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Current standard of care for metastatic castration-sensitive prostate cancer supplements androgen deprivation therapy with either docetaxel, second-generation hormonal therapy, or radiotherapy. We aimed to evaluate the efficacy and safety of abiraterone plus prednisone, with or without radiotherapy, in addition to standard of care. We conducted an open-label, randomised, phase 3 study with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Belgium, France, Ireland, Italy, Romania, Spain, and Switzerland. Eligible patients were male, aged 18 years or older, with histologically confirmed or cytologically confirmed de novo metastatic prostate adenocarcinoma, and an Eastern Cooperative Oncology Group performance status of 0–1 (or 2 due to bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen deprivation therapy alone or with intravenous docetaxel 75 mg/m2 once every 3 weeks), standard of care plus radiotherapy, standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), or standard of care plus radiotherapy plus abiraterone. Neither the investigators nor the patients were masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival. Abiraterone efficacy was first assessed in the overall population and then in the population who received androgen deprivation therapy with docetaxel as standard of care (population of interest). This study is ongoing and is registered with ClinicalTrials.gov, NCT01957436. Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled (one patient subsequently withdrew consent for analysis of his data) and assigned to receive standard of care (n=296), standard of care plus radiotherapy (n=293), standard of care plus abiraterone (n=292), or standard of care plus radiotherapy plus abiraterone (n=291). Median follow-up was 3·5 years (IQR 2·8–4·6) for radiographic progression-free survival and 4·4 years (3·5–5·4) for overall survival. Adjusted Cox regression modelling revealed no interaction between abiraterone and radiotherapy, enabling the pooled analysis of abiraterone efficacy. In the overall population, patients assigned to receive abiraterone (n=583) had longer radiographic progression-free survival (hazard ratio [HR] 0·54, 99·9% CI 0·41–0·71; p<0·0001) and overall survival (0·82, 95·1% CI 0·69–0·98; p=0·030) than patients who did not receive abiraterone (n=589). In the androgen deprivation therapy with docetaxel population (n=355 in both with abiraterone and without abiraterone groups), the HRs were consistent (radiographic progression-free survival 0·50, 99·9% CI 0·34–0·71; p<0·0001; overall survival 0·75, 95·1% CI 0·59–0·95; p=0·017). In the androgen deprivation therapy with docetaxel population, grade 3 or worse adverse events occurred in 217 (63%) of 347 patients who received abiraterone and 181 (52%) of 350 who did not; hypertension had the largest difference in occurrence (76 [22%] patients and 45 [13%], respectively). Addition of abiraterone to androgen deprivation therapy plus docetaxel did not increase the rates of neutropenia, febrile neutropenia, fatigue, or neuropathy compared with androgen deprivation therapy plus docetaxel alone. Combining androgen deprivation therapy, docetaxel, and abiraterone in de novo metastatic castration-sensitive prostate cancer improved overall survival and radiographic progression-free survival with a modest increase in toxicity, mostly hypertension. This triplet therapy could become a standard of care for these patients. Janssen-Cilag, Ipsen, Sanofi, and the French Government.

