CLEOPATRA was a phase 3 study comparing the efficacy and safety of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast ...cancer. In the primary analysis and subsequent reports, progression-free and overall survival were significantly improved in the pertuzumab group compared with the placebo group. Here, we report the end-of-study analysis of CLEOPATRA.
This was a double-blind, randomised, placebo-controlled, phase 3 trial that was done at 204 centres in 25 countries. Eligible patients were 18 years or older, had HER2-positive, metastatic breast cancer, had not received previous chemotherapy or biological treatment for their metastatic disease, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. All study drugs were given intravenously, every 3 weeks. Patients were assigned to receive either pertuzumab or placebo at a loading dose of 840 mg, and 420 mg thereafter; plus trastuzumab at 8 mg/kg loading dose and 6 mg/kg thereafter; and docetaxel at 75 mg/m2, escalating to 100 mg/m2 if tolerated. Pertuzumab or placebo and trastuzumab were given until disease progression; docetaxel was given for six cycles, or longer at the investigators’ discretion. Randomisation (1:1) was done by use of an interactive voice-response system and was stratified by geographical region (Asia, Europe, North America, or South America) and previous treatment (previous adjuvant or neoadjuvant chemotherapy vs none). The primary endpoint was independent review facility-assessed progression-free survival, which has been reported previously. Since the confirmatory overall survival analysis had also occurred before this prespecified end-of-study analysis, analyses presented here are descriptive. Overall survival analyses were based on the intention-to-treat population with crossover patients analysed in the placebo group; analyses were not adjusted for crossover to the pertuzumab group and are likely to be conservative. Safety analyses were based on treatment received; crossover patients were counted in the placebo group up to the day before first pertuzumab dose. This trial is registered with ClinicalTrials.gov, number NCT00567190.
Between Feb 12, 2008, and July 7, 2010, 1196 patients were assessed for eligibility, of whom 808 were enrolled and randomly assigned. 402 patients were assigned to receive docetaxel plus trastuzumab plus pertuzumab, and 406 patients were assigned to receive docetaxel plus trastuzumab plus placebo. Clinical cutoff for this analysis was Nov 23, 2018. Between July 2012 and clinical cutoff, 50 patients crossed from the placebo to the pertuzumab group. Median follow-up was 99·9 months in the pertuzumab group (IQR 92·9–106·4) and 98·7 months (90·9–105·7) in the placebo group. Median overall survival was 57·1 months (95% CI 50–72) in the pertuzumab group and 40·8 months (36–48) in the placebo group (hazard ratio 0·69, 95% CI 0·58–0·82); 8-year landmark overall survival rates were 37% (95% CI 31–42) in the pertuzumab group and 23% (19–28) in the placebo group. The most common grade 3–4 adverse event was neutropenia (200 49% of 408 patients in the pertuzumab group, 183 46% of 396 patients in the placebo group). Five (1%) of 408 patients in the pertuzumab group and six (2%) of 396 patients in the placebo group had treatment-related deaths. One new serious adverse event suggestive of congestive heart failure (pertuzumab group) and one new symptomatic left ventricular systolic dysfunction (post-crossover) occurred since the previous analysis.
Our analysis shows that the previously observed improvements in overall survival with pertuzumab, trastuzumab, and docetaxel versus placebo, trastuzumab, and docetaxel were maintained after a median of more than 8 years of follow-up. The long-term safety and cardiac safety profiles of pertuzumab, trastuzumab, and docetaxel were maintained in the overall safety population and within crossover patients. HER2-targeted therapy has changed the natural history of HER2-positive metastatic breast cancer, with the dual blockade of pertuzumab and trastuzumab, with docetaxel, demonstrating an 8-year landmark overall survival rate of 37%.
F Hoffmann-La Roche and Genentech.
