nils-herrmann/clean_scirepeval huggingface dataset:
Phase I studies of fluorouracil, doxorubicin and vinorelbine without (FAN) and with (SUPERFAN) folinic acid in patients with advanced breast cancer

The Breast Cancer Site Group of the National Cancer Institute of Canada – Clinical Trials Group (NCIC-CTG) undertook two parallel phase I studies to determine the maximum tolerated dose (MTD) and recommended phase II dose of vinorelbine in combination with doxorubicin and fluorouracil (with or without folinic acid) in metastatic breast cancer.  Cohorts of five patients were to receive: (a) fluorouracil 500 mg/m2 and doxorubicin 50 mg/m2 on day 1 only and escalating doses of vinorelbine (15, 20, 25, 30 mg/m2) on days 1, 8 and 15 every 3 weeks (FAN regimen), or (b) fluorouracil 340 mg/m2 and folinic acid 200 mg/m2 on days 1, 2, 3, 4 and 5, doxorubicin 40 mg/m2 on day 1 only and escalating doses of vinorelbine (15, 20, 25, 30 mg/m2) on day 1 and again on day 5 every 4 weeks (SUPERFAN regimen). Eligibility included measurable or evaluable metastatic breast cancer and having received neither previous chemotherapy for metastatic disease nor anthracycline-containing adjuvant therapy.  Of 26 and 12 patients enrolled in the FAN and SUPERFAN regimens, 26 and 12 were evaluable for toxicity and 21 and 9 for response, respectively. Median ages were 60.3 years (41–71 years) and 64.2 years (51–73 years). Both regimens required amendment after the first cohort with an original day-15 vinorelbine dose omitted from the FAN regimen and more prolonged nadir granulocyte counts allowed. Myelosuppression was dose limiting. MTDs in the FAN and SUPERFAN regimens were vinorelbine 25 mg/m2 and 20 mg/m2. Other toxicities included mucositis, septicemia and febrile neutropenia. Peripheral neuropathy and constipation were mild. Of the 21 FAN patients evaluable for response, 3 (14%) had complete responses and 7 (33%) had partial responses, for an overall response rate of 48%; 9 (43%) had stable disease and 2 (9%) had progressive disease as their best response. Of the nine SUPERFAN patients evaluable for response, none had a complete response. There were two (22%) with partial responses, and six (67%) had stable disease and one (11%) had progressive disease as their best response.  The SUPERFAN regimen was too toxic to pursue even at the lowest dose. The recommended phase II starting dose for the FAN regimen was vinorelbine 20 mg/m2. Although these were phase I studies response rates in evaluable patients were less than expected and toxicity did not allow the use of as much vinorelbine in the combinations as had been anticipated. The limited response data from our study would imply that combining vinorelbine with more toxic agents may not enhance response rates and may defeat the advantage of tolerability, especially in elderly patients.
Overview of the Semantics of TCOZ

Object-Z is an extension to the Z language designed to facilitate spec-iication in an object-oriented style. It is an excellent tool for modelling data and operations, but its object semantics are single threaded, operations are atomic, and object control logic is deened implicitly. This makes it diicult to use Object-Z to capture the behaviour of concurrent real-time reactive systems. On the other hand, Timed CSP is good at modelling real-time concurrent behaviour, but has little support for modelling the state of a complex system. This paper describes the semantics of TCOZ, a language blended from Object-Z and Timed CSP. The semantic model adopted is the innnite timed failures model of Timed CSP, extended to include initial state and update events for modelling operations on internal state.
Home enteral nutrition in children: a 14-year multicenter survey

The practice of home enteral nutrition (HEN) represents a relevant aspect of the clinical management of both malnourished children and well-nourished children unable to be fed using an oral diet. The aim of this study was to estimate in an Italian paediatric population over a 14-year period (1996–2009), the clinical relevance and results over time of HEN activity.HEN-computerized database and medical/dietetic charts were evaluated for patients aged at start of HEN <18 years and HEN duration >1 month.During the study period, we recorded 757 HEN programs. HEN began at a median age of 2 years for a median duration of 8.1 months. The complication rate was 14.8%. In the second period of the survey (2003–2009), the main changes concerned the underlying diseases requiring HEN, choice of formula feeding and access route. In 2009, the estimated overall prevalence of HEN was 3.47 and the incidence 2.45 per 100 000 inhabitants from 0 to 18 years of age.The epidemiological data of this study demonstrate that HEN concerns a growing number of Italian children and families. Some aspects of HEN clinical management should be modified to reach the recommended standards.
Genetic Diversity of Cryptosporidium in Children in an Urban Informal Settlement of Nairobi, Kenya

