Neutralization potency of monoclonal antibodies recognizing dominant and subdominant epitopes on SARS-CoV-2 Spike is impacted by the B.1.1.7 variant.

Interaction of the SARS-CoV-2 Spike receptor binding domain (RBD) with the receptor ACE2 on host cells is essential for viral entry. RBD is the dominant target for neutralizing antibodies, and several neutralizing epitopes on RBD have been molecularly characterized. Analysis of circulating SARS-CoV-2 variants has revealed mutations arising in the RBD, N-terminal domain (NTD) and S2 subunits of Spike. To understand how these mutations affect Spike antigenicity, we isolated and characterized >100 monoclonal antibodies targeting epitopes on RBD, NTD, and S2 from SARS-CoV-2-infected individuals. Approximately 45% showed neutralizing activity, of which ∼20% were NTD specific. NTD-specific antibodies formed two distinct groups: the first was highly potent against infectious virus, whereas the second was less potent and displayed glycan-dependant neutralization activity. Mutations present in B.1.1.7 Spike frequently conferred neutralization resistance to NTD-specific antibodies. This work demonstrates that neutralizing antibodies targeting subdominant epitopes should be considered when investigating antigenic drift in emerging variants.

Utility of multigene panel next-generation sequencing in routine clinical practice for identifying genomic alterations in newly diagnosed metastatic nonsmall cell lung cancer.

BACKGROUND: The standard of care in newly diagnosed metastatic non-small cell lung cancer (NSCLC) is to test for aberrations in three genes for driver mutations - ALK, ROS1 and epidermal growth factor receptor (EGFR) - and also for immunohistochemistry to be performed for programmed death-ligand 1 expression level. Next-generation sequencing (NGS), with or without RNA fusion testing, is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) Tiers I-V and X. AIM: Our aim was to analyse NSCLC tumour samples for the prevalence of Tiers I-V mutations to establish guidance for current and novel treatments in patients with metastatic disease. METHODS: NGS was performed employing the Oncomine Precision Assay (without RNA fusion testing) that interrogates DNA hotspot variants across 45 genes to screen 210 NSCLC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022. RESULTS: In our cohort, 161 of 210 (77%) had at least one gene mutation identified, with 41 of 210 (20%) having two or more concurrent mutations. Tier I mutations included 42 of 210 (20%) EGFR mutations (EIA) and five of 210 (3%) MET exon 14 skipping mutations (EIB). Non-Tier I variants included 22 of 210 (11%) KRAS G12C hotspot mutations (EIIB), with a further 47 of 210 (22%) having non-G12C KRAS (EX) mutations. NGS testing revealed an additional 15% of cases with Tier II ESCAT mutations in NSCLC. Forty-six percent of patients also demonstrated potential Tier III and IV mutations that are currently under investigation in early-phase clinical trials. CONCLUSIONS: In addition to identifying patients with genomic alterations suitable for clinically proven standard-of-care therapeutic options, the 45-gene NGS panel has significant potential in identifying potentially actionable non-Tier 1 mutations that may become future standard clinical practice in NSCLC.

p21 as a Predictor and Prognostic Indicator of Clinical Outcome in Rectal Cancer Patients.

The cell cycle plays a key and complex role in the development of human cancers. p21 is a potent cyclin-dependent kinase inhibitor (CDKI) involved in the promotion of cell cycle arrest and the regulation of cellular senescence. Altered p21 expression in rectal cancer cells may affect tumor cells' behavior and resistance to neoadjuvant and adjuvant therapy. Our study aimed to ascertain the relationship between the differential expression of p21 in rectal cancer and patient survival outcomes. Using tissue microarrays, 266 rectal cancer specimens were immunohistochemically stained for p21. The expression patterns were scored separately in cancer cells retrieved from the center and the periphery of the tumor; compared with clinicopathological data, tumor regression grade (TRG), disease-free, and overall survival. Negative p21 expression in tumor periphery cells was significantly associated with longer overall survival upon the univariate (p = 0.001) and multivariable analysis (p = 0.003, HR = 2.068). Negative p21 expression in tumor periphery cells was also associated with longer disease-free survival in the multivariable analysis (p = 0.040, HR = 1.769). Longer overall survival times also correlated with lower tumor grades (p= 0.011), the absence of vascular and perineural invasion (p = 0.001; p < 0.005), the absence of metastases (p < 0.005), and adjuvant treatment (p = 0.009). p21 expression is a potential predictive and prognostic biomarker for clinical outcomes in rectal cancer patients. Negative p21 expression in tumor periphery cells demonstrated significant association with longer overall survival and disease-free survival. Larger prospective studies are warranted to investigate the ability of p21 to identify rectal cancer patients who will benefit from neoadjuvant and adjuvant therapy.

