bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Lopinavir/ritonavir protease inhibitor on the pharmacokinetics of Irinotecan in HIV-infected patients with advanced Kaposi’s sarcoma
Authors: Corona G. , Vaccher E. , Di Gennaro G. , Tirelli U. , Toffoli G. 
Published: March 2020

9558 Background: Irinotecan (CPT11) in combination with HAART has been found active in patients with advanced AIDS-related Kaposi’s sarcoma [Vaccher E et al. AIDS 2005]. Dose-limiting toxicity consisted of persistent leukopenia, suggesting the potential for pharmacokinetic interactions between CPT11 and lopinavir boostered with ritonavir, the protease inhibitor component of HAART. Methods: Six HIV-infected patients with advanced Kaposi’s sarcoma were prospectively treated with CPT11 at a dose of 150 mg/m2, given as a 90-min infusion on days 1 and 10, in absence and in combination with 400mg/100mg LPV/rtv. Pharmacokinetic parameters of the CPT11, the active metabolite (SN38), its glucoronide derivative (SN-38G), and the APC metabolite were investigated over a 50 h time interval at the first day of chemotherapy cycle. A 2-day LPV/rtv washout was allowed before the evaluation of pharmacokinetics of CPT11 alone. The pharmacokinetics of CPT11 in combination with LPV/rtv was determined at day-10 (paired cross over). Results: The mean (± SD) clearance of CPT11 was found significantly lower when CPT11 was administered in combination with LPV/rtv (13.39±3.39 l/h/m2 vs 23.55±7.16 l/h/m2, p<0.05 for CPT11+ LPV/rtv and CPT11 alone respectively). This was associated with a 94.3% reduction of AUC APC oxidized metabolite and with 2.9 and 1.8-fold increase of SN38 and SN38G AUC, respectively. During the CPT11+ LPV/rtv, the ratio SN38/CPT11 AUC was higher (0.031±0.008 vs 0.019±0.006, p<0.05) while the glucoronidation ratio (the AUC ratio of SN38G and SN38) was found significantly lower (5.50±1.43 vs 9.03±2.49, p<0.05) as compared to the administration of CPT11 alone. Conclusions: This preliminary investigation indicates that CPT11 pharmacokinetics can be strongly influenced by the co-administration of LPV/rtv. This leads to a significant increase of AUC SN38 active metabolite, likely associated to an increase of CPT11 activation and in a reduction of SN38 glucoronidation paths, which may have profound effects on pharmacodynamic of CPT11 when used in combination with LPV/rtv -based HAART. No significant financial relationships to disclose.
FDG-PET for the prediction of therapy outcome in patients with high risk soft tissue sarcomas receiving high dose chemotherapy with stem cell rescue
Authors: Wuchter P. , Kasper B. , Dimitrakopoulou-Strauss A. , Egerer G. , Haberkorn U. , Ho A. D. , Strauss L. G. 
Published: March 2020