PurposeStrategic groups research has been hampered by the poor alignment between theory and methods. This has been due in large part to the lack of significance tests for cluster analysis. Now that ...significance tests are available, the theoretical and methodological implications are discussed. The paper aims to discuss these issues.Design/methodology/approachThe theory behind strategic groups is reframed to capitalize on the available significance tests. Subsequently, the significance tests are also modified to fit the proposed theory. Due to this integrative approach, this is both a theoretical and a methodological paper.FindingsIn lieu of significance tests, finding differences in performance emerged as the litmus test for the existence of discrete strategic groups. The concept of strategic groups gradually evolved to fit this requirement. Now that significance tests are available, these legacy effects of the structure-performance link can be removed. This reveals that three conflicting concepts have been sharing the label of strategic groups: strategic categories, interdependent strategic groups and strategic performance groups. The theory also reveals that the significance tests developed in ecological research need modifications for use in strategic groups research.Research limitations/implicationsA theory is proposed for interdependent strategic groups and a significance test of external isolation is proposed as part of this integrative solution.Originality/valueThis integrative solution appears to resolve the historical mismatch between theory and methods that has plagued this field since its inception. This creates a variety of intriguing areas for future research.
The fetal consequences of gestational engineered nanomaterial (ENM) exposure are unclear. The placenta is a barrier protecting the fetus and allowing transfer of substances from the maternal ...circulation. The purpose of this study was to determine the effects of maternal pulmonary titanium dioxide nanoparticle (nano-TiO2) exposure on the placenta and umbilical vascular reactivity. We hypothesized that pulmonary nano-TiO2 inhalation exposure increases placental vascular resistance and impairs umbilical vascular responsiveness. Pregnant Sprague-Dawley rats were exposed via whole-body inhalation to nano-TiO2 with an aerodynamic diameter of 188 ± 0.36 nm. On gestational day (GD) 11, rats began inhalation exposures (6 h/exposure). Daily lung deposition was 87.5 ± 2.7 μg. Animals were exposed for 6 days for a cumulative lung burden of 525 ± 16 μg. On GD 20, placentas, umbilical artery and vein were isolated, cannulated, and treated with acetylcholine (ACh), angiotensin II (ANGII), S-nitroso-N-acetyl-DL-penicillamine (SNAP), or calcium-free superfusate (Ca2+-free). Mean outflow pressure was measured in placental units. ACh increased outflow pressure to 53 ± 5 mmHg in sham-controls but only to 35 ± 4 mmHg in exposed subjects. ANGII decreased outflow pressure in placentas from exposed animals (17 ± 7 mmHg) compared to sham-controls (31 ± 6 mmHg). Ca2+-free superfusate yielded maximal outflow pressures in sham-control (63 ± 5 mmHg) and exposed (30 ± 10 mmHg) rats. Umbilical artery endothelium-dependent dilation was decreased in nano-TiO2 exposed fetuses (30 ± 9%) compared to sham-controls (58 ± 6%), but ANGII sensitivity was increased (−79 ± 20% vs −36 ± 10%). These results indicate that maternal gestational pulmonary nano-TiO2 exposure increases placental vascular resistance and impairs umbilical vascular reactivity.
•Maternal gestational nano-TiO2 exposure increases placental vascular resistance.•Maternal gestational nano-TiO2 exposure is associated with a decreased placental endothelium-dependent response.•Placental and umbilical artery sensitivity to angiotensin II is increased by maternal nano-TiO2 exposure.•Umbilical artery and vein endothelium-dependent dilation is blunted by maternal nano-TiO2 exposure.
