nils-herrmann/clean_scirepeval huggingface dataset:
Mismatch repair status in the prediction of benefit from adjuvant fluorouracil chemotherapy in colorectal cancer.

Some retrospective studies have shown a lack of benefit of 5-fluorouracil (5-FU) adjuvant chemotherapy in patients with mismatch repair (MMR) deficient colorectal cancer. Our aim was to assess if this molecular marker can predict benefit from 5-FU adjuvant chemotherapy. A second objective was to determine if MMR status influences short term survival.



We included 754 patients with a median follow up of 728.5 days (range 1-1097). A total of 260 patients with stage II or III tumours received 5-FU adjuvant chemotherapy, according to standard clinical criteria and irrespective of their MMR status. A tumour was considered MMR deficient when either BAT-26 showed instability or there was loss of MLH1 or MSH2 protein expression.



At the end of the follow up period, 206 patients died and 120 presented with tumour recurrence. Sixty six (8.8%) patients had MMR deficient tumours. There were no significant differences in overall survival (MMR competent 72.1%; MMR deficient 78.8%; p = 0.3) or disease free survival (MMR competent 61.3%; MMR deficient 72.3%; p = 0.08). In patients with stage II and III tumours, benefit from 5-FU adjuvant chemotherapy was restricted to patients with MMR competent tumours (overall survival: chemotherapy 87.1%; non-chemotherapy 73.5%; log rank, p = 0.00001). Patients with MMR deficient tumours did not benefit from adjuvant chemotherapy (overall survival: chemotherapy 89.5%; non-chemotherapy 82.4%; log rank, p = 0.4).



Benefit from 5-FU adjuvant chemotherapy depends on the MMR status of tumours in patients with colorectal cancer. 5-FU adjuvant chemotherapy improves survival in patients with MMR competent tumours but this benefit from chemotherapy cannot be extended to patients with MMR deficient tumours.
Effects of the selective MPS1 inhibitor MPS1-IN-3 on glioblastoma sensitivity to antimitotic drugs.

Glioblastomas exhibit a high level of chemotherapeutic resistance, including to the antimitotic agents vincristine and taxol. During the mitotic agent-induced arrest, glioblastoma cells are able to perform damage-control and self-repair to continue proliferation. Monopolar spindle 1 (MPS1/TTK) is a checkpoint kinase and a gatekeeper of the mitotic arrest.



We used glioblastoma cells to determine the expression of MPS1 and to determine the effects of MPS1 inhibition on mitotic errors and cell viability in combination with vincristine and taxol. The effect of MPS1 inhibition was assessed in different orthotopic glioblastoma mouse models (n = 3-7 mice/group). MPS1 expression levels were examined in relation to patient survival.



Using publicly available gene expression data, we determined that MPS1 overexpression corresponds positively with tumor grade and negatively with patient survival (two-sided t test, P < .001). Patients with high MPS1 expression (n = 203) had a median and mean survival of 487 and 913 days (95% confidence intervals [CI] = 751 to 1075), respectively, and a 2-year survival rate of 35%, whereas patients with intermediate MPS1 expression (n = 140) had a median and mean survival of 858 and 1183 days (95% CI = 1177 to 1189), respectively, and a 2-year survival rate of 56%. We demonstrate that MPS1 inhibition by RNAi results in sensitization to antimitotic agents. We developed a selective small-molecule inhibitor of MPS1, MPS1-IN-3, which caused mitotic aberrancies in glioblastoma cells and, in combination with vincristine, induced mitotic checkpoint override, increased aneuploidy, and augmented cell death. MPS1-IN-3 sensitizes glioblastoma cells to vincristine in orthotopic mouse models (two-sided log-rank test, P < .01), resulting in prolonged survival without toxicity.



Our results collectively demonstrate that MPS1, a putative therapeutic target in glioblastoma, can be selectively inhibited by MPS1-IN-3 sensitizing glioblastoma cells to antimitotic drugs.
Sex differences in the pharmacokinetics of levodopa in elderly patients with Parkinson disease.

Levodopa (LD) is the most effective antiparkinsonian drug used in the treatment of Parkinson disease (PD). Sex differences in the bioavailability of LD have been shown previously. In addition, epidemiological sex differences in PD have been reported, suggesting an involvement of estrogen. In this study, we evaluated the pharmacokinetics of LD in elderly patients with PD to examine the influence of estrogen.



