Symptomatic brain metastases in melanoma.

Although clinical outcomes in metastatic melanoma have improved in recent years, the morbidity and mortality of symptomatic brain metastases remain challenging. Response rates and survival outcomes of patients with symptomatic melanoma brain metastases (MBM) are significantly inferior to patients with asymptomatic disease. This review focusses upon the specific challenges associated with the management of symptomatic MBM, discussing current treatment paradigms, obstacles to improving clinical outcomes and directions for future research.

Immune-related acute kidney injury in Australian non-small cell lung cancer patients: Real-world results.

BACKGROUND: The use of immune checkpoint inhibitors has altered therapeutic paradigms in NSCLC. However, they may cause immune-related toxicities, including acute kidney injury (irAKI), especially when combined with nephrotoxic agents. We investigated the incidence, management and outcomes of AKI in Australian NSCLC patients. METHODS: Medical records from a cancer centre registry were reviewed. AKI was defined and graded on absolute creatinine rise, or rise above baseline. Fishers exact test compared proportions. The Kaplan-Meier method estimated survival, and multiple logistic regression tested for risk factors. RESULTS: Of 449 patients who underwent immunotherapy from 2013 to 2021, the median age was 65 years and 61% were male. Metastatic disease was present in 68% at diagnosis, the remainder had stage Ia-III disease; 70% had adenocarcinoma; and 17% had EGFR mutations. AKI was identified in 65 patients (14.5%) of which 19 were irAKI (4.2%). Within irAKI patients, eleven (58%) had other immune-related adverse events. Median time to irAKI onset was 4 months (IQR 4-6). Seventeen (89%) patients had AKI stage 1 or 2; two had stage 3. Eleven patients developed chronic kidney disease; none required renal replacement therapy. Kidney biopsies demonstrated acute interstitial nephritis (n = 3), acute tubular necrosis (n = 1) and anti-phospholipase A2 receptor negative membranous glomerulonephritis (n = 1). Five patients were rechallenged with immunotherapy; two had recurrent irAKI. The median overall survival for those with irAKI was not reached versus 12 months with no irAKI (HR 0.35, 95 %CI 0.20-0.60, p = 0.01). Risk factors for irAKI included having an additional, non-renal irAE (OR 6.21, 95 %CI 2.35-17.26, p ≤ 0.01); immunotherapy combined with other cancer therapies (OR 5.62, 95 %CI 2.08-16.20, p ≤ 0.01); and ECOG performance status > 1 (OR 4.39 (95 %CI 1.11-14.90, p = 0.02) CONCLUSIONS: The incidence of irAKI was similar to the published literature. Renal recovery was poor, however survival was not compromised. Improved diagnostic and therapeutic strategies for irAKI would benefit this population.

International partnerships in cancer care: Cultural bridging for oncology nurses.

CANO/ACIO's vision for international work is to be a driving force nationally and an influencing force internationally in advancing excellence in cancer nursing across the cancer control spectrum (CANO/ACIO, 2022). To help advance this vision and support the development of members' knowledge, skills, values, and competencies for effective cultural bridging in international partnerships, the CANO/ACIO International Strategy Working Group hosted the "International Partnerships in Cancer Care - Cultural Bridging" workshop at the 2022 CANO/ACIO Annual Conference. Nurses actively engaging in international partnerships were invited to share their expertise and experiences with workshop participants, providing foundational knowledge and practical examples of approaches to cultural bridging in international partnership projects. Facilitated large group discussion allowed for shared exploration of the concepts and approaches in the oncology nursing context. This column presents the key messages identified from the workshop and next steps for CANO/ACIO's international strategy.

Patient needs and resource intensity weighting in the ambulatory care unit.