Endogenous opioid systems regulate neurobiological responses to threatening stimuli. Stimulation of kappa-opioid receptors (KORs) produces analgesia but induces prodepressive-like effects in a ...variety of animal models. In contrast, KOR antagonists have antidepressant-like effects. KORs and their endogenous ligand dynorphin are expressed throughout brain areas involved in fear and anxiety, including the extended amygdala. Here, we examined whether KOR antagonists would affect unlearned fear (anxiety) in the elevated plus maze (EPM) and open field (OF) paradigms and learned fear in the fear-potentiated startle (FPS) paradigm. These studies were designed to accommodate the slow onset (approximately 24 h) and extended time course (>3 weeks) of the prototypical KOR antagonists nor-binaltorphimine hydrochloride (norBNI) and JDTic (3R)-7-hydroxy-N-(1S)-1-(3R, 4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinylmethyl-2-methylpropyl-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide hydrochloride. Rats received an i.p. injection of norBNI (3.0-30 mg/kg) or JDTic (1.0-10 mg/kg) 48 h before EPM testing. One day later, they were tested in the OF, and 5 and 7 days later, they were trained and tested in the FPS paradigm. Both KOR antagonists dose-dependently increased open arm exploration in the EPM without affecting OF behavior. They also decreased conditioned fear in the FPS paradigm. The anxiolytic-like effects of KOR antagonists were qualitatively similar to those of the benzodiazepine chlordiazepoxide in the EPM. The selective serotonin reuptake inhibitor fluoxetine had no effect in the EPM and anxiogenic-like effects in the OF. Our results indicate that KOR antagonists produce a unique combination of antidepressant- and anxiolytic-like effects and suggest that this class of drugs may be particularly effective for the treatment of comorbid depressive and anxiety disorders.
Objectives:
Prior studies demonstrate inconsistent diagnostic strategies for laryngopharyngeal reflux disease (LPR) patients who are offered laparoscopic Nissen fundoplication (Nissen). Superior ...symptom resolution outcomes are demonstrated in patients with accompanying typical gastroesophageal reflux (GERD) symptoms. This study aims to evaluate the efficacy of selecting patients with LPR complaints for Nissen using full column, dual pH impedance catheters (multichannel intraluminal impedance catheters MII).
Methods:
All patients who underwent Nissen for management of LPR symptoms refractory to at least 3 months of twice daily (BID) proton pump inhibitor (PPI) therapy with reflux symptom index (RSI) of 13 or higher and who had demonstrable reflux on MII were included. Pre- and (minimum) 16 week post-Nissen RSI scores as well as LPR-specific complaints were collected.
Results:
Eleven patients met criteria. Nine subjects (5 female, 4 male) had complete data. All 9 (100%) achieved improvement in RSI. The average pre-Nissen RSI was 31.7, and average post-Nissen RSI was 10 (P < .001). Six (67%) subjects dropped below an RSI of 13. Seven subjects (78%) had resolution of their primary LPR symptom, and 6 (67%) subjects had resolution of all LPR symptoms.
Conclusions:
Patients with LPR who are selected using dual pH and full column impedance are likely to demonstrate improvement in RSI following Nissen.
Hepatocyte nuclear factor-1β (HNF-1β) is a Pit-1, Oct-1/2, Unc-86 (POU) homeodomain-containing transcription factor expressed in the kidney, liver, pancreas, and other epithelial organs. Mutations of ...HNF-1β cause maturity-onset diabetes of the young, type 5 (MODY5), which is characterized by early-onset diabetes mellitus and congenital malformations of the kidney, pancreas, and genital tract. Knockout of HNF-1β in the mouse kidney results in cyst formation. However, the signaling pathways and transcriptional programs controlled by HNF-1β are poorly understood. Using genome-wide chromatin immunoprecipitation and DNA microarray (ChIP-chip) and microarray analysis of mRNA expression, we identified SOCS3 (suppressor of cytokine signaling-3) as a previously unrecognized target gene of HNF-1β in the kidney. HNF-1β binds to the SOCS3 promoter and represses SOCS3 transcription. The expression of SOCS3 is increased in HNF-1β knockout mice and in renal epithelial cells expressing dominant-negative mutant HNF-1β. Increased levels of SOCS-3 inhibit HGF-induced tubulogenesis by decreasing phosphorylation of Erk and STAT-3. Conversely, knockdown of SOCS-3 in renal epithelial cells expressing dominant-negative mutant HNF-1β rescues the defect in HGF-induced tubulogenesis by restoring phosphorylation of Erk and STAT-3. Thus, HNF-1β regulates tubulogenesis by controlling the levels of SOCS-3 expression. Manipulating the levels of SOCS-3 may be a useful therapeutic approach for human diseases induced by HNF-1β mutations.