After the oral administration of a tablet of LD 100 mg/carbidopa 10 mg in 128 PD patients (including 91 elderly patients; age at examination, 75 years or older), plasma LD concentrations were measured at 6 points until 180 minutes, and pharmacological parameters were calculated. Then, differences in these parameters between sex were compared.



The area under the curve (AUC) and the AUC adjusted for body weight were found to be significantly greater in the female subjects compared with the male subjects (P < 0.0001 and P < 0.0001, respectively). Furthermore, in the elderly patients, the AUC and the AUC adjusted for body weight were significantly greater among the female subjects (P < 0.0001 and P < 0.0001, respectively).



Even in the elderly cohort, the women had a significantly greater bioavailability of LD. In conclusion, to avoid the development of motor complications during LD treatment, it is important to consider the sex differences in the bioavailability of LD.
Treatment of acute respiratory distress syndrome with recombinant surfactant protein C surfactant.

We performed a phase I/II trial in North America of a recombinant surfactant protein C-based surfactant (Venticute) as treatment for the acute respiratory distress syndrome. Patients were prospectively randomized to receive either standard therapy or standard therapy plus one of two doses of exogenous surfactant given four times over 24 hours. Surfactant administration was well tolerated. No significant treatment benefit was associated with surfactant treatment. Bronchoalveolar lavage of treated patients at 48 hours reflected the presence of exogenous surfactant components, did not show evidence of improved surface tension lowering function, and had interleukin-6 concentrations that were significantly lower than control group values, consistent with an antiinflammatory treatment effect. The presence of exogenous surfactant was not detected in lavage fluid obtained at 120 hours. Future studies might rationally employ larger surfactant doses and a more prolonged dosing schedule.
Effect of caloric restriction on colonic proliferation in obese persons: implications for colon cancer prevention.

Dietary intervention to prevent colon cancer is a major health issue. At present it is not clear which dietary factors modify colon cancer risk. Caloric restriction reduces the incidence of many spontaneous and carcinogen-induced tumors in rodents, but its role in human carcinogenesis is unknown. The relationships of body mass index (BMI), body composition, and resting metabolic rate (RMR) to colon cancer risk are also undefined. In this study involving obese persons, we measured the effect of reducing caloric intake on rectal cell proliferation, a biomarker in colon carcinogenesis, and studied the relation of BMI, body composition, and RMR to rectal cell proliferation. Colonic cell proliferation was measured in rectal biopsies from persons weighing more than 130% of ideal body weight. Follow-up biopsies were performed in patients who enrolled in and completed a 16-week behavior modification weight-reduction program in which caloric intake was reduced. Baseline measurements included body composition by total body electrical conductance, RMR, and BMI. Rectal biopsies were processed for autoradiography following incubation with [3H]thymidine. Epithelial proliferation measurements were evaluable in 35 persons at baseline and in 8 persons before and after caloric restriction. Before caloric restriction, mean (+/- SD) BMI was 38 +/- 4 kg/m2 and percentage of body fat 41 +/- 2%. Subjects reduced their caloric intake by a mean of 34 +/- 4% and their weight by 8.6 +/- 1%. Caloric restriction resulted in a 39% reduction in whole-crypt labeling index (P < 0.001) and a 57% reduction in upper crypt labeling index (P < 0.05) without reduction in crypt depth. Labeling index was unrelated to BMI, RMR, or body composition. We conclude that caloric restriction reduced rectal cell proliferation measurements--intermediate biomarkers related to colon carcinogenesis. BMI, RMR, and body composition were unrelated to colonic proliferation. Caloric restriction may have a role in colon cancer prevention.
Combining urinary detection of TMPRSS2:ERG and PCA3 with serum PSA to predict diagnosis of prostate cancer.

We sought to develop a clinical algorithm combining serum PSA with detection of TMPRSS2:ERG fusion and PCA3 in urine collected after digital rectal exam (post-DRE urine) to predict prostate cancer on subsequent biopsy.



