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Background: Next generation sequencing (NGS) 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 (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT[E]) Tier I-V & X. Allele frequency is also increasingly recognised as an important prognostic tool in advanced cancer. The aim of this study was to determine the genomic mutations in metastatic colorectal cancer (CRC) in an Australian multicultural population and their influence on survival outcomes., Methods: Next generation sequencing with the 50-gene panel Oncomine Precision Assay™ was used on 180 CRC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022., Results: From 180 samples, 147 (82%) had at least one gene mutation identified with 68 (38%) having two or more concurrent mutations. Tier I variants included RAS wild-type [EI] in 73 (41%) and BRAF V600E [EIA] in 27 (15%). Non-tier I variants include 2 (1%) ERBB2 amplification [EIIB], 26 (15%) PIK3CA hotspot mutations [EIIIA] and 9 (5%) MET focal amplifications [EIIIA]. NGS testing revealed an additional 22% of cases with Tier II & III mutations. 43% of patients also presented with potentially actionable Tier III & IV mutations. Patients with concurrent TP53 and RAS mutations had significantly reduced overall survival (6.1 months versus 21.1 months, p <0.01). High KRAS allele frequency, as defined by those with over 20% variant allele frequency (VAF), also demonstrated reduced overall survival (12.1 months versus 42.9 months, p = 0.04)., Conclusions: In addition to identifying patients with genomic alterations suitable for clinically proven standard of care therapeutic options, the 50 gene NGS panel has significant potential in identifying potentially actionable non-tier 1 mutations and therefore may become future standard clinical practice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Nindra et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAF V600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAF V600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAF V600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAF V600 mutations (including BRAF V600K ), which account for ∼10-20% of BRAF V600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Despite the high-demand work environment for field epidemiologists in field epidemiology training programs, little is known about their occupational stress. To identify occupational stress and its related factors, the occupational stress among trainees in field epidemiology training programs in Southeast Asia and Western Pacific regions from 2016 to 2018 was examined using six subscales: Role Overload, Role Insufficiency, Role Ambiguity, Role Boundary, Responsibility, and Physical Environment. Furthermore, the data on the year of training and type of training program as well as the level of burnout, which affects stress-coping strategies, were collected. Fisher's exact tests and logistic regression models were used to examine associations between occupational stress, burnout, the number of years of training, and the type of training program. Sixty-two trainees participated, and there were no significant associations between burnout, the year of training, and type of training program. A burden of occupational stress in Role Overload and Physical Environment was reported by 56% and 53% of respondents, respectively. The trainees affiliated with a university program were less likely to have a burden of occupational stress in Responsibility and Physical Environment. It is concerning that more than half of trainees in the programs experienced occupational stress in Role Overload and Physical Environment. Additional efforts to design improved training programs to reduce occupational stress are warranted.

The findings are reported of an investigation into rhythmic differences between infant-directed speech (IDS) and adult-directed speech (ADS) in a corpus of utterances from Australian English mothers speaking to their infants and to another adult. Given the importance of rhythmic cues to stress and word-segmentation in English, the investigation focused on the extent to which IDS makes such cues salient. Two methods of analysis were used: one focused on segmental durational properties, using a variety of durational measures; the other focused on the prominence of vocalic/sonorant segments, as determined by their duration, intensity, pitch, and spectral balance, using individual measures as well as composite measures of prominence derived from auditory-model analyses. There were few IDS/ADS differences/trends on the individual measures, though mean pitch and pitch variability were higher in IDS than ADS, while IDS vowels showed more negative spectral tilt. However, the model-based analyses suggested that differences in the prominence of vowels/sonorant segments were reduced in IDS, with further analysis suggesting that pitch contributed little to prominence. The reduction in prominence contrasts may be due to the importance of mood-regulation in speech to young infants, and may suggest that infants rely on segmental cues to stress and word-segmentation.

Aims: To compare histological grading of rectal cancer radiotherapy response with pathological staging as a prognostic indicator., Methods: Histological tumour regression was five tier graded in 102 rectal cancer patients treated with preoperative radiotherapy [short course (n = 34), long course (n = 68)]. Differences between these grades and between the two radiotherapy regimes were assessed. These variables, pTMN staging and others were correlated with relapse free survival at 3 years., Results: 22 patients suffered disease recurrence and four died during a mean post-operative follow-up of 40.3 months. There were 52 good responders (tumour regression grades 1-3) and 50 poor responders (tumour regression grades 4-5). Regression was greater following the long course regime (p < 0.0001). Otherwise, there were no significant differences between the response groups and between the two regimes, including the number of lymph nodes found in the resected bowel. Only the pN status correlated with relapse free survival on multivariate analysis (p = 0.0004; HR = 4.26, 95%CI = 1.66-10.93 for pN2 versus pN0)., Conclusions: The number of lymph nodes found for staging was not influenced by either the extent of primary tumour regression or the type of radiotherapy. pN status, but not tumour regression grade, is a reliable predictor of survival.