9562 Background: Dynamic 2-deoxy-2-[18F]fluoro-D-glucose (FDG) PET studies were used to evaluate the FDG kinetics in pts.with high risk soft tissue sarcomas receiving induction chemotherapy consisting of adriamycin and ifosfamide (AI-G) prior to peripheral blood stem cell transplantation. The treatment effect was assessed regarding prediction of therapy outcome. Methods: The ongoing evaluation includes 8 pts. with 17 lesions. 7/8 pts. were classified as grade III with lung or multiple metastases. The restaging data served as reference for the PET data. All pts. were examined initially and after the first cycle of AI-G . The dynamic series were performed over the area of the primary tumor (n=5) or the lung metastases (n=3). SUV, fractal dimension (FD), k1, k2, k3, k4 and the vessel density (VB) were retrieved from the dynamic PET studies. Furthermore, FDG influx was calculated using the rates of the two compartment model and the formula (k1 × k3)/(k2 + k3). Discriminant analysis was applied for data analysis. Results: According to RECIST criteria, 3 pts. showed progressive disease (PD), one pt.stable disease (SD), one pt. no evidence of disease (NED) and two pts. partial remission (PR). Due to the small number of pts., we dichotomized the data in pts. with NED/PR (n=3) and pts. with SD/PD (n=4). Median SUV prior therapy was 8.3 in comparison to 4.3 after one cycle AI-G. Discriminant analysis using only the data of the initial FDG study and a single parameter for input demonstrated the highest correct classification rate (CCR) for VB (73%). The CCR of k1, k2, influx and FD were lower and equal (67%). The SUV of the first study demonstrated a lower CCR of 60%. Using the kinetic data only of the second study, CCR was equal for SUV, influx and FD as single input parameters (70%). Best results were obtained for the combination of VB of the first study and either influx or FD of the second study with a CCR of 89%. Conclusions: The significance of vessel density calculated from the data of the initial PET study and the non-significance for the second PET examination indicated a major change in the angiogenesis within the initial phase of treatment. On the basis of these data prediction of chemo-sensitivity of the tumor and moreover of the therapy outcome might be possible. No significant financial relationships to disclose.
Multiple primary malignancies (MPM) in Israeli patients with soft tissue sarcomas (STS)
Authors: Geva R. , Merimsky O. 
Published: March 2020

9571 Background: An increased incidence of MPM has been reported in association with STS. In a previous series we reported 28 patients out of 375 patients with STS as having second or third additional primary malignancies not all accountable by previous chemotherapy or radiotherapy. In the present series we re-examined the phenomenon in a large Israeli database of adult STS patients. Methods: A retrospective search of the database of approx.1350 adult STS patients who were referred, diagnosed or treated at our center between 1995–2005. Results: A group of 132 patients (F=66, M=66, age 1–87y, median 59y) with STS and at least one additional malignancy was retrieved. Overall, a family history of malignancy was reported by 26%, exposure to carcinogens prior to 1st tumor by 10%. Exposure to carcinogens/RT/Chemo given for the 1st tumor prior to the 2nd tumor was recorded in 61%. Taken together (n=132), STS were associated with a second malignancy arising mainly from the various sites of the urogenital system (18%), breast (17%), GIT (11%), lung (8%), and thyroid (7%). When non-STS was the first malignancy (n=73 at a median age 59y), the main malignancies included breast (23% ), colorectal (11%), melanoma (10%), prostate (8%), thyroid (7%), and bladder (5%). STS as a second primary (n=66) after a median time of 8y, included MFH (28%), LMS (16%), and liposarcoma (15%). The STS originated in a limb in 42%, trunk- 12%, retroperitoneum or viscera-34%, and unknown origin-1%. In the other 6 patients (median age 76.5), STS was the 3rd or more primary tumor. When STS was the first malignancy (n=59 at a median age of 59y), the second primary cancers were diagnosed after a median of 5 years, and included lung (15%), STS of different type (12%), kidney (10%), skin (10%), breast (10%), colorectal (8.5%), prostate (8.5%), and thyroid (7%). Updated survival data will be presented. Conclusions: The incidence of malignancies among patient population of primary STS is higher than the incidence of the same malignancies in the general population. This implies for the need to search for an occult second primary tumor in patients with STS as an integral part of their follow-up. No significant financial relationships to disclose.
Clear cell sarcoma of tendons and aponeuroses: An analysis of 75 cases
Authors: Kawai A. , Nakayama R. , Matsumine A. , Matsumoto S. , Ueda T. , Tsuchiya H. , Yabe H. , Beppu Y. 
Published: March 2020

