bluuebunny/crossref_metadata_2025 huggingface dataset:
Six drugs induction chemotherapy for patients with localised Ewing sarcoma (ES): A pilot study
Authors: Palmerini E. , Bertoni F. , Mercuri M. , Barbieri E. , Longhi A. , Picci P. , Bacci G. , Ferrari S.
Published: March 2020

9537

Background: Vincristine (V), doxorubicin (A), cyclophosphamide (C), ifosfamide (I), actinomycin-D (Ac) and etoposide (E) are the standard drugs active against ES. Feasibility and efficacy of a six drugs induction treatment were investigated in a monoinstitutional study. Methods: Between March 1998 and May 1999, nonmetastatic ES aged ≤ 50 years were enrolled. Induction treatment: VAC (V 2 mg, A 80 mg/m2, C 1200 mg/m2, weeks 0 and 6), IVAc (I 9 g/m2, V 2 mg, Ac 2 mg, week 3), IE (I 9 g/m2, E 450 mg/m2, week 9). Local treatment, surgery whenever possible, was planned on week 12. Maintenance treatment: alternating courses of VAC-IVAc-IE (three times). In surgically treated patients, chemoinduced necrosis was evaluated and graded: grade III (complete necrosis), II (persistence of microfoci of viable tumor cells) and I (persistence of macrofoci of tumor cells). Results: 34 patients were enrolled; median age was 19 years (6–50); 22 were males and 12 females. Site: extremity 22 (65%), axial location 12 (35%). Despite a large use of G-CSF (94% of cycles), grade IV leukopenia was common (60% of cycles). Nevertheless, febrile neutropenia was observed in only 10.6% of cycles. Grade IV thrombocytopenia occurred in 12.5% of cycles. Platelet and red blood cell transfusions were required in 4% and 11% of cycles, respectively. No toxic deaths were recorded. Local treatment: surgery in 24 patients (70%), followed by post operative radiation (RT) in 6 of them; RT in 10 patients (30%). Chemoinduced necrosis was grade III in 29% of patients, grade II in 34% and grade I in 37%. With a median follow-up of 80 months (1–69) 5 years overall survival (OS) was 62%. 5 years Event free survival (EFS) was 56%. 5 years EFS according to site was: extremity 68%, axial location 33% (p < 0.02); according to local treatment was: surgery 61% (with RT 67%), RT 30% (p = 0.027); according to chemoinduced necrosis: grade III 86%, II 50%, I 55% (p = 0.26). Conclusions: The treatment is feasible. Surgery was possible in 70% of patients with a high cure rate for patients with a grade III chemoinduced necrosis.

No significant financial relationships to disclose.
Regression of chemotherapy-refractory metastatic tumor from CD117-negative prostate sarcoma with imatinib mesylate plus thalidomide
Authors: Kok V. C. , Yeh K. , Chang W.
Published: March 2020

9557

Background: Chemoresistant relapsing prostate sarcoma has no standard treatment and the prognosis is extremely poor. Imatinib mesylate may target on tyrosine kinases of platelet-derived growth factor receptor (PDGFR) which has been shown to be important in tumor growth of certain types of soft tissue sarcoma. Thalidomide, itself a potent immunomodulatory agent has exhibited clinical activity in several malignant neoplasms which have been linked to abnormal angiogenesis and tumor vasculature. Case Report: A 38-year-old man who underwent radical cystoprostatectomy in June 2004 for a stage III high-grade soft tissue sarcoma of spindle and round cell type of prostate staged pT2b(8cm) pN0(0/26) M0, received adjuvant radiotherapy up to 6,660 cGy/37Fx postoperatively. Immunohistochemistry study showed vimentin+, CD34+, CD117−, desmin+, SMActind- and S-100−. Distant relapse in lungs was noted in April 2005. Shortly later massive pleural effusion developed. Three cycles of salvage chemotherapy with MAID were given. Tumor assessment disclosed Progressive Disease status and metastatic tumors were chemoresistant. Imatinib mesylate 400 mg once a day plus thalidomide with increment dose to 200 mg/day was chosen as biologic treatment for his devastating condition after an informed consent was obtained. PDGFR immunohistochemistry staining of the paraffin block and gene sequencing are planned. Results: Marked tumor regression reaching very good partial remission and resolution of pleural effusion without recurrence. Dramatic improvement in terms of performance status and cancer-associated symptoms are obvious. Except for skin changes and mild periorbital edema from imatinib, no other significant adverse reactions were noted. Postulated mechanism of action may suggest PDGFR tyrosine kinase inhibition as well as antiangiogenesis. Conclusions: We documented a case of undifferentiated sarcoma of prostate with pulmonary metastases which were refractory to MAID chemotherapy but subsequently regressed on a combination of double biologic agents, imatinib mesylate plus thalidomide.

