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Pancreatic ductal adenocarcinoma (PDA) is characterized by low cytotoxic lymphocytes, abundant immune-suppressive cells, and resistance to immune checkpoint inhibitors (ICI). Preclinical PDA models showed the HDAC inhibitor entinostat reduced myeloid cell immunosuppression, sensitizing tumors to ICI therapy. This phase II study combined entinostat with nivolumab (PD1 inhibitor) in patients with advanced PDA (NCT03250273). Patients received entinostat 5 mg orally once weekly for 14-day lead-in, followed by entinostat and nivolumab. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. Secondary endpoints included safety, duration of response, progression free-survival and overall survival. Between November 2017 and November 2020, 27 evaluable patients were enrolled. Three showed partial responses (11% ORR, 95% CI, 2.4%-29.2%) with a median response duration of 10.2 months. Median progression-free survival (PFS) and overall survival (OS) were, respectively, 1.89 (95% CI, 1.381-2.301) and 2.729 (95% CI, 1.841-5.622) months. Grade ≥3 treatment-related adverse events occurred in 19 patients (63%), including decreased lymphocyte count, anemia, hypoalbuminemia, and hyponatremia. As exploratory analysis, peripheral and tumor immune profiles changes were assessed using CyTOF, mIHC, and RNA-seq. Entinostat increased dendritic cell activation and maturation. Gene expression analysis revealed an enrichment in inflammatory response pathways with combination treatment. Although the primary endpoint was not met, entinostat and nivolumab showed durable responses in a small subset of PDA patients. Myeloid cell immunomodulation supported the preclinical hypothesis, providing a basis for future combinatorial therapies to enhance clinical benefits in PDA. Responses to immune checkpoint inhibitors in patients with pancreatic ductal adenocarcinoma (PDA) remain low and alternative combinatorial approaches are warranted. Here the authors report the results of a phase 2 clinical trial of entinostat (histone deacetylases inhibitor) and nivolumab (anti-PD-1 inhibitor) in patients with metastatic PDA.

Background Approximately 95% of advanced colorectal cancer patients (CRC) have mismatch repair MMR-proficient (MMRp) tumors, which do not respond to PD1 blockade alone. Preclinical studies have shown that combined histone deacetylases (HDAC) and/or DNA methyltransferases (DNMT) inhibition can induce susceptibility to immune checkpoint therapy and inhibit tumor growth. We conducted a pilot trial evaluating PD-1 immune checkpoint inhibitor therapy in combination with DNMT and HDAC inhibitors in MMRp CRC. The study was designed with a biological endpoint of change in immune cell infiltration, to determine the optimal epigenetic combination that optimizes the tumor microenvironment. This trial was designed to test that hypothesis. Results From January 2016 to November 2018, 27 patients were enrolled with median age of 57 (range 40–69) years. Median progression-free survival and overall survival were 2.79 months and 9.17, respectively. One patient in Arm C achieved a durable partial response by RECIST criteria, lasting for approximately 19 months. The most common treatment-related hematological adverse events in all arms were anemia (62%), lymphopenia (54%) and thrombocytopenia (35%), and non-hematological AEs were anorexia (65%), nausea (77%), and vomiting (73%). Conclusions The combination of 5-azacitidine and romidepsin with pembrolizumab was safe and tolerable in patients with advanced MMRp CRC, but with a minimal activity. Further mechanistic investigations are needed to understand epigenetic-induced immunologic shift and to expand the potential applicability of checkpoint inhibitors in this setting.