Globally Cryptosporidium and Giardia species are the most common non-bacterial causes of diarrhoea in children and HIV infected individuals, yet data on their role in paediatric diarrhoea in Kenya remains scant. This study investigated the occurrence of Cryptosporidium species, genotypes and subtypes in children, both hospitalized and living in an informal settlement in Nairobi.



This was a prospective cross-sectional study in which faecal specimen positive for Cryptosporidium spp. by microscopy from HIV infected and uninfected children aged five years and below presenting with diarrhoea at selected outpatient clinics in Mukuru informal settlements, or admitted to the paediatric ward at the Mbagathi District Hospital were characterized. The analysis was done by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) of the 18srRNA gene for species identification and PCR-sequencing of the 60 kDa glycoprotein (GP60) gene for subtyping.



C. hominis was the most common species of Cryptosporidium identified in125/151(82.8%) of the children. Other species identified were C. parvum 18/151(11.9%), while C. felis and C. meleagridis were identified in 4 and 2 children, respectively. Wide genetic variation was observed within C. hominis, with identification of 5 subtype families; Ia, Ib, Id, Ie and If and 21 subtypes. Only subtype family IIc was identified within C. parvum. There was no association between species and HIV status or patient type.



C. hominis is the most common species associated with diarrhoea in the study population. There was high genetic variability in the C. hominis isolates with 22 different subtypes identified, whereas genetic diversity was low within C. parvum with only one subtype family IIc identified.
Estrogenic Effects of Toremifene and Tamoxifen in Postmenopausal Breast Cancer Patients

Intrinsic estrogenicities of the selective estrogen receptor modulators (SERMs) toremifene 60 mg daily or 200 mg daily and tamoxifen 20 mg daily (TOR60, TOR200 and TAM20) were compared in a randomized clinical study in postmenopausal women with advanced breast cancer. The study was open label in three parallel groups. Variables for analysis were serum follicle stimulating hormone (FSH), luteinizing hormone (LH), sex hormone binding globulin (SHBG), estradiol (E2), antithrombin III (AT III), aspartate aminotransferase (ASAT) and vaginal cytology. Clinical efficacy and safety have been reported earlier. A total of 648 patients were randomized (221 to TOR60, 212 to TOR200 and 215 to TAM20). Sera were available for the analysis from 148, 165 and 156 and for vaginal cytology from 98, 93 and 86 patients, respectively. All treatment regimens showed tissue-specific and dose-dependent estrogen agonist effect. In the primary measure of in vivo estrogenicity, effect on hypothalamus–pituitary-axis, all three treatment regimens decreased serum FSH (p < 0.001). TOR200 was more potent than the two other treatments (p < 0.05), but surprisingly, TAM20 was more estrogenic than TOR60 (p < 0.001). As could be expected in postmenopausal women, the treatments had no effect on mean serum E2 concentrations and decrease of serum LH was similar to that of FSH. Estrogenic effect on the liver was seen as dose-dependent increase of SHBG with statistically significant differences between the treatment groups (p < 0.001). Trends of transient ASAT elevations in TOR200 group (p = 0.07) and in all treatment groups AT III decrease (p = 0.1) were seen in the beginning of the treatment. TOR60 or TAM20 did not have an effect on mean ASAT values, and AT III decreased in TAM20 group more than in the two other groups (p = 0.1 compared to TOR60 and p < 0.05 compared to TOR200). Estrogenic effects on vaginal superficial cells were higher in TOR60 and TOR200 groups when compared to TAM20 (p < 0.05). Toremifene and tamoxifen had tissue-specific and partially dose-dependent estrogenic effects in hypothalamus–pituitary-axis, in the liver and in the vaginal epithelium of postmenopausal women. In some tissues tamoxifen 20 may be more estrogenic than toremifene 60 mg/day.
Validity of proposed DSM-5 ADHD impulsivity symptoms in children

