nils-herrmann/clean_scirepeval huggingface dataset:
Phase I pharmacokinetic and pharmacodynamic study of lapatinib in combination with sorafenib in patients with advanced refractory solid tumors.

The epidermal growth factor receptor (EGFR) and ERBB2 (HER2) pathways and vascular endothelial growth factor (VEGF)-dependent angiogenesis have a pivotal role in cancer pathogenesis and progression. Robust experimental evidence has shown that these pathways are functionally linked and implicated in acquired resistance to targeted therapies making them attractive candidates for joined targeting. We undertook this phase I trial to assess the safety, the recommended dose for phase II trials (RPTD), pharmacokinetics (PK), pharmacodynamics (PD), and the preliminary antitumour activity of the combination of lapatinib and sorafenib in patients with advanced refractory solid tumours.



Four cohorts of at least three patients each received lapatinib once daily and sorafenib twice daily together on a continuous schedule. Doses of lapatinib and sorafenib were escalated based on dose-limiting toxicities (DLTs) in the first treatment cycle following a traditional 3+3 design until the RPTD was reached. Additional patients were treated at the RPTD to characterise PK profiles of this combination and to investigate the potential interaction between lapatinib and sorafenib. Serum samples were collected at baseline and then prospectively every two cycles to assess changes in PD parameters. 
Thirty patients with advanced refractory solid tumours were enroled. DLTs were grade three fatigue and grade 3 atypical skin rash observed at dose levels 3 and 4, respectively. The higher dose level explored (lapatinib 1250mg/day and sorafenib 400mg twice daily) represented the RPTD of the combination. The most common drug-related adverse events were fatigue (68%), hypocalcemia (61%), diarrhoea (57%), lymphopaenia (54%), anorexia (50%), rash (50%), and hypophosphatemia (46%). PK analysis revealed no significant effect of sorafenib on the PK profile of lapatinib. Of the 27 assessable patients for clinical activity, one achieved a confirmed complete response, four (15%) had a partial response, and 12 (44%) achieved disease stabilisation. The disease control rate overall was 63%.



Combination treatment with lapatinib and sorafenib was feasible with promising clinical activity and without significant PK interactions. Long term tolerability seems to be challenging.
Assessment by cardiovascular magnetic resonance, electron beam computed tomography, and carotid ultrasonography of the distribution of subclinical atherosclerosis across Framingham risk strata.

Screening for subclinical atherosclerosis has been advocated for individuals at intermediate global risk for coronary heart disease (CHD). However, the distribution of subclinical atherosclerosis test values across CHD risk strata is unknown. We studied a stratified random sample of 292 participants (mean age 59.5 years, 50% women) from the offspring cohort of the Framingham Heart Study who were free of clinically apparent cardiovascular disease. We assessed abdominal and thoracic aortic plaque burden by cardiovascular magnetic resonance (CMR), coronary artery calcification (CAC) and thoracic aortic calcification (TAC) by electron beam computed tomography, and common carotid intima-media thickness (C-IMT) by ultrasonography. We categorized the upper 20% of each measurement as a high level of atherosclerosis and evaluated these variables across clinically relevant Framingham CHD risk score strata (low, intermediate, and high risk). In age-adjusted analyses in men and women, correlations across CMR aortic plaque, CAC, TAC, and C-IMT were low (maximum r = 0.30 for CAC:TAC in women, p <0.005). In men and women, the proportion of subjects with high atherosclerosis test results for any of these measurements increased significantly across Framingham CHD risk score strata (Kruskal-Wallis test, p <0.0001). In the intermediate Framingham CHD risk score category, 14% of men and 25% of women had a high atherosclerosis result on >or=2 measurements. However, different participants were identified as having high atherosclerosis by each modality. For example, in a comparison of the overlap across CMR aortic plaque, CAC, and C-IMT, only 4% of men and 16% of women were classified as having high atherosclerosis on all 3 measurements. In conclusion, in a community-based sample, correlations among subclinical atherosclerosis test results are low, and a substantial proportion has high levels of subclinical atherosclerosis detected on >or=2 imaging tests.
Bone mineral density in patients with prostatic cancer treated with orchidectomy and with estrogens

