiated. This could indicate that the CGA detected many conditions without unmet needs. Older persons may simply accept certain conditions as a normal part of ageing, or perhaps they were already addressed. Furthermore, prioritizing geriatric conditions may have resulted in a selection of interventions, while unfavorable conditions where left untreated. However, recognition and prioritizing may be useful in developing a person-centred approach to care, potentially facilitating shared decision-making and overall efficiency.Finally, although we found a small and transient effect of the intervention for after-hours GP care use, we think that this should be interpreted with caution because of the relatively large number of outcome measures assessed.In this cluster randomized trial, we found no evidence that a one-year multifactorial nurse-led care program was better than current primary care in community-living older people at increased risk of functional decline in The Netherlands. Nevertheless, the implementation of preventive programs in general practice is ongoing in many health care systems throughout the Western world. We may learn from process evaluations why Dutch general practitioners want to implement preventive interventions despite the apparent ineffectiveness of a one-year intervention on functional decline over and above current primary care. In consideration of the ageing of Western societies, increasing task delegation from GPs to nurses warrants further non-inferiority analyses on both quality and costs, and warrants evaluation from a societal perspective to explore whether such programs may still deliver valuable services at acceptable costs and efforts.S1 Fig(DOC)Click here for additional data file.S2 Fig(DOC)Click here for additional data file.S3 Fig(DOC)Click here for additional data file.S1 File(DOC)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOC)Click here for additional data file.S4 Table(DOC)Click here for additional data file.S5 Table(DOC)Click here for additional data file.S6 Table(DOC)Click here for additional data file.S7 Table(DOC)Click here for additional data file.S8 Table(DOC)Click here for additional data file.S9 Table(DOC)Click here for additional data file.S10 Table(DOC)Click here for additional data file.S11 Table(DOC)Click here for additional data file.S12 Table(DOC)Click here for additional data file.S1 Text(DOC)Click here for additional data file.S2 Text(DOC)Click here for additional data file.S3 Text(DOC)Click here for additional data file.S4 Text(DOC)Click here for additional data file.


The effects of first-line chemoradiotherapy on overall survival (OS) may be confounded by subsequent lines of therapy in patients with limited-stage disease small cell lung cancer (LD-SCLC). Therefore, we aimed to determine the relationships between progression-free survival (PFS), post-progression survival (PPS) and OS after first-line chemoradiotherapy in LD-SCLC patients.We retrospectively analyzed 71 LD-SCLC patients with performance status (PS) 0–2 who received first-line chemoradiotherapy and had disease recurrence between September 2002 and March 2013 at Shizuoka Cancer Center . We determined the correlation between PFS and OS and between PPS and OS at the individual level. In addition, we performed univariate and multivariate analyses to identify significant prognostic factors of PPS.r = 0.86, R2 = 0.72, p < 0.05) than PFS . In addition, the response to second-line treatments, the presence of distant metastases at recurrence and the number of additional regimens after first-line chemoradiotherapy were significant independent prognostic factors for PPS.OS is more strongly correlated with PPS (Spearman’s PPS has more impact on OS than PFS in recurrent LD-SCLC patients with good PS at beginning of the treatment. Moreover, treatments administered after first-line chemoradiotherapy may affect their OS. However, larger multicenter studies are needed to validate these findings. Lung cancer is the leading cause of cancer-related mortality worldwide.8PFS and OS are two common endpoints in cancer trials. OS is usually preferred, because it is reliable, precise, meaningful and easily documented by the date of death.Therefore, we analyzed the correlation between PFS and OS and between PPS and OS after first-line chemoradiotherapy in LD-SCLC patients to determine whether PFS or PPS has more influence on OS. We also investigated the prognostic value of baseline and tumor characteristics for PPS.We retrospectively enrolled 71 consecutive patients with recurrent LD-SCLC after receiving first-line chemoradiotherapy at Shizuoka Cancer Center  between September 2002 and March 2013. The inclusion criteria were as follows: (1) histologically or cytologically confirmed SCLC; (2) 20 years of age or older at the time of chemoradiotherapy; (3) Eastern Cooperative Oncology Group performance status (PS) of 0–2 at the beginning of the first-line treatment; (4) first-line treatment with ≥ 40 Gy curative thoracic radiotherapy and platinum doublet chemotherapy, either concurrently or sequentially; and (5) disease recurrence after first-line treatment. The study protocol was approved by the Institutional Review Board of Shizuoka Cancer Center and was conducted in accordance with the Helsinki Declaration of 1964 (revised 2008). Due to the retrospective nature of this study, the need for informed consent was waived.2) was administered on days 1–3 in combination with cisplatin (80 mg/m2) on day 1, cisplatin (25 mg/m2) on days 1–3, or carboplatin (area under the curve = 5) on day 1. These drugs were injected intravenously every 3–4 weeks for maximum 4 courses. Second and third-line treatments included amrubicin, irinotecan, topotecan, gemcitabine, and paclitaxel.LD-SCLC patients were treated with a combination of chemotherapy and radiotherapy. Several different first-line chemotherapeutic regimens were used; etoposide (80 or 100 mg/mThe fractionation schedule for thoracic radio-therapy in LD-SCLC patients was determined by using information from chest computed tomography (CT) to calculate the pretreatment tumor volume. Typically, the total planned dose was 50 Gy when it was fractionated once daily or 45 Gy when it was fractionated twice daily, based on individual physician decision. Furthermore, the maximum spinal cord dose was limited to 45 Gy when the radiation dose was fractionated once daily or to 36 Gy when it was fractionated twice daily. In addition, no more than 35% of the normal lung volume received more than 20 Gy.Thoracic radiotherapy was started either during the first cycle of chemotherapy or after four cycles of chemotherapy. It was suspended if a patient experienced grade 4 thrombocytopenia, neutropenia, radiation pneumonitis, fever caused by infection, a decrease of more than 10 mmHg in arterial oxygen pressure, or difficulty swallowing liquids. After thoracic radiotherapy, PCI (25 Gy in 10 fractions) was administered to patients with a complete or near-complete response, as shown by a scar-like shadow on a chest CT, if the treating physician recommended it.Tumor responses reflect the best overall response and maximum shrinkage. Radiographic tumor responses were evaluated using chest computed tomography at every two courses of chemotherapy according to the Response Evaluation Criteria In Solid Tumors 1.0 as follows: complete response (CR), disappearance of all target lesions; partial response (PR), ≥ 30% decrease in the total diameter of all target lesions relative to the total baseline diameter; progressive disease (PD), ≥ 20% increase in the total diameter of all target lesions relative to the smallest total diameter observed during the study; and stable disease (SD), insufficient change in the total diameter of all target lesions to qualify as PR or PD.15PFS was defined as the time from the beginning of first-line treatment until documented PD or death. In addition, OS was reported as the time from the beginning of first-line treatment until death or censored at the time of the last assessment of disease status. Similarly, PPS was documented as the time from tumor progression after first-line treatment until death or censored at the time of the last assessment of disease status.In this study, we defined treatment-free interval (TFI) as the period from the date of completion of first-line treatment to first relapse. When sequential radiotherapy or PCI were performed as first-line treatment, the date of completion of first-line treatment was defined as the last day of these treatments.Since TFI is known as a predictive factor of second-line chemotherapy, we analyzed patients according to TFI.P-values less than 0.05 were considered to be statistically significant for both one-tailed and two-tailed tests. All statistical analyses were performed using JMP .We used Spearman’s rank correlation and linear regression analyses to determine whether PFS or PPS correlated with OS in LD-SCLC patients. We also applied the Cox proportional hazards model with a stepwise regression procedure to determine prognostic factors for PPS and estimate hazard ratios and 95% confidence intervals. The effects of different prognostic factors on PPS were compared using the log-rank test. Between September 2002 and March 2013, 116 patients with LD-SCLC were treated with chemoradiotherapy, and 71 patients who recurred after first-line treatment were enrolled in this study. Patient characteristics are summarized in r = 0.86, R2 = 0.72, p < 0.05; r = 0.46, R2 = 0.38, p < 0.05; vs. no), and the number of regimens after first-line treatment, were significantly associated with PPS  and the number of additional regimens after first-line treatment are significant independent prognostic factors for PPS (Since OS was more strongly correlated with PPS (Spearman’s  for PPS .vs. PD), the presence of distant metastases at recurrence (yes vs. no) and the number of additional regimens after first-line treatment (< 2 vs. ≥ 2) are significantly different . Specifically, the median PPS in patients without PD after second-line treatment (17.5 months) was significantly greater than that for patients with PD . Furthermore, the median PPS in patients without distant metastases (17.3 months) was significantly greater than that for patients with distant metastases . In addition, the median PPS of patients who received two or more regimens after first-line treatment (16.0 months) was significantly greater than that for patients who received less than two additional regimens .We used these three prognostic factors to construct Kaplan-Meier plots of PPS , which sIn this study, we examined the relationships between OS and PFS or PPS, for recurrent LD-SCLC patients after first-line chemoradiotherapy and found that OS correlates more strongly with PPS than PFS. In addition, we determined that the response to second-line treatment, the presence of distant metastases at recurrence and the number of additional regimens after first-line treatment are significant independent prognostic factors for PPS. To our knowledge, this is the first report of individual-level factors that affect PPS for LD-SCLC patients after first-line chemoradiotherapy.Several previous meta-analyses have assessed the value of surrogate endpoints, such as time to progression for survival in cancer studies.22Our finding that OS is more strongly correlated with PPS than PFS implies that subsequent treatments have more effects on OS than the first line treatment. Therefore, LD-SCLC clinical trials should account for factors that may affect PPS to avoid confounding OS. Actually, this recommendation may apply to SCLC in general, because the two of three significant independent prognostic factors associated with PPS for LD-SCLC patients that we identified in this study, namely, response to second-line treatment and the number of additional regimens after first-line chemotherapy, are also associated with PPS in extensive-stage SCLC patients.14These prognostic factors for PPS also suggest that disease stabilization after disease progression following first-line chemoradiotherapy may allow LD-SCLC patients to receive additional lines of treatment, which could prolong PPS, and consequently, OS. Although a number of treatment choices in SCLC are less than that of NSCLC, the large number of treatment regimens that were used after first-line chemoradiotherapy in this study is mainly due to the increasing number of chemo-therapeutic options, such as amrubicin, irinotecan, and topotecan, for subsequent-line chemotherapy for LD-SCLC. However, treatments with platinum-based chemotherapeutic agents and amrubicin after first-line treatment were not significant prognostic factors for PPS, which suggest that these drugs do not affect PPS or OS. Likewise, treatment with sequential or concurrent chemoradiotherapy was not a significant prognostic factor for PPS; however, relative few patients in this study were treated sequentially, so there may have been insufficient statistical power to detect a significant difference.This study has three major limitations. First, the sample size was relatively small. This limitation is difficult to overcome, particularly in studies that analyze patients with similar backgrounds, because there are relatively few LD-SCLC patients at any given institution. Nevertheless, our institution treats a fair number of these cases and uses unified treatment regimens. Second, the single-center design of our study may limit the generality of our conclusions, so multicenter trials are needed to validate our results in larger patient populations and other clinical settings. Third, since different physicians documented patient responses, the timing of evaluation of PFS and tumor response rates may have been less accurate than if only a single physician had documented all responses. However, this is one of the major limitations of retrospective study, and it is unavoidable. Prospective trials are needed to investigate the validity.In conclusion, PPS has more impact on OS than PFS in recurrent LD-SCLC patients after first-line chemoradiotherapy. In addition, the response to second-line treatment, the presence of distant metastases at recurrence and the number of additional regimens after first-line treatment are significant independent prognostic factors for PPS. These results suggest that treatments administered after first-line chemoradiotherapy affect OS in LD-SCLC patients. However, larger multicenter studies are needed to validate these conclusions in other patient populations and clinical settings.


Health-related quality of life (HRQoL) outcome questionnaire, Scoliosis Research Society (SRS)-30, had been well received since its establishment in 2003. Literatures from Asia on the use of SRS-30 mainly focused on the translation process and validation process, but not on measuring outcomes, particularly in the Chinese community. We carried out a prospective cohort study to evaluate the HRQoL of Chinese AIS adolescents with severe scoliosis after surgery.One hundred and four Chinese AIS patients with severe scoliosis undergoing posterior spinal fusion between 2009 and 2013 were recruited in this study. They completed SRS-30 questions before surgery, before hospital discharge, and at follow-up. Mean scores and percentages of individual scores in different domains, and composite scores in terms of subtotal and total scores were calculated referring to the scoring system. Gender-specific and period-specific descriptive analyses were described. Correlation of mean domain scores at the three time points were explored to look for any time-specific relationship. Linear regression analysis looking for potential risk factors on domain scores at different time points by gender were also carried out.Mean age was 16.28 at surgery, and 83.6% were female. Significant correlations between pre-op scores and scores after surgery were observed in function/activity domain (p=0.05) in males, and pain (p=0.04) and satisfaction with management (p=0.04) domains in females. No gender difference in all 5 domain scores at the 3 time points was found. Pre-op maximum Cobb angle and corrected angle were found to be risk factors on self-image, as well as satisfaction with management, in male and female patients.This is the first report on the evaluation of the clinical HRQoL outcomes of Chinese AIS patients with severe scoliosis after surgery. Medical professionals should pay attention to take care of the difference in personal perceptions of feelings between boys and girls. Special care should also be allocated to AIS patients, and try to arrange earlier surgical intervention. Health-related quality of life (HRQoL) outcome questionnaire, Scoliosis Research Society (SRS)-30, has been well received since its establishment in 2003. Literatures from Asia on the use of SRS-30 mainly focused on the translation process and validation process, but not on measuring outcomes, particularly in the Chinese community.The Scoliosis Research Society-30 (SRS-30) questionnaire is well-known as a standard assessment tool to evaluate patients’ quality of life across five domains: function/activity, pain, self-image/appearance, mental health, and satisfaction with management.