In Dravet syndrome (DS), a rare epileptic and developmental encephalopathy, the effectiveness of a new treatment is predominantly measured in terms of seizure frequency. However, this may not fully ...capture the impact of a treatment on the broader aspects of the syndrome and patients' health-related quality of life (HRQoL). Using a previously published survey which collected data from DS patients and their carers on the broader manifestations of their syndrome, their HRQoL, and their experience of seizures, this study created composite measures of symptom severity to offer new perspectives on the multifaceted aspects of this rare condition.
Survey responses on the severity of physical and psychosocial symptoms were combined with independent assessments of disability and care need, to generate three composite symptom scores assessing the manifestations of DS (physical, psychosocial and care requirements). Variation in HRQoL was investigated in multiple regression analyses to assess the strength of association between each of these composite measures and three forms of seizure measures (seizure frequency, days with no seizures and longest interval without seizures), as experienced over a 4- and 12-week period.
Composite scores were calculated for a cohort of 75 primarily paediatric patients who were enrolled in the study. Strong associations were found between each of the three composite symptom scores and each of the three seizure measures, with the regression coefficient on symptom score highly significant (p ≤ 0.001) in all nine comparisons. Separate regressions using predictors of HRQoL (Kiddy KINDL and Kid KINDL) as the dependent variable were inconclusive, identifying only behavioural/attention problems and status epilepticus as significant predictors of HRQoL.
These results allow the development of a composite score that may be useful in developing a clinical understanding of the severity of DS for an individual patient and establishing their treatment goals. Where measurement of long-term sequalae of disease is not feasible, such as clinical trials, correlation of the composite score with experience of seizures and seizure-free periods may allow a better contextualisation of the results of short-term assessments.
German Clinical Trials Register (DRKS), DRKS00011894. Registered 16 March 2017, http://www.drks.de/ DRKS00011894.
Digital transformation is here to stay. With the emergence of new digital innovations and diverse and rich data sources, only those organisations that can adapt faster and make better, quicker ...decisions will become more competitive. Yet, being a first mover is only the start of the transformation process. Organisations need to address and implement digital strategies to manage and sustain a digital transformation in order to stay with, or ahead of, their competition. In this article, we outline some of the key challenges associated with researching digital transformations within the information systems (IS) field and stress the importance of shifting the focus on how digital transformations are managed and sustained. To explore this further, we launched a Special Issue on "Managing and Sustaining Digital Transformations" and received a large volume of submissions. After a series of reviews and revisions, we were delighted to unearth four excellent articles on this important topic. Our hope with this Special Issue is to improve researchers' abilities to identify the importance of managing and sustaining digital transformations and to encourage them to build on these contributions to better unpack the digital transformation process for the future.
In this article, we describe the iterative participatory design of SOPHIE, an online virtual patient for feedback-based practice of sensitive patient-physician conversations, and discuss an initial ...qualitative evaluation of the system by professional end users. The design of SOPHIE was motivated from a computational linguistic analysis of the transcripts of 383 patient-physician conversations from an essential office visit of late stage cancer patients with their oncologists. We developed methods for the automatic detection of two behavioral paradigms, lecturing and positive language usage patterns (sentiment trajectory of conversation), that are shown to be significantly associated with patient prognosis understanding. These automated metrics associated with effective communication were incorporated into SOPHIE, and a pilot user study identified that SOPHIE was favorably reviewed by a user group of practicing physicians.
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