nils-herrmann/clean_scirepeval huggingface dataset:
Antiproliferative Effect of Lapatinib in HER2-Positive and HER2-Negative/HER3-High Breast Cancer: Results of the Presurgical Randomized MAPLE Trial (CRUK E/06/039).

Not all breast cancers respond to lapatinib. A change in Ki67 after short-term exposure may elucidate a biomarker profile for responsive versus nonresponsive tumors.



Women with primary breast cancer were randomized (3:1) to 10 to 14 days of preoperative lapatinib or placebo in a multicenter phase II trial (ISRCTN68509377). Biopsies pre-/posttreatment were analyzed for Ki67, apoptosis, HER2, EGFR, ER, PgR, pAKT, pERK, and stathmin by IHC. Further markers were measured by RT-PCR. Primary endpoint was change in Ki67. HER2(+) was defined as 2+/3+ by IHC and FISH(+).



One hundred twenty-one patients (lapatinib, 94; placebo, 27) were randomized; of these, 21% were HER2(+), 78% were HER2(-) nonamplified, 26% were EGFR(+). Paired samples containing tumor were obtained for 98% (118 of 121). Ki67 fell significantly with lapatinib (-31%; P < 0.001), but not with placebo (-3%). Whereas Ki67 reduction with lapatinib was greatest in HER2(+) breast cancer (-46%; P = 0.003), there was a significant Ki67 decrease in HER2(-) breast cancer (-27%; P = 0.017) with 14% of HER2(-) breast cancer demonstrating ≥50% Ki67 reduction with lapatinib. Among HER2(+) patients, the only biomarker predictive of Ki67 response was the EGFR/HER4 ligand epiregulin (EREG) (rho = -0.7; P = 0.002). Among HER2(-) tumors, only HER3 mRNA levels were significantly associated with Ki67 response on multivariate analysis (P = 0.01). In HER2(-) breast cancer, HER2 and HER3 mRNA levels were highly correlated (rho = 0.67, P < 0.001), with all Ki67 responders having elevated HER3 and HER2 expression.



Lapatinib has antiproliferative effects in a subgroup of HER2(-) nonamplified tumors characterized by high HER3 expression. The possible role of high HER2:HER3 heterodimers in predicting response to lapatinib merits investigation in HER2(-) tumors.
Whole genome analysis of human papillomavirus type 16 multiple infection in cervical cancer patients.

The characterization of the whole genome of human papillomavirus type 16 (HPV16) from cervical cancer specimens with multiple infections in comparison with single infection samples as the oncogenic potential of the virus may differ. Cervical carcinoma specimens positive for HPV16 by PCR and INNO-LiPA were randomly selected for whole genome characterization. Two HPV16 single infection and six HPV16 multiple infection specimens were subjected to whole genome analysis by using conserved primers and subsequent sequencing. All HPV16 whole genomes from single infection samples clustered in the European (E) lineage while all multiple infection specimens belonged to the non-European lineage. The variations in nucleotide sequences in E6, E7, E2, L1 and Long control region (LCR) were evaluated. In the E6 region, amino acid changes at L83V were related to increased cancer progression. An amino acid variation N29S within the E7 oncoprotein significantly associated with severity of lesion was also discovered. In all three domains of the E2 gene non synonymous mutations were found. The L1 region showed various mutations which may be related to conformation changes of viral epitopes. Some transcription factor binding sites in the LCR region correlated to virulence were shown on GRE/1, TEF- 1, YY14 and Oct-1. HPV16 European variant prone to single infection may harbor a major variation at L83V which significantly increases the risk for developing cervical carcinoma. HPV16 non-European variants prone to multiple infections may require many polymorphisms to enhance the risk of cervical cancer development.
Anti-cholinergic load, health care utilization, and survival in people with advanced cancer: a pilot study.

Anti-cholinergic medications have been associated with increased risks of cognitive impairment, premature mortality and increased risk of hospitalisation. Anti-cholinergic load associated with medication increases as death approaches in those with advanced cancer, yet little is known about associated adverse outcomes in this setting.



A substudy of 112 participants in a randomised control trial who had cancer and an Australia modified Karnofsky Performance Scale (AKPS) score (AKPS) of 60 or above, explored survival and health service utilisation; with anti-cholinergic load calculated using the Clinician Rated Anti-cholinergic Scale (modified version) longitudinally to death. A standardised starting point for prospectively calculating survival was an AKPS of 60 or above.