Post-DRE urine was collected in 48 consecutive patients before prostate biopsy at 2 centers; quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to detect PCA3 and TMPRSS2:ERG fusion transcript expression. Serum PSA was measured by clinical assay. The performance of TMPRSS2:ERG fusion, PCA3, and serum PSA as biomarkers predicting prostate cancer at biopsy was measured; a clinically practical algorithm combining serum PSA with TMPRSS2:ERG and PCA3 in post-DRE urine to predict prostate cancer was developed.



Post-DRE urine sediment provided informative RNA in 45 patients; prostate cancer was present on subsequent biopsy in 15. TMPRSS2:ERG in post-DRE urine was associated with prostate cancer (OR = 12.02; P < 0.001). PCA3 had the highest sensitivity in predicting prostate cancer diagnosis (93%), whereas TMPRSS2:ERG had the highest specificity (87%). TMPRSS2:ERG had the greatest discriminatory value in predicting prostate cancer (AUC = 0.77 compared with 0.65 for PCA3 and 0.72 for serum PSA alone). Combining serum PSA, PCA3, and TMPRSS2:ERG in a multivariable algorithm optimized for clinical utility improved cancer prediction (AUC = 0.88; specificity = 90% at 80% sensitivity).



A clinical algorithm specifying biopsy for all patients with PSA ≥ 10 ng/ml, while restricting biopsy among those with PSA <10 ng/ml to only those with detectable PCA3 or TMPRSS2:ERG in post-DRE urine, performed better than the individual biomarkers alone in predicting prostate cancer.
Clinical response and plasma haloperidol levels in schizophrenia

Plasma haloperidol levels were compared to clinical response during the first 14 days of drug treatment in 14 DSM III-diagnosed inpatient schizophrenic patients using an improved methodology, which utilized predetermined constant dosages and derived a therapeutic range of plasma haloperidol levels from a curvilinear regression analysis. An inverted U-shaped relationship was found which reflected a significant curvilinear correlation (r=0.66, P<0.02) between plasma levels (as assayed by gas chromatography) and improvement on the Serial New Haven Schizophrenia Index. A therapeutic window was suggested by the present study, with optimum patient response associated with plasma haloperidol levels of 4.2–11.0 ng/ml for the first 2 weeks of treatment.
Association between ADAMTS1 matrix metalloproteinase gene variation, coronary heart disease, and benefit of statin therapy.

The purpose of this study was to investigate the association between the Ala227Pro polymorphism in the ADAMTS1 metalloproteinase gene and coronary heart disease and benefit from statin therapy in 2 independent cohorts.



The frequency of the ADAMTS1 227Pro minor allele was 0.24 in 2421 male subjects from CARE, a randomized trial of pravastatin versus placebo. In the placebo arm, homozygotes (6.3% of study population) had a significantly increased risk of fatal coronary disease or nonfatal myocardial infarction (D/MI) compared with noncarriers (OR 2.12, 95% CI 1.07 to 4.19, P=0.03), and in the entire study the benefit of pravastatin in reducing the risk of D/MI was greater in these subjects (OR 0.21, 95% CI 0.06 to 0.69) than in heterozygotes (OR 0.74, 95% CI 0.48 to 1.14) or noncarriers (OR 0.99, 95% CI 0.68 to 1.42; P(interaction)=0.044). Results were tested in 1565 male subjects from WOSCOPS, also a randomized trial of pravastatin versus placebo. Similar to the results in CARE, in the placebo arm subjects homozygous for the minor allele were at increased risk of D/MI (OR 1.72, P=0.052) and in the entire study the benefit of pravastatin in reducing D/MI was greater in these subjects (OR 0.24, 95% CI 0.09 to 0.68) than in heterozygotes (OR 0.73, 95% CI 0.48 to 1.11) or noncarriers (OR 0.65, 95% CI 0.20 to 2.09) (P(interaction)=0.029).



In men not on pravastatin, those homozygous for the 227Pro allele of ADAMTS1 have a nearly 2-fold increased risk of coronary heart disease events compared with noncarriers. In this high-risk group, treatment with pravastatin is highly efficacious, reducing the odds of fatal coronary disease or nonfatal MI by approximately 75%, as compared with 25% in noncarriers or heterozygotes.
Comparison between NSAID and intra-articular corticosteroid injection in frozen shoulder of diabetic patients; a randomized clinical trial.