-4 Over tWe carried out a prospective cohort study using SRS-30 to evaluate HRQoL for Chinese AIS adolescents before and after surgery.One hundred and four (104) Chinese AIS patients  undergoing posterior spinal fusion between 2009 and 2013 were recruited. They completed the SRS-30 questionnaire at 3 time points, 1) just before spinal surgery after hospital admission (pre-op), 2) before hospital discharge (discharge), and 3) 6 months to 3 years after discharge through phone interview (follow-up). The questionnaire was written in Traditional Chinese language, which was the first language of all patients. Informed consent was signed and obtained from every study participant and their legal guardians as required. Ethical approval was obtained from the ethics review board of the joint NTEC/CUHK Ethics Committee.All patients were required to fill out the first 23 questions (section 1), and question 24 to 30 (section 2) were for post-surgery patients. The 30 questions covered 5 domains: function/activity, pain, self-image/appearance, mental health, and satisfaction with management. Answers followed a 5-point Likert scale describing the degree of satisfaction with quality of life (between favourable and unfavourable opinions). Calculation of domain scores followed the suggestion scheme from SRS. A 5-point scale  is used for the calculation of domain scores.Gender-specific descriptive analyses and linear regression modelling were carried out. Surgery related parameters were tabulated by gender. Mean scores in different domains were calculated at 3 time points. Percentages of individual scores in the 5 domains at the 3 time points were tabulated. Pearson's correlations on scores collected at the 3 time points and "change after discharge (follow-up minus discharge)" were also carried out. Effects of potential risk factors  on mean domain scores in male and female patients at the 3 time points were evaluated by linear regression models. All statistical analysis were performed using IBM SPSS version 20.0 . A two-sided p value ≤ 0.05 was considered statistically significant.The mean age was 16.25 years at surgery, and 80.8% were female  on satisfaction with management at follow-up in male patients (Additional files We found that there were gender differences on domain scores. Female patients demonstrated significant correlations on pain and satisfaction with management before and after surgery, and male patients on function/activity. Degree of curve correction after surgery and pre-op maximum Cobb angle were significant predictors of function/activity, self-image/appearance, and satisfaction with management in AIS patients.No significant difference was observed when comparing individual domain scores between male and female patients, at all three time points. This reflects that male and female adolescents have similar feelings and self-awareness in all 5 domains. The effect is still the same after surgery. For malePre-op maximum Cobb angle and corrections of Cobb angles after surgery were two main risk factors on self-image and satisfaction with management, particularly in male patients. Probably the reason is that male patients always had larger pre-op maximum Cobb angle than female patients, which made the degree of surgical correction difficult to match with female patients. Special care should be allocated to AIS patients, and try to arrange earlier surgical intervention, which prevents the ever-progressing spinal curvature making surgical treatment difficult at an advanced stage.Gender differences were found in which female patients demonstrated correlations with pain and satisfaction with management before and after surgery, and male patients with function/activity. Degree of curve correction after surgery and pre-op maximum Cobb angle were significant predictors of function/activity scores, self-image/appearance, and satisfaction with management in AIS patients. Allocation of resources for taking care of patients with problems of self-image and function should take these findings into account.This is the extended abstract of IRSSD 2014 program book .The authors declare that they have no competing interests.Every author performed substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data.BKWN, WWC, JCYC, TPL drafted the article or revised it critically for important intellectual content and obtained final approval of the version to be published.Demographic characteristics of AIS patients by genderClick here for fileMean scores of individual domains and composite scores at Pre-op, Discharge, and Follow-up by genderClick here for filePercentages of patients scoring the 5 domains at Pre-op, Discharge, and Follow-up by genderClick here for fileLinear regression models on the effect of potential risk factors on individual mean domain scoresClick here for file


Migraine is a highly prevalent neuro-vascular disorder. Protein-based serum biomarkers have been assessed in relation to diagnosis and patients' stratification, but general lack of robustness and reproducibility impede widespread clinical utilization. MicroRNAs have emerged as promising biomarkers for multiple conditions such as cancer and recently also for painful conditions.To assesses the potential of applying serum microRNAs as biomarkers for migraine.In an initial screening, 386 microRNAs, previously found in serum, were assessed in six migraineurs in pain-free periods and during migraine attacks. From this, four differentially expressed microRNAs  were selected for further investigation. Validation was performed in a cohort of 8 migraineurs during attack, 8 in a pain-free period and 8 healthy sex- and age-matched controls and in a separate cohort of 12 migraineurs in pain-free period and 12 healthy age-matched controls. In total, serum microRNA expression was analyzed in 48 migraineurs and controls.A significant alteration in more than 30 microRNAs (~8% of the assays) was detected during the screening. Three of the four microRNA were confirmed to have significantly higher expression during migraine attacks compared to pain-free periods. Furthermore, microRNA expression were significantly altered between migraineurs and healthy controls in two independent validation cohorts (n = 16 and n = 24).These preliminary data, proposes microRNAs as potential biomarkers for migraine with applications in patients' stratification, diagnosis or perhaps therapeutic aspects of migraine. Further investigations are warranted.No conflict of interest.


Rabbit antithymocyte globulin  is the most common induction immunosuppression therapy in kidney transplantation. We applied a database integration strategy to capture and compare long-term (10-year) outcome data for US participants in a clinical trial of rATG versus FDA-approved basiliximab.P). Non-inferiority of rATG was assessed using a one-tailed equivalence test .Records for US participants in an international, 1-year, randomized clinical trial comparing rATG and basiliximab induction in deceased donor kidney transplantation were integrated with records from the US national Organ Procurement and Transplantation (OPTN) registry using center, transplant dates, recipient sex, and birthdates. The OPTN captures center-reported acute rejection, graft failure, death, and cancer events, and incorporates comprehensive death records from the Social Security Death Master File. Ten-year outcomes according to randomized induction regimen were compared by Kaplan–Meier analysis (two-sided n = 163) matched OPTN records exactly; the remainder were matched by extending agreement windows for transplant and birthdates. Matches were validated by donor and recipient blood types. By Kaplan–Meier analysis, 10 years post-transplant, freedom from acute rejection, graft failure, or death was 32.6 % and 24.0 % in the rATG and basiliximab arms, respectively (P = 0.09). The incidence of acute rejection with rATG versus basiliximab induction was 21.0 % versus 32.8 % (P = 0.07). Patient survival  and graft survival  rates were numerically and statistically similar for both arms. Comparison of the composite outcome meets non-inferiority criteria even with a 0 % equivalence margin (one-sided P = 0.04). With a 10 % equivalence margin, the odds that rATG is no worse than basiliximab for 10-year risk of the composite endpoint are >99 %.Of 183 US trial participants, 89 %  contains supplementary material, which is available to authorized users. Antibody induction therapy in kidney transplantation is highly effective in reducing acute rejection  and, ultP = 0.34) in preventing the composite quadruple endpoint of acute rejection, delayed graft function, graft loss, or death. However, when analyzed as a more traditional FDA endpoint of acute rejection, graft failure, or death, the differences were statistically significant in favor of rATG (P = 0.02), driven by a lower acute rejection rate in the rATG group  [A pivotal component of the evidence base informing current understanding of the effectiveness of alternative induction regimens in kidney transplantation came from the 10-10 Study, which was the first prospective, randomized, international clinical trial comparing rATG and basiliximab among deceased