Baseline entry to the sub-study was a mean 62 +/- 81 days (median 37, range 1-588) days before death (survival), with mean of 4.8 (median 3, SD 4.18, range 1 - 24) study assessments in this time period. Participants spent 22% of time as an inpatient. There was no significant association between anti-cholinergic score and time spent as an inpatient (adjusted for survival time) (p = 0.94); or survival time.



No association between anti-cholinergic load and survival or time spent as an inpatient was seen. Future studies need to include cognitively impaired populations where the risks of symptomatic deterioration may be more substantial.
Works Title Dietary flavanol intervention lowers the levels of endothelial microparticles in coronary artery disease patients

Current evidence suggests that regenerative v. degenerative endothelial responses can be integrated in a clinical endothelial phenotype, reflecting the net result between damage from risk factors and endogenous repair capacity. We have previously shown that a cocoa flavanol (CF) intervention can improve endothelial function and increase the regenerative capacity of the endothelium by mobilising circulating angiogenic cells in patients with coronary artery disease (CAD). The aim of the present study was to investigate whether CF can lower the levels of circulating endothelial microparticles (EMP), markers of endothelial integrity, along with improvements in endothelial function. The levels of EMP in the frozen plasma samples of CAD patients were measured along with endothelial function (flow-mediated vasodilation, FMD); n 16, FMD data published previously), and these data were compared with those of young (n 12) and age-matched (n 12) healthy control subjects. The CAD patients exhibited significantly increased levels of EMP along with impaired FMD when compared with the healthy control subjects. The levels of CD144þ and CD31þ/412 EMP were inversely correlated with FMD (r 20·67, P1⁄40·01 and r 20·59, P1⁄40·01, respectively). In these CAD patients, the levels of EMP were measured after they had consumed a drink containing 375mg of CF (high-CF intervention, HiFI) or 9mg of CF (macroand micronutrient-matched low-CF control, LoFl) twice daily over a 30-d period in a randomised, double-blind, cross-over study. After 1month of HiFI, the levels of CD31þ/412 and CD144þ EMP decreased (225 and 223%, respectively), but not after LoFl. Our data show that flavanols lower the levels of EMP along with higher endothelial function, lending evidence to the novel concept that flavanols may improve endothelial integrity.
Correlation between intracoronary ultrasound and fractional flow reserve in long coronary lesions. A three-dimensional intracoronary ultrasound study.

Intracoronary ultrasound estimation of the functional significance of intermediate angiographic lesions has mainly been based on measuring the minimal lumen area. These estimates take no account of lesion length and pay insufficient attention to long coronary lesions.



We included 61 lesions with visual angiographic stenosis of 40% to 70% that required treatment with a ≥20mm stent, studied with ultrasound and fractional flow reserve. Three-dimensional analysis of the ultrasound study was conducted offline and blinded to fractional reserve values. Angiographic and ultrasound parameters were correlated with fractional reserve.



From the angiography we obtained data on mean reference diameter (2.87 [0.57] mm), length (29.8 , and severity of stenosis (50.3% [8.7]%). Mean fractional flow reserve was 0.78 (0.09). We found a weak linear correlation (R) between fractional reserve and the ultrasound parameters that did not include lesion length: fractional reserve-minimal luminal area (R=0.4; P=.003). The correlation was stronger when lesion length was included: fractional reserve-volume of plaque (R=-0.65; P<.0005); fractional reserve-length/mean luminal area (R=0.73; P<.0005). The strongest correlation came from the product of mean stenosis by area multiplied by lesion length (R=-0.78; P<.0005).



In long coronary lesions, the correlation between ultrasound-measured minimal lumen area and functional significance is weak. In these cases, estimates of functional significance should incorporate lesion length or be derived from direct fractional flow reserve measurement.
Thrombin generation in mesalazine refractory ulcerative colitis and the influence of low molecular weight heparin

In ulcerative colitis (UC), a state of hypercoagulation has frequently been observed. Low molecular weight heparin (LMWH) has shown beneficial effects as an adjuvant treatment of steroid refractory UC in open trials. We assessed potential therapeutic effects of the LMWH reviparin in hospitalised patients with mesalazine refractory UC, as well as its influence on haemostasis factors. Twenty-nine patients with mild-to-moderately active UC were included in a double-blind placebo controlled trial. All patients had a flare-up of disease under mesalazine treatment. Reviparin (Clivarin®) 3,436 IU anti-Xa/0.6 ml or placebo s.c. was added, and self-administered twice daily for 8 weeks. Patients were monitored for possible adverse events and changes in clinical symptoms. Endoscopical, histological, biochemical and haemostasis parameters were analysed. Tolerability and compliance were excellent and no serious adverse events occurred. No significant differences were observed on the clinical, endoscopical and histological outcome, as compared to placebo. A high intrinsic and extrinsic thrombin potential was found before LMWH therapy. However, the significant reduction in the thrombin generation by LMWH was not related to the reduction in disease activity. The LMWH reviparine reduces thrombin generation in patients with mild-to-moderately active, mesalazine refractory UC, but is not associated with a reduction in disease activity.
Uptake Decrease of Proliferative PET Tracer 18FLT in Bone Marrow after Carbon Ion Therapy in Lung Cancer