The American Psychiatric Association (APA) working group on Attention-Deficit/Hyperactivity Disorder (ADHD) proposed the inclusion of four new impulsivity symptoms. However, they were not included in DSM-5 due to the lack of sufficient evidence. The aim of this study is to investigate the performance of the proposed four ADHD impulsivity symptoms with respect to: (a) ADHD factor structure; (b) performance in predicting clinical impairment; (c) specificity for ADHD diagnosis and (d) best symptomatic threshold to predict clinical impairment. The sample comprised 416 children (31 ADHD subjects according to both DSM-IV and proposed DSM-5, 20 ADHD subjects according to just one diagnostic system and 365 controls) from 12 schools. Diagnoses were derived using semi-structured interviews and ADHD rating scales. Results from confirmatory factor analysis indicate that addition of the four new impulsivity items provided a slightly better factor structure if compared to models including only 18 items. Regression analyses showed that only one of the new impulsivity symptoms (impatient) was part of the list of best predictors of impairment. None of the four new impulsivity items was specifically associated with ADHD diagnosis. The best cutoff point in the hyperactivity/impulsivity dimension for predicting impairment did not change significantly. Overall, our findings suggest that the determination on how to best capture impulsivity dimension as part of the ADHD construct needs more investigation and that there is not enough evidence to include these four assessed impulsivity symptoms as part of the ADHD criteria.
Symptomatic superior vena cava syndrome in hemodialysis patients: mid-term results of primary stenting.

This clinical report details the results of endovascular treatment of symptomatic superior vena cava syndrome due to central vein stenosis or obstruction (CVSO) by stent angioplasty in patients with dialysis-dependent end-stage renal disease. A 3-year retrospective review of two institutional registries identified 25 chronic hemodialysis patients (17 men, 8 women) affected by CVSO who received endovascular treatment. The majority of the patients (n = 19) presented with symptomatic arm, breast, and facial swelling; and 6 patients presented with dialysis-access dysfunction and venous-line hypertension. The etiology of CVSO was before central venous catheter in all but 2 patients. Venography showed 19 cases of stenosis (4 stenoses of superior vena cava, 3 brachiocephalic, 10 subclavian, and 2 axillary veins) and 6 occlusions of the superior vena cava. After percutaneous transluminal angioplasty and primary stent angioplasty, there was an immediate regression of symptoms and arteriovenous fistula preservation in 21 cases; 4 patients received a new arteriovenous fistula after interventional treatment. No procedural major complications or patient deaths occurred. During the follow-up period, we recorded a primary patency rate of 95%, 80%, and 70%, respectively, at 6, 12, and 18 months; and a secondary patency rate of 100%, 95%, and 90%, respectively, at 6, 12, and 18 months. In conclusion, endovascular treatment with primary stenting has proven to be a durable treatment option for hemodialysis patients with CVSO, and this treatment should be considered before dialysis access placement in patients with catheter-induced central vein obstruction.
Enhanced levels and enhanced clonogenic capacity of blood progenitor cells following administration of stem cell factor plus granulocyte colony-stimulating factor to humans.

Administration of hematopoietic growth factors is being used increasingly to obtain populations of blood progenitor/stem cells (PBPC) for clinical transplantation. Here we examined the effect of combining stem cell factor (SCF ) and granulocyte colony-stimulating factor (G-CSF ) versus G-CSF alone in a randomized clinical study involving 62 women with early-stage breast cancer. In the first patient cohorts, escalating doses of SCF were administered for 7 days with concurrent G-CSF administration. At baseline, levels of progenitor cells in the bone marrow or blood were comparable in the different patient groups. As with administration of G-CSF alone, the combination of SCF plus G-CSF did not alter the wide variation in levels of PBPC observed between individuals and did not alter the selective nature of PBPC release, with preferential release of day-14 granulocyte-macrophage colony-stimulating factor (GM-CFC) versus day-7 GM-CFC. However, SCF acted to sustain the levels of PBPC after cessation of growth factor treatment; levels of PBPC were elevated 100-fold at later timepoints compared with G-CSF alone. In addition, the maximum levels of PBPC observed were increased approximately fivefold at day 5 of growth-factor administration. The increased levels of PBPC resulted in significantly increased levels of PBPC obtained by leukapheresis. In a subsequent patient cohort, 3-days pretreatment with SCF was introduced and followed by 7 days concurrent SCF plus G-CSF. The 3-days pretreatment with SCF resulted in an earlier wave of PBPC release in response to commencement of G-CSF. In addition, maximum PBPC levels in blood and PBPC yield in leukapheresis products were further increased. Unexpectedly however, SCF pretreatment resulted in progenitor cells with enhanced self-generation potential. Recloning assays documented the ability of approximately 30% of primary granulocyte-macrophage (GM) colonies from control cell populations to generate secondary GM colonies (n = 1,106 primary colonies examined). In contrast approximately 90% of GM colonies from PBPC after SCF pretreatment generated secondary clones and 65% generated secondary colonies. The action of SCF was not explicable in terms of altered SCF, GM-CSF, or G-CSF responsiveness, but SCF pretreatment was associated with maximum serum SCF levels at the time G-CSF was commenced. These results show that PBPC populations mobilized by different growth factor regimens can differ in their functional properties and caution against solely considering number of harvested progenitor cells without regard to their function.
When study site contributes to outcomes in a multi-center randomized trial: a secondary analysis of decisional conflict in men with localized prostate cancer

