Cabazitaxel shows a consistently greater survival benefit compared to mitoxantrone in patients with mCRPC

Cel. Niniejsza analiza — wtórna do badania TROPIC — ma na celu ocenę czasu przeżycia całkowitego (overall survival, OS) po zastosowaniu kabazytakselu w podgrupach chorych, u których od początku nie uzyskano odpowiedzi na docetaksel (D) i odstawiono docetaksel D z powodu progresji choroby, oraz u chorych, u których uzyskano początkowo odpowiedź na D, lecz u których wystąpiła progresja nowotworu w czasie < 3 miesiące od ostatniej dawki D. U takich pacjentów uzyskanie korzyści z ponownego leczenia D jest mało prawdopodobne, dlatego też potrzebują oni nowych opcji terapeutycznych, takich jak kabazytaksel. Metody. Z 755 chorych z przerzutami raka gruczołu krokowego opornego na kastrację (metastatic castration-resistant prostate cancer, mCRPC), włączonych do badania TROPIC, u 362 (47,9%) nie zaobserwowano początkowej odpowiedzi na D i przerwano jego podawanie. U 155 (20,5%) — w ocenie badacza — obserwowano początkowo od­powiedź na leczenie D, lecz wystąpiła progresja w czasie < 3 miesiące od ostatniej dawki D, a 238 (31,5%) nie należało do żadnej z tych podgrup. Wszystkich pacjentów zrandomizowano do grup otrzymujących kabazytaksel w dawce 25 mg/m2 lub mitoksantron w dawce 12 mg/m2 podawanych dożylnie co 3 tygodnie oraz prednizon, przyjmowany doustnie w dawce 10 mg/dzień. Wyniki. W każdej z podgrup mediana czasu przeżycia całkowitego (OS) dla chorych otrzymujących kabazytaksel była zawsze większa niż w grupie otrzymującej mitoksantron. Największą korzyść wydłużenia czasu przeżycia całkowitego w porównaniu z grupą otrzymującą mitoksantron obserwowano w podgrupie chorych, u których początkowo zaob­serwowano odpowiedź na D, a następnie progresję w czasie < 3 miesiące od ostatniej dawki D {mediana 15,7 miesiąca w porównaniu z 11,6 miesiąca, współczynnik ryzyka HR (hazard ratio) 0,52; 95% przedział ufności CI (confidence interval) [0,35–0,76]}. Mediana czasu przeżycia wolnego od progresji była także znacząco lepsza w tej podgrupie w porównaniu z grupą otrzymującą mitoksantron (2,6 miesiąca w porównaniu z 1,4 miesiąca, HR 0,66 (0,48–0,91). Wniosek. Kabazytaksel w skojarzeniu z prednizonem wykazuje konsekwentnie korzystniejsze działanie na czas prze­życia w porównaniu z leczeniem mitoksantronem w skojarzeniu z prednizonem w każdej z podgrup, w szczególności u chorych, u których zaobserwowano odpowiedź na D zastosowany w pierwszej linii i u których doszło do progresji w czasie < 3 miesiące od ostatniej dawki D, a także u chorych bez początkowej odpowiedzi na D, którzy przerwali jego przyjmowanie w celu kontroli progresji choroby.Aim. This sub analysis of TROPIC study evaluates overall survival (OS) under cabazitaxel in patients who had no initial response to docetaxel (D ) and discontinued D for disease progression and those who initially responded to D but experienced disease progression < 3 months since last D dose. These patients are believed unlikely to benefit from D re-treatment and need new treatment options such as cabazitaxel. Methods. Of the 755 patients with metastatic castration-resistant prostate cancer (mCRPC) enrolled in TROPIC study, 362 (47.9%) had no initial response to D and discontinued it for disease progression, 155 (20.5%) had an initial response to D therapy according to investigator judgment but progressed < 3 months since last D dose and 238 (31.5%) did not belong to these two subgroups. All patients were randomized to receive cabazitaxel 25 mg/m2 or mitoxantrone 12 mg/m2 both every 3 weeks and prednisone 10 mg per os daily. Results. Median OS with cabazitaxel was consistently longer than with mitoxantrone in all subgroups. The highest survival benefit versus mitoxantrone was observed for patients who initially responded to D and then progres­sed < 3 months since last D dose (median OS 15.7 versus 11.6 months, Hazard ratio (HR) 0.52 [95% CI 0.35–0.76]). Median PFS was also significantly improved in the latter subgroup compared to mitoxantrone (2.6 versus 1.4 months, HR 0.66 [0.48–0.91]). Conclusion. Cabazitaxel plus prednisone consistently shows a greater survival benefit compared to mitoxantrone plus prednisone whatever the subgroup considered, including responders to first-line D who progressed < 3 months since last D and pts without initial response to D who discontinued it for disease progression

Citizen views on wood as a construction material: results from seven European countries