Bone mineral density (BMD) and bone mineral content (BMC) were measured in the femoral neck area, trochanteric area and Wards triangle, and in the distal radius of the left forearm before and after 1 year of endocrine treatment in 27 patients with prostatic cancer. Eleven of the patients were treated with orchidectomy and 16 with combined oral and intramuscular estrogens. The patients were free from metastases during the entire observation period. In the orchidectomized patients, BMD and BMC of the distal radius decreased significantly following treatment, whereas no changes were observed in the estrogen-treated patients. These preliminary results demonstrate that estrogens may protect bone in male subjects also and may merit further investigations on larger groups of patients.
Reduced recurrence-free survival after reduced doses of adjuvant chemotherapy in breast cancer: Are groups selected after randomization comparable?

In a recent issue Bonadonna et al. presented a summary of their results with adjuvant chemotherapy of breast cancer (1). The retrospective analysis of dose-response based on ten-year results confirmed previous findings which had suggested that reduced doses of chemotherapy were associated with higher likelihood of recurrence compared to 'optimal doses' (2). This hypothesis has been criticized from various aspects and methodologic problems were recently discussed (3). On the other hand, the concept of a dose-related response is attractive and fits theoretical and experimental models (4). One major question, however, is whether groups that are selected by a post-randomization differentiation by doses of chemotherapy are equivalent to each other and to non-treated patients in relevant aspects. We have analyzed interim results of an on-going trial of adjuvant chemotherapy in breast cancer in Stockholm. A total of 242 patients were eligible for the current analysis. They had been randomised to chemotherapy which was similar to that of the Milan trial (1). Like Bonadonna et al., we found a better recurrence-free survival for patients who had received >84 per cent of the planned dose compared to those who had tolerated <65 per cent of that dose. These percentages were calculated as the ratio of the total dose received to the maximum protocol dose possible prior to treatment failure or death. The doses were mainly reduced due to low WBC or platelet counts. Interestingly, we found that there was a significant correlation between the doses of chemotherapy and the initial WBC (r = 0.29, P<0.001) and platelet count ( r=0 .23 , P<0.01), i.e. the counts before any drug was given. The table gives the mean values of the blood counts by level of dose of chemotherapy in 153 patients who received the planned 12 courses. There is no indication that the blood cell counts are related to prognosis and, even though statistically significant, the correlation coefficients were both small. Despite these circumstances, our findings show that the groups of patients that were distinguished after randomization by the dose of chemotherapy, differed at least in one respect. This, of course, does not rule out the possibility of a dose-related response. It only points to the difficulties in proving this in a retrospective analysis of a prospective trial.
Prognostic importance of temporal changes in resting heart rate in heart failure patients: an analysis of the CHARM program.

Resting heart rate (HR) is a predictor of adverse outcome in patients with heart failure (HF). Whether changes in HR over time in patients with chronic HF are also associated with adverse outcome is unknown. We explored the relationship between changes in HR from a preceding visit, time-updated HR (i.e. most recent available HR value from a clinic visit) and subsequent outcomes in patients with chronic HF.



We studied 7599 patients enrolled in the candesartan in heart failure: assessment of reduction in mortality and morbidity program. We calculated change in HR from the preceding visit and explored its association with outcomes in Cox proportional hazards models, as well the association between time-updated HR and outcome. An increase in HR from preceding visit was associated with a higher risk of all-cause mortality and the composite endpoint of cardiovascular death or hospitalization for HF (adjusted hazard ratio 1.06, 95% confidence intervals, CI: 1.05-1.08, P < 0.001, per 5 b.p.m. higher HR), with lowering of HR being associated with lower risk, adjusting for covariates, including time-updated β-blocker dose and baseline HR. Time-updated resting HR at each visit was also associated with risk (adjusted hazard ratio 1.07, 95% CI: 1.06-1.09; P < 0.001, per 5 b.p.m. higher HR).



