Most have a self-limiting illness, but pregnant women have a mortality of 25%.3 There have been a number of large outbreaks of hepatitis E in Nepal, including one in 2014, which involved more than 10 ...000 cases.4 Earthquake-affected areas are faced with a "perfect storm" of risk factors: large displaced populations with limited access to clean drinking water, lack of sanitary facilities, the approaching monsoon, overburdened health-care infrastructure, large amounts of circulating hepatitis E virus (HEV), and an at-risk population who mostly lack protective antibodies (approximately 70% of the at-risk population lack protective anti-HEV IgG antibodies Basnyat B, unpublished).
During the 2010 school year, a study excavation was carried out on the grounds of the Alone Yizhaq youth village (Alonei Yitzhak; Permit No. A-5819; map ref. 200548-899/712911-3082). The excavation, ...undertaken by the Israel Antiquities Authority and underwritten by the youth village, was directed by D. Weinberger and D. Planer, with the assistance of A. Bachar (administration) and E. Kashi (education department, IAA Central District). The excavation was part of an archaeology study program for tenth graders.
במהלך שנת הלימודים 2010 נערכה חפירה לימודית בתחומי כפר הנוער אלוני יצחק (הרשאה מס' 5819-A; נ"צ 200548-899/712911-3082). החפירה, מטעם רשות העתיקות ובמימון כפר הנוער, נוהלה על ידי ד' ויינברגר וד' פלנר, בסיוע א' בכר (מנהלה) וע' קאשי (שלוחת חינוך מרחב מרכז). החפירה נערכה במסגרת תכנית לימודים בארכיאולוגיה לתלמידי כיתות י'.
In 2007, a study excavation was carried out on the grounds of Bet Guvrin National Park (Area 350; Permit No. A-5110; map ref. 190016-23/612972-82; Fig. 1), prior to the development. The excavation, ...undertaken by the Israel Antiquities Authority, was directed by M. Cohen, E. Klein and D. Weinberger. Fifth graders from schools in Netanya participated in the excavation.
במהלך שנת 2007 נערכה חפירה לימודית בתחומי הגן הלאומי בית גוברין (שטח 350; הרשאה מס' 5110-A; נ"צ 190016-23/612972-82; איור 1), לקראת פיתוח. החפירה, מטעם רשות העתיקות, נוהלה על ידי מ' כהן, א' קליין וד' ויינברגר. בחפירה השתתפו תלמידי כיתות ה' מבתי ספר בנתניה.
From 2005 to 2010, a series of study excavations was held in Tel Afeq (Afek) National Park (Permit nos. A-4455, A-4706, A-5034, A-5356, A-5594, A-5869; map ref. 193691/667793). The excavation, on ...behalf of the Israel Antiquities Authority and funded by the Israel Nature and Parks Authority, was directed by D. Weinberger, P. Gendelman, Y. Shlomo, E. Klein and G. Shaviv, with the assistance of E. Bachar (administration) M. Pielstöker (Israel Antiquities Authority Central District), T. Tsuk (Israel Nature and Parks Authority) and students (fourth graders).
בשנים 2005-2010 נערכה סדרה של חפירות לימודיות בתחומי גן לאומי תל אפק (הרשאות מס' 4455-A-5869 ,A-5594 ,A-5356 ,A-5304 ,A-4706 ,A; נ"צ 193691/667793). החפירות, מטעם רשות העתיקות ובמימון רשות הטבע והגנים הלאומיים, נוהלו על ידי ד' ויינברגר, פ' גנדלמן, י' שלמה, א' קליין וג' שביב, בסיוע א' בכר (מנהלה), מ' פיילשטוקר (מרחב מרכז), צ' צוק (רשות הטבע והגנים הלאומים) ותלמידים בכיתות ד'.