Multi-story wooden buildings are hailed as a favorable means toward reducing the embodied energy of the construction sector. However, the sector's path- dependent nature hinders acceptance of using wood in multi-story construction. As a result, research predominantly focuses on examining the perceptions of construction professionals to identify means of breaking the path dependency. We propose using citizens' perceptions about the use of wood to inform professional decision makers. Our research thus aims to answer two questions: What are citizens' perceptions about using wood as a construction material, and are there country-based cultural differences between these perceptions? To elicit this spectrum of citizen views, an online survey was deployed in Austria, Denmark, Finland, Germany, Norway, Sweden, and the United Kingdom. Qualitative content analysis was used to analyze 6633 open-ended responses to the survey. Respondents held multi-faceted opinions about the physical properties, environmental, social, and economic aspects of using wood as a construction material. Citizens from Finland, Norway, and Sweden expressed discernably different perspectives about the acceptability of using wood than did citizens from Austria, Denmark, Germany, and the United Kingdom. Overall, respondents from all countries expressed high approval for the use of wood in construction.Peer reviewe

Inhibition of STAT3 prevents bone metastatic progression of prostate cancer in vivo

Background: Prostate cancer (PC) metastasizes to the skeleton forming predominantly sclerotic lesions, and there is currently no cure for bone metastatic disease. The transcription factor signal transducer and activator of transcription 3 (STAT3) is implicated as a metastatic driver, but its potential as therapeutic target in bone metastasis has not been investigated. In this study, we evaluated for the first time a STAT3 inhibitor, Napabucasin, as a therapeutic option for bone metastatic PC.Methods: Effects of STAT3 inhibitors, Stattic and Napabucasin, on metastatic potential in PC cells were studied in vitro by assessment of migration capacity, self-renewal potential, and tumorsphere formation. For evaluation of the role of STAT3 in initial skeletal establishment of PC cells as well as in progressed castration-resistant PC (CRPC) in bone, human VCaP prostate cancer cells were inoculated in the tibia of mice which subsequently were treated with the STAT3 inhibitor Napabucasin. Bone specimens were analyzed using computed tomography (CT), immunohistochemistry, and quantitative polymerase chain reaction.Results: The small molecule STAT3 inhibitors Stattic and Napabucasin both effectively impaired metastatic potential of PC cells in vitro. Furthermore, treatment with Napabucasin prevented metastatic establishment in tibial bones in vivo and thereby also the tumor-induced sclerotic bone response seen in vehicle-treated VCaP xenografts. In addition, treatment with Napabucasin of established bone CRPC significantly decreased both tumor burden and tumor-induced trabecular bone volume compared with effects seen in vehicle-treated animals. Anti-mitotic effects were confirmed by decreased Ki67 staining in Napabucasin-treated xenografts compared with vehicle-treated xenografts. Alterations of gene expression in the femoral bone marrow (BM) niche toward the maintenance of hematopoietic stem cells and the myeloid lineage were demonstrated by quantitative real-time polymerase chain reaction and were further reflected by a substantial increase in the number of erythrocytes in BM of Napabucasin-treated mice. Furthermore, a unique pattern of STAT3 phosphorylation in osteoblasts/stromal cells surrounding the areas of tumor cells was demonstrated immunohistochemically in bone xenograft models using several different PC cell lines.Conclusion: Inhibition of STAT3 activity disrupts the bone metastatic niche and targets both the skeletal establishment of PC and advanced bone metastatic CRPC in mice, suggesting STAT3 as a candidate for molecular targeted therapies of skeletal metastatic disease.</div

Hematologic Safety of Radium-223 Dichloride: Baseline Prognostic Factors Associated With Myelosuppression in the ALSYMPCA Trial.

BACKGROUND: Myelosuppression is common in patients with progressive castration-resistant prostate cancer and bone metastases. Radium-223 prolongs overall survival in these patients but may cause myelosuppression; understanding risk factors will improve clinical decision making. We describe hematologic safety of radium-223 in ALSYMPCA and post hoc analyses identifying patients at increased risk for hematologic toxicity. PATIENTS AND METHODS: Hematologic parameters and adverse events were analyzed. Multivariate analyses assessing baseline risk factors for hematologic toxicities were performed separately for radium-223 and placebo patients. RESULTS: Nine hundred one patients received radium-223 (n = 600) or placebo (n = 301); 65% of radium-223 and 48% of placebo patients had the full 6 cycles. Grade 3/4 thrombocytopenia was more common in radium-223 versus placebo patients (6% vs. 2%). Logistic regression analyses identified significant baseline predictors for grade 2-4 hematologic toxicities related to radium-223 treatment: extent of disease (6-20 vs. < 6 bone metastases; odds ratio [OR] = 2.76; P = .022) and elevated prostate-specific antigen (OR = 1.65; P = .006) for anemia; prior docetaxel (OR = 2.16; P = .035), decreased hemoglobin (OR = 1.35; P = .008), and decreased platelets (OR = 1.44; P = .030) for thrombocytopenia. Neutropenia events were too few in placebo patients for a comparative analysis. There were no significant associations between hematologic toxicities and number of radium-223 injections received (4-6 vs. 1-3). CONCLUSION: Radium-223 has a favorable safety profile with a low myelosuppression incidence. Understanding baseline factors associated with myelosuppression may assist clinicians in avoiding severe myelosuppression events with radium-223