Change in HR over time predicts outcome in patients with chronic HF, as does time-updated HR during follow-up. These data suggest that frequent outpatient monitoring of HR, and identification of changes over time, possibly with remote technologies, may identify patients with HF who may be at increased risk of rehospitalization or death.
Drinking and future thinking: acute effects of alcohol on prospective memory and future simulation

It has recently been shown that acute alcohol globally impairs ‘prospective memory’ (PM)—remembering to do something in the future (Leitz et al. in Psychopharmacology 205:379–387, 2009). In healthy, sober individuals, simulating future events at encoding enhances PM performance. We therefore aimed to determine if future event simulation could attenuate the impairing effects of acute alcohol on PM. Using a double-blind independent group design, 32 healthy volunteers were administered a 0.6-g/kg dose of ethanol or matched placebo. PM performance was assessed using a behavioural task, the ‘Virtual Week’, which was adapted to enable future event simulation in both remote and recent contexts. Episodic memory was indexed with a source memory task and planning with the Tower of London task. We replicated the finding of Leitz et al. that acute alcohol consumption impairs prospective memory for event-based tasks. Future event simulation significantly improved PM performance on these tasks and eliminated the PM deficit caused by acute alcohol consumption. This is the first evidence that future event simulation can overcome alcohol-induced deficits in prospective memory and may have important clinical implications for the rehabilitation of chronic alcohol users.
Evaluation of efficacy of the perioperative administration of Venlafaxine or gabapentin on acute and chronic postmastectomy pain.

Postmastectomy pain syndrome is a neuropathic pain syndrome that is known to develop after breast surgery. Preemptive analgesia has been shown to be efficacious in reducing postoperative pain, and may be effective in reducing the incidence of certain types of neuropathic pain. We investigated the analgesic efficacy of Venlafaxine and gabapentin on acute and chronic pain associated with cancer breast surgery.



The study was carried out on 150 patients scheduled for either partial or radical mastectomy with axillary dissection. They were randomized in a double-blinded manner to receive, extended release Venlafaxine 37.5 mg/d, gabapentin 300 mg/d, or placebo for 10 days starting the night before operation. Pain scores were recorded at rest and movement (visual analog scale) at 4, 12, and 24 hours on the first day postoperatively, daily from the second to tenth day postoperatively and visual analog scale in addition to pain character 6 months later. Analgesic requirements were compared between the 3 groups.



Pain after movement was reduced by gabapentin from the second to tenth postoperative day and venlafaxine group in the last 3 days but no difference was found between the groups regarding pain during rest. Gabapentin reduced morphine consumed in the first 24 hours postoperatively. The analgesic requirements from the second to tenth days for codeine and paracetamol were reduced in venlafaxine and gabapentin groups compared to the control group. Six months later, the incidence of chronic pain, its intensity, and need for analgesics were reduced in venlafaxine compared to gabapentin and the placebo group. However, burning pain was more frequent in the control groups than in the gabapentin.



Venlafaxine 37.5 mg/d extended release or gabapentin 300 mg/d have equipotent effects (except on the first day in venlafaxine group) in reducing analgesic requirements, although gabapentin is more effective in reducing pain after movement. Venlafaxine significantly reduced the incidence of postmastectomy pain syndromes (chronic pain) 6 months in women having breast cancer surgery. Gabapentin had no effect on chronic pain except decreasing incidence of burning pain.
Radiotherapy in the management of pancreatic neuroendocrine tumors (PNET): experience at three institutions.

Advanced pancreatic neuroendocrine tumor (PNET) presents a therapeutic challenge as many are unresectable and relatively resistant to systemic therapy with a high malignant potential. We share our experience using concurrent capecitabine or infusional 5-fluorouracil with radiation for patients with resected and locally advanced PNET.



Six patients (two females, four males) with PNET were treated with capecitabine or infusional 5-FU and concurrent radiation.



The median age was 52 years (range: 38 to 63 years), with ECOG Performance Status (PS) 0-1, grade 0-1 weight loss, and grade 0-1 pain. One patient underwent resection with negative margins, two with positive margins, and three had unresectable locally advanced disease. All six patients demonstrated partial radiographic response and sustained local control. The treatment was tolerable with only grade 2 hand-foot syndrome and grade 1 mucositis observed.