No significant financial relationships to disclose.
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

When 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.
Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial development
Authors: Ates Kristin M. , Wang Tong , Moreland Trevor , Veeranan-Karmegam Rajalakshmi , Ma Manxiu , Jeter Chelsi , Anand Priya , Wenzel Wolfgang , Kim Hyung-Goo , Wolfe Lynne A. , Stephen Joshi A. , Adams David R. , Markello Thomas , Tifft Cynthia J. , Settlage Robert , Gahl William A. , Gonsalvez Graydon B. , Malicdan May Christine , Flanagan-Steet Heather , Pan Y. Albert
Published: March 2020

A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain containing endocytic trafficking adaptor 1 and 2 (PHETA1/2, also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, pheta1 and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentations of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient.
Deterioration of muscle force and contractile characteristics are early pathological events in spinal and bulbar muscular atrophy mice
Authors: Gray Anna L. , Annan Leonette , Dick James R. T. , La Spada Albert R. , Hanna Michael G. , Greensmith Linda , Malik Bilal
Published: March 2020

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's Disease, is a late-onset, X-linked, progressive neuromuscular disease, which predominantly affects males. The pathological hallmarks of the disease are defined by selective loss of spinal and bulbar motor neurons, accompanied by weakness, atrophy and fasciculations of bulbar and limb muscles. SBMA is caused by a CAG repeat expansion in the gene that encodes the androgen receptor (AR) protein. Disease manifestation is androgen dependent and results principally from a toxic gain of AR function. There are currently no effective treatments for this debilitating disease. It is important to understand the course of the disease in order to target therapeutics to key pathological stages. This is especially relevant in disorders such as SBMA, where disease can be identified prior to symptom onset, through family history and genetic testing. To fully characterise the role of muscle in SBMA, we undertook a longitudinal physiological and histological characterisation of disease progression in the AR100 mouse model of SBMA. Our results show that the disease first manifests in skeletal muscle, prior to any motor neuron degeneration, which only occurs in late stage disease. These findings reveal alterations in muscle function, including reduced muscle force and changes in contractile characteristics, are early pathological events in SBMA mice and suggest that muscle-targeted therapeutics may be effective in SBMA.
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
Factores asociados a riesgo cardiovascular en estudiantes de bachillerato de un colegio público de la ciudad de Santiago de Cali, Colombia
Authors: Zorrilla-López Carmelina , Ceballos-Santacruz Juan David , Ramírez-Giraldo Christian Daniel , Patiño-Palma Brayan Esneider , Calero-Saa Pedro
Published: March 2020