Across British Columbia Cancer (BC Cancer), oncology nurses work as part of an interdisciplinary team in the outpatient ambulatory care unit (ACU) and support patients across the trajectory of their cancer journey. Previous initiatives, which focused on identifying patient needs and nursing role optimization work, have enhanced role clarity, enabling nurses to articulate their scope of practice and specialty competencies required to best meet the needs of patients and families. However, while the patient needs and fundamental practice elements have been identified to optimize the ACU nursing role, a gap still exists in quantifying the staffing resources required to operationalize the current model of care. To address this gap, a quality improvement project was initiated to develop an internally validated ACU Nursing Resource Intensity Weighting (RIW) tool for projecting baseline staffing requirements. The tool can be utilized to inform strategic and operational planning discussions focused on improving the outpatient model of care in oncology.

Suspected Sunda clouded leopard (Neofelis diardi) predation attempts on two reintroduced Bornean orangutans (Pongo pygmaeus wurmbii) in Bukit Batikap Protection Forest, Central Kalimantan, Indonesia.

In February 2017 and August 2018, respectively, two Bornean orangutans (Pongo pygmaeus wurmbii) reintroduced into the Bukit Batikap Protection Forest in Central Kalimantan were found in weakened physical condition and with deep puncture wounds. The first individual was a sub-adult male, and the second an adult female whose 6- to 8-week-old infant was missing. Both individuals were rescued and transported back to the field base camp for treatment. Experienced veterinarians treating the injuries reported that the type of wounds appeared consistent with those expected from an attack by a large felid. The Sunda clouded leopard (Neofelis diardi) is the largest felid known to inhabit Bukit Batikap Protection Forest, and we suspect that these cases were unsuccessful predatory attacks by this species. Given the severity of his condition when found, the male orangutan would probably have died without medical intervention; however, both orangutans fully recovered following intensive treatment and were successfully returned to the forest. Predation attempts on orangutans are infrequently reported, thus our observations add to the body of knowledge about possible predation by clouded leopards on reintroduced, rehabilitant orangutans.

Ambulatory care unit role optimization for the specialized oncology nurse.

While the role of the specialized oncology nurse in treatment and symptom management is well established, the role in the outpatient setting is not as well defined. Increasing patient complexity, the rising incidence of cancer, and evolving treatment regimens is pressing BC Cancer to reassess its Ambulatory Care Unit (ACU) model of care to better meet patient needs. The purpose of this project was to identify and map the specific role and functional tasks of nurses working in the ACU to specialty competencies for the oncology nurse. A baseline functional role elements list and role-competency map were developed from clinical observations and focus group sessions. This work will help provide role clarity and enable nursing to articulate both the scope of practice and the specialty competencies required to best meet the needs of our patients in the ACU setting. The results of this project can be utilized in strategic and operational planning discussions focused on improving health services for patients and supporting the continued professional development of front-line staff. The approaches utilized may be of interest to others who wish to apply similar methods in their own cancer settings.

Development of a national position statement on cancer patient navigation in Canada.

As the landscape of cancer care in Canada evolves, oncology nursing roles are developed to enhance the patient experience and address the changing needs of patients and families. Cancer Patient Navigation (CPN), an oncology nursing role focusing primarily on person-centred care coordination and system navigation, has become integral to providing high-quality cancer care in many Canadian jurisdictions. Since 2016, a national group of oncology nursing leaders have been engaged in convening and catalyzing our understanding of the role of patient navigation in the Canadian cancer context with the purpose of developing a national position statement on CPN. In this paper, we provide a historical analysis of the development of the forthcoming Canadian Association of Nurses in Oncology (CANO) position statement on CPN. We present an analysis of participant feedback from workshops at the 2016, 2017, and 2018 conferences, and meeting minutes from the National working group over this same time period. This paper serves as a concise historical summary of the evolution of CPN in Canada while providing a template for other groups looking to develop a consensus-based position statement.

Élaboration d'un énoncé de position national sur la navigation des patients atteints de cancer au Canada.