KRAS and BRAF Mutation Rates and Survival Outcomes in Colorectal Cancer in an Ethnically Diverse Patient Cohort.

KRAS and BRAF mutation rates in colorectal cancer (CRC) reported from various mono-ethnic studies vary amongst different ethnic groups. However, these differences in mutation rates may not be statistically significant or may be due to differences in environmental and/or laboratory factors across countries rather than racial genetic differences. Here, we compare the KRAS/BRAF mutation rates and survival outcomes in CRC between ethnic groups at a single institution. We also investigate the contributions of genetic, environmental, and laboratory factors to the variations in KRAS/BRAF mutation rates reported from different countries. Clinicopathological data from 453 ethnically diverse patients with CRC were retrospectively analyzed at Liverpool Hospital, NSW Australia (2014-2016). KRAS/BRAF mutations were detected using real-time PCR (Therascreen kits from Qiagen). Mismatch repair (MMR) status was determined using immunohistochemical staining. Four ethnic groups were analyzed: Caucasian, Middle Eastern, Asian, and South American. Overall survival data were available for 406 patients. There was no significant difference in KRAS mutation rates between Caucasians (41.1%), Middle Easterners (47.9%), Asians (44.8%), and South Americans (25%) (p = 0.34). BRAF mutation rates differed significantly between races (p = 0.025), with Caucasians having the highest rates (13.5%) and Middle Easterners the lowest (0%). A secondary analysis in which Caucasians were divided into three subgroups showed that ethnic grouping correlated significantly with KRAS mutation rate (p = 0.009), with central and eastern Europeans having the highest rates (58.3%). There were no significant differences in overall survival (OS) or disease-free survival (DFS) between the four races. The similarity in KRAS mutation rates across races raises the possibility that the differences in KRAS mutation rates reported from various countries may either not be statistically significant or may be due to environmental and/or laboratory factors rather than underlying racial genetic differences. In contrast, we verified that BRAF mutation rates differ significantly between races, suggesting racial genetic differences may be responsible for the discrepant BRAF mutation rates reported from different countries.

A Functional Polymorphism Downstream of Vitamin A Regulator Gene CYP26B1 Is Associated with Hand Osteoarthritis.

While genetic analyses have revealed ~100 risk loci associated with osteoarthritis (OA), only eight have been linked to hand OA. Besides, these studies were performed in predominantly European and Caucasian ancestries. Here, we conducted a genome-wide association study in the Han Chinese population to identify genetic variations associated with the disease. We recruited a total of 1136 individuals (n = 420 hand OA-affected; n = 716 unaffected control subjects) of Han Chinese ancestry. We carried out genotyping using Axiom Asia Precisi on Medicine Research Array, and we employed the RegulomeDB database and RoadMap DNase I Hypersensitivity Sites annotations to further narrow down our potential candidate variants. Genetic variants identified were tested in the Geisinger's hand OA cohort selected from the Geisinger MyCode community health initiative (MyCode®). We also performed a luciferase reporter assay to confirm the potential impact of top candidate single-nucleotide polymorphisms (SNPs) on hand OA. We identified six associated SNPs (p-value = 6.76 × 10-7-7.31 × 10-6) clustered at 2p13.2 downstream of the CYP26B1 gene. The strongest association signal identified was rs883313 (p-value = 6.76 × 10-7, odds ratio (OR) = 1.76), followed by rs12713768 (p-value = 1.36 × 10-6, OR = 1.74), near or within the enhancer region closest to the CYP26B1 gene. Our findings showed that the major risk-conferring CC haplotype of SNPs rs12713768 and rs10208040 [strong linkage disequilibrium (LD); D' = 1, r2 = 0.651] drives 18.9% of enhancer expression activity. Our findings highlight that the SNP rs12713768 is associated with susceptibility to and severity of hand OA in the Han Chinese population and that the suggested retinoic acid signaling pathway may play an important role in its pathogenesis.