donor transplant recipients perceived to be at increased risk of acute rejection or delayed graft function  . The 278The duration of follow-up in clinical trials is limited by the willingness of patients to participate for extended periods as well as by the ability of investigators to commit the time and resources necessary to track and monitor participants over a number of years. Extended monitoring beyond an initially determined study period may require additional informed consent and always incurs added costs. Consequently, long-term safety and efficacy data are lacking for many drugs in multiple treatment domains, including transplantation . Thus, tSolid organ transplantation is unique among medical specialties in the universal collection of clinical data in national registries in some countries. In the USA, through the mechanism of the Organ Procurement and Transplantation Network (OPTN), as mandated by the National Organ Transplant Act, transplant centers have been required to submit baseline and follow-up clinical data describing all patients listed for and receiving solid organ transplants since 1987 [P = 0.04) [Integration of clinical trial and transplant registry records may circumvent some of the logistical difficulties in conducting long-term clinical studies and the limitations of isolated registry analyses. However, despite the opportunity created by the presence of national transplant registries, examples of the use of this approach in transplantation are limited. We previously linked data from the 10-10 Study with OPTN records to assess 5-year clinical outcomes of US-enrolled participants and found that patients treated with rATG had a lower incidence of a traditional composite endpoint of acute rejection, graft failure or death  .Ten years have now passed since completion of enrollment in the rATG versus basiliximab induction immunosuppression trial. The goal of the current study was to link records for US participants in the 10-10 Study with current OPTN follow-up records to compare long-term efficacy and safety over 10 years after transplantation.n = 141) or basiliximab (n = 137) as part of immunosuppression regimens in deceased donor renal allograft recipients. In all, 66 % of total participants (n = 183) were enrolled at 17 US centers between May 2000 and March 2002. Patient eligibility for trial enrollment was based on prolonged cold ischemia times and donor and recipient risk factors for acute rejection, or delayed graft function, as previously described [Clinical trial data were obtained from a randomized, multi-center international trial involving 278 kidney transplant recipients in the USA and Europe  . The cliTen-year post-transplant follow-up data for US-enrolled trial participants were obtained from OPTN registry data. As mandated by the National Organ Transplant Act, the OPTN collects information on all solid organ transplant recipients and donors in the USA as submitted by OPTN member centers, including transplant date and baseline demographic and clinical information. Post-transplant follow-up information is collected 6 months after transplant, on the first transplant anniversary, and then annually. Center-reported death records are supplemented within the OPTN registry by the national Social Security Death Master File (SSDMF). The Health Resources and Services Administration (HRSA), of the US Department of Health and Human Services, provides oversight to the activities of the OPTN contractor.Corresponding OPTN records for trial participants were first sought using transplant center, sex, and exact recorded dates of transplantation and birth in each data source. As the available trial records provided dates of administration of anesthesia for transplant surgery and transplant surgery may occur overnight, OPTN records for trial participants who were not exactly matched initially were sought using trial-reported surgical anesthesia dates ± 1 day. To account for transcription errors, matches were identified for remaining patients using age instead of month and day of birth, or transplant year instead of month and day of transplant. Final matches were validated by comparing trial versus OPTN reports of donor and recipient ABO blood types.This study was approved by the Saint Louis University Institutional Review Board (protocol number 23175), and by OPTN/HRSA. Because of the anonymity of the patients studied, and the non-intrusive nature of the current research using previously collected records without patient contacts, a waiver of informed consent was granted per the Department of Health and Human Services Code of Federal Regulations . Analyses were performed using limited datasets, compliant with the US Health Information Portability and Accountability Act.Immunosuppression treatment regimens and regimen allocation used in the randomized trial have been reported previously . BrieflyThe 10-year primary efficacy endpoint was the FDA-specified composite triple endpoint of allograft rejection, graft failure, or patient death used in clinical trials of immunosuppression efficacy. Secondary endpoints included acute rejection, death-censored graft failure, and all-cause graft loss, evaluated individually at 10 years post-transplant. Trial-reported events within the 1-year trial period were supplemented with OPTN records to ascertain long-term outcomes. The OPTN queries centers for information on acute rejection according to periods covered by specific reporting forms , but dates of acute rejection within reporting periods are not collected. We defined acute rejection from OPTN records according to center reports that an acute rejection event occurred, taking the event date as the follow-up record date, as per prior methods for identifying acute rejection from OPTN registry data . Acute rMortality was defined as date of death from any cause, as reported within the trial or from OPTN records based on transplant center or the SSDMF reports. Ascertainment of death, including national death registry SSDMF records, was considered complete. Graft failure was defined as the earliest reported date of return to maintenance dialysis or ‘preemptive’ re-transplantation. Times to acute rejection, graft failure, and the composite triple endpoint were right censored at 10 years post-transplant or center-reported loss-to-follow-up.Renal function at annual follow-up was quantified as estimated glomerular filtration rate according to the abbreviated Modification of Diet in Renal Disease equation . Serum cDiagnoses of malignancy, as captured in the trial reports for up to 1 year post-transplant and by OPTN follow-up reports to 10 years, were examined as a safety endpoint. Time-to-malignancy was computed as the time to the date of first reported cancer diagnosis, and also sub-categorized as time to first reported post-transplant lymphoproliferative disorder, non-melanoma skin cancer or other cancer diagnosis.t test for continuous variables, as previously reported [P-value, to assess superiority. The primary analyses compared outcomes at 10 years post-transplant. Non-inferiority of rATG compared with FDA-approved basiliximab for the composite outcome was assessed using a one-tailed equivalence test with α equal to 0.05 and a-priori defined equivalence margins of 0 % and 10 % [Data management and analyses were performed with SAS for Windows software, version 9.3 . Distributions of baseline recipient, donor, and transplant factors according to induction treatment assignment, including missing values, were compared using Fisher’s exact test for categorical factors and the Wilcoxon–Mann–Whitney test or the reported , 10. No and 10 % .t tests.As the prior 5-year linkage study used data extracted shortly after 5 years after trial enrollment , and becn = 163) of patients were exactly matched in both data sources using center, transplant date, sex, race, and date of birth. Recorded transplant surgery or anesthesia dates varied within ± 1 day for 13 patients (7.1 %) who matched exactly on other parameters. Five (2.7 %) patients were matched using age instead of month and day of birth, along with exact matching for the other parameters. Finally, one (0.5 %) patient was matched using transplant year instead of transplant date and one (0.5 %) final match was identified using age and transplant year along with sex and transplant center. The final 183 matches were validated by recipient and donor ABO types in the trial and OPTN records. Additional file Results of the procedures for identifying OPTN reports for US-enrolled trial participants are shown in Fig. As previously reported, 91 of the 183 US participants were randomized to receive rATG induction in the clinical trial and 92 were assigned to receive basiliximab . BaselinP = 0.04) (Table P = 0.04).US participants randomized to