National Survey of Patients’ Bill of Rights Statutes

BACKGROUND Despite vigorous national debate between 1999–2001 the federal patients' bill of rights (PBOR) was not enacted. However, states have enacted legislation and the Joint Commission defined an accreditation standard to present patients with their rights. Because such initiatives can be undermined by overly complex language, we surveyed the readability of hospital PBOR documents as well as texts mandated by state law. METHODS State Web sites and codes were searched to identify PBOR statutes for general patient populations. The rights addressed were compared with the 12 themes presented in the American Hospital Association's (AHA) PBOR text of 2002. In addition, we obtained PBOR texts from a sample of hospitals in each state. Readability was evaluated using Prose, a software program which reports an average of eight readability formulas RESULTS Of 23 states with a PBOR statute for the general public, all establish a grievance policy, four protect a private right of action, and one stipulates fines for violations. These laws address an average of 7.4 of the 12 AHA themes. Nine states' statutes specify PBOR text for distribution to patients. These documents have an average readability of 15th grade (range, 11.6, New York, to 17.0, Minnesota). PBOR documents from 240 US hospitals have an average readability of 14th grade (range, 8.2 to 17.0) CONCLUSIONS While the average U.S. adult reads at an 8th grade reading level, an advanced college reading level is routinely required to read PBOR documents. Patients are not likely to learn about their rights from documents they cannot read.Pfizer Clear Health Communication Initiativ

PANTHER: AZD8931, inhibitor of EGFR, ERBB2 and ERBB3 signalling, combined with FOLFIRI: a Phase I/II study to determine the importance of schedule and activity in colorectal cancer

BACKGROUND: Epidermal growth factor receptor (EGFR) is a therapeutic target to which HER2/HER3 activation may contribute resistance. This Phase I/II study examined the toxicity and efficacy of high-dose pulsed AZD8931, an EGFR/HER2/HER3 inhibitor, combined with chemotherapy, in metastatic colorectal cancer (CRC). METHODS: Treatment-naive patients received 4-day pulses of AZD8931 with irinotecan/5-FU (FOLFIRI) in a Phase I/II single-arm trial. Primary endpoint for Phase I was dose limiting toxicity (DLT); for Phase II best overall response. Samples were analysed for pharmacokinetics, EGFR dimers in circulating exosomes and Comet assay quantitating DNA damage. RESULTS: Eighteen patients received FOLFIRI and AZD8931. At 160 mg bd, 1 patient experienced G3 DLT; 160 mg bd was used for cohort expansion. No grade 5 adverse events (AE) reported. Seven (39%) and 1 (6%) patients experienced grade 3 and grade 4 AEs, respectively. Of 12 patients receiving 160 mg bd, best overall response rate was 25%, median PFS and OS were 8.7 and 21.2 months, respectively. A reduction in circulating HER2/3 dimer in the two responding patients after 12 weeks treatment was observed. CONCLUSIONS: The combination of pulsed high-dose AZD8931 with FOLFIRI has acceptable toxicity. Further studies of TKI sequencing may establish a role for pulsed use of such agents rather than continuous exposure. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number: NCT01862003

HER2-HER3 heterodimer quantification by FRET-FILM and patient subclass analysis of the COIN colorectal trial

BACKGROUND: The phase 3 MRC COIN trial showed no statistically significant benefit from adding the EGFR-target cetuximab to oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer. This study exploits additional information on HER2-HER3 dimerization to achieve patient stratification and reveal previously hidden subgroups of patients who had differing disease progression and treatment response. METHODS: HER2-HER3 dimerization was quantified by 'FLIM Histology' in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy +/-cetuximab. Bayesian latent class analysis (LCA) and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation and cetuximab on progression-free survival (PFS) and overall survival (OS). All statistical tests were two-sided. RESULTS: LCA on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS: 1624 days [95%CI=1466-1816] vs 461 [95%CI=431-504]): Class 1 (15.6%) showed a benefit from cetuximab in OS (HR = 0.43 [95%CI=0.25-0.76]; p = 0.004). Class 2 showed an association of increased HER2-HER3 with better OS (HR = 0.64 [95%CI=0.44-0.94]; p = 0.02). A class prediction signature was formed and tested on an independent validation cohort (N = 152) validating the prognostic utility of the dimer assay. Similar subclasses were also discovered in full trial dataset (N = 1,630) based on 10 baseline clinicopathological and genetic covariates. CONCLUSIONS: Our work suggests that the combined use of HER dimer imaging and conventional mutation analyses will be able to identify a small subclass of patients (>10%) who will have better prognosis following chemotherapy. A larger prospective cohort will be required to confirm its utility in predicting the outcome of anti-EGFR treatment

Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer

OBJECTIVE: Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes.DESIGN: RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants.RESULTS: Fifteen critical RGs are summarised below: RG1: Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment; RG2: Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk; RG3: Pressing need for prevention trials; RG4: Lack of integration of different prevention approaches; RG5: Lack of optimal strategies for CRC screening; RG6: Lack of effective triage systems for invasive investigations; RG7: Imprecise pathological assessment of CRC; RG8: Lack of qualified personnel in genomics, data sciences and digital pathology; RG9: Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices; RG10: Need for novel technologies/interventions to improve curative outcomes; RG11: Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment; RG12: Lack of reliable biomarkers to guide stage IV treatment; RG13: Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution; RG14: Lack of coordination of CRC research/funding; RG15: Lack of effective communication between relevant stakeholders.CONCLUSION: Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years.</p

T cell-inflamed gene expression profile and PD-L1 expression and pembrolizumab efficacy in advanced esophageal cancer

Aim: Investigate the relationship between response to pembrolizumab and expression of the 18-gene T cell-inflamed gene expression profile (TcellinfGEP) or PD-L1 combined positive score (CPS) in esophageal cancer. Materials & methods: This analysis included heavily pretreated patients with advanced/metastatic esophageal/gastroesophageal junction adenocarcinoma or squamous cell carcinoma who received pembrolizumab in the single-arm, phase II study KEYNOTE-180. PD-L1 CPS was evaluated with PD-L1 IHC 22C3 pharmDx. Results: In patients with squamous cell carcinoma, trends toward enrichment for responders were observed for patients with PD-L1 CPS ≥10 tumors. In patients with adenocarcinoma, a trend was observed for TcellinfGEP but not for PD-L1. Conclusion: TcellinfGEP and PD-L1 CPS may enrich for responders to pembrolizumab in patients with esophageal cancer. Clinical Trial Registration: NCT02559687 (ClinicalTrials.gov