Loss of GPNMB Causes Autosomal-Recessive Amyloidosis Cutis Dyschromica in Humans.

Amyloidosis cutis dyschromica (ACD) is a distinct form of primary cutaneous amyloidosis characterized by generalized hyperpigmentation mottled with small hypopigmented macules on the trunks and limbs. Affected families and sporadic case subjects have been reported predominantly in East and Southeast Asian ethnicities; however, the genetic cause has not been elucidated. We report here that the compound heterozygosity or homozygosity of GPNMB truncating alleles is the cause of autosomal-recessive ACD. Six nonsense or frameshift mutations were identified in nine individuals diagnosed with ACD. Immunofluorescence analysis of skin biopsies showed that GPNMB is expressed in all epidermal cells, with the highest staining observed in melanocytes. GPNMB staining is significantly reduced in the lesional skin of affected individuals. Hyperpigmented lesions exhibited significantly increased amounts of DNA/keratin-positive amyloid deposits in the papillary dermis and infiltrating macrophages compared with hypo- or depigmented macules. Depigmentation of the lesions was attributable to loss of melanocytes. Intracytoplasmic fibrillary aggregates were observed in keratinocytes scattered in the lesional epidermis. Thus, our analysis indicates that loss of GPNMB, which has been implicated in melanosome formation, autophagy, phagocytosis, tissue repair, and negative regulation of inflammation, underlies autosomal-recessive ACD and provides insights into the etiology of amyloidosis and pigment dyschromia.

Non-transfusion dependent thalassemia is independently associated with higher alloimmunization risk than transfusion dependent thalassemia and would benefit the most from extended red cell antigen-matching.

BACKGROUND: Alloimmunization prevalence is conventionally used to identify RBCs alloimmunization risk factors among thalassemia patients, but it may be confounded by differences in transfusion exposure especially between non-transfusion dependent thalassemia (NTDT) and transfusion dependent thalassemia (TDT) patients. To better identify thalassemia patients with high alloimmunization risks, we used cumulative incidence of first alloimmunization as a function of RBCs transfused to compare alloimmunization risks between TDT and NTDT and to evaluate other risk factors. We also proposed practical strategies to prevent alloimmunization in thalassemia. STUDY DESIGN AND METHODS: Adult TDT and NTDT patients who had received ≥2 transfusions and no alloimmunization before their first transfusion were included. Alloimmunization was defined as the development of clinically significant alloantibodies. We estimated the first alloimmunization incidence from transfusion by Kaplan-Meier analysis with the horizontal axis expressed as cumulative non-antigen-matched RBC units transfused. We compared this incidence between TDT and NTDT, and analyzed for other alloimmunization risk factors and the alloantibody specificities/frequencies. RESULTS: The alloimmunization prevalence was similar between TDT and NTDT (27% vs. 30% respectively, p = .726). However, for the same transfusion exposure, NTDT had higher alloimmunization incidence than TDT (hazard ratio 8.59, 95% confidence interval [2.25-32.74], p = .002), independent of age at first transfusion and last follow-up, gender, and splenectomy. Anti-E, anti-c, anti-Mia , and anti-Jka were most frequent. DISCUSSION: NTDT has the highest alloimmunization risk and would benefit the most from extended RBC antigen-matching, especially C, c, E, and e. Other blood group antigen-matching should be guided by the patient/donor disparities and alloantibody frequencies in different populations.

The value of first-line chemotherapy and targeted therapy in the treatment of breast cancer.