In March and April 2004-2006, study excavations were carried out beside the 'Chicago' Community Center in Park Ha-Shalom in the city of Lod (Permit nos. A-4277, A-4377, A-4708; map. Ref. ...190700/651330). The excavations, on behalf of the Israel Antiquities Authority and underwritten by the Lod municipality, were directed by D. Weinberger, Y. Shlomo and G. Shaviv, and assisted by A. Bachar (administration) and O. Shmueli (Israel Antiquities Authority Central District). Fourth graders from the city of Lod, taking a year-long course in archaeology, took part in an excavation day during the school year.
בחודשים מרס-אפריל 2004-2006 נערכו חפירות לימודיות לצד מרכז קהילתי 'שיקגו', סמוך לפארק השלום בלוד (הרשאות מס' 4277-A-4708 ,A-4377 ,A; נ"צ 190700/651330). החפירות, מטעם רשות העתיקות ובמימון עיריית לוד, נוהלו על ידי ד' ויינברגר, י' שלמה וג' שביב, בסיוע א' בכר (מנהלה) וא' שמואלי (מרחב מרכז). תלמידי כיתה ד' מהעיר לוד שלמדו ארכיאולוגיה בתכנית שנתית התנסו ביום חפירה במהלך שנת הלימודים.
During the 2006 and 2008-2013 school years, an educational excavation was conducted north of Caesarea National Park (Permits Nos. A-4780, A-5348, A-5611, A-5817, A-6291, A-6410, A-6743; map ref. ...19028-33/71227-32). The excavation, on behalf of the Israel Antiquities Authority, was directed by D. Weinberger, Y. Porath, P. Gendelman, C. Gur and S. Mahajna, with the assistance of E. Bachar (administration) and K. Sari, and the participation of fourth-graders from schools in the Hof Ha-Karmel Regional Council.
במהלך שנות הלימודים 2006, 2008-2013 נערכה חפירה לימודית/חינוכית מצפון לגן הלאומי קיסריה (הרשאות מס' 4780-A-6743 ,A-6410 ,A-6291 ,A-5817 ,A-5611 ,A-5348 ,A; נ"צ 19028-33/71227-32). החפירה, מטעם רשות העתיקות, נוהלה על ידי ד' ויינברגר, י' פורת, פ' גנדלמן, כ' גור וש' מחאג'נה, בסיוע א' בכר (מנהלה) וכ' סארי, והשתתפו בה תלמידי שכבות ד' בבתי ספר במועצה האזורית חוף הכרמל.
In November 2005, a study excavation was carried out at Ha-Gatot Park (The Winepresses Park) on Sprinzak Street in Rishon Le-Ziyyon (Permit No. A-4619; map ref. 180218/652458; Fig. 1), following ...inspection of infrastructure work prior to the installing a water pipe. The excavation, on behalf of the Israel Antiquities Authority and funded by the Rishon Le-Ziyyon municipality, was directed by D. Weinberger and E. Klein (field photography and coin identification), with the assistance of A. Hajian (surveying and drafting), L. Rauchberger and students from the Yadlin School.
בחודש נובמבר 2005 נערכה חפירה לימודית בגן הגתות שברחוב שפרינצק בראשון לציון (הרשאה מס' 4619-A; נ"צ 180218/652458; איור 1), בעקבות פיקוח על עבודת תשתית לקראת הנחת צנרת מים. החפירה, מטעם רשות העתיקות ובמימון עיריית ראשון לציון, נוהלה על ידי ד' ויינברגר וא' קליין (צילום שטח וזיהוי מטבעות), בסיוע א' האג'יאן (מדידות ושרטוט), ל' ראוכברגר ותלמידי בית ספר ידלין.
Cell-free DNA (cfDNA) tests are increasingly being offered to women in the first trimester of pregnancies at a high risk of trisomy 21 to decrease the number of required invasive fetal karyotyping ...procedures and their associated miscarriages. The effect of this strategy has not been evaluated.
To compare the rates of miscarriage following invasive procedures only in the case of positive cfDNA test results vs immediate invasive testing procedures (amniocentesis or chorionic villus sampling) in women with pregnancies at high risk of trisomy 21 as identified by first-trimester combined screening.