receive rATG had higher freedom from the triple endpoint of rejection, graft failure, or death at 1 year post-transplant  Table . SimilarP = 0.09) . With a typical 10 % equivalence margin, the odds that rATG is no worse than basiliximab for 10-year risk of the composite endpoint are greater than 99 % based on the results of this study.By Kaplan–Meier analysis, at 10 years post-transplant, freedom from a composite of acute rejection, graft failure or death was 32.6 % and 24.0 % in the rATG and basiliximab arms, respectively (two-sided P = 0.08) (Table P = 0.07). No patients developed incident registry-reported rejection events after 5 years, such that the 10-year incidence of acute rejection was also 21.0 % in the rATG arm and 32.8 % in the basiliximab arm (two-sided P = 0.07)  Fig. .Fig. 310P = 0.92)    Fig. . Death-c80) Fig. . Combini56) Fig. .Estimated glomerular filtration rate was computed at each annual follow-up time among patients with a reported serum creatinine value on corresponding OPTN follow-up forms. An additional file summarizes causes of missing serum creatinine values, including graft loss, death, or missed reporting  among patients who received rATG or basiliximab in the trial, at 9.5 % and 8.1 %, respectively. The 10-year incidences of skin cancer , post-transplant lymphoproliferative disorder  and other cancers  also did not differ significantly among patients randomized to rATG compared with basiliximab , acute rejection , and need for anti-lymphocyte treatment of acute rejection  at 1 year post-transplant [Maintenance immunosuppression warrants consideration in any study of induction therapies. Cyclosporine, mycophenolate, and low-dose prednisone were used in the 10-10 Study. While the most common maintenance immunosuppression regimen in current US practice is tacrolimus, mycophenolate, and low-dose prednisone, cyclosporine continues to be used as the primary calcineurin inhibitor among many patients internationally. A subsequent randomized comparison of rATG versus the IL2R Ab daclizumab in the context of maintenance tacrolimus, mycophenolate, and low-dose prednisone among high immunologic-risk patients showed that rATG induction was associated with lower rates of delayed graft function , 4 % of matches required broadening of agreement windows for transplant or birthdates, and thus indicate recording errors for these dates in one of the sources; such recording errors cannot be resolved with the current design based on extracted information without direct access to center records. Observed baseline characteristics were well balanced across the included subjects in the two treatment arms, but imbalances in unmeasured characteristics are possible. While the intervention of interest, induction immunosuppression, is solely an early exposure, loss of blinding after the completion of the trial and subsequent unmeasured impacts on other aspects of care is also a potential limitation of the study design.The long-term data presented were also limited by the fields captured in the OPTN registry. For example, histological assessments of the type and severity of acute rejection episodes are not collected by the OPTN. Although center-reported death records were supplemented with the SSDMF and thus considered to be complete, outcomes  that relied solely on center reports could be incompletely captured. Because the OPTN registry incorporates events attributable to prior periods if newly reported by centers after an annual survey, we also re-analyzed 5-year outcomes in the recently extracted data and found slightly higher event rates compared with the prior 2007 extraction  but withConducting clinical trials with long-term follow-up poses many challenges, from financial burdens to the unwillingness of patients, physicians, and commercial and academic sponsors to participate in studies that require years of involvement. Consequently, long-term safety and efficacy data are lacking for most drugs . AlthougIn summary, integrating records from a clinical trial of induction immunosuppression therapies with national transplant registry data enabled ascertainment of long-term follow-up information for 9 years beyond the duration of the original comparative trial. We found that, compared with an FDA-approved induction agent, the benefits of polyclonal induction with rATG for an FDA-defined composite endpoint of acute rejection, graft failure, or death were sustained through 5 years post-transplant. At 10 years post-transplant, rATG induction had comparable efficacy and safety to FDA-approved basiliximab. Our methodology demonstrates an efficient strategy for monitoring the long-term safety and efficacy of therapies examined in clinical trials when registry data for participants are also available. This approach may be extended to clinical trials outside of transplantation.


Anal cancer is a rare disease with an increasing incidence worldwide but, unfortunately, even today the scientific community still has a limited knowledge and limited options of treatment.More than 50% of patients with anal cancer presenting at diagnosis with locoregional disease have good chances of cure with chemoradiotherapy (CT–RT). However, once patients develop metastatic spread, the prognosis is very poor.Human papillomavirus (HPV) is present in more than 80% of anal cancers and while multiple etiologic connections between HPV infection and anal cancer have already been well elucidated, its prognostic and/or predictive role is currently under investigation, especially among immunocompetent patients affected by this disease.In a single-institutional set, we have retrospectively analysed clinical data of 50 consecutive cases homogeneously treated with CT–RT for stage I–III anal squamous cell carcinoma. We found that HPV-positive anal cancers had a statistically significant improved five-year disease-free survival (DFS) compared to HPV-negative group. These findings could be explained by an increased chemo/radiosensitivity of HPV-positive tumours. Further efforts should be directed towards a better understanding of HPV-related oncogenesis and towards designing novel tailored strategies for the management of this disease both in terms of prevention and treatment. Anal carcinoma (AC) is a rare disease in the general population, being estimated at about 1.5 cases per 100,000 people per year worldwide, but with an increasing incidence particularly in women .Several biomolecular and epidemiologic studies have clearly elucidated a strong etiologic connection between AC and high-risk genotypes of HPV , 4, and Factors increasing the risk of HPV infection and/or modulating host response and the persistence of this infection appear to affect the epidemiology of this tumour. Anal intercourse and a high lifetime number of sexual partners increase the risk of persistent HPV infection in men and women, leading eventually to malignancy. Other important risk factors include human immunodeficiency virus (HIV), immunosuppression in transplant recipients, use of immnunosuppressants, a history of other HPV-related cancers, autoimmune disorders, social deprivation, and cigarette smoking .Not surprisingly, AC is no longer a rare disease within specific epidemiologic categories, since among HIV seropositive men the incidence of AC increases to 75–135 per 100,000 and is also higher among HIV seropositive women . TherefoOn the other hand, few studies have so far evaluated the prognostic or predictive role of HPV in AC, especially among the general population and immunocompetent patients.Based on these considerations we have retrospectively reviewed the data of a series of 50 consecutive and immunocompetent cases, treated in our institution between 2000 and 2012. These patients had AJCC (American Joint Committee on Cancer) stage I–III histologically-proven anal squamous cell carcinoma, and had undergone standard treatment with concurrent chemo-radiotherapy (CT–RT). In all patients the presence of HPV infection was assessed by a polymerase chain reaction (PCR) analysis on the tumour biopsy provided at the time of diagnosis before treatment. Genomic DNA was extracted from three 10-μm-thick paraffin sections using QIAamp DNA FFPE Tissue kit , following the manufacturer’s instructions, then 200 ng of DNA were amplified using L1 primers and GP5+/GP6+ primers. For all the PCR procedures, a positive and a negative control were provided. All the positive cases were confirmed in a second round of amplification. The PCR products were detected by electrophoresis with a 2% agarose gel and stained with ethidium bromide and in the presence of HPV infection, we proceeded to do the genotyping by testing the presence of high-risk HPV16, 18, 31, 33, and 45, using specific primers. Inclusion and exclusion criteria as well as the details on