CT perfusion as a potential biomarker for pancreatic ductal adenocarcinoma during routine staging and restaging.

PURPOSE: To evaluate the significance of CT perfusion parameters predicting response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: Seventy patients with PDAC prospectively had CT perfusion acquisition incorporated into baseline multiphase staging CT. Twenty-eight who were naïve to therapy were retained for further investigation. Perfusion was performed 5-42.5 s after contrast, followed by parenchymal and portal venous phases. Blood flow (BF), blood volume (BV), and permeability surface area product (PS) were calculated using deconvolution algorithms. Patients were categorized as responders or non-responders per RECIST 1.1. Perfusion variables with AUC ≥ 0.70 in differentiating responders from non-responders were retained. Logistic regression was used to assess associations between baseline perfusion variables and response. RESULTS: 18 of 28 patients showed favorable response to therapy. Baseline heterogeneity variables in tumor max ROI were higher in non-responders than responders [median BF coefficient of variation (CV) 0.91 vs. 0.51 respectively, odds ratio (OR) 6.8 per one standard deviation (1-SD) increase, P = 0.047; median PS CV 1.6 vs. 0.68, OR 3.9 per 1-SD increase, P = 0.047; and median BV CV 0.75 vs. 0.54, OR = 4.0 per 1-SD increase, P = 0.047]. Baseline BV mean in tumor center was lower in non-responders than responders (median BV mean: 0.74 vs. 2.9 ml/100 g respectively, OR 0.28 per 1-SD increase, P = 0.047). CONCLUSION: For patients with PDAC receiving neoadjuvant therapy, lower and more heterogeneous perfusion parameters correlated with an unfavorable response to therapy. Such quantitative information can be acquired utilizing a comprehensive protocol interleaving perfusion CT acquisition with standard of care multiphase CT scans using a single contrast injection, which could be used to identify surgical candidates and predict outcome.

Parenting an adolescent with complex regional pain syndrome: A dyadic qualitative investigation of resilience.

OBJECTIVES: Adolescent chronic pain exists within a social context, affecting the lives of adolescents, parents, peers, and wider family members. Typically, parental research has focussed on the negative impact on parents associated with parenting an adolescent with chronic pain. However, a small number of studies have identified positive parental outcomes and functioning, with a focus on parental resilience. This study sought to extend existing knowledge by providing a detailed and contextualized understanding of how parental dyads experience and demonstrate resilience in response to parenting an adolescent with Complex Regional Pain Syndrome (CRPS) and the meaning that parents ascribe to these shared experiences. DESIGN: An Interpretative Phenomenological Analysis (IPA) was used to conduct an in-depth qualitative interview study of parents of an adolescent with CRPS. METHODS: Semi-structured interviews were conducted via Skype with eight mother-father parental dyads of an adolescent aged 11-25 years with CRPS. RESULTS: A single prominent theme 'masking reality in the face of pain' dominated the parental discourse and experience of resilience. Resilience was experienced as an incongruence between private distress and the perceived obligation to display socially desirable resilience behaviours to protect their child from their own distress. CONCLUSIONS: Study findings highlight the benefits of strength-based interventions to enhance parental resilience. This is particularly important since parental behaviours have been shown to influence child pain outcomes. Future research should seek to explore resilience in different populations such as lone parents, siblings, and those parenting an adolescent with pain conditions other than CRPS.

'They were aware of who I was as a person': Patients' and health professionals' experiences of using the PEGASUS intervention to facilitate decision-making around breast reconstruction.