Introducción: las enfermedades cardiovasculares son la principal causa de muerte en todo el mundo, lo que las convierte en un problema de interés en salud pública, tanto para países desarrollados, como en vías de desarrollo. La disminución del tiempo dedicado a la actividad física y el aumento de las actividades sedentarias son parte de los muchos factores de riesgo para las enfermedades cardiovasculares. El objetivo fue determinar los factores asociados al riesgo cardiovascular en los estudiantes de una institución educativa de la ciudad de Cali, Colombia. Materiales y métodos: estudio epidemiológico observacional y analítico, con una muestra de 227 estudiantes seleccionados de forma aleatoria, con una confiabilidad del 95%. Para determinar el nivel de actividad física en los escolares, se aplicó el cuestionario internacional de actividad física IPAQ; igualmente, se tomaron medidas antropométricas como peso, talla, perímetro de cintura y cadera. Resultados: el 96% de los participantes presentó riesgo cardiovascular bajo. Así mismo, las variables que mostraron una asociación estadísticamente significativa con el riesgo cardiovascular fueron el consumo de alcohol y el índice de masa corporal, los cuales predicen en un 81 % la posibilidad de tener riesgo. Conclusiones: prevaleció el bajo riesgo cardiovascular y el alto nivel de actividad física en los escolares evaluados, con diferencias significativas respecto al sexo. Los hombres presentan valores más altos en peso, talla y relación cintura/cadera en comparación con las mujeres. Se estableció que los factores asociados con el riesgo cardiovascular son el índice de masa corporal y el consumo de alcohol.
Alterações salivares, sintomas bucais e qualidade de vida relacionada à saúde bucal em pacientes com doenças neuromusculares
Authors: Alves Ferreira Andressa Kelly , Freitas Teixeira de Argôlo Isaura , Marques Soares Maria Sueli , Brito Pereira de Melo Ângelo
Published: March 2020

Introdução: o presente estudo teve como objetivo avaliar o fluxo salivar, sintomas bucais e a qualidade de vida relacionada à saúde bucal em um grupo de pacientes com doenças neuromusculares. Materiais e Métodos: estudo transversal realizado com 30 indivíduos com doenças neuromusculares atendidos no ambulatório de neuroreabilitação de um hospital universitário brasileiro entre outubro e dezembro de 2017. Foram realizados anamnese e determinação do Fluxo Salivar em Repouso e do pH salivar. Para avaliação da qualidade de vida relacionada à saúde bucal foi empregado o questionário Oral Health Impact Profile-14. Aplicou-se análise descritiva dos dados e teste qui-quadrado, adotando-se o nível de significância de 5 % (p <0.05). Resultados: a Esclerose Lateral Amiotrófica foi a doença de base mais preva- lente (50 %). A média de Fluxo Salivar em Repouso foi de 0.44 ± 0.34 ml/min, sendo verificado hiperfluxo em 43.3 % dos pacientes e hipossalivação em 3.3 %. A média do pH salivar foi 6.47 ± 0.57. Os sintomas orais mais frequentes foram disfagia (56.7 %) e xerostomia (43.3 %). A média do Oral Health Impact Profile-14 foi de 5.54 ± 4.93 e 90 % dos pacientes apresentaram algum impacto das condições bucais na qualidade de vida. Os sintomas de disfagia, xerostomia, ardência bucal e sialorreia apresentaram associação estatisticamente significante (p <0.05) com a qualidade de vida relacionada à saúde bucal. As dimensões do Oral Health Impact Profile-14 que apresentaram maiores percentuais foram a inabilidade psicológica (14.5 %) e a limitação funcional (13.5 %). Conclusão: a maioria dos pacientes apresentaram disfunção de glândulas salivares e a presença de sintomas bucais influenciaram negativamente a percepção de qualidade de vida dos indivíduos com doenças neuromusculares.
Prescriptive Analytics for Swapping Aircraft Assignments at All Nippon Airways
Authors: Venkatachalam Saravanan , Acharya Suresh , Oba Kenji , Nakayama Yoshinari
Published: March 2020

The authors describe the implementation of a swapper optimization suite (SOS) for All Nippon Airways. SOS uses optimization models to generate optimal swaps of flight legs among different equipment types for the allotted fleet assignments. All Nippon Airways has integrated SOS into its information systems to incorporate optimization into its decision-making process.
Competitive Personalized Pricing
Authors: Chen Zhijun , Choe Chongwoo , Matsushima Noriaki
Published: March 2020