OBJECTIVE: To investigate the value (survival benefit and cost) of first-line chemotherapy and targeted therapy in breast cancer at a population level. METHODS: Based on guideline recommendations, a model of optimal utilisation was constructed for first-line chemotherapy and targeted therapy in breast cancer, calculating the survival benefit and average cost of all regimens recommended for each treatment indication at 5 years and at 10 years. RESULTS: Survival benefits from chemotherapy and targeted therapy differ markedly depending on the treatment indications. The cost per life-year gained at 5 years is $38,044 for stages I and II, $33,749 for stage III and $ 151,668 for patients presenting with stage IV breast cancer. The cost per life-year gained at 10 years is $ 13,587 for early breast cancer. The most expensive chemotherapy indication in breast cancer is the treatment of metastatic HER2-positive breast cancer costing $330,978 per LYG for a survival benefit of 11% at 5 years falling to zero survival benefit at 10 years. CONCLUSION: There are large differences in value between the different indications for first-course chemotherapy and targeted therapy in the treatment of breast cancer that should be considered when pricing cancer drugs.

Structure-Based Classification Defines the Discrete Conformational Classes Adopted by the Arenaviral GP1.

The emergence of Old and New World arenaviruses from rodent reservoirs persistently threatens human health. The GP1 subunit of the envelope-displayed arenaviral glycoprotein spike complex (GPC) mediates host cell recognition and is an important determinant of cross-species transmission. Previous structural analyses of Old World arenaviral GP1 glycoproteins, alone and in complex with a cognate GP2 subunit, have revealed that GP1 adopts two distinct conformational states distinguished by differences in the orientations of helical regions of the molecule. Here, through comparative study of the GP1 glycoprotein architectures of Old World Loei River virus and New World Whitewater Arroyo virus, we show that these rearrangements are restricted to Old World arenaviruses and are not induced solely by the pH change that is associated with virus endosomal trafficking. Our structure-based phylogenetic analysis of arenaviral GP1s provides a blueprint for understanding the discrete structural classes adopted by these therapeutically important targets.IMPORTANCE The genetically and geographically diverse group of viruses within the family Arenaviridae includes a number of zoonotic pathogens capable of causing fatal hemorrhagic fever. The multisubunit GPC glycoprotein spike complex displayed on the arenavirus envelope is a key determinant of species tropism and a primary target of the host humoral immune response. Here, we show that the receptor-binding GP1 subcomponent of the GPC spike from Old World but not New World arenaviruses adopts a distinct, pH-independent conformation in the absence of the cognate GP2. Our analysis provides a structure-based approach to understanding the discrete conformational classes sampled by these therapeutically important targets, informing strategies to develop arenaviral glycoprotein immunogens that resemble GPC as presented on the mature virion surface.

Web-Based Patient-Reported Outcome Measures for Personalized Treatment and Care (PROMPT-Care): Multicenter Pragmatic Nonrandomized Trial.

BACKGROUND: Despite the acceptability and efficacy of e-patient-reported outcome (ePRO) systems, implementation in routine clinical care remains challenging. OBJECTIVE: This pragmatic trial implemented the PROMPT-Care (Patient Reported Outcome Measures for Personalized Treatment and Care) web-based system into existing clinical workflows and evaluated its effectiveness among a diverse population of patients with cancer. METHODS: Adult patients with solid tumors receiving active treatment or follow-up care in four cancer centers were enrolled. The PROMPT-Care intervention supported patient management through (1) monthly off-site electronic PRO physical symptom and psychosocial well-being assessments, (2) automated electronic clinical alerts notifying the care team of unresolved clinical issues following two consecutive assessments, and (3) tailored online patient self-management resources. Propensity score matching was used to match controls with intervention patients in a 4:1 ratio for patient age, sex, and treatment status. The primary outcome was a reduction in emergency department presentations. Secondary outcomes were time spent on chemotherapy and the number of allied health service referrals. RESULTS: From April 2016 to October 2018, 328 patients from four public hospitals received the intervention. Matched controls (n=1312) comprised the general population of patients with cancer, seen at the participating hospitals during the study period. Emergency department visits were significantly reduced by 33% (P=.02) among patients receiving the intervention compared with patients in the matched controls. No significant associations were found in allied health referrals or time to end of chemotherapy. At baseline, the most common patient reported outcomes (above-threshold) were fatigue (39%), tiredness (38.4%), worry (32.9%), general wellbeing (32.9%), and sleep (24.1%), aligning with the most frequently accessed self-management domain pages of physical well-being (36%) and emotional well-being (23%). The majority of clinical feedback reports were reviewed by nursing staff (729/893, 82%), largely in response to the automated clinical alerts (n=877). CONCLUSIONS: Algorithm-supported web-based systems utilizing patient reported outcomes in clinical practice reduced emergency department presentations among a diverse population of patients with cancer. This study also highlighted the importance of (1) automated triggers for reviewing above-threshold results in patient reports, rather than passive manual review of patient records; (2) the instrumental role nurses play in managing alerts; and (3) providing patients with resources to support guided self-management, where appropriate. Together, these factors will inform the integration of web-based PRO systems into future models of routine cancer care. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000615482; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=370633. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1186/s12885-018-4729-3.