Evaluate baseline factors that may explain the influence of study site on decisional conflict (DC) in men from the Personal Patient Profile: Prostate (P3P) randomized trial.



476 cases from 5 P3P sites were included. Participants completed baseline demographic assessments, 4 subscales of the DC scale at baseline (uncertainty, informed, values clarity, and support), the Expanded Prostate Cancer Index Composite (short form) and the State-Trait Anxiety Inventory. Site data regarding typical practices were collected. Linear regressions were used to model the relation between baseline DC scores and study site adjusting for the list of variables.



Baseline decisional uncertainly (p = 0.001) and informed (p = 0.03) subscales were significantly different across sites. Participant demographic and baseline measures were significantly different (p < 0.05) between sites except for trait anxiety. We identified participant level factors that explained study site differences at baseline for the decisional uncertainty and values clarity subscales: a preferred treatment choice at study entry, whether the study program was accessed at home vs. in clinic, number of doctors consulted pre-study, working status, state anxiety, information from the media or a health care provider, and perceived knowledge level. State anxiety was associated with higher DC across all subscales.



Individual characteristics of men seeking consultation for LPC were associated with DC at baseline, not the site alone; anxiety contributed to higher conflict. These findings will inform future development and implementation of the P3P and other decision support interventions.
Plasma vitamin D and prostate cancer risk: results from the Selenium and Vitamin E Cancer Prevention Trial.

In vitro, animal, and ecological studies suggest that inadequate vitamin D intake could increase prostate cancer risk, but results of biomarker-based longitudinal studies are inconsistent.



Data for this case (n = 1,731) and cohort (n = 3,203) analysis are from the Selenium and Vitamin E Cancer Prevention Trial. Cox proportional hazard models were used to test whether baseline plasma vitamin D (25-hydroxy) concentration, adjusted for season of blood collection, was associated with the risk of total and Gleason score 2-6, 7-10, and 8-10 prostate cancer.



There were U-shaped associations of vitamin D with total cancer risk: compared with the first quintile, HRs were 0.83 [95% confidence interval (CI), 0.66-1.03; P = 0.092], 0.74 (95% CI, 0.59-0.92; P = 0.008), 0.86 (95% CI, 0.69-1.07; P = 0.181), and 0.98 (95% CI, 0.78-1.21; P = 0.823), for the second through fifth quintiles, respectively. For Gleason 7-10 cancer, corresponding HRs were 0.63 (95% CI, 0.45-0.90; P = 0.010), 0.66 (95% CI, 0.47-0.92; P = 0.016), 0.79 (95% CI, 0.56-1.10; P = 0.165), and 0.88 (95% CI, 0.63-1.22; P = 0.436). Among African American men (n = 250 cases), higher vitamin D was associated with reduced risk of Gleason 7-10 cancer only: in the a posteriori contrast of quintiles 1-2 versus 3-5, the HR was 0.55 (95% CI, 0.31-0.97; P = 0.037), with no evidence of dose-response or a U-shaped association.



Both low and high vitamin D concentrations were associated with increased risk of prostate cancer, and more strongly for high-grade disease.



The optimal range of circulating vitamin D for prostate cancer prevention may be narrow. Supplementation of men with adequate levels may be harmful. Cancer Epidemiol Biomarkers Prev; 23(8); 1494-504.
Clinical consequences of delayed addition of adalimumab to methotrexate therapy over 5 years in patients with rheumatoid arthritis.