Au Canada, le paysage des soins du cancer évolue et les infirmières en oncologie sont appelées à jouer de nouveaux rôles afin d'améliorer l'expérience des patients et des familles et de répondre à leurs besoins toujours changeants. L'un de ces rôles, la navigation des patients atteints de cancer (NPC), vise principalement à coordonner les soins centrés sur la personne et à guider les patients dans le système de santé. Dans plusieurs provinces et territoires du Canada, la navigation est devenue essentielle pour offrir des soins de grande qualité aux patients cancéreux. Depuis 2016, des chefs de file des soins infirmiers oncologiques se réunissent au sein d'un groupe national pour synthétiser leur compréhension de la navigation des patients en contexte canadien afin d'élaborer un énoncé de position national sur la NPC. Dans le présent article, nous analyserons l'historique de l'élaboration de l'énoncé de position sur la NPC que publiera prochainement l'Association canadienne des infirmières en oncologie (ACIO/CANO). Nous analyserons également les commentaires des participants aux ateliers tenus dans le cadre des congrès de 2016, 2017 et 2018, de même que les comptes rendus des réunions du groupe de travail national qui ont eu lieu pendant cette même période. Le présent article se veut un sommaire historique concis de l'évolution de la NPC au Canada, ainsi qu'un modèle pour les autres groupes aspirant à rédiger un énoncé de position consensuel.

Regulation of freezing tolerance and flowering in temperate cereals: the VRN-1 connection.

In winter wheat (Triticum spp.) and barley (Hordeum vulgare) varieties, long exposures to nonfreezing cold temperatures accelerate flowering time (vernalization) and improve freezing tolerance (cold acclimation). However, when plants initiate their reproductive development, freezing tolerance decreases, suggesting a connection between the two processes. To better understand this connection, we used two diploid wheat (Triticum monococcum) mutants, maintained vegetative phase (mvp), that carry deletions encompassing VRN-1, the major vernalization gene in temperate cereals. Homozygous mvp/mvp plants never flower, whereas plants carrying at least one functional VRN-1 copy (Mvp/-) exhibit normal flowering and high transcript levels of VRN-1 under long days. The Mvp/- plants showed reduced freezing tolerance and reduced transcript levels of several cold-induced C-REPEAT BINDING FACTOR transcription factors and COLD REGULATED genes (COR) relative to the mvp/mvp plants. Diploid wheat accessions with mutations in the VRN-1 promoter, resulting in high transcript levels under both long and short days, showed a significant down-regulation of COR14b under long days but not under short days. Taken together, these studies suggest that VRN-1 is required for the initiation of the regulatory cascade that down-regulates the cold acclimation pathway but that additional genes regulated by long days are required for the down-regulation of the COR genes. In addition, our results show that allelic variation in VRN-1 is sufficient to determine differences in freezing tolerance, suggesting that quantitative trait loci for freezing tolerance previously mapped on this chromosome region are likely a pleiotropic effect of VRN-1 rather than the effect of a separate closely linked locus (FROST RESISTANCE-1), as proposed in early freezing tolerance studies.

CBF gene copy number variation at Frost Resistance-2 is associated with levels of freezing tolerance in temperate-climate cereals.

Frost Resistance-1 (FR-1) and FR-2 are two loci affecting freezing tolerance and winter hardiness of the temperate-climate cereals. FR-1 is hypothesized to be due to the pleiotropic effects of VRN-1. FR-2 spans a cluster of C-Repeat Binding Factor (CBF) genes. These loci are genetically and functionally linked. Recent studies indicate CBF transcripts are downregulated by the VRN-1 encoded MADS-box protein or a factor in the VRN-1 pathway. Here, we report that barley genotypes 'Dicktoo' and 'Nure' carrying a vrn-H1 winter allele at VRN-H1 harbor increased copy numbers of CBF coding sequences relative to Vrn-H1 spring allele genotypes 'Morex' and 'Tremois'. Sequencing bacteriophage lambda genomic clones from these four genotypes alongside DNA blot hybridizations indicate approximately half of the eleven CBF orthologs at FR-H2 are duplicated in individual genomes. One of these duplications discriminates vrn-H1 genotypes from Vrn-H1 genotypes. The vrn-H1 winter allele genotypes harbor tandem segmental duplications through the CBF2A-CBF4B genomic region and maintain two distinct CBF2 paralogs, while the Vrn-H1 spring allele genotypes harbor single copies of CBF2 and CBF4. An additional CBF gene, CBF13, is a pseudogene interrupted by multiple non-sense codons in 'Tremois' whereas CBF13 is a complete uninterrupted coding sequence in 'Dicktoo' and 'Nure'. DNA blot hybridization with wheat DNAs reveals greater copy numbers of CBF14 also occurs in winter wheats than in spring wheats. These data indicate that variation in CBF gene copy numbers is widespread in the Triticeae and suggest selection for winter hardiness co-selects winter alleles at both VRN-1 and FR-2.