Aberrant Expression of RAD52, Its Prognostic Impact in Rectal Cancer and Association with Poor Survival of Patients.

The DNA damage response enables cells to survive and maintain genome integrity. RAD52 is a DNA-binding protein involved in the homologous recombination in DNA repair, and is important for the maintenance of tumour genome integrity. We investigated possible correlations between RAD52 expression and cancer survival and response to preoperative radiotherapy. RAD52 expression was examined in tumour samples from 179 patients who underwent surgery for rectal cancer, including a sub-cohort of 40 patients who were treated with neoadjuvant therapy. A high score for RAD52 expression in the tumour centre was significantly associated with worse disease-free survival (DFS; p = 0.045). In contrast, reduced RAD52 expression in tumour centre samples from patients treated with neoadjuvant therapy (n = 40) significantly correlated with poor DFS (p = 0.025) and overall survival (OS; p = 0.048). Our results suggested that RAD52 may have clinical value as a prognostic marker of tumour response to neoadjuvant radiation and both disease-free status and overall survival in patients with rectal cancer.

Overexpression of the MRE11-RAD50-NBS1 (MRN) complex in rectal cancer correlates with poor response to neoadjuvant radiotherapy and prognosis.

BACKGROUND: The MRE11/RAD50/NBS1 (MRN) complex plays an essential role in detecting and repairing double-stranded breaks, and thus the potential roles of MRE11, RAD50 and NBS1 proteins in the pathogenesis of various cancers is the subject of investigation. This study was aimed at assessing the three-protein panel of MRN complex subunits as a potential radiosensitivity marker and evaluating the prognostic and clinicopathological implications of MRN expression in rectal cancer. METHODS: Samples from 265 rectal cancer patients treated with surgery and adjuvant chemoradiotherapy, including samples from 55 patients who were treated with neoadjuvant radiotherapy between 2000 and 2011, were analyzed. Expression of MRN complex proteins in tissue samples was determined by immunohistochemistry. Univariate and multivariate analyses were carried out to identify clinicopathological characteristics that are associated with the MRN three-protein panel expression in rectal cancer samples. RESULTS: In Kaplan-Meier survival analyses, we found that high level expression of MRN complex proteins in postoperative samples was associated with poor disease-free (p = 0.021) and overall (P = 0.002) survival. Interestingly, high MRN expression also correlated with poor disease-free (P = 0.047) and overall (P = 0.024) survival in the neoadjuvant radiotherapy subgroup. In multivariate analysis, combined MRN expression (hazard ratio = 2.114, 95% confidence interval 1.096-4.078, P = 0.026) and perineural invasion (hazard ratio = 2.160, 95% confidence interval 1.209-3.859, P = 0.009) were significantly associated with a worse disease-free survival. CONCLUSIONS: Expression levels of MRN complex proteins significantly predict disease-free survival in rectal cancer patients, including those treated with neoadjuvant radiotherapy, and may have value in the management of these patients.

Filamin B Loss-of-Function Mutation in Dimerization Domain Causes Autosomal-Recessive Spondylocarpotarsal Synostosis Syndrome with Rib Anomalies.