We study a model where each competing firm has a target segment where it has full consumer information and can exercise personalized pricing, and consumers may engage in identity management to bypass the firm’s attempt to price discriminate. In the absence of identity management, more consumer information intensifies competition because firms can effectively defend their turf through targeted personalized offers, thereby setting low public prices offered to nontargeted consumers. But the effect is mitigated when consumers are active in identity management because it raises the firm’s cost of serving nontargeted consumers. When firms have sufficiently large and nonoverlapping target segments, identity management can enable firms to extract full surplus from their targeted consumers through perfect price discrimination. Identity management can also induce firms not to serve consumers who are not targeted by either firm when the commonly nontargeted market segment is small. This results in a deadweight loss. Thus, identity management by consumers can benefit firms and lead to lower consumer surplus and lower social welfare. Our main insight continues to be valid when a fraction of consumers are active in identity management or when there is a cost of identity management. We also discuss the regulatory implications for the use of consumer information by firms as well as the implications for management.

This paper was accepted by Juanjuan Zhang, marketing.
Relational Contracts and Managerial Delegation: Evidence from Foreign Entrepreneurs in Russia
Authors: Kulchina Elena , Oxley Joanne
Published: March 2020

We examine the managerial delegation decisions of foreign entrepreneurs and assess how these decisions are shaped by characteristics of the local product and labor market environment. We argue that actual or perceived home bias in court proceedings leads foreign entrepreneurs to place little reliance on formal contracts in their dealings with local agent-managers. Adopting the lens of relational contract theory, we develop hypotheses linking managerial delegation decisions to market conditions associated with stable self-enforcing agreements and test the hypotheses in the context of post-Soviet Russia. Consistent with our arguments, we find that foreign entrepreneurs are more likely to hire an agent-manager in local markets where industry growth creates a substantial “shadow of the future,” where managers’ outside employment options are relatively limited, and where competition and the variability of returns are not so high as to induce defection from an informal agreement. Similar observations on a sample of Russian-owned entrepreneurial firms suggest that these delegation decisions are relatively insensitive to local market conditions but that they are influenced by the density of local reputation networks. Our study thus contributes to understanding of the distinctive features of foreign entrepreneurs’ managerial delegation decisions and reinforces the view that contracting impediments constitute one important aspect of the “liability of foreignness” for entrepreneurial firms.
A Heuristic Branch-Cut-and-Price Algorithm for the ROADEF/EURO Challenge on Inventory Routing
Authors: Absi Nabil , Cattaruzza Diego , Feillet Dominique , Ogier Maxime , Semet Frédéric
Published: March 2020

This paper is part of the special section devoted to the ROADEF/EURO challenge on inventory routing. We propose an extended formulation that we address with a heuristic branch-cut-and-price method. Among the difficulties that we had to face are a fractional objective function, the simultaneous generation of constraints and columns, and a complex pricing problem. We evaluate our approach on the benchmark instances proposed for the challenge.
Knowledge, evidence, expertise? The epistemics of experience in contemporary healthcare
Authors: Mazanderani Fadhila , Noorani Tehseen , Dudhwala Farzana , Kamwendo Zara Thokozani
Published: March 2020

This paper explores how personal experience acquires the status of knowledge and/or evidence in contemporary healthcare contexts that emphasise being both patient-centred and evidence-based. Drawing on a comparative analysis of three case studies – self-help and mutual aid groups; online patient activism; and patient feedback in healthcare service delivery – we foreground: a) the role that different technologies and temporalities play in how experience is turned (or fails to be turned) into knowledge or evidence; b) the role that experts-of-experience, in addition to the more frequently referenced experts-by-experience, play in mediating how, when and why experience is turned into an epistemic resource; and finally, c) how the need to be ‘evidence-based’ remains a persistent, yet at times productive, challenge to how patient and user experiences are incorporated in contemporary healthcare policy and practice. Throughout the paper, we argue that it is necessary to look at both democratic and epistemic imperatives for including patient and service users in healthcare services and policymaking based on their experience.
Linear and nonlinear temperature-dependent transmission/absorption characteristics of cadmium telluride crystal for terahertz generation
Authors: Kumari Archana , Chaudhary A. K. , Venkatesh M.
Published: March 2020