The aim of this study was to investigate the change of 3′-[18F]fluoro-3′-deoxy-l-thymidine (18FLT) uptake in normal bone marrow (BM) after inevitable radiation. Twenty-one non-small cell lung cancer patients who received carbon ion radiotherapy (CIRT) were studied with 18FLT-positron emission tomography/computed tomography (PET/CT) at pre- and post-CIRT. Radiation dose was calculated by radiation planning. Irradiated BM was divided into three groups (<10% of maximum dose, 10–30%, and >30%). 18FLT uptake clearly decreased at >10% irradiated areas and mildly decreased at <10% areas. 18FLT uptake was lowest just after CIRT, somewhat increased at 3 months, and remained unchanged for more than 1 year. There was no significant difference between 10–30% and >30% areas. 18FLT revealed that BM function decreased by small dose such as <4.2–4.4 GyE/1 fraction of CIRT and is eradicated by >4.2–4.4 GyE/1 fraction.
Pilates-based therapeutic exercise: effect on subjects with nonspecific chronic low back pain and functional disability: a randomized controlled trial.

A randomized controlled trial, prestest-posttest design, with a 3-, 6-, and 12-month follow-up.



To investigate the efficacy of a therapeutic exercise approach in a population with chronic low back pain (LBP).



Therapeutic approaches developed from the Pilates method are becoming increasingly popular; however, there have been no reports on their efficacy.



Thirty-nine physically active subjects between 20 and 55 years old with chronic LBP were randomly assigned to 1 of 2 groups. The specific-exercise-training group participated in a 4-week program consisting of training on specialized (Pilates) exercise equipment, while the control group received the usual care, defined as consultation with a physician and other specialists and healthcare professionals, as necessary. Treatment sessions were designed to train the activation of specific muscles thought to stabilize the lumbar-pelvic region. Functional disability outcomes were measured with The Roland Morris Disability Questionnaire (RMQ/RMDQ-HK) and average pain intensity using a 101-point numerical rating scale.



There was a significantly lower level of functional disability (P = .023) and average pain intensity (P = .002) in the specific-exercise-training group than in the control group following the treatment intervention period. The posttest adjusted mean in functional disability level in the specific-exercise-training group was 2.0 (95% CI, 1.3 to 2.7) RMQ/RMDQ-HK points compared to a posttest adjusted mean in the control group of 3.2 (95% CI, 2.5 to 4.0) RMQ/RMDQ-HK points. The posttest adjusted mean in pain intensity in the specific-exercise-training group was 18.3 (95% CI, 11.8 to 24.8), as compared to 33.9 (95% CI, 26.9 to 41.0) in the control group. Improved disability scores in the specific-exercise-training group were maintained for up to 12 months following treatment intervention.



The individuals in the specific-exercise-training group reported a significant decrease in LBP and disability, which was maintained over a 12-month follow-up period. Treatment with a modified Pilates-based approach was more efficacious than usual care in a population with chronic, unresolved LBP.
Safety of percutaneous coronary intervention during uninterrupted oral anticoagulant treatment.

Uninterrupted anticoagulation (UAC) is assumed to increase bleeding and access-site complications. A common consensus is to postpone percutaneous coronary interventions (PCI) to reach international normalized ratio (INR) levels < 1.5-1.8.