Spondylocarpotarsal synostosis syndrome (SCT) is a distinct group of disorders characterized by short stature, disrupted vertebral segmentation with vertebral fusion, scoliosis, lordosis, carpal/tarsal synostosis, and lack of rib anomalies. Mutations in filamin B (FLNB) and MYH3 have been reported for autosomal-recessive and autosomal-dominant SCT, respectively. We present a family with two patients suffering from autosomal-recessive SCT with rib anomalies, including malalignment, crowding, and uneven size and shape of ribs. Whole-exome sequencing revealed a novel p.S2542Lfs* 82 (c.7621dup) frameshift mutation in FLNB. This frameshift mutation lies in the C-terminal-most domain involved in FLNB dimerization and resulted in a 20-residue elongation, with complete familial segregation and absence in 376 normal controls. The mutant p.S2542Lfs* 82 FLNB demonstrated a complete loss of ability to form a functional dimer in transiently transfected HEK293T cells. The p.S2542Lfs* 82 mutation also led to significantly reduced protein levels and accumulation of the mutant protein in the Golgi apparatus. This is the first identified mutation in the dimerization domain of FLNB. This loss-of-function frameshift mutation in FLNB causes autosomal-recessive SCT with rarely reported rib anomalies. This report demonstrates the involvement of rib anomaly in SCT and its causative mutation in the dimerization domain of FLNB.

Sidedness is prognostic in locoregional colon cancer: an analysis of 9509 Australian patients.

BACKGROUND/AIM: Right sided colon cancer (RsCC) is proposed to be a distinct disease entity to left sided colon cancer (LsCC). We seek to confirm primary tumour location as an independent prognostic factor in locoregional colorectal cancer. METHODS: All patients with stage I - III primary adenocarcinoma of colon were identified from the New South Wales (NSW) clinical cancer registry (2006-2013). Primary tumour location (RsCC vs LsCC) survival analyses were conducted using the Kaplan-Meier method, and adjusted hazard ratios for 5-year all-cause mortality (OS) and 5-year cancer specific mortality (CSS) were obtained using Cox proportional hazards regression. RESULTS: We identified 9509 patients including 5051 patients with RsCC and 4458 with LsCC. Patients with RsCC were more likely to be older, female, have a higher Charlson comorbidity index, and have worse tumour prognostic factors. In univariate analysis of all stages combined, those patients with RsCC had a worse overall survival (OS, HR 1.20 95% CI 1.11-1.29, p < 0.0001), although this was not significant in the multivariate analysis (HR 0.96 95% CI 0.89-1.04, p = 0.35). Stage I patients with RsCC had a trend to improved OS (multivariate HR 0.84 95% CI 0.69-1.01, p = 0.07) and a significantly improved CSS (multivariate HR 0.51 95% CI 0.35-0.75, p = 0.0006). In stage II patients with RsCC there was a significantly improved OS (multivariate HR 0.85 95% CI 0.75-0.98, p = 0.02) and CSS (multivariate HR 0.59 95% CI 0.45-0.78, p = 0.0002) compared to LsCC. In stage III patients, those with RsCC had a worse OS (multivariate HR 1.13 95% CI 1.01-1.26, p = 0.032) and a trend to worse CSS (multivariate HR 1.12 95% CI 0.94-1.33, p = 0.22). CONCLUSIONS: Primary tumour location is an important prognostic factor in locoregional colon cancer with an effect that varies by stage. RsCC is associated with lower all-cause mortality in stage II, and higher all-cause mortality in stage III.

Migrant health in cancer: outcome disparities and the determinant role of migrant-specific variables.

BACKGROUND: Multiethnic societies face challenges in delivering evidence-based culturally competent health care. This study compared health-related quality of life and psychological morbidity in a hospital-based sample of first-generation migrants and Australian-born Anglo cancer patients, controlling for potential confounders related to migrant status. Further, it explored the relative contribution of ethnicity versus migrant-related variables. METHODS: Eligible participants, recruited via 16 oncology clinics in Australia, included those over the age of 18, diagnosed with cancer (any type or stage) within the previous 12 months and having commenced treatment at least 1 month previously. RESULTS: In total, 571 migrant patients (comprising 145 Arabic, 248 Chinese, and 178 Greek) and a control group of 274 Anglo-Australian patients participated. In multiple linear regression models adjusted for age, sex, education, marital status, socioeconomic status, time since diagnosis, and type of cancer, migrants had clinically significantly worse health-related quality of life (HRQL; 3.6-7.3 points on FACT-G, p < .0001), higher depression and anxiety (both p < .0001), and higher incidence of clinical depression (p < .0001) and anxiety (p = .003) than Anglo-Australians. Understanding the health system (p < .0001 for each outcome) and difficulty communicating with the doctor (p = .04 to .0001) partially mediated the impact of migrancy. In migrant-only analyses, migrant-related variables (language difficulty and poor understanding of the health system), not ethnicity, predicted outcomes. CONCLUSION: Migrants who develop cancer have worse psychological and HRQL outcomes than Anglo-Australians. Potential targets for intervention include assistance in navigating the health system, translated information, and cultural competency training for health professionals.