Introduction Cholangiocarcinoma (CCA) is an aggressive cancer characterized by high metastatic potential and poor prognosis. Recent advances in understanding the molecular biology of CCA have led to the development of novel therapeutic strategies. However, the immunosuppressive tumor microenvironment in CCA enables immune evasion, which contributes to the limited effectiveness of immune checkpoint inhibitors (ICIs) in metastatic CCA patients. Epigenetic modifications play a critical role in cancer progression. Previous preclinical and clinical work from our group and others demonstrated that the HDAC inhibitor entinostat remodeled the tumor microenvironment and sensitized cancers to immune checkpoint inhibition, resulting in durable radiological responses in a subset of patients. This raises the potential for similar therapeutic strategies in CCA. Methods In accordance with our previously published study involving PDAC patients from the same clinical trial, this phase II, single-center, open-label trial was conducted to assess the efficacy of entinostat in combination with nivolumab in patients with advanced CCA. Patients received oral entinostat at a dose of 5 mg once weekly. After a 14-day lead-in with entinostat alone, treatment was expanded to combine weekly oral entinostat in addition to nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Moreover, we evaluated peripheral immune profiles by high-dimensional mass cytometry by time-of-flight (CyTOF) on cryopreserved paired baseline and on treatment PBMC samples. Results Between November 2017 and November 2020, a total of 13 patients with unresectable or metastatic previously treated CCA were enrolled. Among them, two patients (15%) demonstrated stable disease (SD) as best response, while the remaining eleven patients (85%) demonstrated disease progression (PD). No partial response was observed per RECIST 1.1 criteria. Adverse reaction to at least one study drug occurred in12 patients (92%). Grade ≥ 3 treatment-related AE (TRAEs) were encountered in 5 patients (38%). The most common grade ≥ 3 AEs were decreased cell counts. CyTOF profiling of PBMCs revealed that the HDAC inhibitor mediated immune reprogramming seen in the PDAC was not consistently reproduced for both myeloid and T cell compartments in CCA. Conclusion While the combination of entinostat and nivolumab did not demonstrate clinical efficacy in CCA, the translational insights from this study underscore the complexity of this malignancy. Overcoming the unique immunosuppressive barriers in CCA will require innovative approaches that integrate novel immunomodulatory agents and precision-based strategies to optimize patient outcomes. Trail registration NCT03250273, Trial pre-registration: 8/14/2017, Study Start: 11/06/2017.

We previously reported CHFR methylation in a subset of colorectal cancer (CRC; ∼30%) with high concordance with microsatellite instability (MSI). We also showed that CHFR methylation predicted for sensitivity to docetaxel, whereas the MSI‐high phenotypes were sensitive to gemcitabine. We hypothesized that this subset of patients with CRC would be selectively sensitive to gemcitabine and docetaxel. We enrolled a Phase 2 trial of gemcitabine and docetaxel in patients with MSI‐high and/or CHFR methylated CRC. The primary objective was Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate. Enrolled patients were treated with gemcitabine 800 mg/m2 on days 1 and 8 and docetaxel 70 mg/m2 on day 8 of each 21‐day cycle. A total of 6 patients with CHFR‐methylated, MSI‐high CRC were enrolled from September 2012 to August 2016. The study was closed in September of 2017 due to poor accrual prior to reaching the first interim assessment of response rate, which would have occurred at 10 patients. No RECIST criteria tumor responses were observed, with 3 patients (50%) having stable disease as best response, 1 lasting more than 9 months. Median progression‐free survival (PFS) was 1.79 months (95% confidence interval [CI] = 1.28, not available [NA]) and median overall survival (OS) was 15.67 months (95% CI = 4.24, NA). Common grade 3 toxicities were lymphopenia (67%), leukopenia (33%), and anemia (33%). Although negative, this study establishes a proof‐of‐concept for the implementation of epigenetic biomarkers (CHFR methylation/MSI) as inclusion criteria in a prospective clinical trial to optimize combinatorial strategies in the era of personalized medicine. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? CHFR silencing via DNA methylation has been suggested to be predictive of taxane sensitivity in diverse tumors. The frequent association of CHFR methylation with microsatellite instability (MSI) suggested a possible combination therapy with gemcitabine, because the MSI phenotype may result in sensitivity to nucleoside analogues. WHAT QUESTION DID THIS STUDY ADDRESS? We hypothesized that metastatic colorectal cancer (mCRC), which have CHFR methylation and MSI phenotype were sensitive to gemcitabine and docetaxel, and have designed this Phase 2 trial in biomarker‐selected mCRC to test this prediction. WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? The study enrolled a molecularly defined subgroup of patients with colorectal cancer (CRC) and showed that the combination is safe in this population. Nevertheless, due to poor enrollment and early termination, no conclusions on the primary and secondary end points could be made. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? This study supports the feasibility of implementing DNA methylation markers in a prospective clinical trial and further efforts toward their application as predictive biomarkers for therapeutic agents in defined subsets of patients are warranted.