Identification of candidate CBF genes for the frost tolerance locus Fr-Am2 in Triticum monococcum.

A cluster of eleven CBF genes was recently mapped to the Frost resistance-2 (Fr-Am2) locus on chromosome 5 of diploid wheat (Triticum monococcum) using a cross between frost tolerant accession G3116 and frost sensitive DV92. The Fr-Am2 locus was mapped at the peak of two overlapping quantitative trait loci (QTL), one for frost survival and the other for differential expression of the cold regulated gene COR14b. Seven lines with recombination events within the CBF cluster were used to identify CBF candidate genes for these QTL. The lines carrying the critical recombination events were tested for whole plant frost survival and for differential transcript levels of cold induced COR14b and DHN5 genes. The strongest effect for these traits was associated to the linked TmCBF12, TmCBF14 and TmCBF15 genes, with the G3116 allele conferring improved frost tolerance and higher levels of COR14b and DHN5 transcript at mild cold temperatures (12-15 degrees C) than the DV92 allele. Comparison of CBF protein sequences revealed that the DV92 TmCBF12 protein contains a deletion of five amino acids in the AP2 DNA binding domain. Electrophoretic Mobility Shift Assays (EMSA) confirmed that the protein encoded by this allele cannot bind to the CRT/DRE (C-repeat/ dehydration-responsive element) motif present in the promoters of several cold induced genes. A smaller effect on frost tolerance was mapped to the distal group of CBF genes including TmCBF16. Transcript levels of TmCBF16, as well as those of TmCBF12 and TmCBF15 were up-regulated at mild cold temperatures in G3116 but not in DV92. Higher threshold induction temperatures can result in earlier initiation of the cold acclimation process and better resistance to subsequent freezing temperatures. The non-functional TmCBF12 allele in DV92 can also contribute to its lower frost tolerance.

Tensin stabilizes integrin adhesive contacts in Drosophila.

We report the functional characterization of the Drosophila ortholog of tensin, a protein implicated in linking integrins to the cytoskeleton and signaling pathways. A tensin null was generated and is viable with wing blisters, a phenotype characteristic of loss of integrin adhesion. In tensin mutants, mechanical abrasion is required during wing expansion to cause wing blisters, suggesting that tensin strengthens integrin adhesion. The localization of tensin requires integrins, talin, and integrin-linked kinase. The N-terminal domain and C-terminal PTB domain of tensin provide essential recruitment signals. The intervening SH2 domain is not localized on its own. We suggest a model where tensin is recruited to sites of integrin adhesion via its PTB and N-terminal domains, localizing the SH2 domain so that it can interact with phosphotyrosine-containing proteins, which stabilize the integrin link to the cytoskeleton.

Rap1 GTPase regulation of adherens junction positioning and cell adhesion.

Cell-cell junctions are distributed evenly around the lateral circumference of cells within an epithelium. We find that the even distribution of adherens junctions is an active process that requires the small guanosine triphosphatase Rap1. Cells mutant for Rap1 condensed their adherens junctions to one side of the cell. This disrupted normal epithelial cell behavior, and mutant cell clones dispersed into the surrounding wild-type tissue. Rap1 is enriched at adherens junctions, particularly between newly divided sister cells where it may reseal the adherens junction ring. The regulation of adherens junction positioning could play a role in cell mobility and cell division.