Prospective studies to further investigate the role of chemoradiation in this setting are warranted.
Study of the anti-JCV antibody levels in a Spanish multiple sclerosis cohort.

One of the risk factor to develop progressive multifocal leukoencephalopathy (PML) among natalizumab-treated patients is the presence and high levels of anti-JCV antibodies. Our purpose was to test the association of different clinical and demographic variables with the presence and levels of anti-JCV antibodies in a Spanish cohort of patients with multiple sclerosis (MS) during natalizumab treatment.



All patients with MS from two hospitals with at least one measure of the anti-JCV antibodies levels (2011-2014) were recruited, among them were two PML cases. Anti-JCV antibody levels were assessed using two-step ELISA.



A total of 1061 patients (16·3% natalizumab-treated) participated in this study. The seropositivity rate of anti-JCV antibodies was 58·2%. It increased with age (Pcorrected = 0·00005) and was lower among HLA-DRB1*15:01 carriers (Pcorrected = 0·049). The two patients with PML were HLA-DRB1*15:01 carriers. We had at least three quarterly anti-JCV antibody measurements (index value) from 137 patients, whose levels did not increase during natalizumab treatment. However, 5·8% of these patients had an increase of the index value higher of one point in a maximum of 6 months, something that was more frequently observed (P = 0·054) among patients treated with immunosuppressant prior to natalizumab onset.



Old age and HLA-DRB1*15:01 were the factors that influence positively and negatively, respectively, our anti-JCV antibody prevalence, although our both PML cases were HLA-DRB1*15:01carriers. Most of our patients showed a stable anti-JCV antibody index values during natalizumab treatment.
A phase I pharmacokinetic and translational study of the novel vascular targeting agent combretastatin a-4 phosphate on a single-dose intravenous schedule in patients with advanced cancer.

Combretastatin A-4 phosphate (CA4P) is a novel antitumor vascular targeting agent, the first agent of this class of compounds to enter the clinic. We performed a Phase I trial to determine the maximum-tolerated dose, safety, and pharmacokinetic profile of CA4P on a single-dose i.v. schedule. We also obtained preliminary data on its effect on tumor blood flow using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) techniques and cell adhesion molecules at the higher-dose levels. Twenty-five assessable patients with advanced cancer received a total of 107 cycles over the following dose escalation schema: 18, 36, 60, 90 mg/m(2) as a 10-min infusion and 60 mg/m(2) as a 60-min infusion at 3-week intervals. There was no significant myelotoxicity, stomatitis, or alopecia. Tumor pain was a unique side effect, which occurred in 10% of cycles, and there were four episodes of dose-limiting toxicity at dosages > or =60 mg/m(2), including two episodes of acute coronary syndrome. Pharmacokinetics revealed rapid dephosphorylation of the parent compound (CA4P) to combretastatin A4 (CA4), with a short plasma half-life (approximately 30 min). A significant (P < 0.03) decline in gradient peak tumor blood flow by DCE-MRI in six of seven patients treated at 60 mg/m(2) was observed. A patient with anaplastic thyroid cancer had a complete response and is alive 30 months after treatment. The toxicity profile is consistent with a drug that is "vascularly active" and devoid of traditional "cytotoxic" side effects. Dosages < or =60 mg/m(2) as a 10-min infusion define the upper boundary of the maximum-tolerated dose.
Development of an Economic Model to Assess the Cost Effectiveness of Asthma Management Strategies