9572 Background: Clear cell sarcoma (CCS) of tendons and aponeuroses is a rare malignant tumor that occurs most commonly in the extremities of young adults. Because of the rarity of the disease (1% of all soft tissue sarcomas), most reports about CCS have dealt with a few cases during a long time period. We conducted a multi-institutional study of CCS to clarify the clinical findings and prognostic factors of CCS treated during the era of modern multidisciplinary treatment. Methods: The records of 75 consecutive patients with histologically confirmed CCS treated at the JMOG affiliated institutions between 1980 and 2004 (follow-up; average 44 months) were reviewed. There were 41 men and 34 women with an average age of 36 years (range, 10–71 years). 65 tumors were in the extremities (foot 22, hand 13, thigh 9, others 21) and 10 were in the trunk. The tumor size ranged from 1 to 11 cm (mean, 4 cm). 52 patients presented with localized disease (M0) and 23 with metastatic disease (M1). Results: Surgical excision of the primary tumor was performed in 71 patients (limb-sparing surgery; 56, amputation; 15). Microscopic surgical margin was negative in 60 and positive in 11. 56 patients received chemotherapy (30 with measurable disease) and 17 had radiotherapy. Local recurrence occurred in 16 patients and 48 patients developed metastasis. The 5-year overall survival rate was 47% (M0; 55%, M1; 20%). On univariate analysis, sex (p=0.02), size (p=0.001), depth (p=0.002), TNM stage (p=0.001), IRS group (p=0.001) and surgical margin (p=0.04) were prognostic factors. On multivariate analysis, size (p=0.02) remained to be a significant prognostic factor. Objective response to chemotherapy was observed in 8 (27%) patients. In the group of M0 patients, those who received adjuvant chemotherapy had better prognosis (5-year survival, 65%) than those without chemotherapy (5-year survival, 23%)(p=0.03). Conclusions: The results support the contention that early diagnosis and initial excision with negative surgical margin are essential for favorable outcome of CCS. The role of chemotherapy for CCS should be further investigated. No significant financial relationships to disclose.
Phase III randomized trial of sunitinib malate (SU11248) versus interferon-alfa (IFN-α) as first-line systemic therapy for patients with metastatic renal cell carcinoma (mRCC)
Authors: Motzer R. J. , Hutson T. E. , Tomczak P. , Michaelson M. D. , Bukowski R. M. , Rixe O. , Oudard S. , Kim S. T. , Baum C. M. , Figlin R. A. 
Published: March 2020

LBA3 Background: Two multicenter phase II trials of 2nd line monotherapy with sunitinib (SU11248) in patients (pts) with mRCC showed a response rate of approximately 40% (JCO 2006;24:16–24; Proc ASCO 23, 380s). This international, randomized phase III trial compared the efficacy and safety of sunitinib to IFN-α in treatment naïve pts with mRCC. Methods: Untreated pts with clear-cell mRCC were randomized 1:1 to receive sunitinib (6-week cycles: 50 mg orally once daily for 4 weeks, followed by 2 weeks off) or IFN-α (6-week cycles: subcutaneous injection 9 MU given three times weekly). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate, overall survival, and adverse events. Based on a planned sample size of 690 patients, the trial was designed to have 90% power to detect a 35% improvement in median PFS from 20 weeks to 27 weeks (4.6 months to 6.2 months; 2-sided unstratified log-rank test; significance level 0.05). Results of a planned analysis on the primary endpoint, PFS, are presented in this report. Results: From Aug 2004 to Oct 2005, 750 patients were randomized: 375 to sunitinib, 375 to IFN-α. Baseline characteristics were well balanced, and included pooled median age = 60 and prior nephrectomy = 90%. Median PFS assessed by third-party independent review was 47.3 weeks (95% CI 40.9, not yet reached) for sunitinib vs. 24.9 weeks (95% CI 21.9, 37.1) for IFN-α [hazard ratio 0.394 (95% CI 0.297, 0.521) (p < 0.000001)]. The objective response rate by third-party independent review was 24.8% (95% CI 19.7, 30.5) for sunitinib vs. 4.9% (95% CI 2.7, 8.1) for IFN-α (p < 0.000001). The objective response rate by investigator assessment was 35.7% (95% CI 30.9, 40.8) for sunitinib vs. 8.8% (95% CI 6.1, 12.1) for IFN-α (p < 0.000001). 632 pts (85%) are alive, with 49 deaths on sunitinib arm and 65 deaths on IFN-α arm. 8% withdrew from the study due to adverse event on sunitinib arm vs. 13% on IFN-α arm. Conclusions: These results demonstrate a statistically significant improvement in PFS and objective response rate for sunitinib over IFN-α in first-line treatment of pts with mRCC. [Table: see text]
A randomized phase III trial in patients with advanced adenocarcinoma of the stomach receiving first-line chemotherapy with fluorouracil, leucovorin and oxaliplatin (FLO) versus fluorouracil, leucovorin and cisplatin (FLP)
Authors: Al-Batran S. , Hartmann J. T. , Probst S. , Hofheinz R. , Stoehlmacher J. , Schmalenberg H. , Hollerbach S. , Schuch G. , Homann N. , Jäger E. 
Published: March 2020