This study provides Australian data on the incidence of human papillomavirus (HPV)-related oropharyngeal cancer to aid the debate on extending the HPV vaccination programme to males. The HPV status for 302 oropharyngeal cancers diagnosed between 1987 and 2006 was determined by HPV E6-targeted multiplex real-time PCR/p16 immunohistochemistry. The overall HPV-positivity rate was 36% (94% types 16 and 18). HPV-related cancer increased from 19% (1987-1990) to 47% (2001-2005). HPV data used in conjunction with Australian cancer incidence data 2001-2005 showed that 1.56 cases of oropharyngeal cancer per 100,000 males per year were associated with HPV types targeted by the vaccine. Vaccinating males may substantially reduce the burden of oropharyngeal cancer in Australia., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Fine-needle biopsy (FNB) has been reported as a rapid, minimally invasive technique for the diagnosis of metastatic melanoma. The diagnostic accuracy of FNB was assessed in a consecutive series of 2,204 FNBs of clinically suspicious lesions from patients with previous primary melanomas treated at the Sydney Melanoma Unit, Sydney, Australia, between January 1992 and December 2002. The sensitivity and specificity of FNB were 96.3% and 98.9%, respectively. There were 5 false-positive cases (0.6%), which were verified as metastatic adenocarcinoma (3 cases) or reactive processes (organizing hematoma and chronic osteomyelitis, 1 each). False-negative diagnoses (6.7% of cases) were associated with a variety of clinicopathologic factors, including difficult-to-access anatomic sites (eg, high axilla or deep inguinal), small lesions, and lesional characteristics such asfibrosis, necrosis, or cystic change. FNB is a highly accurate, rapid, and cost-effective procedure for the diagnosis of metastatic melanoma and should be considered as the initial diagnostic procedure of choice in patients with melanoma with clinically suspected metastases.

Aims: With ongoing efforts to target the epidermal growth factor receptor (EGFR)-mediated tumour growth in the treatment of selected human malignancies, there is a need to determine the expression levels of EGFR and to evaluate its prognostic value in various malignancies in the Asia-Pacific region., Methods and Results: A total of 172 patients with head and neck squamous cell carcinomas from Australia, Hong Kong, Singapore, and Taiwan were selected for EGFR detection. Immunohistochemical staining was performed to evaluate EGFR expression. EGFR expression was present in 88.4% (152/172) of all cases tested. Specifically, EGFR expression was found in 91.3% (42/46), 84.6% (22/26), 84.1% (37/44), 96.0% (24/25), and 87.1% (27/31) cases of head and neck squamous cell carcinomas from the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx, respectively. The results demonstrate a stronger EGFR expression in T4 tumours (P=0.017) and later clinical stages (P=0.016). No significant correlation was seen with risk factors, primary tumour site and ethnicity., Conclusions: The majority of head and neck squamous cell carcinomas express EGFR, indicating the importance of studying the efficacy of anti-cancer therapy through this pathway. The results also show similar rates of receptor expression in head and neck squamous cell carcinoma patients from our region compared with other parts of the world.

Kaposi s sarcoma (KS) is a angioformative lesion that classically occurs in elderly Eastern European and Mediterranean males but is also common in immunosuppressed individuals particularly human immunodeficiency virus (HIV)-infected patients. This study investigates the clinical and histopathological features of 47 patients with Kaposi s sarcoma from a teaching hospital in Sydney, Australia, in which 44 cases had adequate clinical follow-up information over a 10-year period. Most of the lesions were of late stage (37/47 cases; 79%), consisting of 11 cases of plaque stage KS and 26 cases of nodular stage KS with only 10 cases of early or patch stage KS. The majority of the HIV-positive cases (23/33; 70%) and all of the HIV-negative (14/14; 100%) cases had late stage lesions (p=0.020; X 2 -test). The histopathological features that were more common in the KS lesions of HIV-negative patients were lesional cell mitosis (p=0.0002), single cell necrosis (p=0.001), apoptosis (p=0.0001) and single cell anaplasia (p=0.0001). The KS lesions in HIV-positive patients tended to have dissecting blood vessels (14/33 cases; 42%) unlike those seen in HIV-negative patients (0/14 cases; 0%) (p=0.004). Most HIV-positive cases (30/33; 90%) were males (p=0.0068); and all these patients (33/33 cases; 100%) were <60 years old, in contrast to HIV-negative patients (1/11 cases; 9%) (p=0.0001). HIV status does not affect the occurrence of multiplicity of KS lesions. However, extracutaneous or visceral KS lesions were more likely to occur in HIV-positive patients (p=0.027). The number of cases of histologically proven KS cases has decreased markedly over the recent 5 year period of 1995-1999 (n=14), which was less than half of the number of the preceding 5 year period, 1990-1994 (n=33). In summary, there are distinct differences in the clinical and histopathological features of Kaposi s sarcoma lesions in HIV-positive and HIV-negative patients. Despite the recent discovery of the HHV8 virus as the initiating and promoting factor of most of the KS lesions, these differences indicated that there might be different mechanisms that occur in HIV-positive and HIV-negative patients in the development of this lesion.