concurrent CT–RT are extensively reported elsewhere .In our study we found that 84% of patients were HPV-positive and, among these HPV genotype 16 was detected in 90% of cases. HPV-positive patients had more advanced disease at diagnosis compared to HPV-negative patients in terms of nodal involvement affecting TNM clinical stage.In particular, within HPV-positive group 2.4% of patients had stage I, 23.8% stage II, 45.2% stage IIIA, 28.6% stage IIIB, and within HPV-negative group 0% of patients had stage I, 62.5% stage II, 37.5% stage IIIA, 0% stage IIIB.In this regard, in the statistical analysis, we decided to apply an adjustment for clinical stage in multivariate analysis since the HPV-positive patients presented a higher rate of nodal involvement .After a median follow-up of four years, we found that five-year DFS in HPV-positive and HPV-negative patients was 92.5% and 50% respectively (p < 0.01). Five-year overall survival (OS) in HPV-positive and HPV-negative patients was 93.3% and 66.7%, respectively (p = 0.12). In conclusion, patients with HPV-positive AC had a strong statistically significant improved DFS compared to that in HPV-negative patients; the same trend was observed for OS, but statistical significance was not reached.Despite its small sample size and retrospective nature, this study shows that HPV infection in AC is a positive prognostic factor for DFS. This could be explained by the better response of HPV-positive AC to CT–RT, as already shown in HPV-positive oropharyngeal squamous cell carcinoma , 9.Certainly a greater patient sample size and longer follow-up might also show in the near future a significant difference in OS between HPV-positive and negative AC.From our perspective, the most intriguing and challenging question is whether HPV-positive AC and HPV-negative AC are two completely different malignancies sustained by different biomolecular features and genetic alterations. Further research should be directed towards investigating which specific pathways are selectively altered in anal cancers which are HPV-positive and those which are HPV-negative, by adopting a comparative approach. This should lead to a better understanding of HPV-related oncogenesis and to the design of novel and personalised tailored strategies for the management of this disease both in terms of prevention and treatment.Preclinical models as faithful as possible to the true HPV-related tumour cell biology should be the right place from which experimental studies can embark upon their challenging road.Currently the vast majority of modern studies, including analysis of E6 and E7 mRNA , 11, PIKDespite its small sample size and retrospective nature, this study shows that HPV infection in anal cancer is a positive prognostic factor for disease-free survival. This could be explained by the better response of HPV-positive anal cancer to chemo-radiotherapy, as already shown in HPV-positive oropharyngeal squamous cell carcinoma.From our perspective, the most intriguing and challenging question is whether HPV-positive anal cancer and HPV-negative anal cancer are two completely different malignancies sustained by different biomolecular features and genetic alterations. Further research should be directed towards investigating which specific pathways are selectively altered in anal cancers which are HPV-positive and those which are HPV-negative, by adopting a comparative approach. This should lead to a better understanding of HPV-related oncogenesis and to the design of novel and personalised tailored strategies for the management of this disease both in terms of prevention and treatment.The authors declare that they have no conflicts of interest.


Low frequency fluctuations (LFFs) of the BOLD signal are a major discovery in the study of the resting brain with functional magnetic resonance imaging (fMRI). Two fMRI-based measures, functional connectivity (FC), a measure of signal synchronicity, and the amplitude of LFFs (ALFF), a measure of signal periodicity, have been proved to be sensitive to changes induced by several neurological diseases, including degenerative dementia. In spite of the increasing use of these measures, whether and how they are related to each other remains to be elucidated. In this work we used voxel-wise FC and ALFF computed in different frequency bands , in order to assess their relationship in healthy elderly as well as the relevant changes induced by Alzheimer’s Disease (AD) and Mild Cognitive Impairment (MCI). We found that in healthy elderly subjects FC and ALFF are positively correlated in anterior and posterior cingulate cortex , temporal cortex (full-band and slow-5), and in a set of subcortical regions (full-band and slow-4). These correlation patterns between FC and ALFF were absent in either AD or MCI patients. Notably, the loss of correlation between FC and ALFF in the AD group was primarily due to changes in FC rather than in ALFF. Our results indicate that degenerative dementia is characterized by a loss of global connection rather than by a decrease of fluctuation amplitude. Resting-state functional magnetic resonance imaging (rs-fMRI) has been widely used to investigate the brain function in the absence of a specific task . The resper se could be of physiological relevance. Biswal and colleagues reported higher values of spectral power in the grey than in the white matter [Functional connectivity (FC) characterizes the degree of LFFs synchronization in the resting brain. It has been largely inferred by seed-based standard correlation analysis or alternatively by data-driven approaches, such as independent component analysis (ICA) . These me matter . Recentle matter . ALFF mee matter , 8.FC and ALFF have been increasingly used to investigate the brain at rest, although the qualitative and quantitative relationship between them still needs to be fully understood. To the best of our knowledge, one single work examined systematically the relationship between FC and ALFF. Di and colleagues showed a widespread pattern of both positive and negative local correlations between network strength  and ALFF in a healthy elderly population . MoreoveIn principle, temporal correlation should be independent from the amplitude of compared signals. However, the fact that several pathological states are characterized by partially co-localized changes in FC and ALFF suggests the existence of a specific relationship between them. For example, Alzheimer's disease (AD) and mild cognitive impairment  patients show altered patterns of FC in specific DMN areas, i.e. posterior cingulate cortex (PCC)/precuneus, lateral temporal, parietal and medial frontal cortex, as well as hippocampus –16. SimiAlthough the majority of resting state studies have focused on a relative wide range of frequency , converging evidence suggests that a finer band subdivision might provide some additional information. Zuo and colleagues, extending the Buzaski framework on neuronal oscillator classes  to BOLD In the present work, we sought to investigate the relationship between ALFF and global FC with a voxel-based approach in the healthy and diseased brain. The main aim of the study was to assess whether the coupling between ALFF and FC depends on anatomical brain localization, frequency band, and pathological conditions. For this purpose, we performed rs-fMRI employing degenerative dementia as a pathological model, and enrolling patients with both AD and MCI. Assuming the existence of a connection between ALFF and the average FC in each voxel with the whole brain, we used a generalized linear model (GLM) to systematically assess to what extent the voxel-wise variance of FC across subjects is explained by the amplitude of the underlying oscillations.Ten patients with a diagnosis of probable AD by NINCDS-ADRDA consensus criteria , 10 amneAge, education and MMSE score distributions were compared among groups via one-way analysis of variance (ANOVA), while a chi-square test was applied to compare gender distribution. Where indicated, two-sample, two-tailed t-tests were performed as post-hoc analyses.The current study was approved by the ethics committee of Santa Lucia Foundation. Every recruited subject (or his/her responsible guardians if incapable) gave written consent before MR study initiation.2, slice thickness = 2.5 mm, 50% skip, flip angle = 70°. Resting scans lasted for 7 minutes and 20 seconds for a total of 220 volumes during which subjects were instructed to keep their eyes closed, to not think of anything in particular and to refrain from falling asleep. A T1-weighted three-dimensional modified driven equilibrium Fourier transform scan  images  were also acquired from all subjects to exclude the presence of remarkable signs suggestive for cerebro-vascular disease, as previously