LBA4016 Background: Cisplatin-based chemotherapy is a standard option in advanced gastric cancer. However, treatment results have been unsatisfactory so far, with a time to progression (TTP) of 3 to 4 months and an overall survival (OS) of 6 to 9 months. In addition, treatment regimens are too intense and toxicity is considerable. The aim of this 2-arm randomized trial was to determine whether FLO prolongs TTP and reduces toxicity as compared to FLP. Methods: Patients (pts) were randomized to receive FLO: F 2600 mg/m2 24 h infusion, L 200 mg/m2, and oxaliplatin 85 mg/m2, every two weeks or FLP: F 2000 mg/m2 24 h infusion, L 200 mg/m2, weekly, and cisplatin 50 mg/m2, every two weeks. The primary end point was TTP. Main secondary endpoints included toxicity, time to treatment failure (TTF), and OS. Based on a planned sample size of 218 pts, the trial was designed to have an 80% power to detect an improvement in median TTP from 3.5 to 5.0 months (1-sided log-rank test; significance level 0.05). Results: 220 pts (FLO/FLP, 112/108) were randomized between Aug 2003 and Jan 2006. Median age was 64 yrs and median ECOG was 1. 162 pts (FLO, 80; FLP, 81) had disease progression and 25 pts (FLO, 18; FLP, 8) are still under treatment. Median TTP was 5.7 months for FLO and 3.8 months for FLP (log-rank p = 0.081, Wilcoxon p = 0.019). Median TTF was 5.3 months for FLO and 3.1 months for FLP (log-rank p = 0.028). Response to FLO (34%) was superior to FLP (27%), with 15% and 30% of pts having disease progression as best response to FLO and FLP, respectively (chi-square for trend p = 0.012). Median treatment duration was 4.3 months with FLO and 3 months with FLP. FLO was associated with significantly less NCI-CTC grade 1–4 leukopenia, nausea, alopecia, fatigue, and renal toxicity and FLP was associated with significantly less peripheral neuropathy (chi-square for trend p < 0.05). Severe adverse events related to treatment were less frequent with FLO (8.9%) as compared to FLP (18.6%; p = 0.046). Conclusions: FLO reduced toxicity and improved efficacy as compared to FLP. This leads us to consider FLO for future studies in combination with targeted drugs to further improve the outcome of pts with gastric cancer. No significant financial relationships to disclose.
Randomized phase III trial of capecitabine/cisplatin (XP) vs. continuous infusion of 5-FU/cisplatin (FP) as first-line therapy in patients (pts) with advanced gastric cancer (AGC): Efficacy and safety results
Authors: Kang Y. , Kang W. K. , Shin D. B. , Chen J. , Xiong J. , Wang J. , Lichinitser M. , Philco M. , Suarez T. , Santamaria J. 
Published: March 2020