Evaluating Systemic Burnout in Medical Oncology Through a National Oncology Mentorship Program.

PURPOSE: Mentorship has a positive influence on trainee skills and well-being. A 2022 Pilot Mentorship Program in New South Wales involving 40 participants revealed high burnout rates in Medical Oncology trainees. As part of an Australia-wide inaugural National Oncology Mentorship Program in 2023 (NOMP23), a national survey was undertaken to assess the prevalence of burnout, anxiety, depression, professional fulfilment, and drivers of distress in the Australian medical oncology workforce. METHODS: NOMP23 is a 1-year prospective cohort study that recruited medical oncology trainees and consultants using e-mail correspondence between February and March 2023. Each participant completed a baseline survey which included the Maslach Burnout Index (MBI), Stanford Professional Fulfilment Index, and Patient Health Questionnaire-4 for anxiety and depression. RESULTS: One hundred and twelve participants (56 mentors, 56 mentees) were enrolled in NOMP23, of which 86 (77%) completed the baseline survey. MBI results at baseline demonstrated that 77% of consultants and 82% of trainees experienced burnout in the past 12 months. Professional fulfilment was noted to be <5% in our cohort. Screening rates of anxiety and depression in trainees were 32% and 16%, respectively, compared with 7% and 2% for consultants. When assessing reasons for workplace stress, two thirds stated that heavy patient load contributed to stress, while almost three quarters attributed a heavy administrative load. Lack of supervision was a key stressor for trainees (39%), as was lack of support from the training college (58%). CONCLUSION: Trainees and consultant medical oncologists demonstrate high rates of burnout and low professional fulfilment. The NOMP23 program has identified a number of key stress factors driving burnout and demonstrated concerning levels of anxiety and depression. Ongoing mentorship and other well-being initiatives are needed to address these issues.

Real-world tolerance and outcomes of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer-Does dose intensity matter?

INTRODUCTION: Fluoropyrimidine and oxaliplatin-based adjuvant chemotherapy delivered as 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), or capecitabine and oxaliplatin (CAPOX) is the standard of care for resected stage III colon cancer. Without randomized trial data, we compared real-world dose intensity, survival outcomes, and tolerability of these regimens. METHODS: Records of patients treated with FOLFOX or CAPOX in the adjuvant setting for stage III colon cancer across four institutions in Sydney during 2006-2016 were reviewed. The relative dose intensity (RDI) of fluoropyrimidine and oxaliplatin of each regimen, disease-free survival (DFS), overall survival (OS), and incidence of grade ≥2 toxicities were compared. RESULTS: Characteristics of patients receiving FOLFOX (n = 195) and CAPOX (n = 62) were evenly matched. FOLFOX patients had a higher mean RDI for both fluoropyrimidine (85% vs. 78%, p < 0.01) and oxaliplatin (72% vs. 66%, p = 0.06). In spite of a lower RDI, CAPOX patients trended toward a better 5-year DFS (84% vs. 78%, HR = 0.53, p = 0.068) and similar OS (89% vs. 89%, HR = 0.53, p = 0.21) compared to the FOLFOX group. This difference was most pronounced in the high-risk (T4 or N2) group where 5-year DFS was 78% versus 67% (HR = 0.41, p = 0.042). Patients receiving CAPOX experienced more grade ≥2 diarrhea (p = 0.017) and hand-foot syndrome (p < 0.001) but not peripheral neuropathy or myelosuppression. CONCLUSION: In a real-world setting, patients who received CAPOX had similar OS rates when compared to those receiving FOLFOX in the adjuvant setting in spite of lower RDI. In the high-risk population, CAPOX appears to demonstrate a superior 5-year DFS over FOLFOX.