described [Data were acquired on a 3T MRI system . All subjects underwent a resting state fMRI scan using a echo planar imaging (EPI) sequence with the following parameters: TR = 2080 ms, TE = 30 ms, 32 axial slices parallel to AC-PC plane, matrix = 64 x 64, in plane resolution = 3x3 mmescribed .3). Normalized images were then smoothed using an 8x8x8 mm3 full width at half maximum (FWHM) Gaussian kernel.Functional images were preprocessed using Connectivity toolbox . The fiBefore statistical analyses, data from each subject underwent physiological noise mitigation. The six parameters of realignment and the first five eigenvectors of the PCA decomposition of the EPI time course averaged over cerebrospinal fluid (CSF) and white matter (WM) were regressed out, following aCompCor approach for physiological noise removal . Data wehttp://www.fil.ion.ucl.ac.uk/spm/), which consists of an iterative combination of segmentations and normalizations to produce a GM probability map [3 FWHM Gaussian kernel, and finally the GM volume (GMV) was computed by summing the relevant modulated partition, multiplied by the voxel volume.The T1-weighted MDEFT images were processed using the VBM protocol  implemenlity map  in MNI slity map . All datVoxel-wise connectivity analysis was carried out using 3dTcorrMap  as prevVoxel-wise based FC computation is less sensitive than FC obtained by using a seed-based approach, which has been adopted among the others by Di and colleagues . NonetheFor each voxel in the brain the filtered time series (0.01–0.073 Hz) was transformed into the frequency domain using a Fast Fourier Transform (FFT) algorithm . The obFor each subject group, the mean effects of ALFF and FC were assessed via one-sample, two-tailed t-tests . Distribution of abnormal ALFF and FC values across groups were evaluated via one-way ANOVA .Z-transformed correlation and ALFF maps from each subject were entered in a second level analysis to assess whether the amplitude of oscillations affects the correlation strength. GLM was applied voxel-wise, considering the FC and ALFF z-scores as dependent and independent variables respectively. Age, gender, education and GM volume were standardized and entered in the model as nuisance covariates. The statistical significance of the regression FC vs ALFF was assessed in each group by one sample, two-tailed t-tests. Within the areas where the regression returned significant coupling in HC, group differences in the strength of correlation were assessed between all experimental groups  by two-sample, two-tailed t-tests. Model estimation and t-contrasts were replicated for each frequency range. The calculation was carried out with custom software implemented in Matlab R2012a .Statistical threshold was set to p < 0.05 after correction for multiple comparison, performed by Monte Carlo simulations . The co2 = 1.9, p > 0.3), although patients were less educated than controls . As expected, MMSE scores were significantly different between all groups . AD patients showed a significant reduction of GMV when compared to both HC and MCI patients . Conversely, despite the presence of a reduction trend in GMV, volumes were not significantly different between MCI patients and HC .Principal demographic, clinical data and GMV estimation are reported in FC and ALFF maps in the full-band range are shown for each studied group in Group averages of FC z-score in the GM  showed aHaving confirmed previous results on the overall spatial distribution of FC and ALFF in healthy controls and patients, we next examined the results of the linear regression between FC and ALFF within each group. Brain regions in which the correlation strength was significantly explained by the amplitude of oscillations in HC are shown in We then investigated the specific effect of disease in those areas showing significant FC vs ALFF correlation in healthy subjects  . HoweverThe separation of LFFs in two distinct frequency ranges (slow-5 and slow-4) demonstrated that the relationship between ALFF and FC is sensitive to the frequency range, and specific patterns of correlation could be identified for slow-5 and slow-4 bands. Although the full-band analysis returned essentially the same areas highlighted by the sub-band analysis, the slow-5 band was clearly more sensitive for couplings in temporal lobe regions. Moreover, slow-5 primarily identified cortical regions, while slow-4 included both cortical and subcortical regions. These results are in agreement with recent studies, which reported that the fluctuations at the higher bound of LFFs are mainly localized in subcortical areas , 8. The A higher fluctuation amplitude in slow-4 as compared to slow-5 has been observed with a symmetrical pattern in the basal ganglia . In contBoth the spatial specificity and the frequency dependence of the coupling between FC and ALFF suggest that the latter measure plays an active role in the generation of synchronization patterns and it is not a simple prerequisite for the emergence of FC. Indeed, the amplitude of BOLD low frequency fluctuations is of physiological relevance, as indicated by many works reporting a coupling between electrophysiological signals and spontaneous BOLD LFFs –49. ALFFOn the other hand, a non-neuronal origin of the FC vs ALFF pattern cannot be excluded a priori. In principle, a common source of physiological noise could also account for their positive correlation pattern. Cardiac and respiratory fluctuations, spontaneous oscillation in carbon dioxide, and many other physiological phenomena have been identified or proposed as source of BOLD fluctuations –59. For The comparison between patients and healthy controls revealed a widespread reduction of the FC vs ALFF coupling, at all frequency bands and in both patient groups, AD and MCI . AdditioDifferent works have reported decreased FC in AD and MCI patients with both seed-based and data driven-analyses , especiaWe observed that the normal pattern of correlations between FC and ALFF  is disruThe anatomical pattern of significant FC vs ALFF coupling observed in HC was found to be disrupted as an effect of AD pathology, as shown by group comparisons. Moreover, when considering the overall FC vs ALFF uncoupling, such a disruption was already detectable at the stage of MCI, indicating such a parameter to be sensitive to early pathophysiological aspects of the disease. Further studies on larger populations are needed to clarify the potential diagnostic value of this biomarker. It is possible that the involved regions could have a key role for the maintenance of the ongoing activity . In the pathological brain, these key regions could be forced to maintain a normal level of activity that, due to the disease, does not produce a comparable degree of synchronization with other brain regions.The present resting-state fMRI study revealed that ALFF is linearly related to FC in spatially segregated patterns that are consistent in a healthy elderly population. This relationship is dependent on the specific range of frequencies within the low-frequency band explored in FC studies. The relationship between FC and ALFF is disrupted in AD as well as MCI, in all the studied frequency bands. According to our findings, this is likely due to a loss of fluctuation synchrony among the involved brain areas rather than to altered local activity.In conclusion, this study suggests that the correlation patterns between ALFF and FC have a neurophysiological correlate, but that ALFF and FC convey partially distinct information, especially as far as the development of changes induced by pathology is involved.S1 Fig-5) for easier identification of most globally connected regions.Group-level t-statistic map showing significant FC on HC in the full-band frequency range. Map result is the same reported in (TIF)Click here for additional data file.S2 Fig(A) f-statistic maps showing significant detectable changes of FC (hot colors) and ALFF values (cold colors) among the three groups of subjects . Of note, only one lateralized frontal region showed a significant change in ALFF among groups. Results were obtained via one-way ANOVA, separately accomplished for FC and ALFF data. The statistical threshold was set at f > 6.48 . (B-E) Post-hoc analyses of the most relevant clusters belonging to FC (B-D) and ALFF (E) changes. For each cluster, group comparisons were performed via two-sample, two-tailed t-tests on the voxel showing the local maximum of f-values. *, p < 0.05; **, p < 0.01; ***, p < 0.001; A, anterior; P, posterior.(TIF)Click here for additional data file.S3 FigFC and ALFF values were averaged in the significant clusters resulting from t-contrasts HC vs AD (A) and HC vs MCI (B) both computed in the FC vs ALFF full-band model see . For the(TIF)Click here for additional data file.