Frozen shoulder or adhesive capsulitis is a relatively common encountered musculo-skeletal disease in which arouses following soft tissue involvement of glenohumeral joint and presents with pain and limitation of shoulder' active and passive motions. The incidence of frozen shoulder among diabetic patients is about 10-20%, stiffness in such patients is more severe and should be managed actively. Local Glucocorticoid injection, NSAIDs and physiotherapy each can relief the symptoms. The aim of this study was to compare the efficacy of glenohumeral injection of Glucocorticoid with NSAIDs in frozen shoulder of diabetic patients.



The randomized clinical trial study conducted during Feb 2009-Aug 2010 on diabetic patients with frozen shoulder that were referred to rheumatology and endocrinology clinics, Yazd, Iran. Diagnostic criteria of capsulitis were pain of shoulder and range of motion limitation in all directions. The patients were divided into 2 groups, patients of first group received NSAID while the latter group were undergone intra-articular corticosteroid injection. After 1 week, home exercise was done for both group and evaluation of the patients after first visit was done likewise 2nd, 6th, 12th and 24th weeks. All registered data were transformed into SPSS-15 software and analyzed.



Totally 57 patients (19 males (33.3%) and 38 females (66.7%) were included in the analysis. There was no significant difference between sex (P=0.4) and age (P=0.19) of patients. No significant relation was detected between 2 groups after 24 weeks according to range of motion in flexion (P=0.51), abduction (P=0.76), external rotation (0.12) and internal rotation (P=0.91). Also any significant difference in pain score was not detected (P=0.91).



Based on our study, both intra-articular corticosteroid and NSAID are effective in treatment of adhesive capsulitis and there is no significant difference between efficacies of these 2 treatment modalities in diabetic patients.
Temporal trends in the use of high-dose potent statins following acute coronary syndrome in Israel.

This study aimed to evaluate factors associated with the prescription of high-dose potent statin (HDPS) therapy following hospitalization for acute coronary events.



Sub-analysis was made using the data of 3,525 patients enrolled in the 2008 and 2010 Acute Coronary Syndrome Israeli Surveys (ACSIS).



Analyses were carried out to identify demographic and clinical factors associated with the prescription of HDPS therapy (atorvastatin 40-80 mg/day or rosuvastatin 20-40 mg/day) at discharge compared with the prescription of lower-dose statins.



Among the study patients, 1,387 (39%) were discharged on HDPS, 1,860 (53%) with lower-dose statin regimens and 278 (8%) with no recommendation for statin therapy. Multivariate logistic regression analysis showed that pre-admission usage of HDPS and participation in the more recent (2010) ACSIS survey were independently associated with a higher likelihood of HDPS prescription at discharge from the index event (odds ratio, OR, 21.07, p < 0.001, and 5.61, p < 0.001, respectively), whereas factors independently associated with a lack of HDPS prescription included age >75 years (OR 0.76, p = 0.03), low-density lipoprotein-cholesterol levels <100 mg/dl on admission (OR 0.67, p < 0.001) and a history of heart failure prior to the index hospitalization (OR 0.54, p = 0.0018). The 30-day compliance with the HDPS regimen was 98%.



The findings show increased use of HDPS therapy in acute coronary syndrome (ACS) patients, although this mode of medical therapy is still underutilized in the important subset of high-risk ACS patients.
Evaluation of epoetin supplemented with oral iron in patients with solid malignancies and chronic anemia not receiving anticancer treatment.

To evaluate the effectiveness and improvement in quality of life (QOL) of epoetin alfa administration supplemented with oral iron as a therapeutic regimen for patients with solid malignancies and anemia of chronic disease (ACD), not receiving chemotherapy and/or radiotherapy.



A total of 100 patients with cancer-related anemia, not subjected to chemotherapy and/or radiotherapy, were randomized to receive for a maximum of 24 weeks either oral iron, equivalent to 200 mg elemental iron once daily, or epoetin alfa 40,000 IU subcutaneously once weekly plus oral iron once daily.