To assess the safety and feasibility of UAC, we analysed retrospectively all consecutive patients (n = 523) on warfarin therapy referred for PCI in four centres with a policy to interrupt anticoagulation (IAC) before PCI and in three centres with a long experience on UAC during PCI. Major bleeding, access-site complications, and major adverse cardiac events (death, myocardial infarction, target vessel revascularization, and stent thrombosis) were recorded during hospitalization. In the IAC group, warfarin was withdrawn for a mean of 3 days prior to PCI (mean INR 1.7). In the UAC group, mean INR value was 2.2. Glycoprotein IIb/IIIa (GP) inhibitors (P < 0.001) and low-molecular-weight heparins (P < 0.001) were more often used in the IAC group. Major bleeding and access-site complications were more common in the IAC group (5.0% vs. 1.2%, P = 0.02 and 11.3% vs. 5.0%, P = 0.01, respectively) than in the UAC group. After adjusting for propensity score, the group difference in access-site complications remained significant [OR (odds ratio) 2.8, 95% CI (confidence interval) 1.3-6.1, P = 0.008], but did not remain significant in major bleeding (OR 3.9, 95% CI 1.0-15.3, P = 0.05). In multivariable analysis, femoral access (OR 9.9, 95% CI 1.3-75.2), use of access-site closure devices (OR 2.1, 95% CI 1.1-4.0), low-molecular-weight heparin (OR 2.7, 95% CI 1.1-6.7) and old age predicted access-site complications, and the use of GP inhibitors (OR 3.0, 95% CI 1.0-9.1) remained as a predictor of major bleeding.



Our study shows that PCI is a safe procedure during UAC with no excess bleeding complications.
The renin-angiotensin receptor blocker azilsartan medoxomil compared with the angiotensin-converting enzyme inhibitor ramipril in clinical trials versus routine practice: insights from the prospective EARLY registry

Patient characteristics and blood pressure-related outcomes in randomized clinical trials (RCTs) differ from clinical practice because of stringent selection criteria. The present study aimed to explore the relationship between clinical trials and clinical practice. We analyzed data from patients enrolled in the "Treatment with Azilsartan Compared to ACE-Inhibitors in Anti-Hypertensive Therapy" (EARLY) registry comparing blood pressure (BP) effects of the angiotensin receptor blocker (ARB) azilsartan medoxomil (AZL-M) with the angiotensin-converting enzyme (ACE) inhibitor ramipril between patients who met the eligibility criteria of a previous RCT and those who did not.



Patients with primary arterial hypertension were consecutively enrolled from primary care offices in Germany into the EARLY registry in a 7:3 ratio for treatment with AZL-M or an ACE inhibitor, provided that they met the following criteria at baseline: 1) no antihypertensive treatment prior to inclusion or a non-renin-angiotensin system (RAS) based monotherapy; 2) initiation of treatment with either AZL-M or an ACE inhibitor alone. Analyses were performed to evaluate BP effects for patients in the EARLY registry who met the selection criteria of a prior RCT (RCT+) versus those who did not (RCT-).



Out of 3,698 patients considered, 1,644 complied with the RCT criteria (RCT+) while 2,054 did not (RCT-). RCT- patients (55.5%) displayed a higher risk profile in terms of age and comorbidities, and a wider spectrum of BP values at baseline, as highlighted by the grades of hypertension and mean BP values. The proportion of patients who achieved target blood pressure control in the RCT+ group was significantly higher for AZL-M versus ramipril (64.1 versus 56.1%; P<0.01), in accordance with the result of the clinical trial. In the RCT- AZL-M group, the proportion of patients who met BP targets was lower (58.1%) than in the RCT+ AZL-M group (64.1%), whereas the proportion of patients with target BP values in the RCT- ramipril and the RCT+ ramipril groups was similar (57.7 versus 56.1%). Thus, in contrast to results for the RCT+ group, in the RCT- group, the target BP attainment rate for AZL-M was not significantly superior to that for ramipril. However, the tolerability profile of AZL-M and ramipril was comparable in both populations. At the 12-month follow-up, death and stroke rates were low (≤0.5%) and adverse events did not differ between the AZL-M and ramipril groups, irrespective of RCT eligibility.



These data confirm that the EARLY population comprised a broader spectrum of hypertensive patients than RCTs, and the differences in patient characteristics were accompanied by disparate rates of blood pressure goal attainment. Overall, the validity of the RCT was demonstrated and confirmed in clinical practice with a broader range of patients with various comorbidities.
Similar Outcomes of Standard Radiotherapy and Hypofractionated Radiotherapy Following Breast-Conserving Surgery

Adjuvant radiation therapy is commonly administered to breast cancer patients who received breast-conserving surgery. However, lengthy treatment times of standard radiotherapy pose certain challenges. Here, we performed a prospective controlled study comparing standard radiation to hypofractionated radiotherapy in terms of efficacy and outcome.