Microsatellite Instability Testing and Prognostic Implications in Colorectal Cancer.

Given the crucial predictive implications of microsatellite instability (MSI) in colorectal cancer (CRC), MSI screening is commonly performed in those with and at risk for CRC. Here, we compared results from immunohistochemistry (IHC) and the droplet digital PCR (ddPCR) MSI assay on formalin-fixed paraffin-embedded tumor samples from 48 patients who underwent surgery for colon and rectal cancer by calculating Cohen's kappa measurement (k), revealing high agreement between the methods (k = 0.915). We performed Kaplan-Meier survival analyses and univariate and multivariate Cox regression to assess the prognostic significance of ddPCR-based MSI and to identify clinicopathological features associated with CRC outcome. Patients with MSI-high had better overall survival (OS; p = 0.038) and disease-free survival (DFS; p = 0.049) than those with microsatellite stability (MSS). When stratified by primary tumor location, right-sided CRC patients with MSI-high showed improved DFS, relative to those with MSS (p < 0.001), but left-sided CRC patients did not. In multivariate analyses, MSI-high was associated with improved OS (hazard ratio (HR) = 0.221, 95% confidence interval (CI): 0.026-0.870, p = 0.042), whereas the loss of DNA mismatch repair protein MutL homolog 1 (MLH1) expression was associated with worse OS (HR = 0.133, 95% CI: 0.001-1.152, p = 0.049). Our results suggest ddPCR is a promising tool for MSI detection. Given the opposing effects of MSI-high and MLH1 loss on OS, both ddPCR and IHC may be complementary for the prognostic assessment of CRC.

Haematological and nutritional prognostic biomarkers for patients receiving CROSS or FLOT.

Background: Neoadjuvant carboplatin and paclitaxel with radiotherapy (CROSS) and perioperative docetaxel, oxaliplatin, calcium folinate and fluorouracil (FLOT) are widely used for gastric (GC), gastro-oesophageal junction (GOJ) and oesophageal cancers (OC). Prognostic and predictive markers for response and survival outcomes are lacking. This study evaluates dynamic neutrophil-lymphocyte ratios (NLR), platelet-lymphocyte ratios (PLR), albumin and body mass index (BMI) as predictors of survival, response and toxicity. Methods: This multi-centre retrospective observational study across 5 Sydney hospitals included patients receiving CROSS or FLOT from 2015 to 2021. Haematological results and BMI were recorded at baseline and pre-operatively, and after adjuvant treatment for FLOT. Toxicities were also recorded. An NLR ≥2 and PLR ≥200 was used to stratify patients. Univariate and multivariate analyses were performed to determine predictors of overall survival (OS), disease free survival (DFS), rates of pathological complete response (pCR) and toxicity. Results: One hundred sixty-eight patients were included (95 FLOT, 73 FLOT). A baseline NLR ≥2 was predictive for worse DFS (HR 2.78, 95% CI: 1.41-5.50, P<0.01) and OS (HR 2.90, 95% CI: 1.48-5.67, P<0.01). Sustained elevation in NLR was predictive for DFS (HR 1.54, 95% CI: 1.08-2.17, P=0.01) and OS (HR 1.65, 95% CI: 1.17-2.33, P<0.01). An NLR ≥2 correlated with worse pCR rates (16% for NLR ≥2, 48% for NLR <2, P=0.04). A baseline serum albumin <33 was predictive of worse DFS and OS with a HR of 6.17 (P=0.01) and 4.66 (P=0.01) respectively. Baseline PLR, BMI, and dynamic changes in these markers were not associated with DFS, OS or pCR rates. There was no association of the aforementioned variables with toxicity. Conclusions: This demonstrates that a high inflammatory state represented by an NLR ≥2, both at baseline and sustained, is prognostic and predictive of response in patients receiving FLOT or CROSS. Baseline hypoalbuminaemia is predictive of poorer outcomes.