Patients in the epoetin alfa group had, from baseline to study end, a mean increase in hemoglobin (Hb) levels of 2.4 g/dL, whereas in the control group the mean Hb level decreased by 0.1 g/dL, (p<0.001). Improvement in QOL as assessed by the LASA and the FACT-An questionnaire were greater in patients in the epoetin alfa group than in the control group (mean change, LASA-energy level: 30.4 mm vs. 0.4 mm, -daily activities: 31.7 mm vs. 0.4 mm, -overall well-being. 32.4 mm vs. 4.9, FACT-An: 43.3 vs. 13.4, respectively). As for ECOG score, patients in the epoetin alfa group had a mean improvement of 0.16 from baseline to study end (control group: 0.06). Improvement in QOL parameters and in ECOG scores correlated positively with increased hemoglobin levels.



Our results suggest that weekly epoetin alfa therapy supplemented with daily oral iron increases Hb levels and improves QOL in patients with solid malignancies and ACD who are not receiving chemotherapy and/or radiotherapy. This regimen offers optimal therapy in this population taking into consideration physician's convenience and patient's compliance.
Comparison of the effects of acarbose and metformin use on ovulation rates in clomiphene citrate-resistant polycystic ovary syndrome.

The aim of this study was to evaluate the effects of metformin and acarbose on insulin resistance, hormone profiles and ovulation rates in patients with clomiphene citrate-resistant polycystic ovary syndrome (PCOS).



Thirty clomiphene citrate-resistant patients were selected randomly and divided into two groups. Group I was treated with 100 mg/day clomiphene citrate and 300 mg/day acarbose 100 mg/day orally, for 3 months. Group II was treated with clomiphene citrate 100 mg/day and metformin 1700 mg/day orally, for 3 months. Serum fasting insulin and glucose, FSH, LH, estradiol, progesterone, prolactin and total testosterone levels plus body mass index (BMI) were measured before and after treatment. Follicle growth was followed by transvaginal ultrasonography.



LH:FSH ratio and total testosterone concentrations decreased (P<0.05) and ovulation rates increased in both groups. Reduction in weight and BMI was only significant in the acarbose group.



Both treatment modalities were effective in the treatment of insulin resistance and improving ovulation rates. Increase in the number of eumenorrhoeic and normoinsulinaemic cases and decrease in the number of insulin-resistant cases were significant in both groups (P<0.05). Ovulation rate was greater in the metformin group in the second month of therapy (P<0.05). Acarbose was found to be a safe and effective agent that could be used in cases with clomiphene-resistant PCOS.
Clinical management of abnormal cytology test results and costs associated with the prevention of cervical cancer in Spain.

To evaluate the clinical management of women with abnormal cervical cytology results, the associated health care resource allocation, and costs in Spain.



A retrospective, observational, multicenter study of 849 women with abnormal cervical cytology results: 162 cases of atypical squamous cells of undetermined significance (ASCUS; 19.1%), 272 cases of low-grade squamous intraepithelial lesions (LSILs; 32.0%), 369 cases of high-grade squamous intraepithelial lesions (HSILs; 43.5%), and 46 cases of cancer (5.4%). Health care resources allocated to the diagnosis and treatment of lesions for a minimum of 2 years from the first abnormal cervical cytology result were assessed from patients' charts.



Histologic diagnosis confirmed 159 cases of cervical intraepithelial neoplasia grade 1 (CIN 1; 18.7%), 120 cases of CIN 2 (14.1%), 295 cases of CIN 3 (34.8%), and 79 cases of cancer (9.3%). Median waiting time to first intervention after an abnormal cytology result was 47 days (diagnostic range = 31-60). The most common diagnostic procedures were colposcopy and additional cytology testing. The principal therapeutic procedure was loop electrosurgical excision. The costs generated according to cytology result were (euro)1,196.80 (ASCUS), (euro)912.43 (LSIL), (euro)1,333.00 (HSIL), and (euro)6,261.30 (cancer). The costs generated according to histology results were (euro)790.10 (CIN 1), (euro)1,131.20 (CIN 2), (euro)1,181.30 (CIN 3), and (euro)7,041.70 (cancer).



Waiting time to the first intervention may be longer than clinically desirable. Direct costs associated with the management patterns of women with abnormal cervical cytology result are high and have important economic consequences to the Spanish National Health System. These results will allow to improve the effectiveness and efficiency of future intervention strategies.