LBA4018 Background: The oral fluoropyrimidine capecitabine has proven efficacy and safety in colorectal and breast cancer. Phase II data in AGC suggested that XP would show comparable efficacy to a standard FP regimen, with potential safety and convenience advantages. This phase III study evaluated XP vs. FP in first-line AGC. Methods: Pts with previously untreated measurable AGC received either oral capecitabine (1000mg/m2 bid d1–14) + cisplatin (80mg/m2 i.v. d1) q3w (XP arm) or 5-FU (800mg/m2/d continuous infusion, d1–5) + cisplatin (80mg/m2 i.v. d1) q3w (FP arm). XP requires 1 day per 3 weeks in hospital; FP requires 5 days. Pts were treated until disease progression or unacceptable toxicity. Primary endpoint: non-inferiority (NI) in progression-free survival (PFS), defined as upper limit of 95% CI of hazard ratio (HR) <1.4 (first test) and <1.25 (second test). Results: From Apr 03 to Jan 05, 316 pts were enrolled in 46 centers/13 countries. Arms were well balanced: median age (years, range) XP (56, 26–74), FP (56, 22–73); median Karnofsky PS 80 (range 70–100) in both arms; male/female (%): XP (64/36) FP (69/31). Median no. of cycles was 5 (XP and FP). Median follow-up is 22.1 months. Primary endpoint was met: HR 0.81 (95% CI 0.63–1.04). XP was superior to FP in terms of overall response rate (ORR, RECIST). Efficacy is presented in the table. Most common treatment-related grade 3/4 adverse events (XP vs. FP) were: neutropenia (16 vs. 19%), vomiting (7 vs. 9%), stomatitis (2 vs. 7%), diarrhea (5 vs. 5%), and anemia (5 vs. 3%). Other grade 3/4 events occurred in <5% of pts. The rate of all-grade hand-foot syndrome was low (22 vs. 4%). Conclusions: XP showed highly significant non-inferiority for PFS and significant superiority for ORR vs. FP with similar safety. These findings suggest that capecitabine should become the fluoropyrimidine of choice for AGC, given the efficacy, reduced hospitalization time and simplified regimen. No significant financial relationships to disclose. [Table: see text]
BIG 1–98: A randomized double-blind phase III study comparing letrozole and tamoxifen given in sequence vs. alone as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer
Authors: Mouridsen H. T. , Keshaviah A. , Mauriac L. , Forbes J. , Paridaens R. , Castiglione-Gertsch M. , Gelber R. , Smith I. , Thuerlimann B. , Goldhirsch A. 
Published: March 2020

LBA528 Background: The Primary Core Analysis (PCA) of BIG 1–98 comparing letrozole (L) to tamoxifen (T) as initial adjuvant endocrine therapy showed that L significantly prolonged disease-free survival (DFS), particularly reducing the risk of relapse in distant sites, compared with T for postmenopausal women with endocrine-responsive breast cancer (BC). The aim of the Second Primary Analysis (SPA) is to compare L and T given in sequence vs. alone. On Mar 15, ‘06, the Data Safety Monitoring Committee (DSMC) will review the results of the 2nd interim analysis of the SPA. We will present safety and efficacy data from this analysis if the DSMC recommends release of the results. Methods: 8028 women were randomized upfront to Tx5 years (yrs) (A), Lx5 (B), Tx2→Lx3 (C), or Lx2→Tx3 (D); 1835 to the 2-arm option of the study (arm A vs. B; Mar ’98 - Mar ‘00) and 6193 to the 4-arm option (arm A vs. B vs. C vs. D; Apr ’99 - May ‘03). The primary endpoint was DFS (time from randomization to first occurrence of invasive BC recurrence, invasive contralateral BC, second non-breast malignancy, or death from any cause). The SPA is comprised of two pair-wise comparisons: arm A vs. C and B vs. D. Only 4-arm patients (pts) alive and disease-free at 2 yrs after study entry (corresponding to the treatment switch for arms C and D) are included. These analyses will determine if the risk of an event beyond 2 yrs is reduced by switching agents. Additional exploratory analyses based on all events and follow-up (FU) for 4-arm pts will be conducted, including the comparison of arm B vs. C. The final SPA is planned for Feb ‘08, after 662 events. In Jan ‘05, the 1st interim efficacy analysis was presented to the DSMC, after 162 events among 3641 pts (excluding those who had an event within 2 yrs or did not yet have at least 2 yrs of FU). The median SPA FU (from 2 yrs after study entry) was 11.1 months. The 2nd interim efficacy analysis will be presented to the DSMC on Mar 15, ‘06 based on data received as of a Dec 21, ‘05. Results: Conclusions: No significant financial relationships to disclose.
The Women’s Health Initiative randomized trial of calcium plus vitamin D: Effects on breast cancer and arthralgias
Authors: Chlebowski R. T. , Johnson K. C. , Kooperberg C. , Hubbell A. , Lane D. , O’Sullivan M. , Cummings S. , Rohan T. , Yasmeen S. , Khandekar J. 
Published: March 2020