This Year 5 analysis of an open-label extension (OLE) study assessed radiographic progression, clinical efficacy, and safety of adalimumab with concomitant methotrexate (MTX) for patients with active rheumatoid arthritis.



In a double-blind study (DE019, NCT00195702), inadequate responders to MTX were randomized to MTX plus either adalimumab 40 mg eow, adalimumab 20 mg weekly, or placebo for 52 weeks. Eligible patients entered an ongoing OLE and received adalimumab 40 mg eow plus MTX. Longterm efficacy and safety were evaluated.



Of 457 patients who had enrolled in the OLE, 304 remained in the study at Year 5, including 112, 107, and 85 from the original adalimumab 40 mg, adalimumab 20 mg, and placebo groups, respectively. Year 5 radiographs demonstrated mean changes in modified total Sharp score for the original adalimumab 40 mg eow and 20 mg weekly groups of 0.8 and 2.6, respectively, versus 3.9 for placebo; 58% from the adalimumab 40 mg eow group had no radiographic progression versus 40% of those who initially received placebo. Of patients who received adalimumab 40 mg eow for 5 years, 26.1% achieved clinical remission (Disease Activity Score 28-joint count < 2.6), had no radio graphic progression (change in modified total Sharp score ≤ 0.5), and had normal function (Health Assessment Questionnaire ≤ 0.5), versus 11.9% of those who initially received placebo. Serious infection rate for 553 patients who received at least one dose of adalimumab was 4.4/100 patient-years.



A 52-week delay in adding adalimumab to MTX led to worse radiographic, functional, and clinical outcomes at Year 5 for most patients who initially received placebo instead of adalimumab.
HLA-matched allo-SCT after reduced intensity conditioning with fludarabine/CY in patients with metastatic breast cancer

Fifteen patients with chemosensitive metastatic breast cancer (MBC) underwent reduced intensity (RIST) allo-SCT between 1999 and 2006. The purpose of this single-center study was to evaluate the feasibility, safety and efficacy of this therapeutic approach. The pretransplant conditioning regimen consisted of fludarabine (25 mg/m2 at days −5 to −1) and CY (60 mg/kg at days −2, −1). Stem cells were from HLA-matched sibling donors. The treatment-related mortality was 2/15 (13%). Median PFS and OS were 144 days (43–509 days) and 303 days (122–1376 days), respectively. The 1-year PFS was 20%, and the 1-year and 2-year OS was 40 and 20%, respectively. No objective tumor responses were observed, but the relatively long PFS does suggest a graft-vs-tumor effect. Although RIST using this CY/fludarabine regimen is feasible, the efficacy in this set of patients was limited. Future clinical trials should be performed to improve the knowledge of mechanisms of antitumor effects in breast cancer.
Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies.

CT-011 is a humanized IgG1 monoclonal antibody that modulates the immune response through interaction with PD-1, a protein belonging to the B7 receptor family present on lymphocytes. The objectives of this phase I study were to assess the dose-limiting toxicities, to determine the maximum tolerated dose, and to study the pharmacokinetics of CT-011 administered once to patients with advanced hematologic malignancies.



Seventeen patients were treated with escalating doses of CT-011 ranging from 0.2 to 6 mg/kg. For pharmacokinetic analysis, blood samples were withdrawn from the patients before and immediately after treatment and at 24 hours, 48 hours, and on days 7, 14, and 21. CT-011 blood levels were assessed with a specific ELISA and derived concentrations were used to calculate pharmacokinetic parameters. Activation of the immune system was assessed by measuring peripheral blood CD4+, CD8+, and CD69+ lymphocytes.



The study showed the antibody to be safe and well tolerated in this patient population. No single maximum tolerated dose was defined in this study. Clinical benefit was observed in 33% of the patients with one complete remission. Pharmacokinetic analyses show that serum Cmax and the AUC of CT-011 increased proportionally with dose. The median t1/2 of CT-011 ranged from 217 to 410 hours. Sustained elevation in the percentage of peripheral blood CD4+ lymphocytes was observed up to 21 days following CT-011 treatment.



A single administration of 0.2 to 6.0 mg/kg of CT-011 is safe and well tolerated in patients with advanced hematologic malignancies.