Randomized clinical trial conducted from April 8, 2014, to April 7, 2016, in 57 centers in France among 2111 women with pregnancies with a risk of trisomy 21 between 1 in 5 and 1 in 250 following combined first-trimester screening.
Patients were randomized to receive either cfDNA testing followed by invasive testing procedures only when cfDNA tests results were positive (n = 1034) or to receive immediate invasive testing procedures (n = 1017). The cfDNA testing was performed using an in-house validated method based on next-generation sequencing.
The primary outcome was number of miscarriages before 24 weeks' gestation. Secondary outcomes included cfDNA testing detection rate for trisomy 21. The primary outcome underwent 1-sided testing; secondary outcomes underwent 2-sided testing.
Among 2051 women who were randomized and analyzed (mean age, 36.3 SD, 5.0 years), 1997 (97.4%) completed the trial. The miscarriage rate was not significantly different between groups at 8 (0.8%) vs 8 (0.8%), for a risk difference of -0.03% (1-sided 95% CI, -0.68% to ∞; P = .47). The cfDNA detection rate for trisomy 21 was 100% (95% CI, 87.2%-100%).
Among women with pregnancies at high risk of trisomy 21, offering cfDNA screening, followed by invasive testing if cfDNA test results were positive, compared with invasive testing procedures alone, did not result in a significant reduction in miscarriage before 24 weeks. The study may have been underpowered to detect clinically important differences in miscarriage rates.
ClinicalTrials.gov Identifier: NCT02127515.
Background and aims
There is limited data regarding the role for systemic treatment in patients with Hepatocellular Carcinoma with Child–Pugh B cirrhosis.
Methods
PRODIGE 21 was a multicentric ...prospective non-comparative randomized trial. Patients were randomized to receive sorafenib (Arm A), pravastatin (Arm B), sorafenib–pravastatin (Arm C) combination, or best supportive care (Arm D). Primary endpoint was time to progression (TTP), secondary endpoints included safety and overall survival (OS).
Results
160 patients were randomized and 157 patients were included in the final analysis. 86% of patients were BCLC C and 55% had macrovascular invasion. The safety profiles of the drugs were as expected. Median TTP was 3.5, 2.8, 2.0 and 2.2 months in arms A, B, C and D, respectively, but analysis was limited by the number of patients deceased without radiological progression (59%). Median OS was similar between the four arms: 3.8 95% CI: 2.4–6.5, 3.1 95% CI: 1.9–4.3, 4.0 95% CI: 3.2–5.5 and 3.5 months 95% CI: 2.2–5.4 in arms A, B, C and D, respectively. Median OS was 4.0 months 95% CI: 3.3–5.5 for patients treated with sorafenib, vs 2.9 months 95% CI: 2.2–3.9 for patients not treated with sorafenib. In patients with ALBI grade 1/2, median OS was 6.1 months 95% CI: 3.8–8.3 in patients treated with sorafenib vs 3.1 months 95% CI: 1.9–4.8 for patients not treated with sorafenib.
Conclusion
In the overall Child–Pugh B population, neither sorafenib nor pravastatin seemed to provide benefit. In the ALBI grade 1/2 sub-population, our trial suggests potential benefit of sorafenib.
Clinical trial registration
The study was referenced in clinicaltrials.gov (NCT01357486).
Graphic abstract
State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin–paclitaxel or ...carboplatin–gemcitabine) or the most active non-bevacizumab regimen: carboplatin–pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin–pegylated liposomal doxorubicin combined with bevacizumab.
This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve AUC 4, day 1) plus gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251.
Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin–pegylated liposomal doxorubicin–bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin–gemcitabine–bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3–21·7) in the experimental group and 11·3 months (8·0–18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7–14·2) in the experimental group versus 11·6 months (11·0–12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68–0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 27% of 332 patients in the experimental group vs 67 20% of 329 patients in the standard group) and neutropenia (40 12% vs 73 22%). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage).
Carboplatin–pegylated liposomal doxorubicin–bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer.
F Hoffmann-La Roche.
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