OBJECTIVE: Many women choose to have breast reconstruction after mastectomy; however, decision-making can be difficult and expectations are often unmet. The PEGASUS intervention (Patient Expectations and Goals: Assisting Shared Understanding of Surgery) was developed to support shared decision-making by helping women and healthcare professionals to clarify and discuss their individual expectations around surgery. This study aimed to explore patients' and health professionals' experiences of using the intervention and its implementation. METHODS: Forty interviews were conducted with participants in a large scale, multi-site trial of the effectiveness of PEGASUS, from 'intervention' (n=16) and 'usual care' groups (n=11), and healthcare professionals (n=13). Data were analysed using thematic analysis. RESULTS: 'Usual care' participants described feeling overwhelmed in decision-making ('bombarded'), often using their own research to break down information ('process of elimination'). In contrast, intervention group participants described PEGASUS providing focus ('focus amongst the frenetic'), and increased connection with clinicians ('more than a number'). Healthcare professionals described increased focus on patient priorities ('shifting focus'), but stressed the need for whole team buy-in ('collective commitment'). CONCLUSIONS: The PEGASUS intervention offered a qualitatively different experience to individuals considering breast reconstruction, with potential to enhance patients' and healthcare professionals' feelings of shared decision-making and patient-centred care. TRIAL REGISTRATION: ISRCTN 18000391 (https://doi.org/10.1186/ISRCTN18000391) 27/01/2016.

Feasibility of wide detector CT perfusion imaging performed during routine staging and restaging of pancreatic ductal adenocarcinoma.

PURPOSE: To evaluate the feasibility of CT perfusion performed during routine multiphase contrast-enhanced CT on a 160 mm wide-coverage 256-slice scanner in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Fifty-seven patients had a CT perfusion acquisition during their routine multiphase CT. Perfusion was performed 5 to 42.5 s (15 passes at 2.5 s intervals) after intravenous contrast administration (4.2-5 ml/s), followed by pancreatic parenchymal and portal venous phases for clinical interpretation. Perfusion maps were generated and blood flow (BF), blood volume (BV), and permeability surface area product (PS) for tumor and uninvolved pancreas were calculated using deconvolution algorithms and compared to existing similar publications. Radiation dose information was recorded and size-specific dose estimate (SSDE) was calculated using body dimensions. RESULTS: Diagnostic quality of standard images was unaffected by performing the perfusion acquisition. Average tumor center BF was 20.8 ± 12.1 ml/100 g/min, BV 2.5 ± 2.1 ml/100 g and PS 15.5 ± 39.4 ml/100 g/min. Average pancreas BF was 90.8 ± 50.2 ml/100 g/min, BV 11.9 ± 4.3 ml/100 g and PS 33.6 ± 27.7 ml/100 g/min. For the perfusion acquisition, mean SSDE was 57 ± 11 mGy, CTDIvol 43 ± 6 mGy and DLP 685 ± 100 mGy-cm. CONCLUSION: Adding a perfusion CT acquisition to standard pancreatic CT protocol is feasible using a wide-detector 256-slice CT scanner and adds quantitative information while maintaining diagnostic quality of the standard of care examination. This novel protocol adds no time or cost to the examination and yields perfusion parameters that are comparable to existing literature using a separate dedicated perfusion protocol.

Polε Instability Drives Replication Stress, Abnormal Development, and Tumorigenesis.

DNA polymerase ε (POLE) is a four-subunit complex and the major leading strand polymerase in eukaryotes. Budding yeast orthologs of POLE3 and POLE4 promote Polε processivity in vitro but are dispensable for viability in vivo. Here, we report that POLE4 deficiency in mice destabilizes the entire Polε complex, leading to embryonic lethality in inbred strains and extensive developmental abnormalities, leukopenia, and tumor predisposition in outbred strains. Comparable phenotypes of growth retardation and immunodeficiency are also observed in human patients harboring destabilizing mutations in POLE1. In both Pole4-/- mouse and POLE1 mutant human cells, Polε hypomorphy is associated with replication stress and p53 activation, which we attribute to inefficient replication origin firing. Strikingly, removing p53 is sufficient to rescue embryonic lethality and all developmental abnormalities in Pole4 null mice. However, Pole4-/-p53+/- mice exhibit accelerated tumorigenesis, revealing an important role for controlled CMG and origin activation in normal development and tumor prevention.