This paper reports on the temperature-dependent investigation of linear
and nonlinear transmission/absorption characteristics of CdTe crystal
in the 300–408 K range using 780–970 nm tunable wavelengths of 140 fs
pulses obtained from a Ti:Sapphire laser at 80 MHz repetition rate.
The same pulses were also used for terahertz generation. The linear
transmission/absorption properties were measured using a specially
improvised temperature-tuned spectrophotometer in the 500–1500 nm
wavelength range. The linear absorption of 750 nm wavelength gradually
increases with respect to a rise in the temperature, and transmission
becomes zero at 408 K. Nonlinear absorption induced by femtosecond
pulses shows a sudden drop of 18% in transmission above the 800 nm
range, due to electron–phonon interaction, which affects the strength
of the terahertz signal. It is also responsible for change in the
temperature along with the linear shift in the refractive index of the
crystal.
Impact of coherence length on the field of view in dark-field holographic microscopy for semiconductor metrology: theoretical and experimental comparisons
Authors: Messinis Christos , Tenner Vasco T. , De Boer Johannes F. , Witte Stefan , den Boef Arie
Published: March 2020

Semiconductor manufacturers continue to increase the component densities on computer chips by reducing the device dimensions to less than 10 nm. This trend requires faster, more precise, and more robust optical metrology tools that contain complex and high-precision optics with challenging imaging requirements. Here, we present dark-field digital holographic microscopy as a promising optical metrology technique that uses optics with acceptable complexity. A theoretical analysis and an experimental demonstration of this technique are presented, showing the impact of the coherence length of the light source on the field of view. Finally, we also present the first holographically obtained images of metrology targets.
Geometrical and physical optics analysis for mm-wavelength refractor telescopes designed to map the cosmic microwave background
Authors: Gudmundsson Jon E.
Published: March 2020

We present a compact two-lens high-density polyethylene (HDPE)

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refractor design that is capable of supporting a 28-deg diffraction-limited field of view at 1-mm wavelengths and contrast it to a similar two-lens refractor using silicon lenses. We compare the optical properties of these two systems as predicted by both geometrical and physical optics. The presented analysis suggests that by relaxing telecentricity requirements, a plastic two-lens refractor system can be made to have a surprisingly large field of view. Furthermore, this HDPE system is found to perform comparably to a similar silicon system across a wide field of view and wavelengths up to 1 mm. We show that for both telescope designs, cold stop spillover changes significantly across the field of view in a way that is somewhat inconsistent with Gaussian beam formalism and simple

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-number scaling. We present results that highlight beam ellipticity dependence on both pixel location and pixel aperture size—an effect that is challenging to reproduce in standard geometrical optics. We show that a silicon refractor design suffers from larger cross-polarization compared to the HDPE design. Our results address the limitations of relying solely on geometrical optics to assess relative performance of two optical systems. We discuss implications for future refractor designs.
Robotic microscopy for everyone: the OpenFlexure microscope
Authors: Collins Joel T. , Knapper Joe , Stirling Julian , Mduda Joram , Mkindi Catherine , Mayagaya Valeriana , Mwakajinga Grace A. , Nyakyi Paul T. , Sanga Valerian L. , Carbery Dave , White Leah , Dale Sara , Jieh Lim Zhen , Baumberg Jeremy J. , Cicuta Pietro , McDermott Samuel , Vodenicharski Boyko , Bowman Richard
Published: March 2020

Optical microscopes are an essential tool for both the detection of disease in clinics, and for scientific analysis. However, in much of the world access to high-performance microscopy is limited by both the upfront cost and maintenance cost of the equipment. Here we present an open-source, 3D-printed, and fully-automated laboratory microscope, with motorised sample positioning and focus control. The microscope is highly customisable, with a number of options readily available including trans- and epi- illumination, polarisation contrast imaging, and epi-florescence imaging. The OpenFlexure microscope has been designed to enable low-volume manufacturing and maintenance by local personnel, vastly increasing accessibility. We have produced over 100 microscopes in Tanzania and Kenya for educational, scientific, and clinical applications, demonstrating that local manufacturing can be a viable alternative to international supply chains that can often be costly, slow, and unreliable.