Asthma is a chronic-episodic disease characterised by acute, symptomatic episodes of varying severity. We developed a Markov model that can be used to estimate the cost effectiveness of alternative asthma treatments. Because of the costs they incur, asthma exacerbations (‘attacks’) requiring intervention by a healthcare professional were a central consideration in the development of the model.  Treatment success was assessed as asthma control, a composite measure based on goals defined in world-wide asthma management guidelines and in terms of quality-adjusted life-years (QALYs). The data from which the transition probabilities were derived came from patients with asthma who received either salmeterol/fluticasone propionate combination (SFC) 50/100μg or fluticasone propionate (FP) 100μg, administered twice daily via an inhaler, in a 12-week, randomised, double-blind, clinical trial. Costs were estimated from resource profiles defined for each of the model states. A key aspect of the model was the use of probabilistic sensitivity analysis techniques to examine the uncertainty in the cost-effectiveness results. Distributions were fitted to transition probabilities and to cost input parameters and values were sampled at random from these distributions using a second order Monte Carlo simulation technique. This produced a distribution for incremental cost effectiveness that was employed to construct 95% uncertainty intervals and to construct cost effectiveness acceptability curves.  In this analysis, the model was run over a 12-week period using transition probabilities derived from the trial data. The results showed that treatment with SFC resulted in a higher proportion of successfully controlled weeks per patient than treatment with FP(66 vs 47%), and higher mean weekly direct asthma management costs (£15.77 vs £11.83; 2000 values). The average incremental cost per successfully controlled week with SFC was £20.83. Probabilistic sensitivity analysis showed that the 95% uncertainty intervals for the incremental cost-effectiveness ratio was −£64.94 to £112.66. In approximately 25% of cases, SFC was dominant (more effective and less costly), but in the remaining cases, it was both more effective and more costly. It was shown that if decision makers are willing to pay approximately £45 for an additional successfully controlled week, SFC will be the more cost-effective strategy in this patient population for 80% of the time.  This is one of the first decision-analytic models of asthma to incorporate probabilistic sensitivity analysis techniques to explore uncertainty. The model’s flexible yet standardised framework permits the cost effectiveness of alternative asthma management strategies in different healthcare settings to be established.
Effectiveness, safety, and acceptability of cryotherapy by midwives for cervical intraepithelial neoplasia in Maharashtra, India.

To evaluate the effectiveness, safety, and acceptability of cryotherapy for cervical intraepithelial neoplasia (CIN) when provided by trained midwives in rural India.



Women with colposcopic findings of CIN lesions suitable for ablative treatment received cryotherapy from trained midwives before the biopsy results were known. Cure rates, adverse effects, and complications were assessed and factors influencing cure rates were evaluated by chi(2) tests. Cure was defined as no clinical or histologic evidence of CIN lesions 6 or more months after treatment.



Of 1068 women treated with cryotherapy, 728 had histologically proven CIN in their pretreatment biopsy specimens; of the 574 reporting for follow-up, 538 (93.7%) were cured (95% confidence interval [CI], 92.1%-96.3%). Cure rates were 96.4% (95% CI, 94.6%-98.1%) for CIN 1 and 82.1% (95% CI, 74.7%-89.4%) for CIN 2 and CIN 3 lesions combined. Minor adverse effects were documented in 5.2% of the women.



Cryotherapy provided by midwives was found to be safe, effective, and acceptable by the women.
Management of SPN in France. Pathways for definitive diagnosis of solitary pulmonary nodule: a multicentre study in 18 French districts

The process of diagnosis and management of solitary pulmonary nodules (SPNs) between 1 and 3 cm is not standardized. This multicentre study investigated how diagnosis of newly discovered SPNs is managed in routine practice. We examined 11,515 radiology reports of patients undergoing chest computed tomography (CT) at all 76 radiology centres in 18 French administrative districts covering 8,220,000 people. Information on diagnostic procedures and treatment administered from discovery to definitive diagnosis of SPN was collected prospectively. We identified 152 cases of newly diagnosed SPNs. Follow-up was complete for 112 patients. The median number of diagnostic tests was 4 and the mean time to diagnosis was 41.4 days. Marked variability was observed in the sequence of diagnostic tests, and 8 diagnostic pathways were identified. Patients' characteristics and radiological features of SPNs influenced the number of tests performed. Referral by specialist, history of smoking and spiculated SPN predicted the performance of at least one invasive procedure (P < 0.01). Definitive diagnosis was a malignant disease in 30 patients (26%). The diagnosis of SPN is a complex process that physicians approach in markedly different ways. Implementing practice guidelines for managing the diagnosis of SPN requires clarification.