The 2 × 2 PEACE-1 study showed that combining androgen-deprivation therapy with docetaxel and abiraterone improved overall and radiographic progression-free survival in patients with de novo metastatic castration-sensitive prostate cancer. We aimed to examine the efficacy and safety of adding radiotherapy in this population. We conducted an open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design (PEACE-1) at 77 hospitals across Europe. Eligible participants were male patients (aged ≥18 years) with de novo metastatic castration-sensitive prostate cancer confirmed by bone scan, CT, or MRI, and an Eastern Cooperative Oncology Group performance status of 0–1 (or 2 in the case of bone pain). Participants were randomly assigned (1:1:1:1) to standard of care (androgen-deprivation therapy alone or with six cycles of intravenous docetaxel 75 mg/m2 every 3 weeks), standard of care plus abiraterone (oral 1000 mg abiraterone once daily plus oral 5 mg prednisone twice daily), standard of care plus radiotherapy (74 Gy in 37 fractions to the prostate), or standard of care plus radiotherapy and abiraterone. Participants and investigators were not masked to treatment allocation. The coprimary endpoints were radiographic progression-free survival and overall survival, analysed by intention to treat in patients with low-volume metastatic disease and in the overall study population. This ongoing study is registered with EudraCT, 2012-000142-35. Between Nov 27, 2013, and Dec 20, 2018, 1173 patients were enrolled and 1172 were randomly assigned to receive standard of care (n=296 [25·3%]), standard of care plus abiraterone (n=292 [24·9%]), standard of care plus radiotherapy (n=293 [25·0%]), and standard of care plus abiraterone and radiotherapy (n=291 [24·8%]). Median follow-up was 6·0 years (IQR 5·1–7·0) at the time of radiographic progression-free survival and overall survival analysis. A qualitative interaction between radiotherapy and abiraterone for radiographic progression-free survival in the population of patients with low-volume disease prevented the pooling of intervention groups for analysis (p=0·026). Adding radiotherapy to standard of care improved radiographic progression-free survival in patients with low-volume disease treated with abiraterone (median 4·4 years [99·9% CI 2·5–7·3] in the standard of care plus abiraterone group vs 7·5 years [4·0–not reached] in the standard of care plus abiraterone and radiotherapy group; adjusted hazard ratio [HR] 0·65 [99·9% CI 0·36–1·19]; p=0·019), but not in patients not treated with abiraterone (median 3·0 years [99·9% CI 2·3–4·8] in the standard of care group vs 2·6 years [1·7–4·6] in the standard of care plus radiotherapy group; 1·08 [0·65–1·80]; p=0·61). For overall survival, the predefined threshold for a statistical interaction was not reached (p=0·12); therefore, the two intervention groups receiving radiotherapy were pooled together for analysis. In patients with low-volume disease, the overall survival was not influenced by radiotherapy (median 6·9 years [95·1% CI 5·9–7·5] for standard of care with or without abiraterone vs 7·5 years [6·0–not reached] for standard of care plus radiotherapy with or without abiraterone; HR 0·98 [95·1% CI 0·74–1·28]; p=0·86). In the overall safety population, 339 (56·1%) of 604 patients who did not receive radiotherapy and 329 (58·8%) of 560 patients who received radiotherapy developed at least one severe adverse event (grade ≥3), the most common being hypertension (110 [18·2%] patients in the standard of care with or without abiraterone group and 127 [22·7%] in the standard of care plus radiotherapy with or without abiraterone group) and neutropenia (40 [6·6%] and 29 [5·2%]). Combining radiotherapy with standard of care plus abiraterone improves radiographic progression-free survival and castration resistance-free survival, but not overall survival in patients with low-volume de novo metastatic castration-sensitive prostate cancer. Radiotherapy reduces the occurrence of serious genitourinary events, regardless of metastatic burden and without increasing the overall toxicity, and could become a component of standard of care in patients with both high-volume and low-volume de novo metastatic castration-sensitive prostate cancer. Janssen-Cilag, Ipsen, Sanofi, and Institut National du Cancer.

The “Great Recession” of 2007 created havoc in the homebuilding industry, more than any other previous economic down cycle. Countless seasoned local homebuilders across the country did not survive. The impact of their failure on the economy, community, employment, lenders, suppliers, and subcontractors was devastating. While previous studies have sought to identify the symptoms and causes of business failure, very little research has been done on home builder business failure due to acts, omissions, characteristics, or other events which are non-financial. Specifically, those that are attributable to the failed entities' top management and leadership during the housing crisis and the Great Recession. Therefore, the purpose of this qualitative inquiry is to uncover those nonfinancial factors and help to fill the gap in the literature. Additionally, we seek to find specific strategies that could be incorporated into the business models of local homebuilders which allow them to anticipate and navigate turbulent economic times. The ultimate goal of such strategies, however, is to shield the organizations of those builders from the negative effects of recessions and allow them to thrive in the aftermath.

Background According to the Catalogue of Transmission Genetics in Arabs, less than half of diseases reported in Lebanese patients are mapped. In the recent years, Next Generation Sequencing (NGS) techniques have significantly improved clinical diagnosis, compared to traditional sequencing methods. Methods A total of 213 analyses by NGS (167 by whole exome sequencing (WES) and 46 by multigene panels tests) were performed on pediatric patients across different regions of Lebanon over a period of two years (December 2015–December 2017). Results Neurological disorders were the most frequent referral demand for both WES and gene panels (122/213). Pathogenic, likely pathogenic, or variants of unknown significance were identified in 69.5% of the WES and panel patients combined. Over half of the patients with such variants had an autosomal recessive disorder. A definite molecular diagnosis (pathogenic or likely pathogenic variants) was achieved in 34.1% and 47.8% of the patients studied by WES and the multigene panels, respectively. Thirty‐three novel variants were found in the cases that were molecularly solved; 26 of these being identified by WES and seven by the multigene panels. In three consanguineous families, autosomal recessive inheritance of genes previously reported as showing dominant inheritance patterns were found. Biallelism was found in six cases, digenism in four cases, and one case was trigenic. Conclusion Our study thus suggests that NGS tools are valuable for an improved clinical diagnosis, and highlights that the increased adoption of such techniques will significantly further improve our understanding of the genetic basis of inherited diseases in Lebanon. We present the results of a study which included a total of 213 analyses by NGS . Thirty‐three novel variants were found in the cases that were molecularly solved; and autosomal recessive inheritance of genes previously reported as showing dominant inheritance patterns were found.

Dravet syndrome, also known as severe myoclonic epilepsy in infancy, is a rare disease characterized by the appearance of different types of seizures in a healthy baby, triggered by various factors and stressful events. We report 8 Lebanese cases referred for molecular analysis of the SCN1A gene. Results were positive in 7 cases and revealed de novo variants at the heterozygous state in different exons of the gene for all except one, where the variant was intronic. Four variants were novel. Confirmation of Dravet syndrome is important for a better follow-up and treatment, preventing the occurrence of status epilepticus and severe neurological deterioration.