Prognosis Discussion and Referral to Community Palliative Care Services in Patients with Advanced Pancreatic Cancer Treated in a Tertiary Cancer Centre.

Advanced pancreatic cancer is associated with a poor prognosis, often less than 1 year. Honest prognosis discussions guide early community palliative care services input, facilitating timely advance care planning and improving quality of life. The aims were to assess if patients were offered prognosis discussions and community palliative care services referral. A retrospective analysis of consecutive case-notes of new advanced pancreatic cancer patients was conducted. Chi-squared test assessed the association with prognosis discussion and community palliative care services referral. In total, 365 cases (60%) had a documented prognosis discussion at any time-point in the treatment pathway; 54.4% during the first appointment. The frequency of prognosis discussion was greater with nurse clinician review at first appointment (p < 0.001). In total, 171 patients (28.1%) were known to community palliative care services at the first appointment. Of those not known, 171 (39.1%) and 143 (32.7%) were referred at this initial time-point or later, respectively. There was a significant association between the referral to community palliative care services at first appointment and the reviewing professional (this was greatest for nurse clinicians (frequency 65.2%)) (p < 0.001), and also if reviewed by clinical nurse specialist at first visit or not (47.8% vs. 35.6%) (p < 0.01). Prognosis discussions were documented in approximately two-thirds of cases, highlighting missed opportunities. Prognosis discussion was associated with clinician review and was most frequent for nurse clinician, as was referral to community palliative care services. Clinical nurse specialist review increased referral to community palliative care services if seen at the initial visit. Multi-disciplinary review, specifically nursing, therefore, during the first consultation is imperative and additive. It should be considered best practice to offer and negotiate the content and timing of prognosis discussions with cancer patients, and revisit this offer throughout their treatment pathway. Greater attention to prognosis discussion documentation is recommended.

Associations between AI-Assisted Tumor Amphiregulin and Epiregulin IHC and Outcomes from Anti-EGFR Therapy in the Routine Management of Metastatic Colorectal Cancer.

PURPOSE: High tumor production of the EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), predicted benefit from anti-EGFR therapy for metastatic colorectal cancer (mCRC) in a retrospective analysis of clinical trial data. Here, AREG/EREG IHC was analyzed in a cohort of patients who received anti-EGFR therapy as part of routine care, including key clinical contexts not investigated in the previous analysis. EXPERIMENTAL DESIGN: Patients who received panitumumab or cetuximab ± chemotherapy for treatment of RAS wild-type mCRC at eight UK cancer centers were eligible. Archival formalin-fixed paraffin-embedded tumor tissue was analyzed for AREG and EREG IHC in six regional laboratories using previously developed artificial intelligence technologies. Primary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: A total of 494 of 541 patients (91.3%) had adequate tissue for analysis. A total of 45 were excluded after central extended RAS testing, leaving 449 patients in the primary analysis population. After adjustment for additional prognostic factors, high AREG/EREG expression (n = 360; 80.2%) was associated with significantly prolonged PFS [median: 8.5 vs. 4.4 months; HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.02] and OS [median: 16.4 vs. 8.9 months; HR, 0.66 95% CI, 0.50-0.86; P = 0.002]. The significant OS benefit was maintained among patients with right primary tumor location (PTL), those receiving cetuximab or panitumumab, those with an oxaliplatin- or irinotecan-based chemotherapy backbone, and those with tumor tissue obtained by biopsy or surgical resection. CONCLUSIONS: High tumor AREG/EREG expression was associated with superior survival outcomes from anti-EGFR therapy in mCRC, including in right PTL disease. AREG/EREG IHC assessment could aid therapeutic decisions in routine practice. See related commentary by Randon and Pietrantonio, p. 4021.

Shared cis-regulatory modules control expression of the tandem paralogs midline and H15 in the follicular epithelium.

The posterior end of the follicular epithelium is patterned by midline (MID) and its paralog H15, the Drosophila homologs of the mammalian Tbx20 transcription factor. We have previously identified two cis-regulatory modules (CRMs) that recapitulate the endogenous pattern of mid in the follicular epithelium. Here, using CRISPR/Cas9 genome editing, we demonstrate redundant activity of these mid CRMs. Although the deletion of either CRM alone generated marginal change in mid expression, the deletion of both CRMs reduced expression by 60%. Unexpectedly, the deletion of the 5' proximal CRM of mid eliminated H15 expression. Interestingly, expression of these paralogs in other tissues remained unaffected in the CRM deletion backgrounds. These results suggest that the paralogs are regulated by a shared CRM that coordinates gene expression during posterior fate determination. The consistent overlapping expression of mid and H15 in various tissues may indicate that the paralogs could also be under shared regulation by other CRMs in these tissues.

Neurotoxic or Neuroprotective? Current Controversies in SCI-Induced Autoimmunity.

Controversy exists regarding the autoimmune response that has been observed following traumatic spinal cord injury (SCI). It is not clear if this represents a protective response by the immune system to prevent further tissue damage, a pathological reaction of the immune system to central nervous system antigens released by the injury, or a combination of both. Experimental evidence indicates that B cells produce auto-antibodies following SCI and that the presence of self-reactive antibodies is associated with tissue damage. Conversely, other studies suggest T cell activity at the site of the injury promotes tissue regeneration. Vaccination with dendritic cells exposed to central nervous system (CNS) antigens dramatically improves recovery of motor function in spinal cord injured rats. Further research is required to determine the nature of post-SCI B cell and T cell responses and to establish efficacy of dendritic cell vaccination therapy in clinical studies. This information is critical for the development of therapies to either suppress or promote immune responses following neurotrauma to improve neurological outcomes.

B-cell maturation antigen, a proliferation-inducing ligand, and B-cell activating factor are candidate mediators of spinal cord injury-induced autoimmunity.

Autoimmunity is thought to contribute to poor neurological outcomes after spinal cord injury (SCI). There are few mechanism-based therapies, however, designed to reduce tissue damage and neurotoxicity after SCI because the molecular and cellular bases for SCI-induced autoimmunity are not completely understood. Recent groundbreaking studies in rodents indicate that B cells are responsible for SCI-induced autoimmunity. This novel paradigm, if confirmed in humans, could aid in the design of neuroprotective immunotherapies. The aim of this study was to investigate the molecular signaling pathways and mechanisms by which autoimmunity is induced after SCI, with the goal of identifying potential targets in therapies designed to reduce tissue damage and inflammation in the chronic phase of SCI. To that end, we performed an exploratory microarray analysis of peripheral blood mononuclear cells to identify differentially expressed genes in chronic SCI. We identified a gene network associated with lymphoid tissue structure and development that was composed of 29 distinct molecules and five protein complexes, including two cytokines, a proliferation-inducing ligand (APRIL) and B-cell-activating factor (BAFF), and one receptor, B-cell maturation antigen (BMCA) involved in B cell development, proliferation, activation, and survival. Real-time polymerase chain reaction analysis from ribonucleic acid samples confirmed upregulation of these three genes in SCI. To our knowledge, this is the first report that peripheral blood mononuclear cells produce increased levels of BAFF and APRIL in chronic SCI. This finding provides evidence of systemic regulation of SCI-autoimmunity via APRIL and BAFF mediated activation of B cells through BMCA and points toward these molecules as potential targets of therapies designed to reduce neuroinflammation after SCI.