Studies have indicated that many, although by no means all, people with epilepsy have difficulty in adjusting to the disorder, manifest by higher rates of psychological and social problems than amongst the general population. A variety of neurological and environmental factors have been hypothesized to contribute to these consequences. It has been suggested that the severity of seizures may be an important factor in determining psychological and social well-being, but very little research has investigated this empirically. This study was therefore undertaken to investigate the relationship between patient-rated seizure severity and adjustment to epilepsy. If greater seizure severity was associated with poorer adjustment, measurement of seizure severity might provide a suitable means of identifying those patients who could benefit from a psychoeducational intervention programme, and may also serve as a useful measure of treatment efficacy. In addition, the research considered the value of Wright's (1990) comprehensive conceptual model for the definition and assessment of adjustment, as much research in the area of adjustment to chronic illness has suffered from insufficient definition and difficulties with measurement. The results indicated that seizure severity was only weakly associated with psychological and illness-related measures of adjustment. These associations would not be sufficiently strong to allow the proposed use of seizure severity as an indicator of poor adjustment, although there may be some value in using this variable as a measure of treatment efficacy in addition to seizure frequency. The conceptual model of adjustment was found to be of value as a framework for guiding operationalisation and measurement of adjustment. Results tentatively confirmed the associations currently suggested within the model and further additions were proposed. Suggestions for future research are made.

Every summer for the past seven years Chicago-based [Bill Hogg] and Ulla Hogg have travelled 14,000km to their five-bedroom, three-bathroom Waimarama home, Windsor Grove, to savour [Hawke]'s Bay's summer climate, local cuisine and most of all, their view. A reinforced stone retaining wall and paving tiles surround the swimming pool, which is heated by a simple solar system. Olive trees grow on the eastern hill slopes, and a line of trees and shrubs form the southern boundary of the property. It's three minutes' walk through a neighbouring walkway to the golden sands of Waimarama Beach where you can put the cray pots out, fish, snorkel, dive and go boating. propertywriter@skyhouse.co.nz --- PROPERTY DETAILS Location: 181D Harper Rd, Waimarama, Hawke's Bay. Size: Land: 10,340m2, house 383m2+ 99m2 verandahs. For sale by: Auction. Price indication: Rateable value (2007) $1.6 million. Agent: Alison Small and Maree Williamson Tremains Real Estate. Ph: 0508 TREMAIN (873-6246) Email: customerservice@tremains.co.nz View online: www.open2view.co.nz ID #195855 ---

[WALKER Rosalind] Le Bas Walker discovers a slice of yesteryear New Zealand in Taupo. --- THE FACTS LOCATION: 128 SH1, Taupo SIZE: House 1802m, land 9942m PRICE INDICATION: GV $1,225,000 AGENT: Angela Nooyen, Harveys Taupo PH: 027 230 0780 EMAIL: angelan@harveys- taupo.co.nz. VIEW ONLINE: www.nz.open2view.com/Property/ 195131 --- CHRISTMAS IS the time we remember the good old days of the bach at the beach. Swimming, sandcastles, sunburn, snarlers on the barbie, snoozing under a shady pohutukawa. \"Our lifestyle here is the classic New Zealand holiday. Barbecues, boating, swimming, reading, going up the mountain skiing,\" says [David Seton]. The property is a central meeting point for the couple's family and friends from around the country. \"The lake in all its moods dominates the property,\" says Seton. \"The lounge room overlooking the lake is the best part of the house. Like watching a fire, you can spend all day watching over the lake.\"

\"When a woman walks into a house, she instantly knows if she likes it,\" says [ADELE]. \"When I walked into this one I thought, this is lovely, in fact we both did.\" \"I love the entrance as I've never had one before, so that's quite fun and it's very spacious.\" \"I like the cupboard laundry. It's still accessible to the light and it's convenient to the outside through double glass doors,\" says Adele.

If you lived on Day's Bay, you'd awake to the sound of gently lapping waves. After an early morning stretch, facing the flickering lights of Wellington, you'd stroll along the beach for morning coffee before boarding the ferry for the 20-minute commute to work. Three steps out of her front door, canoe tucked under her arm, [Rosemary Hickton] crosses the road and slides the vessel into the sea to paddle around the bay and out to Ward Island. Day's Bay offers a beachside lifestyle just 20 minutes' ferry ride from downtown Wellington. Nestled among native bush at the southern end of the sweeping bay, the cottage is sheltered from southerly winds and gets all-day sun.

Paul Armer PH: 021 846-130 EMAIL: paularmer@xtra.co.nz VIEW ONLINE: www.1033river.com ID#CE6422 --- THEY'RE JUST 3km from the CBD of our country's fourth-largest city, yet this home's owners live a private, tranquil riverside lifestyle.