Objective. To investigate whether patients on long-term antisecretory medication need to continue treatment to control symptoms. Methods. A double-blinded randomised placebo-controlled trial in general practices in Denmark. Patients aged 18–90 who were treated with antisecretory drugs on a long-term basis were randomized to esomeprazole 40 mg or identical placebo. Outcome measures were time to discontinuation with trial medication due to failed symptom control analysed as survival data. The proportion of patients stopping trial medication during the one-year follow-up was estimated. Results. A total of 171 patients were included with a median prior duration of antisecretory treatment of four years (range: 0.5 to 14.6 years). 86 patients received esomeprazole 40 mg and 85 patients received placebo. At 12 months, statistically significantly more patients in the placebo group had discontinued (73% (62/85)) compared with the esomeprazole group (21% (18/86); p < 0.001). Conclusions. Long-term users of antisecretory drugs showed a preference for the active drug compared to placebo. However, 27% of patients continued on placebo throughout the study and did not need to reinstitute usual treatment. One in five patients treated with esomeprazole discontinued trial medication due to unsatisfactory symptom control. Discontinuation of antisecretory treatment should be considered in long-term users of antisecretory drugs. This trial is registered with Trial registration ClinicalTrials.gov ID: NCT00120315. The use of acid-suppressive medication is rapidly increasing. In the western world, proton pump inhibitors (PPIs) are second only to statins in expenditures, and antisecretory medication constitutes a substantial part of the medical budget in the Denmark and other western countries –3. Most Antisecretory medication is highly effective for the treatment of peptic ulcer and reflux disease, but it has only sparse effect in the treatment of patients with functional dyspepsia . In primThe aim of the present study was therefore in a placebo-controlled randomised design to investigate if patients on long-term antisecretory medication need to continue treatment to control symptoms in a primary care setting.A total of 146 general practitioners in Denmark were visited, introduced to, and educated in study procedures and signed in as coinvestigators on the required forms from the Danish Medicines Agency (Protocol ID: 2612-2176). Eligible patients were evaluated, enrolled, and followed by their general practitioner from January 2003 to September 2006.Patients older than 17 years with a use of antisecretory treatment (proton pump inhibitors or histamine-2-receptor-antagonists) for at least 56 days during the previous six months were included. Exclusion criteria were alarm symptoms , drug or alcohol abuse, serious or terminal diseases, planned hospitalization during follow-up, allergy to trial medication, and pregnant or fertile females not using safe contraception. Furthermore, patients suffering from oesophagitis, having had prior complicated peptic ulcer, and patients with prior endoscopically verified ulceration and ongoing use of nonsteroidal anti-inflammatory drugs (NSAIDs)/acetylic salicylic acid (ASA) were not eligible. identical placebo was used as the randomised trial medication with a maximum of one tablet a day mimicking the patient's usual treatment. When trial medication was discontinued due to insufficient symptom control, reinstitution of usual antisecretory treatment was left to the GPs' discretion.Long-term users of antisecretory treatment were randomised to continued antisecretory treatment or placebo. Esomeprazole  40 mg or Helicobacter pylori status was investigated with a 13C-urea breath test performed in general practice. During the seven days of discontinuation symptoms, demographics and clinical baseline characteristics of participants were obtained. Eradication therapy was given to any Helicobacter-positive patient . The study was monitored according to Good Clinical Practice (GCP) by the GCP unit at Odense University Hospital, Denmark (Project number 02-004).Both active medication and placebo were manufactured and packed by AstraZeneca, Mölndal, Sweden, in accordance with Good Manufactory Practice (GMP). Trial drug was delivered in identical, sealed containers holding 100 tablets. The local university hospital pharmacy  labelled and randomised the trial drug accordingly using a computer-generated random number block randomisation with a fixed block size of four and a placebo/treatment ratio of one. The pharmacy kept the sequence of allocation concealed throughout the one-year follow-up, thus blinding patients, general practitioners, and researchers. Following seven days of discontinuation of usual antisecretory treatment with allowance of antacids as rescue treatment,Primary endpoint was the time to discontinuation with trial medications (esomeprazole or placebo) due to the participants' need to change back to their usual antisecretory medication, that is, failure to control symptoms with the trial medication at any time point in the one-year follow-up. The proportion of patients stopping trial medication during the one-year follow-up was estimated. Additional analysis was carried out using health-related quality-of-life (MOS Short Form-36)  and geneWe assumed 15–20% of long-term users to be suffering from peptic ulcer disease, 40–45% to be suffering from nonerosive reflux disease, and approximately 40% to be suffering from functional dyspepsia . Based oDuring data analysis, patients remained in the two arms of the study without revealing the intervention, thus allowing a blinded data analysis of the primary endpoint . Primary Helicobacter pylori-positive. During the one-year follow-up, six patients were lost to follow-up; no adverse events were seen, except for one patient developing a black discoloration of the tongue during Helicobacter pylori eradication treatment. Characteristics at baseline are shown in A total of 171 patients found eligible by their general practitioners were accepted to participate in the study ; 17% werp < 0.0001, log-rank) in the placebo group compared with the group receiving esomeprazole. A total of 18/86 (21%) of participants treated with esomeprazole had stopped the trial medication compared to 62/85 (73%) of participants treated with placebo . A statistically nonsignificant tendency towards a more successful continuation with placebo treatment was found for patients with less gastrointestinal symptoms . The subscore regarding reflux symptoms (heartburn and regurgitation) did, however, show less influence on continued placebo treatment (p = 0.29).The present study provides estimates from primary care on the need for continued antisecretory treatment among long-term users. In a randomised, placebo-controlled trial, long-term users of antisecretory treatment were randomised to either continued antisecretory treatment (esomeprazole 40 mg) or placebo. We found that 27% of participants receiving placebo did not stop the trial medication during the complete follow-up.To our knowledge, this study was the first nonindustry initiated drug trial conducted in a primary care setting, which was GCP monitored by a public GCP unit. The randomised design and blinding in the design hindered any contamination between participants in the same practice and allowed a blinded data analysis. The primary care setting is important as 90% of antisecretory drugs are prescribed in primary care  and the Recruitment of patients for the study tended to be slower than expected and only 38% of the coinvestigators (GPs) recruited participants for the study. No differences were, however, found between GPs not including participants compared with active coinvestigators.Based on register data , a largeDue to the absence of consensus on the optimal treatment duration, the design of a discontinuation study was chosen and the discontinuation of trial drug was the primary outcome measure. The fluctuation of dyspepsia symptoms is well known and severity as well as symptoms may vary in the same patient over time . This maRebound acid secretion following discontinuation may occur –20. In tThis is the first placebo-controlled study on discontinuation of an acid-suppressive drug in a group of long-term users, with intervention carried out in primary care, but the results are in line with those of Björnsson et al. , who fouA number of studies examined discontinuation of PPI but without inclusion of a placebo group. A recent study by Murie et al.  includedIt may be objected that placebo treatment is not equivalent to absence of therapy and that 50–60% of patients with gastroesophageal reflux disease are satisfied with placebo on demand . On the We recommend that symptom-based long-term antisecretory treatment in general practice should be interrupted by attempts at discontinuation. In our placebo-controlled study, nearly one-third of the patients were satisfied with placebo treatment. One in five patients treated with esomeprazole had even unsatisfactory symptom control and discontinued trial medication. Deleterious effects of antisecretory drugs have been reported , 27–30,