Expression of Androgen Receptor Splice Variants in Prostate Cancer Bone Metastases is Associated with Castration-Resistance and Short Survival

Background: Constitutively active androgen receptor variants (AR-V) lacking the ligand binding domain (LBD) may promote  the development of castration-resistant prostate cancer (CRPC). The expression of AR-Vs in the clinically most important metastatic site, the bone, has, however, not been well documented. Our aim was therefore to compare levels of AR-Vs in hormone-naive (HN) and CRPC bone metastases in comparison to primary PC and non-malignant prostate tissue, as well as in relation to AR protein expression, whole-genome transcription profiles and patient survival. Methodology/Principal Findings: Hormone-naı¨ve (n = 10) and CRPC bone metastases samples (n = 30) were obtained from  40 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomized men. Levels of full length AR (ARfl) and AR-Vs termed AR-V1, AR-V7, and AR-V567es mRNA were measured with RT-PCR and whole-genome transcription profiles with an Illumina Beadchip array. Protein levels were examined by Western blotting and immunohistochemistry. Transcripts for ARfl, AR-V1, and AR-V7 were detected in most primary tumors and metastases, and levels were significantly increased in CRPC bone metastases. The AR-V567es transcript was detected in 23% of the CRPC bone metastases only. A sub-group of CRPC bone metastases expressed LBD-truncated AR proteins at levels comparable to the ARfl. Detectable AR-V567es and/or AR-V7 mRNA in the upper quartile, seen in 1/3 of all CRPC bone metastases, was associated with a high nuclear AR immunostaining score, disturbed cell cycle regulation and short survival. Conclusions/Significance: Expression of AR-Vs is increased in CRPC compared to HN bone metastases and associated with a particularly poor prognosis. Further studies are needed to test if patients expressing such AR-Vs in their bone metastases benefit more from drugs acting on or down-stream of these AR-Vs than from therapies inhibiting androgen synthesis

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations

Voices at the Borders, Prose on the Margins : Exploring the Contemporary Pashto Short Story in a Context of War and Crisis

This dissertation is a study of contemporary Pashto prose writing in a context of war and crisis based on a corpus of digitally published and/or printed short stories from the 1990s onwards. Out of this larger corpus, 16 stories have been selected and analysed under four topics: "The Terrorist", Female agency: Representations of and by, "The Madman", and Axtar: Longing for peace or imaging disillusion. A central idea is that the analysis should be text-oriented, but the contextualisation of the analysed texts is a secondary important focus. Chapter one presents the material and gives a general context to the study. In the second chapter, after a general conceptualisation of the short story genre, I discuss the borders between prose and poetry. In chapter three I provide an overview of Pashto literature where the aim is to pinpoint certain characteristics of literature in what I call a poeticised community, such as that of the Pashtuns. The fourth chapter contains an introduction to the four topics mentioned above, a summary of each of the four stories belonging to the specific topic with selected parts in direct translation from the Pashto original, as well as a discussion of form and contents of each topic separately. Chapter five consists of a general conclusion. An appendix with the original Pashto text of translated sections is found before the bibliography. One feature that has emerged from this study is the notion of how the narratives are often found to communicate and respond to their immediate surroundings, in time as well as in space. Another important conclusion is that devices normally regarded as belonging to the realm of poetry are not uncommon in Pashto short story writing

Voices at the Borders, Prose on the Margins : Exploring the Contemporary Pashto Short Story in a Context of War and Crisis

This dissertation is a study of contemporary Pashto prose writing in a context of war and crisis based on a corpus of digitally published and/or printed short stories from the 1990s onwards. Out of this larger corpus, 16 stories have been selected and analysed under four topics: "The Terrorist", Female agency: Representations of and by, "The Madman", and Axtar: Longing for peace or imaging disillusion. A central idea is that the analysis should be text-oriented, but the contextualisation of the analysed texts is a secondary important focus. Chapter one presents the material and gives a general context to the study. In the second chapter, after a general conceptualisation of the short story genre, I discuss the borders between prose and poetry. In chapter three I provide an overview of Pashto literature where the aim is to pinpoint certain characteristics of literature in what I call a poeticised community, such as that of the Pashtuns. The fourth chapter contains an introduction to the four topics mentioned above, a summary of each of the four stories belonging to the specific topic with selected parts in direct translation from the Pashto original, as well as a discussion of form and contents of each topic separately. Chapter five consists of a general conclusion. An appendix with the original Pashto text of translated sections is found before the bibliography. One feature that has emerged from this study is the notion of how the narratives are often found to communicate and respond to their immediate surroundings, in time as well as in space. Another important conclusion is that devices normally regarded as belonging to the realm of poetry are not uncommon in Pashto short story writing