LBA6 Background: Calcium (Ca) and vitamin D (D) have been associated with reduced breast cancer and breast density in observational studies. Randomized trials have not evaluated Ca/D supplementation for breast cancer prevention. Methods: We randomized 36,282 postmenopausal women without prior breast cancer from 40 WHI centers to 1000 mg of elemental calcium as calcium carbonate and 400 IU of vitamin D3 (N = 18,176) daily or matching placebo (N = 18,106); 54% were also randomized one year previously to hormone therapy (HT) or placebo; conjugated equine estrogen (CEE) plus medroxyprogesterone acetate or CEE alone (the latter for those with prior hysterectomy). Ca/D effects on hip fracture and colorectal cancer have been reported (NEJM 2006). We report here pathologically confirmed invasive breast cancer as a secondary outcome of the Ca/D trial. Baseline serum 25(OH) D levels (in 1787 women) and serial joint symptoms (pain/stiffness and hand/feet swelling 0–3 scale, in a 6% sample) were also assessed. Results: Breast cancer incidence did not differ between Ca/D and placebo randomization groups (528 and 546 cases in Ca/D and placebo; hazard ratio 0.96; 95 percent confidence interval (CI), 0.85, 1.09). While SEER stage and abnormal mammogram frequency were similar between groups, breast cancers were smaller in the Ca/D group (1.54 cm (1.23), mean (SD) versus 1.71 (1.29), P = 0.05). Total vitamin D baseline intake was associated with lower breast cancer risk in the placebo group. Baseline vitamin D (nmol per liter) deficiency was common (≥30, sufficient (n = 266), 16 ≤ 30, insufficient (277), < 16, deficient (743)) but was not related to joint pain (seen in 72.2%, 74.0%, 74.6%, of sufficiency and deficiency groups, respectively). Joint symptoms were lower in women randomized to CEE alone (P < 0.01) but did not significantly differ by Ca/D group assignment and no significant interactions were seen between HT and Ca/D. Conclusion: Among healthy postmenopausal women, Ca/D supplementation did not reduce breast cancer risk but the cancers in those randomized to Ca/D were somewhat smaller. Exogenous estrogen use but not Ca/D supplementation influences arthralgias. [Table: see text]
Why Shakespeare? Irony and Liberalism in Canonization
Authors: Wilson Jeffrey R. 
Published: March 2020

AbstractWhen scholars consider Shakespeare’s rise and lasting popularity in modern culture, they usually tell us how he assumed his position at the head of the canon but not why. This essay contends that Shakespeare’s elevation in the early nineteenth century resulted from the confluence of his strategy as an author and the political commitments of his canonizers. Specifically, Shakespeare’s ironic mode made his drama uniquely appealing to the political liberals at the forefront of English culture. In their own ways, Shakespeare and his proponents were antiauthoritarian: the literary antiauthoritarianism in his drama (the irony granting audiences the freedom of interpretation) perfectly matched the political antiauthoritarianism (liberalism) advocated by the likes of Adam Smith and John Stuart Mill. Thus it is possible to speak of bardolatry as an allegorical intertext for liberal politics.
Four Narratives and the Enigma of Alterity
Authors: Rassendren Etienne 
Published: March 2020

In this article, the author intends to explore the concept of alterity as otherness through an analysis of four highly differentiated narratives drawn from varied textual sources. The paper argues that alterity is depicted in four different and fluid meanings, namely those of separation, difference, assimilation and co-option, constituting enigmas of alterity. In conclusion, the author comments on the cultural-political process, by which these enigmatic constructs are produced and identifies and explains coercion and consent as the hegemonic impetus for its unfolding presence in current cultural-politics.
Keywords: Alterity and Otherness, Enigmas of Alterity, Assimilation and Co-option