Eighty breast cancer patients (tumor stage pT1-2N0-1M0) who had undergone breast-conservation surgery were randomly divided into 2 groups (40 patients/group). The experimental group received 43.2 Gy to the whole breast in 18 fractions for 24 days with a concomitant boost (50.4 Gy) to the tumor bed. The control group received 45 Gy to the whole breast in 25 fractions for 44 days with a boost to the tumor bed of 59 Gy. Survival, locoregional recurrence, adverse effects, and aesthetic results were all considered for analysis.



The following criteria were included as part of study follow-up: local control, survival, adverse skin reactions, cosmetic outcome, and hematological toxicity. At a median follow-up of 27 months (follow-up rate 100%), there were no statistical differences in any of the categories between the 2 groups. The 2-year survival rate of both groups was 100% without any locoregional recurrence. Although there was some skin toxicity, these instances were not severe and they cleared on their own within 6 weeks. The most common problems encountered by patients were breast fibrosis and altered pigmentation.



A shortened whole-breast hypofractionated irradiation schedule with a concomitant boost is as effective as standard radiation and may be a reasonable alternative following breast conservation surgery.
The CIMESTRA study: intra-articular glucocorticosteroids and synthetic DMARDs in a treat-to-target strategy in early rheumatoid arhtritis.

Treatment of early rheumatoid arthritis (RA) include aiming at disease control with early use of methotrexate (MTX) in monotherapy or in combination with glucocorticoids or other disease-modifying drugs (DMARDs). The CIMESTRA study applied an aggressive treatment with DMARD and intra-articular injections of glucocorticoids (i.a. GC) to control disease activity. This paper reviews the results of the five years' study.



160 patients with early RA (<6 months duration) were randomized to receive MTX 7.5-20 mg/week+cyclosporine (CYA) 2.5-4 mg/kg (combination) or MTX+placebo-CYA (monotherapy). At each visit (week 0, 2, 4, 6, 8, thereafter monthly up to 24 months) patients had steroid injections in all swollen joints. During year 2, CYA/placebo was withdrawn, and hydroxychlorochine added. Clinical responses were assessed by ACR20, 50 and 70, ACR and DAS remission. Radiographic progression by x-rays of hands and feet.



At year 1 (year 5) treatment responses in mono/combination groups were: ACR20: 68% (85%) / 85% (94%), ACR50: 53% (74%) / 68% (88%), ACR70: 44% (63%) / 59% (72%). After year 1, no significant differences between groups were found. Remission rates were: ACR-remission: 28% (52%) / 35% (60%), DAS28-remission: 34% (76%) / 43% (80%). Radiographic progression in both groups was <1TSS unit/year. After 1 and 2 years, 62% and 56% of the injected joints had not relapsed (both groups). Cumulated i.a.GC dose <1mg prednisolone/day. 19% received biologics by 5 years, 16% no treatment (sustained ACR-remission). Baseline magnetic resonance imaging (MRI) bone oedema best predicted radiographic progression after 2 years. Treatments were well tolerated.



MTX and i.a.GC in a treat-to-target strategy over 5 years halted radiographic progression and induced remission in the majority of patients. I.a. GC had in long-lasting effect and cumulated dosages were low.
Carcinoma of unknown primary with gastrointestinal profile: immunohistochemistry and survival data for this favorable subset

Carcinoma of unknown primary with a “gastrointestinal profile” is an emerging, favorable entity. Distinguishing this entity is of increasing significance given the progress in the treatment of colorectal cancer. 74 carcinoma of unknown primary (CUP) patients with CDX2+ tumors were chosen from the databases at M.D. Anderson and Sarah Cannon Cancer Centers between 2004 and 2010. Data on clinical and pathological characteristics including therapy and survival were recorded. 20 patients had ascites on presentation; the predominant sites of metastases included liver (30 %), carcinomatosis (50 %), and nodes (51 %). Based on immunohistochemistry, 2 cohorts were created: Cohort 1—“consistent with lower GI profile” included 34 patients [CDX-2+, CK20+, CK7−] and Cohort 2—“probable lower GI profile” included 40 patients [CDX2+, irrespective of CK7/CK20 status]. Excluding 6 outliers, Cohorts 1 and 2 had 32 and 36 patients, respectively; their median survivals were 37 and 21 months, respectively. On multivariate Cox regression analysis, only liver metastases were found to negatively influence survival. Our retrospective study provides encouraging indications that CUP patients with gastrointestinal profiles benefit from site-specific therapy. We recommend all CUP patients, especially those with abdominal nodes, isolated carcinomatosis or liver metastases, to undergo optimal immunohistochemistry (IHC) to check for a gastrointestinal profile of CUP.